It’s alarming and disheartening to see that the effort to combat Covid is becoming more and more politicized. It’s not just the elements that are inherently political, since they involve government decisions and allocations of resources, like whether to restrict international air travel, mandate quarantines, provide support to households and businesses for lost wages and revenues, and decide who gets first dibs on scarce supplies. It’s that the elements of the debate that the great unwashed public would really like to be in the hands of unbiased trustworthy experts are now as much subject to politics and fashion as whether Covid relief will be means-tested or not.
One of the side effects is Joe Biden making nonsensical statement like “Trust the science.” Science with respect to medicine is regularly a medieval art. Either practically or ethically, we can’t run large scale studies on representative populations. We’re often stuck with observation, experimental-level studies, and correlations as opposed to clear-cut causality. And too often, the people making those studies have reason to over-hype the results, even if it’s just to get their research noticed.
The situation is made worse with the high level of corruption in our society, starting with private equity rentierism in hospitals and emergency services. Experts have complained about corruption in scientific research for decades, to the degree that a lot of the public has become aware of it. Agnotology to muddy the mounting evidence against smoking, and later, against carbon emissions. Vioxx. Oxycontin. Overdiagnosis of behavioral disorders in children, accompanied by unprecedented administration of medications. In medicine, this is the direct result of drug companies and health care providers being more and more driven by commercial rather than patient interest.
Profit pressures have also degraded the doctor-patient relationship. More and more MDs work as employees rather than in their old configuration of independent small businessmen. Their corporate masters regularly not only dictate how many patients to see in the day, but also a lot of their treatment protocols. Allegedly, the latter is driven by the need to get more doctors to adhere to the standards of evidence-based medicine. Some practitioners retort that quite a few patients have problems that don’t fall tidily into adequately researched boxes, and clinicians need to be able to make judgement calls.
None of this is new, but it’s important to remember these issues as the debate over Covid policy continues. The US has backed itself into the corner of having to hope for a medical magic bullet due to our inability to mobilize a society-wide response to Covid. And it’s not just authoritarian China that has done better. Thailand, which has Bangkok, literally the most visited city in the world as its commercial center, has a population of 75 million and has had 60 Covid deaths. Yes that means 60 in total. Alabama, with 4.9 million people, had 56 Covid deaths yesterday.
Even parts of the West that had initial successes, as we know all too well, have backslid spectacularly, loosening up too much in the late summer and fall. And now that the disease is well entrenched, it seems just too daunting to have a strict lockdown for five to six weeks, pay people and business enough to get through a deep freeze, and put in place post lockdown measures with teeth, like serious fines for breaking quarantine (and support during quarantines, like stipends and delivery of food and other supplies). The purpose of this post is not to debate what that program might look like, but to posit that there is one, and that stop-and-go leaky lockdowns are likely to be as costly in human and financial terms in the long term.
So instead, the US is putting all its eggs in the Covid vaccine basket. That is coming at the expense of pursuing other approaches in parallel to reduce the health cost and societal damage of the disease.
As we said early on, if we didn’t get lucky as we did with SARS and have it mutate into a less virulent form, we would need a combination of treatments to reduce disease severity, morbidity and mortality, and vaccines. There was no reason not to pursue both routes aggressively, in parallel. Recall that the fight against AIDS involved both trying to come up with a vaccine as well as experimenting with many drugs and later drug cocktails.
But as we are already seeing, due to the fixation on a vaccine, and Operation Warp Speed adopting a bizarre “first past the post” approach and letting Pfizer enjoy a first mover advantage (rather than trying to the extent possible to compare candidates against each other and see which might be the most suitable for various patient and delivery situations), anyone who questions the unprecedented rushed development and approval of vaccines is treated as an anti-science crank and a threat to public safety. What about “precautionary principle” don’t you understand?
Our IM Doc had to post his reading of the Pfizer article and editorial in the New England Journal of Medicine anonymously out of fear of losing his job. We also received e-mails from doctors supporting IM Doc’s post, including one that argued he’d skipped over some concerns about the Pfizer vaccine.
