April 8, 2012 Texas Medical Board Rules Development P.O.

Box 2018 Austin, TX 78768-2018 Re: Rationale for Voting Against Chapter 198. Use of Investigational Agents To Whom It May Concern: I am writing because I wish to urge members of the Texas Medical Board to reject in its current form Chapter 198. Use of Investigational Agents. This proposed rule change is scheduled for presentation to the Texas Medical Board April 13, 2012. The imprecise and unscientific use of the phrase, stem cells; numerous ethical, clinical, scientific, and regulatory issues that the guidelines treat in inadequate fashion or fail to address; and lack of forthrightness concerning whether the guidelines are supposed to complement or subvert federal regulations governing administration of stem cells all provide reasonable grounds for rejecting the guidelines in their current form. Chapter 198 does not adequately address numerous moral, legal, and medical concerns even though several members of the Adult Stem Cell Research/Treatments Stakeholder Workgroup Group cautioned that the guidelines required additional revisions before being considered for approval by the Texas Medical Board. Prudent and informed counsel, though provided by physicians, researchers, university administrators, and scientists familiar with ethical norms and regulations governing both medical practice and clinical research, was not adequately heeded during the process of preparing the proposed rule change for presentation to the Texas Medical Board. Approval of these guidelines in their current form risks compromising the safety of patients and research subjects in Texas. I want to draw the attention of Texas Medical Board members to seven serious shortcomings with Chapter 198. Use of Investigational Agents. These problems are: 1) Defining and describing stem cells as investigational agents falling within the practice of medicine undermines protections for research participants and patients; 2) Most (though not all) interventions involving administration of stem cells require submitting an Investigational New Drug Application to the FDA and having study protocols approved by Institutional Review Boards;

2 3) Investigational Agents are used in the context of clinical studies involving human research participants and should not be described as therapies falling within the practice of medicine"; 4) Chapter 198 fails to provide clear guidance concerning regulation of adult stem cells at a time when numerous businesses in Texas are marketing stem cells; 5) The guidelines must clearly state that research subjects should not pay for participating in clinical studies; 6) The guidelines must clearly state that research protocols involving administration of adult stem cells cannot be reviewed and approved by private, for-profit Institutional Review Boards; 7) Financial conflicts of interest put into question the integrity of regulatory frameworks. In the sections that follow I elaborate upon the preceding points. 1) Defining and describing stem cells as investigational agents falling within the practice of medicine undermines protections for research participants and patients. According to 198.3 (a), Administering or providing investigational agents constitutes the practice of medicine, and, therefore, must be performed under the direction of a licensed physician who is responsible for compliance with the Medical Practice Act. Use of stem cells in humans shall be considered investigational unless they are used in the conduct of an FDA-approved protocol or until such time as they are approved by the FDA. Section 198.1 states that physicians can administer investigational agents among the therapies that physicians offer their patients. It is worrisome that as a result of Chapter 198s classification of stem cells as investigational agents that are also therapies, Chapter 198 conveys the impression that physicians offering such therapies as part of the practice of medicine need not submit to the FDA Investigational New Drug (IND) applications before administering stem cells to their patients. Submission of study protocols to Institutional Review Boards meeting specified criteria is apparently sufficient. However, Chapter 198.2 states, An investigational agent shall not include(3) products processed or manufactured as human cell, tissue or cellular-or-tissue-based product (HCT/P) pursuant to Sections 351 and 361 of the Public Health Service Act (PHSA) (42 U.S.C. 264; nor (4) a drug, device or biologic pursuant to the federal Food Drug and Cosmetic Act (FDCA). Taken in its entirety, it is unclear exactly how Chapter 198 is supposed to regulate different types of stem cells and procedures involving administration of adult stem cells When referring to administration of stem cells Chapter 198 does not clearly specify what types of stem cells are investigational agents thatdespite their investigational statusdo not require submission of Investigational New Drug applications to the FDA. Chapter 198 uses the phrase stem cells but does not differentiate among various types of stem cells. This failure to make distinctions and specify what types of stem cells can be administered to research subjects without first submitting IND applications to the FDA risks leaving physicians, patients, researchers, Institutional Review Board members, and administrators at universities and hospitals understandably confused about what types of stem cells can be administered as therapies that are part of the practice of medicine. The

