How to Comply with FDA Requirements for Submission of Bioequivalence Data for ANDA (Abbreviated New Drug Application)

  • By: Staff Editor
  • Date: September 30, 2011
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A generic drug is one that is comparable to the innovator (original) drug in dosage form, strength, route of administration, quality, performance characteristics, and intended use. New drugs are covered by patent protection for certain exclusive periods. When the period of exclusivity expires, manufacturers can apply to the Food and Drug Administration (FDA) to sell generic versions.

What is Abbreviated New Drug Application (ANDA)?
Abbreviated New Drug Application (ANDA) is an application for approval of a generic drug. This application is submitted to the FDA Center for Drug Evaluation and Research (CDER) for review and approval. After this, the applicant can manufacture and market the generic drug to provide a safe, effective, and low-cost alternative to the public. Generic drug applications are called “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. 
What is bioequivalence (BE)?
A generic drug must scientifically demonstrate that it performs in the same manner as the innovator drug – this is known as bioequivalence. One way to show this is to measure the time it takes for the generic drug to reach the bloodstream in 24 to 36 healthy volunteers. This gives the rate of absorption of the drug which is then compared to the innovator drug. The generic drug can be successful only if it delivers the same amount of active ingredients to the patient’s bloodstream in the same amount of time. 
Using bioequivalence for generic drug approval was established by the Waxman-Hatch Act. This Act ensures that less costly generic drugs are available without the need for costly and duplicate clinical trials.
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Important facts about generic drugs
Today, in the United States, 7 in 10 prescriptions filled are for generic drugs. The following are some critical facts about generic drugs:
  1. FDA requires generic drugs to possess the same quality and performance as the branded drugs. Though FDA allows for some very small variability in manufacturing process, it has rigorous standards for strength, quality, purity, and potency. 
  2. Research shows that generics work just as well as branded drugs. A study evaluating the results of 38 published clinical trials comparing cardiovascular generic drugs to their branded counterparts found no evidence to show that brand-name heart drugs worked any better than generic heart drugs {Kesselheim, et al., Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis, JAMA. 2008; 300(21)2514-2526}.
  3. The main difference is in the pricing, with the cost of generic drugs being about 80-85% lower than that of the branded ones. Generic drugs help consumers save an estimated USD 8 to USD 10 billion a year at retail pharmacies.
Myths associated with generic drugs
Some common myths associated with generic drugs are clarified in the following Table.
1.       Generic drugs take longer time to act
1.       Generic drugs get approval from FDA only after they show that they take the same time to act
2.       Generics are not as potent as brand-name drugs.
2.       FDA requires generics to possess the same quality, strength, purity, and stability as brand-name drugs.
3.       Generics are not as safe as brand-name drugs
3.       Generics have the same active ingredients and the same risk-benefit profile as their brand-name counterparts.
4.       Generics are often made in substandard facilities.
4.       FDA conducts inspection for generic firms so that they maintain the same standards
5.       Generic drugs cause more side effects.
5.       Side-effect rates are similar as in the case of brand-name drugs.
Requirements to be complied with before seeking FDA approval
The following are the eight requirements generic drugs should fulfill before an application is made to FDA for their approval:
  1. A FDA-approved brand-name drug should be used as the reference. The generic drug should have the same active ingredients, labeled strength, dosage forms, and route of administration as the brand-name drug.
  2. The bioequivalence (BE) of the generic must be similar.
  3. The labeling should be similar to that of the brand-name drug.
  4. The manufacturer must fully document in detail the generic drug’s chemistry, steps involved in its manufacture, and quality control measures.
  5. The raw materials and finished products must meet the U.S. Pharmacopoeia specifications.
  6. The manufacturer must show that the generic drug maintains stability before and after reaching the market and the drug container does not react with the drug.
  7. The firm must provide full description of the facilities it uses to manufacture, process, test, package, label, and control the drug. It should certify that it complies with all federal regulations for current good manufacturing practices.
  8. The FDA conducts an inspection of the manufacturing unit before approval. The FDA inspection ensures that the unit is capable of meeting its manufacturing commitments and maintaining quality consistently.
New FDA regulation
In January 2009, the FDA issued a rule requiring all pharma companies selling generic medications to give bioequivalence data, regardless of whether it supports their application or not. FDA’s final rule on “Requirements for Submission of Bioequivalence Data” (the BE data rule) requires an ANDA applicant to submit data from allBE studies the applicant conducted on a drug submitted for approval.  It should include studies that do not demonstrate that the generic product meets the current bioequivalence criteria. Before 2009, companies were required to furnish only BE studies that supported the generic’s claim.
The US Department of Health and Human Services (HHS) and FDA have published “Submission of Summary Bioequivalence Data for Abbreviated New Drug Applications (ANDAs),” a non-binding, recommendatory document. This is used as guidance for the industry and is available on the internet. This provides recommendations for applicants preparing the “Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD)” for submission to the Food and Drug Administration (FDA). It offers further technical details and the format for application. Harmonization of technical requirements for registration of drugs has been achieved to some extent through international conference on harmonization (ICH) and CTD.
Guidance for preparing and organizing the CTD
Module 1: Administrative Information and Prescribing Information
This module contains documents like labels, specific to each region. For more information on this, one should refer to the General Considerations for Submitting Marketing Applications according to the ICH/CTD Format.
Module 2: Common Technical Document Summaries
This module contains general introduction to the drug, including its pharmacologic class, mode of action, and proposed clinical use. It should not exceed one page, generally. Module 2 should contain 7 sections in the following order:


  1. CTD Table of Contents
  2. CTD Introduction
  3. Quality Overall Summary
  4. Nonclinical Overview
  5. Clinical Overview
  6. Nonclinical Written and Tabulated Summaries
  7. Clinical Summary
Module 2 summaries are described in three separate documents:
  1. M4Q: The CTD - Quality
  2. M4S: The CTD - Safety
  3. M4E: The CTD - Efficacy.
Module 3: Quality
Information on quality should be presented in the structured format furnished in the guidance M4Q.
 Module 4: Nonclinical Study Reports
Nonclinical Study Reports should be presented in the order furnished in the guidance M4S.
Module 5:  Clinical Study Reports
Human study reports and related information should be presented in the order furnished in guidance M4E. 


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