Do drug trials underestimate side effects?

Deadly drugs trials underestimate side effects

One commonly used trick in drug trials is to exclude any group that might make the drug look worse, such as those that are more likely to experience side effects. A good recent example of this is the covid vaccine trials, which largely excluded people with auto-immune diseases (more likely to develop an auto-immune disease after vaccination), people with allergies (more likely to have an allergic reaction to the vaccine), and, of course, the elderly (less likely to develop immunity after getting the vaccine, and more likely to become seriously sick from it).

These three groups are all frequently excluded from trials, and the exclusion is particularly galling when it comes to the elderly, because they are a big segment of the population, and they are also usually the most likely to end up actually using the drugs being tested.

When drug companies have gotten a drug approved, and move on to market the drug, they will studiously avoid mentioning the fact that large segments of the population were excluded from the trials. When drug reps show their flashy powerpoints to gatherings of doctors, say for a new drug to lower blood pressure, they will always present impressive looking graphs of benefit, and they will of course point out how safe their drug was shown to be in the trials. Not once will they mention that the groups of patients the doctors will primarily be prescribing the drug to weren’t even included in the trials.

The doctors will then happily go off and prescribe the drug to multi-morbid 90 year olds, which might explain why prescription drugs are now the third leading cause of death in the western world.

The manipulation of who is included in trials is probably one of the main reasons why findings of side effects always end up being much higher in reality than in clinical trials. It might explain, for example, why muscle pain is a massively common side effect of statins in the real world, while being vanishingly rare in the statin trials (as Dr. Malcolm Kendrick has written about in detail).

A study recently published in the Lancet Healthy Longevity sought to estimate the extent to which drug trials underestimate side effects. It was funded by the UK Medical Research Council and the Wellcome Trust. The study chose as its particular focus people being treated for high blood pressure with a certain class of blood pressure lowering drugs known as RAAS blockers (which includes all drugs with names ending in -pril and all drugs with names ending in -sartan). The advantage with looking at this particular class of drugs is that there are a ton of trials. Every major pharmaceutical company has its own RAAS-blocker. It should therefore be possible to draw relatively broad conclusions about the results – whatever they show, they apply to the entire pharmaceutical industry, not just to a few specific companies. It’s also reasonable to think that the results apply to other classes of drugs too – there’s no reason to think trials of RAAS-blockers have been done differently than trials of other drug classes.

What the study sought to do more specifically was compare the rate of serious adverse events in clinical trials of RAAS-blockers with the rate observed in the real world. A serious adverse event is any event that is potentially life threatening or that results in death, hospitalization or lasting disability. If a trial has been designed in such a way that it is representative of reality, then the rate of serious adverse events in the trial should largely mirror that seen in the real world.

110 trials of RAAS-blockers were identified by the researchers. Of these, 11 were specifically designed to look at older people (i.e. didn’t recruit anyone under the age of 60). The data on serious adverse events from these 110 trials was extracted and compared to real world data on deaths and hospitalizations taken from a UK government funded database of 55,000 people living in Wales, who were being treated with RAAS-blockers. Deaths and hospitalizations are not exactly the same thing as serious adverse events (which as mentioned above also include “life threatening events”, and could for example include someone who is treated in an emergency department after a fall but not admitted to the hospital), but they’re close enough to allow a reasonable comparison.

So, what were the results?

Let’s begin with comparing the trials of older people with the “standard” trials. The relative rate of serious adverse events in the trials of older people was 76% higher than the rate in the standard trials. This shows the importance of including elderly people in drug trials – they are much more likely to experience adverse events of all kinds (including those actually caused by the drug being tested), and excluding them will therefore likely underestimate side effects.

Considering that many of the drugs in common use show marginal benefits at best (statins have, for example, only been shown to prolong life by a few days on average), this is important information. Why? Because a drug that is beneficial, on balance, to a fifty year old, who has a fully functioning kidney and liver, and is therefore unlikely to suffer side effects, could easily be harmful, on balance, to an 80 year old.

That’s why drug studies done on younger people should not be used to guide treatment of older people. No shock there. Everyone already knows that we shouldn’t be extrapolating results from one group to another (even though it happens all the time, as we’ve seen most recently with the covid vaccine trials).

Next we come to the more important, and perhaps more shocking finding.

The real world patients were between 300% and 400% more likely to experience a serious event than the participants in the trials! That is in spite of the fact that the trials, as mentioned above, were using a broader definition of what constituted a serious event. If the trials were representative of reality, then they should have a higher rate of events than is seen in the real world data. Instead they have a rate that is several times lower!

Interestingly, the trials of older people were just as far from the real world results as the trials of younger people. Clearly, doing trials on the elderly is not enough on its own to produce trials that are representative of reality. What’s happening here exactly?

There are three possible explanations, as far as I can see. The first explanation is that the trials are representative of reality, but that the Welsh die and are hospitalized at a rate that is several times higher than people in the countries where the studies were conducted. Many of the trials were conducted in the US, not in Wales. But Wales has a higher life expectancy than the United States, so that seems unlikely. I think we can discount that explanation.

The second explanation is that the trials are unrepresentative in so many different ways that just correcting the age issue doesn’t make a noticeable difference. That’s probably part of the explanation. The average age even in the trials of “older people” was 73, which isn’t very old from my perspective. And those 73 year olds included in the trials were probably at the healthier end of the spectrum.

The third, more sinister explanation, is that the pharmaceutical companies are hiding serious adverse events… But wait a minute, the trials are randomized and blinded, so the people running the drug trials have no way of knowing if someone experiencing a possible side effect is in the treatment group or the placebo group, right?

Yes, that’s right, so the easiest solution, if you want to avoid finding nasty side effects, is to not report them, regardless of which treatment group the participant is in. That will cut down on total adverse events in both groups, which will make any difference between the groups that does exist smaller in absolute terms, and also less likely to reach the level of statistical significance. Voila – the treatment group and the placebo group end up having similar rates of side effects, and the drug company can conclude that the drug is completely safe.

Is that what’s happened here? Are the pharmaceutical companies hiding adverse events? Well, it’s very strange that the real world data shows a rate of serious adverse events that is several times higher than is found in the trials. It’s hard to see how that massive difference could be explained in any other way.

So, how big a problem is this?

Big. Very big. It should shake the very foundations of evidence based medicine. If the drug trials and the real world data show such wildly different rates of adverse events, then it really begs the question how much we can trust the trials at all. It would be perfectly reasonable in this situation to say that all “evidence” produced by pharmaceutical companies is so suspect that it should be dismissed out of hand, and that only independently funded trials should be used as a basis for medical treatment decisions.

The problem with that is that it would mean saying goodbye to most of the trials that form the basis of modern medical treatment, and there is not much to replace them with. This issue could be solved over the longer term through large tax payer funded investments in new independent trials. But there’s no quick fix.