3 guidelinesif the Texas Medical Board thinks it necessary to develop guidelines intended to supplement federal regulations must include a far more detailed account of what types of interventions involving different kinds of stem cells require submission of IND applications to the FDA. 2) Most (though not all) interventions involving administration of stem cells require submitting an Investigational New Drug Application to the FDA and having study protocols approved by Institutional Review Boards Comments made by several members of the Adult Stem Cell Research/Treatments Stakeholder Workgroup as well as correspondence sent by various individuals to the Texas Medical Board suggest that one major reason for classifying stem cells as investigational agents is to permit physicians to administer to patients adult autologous stem cells without first having to submit to the FDA Investigational New Drug applications. As members of the Texas Medical Board presumably know, 21 Code of Federal Regulations 1271 (See Appendix) makes important distinctions concerning how different stem cells, tissues, and cellular and tissue-based products (and methods of processing them) are regulated. Some procedures involving administration of stem cells do not require submission of an IND application to the FDA. For example, physicians are not required to submit IND applications to FDA if they perform procedures in which stem cells are minimally manipulated, are intended for homologous use, are removed from an individual and implanted into the same person during the same surgical procedure, and meet additional standards listed in 21 CFR 271. However, according to 21 CFR 1271, If you are an establishment that manufactures an HCT/P that does not meet the criteria set out in 1271.10(a), and you do not qualify for any of the exceptions in 1271.15, your HCT/P will be regulated as a drug, device, and/or biological product under the act and/or section 351 of the PHS Act, and applicable regulations in title 21, chapter I. What this standard means is that use of many different types of stem cells requires both submission of an Investigational New Drug application to the FDA and approval of research protocols by Institutional Review Boards. According to 198.3 (b), Prior to administering or providing of investigational agents, physicians must have their proposed use either included in an FDA/NIH approved protocol/study or approved by an IRB. This language is misleading. If researchers wish to administer an Investigational New Drug in the context of a clinical trial, there are two major regulatory pathways that must be navigated. Researchers are not free to select whichever option they prefer. First, researchers must submit to the FDA an Investigational New Drug (IND) application. The FDA then has 30 days to decide whether or not to put a hold on the application. Second, research involving investigational agents must be reviewed, evaluated, and approved by an Institutional Review Board. By not being precise about the extent to which investigational agents are similar to or different from what the FDA describes as Investigational New Drugs and by asserting that researchers can submit to the FDA/NIH or an IRB, it appears that Chapter 198, if approved, would dramatically reduce protections for research participants. It is possible that the proposed guidelines are not intended to subvert federal regulations specifying that researchers planning to conduct clinical studies involving Investigational New Drugs must first submit IND applications to FDA. If the guidelines are meant to support this longstanding protection for research projects and are not intended to pose a challenge to federal regulations governing medical

