To date, the FDA has been inconsistent about what safety and efficacy data are necessary for an EUA, said Efthimios Parasidis, professor of law and public health, Ohio State University, Columbus. It is difficult to say if the bar for an EUA is getting progressively tougher or more relaxed based on the three EUAs granted thus far, added a regulatory consultant who is a former FDA official.
The first drug to get an EUA, hydroxychloroquine, had the weakest data, Gilead Sciences’ Veklury (remdesivir) had mediocre data, and the latest EUA recipient, convalescent plasma, had somewhat weaker data in comparison, the consultant added. The authorisations for hydroxychloroquine and chloroquine were later revoked.
At the FDA, there are career scientists who are likely to advocate evidence-based medicine, so FDA Commissioner Stephen Hahn would encounter pushback if he succumbs to political pressure to approve Eli Lilly and Regeneron’s EUA, the consultant added. However, because the US President was treated with Regeneron’s cocktail, it could receive an EUA based on potentially weak data if he pushes for approval and the FDA caves to political pressure, noted the consultant.
Given the urgency of the pandemic, the EUA application for the mAbs is understandable, but the present dataset is only indicative of an efficacy signal, said Dr Robert Shafer, infectious disease professor, Stanford University, California. The two mAb therapies seem to be complementary and have an antiviral effect, said Dr Myron Cohen, associate vice chancellor for Global Health, University of North Carolina, Chapel Hill.
In the LY-CoV555 trial, the mAb did not meet its primary endpoint of viral load reduction at all three evaluated doses of 700mg, 2,800mg and 7,000mg. According to a 7 October presentation, the 11-day viral load reduction at all three doses of LY-CoV555 had a p-value of 0.87. LY-CoV555 appears active, but only the middle dose is statistically different from placebo, said the consultant. In persistently high viral load patients, viral load reduction with the 2,800mg dose versus placebo had a p value of 0.013. In the absence of peer-reviewed data it is difficult to understand if the success in the middle dose was only a statistical issue or another cause, said John Moore, PhD, professor of microbiology and immunology, Weill Cornell Medical College, New York.
REGN-COV2 reduced viral load through Day 7 in the seronegative patient group, which was described posthoc, compared with placebo in the high dose (p=0.03) and low dose (p=0.06), as per a 29 September presentation.
The antiviral effect or viral load reduction with both mAb therapies is unsurprising given preclinical evidence, but more data is needed to justify an EUA, noted Moore. The viral load reduction data still need to be analysed in a peer-reviewed journal to be convincing on the clinical meaningfulness of the secondary clinical endpoints, said Dr Michael Dougan, assistant professor, Medicine, Harvard Medical School, Massachusetts.
In the Eli Lilly study, LY-CoV555 demonstrated an improvement in the Covid-related hospitalisation and emergency room visit secondary endpoint in all doses, Shafer noted. Among 309 patients who received LY-CoV55 at three different doses, the secondary endpoint of the rate of hospitalisations or emergency room (ER) visits was 1.6% compared to 5.8% with 156 patients on placebo (p=0.02). While the patient numbers are small and the trial was not designed for clinical efficacy, the reduction in hospital stay with LY-COV555 is impressive and has meaningful potential, said Dougan.
Regeneron’s mAb cocktail showed efficacy in seronegative patients, indicating mAbs are ideal for patients who have not generated their own immune system response, Shafer said. However, its EUA is unlikely to be restricted to these patients, as these tests are not standard in diagnosing Covid-19 patients, he noted. Still, it could trigger talks for such a test to be integrated in practice, he added.
Eli Lilly’s EUA is focused on high-risk patients, crudely defined as those over age 65 years or with a body mass index (BMI) greater than 35, but the precise definition is awaiting discussions with the FDA, as per a 7 October company call. This high-risk subgroup contains a significant number of patients, said Cohen. It is reasonable for Eli Lilly to limit the EUA to high-risk patients, but detailed data from the group is needed to weigh in on an EUA and guide medical decisions, said Dougan.
Guidelines on how to identify patients who are at risk of progression and should receive the mAb therapies are likely to emerge quickly from physician associations if the therapies get authorised, noted Cohen. Nevertheless, more efficacy data is needed as it would be awkward in practice to only have an EUA for outpatients but not in more severe cases, added Shafer. While more data is needed, there is a possibility additional data may be collected but not publicly released, noted Dougan.
Regarding safety, there is a higher standard in the outpatient setting versus in a hospital setting where patients are constantly monitored, said Chad Landmon, chair, Intellectual Property and FDA Practice Groups, Axinn, Veltrop and Harkrider, Washington DC.
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