"Ensuring Public Trust in an Empowered FDA" - Accelerated Approval

 In the latest issue of New England Journal of Medicine, Drs Ross, Berg, and Ramachandran wrote a paper:

"Ensuring Public Trust in an Empowered FDA". 

The paper discussed the recent trend that FDA is granting drug approval using the accelerated approval pathway - approval based on the biomarker or surrogate end points that are deemed “reasonably likely” to predict clinical benefit. 

The accelerated approval pathway was one of the expedited pathways for drug approval in FDA's guidance "Expedited Programs for Serious Conditions – Drugs and Biologics". The guidance defined the accelerated approval as the following: 

Accelerated approval has been historically used in HIV drug approval and oncology drug approval (mostly successful), however, in recent years, the FDA has increasingly expanded the use of the accelerated approval program beyond HIV and oncology therapies - mainly in the neurology area such as DMD, Alzheimer's disease, and ALS. 

The FDA argued that the FDA should exercise “the greatest flexibility possible” under its statutory authority in considering accelerated approval for drugs for the treatment of serious conditions with unmet medical needs. However, applying "the greatest flexibility possible" can empower the FDA, but it may come with consequences. 

Accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefits, however, the "reasonably likely to predict clinical benefits" can be difficult to prove, and a lot of time is claimed based on conflicting evidence. According to the paper by Drs Fleming and Powers "Biomarkers and Surrogate Endpoints In Clinical Trials", it is extremely difficult to verify a biomarker can be a surrogate endpoint and can reasonably likely predict clinical benefits. 

The authors concluded:

 "An empowered FDA may prioritize using its regulatory authority to enable timely access to innovative products, but to ensure continued trust in the agency, this priority should be balanced against the challenges clinicians, patients, and caregivers face when there is substantial residual uncertainty about product safety and efficacy."

Also noted was that the FDA established a website "Accelerated Approval Program" where drugs approved through accelerated approval pathway were listed and the status of confirmatory trials to prove the clinical benefit was also listed. 'Ongoing' indicates that the confirmatory trial is ongoing; 'verified clinical benefit indicates the clinical benefit has been confirmed; and 'withdrawn' indicates that the clinical benefit has not been confirmed in the confirmatory trials and the drug approved through accelerated approval has been withdrawn. 

Accelerated Approval is a hot topic lately: 

• FDA Issues Draft Guidance Aimed at Improving Oncology Clinical Trials for Accelerated Approval
• Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics
• Top FDA official: Agency needs to start using accelerated approval for gene therapies
• US FDA to take steps to help gene therapies get accelerated approval

The condition for FDA to grant the accelerated approval is that the sponsor is required to do a confirmatory study (either already ongoing or will start right after the accelerated approval) to verify the drug's clinical benefits. A recent article in JAMA titled "Timing of Confirmatory Trials for Drugs Granted Accelerated Approval Based on Surrogate Measures From 2012 to 2021" concluded the following:

"Accelerated approval expedites the marketing of medications based on uncertain efficacy evidence, but the process depends on timely follow-up trials.We found that more than half of so-called confirmatory studies were not completed in the agreed-on time. In contrast with a recent Office of the Inspector General Report of incomplete confirmatory trials, our study includes late completed trials and manufacturer-reported delays. Limitations include shorter follow-up for more recent accelerated approvals and inability to identify reasons for trial delays.

Incomplete confirmatory clinical trials harm patients who are prescribed expensive drugs

despite uncertain clinical benefits. However, drug manufacturers face few consequences for delays. The Consolidated Appropriations Act for 20236 included accelerated approval reforms, such as granting the FDA greater authority to ensure confirmatory trials are under way before approval, mandating progress reports every 6 months by manufacturers, and clarifying procedures for withdrawal if follow-up trials do not find clinical benefit. It will be important to monitor whether these changes lead to fewer delays or whether additional authority is needed to assure that confirmatory trials are completed in a timely manner for the benefit of patients."