The problem is most acute when it comes to the many drugs in common use that only show marginal benefits, such as statins. If the rate of side effects is actually 300% to 400% higher than seen in the trials, then the harms of these drugs could easily outweigh the benefits. In other words, the cost-benefit calculation could shift entirely for many of the most commonly used drugs.

Ok, let’s wrap this up. What can we conclude?

Drug trials do no accurately represent rates of adverse events. It is likely that the true rate of side effects is often many times higher than that seen in drug trials.

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71 thoughts on “Do drug trials underestimate side effects?”

  1. Dr. Rushworth,

    Statins supposedly reduce blood cholesterol. I have read that one of the cholesterols is a precursor to vitamin D production. Does reducing blood cholesterol have any impact on vitamin D levels? Has anyone tested for that?

      1. Hi
        I watched you on Ivor Cummins channel.
        Great video.
        I would really like to buy your book but I won’t buy anything off Amazon. (It’s my little stand against mega/monopoly companies)
        It’s there another way of buying your book? (Smaller online shop?)
        Please let me know .
        Thanks, keep up the good work.
        Pfc

    1. Hi Sebastian
      A drug trial of people taking only that drug has to be different from real life where patients, particularly the elderly, are subjected to multiple medications. I say ‘subjected to’ as you have to be pretty firm to avoid them in my experience. I’m one of the mere 7% of the over 65s in the UK who has escaped the QOF (quality outcome framework) and is not on any prescription meds. When my parents had multiple drugs, I had problems getting side effects accepted that weren’t listed in the usual places. My late father had distressing hallucinations from Apixaban, not listed in the BNF, so not accepted. But, they ceased when the drug was stopped and returned when it was restarted. Finally, I successfully had it stopped when I asked the GP to calculate the risk of stopping, it was tiny, even using those algorithms that ask for all the contributing factors, then add in the average for your age group as well in the usual double counting that ensures you ‘need’ drugs.

    2. Hi asdgamer
      I have just read ‘Vitamin D and Cholesterol’ by Dr David Grimes. He has a theory that since people on statins do not exhibit signs of vitamin D deficiency (to answer your question), then statins act as a vit D analogue. He also points out that statins, as well as blocking cholesterol production, impact on many other systems in the body as does vitamin D. This leads to the interesting question of, in those trials which have shown a little benefit for statins, how can anyone know that it is reducing cholesterol that is the cause of the benefit?!

      1. My husband’s late mother died with severe dementia/Alzheimer’s disease. When I met him she was not suffering from that to any degree that we could ascertain, with hindsight, but she was clearly suffering from some kind of “agoraphobia”, refusing to go out anywhere, having previously been a very sociable woman.

        As she began to show signs of dementia, we looked at her medications, 10 of them. She was on a huge dose of statins, the maximum that a large man would be expected to be on, despite the fact that she was a small, slight woman when I met her. She had had stents fitted at some point, although never had any MI or anything like that. Clearly her GP was unaware that no trials had ever shown benefit of statins for women, whether or not they had heart disease.

        Many of her drugs appeared to me to be prescribed for the side effects of the original few that she may have “needed” (according to the GP’s original prescriptions), but I started to look into the problems with statins, and discovered that memory issues were a huge, but under-reported, side effect. This research is what led me to discover Dr Malcolm Kendrick’s books and blog, as well as Dr Duane Graveline and the research of Dr Beatrice Golomb, the latter two both having made a case for the link with dementia.

        However, we asked for MIL’s bloods to be done to check vitamin D, B12 etc – those 2 being often depleted in dementia cases – the results led to immediate injections of B12 and D3.

        I had wondered about the synthesis of vitamin D and the possible link with cholesterol-reducing drugs. Although not being medically trained, I wondered if part of the statin-dementia link may well be that, being as the brain contains about 25% of the body’s cholesterol, reducing its production with drugs may well be detrimental. Vitamin D deficiency does appear to be a contributing factor to Alzheimer’s and, as we found out when visiting MIL in the care home, there is little opportunity for the residents to obtain vitamin D naturally (kept indoors on sunny days, or smothered in sun block if allowed out!) – although it is said that the elderly are less efficient at producing it (possibly more so as most of them are probably on statins!)

        https://www.alzheimers.net/8-27-14-vitamin-d-and-dementia

        So I wouldn’t be at all surprised if statins are a contributory factor to vitamin D deficiency.

      2. Linda, you say that Dr Grimes ” has a theory that since people on statins do not exhibit signs of vitamin D deficiency…”

        I beg to differ regarding his theory. Symptoms of vitamin D deficiency can be things like muscle pain/weakness, fatigue…all the way up to development of type 2 diabetes and Alzheimer’s/memory issues.

        Funnily enough, side effects of statins also include the same symptoms: muscle weakeness/pain, fatigue, memory issues and increased risk of type 2 diabetes and Alzheimer’s, so I can’t understand how he hasn’t made the connection!!

  2. Dr. Rushworth, I am a big fan of your newsletter and read them with great attention to detail. Your work on exposing the actual benefits of drugs/treatments and their relative risks is impressive and has changed the way that I look at prescription drugs and treatments prescribed by physicians. In this issue, I have to say I am a bit perplexed. I work in the pharmaceutical industry, albeit in small start-up companies and have never seen, not one time, hiding of any adverse event, serious or otherwise, in any trial we have run. It really isn’t possible unless you are totally unethical, which would also have to extend to the study sites and investigators doing the trials. I have not worked in this way in Big Pharma, but my experiences with Big Pharma companies also don’t correspond to the notion that adverse events are hidden, I just don’t see that as possible. I think the more likely possibility is that the trials are very well controlled in specific populations so a benefit can be demonstrated. The label allowed by FDA and EMA would reflect the patient population that was examined in the trial. I would hope that the detail sales staff would include these data in their presentations to doctors, and if they do not, could be in big trouble with the FDA. However, care must be taken to be sure that doctors actually understand the restrictions on the labels. Given that, it is ultimately the doctor’s choice on what to prescribe to a patient. I think the emphasis needs to be placed more on the type of presentations and representations made to doctors, and to doctors not assuming that all medicines are good for all populations of people. My experience with designing trials and reporting results to not correspond to your idea that adverse events are hidden, I just don’t see how that can happen.

    1. Thanks for your comments. It’s certainly possible that I’m wrong about that part. Maybe the entire difference between the trials and reality can be explained by the choice of participants, but the massive difference seen suggests to me that there is more to it – maybe there’s something else I’ve failed to consider. I know of at least a few examples of adverse events that weren’t listed in trial results, so I know it happens, although don’t have any data on how frequently.

