The Tragedy of Lou Lasagna

Editorial Note: This is the 3rd of 6 posts. The first two are Not So Bad Pharma, & April Fool in Harlow. The rest will be The Empire of Humbug 1 & 2 and Brand Fascism. There is an independent debate on some the issues, including my writing style, at Hearing Voices on 1boringoldman. 

In 1956, Lou Lasagna was on his way to being the most famous doctor in the United States.

His career had lifted off four years before when he was recruited to Harvard from an Atlantic City boardwalk by Harry Beecher. Beecher got the money to support Lasagna from the US Army by telling them there was no-one in the universe more qualified than Dr Lasagna to undertake this research of critical importance to the military.

The top-secret research was happening in the department of anesthetics, where Beecher had collected a small group to work on the placebo response. The idea of a placebo response had implications for notions of suggestibility and hypnosis. Militarily, it fed into American concerns about brain washing born in the Korean and Cold Wars.

The placebo response was also the key American contribution to the idea of randomised placebo controlled trials. Randomization came from Britain, where it was pioneered in clinical trials by Austin Bradford-Hill, but it was Beecher’s team of Lasagna, Von Felsinger and others who brought the placebo to the table and helped create the controlled clinical trial we have today.

In 1954 Lasagna moved to Johns Hopkins to create the first Department of Clinical Pharmacology in the country. The boom in new wonder drugs called for new scientific evaluation methods and for a new kind of specialist, who could cut across disciplines.

Lasagna had a ready turn of phrase and was soon a media favourite using radio and TV in the way that others might now use Twitter, Facebook or other social media.   The New York Times, the New Yorker, the Readers Digest and a huge range of periodicals opened their pages to his comments on the issues of the day from nuclear disarmament to women astronauts but in particular medicines.

He engaged in controversies as they arose from the question of whether the new oral contraceptives caused thrombosis, to the effects of the first “statin”, and the question of whether smoking causes lung-cancer. In all these cases he made what we can now see were the right calls: yes – contraceptives caused thrombosis, no – cholesterol lowering was unlikely to be of much benefit, and yes – smoking caused lung cancer.

In the most golden era ever for new Wonder Drugs, his focus was on evaluating them from new opiate and non-steroidal analgesics through to hypnotics.

“Is it such an horrendous leap from the present position to one
where evidence for a drug’s therapeutic potency must be provided
by the manufacturer before a compound is released?”

In 1956, when reviewing the issue of the safety of over-the-counter hypnotic antihistamines, he raised the question of drug effectiveness:

“It is unfortunate that the Food and Drug Administration cannot take regulatory action against a drug whose efficacy for the conditions for which it is offered has not been demonstrated. Adequate toxicity data are required from manufacturers before introducing new drugs: similar requirements as to effectiveness should be included in our federal statute. It appears to be an accepted fact that toxicity and efficacy cannot each be considered separately, in vacuo as it were. Is it such an horrendous leap, therefore, from the present position to one where respectable, reliable evidence for a drug’s therapeutic potency must be provided by the manufacturer before a compound is released?”

For Lasagna this meant something quite different to what it meant for anyone else at the time in that controlled trials offered a means of testing claims about efficacy in a way that had not been possible previously. As of 1962, he had run many of the first placebo controlled trials of antidepressants, analgesics and hypnotics. In his hands the leading antidepressant, imipramine, didn’t differentiate from placebo. Most strikingly he had at that point run the only placebo controlled trial of a drug that had still to be marketed – thalidomide.

The move to a new more critical pharmacology and therapeutics led in 1959 to the creation of The Medical Letter by Arthur Kaller of Consumers’ Research. All of the stars in the new field of clinical pharmacology, Lasagna, Louis Goodman, Walter Modell and others, were on its Advisory Board and wrote for it. Their evaluations of new drugs and trends were hugely influential with medical prescribers.

