Remarkable: Six Drugs Secured Approval Against All Odds, Defying Failed Trials and Sparse Data

The FDA’s recent approvals of certain novel drugs despite failed clinical trials or limited evidence have sparked a debate about whether the agency is moving too quickly or exercising appropriate regulatory flexibility.

One notable trend is the approval of drugs in rare or uniformly fatal diseases, such as amyotrophic lateral sclerosis (ALS), and high-profile approvals like Aduhelm for Alzheimer’s and Qalsody for ALS. These approvals suggest a willingness to be more flexible in such cases.

However, concerns have been raised regarding the FDA’s increasing reliance on single clinical trials for approving novel drugs. A study involving Stanford, Oregon State University, and the McGovern School of Medicine found that the FDA is greenlighting more drugs based on single trials, with pharmaceutical companies required to share results from only two trials. This leaves questions about the selection of these two trials and the outcomes of the other trials.

Another study published in The BMJ in July 2023 revealed that less than half of new drugs approved in the U.S. and Europe provide genuine therapeutic value to patients. Cancer therapies were identified as a major contributor to this issue.

On the flip side, there have been instances where the FDA has taken action to address ineffective medicines. Takeda’s mobocertinib, for example, was withdrawn from U.S. and global markets after failing to meet primary endpoints in a confirmatory trial. Similarly, the FDA withdrew approval for Covis Pharma’s preterm birth drug Makena in April.

BioSpace has highlighted several therapies approved by the FDA over the past seven years that failed to meet Phase III endpoints or lacked consistent proof of efficacy, raising questions about the agency’s approval processes and criteria.

This ongoing debate underscores the delicate balance between facilitating access to potentially life-saving treatments for patients with rare or serious diseases and ensuring the safety and effectiveness of new drugs. It also highlights the importance of ongoing scrutiny and evaluation of the FDA’s regulatory decisions to maintain public trust and prioritize patient welfare.

Ipsen’s Sohonos

The FDA’s approval of Ipsen’s Sohonos (palovarotene) for the ultra-rare genetic disease fibrodysplasia ossificans progressiva (FOP) on August 16th marked a significant milestone, but it came after a challenging journey.

Initially, the FDA rejected the New Drug Application (NDA) for palovarotene in December 2022, citing the need for additional clinical trial data. However, Ipsen persevered, and the FDA accepted their resubmitted NDA in March of the following year.

The pivotal Phase III trial faced hurdles, including the drug appearing to cross a prespecified futility boundary. Ipsen contended that the Phase III results were influenced by statistical discrepancies and biases inherent in using historical controls.

In the lead-up to an advisory committee meeting in June, the FDA seemed to align with Ipsen’s perspective, stating that it was reasonable to consider alternative, more appropriate analyses to evaluate the drug’s efficacy. External advisers also voted decisively, with an 11-3 verdict in favor of palovarotene, believing that its benefits outweighed the associated risks.

This case highlights the complexity and nuances involved in drug approval processes, especially for ultra-rare diseases where traditional clinical trial designs may not be suitable. It underscores the importance of open dialogue, rigorous evaluation, and adaptability in regulatory decisions, ultimately serving the interests of patients with these exceptionally rare conditions.

Sarepta’s Elevidys

The FDA’s approval of Sarepta’s Elevidys in June marked a groundbreaking moment for the treatment of Duchenne muscular dystrophy (DMD). This approval was granted despite the medicine failing to meet its primary functional endpoint in a randomized trial.

Elevidys received accelerated approval based on data demonstrating its ability to increase the expression of the micro-dystrophin protein. The FDA considered this biomarker “reasonably likely to predict clinical benefit” in DMD patients aged four to five years.

As part of the approval conditions, the FDA has mandated that Sarepta conduct a study to confirm the clinical benefit of Elevidys. lists an ongoing Phase I/II study designed to assess the therapy’s safety and efficacy, with an expected completion date of April 2026.

This regulatory decision showcases the FDA’s willingness to prioritize potentially life-changing treatments for patients with serious conditions like DMD, even when traditional endpoints are not met, while maintaining a commitment to rigorous evaluation through post-approval studies. It underscores the agency’s dedication to finding innovative ways to accelerate access to promising therapies for patients in need.

Biogen’s Qalsody

Biogen’s approval of Qalsody (tofersen) in April for the treatment of superoxide dismutase 1 (SOD1)-ALS, a rare subtype of ALS, is another notable example of the FDA’s use of the accelerated approval pathway for drugs addressing unmet medical needs.

Qalsody’s approval was based on its effect on a surrogate endpoint, neurofilament light chain (NfL), after it failed to meet the primary endpoint in the Phase III VALOR study. The primary endpoint was a statistically significant change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) from baseline to week 28.

However, Biogen was able to demonstrate that early initiation of Qalsody led to a slowing of the decline in function and strength in SOD1-ALS patients based on combined analyses of 12-month VALOR data and the associated open-label extension study.

