The FDA's rigorous drug review process, often referred to as the "gold standard," ensures that medications are both safe and effective before they reach patients. This standard, which has evolved since 1906, emphasizes the importance of substantial evidence derived from adequate and well-controlled investigations. Recent discussions about returning to this gold standard raise important questions about the future of drug approvals and the potential impact on pharmaceutical innovation.
Historical Context of the Gold Standard
Initially, the FDA did not conduct premarket reviews of drugs. The 1938 amendments required premarket review focusing on safety. The 1962 amendments, prompted by the thalidomide tragedy, mandated that the FDA approve drugs only if they were proven both safe and effective through substantial evidence. This evidence must come from adequate and well-controlled investigations conducted by qualified experts. The FDA's interpretation of "safe and effective" means that a drug's benefits must outweigh its risks. "Substantial evidence" is defined as evidence from adequate and well-controlled investigations, including clinical investigations, by qualified experts.
Accelerated Approval Pathways
In response to the urgent need for AIDS treatments, the FDA introduced accelerated approval pathways in 1992. This allows for the approval of drugs for serious or life-threatening diseases based on their effect on a surrogate endpoint reasonably likely to predict clinical benefit. This approach expedites the availability of promising therapies while requiring post-approval studies to verify and describe the clinical benefit. Congress codified this approach in 1997, revised it in 2012, and reformed the post-approval study requirement in 2023. Accelerated approval has been used for drugs treating cancers and rare diseases.
Potential Shifts and Implications
Calls to return to a stricter interpretation of the gold standard could have significant implications for drug development. This might mean reducing the use of adaptive trial designs, real-world evidence, and digital apps in evaluating drugs. It could also involve mandating at least two randomized controlled trials for approval, potentially slowing down the process and increasing costs, especially for rare disease therapies. Concerns have been raised that limiting the use of accelerated approval pathways could delay access to critical treatments for patients with serious illnesses.
Exceptions to the Standard
There are statutory and practical exceptions to the drug review standard. In 2004, Congress established emergency use authorization, which permits FDA to authorize (rather than approve) for emergency use a drug (or device) that does not meet the approval standard if it is needed to address a domestic, military or public health emergency, and “based on the totality of scientific evidence ... it is reasonable to believe that ... the product may be effective.” FDA also permits the distribution and use of unapproved versions (typically imported or compounded drugs) of approved drugs when the approved drugs are in shortage.
Impact on Innovation and Patient Access
A more rigid application of the gold standard could discourage pharmaceutical companies from investing in the development of new drugs, particularly for rare diseases or conditions where clinical trials are challenging to conduct. The increased cost and time associated with stricter approval requirements could reduce the potential return on investment, leading to fewer drugs being brought to market. This, in turn, could deny patients access to potentially life-improving or life-saving treatments.
