FDA Tackles Broken Generic Drug Application Process

Today nearly 84 percent of all prescriptions filled in the U.S. are generic.The generic industry’s trade group, the Generic Pharmaceutical Association (GPhA), has released figures that show the impact of generic drugs: over the last 10 years, generic drugs have saved consumers in excess of 1.2 trillion dollars. At the same time, the FDA has been making steady progress in narrowing the gap between brand drugs and generic drugs in terms of quality and efficacy.

To that end, in January 2014, the FDA published in the Federal Register that it is seeking input from key stakeholders on how to improve the Abbreviated New Drug Application (ANDA) submission process.

The agency has cited poor and incomplete ANDA submissions as a significant impediment to generic drug approvals. Specifically, the FDA is interested in hearing about any difficulties sponsors are having developing and preparing their ANDA submissions that the agency could help address, by providing more or better information to industry.

Generic bioequivalence

The FDA defines a generic drug product as one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics, and intended use. Generic drug applications are termed “abbreviated” because they are generally not required to include preclinical (animal) nor clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent – that it performs in the same manner as the innovator drug.

Clinical performance alone may demonstrate that the drug is capable of being bioequivalent, but it is the manufacturer’s diligence in ensuring consistency of materials and processing along with their quality management system (QMS) that certify the quality and efficacy of a lot on an ongoing commercial basis. Historically, these elements were based upon a documentation-intensive quality philosophy predicated on a system of inspection and testing. The framework that supported this quality approach has always been a key component of the ANDA submission.

New framework

In 2004, after extensive industrydialogue, the FDA changed the paradigm and issued its revised cGMP guidance Pharmaceutical cGMPs for the 21st Century- A Risk Based Approachadvocating a science-based rather than inspection-based approach to product quality and control. With this new philosophy the FDA instituted a framework to raise the level of science associated with generic drug development and drug applications that it termedquestion-based review (QbR). QbR provides generic drug manufacturers with a list of specific requirements essential to creating an approvable ANDA and emphasizing the chemistry, manufacturing, and controls (CMC) evaluation. This QbR process began in early 2005 shortly after the issuanceof the 2004 guidance to achieve the objectives of product quality through performance-based specification, continuous improvement through risk assessment, standardization of review questions, and reduced CMC review. The spirit of this guidance is to speed access to generic medicines.

The GPhA echoes the principles of the 2004 guidance citing a commitment to the principles of scientific rigor directly in its website discussion on quality.

The drive to improve the system is not altruistic by any measure but rather is a direct result of the Generic Drug User Fee Amendments (GDUFA) signed into law on July 9, 2012.With the enactment of GDUFA, the Office of Generic Drugs (OGD) committed to expedite the availability of high-quality, lower cost generic drugs by bringinggreater predictability to the review times for ANDAs and associated amendments and supplements. The OGD agreed to specific performance review metrics to reduce the time to bring a generic drug to market compared to typical preGDUFA review times. However, OGD’s review is often hindered by the quality of the ANDA submissions.

Despite the QbR approach, the FDA has seen continuing issues with ANDA applications. The agency provided a summary of the six largest reoccurring issues in the notice; filing, chemistry, sterility assurance, bioequivalence, fatal flaws in the design itself, and drug master file discrepancies.

While there are procedural deficiencies cited regarding incomplete or missing forms, some of the recurring issues are alarming and contradict any notion of a commitment to scientific understanding as a basis for drug quality.

Another look at ANDA

To assist in revamping the ANDA process, the FDA has asked the public and industry to answer some basic questions.

These four questions reflect an agency that is not only interested in collaborating with the generic industry to debug the process but also knows that the GDUFA funds will give them the ability to follow through on any changes agreed on.

  1. What aspects of the ANDA application process are confusing or not well-defined?
  2. What problems do ANDA applicants encounter when developinga submission that FDA could help address?
  3. Prior to GDUFA, were ANDA submissions consistently slowed or stalled at certain recurring review points post-filing? If so, why?
  4. How should FDA share suggestions for improving ANDA submissions with industry, beyond issuing regulatory guidance?

My question is this: Is the poor quality of ANDAsubmissions a result of confusion on the filing company’s part, or is it an unwillingness to do the work to gain the necessary scientific understanding? The most recent U.S Supreme Court decisions making “pay for delay” illegal raise the stakes for not being first to file.

In 2013, the FDA shocked us bywithdrawing Welbutrin, an approved generic that had met scientific requirements for comparability, after years of complaints from patients that it did not behave in the same way as the brand product. The million-dollar fine levied to Ranbaxy for serious GMP issues that include clinical fraud has cast a dark cloud over the safety and efficacy of generic drugs.

This overture to industry by FDA is motivated partially by a legal commitment from GDUFA and, I believe, by a genuine desire to improve not only the ANDA submission process but to ensure the safety and efficacy of the drugs manufactured. It remains to be seen if the generic drug industry can live up to their commitments and save the public money but also bring high-quality, low-cost drugs to the general public: the true goal of the Hatch-Waxman Act.


  1. Code of Federal Register [Docket No. FDA-2014-N-0032]
  2. Generic Pharmaceutical Association http://www.gphaonline.org/issues/quality
  3. Public Law 112-144, Title III
  4. Federal Trade Commission vs. Actavis http://www.supremecourt.gov/opinions/12pdf/12-416_m5n0.pdf
  5. Hatch-Waxman Act –http://en.wikipedia.org/wiki/Drug_Price_Competition_and_Patent_Term_Restoration_Act