Six FDA-Approved Drugs That Failed Primary Endpoints: Regulatory Flexibility in the Face of Unmet Medical Needs
Ipsen
Biopharmaceutical Manufacturer
Preface
In recent years, several new drugs have either failed in clinical trials or lacked sufficient clinical evidence but still received FDA approval. These approvals were not impulsive decisions by the FDA; they were typically aimed at addressing the situation of having "no available treatment," whether it was the approval of Aducanumab for treating Alzheimer's disease (AD) orAmyotrophic Lateral Sclerosis (The approval of Tofersen for ALS reflects the increasing regulatory flexibility of the FDA.
The original intention of the FDA was to provide more treatment options for patients who have no available drugs, but such an approach has also been questioned by many.
A study by Stanford University, Oregon State University, and McGovern Medical School found that the FDA is approving more new drugs based solely on the results of a single clinical trial, which they believe: has led to the submissionNew DrugPharmaceutical companies applying for listing only need to select the results of two clinical trials from numerous trials., and explain the reasons for selecting these two trials, as well as the issues that arose in other clinical trials.
Based on this, this article studies multiple drugs approved by the FDA in the past seven years that failed to meet the Phase 3 clinical endpoint or did not provide sufficient proof of efficacy, and selects six representative approval cases to share with everyone.
Palovarotene（Sohonos）
On August 16, 2023, the FDA approved Ipsen's Palovarotene (Sohonos)., for the treatment of the ultra-rare genetic disorder —— Fibrodysplasia Ossificans Progressiva (FOP),The reason for the approval is that the FDA noted Palovarotene "crossed the pre-specified futility boundary" in a Phase III trial.
For Ipsen, this approval marks a climax on their long and winding road.
In December 2022, the FDA rejected the marketing application for Palovarotene and requested more clinical trial data. In March this year, Ipsen resubmitted the new drug marketing application for Palovarotene.
Ipsen has consistently claimed that the results of the Phase 3 clinical trial were due to statistical differences and biases arising from the use of historical controls. In the briefing document released prior to the FDA's advisory committee meeting in June, the FDA appeared to agree with Ipsen’s statement, noting: "It is reasonable that we will consider using other more appropriate methods to evaluate efficacy." The advisory committee also concluded that the benefits of Palovarotene outweigh its associated risks, voting 11 to 3 in favor.
Elevidys
In June 2023, Sarepta's gene therapy Elevidys for the treatment of Duchenne Muscular Dystrophy (DMD) failed to meet the primary functional endpoint in a randomized trial, butConsidering this is the first gene therapy for treating DMD, the FDA still approved Elevidys.
The basis for Elevidys receiving accelerated approval is its ability to increase the expression of trace amounts of dystrophin, a biomarker that the FDA considers potentially predictive of clinical benefit in 4-5 year-old DMD patients.
However, the FDA did not approve Elevidys so easily, but added an approval condition, requiring Sarepta to complete a study namedEmbark's Phase 3 Clinical TrialResearch to Ensure the Clinical Efficacy of Elevidys.Unfortunately, on October 30, 2023, Sarepta announced that the Phase 3 trial did not meet its primary endpoint.
Tofersen(Qalsody)
On April 26, 2023, the FDA approved the antisense oligonucleotide (ASO) therapy Tofersen (Qalsody), developed by Biogen, for the treatment of amyotrophic lateral sclerosis caused by superoxide dismutase 1 mutation (SOD1-ALS). This is the first FDA-approved therapy for treating hereditary ALS. It is also the first ALS therapy to receive accelerated approval based on biomarkers, althoughThe approval of the drug was based on a surrogate endpoint.
Previously, in the VALOR Phase 3 study, Tofersen did not meet its primary endpoint, as there was no statistically significant change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) from baseline to Week 28.BiogenSeeking FDA Approval for Tofersen Based on NfL.
Like Elevidys, Tofersen also received approval through the FDA's accelerated approval pathway, which allows regulatory agencies to approve drugs when there is an unmet medical need and evidence of efficacy on a surrogate endpoint. For Tofersen, this surrogate endpoint is neurofilament light chain (NfL).
