According to a study recently published in JAMA Network Open, more recent drug and biologic approvals by the United States Food and Drug Administration (FDA) were based on fewer trials, with less rigorous designs but longer trial durations over time. The study, which examined 273 new drugs and biologics approved by the FDA for 339 indications from three different time periods: 1995-1997, 2005-2007, and 2015-2017. It found that more recent approvals “increasingly used special regulatory programs and were based on fewer pivotal trials. When aggregated by indication, these trials had less rigorous designs but longer trial durations over time.”
Older guidance from the FDA states that at least two late-phase clinical trials were needed for an approval. However, the FDA has started to deviate from that standard in certain situations, especially situations in which the performance of multiple studies may be unnecessary or unethical, such as for products to treat rare diseases.
The use of special regulatory programs in recent decades, starting with Fast Track in 1988, has shown that the FDA will accept filings based on more limited data in certain circumstances. Also, in recent decades, drug development has shifted from treatments for common diseases to smaller, genetically defined indications. These trends may suggest that the FDA, therefore, has come to require companies to run two pivotal clinical trials less frequently in recent years.
The study found that from 1995 to 1997, 80.6 percent of drugs approved completed two pivotal trials, as compared to 60.3 percent from 2005-2007 and 52.8 percent from 2015-2017. This means that the proportion of drugs that obtained FDA approval based on two pivotal trials fell almost 30 percentage points over the course of 20 years.
The trend is even more noticeable among drugs that came to market in one or more of the FDA’s special regulatory programs. Among drugs that came to market in one of those programs, the number that were backed by two pivotal trials fell from 75 percent from 1995-1997, as compared to 38.1 percent from 2015-2017.
Over time, the proportion of pivotal trials that were randomized or double-blinded fell, although even in 2015-2017, most studies continued to support filings for approval with those best practices. The analysis also found that most sponsors of clinical trials moved away from clinical endpoints and into surrogate measures.
While one may interpret the findings to mean the FDA has lowered its approval standards, the study authors actually noted that they found evidence that standards are becoming more rigorous in some ways. For example, the authors note that the proportion of approvals supported by at least one trial that ran for at least six months rose 20 percentage points from the period of 1995-1997 to the period running from 2015-2017.
The authors of the study conclude that the research “suggests an increasing need for continued evaluation of therapeutic safety and efficacy after approval,” in addition to “continued development of life cycle evaluation methods, including enhanced requirements that ensure studies are undertaken and reported.”