GENERIC DRUGS IN THE U.S.

: GENERIC MARKET AND REGISTRATION CHALLENGES

Gordon Johnston, R.Ph., M.S.

Nexgen China 2012 Shanghai, China March 27, 2012

OVERVIEW OF PRESENTATION
Brief overview of U.S. generic market Current ANDA review time frames and metrics Highlights in ANDA registration process and requirements New trends impacting U.S. ANDA registration
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U.S. INCENTIVES TO UTILIZE GENERIC DRUGS

Health care costs continue to rise in the U.S. Aging population increases utilization of prescription drugs Both government and private sector working to control health care costs Generic drugs are part of the solution
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U.S. INCENTIVES TO UTILIZE GENERIC DRUGS (CONT)

Government programs promote generic drug use
Higher reimbursement for pharmacists to dispense generics Lower co-pay for patients

INCENTIVES FOR PATIENT USE OF GENERIC DRUGS IN THE U.S.

GENERIC COMPETITION & DRUG PRICES

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 52% 44% 39% 33% 26% 26%22% 23% 21%20% 20%24% 15%13% 11% 9% 8% 6% 94%

Average Relative Price (avg generic/brand)

11

13

15

17

19
6

Number of Generic Manufacturers

GENERIC SAVINGS
$160.0 $140.0 $121 $120.0 $101 $100.0 $80.0 $60.0 $40.0 $20.0 $0.0 $51 $55 $78 $60 $65 $69 $86

Savings by Year ($ in billions)

$139

$158

2000

2002

2004

2006

2008

2010

(Source: GPhA/IMS Health, Savings: An Economic Analysis of Generic Drug Usage in the U.S., September 21, 2011)

GENERIC SAVINGS OVER TIME ($ BILLIONS)

$180 $160 $140 $120 $100 $80 $60 $40 $20 $0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Older Generics

Newly Genericized Products

(Source: GPhA/IMS Health, Savings: An Economic Analysis of Generic Drug Usage in the U.S., September 21, 2011)

$98 BN AT RISK TO GENERIC COMPETITION IN THE US BY 2015

Value of products at risk 2004-2015

$98 bn

Source: IMS Health, MIDAS, Market Segmentation, Sep 2010

GENERIC DRUG REVIEW AND APPROVAL TIME FRAMES IN THE U.S.

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OFFICE OF GENERIC DRUGS

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Office of Generic Drugs

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ANDA FILING PROCESS AND IMPORTANT CONSIDERATIONS

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NDA (BRAND) VS. ANDA (GENERIC) REGISTRATIONS IN THE U.S.

Chemistry Manufacturing Controls Labeling Testing Bioequivalence (Bioavailability) Animal Studies Clinical Trials

Chemistry Manufacturing Controls Labeling Testing Bioequivalence

DRUG PRODUCTS GENERIC FORMULATIONS

Pharmaceutical Equivalence Same active ingredient Same strength Same dosage form Same route of administration Comparable labeling Bioequivalence In Vivo Studies PK PD Clinical In vitro Studies Therapeutic Equivalence

A Therapeutic Rating (A substitute)

CRITICAL DEFINITION: ACTIVE INGREDIENT

Same active ingredient = same active moiety and same salt or ester as the brand product * Typically may differ in polymorphic or other physical property

INACTIVE INGREDIENT LEVELS JUSTIFICATION

Must be at or below a level previously used for a product with the same route of administration Compare using a single dose in Inactive Ingredient Database (IID) Compare using maximum daily intake for total daily exposure to inactive Must submit Pharmacology/Toxicology data for the inactive if it cannot be justified via IID or reference to another approved drug product

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INACTIVE INGREDIENTS
General
Generic product must contain inactive ingredients that have been previously approved for that dosage form Inactive ingredients may not exceed the amount previously approved per dose or total daily exposure

Parenteral
May differ only in preservative, buffer or antioxidant

Ophthalmic/Otic
May differ in preservative, buffer, substance to adjust to toxicity, or thickening agent but may require in-vivo studies if formulation is not Q1/Q2

Topical
May differ but must characterize and demonstrate differences do not affect safety or efficacy.

WHEN CAN ANDAS BE SUBMITTED?

New Chemical Exclusivity
Submit after expiry of NCE, or After 4 years of NCE IF there is a patent and you submit a paragraph IV patent challenge

Patents or Other Types of Exclusivity

ANDAs can be submitted at any time

ORANGE BOOK
APPROVED DRUGS

PATENTS

EXCLUSIVITY

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HIGHLIGHTS OF THE ANDA REVIEW PROCESS AND REQUIRED INFORMATION

APPLICANT

ANDA Review Process:

ANDA
Application Review

Refuse to Receive Letter

M ost are eventually filed

Acceptable & Complete

Y Request for Plant Inspection N Chemistry Review N Micro Review

Micro OK?