      I’ve sat in on multiple presentations by drug reps, and so know from first hand experience that they don’t routinely provide details on inclusion and exclusion criteria, or the age and underlying health status of the participants

      1. Try looking at Bret Weinsteins work on lab rats inbred extra long telemeres masking side effects. Ie the test rats are not representative of real rats – they are “SuperRats” that exhibit genetically superior biological strength.

    2. There’s a book “Side Effects” about how trial data was manipulated for antidepressants. Eventually it resulted in a few billion dollars in fines for the drug company. Most of it wouldn’t come out if not for the efforts of one whistleblower and a legal team in NY who pursued the issue against all odds. It almost never saw the light of day, the book describes it in detail.
      So, I wouldn’t be surprised if similar issues with other drugs just never get picked up.

    3. Dear Mark,
      During the decade 1998-2008 there was a big scandal with Pfizer and it drug Neurontin. It started with a lawsuit for off-label promotion (about 90% of the prescriptions of Neurontin were off-label) and was followed by another lawsuit for manipulation of the studies by Pfizer because there was no evidence supporting the off-label promotion. In total, if I remember well, Pfizer faked or manipulated about 12 studies.

      Pfizer plead guilty and paid 430 million and Neurontin is still on the market.

      Wish you a good read

      https://www.nytimes.com/2008/10/08/health/research/08drug.html

      1. This is not clinical fraud, or a failure on the part of the scientists, medical officers, FDA personnel or clinical investigators when attempting to get a new therapy to market. What you are talking about here is sales fraud. I agree this happens. But that did NOT occur during the development of the drug for the intended purpose. It is SALES fraud, not development fraud or anything related to falsifying data or lying to the FDA. Let’s be clear about that, the two are not even remotely the same.

    4. I do not agree. One of the studies was a five-year Spanish study completed in 2004 that investigated Neurontin as a possible treatment for bipolar disorde. Researchers on the study originally found that Neurontin patients did no better than those on a placebo. But by the time it was published in 2006, the study’s conclusions had been changed to claim that the results indicated a benefit from Neurontin.

      According to the Journal, prior to publication, the lead researcher on the Spanish study had modified the scale used to assess how severely patients exhibited bipolar bipolar disorder.

    5. Mark Mugerditchian,

      My understanding is that drug companies (and others) have developed a number of ways to avoid reporting adverse effects. The most obvious is to not publish such studies, but that is wasteful of RCT effort. Better if the study is designed to limit adverse effects.

      A run-in period is one example given in the video linked below: a pool of experimental volunteers is selected and all are put onto the drug of interest for some period. Those who don’t drop out during the run-in are then randomised to treatment and control groups for the formal study. This has the advantage of seeming to be just a screening of the group for those who might be likely to drop out, but why do people drop out? Adverse effects is a major reason.

      Anyway, a short but interesting talk from a disillusioned investigative reporter whose career was destroyed when she dared to question the safety and usefulness of statins:

      1. The problem with your theory is that adverse events on run-in treatment (which is almost always a placebo, not any form of active treatment) also have to be collected and reported!

      2. Dave Walter,

        As Jim said, the collusion that is required to “hide” AEs of any type is immense. You need the CMO at the drug company, you need the clinical investigators, you need the pharmaceutical scientists, the safety review boards, the clinical investigator, the clinical site’s review boards, the clinical research organization, and it goes on and on. It is nearly impossible to hide AEs of any type.

        Now, I understand your issue with the lead in period but let me expand on how clinical trials are conducted. The way to get a drug approved is to narrow the patient population to a point where the drug will make financial sense, that is to say, has enough clinical benefit in a particular population to have a positive effect on the patient, while having enough patients to treat. Once that threshold is met, the goal is to expand the labeling, through additional clinical studies, to show a clinical benefit with an expanded population. You may not think this process is a good one, but this is now many products are brought to market. The utility of the product is supposed to be controlled by the label which should and does contain an identification of the patient population for which the drug is applicable.

        This scientific process is not easy to corrupt. There are too many people involved. It doesn’t mean that it never happens, and I suppose there are unscrupulous people who make this happen. But the VAST majority of products are approved in this manner, and it is with the FDA’s blessing, who have caring scientists and doctors wanting to do good, at least that is my experience.

        The problem with statins, in my view, is that they were approved on basically structure function claim, that reducing cholesterol “must” have a benefit, without the actual benefit tested. Dr. Rushworth has demonstrated time and again that statins do not show any real clinical benefit. That is not the fault of the clinical trials themselves, it is a failure on the part of the FDA and drug industry who worked to get medicines to the market without showing an actual clinical benefit, that lowering cholesterol MUST have a benefit without showing the actual benefit. In their desire to help solve actual problems in the world, they had a faulty premise in the beginning. I actually don’t have much of an issue with this approach, if the FDA allowed the drug to be marketed with follow-up studies in the patient population to see if there is an actual clinical benefit, but only if the drugs could be demonstrated as safe. I have long advocated for this type of approach and believe that drugs could be brought to the market faster, perhaps in some limited manner, and the drug companies could re-coup some of their investment, but the hammer would come down when the clinical benefit is not demonstrated. This would require a new approach to drug approvals and safety-data reporting after the drug is marketed.

        Back to my original idea. If there are no good biomarkers for examining the effectiveness of a treatment, then we are left with attempting to show a clinical benefit using patient reported outcomes, symptom relief. These tools are accurate and have been validated and are good tools to use, albeit a bit cumbersome, but they create some risk in getting a drug approved due to noise in the patient population. So, a drug company wants to limit the study population as much as possible to reduce the amount of AEs and maximize the positive outcomes. As I said earlier, this approach may limit the market size which the drug company needs to consider when testing new medications. We all understand that a drug company answers to shareholders and must produce profits, there is nothing wrong with that, they are a business like any other. It is unreasonable to think that a drug company will invest 10s or 100s of millions of dollars on a drug that they cannot market to earn a profit. (I realize that some think this is not the correct way to do things, but you don’t get something for nothing unless you desire some kind of government run drug development which would have it’s own undesirable outcomes) Again, nothing wrong with limiting the patient population so the drug doesn’t hurt people and has a significant enough benefit to be a profitable drug.

        Lastly and I’ll end with this, drug development is complex, it involves the FDA, the drug companies, clinical investigators and a host of others, each have their own independent review boards and their own ethical checks. The biggest part of the process that is open to collusion and fraud, in the drug development and approval process, at least in my view, is the actual approval process which the FDA has basically outsourced to industry review boards. That is not so say that this is a horrible way to do things, these meetings are held openly and transparently. But if there is going to be some “spin” applied to the data, that is the place where there is the most risk, and the FDA usually accepts that industry review board’s recommendation for approval or not. That process needs to be carefully examined and carefully administered.

      3. Jim and Mark,

        Thanks for your detailed responses. I think you are both making honest arguments and I hope you are right that there is more good than bad going on in current drug research. Perhaps the regulatory structure is hard to beat – but it doesn’t seem that from the medical literature overall, as Ioannidis et al. have shown.

