- Re: Dr Peter Doshi, BMJ ed. on changing definition of vaccine Archived Message
Posted by Sinister Burt
on December 4, 2021, 11:48 am, in reply to "Re: Dr Peter Doshi, BMJ ed. on changing definition of vaccine"
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I've read the second article now - the first half, pasted below, covers some claims that I think were posted here previously about the flakiness of the Pfizer trial - and seems to me to comprehensively debunk them (eg the dodgy Ventavia lab ran three out of 153 labs, covering ~1,000 out of 44,000 overall) - what does anyone else think? (refers to some tweets - visit the link to see them) https://sciencebasedmedicine.org/what-the-heck-happened-to-the-bmj/ "...For this post, I’m going to focus primarily on the article about the Pfizer clinical trial because it is the one that most resembles actual journalism, albeit just barely given that its sourcing is a bit sketchy and its framing is relentlessly one-sided and clearly designed to leave the reader with exactly the sort of message that antivaxxers are taking from it, namely that Pfizer is corrupt and was careless about oversight of the massive clinical trial of its COVID-19 vaccine in 2020. Thacker’s articles about the “lab leak” hypothesis published in The BMJ in general don’t even try to resemble investigative journalism (not that I won’t briefly cover them). Basically, it’s hard not to wonder what the heck has happened to The BMJ, in much the same way I recently wondered what the heck happened to John Ioannidis, a scientist whom I used to admire greatly until his turn into COVID-19 contrarianism and minimization. I will also preface the remainder of the post by emphasizing that, if Thacker’s report is accurate, there did appear to be some significant problems with the three sites in Texas managed by Ventavia, the company that ran the clinical trials. However, the overall impression given by the article is that the entire enterprise should now be questioned, Thacker’s Competing Interests statement that he “has been doubly vaccinated with Pfizer’s vaccine” notwithstanding. In other words, narrative matters. Context matters. Framing matters. Everything about Thacker’s article frames the clinical trial and Pfizer in the worst possible light. It’s almost as though the report is custom-made to provide grist for antivax conspiracy theories, and it definitely succeeds at doing just that. Whatever good some of the report might do, that The BMJ commissioned this report and failed in its “fact checking” to realize that every good propagandist knows how to spin verified facts into deceptive narrative does not speak well of what has happened to the journal, particularly in light of other articles it has published. Thacker’s whistleblower report on Ventavia and Pfizer I will begin by discussing what Thacker reports in his article, starting with this framing right at the beginning of the report, and I will quote liberally citing the same Creative Commons license that Children’s Health Defense cited when it republished the article in its entirety: In autumn 2020 Pfizer’s chairman and chief executive, Albert Bourla, released an open letter to the billions of people around the world who were investing their hopes in a safe and effective covid-19 vaccine to end the pandemic. “As I’ve said before, we are operating at the speed of science,” Bourla wrote, explaining to the public when they could expect a Pfizer vaccine to be authorised in the United States. But, for researchers who were testing Pfizer’s vaccine at several sites in Texas during that autumn, speed may have come at the cost of data integrity and patient safety. A regional director who was employed at the research organisation Ventavia Research Group has told The BMJ that the company falsified data, unblinded patients, employed inadequately trained vaccinators, and was slow to follow up on adverse events reported in Pfizer’s pivotal phase III trial. Staff who conducted quality control checks were overwhelmed by the volume of problems they were finding. After repeatedly notifying Ventavia of these problems, the regional director, Brook Jackson, emailed a complaint to the US Food and Drug Administration (FDA). Ventavia fired her later the same day. Jackson has provided The BMJ with dozens of internal company documents, photos, audio recordings, and emails. Notice the framing. Contrary to Bourla’s statement, the narrative goes, “several” (three, actually, as it turns out) sites in Texas run by Ventavia were supposedly flouting clinical trial safety and unblinding patients, but an intrepid whistleblower reported them. Whistleblower narratives can be valuable, but they can also be potentially misleading, particularly when used as grist for a report by someone like Thacker. After all, whistleblowers often have their own axes to grind. That characteristic in and of itself is not a reason to dismiss (or not to protect) whistleblowers, but it is a reason to be cautious about basing conclusions on their claims alone, particularly a whistleblower who was employed by the company for just two weeks, as was the case with Jackson. Similarly, when evaluating reports of problems with the conduct of a clinical trial, it is important to consider the actual details and context of the reported violations. In this case, Thacker mixes reports from Jackson that might have impacted trial data and safety with reports that could not possibly have. More than that, Thacker gleefully mixes the two, starting thusly in the more detailed discussion of his findings: Exasperated that Ventavia was not dealing with the problems, Jackson documented several matters late one night, taking photos on her mobile phone. One photo, provided to The BMJ, showed needles discarded in a plastic biohazard bag instead of a sharps container box. So apparently Ventavia was careless