it didn’t work…

Posted on Monday 15 August 2016

Well, I couldn’t do it. I thought I could just log the last post and keep my mouth shut, but it didn’t work. I made the mistake of reading this article again. So with apologies, I have some more things to say:
New England Journal of Medicine. 2016; 375:405-407.

… A key motivation for investigators to conduct RCTs is the ability to publish not only the primary trial report, but also major secondary articles based on the trial data. The original investigators almost always intend to undertake additional analyses of the data and explore new hypotheses. Moreover, large, multicenter trials with large numbers of investigators often require several articles to fully describe the results. These investigators are partly motivated by opportunities to lead these secondary publications. We believe 6 months is insufficient for performing the extensive analyses needed to adequately comprehend the data and publish even a few articles. Once the investigators who have conducted the trial no longer have exclusive access to the data, they will effectively be competing with people who have not contributed to the substantial efforts and often years of work required to conduct the trial.

… In summary, we recommend that the ICMJE come together with trialists and other stakeholders to discuss the potential benefits, risks, burdens, and opportunity costs of its proposal and explore alternatives that will achieve the same goals efficiently. Moreover, we recommend modifying the proposal as follows. First, the timeline for providing deidentified individual patient data should allow a minimum of 2 years after the first publication of the results and an additional 6 months for every year required to complete the study, up to a maximum of 5 years. Second, to enhance readers’ confidence in published data, an independent statistician should have the opportunity to conduct confirmatory analyses before publication of an article, thereby advancing the ICMJE’s stated goal of increasing “confidence and trust in the conclusions drawn from clinical trials.” Finally, persons who were not involved in an investigator-initiated trial but want access to the data should financially compensate the original investigators for their efforts and investments in the trial and the costs of making the data available.
I ran across a blog post that mirrored some of my reactions and brought up a few interesting points that hadn’t occurred to me:
by Glyn Moody
August 8, 2016
This NEJM article sounds like Nero playing his violin while Rome burns to me. I can think of nothing in Medicine that comes even close the level of corruption achieved in the distortion of Clinical Trial results in the fifty years since the Kefauver-Harris Amendment made trials a pre-requisite for drug approval – something that was intended to be a reform, a check on the often inert patent medicines of the day. There’s nothing wrong with that piece of legislation itself. It’s what people did with these clinical trials that has wreaked so much ongoing havoc.

While the standard for approval is low, FDA approval isn’t intended to direct clinicians. It simply means that the drug has demonstrated medicinal properties and is deemed safe for human use. The malignant problem has arisen from the version of those trials that has made it into the medical literature, regularly inflating efficacy, downplaying toxicity, and laying a base for advertising campaigns that opportunize on our patien’ts desire for symptom relief and/or wellness. The aura of FDA approval and publication in the scientific literature has been parlayed into billions of dollars in ill-gotten profits. Worse, it has catapulted medication induced mortality and morbidity into the majors.

Clinical Trials are referred to as "research" and the people in charge of these studies call themselves "researchers." Research is exploration in search of new findings. These clinical Trials aren’t research, they’re product testing – governed by strict rules to be validating. And so many of the published results make a mockery of these basic rules: Randomization, Double Blinding, Preregistration of Outcomes followed by Replication of positive results. The NEJM article describes a mythical process bearing little resemblance to what actually happens in these largely commercially conducted trials. The analysis could, and perhaps should, be done the day the trial ends and the blind is broken. If they want to play around with the data for some kind of exploratory research, they could simply hold on to the original protocol directed analysis until their other data play is finished. Truth-be-told, this plea for time to play around with the data is an admission of guilt – Hypotheses After Results Known!

But the regularity of corruption in Clinical Trial reporting in the medical journals trumps any argument they might muster, any violin they might play. This is likely the biggest scandal in the history of Medicine. Rome really is on fire…
    donald klein
    August 16, 2016 | 12:40 AM

    The most difficult and argumentative decisions usually revolve about two abstractly stated positive goals in conflict. We wish to reward the investigators’ hard work . That’s a puzzle, so the resort to the patent monopoly argument over future utility can be accepted as correct. The other view is that contributions to the public health should not be stifled by monopolies even if temporary.
    Stated abstractly no useful conclusion is apparent. It appears that some sort of arbitrary allegiance is required and we all know that arbitrariness is unacceptable.
    Unpacking may be helpful. The investigators’ reward package is quite complex. At the time of publication they have already received more or less adequate financial support, academic recognition by the otherwise ignorant administrative staff ,the increased possibility of promotion,the attraction of interest,disbelief and controversy, that their coterie of concerned scientists may proffer, if they notice.
    None of these are dependent on prolonged monopoly of new knowledge.Evidence that such monopoly is beneficial is not obvious.
    Conversely, the argument for immediate public display suggests a controversial tidal wave of mistaken findings and ideas. Therefore some sort of prepublication peer review appears necessary. Unfortunately,the current peer review system of unpaid academics ,skimming the articles summary statistics,as provided by very interested parties( not only Pharma but academic allegiance effect) is clearly an inadequate journal stop-gap.So if this suggestion is to have real consequences ,the peer review system suggested must have little resemblance to the current cripple and evidence that it can be supported and occur needs to be established.
    Is anything likely to happen? Not until sufficient public are informed and activated. The expression of much too abstracted views does not help public understanding. Its effect is to bedazzle into obscurantism and apathy.
    The generally helpful contradictory approach is to insist that the referents of the abstractions be spelled out.Judgments as to comparative worth may be clarified. Arguments centering solely on abstractions are best dealt with by ignoring them as almost certainly fruitless.
    Don Klein

    August 16, 2016 | 2:03 AM

    “Is anything likely to happen? Not until sufficient public are informed and activated.”
    That the activation of sufficient colleagues continues to be so elusive remains a sad source of wonder to me.

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