I felt I could share this one from Dr. Harvey Risch, Professor of Epidemiology at Yale School of Medicine, since it restates positions he has taken publicly:
I read your essay from the internist critical of the vaccine data and policies that have come out so far. I strongly share his/her concerns. I have been working in Covid early outpatient treatment since March of this year and you are probably aware of the massive propaganda war being conducted against outpatient treatment by pharma companies, vaccine companies, FDA, NIH, WHO, as well as the numerous academic pontificators who have never treated even one Covid outpatient.
I am involved in two private email groups comprised largely of MDs discussing evidence for Covid early outpatient treatment. We have published a number of papers (e.g., https://www.amjmed.com/article/S0002-9343(20)30673-2/fulltext) as well as op-eds such as the following:
Because of the mainstream media censorship of our position that early outpatient treatment is safe, successful, inexpensive and would largely solve the pandemic without necessity of or even better than vaccines, most of our messaging has appeared on the political right. However, we span the political spectrum as can be seen by a recent article here:
We are all actively working as best we can to bring clinical relief to patients. Thanks very much, and thanks for publishing IM Doc’s outstanding critical analysis.
My best wishes–
Since this is a finance and economics site out to promote critical thinking, we are in a better position to analyze institutional behaviors and failings than weigh in on a controversy like hydroxychloroquine, where we have been providing links to studies on it. However, it’s been obvious that Trump’s ham-handed advocacy generated knee-jerk prejudice against it. While critics point to research showing it hasn’t been effective, even at our remove, it appears that most of the studies on it have been of hospitalized patients, which is not use case recommended by advocates. They instead contend that it is effective as a prophylactic and/or as an early intervention. We must confess to not having had the time to parse out the studies that focus only on those cases. But the more general point it the media noise has downed out serious consideration of the data.
Several readers sent a link to a new article in STAT which raised new concerns about the rushed approval of the Pfizer vaccine. Needless to say, STAT is recognized as being above the political fray. From Did the FDA understaff its review of the Pfizer/BioNTech vaccine?:
In what is arguably the most important decision the Food and Drug Administration has made this year — its emergency use authorization of the Pfizer/BioNTech Covid-19 vaccine — the agency apparently assigned only a single reviewer in each of two key scientific disciplines (clinical and statistics) to do the work in three weeks that usually takes months to do….
Unlike its counterparts in other countries, the FDA is believed to be the only drug regulator in the world that consistently receives and reviews patient-level data from the clinical trials that underpin drug and vaccine approvals. To perform such rigorous analyses, the FDA typically spends around 10 months (a mere six months for applications given “priority review” designation) in an effort that involves reviews by experts representing various scientific disciplines: clinical medicine, statistics, pharmacology, chemistry, pharmacovigilance, and more…
Given the urgency of the pandemic, the review of the Pfizer/BioNTech vaccine was conducted far faster than usual. The centerpiece of the analysis was data from the company’s 44,000-participant Phase 3 trial. FDA reviewers had just three weeks, from Nov. 20 to Dec. 11, to complete their analyses. It was a monumental task, which raises the question: Why didn’t the FDA devote additional reviewers to it? According to the FDA’s review memo, some scientific disciplines, such as pharmacovigilance, had multiple reviewers involved. But the two disciplines tasked with examining the clinical trial data and results, the clinical and statistical reviewers, were seemingly left to do their work solo.
This seems wholly inadequate on at least two levels. First, without additional reviewers it is hard to comprehend how the work of several months could be squeezed into a matter of 22 days (including Saturdays and Sundays). In-depth review calls for examining patient-level data — a large feat that involves auditing and reviewing individual case records as well as independently rerunning analyses on the raw data.
Epidemiologist Ignacio had already raised another concern: that the high frequency of strong adverse reactions meant the study was unblinded to those patients:
First and foremost, we are looking to very transient results obtained in a period too short to be relevant to evaluate the efficacy of the vaccine. It is well known that vaccines induce antibody peaks just about 12 days after the second shot. We are looking at this peak. Very relevant regarding the possibility of some short lived sterilizing protection in the upper mucosa.
