Fda 2010 N 0477 0011

Page 1 U.S.
DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) + + + + +
FOOD AND DRUG ADMINISTRATION (FDA) + + + + + PART 15 PUBLIC HEARING ON APPROVAL PATHWAY FOR BIOSIMILAR AND INTERCHANGEABLE BIOLOGICAL PRODUCTS + + + + +
TUESDAY, NOVEMBER 2, 2010 + + + + + The Panel convened at 8:30 a.m. in Building 31, Room 1503 of the White Oak Campus of the Food and Drug Administration, located at 10903 New Hampshire Avenue, Silver Spring, Maryland, Rachel Behrman, Presiding Officer, presiding. PANEL MEMBERS PRESENT: RACHEL BEHRMAN, M.D., M.P.H., Presiding Officer BARRY CHERNEY, Ph.D. DENISE ESPOSITO, J.D. JOHN K. JENKINS, M.D. DIANE MALONEY, J.D. HEIDI C. MARCHAND, Pharm.D. MARK I. SCHWARTZ, J.D. ROBERT A. YETTER, Ph.D. Neal R. Gross & Co., Inc. 202-234-4433
Page 2 PRESENTERS: MARCIA BOYLE JANET WYATT, Ph.D., RN, CRNP, F.A.A.N.P. SETH GINSBERG DAVID BROMBERG, M.D., F.A.A.P. SHEIN-CHUNG CHOW, Ph.D. GRAHAM JONES, Ph.D., D.Sc. JEFFREY MAZZEO, Ph.D. LASZLO ENDRENYI, Ph.D., D.Sc. JAMES LOVE SARA CRAGER
JONAH HOUTS STEVEN MILLER SCOTT REID, Pharm.D. STEVEN RUSSEK, R.Ph. GREGORY SCHIMIZZI, M.D. JIM SHEHAN F. OWEN FIELDS, Ph.D.
RIVKA RIVEN-KREITMAN SUMANT RAMACHANDRA, M.D., Ph.D., M.B.A. SATISH TRIPATHI, Ph.D. ROGER L. WILLIAMS, M.D. Neal R. Gross & Co., Inc. 202-234-4433
Page 3 T-A-B-L-E O-F C-O-N-T-E-N-T-S Presentations: Presiding Officer Opening Remarks, Rachel Behrman, M.D., MPH. . . . . . . . . Marcia Boyle, Immune Deficiency Foundation. . . . . . . . . . . . . Janet Wyatt, Ph.D., RN, CRNP, F.A.A.N.P, Arthritis Foundation. . . . . . . . Seth Ginsberg, Global Healthy Living Foundation. . . . . . . . . . . . . David Bromberg, M.D., F.A.A.P., American Academy of Pediatrics . . . . . . . Break Shein-Chung Chow, Ph.D., Duke University School of Medicine. . . . . . . . . . . 65 Graham Jones, Ph.D., D.Sc., Northeastern University and Jeffrey Mazzeo, Ph.D., Waters Corporation. . . . . . . . . . . 79 Laszlo Endrenyi, Ph.D., D.Sc., University of Toronto . . . . . . . . . . . . . . . . 95 James Love, Knowledge Ecology International . . . . . . . . . . . . .102 Sara Crager, American Medical Students Association and Universities Allied Essential Medicines . . . . . . . . Jonah Houts, Alliance for Affordable Medicine. . . . . . . . . . . . . . Dr. Steven Miller, Express Scripts, Inc.. Troyen Brennan, M.D., CVS Caremark Corporation . . . . . . . . . . . . for . .114 . .124 . .133 . .143
. . .5 . . 12 . . 19 . . 36 . . 49
Steven Russek, R.Ph., Medco Health Solutions . . . . . . . . . . . . . . .176 Lunch Gregory Schimizzi, M.D., Coalition of State Rheumatology Organizations. . . . . . . . . .197 Jim Shehan, Novo Nordisk, Inc.. . . . . . . .215 F. Owen Fields, Ph.D., Pfizer, Inc. . . . . .228 Rivka Riven-Kreitman, Teva North America. . .245 Neal R. Gross & Co., Inc. 202-234-4433
Page 4 Break
Presentations: (continued)
Sumant Ramachandra, M.D., Ph.D., M.B.A., Hospira, Inc. . . . . . . . . . . . . .255 Satish Tripathi, Ph.D., Biomedical Consulting International, Inc. . . . . . . . . . .271 Roger L. Williams, M.D., The United States Pharmacopeial Convention (USP). . . . 280
Public Comment:
Michael Behan, Chief Counsel and Legislative Director for U.S. Senator Bernie Sanders . . . .293 Bill Vaughan, Consumers Union . . . . . . . . . . . .301
AIDS Institute James Sykes . . . . . . . . . . . . . .306 Neal R. Gross & Co., Inc. 202-234-4433
Page 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. BEHRMAN: P-R-O-C-E-E-D-I-N-G-S 8:33 a.m. Good morning and
welcome to the Biosimilar Part 15 hearing. Good morning to both the attendees in the conference center and those viewing the hearing through our live webcast. Welcome to the Part 15 hearing on the Approval Pathway for Biosimilar and Interchangeable Biological Products. I am
Rachel Behrman, Associate Director for Medical Policies and Drug Evaluation and Research. will service as presiding officer for this hearing. Before we begin I'll provide a few housekeeping announcements. Please turn off I
any mobile devices as they may interfere with the audio in this room. We ask that all The doors
attendees sign in on both days.
will open at 7:30 a.m. again tomorrow and the public hearing will begin at promptly 8:30 a.m. We are scheduled until 4:30 p.m. today Neal R. Gross & Co., Inc. 202-234-4433
Page 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 and tomorrow. Restrooms are located in the lobby to the left and right hallways. We are
planning for one 15-minute break during the morning session and one 15-minute break during the afternoon session. Today's lunch break is There will
scheduled from 11:55 to 12:55 p.m.
be sandwiches, salads, and beverages available for purchase in the lobby. The purpose of today's hearing is to create a forum for interested stakeholders to provide input regarding the agency's implementation of the subtitle of Patient Protection and Affordable Care Act, the Biologics Price Competition and Innovation Act of 2009. BPCI Act amends the Public Health Service Act and other statues to create an abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with an FDA licensed reference biological product. FDA will take the
Neal R. Gross & Co., Inc. 202-234-4433
Page 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 information obtained from the public hearing into account in its implementation of the BPCI Act. The agency is interested in hearing from stakeholders regarding the agency's implementation of the statute on all issues. Chief among them, scientific and
technical factors related to the determination of biosimilarity interchangeability, the type of information that may be used to support a determination of biosimilarity interchangeability, development of a framework for optimal pharmacovigilance for biosimilar and interchangeable biological products, scope of the revised definition of a biological product, priorities for guidance development, scientific and technical factors related to reference practical exclusivity, scientific and technical factors that may inform the agency's interpretation of private class as it relates to the available regulatory pathways for certain protein products during the 10Neal R. Gross & Co., Inc. 202-234-4433
Page 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 year transition period following the enactment of the BPCI Act, and the establishment of the user fee program for biosimilar interchangeable biological products. I would now like to ask the FDA panel members to introduce themselves. DR. CHERNEY: Barry Cherney,
Deputy Director, Division of Therapeutic Proteins, CDER. MS. ESPOSITO: Denise Esposito,
from CDER, Office of Regulatory Policy. DR. JENKINS: John Jenkins. I'm
the Director of the Office of New Drugs in CDER. I'm also the Chair of the CDER
Biosimilars Review Committee. MS. MALONEY: Good morning. I'm
Diane Maloney, Associate Director for Policy at the Center for Biologics. DR. MARCHAND: Good morning. I'm
Heidi Marchand from the Office of Special Health Issues, Office of Commissioner. MR. SCHWARTZ: Good morning. Mark
Page 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 agenda. Benton. Bob Yetter. Schwartz, Associate Chief Counsel, Drugs and Biologics. DR. YETTER: Good morning. I'm
I'm the Associate Director for
Review Management in the Center for Biologics Evaluation and Research. I'm the Chair of the
CBER Biosimilars Committee. DR. BEHRMAN: I would like to note
that these are not in the prepared remarks. This represents a subset of many people in the agency who are working very hard on this issue who have day jobs in addition to, many of whom are sitting in the front row and have joined us. I would also like to thank Sandra Many of you speakers are very
familiar with her for keeping not only this meeting but the program held together. And
the staff of the Office of Medical Policy for coordinating this meeting. Turning to the speakers on the We have an agenda of speakers from 21 Neal R. Gross & Co., Inc. 202-234-4433
Page 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 organizations today and 21 organizations tomorrow, although we appear to have a no-show today. We've scheduled presentations slots.
In order to keep to the agenda as closely as possible, I will go over some ground rules. First, this meeting is informal. The rules of evidence do not apply. No
participant may interrupt the presentation of another participant. Only FDA panel members
will be allowed to question a presenter. FDA may recall a presenter for additional questions at the end of the day assuming time allows and the presenter remains available. Public hearings under Part 15 are
subject to FDA policy and procedures for electronic media coverage of FDA public administrative proceedings. Representatives of the electronic media may be permitted subject to certain limitations to videotape, film, or otherwise record FDA's public administrative proceeding including the presentation of the speakers Neal R. Gross & Co., Inc. 202-234-4433
Page 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 today. The meeting will be transcribed and
copies of the transcript may be ordered through the docket or accessed on our website approximately 30 days after the public hearing. Each registered speaker has been given an eight-minute slot on the agenda with seven additional minutes allowed for FDA panel members to ask questions. If a speaker goes
over the eight-minute slot, the time allotted for questions will be reduced accordingly. will do that. You'll notice the buttons. I We
will follow those. For those of you who did not register to make an oral presentation but would like to present your comments, you may speak during the open comment period at the conclusion of the hearing if time permits. This hearing is not, however, your last chance to comment. The docket will stay
open until December 31 and we strongly encourage all interested parties to comment. Neal R. Gross & Co., Inc. 202-234-4433
Page 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 We do take these comments very seriously. Please see the Federal Register notice for details. The majority of speakers will be addressing the questions listed in Section 2 of the Federal Register notice for this public hearing. Again, given the full agenda we
request that each speaker keep to the allotted time so that we are able to keep to our tight schedule. Thank you for your interest and participation today. We look forward to a We will proceed with
very productive meeting. the presentations.
The first speaker, I
believe, is Marcia Boyle, President and Founder of the Immune Deficiency Foundation. Welcome. MS. BOYLE: Thank you very much I appreciate
for having this meeting today. the efforts of the Food and Drug
Administration for taking the time to discuss this very critical issue. Neal R. Gross & Co., Inc. 202-234-4433
Page 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 My name is Marcia Boyle and I'm the president and founder of the Immune Deficiency Foundation, or IDF. Founded in
1980 IDF is the national patient organization dedicated to improving the diagnosis, treatment, and quality of life of persons with primary immunodeficiency diseases through advocacy, education, and research. I'm also the mother of a now grown son living with a primary immunodeficiency disease. Therefore, I'm here to talk to you
today about key issues for patients and parents everywhere. As you may know, patients with primary immunodeficiency are unique. They
represent a diverse group of genetic or intrinsic defects of the immune system all with one key similarity, lack of a fully functioning immune system to fight infections. Given that, many of these patients require lifelong therapy so they can live healthy, productive lives. Currently many of
Page 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 these individuals, including my son, require lifelong immunoglobulin therapy to replace the antibodies that fight infection that their bodies do not produce. IDF estimates that
approximately 55,000 individuals in the US today with primary immunodeficiency receive such therapy. Immunoglobulin therapy is a very complex biologic. Unlike insulin in which the
amino acid sequence is known, the overall structure is well characterized and the manufacturing process largely involved recombinant DNA technology. Immunoglobulin
products do not have a specified amino acid sequence or well characterized structure. Therefore, each manufacturer relies heavily upon strict manufacturing processes to produce the overall product. To highlight its complexity, recently there was a world-wide withdrawal of immunoglobulin product due to increased reports of serious thromboembolic events in Neal R. Gross & Co., Inc. 202-234-4433
Page 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 some cases leading to death. The root cause of these events is thought to be due to a slight change in manufacturing process which was approved by the FDA. So you can understand my hesitation
for any shortened approval process for biological medications if the current regulatory structure appropriately involving the FDA can still result in patient deaths and other serious adverse events. Patients respond to each currently FDA approved immunoglobulin therapy differently. According to the 2008 IDF
national treatment survey which is a survey of our patients with antibody deficiencies requiring immunoglobulin replacement, over two-fifths, or 41 percent of the patients tolerated some immunoglobulin therapy products better than others. Of the patients reported having a side effect or reaction they would describe as serious from their immunoglobulin therapy, 28 Neal R. Gross & Co., Inc. 202-234-4433
Page 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 percent reported having a serious side effect or reaction when they tried a new immunoglobulin product for the first time and 13 percent had a serious side effect or reaction when they switched products. Due to the seriousness of these reactions some patients have taken drastic steps to avoid having these problems including 24 percent who refused a particular product and 15 percent who delayed their infusion due to concerns about product tolerability. I look forward to continuing to work with the FDA to ensure that the approval pathway for biosimilar products addresses key issues of importance to IDF. Specifically,
given the potential differences in therapeutic responses any approval pathway needs to include clinical and nonclinical trials. Given the very nature of biologic products, FDA should not waive the requirement for clinical studies. In fact, FDA should
rely most heavily on clinical studies, not Neal R. Gross & Co., Inc. 202-234-4433
Page 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 animal studies. Further, like the EMA in Europe the FDA should exclude immunoglobulins from its biosimilar pathway. In fact, I believe
the EMA excluded a whole class of plasmaderived therapies from the biosimilar pathway. To determine whether a potentially interchangeable product can be expected to produce the same clinical result as the reference product in any given patient, FDA must require clinical trials to demonstrate that the two products provide the exact same clinical result in a large cohort of patients. Given the potential for adverse reactions the FDA must also require additional post-marketing surveillance. IDF recognizes
the need for patients to maintain careful monitoring of their medications but the patient cannot be the only entity providing such monitoring. Because of the many unanswered questions surrounding the safety of Neal R. Gross & Co., Inc. 202-234-4433
Page 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Other questions from the panel? I'll ask you one. You say very strongly that Can you biosimilars the FDA should take all steps necessary to prohibit automatic substitution. Thank you again for this opportunity. As you consider the new framework, please ensure that each biosimilar has clinical trials to establish the safety and efficacy of biosimilars, ensure that the current shortened review process does not include immunoglobulins, provide for strong post-market surveillance for biosimilars, and prohibit automatic substitution. very much. DR. BEHRMAN: Thank you for your Thank you
immunoglobulins should be excluded.
explain a little bit why you think that is the case and what particular aspect of the abbreviated pathway set forth in the statute you feel is inappropriate for immunoglobulins. MS. BOYLE: For global
Page 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 harmonization the EMA did exclude plasmaderived product for many reasons. Because of
their complexity the patients who have immune deficiencies react differently. They are not
going to react the same way as another individual. As far as I'm concerned, there is no conceivable way in which a new product would not go through the same strict guidelines that the current immunoglobulin products go through. The manufacturing of They have They are all
these products are different. different viral inactivation.
looked at as unique products by the FDA and patients react very differently. DR. BEHRMAN: Thank you.
Thank you.
The next speaker is Janet Wyatt from the Arthritis Foundation DR. WYATT: Good morning. My name
is Janet Wyatt and I'm a national board member of the Arthritis Foundation and chair of the Public Policy Committee and I have rheumatoid Neal R. Gross & Co., Inc. 202-234-4433
Page 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 arthritis, or RA. I'm here today as a patient and to share my views with you on behalf of the approximately four million Americans with rheumatoid arthritis and other forms of inflammatory arthritis. I'm also here on behalf of the 300,000 children who are also suffering from a form of inflammatory arthritis commonly referred to as JRA. Despite growing research
there is no cure for RA or JRA and current treatments cannot permanently stop the pain and prevent deterioration of bones and joints. A little over 10 years ago a diagnosis of RA or JRA would have meant that patients like myself could look forward to a future of gnarled joints, chronic pain, loss of function, and often complete disability. Because of the innovative scientific breakthroughs in biomedical research, the trajectory of this disabling disease has been radically altered through Neal R. Gross & Co., Inc. 202-234-4433
Page 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 treatment with biologics. For the last six years my symptoms have been managed through the use of a biologic injectable preparation. I'm truly
grateful for this life-transforming therapy. Patients with RA and inflammatory arthritis are aware that today the best form of treatment for management of symptoms is biologic therapy. However, for many people with arthritis access to biological therapies is limited or non-existent due to their high cost and limited availability. For these patients
new biosimilars represent great promise to improve their access to safe, effective, and cost effective options. I want to thank the Food and Drug Administration for the opportunity to present remarks at today's hearing and on behalf of the Arthritis Foundation I greatly appreciate the willingness of the FDA to listen to stakeholders, especially representatives from Neal R. Gross & Co., Inc. 202-234-4433
Page 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the patient community. My remarks today will focus on three main topic areas based on the questions in the Federal Register announcement. question. First
What does the patient need to know
about the reliability, safety, and efficacy of biosimilars? biologics. Patients want and need access to We also want access to lower cost
alternatives to the current array of biologic products. We need assurance that any and all biosimilar products that arrive on the market have been tested and confirmed to be as safe and effective as the innovator product. Of
most importance patients with inflammatory arthritis need to be assured that biologic and biosimilar therapies will be of high quality, accessible, safe, and effective. Inflammatory and rheumatoid arthritis have serious and disabling and, indeed, life-threatening risks. While the
health risks associated with untreated disease Neal R. Gross & Co., Inc. 202-234-4433
Page 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 are serious, the health risks associated with biologic therapy are also serious. Patients
do not make the decision to start biologic therapies lightly. When new biosimilar therapies become available, patients will need to be assured that the overall risk profile of the biosimilar is no greater than that of the innovative biologic. Any difference between
potential side effects of a biosimilar product versus a biologic product must be clearly noted so that patients and providers can be aware of the different health risk profiles and make the best treatment decision. Patients also want to know that the biosimilar will work for them. As
mentioned earlier, biologics don't always provide the treatment benefit for every patient with the same diagnosis. The response rate from the population as a whole for biosimilars should be carefully studied. The biosimilar should
Page 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 provide a similar therapeutic response profile as the biologic product. The Arthritis
Foundation believes requiring clinical evidence of the efficacy of biosimilars is absolutely essential for ensuring patient and provider confidence and biosimilar projects. Biosimilar manufacturers need to provide clinical evidence that biosimilars work as well or better than the innovator product. We look forward to patient-based
research to help evaluate the biosimilars and provide the objective measures needed for appropriate FDA approval of this new product. The Arthritis Foundation as an organization representing patients strongly recommends that the FDA require clinical evidence that these new biosimilars work in people with active disease. Second issue. Why is a robust
surveillance system so critical for pharmacovigilance? The Arthritis Foundation
strongly urges the FDA to ensure the highest Neal R. Gross & Co., Inc. 202-234-4433
Page 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 level of pharmacovigilance for biologics and biosimilars. When considering the potential
risk related to switching from a biologic to a biosimilar patients must be able to expect the same clinical result including known side effects. One aspect of this assurance is through appropriate testing and validation of a new biosimilar. The clinical testing
periods need to be long enough and the sample size large enough to know the real results and the real outcome of this new product. To assess the new biosimilar the FDA should require a reasonable period of clinical response observation over an appropriate period of time. The same standard
of pharmacovigilance should be in place and reinforced for the biosimilars as for the biologic product. Stage 4 post-marketing surveillance studies will help to gain additional data and real world observations of Neal R. Gross & Co., Inc. 202-234-4433
Page 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 how these new medications actually perform. Consumers need access to more data that will demonstrate the effectiveness of biologics and the biosimilars based on age, gender, and other factors. The Arthritis Foundation strongly recommends that the FDA require post-marketing studies including a possible registry surveillance for these new approved biologics and biosimilars. Stringent post-marketing surveillance for patients treated with any new approved biosimilar or newly approved biologic should be an element of the FDA's regulatory oversight. The FDA's regulatory oversight
should also include the involvement of patient groups such as the Arthritis Foundation. The Arthritis Foundation is indeed ready to work in partnership with the FDA to share important regulatory and health-related information and to communicate the value, insight, and knowledge that can be gained from Neal R. Gross & Co., Inc. 202-234-4433
Page 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 patient related biologic and biosimilar drug registries. The Arthritis Foundation and its patient members believe it is essential that consumers have complete knowledge, disclosure and consent when using a biosimilar product. A patient in his or her position need to know exactly what is being prescribed and used. At a molecular level biologics are structurally different. Biosimilars are not
exact replicas of the innovator biologic. There will be subtle product variations in cell lines and manufacturing processes that can have significant and serious consequences. Each biologic product must have a clear specific label. The labeling of the
biosimilar should be as clear as possible so that the patient, the pharmacist, and the health provider know exactly which product the patient is receiving. As always, it is essential that the provider, the pharmacist and the patient Neal R. Gross & Co., Inc. 202-234-4433
Page 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the panel? Neal R. Gross & Co., Inc. 202-234-4433 Mr. have clear access to drug information. The
overall tracking, reporting, and surveillance systems should be strengthened for both physicians and patients so that reporting of side effects and adverse events biosimilars is available. We ask that the agency's response to adverse events also be appropriately based on the severity of the risk. This is why a
strong system to uniquely name and categorize and label biosimilars is so critical. We also believe it is important for the FDA to communicate with patient groups. I know my time is up so I wanted to
just close by saying we encourage the FDA to expeditiously create a regulatory pathway that provides appropriate oversight and ensures patient safety and access to potentially lower biologic products. Thank you. Thank you for your
DR. BEHRMAN:
Page 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 question. Schwartz. MR. SCHWARTZ: I have one
It's actually a quick two-parter.
You notes indicate -- your submission indicates that FDA should consider new ways to involve the patient community in observing and reporting adverse events. Do you have any
suggestions or examples as to ways in which we can involve the patient community to observe these adverse events? MS. BOYLE: Within the Arthritis
Foundation we have a number of platforms that are available for patients to share information about their disease as well as their response to various therapies. There is
a great deal of electronic communication that takes place. We at the Arthritis Foundation also encourages patients to enroll in a variety of new registries that are available. I think we are very much interested in helping to develop a registry process through which Neal R. Gross & Co., Inc. 202-234-4433
Page 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 patients can then communicate directly with a group of healthcare providers and scientists about their response. MR. SCHWARTZ: one quick follow-up. Thank you. Just
Just curious as to
whether or not your organization's position is that Stage 4 surveillance studies be required in all instances. presentation. MS. BOYLE: We do strongly support It was unclear from your
Stage 4 clinical trials which is really posttherapy, post-introduction of therapy followup. We understand that is often recommended
but not necessarily mandated in many situations. We find that it is of benefit to
patients to be involved in Stage 4 trials. Thank you. DR. JENKINS: you don't mind. DR. BEHRMAN: for five minutes. DR. JENKINS: You emphasized the We still have you One more question if
Page 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 importance of a robust clinical program comparing the biosimilar to the innovator reference product. I'm wondering has your
organization given any thought to how large that clinical program should be? Are we talking about 100 patients, a thousand patients, 10,000 patients? Where
would you think it would be an adequate level of preapproval evaluation to be adequate to meet the goals that you outlined in your presentation? DR. WYATT: We very much As a patient
appreciate that question.
representative I'm not available to provide specific numbers in response to your question but I am sure that the Arthritis Foundation could come up with some good scientific recommendations based on that question. There are hundreds of thousands of patients, if not millions of patients, taking biologic products to manage their inflammatory arthritis. We are for sure looking for a Neal R. Gross & Co., Inc. 202-234-4433
Page 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 critical. large enough sample size that will be able to produce the scientific and statistical rigor necessary to deem those products safe. DR. BEHRMAN: MS. MALONEY: communication. Ms. Maloney. I had a question on
You touched on it at the end Can
but I think your time was running out.
you just touch briefly on what communication issues you see that might be unique in the area of biosimilars? DR. WYATT: Particularly the
labeling issues we believe are very important. There often is confusion among many of us taking biologic products because we start one and perhaps have to stop that one because we don't get the therapeutic benefit and need to start a different one. The labeling we think is really Also we believe that there should
be no changes in the prescriptive dispensing of the product based on a pharmacist decision to substitute a "generic" so labeling we think Neal R. Gross & Co., Inc. 202-234-4433
Page 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the panel? MS. MALONEY: I had one. I is important. The biologics right now have a
different pathway, many of them in terms of action so that kind of communication and that knowledge about biosimilars need to be communicated with patients. Patient groups are very anxious to learn more about the product that they take. As part of that it's got to be what the safety and expected potential side effects be shared with patient groups as well. answers your question. DR. BEHRMAN: Other questions from I hope that
apologize for butchering your first name. Usually I reserve that for last names but I've made an exception. You talked about that the
efficacy profile should be the same but when you talk about the safety profile I thought you said that -- this is what I want to clarify -- the safety profile could Neal R. Gross & Co., Inc. 202-234-4433
Page 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 conceivably be different as long as it was appropriately delineated and articulated and communicated to patients. point was? DR. WYATT: There are certainly I Is that what your
risks associated with biologic therapies. think what we are interested in is really understanding what those risks are.
Based on
the nature of the disease and the conversation that the patient has with their healthcare provider, it may be that a decision to choose biological therapy because of a different risk profile is indeed the best decision for that particular patient. I think we are looking for safe effective therapies, high quality. Make sure
the manufacturing process is also high quality. But there may be a different risk
profile with some biosimilars than there are with the biologics. As long as that
information is made available, I think patients and their providers can then have a Neal R. Gross & Co., Inc. 202-234-4433
Page 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. conversation. DR. CHERNEY: In your talk you
didn't directly discuss the issue of interchangeability. that? DR. WYATT: We do. I believe it's Do you have a position on
in the testimony offered that interchangeability should be based on a very careful decision between the patient and the provider, and potentially even the pharmacist so that there is a full disclosure and a complete understanding of all of the risks associated with that. There should not be any
interchangeability without knowledge of the patient and the provider. DR. BEHRMAN: Thank you for your
We encourage the Arthritis
Foundation to address Dr. Jenkins' comment or question in the docket. Thank you very much.
Our next speaker is Coco Jervis from Treatment Action Group. No?
If not, our next speaker -- we Neal R. Gross & Co., Inc. 202-234-4433
Page 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 will try to accommodate Mr. Jervis should he arrive late. Our next speaker then will be
Seth Ginsberg from the Global Healthy Living Foundation. MR. GINSBERG: I have no
disclosures to make today regarding my travel. The Global Healthy Living Foundation accepts grants and charitable contributions from many pharmaceutical companies as well as government, private foundations, and individuals. Good morning. On behalf of the
Global Healthy Living Foundation I want to thank this committee for allowing me to speak today. Global Healthy Living Foundation is a
501(c)(3) patient advocacy group that works to improve the quality of life for people with chronic disease often focusing on those least likely to advocate for themselves. We focus on several disease states and the people who live with these diseases including more than 42,000 members of Neal R. Gross & Co., Inc. 202-234-4433
Page 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 creakyjoints.org, creakybones.org and redpatch.org, our arthritis, osteoporosis, and psoriasis patient advocacy groups respectively. My name is Seth Ginsberg and I'm the co-founder of the Global Healthy Living Foundation and its communities. I was
diagnosed with spondylar arthropathy at 13. At 18 I went away to college, 200 miles from home and in pain. I quickly realized there
was a need for a positive supportive community, experts and other patients alike with whom to share strength and experience. For the past 11 years the Global Healthy Living Foundation has incorporated additional conditions and advocated for patients within the private health insurance, Medicaid, and Medicare communities in order to help ensure access to care. It is in this outreach context that I am speaking here today representing our members nearly 70 percent who take, or are who Neal R. Gross & Co., Inc. 202-234-4433
Page 38 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 considering taking, biologics. This subgroup
is mostly female ranging in age from their mid-20s to their 70s. The word represent does not properly define the relationship between Global Healthy Living Foundation and our members. It is a cold word that falls short
in describing our commitment or our activities. Allow me to explain our commitment and why biosimilars are so important to us. Imagine yourself for just a minute at a circus looking up to the top of the tent at a highwire performer. When we watch her make her
way across that wire we are doing more than watching. We are feeling her every move and
when she slips and then regains her balance, we gasp in empathy. When she reaches the If she
other side, we applaud and exhale.
falls, we fall with her and become silent as people gather around to help her. will get up and take a bow. We hope she
We in the
Page 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 it. audience emotionally participate in her walk across that wire. We are walking with her.
Frans De Waal, the famous primatologist and author, recounts in his latest book The Age of Empathy this feeling we have watching high-wire acts. He uses the
German word einfuehlung to describe it which translates as feeling into. At the Global Healthy Living Foundation we have einfuehlung because many of the 42,000 of us are on the high-wire ourselves living with a disease, putting our faith and hope in a biologic. We and our
families gasp when it doesn't work and we applaud and exhale when it does. Not everyone
involved in the delivery of our healthcare has einfuehlung. For example, payers do not have They cannot have it because they don't They live with the
live with the disease.
business of the disease and that doesn't even bring them into the einfuehlung tent. Neal R. Gross & Co., Inc. 202-234-4433 We're
Page 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 not sure they even want to be there because feeling into is a luxury too dear for today's shareholder-run business model they have adopted. If they did have einfuehlung, they would book no deviation from the proven process and the established product that makes up the biologics market today. welcome new biologics. They would
As the American
College of Rheumatology clearly states, they would respect the differences and allow physicians to prescribe the biologic they think will work best for their patient. Having said all this, we are not against biologics. We want maximum choice for
our members and biosimilars can help reach this goal. That maximum choice, however, has
to meet their expectations in five key areas and we are not sure biosimilar proponents are ready to meet our members' expectations. The key areas are: (1) pre-marketing clinical data Neal R. Gross & Co., Inc. 202-234-4433
Page 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that ensures biosimilars are safe and effective. (2) Even if it looks like the reference biologic, it may not act like the reference biologic. And, as the scientists
say, determinations of comparability cannot be made for products that are not comparable. This is why we need clinical trial experience. We cannot extrapolate indications across biosimilars. (3) Biosimilars cannot be
considered as interchangeable with the biologics they attempt to copy. They are not That
identical generic versions of biologics. is why nobody calls them generics.
(4) There must be post-marketing clinical and safety studies. (5) There must be a way for patients, physicians, and government agencies to clearly differentiate between biosimilars and the original biologics and to track the molecules to their origin by manufacturer and Neal R. Gross & Co., Inc. 202-234-4433
Page 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 batch. We do it with eggs. We must do it with
biosimilars. Again, paraphrasing from the scientific community, biologics are not produced through strict adherence to a defined chemical process but through a complex process that involves living cells and organisms. There is much that can go wrong if we ignore or under estimate the unique and complicated path biosimilar producers must navigate. As I understand it, if biosimilars went through this process, the cost involved some say would make them as expensive as the innovative biologics they seek to mimic. And
with no cost advantage their relevance as a treatment protocol is in question by those in the business of the disease. So in order to keep these cost down, in order to make the business case for biosimilars the process of making, identifying, and prescribing them deviates from the rigid science and learned art that Neal R. Gross & Co., Inc. 202-234-4433
Page 43 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 determines how original biologics are brought to market and this deviation is responsible for their success. Nomenclatures which allow tracking to a specific manufacturer could be lost and patient and physician understanding of exactly what drug is being used and from whom also could be lost. We think this loss is
unacceptable and represents a step backward for science, for physicians, and for us patients. We do not know how much this step backward will cost in patient care and confidence in our healthcare system and its ability to deliver safe and effective treatment protocols. But cost in these terms Savings
isn't the issue with biosimilars. are.
Contrary to what some people hearing me speak today might think, I need to say again we are not against biosimilars or saving money in healthcare. We are against
Page 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 using biosimilars as the vehicle for making money by disregarding the standards and practices that have created the biologics miracle. I know that I just used the word miracle in front of a panel of scientists. Maybe not the best choice of words but remember einfuehlung, feeling into. the high-wire performer. constituency. Remember
Remember our
Biologics to us are the miracle
that has allowed our members to go back to work, to stop the progression of their disease, to allow the word "remission" to creep into the autoimmune lexicon. Biologics have taken away pain. They have allowed a grandmother and a great grandmother and a mother to hold their children close and make the world a little better, a little safer, and a little more welcome. We are not willing to welcome a new protocol that does not hold these promises Neal R. Gross & Co., Inc. 202-234-4433
Page 45 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 question. comments. as a priority. Thank you all very much for
allowing me to speak on this election day. DR. BEHRMAN: Thank you for your
Other questions from the panel? MR. SCHWARTZ: I do have one
In your key areas, the third area
where you say biosimilars cannot be considered as interchangeable, just seeking clarification is it your position that the agency should not under any circumstances approve biologics as interchangeable under the Biologics Price Competition and Innovation Act? MR. GINSBERG: Ultimately it's our
feeling that we need to look around the corner in the best interest of our patients and our members. We have to be sensitive to the fact
that the system that we live in today under traditional payers will seek every opportunity to save money. If they are interchangeable,
we feel that they could potentially destabilize patients and switch them midstream, mid-therapy. That is what we are most
Page 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 concerned about. MR. SCHWARTZ: DR. BEHRMAN: MS. ESPOSITO: Thank you. Ms. Esposito. If I understood
your presentation correctly from a pharmacovigilance perspective, you are advocating being able to trace a particular dose back by manufacturer and by batch. questions about that. The first is what kind of information do you think the patient needs on that front and how would they access it. The Two
second one is whether you thought about from the manufacturer perspective and from the agency's perspective how that information would be differentiated and captured. MR. GINSBERG: So I live in New
York City and two days after the egg calamity this summer, that I'm sure you're all aware of here, everyone in this building actually, two days later there were postings on the shelves in the supermarkets clearly stating where the Neal R. Gross & Co., Inc. 202-234-4433
Page 47 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 disruptive eggs were from in Iowa and clearly pointing out to the consumer that they should check and see that these eggs are, indeed, from Iowa. We need something equivalent. need something for patients who put these liquids in their body via injectables or infusions or any other way to be completely comfortable knowing where it came from and who made it so if and when there are problems, we can effectively and immediately trace them and understand what those problems are and the sources of them. I don't mean to over We
simplify the complexity of your question but that's the way we see it. DR. JENKINS: I notice on your
point No. 2 in your presentation that you don't think we should extrapolate indications across biosimilars because you think there needs to be clinical trial experience. I'm wondering again in follow-up to one of the earlier questions do you view Neal R. Gross & Co., Inc. 202-234-4433
Page 48 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that as an absolute? For example, some
biologics have multiple disease indications. In the case where FDA found for one of those indications the data to be adequate to approve that biologic is a safe and effective biosimilar, could you not see any situations where that information along with other animal data or in vitro data might allow for extrapolating to one of the other indications without a new clinical trial or do you think those separate indications should always be supported by clinical trial data? MR. GINSBERG: Again, I think that
in the spirit of keeping these drugs as safe as possible we should understand the safety and efficacy of all indications that the biosimilars seek to treat so, yes. DR. CHERNEY: You indicated that
you thought that we couldn't determine the sameness or biosimilarity of biologics but biologics represent a vast array of different complexities. Is there any level where you Neal R. Gross & Co., Inc. 202-234-4433
Page 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 question. think that some more simple molecules that would be amenable to the biosimilar pathways? MR. GINSBERG: That's a good
Without the scientific background
to justify a responsible answer to that question I can't say for sure. DR. BEHRMAN: from the panel? Any other questions
Thank you for your comments. Thank you. Okay. Our next
MR. GINSBERG: DR. BEHRMAN:
speaker is David Bromberg from the American Academy of Pediatrics. DR. BROMBERG: Good morning. My
name is Dr. David Bromberg and I'm a pediatrician with 31 years of experience treating children in a private practice in Frederick, Maryland. I'm here today in an
official capacity representing the American Academy of Pediatrics. Thank you for the opportunity to provide comments to the Food and Drug Administration on the implementation of the Neal R. Gross & Co., Inc. 202-234-4433
Page 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Biologics Price Competition and Innovation Act. As a practicing pediatrician I have seen
firsthand that from birth biologics play an integral role in sustaining and improving the life and health of children. Pediatricians use biologic products to cure life-threatening illnesses, manage chronic health conditions, and prevent devastating communicable diseases. importance of biologics to children necessitates that we encourage the development of new and innovative products. We must, however, also work to increase access to these medications because biological products are often very expensive. A regulatory pathway for the approval of generic forms of these medications is needed to lower cost and improve access. The AAP The
urges that this be accomplished without compromising the safety and quality of care to children. As Congress worked to create a new Neal R. Gross & Co., Inc. 202-234-4433
Page 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biologics pathway the American Academy of Pediatrics successfully advocated that existing laws to improve therapeutics to children be appropriately applied to biologics as well. The Academy has worked for decades to ensure that medicines used in children are studied in children. The physiology of