4 research and oversight of Investigational New Drugs then the guidelines need to be revised to indicate that IND applications must be filed with FDA and Institutional Review Boards must review research protocols whenever investigational new drugs are used in clinical studies. If the Texas Medical Board wishes to challenge federal regulations by creating a new regulatory model for clinical researchers in Texas then members of the board should understand that there will likely be serious consequences for researchers and research institutions that fail to submit IND applications to the FDA when they are required by federal regulations to take this action. Upon discovery of such violations by the FDA, the Department of Health & Human Services Office for Human Research Protections, and/or the National Institutes of Health, researchers at medical centers and universities in Texas could lose federal research funding and be subject to additional disciplinary measures, and the Office for Human Research Protections could halt clinical studies at institutions where researchers fail to conduct research in a manner that conforms to federal regulations. Failure to conform to Federal regulations governing IND applications could have significant consequences for researchers and research centers in Texas. These outcomes must be considered in addition to taking into account possible increase in risks to patients and research participants. 3) Investigational Agents are used in the context of clinical studies involving human research participants and should not be described as therapies falling within the practice of medicine. According to 198.1, The purpose of this chapter is to recognize that physicians should be allowed a reasonable and responsible degree of latitude in the kinds of therapies they offer their patients. The Board has determined that use of investigational agents constitutes the practice of medicine and is, thus, subject to all applicable statutory and regulatory provisions of the Medical Practice Act and Board Rules unless otherwise specifically stated. The language used in Chapter 198.1 is problematic because it fails to make key distinctions between research and therapies or treatments. This conflation of categories is also evident in the title of the group assigned to develop these guidelines: Adult Stem Cell Research/Treatments Stakeholder Workgroup. Therapies, in both the practice of medicine and common parlance, can be taken to mean established treatments rather than experimental, clinically unproven interventions requiring oversight as investigational research. Likewise, the phrase use of investigational agents constitutes the practice of medicine could be taken to mean that use of investigational agents falls within established medical practice or existing standard of medical care. However, the language of investigational agent combined with reference to Institutional Review Boards and research elsewhere in Chapter 198 highlights the importance of emphasizing that provision of investigational agents falls within the scope of medical research rather than the existing standard of medical care in which physicians can exercise a reasonable and responsible degree of latitude in offering established treatments to their patients. Prior to approving Chapter 198 the Texas Medical Board needs to revise the guidelines and emphasize that investigational agents are experimental, provide no assurance of benefits to research participants, can cause harm (including death) to research subjects, and do not fall within the realm of established, evidence-based practice of medicine. Indeed, the point of providing investigational agents within the context of clinical trials is to determine whether or not, through careful research and determination of safety and efficacy, investigational agents should become part of the practice of medicine.

5 Language used in the current version of the guidelines risks promoting the therapeutic misconception. This phrase points to a common misunderstanding in which research subjects enroll in clinical studies but mistakenly assume that they will experience personal therapeutic benefit as a result of participating in clinical research. There are many studies (particularly Phase I studies) where investigational agents are tested for safety rather than efficacy and research participants should have no expectation of individual therapeutic benefit. In other studies some research participants receive placebos rather than investigational agents. As currently drafted, the guidelines promote the therapeutic misconception instead of attempting to dispel it by better acknowledging the risks that can accompany participating in clinical research involving administration of investigational agents. When safety and efficacy of investigational agents are not yet established, it is misleading and dangerous to describe such agents as therapies and treatments. 4) Chapter 198 fails to provide clear guidance concerning regulation of adult stem cells at a time when numerous businesses in Texas are marketing stem cells. To provide one germane example of how adult autologous stem cells are already being administered to patients in Texas, numerous reports indicate that Celltex Therapeutics Corporation cultures, processes, expands, and banks adult autologous stem cells at its facility in Sugar Land, Texas. These stem cells are reportedly being administered to patients at clinics in Houston and possibly elsewhere within Texas. The stem cells processed and banked by Celltex are obtained from adipose tissue. The stem cells are then cultured and expanded over a 3-4 week period at the Celltex processing lab and stem cell bank. These cells are subsequently transported to clinics in Texas and administered to patients. Celltexs website is under construction and provides no information concerning precisely how cells are processed and expanded. In addition, although Celltex executives report that the company provides stem cells to physicians who administer the cells in the context of clinical trials, whatever trials the company is conducting alone or with its business partner RNL Bio are not listed in the Clinicaltrials.gov registry (http://clinicaltrials.gov/ct2/home) and database. (This database contains both federally funded clinical trials and privately funded clinical trials conducted in the U.S. and elsewhere.) Given the paucity of publicly available information concerning how Celltex Therapeutics processes and expands stem cells, caution is required when asserting whether stem cells administered by Celltex fall within the category of human cells, tissues, and cellular and tissue-based products that require submission to the FDA of an Investigational New Drug application. However, what is known is that Celltex processes, cultures, and expands stem cells for approximately one month. Precisely what occurs during this lengthy period is unclear because Celltex has made so little information about technical aspects of its operation publicly accessible. Drawing upon accounts of companies that have publicly disclosed how they prepare stem cells prior to administration, processing could include expansion using growth factors and reagents, centrifuging, placement in culture media, exposure to enzymes, cryopreservation, and additional steps. Given the amount of time Celltex maintains stem cells outside the body, and the numerous steps that presumably are required to isolate, culture, process, and cryogenically bank stem cells, there is reason to question Celltexs claim that its cells are minimally processed and can be administered to patients without first submitting an Investigational New Drug application to the FDA. It is also worth noting that the stem cells Celltex obtains from adipose tissue are reportedly administered by physicians to individuals with such illnesses as multiple sclerosis and Parkinsons disease.

