The FDA accelerated drug approval program: benefits and limitations
The aim of the US Food and Drug Administration’s Accelerated Approval Program (AAP) is to expedite the development of new therapies that address an unmet need in the treatment of serious diseases.1 However, recent controversies regarding AAP drugs have brought the program under severe scrutiny. We discuss the pros and cons of the program and how they impact its future.
What are the benefits of the AAP?
The major benefit of accelerated approval is that it enables faster access to therapies for serious indications that otherwise have no, or less effective, treatment options. This program is particularly useful for chronic diseases, where the course of the condition is long and determination of the clinical endpoint would take a long time.2 Accelerated approval is based on an endpoint that can likely predict clinical benefit, either via a non-clinical surrogate endpoint or an intermediate clinical endpoint.1 For example, in cancer and HIV, determination of drug effect on survival or morbidity can take a long time because the course of these diseases are long. This results in delayed drug approval and patient accessibility to treatments that could be critical for survival. However, clinical benefit for HIV and cancer can be predicted by evaluating the effect of the candidate therapy on viral load and tumor growth, respectively, which can be determined in a shorter time frame, leading to shorter clinical trials and the potential for faster approval and patient accessibility.2
Since the conception of the AAP, 49.5% of the drugs granted accelerated approval have been granted full approval within a median period of 3.2 years; 6.3% have been withdrawn and 44.3% are pending full approval (being on the market for a median of 1.9 years).2 The low rate of withdrawal relative to the rate of full approval could be considered an indication of the success of the AAP. Nevertheless, the program has several limitations.
What are the limitations of the AAP?
Uncertainty regarding drug safety and effectiveness
For AAP drugs, uncertainty regarding safety and benefits can arise because of inappropriate surrogate endpoints, lack of a meaningful threshold that indicates clinical benefit, and inappropriate study designs such as non-randomized, non-blinded, and inadequately controlled studies.2 For example, in the present controversy regarding Biogen’s(Nasdaq: BIIB) aducanumab (Aduhelm) for Alzheimer’s disease, the endpoint considered for approval was decrease in amyloid plaque levels in the brain; a prominent concern is that this endpoint is unvalidated and does not accurately predict clinical benefit.
Delayed confirmatory trials
Confirmatory trials are critical for ensuring the safety and effectiveness of therapies approved through the AAP. Experts consider that five years is a generous time span for completing confirmatory trials.2 As of April 2021, among drugs for which five years have passed since approval, 76.5% have been granted full approval; 10.3% have been subjected to withdrawal of approval. However, 13.1% (19 drugs) have remained in the market for a median of 9.5 years, without evidence for the granting of full approval.
Full approval despite insufficient evidence
A major concern among stakeholders is that the FDA’s criteria for full approval are not sufficiently high.2 In multiple instances, the agency has granted full approval even when the confirmatory trial results are ambiguous due to lack of randomization and blinding. In other instances, the endpoints considered for full approval do not demonstrate sufficient clinical benefit. For example, improvement in progression-free survival is considered insufficient evidence for full approval when improvement in overall survival has not been demonstrated. However, the FDA granted full approval to multiple AAP oncology drugs, such as bevacizumab (Avastin; Roche [ROG: SIX]), solely on the basis of progression-free survival.
Lack of stringent post-marketing regulatory requirements
The FDA’s post-marketing requirements have been considered unnecessarily generous, such as its requirements for bedaquiline (Sirturo; Johnson & Johnson [NYSE: JNJ]), which was granted accelerated approval in 2012 for multi-drug resistant tuberculosis.2 In the clinical trial on which accelerated approval was granted, although the benefits were determined to outweigh the risks, the number of deaths in the bedaquiline treatment arm was five times that of the placebo arm. However, the FDA’s requirements allowed the company to begin confirmatory trials a year after approval, with results to be submitted 10 years after approval (2022). Considering the number of deaths in the previous trial, more stringent post-marketing requirements might have been appropriate, such as a requiring confirmatory evidence within a shorter period.
Non-withdrawal from the market despite FDA recommendation
When confirmatory trials demonstrate insufficient or no clinical benefit, the FDA may withdraw the accelerated approval status for these drugs. However, there have been delays in executing the market withdrawal of such products, meaning drugs have remained on the market without evidence of clinical benefit. A current example is AMAG Pharmaceuticals’ 17-hydroxyprogesterone caproate (Makena),2 which was granted accelerated approval in 2011 for pre-term birth prevention but which did not show sufficient clinical benefit in confirmatory trials. Although the FDA recommended its withdrawal from the market, upon the company’s request in August 2021, the agency granted a public hearing to discuss this decision.3 Meanwhile, the product remains approved and available on the market.
High cost, uncertain benefit
The high cost of specialty drugs that receive accelerated approval creates concerns about whether the cost justifies the uncertain clinical benefit of these drugs. For example, the AAP drug olaratumab (Lartruvo; Eli Lilly [NYSE: LLY]), indicated for metastatic soft tissue sarcoma, was priced at $106,000 for six months of treatment.2 However, it showed no survival benefit in confirmatory trials.
The Future of the AAP
The above challenges and recent controversies around drugs granted accelerated approval indicates the need for reforms in the AAP. An April 2021 Whitepaper by the Institute for Clinical and Economic Review (ICER) outlines some potential reforms, including:2
- public justification of the FDA’s selection criteria for surrogate endpoints
- requiring increased use of randomized trials to reduce uncertainty at the time of accelerated approval
- a visual alert regarding accelerated approval status on product labels
- enforcing requirement for confirmatory trial completion
- “sunset” accelerated approvals, where accelerated approval is automatically withdrawn upon failure to provide confirmatory evidence by a predetermined date
- a pathway for safety-evidence-based accelerated approval for life-threatening conditions with no approved treatment.
Furthermore, stakeholders can work together to increase reimbursement options for AAP drugs.
Stakeholders and policymakers should consider and extensively discuss potential reforms so that a balance can be achieved among innovation, early access to critical treatments, certainty regarding clinical benefits and risks, and decreased treatment costs.
24-09-2021
https://www.thepharmaletter.com/
References:
- US FDA. Guidance for Industry, Expedited Programs for Serious Conditions – Drugs and Biologics. Available at: https://www.fda.gov/media/86377/download [Accessed September 15, 2021]
- Institute for Clinical and Economic Review (April 26, 2021). Strengthening the accelerated approval pathway: An analysis of potential policy reforms and their impact on uncertainty, access, innovation, and costs. Available at: https://icer.org/images/2021/04/Strengthening-the-Accelerated-Approval-Pathway-_-ICER-White-Paper-_-April-2021.pdf [Accessed September 15, 2021]
- GlobeNewswire (August 19, 2021). Covis Pharma announces FDA's decision to grant public hearing for only FDA-approved treatment to reduce preterm birth in indicated patients. Available at: https://www.globenewswire.com/news-release/2021/08/19/2283797/0/en/Covis-Pharma-Announces-FDA-s-Decision-to-Grant-Public-Hearing-for-Only-FDA-Approved-Treatment-to-Reduce-Preterm-Birth-in-Indicated-Patients.html [Accessed September 19, 2021]