children is different than that of adults and this changes how they observe, metabolize, eliminate, and respond to medications. It is because of these significant differences that it is important to remember that children are not just little adults and they must whenever possible have the benefit of age-specific therapeutic safety and efficacy data specific to them. Two laws, the Best Pharmaceutical for Children Act, and the Pediatric Research Equity Act, have taken giant strides towards achieving these goals. The academy has
greatly appreciated its partnership with FDA Neal R. Gross & Co., Inc. 202-234-4433
Page 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 on the implementation of these two laws and is proud that to date over 397 drugs have been relabeled with pediatric information as a result. The AAP looks forward to working with
FDA to renew and strengthen these laws when they are up for reauthorization in 2012. The new biologics law has applied to biologics the pediatric exclusivity previously offered only to drugs. An
innovator biologic will now be able to receive an additional six months of marketing exclusivity offered by BPCA if it completes studies in children as outlined by a written request by FDA. The AAP welcomes this expansion of BPCA as a significant innovation for children. The academy urges both FDA and innovative biologics companies to begin thinking now about gaps in pediatric data for currently marketed biologic products. We urge these companies to quickly enter into dialogue with the agency about its Neal R. Gross & Co., Inc. 202-234-4433
Page 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 ideas for needed pediatric studies. This
planning is particularly important for those biologics that may lose marketing exclusivity in the next few years and, therefore, have a narrow window during which pediatric exclusivity can be granted. Although the BPCI does not make changes to how BPCA operates, it's expansion to biologics necessitates timely planning by FDA and subsequent guidance to industry. The
Institute of Medicine is currently convening a panel to look into issues related to BPCA and PREA. This will include consideration of
biologic products and testing in children. However, pediatric exclusivity for biologics is now law and FDA and industry should not wait until the conclusion of the IOM process to move forward on pediatric studies. The AAP applauds the success of the
Pediatric Review Committee, PeRC, which since 2007 has provided invaluable internal guidance to FDA's reviewing divisions on the operation Neal R. Gross & Co., Inc. 202-234-4433
Page 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 of BPCA and PREA. The PeRC has significant experience working to improve the consistency and quality of written requests issued by the Center for Drug Evaluation and Research. We
urge the Center for Biologics Evaluation and Research to reach out to PeRC for guidance as it implements its own process for issuing written requests for biologics under BPCA. Since its enactment in 2003 the Pediatric Research Equity Act has applied to new biologics. However, under the new
biologics law biosimilar products are now subject to the pediatric testing requirements of PREA. This means that biosimilar
applicants that do not meet the higher standard of interchangeability will need to complete assessments in the pediatric population. These studies will help ensure that biosimilar product is safe for use in children and labeled with appropriate dosing Neal R. Gross & Co., Inc. 202-234-4433
Page 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 information. The academy strongly urges FDA'S
review divisions to engage applicants for innovator or biosimilar products as early as possible in the overall product development process to discuss pediatric studies. As required by Public Law 110-85, the Food and Drug Administration Amendments Act, FDA conducted a retrospective review of information submitted and action taken in response to PREA. FDA identified 862 waivers or deferrals for drugs or biologics during the period covering January 1, 2004 to September 27, 2007. The academy is pleased that as a
result of this law the PeRC is now reviewing plans to waive or defer pediatric studies and believes the PeRC's role will reduce inconsistencies or errors made in the PREA process. However, the application of PREA to a biosimilar product should be considered de novo. A waiver or deferral granted to an Neal R. Gross & Co., Inc. 202-234-4433
Page 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 innovator product should not simply be transferred to a biosimilar. Additionally,
PREA should apply to biosimilar products even if the innovator product was approved prior to PREA or to the pediatric rule. This new regulatory pathway has the potential to improve access to expensive medications that are vital to the health of children. We must remember, however, to
balance these benefits with recognition that children are a vulnerable population. Biologics are highly complex therapeutic products and the new pathway must adequately address the unique needs of children in assuring that the medicines they take are both safe and effective. The decision to substitute interchangeable biological products should ideally be made by the treating physician and should never be made without the physician's knowledge. A patient's response to a biologic
product can be much less predictable than in Neal R. Gross & Co., Inc. 202-234-4433
Page 57 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the case of a small molecular drug and this is especially true for children. For this reason the AAP believes that the substitution of interchangeable biologics for children must not occur at the pharmacy level without notification of the doctor. The best judgment of the treating
physician can also be affected by insurance coverage decisions. The impetus behind this law is increasing patient access to important therapeutics where children can be left without lifesaving medicine if an insurance company decides not to cover particular treatments. Not only must insurance companies
pay for biologics but they must also not refuse payment for branded biologics if specifically prescribed to the patient for legitimate medical reasons. The mechanism of action of biologics is often unknown and adverse side effects can be unpredictable. This
Page 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 panel? DR. JENKINS: I'm wondering about comments. Are there questions from the uncertainty necessitates the robust postmarketing surveillance and requirements for post-marketing studies, if necessary, to ensure safety. This is especially crucial for children because as a small population is often difficult to detect dangerous safety signals in pediatric clinical trials. We urge
FDA to use its authority to make certain that appropriate monitoring of marketed products take place when issues of child safety is at stake. We look forward to working with the FDA to implement the Biologics Price Competition and Innovation Act for the benefit of child health. Thank you for the
opportunity to speak to you to you today. DR. BEHRMAN: Thank you for your
Page 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 your thoughts about the intersection between BPCA and the new biosimilars legislation. you know under BPCA the sponsors can decide whether or not to respond to the written request so in that sense it's voluntary that they decide whether to conduct the studies that FDA has requested. In reward they get the six months of additional exclusivity. If the bar for a As
biosimilar approval is set too high, and I think we have heard some comments earlier that are advocating for a fairly high bar for setting of the biosimilar, it would seem to take away any incentive for the innovator to actually respond to the written request because they wouldn't be at risk of losing their marketing exclusivity even when it expires because there would be no biosimilar. How do you bridge between the incentive for the innovator to conduct pediatric studies in response to the written request and setting the bar for the biosimilar Neal R. Gross & Co., Inc. 202-234-4433
Page 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 approval at a level that would actually potentially lead to some real competition? DR. BROMBERG: Obviously from the
academy's standpoint the goal is to have all these products available to children in the most efficacious way without the possibility of not well testing these and making sure that the metabolism route for children is not different. The balance for industry is hard for me to determine on how they are going to look at those issues. industry end question. I can't answer the Our goal would be to
have these available as quickly and easily as possible for children while we monitor for safety and efficacy of the drug. DR. JENKINS: Just a follow-up.
Under the current paradigm essentially there's unending exclusivity for these biologic products because there had previously not been a biosimilars pathway and there was also not a BPCA written request pathway because it Neal R. Gross & Co., Inc. 202-234-4433
Page 61 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 really made no sense to extend the exclusivity when there was no pathway for a biosimilar. I'm just trying to figure out how are we going to walk carefully in that conundrum that if we set the standards for biosimilars so high that it makes it essentially impossible to get a biosimilar approved, there is no incentive for the innovator to conduct those pediatric studies that we might ask for. We can't require them to conduct those studies and we can't require the biosimilar to conduct the studies because they are not going to be approved. There is a real
conundrum there based on where the standard is set for a biosimilar approval. DR. BROMBERG: solution to that. And I don't have a
I recognize the conundrum. Ms. Marchand. Dr. Bromberg, thank In
DR. BEHRMAN: DR. MARCHAND:
you very much for your comments today.
your submitted written comments, and as you Neal R. Gross & Co., Inc. 202-234-4433
Page 62 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 stated, the AAP believes the substitution for interchangeability of biologics for children must not occur at the pharmacy level without the notification of the doctor. I was wondering if you could expand on those comments and address things such as formularies that might be agreed upon and are available either at the state level or if there is something at the federal level as an agreed interchangeability or whether that needs to be something in a prescription type document. DR. BROMBERG: I think that we're
launching into a lot of new territory and it's going to be unclear where we are going to end up as new products become available and they become available quicker it's going to be hard to know exactly what the interchangeability rules are and formulary rules are and are they going to apply to these products. At this time I think that we do work with formulary and that we get notified Neal R. Gross & Co., Inc. 202-234-4433
Page 63 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 on formulary on acceptability for a patient and then to make an acceptable change. assume the same process would occur with biologics. DR. JENKINS: Another point along I
that line is does the academy have a position on the naming of a biosimilar product? established name, not the trade name. think that it should be the same as the innovator or should there be differences so that you can, in fact, distinguish between them in the prescribing? DR. BROMBERG: I think the The Do you
academy's position is that we provide a system that is as clear as possible for the prescriber so that they can know exactly what they're working with and what they're prescribing to the patient. DR. JENKINS: The example I could
give you is recently for some of the botulinum toxins we have taken the approach of giving them different names to help emphasize that Neal R. Gross & Co., Inc. 202-234-4433
Page 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 they are not, in fact, the same or interchangeable so that's leading to instead of them just being called botulinum toxins they have a prefix that starts in front of the word that will be unique across the manufacturers of the products. Do you think that would an appropriate approach to a biosimilar? filgrastim. Take
Should the follow-on biosimilar
have a prefix added to the word filgrastim so you can distinguish it from someone else's product? DR. BROMBERG: I think as long as
we work towards clarity and clear communications on these products that would be acceptable. MS. MALONEY: with regard to PREA. I have a question
You talked about that
the application of PREA to biosimilars should be de novo. I just want to understand in the
instance where the innovator would have done studies in children, then is it the academy's Neal R. Gross & Co., Inc. 202-234-4433
Page 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 arrived? comments. DR. BROMBERG: DR. BEHRMAN: No. Thank you. Has Mr. Jervis We will position that such studies also should be done with the biosimilar clinical studies? DR. BROMBERG: Yes. It should go
through the review process but not automatically accept that the biosimilar is going to have the same efficacy and same metabolism in children as the innovator. DR. BEHRMAN: Thank you for your
Shall we break now?
take a 15-minute break. 9:45. Thank you.
We will reconvene at
(Whereupon, at 9:32 a.m. the above-entitled matter went off the record until 9:48 a.m.) DR. BEHRMAN: Welcome back. Our
next speaker will be Shein-Chung Chow from Duke University. DR. CHOW: Good morning. First I
would like to thank the committee for giving Neal R. Gross & Co., Inc. 202-234-4433
Page 66 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 me the opportunity to speak here. It's a
great honor for me to be here to share with you some of my thoughts on the scientific factors of the biosimilarity and interchangeability. My name is Shein-Chung Chow. a professor of biostatistics and bioinformatics from Duke University School of Medicine. Due to time constraints I will only I'm
focus on some critical scientific factors for the biosimilarity. I will focus on the study
endpoints criteria for biosimilarity, study design and the statistic methods. For the interchangeability I will talk a little bit about FDA's perspective, measure, and criterion and statistical methods. Then I would also like to propose
the study design for assessment for addressing the interchangeability. For the study endpoints if the surrogate endpoints such as the pharmacokinetics for the drug absorption is Neal R. Gross & Co., Inc. 202-234-4433
Page 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 used, it is suggested that we should follow the pathway for addressing the bioequivalence for the drug product under the fundamental assumption, bioequivalence assumption, that the pharmacokinetic responses could be predictive of clinical outcomes. If the clinical endpoints is chosen to address the biosimilarity, I think that we would suggest that we should follow the FDA's recent guidance on the noninferiority clinical trials. For the criteria for the biosimilarity we feel that an appropriate criteria for the biosimilarity should be able to address both the average and the variability because I think most of the biosimilar products are known to be sensitive to small change and variation of the environmental factors and the designs so they are highly variable. In addition, we suggest the probability-based criteria be used because it Neal R. Gross & Co., Inc. 202-234-4433
Page 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 can take variability into consideration and it is more stringent in order to address the degree of similarity. I think we would That means
recommend disaggregated criteria.
the disaggregated criteria 140 - an average of 140 variability be considered. Unlike the 150
- criteria fits the criteria for the assessment of bioequivalence for the drug product. We feel a more flexible criteria which would allow us to adjust for the variability and/or therapeutic index of the reference product should be considered. All
these recommendations are based on a list in a recent publication of the Journal of Biopharmaceutical Statistics. Regarding the study design, I think for the assessment of biosimilarity the design of choice will include crossover design, a parallel design. I think we feel
that the parallel group design is a more suitable design for the biosimilar product, Neal R. Gross & Co., Inc. 202-234-4433
Page 69 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 especially for those products with relatively long half-lives. However, I think that under this design I think it cannot provide independent estimate for the intra-subject variability. In the alternative we may consider a two-stage design. The first stage actually is a
crossover design and the second stage is a parallel design. The first stage with a limited number of subjects to get some information. Then I think the second stage we can really use the information to assess the biosimilarity. Under the valid study design and the criteria, some statistical methodology are necessary to develop. Most statistical
methods include statistical methods for the assessment of biosimilarity of follow-on biologics, statistical methods for the interchangeability of follow-on biologics and the statistical methods for the comparability Neal R. Gross & Co., Inc. 202-234-4433
Page 70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 in the immunogenicity and the statistical methods necessary to develop for the - to cover the CMC issues. Also statistical methods for the comparability in the manufacturing process following the ICH Q5 guidelines on the quality of the biotechnology product. Regarding the interchangeability from the FDA's perspective that interchangeability include a concept of socalled switching and alternating. Our
interpretation of the switching is switch from the one biologic product to another. For
example, it's from the reference product to a test product. Of course, I mean that's not including the change, the switch from the T to R and T to T alternating following the switch from the one biologic product to another and then switch back to the original biologic product. This way we will focus on the
reference product to the test product and then Neal R. Gross & Co., Inc. 202-234-4433
Page 71 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 back to the reference product. Under this the definition of switching and alternating the measure criteria and the statistical methods for the assessment of the switching and the alternating should be developed accordingly. Here I would like to propose a study design. In order to address switching
I think in a balanced design -- this is a typo. It should be 4 x 2 crossover design.
That means we have four sequence and a twodosing period, TT, RR, TRRT. In order to
address the alternating study design where the 2 x 3 dual design which is the two sequence of three period design is TRT RTR. In order to address both the switching and alternating modify the balance design may be useful which is TT, RR, TRT, RTR. If you don't like any of these
possibilities, we can consider the bridging study using the biomarker data in conjunction with a parallel group design. Neal R. Gross & Co., Inc. 202-234-4433
Page 72 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Here I would like to propose some statistical methodology based on the possibility to develop the biosimilar index and the so-called biosimilar index based on the reproducibility probability for claiming biosimilarity. The use of the biosimilar
index first takes the variability into consideration. Second, it's a way to be able to address how similar is similar. Then it
provides an opportunity for addressing the global biosimilar across different domains. Also it provides opportunity for address the interchangeability. I would like to conclude my presentation with this slide for biosimilarity. In addition to the surrogate
endpoints such as the pharmacokinetic responses the clinical endpoints are necessary to consider. Criteria for biosimilarity
should focus on the variability in addition to the average. Neal R. Gross & Co., Inc. 202-234-4433
Page 73 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Jenkins. DR. JENKINS: I notice you comments. Questions from the panel? Dr. choice. Parallel design is the design of The biostatistical methods are
necessary to develop before the establishment of a drug specifications, comparability in immunogenicity, and comparability in the manufacturing process, and for interchangeability which include the switching and alternating, and in the higher order crossover design are necessarily employed. The bridging study using biomarker data in conjunction with a parallel group design may be considered. Thank you. Thank you for your
DR. BEHRMAN:
reference for the clinical study design the recent non-inferiority guidance that we published. trepidation. I do this with a little I'm not a biostatistician but
that study design is for establishing that a Neal R. Gross & Co., Inc. 202-234-4433
Page 74 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 new product is safe and effective versus here we are looking at saying that the biosimilar is similarly effective and safe to the reference. The non-inferiority design is a one-sided statistical test. The statute calls
for no clinically meaningful difference between the biosimilar and the reference. Wouldn't there need to be a two-sided statistical test to make sure that you're not significantly better? DR. CHOW: Right. I think for the
non-inferiority actually that should be included already. When we talk about a
biosimilar, I think that we should stick to the equivalency. be two sided. The reason why I recommend the use of the guidance is because I think the statistical methodology with the selected noninferiority margin has been well established. Once we have established that, the nonNeal R. Gross & Co., Inc. 202-234-4433 In other words, that would
Page 75 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 inferiority gives a chance to test for the superiority. I think for our case we should probably limit it to the equivalency. Otherwise, I think if you show that one product is superior to the other one, this is not really similar. It becomes better and
that is out of the scope of biosimilarity. DR. JENKINS: So in that two-sided
testing model should the criteria be the same for inferiority and superiority? Should they
be symmetrical or should they be different on the bottom and top sides of that evaluation? DR. CHOW: The criteria should be
the same because I think the non-inferiority margin according to, I think, in our opinion equivalent to the so-called biosimilarity limit. That should be the same. DR. BEHRMAN: Other questions?
Following up on Dr. Jenkins' question, do you have any comments to make on what you might think if we do accept the premise that it's Neal R. Gross & Co., Inc. 202-234-4433
Page 76 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 equivalence and that the margin should be the same, the potential size of the studies as well? DR. CHOW: Could you repeat again? Dr. Jenkins asked
DR. BEHRMAN:
you two very crucial questions; should it be an equivalence design and, if so, should the margins be the same for inferiority and superiority. You answered yes. Do you want
to comment at all on what you think the implications for study size might be? DR. CHOW: I think for the test
for the non-inferiority and the test for equivalency the sample size will be different. That has something to do with the upper level. For example, for the bioequivalence we consider 90 percent. That means you use the I think that we can
5 percent on each side.
control the size based on that depending upon how similar you want to establish. DR. BEHRMAN: DR. CHERNEY: Dr. Cherney. Yes. You mentioned
Page 77 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that statistical methods are necessary for development and establishment of product specification. that? Can you expand a little bit on
Are you talking about just statistics
looking at the biosimilar product or a comparative statistic across both the innovator reference product and the biosimilar? What types of numbers or sampling
sizes would you expect in those type of things? DR. CHOW: The product
specifications that I referred to is because I think once we have the follow-on biologic it's going to compare with the innovator so you still have some kind of criteria in terms of what percentage you consider they are the same. In other words, if you have set up something as specification, you can compare the reference with the reference so you can establish that even from the same product due to the variation they will not perform Neal R. Gross & Co., Inc. 202-234-4433
Page 78 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 identically so I think we want to see even with the same product within what percentage they are considered the same, similar. That's
what I mean by the product specification. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. Following up on the
same slide, the next point on your statistical methods is about immunogenicity and you have clinically meaningful immunogenicity for some products is very rare. What testing would you
use to show that for something that occurs one in a thousand for the reference product how would you go about reaching assurance that the biosimilar is, in fact, similar for such a rare event? DR. CHOW: For immunogenicity all
the manufacturing process depending upon the so-called margin, I mean what are your similarity. Because, I think if the event
rate is very low, then I think there are several methods that we can consider. example, we can consider the so-called Neal R. Gross & Co., Inc. 202-234-4433 For
Page 79 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. DR. CHOW: Thank you. The next slot will probability statement. In other words, I think that we want to make sure that the chance of doubling one event is lower than some prespecified number or something like that. I think with
this kind of different domain I think your criteria margin may not be the same. For example, some people consider like 20 percent difference of things like that. That may not be applicable to each of
these different domains. DR. BEHRMAN: Thank you for your
DR. BEHRMAN:
be shared by Graham Jones from Northeastern University and Jeffrey Mazzeo from Waters Corporation. DR. JONES: Thank you, Rachel. Prepare the panel
It's a pleasure to be here.
now for what will become a chemistry lesson. We're going to talk about how we characterize Neal R. Gross & Co., Inc. 202-234-4433
Page 80 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 these protein therapeutics and the use of technology. By way of introduction firstly, Northeastern University is a University in Boston Massachusetts and it has within its boundaries an institute which is highly relevant. It's the Barnett Institute for
Chemical and Biological analysis and for the past 30 years it has been devoted to the separation and analysis of protein and producing excellent research papers on those topics that is now extremely relevant to the debate in hand. I'm joined on the podium in a few minutes by Jeff Mazzeo. Waters Corporation
supply a great deal of instrumentation to our laboratories and we're going to share some exciting results in the next few minutes. We can spend probably a whole month talking about this category of science but I think it's more relevant to focus on some testimony which was presented by Steve Neal R. Gross & Co., Inc. 202-234-4433
Page 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Kozlowski from the FDA due to a congressional committee last year and this was really a call for new methodologies to be developed. We responded to this in the academy working with industrial manufacturers. There are three main area, post-translational modification, three-dimensional structure, and protein aggregation. These were three areas that Steve opined on that we needed better tools and technologies to understand these properties and proteins and how they then relate to the emergence of biosimilars and interchangeability. Taking this challenge up the technology actually does exist and has existed for several years. The question is how you
implement it and what tool you use, what's appropriate for the job. When it comes to
protein similarity there are a myriad of complication factors to consider. On top of that we want to develop Neal R. Gross & Co., Inc. 202-234-4433
Page 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 technologies and publish them which are going to be proven and reliable and, therefore, any laboratory in theory around the world will get the same result analyzing the same product using the similar platform. For that it's not just a question of identifying the method. It's a question of
training the employees and training the regulators in many regards on what this data is, what its limitations are, and how one goes about using it. To that end we are now in the
process of establishing a public/private partnership at Northeastern. It will be the
Biopharmaceutical Analysis Training Laboratory and this will be a joint effort between Northwestern University and Waters Corporation. It will open in the summary of
2011 and its mission is to proselytize best research methods in the analysis of protein therapeutics, biosimilars, methods development, and most importantly training of personnel in the biopharmaceutical industry on Neal R. Gross & Co., Inc. 202-234-4433
Page 83 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 how to use the technologies which are relevant and publicizing those methodologies in outreach fora such as today. about this development. I'm very excited
We're actually doing We've been
a lot of the work as we speak.
training people from the FDA and from industry the past year and this will become more formalized in the summer of 2011. Let's get back to the task in hand and I'll share some data with you on these three areas. Post-translational modifications
I will take and then Jeff will talk on the last two topics. Just a simple analysis here.
There's a lot of chemistry here we don't need to worry about but you'll recognize this, factor 9 blood constituent and this is recombinant factor 9 which has been subjected to analysis using liquid chromatography mass spectrometry. This is a commercial instrument you can buy it off the shelf. Do an enzymatic
digest, work up the sample and you will see Neal R. Gross & Co., Inc. 202-234-4433
Page 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 differences between recombinant factor 9 and humanoid factor 9. The difference is on one
site here we can see a difference in coag cozylation. There's a fucosyl located here on
the human sample and not on the recombinant sample so these are not identical. They are not similar and you can determine where that is very easily and very rapidly. This is an analysis that takes
approximately one hour so post-translation modifications can be analyzed very easily by mass spectrometry. Another example. We all remember
the heparin crisis where all the sulfated chondroitin sulfate contaminated heparin. The
technique that was used to determine that was nuclear magnetic resonance, NMR so to speak. There is paper reporting this. We are actually using this now combining NMR with liquid chromatography and mass spectrometry to analyze extremely complex proteins and get three-dimensional structures Neal R. Gross & Co., Inc. 202-234-4433
Page 85 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 from them. We are developing interfaces We're going to
between these devices.
mainstream this methodology. It's extremely exciting and we can now analyze O-glycans which are a class of derivatives which are extremely hard to analyze previously using any other methodology. The basic tenant here is the You need to have Couple
right tool for the job here.
NMR to analyze O-glycans successfully. it with mass spectrometry and separation science and you get complete coverage.
Last slide here is focused on isomerization. Isoaspartic acid can be Isomerizations
immunogenic and guess what?
can take place in proteins so isoaspartic acid an isomerize either through direct analysis or through deamidation. isomerizations. This is a sample taken of beta amyloid protein. We can detect these Again, We can now detect these
differences down to 0.5 percentage.
Page 86 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the method here is a special type of mass spectrometry that works extremely well. The
take-home message here is that analyzing the post-translational modifications can be done with existing technology and it's a highly exciting field. Jeff is going to come up and talk about three-dimensional structures. DR. MAZZEO: Thank you, Graham.
Moving on now and talking about threedimensional structures, I show you here this structure of tissue plasminogen activator, a very complex protein that has many potential sites for disulfide bonds. In fact, some recent work, again done at Northeastern, demonstrate that using newer ionization techniques and newer fragmentation capabilities we can actually fully map all the disulfides that are present in this particular protein. actually 17 disulfide. In this case it's
This type of
information is critical to demonstrate that Neal R. Gross & Co., Inc. 202-234-4433
Page 87 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the protein has been properly folded. Another area of three-dimensional structure analysis that's gaining a lot of interest in the industry and people are using this today in the innovator market is to use something called hydrogen-deuterium exchange mass spectrometry. In this particular technique we place the protein in a solution of D20 and the amide hydrogens that are present will exchange with those deuterium atoms. The amount of
exchange is determined by the overall structure of the protein. You can see that in this particular case what was done by some work that was published recently is we looked at an antibody with and without the glycans attached. Using this technology we can
determine which regions of the protein now become more exposed as a result of the fact that the glycans have been removed. Finally, in the area of Neal R. Gross & Co., Inc. 202-234-4433
Page 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 aggregation another new technology which can now be applied to this is something called ion mobility spectrometry. This essentially can
be analogous to doing electrophoresis in the gas phase. What we are able to do now is
separate proteins based on their size and shape. In this particular example we're looking at insulin and insulin dimer which by mass spectrometry have exactly the same mass to charge ratio. However, when we put the
additional dimension of ion mobility drift time into the equation here, you can see that we can actually separate out the triply charged monomer and a six-charge dimer, exact same master charge, but by adding mobility we can separate them and we can actually measure their cross-sectional area. We believe that
this particular tool will be very useful, again, for studying aggregation. This is just now showing you the application of this particular method which, Neal R. Gross & Co., Inc. 202-234-4433
Page 89 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 panel? DR. CHERNEY: Yes. Concerning the by the way, is very rapid. literally a minute or two. It's completed in We can look at
different insulins and insulin analogs and quickly determine the level of dimer and monomer that is present. As I conclude, I would just like to go back to the BATL slide and say that we are here to represent what's capable with respect to analytical science. We want to act
as a resource to you as you consider regulations both for innovator products, as well as biosimilars, and we look forward to working with our partner Northeastern on this training laboratory. chance to comment. DR. BEHRMAN: your comments. Are there questions from the Thank you both for We thank you for the
aggregate, your technique you mentioned was looking at dimers and trimers, I guess, and Neal R. Gross & Co., Inc. 202-234-4433
Page 90 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 monomers. We are also interested in higher
aggregates like even up to 10 microns in size that existing techniques have a difficulty in looking at them and providing information. Can you give us some insights into those ranges of aggregates, too? DR. MAZZEO: The larger proteins
when you're looking at things that are as much as a 10 monomers attached, the ion mobility may not be appropriate. However, there are
other analytical technologies such as light scattering and subvisual particle size measurements which we believe would be probably more appropriate for something like that. DR. CHERNEY: I thought the light
scattering technique particle size, some of those between the size ranges of 0.1 micron and 2 microns. Do you have a technique that
can measure those particle sizes? DR. MAZZEO: That's not our
particular area of expertise at Waters but Neal R. Gross & Co., Inc. 202-234-4433
Page 91 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 there are other people in the industry who have commented on light scattering ability to measure that particular size. DR. CHERNEY: CMC. I saw some
very nice techniques looking at individual modifications but one of the issues that arises is not only just modification but the interactions between different modifications on the same molecule. The actual total distribution of this within the context of the molecule itself so the actual range of different types of molecules in a preparation is of interest. Do
you have any comments on how one might look at that actual range in distributions? DR. MAZZEO: One of the things
that's true about a lot of the measurements for high-order structure at this stage they are able to pick up gross differences between molecules. I think if you have a very subtle
change, they are probably not at the stage where they can actually differentiate that. Neal R. Gross & Co., Inc. 202-234-4433
Page 92 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 What I would say is that because of the sensitivity and dynamic range that we have with LC/MS today, we can actually detect individual differences. Let's say, for
instance, deamidation down to a level as low as 0.05 percent. Your follow-up question,
though, how do I correlate that to be over a molecule I think is still a work in progress. I think we will see tremendous strides in that area. DR. JENKINS: Can you comment on
the ability of these techniques to characterize the active ingredient based on comparison of formulations? So for the
biosimilar exercise the biosimilar company is probably going to have the formulation of the reference product. They are not going to have the active ingredient of the reference product so what is the ability of these techniques to look at the active ingredient across those formulations given the inactives that may be Neal R. Gross & Co., Inc. 202-234-4433
Page 93 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 added to the reference formulation, various stabilizers or other proteins even that might be in there. What's your ability to use these
techniques across formulation versus across purified active ingredients? DR. MAZZEO: good question. I think it's another
I would say that some of the
techniques deal very well with formulation and additives would be independent of it. I think
some of them less so and will certainly be influenced by it. I would also argue that the formulation additive is certainly going to affect the high-order structure potentially as well. Ideally you would like to be able to
measure it in the presence of those. Obviously in a short period of time we couldn't go into great detail here today on the capabilities and limitations of these techniques but we would be happy to discuss in more detail what those capabilities and limitations are with your scientific staff Neal R. Gross & Co., Inc. 202-234-4433
Page 94 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 question. at a later date. DR. BEHRMAN: DR. CHERNEY: Any other questions? I had one other
One of the issues that comes up is
that proteins are not static rigid molecules. They have a certain confirmation but in order for biological activity to occur, they need changes in the confirmation of proteins so they move and they change their shape. Can
you tell us about the sensitivities of your high-ordered structure assays to look at that type of issue? DR. MAZZEO: Yes. In fact, I
think that the technology which we really think has a lot of promise to do that would be this hydrogen-deuterium exchange because the way that you do this experiment it's typically a time course experiment. You expose the protein to the D20 for different time periods and that allows you to get some insight into protein dynamics as far as what's happening over time. I think
Page 95 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Endrenyi. comments. that you'll see a lot more in this area that will address that question. DR. BEHRMAN: Thank you for your
I would encourage you to submit the
additional information in reference to Dr. Jenkins' question to the docket so we can evaluate it. For those who are standing or perched, there are chairs scattered throughout. and sit. Our next speaker is Laszlo Was I close? DR. ENDREYI: I'm Laszlo Endrenyi Please feel free to come forward
from the University of Toronto but I'm a professor emeritus. I appreciate the
opportunity to make a presentation here. First, I would like to present some terms which come from the small molecular world, prescribability. We first took drug
product which are provided to naive subjects who have not yet received any of these forms. Neal R. Gross & Co., Inc. 202-234-4433
Page 96 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Switchability. The drug product
is provided to a subject who has already received one form and is switched to another formulation. Nothing is repeated switching
from one form to another, from reference to test, test to test, back to reference. important for interchangeability. That's
This may
take place possibly without the intervention or even information to the healthcare provider. That is a serious issue. Statistical considerations for prescribability, switchability and interchangeability. Crossover studies are
when each drug product is administered to each subject so each subject receives more than one form, preferably all forms. In this case one can apply switchability and interchangeability because that is information for that, at least from the kinetic side. Parallel group studies,
each drug product is administered to a different group of subjects. In this case
Page 97 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 word. there is no information for switchability and interchangeability and only prescribability can be applied. To summarize this, this refers to switching or substitution on average, not to everything. Switchability refers to Here the
substitution within individuals.
question is when testing for switchability, is switching from one form to another comparable to the switching when the same form is administered repeatedly? reference. Is the risk of switching from one form to another reference to test not greater, or actually comparable to the risk when the same form, the reference, is administered repeatedly. In this case again we need Reference versus
crossover design to establish switchability and to make it possible. In biosimilarity it's a different We talk about similar drugs you already
know and we talked about but not identical. Neal R. Gross & Co., Inc. 202-234-4433
Page 98 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The problem with biosimilarity is that there are several factors contributing, or several modules contributing. You've heard about analytical, biophysical, biological characterization, quality and structure of the biological product. Manufacturing is highly relevant.
There are several factors which need to be considered for biosimilarity or biocomparability. At times more changes in some of the factors give us a large deviation in clinical outcomes. This may occur on average There are
but especially in individuals.
several factors as some of these may be for sensitivity and, of course, large deviations. Some and we're not always sure which and when this sensitivity will arrive. Now, here is the BPCI Act and some section and the main message here that this section of 351(k)(3) distinguishes between biosimilarity and interchangeability, but it's Neal R. Gross & Co., Inc. 202-234-4433
Page 99 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 this section that makes this distinction and the BPCI Act in other sections is not always clear on this distinction. In some cases -- actually, there are several sections of BPCI Act that tells of biosimilarity and interchangeability are a bit smudged out. They are important distinctions. Another section of this Act Subsection (b)(3) states that for interchangeability the standards described in Subsection (k)(4) which really makes definitions of the interchangeability and switching. This standard if these are
satisfied, then the substitution can take place without the intervention of the healthcare provider who prescribed the referenced product. This subsection is very important and it provides a very permissive stipulation and this is the law. If there is
interchangeability, then actually the healthcare provider need not be involved. Neal R. Gross & Co., Inc. 202-234-4433
Page 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 That's really very serious to my mind. Now, again to repeat it is necessary -- biologics often have long halflife. In this case crossover study would be
ineffective and federal group designed studies would be performed. If federal group studies
are performed, there is no basis in those studies to establish even pharmacokinetic basis for switchability and interchangeability. On the other hand, if the
half-life is reasonably short, one can establish pharmacokinetic basis for switchability and interchangeability. However, even in these cases there are all those other factors and modules which call for caution, as I mentioned, sensitivity to small changes in conditions. Therefore, even in
this case looking at those other factors, caution should be exercised when considering switching. To conclude, in the small molecule world switching and alternating is generally Neal R. Gross & Co., Inc. 202-234-4433
Page 101 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 you. DR. ENDREYI: DR. BEHRMAN: Thank you. The next speaker is comments. Questions from the panel? Thank reasonable. FDA has relied on these federal
