Academic researchers found FDA has approved precision medicines 1.7 years faster on average than nonprecision medicine and with substantially less premarket evidence, which they cautioned could expose patients to unknown risks and uncertain benefits. While the decreased review time speeds up marketing and lowers development costs, it also necessitates waiting for years to collect postmarket data to glean potential adverse events, the researchers concluded in a May Health Affairs article.
FDA has approved a handful of drugs in the emerging field of precision medicine, in which products are targeted at patients based on their genetic characteristics or the genetics of their disease-causing organisms.
Jonathan Darrow, a member of the faculty at Harvard Medical School and one of paper’s authors, said that FDA’s accelerated approach to approving precision medicine was controversial among the study authors. Darrow, speaking at a Health Affairs briefing May 8, was at first hesitant to state an opinion on the approach. Instead, he highlighted a few results of the study, which analyzed all the new therapeutic drugs and biologics approved by FDA’s drug center from Jan. 1, 2013, to June 30, 2017.
The study, “Precision Medicines Have Faster Approvals Based on Fewer and Smaller Trials Than Other Medicines,” found the average development and review times for nonprecision medicines was 7.5 years, while the development and review time for precision medicines averaged 5.8 years. The approval of precision medicines was based on smaller and fewer trials than that of nonprecision medicines, since many of the medicines were designated for accelerated review pathways. However, even when compared to breakthrough-designated nonprecision medicines, breakthrough-designated precision medicines were often developed and reviewed faster, the study found.
A few of the study’s highlights:
- Eighty-five percent of precision medicines were granted priority review designation by the FDA, versus 48 percent for nonprecision medicines.
- Trials for breakthrough-designated precision medicines were nearly twice as likely as breakthrough-designated nonprecision medicines to use neither a placebo nor an active comparator (58 percent versus 32 percent). Precision medical trials were also less likely to be randomized or blinded compared to nonprecision medical trials.
- The treatment arms of precision medical trials had a median number of 212 participants, whereas for nonprecision medicines the number was 336 participants.
The study, conducted by researchers at Harvard and The University of Queensland in Australia, raised concerns about the disparity between the two sets of numbers. “Having fewer clinical trials with characteristics associated with rigorous scientific methods (such as randomization and blinding) may affect the quality and reliability of the data used by FDA to approve these drugs,” the study found. “Trials that use small numbers of patients may also be less likely to reveal adverse events.”
The lack of extensive clinical trial data necessitates rigorous post-marketing data collection, and the reliance on real-world evidence carries risks, the authors cautioned.
“Unfortunately, many patients may sometimes have to wait for years after a product’s approval to obtain additional evidence of its benefits and risks, as many FDA-required postapproval commitments have not been completed in a timely fashion,” the study concluded. “Until enough postmarketing data have been collected, patients may be exposed to unknown risks and uncertain benefits[.]”
But Darrow focused on the benefits of faster development times at the recent Health Affairs briefing. When the moderator pressed him to give an opinion on the study results, Darrow argued that a shorter clinical development period gets medicine into the hands of patients sooner and makes development a less-expensive process for companies, which he said will encourage further research into such products.
However, the study itself cautioned that an increase in precision medicine applications could drain FDA resources. “[S]pecial designations such as breakthrough therapies are highly resource intensive for the FDA, and an influx of sponsors seeking to develop precision medicines and obtain breakthrough therapy designation may further strain limited regulatory resources,” the report states, before noting that the FDA Reauthorization Act of 2017 allocated more funding to the agency’s breakthrough therapy program to keep up with the large number of drugs receiving that designation.
Still, in remarks that seemed to cast doubt on breakthrough programs rather than praise them, Darrow referred to a separate paper he co-authored that critiqued FDA’s breakthrough therapy designation more generally.
Compared with non-breakthrough designated medicines, Darrow said, “what we found is that in the area of oncology breakthrough medicines, there was no statistically significant difference in terms of efficacy, in terms of safety, or in terms of the innovativeness of the drug based on the mechanism of action.”
The paper was released in April and drew sharp criticism from the head of a prominent advocacy organization.
“Although the validity of the breakthrough designation was questioned recently in a tone-deaf article in the New England Journal of Medicine, this designation has provided patients with tremendous benefit since it was passed into law in 2012,” wrote Jeff Allen, president of Friends of Cancer Research, in an opinion piece for STAT. “The NEJM article by Jonathan J. Darrow and his colleagues at Harvard Medical School was numb to both the actual patient experience and how patients may define a significant advance over an existing therapy.”