At this point Lasagna had written more on controlled trials and the necessity for them than anyone else in America. His contributions on these and on how clinical practice could be improved or cleaned up led to recruitment offers from NIH, Langley Porter and elsewhere. The Squibb Institute offered to quadruple his Hopkins’ salary. But he stayed put to continue a mission to put Clinical Pharmacology on the map.

Informed consent

He took another radical step in early 1962, when with Beecher he laid the basis for introducing informed consent to medical research. Informed consent first appears in medical practice after a series of court cases in the late 1950s involving patients being treated for breast cancer or with ECT.

By 1960 an increasing number of patients were being given investigational new drugs with no idea that these drugs had not been approved. Lasagna flagged up the need for informed consent in such cases, produced the first consent forms and had them built into FDA regulations. In so doing he brought informed consent into research and later into mainstream medicine.

The Kefauver Hearings

The 1950s were a glory decade for the pharmaceutical industry. But despite articles everywhere proclaiming a cornucopia of Wonder Drugs, a new set of discontents with the practices of the pharmaceutical industry emerged. The discontents were brought to public focus by a Democratic senator from Tennessee, Estes Kefauver.

Kefauver’s interest was stimulated when members of his staff found that several versions of the same antibiotic, marketed by different companies, had identical prices, and that the prices being charged were of the order of a 1000% of the price of manufacture.

As they explored the issues, Kefauver’s staff found evidence companies were secretly engaging in cartel practices to maintain the price of medicines, and corrupting doctors with backhanded payments to prescribe on-patent and more expensive drugs.

Lasagna was on Kefauver’s team. He briefed on advertising, the AMA, drug development, testing for efficacy and safety. He had not been scheduled to testify but was pressed into it at the last minute as a previous expert was withdrawn because of a suspect political background. He testified on advertising, pricing, efficacy and other issues.

Advertizing had become a key concern. There was the sheer volume. As Walter Griffith of Parke Davis told Kefauver “the ethical pharmaceutical industry of this country” had turned out “3,790,908,000 pages of paid journal advertising” and “741,213,700 direct mail impressions”.

“Madison Avenue discovers Medicine Avenue”

But of greater concern was that Madison Avenue in Lasagna’s words had discovered Medicine Avenue.  The new marketing campaigns were much slicker and adverts were commonly misleading and in many cases downright fallacious.

Kefauver’s staff unearthed one advert for an antibiotic which featured two chest x-rays giving the impression of clinical improvement when the x-rays in fact came from two different patients neither of whom had had the antibiotic featured.  As Dale Console, of the Squibb Institute put it: “If an automobile does not have a motor, no amount of advertising can make it appear to have one.  On the other hand, with a little luck, proper timing, and a good promotion program, a bag of asafetida with a unique chemical side chain can be made to look like a wonder drug”.

Yet other concerns lay in drug company practices of withholding safety data on drugs, along with their lack of testing of new drugs on animals prior to marketing to humans. As one wag put it, companies didn’t do animal testing believing that it was less expensive to test a drug on humans.

There was another niggling issue – the regulators had no procedures in place to ensure a drug worked. The 1938 Act solely required companies to demonstrate safety in a number of patients without even basic toxicology testing in animals. As Kefauver’s staff noted, if a drug didn’t work for a condition for which it was marketed or worked less well than an already available product, then it was inherently unsafe.

These discontents led, in 1959, to the establishment of the Kefauver – Harris Senate hearings, which began on December 7 1959. Kefauver’s main target was the patent system, which he thought was responsible for the artificially high prices American patients uniquely faced. Kefauver’s staff produced figures to show that out of 77 countries they surveyed, 28 allowed product patents and in these countries the prices of drugs ranged from 18 to 255 times higher than in the non-patent countries, with both American-made and European-made drugs costing far less in Europe than in America.

“anyone who dares seek the truth
will be accused of being a persecutor”

But as Kefauver found, “These drug fellows pay for a lobby that makes the steel boys look like popcorn vendors. … anyone who dares seek the truth will be accused of being a persecutor”. Up for re-election in 1960, he found himself branded a “socialist hellbent on ruining healthcare”.