studies establishing bioequivalence and then enabling the switching in the alternative. Biologics is very different. In many cases only federal designed studies can be pursued which do not make interchangeability possible, and even if some crossover studies can be performed, there are all those other factors which one would have to look at and see whether they don't cause any trouble. Generally speaking
switching and alternating should be pursued only with very substantial caution. you. DR. BEHRMAN: Thank you for your Thank
James Love from Knowledge Ecology International. Neal R. Gross & Co., Inc. 202-234-4433
Page 102 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 it. MR. LOVE: I'm going to talk a MR. LOVE: Thank you very much. I assume
We submitted a written statement.
that was distributed to the committee. DR. BEHRMAN: Yes. The panel has
little bit about what was in that submission and add two additional points that were not in the submission. The primary issue that we've tried to focus on in our comments are the concerns that we have about the data exclusivity provisions in the biosimilars legislation. And specifically draw attention to the committee to in 2008 the -- this is on the second page that I'm going to be sort of focusing on in my verbal here. third page. I'm sorry, the
Just go the very end of it. In 2008 the World Health
Organization adopted a Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property. It was agreed to
Page 103 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 by consensus. It was supported by the United
States Government. In Element 6.2 of that Global Strategy in the area of actions to be taken to improve delivery and access to medicines, it called upon governments to -- governments would be establishing and strengthening mechanisms to improve ethical review and regulate the quality, safety, and efficacy of health products and medical devices. Subparagraph g, "Promote ethical principles for clinical trials involving human beings as a requirement of registration of medicines and health related technologies with reference to the Declaration of Helsinki and other appropriate text on ethical principles for medical research involving human subjects including good clinical practices." I then call your attention in a text that just follows this on my written submission. That is the two paragraphs that
I think are particularly relevant to the Neal R. Gross & Co., Inc. 202-234-4433
Page 104 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilars legislation from the Helsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects. First paragraph 20, "Physicians may not participate in a research study involving human subjects unless they are confident that the risks involved have been adequately addressed and can be satisfactorily managed. Physicians must immediately stop the
study when the risks are found to outweigh the potential benefits or where there's conclusive proof of positive and beneficial results." 21, "Research involving human subjects may only be conducted if the importance of the objective outweighs the inherent risk and burdens to research subjects." The relevance to the ethical pathways legislation is as follows. If there
are no patent barriers to a biologic drug but in order to register it you have to prove to the FDA that the drug is safe and effective. Neal R. Gross & Co., Inc. 202-234-4433
Page 105 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 In some cases, in many cases, there will have been an evidence that has already been established through clinical trials by other people, not the person trying to introduce the biosimilar drug. For
example, the originator of the product. During the period of the data exclusivity, during the 12 years that currently exist, what the generic competitor will do will be essentially replicate tests to where the results are already known in order to satisfy the FDA requirements for safety and efficacy. In our opinion, and in the opinion of many experts, this is a conflict with the Helsinki rules on repetition of clinical trials. This issue is being examined in
Europe in the context of a redundant test on animals and is the subject of a new proposal in a trade agreement between Canada and the European Union that would actually prevent Canada or the European Union from replicating Neal R. Gross & Co., Inc. 202-234-4433
Page 106 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 trials involving animals when it was considered to be violating these ethical principles in repeating trials. In the alternative in the EUCanadian trial involving vertebrate animals is to enter into cost-sharing agreements with the originator of the data so that the generic competitor contributes a fair share of the cost of the drugs including the cost associated with the risk and capital cost involved in the trial. Senator Sanders and the United States Senate has introduced legislation recently. It has the support of a number of
consumer and public health groups, Senate Bill 3921 which will introduced next session which goes to this issue and proposes a certain way of addressing the area when there is ethical conflicts. Our main comment is that the United States Government should not have a regulatory system which at its root Neal R. Gross & Co., Inc. 202-234-4433
Page 107 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 anticipates the generic competitor would violate articles 20 and 21 of the Helsinki Declaration. The only other two things I wanted to mention is I think as it relates to data exclusivity there has to be rules to address the case where there is an abuse of the rights or a shortage or something like that to also not have the period of exclusivity. whole method of registrative product. An example would be there is a current dispute involving Fabrazyme, a biologic drug for the treatment of Fabry's disease. There is a shortage right now and It's this
there has been a shortage for some time. We're working with patients, one of which is in dialysis right now because of the shortage of the drug, where they are trying to bring to the market -- they have asked the NIH to grant them a license on the patent so they can try to register a generic substitute for people that can't get this very Neal R. Gross & Co., Inc. 202-234-4433
Page 108 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 panel? MR. SCHWARTZ: Mark Schwartz. comments. Are there questions from the expensive but in short-supply drug. Finally, on the issue of the biosimilars thing, I would suggest that the administration revisit the issue of the way the transparency of the patents are created which can be contrasted to the method that is used by the FDA in the Orange Book process for pharmaceutical drugs where there is more known about the patent landscape. Just to let you know that we are not persuaded that having people sign nondisclosure agreements and having the patent landscape be secret on biologic drugs makes much sense. Thank you very much. DR. BEHRMAN: Thank you for your
Just a quick question regarding your submission. On the first page, you say that
in effect the legislation requires second or Neal R. Gross & Co., Inc. 202-234-4433
Page 109 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 subsequent applications for FDA approval to duplicate clinical trials. Perhaps this is a
semantic issue, but in what way are the clinical trials duplicative if it has not been established that the products are the same in any way? I was hoping you could elaborate. MR. LOVE: A critical part of the
biosimilars legislation is not to require the generic competitor to prove everything as if it was a regular submission for a new drug to rely upon some of the evidence that was done by the originator as to the safety and efficacy and the benefits of the product. The only reason for having 12-year data exclusivity is it's considered to be that after the 12 years that people will in fact make those reliances. Otherwise, there would
be no need whatsoever for data exclusivity if it wasn't anticipated that there would be both a period of nonreliance and a period of reliance. Reliance is illegal for 12 years Neal R. Gross & Co., Inc. 202-234-4433
Page 110 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 and then it's permitted after 12 years. What
we're saying is the period when reliance is not permitted is the period when the only alternative to the generic company is to replicate the trials they would have otherwise relied upon. DR. BEHRMAN: MS. MALONEY: Ms. Maloney. I've actually heard
you use the word "generic" and here we're talking about -MR. LOVE: Biosimilars. I just wanted to
MS. MALONEY:
make sure I understood, and also the position. Are you taking the position that there should never be clinical trials then for biosimilars? MR. LOVE: Not whatsoever. I just
think if you look at the Helsinki Declaration, which has been endorsed by the United States in the context of the World Health Assembly, you should follow the guidance that they have there. If there is a trial where you know Neal R. Gross & Co., Inc. 202-234-4433
Page 111 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 what the answer is or the risks do not outweigh the benefits, you shouldn't force someone to do that test if you have an alternative of relied-upon data that has already been done. The main thing is that Europe is moving to say that you shouldn't do repeat experiments on rats, dogs, pigs, and monkeys if they think the replication of the trial violates ethical standards. We're asking that
people also be treated in the same way, that the replication of clinical evidence where there is no scientific and medical basis for doing it. Now, on the other hand, if there are trials where there is a persuasive medical reason and the FDA believes it's necessary to have additional trials, that's an entirely different matter. Of course, we fully support
the role and the responsibility of the FDA to order such trials. DR. BEHRMAN: Dr. Jenkins.
Page 112 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. JENKINS: I'm wondering how
you reconcile that position with the comments we heard earlier that you absolutely have to have clinical trials to assess the biosimilar products, that you can't just rely on the in vitro assessments of biochemical comparability or any animal studies. different product. We heard arguments earlier that those clinical trials are necessary to assess whether there are, in fact, differences between the new product and the reference product. How do you reconcile your position The biosimilar is a
of not repeating what you think you already know with the arguments that others take that you don't know yet that the biosimilar is, in fact, biosimilar until you do the clinical trials. MR. LOVE: I think there are cases
where you are going to require people to do testing and evidence where you're not dissuaded that there is any other alternative. Neal R. Gross & Co., Inc. 202-234-4433
Page 113 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 If you look at the legislation, there's 12 years when you cannot rely and then there's a period after that when people are free to rely on previously established tests. That's really the problem. It's
not that there are not cases where you have to do testing. The problem is that there's cases
where you would actually do a different test or you do fewer tests if you could rely upon the previous test. Essentially in the period of the data exclusivity, you're putting the biosimilar competitor in a legal position where they have to replicate evidence that they could otherwise avoid having had done if they would have been allowed to rely upon it. That's the whole purpose of the data exclusivity regime. You wouldn't have a
12-year data exclusivity regime if what I was saying was completely irrelevant because it would never be an issue. You would never ever
have to worry about it because the FDA would Neal R. Gross & Co., Inc. 202-234-4433
Page 114 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 never really allow you to rely upon other trials. You know and we know that the 12year period is there for a good reason and that is because there will be instances and they will important instances where the biosimilar firm will want to rely upon the evidence that is provided with the trial. may not be the complete dossier that they submit to the FDA but it would be something that they would want to use as part of the argument to register the product. DR. BEHRMAN: questions from the panel? Thank you for your comments. Our next speaker is Sara Crager, American Medical Students Association, Universities Allied for Essential Medicines. MS. CRAGER: Hi. Firstly, I would Are there other It
like to thank the panelists for the opportunity to speak at this hearing. I am a
medical student who will be graduating this Neal R. Gross & Co., Inc. 202-234-4433
Page 115 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 May from Yale University. I'm speaking today on behalf of the American Medical Students Association and Universities Allied for Essential Medicines which collectively represent over 60,000 future doctors as well as future scientists and leaders in health policy. The next
generation of doctors is looking toward the future where biologics play an increasingly important role in the way we practice medicine. It is of the utmost importance for us to be fully competent in the safety of the drugs we will be prescribing and we remain committed to the continuation of two innovations resulting in novel treatments. But we cannot lose sight of the fact these innovations have no benefit to patients unable to afford them. We are, therefore, highly
invested in the outcome of the efforts to establish a regulatory pathway for the approval of follow-on biologic products. Neal R. Gross & Co., Inc. 202-234-4433
Page 116 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The small molecules generics industry has been incredibly effective at expanding access to medicines and reducing costs while at the same time maintaining patient safety and preserving innovation. This has resulted in over $700 billion in savings in the last decade without the disastrous effects on pharmaceutical innovation that were predicted when this pathway was initially being developed. There are obviously significant differences between small molecule generics and follow-on biologic products, and the development of the successful regulatory pathway cannot straightforwardly replicate the framework created by the Hatch-Waxman Act. However, attempting to apply some of the principles that have been responsible for the great success of the small molecule generics industry to the implementation of the BPCI Act would help ensure that an abbreviated biosimilars pathway can deliver maximal Neal R. Gross & Co., Inc. 202-234-4433
Page 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 therapeutic and financial benefits to patients. One of our major concerns is that the statutory provisions set out in the BPCI Act may fail to create a strong "biogenerics" industry and would rather mainly result in the growth of a "biobetters" industry. While
there is certainly value in making progressive improvement to existing treatment, this will not be highly effective in reducing cost to patients. The already high barriers to biosimilar entry combine with numerous additional barriers set out in the current law may persuade companies to develop their product as novel products that may be incrementally different from biologics already on the market. If we do not address the factors that would be biosimilar companies to opt to focus mainly on a biobetters approach or just simply use the BLA to gain approval for their Neal R. Gross & Co., Inc. 202-234-4433
Page 118 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilar drug, it could lead to a situation far more closely resembling brand-to-brand competition rather than true generic competition, and is unlikely to result in maximal cost savings. In this context we believe it will be important to address the implementation of the data exclusivity provisions in the BPCI Act. Section 7(c) allows for an additional
12-year period of data exclusivity for in modification to the structure of the biological product resulting in a change in safety, purity, or potency. In addition, the demonstration of a new indication, route, dosing schedule, form, delivery system, delivery device or strength will also be eligible for an additional 12-year period if it is resulting from altering the reference product in such a way that could be argued to qualify as a modification to the structure of the biological product. Neal R. Gross & Co., Inc. 202-234-4433
Page 119 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 These provisions introduce uncertainty into the market that could discourage biosimilar manufacturers. We
believe this will create problems with regard to both affordability and innovation. This prolonged period of data exclusivity applied to each incrementally altered version of the original reference product has the potential to result in biosimilar competition being perpetually relegated to older versions of the drug for which there is a diminished market. It would also allow originator companies to initiate development of new versions of their drugs well in advance of patent expiration. Moreover, while these
additional data exclusivity periods are justified as being necessary to ensure continuing innovation, they may, in fact, merely serve to incentivize lower-risk approaches of continuously making small incremental improvements to existing Neal R. Gross & Co., Inc. 202-234-4433
Page 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 treatments rather than maintaining focus on higher risk research leading to significant breakthroughs for unmet clinical needs. We believe that a strategy to mitigate this potentially significant barrier would be to establish a specific definition for the term modification to the structure of the biological product. Currently this term
could be subject to enormously broad interpretation as to what actually constitutes a structural modification. More narrowly defining this term to set a higher bar for the types of modifications that will, in fact, be awarded additional terms of data exclusivity will help address the issues related to both impeding biosimilar competition as well as incentivizing innovation mainly focused on incremental improvement. One useful approach may be to define exclusion criteria for the types of structural modifications that are eligible to Neal R. Gross & Co., Inc. 202-234-4433
Page 121 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 receive these additional 12-year periods of data exclusivity. The handling of this and many other variables will be important to creating a framework that incentivizes the development of truly innovative treatments while simultaneously creating generic-like competition for existing biologics. We believe that a key element of this process will be the preservation of sufficient flexibility to allow for the rapid integration of new technological advances into the regulatory framework for biosimilars. We hope that these advances will lead to progressive decreases in the scope of clinical trials that are found to be necessary to ensure patient safety as that the decreased requirements for clinical trials is a critical variable underlying the dramatic cost savings seen with small molecule generics. We also believe that it will be critically important to proactively educate Neal R. Gross & Co., Inc. 202-234-4433
Page 122 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 doctors and medical students about biosimilars so that they will be comfortable making wellinformed decisions about prescribing these drugs to our patients. An essential question moving forward is this: Rather than creating an industry that generates a large number of different essentially branded versions of the same drug, how can we facilitate an environment that will promote true innovation and more closely approximate the competition and cost savings seen in small molecule generics industry? As future physicians who will be responsible for administering biosimilar drugs to patients we are fully committed to the paramount importance of ensuring patient safety during this process of establishing a biosimilars industry. But we do not believe
that safety and affordability must be inherently inconsistent requirements for biosimilars. Neal R. Gross & Co., Inc. 202-234-4433
Page 123 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 panel? comments. Are there questions from the Thank you. Our next speaker is Jonah Houts Neal R. Gross & Co., Inc. 202-234-4433 If it is believed that the technologies do not yet exist to both maintain strict patient safety requirements and determine comparability without extensive clinical trials, let us find ways to promote the development of these technologies. extent that they already do exist let us integrate them. While there remain clear challenges to creating a biosimilars industry that parallels the small molecule generics industry's enormous success in decreasing cost, maintaining patient safety, and preserving innovation, let us keep it firmly in mind that this is our goal and that our proposal of moving forward should be consistent with this. Thank you. Thank you for your To the
DR. BEHRMAN:
Page 124 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 from the Alliance for Affordable Medicine. MR. HOUTS: Thank you very much
for having me and all of us out to speak today to members of the FDA here. A little bit of
history on the Alliance for Affordable Medicine. We are formerly the Coalition for
a Competitive Pharmaceutical Market. We are a group of purchasers and payers and employers, innovator and generic drug manufacturers who all coalesce around the idea about increased competition, expanded access to lower cost pharmaceuticals including generics and biogeneric drugs. We were among
the first supporters of a pathway for the approval of biogenerics and really can't tell you how happy we are to be here today. One point I want to make just in response to some previous speeches is really about safety and clinical evidence first. all the members of the Alliance it always comes down to the safety of the end-user and the patient first. That's primal before For
Page 125 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 economic decision making. I just want to make
sure that the Alliance is on record there. The FDA put forth some great questions for folks to respond to. Unfortunately given the limited time I'm only going to respond to the questions on guidance documents and market exclusivity. You will
have an opportunity to hear from other members of the Alliance later today. So when Congress had the decision to choose from multiple different pathways and biogeneric schemas they chose in their wisdom one that really deferred to the FDA for scientific judgment because the folks here in this room certainly are best equipped to make decisions about what information is necessary to review any sort of prescription drug applications. The Alliance's concern is that guidances could actually be counter to this charge of deferring to up-to-date scientific standards. In our experience guidances aren't Neal R. Gross & Co., Inc. 202-234-4433
Page 126 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 expedient. develop. The first guidance after HatchWaxman was passed took many years to be done. In fact, we are here seven months after the passage of the Affordable Care Act and think that realistically we're some time away from some of the guidances that we could be looking at, or the agency is looking at putting forward. Also, the guidance document seemed to solidify things that are ephemeral, things that will change in time, manufacturing technology, some of the evaluatory evidence we just saw a few minutes ago that may not belong in the guidance document. Lastly, the guidance documents don't have the same force as rulemaking. They They are typically slow to
really are advisory and perhaps not the best use of the agency's resources. What the
Alliance would recommend to the agency is developing guidance documents that serve one Neal R. Gross & Co., Inc. 202-234-4433
Page 127 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 key purpose which is expediting the development and market entry of biosimilar and biogeneric products. This is both consistent with the legislation's intent and with the agency's public health mission because there are still people in line who do not have access to these products. There are thousands of patients paying thousands of dollars a month for these prescription drugs who still don't have access, or may not have access rather. Some of the types of guidance that have been discussed might be mandatory class guidance which the Alliance feels would be too prescriptive and not adaptive. We also think that it is a bit of a red herring to say that the agency doesn't have the expertise to consider a biogeneric application in the absence of class-specific guidance when, in fact, the agency has decades of experience with the products that started Neal R. Gross & Co., Inc. 202-234-4433
Page 128 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 improving. when they were considering the initial application of the innovator product. Technology is constantly I mentioned characterization of
products, packaging, storage, even manufacturing technologies that constantly change and putting these things in guidance documents wouldn't be appropriate. They also
may be inflexible to clinical investigation and how different those can be based on different products. that this morning. Sometimes human clinical trials are unnecessary and sometimes human clinical trials are unethical and the agency has to be opened to other analytical technologies that may be able to answer questions better, faster, safer, less expensively exposing fewer patients to clinical trials than is necessary. Now I want to turn my attention to exclusivity for a couple minutes. As we are We've heard about some of
aware, the BPCI included a 12-year period of Neal R. Gross & Co., Inc. 202-234-4433
Page 129 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 market exclusivity which is more than double or what Congress has afforded in Hatch-Waxman for innovator Food, Drug and Cosmetic Act products. In fact, there was already legislation that's been introduced to extend this period of time for certain classes of drugs so this exclusivity number may, in fact, be more of a moving target than we realized. The incentive for bringing a product to market on top of the market exclusivity is our patent system that produces both process and true innovation. ability to price products however manufacturers like when they bring them to market. We have a very, very rich monopoly Also the
protection for innovators in this space. We think that the agency is rightly concerned about the unnecessary application of this 12-year exclusivity period, particularly in this case, one of your questions about corporate ownership. We Neal R. Gross & Co., Inc. 202-234-4433
Page 130 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 believe that to be consistent with HatchWaxman exclusivity applies to a product and follows that product and not to an application sponsor or any sort of related entity who is related to an application. We also see a very persistent problem in the legislation with evergreening. By this we mean tactics of product life cycle extension that will continually renew a 12year exclusivity period. We see this Every
frequently on the small molecule side.
time a drug comes to market with an XL, XR, SR these technologies exist. In fact, a little cottage industry has come together around biotech and small molecule products to help manufacturers glycosylate and pegylate their product in order to make small improvements that will then reset the clock. It's not just bringing
the new product to market. It's timed in such a way that they can bring a new product to market, move market Neal R. Gross & Co., Inc. 202-234-4433
Page 131 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 share to the new product. retire the earlier product. In some cases even It really
obviates the utility of a biosimilar or biogeneric entirely if there is no product on the market for them to compete with. Our preference had been a tiered exclusivity period like Hatch-Waxman. If this
were the case, the question of what you do with minor product improvements is solved for with a plus X or plus Y period of time. in the absence of that we feel that application sponsors should file a new BLA that shows significant advantages to warrant a new 12-year exclusivity period. We have additionally identified five criterion where the exclusivity period should not be renewed. completely honest. I have to be But
I dropped out of high
school chemistry so you'll have to bear with me as I pronounce these words. We are talking
about structural changes due to posttranslational events, similar saccharide Neal R. Gross & Co., Inc. 202-234-4433
Page 132 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 panel? Dr. Marchand. DR. MARCHAND: your comments. Thanks again for comments. Are there questions from the repeating units, glycosylated protein products that differ in structure due to posttranslational events, products bound to an identical sugar backbone, and closely related complex partly definable biological products. Again, I can't thank you enough for being about to come and talk about these two issues today. I look forward to
submitting more to the docket. DR. BEHRMAN: Thank you for your
I just wanted to clarify your
position is that guidance would slow the process for advancing this legislation into full implementation. The good guidance practice does allow for public comments to be submitted as they are being developed. How might you
Page 133 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the panel? Thank you for your comments. MR. HOUTS: DR. BEHRMAN: Thank you. Our next speaker is suggest the public should offer their insight and input into developing perspective in implementation of the legislation? MR. HOUTS: I think forms like
this are critically important in allowing the public to offer their input. I didn't mean to
imply that all guidances will delay the market entry of biogenerics and biosimilars, but they could. I want to put that on the agency as
part of the rubric so that we're constantly trying to meet the objective of getting more of these products to patients to meet their medical needs. DR. BEHRMAN: Other questions for
Steven Miller from Express Scripts. DR. MILLER: I want to thank the As you know,
agency for having us today.
Express Scripts has been very active in the Neal R. Gross & Co., Inc. 202-234-4433
Page 134 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 support of the pathway for the FDA for biologics for many years. As part of my background I am a transplant nephrologist by training so I have been dealing in the area of biologics for over 20 years. I'm the former chief medical
officer and senior vice president for Washington University and Barnes-Jewish Hospital. Five-and-a-half years ago I moved to Express Scripts. As you know, Express
Scripts is a large part of serving biologics. We actually represent the pharmacy benefit for almost 60 million Americans including nine million people within the Department of Defense. As a major procurer of biologics we are also part of the distribution system for these products. We operate REMS programs We are extremely
to assure their safety.
hopeful that the pathway they produce will result in robust competition to counter the Neal R. Gross & Co., Inc. 202-234-4433
Page 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 rapidly increasing market prices that people are experiencing, especially in a time of enormous increase in both utilization and product growth in the pipeline. This gives us insight into what is being experienced by patients, providers, payers, employers, and manufacturers. Hopefully we can add a little bit. We're One
going to take on just a small amount. issue within the entire framework to be
discussed today and that's the naming of the biosimilar products. As you all know, the statute is actually silent on the naming, but Congress' intent was that we should have this robust balance between innovation and patient's interest. Currently there is a system that actually has worked quite well and that is the system of having NDCs actually allows for all the important aspects you need for the safety attribute but still allows for competition in Neal R. Gross & Co., Inc. 202-234-4433
Page 136 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the marketplace so a unique product name for each product is probably not required. So there are three major buckets in which this falls into being important. is for tracking products. for recalling products. patient confusion. One
The second would be The third is about
I would like to address
each of them briefly. When it comes to tracking products there is already brand generic and biosimilar products in the marketplace and your existing system actually works because adverse events are not recorded solely on the base of a unique name. In fact, CDER requires the NDC which unique identifies the product even when it's a multi-source product. Your existing
systems for tracking adverse events has been very successful even when there is a lot of multi-source generics, brand, and biologic products. The second issue would be managing Neal R. Gross & Co., Inc. 202-234-4433
Page 137 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product recall. And as you know, again, the
existing system using NDCs and lot numbers have actually worked quite effectively. In
fact, a great example of this occurred just in September of this year when there was a recall of Epogen. As you know, this was a lot specific problem and it went across multiple branded companies. Because of the ability to
use NDCs and lot numbers, they were able to withdraw the specific lots from the marketplace ensuring safety but not having to be required to recall the entire product off the market. So it works. If the INN was the smallest unit for analysis, you would actually have to recall the entire product off the marketplace and not those specific lots in which the complications were noted. Again, your
existing system that you've created through science and knowledge has actually stood well. The final area would be patient and Neal R. Gross & Co., Inc. 202-234-4433
Page 138 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 physician confusion. Now, to have confusion
you have to a priori make an assumption that the biosimilars and the innovator products are going to have different clinical effects. Which, in fact, if the products are approved they won't have different clinical effects because that's your charge. So, under the
current system both pharmacists, eprescribers, doctors dispense by the NDC. When a physician wants to use a specific product, they by law have the ability to do that and prevent substitution. Again, the
current system works to prevent confusion for both patients and prescribers. Right now we already have products that share a name so we have multiple classes; erythopoietins, somatotropin, interferon, most recently the alglucosidase alfas all have similar names, or the same INN. Adverse reporting, product recall, and prescriber and patient confusion are currently avoided because the current system Neal R. Gross & Co., Inc. 202-234-4433
Page 139 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 panel? comments. Are there questions from the I actually have one. So Platt et al. works. We would advocate that you adopt the
current system as you move forward with biosimilars. here today. DR. BEHRMAN: Thank you for your Thanks for the opportunity to be
published in the last six to eight months a paper discussing this in terms of pharmacovigilance and our ability, the administration's ability to track these products, many of these products by NDC codes and concluded that because, in fact, they're built to CPT codes. In fact, we would be
unable to track them without some change to the system, some form of unique name. sounds like you're arguing opposite. DR. MILLER: I think when you look It
at how it's actually handled at the pharmacy level the NDC codes and lot numbers are what is tracked so I believe that if you have a Neal R. Gross & Co., Inc. 202-234-4433
Page 140 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 recall, and this is put into place and show to the efficacious even in September with the EPO example, we are still able to identify lots and go after those. What's really also unique about biosimilars remember is that the prescriber community, the dispensing community, and the patient community are much smaller. If you
can already do this for enormous populations across lipid-lowering agents and other things, you should be able to do this efficaciously in the biosimilar's arena also. DR. BEHRMAN: any other questions? Dr. Jenkins. Oh,
All right.
Thank you for your comments. We are running ahead of schedule. Turns out this group is far more compliant than our recent meeting on patient medication information. yourselves. You should be proud of Are there any speakers that the
panelists wish to ask additional questions of who might still be present? Neal R. Gross & Co., Inc. 202-234-4433
Page 141 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 I do have a question for Mr. Love if he's still present. really doing well. Good. No rush, we're
So you expressed, I would
say, concern about the way the statute is written in terms of the exclusivity provisions. You counseled the agency to think
very carefully about duplicative testing. We said publicly, repeatedly in testimony before Congress, we published and talks and so forth that we believe duplicative testing, whether be it animal or human, is unethical. What precisely is the advice you
are trying to provide us given the construct of a statute that we have been asked to implement? MR. LOVE: If it's a case that you
have no discretion under the statute, then you can't do anything when you're implementing regulations. As a panel I think you could certainly note, though, that if you believe the legislation, which is new, which Congress Neal R. Gross & Co., Inc. 202-234-4433
Page 142 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 legislation. is going to be doing oversight, if you think this is a problem that is treated unsatisfactorily in the current regime and that you -- I mean, you may have -- I'm not sure. It's a complicated enough piece of I couldn't tell you legally
whether you have the right to rely -- I mean, to waive the exclusivity if there is an overriding public interest in another area. I do a lot of work in drug registration in other countries and there are cases when they feel that the exclusive rights and data registration, for example, or industry and drugs, for example, are for AIDS in a lot of countries. When that is a barrier to getting a generic product, sometimes they simply waive some or all of the normal registration requirements or overcome that if you think there is a compelling interest reason to do that. Neal R. Gross & Co., Inc. 202-234-4433
Page 143 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to speak? I know in the fadrazone case it's problematic because there's not enough drug to keep people well and people are getting sick as a result of the shortage on that biologic product. The FDA has encouraged a competitor to register its product, so I don't really know how much discretion you have if you think there is either an abuse or a public interest that is in conflict with the normal rule. If you don't feel you have enough
flexibility in that area, I think you have a duty to explain that to the public and encourage the political leaders to address that. DR. BEHRMAN: Thank you.
I'm looking at Sandy and we have an hour set aside for lunch. our break? Okay. Shall we take
We can't feed you.
Troyen Brennan, are you prepared Is anyone here? Are any of you Please introduce
speakers in -- terrific.
Page 144 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Scott Reid. flexible. DR. REID: No problem. My name is you. DR. REID: I was preparing to yourself. Are you still representing CVS
Caremark Corporation? DR. REID: Yes. Terrific. Thank
DR. BEHRMAN:
start off with good afternoon but I'll change that to good morning. DR. BEHRMAN: Thank you for being
I'm senior vice president of
specialty pharmacy operations for CVS Caremark. CVS Caremark has been a leading
proponent of providing FDA with the statutory authority to develop an approval pathway for biogeneric products. CVS Caremark is the largest provider of prescription and pharmacy care in the nation with over 1 billion prescriptions filled or managed annually. We employ over
24,000 pharmacists who work in our 7,000 CVS Neal R. Gross & Co., Inc. 202-234-4433
Page 145 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 pharmacy retail stores, 44 retail specialty pharmacies, 18 specialty mail pharmacies, and six high-volume traditional med mail order pharmacies. As such, we have a critical role to play with respect to many aspects of biogeneric utilization. We appreciate the
opportunity to provide stakeholder input to the FDA as it addresses the implementation of the statutory biosimilar approval pathway. In keeping with our mission to improve the lives of those we serve by making innovative and high-quality medicines accessible and affordable for patients and our payer clients, we are committed to slowing the growth of prescription drugs spend and supporting true competition, safety, and innovation. We support a science-driven approval process that prioritizes patient safety and empowers the FDA to use its expertise to determine on a case-by-case basis Neal R. Gross & Co., Inc. 202-234-4433
Page 146 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 what data is needed for approval of interchangeable generic biosimilars. This past September, a Congressional Budget Office study in a report that came forth shed light on the immense savings potential of generic drugs and the effects of using generic drugs on Medicare prescription drug spending. CBO found in that study that prescription drug costs in 2007 were reduced by $33 billion thanks to generic prescriptions of brand name drugs. Further, the study went
on to note that the generic versions of brand name biologic drugs will have important implications for the cost of drug spending in the future. I have three areas I would like to make specific comments on, the first being pharmacovigilance. I would like to begin by
addressing the current pharmacovigilance model and the impact of biosimilar approvals on its evolution from a pharmacy perspective. Neal R. Gross & Co., Inc. 202-234-4433
Page 147 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 When it comes to medication safety and the need to protect patients from the risk associated with medication use, CVS Caremark is firmly committed to fulfilling its professional obligation and responsibilities as an active and dependable member of the team of healthcare organizations and practitioners charged with improving the healthcare system's ability to mitigate those risks. Pharmacy, as you know, contributes to FDA and industry pharmacovigilance monitoring in a number of different ways including adverse drug event reporting, patient education and counseling, concurrent medication therapy management to identify and resolve drug safety issues at a patient specific level, dispensing information, tracking and REMS program implementation and management. As you know, pharmacies perform many of the front line administrative dispensing and clinical activities that must Neal R. Gross & Co., Inc. 202-234-4433
Page 148 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be done to effectuate existing pharmacovigilance programs. Current pharmacy practices including medication therapy management are designed to present information about a prescribed drug in a context where information about the safety of the drug and its role and therapy is balanced, and patients have an opportunity to ask questions directly of the pharmacist. As FDA considers various approaches to ensure appropriate pharmacovigilance for biosimilars and interchangeable products, CVS Caremark is concerned that no added burdens be placed on pharmacies and other healthcare providers that would inhibit patient access to these lifesaving medications as has been mentioned in other FDA hearings. CVS Caremark recommends that FDA maintain consistency with respect to requirements for pharmacovigilance between Neal R. Gross & Co., Inc. 202-234-4433
Page 149 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilars and brand innovator products in this space. Preapproval: Bioequivalence should be established for biosimilar products using the same standards and procedures in place for non-biologic generic drugs. Post-approval:
The same pharmacovigilance process in place for the innovator product can be used with modifications as may be necessary to comply with intellectual probably rights of the innovator or other considerations. The second issue I would like to address is the unique nonproprietary name. Regarding the issue of identification of these products, alignment of reimbursement is sent between the prescriber, payer, pharmacy, and patient is an important factor to consider in the decision to assign a unique nonproprietary name for each specific product. While we believe, as similar to the prior speaker that a single identifier can be used for all products, there are Neal R. Gross & Co., Inc. 202-234-4433
Page 150 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 exceptions. In particular for those
medications that are currently covered under Medicare Part B as in Boy. Today there is precedent of combining innovator and generic products under single billing codes including Medicare Part B. In the event that this happens should the
physician write the innovator product if the fulfilling pharmacy is reimbursed at a category price based on the average selling price that includes the lower-cost generics. This phenomena will result in pharmacies receiving inadequate reimbursement to cover their cost for the innovator product while having limited opportunities such as plan design to influence the prescribing of a lower-cost biosimilar. In the absence of changes to current billing processes for drugs covered under the Medicare Part B benefit, FDA should assign biosimilars a unique nonproprietary name and designate these products as fully Neal R. Gross & Co., Inc. 202-234-4433
Page 151 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 interchangeable A-rated generics in order to maintain appropriate reimbursement and to support the incentives to prescribe the lowercost alternative. This is consistent with the Congressional intent with respect to encouraging access to affordable biologic medicine by aligning the incentives for payer, patient, and provider to choose a biosimilar. CVS Caremark encourages FDA to work with the Centers for Medicare and Medicaid services to adopt a regulatory construct that achieves this objective. Finally, on the issue of interchangeability I would also like to make a few comments surrounding the interchangeability of these products. As
