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Regulatory Focus™ > News Articles > 2020 > 4 > Study tracks sharp drop in FDA approvals based on 2 pivotal trials

Study tracks sharp drop in FDA approvals based on 2 pivotal trials

Posted 24 April 2020 | By Nick Paul Taylor 

Study tracks sharp drop in FDA approvals based on 2 pivotal trials

The proportion of drugs approved by the US Food and Drug Administration (FDA) on the strength of two or more pivotal trials fell by almost 30 percentage points over the past 20 years, according to an analysis published in JAMA Network Open.
Guidance from the late 1980s, when FDA set down its thinking on the data needed to win approval, indicate that at least two late-phase clinical trials were needed. However, FDA has long deviated from that standard in situations – for example, for products to treat rare diseases – where the performance of multiple studies would be unnecessary, unethical or otherwise unwise.
The implementation of special regulatory programs in recent decades, starting with Fast Track, has firmed up FDA’s position on when it will accept filings based on more limited data. FDA adopted the programs against the backdrop of a shift in drug development from treatments for common diseases such as hypertension to those for smaller, genetically defined indications. Together, the two trends would suggest that the agency has come to require companies to run two pivotal clinical trials less frequently over the years.
To assess if that assumption is true, researchers at Yale School of Medicine analyzed FDA approvals at three time points: 1995 to 1997, 2005 to 2007 and 2015 to 2017.
The analysis showed 80.6 percent of drugs approved from 1995 to 1997 came to market after completing two pivotal trials, as did 60.3 percent in the 2000s and 52.8 percent in the 2010s. The upshot is the proportion of drugs that won FDA approval based on two pivotal trials fell almost 30 percentage points, or just over a third (34 percent), over 20 years.
The trend is even more pronounced among drugs that came to market via one or more of FDA’s special regulatory programs. Among those drugs, the proportion coming to market backed by two pivotal trials fell from 75 percent in the 1990s to 38.1 percent in the 2010s.
The analysis also showed a shift toward approval of treatments for smaller indications and a focus on accelerating speed to market. Over time, the proportion of pivotal trials that were randomized or double-blinded fell, although even by the 2010s most studies used to support filings for approval followed those best practices. Similarly, the analysis indicated that sponsors moved away from clinical endpoints and into surrogate measures.
While the findings could be interpreted as demonstrating a lowering of approval standards at FDA, the investigators noted that they also found evidence that standards are becoming more rigorous in some ways. Notably, the proportion of approvals supported by at least one trial that ran for six months or more rose 20 percentage points from the 1990 to the 2010s.
Even so, the study “suggests an increasing need for continued evaluation of therapeutic safety and efficacy after approval,” the investigators said, as well as “continued development of life cycle evaluation methods, including enhanced requirements that ensure studies are undertaken and reported.”
JAMA Network Open

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