6 Chapter 198 needs to be forthright about how the Texas Medical Board intends to regulate companies that directly administer adult stem cells to patients or process and bank stem cells before providing them to physicians who then administer them to patients. In particular, Chapter 198 needs to clearly state how the guidelines are supposed to regulate procedures involving more than minimally manipulated stem cells. According to federal regulations, prior to administration of such cells it is necessary to first submit IND applications to the FDA and establish whether or not the FDA places a hold on the application. By not being precise about which stem cells and interventions involving administration of stem cells fall within the category of investigational agents, there is genuine danger that the Texas Medical Board will signal to companies and clinics that physicians in Texas are free to administer adult stem cells to patients without first having to provide to the FDA Investigational New Drug applications containing information about animal pharmacology and toxicology studies, manufacturing information, clinical protocols, and investigator information. The larger the gaps in the guidelines, the greater the likelihood that companies and clinics will flock to Texas and exploit cracks in the governance of stem cells. 5) The guidelines must clearly state that research subjects should not pay for participating in clinical studies. Chapter 198 addresses administration of investigational agents but does not specify how the Texas Medical Board proposes to address circumstances in which researchers seek payment from research participants. There are numerous reasons why research participants should not pay for participating in studies in which they receive investigational agents. In the context of Phase I studies, agents are tested primarily for safety. Research participants in Phase I studies are informed that they should expect no personal therapeutic benefit as a result of participating in such studies. In later phase clinical trials, investigational agents are often tested against placebos. Research participants are randomly distributed to different arms of studies and are blinded as to whether they receive investigational agents or placebos. The purpose of such studies is to disturb clinical equipoise by seeing whether investigational agents are more efficacious than placebos. If researchers knew with certainty in advance of conducting studies that the investigational agents they plan to test are superior to placebo then there would be no ethical, legal, or scientific justification for administering placebos to research participants. In randomized and blinded clinical studies involving placebos, research participants do not know whether they will receive placebos or investigational agents, and whether the investigational agent is superior to placebo is not yet established. Research participants should not have to pay for participating in such studies. They are not being offered established treatments with prospect of individual benefit to them. To the contrary, research participants can experience no benefit, have serious adverse events, or die as a result of receiving an investigational agent in the course of a clinical study. This uncertainty concerning outcomes is the basis both for strict oversight of clinical research and not charging research subjects for participating in clinical studies. Research participants should not be charged when participating in clinical studies in which they receive investigational agents. Celltex reportedly processes and banks adult autologous stem cells and then provides these cells to clinics in Texas. Clients of Celltex reportedly pay $20,000 to $30,000 to have stem cells processed, stored, and then administered to them in the context of clinical trials. (Whether all patients receiving stem cells stored and processed by Celltex are enrolled in clinical trials is unclear.