discussed by many commentators, unlike small molecule drugs, biologics necessarily require different cells and manufacturing processes from the respective innovator product. As the FDA considers how best to Neal R. Gross & Co., Inc. 202-234-4433
Page 152 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the panel? Dr. Jenkins. DR. JENKINS: Can you restate your determine whether a proposed interchangeable biological product can be expected to produce the same clinical result as the reference product in any given patient, CVS Caremark cautions that the market will need a mechanism to understand any FDA designation other than that of an A-rated interchangeable product. Because interchangeability is a pharmacy-driven activity that occurs in practice at the point of dispensing, any new interchangeability designation will impact the adoption and use of the biogeneric product. In closing we commend FDA for its open and inclusive process that implements the statute, and thank you for the opportunity to speak today. DR. BEHRMAN: Thank you for your
position on the unique nonproprietary name? Neal R. Gross & Co., Inc. 202-234-4433
Page 153 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 I think I heard you say you didn't think that was necessary but in some cases you thought it would be necessary, so I'm a little confused about your thoughts on unique nonproprietary names. The previous speaker said no I think
in all cases that they didn't think a unique name was needed. DR. REID: Yes. I think I'm
referring here to a specific exception as it relates to the Medicare Part B benefit. Under
that benefit the types of financial incentives that are in place that drive generic utilization under most other benefits, particularly pharmacy benefit, are not there with Medicare Part B. What you will find, I think it was seen in the introduction over the last two years of a couple of generics in the specialty pharmacy space that being epoprostenol as well as tacrolimus. What we found was that at the time that the prescription for the innovator Neal R. Gross & Co., Inc. 202-234-4433
Page 154 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product was written any attempt to get that physician to prescribe the alternative in both instances was not possible because their basic reason was if it's not going to benefit the payer -- excuse me. If it's not built into a
benefit and it's not going to be cost advantageous to the patient, I'm going to go with the innovator product. In that instance because of the way that's constructed and those products are generally being reimbursed under a J code and not the NDC which is what the prior speaker spoke to and that we agree with. We think that this needs to be addressed because there's a lot of these biosimilar products that may come out of the pipeline that will be reimbursed under the Part B benefit. DR. BEHRMAN: Dr. Marchand. DR. MARCHAND: Again, thank you I just wanted to Other questions?
very much for your comments.
Page 155 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 clarify what your thinking would be to the originator that might have a pharmacovigilance plan, something like a REMS or risk evaluation mitigation strategy. Would you envision that
those requirements for marketing of a biosimilar product would also be in place for the biosimilar product? that effect? DR. REID: Yes. I think we would Could you comment to
expect that if a REMS is required for a biosimilar that the innovator product also have that. That may also be an assumption
that I'm making, or we're making, but we would expect one to be treated the same as the other. MR. SCHWARTZ: Quick question
regarding your final bullet before your conclusion. You talk about for parenterals
that are interchangeable switching a patient to a biogeneric would likely require retraining by the provider that may dissuade and physicians from switching. Neal R. Gross & Co., Inc. 202-234-4433
Page 156 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 I guess I'm just wondering what, if any, solution do you have to that problem? It may very well be a problem that does not have a solution but it just seemed a little out of place to be presenting something like that without providing some sort of remedy. DR. REID: Sure. Again, I think
this is something that we have observed over many years in the specialty pharmacy space which has primarily been driven by selfadminister injectable products. Sometimes those products are put in the marketplace with unique injection devices that facilitate a patient's ability to prepare as well as self-administer their medications. In some of those categories what you will find is that in a way to try to differentiate one product from another product where you have multiple products in a given class. They will try to come up with the next
and best injection device. Neal R. Gross & Co., Inc. 202-234-4433
Page 157 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 When you begin to look at biogeneric products and some of the experience we've seen on that are in the growth hormone space, very often those biosimilars are not coming from market with the injection device which will require the patient to have to go through additional training which they may not be able to handle physically, frankly, such that they are going to have to be taught to prepare the medication, basically, possibly reconstitute it, draw it up in a syringe, and actually have the physical ability to actually administer a syringe versus these simple injection devices. If that should occur, and we have seen this become a deterrent to the use of some of these lower cost brand of generics, if you will. Basically the prescriber will decide
not to move the patient out of the product. One of the things that has been done out there is that, you know, where it's available or where it's compensated pharmacies will work Neal R. Gross & Co., Inc. 202-234-4433
Page 158 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 with home health agencies or have patients come into their pharmacies to be taught how to prepare and self-administer the product. does lead to some dissatisfaction. lead to some disruption. MS. ESPOSITO: With respect to the It can It
agency's development of a naming system for biosimilars in the event that the agency goes with either a unique nonproprietary name or a prefix or suffix, can you speak to from a large pharmacy perspective any considerations the agency should have in mind? For example, information technology issues that would facilitate or create an obstacle toward tracking unique nonproprietary names with prefixes or suffixes? DR. REID: Well, similar to the
prior speaker's comments around the NDC code, those are obviously a fundamental part of all pharmacy dispensing adjudication systems today, and I support the notion. We support
Page 159 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the notion. make sense. To the extent an unique identifier needs to be used, and there's reasons for that, hopefully we can leverage the NDC as best we can for some kind of a modifier, either a prefix or suffix. But I think what We're trying to leverage that and
would be required there possibly will have to be alterations for our dispensing and adjudication technology which will cost money. DR. BEHRMAN: MS. MALONEY: Ms. Maloney. Thank you. My
question goes to the adverse event reporting. You talked about the role you play in pharmacovigilance. Could you just talk a
little bit about the adverse event reporting you're doing, to whom, and then how you might see that need to change, if at all, with regard to biosimilars. DR. REID: As you know, I think
historically under the FDA regulations pharmacies have been exempt from formal Neal R. Gross & Co., Inc. 202-234-4433
Page 160 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 reporting of required reporting of adverse drug events. We typically have done so under I think what we have seen
a voluntary basis.
over the last couple of years is that the interpretation of that language has begun to change. Not all but there are some companies that are beginning to expand their pharmacovigilance activities trying to improve upon it, tighten it up, and they are beginning to place burdens on pharmacies to operate under a reporting mechanism that frankly mimics exactly what manufacturers are required to do. The fact that it differs across products and across entities and I have seen probably in the last probably 12 months five or six new products come on the market. has expanded and more timely. It
In other words,
patient experiences a side effect today we need to have a report by tomorrow morning in our offices because the FDA requires it. Neal R. Gross & Co., Inc. 202-234-4433
Page 161 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Those types of requirements place significant burdens on pharmacies that they are not prepared to deal with today. When it
comes to my remarks, what we would like to see is that as these products roll out the extent to which adverse event reporting is part of it there is some consideration of the burden that pharmacies bear on that and the FDA gives them direction in that regard. Then in terms of the REMS programs out there we dispense today over 50 medications that have a REMS program attached to it either from the standpoint of a medication guide or a more complicated one with elements to assure safe use. We would just like to see more and more of the standardization, if you will, of those requirements so that it facilitates a pharmacy's ability to comply and to support those mitigation strategies. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. I'm looking at your
Page 162 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments about the interchangeability and the reference to the AB rating system that's used in the small molecule world. I'm wondering if you look down the road hypothetically to a place where we have several biosimilars approved for an innovator product, some are biosimilar and maybe one or more have been determined to be interchangeable. How would the system in your
view handle ensuring that the biosimilar products that are not interchangeable would not be interchanged, and the interchangeable product would be interchanged? In the absence of unique nonproprietary names how would you see that working in reality if we do find ourselves in the situation of multiple approved biosimilars. Some are just biosimilar and
others are biosimilar interchangeable. DR. REID: At least on our pharmacy payment systems where adjudication system are basically supporting the management of those Neal R. Gross & Co., Inc. 202-234-4433
Page 163 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 benefits and payment of those prescriptions I would say that today all the major companies, all the major PBMs, even probably the middle tier ones, have built into their system the ability to designate certain products differently from others using certain codes. In some ways you're building intelligence into the system so that when a particular drug with a particular NDC is loaded into the system. Basically the profile on that particular product that could have multiple designations with support making sure that those decisions are made and made properly. They are used
today in some regards relative to formulary systems. When products are on formulary or
not formulary same type of approach would be used. DR. JENKINS: So, if I understand
you correctly, you're thinking that the pharmacy management systems could handle distinguishing the products and assuring that the right one was dispensed. Any thoughts
Page 164 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 about how that would be handled on the prescriber end? How would they be able to
keep track of which products are substitutable and which ones are not? DR. REID: To the extent there
continues to be broad adoption of these prescribing systems, I would think that physicians might have access to that information as well which is really the ordering part of a pharmacy transaction today. I think in some ways they may need to depend upon the support they have in their particular practice where they have an electronic medical record or other types of technology. They would be able to leverage
that, although not everybody has that today. We are probably still a long ways off from having that. Probably those
physicians are going to have to do it the old fashioned way having cheat sheets kind of pasted up in their office to remind them to prescribe this particular drug, this is what Neal R. Gross & Co., Inc. 202-234-4433
Page 165 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 applies. I think where the big challenge will come is for those medications that are currently covered under a medical benefit where the systems do not have the capability necessarily today to help support that kind of decision making. DR. BEHRMAN: I have one question,
back to pharmacovigilance and the FDA's ability to track a product. If you have
concerns if we were to either rely on the NDC or we had some form of unique identifier or prefix, and so forth, if you have concerns about your ability to bill, what would be your comments or advice to systems such as Sentinel or National Safety Surveillance Initiative, where we rely very heavily on billing data. If these products are billed under, if you will, a group code how are we going to track them in a system like that which is really the future of pharmacovigilance? Neal R. Gross & Co., Inc. 202-234-4433
Page 166 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 standpoint? DR. BEHRMAN: DR. REID: Precisely, yes. DR. REID: From a safety
I'm not prepared to
comment on that at length today but I think when you look at pharmacovigilance there are different ways to approach it. You can
approach it certainly retrospectively and try to understand what happened after it happened which I think, you know, a transaction type mechanism would support. I think the profession of pharmacy today and where pharmacy has come as more of a clinical profession versus just a dispense of medication, I think we're looking ore and more at prospective mechanisms to identify potential risk and take action before those events occur. In that case that type of an
approach would not probably support it. DR. BEHRMAN: Thank you. Since we
have the luxury of time and this is a crucial patient safety issue, Dr. Miller, could I ask Neal R. Gross & Co., Inc. 202-234-4433
Page 167 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 you to also address since you took a very strong stand about relying on the NDC and no need for unique identifiers. Could you
discuss that in the context of the Sentinel initiative and our ability to track products to marketplace based on billing data. DR. MILLER: great questions. No, those are all
As you know, the NDC system
does work and the sophistication of the system is actually improving, especially as you add e-prescribing. Some of the events that you
all bring up are actually currently holes in the system and probably aren't fixed just by the unique name as we've experienced in the marketplace. There are going to be times. don't want to be misinterpreted. I
There are
going to be times when you are going to have to have a unique name for a product, but should these be biosimilars and they actually had the same clinical efficacy. Then they are going to be able to Neal R. Gross & Co., Inc. 202-234-4433
Page 168 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be tracked at the NDC level. If a product is
uniquely different, than that product is probably going to require a different pathway or a different name so you are going to have to make that determination at the FDA. The best way for us to identify adverse events is down to the individual lots because as you know in history, many of the product recalls have actually not been product wide but they have actually been individual lots of the product. Having that data down to the individual lot number and NDC has actually been what has held this in best stead. As the
system gets more complex, though, obviously there is going to be a burden both on the physician through prescribing and through the dispensing systems to be better able to track those problems. It's going to require the adoption of the Sentinel safety system probably to not rely on J-codes as we historically have Neal R. Gross & Co., Inc. 202-234-4433
Page 169 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 because, as the previous speaker identified, especially on the medical side, we aren't distinguishing those on the safety systems. It's currently being done at the billing level, not at the lot dispense level. DR. BEHRMAN: Oh, please. DR. JENKINS: I didn't know if the Thank you.
rules would allow me to recall Dr. Miller or not but since you did, I would like to take advantage of that. In your presentation, the one I'm still having the most trouble with is about tracking adverse events because while the reporting system may include a field for NDC number, I think it's very rare that we get that level of information in a spontaneous adverse event report. We often get very
limited information in those settings. I'm thinking about at least possible scenarios, kind of large scenarios of where you might actually see differences. Neal R. Gross & Co., Inc. 202-234-4433 You
Page 170 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 keep referring to the fact that, well, if we approved it as biosimilar, it must be the same but there are at least two scenarios I can imagine. One would be there truly is a rare adverse event with the biosimilar that you don't see with the innovator but we didn't detect it in our preapproval analysis because the sample size was too small. I'm wondering
how would we differentiate between what products we're seeing those rare adverse events reported for to track them back and maybe understand that it is a difference between the products. Secondly, we can't assume that even the innovator is the biosimilars stay the same all the time. There's constant changes
in manufacturing, scaling up, processes or making changes to the formulation that could introduce new safety or efficacy concerns that would need to be picked up in the adverse event system. Neal R. Gross & Co., Inc. 202-234-4433
Page 171 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Those get vetted before they're approved by FDA but there is always a possibility that something will get approved that does, in fact, have a clinical consequence that we didn't detect or weren't aware of. I'm still wondering about for spontaneously reported adverse events where I think it's extremely rare for the NDC code to be on the report how do you think we would be tracking back to the appropriate product? it because these are mainly injectables and often delivered through different mechanisms than the oral outpatient products that maybe we're thinking about mostly? we would track it back? DR. MILLER: I think you actually How do you think Is
answered your own question that the difference -- the imperfect system we have now actually has that problem even amongst lots so even having that unique name does not actually detect you on the branded side currently. Neal R. Gross & Co., Inc. 202-234-4433
Page 172 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 We're going probably have that same hole in the system when we add the biosimilars because the system is imperfect. You actually are going to have -so the damage you have is obviously the smaller number of patients and the more narrow distribution system of these products. That,
in fact, is an imperfect system that currently plagues both the branded side and will plague the biosimilar side. DR. JENKINS: Right. It's
definitely an imperfect system on the small molecule side but at least on the small molecule side we have much more certainty that, in fact, the active ingredients between the products are the same. With the biosimilars, even with the scrutiny that we would expect to apply and we heard about earlier, there is always going to be some level of residual, I think, uncertainty that the active ingredient is, in fact, the same and there aren't disulfide Neal R. Gross & Co., Inc. 202-234-4433
Page 173 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 bonds or structural differences that could figure a different profile of rare adverse events. You're right, the current system isn't perfect but I'm just concerned that we're adding another factor with the biosimilars, that being the inability to be as confident about the active ingredient being the same as we can for small molecules. DR. MILLER: So the solution
actually is even amongst lots now is adhering to actually entering the NDC. It's not asking You
to add now two different unique things.
really want the system to be as simplistic as possible. If the solution is you have to be able to track either an originator product or a biosimilar product down to the NDC and lot, then enforcement of the submission of the information is the solution, not adding yet another name that is going to be dropped. DR. BEHRMAN: So you mean
Page 174 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 something like an NDC plus that would have even additional information? DR. MILLER: Well, it's NDC down
to the lot level and to NDC plus but adding another unique name is probably either way you're going to have a flaw in the system and that plagues both the innovator current products and differences in lots and it will plague the biosimilars. for that industry. DR. JENKINS: Just do I can try to It won't be unique
be clear, what you're saying is that the effort should be directed at insuring that the reporters of the adverse event provide more complete information such as the NDC or the lot number to allow for tracking back to what the product was versus introducing a new nonproprietary name into the system. Do you think we would be more effective in encouraging reporters to be more complete than we would in having a separate name and getting the information that way? Neal R. Gross & Co., Inc. 202-234-4433
Page 175 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. MILLER: I'm obviously not an
expert in this area but I would guess that you're actually asking -- the current system works somewhat because of the simplicity of the current system. If you make it overly
complicated by having both, an NDC and a unique name, you would give yourself the opportunity to have multiple problems. If you use a unique NDC and lot number, you can actually then recall products and identify products down to the individual lot where there frequently is the problem and not at the level of the total product. was actually the situation with ECO in September. DR. JENKINS: I think one aspect This
of these products, or most of these products, that probably goes along with your suggestion is the fact that they do tend to be injectables where the remnants of the product might still be available to find that lot number. Neal R. Gross & Co., Inc. 202-234-4433
Page 176 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Thank you. Our next speaker is Steven Russek from Medco Health Solutions. MR. RUSSEK: name is Steven Russek. Good morning. My Whereas outpatient distributed oral products are often packaged into a different bottle that doesn't retain the connection back to that larger bottle that's on the pharmacy shelves. That may be one
aspect of these products that would help in tracking back. DR. BEHRMAN: Other questions?
I am a pharmacist and
serve as vice president of a professional practice and I'm chief clinical officer for Accredo. Accredo is one of the nation's
largest dispensers of biologic drugs. I'm participating today on behalf of Accredo as well as our parent company Medco Health Solutions. Before I start, though, I would like to address some of the questions that Neal R. Gross & Co., Inc. 202-234-4433
Page 177 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 were asked other folks. The first one is I'm
going to assume in my comments, especially around interchangeability, that the scientists have addressed the health and safety issues. I just want to affirm that is No. 1. These products need to be effective, need to be safe. Once that's
established through the science, and we saw some examples, moving forward from there is where I'm going to pick up. As far as REMS once again as a specialty pharmacy we manage over 50 REMS products, some which have very specific and clinically acute responsibilities on behalf of the pharmacy. If a biosimilar interchangeable
or not was to come to market, that product should have the same scrutiny, the same vigilance, and the patient should be afforded the same safety monitoring. Lastly, on the difference between a product that comes out as a biosimilar and another one that comes out as a biosimilar Neal R. Gross & Co., Inc. 202-234-4433
Page 178 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 interchangeable. Again, thinking on my feet
here, I haven't given this a lot of thought but I would think perhaps on the product that is not interchangeable, that's where a suffix or prefix would make sense because we're not saying that it is the same product at that point. Where the product has gone through the hurdles and has established itself as interchangeable, then as we do with our small molecules, I'll use the term generic here, but the generic name or the international nomenclature should be the same so there's not confusion with patients seeing something different on their bottle or on their syringe or a physician being confused is this actually the same product. I would recommend that.
Then I do support Dr. Miller's statement that I don't believe the problem is in the nomenclature. It's in the system. NDC
has proven to be the way to get to the product and to the batches and to the lots. Neal R. Gross & Co., Inc. 202-234-4433
Page 179 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 What we've seen in recalls many times it is a specific batch, a specific lot, or an individual product. We do see with some
P codes, the mingling of generic brands, multiple brands which, again, just reporting that doesn't really give much pharmacovigilance. Back to my statement.
Medco is the leading healthcare company that is advancing the practice of pharmacy working to improve the healthcare system by driving greater efficiencies and introducing interventions that significantly improve the quality of patient care. Medco lauds the FDA's efforts to bring biosimilars to the marketplace in a meaningful way. I'm here to stress the
importance of the pathway that allows the healthcare system to achieve maximum savings while providing the highest quality of pharmaceutical care. I want to make the statement that health and safety is not necessarily Neal R. Gross & Co., Inc. 202-234-4433
Page 180 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 incompatible with providing access to patients and reducing total healthcare cost. see here is -- this is later in my presentation but since it's up is the fact that we see a gradual increase of 15 to 20 percent year over year in the cost of biologic pharmaceuticals. This is a trend and a trend is defined as the difference between one year and the other and the cost of providing those products. There is no generic or biosimilar What you
relief with this trend. This is being very impactful to both government as well as providers as well as the patients because a lot of these costs come out of increased co-pays or in the case, as you are well aware, of what's happening in government supporting more and more of our patients. This slide shows the importance of what I'm about to talk about because we have to find a way to continue to provide access to Neal R. Gross & Co., Inc. 202-234-4433
Page 181 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 patients do these very important lifesaving medications and, at the same time, start to bring down this curve as we have been very successfully able to do with our generic products saving over $700 billion in the last 10 years by being able to use interchangeable generic products to reduce this curve. Otherwise, you can see the trajectory into '12 and without biosimilars and interchangeable biosimilars there will be no relief. I want to talk about making sure that as many biosimilars as possible are approved as interchangeable and, again, safety being assumed and effectiveness. And assuring
that biosimilars of the same class are grouped together under the same reimbursement code and that will encourage the use of the biosimilars. And not granting additional years of exclusivity beyond the mandatory 12-year period. I have already started to talk about
the trend and the importance of being able to Neal R. Gross & Co., Inc. 202-234-4433
Page 182 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 find relief from this trend line that will continue to grow. Accredo is headquartered in Memphis, Tennessee and provides specialty pharmaceutical and related services to patients with complex and chronic conditions who are unique therapeutic resource centers consisting of clinical teams of pharmacists, nurses, and ancillary staff each focused on their unique specialty condition including oncology, multiple sclerosis, hepatitis C, and autoimmune diseases. The parent company Medco with real-time management of prescription drugs, small and large molecule, by integrated pharmacy and medical databases and guided by national accepted evidence-based protocols have closed more than 1.5 million gaps in clinical care in 2009. That was estimated at
saving the healthcare system over $700 million. Closing gaps in clinical care Neal R. Gross & Co., Inc. 202-234-4433
Page 183 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 includes monitoring for medication compliance. Is the patient taking their medication? Ensuring patient's treatment in compliance with national accepted protocols, and helping patients save money using generic medications. I'm afraid today we're seeing both in large and small molecules more patients not taking their medications because it's not affordable, not becoming accessible, and biosimilars again, especially the interchangeable ones will start to relieve that. In addition, Medco works closely with payers to manage drug cost while providing high-quality care to patients including utilization of drug formularies. The formularies are a key way that we have been very successful in introducing generics and having them used by physicians and patients again bringing down cost significantly. This allows us -- this being the Neal R. Gross & Co., Inc. 202-234-4433
Page 184 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 interchangeable generic products have allowed us to generate significant cost savings for public and private employers, plant sponsors, patients and providers. To that end Medco supports the efforts of the U.S. Department of Health and Human Services, both the FDA and the U.S. Centers for Medicare and Medicaid services, and working to establish an abbreviated pathway for biological products that are demonstrated to be biosimilar and/or interchangeable. Medco supports the FDA's efforts to establish regulations that create pathways to bring reliable and as many interchangeable biosimilar products to market as possible to achieve maximum savings while providing the highest quality of pharmaceutical care to patients. We also support the FDA's proposed pathways for biosimilars which demonstrate they are highly similar to the reference Neal R. Gross & Co., Inc. 202-234-4433
Page 185 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product, again the science, produces the same clinical results, and there is no meaningful differences to the reference products. Again,
assuming that those are proven through the clinical and scientific communities, then the interchangeability we would support for these products. For biosimilar products which meet these criteria the FDA should allow the determination of interchangeability using high standards that will provide a significant degree of comfort to patients and medical professionals and encourage the FDA to provide clear guidance to the manufacturers how to seek this designation. I believe that's key. Very
I see a red light there.
quickly, grouping together biosimilars in the same class under the same reimbursement code. By doing that, that will encourage the use of biosimilars economically. Otherwise, if they
have different CPT codes, then the savings would not be as predominant and, therefore, Neal R. Gross & Co., Inc. 202-234-4433
Page 186 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 one. comments. Questions from the panel? I have bringing down the whole class by including the biosimilars in those classes. The exclusivity. We want to
support the fact that exclusivity being 12 years, but actually it's 13 years when you add the extra year of exclusivity for the innovator of the biosimilar and 13-and-a-half years as a pediatric FDA should be very conservative in allowing that period to be extended. about that. And then, as I mentioned, trend is important that the industry, the patients, the payers need to start to bring this curve down and the best way to do that is by interchangeable, safe, effective biosimilars. DR. BEHRMAN: Thank you for your I think other speakers have talked
Why do you believe it is so key that
they be billed under the same code? MR. RUSSEK: Because if they have
Page 187 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 different codes, and with some of the reimbursement of ASP plus and so forth, then the -- let me answer in another way. putting them together brings the whole category down and, therefore, there is an incentive to use the cheapest drug in that CPT code which would be the biosimilar or the interchangeable biosimilar when they start competing. When they're different, then they could be priced separately and there could actually be no financial or even negative financial incentive to use the biosimilar which actually saves money for the payer. DR. BEHRMAN: Picking up on your By
point that patient safety is obviously key and paramount. If they billed by the same code
and, again, the system such as Sentinel that will rely on billing data, electronic health workers are not here yet so we will rely on billing data, how would you suggest we proceed with those sorts of systems? Neal R. Gross & Co., Inc. 202-234-4433
Page 188 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 MR. RUSSEK: Again, I was
listening to Dr. Miller and I agree the system is the problem. You must have an NDC code.
You should have a lot number in order to really know what you're dealing with. Even if we just sent you a name of a product, we don't know if it's something with a whole product, a whole protein, or was it the way that was made. Perhaps the way it
was stored or maybe something unique to that patient the way they handled the product. Putting extra names on and confusing the public and the prescribers and pharmacy to get to an end result which is very achievable by requiring NDC, one NDC per product, and lot numbers really will give FDA the information they need to understand what's going on with this vigilance, this report. DR. BEHRMAN: billed by the CPT code. But it will be Who would then -- I
presume it's an injectable in an oncologist office, for example, so they bill by the CPT Neal R. Gross & Co., Inc. 202-234-4433
Page 189 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 code, where would the NDC code be entered so that it would be traceable in a pharmacovigilance system? MR. RUSSEK: require that. our practice. Some health plans
I have to, I guess, talk from Even when we do bill under
medical we are capturing always the NDC code, always the lot number when we get an adverse event reported to us by a patient. We've had
situations where we have began recalls because we have seen a certain lot of a certain product starting to give us unique interactions of patients. A lot of patients
starting to have hives and we don't see that but we are able to get right down to the product and to the lot number. DR. BEHRMAN: MS. ESPOSITO: Ms. Esposito. It sounds like
you're advocating that biosimilars of the same class be grouped under the same billing code. Are you able to speak to how that relates to Dr. Reid's comment on the Medicare Part B Neal R. Gross & Co., Inc. 202-234-4433
Page 190 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 problem with reimbursement when the same billing codes are used for different products? MR. RUSSEK: Well, I'm not sure.
I believe that the difference would be how that unit is priced. If it's priced based
only on the biosimilar, then you have a problem when the branded product is required. If it's interchangeable and there is support for using the interchangeable product, then there is support to use the biosimilar. If you think of vancomycin, I
believe last time there was almost 70 different NDCs within that one CPT code of different pricing of generics and brands and so forth. What it does is it drives the use of the lesser-cost drug because of the reimbursement. Scott and I will have to dual
it out and come up with a conclusion but that's a difference. DR. BEHRMAN: You emphasized the
importance of interchangeability in terms of Neal R. Gross & Co., Inc. 202-234-4433
Page 191 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 lowering cost. Do you believe that in the
absence of scientific evidence to support interchangeability so that there might be products that are biosimilar but not interchangeable do you believe that will also impact class? MR. RUSSEK: categories as I see it. There are three One is biosimilar and
there will be a reduction in cost because that is the only way that product is going to come to market so that would be X. There will be interchangeable biosimilar which would be one product at that time. That will be for the first year or year That will, again, bring in some
and a half.
cost reduction and the product will be more readily used and, therefore, there will be another layer of savings so X plus X. Once we get to the point we have two or three manufacturers manufacturing that biosimilar competing with each other, and that's what we see in the generic world, Neal R. Gross & Co., Inc. 202-234-4433
Page 192 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that's where the real value comes to the government, to the payers, to the patients. We have to work through that. At
different points if no one else can replicate the biosimilar than the first company, then they are going to have a product and they will be value priced. If there is the opportunity like we see in some categories, and I think growth hormone is the one everyone looks to, there's a lot of opportunity for competition there that will start to bring the price down, especially when the pharmacist can be part of that equation to get the best price for his patients and start to pass that on through proper coding to the payer community. DR. BEHRMAN: To the previous
speaker, if the drug was associated with, or a biological drug was associated with a device that required additional or special patient education, then would you see that as potentially interchangeable or not? Neal R. Gross & Co., Inc. 202-234-4433
Page 193 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 MR. RUSSEK: Yes. If the
pharmacy, or the physician, will take time to train the patient, and we do that all the time, even starting a patient on a new device. When we start out most people have not injected themselves recently so they have to go through training. The devices are very clever, very unique for people with needle phobia and so forth. Some of them are still you
reconstitute and you draw a product so, yes, there would be training. Back to another question, though, to another group is going back and forth between products. that. I'm not an advocate of
I think once a patient is moved to an
interchangeable product, and we do that with generics, even tablets. They are on a red tablet and then even though we know generically it's the same, we don't want to send them a green tablet next month and then a pink tablet. Once a patient
Page 194 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 is moved, trained, comfortable, getting results, I don't think we should be going back and forth. DR. BEHRMAN: So if Medco ships
the red tablet and then now can get the green tablet for generic at half the price, you stick with the red tablet? MR. RUSSEK: In generics -- no.
What I'm saying is when we make a relationship with a generic company it's a long-term relationship so we are getting the green tablet generic for the patients. If we have
to go to another tablet, then there is an education that goes on, but moving patients back and forth between injectables or other generics is not good practice. DR. BEHRMAN: So you don't really
see it as a switching which is talking about it back and forth. You see it as a one time
you can go to this cheaper alternative and stick with it. MR. RUSSEK: I'm saying that would
Page 195 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be best practice to keep the patient on that one product and not be moving back and forth. DR. BEHRMAN: Ms. Marchand. DR. MARCHAND: the previous speaker. Question also for Any other questions?
It was being raised the Having for a
interchangeability question.
biosimilar being able to document dosage, form, and strength are similar. I guess the question is in thinking about the interchangeability and/or qualifications for biosimilar does the presentation for the product need to be the same? If it's in a self-injectable syringe
does the biosimilar also need to be in a selfinjectable syringe? MR. RUSSEK: No, I don't think so
unless that particular route of administrative has a therapeutic affect. If it's just for
convenience, then it becomes an economic question as to does the patient and/or the payer, what is the financial offset between a Neal R. Gross & Co., Inc. 202-234-4433
Page 196 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Neal R. Gross & Co., Inc. 202-234-4433 nifty device and a basic device and who pays for that. Again, just for convenience. Once
you have a patient who is needle phobic, for example, and needs to have something where the needle is hidden, then that's a different story. DR. BEHRMAN: I would like to
thank the last two speakers for being flexible and moving up and we're back on schedule. Lunch is available for purchase in the lobby and we will resume at 5 minutes to 1:00. Thank you. (Whereupon, at 11:57 a.m. the meeting was adjourned for lunch to reconvene at 1:01 p.m.)
Page 197 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Thank you. DR. BEHRMAN: DR. SCHIMIZZI: Good to go. Good afternoon. session. Schimizzi. DR. BEHRMAN: A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 1:01 p.m. Before we begin,
there is no requirement to register for the open public discussion but just so we have a sense of how many people may want to speak so we can allot time accordingly, if you are interested in speaking, if you could see Sandy Benton in the back of the room -- she's waving her hand -- somewhere now and the break and just let her know so we'll have a sense of how many of you have something you want to say. Welcome back to the afternoon Our first speaker is Gregory Am I close? Coalition of State
Rheumatology Organizations. DR. SCHIMIZZI: Good afternoon.
My name is Gregory Schimizzi and I'm a practicing rheumatologist from Wilmington, Neal R. Gross & Co., Inc. 202-234-4433
Page 198 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 North Carolina representing the Coalition of State Rheumatology Organizations. I
appreciate the opportunity to be here and speak with you today. Ours is a national entity composed of 26 state and regional member societies representing private practice rheumatologists in the United States. We endeavor to promote
excellence in care and access to care for patients with autoimmune diseases. Rheumatologists are keenly aware of the dramatic long-term life changing improvements in thousands of Americans with autoimmune diseases since the introduction of biologic agents about 10 years ago. These
agents have provided significant impact on our patients' quality of life by preventing disability, decreasing morbidity, and lowering mortality where other conventional agents have failed. These medications are expensive and rheumatologists support the developments Neal R. Gross & Co., Inc. 202-234-4433
Page 199 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 of less expensive alternatives as long as they are proven to be safe, well tolerated, and preferably have fewer and certainly no more side effects than the innovator products. It is our opinion that the approval pathway for follow-on biologics must include clinical trials for all products should foreclose the ability for interchangeable products at this time and prohibit automatic retail substitution by assigning a unique nonproprietary name. I will focus on these key issues, biosimilarity, interchangeability, and pharmacovigilance regarding patient safety. First, biosimilarity. Biologics are protein
molecules produced by very complex manufacturing processes involving genetic engineering and are products of mammalian, bacterial, or other living cell cultures. By virtue of their targets, origins, and protein nature these agents affect immune function. They can themselves
Page 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be immunogenic and they require the highest level of purity and consistency. stark contrast to generic drugs. Other generics are produced by organic chemistry processes and are required to comply with FDA reviewed efficacy and safety standards before marketing. But the This is in
complexity of biologics and their potential for other effects demand that new standards be developed to address this new group of products. A responsible obligatory process needs to consider the structural as well as functional features of the new agent with particular emphasis on differences relative to the referenced innovator compound already available. It is not enough for follow-on biologics to have similar effectiveness targeting an in vivo cytokine receptor or cell surface molecule. Considering the meaning of
biosimilar and approval under an abbreviated Neal R. Gross & Co., Inc. 202-234-4433
