Generics: Getting Beyond “File First, Figure it Out Later”

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A GAO report analyzes some of the reasons why so few generics are approved the first time around. NIPTE has proposed a program that would address these issues

Generic pharmaceuticals now account for more than 90% of all prescriptions issued in the United States.  However, the generic pharmaceuticals’ pipeline flow is anything but smooth. A report issued on Aug. 7, 2019 by the US Government Accountability Office (GAO) traces part of the problem to issues with FDA review. The study found that FDA approved only 12% of the 2,030 generic drug abbreviated new drug applications (ANDAs) submitted between 2015 and 2017 during the first review cycle.  Often, this could be traced to incomplete applications and quality problems with the drug or issues found during site inspections. In addition, reviews of complex formulations, notably ophthalmic therapies, were often held up.

However, GAO also found that FDA reviewer comments varied in clarity and substance. Applicants that had filed incomplete ANDAs in the past were also found to be at higher risk of having their applications rejected during the first cycle, GAO’s analysis found. Another problem was that labeling changes required for the equivalent name brand drug were often made late in the ANDA review cycle, delaying approval of the generic. 

FDA recently introduced changes designed to improve communication between reviewers and applicants and developed templates designed to help make the review process more consistent, the report noted. However, GAO recommends that the agency take additional steps to improve the consistency of reviewer comments and that it also looks into the timing required for brand-name drug labeling changes.

The GAO report focused on FDA’s contribution to the problem, but also noted a tendency for applicants to rush to file applications despite gaps in process knowledge that translate into incomplete ANDAs. Focusing on this same tendency, but from the developer’s side, was an analysis of FDA data (1) by the National Institute for Pharmaceutical Technology and Education (NIPTE), which noted that this tendency to rush to file is having a serious impact on the generics pipeline. Over half of the generic drugs approved by FDA either never reach the market or are only commercialized after a delay. Of the 1,600 generic pharmaceuticals that FDA approved in 2017 and 2018, about 43% were not on the market by the start of 2019. In addition, many potential generics either never even make it to the review stage. 

The NIPTE analysis concludes thatscale-up issues, process validation, and repeatability can pose challenges, worsened by pressures to file first without incorporating adequate risk analysis and understanding potential sources of variability, which NIPTE describes as gaps in prior knowledge. 

To counteract these problems, NIPTE has proposed a “New Prior Knowledge” concept that would make crucial process and product information available to improve the quality of the first application and increase the likelihood of more ANDAs being approved during the first review cycle.

Ajaz Hussain, director of NIPTE, discussed the concept with Pharmaceutical Technology.“The generics system works only when more than five generic companies can compete for the market,” he said. Although simple dosage form small-molecule generics may not pose a problem, generic pharmaceutical formulations are now more complex, he said, and mechanisms such as the technical citizen’s petition to block approval or assessment of therapeutic equivalence require additional work,” he says.

PharmTech: What is the New Prior Knowledge concept and what is its goal?


Hussain:  The ‘time-cost-quality’ constraint and the Hatch-Waxman incentive to ‘file first’ in the development of generic drugs can often be a cause for a ‘file-first figure it out later’ approach, in which a manufacturer receives multiple complete response letters, necessitating multiple review cycles. Furthermore, the available information and prior knowledge about API and patient, product and process related failure modes are often not published in peer-reviewed scientific literature. What is published can be highly variable, which increases the likelihood that such failure modes will remain unaccounted for, despite the multiple review cycle process.  

As a result, the efficiency of the nation’s generic drug system remains suboptimal and prone to frequent negative media coverage in the form of warning letters and import alerts, which erodes the trust and assurance that patients need in order to experience equivalent therapeutic outcomes in the real world. ‘New Prior Knowledge’ (NPK) would fill this gap by having NIPTE universities conduct research to make available critical information and knowledge needed for quality by design of generic drug products so that multiple generic companies would be able to use the information and compete with high-quality ANDA submissions.  

NPK would provide a mechanism for defining important generic products and identify what are the technical challenges that have to be addressed, design research programs around those challenges, and then fund it so that information and knowledge can be curated and published so that it eventually becomes available to all generics companies to inform their own development programs, and to FDA to improve its own programs. 

PharmTech: What led to the idea?

Hussain: The notion of NPK is based on my experience at Sandoz and collaboration with Momenta; particularly lessons that were learned in the development of generic enoxaparin, generic glatiramer acetate injection, and biosimilars. Sandoz identified sources of variability and reference products and studied reference product so exquisitely, in order to know the lot to lot variability and failure mode of every component. It took a lot of effort and we were analyzing and understanding failure modes and sources of variability with the most modern set of orthogonal analytical tools.  We wanted a deep understanding of the sources of variation and the failure modes so that we could design equivalent products with more confidence, and without failure rates in manufacturing. Only a few companies have the resources to do that.

Where this information was private at Sandoz, NIPTE would create a public program to generate NPK by characterizing multiple lots of reference products via a set of advanced orthogonal analytical methods (going way beyond basic USP testing requirements). 

PharmTech: Knowing the inevitability of patents ending and generics being developed, could branded drug companies be expected to share any of this information near the end of a drug’s life cycle?

Hussain: I do not believe they would.  NIPTE and its 18 member schools seeks to organize a disciplined mechanism to select drugs and drug products that are difficult to develop and pose a risk of therapeutic inequivalence in the real world.  NPK research would be multidisciplinary and among other things, identify failure modes and methodology for analytical characterization.  This NPK would be peer-reviewed, curated, and disseminated publicly, in time for generics companies to inform their development programs and improve the quality of their ANDA submissions.  FDA would also be able to utilize NPK for their guidance development and to organize their review process.  Associated with NPK would also be considerations for education, training, and certification of a community of pharmaceutical knowledge.

PharmTech: Is NIPTE doing anything to help train FDA reviewers? 

Hussain: Several years ago, NIPTE had developed and conducted an elaborate pharmaceutical technology education program for FDA chemistry, manufacturing, and controls (CMC) review staff. Over the years NIPTE has continued to conduct other specialized training programs for FDA reviewers. At FDA’s request, NIPTE is currently in the process of developing a comprehensive education program for FDA review staff in the Office of Pharmaceutical Quality.


1. US Government Accountability Office (GAO), Report to Congressional Committees, Generic Drug Applications, August 2019.
2. A Hussain, V. Gurvich, and R. Morris, AAPS PharmSciTech20 (3), 140 (2019).