He was re-elected comfortably, but he had few friends. Despite Kefauver having been the 1956 Democratic vice-presidential candidate, Kennedy was not a friend. The administration was trying to get Medicaid through Congress and did not want to antagonize the pharmaceutical industry.

Prior to 1960, the American Medical Association (AMA) had run a unit to evaluate new drugs and maintained a list of drugs to avoid. This in the late 1950s was leading to falling advertising revenues in the Association’s Journal, the Journal of the American Medical Association (JAMA).

The AMA was gearing up to fight Kennedy’s plans for Medicare and Medicaid and was dependent on the revenue from advertising in its journals. It disbanded its evaluation unit.

Kefauver had no support from the AMA for a requirement that companies prove their drugs work before they are let on the market. Everyone agreed that new drugs should be effective but there was incomprehension on the question of an explicit test for effectiveness. The dance was subtle, as these exchanges show.

Sen Kefauver: If you want a drug to be efficacious before it is placed on the market, why not make that a condition as to placing it on the market? I do not understand.

Dr Hussey (AMA): It seems to me it is a condition under existing practice before it is placed on the market.

Sen Kefauver: But if that is what the law means now, then why do you object

What Hussey and others were saying was that when doctors gave a drug to a patient prior to its official marketing and saw the patient improve in some way that this was evidence that it worked. Most drugs obviously work but controlled trials had begun to cast doubt on the validity of medical testimonials of this type.

Sen Kefauver: The FDA has had a very satisfactory experience in evaluating the efficacy as well as the safety of antibiotics and diabetic drugs, is that so?

Dr Lasagna:  Yes sir.

Sen Hruska (Rep): If that is true, why do we need another law?

The Kefauver hearings centered on 4 drug groups – the steroids, tranquilizers, anti-diabetic drugs and antibiotics. Diabetic drugs obviously lower blood glucose levels and antibiotics obviously kill germs in a petri dish or not. A decade later as it turned out, one of the first oral anti-diabetic drugs, tolbutamide, whose efficacy FDA had no reason to doubt, ran into serious problems when a large independent controlled trial showed it led to a greater loss of life than other treatment options.

By 1962, the debate about efficacy however appeared academic. Without allies, Kefauver’s bill (S. 1552) was eviscerated by his congressional opponents to make it more company friendly. His hearings came to a stop.

The Doctors’ Dilemmas

Lasagna’s role in briefing Kefauver’s committee and in testifying gave him access to a huge amount of material on the state of play between medicine and the drug industry that was grist to the mill of a book he was writing “The Doctors’ Dilemmas”.

His agent had made a first overture to Harper Brothers about a possible book in 1958 getting a response from the boss, Evan Thomas, who said that: “I don’t see what holds the Lasagna material together as a book but I really like this guy. Why not get him to write a book. He’s good.”

The Doctors’ Dilemmas was published by Harpers in Spring 1962. It got all the razzmatazz of a big trade launch.

The reviews were glowing. Beecher wrote:

“The Doctors’ Dilemmas has my awed admiration. I cannot think of anybody in this country or Europe who could have written this book other than Dr Lasagna. I am sure it will lead to a great deal of discussion in the areas he has dealt with so beautifully.”

Mike Gorman, the leading K-Street lobbyist of the day, gave it to President Kennedy and assured Lasagna that Kennedy had read it and that in particular Lasagna’s chapter on the AMA had shaped Kennedy’s thinking on the forthcoming Medicare bill and that his material on psychiatric drugs would also shape Kennedy’s mental health legislation scheduled for 1963.

Not everyone was enthusiastic. The front cover of the British edition of the book made it clear that “Dr Lasagna examines his profession describing its follies, fads, frauds – and achievements”. The American Medical Association was one of his primary targets and a review of the book in The Lancet concluded with the statement:

“The book has quite a good index, though for no obvious reason.”