Labeling Review

Bioequivalence Review

PreApproval Inspection Results OK?

Chemistry OK?

Labeling OK?

Bioequivalence OK?

Approval Withheld until Results Satisfactory

APPROVED ANDA

Complete Response Letter

Bio Deficiency Letter

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ANDA Completeness and Acceptability Checklist

http://www.fda.gov/AboutFDA/CentersOffices/cder/ucm119100.htm*

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CTD FORMAT/ ANDA CONTENT

Module 1: Administrative
Regulatory Labeling

Module 2: Summaries
Summary information for Chemistry and Bioequivalence Summary of Module 3 and Module 5

Module 3 Quality Module 5 Clinical/Bioequivalence

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MODULE 1: ADMINISTRATIVE
1.3.5 Patents (listed in Orange Book)
Paragraph I Paragraph II Paragraph III Paragraph IV
Must provide Statement of Notification

Method of Use or Little viii (Section VIII) No Relevant Patents

1.3.5 Exclusivity
Exclusivity statements must be included even if the product is not entitled to any marketing exclusivity New Chemical Entity (NCE-1 rule if providing a PIV certification) Pediatric Exclusivity

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MODULE 1: ADMINISTRATIVE
1.1.2 Signed and Completed Application Form (356h) (21 CFR 314.94(a)(2)) Firms should refer to the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Firms should utilize USP nomenclature when the finished drug product is designated as USP. 1.2 Cover Letter
Use cover letter to highlight any key issues for the reviewer/alerts reviewer to specific areas of attention Address any issues or previous communications with the Agency Form FDA 3674 (ClinTrials.gov requirements)
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MODULE 1: ADMINISTRATIVE
1.4.1 Letters of Authorization
Active Pharmaceutical Ingredient DMF
The DMF must be submitted prior to or at the same time the ANDA is submitted Container Closure Components DMF (Type III)

U.S. Agent required for ANDA holders located outside of the United States

1.12.11 Basis for Submission

Must include name of the Reference Listed Drug as designated by the Electronic Orange Book Include NDA number on Basis for Submission
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MODULE 1: ADMINISTRATIVE
Labeling
Proposed package insert (Word and PDF files required) Container and Carton Labels for all strengths and fill sizes Patient leaflet (where applicable) Structured Product Labeling (SPL) Side by Side Annotation of container and carton labels compared to the RLD with all differences highlighted and explained

1.14.3 Listed Drug Labeling

Side by Side Comparison of package and patient insert with all differences highlighted and explained MOU certification carve out (where applicable) Clean copy of the RLD package insert, container and carton labels for all strengths
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MODULE 2: SUMMARY
2.3 Quality Overall Summary
Roadmap for ANDAtells the story of product development, critical process parameters, critical attributes for drug product Summary of Chemistry information from Module 3 Information should be submitted in a single continuous file in both PDF and Word format Be sure that data in QOS matches data in Module 3 Example of QOS can be located on the OGD website.

2.7 Clinical Summary

Summary of Bioequivalence information from Module 5 Information should be submitted in both PDF and Word format Bio Summary Tables 1-8 should be located here

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MODULE 3: QUALITY
Most critical module of ANDA
Most deficiencies in ANDA relate to Module 3

Chemistry, Manufacturing and Controls Drug Substance (3.2.S.) Drug Product (3.2.P.) Executed Batch Records (3.2.R.) Follow eCTD format47 CMC general guidances and 6 ANDA specific CMC guidances. Become familiar with FDA guidances when preparing an ANDA!

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MODULE 3: QUALITY
3.2.S.2 Manufacture
Drug Substance Manufacturer Address of the actual site of manufacturing activity Contact person including phone, fax and email address Testing Labs Same information as above Type of test (be as specific as possible) Components being tested Stage of the product being tested Hyperlink to cGMP certifications
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MODULE 3: QUALITY
3.2.S.2 Manufacture
Control of Drug Substance
Specifications Analytical procedures if non-USP Validation of analytical procedures of non-USP Spectra and Chromatograms for the identification of the active ingredient Samples statement of availability (21 CFR 314.50(e)(i)) Certificates of Analysis
API manufacturer release COA Drug product manufacturer acceptance COA

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SAMPLE FORMAT FOR LISTING ESTABLISHMENTS

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MODULE 3: QUALITY
3.2.P.3.1 Manufacturer
Drug product manufacturer Exact address of the site of manufacturing activity Contact person including phone, fax and email address Testing Labs Same information as above Type of test Components being tested Stage of the product being tested Hyperlink to cGMP certifications

