Clinical trial gamesmanship has become a bigger problem over my lifetime as a doctor. I think part of the problem is lower bar for approval at FDA. When they lower the standard to approve new drug or device, clinical trials will lower endpoint bar to meet it. In 1990s, FDA required ICDs demonstrate reduction in total mortality for approval. Now, CCM and phrenic nerve stimulation for sleep apnea approve with much lower standard.
Precisely. Only when regulators reject BS studies for new approvals or labelling indications, will Pharma consistently perform the studies in a manner that will reach a higher bar. Doing the absolute minimum necessary is the very essence of human nature.
Wise commentary by J. Mandrola. Science must get to the root of the problem to understand it and define treatment strategies. Trials are experimentation, sometimes necessary and useful, but if they do not lead us to an understanding of what is underlying they are of reduced usefulness. Bravo once again, J.M.
It sounds like the problem is marketing needs to be removed from research. I am not sure how to do that. I am just a housewife, but I will tell you, I have never seen people distrust the medical field at this level. I know this is going to sound crazy, but I think returning manufacturing to the USA is a good idea. We need REAL industry. People cannot be a product in a health system factory and make an economy that is real. The education system needs to change. IT used to be that people had a calling to say be a doctor, or a teacher. They wanted to help people. It was in their nature. Then something changed, MONEY. School is about the money, jobs are about the money. I know they need the money for the research, but there is something wrong with the focus.
Congratulations on your sharp critical analysis, with which I fully agree.
I would trace your question regarding the purpose of clinical trials back to the early days of so-called “scientific medicine,” which emerged with the biomedical model in the late 19th century—a time when ignorance of the health-disease continuum was almost absolute. Back then, scientific research was driven by genuine philanthropy and guided by what we now call true uncertainty or equipoise—meaning there was no preconceived expectation about the outcome of a study, and results were always unexpected and thus embraced as new knowledge.
However, with the advent of the first randomized controlled trial (streptomycin for tuberculosis in WWII veterans) and especially since the 1970s—with the burden of peer review for both protocols and journals—the landscape began to shift. A Machiavellian expectation arose: the need to produce positive results to justify the effort involved in planning, designing, sampling, and conducting a study, as well as collecting and analyzing independent data. These positive findings were needed to validate not only the researchers’ efforts but also the financial and logistical support of sponsors, who now “assume the risk of investment”—often lasting years and costing hundreds of millions of dollars.
In this new framework, the true purpose of clinical trials today has increasingly become one of extrinsic interest, meaning: ensuring economic returns (often of several orders of magnitude) rather than achieving social value, patient benefit, or the advancement of knowledge. Yet more often than one might think, a negative result is actually far more useful—and effective—than a (possibly false) positive.
That is why, in my course on the epistemology of biomedical research, I always tell my students:
“In biomedical research—especially when funded by industry—assume the worst, and you’ll likely be right.”
A second fundamental aspect is to analyze whether the research questions truly respond to real and meaningful needs. In each case, we must hold in mind (to contrast with that of the researchers) the most clinically significant outcome variable for patients.
With this mindset—that every modern clinical study is false until proven otherwise—we must begin to carefully examine the key elements, especially in study design, patient selection, and the measurement of exposure and outcome variables. These are critical for identifying, sensitively and effectively, the Fake News that often accompany modern research. That, in itself, could be the null hypothesis we must now work to reject—unless proven otherwise.
I do not agree that STRIDE was purely to advance the drug indication. It was not a ‘perfectly’ designed trial with no blinding, but it did add to important understandings of treatment for PAD. for instance, the ABI was higher in patients receiving treatment, along with greater walking distance, greater weight lost and less revascularization. All these are meaningful for both the patients and the physicians.
Soooo right. These 2 drug classes are so abused by Big Pharma and their willing minions in cardiology so as to make them both a laughing stock out of both of them. As I've taught for years " the heart is too important an organ to be left to a cardiologist." The "flozins" are osmotic diuretics. The question is them vs an extra 20 or 40 of lasix. Pharma will never allow that nor will their minions ever study that simple question.
Dr Mandrola, solution can come once more people sharpens critical appraisal skills like you do, thank you It has been frustrating to see how low the critical sense of health professionals and the general public has become. Way too many study designs with tricks; lack of important data; direct or indirect conflicts of interest; creative interpretations; lack of replicability... This way, it has become very easy to sell insignificances dressed up as relative significances in the name of Science and resounding amens.
Absolutely correct. When coaching less experienced clinicians on evaluating the medical literature, first thing emphasized is to establish credibility of the results; is this even worth reading? So start with truly peer-reviewed journals, establish what was the tested null hypothesis, and critically what was the methodology used to test that hypothesis. If it can't answer the question, don't bother to read it. Unless it's a validation study, "me, too" trials waste time and money.
Clinical trial gamesmanship has become a bigger problem over my lifetime as a doctor. I think part of the problem is lower bar for approval at FDA. When they lower the standard to approve new drug or device, clinical trials will lower endpoint bar to meet it. In 1990s, FDA required ICDs demonstrate reduction in total mortality for approval. Now, CCM and phrenic nerve stimulation for sleep apnea approve with much lower standard.