        Maybe I’m looking at these problems from outside the pharmaceutical research forest and what I am seeing is a sick forest. I think you two may be surrounded by trees that look pretty healthy and are not really seeing the rest of the forest.

        I certainly do agree with Mark on regulatory capture being the most worrying – and it has become so blatant now, that it cannot be denied. Also:

        “Again, nothing wrong with limiting the patient population so the drug doesn’t hurt people and has a significant enough benefit to be a profitable drug”

        This is certainly true up to a point and easy to understand – I would not like to be involved in a study that might harm many of its subjects. However, it is open to manipulation and we get these strange results, as Sebastian notes, where vaccines have not been adequately tested on what would be the most obvious target populations. It is tricky, I understand this, but the trust in the pharmaceutical industry has been severely eroded and it is now difficult to suspend disbelief.

        I would hope most RCTs currently use actual placebos – I would like to see some figures on this though before making up my mind. How many trials are using other drugs or vaccines instead of sugar pills or saline injections?

        There seems to be a trend in vaccination research to use other vaccines as the control. I was reading about a project on a malaria vaccine with the same approach. I know it is complicated – if you can’t give a child with a high risk of malaria the vaccine, then at least you can protect them from another disease.

        But vaccines seem an especially bad choice for cutting corners – you can not unvaccinate someone and a child will have to live with any long-term effect for a long time.

        Jim – it isn’t my theory about the purpose of run-in periods – it is that of medical scientists who study pharmaceutical development.

        Anyway, good to hear from people in the industry who want to be doing the right thing.

    6. You might have the same problems as other technological fields. If you are developing a machine or a computer program, the environment in the lab might be much better than what you have in real life. If you take a machine from a clean lab where it worked perfectly to a warehouse where there is significant amount of dust, the machine might very quickly stop working as intended! Or if a car is developed in, for example, California and then sold to northern Europe and snow happens…
      As you can’t make a perfect lab/test evironment, it might be that medicine require a better way of following up patients. I read a lot about doctors prescribing too many different medicines to one person, where the different kinds then interfering with one another. I kind of get the feeling like the doctors never really know if it goes well or not though. They mostly do “prescribe and forget” it seems.

  3. It’s ridiculously hard to “hide” SAEs in a clinical trial. In 15 years in clinical research I’ve come across one failed attempt to do so and one incident of SAEs being “forgotten” to be reported. I can’t obviously rule out that I have missed others. Some SAEs will go missing unreported in trials because there can be months between study visits and investigators vary in how closely they quiz the patient on what has happened in the mean time. The devil is mostly in the details of the inclusion and exclusion criteria, as you state, but it isn’t that simple either.

    Often the patients that get treated in the real world are less sick than those in the trials – anything oncology (until recently at least) was usually Phase threed in essentially terminally ill patients with advanced metastatic tumours. That also stacks the deck – in favour of seeing a response in a reasonable amount of time if the product is effective. However, this practice also stacks the deck in favour of seeing a worse safety profile. Note that this is ethical if if means you can expose fewer patients to risk to get a scientifically valid result.

    Not surprisingly when you do registries of cancer patients you tend to see fewer adverse effects, and that the underlying demographic is actually younger, has fewer comorbs, and fewer AEs.

    So, it depends. The difference in trial demographic and real world demographic can go either way with corresponding effects. There’s no such thing as a perfect trial, of course populations that are likely to respond (and sometimes less likely to have an AE) tend to get selected for trials. The final approval should take all of this into account but doesn’t always, and physicians should be more aware of this than, in my experience, they are.

    And finally, on the covid vaccines, if autoimmune disorders, allergy, and advanced age were exclusion criteria for the trials, why is hypersensitivity the only contraindication listed on the SmPC? I think we should be told.

    1. Thanks, that’s interesting. I don’t have the personal insight in to the pharmaceutical industry to be able to say exactly what’s going on – all I can conclude is that something is clearly going on and then speculate as to what. Here’s a study from PLoS Medicine which found that unpublished versions of studies consistently report higher rates of adverse events than the published versions, which is odd. Do you have any thoughts on what could explain it?

      https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002127

      I’ve written previously about the groups included in the covid vaccine trials here:

      https://sebastianrushworth.com/2021/01/10/are-the-covid-vaccines-safe-and-effective/

      1. From a very brief look there are two things – likely inclusion of studies not subject to AE reporting like a drug clinical trial is, and the age of some published studies (pre-CONSORT). A big flag is them talking about studies reporting AE relative risk which is (almost) never done in clinical research because multiple testing will throw up more false positives than 45 cycles of PCR in a pop-up Covid lab.

        CONSORT requires information on AEs to be included in a publication of a clinical trial these days, so that only 46% of “published sources” included is odd. For space reasons, there will be a lot less information on AEs in an academic publication than in a study report. That will not change until the journals wake up to the fact that page count is now irrelevant.

        I would prefer to see just the matched analysis, CSR versus publication. I would be astonished to see any unexplainable differences (e.g. interim analysis versus final analysis) in that comparison, certainly for any publication in the last 10 years. I will take a closer look later.

        All AEs that are reported to the trial investigator (doctor for the patient in the trial) get reported to the sponsor and end up in their database and clinical study reports. A digest of that data will end up in a published manuscript (if there is one). This is one of the less error-prone and least manipulable aspects of a clinical trial. Now that everything is documented electronically, instantaneous data transfer to the sponsor (sometimes while the patient is sitting in the office), audit trails etc, it is pretty much impossible to lose events, whether intentionally or negligently. There are far, far bigger things that can go wrong, or be “nudged” (like careful selection of study population)! I wouldn’t (and don’t) go looking among AEs for indicators of those little but clever aspects of trial conduct that nudge the result in the desired direction.

      2. Suggest anyone interested in the behaviour of pharmaceutical companies reads the work of Peter Goetzche.

      3. Jim, I think your confidence in big Pharma is misplaced.
        The Merck VIOXX is a case in point, they carried on selling it despite knowing it was a killer.

      4. Regarding what goes on in pharma trials, there are several excellent books that I’ve read – all very shocking.

        “Deadly Medicines and Organised Crime” by Dr Peter Gøtzsche
        “Bad Pharma” by Dr Ben Goldacre
        “Doctoring Data” by Dr Malcolm Kendrick
        “Pharmageddon” by Dr David Healey
        “Big Pharma” by Jacky Law

        Gøtzsche actually worked in the pharmaceutical industry before qualifying as a doctor, so has seen it all from the inside too.

      5. A 78 y/o friend had a stroke in the weeks following her second Covid vaccine. If she had been under 50, this would have been flagged as a potential vaccine AE. However, because of her age it is just assumed that it was “natural”. Not keeping records that can be compared with expected levels of all sorts of events in the vaccine roll out is a very serious problem. Until some analysis emerges somewhere in the world, I will not take the vaccine because I have a confirmed history autoimmune arthritis and thyroiditis.