Adequate & well-controlled trials

By the time The Doctors’ Dilemmas was launched in March 1962, Kefauver ‘s hearings had been consigned to the dustbin of history. But on May 19 the Daily Journal reported rumblings from Europe about birth defects on a sleeping pill, thalidomide, scheduled for launch by Richardson-Merrell in the United States.

The rumblings were picked up by the Washington Post whose leading healthcare reporter Morton Mintz reported on July 15 that Frances Kelsey of the FDA had kept thalidomide off the American market. This inspired piece created the myth of Frances Kelsey. It also did more than Kelsey had done to make it impossible for the FDA to approve thalidomide.

Three weeks later on August 5 Marilyn Monroe died from an overdose of  barbiturate sleeping pills.

On August 13 Newsweek ran an article ‘Tragedy from a pill bottle: some sad lessons learned’ featuring pictures of limbless babies born in Britain along with bottles of thalidomide from different countries, a picture of the German doctor Siegfried Lenz who had nailed down the link between the drug and birth defects and pictures of Frances Kelsey and George Larrick, the commissioner of FDA.

In September Kefauver’s Bill was rushed back to Congress, passing through both Houses on the one day, the only time a bill has ever passed through both houses on the same day except when the United States has gone to war. It was signed into law by President Kennedy on October 10.

Kefauver, in fact, got nothing of what he wanted on patents or pricing. The major difference in the 1962 bill compared with earlier bills was that where the Federal Food, Drug and Cosmetics Act of 1938 had given the FDA the power to evaluate the safety of new drugs they were now commissioned to evaluate the safety and effectiveness of new drugs. Where before they had been asked to look at whether the drug was safe, they were now asked to look at whether it was safe and effective.  And where before they had been asked to look at whether the drug was safe for use they were now asked to look at whether the drug is safe for use and whether a drug is effective in use.

Regulation CFR 310.3(4) states FDA is concerned with the new use of a drug in diagnosing, curing, mitigating, treating, or preventing a disease or to affect a structure or function of the body.

But how was effectiveness to be determined? The key issue was the role that evidence would play in determining the safety and effectiveness of new drugs. The FDA was pushing for a wording that stated that the preponderance of the evidence should show that the drug worked. The pharmaceutical industry wanted preponderance to be replaced by the word substantial.

The compromise position as put forward by John Blair who worked for Kefauver was to argue that the evidence should consist of:

“Adequate and well controlled studies carried out by experts with scientific training”.

This when translated into practice came to mean two placebo controlled trials. The wording came from Lasagna.

Nothing in the 1962 Amendments made a future thalidomide any less likely. The thalidomide application had already been turned down – under the 1938 Act.

If Marilyn Monroe?

There had as of 1962 only been one placebo controlled trial of any drug before it had come to market. This had been undertaken by Lasagna on Merrell’s new hypnotic, thalidomide. It showed thalidomide to be effective and safe. When the drug was held up by bureaucratic delay within FDA in 1961, Lasagna was approached by Richardson-Merrell to lobby with FDA on behalf of their drug. He did so.

Soon after the FDA hearings the media got wind of the fact that Lasagna, one of the major critics of the pharmaceutical industry, had been a supporter of thalidomide and had lobbied on its behalf. He was quizzed and defended his position by saying that:

“if Marilyn Monroe’s physician had been
able to prescribe 
that drug instead of barbiturates
she might still be alive.”

In the wake of the thalidomide scandal George Larrick was in time shunted to one side and the hunt was on for a new FDA commissioner. The Blue Sheet reports:

“A sigh of relief was heard in industry quarters when Lasagna, whose name was rumored to have been seen at the head of a list of candidates, indicated he was not one of them.

“The lively Hopkins pharmacologist and author told ‘The Blue Sheet’ the job had not been offered to him and anyhow his special expertise was in a limited part of FDA’s broad responsibilities. He is quoted in other quarters as feeling that a man would have to relish punishment to take the job.”