7 Numerous reports suggest that patients have received stem cell infusions outside the context of IRBapproved clinical trials.) Given that such activity is already occurring in Texas, Chapter 198 must be redrafted to make clear to researchers, research facilities, and companies involved in clinical research that research subjects must not be charged for participating in clinical studies in which they are administered investigational agents and/or placebos. Furthermore, the Texas Medical Board should take steps to ensure that individuals who have already paid to participate in clinical studies involving administration of adult stem cells are reimbursed. It is strange that this issue is not addressed by Chapter 198 given that one member of the Adult Stem Cell Stakeholder Workgroup is a senior executive at a company that reportedly charges patients for participating in clinical studies that involve administration of stem cells. 6) The guidelines must clearly state that research protocols involving administration of adult stem cells cannot be reviewed and approved by private, for-profit Institutional Review Boards. Chapter 198.3 (b) states, Prior to administering or providing of investigational agents, physicians must have their proposed use either included in an FDA/NIH approved protocol/study or approved by an IRB. The IRB must: (1) be affiliated with an academic setting or a Texas licensed hospital; (2) be accredited by the Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP); (3) be registered by the U.S. Department of Health and Human Services Office for Human Research Protection, pursuant to 21 CFR Part 56; or (4) have received national accreditation by an organization acceptable to the TMB. One significant problem with appearing to provide the option of submitting Investigational New Drug applications to the FDA or submitting study protocols for review to IRBs (if this framework is what the guidelines intend to promote) is that quality of IRB review is variable. Furthermore, some IRBs can experience financial pressures to approve research protocols if they wish to remain in business. Chapter 198 does not explicitly mention private, for-profit Institutional Review Boards. However, Celltex Therapeutics states that it submits study protocols to a private, for-profit IRB known as Texas Applied Biomedical Services (TABS). Chapter 198 must directly address whether or not researchers can submit clinical studies involving use of investigational agents to private, for-profit IRBs. If Chapter 198 permits submission of clinical studies to private, for-profit Institutional Review Boards there is risk that researchers will engage in IRB shopping. What this means is that when researchers encounter barriers to having their clinical studies approved by IRBs they simply continue searching for an IRB until they find one that approves whatever studies they wish to conduct. It is imperative that Chapter 198 place constraints on which IRBs are permitted to review clinical protocols involving administration of adult stem cells. 7) Financial conflicts of interest put into question the integrity of regulatory frameworks Dr. Stanley Jones, a member of the Adult Stem Cell Research/Treatments Stakeholder Workgroup, is Vice Chairman and Chief Medical Officer at Celltex Therapeutics. As a member of the Workgroup he presumably was tasked with helping develop robust framework for governance of adult stem cells and minimizing risks to patients and research subjects. As a senior executive for Celltex he has duties to advance that firms interests. There is reason to be concerned about Dr. Jones inclusion as a member of the Workgroup.

8 In correspondence with Dr. Linda Gage-White, Medical Director of the Texas Medical Board, Dr. Jones appeared to advocate eliminating both the requirement for submission of Investigational New Drug applications to the FDA and the need for review of research protocols by Institutional Board Review. Instead, he proposed letting physicians administer stem cells to patients and periodically submit data directly to the Texas Medical Board. Had Dr. Jones recommended oversight model prevailed during drafting of Chapter 198, and had his proposal been approved, the Texas Medical Board would have taken the remarkable step of supplanting both the FDA and Institutional Review Boards in providing regulatory oversight of stem cells. I mention this point to draw attention to the risks associated with letting someone with a direct financial interest in a company that reportedly processes and banks stem cells and then makes these stem cells available to clinics play a significant role in the development of guidelines intended to regulate administration of adult stem cells. I have no insight into whether Dr. Jones financial conflict of interest or the financial interests of other members of the working group (if there are any additional financial conflicts of interest) in any way played a role in influencing debate among members of the group and shaping the guidelines submitted to the Texas Medical Board. However, it is troubling that Dr. Jones both interacted with board members as a participant in development of guidelines for use of investigational agents and lobbied the Texas Medical Board using Celltex Therapeutics letterhead and writing in his capacity as Vice Chairman and Chief Medical Officer of Celltex. Financial conflicts of interest can prompt questions about integrity of regulatory frameworks. As a member of the Adult Stem Cell Research/Treatments Stakeholder Workgroup, Dr. Jones primary responsibility was to improve quality of deliberation in the group and help craft a comprehensive policy governing administration of adult stem cells. It is cause for concern that while serving in this capacity he was also lobbying the Texas Medical Board as a senior executive at Celltex and apparently acting as an agent advancing that companys interests. Within Texas, support for administration of adult stem cells and the development of an adult stem cell industry is predicated upon the understanding that Texas has potential to become a national and international leader in this area of medical research and clinical practice. This objective is laudable. However, the guidelines currently presented to the Texas Medical Board in the form of Chapter 198 fail to incorporate adequate protections for research participants, use imprecise wording, do not make important distinctions among different types of stem cells and stem cell procedures, do not adequately differentiate between treatment and research, and convey the impression that researchers need only seek approval from local Institutional Review Boards and do not also have to submit Investigational New Drug applications for stem cell interventions that according to federal regulations require submission of IND applications. If the guidelines are not substantially revised before the Texas Medical Board approves them, then it is possible that Texas could become a magnet for unscrupulous individuals who perceive a lax regulatory environment as an opportunity to profit from ill, vulnerable, and in some cases desperate individuals. I hope that members of the Texas Medical Board understand that if Chapter 198 does not incorporate better safeguards for protection of patients and research subjects Texas could become a state where seriously ill patients are preyed upon by unscrupulous hucksters more concerned with profits than promoting patient safety and protecting research participants. In addition to putting vulnerable individuals at significant risk of both physical and financial harm, such a development would cause considerable damage to Texas reputation for medical care and scientific research. I urge the Texas Medical Board not to approve the current version of Chapter 198. Instead, if the Texas Medical Board seeks to draft guidelines governing administration of adult stem cells, it must develop a far more

