Intended for healthcare professionals

Rapid response to:


Molnupiravir’s authorisation was premature

BMJ 2022; 376 doi: (Published 03 March 2022) Cite this as: BMJ 2022;376:o443

Rapid Response:

Re: Molnupiravir’s authorisation was premature

Dear Editor

Professor Brophy's editorial on Merck's MOVE-OUT trial of molnupiravir [1] raises important concerns. There are other issues with this clinical trial and related studies of molnupiravir. These concerns question the reliability of evidence supporting widespread use of molnupiravir:

1. In the MOVE-OUT trial, there was no overall benefit for molnupiravir versus placebo for resolution of COVID-19 related signs and symptoms [2] (Figure S4, Supplementary Appendix). Of 15 clinical symptoms analysed, only two showed significant benefits over placebo.

2. In the UK PANORAMIC trial [3], coordinated by Oxford University, outpatient with COVID-19 are randomised patients to either molnupuravir or standard of care. The inclusion criteria and primary efficacy endpoint (hospitalisation or death) are similar to Merck's MOVE-OUT trial, with two exceptions: the PANORAMIC trial includes vaccinated patients, and is run during the Omicron wave. In the MOVE-OUT trial, vaccinated patients were excluded. Now that most North American and European patients at highest risk of hospitalisation have been vaccinated, the results from PANORAMIC should be far more clinically relevant, when announced, than those from the MOVE-OUT trial.

3. By March 8th 2022, close to 14,000 patients had been enrolled in PANORAMIC [3]. As explained in Professor Brophy's editorial [1], the MOVE-OUT trial was terminated early for ethical reasons after only 770 patients had been evaluated. By contrast, the PANORAMIC trial, with the same inclusion criteria and primary endpoint but with close to 14,000 patients enrolled so far, is still continuing. Rates of hospitalisation or death are likely to be far lower among vaccinated patients and with Omicron infection in PANORAMIC, compared with MOVE-OUT, conducted in unvaccinated patients infected with more severe previous variants. In PANORAMIC, the original sample size calculation of 10,000 patients assumed a 3% hospitalisation rate for standard of care, with a 33% reduction to 2% for patients taking molnupiravir. This trial sample size is now 40% higher than originally planned, suggesting that hospitalisation could be even lower than originally predicted. This suggests that the clinical benefits of molnupiravir, and associated cost-effectiveness, could be far lower for vaccinated patients in the current Omicron wave.

4. In July 2021, results from an Indian clinical trial of molnupiravir were announced by press release, from a company called Hetero [4]. According to the Indian Clinical Trials Registry, recruitment to the Hetero trial started on 24th May 2021 and then results from the first interim analysis of 741 patients were announced on July 9th. How did Hetero manage to recruit 741 patients, follow them all up for 14 days, validate the database, conduct the statistical analysis and announce the results, in under 7 weeks? This would be a record for any COVID trial, anywhere in the world.

5. The results from the Hetero trial of molnupiravir showed a significant benefit for hospitalisation only for the first 741 patients in the initial press release on July 9th 2021. Results from 477 patients recruited after this were then announced at a recent conference [5], but among these additional patients there was no significant difference in hospitalisation rates between the treatment arms. The rates of hospitalisation fell significantly in the control arm among these additional patients, with no explanation. Why was there such a large difference in outcomes between the first and second phases of the trial?

6. In the Hetero trial, there were highly significant benefits seen for a range of endpoints: clinical recovery, [2] point improvement on WHO scale and viral clearance [4,5]. However in the equivalent analyses of the MOVE-OUT trial, these benefits were not seen - why was there such a difference in outcomes between the two trials of molnupiravir?

7. Two other randomised trials of molnupiravir in India were terminated, apparently for lack of efficacy, but the results were never presented or published. [6]

In summary, the current evidence base for molnupiravir raises more questions than answers. It is not clear whether regulatory authorities have been granted access to patient-level databases from the Indian trials of molnupiravir. It would make sense to wait for results from the Oxford PANORAMIC trial before decisions on the wider use of molnupiravir are taken.


1. Brophy J. Editorials: Molnupiravir’s authorisation was premature
BMJ 2022; 376 doi: (Published 03 March 2022)Cite this as: BMJ 2022;376:o443
2. Supplement to: Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. DOI: 10.1056/NEJMoa2116044. Available online at:
March 8th 2022, date last accessed
3. Oxford University PANORAMIC trial. Platform Adaptive Trial of Novel Antivirals for Treatment of COVID-19 in the Community. Available at: March 8th 2022, date last accessed
4. Hetero press release. Hetero Announces Interim Clinical Results from Phase III Clinical Trials of Molnupiravir conducted in India. Available at:
5. Kumarasamy N, Saha B, Jindal A et al. Phase 3 trial of molnupiravir in adults with mild SARS-CoV-2 infection in India. Conference on Retroviruses and Opportunistic Infections (CROI 2022 Virtual), February 2022. Abstract Oral O-9.
6. Two Indian Drugmakers to end trials of Merck drug for moderate COVID-19. Available at:

Competing interests: No competing interests

08 March 2022
Andrew M Hill
Senior Visiting Research Fellow
Department of Pharmacology and Therapeutics, University of Liverpool
Liverpool L69 3GF, United Kingdom