Others wondered what else might be in store for him. He was a regular attendee at White House functions and got on well with Hubert Humphrey. In 1966 Alvan Feinstein, later the founder of clinimetrics, wrote to him from Yale with a pair of side by side photos of Mr Humphrey and Dr Lasagna snipped from a local newspaper, suggesting this might be a future Democratic ticket.

He took part in forums in London and other European capitals where he was seen as a liberal revolutionary in opposition to both pharmaceutical companies and his own profession.

Lasagna’s misgivings

Despite being the poster boy of the new science of drug evaluation, Lasagna had deep misgivings about the 1962 regulations. Thirty years later he said:

“in contrast to my role in the 1950s which was trying to convince people to do controlled trials, now I find myself telling people that it’s not the only way to truth.

“My favourite quotation was taken from Austin Bradford Hill’s Heberden Lecture in 1965: “If one came to the conclusion that the only way to find out the truth about a medication was to use a controlled clinical trial, it would mean not that the pendulum had swung too far but that it had come completely off its hook”.

“In another part of the paper [Hill] comes up with something else that I have been trying to sell to people with not an awful lot of luck. What he said was that a controlled trial does not tell the physician what he would like to know which is how do I know in advance without engaging in trial and error which antidepressant is better for Mr Jones or Mrs Smith. That’s what doctors and patients would like to know. We don’t do that”.

Hill and Lasagna had similar roles in the US and UK but Hill hadn’t enshrined clinical trials in legislation or in a bureaucratic apparatus. Lasagna had and could see the problems. This may have played a part in his involvement in the Panalba case and in what many see as his downfall.

The Panalba Affair

Following the 1962 Amendments, FDA put in place the Drug Efficacy Study Initiative (DESI), to review older drugs on the market to determine whether there was adequate evidence of their effectiveness. This involved panels of experts drawn from the National Academy of Science and National Research Council, who adjudicated on drugs licensed from the 1950s or earlier. It led to a large scale culling of many effective older drugs if companies invited to run clinical trials to demonstrate their efficacy chose not to. (See E.Shorter: Before Prozac)

In 1969, FDA’s DESI process made its most controversial decision when it recommended the removal of Upjohn’s Panalba from the market. Panalba was a combination antibiotic comprising novobiocin and tetracycline. FDA was then pharmacologically puritan. It disapproved of combination antibiotics in principle. They encouraged lazy medical practice – rather than work out what the patient actually had, doctors just took a scatter-gun approach.

There were grounds to think novobiocin simply added to the burden of side effects of the combination. There were a number of deaths – 12 to 15 more per year than might be expected. Was the number excessive? Panalba sold in vast quantities – in 1969 it accounted for 12% of Upjohn’s income.

But did the new 1962 amendments give FDA a basis to remove Panalba from the market? Congress had specifically rejected any consideration of comparative efficacy.  If a drug was thought to be possibly weaker than older drugs on the market, but still met criteria, it had to be licensed. Without this Prozac and Zoloft would likely never have been licensed.

The DESI experts argued that while the criterion for licensing an antibiotic was superiority against placebo, in the case of a combination antibiotic the criterion must be adequate and well-controlled trials showing superiority against each of the individual components of the combination. There were no RCTs at the time in which any combination of drugs had proven superiority to each of its individual parts.

The experts recommended removal. FDA requested Upjohn do so. Upjohn fought back, engaging the Nixon administration on its side, and taking the issue to the Supreme Court.

Lasagna was on the record as viewing fixed dose combination antibiotics as irrational. He was also in favor of regulation being open to input from experts outside the regulatory apparatus and not just leaving it to the bureaucrats, as was happening with DESI.

So it was then a jaw-dropping moment when Lasagna rode to Upjohn’s rescue arguing that FDA’s regulations on fixed combination therapies were scientifically unreasonable. The drug was in such widespread use, that while it had evidence for adverse effects, aggregated medical wisdom suggested it was certainly efficacious.