    2. Based on what I read, there are both active and passive run in periods. Here’s one link:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377048/

      The study analyzed 470 RCTs. They conclude that industry run trials use run in periods much more frequently and that in 88% of trials with run in periods reporting was incomplete, “precluding a meaningful assessment of the impact of the run in period on the validity of trial results”.

      They also say that “exclusions in run in periods may be considerable”. In one trial on the effect of opioids on lower back pain, 42% of participants were excluded during the run in period.

  4. Hello Dr Sebastian
    I sent this letter to my GP after my second vaccination, it has not been acknowledged. It may be of interest to you no one else seems to be.
    It was an unpleasant experience and I would appreciate your opinion, which I am more than willing to pay for.
    Almost 82yrs, a pacemaker, bundle branch block left and right etc my inclination is to decline the next offer of a booster.

    Regards
    Graham Hamblin

    Dr Law
    For your information:
    I had no ill effects from the initial vaccination on 19/1/21 but since the second I have had daily, several severe attacks of Raynaud’s Syndrome my fingers and palms going white followed by them becoming cyanosed and painful, the left worse than the right. Even when inside keeping warm.
    I have had Raynaud’s in the past, but not recently, never so sustained and severe as this, I thought it worth bringing to your attention. Otherwise I feel fit and well.
    I have Nifedipine MR 10mg tablets which I am taking and do not need to see the doctor.

    Graham Hamblin
    Burton upon Trent

    1. I am 68 and had Raynaud’s condition when much younger, i.e. 20s, 30s. A healthy diet put paid to it although I still have poor peripheral circulation.

      If the vaccine has caused health problems, maybe one has to adopt a healthier diet to combat the effects of the vaccine. It’s a ridiculous situation, though.

    2. Have you looked into the reports from Canadian MD Charles Hoffe?

      https://www.youtube.com/watch?v=5sIWb9GTbbE

      He has also been punished for reporting his concerns of serious side effects of the Moderna vaccine – and was not allowed to work as an emergency room doctor anymore. Recently his private practice burned down.

      It is obviously very risky to report unwelcome information.

    3. My husband also had Renaud’s appear out of the blue in the weeks following his vaccination. Seems OK now, but he is reluctant to take the second shot. My neighbour had very painful tingling and burning in her hands after her second, a milder version of what Eric Clapton had. Hers resolved but Clapton seems to have a continuing disability.
      Neither were reported as adverse effects.

  5. Hi Dr. Rushworth
    Your article on drug trials underestimating side effects is consistent with the following:

    It is reported that articles in peer reviewed journals are ghost written by people working with the pharmaceutical industry and then the authorship attributed to credible medical professionals when published in medical journals. See https://www.bitchute.com/video/2l9qdpBosjHh/ and The Illusion of Evidence-Based Medicine: Exposing the crisis of credibility in clinical research, by Jon Jureidini (Author), Leemon B McHenry (Author).

  6. So it seems what ends up happening is that the RCTs generally focus on low-risk populations, for ethical and marketing reasons, which have fewer AEs in the results. Then you have “field trials” after approval, where AEs are discovered in high risk populations, and the retrospective studies end up exposing the mess.

    If you’re in pharma, it may be hard to justify spending research money on finding AEs in populations when those AEs haven’t yet been shown to be a problem. That would end up removing funding from other projects where both the company and consumer might benefit. And recall that pharma are often in a race with one another to find products for the market. And they are in a race to replace products soon to have generic status. Pharma management are ethically bound to generate profit for their stockholders. They also have to not do harm, of course, but suspicion of harm isn’t strong enough a case perhaps to justify spending research money on possibilities that might do harm to both the company _and_ consumers with respect to denying funds to other projects. Risk analysis isn’t limited to medicine.

    One of the known problems with RCTs is that their results often don’t correspond to what you see in the field, which is precisely one of the advantages of retrospectives. For work in the field, one might legitimately say that retrospectives are the “gold standard.”

    RCTs will never be able to discover all 2nd- and 3rd-order effects, so retrospectives will _always_ be needed to help flesh out the field data.

    Retrospectives seem to be useful:

    1) to suggest possible solutions (perhaps, because of a time factor, such as a viral epidemic, they are necessary as an immediate, perhaps temporary solution) and

    2) to discover AEs from field data.

    A wise craftsman has multiple tools in his toolbox.

  7. Ok, you pharma guys–I have a question for you. With strong retrospective data suggesting benefit for several repurposed drugs, why hasn’t pharma done any adequate studies of those drugs for use in treating covid?

    Any RCTs done by pharma look to be one of the following:

    1) late treatment (looks “designed to fail”) or

    2) underpowered studies of low-risk patients (looks “designed to show statistical lack of benefit”).

    Is this a problem caused by perspective and incompetence? (I _really_ have a hard time seeing this as I’ve not worked in either medicine or pharma and I saw the problems a year ago.)

    The _key_ question with regards to covid antivirals is whether they reduce hospitalization given early to high risk patients. (We assume that morbidity and mortality will decline if hospitalizations decline for the time being and leave it to retrospectives to follow up.)

    Pharma has yet to seriously address this question.

    Will anyone from pharma step up to answer my question?

    1. I’ll give it a try.

      First, FDA has banned all treatments for COVID. Why? I suspect there is some collusion between the agencies of our government. An EUA can only be issued if there are NO effective treatments available. Many people stand to gain for the exclusive use of a vaccine, especially pharma and certain people in the government as holders of patents or interested parties to those patents. Therefore, the FDA clamped down on the use of treatments. This may sound somewhat conspiratorial in nature, but it is a valid explanation.

      Second, and no surprise, the treatments are inexpensive, hence, not a big income source for pharma.

      Take the two together, and you have a plausible answer to your question.

      1. Thanks for playing.

        However, you haven’t answered my questions about the studies which _have_ been done by pharma wrt covid antivirals: designed-to-fail and designed-to-show-lack-of-statistical-benefit studies. And it looks like more worthless studies keep being added, so pharma doesn’t look like it’s stingy.

        So there _have_ been studies of inexpensive repurposed drugs by pharma and their agents. I can’t buy into the incompetence argument. The CDC issued guidance to treat high risk influenza patients early with antivirals in Jan. 2020. So I am left with the prima facie corruption hypothesis.

    2. There’s also the “overdose the patient and declare the drug unsafe” approach that was used to have HCQ banned.

    3. But I think he did provide a plausible answer to that question. Emergency Use Authorization’s are only given out by the FDA when there are no other available treatments. So pharma companies conduct sham studies where they either underdose or overdose available, low-profit treatments to “prove” that they don’t work. Then they get the EUA on the big money maker, the vaccine.