Aducanumab（ADUHELM）
In June 2021, Biogen and Eisai's Aducanumab received accelerated approval from the FDA for the indication of Alzheimer's disease, which may be one of the most controversial approvals in FDA history.
In March 2019, Biogen and Eisai announced the discontinuation of further development of Aducanumab after analyzing the trial data, deeming its efficacy not statistically significant. However, a few months later, the companies reversed their decision, stating that a comprehensive data analysis revealed the EMERGE Phase 3 trial had met its primary endpoint in the highest-dose subgroup.
However, the FDA pointed out,Aducanumab's accelerated approval was based on the positive outcome of a surrogate endpoint in the Phase 3 clinical trial, which showed a reduction in amyloid plaque levels in patients' brains.The FDA stated that the reduction of amyloid plaque deposition may be beneficial to patients. However,The Peripheral and Central Nervous System Drugs Advisory Committee nearly unanimously rejected the proposal., believing that there is not enough evidence to prove that Aducanumab can slow down cognitive decline. In the end, three committee members resigned due to the FDA's decision.
Lurbinectedin（Zepzelca）
In June 2020, the FDA granted accelerated approval to Lurbinectedin (Zepzelca) for the treatment of adult patients with metastatic small cell lung cancer (SCLC) whose disease has progressed after platinum-based chemotherapy. This is the first new drug approved by the FDA for second-line treatment of SCLC since 1996.
This approval was based on an open-label, single-arm phase II basket trial (NCT02454972), which enrolled 105 subjects with SCLC who had received first-line platinum-based chemotherapy. The results showed that the ORR of Lurbinectedin as a second-line treatment for SCLC reached 35.2%, with an additional 35 patients achieving stable disease, resulting in a disease control rate of 68.6%. The median duration of response (DOR) was 5.3 months.
However,After just 6 months, the drug showed no significant difference in OS compared to chemotherapy in a larger Phase 3 trial.However, Lurbinectedin is still on the market, with sales reaching $70.3 million in Q2 2023.
Pimavanserin（Nuplazid）
On April 29, 2016, the FDA approved Acadia's Pimavanserin (Nuplazid), indicated for hallucinations and delusions associated with psychotic disorders in Parkinson's patients. Pimavanserin is the first drug approved for this indication. The drug's approval by the FDA was based on a clinical trial involving 199 participants.Despite the drug's failure in two other trials.
As an atypical antipsychotic, Pimavanserin carries a black box warning: it increases the risk of death in elderly patients with dementia-related psychosis. However,Since no atypical antipsychotic drugs were approved for this patient population at the time, the FDA still agreed to the drug's approval.
Two years later, CNN reported that there had been 700 deaths related to Pimavanserin, prompting the FDA to reevaluate the drug's safety. After the FDA's final analysis, it was found that Pimavanserin did not present any new or unexpected safety risks, and the benefits of the drug still outweighed the risks.
However, in August 2022, the FDA rejected the supplemental new drug application for Pimavanserin for the treatment of hallucinations in Alzheimer's disease psychosis due to "interpretability" issues with the study data.
Summary
Around 2015, the FDA's approval rules became more flexible. However, some approvals seemed overly aggressive, with numerous cases of confirmatory trial failures after accelerated market entry, a situation the FDA has evidently become aware of.
Since 2022, the FDA has successively introduced a series of policies, such as...Conduct verification tests as required, and needSubmit progress reports twice a year, etc. Moreover,The FDA is also trying to provide assistance in the implementation of clinical trials, such as offering strategic guidance to the industry, assisting with clinical trial registration, and encouraging innovative trial designs.
In summary, the ultimate goal of this series of reforms is to find the optimal balance between rigorous drug efficacy and safety verification and the time it takes to provide medication to patients.
1.https://www.biospace.com/article/6-drugs-approved-despite-failed-trials-or-minimal-data-/
2.FDA Official Website
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