# Presentation: 000985

## The FDA Process for Approving Generic Drugs

**Gary J. Buehler, R.Ph**
**Director**
- October 29, 2002

- Blue Cross Blue Shield of Michigan
- Continuing Medical/Pharmacy Education Program

## Did you know that generic drugs...

- Are safe and effective alternatives to brand name prescriptions
- Can help both consumers and the government reduce the cost of prescription drugs
- Are currently used in 44% of all prescriptions dispensed

## And...

- Save an average of $45.50 for every prescription sold
- Currently save consumers $56.7 billion/year
- Can save consumers an additional $1.32 billion/year for every 1% increase in the use of generic drugs

- Source:  National Association of Pharmaceutical Manufacturers, December 15, 2000

## Hatch-Waxman Amendments   to FFD&C Act - 1984

- Considered one of the most successful pieces of legislation ever passed
- Created the generic drug industry
- Increased availability of generics
- 1984   12%  prescriptions were generic
- 2000   44%  prescriptions were generic - yet only     8% of revenue for prescription drugs
- Compromise legislation to benefit both brand and generic firms

**Continued**

## Hatch-Waxman Amendments   to FFD&C Act - 1984

- Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities (do not have to repeat expensive clinical and pre-clinical trials)
- Allowed patent extensions and exclusivities to innovator firms

## Office of Generic Drugs

## Office of Generic Drugs

## Office of Generic Drugs

## NDA vs. ANDA Review Process

- Brand Name Drug		Generic Drug
- _NDA__ __Requirements__	__	__ANDA Requirements_
- 1.  Chemistry			1.  Chemistry
- 2.  Manufacturing		2.  Manufacturing
- 3.  Controls				3.  Controls
- 4.  Labeling				4.  Labeling
- 5.  Testing				5.  Testing
- 6.  Animal Studies
- 7.  Clinical Studies		6.  Bioequivalence
- 8.  Bioavailability

**NDA vs. ANDA Review Process**

## What are the requirements for a generic drug?

**What are the requirements for a generic drug?**

- Labeling
- Chemistry/Microbiology
- Bioequivalence
- Legal

## How do we assure the quality of generic drugs?

**How do we assure the quality of generic drugs?**

- First 5 steps of review process are identical to NDA process
- Bioequivalence for complicated products is discussed with the same staff that reviewed the brand product
- FDA has experience with the product
- Scientific literature published
- Product is known to be safe

## Slide 12

## What are the requirements for a generic drug?

**What are the requirements for a generic drug?**

-  Same active ingredient(s)
-  Same route of administration
-  Same dosage form
-  Same strength
-  Same conditions of use
- Compared to reference listed drug (RLD) - (brand name product)

## Labeling

- “Same” as brand name labeling
- May delete portions of labeling protected by patent or exclusivity
- May differ in excipients, PK data and how supplied

## Chemistry

- Components and composition
- Manufacturing and controls
- Batch formulation and records
- Description of facilities
- Specs and tests
- Packaging
- Stability

## Examples of Information Covered in a Chemistry Review

- Qualitative and quantitative listing of all active and inactive ingredients; including grade of each component

**Continued**

## Examples of Information Covered in a Chemistry Review

- Review of manufacturing and controls includes evaluation of:
- Process for manufacturing
- Controls (Inspections, sample points, test, methods, acceptance criteria) in place from the receipt of the raw material to the labeling and storage of the finished product; includes the Certificate of Authorization (COA) from the raw material manufacturer and the firm’s own testing and specifications in a COA
- Synthesis of the active pharmaceutical ingredient(s) (API) (raw material, drug substance) or authorization to reference a Drug Master File (DMF)

**Continued**

## Examples of Information Covered in a Chemistry Review

- Impurity profile of the API
- Stability of the API
- Characterization of degradation products with drug substance and drug product
- Microbiological testing when appropriate (Reviewed by Microbiologists)

**Continued**

## Examples of Information Covered in a Chemistry Review

- Batch formulation and batch records
- Manufacturing record provides a representation of the formula, manufacturing instructions, description and size of manufacturing equipment

**Continued**

## Examples of Information Covered in a Chemistry Review

- Description of the manufacturing facilities in general; identification of all firms and facilities involved
- Stability profile (with information on such things as container/closure system); adequacy of protocol and methods
- Evaluation of methods validation information prior to laboratory evaluation

## Examples of Information Covered in a Chemistry Review

- Container/Closure Systems
- Environmental Assessment compliance

## Manufacturing Compliance Programs

- Purpose - To assure quality of marketed drug products
- Mechanisms - Product Testing
- Surveillance
- Manufacturing/Testing plant inspections
- Assess firm’s compliance with good manufacturing processes

## APPROVED

**U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES**
**PUBLIC HEALTH SERVICE**
**FOOD AND DRUG ADMINISTRATION**
**CENTER FOR DRUG EVALUATION AND RESEARCH**
**OFFICE OF INFORMATION TECHNOLOGY**
**DIVISION OF DATA MANAGEMENT & SERVICES**

**APPROVED**
**DRUG PRODUCTS**

**WITH**
**THERAPEUTIC EQUIVALENCE EVALUATIONS**
**22****nd**** EDITION**

**THE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER**
**SECTION 505 OF THE FEDERAL FOOD, DRUG, AND**
**COSMETIC ACT.**

**2002**

**Electronic Orange Book -**** ****http://www.fda.gov/cder/ob/**

## All FDA approved drug products listed         (NDA’s, OTC’s & ANDA’s)
Therapeutic equivalence codes
“A” = Substitutable
“B” = Inequivalent, NOT Substitutable
Expiration dates:  patent and exclusivity
Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products

- Therapeutic equivalence codes
- “A” = Substitutable
- “B” = Inequivalent, NOT Substitutable
- Expiration dates:  patent and exclusivity
- Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products

