Do FDA’s Reforms Need Reforming? Report Looks Back on 4 Decades

Regulatory NewsRegulatory News | 14 January 2020 |  By 

A new report appearing in JAMA on Tuesday outlines why the reforms at the US Food and Drug Administration (FDA) over the past four decades may need further changes.
The most significant of those changes, according to the authors, include FDA’s commitment to review applications for new drugs and biologics in less time; the creation of expedited review programs at FDA, including priority review, fast track, breakthrough therapy designations and accelerated approval; and new incentives for bringing products to market and conducting pediatric studies.
Overall, the authors found that the use of FDA’s expedited programs has increased over the last three decades, from half (48%) of drugs approved from 1986-1996 qualifying using one or more expedited programs to two-thirds (64%) of drugs approved from 2008-2018 using such programs.
Harvard professors Jonathan Darrow, Jerry Avorn and Aaron Kesselheim chart the increase in the use of these programs and designations and note that “the legally mandated requirement that efficacy claims be supported by ‘adequate and well-controlled’ trials has become more flexible and controversial.”
The number and characteristics of pivotal studies used to support the approval of new drugs has also changed dramatically over time. “The proportion of new approvals supported by at least two pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively,” the authors write, though they note that the number of patients studied in aggregate did not change significantly between the two periods.
But the authors found that amid reforms aimed at accelerating the development and review of new medicines, the time necessary to take a drug from clinical testing to FDA approval remained relatively flat over the decades, increasing slightly from 7.8 years from 1986-1996 to 9.1 years from 2008-2017.
They offer some explanation for why development times have held steady overall: “The resistance of total development times to efforts to shorten them could be the result of more submissions of applications for rare disease drugs, which can sometimes pose trial recruitment challenges; a shifting emphasis to more challenging therapeutic categories, such as central nervous system disorder treatments; longer time horizons needed to establish efficacy when early intervention is important (e.g., cancer); or other factors.”
Notably, one category of products has bucked that trend. Citing previous research, the authors point out that the development time for breakthrough-designated drugs is much shorter than others, at just under five years for those approved through 2016.
Some of the differences in development times for breakthrough drugs stem from the fact that FDA has approved those products based on fewer and earlier stage studies.
“One study found that 52% (16/31) of all breakthrough designated drugs approved between 2013 and 2016 were approved on the basis of Phase I or Phase II trials, 45% (14/31) on the basis of a single trial, and 42% (13/31) without using either an active or a placebo control,” the authors write, noting that the findings were more pronounced for oncology drugs.
Similarly, the proportion of orphan drugs approved has increased from 18% of approvals from 1984-1995 to 41% from 2008-2018. In 2018, four-fifths (81%) of newly approved drugs qualified for one or more expedited program and more than half (58%) received orphan designation.
The authors also note that advances in understanding the genetic underpinnings of many diseases will increasingly make it possible to divide common diseases such as lung cancer into smaller, genetically defined subtypes.
 “Despite the political popularity and perceived success of many of the programs implemented since the 1980s, the facilitated review processes they made possible appear to have led to both the benefits of earlier access, as well as the potential disadvantages of rapid approval of treatments with clinical outcomes that are not adequately characterized,” the authors write.
In an accompanying editorial, Joshua Sharfstein, vice dean for public health practice and community engagement at Johns Hopkins Bloomberg School of Public Health, writes that “the overall picture is not of a struggling FDA, but rather of a regulatory process that has evolved over time into a thicket of special programs, flexible review criteria, and generous incentives.”
Sharfstein, who previously served as FDA’s Principal Deputy Commissioner from 2009 to 2011, notes that it would be difficult to calculate the total impact of these reforms, but suggests a new set of reforms to fine tune.
Specifically, he says that “Congress and the FDA should rationalize the various programs for expedited review,” to address competition concerns surrounding orphan drugs and ensuring products that receive fast track and breakthrough designation are more likely to provide greater benefits to patients.
Sharfstein also proposes strengthening FDA’s risk evaluation and mitigation strategies (REMS) program, recalibrating pediatric exclusivity incentives and looking to new measures to generate more definitive evidence for products granted accelerated approval.


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