Page 201 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 pathway, it is important to emphasize that minor differences in primary amino acid sequences can cause significant alterations in protein molecules secondary and tertiary structures resulting in a biosimilar protein with vastly different effects. The effects on the targeted cytokine receptor or surface marker protein or other substance and the potential for immune stimulation may very considerably including differences and affinity of profile, differential propensity for adverse reaction, and even pharmacodynamic properties all resulting from amino acid substitutions in key locations. Interchangeability. Practicing
rheumatologists believe that there is no sufficient scientific understanding of potential biosimilars to allow for an interchangeability of biologic products at this time. While we hope that advances in
scientific knowledge will provide such Neal R. Gross & Co., Inc. 202-234-4433
Page 202 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 standards in the future, they simply do not exist. Therefore, in the interest of our patients relying on biologic products I urge the FDA to foreclose this avenue until the science advances in this area. Anything short
of barring interchangeability at this time would be detrimental to patient safety and would erode physician confidence in prescribing these medications. Patient safety and pharmacovigilance. Patient safety must be
paramount in considerations regarding approval of follow-on biologics. Adequate and
appropriate FDA preapproval evaluation as well as post-marketing surveillance must be included. Clinical trials to ensure that a
follow-on biologic is safe, effective, and free of different immunologic consequences not associated with the parent compound are necessary to provide patients and physicians with the confidence they need in these new Neal R. Gross & Co., Inc. 202-234-4433
Page 203 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 agents. There simply is no substitute for
testing these products given their degree of complexity and their effects. A good example of one such occurrence is the pure red blood cell aplasia that was linked to an erythropoietin like molecule follow-on agent after it was used in over 90 countries. One case of aplasia A
occurred in every 5,000 patients exposed. great deal of investigation was required before the cause was ultimately defined.
As far as TNFs go, we have seen a variety of positive responses and adverse reactions to TNF-alpha blockers. Adverse
affects vary among different patients with the same disease who are given the same ZTNF blocking agent or may vary in a single patient who receives different TNF agents. All adverse reactions are not always identified at the time of approval of these products. A 2008 report published in
JAMA found that 41 of 174 biologics approved Neal R. Gross & Co., Inc. 202-234-4433
Page 204 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 since 1995 were the subject of 82 regulatory actions regarding safety. In that study the
probability of a first safety-related regulatory action was 14 percent three years after approval and 29 percent 10 years after approval. The FDA should provide a unique nonproprietary name for each biologic product. This is the only certain way to track postmarketing differences in monitoring adverse events. Furthermore, the physician should
always be involved in decisions regarding selection of the specific biologic agent being dispensed to the patients. Automatic retail substitution of biologics is not appropriate. A unique
nonproprietary name ensures that the patient receives the prescribed product, enhances traceability in the event of adverse postmarketing experience, prevents inadvertent substitution and contributes to a reduction in medical errors. Neal R. Gross & Co., Inc. 202-234-4433
Page 205 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Nonproprietary names are the primary means for patients and practitioners to correctly identify products. Patients
often do not retain product packaging that main contain other identifying information or lot numbers for manufacturers. Without the ability to distinguish the product by name most patients will resort to referencing the class of the product or the most widely advertised product. This will
hinder efforts to identify the source of a new problem, accurately associate patient experience with the specific product and will thwart the development of a meaningful safety profile for each medication. Follow-on biologic labeling must provide accurate, specific, and comprehensive information about the actual product, not the reference product. The physician and patient should be able to easily see the data on the actual product which is contrary to what the EU Neal R. Gross & Co., Inc. 202-234-4433
Page 206 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 currently does and the indications for which that product is approved and those for which it not approved. In order to facilitate
informed decision making clear information must be readily available to the physician and patient. In summary, we support the development of follow-on biologics as this will improve access to care for patients with serious rheumatologic and autoimmune diseases as long as the pathway for approval assures safety and efficacy of these agents and their immunologic affects are studied. Clinical trials are paramount since desired and adverse effects of follow-on agents may differ from the parent innovator compound. Once again, for patient safety
reasons we urge the FDA to foreclose the ability for interchangeability at this time and to maintain transparency for matching what is prescribed and what is dispensed. When examining potential risks Neal R. Gross & Co., Inc. 202-234-4433
Page 207 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Any questions from the panel? Mr. Schwartz. MR. SCHWARTZ: When you talk about regarding interchangeability FDA must not only require specific clinical studies examining those substitutions within human subjects, but also needs to require additional postmarketing surveillance to monitor for new potential risks. Finally, the FDA should insist on a unique nonproprietary name for each biologic product. Once again, I offer my sincere
thanks to the FDA for having this public hearing and to discuss key issues of relevance to rheumatologists, other physicians, patients, and other stakeholders. DR. BEHRMAN: Thank you.
Thank you for your
for the time being not allowing for licensing of interchangeable biological products, if you could just clarify for our purposes are you referring to the fact that the legal standard Neal R. Gross & Co., Inc. 202-234-4433
Page 208 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 under the biologics price competition and innovation act would not be met currently. Or that even if it is met the scientific understanding as to what are the consequences of switching or alternating between the reference product and the interchangeable product is not sufficiently well known to allow for interchangeability. DR. SCHIMIZZI: From our
perspective I don't think that interchangeability is possible at this time, true interchangeability. I think
interchangeability is a desirable concept and I think that is where we should focus on perhaps getting someday. At this point in time I don't think interchangeability is possible. I
didn't refer to licensing a substance as interchangeable. I just don't think that a
follow-on biosimilar at this point in time can be determined to be interchangeable. DR. BEHRMAN: Dr. Jenkins.
Page 209 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. JENKINS: You take a pretty
strong stand on the unique nonproprietary name. We heard some other presenters this Can
morning with a different take on that.
you comment on why you think it's so important relative to the reasons they thought it was so important to go the other direction? DR. SCHIMIZZI: Dr. Jenkins, I'm Thank you.
so glad you asked that question.
You know, I was talking to some of the audience members today and some of these people here are not just professionals in their field and well known investigators and leaders of industry and pharmaceutical companies, etc., but most of us are patients. If you have a medication in your pocket right now I want to know do you know the NPI number or lot number? I'll bet you to
every last person in this room not a single person in this room can tell you what is the NPI number or the lot number of the product that they had in their pocket or their purse Neal R. Gross & Co., Inc. 202-234-4433
Page 210 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 but they can tell you the name. They can tell you if it's a generic or they can tell you if it's a brand name product. So the point is my patients --
I have a really difficult time getting my patients to take their medication home in a proper manner. Some of these medications, of course, need to be refrigerated and I'm afraid some patients where I live and work they might throw the medication in the back of the truck next to the dog box. The NPI and the lot
number is a little bit more sophistication than I can expect from patients. In the real world patients know the name of the medication, they know whether it's a generic, they know if it's a brand name, and they can tell you if they've had any problems with it but that's all. The
pharmacists and the pharmacy company they can tell you different but not the patient. As far as interchangeability, you Neal R. Gross & Co., Inc. 202-234-4433
Page 211 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 know, my patients they might start with one particular insurer. Caremark and E-Scripts
and all of the other pharmacy benefit managers, they are happy to take your business but if your company, aside from the U.S. Government, switches to a different PBM, that PBM is not going to have the same generic. Although CuraScripts or Express Scripts will have the same generic, the patient may not and the patient is going to get switched every contract year or every other contract year and down to almost every patient. It's important for the patient to know what they're getting and it's important for the physician to know what's being dispensed. DR. JENKINS: another question also. Let me ask you We talked some this How
morning about what should be the bar? high should the bar be set for showing biosimilarity?
You've suggested that for the
time being, at least, we take off the table Neal R. Gross & Co., Inc. 202-234-4433
Page 212 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the interchangeable option. Under that scenario a biosimilar would have to be specifically prescribed by the physician. If in the context of the law
that says no clinically meaningful differences, how high do you think we should set the bar? How much assurance should we have that they are, in fact, pretty close to being the same versus how much do you think there is room for some variability there since you are going to be making the decision which to prescribe? DR. SCHIMIZZI: I think it's okay
to have some variability but I think that variability needs to be known and defined. don't feel comfortable giving a patient a medication that is labeled a biosimilar when I'm not absolutely certain that this particular product isn't going to induce a new immunologic response that the patient did not have to the innovator compound. Neal R. Gross & Co., Inc. 202-234-4433 I
Page 213 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 There are several chimeric molecule antibodies that we use in rheumatology. There are several TNF The
inhibitors that we use as well.
development of anti-HACA antibodies or a new autoimmune syndrome like drug-induced lupus doesn't occur with all of these. occur with one. Some of them may induce a secondary type of psoriasis in psoriatic patients but not all of them. Why is that? It may only
I believe that if it can be shown that a biosimilar has adequate efficacy comparable to the parent compound, has side effects similar to the parent compound, and if there are any differences those be elucidated and I have no problem with having that agent on the market. I think that's appropriate. To
blindly put a label of biosimilar just because a compound has an infinity for the same target, receptor, cytokine or self-service marker is not enough. I think clinical trials
Page 214 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 are absolutely essential. DR. BEHRMAN: DR. MARCHAND: comments today. Dr. Marchand. Thank you for your
I wanted to clarify your
comment in what was submitted to us and that is that the physician should always be involved in decisions regarding selection of the specific biologic agent. I'm wondering if you can expand on that slightly and also indicate if the intention is for each individual physician is to be involved in each individual patient, or rather you're thinking is more in terms of the Coalition for State Rheumatology Organizations, for example, could make a general recommendation for particular patient groups or types. DR. SCHIMIZZI: Well, it's
interesting that we in rheumatology see different patients from different areas of the country and they have different immune system responses. For instance, in the southwest Neal R. Gross & Co., Inc. 202-234-4433
Page 215 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 much. DR. BEHRMAN: Our next speaker is the panel? Thank you for your comments. DR. SCHIMIZZI: Thank you very where there may be many more Hispanic patients than in the northeast or Midwest there may be a lot more lupus-like reactions to medications. I don't think a single entity can make that determination. I think that
determination needs to be made on the basis of an individual person and a population being treated. Perhaps even the family history. I
think that it's important for the physician and the patient to be involved in that decision based on what is known about the product being prescribed and is the biosimilar included. DR. BEHRMAN: Other questions from
Jim Shehan from Novo Nordisk. MR. SHEHAN: Good afternoon. I
Page 216 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 parts. thank FDA for convening this panel and allowing our company to present its views on implementation of the Biologics Price Competition and Innovation Act. My presentation will have two I will first describe some overarching
principles that Novo Nordisk believes should guide FDA in implementing the law. I will
then discuss Novo Nordisk's views on three topics identified by FDA in its notice. (1) The statutory definition of biological products; (2) the application of the 12-year exclusivity period to innovative next-generation products; and (3) the provisions that transition products like insulin and drugs -- insulin and human growth hormone from drugs to biologics. We urge FDA as it moves forward on all initiatives related to the BPCIA to make patient safety the agency's paramount concern. We also urge the agency to look closely at the experiences and standards established by the Neal R. Gross & Co., Inc. 202-234-4433
Page 217 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 European Medicines Agency. The European Biosimilar framework has been operating since early 2006 and has been a scientific and regulatory success. illustrates the possibilities and the challenges of biosimilars. Fourteen products It
have been approved, one application has been rejected, and three applications have been withdrawn. The overarching principles. First, given the current state of science extensive comparative characterization of biosimilars with their reference products is necessary. Characterization alone cannot
detect all clinically significant differences between products. To protect patients, comparative nonclinical and clinical testing of biosimilars is generally necessary. European experience with biosimilar applications for three varieties of insulin -fast acting, long acting, and a mixture -- is Neal R. Gross & Co., Inc. 202-234-4433 The
Page 218 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 instructive. In that case, without
comparative clinical testing, critical differences between the products would not have been detected and patient welfare may have been compromised. Second, FDA generally should license a biosimilar only for indications supported by the biosimilar sponsor's own clinical data. As in Europe the applicant
should be permitted to extrapolate from those data to receive approval for unstudied indications only if the extrapolation is scientifically justified. FDA should proceed particularly cautiously with respect to extrapolation where individuals in the unstudied population may have different physiological responses to the drug. Third, FDA should proceed cautiously when implementing the interchangeability provisions. The statute
permits interchangeability designation only if Neal R. Gross & Co., Inc. 202-234-4433
Page 219 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the product can be expected to have the same clinical result in any given patient. And in
the case of products that are used more than once when there are no risks inherent in alternating between the reference and the biosimilar products. Novo Nordisk believes
that this is an appropriately high safety standard. Fourth, all biologics should have unique names. This will promote
pharmacovigilance efforts by ensuring complete traceability of products throughout the health delivery system and along with an effective tracking system, unambiguous identification of the product associated with a particular adverse event. Fifth, the labeling of each biosimilar should clearly state that it is a biosimilar and whether the biosimilar has been approved for all of the indications of the reference product and, if not, identify the reference product indications for which the Neal R. Gross & Co., Inc. 202-234-4433
Page 220 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilar lacks approval. It should identify the specific product tested in each clinical trial described in the labeling and it should state whether the biosimilar has been deemed interchangeable with the reference product. Any differences between the products should be clearly disclosed. Let's move to the definition of biological product. Congress amended the
statutory definition of biological product to provide the proteins except chemically synthesized polypeptides are within its scope. The statue unambiguously describes the one scientific and technical factor that FDA must consider in implementing the statute. That is the method of the product manufacturer. Whether a product is a protein,
a peptide, or a polypeptide, it is excluded from the definition of biological product only if it is manufactured using chemical synthesis. Moreover, only polypeptides are Neal R. Gross & Co., Inc. 202-234-4433
Page 221 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 excluded when they are chemically synthesized. To determine whether a polypeptide is chemically synthesized, FDA should consider the features of its manufacturing process including, (1) whether the source material is biological in nature, notwithstanding any subsequent chemical modification; (2) whether living cells are used in the manufacture; and (3) if so, whether the cell bank used is unique. Any product subject to FDA or ICH
quality guidances on biological products would fall within the definition of biological. This includes proteins and polypeptides that are produced from recombinant or non-recombinant cell culture expression systems and that can be highly purified using appropriate analytical procedures. Biotechnology-derived insulins and somatotropin are biological products under the new definition. They are proteins, or amino
acid chains as FDA has noted previously, and Neal R. Gross & Co., Inc. 202-234-4433
Page 222 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 they are not chemically synthesized. Next, exclusivity for next generation innovative products. Innovative
next generation products, which must be supported by full data packages, often represent important improvements or beneficial alternatives to existing products. For example, substitution of a single amino acid in recombinant insulin resulted in an analog, NovoLog produced by Novo Nordisk, with significantly shorter time of action than human insulin and a unique safety profile as well as important benefits including enhanced real time flexibility for millions of patients who suffer with diabetes. It is, thus, clearly in the interest of public health to provide incentives for development of innovative next generation products. I can, however, be
difficult for a manufacturer to predict at the beginning of the development program the exact advantages or safety issues that will result Neal R. Gross & Co., Inc. 202-234-4433
Page 223 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 from structural modification. Only when major investments in research and development and the performance of extensive clinical trials are the full properties of innovative next generation products apparent. Accordingly, the statute provides that such innovative products are entitled to exclusivity if they reflect any structural modification resulting in any change in the product's safety, purity, or potency. approach applies to all structural modifications without qualification. It thus This
applies to changes to the amino acid sequence, pegylation, and glycosylation, among other changes. It also applies to all changes in safety, purity, or potency without qualification. The statute does not permit,
for example, an inquiry into clinical superiority of these products. Last, the transition provisions. Neal R. Gross & Co., Inc. 202-234-4433
Page 224 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the panel? Ms. Esposito. Neal R. Gross & Co., Inc. 202-234-4433 Under the statute the sponsor of an innovative transitional product may submit an NDA instead of a BLA during the transition period that expires in 2020. The plain language of the statute indicates that FDA must defer to the sponsor's choice of pathway during the 10-year period. A new insulin or somatotropin product supported by a full application is an example of such an innovative transitional product. Finally, FDA should provide guidance clarifying how the exclusivity provisions of the BPCIA will apply to transitional products after they have been deemed approved under Section 351 in 2020. This will provide sponsors with the certainty that they need to make decisions going forward. Thank you for your time. DR. BEHRMAN: Thank you for your
Page 225 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 MS. ESPOSITO: In speaking of
exclusivity in your remarks and the provision of the statute that relates to structural modifications, you are advocating an expansive view of a structural modification that would permit exclusivity potentially to restart. In your remarks you stated that the statute does not permit any inquiry into clinical superiority. Can you expand on what
you mean by that and how that relates to the language in the statute focusing on safety, purity, and potency? MR. SHEHAN: Yes. Again, if we go
to the language of the statute it talks about structural modifications and then differences in safety, purity, or potency. superiority. It doesn't say
It's simply differences. So I
think that is the standard that the agency should be focused upon. DR. BEHRMAN: Other questions? You said to I
have one question on labeling.
state whether it's a biosimilar and whether Neal R. Gross & Co., Inc. 202-234-4433
Page 226 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 you answer. it's been approved for all the indications, and identify the indications that it lacks, so that if the innovator then later was licensed for a new indication, the biosimilar would have to update its labeling to reflect that it did not. And in your view -- I should let You're nodding yes. And then in
your view could a product be interchangeable for a subset of indications? Obviously, you
believe it could be biosimilar for a subset of indications. MR. SHEHAN: I think in each case
you have to go back to the standard of whether the product has been shown to meet one biosimilar requirement in the statute standard and then even higher interchangeability standards. DR. BEHRMAN: In each case,
therefore, you believe that the biosimilar could be licensed for not only a subset of the indications of the reference product but also Neal R. Gross & Co., Inc. 202-234-4433
Page 227 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 could be interchangeable for a subset of those indications? MR. SHEHAN: If the standard has
been met, but you're going to have to, in each case, meet the standard. That's why we're
calling out if there are differences between the reference product and the biologic. an issue of patient safety. It's
If it hasn't been
shown to meet the standard in a particular indication, the patient and the healthcare professional should be informed of that. DR. BEHRMAN: Would you be at all
concerned about the implications for practiced medicine? I think a previous speaker spoke a
little bit to what patients generally do and don't know about their products and whether, if it was a product that was interchangeable for one indication, if there would be -- it might be difficult to surmount the presumption that it's interchangeable for all indications, for example. MR. SHEHAN: It will pose
Page 228 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 from Pfizer. DR. FIELDS: Good afternoon. I'm challenges, yes. DR. BEHRMAN: from the panel? Thank you for your comments. Our next speaker is F. Owen Fields Any other questions
Owen Fields. I'm in regulatory strategy at Pfizer. Today I'm going to present only some And I note
highlights regarding key issues.
that all of our points are expanded on in the full submission. To begin with, comparative clinical endpoints that, of course, are going to be necessary for assessing the impact of differences, I state the obvious to start with. The objective of biosimilar product
development is to establish that the safety and efficacy of the biosimilar is not different in a meaningful way from the reference product. Conceptually, the best way to do Neal R. Gross & Co., Inc. 202-234-4433
Page 229 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 this is to conduct a comparative study using the endpoints and population that will most effectively and efficiently establish clinical similarity. We note that the innovator drug is often already validated, more sensitive, and often secondary endpoints correlate with primary endpoints. Given this, the use of
endpoints that have greater discriminatory potential should be acceptable as long as there's adequate justification. I also note that in some cases the use of such endpoints may actually be required to make biosimilar product development economically feasible through the intensity of the reference product primary approval endpoint and survival is an obvious example of such a phenomenon. The question of equivalence versus non-inferiority designs has been subject to much discussion and global guidance development and was, in fact, brought up Neal R. Gross & Co., Inc. 202-234-4433
Page 230 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 earlier today. However, in practice most
biological products actually fall into one or two pharmacodynamic classes. The first class are those that have a dose response on both sides of the approved dose, and cytokines are often in this class. For this class, equivalent should
clearly be the standard clinical trial design because efficacy greater than the reference product is not only feasible but would clearly be a clinical concern. The second class are those that pharmacodynamically saturate the target at some level and these are generally used at or near the maximum level of clinical effect. Many antibodies, whether they be anti-cytokine antibodies or oncology antibodies, actually fall under this class. For this class the target has generally been completely biologically neutralized at the approved dose and noninferiority designs should be justifiable, Neal R. Gross & Co., Inc. 202-234-4433
Page 231 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 again on a case-by-case basis, as pharmacodynamic activity above the level of the reference product is considered unlikely. Regarding when studies are unnecessary, extrapolation is a key issue. The concept of extrapolation between subpopulations within an indication and from indication to indication is really a key topic to address when considering what clinical studies can be omitted. In Pfizer's view extrapolation of data from one population within an indication to another population within that same indication should often be acceptable, again with the appropriate support, and considered on a case-by-case basis, while extrapolation of efficacy data across entirely unrelated indications will less often be appropriate given differences in pathophysiology and the site of tissue action. We also note that carefully designed programs that include orthogonal Neal R. Gross & Co., Inc. 202-234-4433
Page 232 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 data, for example, from two or more reasonably different indications, may, on a case-by-case basis be able to support a broader label. Regarding interchangeability, Pfizer notes that the relevant language for interchangeability provides a much higher scientific standard than applies to noninterchangeable products. This has already
been the subject of a lot of discussion today. We note that there are no clinical means, experimental means that is, for establishing sameness in any given patient or population. And in fact, even showing 90
percent maintenance effect in a comparative clinical trial is often economically infeasible. Also, from a practical perspective, interchangeability, we believe, would need to be established for each reference product indication. That's because
of the way prescriptions are administered in a pharmacy. They would have to specify which Neal R. Gross & Co., Inc. 202-234-4433
Page 233 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 indication the prescription is for to make it practical to have a product that's interchangeable for one indication and not others. Given the above factors and potential immunogenicity issues, we think an interchangeability standard may need to rest on a showing of compositional and functional sameness in order to predict clinical sameness. This is because there is no other scientific method that will allow confident prediction of the same clinical result in any given patient. Currently, this may only be feasible for small, homogenous, functionally simple biologics manufacture and standard highly reproducible production system. Regarding patient safety and pharmacovigilance, FDA's proposal that interchangeability or biosimilarity be reflected in name prefixes or suffixes does not encompass the range of products that will Neal R. Gross & Co., Inc. 202-234-4433
Page 234 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 exist. As has been discussed earlier, many
biologicals have multiple indications. The market will eventually include subsequent entry products that are not developed as biosimilars, biosimilars with adequate data to support similarity for all indications, products with data adequate to support a subset of indications and these will, of course, come in various flavors, as well as interchangeable biosimilars. Given this and given pharmacovigilance requirements, Pfizer supports each subsequent entry and biological product having its own unique identifier. example would be a nonproprietary name with the manufacturer's name as a suffix and its own label and the label would need to include a prominent statement regarding its biosimilarity for interchangeability and with regard to each indication. Regarding the use of supported data, fundamentally it's the drug substance Neal R. Gross & Co., Inc. 202-234-4433 One
Page 235 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that has pharmacological activity in the body. Given this, differences, if any, between U.S. and foreign license drug substances should be of the largest concern. Obviously, there should be concerns with the effect of the drug product on the drug substance. addressable, however. This will sometimes be Several possible
scenarios are likely to exist, broadly defined admittedly. They will be things that shade
one or more of these classes. You can have a U.S. and foreign license drug substance that is essentially the same. The product is nearly the same. U.S.
license and foreign license drug substance is the same and the drug product differs. Finally, the U.S. and foreign license drug substances differ. And we have some
definitions as to what the terms and quotes mean in our full submission. In our view, No. 1 may be addressable with the bridge. No. 2 may be
Page 236 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 addressable with a very strong bridge. No. 3
would likely require separate development and may actually be a bridge too far. Regarding the definition of a biological product, we believe the primary distinction between a chemically synthesized peptide and a protein should be based on structural complexity and whether a biological production system is the only practical means of synthesis. Generally peptides that are small enough to be chemically synthesized would be structurally simple and there would be a basis to handle them as nonbiological products. They often lack complicated structural features and often same as for these products can be shown. Most proteins, on the other hand, above a certain molecular weight, will not fold properly if they are manufactured outside of a biological system and this or tertiary structure might suggest a rough dividing line. Neal R. Gross & Co., Inc. 202-234-4433
Page 237 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 For these products, sameness is much more difficult to show. We note that FDA is going to face products on the border line between these two definitions and we think the agency should consider adapting the request for designation process to address the appropriate review authority for these products. We also note that antibody-small molecule conjugates' classification should be immediately clarified given the intent of the legislation and the new definitions provided in the legislation, as well as regulatory science considerations. In closing, the new pathway will require a great deal of regulatory policy development. At the same time, new product We should all
development is ongoing.
recognize the challenges this is going to present. Collaboration will probably be the
best way to address these challenges. And in our view, the questions Neal R. Gross & Co., Inc. 202-234-4433
Page 238 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the panel? Dr. Jenkins. DR. JENKINS: I think you're the addressed in the hearing notice indicate that FDA is taking a very constructive and proactive approach to solving these challenges. With that I'll stop and take
clarification questions on the highlight presentation or on the full submission. DR. BEHRMAN: Thank you for your
first one today to bring up the issue about using foreign license products in the U.S. application process. You listed it on your
slide under use of supportive data and information. Can you say more about where do you think that data derived with foreign products as a reference fit into the U.S. approval scheme? Is that simply supportive
data or do you see situations where it could serve as the pivotal data called for under the Neal R. Gross & Co., Inc. 202-234-4433
Page 239 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 statute for the biosimilar comparison? DR. FIELDS: The primary practical
issue that companies are going to run into is use of global studies which will sometimes be necessary and you will have a drug product that needs to be sourced from two different locations. The first sort of issue that is
going to come up is whether it's appropriate to pull data from using foreign drug product in some of the centers with U.S. data. that's one practical. Now, whether you could base an entire approval based on data with a foreign drug product, I think that would depend on the class in which it falls. If you did that -So
I'm not an attorney but if you did that, I would guess that legally, then, the pivotal data would not actually be the clinical data. The pivotal data would be the data showing what is very, very, very close similarity between the foreign product and the U.S. product. Does that answer make sense? Neal R. Gross & Co., Inc. 202-234-4433
Page 240 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. JENKINS: One of your
scenarios, your No. 1 scenario, is U.S. license and foreign license drug substance is the same, product is nearly the same. Nearly
the same might mean that it has the foreign label versus the U.S. label. DR. FIELDS: DR. JENKINS: In one extreme, yes. How would the
biosimilar sponsor be able to demonstrate that scenario actually applies? They are not the
innovator, manufacturer and unable to know how the innovator manufactures the drug and where they ship it, how they label it. How would you envision the biosimilar sponsor would support their assertion that the biologic that is sold in the United States and the biologic that is sold in Europe are the same product with different labels? DR. FIELDS: That would only be
possible with extremely thorough analytical characterization. Another thing that should
Page 241 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the panel? DR. CHERNEY: Well, in regard to be noted is that the site of manufacture of drug substances is often publicly available in regulatory documents. But you are correct, it could be possible to have two different drug substance manufacturing processes running in the same plant and there would be no data supporting that, so there would be no data available to the sponsor. That's why we believe if a
bridge needs to be built, it needs to be extremely, extremely robust in that case. We view the bridge between a biosimilar product and a reference product as potentially an eloquent suspension bridge. think that kind of bridge would have to be virtually showing identity between two products. DR. BEHRMAN: Other questions from We
that bridge, I think you mentioned earlier that you thought that you couldn't get Neal R. Gross & Co., Inc. 202-234-4433
Page 242 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 complete chemical identity between products. And at a certain structural complexity you would not want to have the products interchangeable because of the issues with complete chemical identity except for rather small, less complex molecules. How does that fit into the use of nonlicensed products and comparison to that, since the comparisons will have some weaknesses you won't be able to show complete identity between those either? DR. FIELDS: Your point is that
maybe smaller, more homogenous, easy to characterize molecules may fit into the paradigm that I presented a little better? DR. CHERNEY: Well, perhaps. Your
logic with interchangeability is if it's too complex, you can't define it well enough physicochemically to allow for interchangeability. But if you are
extrapolating all this data and you say the molecule is too complex to fully define, then Neal R. Gross & Co., Inc. 202-234-4433
Page 243 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 what permits you to extract that data? DR. FIELDS: I think the answer is If it's
the different legal standards.
interchangeable, there is no physician involved in making the decision for the patient to get the drug. That is why that standard has to be extraordinarily high. When the patient
asks their pharmacist, is it the same and is it the same for me, the pharmacist has to be able to say, "Yes, FDA has determined that it is the same." For biosimilarity, the standard is a bit looser. It's a high level of similarity
and, therefore, it may be possible to extrapolate foreign data into a U.S. approval package. DR. BEHRMAN: had a question? MR. SCHWARTZ: DR. BEHRMAN: have just one. No, no question. Other questions? I Mr. Schwartz, you
On slide 6, I thought you
Page 244 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 confusion. stated pretty clearly that you believe it would need to be established for each reference indication about population interchangeability so you don't see a subset. Then on slide 7, when you're talking about pharmacovigilance and naming, the last bullet point seems to imply that perhaps that's not the case. DR. FIELDS: Sorry if there is any
That means that some will be Other ones
designated as interchangeable. will not.
That was not to imply that a
product would be interchangeable for one indication and not the other. I'm not clear
how you would even administer that, as I said, at the pharmacy level. DR. BEHRMAN: you for the clarification. comments. DR. FIELDS: DR. BEHRMAN: Thank you. Our next speaker is Right. Okay. Thank
Thank you for your
Rivka Riven-Kreitman from Teva North America. Neal R. Gross & Co., Inc. 202-234-4433
Page 245 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 afternoon. Kreitman. MS. RIVEN-KREITMAN: Good
As you said, my name is Rivka I am the head of the Innovative
Research and Development Global Group Teva. Thank you for the opportunity to present Teva's position. Teva is the world's largest generic company and the 11th largest global pharmaceutical company. Over the last 10
years, Teva invested heavily in biosimilars by establishing R&D, manufacturing infrastructure, acquiring technologies, developing partnerships in the field. We also
have experience in bringing biosimilar product in the European marketplace. Teva is developing a broad and deep pipeline of biosimilars that target serious medical conditions with the aim of providing better health to more patients at more affordable prices. We consider the establishment of biosimilar pathways in the U.S. as an Neal R. Gross & Co., Inc. 202-234-4433
Page 246 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 important initiative that could improve excess of these highly expensive products and reduce the economic burden of biotech drugs that are currently costing the U.S. healthcare system which are currently expected to exceed $50 billion this year. When determining the requirements for establishment of biosimilarity, Teva believes that a balanced approach is needed. On one hand, the complex nature of biologics warrants a cautious approach and solid clinical evidence of similarity is needed before the FDA recognizes the product is biosimilar. On the other hand, conducting unnecessary clinical trials raises ethical concerns and needlessly increases development cost which may render biosimilars less affordable to patients. The quality standards for a biosimilar should be set at a very high level. That is very clear for us. The reference
Page 247 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product should be thoroughly characterized and the biosimilar should be developed to be within the variability range of the reference product. Any biosimilar development program should include a robust pivotal clinical trial in one indication which will demonstrate similarity of the innovator's reference product in terms of safety and efficacy. Once biosimilarity has been established in one indication, the applicant could seek other indication of the innovator products that share the same mechanism of action. Robust pivotal clinical trial in
safety measures must be undertaken to ensure public confidence in patients taking a biosimilar product. We believe that the biosimilar product should have the same INN number as the innovator and the differentiation should be only by its trade name. In order to avoid
unnecessary replication of clinical studies, Neal R. Gross & Co., Inc. 202-234-4433
Page 248 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 documented evidence of data generated in studies using the innovative reference for that in one region should be acceptable in other regions. Post-marketing studies may be justified when there is a scientific rationale and a clear safety or efficacy need. We
believe that interchangeability should be allowed once biosimilarity has been established following a development program which includes a robust pivotal clinical trial. Thank you. DR. BEHRMAN: presentation. Questions from the panel? Dr. Jenkins. DR. JENKINS: You mentioned that Thank you for your
Teva has experience bringing biosimilar products to Europe to marketing. It ties into
the question I asked earlier about how should FDA be looking at those data that were generated to lead to the approval for Neal R. Gross & Co., Inc. 202-234-4433
Page 249 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 licensing of the biosimilars in Europe when those same biosimilar sponsors come to the United States and say, "Here's the package we gave EMEA. They found it acceptable. We used
a non-U.S. licensed reference product but we think you can use the same package here." What is your thinking about our ability to use the European trials that were done, preclinical data, non-U.S. reference products? MS. RIVEN-KREITMAN: As I said
before, we believe that we can use the same data. Usually the manufacturing of the
product actually is the same by the innovator. It's the same manufacturing sites that are being sent both to the U.S. and Europe in many cases. I believe that it's unnecessary to
repeat these studies. The other point that I said before is that you need to characterize the product of the innovator. Actually the difference in
the product itself, whether they go into Neal R. Gross & Co., Inc. 202-234-4433
Page 250 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 different manufacturing or scalability or whatever is almost in the same range of biosimilarity, so I believe it can be used. DR. BEHRMAN: MS. MALONEY: Ms. Maloney. I just wanted to ask
you a question about the bullet you had about once you establish biosimilarity for one indication, that the applicant can seek other indications if it was the same mechanism of action. What additional data, if any, do you
think might be needed in that instance? MS. RIVEN-KREITMAN: If the
mechanism of action is really established very well and it's very clear, I believe there is no additional data that is required. However,
as I said, sometimes Phase 4 will be required to acquire additional information, maybe on safety or efficacy or mechanism or whatever it is. As I said, if the mechanism of action is very clear, we believe that you can extrapolate the indication to the other Neal R. Gross & Co., Inc. 202-234-4433
Page 251 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 indications once you've showed biosimilarity. DR. CHERNEY: I understand that
you said that interchangeability should be allowed once you meet the statutory requirements for interchangeable. My question
is that, after a manufacturer gets approval they continue manufacturing, they make changes, the reference product manufacturer makes changes. Both of them are making
