FDA Accepting Less Data, More Surrogate Endpoints in Trials

Marcia Frellick

January 15, 2020

Over the last four decades, the US Food and Drug Administration (FDA) has loosened its requirements for approving new drugs, increasingly accepting less data and more surrogate endpoints in clinical trials, and shortening its reviews, according to a new analysis.

Jonathan J. Darrow, SJD, JD, MBA, with Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and coauthors analyzed data from 1983 to 2018. The review was published online January 14 in the Journal of the American Medical Association.

Among the evidence is that from 1995 to 1997, 80.6% of new drugs were approved on the basis of two pivotal trials — but that number dropped to 52.8% from 2015 to 2017.

Additionally, the average number of new drug approvals, including biologics, went from 34 from 1990 to 1999, to 25 from 2000 to 2009, to 41 from 2010 to 2018. New biologic approvals grew from a median of 2.5 from 1990 to 1999, to five from 2000 to 2013, to 12 from 2014 to 2018.

The number of drug applications that included at least one pivotal trial comparing an experimental medicine with another drug (as opposed to placebo or historical controls) decreased from 44% to 29%.

A number of programs were enacted during the study period that led to faster approvals:

  • The Orphan Drug Act (1983) gave incentives for developing treatments for rare diseases.

  • Fast-Track (1988) was intended to speed new therapies to market for serious and life-threatening conditions by, among other things, skipping phase 3 trials.

  • Accelerated approval (1992) was similar to the Fast-Track program but allowed the use of more surrogate endpoints in trials on which approval was based.

  • With priority review (1992), the FDA committed to first-cycle review deadlines for new drug applications of 6 months for priority applications and 12 months for standard applications. (That period was shortened to 10 months by 2002.)

  • With the Breakthrough Therapy (2012) designation, experimental therapies became eligible for expedited response timelines during clinical development.

The authors urge caution after reviewing the trends over the decades as the FDA navigates the balance between faster approval and maintaining rigorous testing.

"While retaining policies that encourage efficient review, Congress and other government officials should also consider the implications of less rigorous clinical outcome requirements and whether the current complex array of regulatory programs should be simplified," the authors write.

It's unclear from the review whether the less stringent regulation has hurt the drug development process overall.

In an accompanying editorial, Joshua M. Sharfstein, MD, with the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, points to a 2018 study by Hwang and colleagues in the Journal of Clinical Oncology that found "there were no differences between breakthrough and nonbreakthrough medications in response rates, new mechanisms of action, mortality, or serious adverse events."

However, Sharfstein adds that there have been some very positive effects from expedited pathways.

Sharfstein, who was the FDA's Principal Deputy Commissioner from March 2009 to January 2011, notes that because of the changes some very promising drugs are now in the pipeline.

He cites the expedited pathways to approve givosiran (Givlaari, Alnylam) to reduce porphyria attacks by 70% in a randomized, controlled trial; the first medication that targets the most common genetic defect in cystic fibrosis, (elexacaftor/ivacaftor/tezacaftor) (Trikafta, Vertex Pharmaceuticals); and entrectinib (Rozlytrek, Genentech), a cancer treatment that targets a common gene marker.

Sharfstein proposes several ways to make reform at the FDA safer and more effective.

One is strengthening its oversight of postmarketing safety for medications that offer major benefits but also come with serious risks.

He gives an example of a time when more oversight was needed with the Risk Evaluation and Management Strategies (REMS) program under which Congress granted the FDA powers to monitor and restrict patients who might be harmed.

Sharfstein writes, "[T]he FDA had evidence of significant use of transmucosal fentanyl products in patients who were not tolerant to opioids (a contraindication that the REMS program was designed to prevent) but did not investigate or remove prescribing authority from any physicians."

He also urges Congress and the FDA to review which programs should be expedited.

"For example, companies have found ways to use orphan drug approvals to box out competition for some of the country's most popular drugs, far beyond what the Orphan Drug Act intended," he writes. "Fixing the system requires, at a minimum, promoting meaningful competition for non-orphan uses."

The study authors note that the proportion of drugs approved through an Orphan Drug Act designation has more than doubled since its enactment in 1983, increasing from 18% (55/304) in the period 1984 to 1995 to 41% (154/380) in the period 2008 to 2018.

Sharfstein concludes, "If the point of 4 decades of FDA reform was to find new cures faster, the point of reforming FDA reform should be to increase the effectiveness and efficiency of this search, propelling the discovery of needed therapies forward while supporting the ability of the health care system to bring these advances to the patients who need them."

The work was supported by Arnold Ventures and by grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation.

The study authors have disclosed no relevant financial relationships. Sharfstein reports serving as Principal Deputy Commissioner of the US Food and Drug Administration from March 2009 to January 2011 and receiving funding from Arnold Ventures for work related to drug pricing.

JAMA. Published online January 14, 2020. Abstract, Editorial

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