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  1. Regulatory Science in Action

A CDER Study of Factors that May Predict the Likelihood of Generic Drug Marketing Applications

Regulatory Science Impact Story


CDER researchers are investigating how drug characteristics, regulatory actions, and economic factors influence whether generic drugs become available for a brand-name drug.

High prices for prescription drugs, which in 2017 accounted for approximately 17% of total personal U.S. health care services, remain a major public health concern, and expenditures are projected to grow significantly through 2022 due to expensive new brand-name products.1 Fortunately, generic drugs are estimated to have saved around $1.7 trillion in U.S. health care costs over the last decade,2 but many brand-name drug products do not face generic competition.3

Identifying Factors that Influence Generic Drug Development

To identify measures that might accelerate the development of generic drug products, CDER researchers recently investigated factors that might predict the likelihood that an abbreviated new drug application (ANDA), relying on a given reference (approved) drug product, would be submitted to the FDA.4 The investigators compiled proprietary data related to ANDAs and other internal or public information maintained by FDA, as well as published information on drug sales, to learn whether a drug’s characteristics, or factors related to its regulatory history or market sales were predictive of an ANDA submission.

All ANDA submissions were compiled for 400 brand-name drugs for which it had become lawful to submit an ANDA between 2011 and 2017. Of these 400 drugs, 140 had been originally approved as new chemical entities (NCEs) (i.e., they did not contain active ingredients that had previously been approved and had thus been granted a period of market exclusivity) and 260 did not have NCE exclusivity (and thus were immediately subject to generic competition on approval). These two groups were analyzed separately for the factors that influence the likelihood of an ANDA submission.

Key Findings of the Study

ANDA submissions occurred for more than half of the NCE products within the first two weeks after those ANDAs could be lawfully submitted. For these drugs, an application for a generic was more likely to occur if the brand-name drug had generated higher revenues. For example, if market exclusivity resulted in annual revenues greater than $250 million for up to a four-year period after the approval date, an ANDA submission for the given reference product was nearly four times more likely to be submitted than for a product generating sales of less than $10 million (Figure 1). A similar trend was observed in the non-NCE group, although the association with sales was not statistically significant. By contrast, designation of a brand-name product as a complex drug (for example, due to its structure, composition, or its mode of delivery) was negatively associated with ANDA submission for both NCEs and non-NCE drugs. The researchers suggested that this result could be explained by challenges in characterizing complex drug substances or drug products, or in developing methods for assessment of the bioequivalence of drug-device combination products or products using complex delivery technologies.

For non-NCE drugs, the data also suggested a strong positive association between the availability of a published product-specific guidance (PSG) before an ANDA submission and an increased likelihood of ANDA submission. PSGs are publicly available documents that describe the FDA’s current thinking and expectations on how to develop generic drug products for a given drug or drug class and are meant to help sponsors identify most appropriate methodology for generating the evidence needed for ANDA approval. Non-NCE drugs for which there was a PSG were approximately 3.8 times more likely to result in an ANDA submission than non-NCE drug products for which no PSG had been published (data not shown).

Patents did not have a significant effect on the likelihood of ANDA submission, consistent with previous findings showing, in the case of large-revenue drugs, that sponsors will challenge the patent even when they are unlikely to win, meaning that higher sales are associated with more pre-generic approval patent challenges (commonly referred to as “Paragraph IV” challenges).5


The CDER investigators found that the timely development of PSGs, including those for complex generics, along with prioritizing complex generic drug research, may facilitate ANDA submissions and promote drug price competition. FDA’s Office of Generic Drugs will continue to communicate best practices and clear recommendations before NCE drugs become eligible for generic competition to help ensure timely ANDA submissions and thus increase generic drug price competition. Increasing generic drug competition may in turn help patients to have access to more affordable therapies, which is a critical part of the CDER mission.

How can this work advance drug development? This retrospective study of the association of drug characteristics and regulatory and economic variables with ANDA submission helps FDA to understand the effects of its practices and policies as it seeks to advance generic drug development. The findings underscore the importance of product-specific guidance in assisting sponsors who wish to submit applications for generic products, especially for those that are alternatives to complex drugs.



Figure 1.  CDER researchers found that new chemical entity drugs with higher sales were more likely to have Abbreviated New Drug Applications submitted, while the opposite was observed for more complex drugs.


Figure 1. CDER researchers found that new chemical entity drugs with higher sales were more likely to have Abbreviated New Drug Applications submitted, while the opposite was observed for more complex drugs. Results are based on Cox proportional hazards analyses. (A higher hazard ratio indicates that the drug was more likely to have an ANDA submission for a generic at any given time after its exclusivity expired.) HR = hazard ratio; CI = 95% confidence interval; LCL = lower 95% confidence limit; HCL = higher 95% confidence limit; ANDA = abbreviated new drug application.

1Office of the Assistant Secretary for Planning and Evaluation. U.S. Department of Health & Human Services. Observations on trends in prescription drug spending. 2016. Accessed 18 Sept 2018.
2Association for Accessible Medicines. 2017 Generic drug access and savings in the U.S. Report. 2017. Accessed 02 Feb 2018.
3U.S. Food and Drug Administration. List of off-patent, off-exclusivity drugs without an approved generic. 2018. Accessed 27 May 2019. And the Pew Charitable Trusts. FDA Approves More Generic Drugs, but Competition Still Lags. February 2019. Accessed 27 May 2019.
4Wittayanukorn S, Rosenberg M, Schick A, Hu M, Wang Z, Babiskin A, Lionberger R, Zhao L. Factors that have an Impact on Abbreviated New Drug Application (ANDA) Submissions. Ther Innov Regul Sci. 2020 Jun 3. doi: 10.1007/s43441-020-00163-x.
5Grabowski H, Long G, Mortimer R, Boyo A. Updated trends in US brand-name and generic drug competition. J Med Econ. 2016 Sep;19(9):836-44. doi: 10.1080/13696998.2016.1176578. And Gleklen J, Smith K. Generic drugmakers will challenge patents even when they have a 97% chance of losing: the FTC Report that K-Dur Ignored. Competition Policy International 2012 Sep 13.

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