about disposing of sharps. That’s definitely sloppy lab practice, if it happened, although I feel obligated to point out that we don’t know if this was one screwup or a common problem. Either way, Ventavia’s handling of sharps couldn’t possibly have affected the results of the clinical trial and is more a concern of OSHA violation than any concern that the FDA should look into that could have resulted in data compromise or compromise of the safety of patients. It’s interesting to me that Thacker chose to lead with this tidbit in the section after his introduction, when he started to go into more detail about his more general charges listed in the introduction, given that it has nothing to do with data integrity. I understand that he’s trying to frame the story as one of poor laboratory management, but, really, this accusation seems to have been inserted at the beginning in order to provide what I like to call a “Yuck!” factor, to get the reader to feel disgust on a visceral level towards the company, before going into the more mundane and difficult-to-explain issues of clinical trial management. It’s a very transparently manipulative framing tactic akin to how Thacker likes to paint genetically modified organisms (GMOs) as “unnatural” and “Frankenfood”. The “yuck” factor having been established, Thacker then continues: Early and inadvertent unblinding may have occurred on a far wider scale. According to the trial’s design, unblinded staff were responsible for preparing and administering the study drug (Pfizer’s vaccine or a placebo). This was to be done to preserve the blinding of trial participants and all other site staff, including the principal investigator. However, at Ventavia, Jackson told The BMJ that drug assignment confirmation printouts were being left in participants’ charts, accessible to blinded personnel. As a corrective action taken in September, two months into trial recruitment and with around 1000 participants already enrolled, quality assurance checklists were updated with instructions for staff to remove drug assignments from charts. Notice the contrast between what Thacker writes in the introduction, in which he claims that Ventavia unblinded patients, not that “inadvertent unblinding may have occurred”. There’s a huge difference between the two. Think about it. Leaving the printouts in patient’s charts might have compromised blinding in some cases and was definitely a sloppy practice (and was corrected), but Thacker quite noticeably presents zero evidence that unblinding ever actually occurred, despite stating unequivocally right at the beginning of the article that patients were “unblinded”. Which message do you think that readers will come away with, the one saying that Ventavia definitely unblinded patients or the one saying that unblinding “may have” happened? I find it even more telling that the scope of problem is not mentioned until more than halfway into the report, where it’s revealed that Ventavia ran three sites in Texas out of the 153 total clinical sites participating in the Pfizer trial and signed up a small fraction (~1,000 by the time the whistleblower was fired) of the trial’s over ~44,000 subjects. Note again the framing, “Early and inadvertent blinding may have occurred on a far larger scale”. This is clearly meant to imply more than just the Ventavia sites, given the context. Of course, Thacker reports almost as an afterthought that appropriate corrective measures were eventually instituted at this one site. One could certainly argue that Ventavia took longer to institute these corrective policies than it should have, but, even so, when I looked at the details of the actual claims made they do not support the insinuation that wide-scale inadvertent unblinding had occurred in the Pfizer trial. Thacker does something even more deceptive as well. According to an anonymous source: After Jackson left the company problems persisted at Ventavia, this employee said. In several cases Ventavia lacked enough employees to swab all trial participants who reported covid-like symptoms, to test for infection. Laboratory confirmed symptomatic covid-19 was the trial’s primary endpoint, the employee noted. (An FDA review memorandum released in August this year states that across the full trial swabs were not taken from 477 people with suspected cases of symptomatic covid-19.) “I don’t think it was good clean data,” the employee said of the data Ventavia generated for the Pfizer trial. “It’s a crazy mess.” Again, note the juxtaposition. These 477 patients who reported COVID-19 symptoms but never received nasal swabs were across the entire trial of well over 40,000 subjects, but the way it’s phrased, not put into context of the size of the entire trial, makes this sound like a huge number. As has been pointed out, though, this is deceptive framing that leaves out some very important information: In other words, the FDA and Pfizer did the appropriate analysis and demonstrated that the missing PCR test results for SARS-CoV-2 were similar in both the control and experimental groups and that excluding them had minimal effect on the estimated vaccine efficiency found by the trial. One would think that this would be an incredibly important thing to mention in order to put the figure of 477 people with COVID-19 symptoms within seven days of a dose who were not tested into proper context. Thacker’s implication that these 477 cases had an impact on the results of the trial is a big nothingburger that Thacker tries to turn into a gourmet double-decker burger of doubt. Let’s look at some of the other charges from the whistleblower, listed in Thacker’s report in addition to the two main charges of “unblinding” (which might have happened, but Thacker never establishes to have actually happened and, if it ever did, what the frequency was) and failure to swab every subject