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The FDA has granted full approval of the Pfizer COVID vaccine, in record time, based on less than 6 months of data on 44,000 patients. They are said to have presented 360,000 pages of data to the FDA. That’s about 9 pages per trial patient, a rather de minimis amount of information collected over a very short period of time. What we “know” is that the incidence of serious side effects, which include myocarditis in pericarditis, appears to be very low, and most cases of these appear to be mild with full patient recovery over a few days. Or so the data from Pfizer suggests. Blood clot data seem to be better than with the J and J vaccine, though even that is of very low risk, we are told. Pfizer acknowledges that the actual incidence and course of these complications are not known precisely. The updated package insert continues to say that no guidance on use of the vaccine in pregnancy can be provided. It is not approved in pregnancy. So if you want to go shopping for maternity clothes in NYC, yer on yer own. The thousands of deaths reported on the VAERS site attributed to the vaccine apparently played no role in the FDA’s review leading to full approval of the vaccine.
This is not your father’s FDA. Being a crotchety old-timer I remember the good old days when the FDA took half a century to finally approve Metformin for use in diabetes (thought by the FDA, erroneously, to be a very highly dangerous and potentially lethal drug) even with 270,000 patient-years (many millions of pages) of data from Canada alone showing no deaths at all from the drug. (The drug is so safe it can be used in Pregnancy. Indeed, it turns out to be a drug that enhances fertility in patients with PCOS, and may reduce miscarriages in those patients). And then it took the three greatest diabetologists of the time (Ralph DeFronzo, Alan Garber, Gerald Reaven) 10 years to convince the FDA to approve it. Then it took a gutsy pharmaceutical company, Bristol Meyer Squibb, to market it. The first five years it was on the market the airwaves were saturated with ads: Have you had a loved one die from taking metformin? Call our law firm! The ads ceased after about 5 years when the lawyers finally realized they were wasting their ad money. Today, you can regale yourself reading on the internet all the calamitous results of taking metformin. The irony with metformin was that data from a small subset of patients in the UKPDS study of diabetes had suggested that metformin might reduce all-cause mortality in obese type 2 diabetes patients by almost 50%! Thus, a fifty-year delay in approval, during a massive increase in the number of patients with type 2 diabetes, a leading cause of mortality, may have cost many tens or hundreds of thousands of lives, or more. Meanwhile, metformin was being used worldwide from the 1940s. Just not in America, until 1995, courtesy of the FDA. This history seemed to confirm the viewpoint of those who feel that the purpose of the FDA is to keep life-saving medicines out of the hands of American patients.
Following just a few short years on from the Metformin glacial but ultimate approval, were the Rezulin Wars. Rezulin, a novel drug that messes with genes (a “PPAR gamma agonist”, that is, a “Peroxisome-Proliferator Activator Receptor-gamma agonist–at the time Rezulin was released, most physicians didn’t know what a peroxisome was, as these subcellular organelles had only recently been described), was, for practicing diabetologists, something of a wonder drug. It improved insulin sensitivity (the primary problem in type 2 diabetes is insulin resistance), improved vascular reactivity (which is rather markedly abnormal in insulin-resistant states), and tended to prevent ongoing loss of insulin production capacity in the pancreas. It was approved for use in 1997 and within a couple of years, I had 700 patients on the medication. I was practicing in south Louisiana at the time, in the heart of Cajun country, and type 2 diabetes was, and is, a terrible scourge there. Diabetologists across the nation and around the world were using it extensively in patients that had poor blood sugar control on sulfonylureas, metformin, and insulin, our only other options, beyond diet and exercise, for diabetes management at that time. In my experience, it was a highly useful addition to the pharmacopeia for type 2 diabetes management. There were risks that were manageable, such as fluid retention and weight gain, which tended to be limited. There were fears of inducing congestive heart failure, but that was more of a problem of fluid retention, and claims that Rezulin (or its following congeners, Actos and Avandia) caused congestive heart failure were specious (yet today many experts will contest that statement). Indeed the likelihood is that, used appropriately, this class of medication reduces the risk of heart failure, which is elevated in type 2 diabetes.
