The Results of Merck’s MOVe-OUT Study are in and...They’re not as Great as Expected
The final results do not live up to the interim results. Why would there be a discrepancy?
Today Merck released the final results of their MOV-OUT study, a study that examined Molnupiravir’s effectiveness as either a prophylactic or early treatment option for SARS-COV2. Unlike the interim results released at the beginning of October, the final results don’t seem to live up to the hype.
As noted in the press release (emphasis mine):
KENILWORTH, N.J. & MIAMI--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics today provided an update on the MOVe-OUT study of molnupiravir (MK-4482, EIDD-2801), an investigational oral antiviral medicine for COVID-19. Data are now available from all enrolled participants (n=1433). In this study population, molnupiravir reduced the risk of hospitalization or death from 9.7% in the placebo group (68/699) to 6.8% (48/709) in the molnupiravir group, for an absolute risk reduction of 3.0% (95% confidence interval [CI]: 0.1, 5.9; nominal p-value=0.0218) and a relative risk reduction of 30% (relative risk 0.70; 95% CI: 0.49, 0.99). Nine deaths were reported in the placebo group, and one in the molnupiravir group. The adverse event profile for molnupiravir remained consistent with the profile reported at the planned interim analysis.
Based on the study design, the definitive evaluation of efficacy was considered complete at the planned interim analysis, when the statistical criterion for success was met and enrollment in the study was discontinued at the recommendation of the external Data Monitoring Committee and agreed to by the U.S. Food and Drug Administration (FDA). As previously reported, at the planned interim analysis, molnupiravir significantly reduced the risk of hospitalization or death from 14.1% (53/377) in the placebo group to 7.3% (28/385) in the molnupiravir group (absolute risk reduction 6.8%; 95% CI: 2.4, 11.3; p=0.0012), for a relative risk reduction of 48% (relative risk 0.52; 95% CI: 0.33, 0.80).
I previously wrote about the concerns from the interim analysis which you can see here. At that time I made sure to remind people to remain skeptical until the rest of the results are in, in case the results are not what they are being made out to be. What we can see now, when comparing the interim and final data, is a pretty decent discrepancy between the two datasets.
Of note, one of the biggest standout points is that the interim data included about half of the actual participants. At that time, ~40% of the participant outcome data was missing. It was strange the amount of praise that Molnupiravir was receiving at the time when nearly half of the data was missing.
And this did not occur with just Merck’s detractors. Many independent outlets commented on the fact that many in the media rushed to quell any notion that Molnupiravir would be an effective treatment if it meant fewer people would receive vaccinations. Some of these independent journalists argued against this stance being taken by those in the media, a stance that I objectively agree with. However, none of them questioned many of the strange results in this study, a big one being that the study was not even completed! This piece was overlooked and tended not to be mentioned.
So why would half of the data remain unreleased until now? Well, let’s compare the results and see.
Another thing to point out is that the interim data indicated no deaths in the treatment group, whereas the placebo group saw 8 deaths. At that point I noted that the death rate was relatively low so even though the treatment group saw no deaths the low death rate may have masked that information.
However, the final results indicate that the treatment group did see one death while the placebo group had a total of 9. Again, that death rate is relatively low, however the difference between the interim and final results was the addition of one death to each trial group, a discrepancy that seems unusual.
Remember that studies are conducted with the intent to act as a representation of the population as a whole. In many instances, many variables take place to give the results provided, and most of the time those variables are taken into consideration. Regardless, we assume that the results should be representative of a population. In the case of interim results, we should expect that the interim results may be representative of the final results to some degree.
In this instance we can exclude the single treatment death from the treatment group as that would be hard to discern and predict from the interim data. However, what we should expect to see is that the placebo group should include more deaths when the other 40% of the results are included. It most likely wouldn’t be an additional 8, but the idea that only 1 additional death occurred in the other 40% of the population study seems far lower than would be expected from the interim data.
