Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort studyBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h4633 (Published 23 September 2015) Cite this as: BMJ 2015;351:h4633
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The authors show that non-first-in-class (non-FIC) drugs are increasingly gaining access to regulatory programs that are intended to assist the development of drugs for rare or serious conditions. These “expedited programs”, as designated by the authors, include the accelerated approval pathway and the fast-track, orphan, and priority review designations. The authors suggest that these programs may be associated with greater safety risks, and their results raise an important policy question: do non-FIC drugs that have utilized at least one of these “expedited” programs have a higher incidence of post-market safety events?
We studied this question using an internal Food and Drug Administration (FDA) data set containing all non-diagnostic new drugs (including biologics) received by the beginning of fiscal year 1997 (October 1st, 1996) and subsequently approved and launched before December 31st, 2009. During this time period the FDA approved 305 new drugs: 86 were non-FIC drugs that were granted access to an “expedited program”; 116 were non-FIC drugs that underwent the standard development and review process; and 103 were FIC drugs. We measured unanticipated serious drug safety problems using post-market drug safety withdrawals and post-market boxed warnings that were reported up to Dec 31st, 2013.
The data indicate that non-FIC drugs in an “expedited program” were actually less likely to undergo a safety withdrawal than their counterparts. Specifically, 1 out of 86 expedited, non-FIC drugs were withdrawn for safety reasons compared to 5 out of 116 non-expedited, non-FIC drugs.
We expand the above analysis by adding boxed warnings as a post-market drug safety outcome. Non-FIC drugs that underwent an “expedited program” were slightly more likely to have a new boxed warning or be withdrawn for safety than non-FIC drugs that underwent the standard process. 18 out of 86 expedited, non-FIC drugs experienced either a post-market safety withdrawal or boxed warning whereas 18 out of 116 non-expedited, non-FIC drugs underwent either event. However, a chi-square test indicates this difference is not statistically significant at the standard 5 percent level, with a p-value of the test of roughly 0.30.
Our analysis does not support the hypothesis that granting non-FIC drugs greater access to expedited programs substantially increases post-market risks. The results indicate, for drugs treating an unmet medical need, that the FDA is more likely to add a boxed warning than to call for a safety withdrawal, while the opposite may be the case for drugs with therapeutic alternatives. It is also important to note that, although these regulatory programs have been described as “expedited”, each program has different implications for drug development, and none of them lower the regulatory standards of “substantial evidence” of effectiveness and a positive overall benefit/risk assessment. These programs are also targeted towards serious, untreatable, and often rare conditions, for which patients and society have called for greater tolerance of risks and uncertainty. We will continue to monitor these outcomes as more data accumulate, and we thank the authors for their valuable contribution.
Competing interests: No competing interests. Disclaimer: The views expressed in this article are those of the authors and are not intended to represent the opinions of the Food and Drug Administration
Re: Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study
A key issue raised in this interesting report is the concern over the sufficiency of clinical data used by FDA to render approval decisions in a climate where expedited review of pharmaceuticals is being carried out on an ever-increasing proportion of submitted applications. With so many ‘rapid process’ categories with complex and overlapping inclusion criteria, post-marketing follow-up is critical, as the authors note. I am writing to call attention to another aspect of the evolving clinical research enterprise that impacts the speed and quality of FDA submission reviews - quality and integrity of the data.
Effectively ensuring clinical trial data integrity has been successfully achieved by alignment of clinical investigative sites with operational and quality system expertise provided by Site-Specific Research Organizations (SSRO) 1. The existing clinical trial approach accepts poor patient enrollment and after-the-fact data review as a given. Current GCP guidelines include general quality standards, but do not require documented specific quality processes at the sites to ensure study procedures and data collections are completed as intended by the study protocol.
A proposal before the FDA comprises two adjustments to the clinical research enterprise that address accelerated approval review and decision as well as assurance of maximum study data integrity.2 First, any study using a confirmed quality systems approach to study management would receive expedited approval review. In addition, revision of Form 1572 is proposed to specifically allow investigators to delegate clinical trial operational aspects to an SSRO (formerly termed “SS-CRO”) vendor. Implementation of these changes can be accomplished without adjustments to federal regulations and would automatically provide the high quality data sets needed to support the rapid agency review provided. This category of expedited review would naturally integrate the needed process improvements at clinical investigative sites to support the improvement of clinical data review hoped for by all stakeholders in the clinical research community. Countless other positive adjustments to the clinical testing part of the drug development pathway would accompany this SSRO approach.
1. Usala, AL: “Clinical Trial Compliance Issues Affecting Data Integrity.” Food and Drug Law Institute: Bringing Your Pharmaceutical Drug to Market (DiSpirito, Hall and Hill, eds). Washington, DC, The Food and Drug Law Institute, 2015.
2. Usala AL and DiSpirito NP: “Can FDA Accelerate Clinical Trial Timelines and Completion Using Documented cGMP Processes?” Food and Drug Policy Forum 13: 1-17, 2013.
Competing interests: Dr. Klann is employed by CTMG, Inc., an SSRO service provider.