Precisely. Only when regulators reject BS studies for new approvals or labelling indications, will Pharma consistently perform the studies in a manner that will reach a higher bar. Doing the absolute minimum necessary is the very essence of human nature.
Wise commentary by J. Mandrola. Science must get to the root of the problem to understand it and define treatment strategies. Trials are experimentation, sometimes necessary and useful, but if they do not lead us to an understanding of what is underlying they are of reduced usefulness. Bravo once again, J.M.
It sounds like the problem is marketing needs to be removed from research. I am not sure how to do that. I am just a housewife, but I will tell you, I have never seen people distrust the medical field at this level. I know this is going to sound crazy, but I think returning manufacturing to the USA is a good idea. We need REAL industry. People cannot be a product in a health system factory and make an economy that is real. The education system needs to change. IT used to be that people had a calling to say be a doctor, or a teacher. They wanted to help people. It was in their nature. Then something changed, MONEY. School is about the money, jobs are about the money. I know they need the money for the research, but there is something wrong with the focus.
Dear Dr. Mandrola,
Congratulations on your sharp critical analysis, with which I fully agree.
I would trace your question regarding the purpose of clinical trials back to the early days of so-called “scientific medicine,” which emerged with the biomedical model in the late 19th century—a time when ignorance of the health-disease continuum was almost absolute. Back then, scientific research was driven by genuine philanthropy and guided by what we now call true uncertainty or equipoise—meaning there was no preconceived expectation about the outcome of a study, and results were always unexpected and thus embraced as new knowledge.
However, with the advent of the first randomized controlled trial (streptomycin for tuberculosis in WWII veterans) and especially since the 1970s—with the burden of peer review for both protocols and journals—the landscape began to shift. A Machiavellian expectation arose: the need to produce positive results to justify the effort involved in planning, designing, sampling, and conducting a study, as well as collecting and analyzing independent data. These positive findings were needed to validate not only the researchers’ efforts but also the financial and logistical support of sponsors, who now “assume the risk of investment”—often lasting years and costing hundreds of millions of dollars.
In this new framework, the true purpose of clinical trials today has increasingly become one of extrinsic interest, meaning: ensuring economic returns (often of several orders of magnitude) rather than achieving social value, patient benefit, or the advancement of knowledge. Yet more often than one might think, a negative result is actually far more useful—and effective—than a (possibly false) positive.
That is why, in my course on the epistemology of biomedical research, I always tell my students:
“In biomedical research—especially when funded by industry—assume the worst, and you’ll likely be right.”
A second fundamental aspect is to analyze whether the research questions truly respond to real and meaningful needs. In each case, we must hold in mind (to contrast with that of the researchers) the most clinically significant outcome variable for patients.
With this mindset—that every modern clinical study is false until proven otherwise—we must begin to carefully examine the key elements, especially in study design, patient selection, and the measurement of exposure and outcome variables. These are critical for identifying, sensitively and effectively, the Fake News that often accompany modern research. That, in itself, could be the null hypothesis we must now work to reject—unless proven otherwise.
Dr. Mandrola, shall we begin this task?
Warm regards,
______________________
Jairo Echeverry Raad MD
Totally agree. Indication creep vs Knowledge expansion.
I do not agree that STRIDE was purely to advance the drug indication. It was not a ‘perfectly’ designed trial with no blinding, but it did add to important understandings of treatment for PAD. for instance, the ABI was higher in patients receiving treatment, along with greater walking distance, greater weight lost and less revascularization. All these are meaningful for both the patients and the physicians.
Soooo right. These 2 drug classes are so abused by Big Pharma and their willing minions in cardiology so as to make them both a laughing stock out of both of them. As I've taught for years " the heart is too important an organ to be left to a cardiologist." The "flozins" are osmotic diuretics. The question is them vs an extra 20 or 40 of lasix. Pharma will never allow that nor will their minions ever study that simple question.
Dr Mandrola, solution can come once more people sharpens critical appraisal skills like you do, thank you It has been frustrating to see how low the critical sense of health professionals and the general public has become. Way too many study designs with tricks; lack of important data; direct or indirect conflicts of interest; creative interpretations; lack of replicability... This way, it has become very easy to sell insignificances dressed up as relative significances in the name of Science and resounding amens.
Absolutely correct. When coaching less experienced clinicians on evaluating the medical literature, first thing emphasized is to establish credibility of the results; is this even worth reading? So start with truly peer-reviewed journals, establish what was the tested null hypothesis, and critically what was the methodology used to test that hypothesis. If it can't answer the question, don't bother to read it. Unless it's a validation study, "me, too" trials waste time and money.
Agree these are both pathetic studies. It is incredible they were deemed worthy of podium time at a major meeting.
That DapaTAVI did not have placebo control is absolutely gobsmacking.
If I read it correctly Stride patients lost 20 more pounds than placebo. If they could not walk a few feet more the drug would be toxic ..