**“****Orange Book****”**

## B-Rated Drugs

- Exist because of the evolution of      FFD & C Act
- FFD & C Act 1938 - safety only
- 1962 Amendments - Added effectiveness requirement
- DESI program to assess efficacy of drugs approved between 1938 and 1962
- 1970 - Regulation initiating the ANDA procedure

**Continued**

## B-Rated Drugs

- 1977 - Bioavailability/Bioequivalence (BA/BE) regulations finalized
- Required BA data in NDAs; BE data in ANDAs
- Divided DESI effective drugs - products that needed BE shown in vivo and in vitro (bio problem drugs) and products that BE may be shown in vitro only (non-bio problem drugs)
- Many bio problem drugs approved as safe and effective before 1977 - in vivo determination of BE deferred for reasons such as inadequate methodology
- FDA determined BA/BE regulations could not be used retrospectively

**Continued**

## B-Rated Drugs

- 1984 Hatch-Waxman - gave FDA _statutory_ authority to require a demonstration of BE before an ANDA could be approved.  No longer allowed approval of bio problem drugs
- Products for which in vivo demonstration of BE was deferred are listed as therapeutic inequivalent or “B” rated
- Those still appearing in the Orange Book are about 3% - FDA does not have data demonstrating equivalence _or_ inequivalence

## Definition of Bioequivalence

**Definition of Bioequivalence**

- Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions

## Bioequivalence Example

## Purpose of BE

- Therapeutic equivalence (TE)
- Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring
- The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner

## Model of Oral Dosage Form Performance

## Clinical/PD Dose-Response

## Plasma Concentration-Dose

## Approaches to Determining Bioequivalence (21 CFR 320.24)

- In vivo measurement of active moiety or moieties in biologic fluid
- In vivo pharmacodynamic comparison
- In vivo limited clinical comparison
- In vitro comparison
- Any other approach         deemed appropriate by FDA

- FeV1 Albuterol
- Blanching Study
- Topical Corticosteroid

- Topicals
- Nasal Suspensions

- Questran - Binding Studies
- Nasal Solutions-Sprayer Evaluation
- Propofol - Droplet Size

## Single-dose, two-way crossover, fasted
Single-dose, two-way crossover, fed
Alternatives
Single-dose, parallel, fasted
Single-dose, replicate design
Multiple-dose, two-way                     crossover, fasted
Clinical endpoint study

- Single-dose, two-way crossover, fed
- Alternatives
- Single-dose, parallel, fasted
- Single-dose, replicate design
- Multiple-dose, two-way                     crossover, fasted
- Clinical endpoint study

**Study Designs**

- Long Half-Life (wash-out)
- Amiodarone, Etidronate

- Highly Variable Drugs

- Less Sensitive
- Clozapine (Patient Trials)
- Chemotherapy Trials

- Topicals
- Nasal Suspensions

## Waivers of In Vivo Study Requirements

- Definition
- Criteria (21 CFR 320.22)
- In vivo bioequivalence is self-evident
- Parenteral solutions
- Inhalational anesthetics
- Topical (skin) solution
- Oral solution
- Different proportional strength of product with demonstrated BE

## Statistical Analysis (Two One-sided Tests Procedure)

- AUC and Cmax
- 90% Confidence Intervals (CI) must fit between 80%-125%

## Statistical Analysis 80 - 125 %

- What does this mean?
- Can there be a 46% difference?
- What is a point estimate?
- What is a confidence interval?

## Statistical Analysis

- Bioequivalence criteria
- Two one-sided tests procedure
- Test (T) is not significantly less than reference
- Reference (R) is not significantly less than test
- Significant difference is 20% ( = 0.05 significance level)
- T/R = 80/100 = 80%
- R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)

## Possible BE Results (90% CI)

## Narrow Therapeutic Range (NTI) Drugs

- Drug Products that are subject to therapeutic drug concentration or pharmacodynamic monitoring
- Examples are: Digoxin, Lithium, Phenytoin, Warfarin
- Traditional bioequivalence limit of 80-125% is unchanged for these products

## Generic Warfarin10mg Tablets

- 		AUC0- 	AUC0-	Cmax

## Warfarin Bioequivalence Example

## In Vivo Bioequivalence Inspections

- Covers clinical and analytical components
- Objectives
- Verify quality and integrity of the scientific data
- Ensure rights and welfare of human subjects are protected
- Ensure compliance with the regulations and promptly follow-up on significant problems (research misconduct; fraud)

## Generic Drug Education Program

- Congress acknowledged overall need for educational program
- FY‘02  $400,000 allocation
- Program to educate the public on the quality of generic drug products

## Physician Focus Group Findings

- MDs know little about FDA review and approval process--especially how it differs for generic products
- Lack of knowledge and understanding of bioequivalence (sameness) evaluation testing
- “Placebo” effect - product looks different
- Need more information

## Getting the Message Out

- Target health care providers (Physicians, Pharmacists) as well as consumers
- Continuing Education (CE) Programs
- Office of Training and Communications (OTCOM) Specialists in CDER

## Educational Program Activities

**Educational Program Activities**

- Print PSA	Focus TestingBrochures	NAPs ArticlePosters	Give-AwaysWeb Site Consumer Page	Bus/Train AdsMagazine Ads	Movie Theater Ads

## Slide 49

## Slide 50

## Slide 51

## Generic Drug Education Program Posters

- Contact: Ellen Shapiro
- 		Director, Div. of Public Affairs
- 		Center for Drug Evaluation and Research
- 		phone: 301-827-1667
- Web address:
- www.fda.gov/cder/consumerinfo/DPAdefault.htm

## Office of Generic DrugsCenter for Drug Evaluation and Research