Ethical Considerations for FDA Accelerated Approval

The U.S. Food and Drug Administration (FDA) recently granted accelerated approval of a treatment for adults with metastatic biliary tract cancer—a condition with less than a 5 percent five-year survival. Doctors explained that this approval addresses the unmet need for effective treatment for patients with this disease.

The process of getting FDA approval for a new drug takes, on average, 10 years and hundreds of millions of dollars. This extensive process risks leaving patients who suffer from severe or life-threatening conditions without access to treatment during this time.

For a drug to receive traditional FDA approval, developers must conduct studies that prove that the drug produces a clinical benefit—defined as a positive impact on the patient’s health—in patients with a certain condition. FDA then uses this data to determine whether the treatment’s clinical benefits outweigh its risks. If the benefits prevail, FDA grants the drug approval.

Recognizing that the length of the approval process may harm patients with untreatable conditions, FDA passed regulations that allow for accelerated approval of drugs that are likely to be effective in treating serious or life-threatening conditions. Rather than basing approval on clinical benefit, FDA evaluates whether a drug has a positive effect on a “surrogate endpoint.”

A surrogate endpoint is a medical indicator or sign that is reasonably likely to predict a clinical benefit. For example, a tumor shrinking in response to treatment is a surrogate endpoint that likely predicts the clinical benefit of increased survival rate or improved quality of life in cancer patients. Clinical trials that use surrogate endpoints more quickly produce results that can be used to seek accelerated approval.

Surrogate endpoints, however, are not always accurate predictors of a treatment’s effectiveness. To ensure that an accelerated drug actually produces a clinical benefit, FDA requires developers to conduct post-approval clinical trials that verify the benefit predicted by the surrogate endpoint. If trials confirm the clinical benefit, FDA grants the treatment traditional approval. Failure to conduct post-marketing studies diligently can result in FDA withdrawing its approval.

Accelerated approval has improved outcomes and treatment options for patients with severe medical conditions. For example, 59 cancer drugs received accelerated approval between 2013 and 2023. The process, however, has been heavily criticized.

In 2021, FDA granted accelerated approval to aducanumab, making it the first approved Alzheimer’s disease treatment. In doing so, FDA acted against its advisory board’s recommendation that aducanumab not be approved. This decision created controversy. Researchers and medical professionals questioned whether the surrogate endpoint actually predicted that the drug was effective in treating Alzheimer’s. After its approval, aducanumab studies failed to show improvements in patients’ cognitive abilities but caused severe side effects—including brain swelling, microhemorrhages, and hallucinations.

Aducanumab manufacturers discontinued the drug in November 2024.

In the wake of the aducanumab controversy, opinions remain mixed concerning whether accelerated approval is justified and ethical.

In this week’s Saturday Seminar, scholars explain the problems and benefits of accelerated approval and propose solutions.

• FDA’s approval of aducanumab was supported by clinical pharmacology standards, argues former director of FDA’s Division of Pharmacometrics Yaning Wang in an article in Alzheimer’s and Dementia: Translational Research and Clinical Interventions. Contrary to criticisms that FDA ignored recommendations from its advisory board, Wang explains that the agency conducted additional analyses that supported the surrogate endpoint used in previous trials. These analyses, Wang contends, supported FDA’s accelerated approval decision. Wang acknowledges flaws and complexities that occurred during the approval process but defends the necessity of FDA’s use of novel analyses in this complex case. To promote continued progress toward developing a cure for Alzheimer’s, Wang urges scientists to publish drug development studies to counter non-scientific criticisms of aducanumab.
• In a recent article in Bioethics, Mattia Andreoletti and Alessandro Blassimme of Switzerland’s ETH Zurich argue that six conditions must be met for accelerated approval to be ethically acceptable. Andreoletti and Blassimme suggest that the four principles of bioethics—beneficence, nonmalfeasance, justice, and respect for persons—can be sufficiently met by requiring six conditions: moral solicitude, evidence, risk mitigation, impartiality, sustainability, and transparency. To achieve these conditions, Andreoletti and Blassimme recommend regulations that clearly define medical conditions and acceptable evidentiary levels, propose improvements for clinical trials, create independent review systems for conflicts of interest, incorporate health technology assessment bodies, and mandate transparent labels for accelerated approval drugs.
• Due to the difficulty of withdrawing a regular approval, Ian T. T. Liu, Aaron S. Kesselheim, and Edward R. Scheffer Cliff of Harvard Medical School recommend in a recent article in JAMA Network confirmatory trials to determine which accelerated approval drugs are effective. Liu, Kesselheim, and Cliff found that 29 of the 46 cancer drugs that went through accelerated approval and were considered for regular approval received it. Liu, Kesselheim, and Cliff, however, determined that nine of these drugs did not increase patients’ survival rates or quality of life. To avoid wasting FDA’s time with approval processes for ineffective drugs, Liu, Kesselheim, and Cliff  recommend confirmatory trials for all accelerated approval cancer drugs before conversion to regular approval.
• Unlike the criteria that FDA uses in its accelerated approval decisions, the European Medicines Agency relies on benefit-risk assessments and a narrower set of treatments to approve potentially life-saving drugs, Jinping Xie of China Pharmaceutical University contends in a recent article in BMJ Open. Although drugs approved through these processes are not supported by complete trial data, 30.4 percent of oncology drugs in the United States and 19.2 percent of oncology drugs in the European Union were overdue for completed postmarketing obligations, Xie notes. Xie argues that both FDA and the European Medicines Agency should enhance the transparency of postmarketing studies for drugs that are approved through an accelerated process.
• In an article in the Journal of Law, Medicine & Ethics, Matthew Herder of Canada’s Dalhousie University argues that FDA needs structural reform in light of controversy surrounding the agency’s use of accelerated approval. Herder contends that although FDA’s current regulatory framework expedites access to medications for serious conditions, accelerated approvals can lead to misleading claims of efficacy in treating serious conditions. Herder suggests that Congress should create an administrative body independent from FDA to assist in approval decision-making. Because FDA is a “political animal,” Herder warns, greater oversight mechanisms are needed to prevent public and private sector relationships from interfering with approval decisions. FDA, at the same time, must encourage ethical cooperation between pharmaceutical companies and regulators, Herder concludes.
• FDA should exercise its post-market authority over accelerated approval drugs in a way that balances the flexibility it exercises in accelerated approval determinations, Holly Fernandez Lynch of the University of Pennsylvania Perelman School of Medicine and several coauthors argue in an article in JAMA Health Forum. Despite FDA’s authority to withdraw approvals, the Fernandez Lynch team explains that it often fails to enforce deadlines and hesitates to withdraw approval. The Fernandez Lynch team proposes that FDA extend its postmarket authorities using the same sections of the Food, Drugs, and Cosmetics Act that authorized the accelerated approval regulations. In general, the Fernandez Lynch team contends that FDA should impose stricter post-approval requirements when it relaxes approval criteria for drugs with uncertain benefits.