changes without the knowledge of what changes each are doing. Products can drift over the
life cycle of the product. How do you maintain that the products are interchangeable throughout the life cycle of a product? MS. RIVEN-KREITMAN: good question. That's a very
I think this question is
relevant also for the innovator product per se because how do you assure that when they scale up, change manufacturing sites and so forth they maintain the same product? You control
it very closely in the development of the innovator and it's the same for the Neal R. Gross & Co., Inc. 202-234-4433
Page 252 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilar. You cannot drift totally from the
originator product. DR. CHERNEY: I would argue that
they may not be the same because, in the situation of a biosimilar, both products are on the market at the same time. manufacturer makes changes within manufacturing, the one product will replace ultimately the other product so they are not on the market for any period of time so they are not substituting back and forth between products from two different manufacturing processes, typically. MS. RIVEN-KREITMAN: situation with the biosimilar. Similar Once you scale When a
up or change manufacturing you won't drift back so I don't see how it's different. DR. BEHRMAN: Could I just ask for Maybe I
clarification on your last bullet? misunderstood.
It says, "Interchangeability
should be allowed once biosimilarity has been established." Neal R. Gross & Co., Inc. 202-234-4433
Page 253 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Do you mean once biosimilarity has been established and then once interchangeability has been established, or do you see interchangeability as following automatically from biosimilarity? MS. RIVEN-KREITMAN: I think that
once biosimilarity has been established both on the chemistry level, the clinical level and so forth, then interchangeability should be granted. DR. BEHRMAN: You don't see any
need for any additional studies? MS. RIVEN-KREITMAN: DR. BEHRMAN: clarification. Any other questions? MS. MALONEY: Ms. Maloney. No.
Thank you for that
Just on the naming.
Your bullet talked about that you think the name should be the same but could you just talk a little bit about the rationale behind it? I'm not sure if I heard that. MS. RIVEN-KREITMAN: Well, I think
Page 254 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Okay. the panel? Thank you for your comments. Sandy, are we ready for a break? We're ready for a break, so we'll take that giving it a different INN number is very confusing. Again, it links to the
interchangeability issue so we could give it a different INN number and then it makes it very complicated to exchange it at the pharmacy level. So we think the branded name
should reference between the two products but not the INN number because it's the same product. DR. BEHRMAN: Other questions from
a 15-minute break and we will return at 10 after 2:00. Thank you. (Whereupon, the above-entitled matter went off the record at 1:56 p.m. and resumed at 2:13 p.m.) DR. BEHRMAN: We'll resume, if
everyone could take their seats. Our next speaker is Sumant Neal R. Gross & Co., Inc. 202-234-4433
Page 255 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 right. Ramachandra. DR. RAMACHANDRA: Thank you. Great. Yes. You got it
Again, my name is Sumant Ramachandra. I'm the Senior Vice President for Research and Development Regulatory Medical Affairs and Hospira's Chief Scientific Officer. Hospira is a Lake Forest, Illinois-based company and it's a global leader in generic injectables. And Hospira is
the only U.S.-based company currently marketing biosimilars through the globe. We have two approved biosimilar products, Retacrit, a biosimilar EPO and Nivestim, a biosimilar filgrastim. Retacrit is being sold in the EU and Nivestim is on the market in the EU and approved in Australia. Thank you for giving me the opportunity to speak here today. Hospira
supports the overarching premise of the Neal R. Gross & Co., Inc. 202-234-4433
Page 256 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilar pathway to expand access to highquality, lower-cost, life-enhancing and lifesaving biologic medicines. So, we appreciate
having the chance to be part of this public meeting and look forward to partnering with the FDA in the development of a biosimilar approval pathway. Today I'm going to talk about five topics relevant to this implementation effort: biosimilarity, reference products, extrapolation, interchangeability and pharmacovigilance. The first topic I'd like to comment on is biosimilarity. Modern
bioanalytical and protein characterization tools provide the foundation for a sciencebased determination of biosimilarity. A variety of analytical approaches can be used, depending on the type of molecule. no single approach for determining biosimilarity. However, the scientific tools do exist to characterize both biosimilar and Neal R. Gross & Co., Inc. 202-234-4433 There is
Page 257 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 reference products proteins. These tools
include analytical and biologic assays that can assess important product characteristics, including primary and higher order structure, post-translational modifications such as glycosylation, product variance and impurities. The assessment of structural differences should follow a hierarchy of testing that begins with in vitro physicochemical analysis and progressing sequentially through receptor binding assays, cell-based biologic assays, in vivo animal testing and finally the studies in humans. Additionally, incremental requirements for nonclinical and clinical data should be evaluated on a case-by-case basis depending on the complexity of the molecule and its clinical use. When the FDA is determining what testing is needed, they should consider a number of things, such as ethical concerns Neal R. Gross & Co., Inc. 202-234-4433
Page 258 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 regarding unnecessary human or animal testing and the availability of both literature and experimental data regarding structure and biologic relationships for the product. The next thing I'd like to comment on is the issue of reference products. The
use of EMEA-approved reference product in pivotal biosimilar or clinical trials should be permitted with appropriate bridging data to the U.S.-licensed product. Depending upon this product, this bridging data would be comprised of physicochemical comparability data, nonclinical studies and/or PK/PD studies. We would also like to see global harmonization so that trials are not replicated unnecessarily based on different regulatory guidances among highly regulated countries. We recognize that global
harmonization is ambitious and cannot happen overnight, but it is something we think is an attainable goal and is in the best interest of patients worldwide. Neal R. Gross & Co., Inc. 202-234-4433
Page 259 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Extrapolation of clinical data from one indication to the other indication should be allowed with proper scientific justification. Typically, if the mechanism of
action is well understood for a particular compound, extrapolation of indications can be scientifically justified. Even when
originator products go through major manufacturing process changes, the new product, in most cases, is allowed on the market by justifying extrapolation of safety and efficacy-based data on a nonclinical comparability exercise only. Interchangeability. Hospira
recommends that the FDA approach the requirements for achieving interchangeability on a case-by-case basis. Clinical data
requirements should be scientifically determined with the aim of minimizing patient exposure to trials. The clinical requirement
should reflect how products will be used by physicians. For example, patients have been Neal R. Gross & Co., Inc. 202-234-4433
Page 260 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 routinely switched to a biosimilar from a reference drug in European clinical practice based on our experience. Requirements for approval, including an interchangeability determination, should be based on the safety and efficacy profile of the reference drug. The last issue I'd like to comment on is pharmacovigilance. The same
pharmacovigilance system should be used for originator biologic and biosimilar products. These requirements should be consistent across the board so that biosimilar and originator companies are held to the same high standards. This is another example of why global harmonization of trials is important. It would allow us to have the same global pharmacovigilant system based on the same data from the beginning of approval to market, post-market follow-up. Another point I'd like to raise is the issue of INN naming. Unique
Page 261 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 nonproprietary names are not needed for biosimilars. INN is a nomenclature system for a drug substance. It has never been the primary means for managing clinical decisions by physicians. It is only one of several components that together make up a robust track and trace system which already includes things like product name, brand name, INN name, manufacturer, NDC number and lot numbers. In conclusion, I'd like to summarize the five issues I've discussed today. Biosimilarity can be proven by using modern scientific tools to characterize proteins. Reference products from a single global source can be scientifically justified. Extrapolation from one indication to the other indications should be allowed with proper justification from the sponsor. Interchangeability requirements Neal R. Gross & Co., Inc. 202-234-4433
Page 262 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions? DR. JENKINS: Dr. Jenkins? I'd like to probe a should reflect how products will be used in medical practice. And finally, pharmacovigilance systems should be the same for biosimilar and originator products. Again, I do appreciate the opportunity to be here today. Hospira looks
forward to partnering with the FDA on the implementation of the biosimilar pathway. Thank you. DR. BEHRMAN: Thank you for your
little bit further your slide on the reference product. So, taking a hypothetical or not so
hypothetical situation of a product, a biosimilar that's been approved in Europe where they had preclinical data and clinical data, comparing to a EU-licensed product. would you then envision that that would be translated into a U.S. approval? What would How
Page 263 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be the requirements that you're describing for bridging? DR. RAMACHANDRA: Absolutely. So,
at minimum the bridging data should comprise of stringent physical chemical comparability data. There should be some level of nonclinical studies to show the same level of effectiveness. And PK/PD studies should be So, some level of
encompassed in the package.
clinical PK/PD study should be included as part of this bridging to the U.S. reference product. DR. JENKINS: Just to be clear
then, are you suggesting that the EU licensed project and the U.S. reference product would be the subject of the bridging you're describing? That the sponsor of the U.S.
biosimilar would have to have the EU reference and U.S. reference and do all that comparability testing and present that as part of their application? DR. RAMACHANDRA: There's two
Page 264 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 things that occur. One is the catch-up phase. Right now we have, for example, EPO approved in Europe as well as filgrastim, and we are in the process obviously for EPO to seek approval in the U.S. There would be some level of In the ideal state we
bridging required.
would actually have global harmonized trials where you would do this level of PK/PD testing within one study and be able to show that the characterization of the EU reference product is similar to the characterization of the U.S. reference product. If you find that there are differences between the two, you will then seek to do different clinical trial paths, especially for the reference product. DR. JENKINS: So with that
approach that you're suggesting, how do you line that up with the language of the statute that talks about biosimilar to a U.S. reference product, a U.S.-licensed reference product? So when you work your way through
the scientific data and the statutory language Neal R. Gross & Co., Inc. 202-234-4433
Page 265 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 how do you line those up? DR. RAMACHANDRA: So, again, in
the ideal state, if you do global harmonized trials, you would have sufficient patients on the U.S. reference product within the same clinical trial that you may have patients on a EU reference product. But that's in the
ideal situation if you're able to conduct trials globally. In the situation that we are in we are going to use for EPO our European database because we have significant experience in Europe, but we do plan to do U.S.-based trials and replicate some of the data that we are doing in Europe both based on efficacy and safety. Because today we do not believe there's a pathway for the one I just described from a global harmonized perspective. So we do have to replicate some of the studies. And it does unnecessarily put patients into randomized clinical trials to show that difference. Neal R. Gross & Co., Inc. 202-234-4433
Page 266 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The objective of the pathway should hopefully be that we can get to a global standard and the onus will be on the sponsors to show the references are generally similar. DR. BEHRMAN: Other questions?
I had one for pharmacovigilance. So you have two products launched. Do you
have registries ongoing, and where are your pharmacovigilance programs, and how do they address in particular interchangeability? DR. RAMACHANDRA: Yes. So, we do
have registries ongoing. In EPO we have a registry that has just finished enrollment, we call the Pasco study, for the IV infusion of EPO. And then we have one started for the
subcutaneous administration of EPO, both in Europe. We have both safety follow-up, as well as general efficacy follow-up within those particular trials. And those are being
used, obviously, in justification for our Neal R. Gross & Co., Inc. 202-234-4433
Page 267 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 European experience. We're more than willing
to submit that data to the FDA, as we have had in discussions with the Agency already. In terms of interchangeability, in Europe we did two pivotal trials for EPO, and I'll give you the EPO example. One of the
trials was a parallel design trial, and the other one was a switching trial back and forth. And it allowed to show both parallel design in that particular trial as well, as patients had gotten the referenced product being switched to the Hospira EPO product. And the Hospira EPO exposed patients being switched to the referenced product in Europe. And we had shown in both studies that we had met all the endpoints as well as all the safety parameters both for efficacy and safety. DR. CHERNEY: I'd like to ask a
question on interchangeability and the ability to maintain that throughout the product life cycle. Could you take your prospective on Neal R. Gross & Co., Inc. 202-234-4433
Page 268 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that question? DR. RAMACHANDRA: Yes. We believe That
interchangeability is a high hurdle.
means, because of the comments that were made here today, interchangeability is an ideal state, and you should really aim for that. But the reality is you have to show sufficient data to make sure that the product -- when compared to each other -- are not only biosimilar, but they're safe when a patient is switched from one product to another. Interchangeability also does not make sense in every clinical setting. It
makes sense on a case-by-case basis. In shortterm treatment of biologic products, interchangeability may not be something you want to expose a patient to if they're getting anymore from two to four doses. But in
chronic exposure patients, interchangeability is something you would want to explore, because the reality is that clinical practice will drive you there eventually, and you want Neal R. Gross & Co., Inc. 202-234-4433
Page 269 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to have that data proactively rather than finding things in the post-market setting. DR. BEHRMAN: Okay. Do you want
to pursue your drift question, or shall I? DR. CHERNEY: Well, I think that
was the question -- was whether products once they're approved for interchangeability, okay, so you have interchangeability designation and you approve it. But then both manufacturer process will drift away from each other. The product can potentially drift. You stay
consistent with your own product, but you're not referring back to the original innovator's product. DR. RAMACHANDRA: DR. CHERNEY: Sure.
So how do you
maintain that interchangeable status then? DR. RAMACHANDRA: So from a CMC
perspective, when the referenced product is initially approved and as it goes through its life cycle, there are sufficient release criteria established for a particular product. Neal R. Gross & Co., Inc. 202-234-4433
Page 270 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 There are batch-to-batch variances even within the originator product, even from the same manufacturing plant, when a lot is released, from lot to lot. But they meet specific release criteria. What we propose is that the biosimilar company, the sponsor, also aim to stay within -- to be considered a biosimilar within that reference range. And that's the
best way of limiting this issue of drift. Because it actually allows the originator company to make the necessary changes, but they stay within the release criteria and, therefore, the biosimilar sponsor company does the same, because it aims to be within the same confidence interval in terms of its release criteria. That is the best way to
approach that particular issue. If you allow the originator product to start drifting, that itself will cause problems, because they're drifting away from their release criteria from a CMC Neal R. Gross & Co., Inc. 202-234-4433
Page 271 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 everyone. perspective. DR. BEHRMAN: Any other questions?
Thank you for your comments. DR. RAMACHANDRA: DR. BEHRMAN: Thank you.
Our next speaker is
Satish Tripathi from Biomedical Consulting International. DR. TRIPATHI: Good afternoon,
My name is Satish Tripathi, and I'm
the President and CEO of Biomedical Consulting International. We are a company that is
headquartered in Chicago and also have branches in London, Mumbai, New York and Tokyo. The Biomedical Consulting International, some of you are familiar with, many of you are not. Center of Excellence. We are a regulatory We are a one-stop shop
to assist companies -- as well as the governments -- in the worldwide development and registration of biotech products, including biosimilars. We also do small Neal R. Gross & Co., Inc. 202-234-4433
Page 272 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 molecules and medical devices as well. Until recently, we have been assisting drug and biotech companies. Now we
are actively working with companies who are generating biosimilar portfolio. With that, I would like to thank FDA for the opportunity to share some of our thoughts of about 58 consultants that we have worldwide who are trying to help out some of our customers. I would also like to thank our earlier colleagues who has pretty much covered a lot of things that I'll be sort of talking about. And they are Sumant from Hospira,
Rivka from Teva, Owen from Pfizer and Jim from Novo Nordisk. I'll be covering areas such as the CMC, the preclinical and areas around interface. On the biosimilarity side of CMC and the medical characterization is the key, as has been talked about for quite a bit. Neal R. Gross & Co., Inc. 202-234-4433 It
Page 273 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 is important to prioritize the support comparability of the biosimilar with the innovative product. The assay for potency must be robust and be based on clear statistical limits. The parallel line of post
demonstrates similar activity to the reference standard and the usual limits can be incorporated to test the precision of the assay performance. The analytical tools
double up for relief testing should be validated. Other analytical test validation for widening support for comparability of the biosimilar to the referenced product only need to be qualified. Post-translate and
modifications need to be thoroughly reviewed., as these can influence PK and PD and have the potential to become a safety concern that has been seen in some of the drugs. Data from accelerated stability testing provide the framework for Neal R. Gross & Co., Inc. 202-234-4433
Page 274 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 understanding, the degradative pathways and defining the storage conditions and shelf life. Comparison of the properties of the biosimilar and the referenced product is important. On the pharmacology/toxicology side, clearly a biosimilar double-up -agonist -- or the antagonist activity of the biological reference or the innovator product, and therefore it must demonstrate comparability activity in the appropriate similar pathway. is critical. If the modality of the activity is based solely on binding, then a binding potency assay may be appropriate, but should be supported with the relevant data demonstrating cell-based changes in signaling. In many cases cell-based signaling assays are the only alternative to animal models, which tend to be less precise. On the clinical safety side, Neal R. Gross & Co., Inc. 202-234-4433 The choice of the bioassay
Page 275 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 indications of specific approval should demonstrate safety in this classification population. Depending on the results from
biochemical comparability, a focus on immunogenicity, testing may be needed. Efficacy side. The biosimilars The level of
should have acceptable efficacy.
efficacy will depend on indications sought. They're the same protein backbone, efficacy should generally be not an issue; since a biosimilar will be produced in a biological system different from that of the referenced material, the post-translational modifications will be different, for most part. The post-translational modifications could impact long-term immunodensity, and hence forth the immunodensity part is critical. It is well
documented that neutralizing antibodies can double up in some patients, and the antibodies can reduce the efficacy of the reference trial. It is also possible that a biosimilar Neal R. Gross & Co., Inc. 202-234-4433
Page 276 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 could be more efficacious than the referenced drug in such circumstances. that in mind. When should FDA consider finding that animal studies are unnecessary? A couple You should keep
of thoughts. If biochemical comparability is established between the referenced product and the biosimilar and clinical data show no safety issues, and the second is: no new
excipients or impurities present in the biosimilar product that were not there in the referenced product. If there are new excipients or impurities in the biosimilar product, then these should be either within the acceptable limits of the Blue Book or the Book of Inactive Ingredients, although safety should be fully documented through published literature of previous animal studies. Okay. When should FDA consider
finding that clinical studies are unnecessary? If biochemical comparability is established Neal R. Gross & Co., Inc. 202-234-4433
Page 277 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 and there are no issues from animal studies and in vitro applications shown, there may not be a need for a clinical study. The need for
a clinical study, however, in many cases should be determined on a case-by-case basis, and there could be instances when there would be a need for that. Interchangeability should be shown in the desired patient population by a small clinical study. The number of patients can be
determined on a case-by-case basis. For example, interferon products are often not interchangeable because of manufacturing process changes, strength and type. User fees. During the next PDUFA
negotiations, a case should be made that Congress authorizes transfer of unused PDUFA money to cover for the expenses of what might become an Office of Biosimilar Drugs at the FDA. Alternatively, a small user fee could be
levied to supplement the budget allocated to the other office. The reason for a small fee
Page 278 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the panel? Neal R. Gross & Co., Inc. 202-234-4433 Dr. is that it will not cause hardship to the users that are small or the medium size. Serious consideration should be given to waive the user fee for small businesses. What type of guidance? guidance should preferably cover the scientific aspects of both biosimilarity and interchangeability. Since most companies in FDA
this field are actively working on multipotential biosimilars, as we have seen in our consulting practice, and earlier -- hopefully by June of 2011; we want to stress goals -publication of the guidance would be very helpful. The Agency should consider obtaining
all the help that it can through its stakeholders, including consultants, to speed up the process of writing and finalizing those guidances. Thank you very much. DR. BEHRMAN: Thank you for your
Page 279 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Cherney? DR. CHERNEY: Yes. I saw from
your talk that you said that, depending on the results of biochemical comparability study, may not need to do any clinical testing. we've heard from a number of speakers here today saying that, when you do a biochemical assessment, it's not sufficient to assure biosimilarity. So, could you explain further But
your thinking on this topic? DR. TRIPATHI: Yes. What I
actually said was that the clinical study would not be needed, but I also said that in many cases it actually would be needed, on a case-by-case basis. So there could be And I
examples where it may not be needed.
think we probably will have -- will probably be writing that as a part of our submission to the docket in December. DR. CHERNEY: So you've had no
specific example in mind when you were saying clinical tests would not be needed -Neal R. Gross & Co., Inc. 202-234-4433
Page 280 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 much. DR. TRIPATHI: I don't have one
right now, but I think there are some clinicians who have provided us some materials that would be provided to the Agency as a submission to the docket. DR. BEHRMAN: Other questions?
Well, thank you for your comments. DR. TRIPATHI: DR. BEHRMAN: Roger Williams from USP. DR. WILLIAMS: Yes, thank you very Thank you. Our next speaker is
It's a privilege and a pleasure to
address the Part 15 Panel and to talk about USP's contribution to the Biologics Price Competition and Innovation Act of 2009. USP has a special role in speaking to the panel that accords with our role in law. I'm also speaking here at the urging both of my Convention, as well as Board of Trustees, in order to further the Agency's understanding of the value and importance of Neal R. Gross & Co., Inc. 202-234-4433
Page 281 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 our legally recognized public standards, and to offer our expertise as a neutral scientific resource as FDA works to implement the Act. USP has a complex system of volunteer bodies. It is a volunteer body at its heart, and all the decisions of the organization are made by volunteers. USP is unique amongst pharmacopeias of the world, in that it is a private body working in the public interest as a 501(c)(3), and it receives no governmental support for its primary standard-setting activities. Yet, since 1906 USP has been
closely connected to FDA in law and has shared a common tradition of working to protect American patients and consumers. At heart, the pharmacopeia is based on a simple concept, namely that the Convention creates a committee to revise the pharmacopeia. The first meeting of that Convention occurred in 1820 and has met at ten-year intervals since then to 1943, and Neal R. Gross & Co., Inc. 202-234-4433
Page 282 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 then five-year intervals thereafter. FDA has always had a prominent and honored place at our Convention, and we were proud to receive Margaret Hamburg -- Dr. Hamburg, Commissioner of Food and Drugs -- who spoke about the value of our joint activity to set public standards. That position was
echoed recently by letters from Dr. Woodcock in the Center for Drug Evaluation and Research, which encouraged us to have up-todate relevant modern standards. I direct a staff of approximately 600, who work to support the volunteers in the convention membership, the Board of Trustees, and the Council of Experts. This is the structure of the Council of Experts in the revision cycle, which runs from 2010 to 2015. If you look at
the titles of the white boxes, you'll see 20 committees. And they are chaired by distinguished scientists from the United States and other countries who were elected at Neal R. Gross & Co., Inc. 202-234-4433
Page 283 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the Convention in April of 2010. If you look at the names of these committees, you will see a large majority of them are setting standards that can serve to support the Biosimilars and Interchangeability Act that was concluded in law in 2009. And
many of these committees are actively working now to create both monographs and general chapters that can support the work of the FDA. Taking into account the membership of these committees as well as the chairs, there are approximately 325 volunteer scientists from all over the globe who are working now to support the official standards in the United States Pharmacopeia and the National Formulary. Now, USP does have an important relationship to the work of the Federal Government and the Food and Drug Administration in law. This relationship was
built approximately a 100 years ago, working with Dr. Wiley, who was President of the USP Neal R. Gross & Co., Inc. 202-234-4433
Page 284 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Convention, working with distinguished volunteers in the pharmacopeia of the time. As you can see, we are in the early portion of the law, begun in 1906 with the Pure Food and Drug Act, and also continuing with the 1938 legislation that resulted in the current Food, Drug and Cosmetic Act and the creation of the Food and Drug Administration. We have a very fundamental role in law, in that we create standards for drugs -including biologics -- that are enforceable by the FDA, and stand in good relationship to the GMPs of the FDA that were created with the 1962 legislation. We sent standards for strength, quality and purity, and those accord well with the quality provisions of ICH as well as the strength, purity and potency provisions of the new Act. Later on, a requirement was put in the CFR, the regulations for compendial Neal R. Gross & Co., Inc. 202-234-4433
Page 285 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 identity standards. And U.S. creates a very
important identification test; the importance of that test was documented with the heparin catastrophe in the United States, where the identification test required substantial strengthening in order to prevent the adulteration that occurred with oversulfated chondroitin sulfate. USP has many other roles in law, and here you see in the middle bullet a 502(e)(3) requirement that gives USP authority for creating established names, unless FDA chooses to create a name by a rulemaking. USP has the view that this requirement will benefit both the biosimilars legislation, and applies to all drugs and biologics. USP also has a role in misbranding, which you see at 502(g). Now, in the current Public Health Service Act there is a statement at 262(j) which indicates that the provisions of the FDC Act do also apply to the Public Health Service Neal R. Gross & Co., Inc. 202-234-4433
Page 286 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Act, and in that context we believe that biologics approved under the Act, including the new K pathway, accord with the adulteration, misbranding and naming provisions of the Food, Drug and Cosmetic Act. In consequence, an official monograph in UPS is available, the biologic product must conform. And USP is receiving
now monographs for biologic products that are subject to the K pathway provisions. These are USP compendia. At the
top you see two official compendia, the United States, the United States Pharmacopeia and the National Formulary -- now moving into their 34th and 29th iterations -- and you see associated with them physical reference materials that support the procedures of the specification of our monographs. USP also has other compendia that speak to dietary supplements and food ingredients. And we also have a public notice
and comment process that speaks to both drugs Neal R. Gross & Co., Inc. 202-234-4433
Page 287 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 equivalence. -- the Pharmacopeia Forum -- and our food standards, the FCC Forum. And we provide
other resources as well to our constituencies. I'd like to speak a word about I was privileged when I was at
FDA to participate actively in a number of studies that spoke to the general issues of equivalence. Here is a key article that articles the importance of naming conventions. Many issues arising in the field of equivalence are clouded by an absence of consisting naming conventions. And I'm
pleased to see both in the Act and the FDA's Federal Register notice an emerging nomenclature for equivalence as applied to biologics, biosimilars and interchangeable biologics. We all understand that the concept of equivalence testing is based on a hypothesis that differs from the new drug efficacy and safety standard, which is Neal R. Gross & Co., Inc. 202-234-4433
Page 288 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 frequently a difference comparison. And
understanding the difference between those two hypotheses is critical to an informed understanding of the studies needed to be done. I might mention that coming to USP as I did 20 years ago -- I think I'm a little past that slide -- I found at USP that our issues in equivalence were very similar to those that I encountered at FDA. Equivalence is a general problem facing regulatory and compendial bodies. And I'm delighted to say that FDA has a guidance - on its webpage, I believe -- that speaks to concepts of individual bioequivalents, many of which were discussed earlier and today. Now in moving towards our current work on biologics, I might mention that USP has been involved in biologics throughout its 190 year history. In fact, if you looked at the first Pharmacopeia of the United States, you would see complex substances drawn from Neal R. Gross & Co., Inc. 202-234-4433
Page 289 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 nature. In the 20 century USP created its first biologics standard in 1904. And we have continued to create biologic standards since that time, both documentary and reference materials, including standards for insulin and many well known biologics that we use today. USP is advancing an approach that speak to vertical standards and horizontal standards. Those are terms of art, where the
vertical standard speaks to the monograph itself, but the horizontal standard speak across product classes and monographs in a way that we find could be especially useful to FDA and manufacturers as they work to support the new law created in 1929. A particular example of this is our potency chapters, which have occupied our attention for several years. It's a suite of
general chapters that talk about how the potency test might evolve and be applied to specific products and ingredients. Neal R. Gross & Co., Inc. 202-234-4433
Page 290 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Vertical standards are the monographs themselves, while the horizontal standards speak to procedures with or without reference materials, and with or without acceptance criteria. Those horizontal standards, as I say, can be used broadly across different product classes. I might also say that USP has an approach to assist manufacturers in meeting the new Act, which is a pending standard that would allow a monograph to emerge at USP, coincident with the FDA evaluation process and potential approval. These are examples of some general chapters that are now concluded or in progress at USP that speak to biologic products, with accompanying reference materials. And the
general theme here is that these horizontal standards on the left can support, for example, a Silverstein monograph which is evolving to official status in USP as a Neal R. Gross & Co., Inc. 202-234-4433
Page 291 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Are there any questions? Well, thank you. No, we have time vertical standard. And here's a general chart that shows how these product class -- suite of general chapters -- can speak broadly in terms of overarching guidance, common product class, quality attributes -- those have become the test of the monograph -- the analytical procedures, ancillary materials, and then the monographs themselves. In closing, I would like to thank the Panel for their time. I was privileged to work at FDA at the time of Hatch-Waxman, and I'm privileged to participate again in this exciting new Act, which I know will challenge
all of us from a science and technical perspective, but yet bring great benefit to patients and practitioners. Thank you very much. DR. BEHRMAN: Thank you for your
Page 292 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 for one question. DR. CHERNEY: Okay. I just
wondered about the utility of the monographs that you will develop for the determination of biosimilar? Could you discuss that a little
bit -- of how you see the monographs being used in biosimilar determinations? DR. WILLIAMS: I actually think
they can offer great advantage from several standpoints. I might talk about some of the
naming issues that we've talked about today. For example, the ingredient monograph might have different names to accord with some of the discussions that have come about today, as well as the Federal Register notice. But the product monograph might have
just a single name. Now, that ingredient name could appear someplace on the label as a means of tracking, but still the product name itself might be used by practitioners and patients in a way that promote good dosing regimens and Neal R. Gross & Co., Inc. 202-234-4433
Page 293 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 don't lead to medication errors. The monograph itself would consist of test procedures and acceptance criteria for critical quality attributes. And as I say,
those horizontal standards create procedures, with or without acceptance criteria, that might be used to benefit all manufacturers. DR. BEHRMAN: Thank you.
We're now ready for the open public comments. When you approach the
microphone, if you could identify yourself, your affiliation, and try to limit your comments to eight minutes. MR. BEHAN: Thank you. I'm Michael
Hello.
Behan, Chief Counsel and Legislative Director for U.S. Senator Bernie Sanders. I've come to comment on a particular aspect of the new biologics law. And to begin with, I would like to read a letter that the Senator submitted to Commissioner Hamburg today on the subject. "Dear Commissioner Hamburg: Neal R. Gross & Co., Inc. 202-234-4433 Thank
Page 294 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 you for hosting the important Food and Drug Administration Hearing on November 2nd and 3rd, 2010, on the Approval Pathway for Biosimilar and Interchangeable Biological Products. I write to call your attention and the attention of the Panel members to an important defect in the Biologics Price Competition and Innovation Act of 2009, the first instance of which I am aware of a licensing barrier that in effect legislatively mandates that an applicant for marketing approval violate the ethical standards set out in, among other ethical codes, to which the United States, its doctors and researchers adhere, Article 20 of the Declaration of Helsinki on Ethical Principals for Medical Research Involving Human Subjects. I refer to the 12-year period of data exclusivity included in the new law, which would prevent an applicant for marketing approval of a biosimilar or bioequivalent Neal R. Gross & Co., Inc. 202-234-4433
Page 295 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product from relying on existing data establishing safety and efficacy of a product. Setting aside for the moment the relevant fact that such clinical trial data will likely have been paid for in large part by the taxpayer, my concern is with the ethical implications of such a bar to reliance on the data. An applicant for licensing
approval of a bio-equivalent or biosimilar product is left with only one option, short of abandoning its product, which is to repeat clinical trials to answer questions that have already been answered. Article 20 of the Helsinki Declaration states in pertinent part: 'Physicians must immediately stop a study when the risks are found to outweigh the potential benefits, or when there is conclusive proof of positive and beneficial results.' Yet a 12
year data exclusivity period by design requires exactly that; the conduct of a clinical trial despite the fact that Neal R. Gross & Co., Inc. 202-234-4433
Page 296 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 conclusive proof of positive and beneficial results already exist. By establishing such a de facto requirement, the biologics industry has achieved something quite profound; a virtually absolute bar to competitors for a full 12 years for market entry of a new product, regardless of the patent status of the product and despite that the industry itself reports that R&D costs for biologics are roughly equivalent to those of small-molecule drugs, for which a 12-year data exclusivity period is not in place. While such a stifling of competition is bad for our economy and for health outcomes, among other things, its implicit requirement that companies, doctors and researchers must conduct unethical clinical trials in order to bring an affordable, equivalent product to the market crosses a new line. My legislation, S. 3921, the Neal R. Gross & Co., Inc. 202-234-4433
Page 297 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Ethical Pathway Act of 2010, would reform this indefensible requirement and is based on a simple premise. The U.S. Government should
honor and respect international ethical standards for medical research, including the Declaration of Helsinki, by avoiding unnecessary repetition of clinical trials on human subjects. It is pro-patient, pro-
research and pro-taxpayer, while providing for a system of cost-sharing for drug registration data that will protect the legitimate financial interests of the innovators.
S.3921 would mandate that applicants for drug marketing approval -- including generic and biosimilar producers -- be allowed to rely on existing test data when applying for marketing approvals, subject to paying an appropriate share of the cost to rely upon the results of such trials. I urge the Food and Drug Administration to pay close attention to the ethical implications of the new law that it Neal R. Gross & Co., Inc. 202-234-4433
Page 298 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Sanders." I'd just like to follow up -since I see the light is still green -- with a few further pieces of information about what the bill that Senator Sanders has introduced would do. It would direct the Secretary of HHS through the FDA Commissioner to establish a cost-sharing mechanism by which an applicant would be able to rely upon existing data. The applicant relying on such data would be required to pay a reasonable and fair fee to the entity that bore the costs of producing the relied-upon data or to the rights holder, thus sharing in the costs of the data. This arrangement could be arrived at in one of the following three ways: Neal R. Gross & Co., Inc. 202-234-4433 has been charged to implement, and to recommend to Congress that this fundamental flaw be addressed legislatively as soon as possible. Sincerely, U.S. Senator Bernard
Page 299 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The holder of the rights over the data and the applicant could voluntarily negotiate a reasonable and fair fee and authorize reliance upon the data; If either party failed to voluntarily negotiate or such negotiation failed to produce such an agreement, the holder and applicant could be referred to binding arbitration by the FDA Commissioner to determine a reasonable and fair fee for reliance upon the data. If either party refuses to participate in such binding arbitration -- or the Commissioner chooses to do so -- the Commissioner would determine a reasonable and fair fee. Determination of a reasonable and fair fee would take into considerations the following factors: the actual out-of-pocket costs of the applicable clinical investigations; the risks of the investigations as Neal R. Gross & Co., Inc. 202-234-4433
Page 300 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Panel? Neal R. Gross & Co., Inc. 202-234-4433 comments. Are there any questions from the reflected in the probabilities that similar investigations result in successful applications for marketing; 3) any federal grants, tax credits or other subsidies that reduce the net costs of the investigations, and; 4) the expected share of the global market for the product involved by the party seeking to seeking to rely upon the investigations for marketing approval -excuse me -- and; 5) the amount of time the holder and holders of the relevant applications or licenses has benefitted from exclusive rights, and the cumulative revenue earned on the products that relied upon the regulatory test data at issue. Thank you very much. DR. BEHRMAN: Thank you for those
Page 301 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the time. I'm Bill Vaughan with Consumers Union, the folks who publish Consumer Reports with about 8 million plus subscribers, and we spend a lot of time trying to help people get a good deal on, of course, safe drugs. This The letter will be placed in the docket for the meeting. very much. MR. BEHAN: DR. BEHRMAN: parties that wish to -MR. VAUGHAN: Well, thank you for Thank you. Are there other Great. Thank you
is the FDA and we know you approve safe drugs, and that's the premise on what we're doing here. But we're very, very worried about