      It’s not incompetence. It’s intentionally eliminating low-profit options so that the high-profit option gets approved.

      1. Sure, there is a plausible explanation about EUAs, but you aren’t seeing my points either.

        If pharma isn’t colluding to undercut inexpensive treatments, why did it advance studies which actually undercut inexpensive treatments. Secondly, if pharma is playing fair and not engaging in corruption, why did it fail to test antivirals adequately (early treatment of high risk patients). Pharma’s tests were an obvious sham.

        How can pharma avoid charges of corruption and harming the public interest for what it did as regards worthless studies of inexpensive antivirals to treat covid?

        And who in pharma and what level might be responsible for planning the fraudulent research? I don’t see how it can be sales and marketing.

  8. —“Might the standard lab mice not be good to detect medical side effects due to ultralong telomeres et c? “—
    What about the possible consequences on your topic of Bret Weinstein’s hypothesis (when he was a graduate student – it was later confirmed) that standard lab mice (in the US mostly from the Jackson’s laboratory) have ultra long telomeres (in contrast to their wild ancestors) and (if I got it correctly) are very prone to get tumors but also that their tissues that are less sensitive to toxicities:
    “Candidate pharmaceuticals are tested on mice to see if they cause abnormal growths, but with compromised telomeres, it might be difficult to get an accurate assessment of cancer risks. …

    At the same time, we may be underestimating drug toxicities. Testing a drug or other chemical compound for systemic toxic effects on mouse tissues could be problematic if they dramatically exceed our own tissues’ ability to repair. As a result of enhanced cell renewal, a mouse with long telomeres could have a radical capacity to heal, thus masking toxic effects that humans would suffer.
    https://oncobites.blog/2020/07/29/modeling-aging-and-cancer-are-lab-mice-different-from-their-wild-cousins/
    Lots of videos on Youtube by the way in which Weinstein talks about this topic. I got the impression that the interest from the establishment (journals et c) to study this further is very low.

  9. I am not specifically referring to the Covid arena, but to any study that uses a placebo for comparison with the active agent.
    I have become aware that ‘designer’ placebos are in use that themselves produce similar side effects to the active agent, thereby de-emphasising the presence of those side effects in the study results.
    The placebo is thus no longer a small dose of sugar, but may even be a product that already has approval and can be argued to be a safe and valid comparator (even though that product itself might have been tested against a designer placebo). For example, in testing a vaccine against disease B, the placebo might be a vaccine already in use against disease A (arguably similar).
    In this way, houses of cards can be built up on what is a very shaky initial product approval.
    It reminds me of the way relative risk and effectiveness is used to obscure absolute risk and effectiveness, thereby obscuring another very important part of the story.

  10. If evolutionary biologist Bret Weinstein is correct the problem is even deeper. He says that the telomeres – the end caps of chromosomes that shorten with age and repetitive replication – are abnormally long in the very inbred experimental animals used in most pharmaceutical research. His claim is that this renders them more easily able to repair their cells which in turn makes adverse effects go away. So even before the human use begins the safety results are suspect. The animals are inbred to make them genetically similar, but the inbreeding procedures themselves create these youthful rat and hamster populations. Weinstein’s work seems to be buried in the dustbins of medical literature. What a surprise, right?

  11. I’m 73 and do not take any prescription drugs. I’ve had problems with medical doctors and developed a disrespect for major pharmaceutical companies.

    My early reading about how testing of the 3 available vaccines was rushed and then given emergency approval almost assured I wouldn’t take the jabs. Then I read that they were not tested on anyone over 55.

    I think accepting the jabs is riskier for me than my normal cautious behavior. So far, so good.

    I recently posted to a vaccination discussion on a social website called nextdoor. I briefly explained why I was not accepting a vaccination. My post was erased within 10 minutes.

    1. Having your post deleted from Nextdoor is no loss, believe me, as I wasted many hours on discussions in my local site that I would be called names and reported to the censors when it became evident that I had the best argument. We know that the Biden Admin is “working with socials to monitor those who spread ‘misinformation,’” which is Liberalese for “ideas we do not agree with.” Depopulationists and eugenicists coerce and entice us to take their jabs. And they want it mandatory, or as I heard on tv by multiple taking heads, to make it as uncomfortable on us as possible. I have not made up my mind, remaining open-minded, but so far, I must admit I have not seen the weight on the side of benefit versus risk. IF all goes well, I MAY have an advantage (if I am one of the 1% actually to contract the disease) of avoiding severe progression, but I also risk suffering adverse events. We still don’t know the long-term effects. So, here I sit, using common-sense precautions and with a medicine chest full of early treatment anti-virals – just in case – which I had to go out-of-state and online to obtain. My corporate doc would not prescribe any of them to me because they aren’t “standard of care.” Their “standard of care” is to stay home for two weeks and go to the emergency hospital if you can’t breathe. Sheesh, what a standard.

  12. Thank you for another helpful article Dr. Rushworth.

    All kinds of people/conditions are excluded from studies — intentionally and unintentionally. There is no random group of volunteers. Some of this skews the results. When i was in graduate school i took part in several medical studies. They were age restricted to about 25-65, excluded women of childbearing age, and only included healthy people. Practically, participants had to have somewhat flexible schedules and the financial benefit had to be worth it, excluding anyone with a demanding or well-paying job.

    Also
    “…then it really begs the question how much we can trust the trials at all.”
    I don’t know the right wording, but “demands that we ask…” is a possibility.
    “Begging the question” has a different meaning — https://en.wikipedia.org/wiki/Begging_the_question

  13. Dr. Rushworth,

    Dr. Peter Breggin ( https://breggin.com/brief-bio/ ) has investigated Big Pharma for many years. He’s had access to internal documents at major drug companies like Eli Lilly because of his involvement as an expert witness in high profile court cases. He has published many books over the years.

    If you go to that Breggin bio link above, you’ll get a good idea of his background, but if you download his “full Bio” you’ll want to know more.

  14. “Breaking the blind” isn’t hard in a trial testing blood pressure lowering meds since control group will have higher numbers than treatment group.

    1. A colleague who did several antidepressant trials said he was virtually never blind after he had seen a patient. I was involved in one of the rare studies of the mood effects of 10 mg morphine or saline placebo in normal young men (virtually all studies are done in addicts or post addicts). The nurse administering the injection guessed right within 10 min of administration for 59/60 subjects. We reported that the nurse was essentially unblind, but most studies do not even ask personnel with patient contact to record their guess as to group membership.

  15. One thing that may be worth discussing in this context is the ‘nocebo’ effect, where patients who anticipate a particular side effect then do so with increased frequency than if ‘naive’.
    This may a particular effect with statins and muscle pain.

