FDA Accelerated Approval Pathway: Controversies and Reform

Sophia Phillips, M.S, Thomas Eagen, PhD, & Diana Zuckerman, PhD

Accelerated approval is a pathway used by the Food and Drug Administration (FDA) to speed up the drug approval process, with the goal of bringing new treatments to the market more quickly. Approval is based on clinical studies which evaluate changes to biological measures, known as surrogate endpoints or biomarkers, that are predicted to impact clinical outcomes like survival, physical function, or quality of life. Statistically significant improvements in these surrogate endpoints can be measured in fewer months than it may take to measure clinical benefits, but may not last as long. Approval is granted with the expectation that additional studies will be completed to confirm that the biological changes lead to clinically meaningful outcomes that are important to patients. When used properly, this pathway can help patients more quickly access new treatments for unmet needs, and may even save lives. However, recent controversies of drugs granted accelerated approval have raised important questions about the evidence needed to determine whether the benefits outweigh the risks in the short-term or the long-term, and what can be done to improve the pathway.

A broad range of drugs have been granted accelerated approval, from treatments for cancer to sickle cell disease to drug-resistant tuberculosis. Some approvals were widely applauded, while others were widely criticized. For example, the drug imatinib, used to treat a type of leukemia, has extended the lives of patients by decades. After being granted accelerated approval, it completed a successful post-market confirmatory study within two years. In contrast, the drug Makena to prevent pre-term birth is a noteworthy example of a drug that was on the market for over a decade before confirmatory studies determined that it failed to reduce pre-term birth rates. The accelerated approval of Aduhelm for the treatment of Alzheimer’s Disease has also been controversial, because the studies submitted to the FDA did not show that it improves cognitive functioning but found that 40% of patients experienced brain swelling or brain bleeds.

This article will provide an overview of the pathway and highlight research that exposes the need for reform.

Origins of Accelerated Approval

The FDA accelerated approval pathway began in 1992 as a result of the HIV/AIDS crisis in the 1980s. Patients were dying because there was a lack effective treatments due to the large backlog of drug applications and slow governmental processes. This lack of lifesaving treatments led to criticism from activist groups, members of Congress, and pharmaceutical companies, which resulted in reform at the FDA and creation of the accelerated approval pathway. As of December 31, 2022, the FDA’s Center for Drug Evaluation and Research (CDER) has approved 290 drugs since the program began.

Requirements for the Pathway

In order to enter the accelerated approval pathway:

  1. The drug must treat a serious condition.
  2. The drug must fill an unmet medical need based on a surrogate endpoint.
  3. Sponsors must agree to complete confirmatory trials to confirm the “predicted effect on irreversible morbidity or mortality or other clinical benefit.”

Accelerated approval is usually based on changes to a surrogate endpoint in a randomized clinical trial. For example, a cancer drug may shrink a tumor in the short-term rather than needing to prove that it improves patient survival in the longer-term. Once a drug is approved through this pathway it can be sold during the years that one or more additional trials are conducted to confirm the drug has a statistically significant and clinically meaningful benefit. If the health benefit of the drug is not confirmed, there is a lengthy process to take it off the market. The average time for removal after accelerated approval is granted is seven years. The drug company usually withdraws the approval voluntarily after a negative vote from an FDA Advisory Committee or pressure from the FDA. Since December 2020, 20 accelerated approval drugs or indications were withdrawn by sponsors when they failed to confirm any meaningful clinical benefit.

Data from Confirmatory Trials

A review of the accelerated approval pathway from the Department of Health and Human Services Office of the Inspector General found that of all 278 drug applications granted accelerated approval, nearly 40% have incomplete confirmatory trials, with 35 not completing at least one trial by its original planned completion date. The review identified four drugs with confirmatory trials that are delayed for between 5 years to nearly 12 years past their original completion dates. It was estimated that Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for drugs granted accelerated approval with incomplete confirmatory trials that post-date their original planned completion dates. Patients, providers, and payors have no way of knowing if the drugs are clinically effective if confirmatory trials are never completed.

Costs of Accelerated Approval Drugs

The cost of these unproven drugs is another area of concern. The FDA does not consider prices in their approval decisions. Prices are decided by the company that makes the product. Patients and insurance companies bear the heavy burden of paying for these new drugs that may not improve patients’ health and may cause expensive complications.