From the beginning of availability of Rezulin, cases of liver failure in patients taking Rezulin were reported. Then a sort of hysteria occurred. The FDA, which had approved the drug under somewhat unusual circumstances (the initial reviewer claimed liver toxicity, using outdated methods of assessing elevated liver function tests, which the pharmaceutical company disputed and the reviewer was removed from the case–the history had resonance with the movie The Fugitive with Harrison Ford and Tommy Lee Jones released in 1993) with its reputation on the line, looked seriously into claims of liver failure induced by the drug. Recommendations for checking liver function tests periodically in patients taking the drug were promulgated by the FDA. These recommendations were made more and more stringent as more and more cases of liver failure were reported. Lawsuits began to be filed. Clinics sprang up across the nation to offer liver transplantation to patients with liver failure induced by Rezulin. David Graham, the FDA official in charge of oversight on Rezulin, kept issuing guidelines on liver function testing, until testing was recommended monthly for about 18 months, then periodically thereafter. A patient who was on a study protocol at the NIH died suddenly of liver failure while on Rezulin, which caused something of a firestorm in that venerable institution. More lawsuits were filed. Ultimately, a large class-action suit was filed against Parke Davis, the company with ownership of the drug.
Parke Davis, however, refused to settle any claims. The cases of liver failure in patients taking Rezulin were hard to attribute to Rezulin directly, given that liver failure occurs at a baseline incidence of 1 in 30,000 patients with type 2 diabetes, mostly attributed to steatohepatitis (hepatitis induced by fat in the liver, which is extremely common in type 2 diabetes). Indeed, the incidence of liver failure in diabetes patients taking Rezulin was also 1 in 30,000, the same as patients not taking Rezulin. Rezulin happened to be a drug that was being used in the exact patients prone to liver failure from steatohepatitis. (Subsequent research on another member of the class, Actos, showed that the drugs actually remove fat from the liver and do indeed reduce liver failure in steatohepatitis. Patients with steatohepatitis are treated with Actos now). Nevertheless, a great deal of sophisticated testing was done to try and figure out how Rezulin caused liver failure. Nothing could ever be demonstrated unequivocally. Prestigious diabetologists continue to believe that something about Rezulin caused in to induce liver failure. That, however, regardless of the Wikipedia page on Troglitzone (the generic name of Rezulin) that would lead one to believe that advanced science has demonstrated the mechanism of liver toxicity of the drug, has in actuality never been demonstrated.
Over the three years that Rezulin was on the market, the incidence of liver failure in patients taking Rezulin failure fell from 1 in 30,000 the first year, to 1 in 60,000 the second year, and to 0 cases in the third year. The data suggested that Rezulin was saving livers! At the height of the Rezulin wars, I reviewed all of the cases of liver failure in patients taking Rezulin that were reported in the literature. In none of them could liver failure be attributed to Rezulin with certainty. Evidence of liver failure due to Rezulin in a given patient was categorized as probable, possible, or uncertain. Most cases were uncertain. A few were possible Fewer still were probable. There was no definitive evidence that Rezulin caused liver failure. Nevertheless, the hysteria that took hold persisted, in my view something akin to the hysteria over child sexual abuse in the McMartin, Snowden, and Amirault daycare center cases of a prior decade. The legal assault on Warner/Parke Davis, then Pfizer, which acquired the drug, continued and escalated. The medical profession got in of the act, opening liver transplant centers across the nation that advertised to Rezulin takers their services. There was a sort of collective psychosis.
Meanwhile, in my solo office in Thibodaux, LA, I continued checking LFTs monthly on my patients on Rezulin. Over 3 years, not a single one showed any elevation of liver function tests. Indeed, in the entire State of Louisiana, there were no cases of liver failure in patients on Rezulin.
After Rezulin had been on the market for 3 years, in the Spring of 2000 (Campaign season, Bush v. Gore, Clinton in the White House), Jane Henney, the FDA Commissioner held a press conference regarding Rezulin. She was under great pressure to recall it. Nevertheless, in a courageous act of Science, she announced that the FDA was not going to ask for the withdrawal of Rezulin (the FDA, contrary to popular understanding, is not a scientific body at all, but a policing entity, empowered to require the demonstration of safety and efficacy in food, drugs, and medical devices, and does not have “post-marketing” authority; that is, once the FDA has approved a medication, it cannot legally require the removal of a drug from market; it can ask the pharmacy company to do so, and that is usually sufficient to get the pharmaceutical company to withdraw the medication from market). There was a firestorm from the Plaintiffs bar. It is said that Jane Henney immediately got a call from the Clinton White House; the President was not happy with her decision. In a campaign season, and a plaintiffs’ bar to appease, Henney’s decision, based on science though it was, was NOT the decision the White House wanted. Either Rezulin or Henney was going to go. Within a week, Henney held another press conference to announce the request of the FDA for the withdrawal of Rezulin. The drug company acquiesced, and Rezulin was gone.
