1022 Veklury Approval
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Gilead’s Veklury becomes first FDA approved COVID-19 therapy, with NIH adaptive trial as focal point

Oct 23, 2020 | 1:16 AM GMT

Data from NIH’s master protocol trial was the cornerstone for the first FDA approval of a COVID-19 therapy, granted to Gilead’s Veklury Thursday.

The approval highlights the critical role of master protocols for generating substantive evidence on a tight timeline, the relatively limited value of open-label studies, and the challenges of interpreting clinical trial results in the context of a rapidly evolving standard of care.

The nucleotide analog from Gilead Sciences Inc. (NASDAQ:GILD) is approved to treat COVID-19 patients requiring hospitalization who are 12 years of age and older, and weighing at least 40 kg. FDA granted the application fast track and priority review designations, as well as a Material Threat Medical Countermeasure priority review voucher.

In its analysis FDA said Veklury remdesivir demonstrated efficacy in the ACTT-1 Phase III adaptive master protocol trial, sponsored by NIH’s National Institute of Allergy and Infectious Disease (NIAID). The agency said two Phase III trials sponsored by Gilead “provided supportive evidence of efficacy,” while noting the “inherent limitations” of their open-label design. 

Critics of the approval including Peter Bach cited the mixed results for Veklury across trials. Data from WHO’s SOLIDARITY master protocol trial showed Veklury did not reduce mortality, initiation of ventilation or duration of hospitalization.

Bach also said the relevance of the control groups in the two studies that had them is limited because there is “a whole raft of different approaches we are taking today” including the use of dexamethasone in severe patients and anticoagulation strategies. “It is not the same condition/treatment/outcome it was when those trials were conducted,” he wrote in an email to BioCentury.

But former FDA Commissioner Scott Gottlieb thinks the magnitude of the crisis means regulators can’t hold out for home runs.

“We need to accept singles and doubles when it comes to developing treatments for COVID-19, given the scope of the crisis, and how quickly we’ve moved treatments into development,” said Gottlieb. “Based on the available evidence, remdesivir looks like a solid single, and maybe in time better. That can be meaningful for patients.”

The approval comes less than six months after Veklury received emergency use authorization (EUA) from FDA. Concurrently with the approval, FDA revised Veklury’s EUA to authorize its use in suspected or confirmed COVID-19 in hospitalized pediatric patients weighing between 3.5 kg and 40 kg.

Japan’s Ministry of Health, Labour and Welfare approved the therapy via an exceptional approval pathway one week after FDA issued its EUA in May; the European Commission approved the therapy on July 3.

The standard to receive EUA, which can be revoked at any time, is that it is reasonable to believe that a product may be effective, and that its known and potential benefits outweigh its known and potential risks, based on the totality of scientific evidence available.

In contrast, FDA approval requires substantial evidence of effectiveness and a demonstration of safety for the drug’s intended use, as well as a benefits-risk assessment based on rigorous scientific standards to ensure the product’s benefits outweigh its risks for the intended population.

In its analysis, the agency said it did not convene an advisory committee for the application because “there were no issues identified that would benefit from discussion by an Advisory Committee.”

The availability of an FDA-approved standard of care raises the question whether other trials will have to be modified to include Veklury as a control arm.

Saved by recovery 

The double-blind, randomized, placebo-controlled ACTT-1 trial compared 10 days of treatment with Veklury to 10 days of treatment with placebo in patients hospitalized with mild, moderate or severe disease, and showed the median time to recovery was five days faster in the treatment versus control group, at 10 days versus 15 (p<0.001). Recovery was defined as either being discharged from the hospital, or being hospitalized but not requiring supplemental oxygen and ongoing medical care.

In a subset of patients who required oxygen support at baseline, the compound reduced time to recovery from 18 to 11 days. It also met a secondary endpoint of reducing the incidence of new mechanical ventilation or ECMO in these patients. The ACTT-1 data showed a trend toward reducing all-cause mortality in patients treated with Veklury that was not statistically significant. 

Data were published in The New England Journal of Medicine on Oct. 8.

Gilead’s SIMPLE-Severe trial evaluated the safety and efficacy of five days versus 10 days of Veklury in hospitalized patients with severe COVID-19, and showed similar performance in the two arms. FDA said “the absence of a standard-of-care alone arm limited the interpretability of the data.”

Gilead’s report of a survival benefit for the cohorts treated in the SIMPLE-Severe trial compared with a real world data cohort receiving standard of care was not included in FDA’s analysis.

The company’s SIMPLE-Moderate trial evaluated the safety and efficacy of five days versus 10 days of Veklury, compared with SOC in hospitalized patients with moderate COVID-19. Here, a five-day course of treatment showed statistically improved clinical outcomes compared with SOC (p=0.017) as assessed on a seven-point ordinal scale; the effect did not reach statistical significance for the 10-day course.

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