3.2.P.3.2 Batch Formula

Include theoretical yield for the exhibit as well as the commercial batch

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MODULE 3: QUALITY
3.2.P.1. Description and Composition of the Drug Product
Provide unit composition of each inactive using the same unit of measurement Provide complete qualitative and quantitative breakdown for flavoring and coloring agents if not listed in IID at the levels proposed Justification of inactive ingredients based on Inactive Ingredient Database (IID)

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MODULE 3: QUALITY
3.2.P.3.3 Description of Manufacturing Process
A flow diagram should be presented that illustrates the manufacturing process (i.e. when an excipient is added). Blank Master Production Batch Records
Firms may request a maximum production scale-up of theoretical yield of the exhibit batch

10X the

Reprocessing Statement Cite 21 CFR 211.115 and 314.70(b) and state that no reprocessing will take place until a Prior Approval Supplement has been submitted and been approved.

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MODULE 3:QUALITY
3.2.P.4 Control of Excipients
Source of inactive ingredients (names and addresses of suppliers/manufacturers) Suppliers COA Analytical Procedures Should be submitted if procedures used are not USP/NF procedures. Validation of Analytical Procedures where appropriate Applicants COA

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MODULE 3: QUALITY
3.2.P.5 Controls of Drug Product
Specifications Analytical Procedures submit when a non-USP procedure is used Validation of Analytical Procedures submit when a non USP procedure is used Samples statement of availability (as per 314.94(a)(10)) COA for Finished Drug Product Characterization of Impurities
Identify all impurities List any expected impurities
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MODULE 3: QUALITY
3.2.P.7 Container Closure System
Summary of Container Closure System Components Specification and Test Data Packaging Configuration and Sizes Container/Closure Testing Moisture-permeation, Light Transmission, etc. Source of Supplier and Suppliers Address

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MODULE 3: QUALITY
3.2.P.8 Stability
Stability protocol Proposed expiration date of drug product Tentative maximum of 24 months based on 3 months of accelerated stability*

* Stability requirements may change soon

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CURRENT STABILITY REQUIREMENTS

Stability Guidance for Generic Drugs

Current expectations (one lot):

Study

Storage Condition

Minimum time period covered by data at submission 3 months 3 months

Long-term Accelerated

25C 40C 2C/75% RH 5% RH

*Discussion is ongoing to make expectations more in line with ICH Q1 requirements

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MODULE 3: QUALITY
3.2.P.8.3 Stability Data
Data from four time points should be submitted - 0, 1, 2, and 3 months Must submit minimum of 3 months accelerated stability conducted under stressed conditions of 40C and 75% RH or 25C and 60% RH for refrigerated products For liquid dosage forms, the stability testing must be performed for the container in a horizontal or inverted position This data should be provided even if the product fails under stressed conditions. Batch number must be the same as the exhibit batch

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MODULE 3: QUALITY
3.2.R Drug Product
Executed Batch Records for the drug product Solid Oral Dosage Forms:
Exhibit Batch must be a minimum of 100,000 units or 10% of the proposed production batch Must completely package the exhibit batch in containers proposed for marketing

Parenteral Products:
Must package a minimum of 10% of the exhibit bulk in each vial size(container) proposed for marketing Scale-up should be based upon actual packaged amounts

You must provide a complete reconciliation detailing the disposition of all dosage units in a reconciliation summary table
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RECOMMENDED FORMAT FOR RECONCILIATION SUMMARY

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MODULE 5: BIOEQUIVALENCE
5.3.1.2 BA/BE Study Reports
For products requiring bioequivalence studies, the study information is submitted in this section In-Vivo Studies In-Vitro Studies Studies with Clinical Endpoints Skin Irritation/Sensitization Studies Pharmacokinetic studies must meet BE criteria (90% CI of 80-125, C max, AUC). Automatic Refuse to Receive issue if BA/BE study fails criteria

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MODULE 5: BIOEQUIVALENCE
Module 5: Clinical Study Reports
Bioavailability and Bioequivalence Studies
Study Type and Protocols Study Results and Reports Dissolution Studies

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MODULE 5: BIOEQUIVALENCE
5.3.1.3 In Vitro-In-Vivo Correlation Study
Dissolution data must be provided for 12 dosage units. The dissolution data should compare the proposed product to the reference listed drug for each strength that the applicant is seeking approval. Applicant must also provide mean, range and standard deviation for each time point. Dissolution data is required for all solid oral dosage forms, suppositories and oral suspensions

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BE STUDIES
Usually two-way crossover, single-dose study Normal volunteers ~ 24-36 subjects Fasting
BE criteria: 90% CI between 80 and 125%
AUC Cmax

Fed (90% CI between 80 and 125% for AUC and Cmax)

http://www.fda.gov/ohrms/dockets/ac/00/slides/3657s2_08/sld002.htm

BIOEQUIVALENCE STUDIES
Systemically active generic drugs PK Locally acting generic drugs: PD and PK* data Locally acting generic drugs - clinical data

* As appropriate

WHEN ARE FED BE STUDIES REQUIRED?