    Two papers of interest are

    https://www.bmj.com/content/bmj/372/bmj.n135.full.pdf

    In this paper, 200 patients who had or were considering giving up statins because of muscle pain were flipped 6 times for 2 month periods between statin and placebo in a double blind allocation. There was no difference in the incidence of muscle pain between the statin and placebo periods.

    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31075-9/fulltext

    This was a study in 2 phases. The first phase was a double blind study of statin vs placebo, and then a subsequent open label non-blinded non randomised study of statin and placebo. The incidence of muscle pain in the first study was no different between the statin and placebo patients. In the open label study, the statin patients had an increased incidence of muscle pain than the placebo group (hazard ratio 1.41).

    This effect could be one explanation for the difference in reported side effects in the ‘real world’ compared with the ‘laboratory’.

    1. That is an interesting thought, and could certainly be part of the explanation. Although the nocebo effect should play much less of a role when it comes to serious side effects than it does with mild side effects.

      As to statins – both those studies were using low dose atorvastatin (10 mg in one and 20 mg in the other), so I don’t think one can conclude from them that statins don’t cause muscle pain. If they really wanted to test the hypothesis they would have gone with 80 mg.

      1. I seem to recall that a lot of the older statin trials had run-in periods as well which would serve to eliminate a significant proportion of more sensitive participants. This would also explain why lower levels of adverse events were reported relative to the general population.
        I also believe that athletes report significantly higher levels of adverse events in terms of muscle pain. It does not take a genius to work out why, given the statin induced interruption in the energy supply in muscle tissue. They would not be overrepresented in drug trials either.
        The other interesting thing is the reluctance of the Cholesterol Treatment Trialists to provide full transparency into the adverse events database that they have. Clearly it is not in the interests of the Pharma companies funding them to have any sort of transparency into the true levels of adverse events reported.

    2. It’s unclear to me whether the pain is due to cramping or normal use (or perhaps chemically-induced cramping leading to long term damage).

      Muscles can be taught to cramp with certain (perhaps chemical) stimuli. Perhaps statins act in an adjunct role to the learning process and their effect persists after removal, so that one might wrongly conclude that statins were merely associated with cramping, not causative.

      The vitamin D angle needs more research, I think.

      1. The muscle problems are probably due to the effect on production of Co enzyme Q 10. This is produced on the same metabolic pathway in the liver as cholesterol. It is essential in providing energy to muscles. Anybody taking a statin should supplement with this. Indeed Merck had a patent for including it with one of their first statins but nobody else was doing it and it would have made their product less competitive so they dropped it’s inclusion in the pill. So they knew right from the beginning that muscle pain and weakness would be a problem.

  16. One possible explanation of the discrepancy in reported outcomes that Dr Rushworth did not mention is that the drug companies simply lie. That is, they receive all the trial data, then report other data that they have made up. The “Big Lie” works well in politics and advertising; why should it not work in medicine?

    As I see it, such lies and deception are inevitable when everyone is preoccupied with money. Let’s face it: the corporations have one legal duty and one alone – to earn as much money as possible for their shareholders and employees. (Well, technically just the shareholders, but “Thou shalt not bind the mouths of the kine that tread the grain”).

    A great deal of effort has gone into persuading us all that the current Western systems of “democracy” and “free market capitalism” are for the best in the best of all possible worlds.

    But it just ain’t so. As Aristotle (no fool) observed 2400 years ago, you cannot have democracy through elections because the rich simply buy votes, and so you end up with plutocracy. And the “free market” isn’t free, nor a market. No market can even exist without rules and sanctions, and every government puts both feet into the scales. Moreover every free market migrates rapidly towards monopoly, monopsony or both. The quotation from Adam Smith that is supposed to show that the best way to enrich everyone is to have a Hobbesian fight of all against all actually shows nothing of the kind.

    If nobody plans ahead, everything more than a year or two in the future is left to chance – or selfish greed. That’s why our population is way above sustainability, pollution is out of control, our waterways are turning to toxic sludge, and the Great American Political Experiment is rapidly heading towards violent chaos.

  17. The next article I read after this one was “Time to assume that health research is fraudulent until proven otherwise?”
    https://blogs.bmj.com/bmj/2021/07/05/time-to-assume-that-health-research-is-fraudulent-until-proved-otherwise/

    That article provides some frightening facts and figures about the prevalence of deliberate, systematic, cynical fraud – and how often it passes undetected, or at least goes unpunished. Richard Smith writes that “In her book Research Misconduct Policy in Biomedicine: Beyond the Bad-Apple Approach [Barbara K. Redman] argues that research misconduct is a systems problem—the system provides incentives to publish fraudulent research and does not have adequate regulatory processes”.

    The most worrying aspect of that statement is that it assumes researchers will cheat and lie if they stand to gain and are unlikely to be found out.

    Nowhere in the article did I find either word “honesty” or the word “integrity”.

    1. The original concept of science was that it would perform corroboration.

      “Robert Boyle…was one of the most prolific figures in the scientific revolution and the leading scientist of his day. He was a proponent of the mechanical philosophy which sought to explain natural phenomena in terms of matter and motion, rather than appealing to Aristotelian substantial forms and qualities. He was a champion of experimental science, claiming that theory should conform to observation and advocating openness in the publication of experimental results, the replication of experiments for empirical corroboration, and the importance of recording even those experiments that failed, at a time when these ideas were revolutionary. He defended and developed the distinction between primary and secondary qualities and supported it with detailed experimental evidence. With the help of his colleague Robert Hooke (1635-1703), he designed and improved an air pump capable of creating and sustaining a vacuum and used it to perform many famous experiments, investigating things like respiration, disease, combustion, sound, and air pressure. He discovered Boyle’s law, which shows that the volume and pressure of a gas are proportionally related. He used empirical evidence to refute both the four-element theory of Aristotle and the more recent three-principle theory of Paracelsus (1493-1541). Finally, many historians of science consider him to be the father of modern chemistry.”

      https://iep.utm.edu/boyle/

      Corroboration can be prohibitively expensive and competing pharma might lie about results so as to prevent a competitor from bringing a product to market. Not to mention that spending millions to corroborate a competitor’s results might not be in pharma’s interest.

      If we stipulate that only govt. should fund research, because it isn’t seeking profit, do we have any assurance that somehow we can keep corruption out of the process? There is a cornucopia of historical examples of government and corruption going hand in hand.

      This is a difficult problem.

      1. By “corroboration”, I meant “corroboration of experimental results.” If results cannot be repeated, there is a problem.

  18. Thanks Dr Rushworth,
    Most interesting. I have stopped statins, never felt better.

    As far as trust in the the Journals and research reports go its very evident that they cannot be trusted. The simple fact if you look at the influence Gates has over the industry and the media its is clear that they cannot be trusted as much as Gates himself has been shown to harbour ill intent and a desire for population reduction using vaccines. He has admitted this is a Ted Talk in Feb 2010. It was filmed and recorded.
    When one sees the influence of Gates over the Health Industry, it makes one realise how dangerous this man is.