FDA’s general counsel responded that Lasagna’s rhetoric:

“stands in bold contradiction to every scientific precept he has advocated publicly and to his profession”.

Perhaps used to handling the media, he thought he could ride the storm. He wrote to the editors of The Medical Letter that:

“I have never prescribed Panalba in my life, and probably never would have.  My main objection to the way this problem was handled was that it did not represent due process”.

In his view the problem was that the matter was being decided behind closed doors and apparently arbitrarily. Nevertheless, The Medical Letter publicly dropped him from its Advisory Board. Close collaborators like Louis Goodman distanced themselves from him and expressed dismay at his position.

The Supreme Court ruled in favor of FDA. Upjohn lost. FDA lost its commissioner. Lasagna also lost. He left Hopkins’ for Rochester University a year later. There he set up the Center for the Study of Drug Development. It was a time when Institutes like this were being set up – Silvio Garattini set up the Mario Negri Institute.

From this position he argued that FDA had become the slowest agency in the world to license new drugs and Americans were losing out. He provided the first estimates of the development costs of new drugs. He chaired a committee that tackled the crisis that the licensing of drugs for AIDs posed FDA – this led to an accelerated approval process and later the Prescription Drug Users Fee Act (PDUFA).

All these positions were regarded as favoring industry, and industry funding for the Center was noted. By the 1980s it had become customary to view him as a business-friendly conservative – an astonishing transformation.


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Pharmageddon

Pharmaceutical companies have hijacked healthcare in America, and the results are life-threatening.

 

Dr. David Healy documents a riveting and terrifying story that affects us all.

 

University of California Press (2012)

 

Available on Amazon.com

 

Comments

  1. Irene Campbell-Taylor says:

    Apart from latter views of his position, the comment by Lasagna on due process is a fascinating one, especially when taken to its logical conclusion. In the US, Due Process has a very specific meaning related fundamentally to the Constitution. If we take the criteria as outlined by the US Supreme Court and interpret them with respect to release of drugs into the market, I suggest we find something that ought to resemble the following:
    Procedural due process:
    An unbiased tribunal. (FDA)
    Notice of the proposed action and the grounds asserted for it.(Approval of a drug)
    Opportunity to present reasons why the proposed action should not be taken. ( Reasons for not approving a drug based on valid evidence.)
    The right to present evidence, including the right to call witnesses.(The right to inspection of raw data.)
    The right to know opposing evidence. (As above)
    The right to cross-examine adverse witnesses.(The right to question the researchers and others responsible.)
    A decision based exclusively on the evidence presented. (Assuming validity after all of the above conditions are met.)
    Opportunity to be represented by counsel. (Examination conducted by unbiased experts.)
    Requirement that the tribunal prepare a record of the evidence presented.(Publication of all results.)
    Requirement that the tribunal prepare written findings of fact and reasons for its decision. (As above).
    There is no equivalent to US Due Process in the UK, the Magna Carta notwithstanding, but in Canada the Charter of Rights and Freedoms is roughly equivalent. The legal and ethical question then is this: If the above criteria are not met, are patients prescribed these drugs not being put into danger with threat to life and health? Is this not a constitutional matter for the courts and if not, why not? Class action anyone?

  2. It’s amazing to think that the placebo effect didn’t enter medicine until the 1950’s. I’d always thought it began with the “Hawthorne Effect” discovered in Chicago around 1930, by Elton Mayo from the Harvard Business School, who was just trying to make General Electric a little richer. Mayo’s original goal was to study the effect of physical variants such as lighting changes on the productivity of assembly-line workers at GE’s massive Hawthorne Works. He recruited a test group of young immigrant women in their teens and early twenties. To his befuddlement, however, he couldn’t determine which lighting condition was best. Everything worked – no matter which way he varied the group’s production environment, they out-performed their peers back on the line. The experiment itself was more powerful than the official “dependent variable” being studied.