Still, Parke Davis/Warner/Pfizer did not capitulate to the Plaintiff’s attorneys in their class-action suit. So the attorneys upped the ante. In the State of Louisiana, that went like this: The attorneys (coordinated through the law offices of the infamous Morris Bart, whose plaintiff’s attorney billboard ads festoon I-10 as it runs through the litigation h— holes of Louisiana and Mississippi) sent letters to the patients who had signed up for the class action suit informing the patients that they (the attorneys) were going to file suit against their doctors directly, unless the patient returned a signed form indicating that he or she did not want to sue the doctor. The patients who received the letters did not really grasp what was being proposed, and mostly just discarded the letters. So the attorneys sued the doctors. In Louisiana, there was an instant outcry from many physicians who were served notice of the suits, threatening to counter sue for malicious litigation. The strategy of the attorneys appeared to be one of intimidation, hoping to get some intimidated physicians to agree to testify that Parke Davis had not sent them the required warning letters on liver testing, in exchange for the attorneys withdrawing the litigation against the physician. No physician to my awareness succumbed to that attempt at legal blackmail.
I was served 7 lawsuits from patients that I had treated with Rezulin. None had had any damage from taking Rezulin. To the contrary, all had benefitted with much-improved diabetes control from the medication. Nevertheless, there was a sort of tacit allegation in the suits that simply by prescribing Rezulin, the doctor had perpetrated some immense cosmic harm on the patient, who could never recover from such (totally illusory) harm, and for which adequate compensation could never be made. A new theory of torts.
I called each of the patients to ask if they were aware that they were suing me. None of the patients was aware of the suit. All of the patients said they didn’t want to sue me. 5 of the patients sent letters to the attorney and the court asking that the suits be withdrawn. One patient, an elderly lady who lived with her nephew, said that although she didn’t want to sue, she was being intimidated by her nephew, who had signed her up for the class action suit and wanted to get some money, and was afraid of him such that she was afraid to withdraw the suit. The seventh patient averred that she would write a letter to withdraw the suit, but never did.
In Louisiana, State law has established a patient’s compensation board that has to adjudicate malpractice claims before they can go to court. A panel of experts, one for the plaintiff, one for the defense, and one independent expert are assigned to review the case under litigation and opine on the merits of the case, either malpractice or no malpractice. Whatever the outcome of this review, the case can be filed in court. Of course, if the outcome is no malpractice, the plaintiffs have an uphill battle. If the outcome is malpractice, the defense is likely to settle. In the Rezulin cases, the plaintiffs’ attorneys were applying legal pressure and were likely to pursue litigation even if the review panel found no malpractice, until they got their settlement out of Parke Davis/Warner/Pfizer.
Since virtually all of the potential experts who could serve on the review panels were being sued, and thus had a conflict of interest, there was an impasse. Finally, an eminent academic endocrinologist from New Orleans, Dr. Blondie, who had only engaged in bench research since before the advent of Rezulin, and had never prescribed Rezulin, and hence was not being sued, was dragooned into serving on almost all of the panels as a defense expert. It took 4 to 5 years to clear all of the cases. To my awareness, there was no malpractice noted in any of the cases (including my two cases that went to the panel).
By the time these cases had cleared the docket in Louisiana, Parke Davis/Warner/Pfizer had finally agreed to a settlement, something on the order of $500 million, with the plaintiffs’ attorneys. I’m sure the patients got a pittance, and the attorneys got a windfall. Once that happened, the plaintiff attorneys sent letters to all of the physicians that they had sued, agreeing to withdraw the suits if the physicians would sign documents promising not to counter sue. They had their money. My malpractice attorney (assigned by my malpractice insurer, Medical Protective) advised me to sign the papers, which I did. So ended the Rezulin Wars. For me, the experience was sufficiently unsettling and demoralizing that I closed my solo practice in Thibodaux and took a position with a large multi-specialty group in another state.
But, the glitazone wars continued. Actos (Pioglitazone) came under attack for supposedly causing heart damage (it does not). It was almost withdrawn from the market. Subsequent (poorly done) studies showed that it may have cardiac benefit. Avandia (rosiglitazone), likewise, came under attack for supposedly causing heart damage.
These medications, in very rare instances, appeared to cause a flash pulmonary edema that could be life-threatening. Stopping the medication resulted in a rapid recovery of the patient. To this day, the top experts in diabetes misconstrue and misunderstand this phenomenon. Epidemiologic studies (perusing claims data from insurance companies) seemed to show a slight signal of cardiac harm from these drugs, but this is extremely low-quality data. That signal was likely due to the very few cases of flash pulmonary edema that were confused with a congestive heart failure diagnosis, which could not be ascertained from such poor quality data. So, Steven Nissan, a cardiologist at the Cleveland Clinic, produced a “meta-analysis” of studies using Avandia. The paper was published by the New England Journal of Medicine in 2007.