9 comprehensive, detailed, and robust regulatory framework that uses both state law and federal regulations to promote credible, ethical stem cell research while protecting patients and research subjects from clinically unproven and potentially unsafe interventions. In writing this letter I contact you as an individual faculty member at the University of Minnesota Center for Bioethics. I doubt that I need to mention this point but let me nonetheless indicate that I do not write on behalf of the institution of the University of Minnesota. Please feel welcome to contact me at 612.626.4830 or turne462@umn.edu if you have any questions or concerns in response to this letter. Yours sincerely,

Leigh Turner, PhD Associate Professor Center for Bioethics University of Minnesota N520 Boynton, 410 Church Street SE Minneapolis, Minnesota 55455 Phone: 612.626.4830 Email: turne462@umn.edu Fax: 612.624.9440 cc: Mari Robinson, J.D. Linda Gage-White, M.D.

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Appendix According to Section 1271.10: (a) An HCT/P is regulated solely under section 361 of the PHS Act and the regulations in this part if it meets all of the following criteria: (1) The HCT/P is minimally manipulated; (2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent; (3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and (4) Either: (i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or (ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and: (a ) Is for autologous use; (b ) Is for allogeneic use in a first-degree or second-degree blood relative; or (c ) Is for reproductive use. (b) If you are a domestic or foreign establishment that manufactures an HCT/P described in paragraph (a) of this section: (1) You must register with FDA; (2) You must submit to FDA a list of each HCT/P manufactured; and (3) You must comply with the other requirements contained in this part. Section 1271.15 notes the following exceptions: (a) You are not required to comply with the requirements of this part if you are an establishment that uses HCT/P's solely for nonclinical scientific or educational purposes. (b) You are not required to comply with the requirements of this part if you are an establishment that removes HCT/P's from an individual and implants such HCT/P's into the same individual during the same surgical procedure. (c) You are not required to comply with the requirements of this part if you are a carrier who accepts, receives, carries, or delivers HCT/P's in the usual course of business as a carrier. (d) You are not required to comply with the requirements of this part if you are an establishment that does not recover, screen, test, process, label, package, or distribute, but only receives or stores HCT/P's solely for implantation, transplantation, infusion, or transfer within your facility. (e) You are not required to comply with the requirements of this part if you are an establishment that only recovers reproductive cells or tissue and immediately transfers them into a sexually intimate partner of the cell or tissue donor. (f) You are not required to register or list your HCT/P's independently, but you must comply with all other applicable requirements in this part, if you are an individual under contract, agreement, or other arrangement with a registered establishment and engaged solely in recovering cells or tissues and sending the recovered cells or tissues to the registered establishment. Section 1271.20 then states: If you are an establishment that manufactures an HCT/P that does not meet the criteria set out in 1271.10(a), and you do not qualify for any of the exceptions in 1271.15, your HCT/P will be regulated as a drug, device, and/or biological product under the act and/or section 351 of the PHS Act, and applicable regulations in title 21, chapter I.