On that note, one has to question whether the interim data may have been cherry picked in order to give Molnupiravir a much greater appearance of being effective. Not only does this mean the relative death risk may have been fudged between the two test groups, it also means that the relative death risk in the placebo group is far lower than would originally have been far lower than reported.
From the interim data, 8/377 placebo group participants died, around 2.12% of the participants. However, with the new dataset that contains 699 placebo participants, a death rate of 9/699 comes to 1.29%, about half of what was originally reported (~40% lower).
This should really highlight how easily statistics can be manipulated and reported. I highly doubt many people would question why the final results don’t seem proportional to what was reported in the interim data. Know this does not mean that true manipulation may have occurred, but it doesn’t disabuse the idea when this helps provide Molnupiravir with high praise and a large push for its approval.
This becomes even more egregious when we look at the hospitalization and death rates. In the interim data, the reported hospitalizations and deaths between the placebo group and the treatment group were 53/377 and 28/385, respectively.
Compare that to the final results, and once again the discrepancy is egregious.
The final results indicate that the placebo group had a hospitalization and death rate of 68/699 while the treatment group had a hospitalization and death rate of 48/709. Again, the difference here is shocking.
There was only an increase of 15 in the placebo group, taking the rate from 14% in the placebo group to 9.7%, a decrease in hospitalization and deaths by nearly a third relative to the interim data.
The rate of hospitalizations & death in the Molnupiravir group remained relatively the same, but there was an even greater number of hospitalizations & deaths in the Molnupiravir group than in the placebo group (an additional 20 versus an additional 15, respectively). Again, the interim data does not seem representative of the final data, and one has to wonder if that was done intentionally.
I always found it strange that the relative reduction between the two groups was around 50% based on the interim data. Remember that this data was plastered all over the media and became a huge talking point. I mean, who wouldn’t want to see a relative reduction of hospitalizations and deaths by nearly a half?
Well, what are the new relative reduction rates with the final data? 30%
Sure, that’s still a decent reduction, but that’s far from the number that was being reported, and we have to question why there is such a huge shift in the numbers.
Here, we can see that the Molnupiravir group remained relatively the same, and yet the data for the placebo group was far better in the final data. Again, maybe the researchers just happened to have far more people who fared better in the latter 40% of the data, or it could be that results were cherry picked to give a much greater rate of hospitalizations and death in the placebo group, which surprisingly gave a fairly rounded 50% relative reduction.
Remember that there are many ways that data can be manipulated, and when the actual rate of hospitalization and deaths are lower than were being reported we should not be surprised to see the relative reduction rate decrease as well.
On its own the data doesn’t spell doom. It does indicate a reduction in hospitalizations and death.
But the phenomenal interim data was what was used to push for EUA approval, and it was the interim data that was used to compel the UK to adopt the drug’s usage. Instead of taking the precautionary approach and wait until more data came out, most in the healthcare industry and media apparatus dove head first into the belief that this drug may be the be-all, end-all of the pandemic, and the final results clearly indicate that this may not be the case.
I always prefer to play devil’s advocate. Even if I find data concerning, I would rather elicit the precautionary principle and wait for more results to come out than to resort to histrionics and paranoia.
Well, the results are in, and the results paint a much different story than we were being fed. I have told people to remain skeptical, and we would need to wait and see what the rest of the results from these studies indicate. And now, not only do the results seem worse, it leaves me to doubt whether the initial data was reported to artificially paint a glossy picture over Molnupiravir. It also indicates that something more nefarious, such as data manipulation, may be at play.
Merck knows full well what results they need in order to be granted approval, and the discrepancies between the interim and final data indicate that something may have taken place.
It has become my mantra to say that people are allowed to be upset and angry, but they are not allowed to be surprised, because being surprised means you haven’t been paying attention.
So if these results surprise you, congratulations, because you may not have been paying close enough attention to the details.
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