    The “Hawthorne Effect” is often reduced to the tendency of people to change their behavior simply as a result of being watched. But as Mayo recognized, the experiment meant more than that to the young women at GE. It brought them the camaraderie of working in a close-knit group, the novelty of actually being listened to by their superiors, and a little something new each day. The productivity increase generated by these “human factors” outstripped an earlier study of bonus pay for extra production in a shop staffed by more experienced workers.

    Where Medicine Avenue might have seen the Hawthorne Effect as just an obstacle – a noise drowning out the main signal – Madison Avenue (and Wall Street) was fascinated by it. Selling the sizzle, not the steak, had always been a virtue to them. And if you can get people to do “steak” work for “hamburger” pay plus a little sizzle, that’s a triumph. The study of “human factors” in business was off to the races, and has been used both for good and for ill ever since. I wonder if drug researchers ever took note of the Hawthorne Effect, especially those studying psychotropic medications – and did it ever spark anyone’s interest in studying those “human factors” in their own right?

    There’s a great archive on the Hawthorne Effect from Harvard here:
    http://www.library.hbs.edu/hc/hawthorne/

  3. Edward Opton says:

    I have long been puzzled by the seemingly very late development of the randomized controlled trial. Why was it a novelty in the middle of the Twentieth Century? The statistics of probability were no longer new. The term “placebo” had long been in use, so the placebo effect must have been well known for a long time.

    I wonder if the key factor was the invention of the electrically powered adding and multiplying machine, which drastically reduced the time consuming labor of statistical analysis.

    Any observations from historically minded readers would be welcomed.

    • David_Healy says:

      Edward – its not about placebo or statistics. The key point is skepticism. An RCT is really about rejecting a claim. A willingness to jettison hope. As in the Womens’ Health Initiative HRT study. We still haven’t got there even now – most RCTs now are used to fuel therapeutic bandwagons rather than stop them in their tracks.

  4. Dr. Healy,
    Thank you for your recent talk at Queen’s University on this topic, which I enjoyed.

    My question relates to your assertion that regulatory efforts centred on RCTs has done the public a disservice.

    Past experiences suggest that patients who are suffering from a desperate medical conditions are vulnerable to minimizing harms and exaggerating benefits of treatment. Autologous bone marrow transplants for solid tumours, Zamboni procedure for MS, Acetylcholinesterase inhibitors for Alzheimer’s, etc were so fervently embraced by patients and all proved to be of little to no efficacy. Population-based RCTs continue to provide proof that a therapy is expected to be of sufficient effectiveness in a wide enough range of population to warrant authorization to enter the medical market. Medical therapy rests on balance of risk and benefit; to advocate providing investigational drugs without RCT clearance to patients based on the assertion that they may have sufficient variation from the “average” patient is irresponsible and dangerous.

    RCTs were never meant to be designed to detect rare adverse events, nor effect of the drugs outside its strict environment, though they do provide an idea. The former is the role of post-marketing pharmacosurveillance studies. Relating thalidomide’s positive RCT results to Kefauver-Harrison amendment’s failure is frankly wrong.

    The presence of the Kefauver-Harris amendment protects the public by requiring demonstration of efficacy and having “dispassionate” physicians blinded to the treatment allocation prescribe the drugs in its investigational phase. It serves public interest. Senator Kevaufer originally wanted comparative effectivness as condition for drug approval and patent limitation. Rather than dismantle his efforts, should we not be strengthening this through open access to trial data, demanding for active placebos in RCTs and reducing Conflict of Interest of physicians?

    • Healy David says:

      Yan

      Agree completely that patients and doctors are biased toward benefit and missing harms. But RCTs as used to regulate treatments don’t temper our bias toward benefit and risk of missing harms – they do the opposite – as with cholinesterase inhibitors and antidepressants they give the impression there is effectiveness when at best there is an effect and likely increased mortality and because of the focus on primary outcome measures they enable companies to say that no harms have in fact been demonstrated in these trials that are supposedly the definitive word on what the drugs does.