This case underscores how the FDA can use surrogate endpoints to grant accelerated approval for drugs addressing serious conditions with unmet needs. It reflects the agency’s flexibility in evaluating therapies that may not meet traditional endpoints but offer meaningful clinical benefits to patients facing devastating diseases like ALS.

Biogen and Eisai’s Aduhelm

The FDA’s approval of Aduhelm (aducanumab) in June 2021 was indeed one of the most controversial approvals in recent history, sparking intense debate and commentary within both scientific and mainstream circles regarding the drug’s efficacy and merits.

The journey to Aduhelm’s approval was marked by twists and turns. In March 2019, Biogen and Eisai initially announced their decision to discontinue the development of aducanumab after a futility analysis indicated its potential ineffectiveness.

However, several months later, they reversed their stance, asserting that a comprehensive data analysis revealed that the Phase III EMERGE trial had achieved its primary endpoint in a subpopulation receiving the highest dose of the drug.

The FDA’s approval of Aduhelm was based on its capacity to induce a significant dose-and time-dependent reduction in amyloid beta plaque, a well-established biomarker for Alzheimer’s disease. This reduction was observed in patients receiving Aduhelm, while those in the control arm of Biogen’s three studies showed no reduction in these plaques.

Nevertheless, the FDA’s decision to grant approval for Aduhelm was met with significant controversy, particularly in light of a nearly unanimous vote by its Peripheral and Central Nervous System Drugs Advisory Committee, which concluded that there was insufficient evidence to demonstrate that the drug effectively slowed cognitive decline. The contentious nature of this decision led to the resignation of three committee members.

Aduhelm’s approval serves as a prominent example of the challenging balancing act that regulatory agencies face when evaluating novel treatments for serious diseases, particularly when the evidence regarding their efficacy is subject to debate.

The decision underscores the complexities involved in determining the potential benefits and risks of new therapies for conditions like Alzheimer’s, where effective treatments remain desperately needed.

Jazz Pharmaceuticals and PharmaMar’s Zepzelca

The journey of Zepzelca (lurbinectedin) in the treatment of small cell lung cancer (SCLC) is marked by a stark contrast in trial results, highlighting the complexities of drug development and the role of real-world effectiveness.

Zepzelca initially secured accelerated FDA approval in June 2020 for the treatment of SCLC that had progressed after platinum-based chemotherapy. This approval was based on the results of an open-label monotherapy study involving 105 patients. The trial demonstrated an overall response rate of 35% and a duration of response of 5.3 months.

However, just six months later, in December of the same year, Zepzelca faced a setback when it failed to meet the primary endpoint in a much larger Phase III trial. In this larger trial involving 613 patients, Zepzelca combined with doxorubicin did not show a significant improvement in overall survival when compared to the physician’s choice of topotecan or cyclophosphamide/doxorubicin/vincristine.

Despite the mixed trial results, Zepzelca remains on the market and has generated significant sales for Jazz Pharmaceuticals. The drug’s continued presence highlights the complexities of evaluating real-world effectiveness and the potential benefits it may offer to some patients, even when it falls short of meeting specific clinical trial endpoints.

The case of Zepzelca underscores the importance of ongoing evaluation, post-marketing studies, and individual patient considerations in the field of oncology, where treatment options are often limited, and even modest clinical benefits can make a meaningful difference in patients’ lives.

Acadia’s Nuplazid

The approval of Acadia Pharmaceuticals’ Nuplazid (pimavanserin) in 2016 for the treatment of hallucinations and delusions associated with psychosis in Parkinson’s disease marked an early instance of the FDA’s trend toward greater regulatory flexibility, particularly in addressing unmet medical needs.

Nuplazid was the first medication approved for this indication, and its approval was based on demonstrated efficacy in a six-week clinical trial involving 199 participants. It’s worth noting that the drug had failed in two other trials.

As an atypical antipsychotic, Nuplazid came with a boxed warning due to an increased risk of death associated with this drug class in older individuals with dementia-related psychosis. At the time of its approval, there was no approved atypical antipsychotic for this patient population.

However, concerns about Nuplazid’s safety profile emerged in subsequent years. Monitoring data indicated an association with more than 700 deaths, leading to a reevaluation of its safety by the FDA. In August 2022, the FDA rejected a supplemental New Drug Application for pimavanserin (Nuplazid) for the treatment of hallucinations linked to Alzheimer’s disease psychosis due to “interpretability” issues with the study data.

The case of Nuplazid underscores the complex balancing act faced by regulatory agencies when evaluating drugs for conditions with limited treatment options. While regulatory flexibility can facilitate access to potentially beneficial treatments, it must be accompanied by rigorous post-approval monitoring and evaluation to ensure both safety and efficacy in real-world settings.

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