Dr. Nissan’s article violated pretty much all of the criteria for a meta-analysis. He simply pulled data off the website of Glaxo Smith Kline regarding its premarketing studies of Avandia. He included other large trials that had been previously published and data off the FDA website. Then he used an inappropriate statistical method to analyze the data. The statistical method he used is called the Peto method. It was developed by a British cardiologist for analysis of the very large Statin trials on heart disease, that had large treatment and control populations of equivalent sizes and few overall events. Unfortunately, the method had been shown to be invalid if used to analyze data that included treatment groups that were much larger than control groups, which was the case with most of the data he pulled off the Glaxo Smith Kline website (as is typical for pre-marketing studies). Further, the Peto method is inapplicable if any of the studies included contained either treatment or control groups with no events. This was the case with some of the data Dr. Nissen included in his ‘meta-analysis.’ Daniel Drucker, a pre-eminent diabetologist at the University of Toronto, gave a presentation at the annual meeting of the Endocrine Society, that was underway when the article became available, that utterly destroyed any claim to legitimacy the author or the New England Journal advanced for the study.
The lead peer reviewer for the New England Journal of Medicine, Steve Haffner, a pre-eminent researcher in Diabetes and cardiovascular epidemiology at the University of Texas, San Antonio, broke with protocol and held a press conference to announce that he had been the lead reviewer on the article and that he had advised the New England Journal of Medicine not to publish the paper, given its very shaky claim to legitimacy. He was very upset that the Journal had published the article. He was so upset that he made the following statement regarding the article: In publishing this article, the New England Journal of Medicine has become like a British Tabloid, minus the picture of the bare-chested woman on page 3.”
Needless to say, the NEJM and Dr. Hafner parted ways.
It was quite evident that the publication of the article was a political decision. At the time of the release of the article by the NEJM, Henry Waxman, Democrat from Beverly Hills, was chairing a committee in the House that was marking up re-authorizing legislation for the FDA. The goal was to add post-marketing regulatory authority to the FDA (as noted above, the FDA does not have authority to force pharmaceutical companies to remove products from market once they are approved). Dr Nissen was rumored to be interested in becoming head of the FDA. The New England Journal of Medicine provided a copy of the article to Henry Waxman at the very moment that it put the article on the internet, pre-publication, so that Waxman was probably the first person other than the author, the editors of the NEJM, and the peer reviewers to see the article. He immediately held a press conference on the steps of the Capitol, waving a copy of the article, declaiming that this was the proof that the FDA needed post-marketing regulatory authority. So the entire effort was purely political.
Henry Waxman didn’t get post-marketing regulatory authority for the FDA. But the FDA used the bogus article to get the drug company to place Avandia in a category that severely restricted its use, to those who had particular research protocols. Practicing physicians could no longer prescribe it. And, going one step further, the FDA established a policy based on that bogus article, that all new diabetes drugs had to have pre-marketing studies on cardiac safety before the FDA would approve them. AS it turned out, there was a silver lining to this requirement. Two new classes of diabetes medicines that have come out since that time, the Glucagon-like peptide analogs (GLP-1 analogs) such as Trulicity, Ozempic, and Bydureon, and the SGLT2 inhibitors (Jardiance, Farxiga) have been shown to have considerable cardiac (as well as renal) benefits. So there can be no baseless attack on these meds, though of course they have certain risks and caveats to their use.
With all, many practicing physicians such as myself have long since lost all respect for the FDA. WE see it as a somewhat seedier and onerous federal agency than the ATF. One of those Progressive Era boondoggles that have almost certainly done more harm than good for the nation, like the Federal Reserve. And just as politicized as the Department of Justice, under, take your pick, Ramsey Clark, Bobby Kennedy, John Mitchell, Janet Reno, Eric Holder, Merrick Garland, etc., etc.
Thus, I for one see the very rapid full authorization of the Pfizer vaccine as a purely political, and certainly not a scientific action. Whatever the merits of the vaccine, issuing a full FDA authorization for what appear to be entirely political reasons to force mandates on the public, is likely to cause more distress and harm than benefit. Given the performance of the vaccine, it is not going to eradicate COVID. The vaccine should be approached now in a similar fashion as the flu vaccines (which I am about to get). Encourage appropriate individuals to get the vaccine. Force no one. Present the data, and updates on the data, on efficacy and safety in a balanced, scientific manner. Allow treatments, such as the Regeneron monoclonal antibody cocktail. and, yes Ivermectin and others, to be utilized appropriately.Published in