    He organised the EVENT 201 October 2019.
    This was the precursor to this Covid event being foisted on the world.
    Representatives from the World Economic Forum, the Centers for Disease Control and Prevention, Johns Hopkins University Population Center, the World Bank, the Chinese government and vaccine maker Johnson & Johnson were among those at the event, which was organized by Bill Gates and, too coincidentally, simulated a worldwide pandemic triggered by a novel coronavirus- Mercola was the source

    There are two very interesting pieces in the UK publication conservativewoman written by Karen Harradine.

    The first one is The megalomania of Bill Gates.

    The second one series of four parts
    Bill Gates and the world health juggernaut.
    Revealed, how Bill Gates’s influence spreads virally into UK public health policy
    It cover his influence on the WHO, Unicef and the World Bank.
    The influence of Gates over British public health and Covid-19 policy
    The influence of Gates over GF-funded universities and scientific institutions

    Then another series on his influence over the media. Bill Gates’s stranglehold on the MSM.

    Once one looks at how much influence he has on the journals news media is scary,
    One of the most well-known “fact-check” websites, PolitiFact.com, which heavily counters
    unflattering “conspiracy theories” concerning Bill Gates, is funded by the Poynter Institute, which is partly funded by Bill Gates.

    Public records show that the Bill and Melinda Gates Foundation funded the academic,
    Prof. Neil Ferguson of Imperial College, who persuaded governments that “lockdowns”
    were necessary, until mass global vaccinations could be rolled out. Gates has long
    promoted vaccinations over all other forms of improving public health, such as clean
    water and nutritional improvement, with his founding of the GAVI Alliance and
    the “Decade of Vaccines” – Principia Scientific

  19. Hello, Dr. Rushworth. My question is a bit off-topic, except that it relates to the argument that in general, pharmaceuticals are underestimated in terms of their potential harms, as well as over-prescribed.

    There has been some talk in the media, including some mention within the medical literature, about the possible use of Ozone therapy as a treatment for Covid-19.

    Doctors who use the treatment claim that, when done correctly, it is safe and effective. In the US, the USDA has stated that ozone is toxic and has no known medical use.
    In your opinion, is there any evidence in favor of ozone that could at least justify further research? Or do you consider ozone therapy to be a sort of snake oil?

    I wonder of you might consider posting an article on this topic, if it interests you.
    I also recall that during the 1990s, there were claims that ozone therapy could cure HIV/AIDS.

  20. I am afraid you are right Sebastian. I speak from the U.K. and am 76yrs. old, though it is probably much the same in any country/health system.
    The fact is the patient can not trust the doctors, the drug companies, the health system, the government or any one else to help us live as long as we would like, or as well as we would like.
    As far as possible I search out herbal remedies, old fashioned ‘treatments’, may be, ‘alternative’ medicine.
    The inter net helps but particularly since covid19 that has been censored.

  21. I know the inside of CROs, start-ups and Pharma giants and left because the ethical standards of clinical research had fallen to where I had to choose between walking away from a lucrative, successful clinical research career of over 20 years or compromising my personal code of conduct. I chose to risk homelessness. So too did others.
    There were many years’ battle between Research and Marketing divisions over ‘spiel’ – research wanted doctors told ‘bad’ news as well as good, S&M wanted only ‘good’. When S&M won, the Press got a scandal re-balancing the rowing divisions.
    In research, one way of not finding what you do not want to find is to not look where the theory suggests it might be. No evidence and no problem are separate issues, but analytic thinking is rare.
    And, one way of reducing ‘bad’ news is to make the reporting process unbearably onerous for those doing the reporting.
    Introduction of such tactics was unstoppable. I and others had fought a long battle against the falling standards of the top and their ‘followers’. Over the years we became heavily out-numbered until there were very few of us, globally.
    Originally, study protocol titles were: ‘to study the safety and efficacy of …’. Researchers, being fit and healthy, are unaware they may ever need medication. So, safety is not for them. Whereas efficacy is what pays their salaries. So, from their point of view, efficacy is for self, safety for others.
    Those original titles served others first, self second – good table manners. And, that was the mind-set of the way studies were designed and run. And we did not know, so we looked to find out, study, investigate.
    Those original style early phase clinical research studies found accuracy without putting many at risk. Subsequent phase 3 studies expanding the applicability taking already found warnings into account. Whole development programmes were often binned due to unacceptably high risk to others being found, despite Company’s astronomic expenditure going down the drain.
    As society’s culture became fast buck instant gratification, me, me , me, the protocol titles changed to: ‘to show efficacy and safety’ and ‘proof of concept’ – serving self first, others second (if remembered), self knew it all, prove self right. No study, no investigation, not looking to find out. Some consciously intentionally but mostly basic mind-set, same as society at large and all other ‘research’.
    ‘Real-life’ is too complex to bring risk to light before thousands suffer – bigger danger than original type studies. ‘Fast-buck, me, me me shows’ are the biggest danger, giving false security, closed eyes.

  22. After 18 months of covid running rampant, still only 11% of the US population has been exposed, if you believe official figures. And covid is supposedly extremely infectious with a high R-value.

    An alternative view (mine) is that 7x the official figures have been exposed and there is corroboration that exposure levels are much higher than official case counts from serum antibody studies.

    https://academic.oup.com/ije/article/50/2/410/6146069?login=true

  23. There seems to be some misapprehension that the (US) FDA is a body with legal/scientifc integrity, good intentions, and high levels of ethics. Decades of experience suggests that it is more about money (for individuals and companies) and politics than about public health. Some examples
    2002 Monsanto and approval of rBGH: https://www.bibliotecapleyades.net/ciencia/ciencia_monsanto46.htm
    2018 AstraZeneca sneaks a bad drug through: https://www.sciencemag.org/news/2018/07/fda-s-revolving-door-companies-often-hire-agency-staffers-who-managed-their-successful
    2019 There are consultancies who help companies navigate the FDA: https://www.fdamap.com/conflict-of-interest-and-fda-revolving-door.html

  24. Great stuff. I highly recommend David Healy’s work on this – particularly Pharmageddon. He goes into grave detail about how Pharma manipulates RCTs to exaggerate benefits and reduce harms. The key to this is that they never share the raw data, so it can never be independently analyzed.

  25. I would also add that, despite assertions by some people in the comments that “science is very hard to corrupt”, apparently editors-in-chief of four major medical journals seem to think otherwise as all four of them went on record decrying the current state of medical research.

    On Dr Kendrick’s blog someone posted a link to a piece in BMJ by Richard Smith. In it he proposes to consider all research coming from Pharma to be false unless proven otherwise.

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