biologics and the high price which is causing people to self-ration and in some cases do without, and it's certainly putting huge pressures on our government. And we believe that, without strong FDA action, there will be no end to Neal R. Gross & Co., Inc. 202-234-4433
Page 302 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biologics' sky-high pricing. And with
biologics so clearly the medicines of the future, these ever-rising prices are a consumer and societal disaster. Urgency. We urge the FDA to put
some more urgency into this -- wish this hearing had been the day after the enactment of the new law. We need to find a way to
protect the public health by approving safe biosimilars through, say, your existing systems so we can catch up with the Europeans in approving money- saving generics that have proven to be safe. This afternoon in this room, it's felt rather surreal. Outside the room there
is a political revolution. There is a wave of people coming who will want to save money and cut government spending. And at some point
that will spill into public health spending, perhaps Medicaid. How can the States, with
their balanced budget constitutional amendments, pay for this increasing number of Neal R. Gross & Co., Inc. 202-234-4433
Page 303 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biologics, unless we find some pathway soon to getting some price breaks? Like several others before, unless the FDA is aware of any safety problems in the EMA's approved biosimilars -- and I hope that you'll all be Frances Kelsey fact-checkers on this; maybe she would come out of retirement or something -- but if these European approved drugs are safe, find some abbreviated way or abbreviated pathway to get them into our market if they have found to be effective and not to -- you know, I think the French striking, but I don't see them dying in the streets from the biosimilars that they have in Europe. Safety, though, is an awfully important issue. And on safety, as one major
study has noted, all biologics, all biologics need to be closely monitored, especially the first approved in a class. And while a
sentinel system is several years away -- maybe three or four years away -- the FDA should Neal R. Gross & Co., Inc. 202-234-4433
Page 304 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 plan now, we hope, to make sure that special sentinel monitoring is conducted of all biologics. And that would be a lot cheaper than the idea of phase 4 RCTs. If necessary, a portion of any user fee revenue could be dedicated to these post-market safety efforts. be careful. And on user fees,
We believe, in the past, fees
coupled with rigid performance delivery standards or guidelines has created some severe problems, certainly in the chemical drug area. And, if applied to FOBs, could
create pressures that could lead to safety problems. To ensure protection against the pressure to approve that the users are prone to apply, we urge safeguards such as: all of
the staff involved in a review publicly sign off on the decision, attesting that they feel that they have had enough data and enough time to make a sound decision. And education on biosimilars. Neal R. Gross & Co., Inc. 202-234-4433
Page 305 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 This is going to be confusing for folks. think the AMSA person mentioned that. Perhaps a small amount of the user fees could be employed to educate both physicians and consumers about the quality and the pros and cons, the differences of biosimilars, to offset what's clearly a lot of badmouthing going on on the idea of generics. Evergreening. On evergreening we I
share the concerns of the AMSA representative, Sara Crager, this morning. Unless the FDA can
develop a way to prevent relatively minor changes qualifying for repeated exclusivity, the new law just isn't going to work. kind of useless. It's
And it's full employment for
lawyers, but it's not going to get us much in the way of new drugs. And we hope you could set really meaningful standards for what could qualify for, my gosh, another 12 years. And I have to say, listening today to all the different speakers, it really is humbling, the complexity, and it must be Neal R. Gross & Co., Inc. 202-234-4433
Page 306 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Any questions from the panel? Thank you. And one more public speaker. MR. SYKES: Good afternoon. No. incredibly frustrating to you all. It seems that everybody wants absolutely perfectly safe drugs, which I don't think any exists. And
most of us would like them to be a little bit cheaper. And they all vary all over the lot.
And I think it just points to the fact that we need to hold hands and trust you on a case-bycase basis to do your duty -- which you're trying to do -- and start this process. Don't
get bound up in tight inflexible things or guidelines that are hard to change and grounds for getting sued and stuff. But let's
approach each of these as an important public health item that we need to start addressing. Thank you very much. DR. BEHRMAN: Thank you for your
And I promise I won't keep you Neal R. Gross & Co., Inc. 202-234-4433
Page 307 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 long. My name is James Sykes. I am
Director of Global Programs and Policy at the AIDS Institute here in Washington, D.C. We
are a not-for-profit public policy research advocacy organization whose mission is to promote social action, action for social change through social policy research, advocacy and education. The AIDS Institute, along with a number of our community partners, advocated in support of a comprehensive health care reform. We stood in support of the Congress' effort to provide quality health care for those who cannot afford it. We stood in opposition of any legislation that would, in our opinion, block the flow of innovation of drugs for the treatment of not only HIV/AIDS, but other diseases and conditions. The AIDS Institute stood in support of the 12-year period of data Neal R. Gross & Co., Inc. 202-234-4433
Page 308 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 exclusivity relative to biologics and biosimilars. Since 1987 we have witnessed the development of approximately 32 drugs for the treatment of HIV/AIDS. These innovations have
turned what was once a terminal illness into a potentially chronic manageable condition. Technology, research and innovation have expanded the horizon of possibilities for saving lives. of biologics. We have witnessed the transformation of HIV/AIDS care and treatment from one drug, AZT, to over 32 drugs in just the past 23 years. We have seen the HIV drug The new frontier is in the area
regimen transform from upwards of 12 pills a day to just one pill a day. Now we are witnesses to the unlimited possibilities of biologics. Two
sets of biologics, Procrit and Aranesp, are already being used to effectively treat HIVrelated anemia, as well as anemia related to Neal R. Gross & Co., Inc. 202-234-4433
Page 309 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 kidney failure in chemodialysis -- in chemotherapy. Excuse me. The promises of biologics and biosimilars are there and, as promising as they are, the AIDS Institute believes the safety of these compounds should be of paramount concern. Biologics are large
complex proteins that are immunogenic, and thereby able to elicit a immune response. We also know that no two biologics are the same. This was the reason for our
support of the 12-year of data exclusivity. And we think that robust comprehensive testing requirements, and considering all the current state of the science, should be included in their deliberations here. We also think that, given the fact that no two biologics made by different manufacturers are identical, biosimilars must not be treated like generic drugs. There must
be safeguards in place to help health care providers avoid inappropriate substitution of Neal R. Gross & Co., Inc. 202-234-4433
Page 310 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 a biosimilar for the innovative products without physician knowledge and approval. And lastly, we think that biosimilars should be named different from the referenced compound and other biosimilar products. This will help ensure that both
health care professionals and patients can report any adverse events accurately and facilitate physician choice of compounds. The AIDS Institute appreciates this opportunity to comment on the implementation of the BPCI Act. We ask that
patient safety be the major consideration in your deliberations when it comes to biologics and biosimilars. We believe that the best way
forward for regulating biosimilars would be through a thoughtful and thorough, open and transparent process that considers the current state of the science and ensures patient safety. Thank you for this opportunity. DR. BEHRMAN: Thank you for your
Page 311 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 schedule. So on behalf of the FDA Panel, I'd like to thank the speakers for their presentations and all in the audience, whether in person or by webcast, for your attention to the issues discussed in today's meeting. We had a very interesting day, full of insightful comments that will be considered by FDA in our decision-making. We look forward to another productive day tomorrow. Neal R. Gross & Co., Inc. 202-234-4433 comments. Any questions from the speakers? Now if I could just ask the last two speakers to make sure your comments get into the docket. Thank you. I have to submit them
MR. SYKES: electronically. DR. BEHRMAN:
Right.
Okay.
Does the Panel wish to recall any speaker, have any additional questions? All right. We are ahead of
Page 312 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Neal R. Gross & Co., Inc. 202-234-4433 Please remember that the doors will open at 7:30 a.m. and the meeting will resume promptly at 8:30 a.m. Today's meeting is concluded, and thank you for your participation. (Whereupon, at 3:12 p.m. the meeting was adjourned.)
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A AAP 50:18 52:4,15 53:19 57:3 62:1 AB 162:2 abandoning 295:11 abbreviated 6:19 18:20 116:21 184:9 200:22 303:9,10 ability 43:15 91:2 92:12,20 93:3 129:14 137:9 138:11 139:11,12 147:9 156:14 157:12 161:19 163:5 165:10,14 167:5 199:8 205:7 206:19 249:8 267:20 able 12:9 25:4 32:1 46:7 52:10 67:14 72:9 88:5 91:19 93:15 128:17 137:10 140:3,11 157:8 164:2,15 167:22 168:18 173:17 181:4,6,22 189:15,21 195:8 205:21 232:3 240:9 242:10 243:11 264:9 265:8 298:15 309:9 above-entitled 65:16 254:17 absence 127:20 131:11 150:18 162:14 191:2 287:12 absolute 48:1 296:6 absolutely 24:5 112:3 212:19 214:1 263:3 306:2 absorption 66:22 abuse 107:7 143:9 academy 3:8 49:12 49:19 51:1,6,21 52:17 55:1,14 63:6 81:5 academy's 60:4 63:14 64:22 accelerated 273:21 accept 65:5 75:22 acceptability 63:1 acceptable 63:2 64:16 229:10 231:14 248:3 249:4 275:7 276:15 acceptance 290:5 293:3,6 accepted 182:17 183:4 accepts 36:7 access 21:11,15 22:7,8 26:2 28:1 28:18 37:19 46:12 50:14,18 56:7 57:11 103:5 116:3 124:12 127:7,12 127:12 148:17 151:7 164:8 180:1 180:22 198:9 206:9 256:1 accessed 11:3 accessible 22:18 145:14 183:9 accommodate 36:1 accompanying 290:18 accomplished 50:19 accord 284:17 286:3 292:13 accords 280:17 account 7:2 283:10 Accredo 176:16,16 176:18 182:3 accurate 205:17 accurately 205:12 310:8 achievable 188:15 achieve 179:18 184:17 achieved 296:5 achieves 151:12 achieving 51:21 259:16 acid 14:10,14 85:14 85:16 201:2,14 221:22 222:9 223:14 acquire 250:17 acquiring 245:12 act 6:14,15,17,18 7:3 8:2 41:4 45:12 50:2 51:19 51:20 54:11 55:8 58:15 89:9 98:19 99:2,5,8 116:16 116:21 117:5 118:9 126:6 129:3 208:2 216:4 280:15 281:3 283:6 284:5,8,20 285:20,22 286:1,2 286:5 287:14 290:11 291:14 294:9 297:1 310:12 acting 217:22,22 action 33:4 35:21 55:9 57:20 102:21 166:17 204:4 222:12 231:20 247:14 250:10,13 250:21 259:5 301:22 307:7,7 actions 103:4 204:2 activator 86:12 active 24:18 92:13 92:19,21 93:5 133:22 147:6 172:15,21 173:8 actively 272:4 278:9 283:7 287:6 activities 38:9 147:22 160:9 281:13 activity 94:7 152:9 231:2 235:1 273:7 274:8,11,14 282:6 acts 39:6 actual 91:10,12,15 205:18,21 299:20 acute 177:14 adapting 237:6 adaptive 127:16 add 102:8 135:8 167:10 172:2 173:13 186:5 added 64:10 93:1 148:15 adding 88:16 173:6 173:20 174:4 addition 9:12 67:21 72:17,21 118:14 183:13 additional 10:12 11:8 17:15 25:22 37:16 52:11 59:9 88:12 95:5 102:8 111:18 117:14 118:9,18 119:17 120:15 121:1 140:21 157:7 174:2 181:19 192:20 207:4 250:10,15,17 253:12 311:10 additionally 56:2 131:15 257:15 additive 93:13 additives 93:9 address 35:18 56:14 62:6 67:8 67:15 68:2 71:8 71:13,16 72:10,13 95:2 107:6 117:19 118:7 120:16 136:7 143:14 149:13 167:1 176:22 200:10 231:9 237:7,21 266:11 280:13 addressable 235:8 235:22 236:1 addressed 104:8 154:15 177:4 238:1 298:3 addresses 16:14 145:9 addressing 12:5 66:18 67:2 72:11 106:18 146:20 306:14 adequate 31:8,9 48:5 202:14 213:13 229:11 234:6,7 adequately 56:14 104:8 adhere 294:16 adherence 42:5 adhering 173:11 adjourned 196:14 312:7 adjudication 158:21 159:10 162:21 adjust 68:11 administer 156:11 157:13 244:15 administered 96:14 96:21 97:11,16 232:21 administering 122:15 administration 1:4 1:13 12:21 21:18 49:22 55:7 108:4 266:17 283:20 284:9 294:2 297:21 administration's 139:12 administrative 10:17,21 147:21 195:18 admittedly 235:10 adopt 139:1 151:12 adopted 40:4 102:20 adoption 152:12 164:6 168:20
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adulteration 285:7 286:4 adults 51:9,14 advance 119:15 advances 121:12 121:14 201:21 202:6 advancing 132:18 179:9 289:8 advantage 42:15 169:11 292:9 advantageous 154:7 advantages 131:13 222:22 adverse 15:10 17:14 28:5,8 29:7 29:10 57:21 136:12,18 138:20 147:13 159:13,16 160:1 161:6 168:7 169:14,18 170:6 170:11,21 171:8 173:2 174:14 189:8 201:12 203:13,14,19 204:10,19 206:15 219:16 310:8 advertised 205:10 advice 141:12 165:15 advisory 126:19 advocacy 13:8 36:16 37:3 307:6 307:9 advocate 36:19 139:1 193:15 advocated 37:16 51:2 307:11 advocating 46:7 59:12 189:19 225:4 Affairs 255:7 affect 93:14 195:19 199:22 affiliation 293:12 affinity 201:11 affirm 177:5 afford 115:19 307:15 affordability 119:5 122:20 affordable 3:17 6:14 124:1,5 126:6 145:14 151:7 183:9 245:20 246:19 296:20 afforded 129:2 177:18 afraid 183:6 210:9 afternoon 6:6 144:7 197:13,17 197:20 215:22 228:7 245:2 271:8 302:14 306:21 age 26:4 38:2 39:5 agencies 41:19 158:1 agency 7:4 9:11 45:9 52:22 126:9 126:21 127:18,21 128:15 129:18 133:9,21 141:6 158:8,12 216:21 217:1 225:18 237:5 267:3 278:14 280:4 agency's 6:12 7:6 7:20 28:7 46:15 126:20 127:5 158:7 216:20 280:21 agenda 9:22,22 10:4 11:7 12:7 agent 200:14 203:7 203:17 204:13 213:17 214:8 agents 140:10 198:15,16,19 199:21 203:1,18 206:12,16 age-specific 51:16 aggregate 89:21 aggregates 90:2,6 aggregation 81:8 88:1,20 ago 20:14 126:15 134:10 198:15 283:21 288:7 agonist 274:8 agree 154:13 188:2 agreed 62:7,10 102:22 agreement 105:20 299:7 agreements 106:6 108:12 ahead 140:16 311:11 AIDS 4:21 142:15 307:4,10,21 309:5 310:10 aim 245:18 259:19 268:6 270:7 aims 270:15 al 139:8 alfas 138:18 alglucosidase 138:18 aligning 151:8 alignment 149:15 alike 37:12 Alliance 3:17 124:1 124:5,20 125:2,9 126:21 127:15 Alliance's 125:19 Allied 3:16 114:18 115:4 allocated 277:21 allot 197:7 allotted 11:10 12:8 allow 38:10 40:11 43:4 44:13 48:9 68:11 114:1 119:13 121:11 132:21 169:9 174:16 185:9 201:19 208:8 233:12 242:19 260:17 270:19 290:12 allowed 10:10 11:8 44:11,16 113:16 184:1 248:9 251:4 252:21 259:3,10 261:20 267:9 297:15 allowing 36:14 45:2 133:5 186:9 207:19 216:2 allows 10:13 94:20 118:9 135:20,22 179:17 183:22 270:11 alterations 159:9 201:3 altered 20:22 119:8 altering 118:19 alternating 70:11 70:18 71:3,5,13 71:17 73:8 100:22 101:12 208:5 219:5 alternative 69:6 101:3 106:4 110:4 111:4 112:22 151:4 154:2 194:20 274:20 Alternatively 277:20 alternatives 22:9 199:1 222:7 ambitious 258:19 amenable 49:2 amended 220:10 amendments 55:7 302:22 amends 6:17 America 3:25 244:22 American 3:8,15 40:9 49:11,18 51:1 114:17 115:3 281:16 Americans 20:4 134:14 198:13 amide 87:10 amino 14:10,14 201:2,14 221:21 222:9 223:14 amount 87:11 135:9 300:12 305:3 AMSA 305:2,10 amyloid 85:21 analog 222:10 analogous 88:4 analogs 89:3 analysis 80:8,10 82:14,19 83:13,18 84:9 85:17 87:3 137:16 170:8 257:11 analytical 89:9 90:11 98:4 128:16 221:17 240:21 256:18 257:2 273:10,13 291:7 analyze 84:21 85:5 85:7,10 analyzed 84:11 analyzing 82:4 86:3 ancillary 182:9 291:8 and/or 68:12 184:11 195:11,21 258:13 anemia 308:22,22 animal 17:1 48:8 112:7 141:11 257:13 258:1 274:20 276:5,19 277:1 animals 105:19 106:1,5 announcement 22:4 announcements 5:16 annually 144:21 answer 49:5 60:12 111:1 128:17 187:3 226:8 239:22 243:2
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295:12 answered 76:9 171:18 295:13 answers 33:12 antagonist 274:8 antibodies 14:3 213:2,5 230:16,17 230:17 275:19,20 antibody 15:15 87:17 antibody-small 237:9 anticipated 109:19 anticipates 107:1 anti-cytokine 230:16 anti-HACA 213:5 anxious 33:7 anymore 268:18 aplasia 203:5,8 apologize 33:16 apparent 223:6 appear 10:2 292:19 applaud 38:19 39:15 applauds 53:19 applicable 79:10 299:21 applicant 218:9 247:11 250:8 294:12,21 295:8 298:14,16 299:2,8 applicants 54:16 55:2 297:13 application 55:20 64:19 88:22 127:20 128:2 129:20 130:3,5 131:12 216:12 217:7 224:9 238:14 263:21 applications 109:1 125:18 217:8,21 277:2 300:3,13 applied 51:4 52:7 54:11 88:2 97:3 119:7 287:16 289:21 304:12 applies 130:2 165:1 223:12,14,17 232:7 240:10 285:16 apply 10:7 56:3 62:20 96:17 116:17 172:18 224:13 285:22 304:17 applying 297:16 appreciate 12:19 21:20 31:13 95:16 145:7 198:3 256:3 262:6 appreciated 51:22 appreciates 310:10 approach 63:21 64:8 117:21 120:20 163:16 166:7,8,19 223:12 238:3 246:9,11 256:20 259:15 264:17 270:18 289:8 290:10 293:10 306:13 approaches 119:21 148:12 256:18 appropriate 24:13 25:8,16 28:17 54:22 58:10 64:8 67:13 81:19 90:10 90:14 103:16 128:8 148:12 151:2 171:11 202:15 204:16 213:18 221:17 231:15,18 237:7 239:8 258:9 274:11,16 297:17 appropriately 15:8 28:8 34:2 51:4 219:7 approval 1:6 5:9 6:19 15:6 16:13 16:17 24:13 50:16 59:10 60:1 61:16 109:1 115:22 117:22 124:15 144:16 145:10,20 146:1 199:6 200:22 202:13 203:20 204:5,6 206:11 218:11 220:1 229:16 238:20 239:13 243:16 248:22 251:6 256:7 260:4 260:19 262:22 264:4 275:1 290:14 294:3,13 294:22 295:9 297:14 300:10 310:2 approvals 146:21 297:17 approve 45:10 48:5 269:9 301:14 304:16 approved 15:4,12 26:9,13,13 56:4 61:8,14 138:5 162:6,17 170:2 171:2,3 181:13 203:22 206:2,3 217:7 219:20 224:15 226:1 230:6,21 255:14 255:19 262:18 264:2 269:7,20 286:2 303:5,8,20 approving 302:9 302:12 approximate 122:11 approximately 11:4 14:5 20:4 84:10 282:12 283:12,21 308:4 April 283:1 Aranesp 308:20 arbitration 299:9 299:13 area 32:10 45:6 81:6 87:2,22 88:18 90:22 92:10 95:1 103:4 106:18 134:5 137:22 142:10 143:12 175:2 202:6 304:12 308:10 areas 22:3 40:18,21 45:6 81:9 83:11 146:17 214:20 272:17,18 arena 140:12 argue 93:12 252:3 argued 118:20 arguing 139:18 argument 114:12 arguments 112:9 112:15 arises 91:7 arising 287:11 arrangement 298:21 array 22:9 48:21 arrive 22:12 36:2 98:18 arrived 65:12 298:21 art 42:22 289:10 arthritis 3:6 19:18 19:21 20:1,5,6,9 21:6,11,20 22:16 22:20 24:2,14,21 26:6,17,18 27:3 29:11,18 31:16,22 35:17 37:2 arthropathy 37:8 article 287:9 294:16 295:14 articles 107:2 287:10 articulated 34:2 aside 143:18 211:5 295:3 asked 76:5 107:20 141:14 177:1 209:9 248:20 asking 111:10 173:12 175:3 asks 243:9 ASP 187:2 aspect 18:19 25:7 175:16 176:6 293:18 aspects 135:21 145:6 278:7 assay 273:4,10 274:16 assays 94:11 257:2 257:12,13 274:19 Assembly 110:19 assertion 240:16 assess 25:13 69:13 112:4,10 257:3 assessing 228:15 assessment 66:18 68:8,18 69:19 71:4 257:8 279:8 assessments 54:18 112:6 assign 149:18 150:21 assigning 199:11 assist 271:19 290:10 assisting 272:3 associate 5:11 8:17 9:1,4 205:12 associated 22:22 23:1 34:6 35:13 106:10 147:3 192:18,19 202:20 219:15 286:16 Association 3:16 114:17 115:3 assume 63:3 102:2 170:15 177:2 assumed 181:14 assuming 10:13 185:4 assumption 67:4,4 138:2 155:12 assurance 22:11 25:7 78:13 212:8 assure 134:20
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paper 84:18 139:10 papers 80:11 paradigm 60:18 242:15 paragraph 104:4 paragraphs 103:21 parallel 68:20,21 69:9 71:22 73:1 73:11 96:20 267:7 267:9 273:6 parallels 123:11 parameters 267:17 paramount 122:17 P 187:17 202:13 P 179:4 206:14 216:20 package 243:17 309:7 249:3,6 263:9 paraphrasing 42:3 packaged 176:2 parent 176:19 packages 222:5 182:13 202:20 packaging 128:5 206:16 213:14,15 205:4 parenterals 155:18 page 102:16,18 parents 13:13 108:21 part 1:6 5:4,8 paid 295:5 10:14 33:9 109:7 pain 20:12,17 114:11 133:10 37:10 44:15 134:3,12,18 150:3 panel 1:12,17 8:6 150:6,20 153:10 10:9 11:8 18:15 153:15 154:18 28:22 33:14 44:6 158:20 161:6 45:4 49:8 53:12 164:10 189:22 58:21 73:15 79:20 192:13 256:4 89:19 101:17 263:11,20 275:14 102:4 108:18 275:18 279:18 114:14 123:21 280:13 295:5,15 132:13 133:15 participant 10:8,9 139:8 141:20 participate 39:1 152:19 186:19 104:5 287:6 207:16 215:16 291:13 299:13 216:1 224:21 participating 228:3 238:9 176:18 241:19 248:15 participation 12:12 254:11 278:22 312:5 280:13,17 291:11 particle 90:12,17 294:7 300:22 90:20 306:18 311:9,13 particular 16:9 panelists 114:20 18:19 34:14 46:7 140:21 57:14 86:20 87:8 overcome 142:20 overly 175:5 overnight 258:20 overriding 142:10 oversight 26:15,15 28:17 142:1 oversulfated 285:7 Owen 2:17 3:25 228:5,8 272:15 ownership 129:22 O-F 3:1 O-glycans 85:5,10 87:15 88:8,19,22 60:21,22 61:2 205:12,20 206:6 90:22 91:3 150:1 67:2 115:21 206:17 210:21 163:8,9,10 164:13 116:10,15,22 211:10,10,13,13 164:22 195:18 124:14 134:1,21 212:17,21 214:12 200:15 211:2 144:16 145:10 214:16 215:11 212:20 214:16 168:3 179:17 216:20 218:4 219:15 227:9 184:10 199:6 219:2 227:8,10 259:5 266:11,21 201:1 206:11 232:12 233:14,18 267:10 269:22 224:7 237:15 243:6,8 259:19 270:18 289:17 256:1,7 262:9 268:10,17 277:9 293:18 265:17 266:1 310:13,19 particularly 32:11 274:12 286:3,10 patients 13:12,14 53:2 103:22 294:3 297:1 303:1 13:20 15:11,15,17 129:21 153:14 303:10 15:20 16:7 17:13 218:14 pathways 7:21 49:2 17:17 19:3,15 parties 11:22 301:6 104:19 125:11 20:16 21:6,13 partly 132:5 184:14,21 245:22 22:7,15 23:2,6,12 partner 89:13 274:1 23:15 24:15 25:4 partnering 256:5 patient 6:13 13:4 26:12 28:4 29:13 262:8 15:9 17:10,19 29:19 30:1,16 partners 307:11 20:2 22:1,5 23:19 31:6,7,7,20,20 partnership 26:19 24:5 26:16 27:1,4 33:6 34:3,22 51:22 82:13 27:7,18,20,22 37:12,17 41:19 partnerships 28:13,18 29:6,9 43:11 45:15,21 245:13 31:13 33:7,11 47:6 107:16 parts 216:6 34:10,14 35:9,15 115:18 117:2,11 party 299:5,12 36:16 37:3 40:13 122:4,16 127:9 300:9 43:6,13 46:11 128:19 133:12 Pasco 266:15 57:11,18 63:1,18 135:6 138:14 pass 192:15 116:5 121:17 145:14 147:2 passage 126:6 122:17 123:3,13 148:8 158:1 172:6 passed 126:4 124:22 136:7 178:14 180:1,15 pasted 164:21 137:22 138:21 180:19 181:1 patent 104:20 140:8,18 145:20 182:6 183:5,7,15 107:21 108:9,12 147:14,16 148:17 183:20 184:4,19 119:16 129:12 149:17 151:9 185:12 186:13 296:8 152:4 154:7 189:13,13 192:2 patents 108:5 155:19 157:6,19 192:15 194:12,14 path 42:10 160:20 166:22 198:10,17 202:4 pathophysiology 177:18 179:13 202:21 203:9,15 231:19 183:2 187:16 204:14 205:2,3,8 paths 264:14 188:11 189:9 206:9 207:13 pathway 1:6 5:9 192:20 193:3,4,16 209:15 210:4,6,10 6:19 16:14,17 193:22 195:1,21 210:14,15 211:1 17:4,6 18:20 196:3 199:14 213:11 214:20 28:16 33:3 50:16 202:8,11,12 215:1 217:17 51:1 56:6,13 203:17 204:17 222:15 227:15
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245:19 246:19 247:16 258:22 259:22 265:4,6,21 267:11,13 268:19 275:20 277:10 281:16 291:17 292:21 310:7 patient's 56:21 135:16 156:14 183:3 patient-based 24:10 pay 57:16 297:21 298:17 302:22 payer 145:15 149:16 151:8 154:5 187:14 192:16 195:22 payers 39:18 45:18 124:9 135:7 183:14 186:14 192:2 paying 127:10 297:17 payment 57:17 162:21 163:1 pays 196:1 PBM 211:6,7 PBMs 163:3 PD 273:18 PDUFA 277:15,17 pediatric 51:19 52:3,8,19 53:1,5 53:15,18,20 54:11 54:14,18 55:5,16 56:5 58:8 59:21 61:9 186:8 pediatrician 49:15 50:2 Pediatricians 50:6 Pediatrics 3:8 49:12,19 51:2 pegylate 130:17 pegylation 223:15 pending 290:11 people 9:10 21:10 24:18 36:17,21 38:21 43:19 79:8 83:6 87:4 91:1 105:4 107:22 108:11 109:16 111:11 112:20 113:3 127:7 134:15 135:1 143:3,3 193:5,9 197:6 209:12 301:12,18 302:17 peptide 220:19 236:7 peptides 236:11 PeRC 53:20 54:2,7 55:15 percent 15:17 16:1 16:4,9,10 37:22 76:17,18 79:9 92:6 180:6 204:4 204:5 232:14 percentage 77:16 78:2 85:22 perched 95:9 PeRC's 55:17 perfect 173:5 perfectly 306:2 perform 26:1 77:22 147:20 performance 223:3 273:10 304:9 performed 100:6,7 101:8 performer 38:14 44:9 period 8:1 11:17 25:14,16 55:13 71:12,15 93:17 105:7 107:9 109:20,20 110:2,3 113:3,11 114:4 118:10,18 119:6 128:22 129:7,21 130:10 131:7,10 131:14,16 181:21 186:9 216:13 224:3,7 252:10 294:19 295:20 296:12 307:22 periods 25:10 94:20 119:17 121:1 permanently 20:12 permissive 99:19 permit 223:19 225:6,8 permits 11:18 218:22 243:1 permitted 10:19 110:1,3 218:10 258:9 perpetually 119:10 persistent 130:6 person 105:4 209:19,20 215:8 305:2 311:16 personnel 82:22 persons 13:6 perspective 46:6,14 46:15 66:15 70:9 133:2 146:22 158:11 208:10 232:18 265:18 269:19 271:1 291:16 persuade 117:15 persuaded 108:11 persuasive 111:16 pertinent 295:15 Pfizer 3:25 228:6,9 232:5 234:12 272:15 Pfizer's 231:11 pharmaceutical 36:9 51:18 108:8 116:8 124:7 179:20 182:5 184:18 209:14 245:9 pharmaceuticals 124:12 180:7 pharmacies 145:2 145:2,4 147:20 148:16 150:13 157:22 158:2 159:22 160:11 161:2,8 pharmacist 27:18 27:22 32:21 35:10 148:10 176:13 192:13 243:9,10 pharmacists 138:8 144:22 182:8 210:20 pharmacodynamic 201:13 230:3 231:2 pharmacodynam... 230:13 pharmacokinetic 67:5 72:18 100:8 100:12 pharmacokinetics 66:22 pharmacological 235:1 pharmacology/to... 274:6 pharmacopeia 281:17,20 283:15 284:2 286:13 287:1 288:21 Pharmacopeial 4:10 pharmacopeias 281:9 pharmacovigilan... 7:13 24:21 25:1 25:17 46:6 139:11 146:19,20 147:11 148:2,13,22 149:7 155:2 159:15 160:9 165:9,22 166:6 179:7 189:3 199:14 202:12 219:11 233:19 234:12 244:6 256:12 260:9,10 262:3 266:7,10 pharmacovigilant 260:18 pharmacy 57:6 62:3 134:13 139:20 144:13,19 145:1 146:22 147:10 148:3 149:16 150:9 153:14,19 156:9 158:11,21 162:20 163:20 164:10 166:12,13 176:5 177:12,15 179:10 182:16 188:14 193:2 210:20 211:3 232:22 244:16 254:6 pharmacy's 161:19 pharmacy-driven 152:9 Pharm.D 1:21 2:13 phase 88:5 250:16 264:1 304:4 phenomena 150:12 phenomenon 229:18 phobia 193:9 phobic 196:3 physical 157:12 263:5 286:16 physically 157:8 physician 43:6 56:19 57:8 138:1 138:10 150:8 154:2 168:17 178:16 193:2 202:9 204:11 205:20 206:5 211:15 212:4 214:6,11 215:10 243:4 310:2,9 physicians 28:4 40:12 41:19 43:10 104:4,9 122:14 155:22 164:8,19 183:19 202:21 207:12 259:22 261:5 295:16 305:5 physician's 56:20
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physicochemical 257:11 258:12 physicochemically 242:19 physiological 218:17 physiology 51:8 Ph.D 1:19,22 2:2,4 2:5,6,7,17,20,21 3:5,10,12,12,13 3:25 4:5,7 pick 91:19 177:10 picked 170:21 Picking 187:15 piece 142:6 pieces 298:9 pigs 111:8 pill 308:17 pills 308:16 pink 193:22 pipeline 135:4 154:17 245:17 pivotal 238:22 239:17,19 247:6 247:14 248:11 258:8 267:5 PK 273:18 PK/PD 258:13 263:8,10 264:8 place 25:17 29:17 58:11 85:16 87:9 96:8 99:15 140:1 149:5,7 153:12 155:6 156:5 160:11 161:1 162:5 282:3 296:13 309:21 placed 148:15 301:1 plague 172:9 174:9 plagues 172:9 174:7 plain 224:5 plan 102:21 150:16 155:3 265:13 304:1 planning 6:4 53:2,9 plans 55:16 189:4 plant 184:3 241:7 270:3 plasma 17:5 19:1 plasminogen 86:12 platform 82:5 platforms 29:12 Platt 139:8 play 50:3 115:9 145:6 159:14 please 5:16 12:2 18:5 95:10 143:22 169:7 312:1 pleased 55:14 287:14 pleasure 79:20 280:12 plus 131:10,10 174:1,4 187:2 191:18 301:11 pocket 209:17,22 podium 80:14 point 34:4 47:17 63:5 78:7 124:17 152:10 178:7 187:16 191:19 208:16,20 210:4 242:12 244:7 249:19 260:21 302:18 pointing 47:2 points 102:8 192:4 228:11 306:6 Policies 5:12 policy 8:11,17 9:19 10:15 19:22 115:7 237:16 307:3,5,8 political 143:14 302:16 polypeptide 220:19 221:2 polypeptides 220:13,22 221:14 population 23:21 54:19 56:11 58:6 215:8 218:16 229:2 231:12,13 232:13 244:3 275:3 277:9 populations 140:9 portfolio 272:5 portion 284:4 304:5 pose 227:22 position 27:7 30:6 35:4 45:9 63:6,14 65:1 110:13,14 112:2,13 113:13 132:17 152:22 245:6 282:7 positive 37:11 104:12 203:13 295:19 296:1 possibilities 71:20 217:5 308:9,19 possibility 60:6 72:3 171:3 possible 10:5 26:8 27:17 48:15 51:15 55:4 60:15 63:15 97:19 101:7 154:3 169:21 173:15 181:12 184:16 208:11,17 235:8 240:21 241:5 243:15 275:22 298:4 possibly 96:8 157:10 159:8 post 30:11 58:1 131:21 132:2 204:9,19 207:4 273:6 postings 46:21 Post-approval 149:6 post-introduction 30:12 post-market 18:10 260:20 269:2 304:7 post-marketing 17:16 25:20 26:7 26:11 41:16 58:3 202:16 248:5 Post-translate 273:16 post-translation 84:10 post-translational 81:6 83:11 86:4 257:5 275:13,15 potency 118:13 223:11,18 225:12 225:16 273:4 274:16 284:19 289:18,21 potential 16:16 17:14 23:10 25:2 33:10 56:7 76:2 86:13 104:11 119:9 146:6 166:17 200:8 201:9,19 206:22 207:6 229:10 233:6 273:19 278:10 290:14 295:17 potentially 17:7 28:18 35:10 45:20 60:2 93:14 120:5 192:22 225:6 241:14 269:11 308:7 practical 7:18 232:17 233:2 236:9 239:2,11 practice 49:16 115:10 132:20 152:10 164:13 176:15 179:9 189:6 194:16 195:1 198:7 230:1 260:2 262:2 268:21 278:11 practiced 227:13 practices 44:3 103:18 148:3 practicing 50:2 197:22 201:16 practitioners 147:7 205:2 291:17 292:21 PREA 53:13 54:1 54:15 55:10,18,20 56:3,5 64:18,19 preapproval 31:9 149:3 170:8 202:15 precedent 150:4 precise 274:21 precisely 141:12 166:3 precision 273:9 preclinical 249:9 262:19 272:18 predict 222:20 233:9 predictable 56:22 predicted 116:9 prediction 233:13 predictive 67:6 predominant 185:22 preferably 96:16 199:3 278:6 preference 131:6 prefix 64:4,10 158:10 159:7 165:13 178:5 prefixes 158:16 233:21 premise 75:22 255:22 297:3 301:15 preparation 21:4 91:13 prepare 79:20 156:15 157:10 158:3 prepared 9:9 143:20 161:3 166:4 preparing 144:6 prescribability 95:20 96:12 97:2 prescribe 40:12 151:3 154:2
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150:8,14 151:21 264:10,12,15,20 152:2,4,7,12 264:21 265:5,7 154:1,8 155:6,7 267:11,12,14,21 155:11 156:19,19 268:8,11 269:11 157:19 158:3 269:12,14,19,22 162:7,13 163:11 270:2,20 273:3,15 165:10 167:19 274:4,9 276:7,11 168:1,2,9,9,11 276:12,14 286:8 171:11 173:17,18 289:13 290:8 174:17 175:13,20 291:3,5 292:16,20 177:16,21 178:3,6 295:1,2,10,11 178:8,17,21 179:3 296:7,8,20 300:8 185:1 188:7,8,11 production 233:17 188:16 189:12,16 236:9 190:7,10 191:10 productive 12:13 191:13,16 192:6 13:22 311:22 193:11,17 195:2 products 1:7 5:10 195:13 204:8,18 6:20 7:14,22 8:4 205:4,8,9,10,13 14:14 15:18 16:5 205:18,19,22 16:14,20 17:12 206:2 207:9 208:6 19:11,12,14 22:10 208:7 209:21 22:12 28:19 31:21 210:4 212:20 32:3,14 41:7 50:7 215:13 219:1,15 50:12,15 52:20 219:21,22 220:3,6 53:14 54:13 55:3 220:10,11,17,18 56:3,13,18 58:10 220:20 221:10 60:5,20 62:16,20 224:2,8,10 226:9 64:6,15 67:17 226:15,22 227:7 69:1 78:10 89:11 227:17 228:17,21 103:10 109:5 229:14,16 230:10 112:5 115:22 231:3 232:20 116:13 117:16 233:2 234:14 127:3,8,22 128:5 235:6,14,16 236:5 128:11 129:4,14 237:17 239:5,9,14 130:16 132:1,3,5 239:21,22 240:4 133:12 134:19 240:18 241:13,13 135:12 136:5,6,9 244:13 245:14 136:11,21 138:3,5 246:13 247:1,4,9 138:15 139:13,13 247:17,19 249:5 144:17 148:14 249:14,20,22 149:1,4,15,22 251:8,12,14,17,20 150:5,22 151:17 252:2,8,9 254:9 154:10,16 156:11 257:3,6 258:4,7 156:12,20 157:2 258:10,11 259:10 160:16,18 161:5 261:8 262:16,17 162:11 163:5,15 262:20 263:12,15 163:21 164:3 165:18 167:5 170:11,14 171:14 172:7,16 174:8 175:10,11,17,17 176:2,6 177:6,13 180:11 181:5,7 184:1,10,16 185:3 185:7,8 190:2 191:4 193:15 199:4,7,9,18 200:11 201:20 202:4 203:2,21 205:3 207:20 216:12,14,15 217:6,13,16 218:3 219:3,6,12 220:7 221:11,20 222:3,4 222:7,19 223:6,8 223:21 224:14 227:16 230:2 232:8 233:22 234:4,7 236:14,16 237:1,4,8 238:13 238:19 241:17 242:1,3,8 246:2 247:13 248:19 249:10 251:11,13 252:5,12 254:7 255:15 256:10 257:1 258:6 259:8 259:21 260:11 261:17 262:1,5 266:8 268:15 269:6 271:21 277:12 286:9 289:22 290:17 294:5 300:16 310:1,6 product's 223:11 profession 166:12 166:14 professional 147:5 176:14 227:11 professionals 185:13 209:12 310:7 professor 66:7 95:16 profile 23:7 24:1 33:19,20,22 34:13 34:19 163:10 173:2 201:11 205:15 222:13 260:7 profiles 23:13 profound 296:5 program 8:3 9:18 31:1,5 147:18 161:12 222:21 247:5 248:10 programs 134:19 148:2 161:10 231:22 266:10 307:3 progress 92:8 290:16 progressing 257:11 progression 44:12 progressive 117:8 121:15 prohibit 18:2,11 199:10 project 263:15 projects 24:6 prolonged 119:6 prominent 234:18 282:2 promise 21:14 94:15 306:22 promises 44:22 309:3 promising 309:4 promote 103:11 122:10 123:5 198:8 219:10 292:22 307:7 promptly 5:21 312:3 prone 304:16 pronounce 131:20 proof 104:12 295:18 296:1 propensity 201:12 proper 192:16 210:7 259:3 261:21 properly 38:5 87:1 163:13 236:20 properties 81:11 201:13 223:5 274:3 Property 102:22 proponent 144:15 proponents 40:19 proposal 105:19 123:16 233:19 propose 66:17 71:7 72:1 270:6 proposed 152:1 184:20 proposes 106:17 pros 305:6 proselytize 82:18 prospective 166:16 267:22 protect 147:2 217:17 281:15 297:11 302:9 protection 6:14 129:17 304:15 protein 7:22 80:1 80:10 81:8,20 82:19 85:21 86:13 86:20 87:1,9,13 87:19 94:19,21 132:1 188:8 199:15,21 201:4,5 201:8 220:18 236:7 256:15 275:9 proteins 8:9 81:12 84:22 85:16 88:6 90:7 93:2 94:5,8 220:12 221:13,21 236:18 257:1 261:16 309:8 protocol 42:16 44:22 protocols 43:16 182:17 183:4 proud 52:2 140:19
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282:4 prove 104:21 109:9 proven 40:6 82:2 178:21 185:4 199:2 261:14 302:13 provide 5:15 6:12 17:12 18:9 23:18 24:1,8,12 31:14 49:21 63:14 69:4 141:13 145:8 174:14 180:22 185:11,13 201:22 202:21 204:7 205:17 220:12 222:17 224:11,16 256:16 273:22 287:2 307:14 provided 53:21 95:21 96:2 114:8 198:16 237:12 280:3,4 provider 24:6 27:19,22 34:11 35:10,15 96:10 99:16,22 144:19 151:9 155:21 providers 23:12 30:2 34:22 135:6 148:16 180:14 184:4 309:22 provides 28:17 72:11,13 99:19 182:4 223:7 232:6 providing 17:19 90:4 144:15 156:6 179:19 180:1,10 183:15 184:17 245:19 297:9 provision 225:2 provisions 102:13 117:4 118:8 119:1 141:6 216:15 218:21 223:22 224:13 284:18,19 285:21 286:5,10 pro-patient 297:8 pro-taxpayer 297:9 psoriasis 37:3 213:10 psoriatic 213:10 public 1:6 4:13 5:21 6:17 7:1 10:14,16,21 11:4 12:6 19:22 55:6 102:21 106:15 127:6 132:21 133:1,6 142:10 143:9,13 184:3 188:13 197:5 207:10 222:17 247:16 256:4 281:1,10 282:7 285:19,22 286:21 293:10 302:9,19 306:13,20 307:5 publication 68:15 278:13 publicizing 83:2 publicly 141:8 241:2 304:18 public/private 82:12 publish 82:1 301:10 published 73:20 87:16 139:9 141:9 203:21 276:18 pull 239:9 purchase 6:9 196:10 purchasers 124:8 pure 203:5 284:5 purified 93:5 221:17 purity 118:13 200:2 223:11,18 225:12,16 284:17 284:19 purpose 6:10 113:17 127:1 purposes 207:21 purse 209:22 pursue 269:4 pursued 101:6,12 193:13 195:5,7,10 put 47:6 88:11 195:21 209:9 125:3 133:9 140:1 211:18 225:21 156:12 213:19 229:19 243:19,20 265:20 284:21 248:20 250:6 302:5 251:5,16,16 putting 39:12 267:20 268:1 113:12 126:9 269:4,6 292:1 128:7 187:4 questions 10:12 188:12 301:19 11:9,11 12:5 P-R-O-C-E-E-D-... 17:22 18:15 22:3 5:1 28:22 33:13 45:4 p.m 5:22 6:7 46:9 47:22 49:7 196:15 197:2 58:20 73:15 75:19 254:18,19 312:6 76:6 89:18 94:2 101:17 108:17 Q 114:14 123:20 qualification 125:4,6 128:17 223:13,19 129:22 132:12 qualifications 133:14 139:7 195:12 140:14,21 148:9 qualified 273:16 152:19 154:19 qualify 118:20 167:8 176:8,22 305:19 186:19 195:3 qualifying 305:13 207:16 215:15 quality 13:6 22:17 224:21 225:20 34:16,18 36:17 228:2 237:22 50:20 54:4 70:6 238:5,9 241:18 98:6 103:9 179:13 243:21 248:15 179:19 184:18 253:16 254:10 198:17 221:11 262:13 266:6 246:20 256:2 271:2 278:22 284:17,18 291:6 280:6 291:21 293:4 305:5 295:12 300:21 307:14 306:18 311:2,10 question 10:10 quick 29:3 30:5 22:5 29:3 30:18 108:20 155:16 31:13,15,18 32:5 quicker 62:17 33:12 35:19 42:16 quickly 37:10 45:6 47:14 49:4,6 52:21 60:14 89:4 60:13 64:17 75:20 185:17 81:17 82:6,7 92:6 quite 135:19 137:3 93:7 94:4 95:2,6 272:22 296:5 97:8 108:20 122:5 quotes 235:19 131:8 141:1 Q5 70:6 155:16 159:13 R 165:8 171:18 R 70:18 RA 20:1,11,15 21:6 Rachel 1:14,18 3:3 5:11 79:19 radically 20:22 raise 260:21 raised 195:6 raises 246:16 Ramachandra 2:20 4:5 255:1,2,5 263:3,22 265:2 266:12 268:2 269:15,18 271:4 randomized 265:21 range 91:12,15 92:2 233:22 247:3 250:2 270:9 ranges 90:6,18 ranging 38:2 rapid 89:1 121:11 rapidly 84:9 135:1 rare 78:10,15 169:16 170:5,11 171:9 173:2 rate 23:20 78:20 rating 162:2 ratio 88:11 rationale 248:6 253:20 rats 111:8 RCTs 304:4 reach 40:16 54:7 reaches 38:18 reaching 78:13 react 19:4,5,15 reaction 15:21 16:2 16:5 201:12 reactions 16:7 17:15 203:14,19 215:3 read 293:19 readily 191:17 206:5 ready 26:19 40:20 254:13,14 293:9 real 25:11,12,22 60:2 61:14 192:1
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syndrome 213:6 synthesis 220:22 236:10 synthesized 220:13 221:1,3 222:1 236:6,12 syringe 157:11,13 178:15 195:14,16 system 13:17,19 24:20 28:10 43:14 45:17 63:14 106:22 118:16 129:12 134:18 135:18,20 136:12 137:2,20 138:8,13 138:22 139:2,17 158:7 162:2,9,21 163:4,8,9 165:20 167:8,9,13 168:15 168:21 169:15 170:22 171:19 172:2,3,7,8,12 173:4,14 174:6,18 175:3,5 178:20 179:11,18 182:20 187:18 188:2 189:3 214:21 219:13,14 233:17 236:9,21 246:4 260:10,18 261:2,7 275:12 281:4 297:10 303:21 systems 28:3 136:18 158:21 162:21 163:15,20 164:7 165:5,15 168:18 169:3 187:22 221:16 262:4 302:11 system's 147:8 S-E-S-S-I-O-N 197:1 S.3921 297:13 T T 70:17,18,18 table 211:22 tablet 193:19,21,22 194:5,6,7,12,13 tablets 193:18 tacrolimus 153:20 tactics 130:8 take 6:22 12:1 18:1 33:8 37:22 38:22 56:16 58:11 59:14 64:8 65:13 68:1 83:12 85:16 96:8 99:14 112:15 135:9 143:18 166:17 169:10 193:2 209:1,4 210:6 211:4,22 238:4 254:14,21 267:22 299:18 taken 16:7 44:15 51:20 55:9 63:21 85:20 103:4 takes 29:17 72:7 84:9 take-home 86:3 talk 13:11 33:20 35:2 66:15 74:14 79:22 83:12 86:7 97:21 102:6 132:7 155:18 159:15 180:21 181:11,21 189:5 207:18 253:20 256:8 279:3 280:13 289:20 292:10 talked 33:18 64:18 97:22 159:14 186:10 211:18 253:18 272:22 292:11 talking 31:6 77:4 80:20 86:10 110:10 131:20 194:18 209:10 244:5 272:13 talks 141:10 225:14 264:19 target 129:9 213:21 230:13,19 245:17 targeted 201:7 targeting 200:20 targets 199:20 task 83:9 taught 157:9 158:2 tax 300:4 taxpayer 295:6 team 147:6 teams 182:8 technical 7:8,17,19 220:15 291:15 technique 84:16 87:8 89:21 90:17 90:19 techniques 86:17 90:3 91:5 92:12 92:20 93:4,8,20 technological 121:12 technologies 81:11 82:1 83:1 90:11 103:14 123:2,6 128:6,16 130:13 245:12 technology 14:13 80:2 81:16 86:5 87:18 88:1 94:14 126:14 128:3 158:14 159:10 164:15 308:8 tell 94:10 124:15 142:7 209:20 210:1,2,3,18,21 tells 99:5 tenant 85:8 tend 175:19 274:21 Tennessee 182:4 tent 38:13 39:22 ten-year 281:22 term 120:7,8,12 178:11 268:15 terminal 308:6 terms 33:3 43:16 77:15 95:19 120:15 139:10 141:5 161:10 190:22 214:13 235:19 247:9 267:4 270:16 289:10 291:4 terrific 143:22 144:4 territory 62:14 tertiary 201:4 236:21 test 70:15,22 74:6 74:10 75:1 76:12 76:13 96:6,6,6 97:14 105:18 111:3 113:8,10 273:9,13 285:2,3 285:5 289:21 291:7 293:3 297:16 300:16 tested 22:13 220:3 testimony 35:7 80:22 141:9 testing 25:8,9 53:14 54:14 60:7 75:10 78:10 97:8 112:21 113:7 141:7,11 203:2 217:18 218:2 257:10,14 257:21 258:1 263:20 264:8 273:11,22 275:5 279:5 287:20 309:13 tests 105:10 113:4 113:9 279:22 Teva 3:25 244:22 245:4,7,10,16 246:8 248:18 272:15 Teva's 245:6 text 103:16,20 thank 9:15 12:11 12:18 18:3,11,13 19:15,16 21:17 28:19,20 30:4,17 35:16,19 36:14 45:1,3 46:2 49:8,9 49:20 58:16,18 61:20 65:8,10,14 65:22 73:12,13 79:12,14,19 86:9 89:14,16 95:3 101:13,15,17,19 102:1 108:14,15 114:15,20 123:17 123:18,21 124:2 132:6,10 133:16 133:17,20 139:5 140:15 143:16 144:4,9 152:15,17 154:21 159:12 166:20 169:6 176:9 186:17 196:8,12 197:18 207:13,14 209:9 214:3 215:17,18 216:1 224:18,19 228:4 238:7 244:17,18,20 245:5 248:12,13 253:14 254:12,16 255:3,20 262:10 262:11 271:3,4 272:6,11 278:19 278:20 280:7,8,11 291:10,18,19,22 293:8,13,22 300:18,19 301:2,4 301:7 306:15,16 306:19 310:21,22 311:5,14 312:5 thanks 132:15 139:3 146:11 207:10 theme 290:19 theory 82:3 therapeutic 8:8 16:16 24:1 32:16 51:16 56:13 68:12 117:1 182:7 195:19 therapeutics 51:3 57:12 80:1 82:20 therapies 17:6 21:11 22:17 23:4 23:5 29:15 34:6
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34:16 therapy 13:21 14:2 14:7,8 15:12,18 15:22 21:5,9 23:2 30:12,12 34:12 147:15 148:4,8 thing 108:3 111:6 240:22 258:5 things 62:6 77:10 79:9 90:8 91:16 107:4 126:12,12 128:7 140:10 157:20 173:13 235:10 257:22 261:8 264:1 269:2 272:13 296:16 306:10 think 18:18 29:21 31:8 32:7,18,22 34:7,15,21 40:13 43:8,20 46:11 47:18,19 48:11,13 49:1 59:11 62:13 62:21 63:9,13 64:7,13 67:8,16 68:3,18,20 69:3,4 69:12 71:9 74:12 74:15,19 75:3,5 75:15,16,22 76:10 76:12,18 77:13 78:1,19,20 79:2,5 79:6 80:21 91:20 92:8,9 93:6,9 94:14,15,22 103:22 107:5 110:17 111:9 112:14,19 126:6 127:17 129:18 133:4 139:19 141:6,20 142:1,20 143:9,12 153:1,1 153:5,6,8,16 154:14 155:9 156:7 159:7,20 160:3 164:7,11 165:2 166:5,10,12 166:15 169:16 171:9,10,15,17 172:20 174:19 175:16 178:3 186:10 190:11 192:9 193:16 194:2 195:17 208:10,12,14,17 208:19 209:5 212:6,10,14,15 213:18,22 215:5,6 215:10 225:18 226:13 227:14 233:6 237:5 238:11,18 239:14 241:15,21 243:2 249:6 250:11 251:16 253:6,18 253:22 254:6 258:20 269:5 279:17 280:2 288:7 292:8 303:12 305:2 306:3,6 309:13,17 310:3 thinking 52:18 155:1 163:19 169:20 171:15 178:1 195:11 214:13 249:7 279:10 third 45:6 102:18 136:6 218:19 thorough 240:21 310:17 thoroughly 247:1 273:17 thought 15:3 31:4 33:20 46:13 48:19 90:16 153:2 178:2 209:6 241:22 243:22 thoughtful 310:17 thoughts 59:1 66:3 153:4 163:22 272:8 276:6 thousand 31:7 78:12 thousands 31:19 127:9,10 198:13 three 22:3 71:15 81:6,9 83:11 86:10 136:3 146:17 191:7,20 204:4 216:9 217:8 217:21 298:22 303:22 three-dimensional 81:7 84:22 86:8 87:2 thromboembolic 14:22 throw 210:11 thwart 205:14 tier 163:4 tiered 131:6 ties 248:19 tight 12:9 306:10 tighten 160:10 time 10:13 11:10 11:18 12:9,21 16:3 25:16 28:14 32:7 62:21 66:9 88:13 93:18 94:18 94:20,22 107:15 116:4 125:5 126:7 126:13 129:7 130:12 131:10 135:2 153:21 166:21 170:17 181:2 190:12 191:14 193:2,4 194:19 197:7 199:9 201:21 202:7 203:20 206:19 207:19 208:11,16,20 210:5 211:22 222:11,14 224:18 237:17 252:6,10 284:2 289:5 291:11,12,22 300:12 301:8,12 304:20 timed 130:21 timely 53:9 160:19 times 98:11 167:16 167:18 179:2 tissue 86:12 231:20 titles 282:19 TNF 203:18 213:3 TNFs 203:12 TNF-alpha 203:14 today 5:22 10:1,3 11:1 12:12,19 13:12 14:6 20:2 21:7 22:2 36:6,15 37:21 40:8 43:20 45:17 49:17 58:17 61:21 83:3 87:5 92:3 93:19 115:2 124:3,16 125:9 132:8 133:21 135:11 139:4 150:4 152:16 158:22 160:20 161:3,11 163:2,14 164:10,16 165:6 166:5,13 176:18 183:6 198:4 209:11 214:4 228:9 230:1 232:9 238:12 255:21 256:8 261:13 262:7 265:16 268:5 279:7 288:16 289:7 292:11,15 293:21 305:20 today's 6:6,10 21:19 40:2 311:17 312:4 Tokyo 271:14 tolerability 16:11 tolerated 15:18 199:2 tomorrow 5:20 6:1 10:2 160:21 311:22 tool 81:18 85:9 88:19 tools 81:10 256:16 256:21 257:1 261:15 273:10 top 38:13 75:13 81:22 129:11 286:12 topic 22:3 231:8 256:13 279:10 topics 80:12 83:13 216:10 256:9 Toronto 3:14 95:15 total 91:10 175:13 180:2 totally 252:1 touch 32:8 touched 32:6 toxins 63:21 64:3 trace 46:7 47:11 261:7 traceability 204:19 219:12 traceable 189:2 track 41:21 139:12 139:16 164:3 165:10,20 167:5 168:18 170:12 171:16 173:17 204:9 261:7 tracked 139:22 168:1 tracking 28:2 43:4 136:5,9,18 147:18 158:15 169:14 171:11 174:16 176:7 219:14 292:20 trade 63:8 105:20 247:21 tradition 281:15 traditional 45:18 145:3 train 193:3 trained 194:1 training 82:8,8,14 82:21 83:6 89:14 134:4 157:7 193:7 193:12 trajectory 20:21
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142:3 unstudied 218:11 218:16 untreated 22:22 unused 277:17 update 226:5 upper 76:15 UPS 286:7 upwards 308:16 up-to 282:10 up-to-date 125:21 urge 52:21 54:6 58:8 202:4 206:18 216:18,21 297:20 302:5 304:17 urgency 302:5,6 urges 24:22 50:19 52:17 55:1 urging 280:20 use 21:3 50:6 54:21 58:9 69:13 72:6 74:18 76:17 78:11 80:1 81:18 83:1 87:5 93:3 110:9 114:11 117:22 126:20 137:10 138:10 145:21 147:3 152:12 157:16 161:15 175:9 178:11 181:6,17 185:19 187:6,13 190:10 190:16 213:2,4 229:8,13 234:21 238:15 239:4 242:7 249:6,8,12 257:19 258:7 265:11 289:7 useful 71:18 88:19 120:20 289:14 useless 305:15 user 8:3 277:15,20 278:4 304:6,7 305:3 users 278:2 304:16 uses 39:6 USP 4:10 280:10 280:16 281:4,8,13 283:17,22 285:9 285:11,13,17 286:8,11,19 288:6 288:8,18 289:2,8 290:9,12,17,22 USP's 280:14 usual 273:8 Usually 33:17 249:13 utility 131:3 292:3 utilization 135:3 145:7 153:13 183:16 utmost 115:12 U.S 1:1 4:17 184:6 184:7 211:5 235:2 235:12,14,17 238:13,19 239:10 239:21 240:2,6 243:16 245:22 246:4 249:16 255:12 258:10 262:22 263:11,15 263:17,19 264:5 264:11,19,20 265:5,13 285:1 293:16 297:3 298:5 variance 257:6 variances 270:1 variation 67:18 77:22 variations 27:12 varieties 217:21 variety 29:20 203:13 256:18 various 29:15 93:1 148:11 234:9 vary 203:15,17 306:5 vast 48:21 vastly 201:6 Vaughan 4:18 301:7,9 vehicle 44:1 verbal 102:17 version 119:8 versions 41:14 119:11,15 122:8 146:13 versus 23:11 74:1 93:4 97:11 157:13 166:14 174:17 212:10 229:19 240:6 vertebrate 106:5 vertical 289:9,11 290:1 291:1 V vetted 171:1 valid 69:15 vice 134:7 144:12 validated 229:6 176:14 255:5 273:12 videotape 10:20 validation 25:8 view 47:22 162:10 273:13 225:5 226:7,9 value 26:21 117:8 231:11 235:21 192:1,7 280:22 237:22 241:12 282:6 285:14 vancomycin 190:11 viewing 5:6 variability 67:16 views 20:3 216:2,9 68:1,6,12 69:5 vigilance 177:18 72:7,21 212:11,15 188:18 212:16 247:3 violate 107:2 variable 67:20 294:13 121:19 violates 111:10 variables 121:4 violating 106:2 viral 19:13 virtually 241:16 296:5 virtue 199:20 vital 56:8 vitro 48:8 112:6 257:10 277:2 vivo 200:20 257:13 voluntarily 299:2,6 voluntary 59:5 160:3 volunteer 281:5,5 283:12 volunteers 281:7 282:13 284:2 vulnerable 56:11 warrants 246:11 Washington 134:8 307:4 wasn't 109:19 watch 38:14 watching 38:16 39:6 Waters 3:13 79:17 80:15 82:16 90:22 wave 302:16 waving 197:9 Waxman 126:4 130:2 way 19:5,8 38:15 41:18 47:8,15 60:6 70:21 72:9 80:3 89:1 94:17 W 106:17 108:4 Waal 39:3 109:3,6 111:11 wait 53:17 115:10 118:20 waive 16:20 55:16 130:21 141:4 142:9,18 278:3 154:10 156:18 waiver 55:22 164:20 168:6 waivers 55:11 174:5,22 178:21 walk 39:1 61:4 179:16 180:22 walking 39:2 183:17 186:15 want 21:17 22:7,8 187:3 188:9,9,11 23:15 33:21 36:13 191:10 204:9 40:1,15 64:20 228:20,22 232:21 76:9,20 78:1 79:3 237:21 264:21 81:22 89:9 114:7 270:10,17 289:13 114:11 124:17 292:22 302:8 125:1 128:20 303:9 305:12,17 133:9,20 167:17 310:15 173:14 177:5 ways 29:5,8 123:5 179:21 181:11 147:12 163:7 186:3 193:21 164:11,17 166:7 197:6,12 209:17 298:22 242:3 268:17,20 weaknesses 242:10 268:22 269:3 webcast 5:7 311:16 278:12 302:17 webpage 288:14 wanted 28:14 107:4 website 11:3 110:12 132:16 weight 236:19 154:22 214:4 welcome 5:4,8 250:5 12:17 40:9 44:20 wants 138:10 306:2 44:21 65:18 warrant 131:13 197:13
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DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) + + + + +

