FDA Accelerated Approval Market Withdrawal Drug Review

In 1992, the FDA implemented the accelerated approval system in response to the HIV/AIDS epidemic, allowing drugs to be approved based on reasonably likely predictions of clinical benefits using surrogate endpoints. This allowed pharmaceutical companies to begin selling the drug, with the condition that they conduct confirmatory trials. Since its establishment, this pathway has helped bring nearly 300 new drugs to market, many of which are used to treat unmet medical needs. Recently, Pfizer's decision to withdraw its sickle cell disease treatment, Oxbryta, from the global market has raised widespread industry concern, as well as concerns about the value of the accelerated approval system. This article summarizes five drugs that have been granted accelerated approval in recent years but later withdrawn from the market.

Pfizer's Oxbryta

Withdrawal Date: September 2024

Oxbryta is a hemoglobin polymerization inhibitor, approved in November 2019 under accelerated approval as the first drug specifically targeting the underlying cause of sickle cell disease (SCD). It works by increasing the affinity of hemoglobin for oxygen, thereby inhibiting the polymerization of sickle hemoglobin and the destruction of red blood cells. In November 2019, the FDA accelerated approval of Oxbryta for the treatment of adults and children aged 12 years and older with SCD. 

In December 2021, the FDA expanded the drug's indication to include SCD patients aged 4 years and older. Since its first approval in 2019, Oxbryta has been approved in over 35 countries globally. Initially developed by Global Blood Therapeutics, the company was acquired by Pfizer for $5.4 billion in 2022. According to Pfizer's financial report, Oxbryta generated $328 million in global sales in 2023. 

During the European Medicines Agency review, a study involving 236 patients showed that 8 deaths occurred in the treatment group compared to 2 in the placebo group. Another study focused on leg ulcers showed 8 deaths out of 88 patients. In 2024, Pfizer voluntarily announced the withdrawal of all batches of Oxbryta from the markets where it had been approved and would halt all ongoing clinical trials and global expanded access programs. 

Pfizer stated, "The decision is based on clinical data indicating that the overall benefits of Oxbryta in SCD patients are no longer outweighing the risks. Data show an imbalance of vaso-occlusive crises and fatal events, requiring further evaluation." 

Despite Oxbryta's withdrawal, patients now have more treatment options, including two gene therapies, Lyfgenia and Casgevy, which the FDA approved last year.

Biogen and Eisai's Aduhelm

Discontinuation Date: January 2024

Aduhelm became one of the most controversial FDA approvals in recent history, receiving approval in June 2021 as a treatment for Alzheimer's disease. The Peripheral and Central Nervous System Drugs Advisory Committee strongly recommended rejection of the drug, voting that the evidence from the Phase III EMERGE and ENGAGE trials was insufficient to determine its efficacy. 

On June 7, 2021, despite opposition from independent experts, the FDA accelerated Aduhelm’s approval, stating that the drug was suitable for all Alzheimer's patients, not just those with early-stage Alzheimer's as included in the clinical trials. This led to the resignation of one member of the FDA's expert advisory committee in protest. 

Due to these controversies, the drug performed poorly commercially. Continuing clinical research became a burden due to lack of market success, and the trials were expected to take until 2026 to complete at a significant cost. 

Meanwhile, competition in the Alzheimer's drug market forced Biogen to focus its limited resources on Leqembi, which was approved by the FDA in July 2023 as the first anti-amyloid beta treatment for Alzheimer's. In January 2024, Biogen, which was fully responsible for the marketing of Aduhelm, ceased all development and commercialization activities to focus resources on Leqembi.

Takeda's Exkivity

Withdrawal Date: October 2023

On October 2, 2023, Takeda announced, after discussions with the FDA, that it would voluntarily withdraw Mobocertinib (EXKIVITY?) from the U.S. market. 

Mobocertinib received accelerated approval from the FDA on September 15, 2021, for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations in adults who progressed during or after platinum-based chemotherapy. In January 2023, Mobocertinib received conditional approval from the NMPA (National Medical Products Administration). The approval was based on the Phase I/II EXKIVITY trial. Data presented at the 2021 ASCO meeting showed an impressive median overall survival (OS) of 24 months in the platinum-based chemotherapy group. Despite this impressive efficacy, the Phase I/II trial was insufficient, and Phase III confirmatory trials (Exclaim-2) were needed. However, Exkivity failed to demonstrate efficacy in the Exclaim-2 trial, leading the company to voluntarily withdraw the drug from the market in October 2023.

TG Therapeutics' Ukoniq

Withdrawal Date: June 2022

In the oncology field, TG Therapeutics' Ukoniq faced a fate similar to Pfizer's Oxbryta. After receiving accelerated approval in February 2021 for the treatment of lymphoma, the FDA withdrew the approval in June 2022 after updated data showed an increased risk of death in patients treated with the phosphoinositide 3-kinase (PI3K) inhibitor. 

The approval of Ukoniq for marginal zone lymphoma and follicular lymphoma was based on the overall response rate from the Phase II UNITY-NHL trial. However, in February 2022, after assessing clinical data showing that "patients taking this drug had an increased risk of death," the FDA initiated a safety investigation and ultimately withdrew the approval.

Gilead's Zydelig

Withdrawal Date: January 2022

Another withdrawn PI3K inhibitor was Gilead's Zydelig. It was approved in July 2014 under the accelerated approval pathway for third-line treatment of relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL). In FL, the overall response rate (ORR) was 54%, and in SLL, the ORR was 58%, with a duration of response (DOR) of 11.9 months, supporting its approval. 

However, Zydelig was associated with four black-box warnings, including risks of fatal liver issues. 

In March 2016, serious adverse events, including infection-related deaths, led to warnings and investigations by both the EMA and FDA. Gilead subsequently announced the suspension of all clinical trials involving Zydelig and stated it would no longer seek to develop it as a first-line therapy for hematological cancers. On January 14, 2022, Gilead voluntarily withdrew Zydelig’s indications for FL and SLL, effectively removing the drug from the market. 

Currently, the safety of PI3K inhibitors has become a significant concern for the FDA, with advisory committees recommending halting single-arm clinical trials of PI3K inhibitors due to safety concerns.

The accelerated approval pathway primarily relies on biomarkers that can predict subsequent clinical benefits, but confirmatory trials are often delayed. 42% of such trials start more than a year after approval or have not yet begun, and these subsequent studies are rarely completed on time. This leads to the continued marketing of drugs that may have “potentially harmful effects” and “insufficient benefits.” Oxbryta has been on the market for nearly five years, while Gilead's Zydelig has been providing treatment to lymphoma patients for over seven years. In contrast, biomarkers are reliable surrogate endpoints in rare genetic diseases, representing the root cause of the disease. Therefore, genetic diseases where a correlation can be demonstrated between biomarkers and disease causes are more suitable for the accelerated approval pathway.

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Evolving FDA Accelerated Approval Pathway Suffers Spate of Withdrawals

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