FDA Highlights the Importance of Confirmatory Studies

Just before the change in administration, FDA officials unveiled two documents attesting to the need for randomized clinical trials to ensure the safety and efficacy of new medical products and added indications. The analyses emphasize the importance of adequate clinical research at a time of mounting pressure to permit sponsors to adopt more flexible research models and to rely more on data from other sources in testing biopharmaceuticals and other regulated therapies.

As part of the debate on allowing greater leeway in how FDA controls off-label communications of medicines, the agency issued a memorandum Jan. 18, 2017 that addresses the public health issues involved in greater sponsor promotion of unapproved product uses. One outcome, says FDA, could be reduced incentives for sponsors to conduct the clinical studies needed to confirm the safety and efficacy of added indications.

At the same time, FDA also released a report that documents the value of large, confirmatory, phase 3 studies in ensuring the safety and efficacy of experimental medical products. The analysis, “22 Case Studies Where Phase 2 and Phase 3 Trials had Divergent Results,” discuses 22 development programs where promising phase 2 clinical trial data was not confirmed in larger phase 3 trials for certain drugs, vaccines and medical devices.

The FDA analysts identified safety and efficacy failures in cases when phase 2 studies were relatively large, and also when the product was already approved for another condition. In some examples, the phase 3 study revealed that short-term results found in a phase 2 study were not associated with long-term benefit, or that the product had toxicity that was not uncovered in the phase 2 study. The analysts conclude that RCTs of sufficient size and duration remain the gold standard for determining whether there is an acceptable benefit/risk profile for a new therapy. More flexible and advanced research methods may support the use of non-traditional study designs and data sources, but controlled trials remain vital for generating critical evidence across all types of products, patients, and diseases. 

Separately, the 62-page memorandum on “Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products” raises concerns that policies permitting sponsors to discuss unapproved uses of medical products might discourage or interfere with the conduct of controlled clinical studies to document the safety and efficacy of those added indications. FDA says it aims to strike “a careful balance” between allowing some communication on off-label uses where better information is not available, and encouraging the continued development and approval of medical products to meet underserved patients. But the agency notes that patients may be reluctant to participate in clinical trials, where they may receive placebo, if the therapy is widely available off-label.

FDA published this memorandum along with two new draft guidances intended to clarify how biopharma companies may discuss information not on approved labels and may present health care economic information on both unapproved drugs and on new indications to knowledgeable payors and formulary committees. The memorandum provides background on rules and policies related to industry off-label communications and details the shortcomings of various alternative approaches to regulating such promotional activities. 

In emphasizing the need to consider public health factors along with First Amendment protections, the document discusses the importance of motivating the development of safe and effective therapies through processes that protect human subjects receiving experimental treatments. And it comments on the importance of ensuring that product labeling is accurate, and that promotional information is reliable.