      I agree with you that patents are a key issue, and that access to the data from company RCTs is important but not crucial (See Marilyn’s Curse next week) – I don’t agree that conflict of interest is, don’t think that active placebos help, believe comparative effectiveness cannot be established in RCTs except when there are hard outcomes like mortality. But beyond that I think RCTs are broken. See Marilyn’s Curse when posted.

      David

      • Thank you, Dr. Healy, for your comments. I assume by “RCTs as used to regulate treatments”, you mean use of surrogate end points, and I agree with you completely on that point.

        However, if you are alluding to confounding by indication, whereby harms are attributed to a therapy due the effect it’s trying to prevent (e.g., the bias that concludes “people on aspirin for MI prevention die earlier than the population not on aspirin, so aspirin must be causing them to die” while forgetting that people taking aspiring for MI are taking them because they have higher CVD risk factors to begin with), we have already devised a solution to this in the form of randomization, which distributes baseline risks equally between the intervention and control arms.

        You mention on another blog post that “[f]or instance, where superficially similar problems can be caused by both drug and illness, such as suicidality on antidepressants, RCTs may perversely show that drugs that clearly cause a problem seemingly don’t cause it.” This conundrum can easily be prevented by matching the baseline risk factors of the placebo and active arms of the study, discussed above. For example, let’s say an SSRI at end of a trial achieves less suicide-related mortality compared to placebo, then there is no other explanation than the conclusion that its suicide-preventing effects (efficacy) must have outweighed its ability to cause suicide (side effect), within the characteristics/risk profile of the patients in which it was tested.

        In light of what I have discussed, I would appreciate an elaboration of your statement from your LRB review, “RCTs tell us almost nothing about cause and effect. They discover nothing. They likely block the discovery of many treatments.” Of course, RCTs are not the be-all and end-all; Bradford Hill criteria tell us that there needs to be other accompanying factors (ie. biological plausibility, dose-response) to prove causality. But RCTs are part of that answer. There is distortion of RCTs to suit pharma needs (ie. surrogate end points, trials using selective patient groups, etc); we can change that. But let there be no confusion that RCTs as a methodology remains robust. Let’s not throw the baby out with the bathwater.

        Looking forward to your post next week.

        • David_Healy says:

          Yan

          Thanks for this. It will be clearer in Marilyn’s curse. This is not confounding by indication. Many people hearing the issue for the first time think it is confounding by indication when in fact its not. There are two issues here – one is the use of the word cause. I agree some antidepressant trials can show a preservation of lives and some a loss of lives but this has only an indirect implication for whether the drug causes suicide or not. The other aspect is the illness and the drug, where both the dose of the illness and dose of the relevant action of the drug can vary and in varying can lead to different outcomes. These are not issues that can be sorted by randomization. This will be hopefully laid out in more detail in MC

          David

    • Ah, yes, but some supporters like plcoiies that are supported by evidence ;-)A point there, though: if you encourage people to look at the evidential support for plcoiies, you get the impression they tend to comment on that. The folic acid supplementation issue, for example, is not a bad example. Peter Dearden has raised .

  5. 1. Would you please explain the “myth of Frances Kelsey?

    2. The German doctor was Widukind Lenz, not Siegfried Lenz.

    Thank you. I look forward to receiving your explanation.

    • David_Healy says:

      Michael – thanks for this – mistake on my part re Lenz.

      Re Frances Kelsey, the usual story is that she single handedly saved the US from thalidomide for which she got a Congressional Medal of Honor from JFK. But in fact Morton Mintz’s piece on july 15th 1962 made it pretty well impossible to licence thalidomide. This was ironically called “heroine” of FDA keeps bad drug off the market. In this he pretty well created the narrative that gave Kelsey the credit.

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