Too Fast or Too Slow? Debate Intensifies over FDA Regulatory Requirements

Jill Wechsler

The surge in new drugs gaining FDA approval based on small, early clinical studies and fast-track reviews has raised concerns about patients being exposed to unsafe therapies with limited benefits. At the same time, patient advocates complain that FDA testing requirements and lengthy review process delays access to potentially life-saving remedies. A main point of agreement is that products approved based on preliminary evidence should be priced much lower than the usual steep launch prices, until further research can document long-term efficacy and safety.

Certainly, FDA is expediting the development and review of most innovative therapies, including many new cancer drugs and therapies for rare diseases that often are approved based on clinical trials with very few enrollees. In 2018, the Center for Drug Evaluation and Research (CDER) provided priority review for 43 of 59 novel new drugs; of the total, 14 had breakthrough therapy status, and 24 benefited from fast track designation. CDER’s annual report on new drug approvals for 2018 celebrates its success in speeding many important medicines through the regulatory and review process with greater efficiency and predictability to support innovation and respond to patient demands.

Even more limited evidence often supports approval of highly innovative cellular and gene therapies, as more cutting-edge treatments emerge designed to replace, repair, or inactivate a gene linked to a serious or fatal condition. The Office of Tissues and Advanced Therapies (OTAT) in FDA’s Center for Biologics Evaluation and Research (CBER) received more than 400 INDs for cellular and gene therapies in 2018, many qualifying as breakthroughs and for the Regenerative Medicine Advanced Therapies (RMATs) designation for products providing evidence of treating, modifying, or curing a serious or life-threatening condition. For such therapies, FDA offers sponsors extra assistance in developing innovative testing and production methods, expedited review, and flexibility in meeting regulatory requirements.

The debate over increased FDA fast-tracking recently heated up with publication in JAMA Internal Medicine of an article questioning the safety and efficacy of the growing volume of drugs benefiting from FDA accelerated approval. This examination of the impact of fast-track development and review follows the decision by Eli Lilly to halt marketing of its cancer drug, Lartruvo, in April due to data from a post-approval study indicating that the treatment does not prolong lives of advanced-sarcoma patients. FDA approved the drug in 2016 based on a small study that showed evidence of patients living longer with the drug.

To many observers, this outcome, while disappointing, reflects how more expeditious drug development and approval programs are designed to work. Ellen Sigal, chair and founder of  Friends of Cancer Research, commented on the JAMA report that FDA’s breakthrough program and other expedited initiatives reflect patient wishes to assume more risk in seeking remedies to urgent medical threats, and that delaying approval until a sponsor gains evidence that a therapy extends overall survival would deny potential cures to thousands.

In fact, many new therapies receiving accelerated approval show evidence of serious side effects and carry strong warnings to limit use to patients with severe conditions and no alternative treatment options. In June, FDA approved a new use of Soliris injection from Alexion Pharmaceuticals to prevent serious visual impairment and paralysis in patients with certain antibodies linked to this condition. Due to possible fatal infections associated with intravenous use of the drug, FDA required restricted use and boxed warnings for this additional use. Another new drug benefiting from accelerated approval is Xpovio from Karyopharm Therapeutics to make it available for adult patients with multiple myeloma, who relapse after treatment with at least four other therapies, and have no alternative treatment options available.  

For therapies approved based on limited testing, it is important for investigators to track adverse events closely and to examine fully how well surrogate endpoints predict real-world overall survival. While longer clinical trials and more confirmatory studies could provide additional evidence of a drug’s potential impact, such requirements would add to product costs and delay access to treatment. FDA and the research community need to ensure that sponsors follow up on initial accelerated approvals with additional studies to assess longer term benefits, despite difficulties in conducting clinical trials on already approved products. At the same time, there is growing support for compelling biopharma companies that benefit from expedited regulatory programs to limit prices on new products until post-approval studies confirm that the treatment has long-term benefits.

Jill Wechsler is the Washington Correspondent for Applied Clinical Trials