who reported COVID-19 symptoms: Participants placed in a hallway after injection and not being monitored by clinical staff Lack of timely follow-up of patients who experienced adverse events Protocol deviations not being reported Vaccines not being stored at proper temperatures Mislabelled laboratory specimens, and Targeting of Ventavia staff for reporting these types of problems. I’ll deal with the mislabeling of specimens first because it’s the easiest. This is the only place where Thacker makes this claim. A common theme you’ll be hearing from me is that details matter, and Thacker’s piece is notably lacking in details. How many specimens? What was the specific mislabeling? Without knowing these details, there is no way to determine how serious the problem was or if it could possibly have affected the clinical trial data significantly. Think of it this way. There’s a huge difference between one or two (or a handful of) specimens being mislabeled and the error caught and corrected and large numbers of specimens mislabeled so that they became useless because there was insufficient information to allow the investigators to correct the mislabeling. Which happened? We don’t know. Thacker doesn’t tell us. He just tells us it was awful. Now, let’s move on to the first claim on the list (participants in the hallway). That is obviously less than ideal, even if it happened only once, but, again, details matter. Thacker never reports how often this happened or how many subjects were treated this way. He seems to imply that subjects were left standing in the hallway (or maybe I’m reading too much into this). Were there chairs? Again, this would have been less than ideal, particularly if monitoring was lax, but Thacker gives no details to let me as someone who’s dealt with clinical trials over his career come to a judgment. Moreover, even if this did happen, it would have been incredibly unlikely that it affected the results of the trial from these sites. The next example is also curious. Thacker states that his whistleblower reported that Ventavia staff were “slow to follow up on adverse events”, but these are the only two examples that he could apparently find: Ventavia was not keeping up with data entry queries, shows an email sent by ICON, the contract research organisation with which Pfizer partnered on the trial. ICON reminded Ventavia in a September 2020 email: “The expectation for this study is that all queries are addressed within 24hrs.” ICON then highlighted over 100 outstanding queries older than three days in yellow. Examples included two individuals for which “Subject has reported with Severe symptoms/reactions … Per protocol, subjects experiencing Grade 3 local reactions should be contacted. Please confirm if an UNPLANNED CONTACT was made and update the corresponding form as appropriate.” According to the trial protocol a telephone contact should have occurred “to ascertain further details and determine whether a site visit is clinically indicated.” Again, coming back to my theme, details matter, and I bet that Thacker knows that a Grade 3 local reaction sounds horrible to the average reader, who won’t know what it is. In fact, a grade 3 local reaction is just that, local. Vaccine reaction grades, both local and systemic, are defined in this document, with a Grade 3 local reaction to the injection being a one that meets certain criteria; e.g., requiring the use of narcotics for pain, being greater than 10 cm in diameter, causing significant discomfort at rest that interferes with daily activities, association with a high fever or heart rate, and the like. These are not potentially life-threatening reactions and do not require hospitalization. (If they did require hospitalization or were life-threatening, that would automatically upgrade them to Grade 4.) While it’s obviously less than ideal that it took more than 24 hours to contact these patients, failure to do so for two patients is not such an incredible lapse that it invalidates the trial or is consistent with patients being endangered by the trial. Regarding Thacker’s report of protocol deviations not being reported, I’m a bit confused, given this passage: Documents show that problems had been going on for weeks. In a list of “action items” circulated among Ventavia leaders in early August 2020, shortly after the trial began and before Jackson’s hiring, a Ventavia executive identified three site staff members with whom to “Go over e-diary issue/falsifying data, etc.” One of them was “verbally counseled for changing data and not noting late entry,” a note indicates. At several points during the late September meeting Jackson and the Ventavia executives discussed the possibility of the FDA showing up for an inspection (box 1). “We’re going to get some kind of letter of information at least, when the FDA gets here . . . know it,” an executive stated. It sounds as though protocol violations were reported to the company, which took corrective action. You can argue if it acted fast enough or was tough enough on the staff involved, but I’m getting mixed messages here. I also note that, although Thacker claims that Ventavia “falsified data” in the very introduction of his report, this is the only mention of “falsifying data” that occurs anywhere else. There is no description of any specific incidents of “falsifying data” listed, only a memo mentioning three staff members, one of whom was apparently counseled about “changing data and not noting late entry.” One also notes that this memo comes from early August 2020, shortly after the trial began, which means that Ventavia intervened before that many patients could have been signed up. This is truly thin gruel to make sensationalistic claims about “falsifying data” in the introduction in such a way as to make it sound as though the practice was widespread. Basically, we don’t