The Covid19 pandemic has transformed human communications in the U.S.
Most business meetings are (still) being conducted via Zoom or a variety of similar services, in lieu of in-person meetings. Scientists have relied on preprints instead of peer-reviewed publications; increasingly, preprints are even abandoned in favor of press releases. Merck's Covid19 pill, known as molnupiravir (MOV), represents a case in point. (The Pfizer pill is another example.)
Previously, I have mentioned how press releases have been used to seed public opinion prior to any preprints or peer-reviewed publications being available (link). Merck just took this to the next level. When I first researched MOV, I looked for a preprint or a journal article, and I couldn't find any. This is weeks after the FDA advisory board recommended to authorize molnupiravir. This practice means independent observers are blocked from seeing any data, except those selected to support the pharma's findings.
Thus, I had to pull together information from different places. There are three press releases by Merck, a FDA briefing document - which is a report by FDA analysts about the second of Merck's press release, with an erratum in which they disclosed misprinting the value of the key efficacy metric (52% instead of 48%), an Addendum to the FDA briefing document - in which the FDA acknowledged Merck's third press release containing revised data, without comment. No detailed protocol related to the trial has been released, and I have to work with an incomplete and extremely abridged version uploaded to ClinicalTrials.gov.
Those documents are substantively different from a research article - as they present specific conclusions, and offer only data in support of those conclusions. They leave more questions than they answer.
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In this post, I trace how information about Merck's pill was staged in an apparent joint production with the FDA.
The FDA convened a meeting of advisors right after Thanksgiving holiday on November 30, 2021. Reference materials were released ahead of the meeting, the key document being a briefing document prepared by FDA analysts who reviewed the Merck data. This document made no reference to the final result but reported the interim results, which were almost twice as good. The prespecified primary endpoint was a difference in event rates (3% at final analysis, 7% at interim); nevertheless, they computed a relative ratio since that sounded more impressive. They then misprinted this number as 52% when it was 48%, an embarrassing mistake disclosed in a separate Erratum. Why they didn't correct the original report directly, I cannot understand. This practice is similar to the New York Times putting up a correction several days after an article went to press, tucked into a corner in the back pages, unlikely to be noticed by most readers.
Meanwhile, on Black Friday (Nov 26), the day after Thanksgiving, Merck issued a third press release announcing the final outcomes. This announcement came out literally two working days before the FDA meeting.
In an "Addendum" to the main report, the FDA analysts acknowledged being informed of the final analysis on Nov 22, four days before the press release. This development should have caused a five-star alarm as their primary briefing document would now be misleading readers. Instead of revising the briefing document, and pushing back the meeting of advisors if necessary, they continued. They now added an "Addendum".
The very first paragraph of the Addendum repeats the "50%" improvement talking point.
The second paragraph acknowledges receiving new data from Merck, and refers readers to Merck's own addendum.
The third paragraph tells us how many people were in the trial.
The fourth paragraph repeats the (now meaningless) interim analysis results again!
What are they waiting for? Finally in the fifth paragraph, at the bottom of the page and continuing on the next page, they described the full analysis results.
Were the FDA analysts alarmed by the drastically reduced effect at full analysis? You would not know based on reading the Addendum. The fact that the primary endpoint value dropped from 7% to 3% apparently did not cause any concern. Here is the sixth paragraph that appeared after they stated the final results:
The Agency continues to evaluate the known and potential benefits and risks of MOV considering the results from all randomized participants. During the meeting, the Agency will provide additional key safety and efficacy results based on all 1433 randomized participants (full population). The review issues and benefit/risk assessments may therefore differ from the original assessments provided in the briefing document which was based on the interim analysis.
I reviewed the slides presented at the meeting, and I didn't find any additional information on efficacy.
This situation reminds me of the interim analysis of the Moderna vaccine (link). The FDA briefing document endorsed data that did not meet the FDA's requirement of half the participants reaching 6 months of follow-up while acknowledging that they have received updated data that did not make it to the briefing document.
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What is the harm of science by press releases?
Look at the following list of key information that are absent from those press releases:
- What is the study period? No dates were given in any of the documents about the Phase 3 trial.
- What is in the placebo pill? (There were 3 times as many dropouts from the placebo group as from the treatment group.)
- How is the analysis subset (the so-called overall mITT population) defined?
- How many people were excluded for what reasons, across each arm?
- What are the demographic data of each arm?
- What happened during the follow-up process? How is it possible that the investigator can't determine if a participant was hospitalized or dead?
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There are several other interesting tidbits I gathered that didn't make it to the last post.
The trial defines someone as having high risk of having a severe outcome if they meet one or more of the following criteria: 60 years old +, diabetes, obesity, chronic kidney disease, serious heart conditions, chronic obstructive pulmonary disease, active cancer.
At first glance, they obviously succeeded in selecting a subset that has high chance of severe disease as the event rate (on placebo) was 10%. On the other hand, this group does not seem as high-risk as advertised, based on the very limited information that was published.
Surprisingly, only 14% of the study population was 60 years old+, and only 3% above 75. About 14% have diabetes. Think about that for a moment. If everyone above 60 years old have diabetes, then no one under 60 years old in the trial have diabetes. If no one above 60 years old have diabetes, then 14% of the under-60 have diabetes.
I find it odd that only 14% were over 60. I'd think that many of the other serious conditions are correlated with age so if you pick a random cancer patient or a random person with serious heart conditions, the person is more likely to be older than younger. Thus, I'm imagining that the trial enrolled older but healthy people, and younger people with more comorbidities. We can't be sure since they didn't disclose any details.
Also, it appears that the most at-risk are excluded from the trial. According to the abridged protocol on ClinicalTrials.gov, they excluded anyone who "is on dialysis or has reduced estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2 by the Modification of Diet in Renal Disease (MDRD) equation." That would mean someone with chronic kidney disease can only participate in the trial if they are not on dialysis. The protocol lists many other exclusions.
Merck counts hospitalizations and deaths on "all causes". This practice differs from what was used in the vaccine trials, when each case was adjudicated as to whether it is related to Covid-19. We don't have the Merck protocol so we don't know if any adjudication was used.
The study population was almost entirely recruited outside North America. There were only 18 participants from North America, and 40 from Western Europe. Most of the participants came from Latin America or Russia.
Hey Kaiser,
So the brief i read say no success in hospitalised high risky group right? Also had some comments on mutagenicity and public health. This mutations in antibody also relevant on vaccines?
On mechanism I read this ( but not sure on how accurate. https://unglossed.substack.com/p/doppelganger
Posted by: A Palaz | 12/26/2021 at 06:14 PM