Philadelphia Reflections

The musings of a physician who has served the community for over six decades

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Pharmaceuticals:The Coonskin Hat

CONVENE A TWO-YEAR BLUE RIBBON COMMISSION REPORT ON MODIFICATION OF THE PURE FOOD AND DRUG ACT.The issue is this: The original Pure Food and Drug Act only required proof of safety before a drug could be sold. The Kefauver, or efficacy, requirement was added in 1962, triggered by the Thalidomide tragedy which has no real bearing on the matter. A manufacturer is required to demonstrate efficacy of a drug for some condition, in addition to safety alone, before he can sell it. The cost of new drug introductions has markedly increased by billions of dollars for double-blind studies, and inevitably consumer price rises must make up for it. A number of benefits of this efficacy requirement have been demonstrated, including a reduction of patent remedies with uncertain value, and increased public confidence in their healthcare. To a certain degree, the FDA has supplanted the role of the medical profession in creating dependence on evidence-based prescribing, approved by the FDA rather than by professional circles, and that malpractice claims are part of the hazard. It is true that proof of important efficacy can justify the use of drugs which otherwise have recognized dangers. Disruption of corporate balance, favoring larger corporations, can be surmised. Therefore while it is not obvious that the Kefauver Amendment should be abolished, it is likely that important financial savings might be expected from modification of its cost impositions.

Senator Estes Kefauver of Tennessee, who ran for President wearing a coonskin hat, left a legacy of high pharmaceutical costs according to his opponents, but among his supporters he wears the halo of defeating deceptive practices. It is reported that in Kefauver's time the idea floated around, that the Food and Drug Administration should mandate a program of tests to prove that all of these new drugs were good for something, not just that they were safe to take. Otherwise, it was thought, a great many innocent citizens would be induced by advertising to take worthless patent remedies. For many decades, the American Medical Association had denounced something it called "Quackery", which sort of sounded as though they had the same idea. Homeopathy, which at that time competed fiercely with the AMA, repeatedly thundered however it was better to take useless pills than use those dangerous remedies like bleeding and purging. To impartial observers, it sounded as though these two medical competitors were attacking each other in code. The Latin phrase, Primum non nocere ("At least, do no harm.") resurfaced in common parlance. Kefauver was running for President, he seemed to have an issue, and the Kefauver Amendment passed into law.

Let's have a look at the implications. The Pure Food and Drug Act had quite sensibly demanded proof that a new remedy was harmless, or at least harmless in the doses usually employed; otherwise, the drug could not be legally sold or advertised. A new drug had to be safe. However, many chemicals are useful in small doses, but entirely poisonous in large amounts, so it might seem reasonable to qualify approval by outlining the circumstances of safe use. However, the Kefauver Amendment seems to be more directed toward a quackery danger, where the public interest is more the protection of the public purse. In any event, the specifics of the law promote civil servants into scientific umpires without major focus on their scientific qualifications. The Kefauver Amendment provided that an acceptable drug had to be proven scientifically efficacious, as well as safe. So the burden of proof was on the drug manufacturer whereas evaluating that proof shifted to the civil servants instead of resting on professional consensus. With billions at stake, the manufacturer had both an incentive to find new cures, and a further incentive to find evidence of efficacy. Concealment of evidence was a constant possibility, so the civil servants became wary and increasingly conservative. As judged by the outcome, pre-release testing was required to be increasingly expensive.

Somehow the incentives got twisted, in what started as a benevolent effort to protect the public. The thalidomide disaster is credited with imposing useful conservatism on decisions. But two decades later, thalidomide is proving useful for many otherwise hopeless cases of cancer. Could this doubly unfortunate experience have been improved, somewhat? Thalidomide is not good to give to pregnant women, that's pretty clear. But does that mean nothing should be marketed until it is tested on pregnant women? Maybe it does, but that was a very expensive decision to make. And it should not be made by trial lawyers, or fear of trial lawyers.

There are many such quandries about the amendment, and it is time to review the experience. Maybe this is the best we can do, but I doubt it. The nation needs to impanel a group of experts, give them two years, and ask what they conclude.


Antibiotics were bursting on the public news at this time, so it was clear a drug might be efficacious for many conditions. Was it to be required that a new drug must be proven efficacious for all those conditions before it could be sold at all? The result of this quandary was that a new drug must be proven to be efficacious for at least one condition. It didn't take long for the industry to figure out what to do about this ruling; just spend the money to prove that the drug was efficacious for the easiest condition imaginable, one that had a dozen existing remedies that were as good as or better for the condition. That would satisfy efficacy, at perhaps considerably lesser cost than for the usage that was really planned.

Or the opposite situation, illustrated by aspirin. Aspirin had been used for a century for headaches, when the astonishing discovery was made that half an aspirin daily would reduce the incidence of strokes and heart attacks, by at least half. Was the law to be revised, to take account of the second condition without disturbing the first one? If Congress wants to muck around in this huge area, they had better enlarge the Washington offices of Congressmen hugely, just to keep all the archives of pharmacology, in several languages, going back at least a century. The situation cries out for delegation of the decisions to more specifically trained experts, except for fear that someone will inevitably die of a mistake, and the trial lawyers who are abundant in Washington will sue, and somebody will lose his seat in Congress; can't allow that to happen.

Meanwhile, the clinical trials industry has flourished. It happens that I was one of the twenty or so founding attendees of the Association of Clinical Trials, which now attend concurrent meetings in hotels around the world with thousands in attendance. The meetings are filled with speakers bearing slides, boasting to each other of experimental groups in the thousands, and grant money in the millions. The amount of money spent on this sort of rote research is simply unimaginable. No doubt, useful scientific knowledge surfaces as a result of this effort. Somebody needs to compile the amount of waste which is created when some vice-president up the line, decides to abort the research because its potential profitability has been calculated to be low.

And where does that leave the doctor? He has spent years studying the disease, and the chemicals, and the risks. Is he to be deprived of having a conference with the patient and/or family, explaining the risks and what he considers to be the chances of the patient for a cure? Perhaps the family doctor, depicted in the painting as pondering the chances of the little boy on an ironing board, does not have the necessary experience. But surely the super-specialist, sitting by his computer in a sixty-story office building, can be trusted to take now-or-never chances with his willing patient. Because the chance to cure the patient may only come around once, and someone has to be empowered to assume the risk of being wrong. The trial bar probably is sincere in protesting they have no reluctance to see a better appeals system evolve, or a better system of best-efforts experimentation. But it will take a long time to repair the existing damage; the trial lawyer knows very well what the doctor probably thinks of him, based on a long experience of his own or his trusted colleague's stories to the effect that, well, you can't trust any of them.

Let's repeat what has just been said. Safety is not the present issue; it is to be assumed the Food and Drug Administration has approved the evidence that the drug is safe to use, submitted the evidence to a panel of experts, and has received an opinion that the drug is safe. Let us also assume that the doctor has a hunch or some happenstance experience that it might be good for some condition, and wants to try it. Does this warrant the requirement that, before the doctor may use the drug, millions or even billions of dollars must be spent on research showing that the drug is good for something or other, not necessarily the intended usage?

In the early days of this legislation, a reassuring paragraph was put on the leading page of the Physician's Desk Reference, still given free to every physician:

Once a product has been approved for marketing, a physician may choose to prescribe it for uses or in treatment regimens or patient populations that are not included in the approved labeling.
However, these reassuring words are preceded by language wrapped around an entirely different threat:
The FDA regards the words "same in language and emphasis" as requiring VERBATIM use of the approved labeling providing such information.


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