know if falsification occurred, if it occurred how often it occurred, or what the specific “falsifications” were. Indeed, the phrasing of the memo could have indicated that the changing of data, which could have been the correction of errors for all we know, and not noting a late entry could have been discussed in the context of how even minor violations like that could be interpreted as falsifying data. Again, we just don’t know, and Thacker doesn’t tell because he doesn’t have evidence. (If he did, you know he would have cited more than just a cherry picked quote from a memo, which is very thin gruel indeed to base a charge of “data falsification” on.) As for vaccines not being stored at the appropriate temperature, the Pfizer vaccine needed to be stored at -70°C (and was known at the time to be good for at least six months at that temperature), thus requiring either a -80°C freezer or dry ice. Once it’s thawed, the vaccine was reportedly at the time good for five days in a refrigerator. Knowing these parameters, details (of which Thacker provides none) matter. How far off were the temperatures? For how long? How many doses of vaccine were involved? If, for example, a single vial of vaccine were left out on the bench at room temperature for several hours, that would be a rather trivial violation compared to the situation where a whole shipment was stored in, for instance, a standard -20°C freezer rather than a -80°C freezer. We have no way of knowing how serious or prevalent this problem was. More importantly, Thacker doesn’t report whether the vaccines stored at an incorrect temperature were ever administered to clinical trial subjects or whether they were discarded, which matters a whole heck of a lot when it comes to vaccine trial safety and efficacy, particularly given that administering such vaccines would actually result in a lower vaccine efficacy because presumably they would lose potency the longer they were stored at too warm a temperature. Leave it to Thacker, though, to make it seem as though huge numbers of vaccine doses were messed up by being improperly stored. The last item in Thacker’s list, if true, is the most damning charge, that Ventavia targeted employees for speaking out. It’s hard to tell if this were truly the case with Brook Jackson, but I will concede that the optics aren’t great. On the other hand, Thacker reports that Ventavia fired her the same day that she sent a complaint to the FDA detailing her concerns. It’s unlikely that the FDA contacted the company the same day of a complaint. (The FDA generally doesn’t move that fast.) Yet, Thacker goes out of his way to imply that the reason she was fired is that she ratted out Ventavia to the FDA. Similarly, it’s a bit disturbing that none of the Ventavia sites were among the sites audited by the FDA. On the other hand, there are always minor errors in trials of this size, particularly when they’re undertaken in haste, as the vaccine trials were in the middle of a pandemic. It’s impossible to know if the problems at Ventavia sites reported by Thacker rise to the level that they could have impacted the results from that site to a significant degree. In the end, we’re left with a lot of smoke, but no clear fire. There clearly were some problems with Ventavia, which ran three clinical trial sites and signed up a small fraction of the total clinical trial subjects for the entire trial. Again, that’s not good. We have Brook Jackson and an anonymous source claiming that the environment at Ventavia was beyond the pale compared to previous places where they’d worked, coupled vaguely described incidents and allegations without even good examples or estimates of how prevalent the problem was. It’s also reported that Pfizer did audit the company and was apparently sufficiently satisfied to use it again. Of course, to Thacker, Pfizer (or any other large pharmaceutical company) is pure evil; so you can’t trust that. I would counter that, if one site’s data were so unreliable due to problems of the sort that Thacker reported, then pure profit motive would provide a strong reason for a pharmaceutical company to cut that company loose, rather than risk the FDA ever finding out. None of this is to say that nothing should be done. Assuming that Thacker’s allegations are not a huge exaggeration, at the very least an FDA audit would be a good idea. At the very worst, even though it’s standard practice to do sensitivity analyses to look for variation in results, protocol deviations, failure to do follow-up testing, etc., between sites in a large clinical trial like this, in the worst case scenario, the data from the subjects enrolled at Ventavia sites could be excluded and the rest of the subjects reanalyzed. My guess is that, even if this most extreme step were to be undertaken, it would make minimal difference in the results of the trial. Basically, Thacker takes fairly uncontroversial observations (e.g., that the FDA is underfunded and doesn’t audit sites as often as it should, something I’ve noted multiple times in my posts for SBM about cancer quack Stanislaw Burzynski and his bogus clinical trials, for instance) and combines them with vague reports of what are probably mostly minor violations played up as huge, impactful violations: Again, the most disturbing thing about the report is the question of whether Ventavia did, in fact, retaliate against Jackson for her having agitated about problems at the site, even if the timeline suggests that it’s probably impossible for her having reported her concerns to the FDA to have been the reason she was fired. If that’s the case, then there should be an investigation and harsh penalties applied to Ventavia. The rest of the report is just Thacker being Thacker, trying to turn a molehill into the proverbial mountain, as long as it fulfills his purpose of demonizing big pharma." |