Second, the high reactogenicity of the vaccine, way higher than the placebo, removes one of the blindnesses of the trial. You know if you are a recipient of the vaccine. As IM Doc says, the reactogenicity is way above what can be considered normal or standard and with potential to be problematic, and a behaviour changer in the recipients which can have very significant effects in the numbers observed obtained in so short times after vaccination. This effect will be diluted by time in later reviews but it can be quite important in the first review.
STAT agreed that the effective unblinding was a concern:
One of us (P.D.) raised questions about potential unblinding in the trials through the vaccine’s side effects, as well as about the confounding effects of fever- and pain-reducing medications, which participants in the vaccine arm took three to four times more often than those in the placebo arm. Yet the FDA’s review shows no evidence that any of its scientists investigated either of these issues, and without more scientific staff devoted to the task it is hard to imagine how they could.
Finally, I wanted to return to a controversy that readers batted about in Links yesterday, because it ties in with the high odds that the FDA did little or no vetting of patient data.
We asked readers to help us understand the significance of this statement on page 41 from the FDA’s EUA review memorandum on the Pfizer vaccine trials:
Among 3,410 total cases of suspected but unconfirmed COVID-19 in the overall study population, 1,594 occurred in the vaccine group vs. 1816 in the placebo group.
Suspected COVID-19 cases that occurred within 7 days after any vaccination were 409 in the vaccine group vs. 287 in the placebo group. It is possible that the imbalance in suspected COVID-19 cases occurring in the 7 days postvaccination represents vaccine reactogenicity with symptoms that overlap with those of COVID-19.
Back to this post. Reader Diuretical pointed to this section from page 13 of the EUA memo:
If, at any time, a participant develops acute respiratory illness, an illness visit occurs. Assessments for illness visits include a nasal (midturbinate) swab, which is tested at a central laboratory using a reverse transcription- polymerase chain reaction (RT-PCR) test (e.g., Cepheid; FDA authorized under EUA), or other sufficiently validated nucleic acid amplification-based test (NAAT), to detect SARS-CoV-2.
First, one is led to believe that it was only those who developed acute respiratory illness were tested. Note that one of the features of Covid is that it can present with other symptoms, such as loss of smell. WebMD reported based on a large-scale study in China that:
In about one-quarter of patients in the new study, diarrhea and other digestive symptoms were the only symptoms seen in mild COVID-19 cases, and those patients sought medical care later than those with respiratory symptoms.
So it looks possible that Pfizer may have classified Covid symptoms too narrowly and missed a meaningful number of mild cases.
Another issue is the reliability of the PCR tests. Their positive results are reportedly quite accurate in symptomatic patients. However, the PCR test has a fairly level of false negatives:
Researchers at John Hopkins University declared that the false negative ratio of RT-PCR test in patients infected with COVID-19 is approximately 1 in 5.
I invite readers to try their own sensitivity analyses of the data above and see what they come up with. Recall that the headline results for the Pfizer vaccine were 168 cases in the placebo group versus 8 in the vaccine group.
As to why we are continuing to examine the data, recall again that this is an mRNA vaccine, a technology never used at scale in humans, let alone planned to be population wide. This is a completely different beast than traditional vaccines. Igancio set forth the stakes:
How on hell it is possible to approve a vaccine that uses a platform with 0 experience on the basis of so little data? Have we forgotten, again and again, the precautionary principle? These 8 infected after a couple of months from the trial start compared to 168 in the placebo group is enough to approve something for thousands of millions? Have we forgotten previous mistakes? Is 8 enough to have any information on adverse effects and serious adverse effects? Can we rule out antibody-enhanced disease on the basis of 8 reported infections? No way, no way, no way. Please, remember this, RNA vaccines have NO history of deployment, these are a big unknown and, if anything, the most thorough research and follow up of the trials should be carefully done before approval, before delivering an unknown to the masses.
In other words, there were solid reasons for the bar for approving a mRNA vaccine to higher than for a conventional vaccine, or alternatively, for its initial subjects under the EUA to be medical personnel who volunteered to take it. That is an obvious top priority group, capable of informed consent. Instead it’s being rolled out on a mass basis.
Perhaps Pfizer and the public generally will be lucky and the vaccine will live up to its promises. But this is too important a gamble to be betting on Lady Fortune.