Page 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. BEHRMAN: P-R-O-C-E-E-D-I-N-G-S 8:33 a.m. Good morning and

attendees sign in on both days.

scheduled from 11:55 to 12:55 p.m.

Neal R. Gross & Co., Inc. 202-234-4433

Biosimilars Review Committee. MS. MALONEY: Good morning. I'm

Neal R. Gross & Co., Inc. 202-234-4433

I'm the Associate Director for

CBER Biosimilars Committee. DR. BEHRMAN: I would like to note

Page 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 today. The meeting will be transcribed and

very productive meeting. the presentations.

The first speaker, I

Neal R. Gross & Co., Inc. 202-234-4433

immunoglobulins should be excluded.

Neal R. Gross & Co., Inc. 202-234-4433

these products are different. different viral inactivation.

What does the patient need to know

Neal R. Gross & Co., Inc. 202-234-4433

surveillance system so critical for pharmacovigilance? The Arthritis Foundation

Page 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 question. Schwartz. MR. SCHWARTZ: I have one

It's actually a quick two-parter.

but not necessarily mandated in many situations. We find that it is of benefit to

Neal R. Gross & Co., Inc. 202-234-4433

appreciate that question.

You touched on it at the end Can

but I think your time was running out.

Page 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. conversation. DR. CHERNEY: In your talk you

We encourage the Arthritis

Page 38 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 considering taking, biologics. This subgroup

other side, we applaud and exhale.

Neal R. Gross & Co., Inc. 202-234-4433

live with the disease.

identical generic versions of biologics. is why nobody calls them generics.

Page 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 batch. We do it with eggs. We must do it with

isn't the issue with biosimilars. are.

Neal R. Gross & Co., Inc. 202-234-4433

Biologics to us are the miracle

Other questions from the panel? MR. SCHWARTZ: I do have one

In your key areas, the third area

Neal R. Gross & Co., Inc. 202-234-4433

Page 48 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that as an absolute? For example, some

Without the scientific background

MR. GINSBERG: DR. BEHRMAN:

Page 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 ideas for needed pediatric studies. This

Page 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 information. The academy strongly urges FDA'S

Page 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 innovator product should not simply be transferred to a biosimilar. Additionally,

Neal R. Gross & Co., Inc. 202-234-4433

Neal R. Gross & Co., Inc. 202-234-4433

I recognize the conundrum. Ms. Marchand. Dr. Bromberg, thank In

DR. BEHRMAN: DR. MARCHAND:

you very much for your comments today.

Should the follow-on biosimilar

You talked about that

Shall we break now?

take a 15-minute break. 9:45. Thank you.

Page 66 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 me the opportunity to speak here. It's a

recommend disaggregated criteria.

I think in a balanced design -- this is a typo. It should be 4 x 2 crossover design.

non-inferiority actually that should be included already. When we talk about a

that is out of the scope of biosimilarity. DR. JENKINS: So in that two-sided

5 percent on each side.