November 25, 2020 — Under FDA law, approval of a new drug requires substantial evidence of effectiveness and a demonstration of safety for the drug’s intended use(s). The approval of remdesivir (Veklury) for the treatment of patients hospitalized with COVID-19 met this legal and scientific standard.
Randomized, controlled trials are the gold standard for evaluating the safety and effectiveness of drugs. FDA’s approval of remdesivir (Veklury) was supported by the agency’s independent, in-depth analysis of data from three randomized, controlled clinical trials that included patients hospitalized with mild-to-severe COVID-19. This included the ACTT-1 trial sponsored by National Institute of Allergy and Infectious Disease (NIAID) and the “SIMPLE” trials (GS-US-540-5774 and GS-US-540-5773) sponsored by Gilead Sciences Inc. The most compelling evidence of effectiveness was provided by the NIAID-sponsored ACTT-1 trial, with its rigorous trial design.
The Basis of Approval
The ACTT-1 trial was a randomized, placebo-controlled, double-blinded trial in 1,062 hospitalized subjects with mild, moderate and severe COVID-19 who received Veklury (n=541) or placebo (n=521), plus standard of care. The primary goal of the ACTT-1 trial was to look at the time to recovery of hospitalized patients. Recovery was defined as either being discharged from the hospital or being hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery from COVID-19 was 10 days for the Veklury group compared to 15 days for the placebo group, a difference that was highly statistically significant. The odds of clinical improvement at Day 15 were also statistically significantly higher in the Veklury group when compared to the placebo group. The overall 29-day mortality was 11% for the Veklury group vs 15% for the placebo group; this difference was not statistically significant.
GS-US-540-5774 was a randomized, open-label multi-center clinical trial of hospitalized adult subjects with moderate COVID-19 that compared treatment with Veklury for five days (n=191) and treatment with Veklury for 10 days (n=193) with standard of care (n=200). Researchers evaluated the clinical status of subjects on Day 11. Overall, the odds of a subject’s COVID-19 symptoms improving were statistically significantly higher in the five-day Veklury group at Day 11 when compared to those receiving only standard of care. The odds of improvement with the 10-day treatment group when compared to those receiving only standard of care were numerically favorable, but not statistically significantly different.
GS-US-540-5773 was a randomized, open-label multi-center clinical trial of hospitalized adult subjects with severe COVID-19 that compared treatment with Veklury for five days (n= 200) and treatment with Veklury for 10 days (n= 197). Researchers evaluated the clinical status of subjects on Day 14. Overall, the odds of a subject’s COVID-19 symptoms improving were similar for those in the five-day Veklury group as those in the 10-day Veklury group, and there were no statistically significant differences in recovery rates or mortality rates between the two groups.
FDA’s review of the scientific evidence from the ACTT-1 trial, combined with its review of the “SIMPLE” trials sponsored by Gilead Sciences Inc., supported the Agency’s determination that the standard for substantial evidence of effectiveness and demonstration of safety as required for new drug approval was met. Full information regarding the data and evidence used to approve Veklury can be found in the “Combined Cross-Discipline Team Leader, Division Director, and ODE Director Summary Review .”
The SOLIDARITY Therapeutics Trial
FDA is aware of the preprint describing the results of the SOLIDARITY trial, a World Health Organization-sponsored, open-label, randomized trial comparing different investigational interventions plus standard-of-care to standard-of-care alone in hospitalized patients with COVID-19. One of the drugs studied in SOLIDARITY was Veklury. The SOLIDARITY trial’s primary goal was to assess for effects of treatment interventions on in-hospital mortality. Like the ACTT-1 trial discussed above, the SOLIDARITY trial did not find a statistically significant difference in mortality between the Veklury arm and the standard-of-care arm.
While both the SOLIDARITY trial and the ACTT-1 trial contribute to our understanding of interventions to help treat COVID-19, the two clinical trials had different trial designs and primary goals. The design of ACTT-1 (i.e., randomized, placebo-controlled, double-blinded) was better suited to rigorously assess a time to recovery endpoint compared to a trial with an open-label design, such as the SOLIDARITY trial. Based on the findings of the ACTT-1 trial, benefit to patients for Veklury was demonstrated including a shorter time to recovery and better odds of clinical improvement. The SOLIDARITY results do not refute these findings of benefit to patients.
COVID-19 has had a devastating impact on the U.S population and the world at large. FDA has responded by working closely with stakeholders to facilitate the development of safe and effective therapeutics for COVID-19. This has led to the issuance of emergency use authorizations (EUAs) for small molecules and monoclonal antibodies, and recently to the approval of Veklury, the first drug approved for the treatment of COVID-19 in certain hospitalized patients.
FDA oversight of drugs does not end with approval; the FDA is empowered by statute to ensure the safety, efficacy, and high quality of approved and marketed drug products, including Veklury. However, FDA does not regulate drug prices, which are set by manufacturers and distributors. FDA also does not take potential pricing into account when conducting reviews on the efficacy, safety and quality of drug products.
Posted: November 2020