Fed bioequivalence necessary
For IR products, when RLD label mentions effect of food on absorption or administration For all Modified-release products If label states not to take drug on an empty stomach, conduct only a fed BE study

THE MOST ACCURATE, SENSITIVE AND REPRODUCIBLE METHODS FOR DETERMINING BIOEQUIVALENCE (21 CFR 320.24)
In vivo PK studies measuring blood concentrations In vivo measurements of urinary excretion concentrations In vivo testing in humans to measure acute pharmacological effect (PD studies) Well-controlled clinical trials

SPECIAL REQUIREMENTS/CHALLENGES
Modified-release dosage forms Oral/nasal inhalations (drug-device combinations) Peptides Liposomal products Non-absorbed oral solid dosage units Transdermals

EMERGING ISSUES AND DEVELOPMENTS FOR THE U.S. GENERIC INDUSTRY

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RECENT DEVELOPMENTS IMPACTING GENERIC DRUG REGISTRATION

Quality by design implementation New stability requirements for ANDAs Generic drug user fees Biogenerics and biogeneric user fees

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Quality by Design and Drug Product Quality

Therapeutic Equivalence Bioequivalence by Design Bioequivalence: Commercial Scale IVIVR or IVIVC PAT Surrogates

Enhance Quality of Drug Products

QbD

Drug Product Stability Formulation Stability by Design

Robust Commercial Manufacturing Excipients Selected Classify CPPs versus non-CPPs Understanding CPP Process Space
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QUALITY BY DESIGN

OVERVIEW OF QBD
Labeled Use Safety and Efficacy

DEFINE Quality Target Product Profile

DESIGN Formulation and Process

IDENTIFY Critical Material Attributes and Critical Process Parameters

CONTROL Materials and Process

TARGET

DESIGN and UNDERSTANDING Yu. Pharm . Res. 25:781-791 (2008)

IMPLEMENTATION
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SIGNIFICANCE OF QUALITY BY DESIGN

QUALITY BY DESIGN
FDA is already asking QbD questions Carefully evaluating development activities for:
Product development Process development Justification for specifications

Must incorporate QbD principals at the time of product development to satisfy FDA requirements

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NEW STABILITY REQUIREMENTS UNDER DISCUSSION BY FDA

Stability
Study Long-term Storage Condition 25C 2C/60% RH 5% RH 30C 2C/65% RH 5% 40C 2C/75% RH 5% RH Minimum time period covered by data at submission 6 months

Intermediate Accelerated

6 months 6 months

Also under consideration at submission 3 batches for ANDA filing/batch sizes under discussion
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GENERIC DRUG USER FEE PROGRAM

Fee Sources*
Annual establishment fee for finished dosage form manufacturers and API manufacturers ANDAs Prior Approval Supplements Drug Master File (New DMFs or DMFs that allow reference by ANDAs for the 1st time after October 1, 2012)

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GENERIC DRUG USER FEE PROGRAM

Key program attributes

5 year program $299 million in user fees annually Effective October 1, 2012

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GENERIC DRUG USER FEE PROGRAM

GMP Inspections Bienniel inspection parity for foreign and domestic facilities by year 5 Risked based flexibility (up to 3 years between inspections) in early years of program

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BIOSIMILAR/BIOGENERICS IN THE U.S.

FDA will accept abbreviated applications for biological products Very complex compared to ANDA approval process Most will require abbreviated clinical studies along with extensive analytical characterization data to demonstrate that the biogeneric is:
- Highly similar - No clinically meaningful differences

FDA recently issued draft guidances

Eligible for interchangeability determination by FDA

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BIOSIMILAR USER FEE PROGRAM

Annual Establishment Registration Fee: Paid annually by each establishment listed in the application Product Development Fee: If designed appropriately to provide meaningful early feedback, paid annually by sponsors and deductible from the Application Fee Application Fee: One-time fee paid at time application is submitted
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BIOSIMILAR USER FEE

Same timing and performance goals as established by FDA CDER/CBER procedural guidance under PDUFA would apply Formal meetings Special protocol assessments Formal dispute resolution Review of clinical hold responses Evaluation of proprietary names

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USEFUL INTERNET WEBSITES

CDER Website (Guidance Documents)
http://www.fda.gov/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/ucm064964.ht m

Individual Product Bioequivalence Recommendations

http://www.fda.gov/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/ucm075207.htm

Electronic Orange Book

http://www.accessdata.fda.gov/scripts/cder/ob/d efault

US Pharmacopeia
http://www.uspnf.com/
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THANK YOU FOR THE OPPORTUNITY TO BE PART OF TODAYS PROGRAM

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