The growth of prices for new drugs has outpaced growth in prices for all other health care services. A study of initial prices for newly marketed brand-name drugs from 2008 to 2021 found that accelerated approval drugs had a median price of $168,344 per person per year. This exceeded the median price for all new oncology drugs ($155,091) and biologics ($84,508) (including regular approvals and accelerated approvals).

One example of the impact of high prices of accelerated approval products is the Alzheimer’s treatment, Aduhelm, which was initially listed for $56,000 per person, per year and required brain scans as well. Following approval, the Centers for Medicare and Medicaid Services (CMS) announced a 14% increase in Medicare Part B premiums for 2022, with approximately half of the increase attributed to the need to generate revenue to pay for Medicare patients taking Aduhelm. A decade earlier, Avastin was removed from market 4 years after being granted accelerated approval for metastatic breast cancer, having more than $2 billion in annual sales. Makena, a drug to prevent pre-term birth, has not demonstrated clinical benefit yet cost pregnant patients approximately $30,000 per pregnancy in the 12 years since being granted accelerated approval.

Better health outcomes may be worth higher costs, but research shows that more expensive drugs are often not more effective. From 2012 to 2017, CMS spent $40.3 billion for accelerated approval drugs that did not evaluate clinically meaningful benefits to patients in their confirmatory trials, yet were awarded full approvals. Additionally, cancer drugs accounted for approximately 85% of all accelerated approvals granted in the past decade, but a 2022 study looking at cancer care expenditures in the U.S. found that increased spending for cancer drugs did not improve cancer mortality rates. With reports claiming Medicare insolvency by 2031, the costs associated with unproven, accelerated approval drugs need to be reevaluated.

The Future of Accelerated Approval Reform

Reforms are needed to reduce or eliminate the loopholes of the accelerated approval pathway that allow ineffective, unsafe, unproven, and expensive drugs to linger on the market for months or years. When the FDA does not enforce criteria and timelines for confirmatory studies, companies have no incentive to remove their products from the market. The FDA should limit and enforce the number of years that companies have to conduct confirmatory studies to demonstrate benefit. For example, FDA should deny accelerated approval until a confirmatory trial is well underway, which will make it more likely that the study will be completed in a timely manner, or at all. An analysis published in January 2023 found that products that began confirmatory trials prior to approval had significantly faster conversion to traditional approval or withdrawal than those without. It can be difficult, if not impossible, to conduct a randomized trial involving a medical product that is already approved by the FDA. FDA also needs clear authority to quickly remove drugs from the market if trials are not conducted in a timely manner, or if the “confirmatory” studies fail to confirm that the benefits outweigh the risks. Fortunately, in November 2022 the FDA advised pharmaceutical companies that confirmatory trials need to be substantially enrolled for an accelerated approval to be granted. However, FDA officials have publicly stated that there would be exceptions.

After the FDA’s announcement, the 2023 Omnibus package included reforms to accelerated approval that codified (entered into law) FDA authority to enforce confirmatory trial requirements and product withdrawals. The final version passed by Congress was a compromise. Some members of Congress wanted the FDA to automatically remove products from the market if confirmatory studies were not completed in a timely manner, but instead the bill encouraged post-approval studies to be underway prior to approval, but did not specify a maximum number of years for completion of the study. The bill also created a council within the FDA to closely monitor and promote proper use of the accelerated approval pathway. This council is comprised of individuals who previously supported controversial accelerated approval decisions, so it is unclear whether the council represents reform for the pathway. Additional legislation is essential to ensure companies follow through with post-market clinical trial timelines and grant FDA authority to remove products from the market.

The accelerated approval pathway is intended to drive innovation and more quickly bring drugs for serious and life-threatening conditions to the market. According to the Institute for Clinical and Economic Review (ICER), an organization that conducts independent evaluations on the value of medical products and treatments, as of 2021, 125 (49.4%) of accelerated approval drugs have gone on to receive full approval and provide meaningful therapeutic benefit to patients. However, the pathway needs to be improved to ensure prompt confirmatory trials and timely removal of ineffective, inferior, or unsafe drugs. These reforms will also reduce medical costs so that we are no longer paying for products that have little or no value.