A Flaw in the System: Page Two

When Dr. Joseph Sadusk said Parke-Davis’s efforts had been “minimal” he selected the right word. I know this from firsthand experience. A few years ago Mr. Williams changed his mind about Parke-Davis staying apart from our Foundation and graciously arranged for three members of the research staff to meet with us on the subject of Parke-Davis’s Dilantin package insert. (This package insert is discussed below.)

At this meeting, I met the senior research officer of Parke-Davis. When we finished our discussion he mentioned that the FDA had not approved Parke-Davis’s application for the use of PHT in cardiac arrhythmias. The reason, he said, was that the company did not supply cardiograms requested by an individual in the FDA. The research officer said, “We could get them for $100,000 but why spend the money, all the cardiologists are using PHT anyway.” I won’t take sides in this hassle between the FDA and Parke-Davis. There was foolishness to spare. (PHT is so widely used for cardiac arrhythmias that AMA Drug Evaluations has it in the category of antiarrhythmic agents.) But you’d think Parke-Davis would have considered it a privilege to spend the $100,000.

A few weeks after this, a physician applied to our Foundation for a modest grant ($6,000). He had done interesting preliminary work on the use of PHT as a protection against brain damage after cardiac arrest. We intended to make the grant, but it occurred to me that the new Parke-Davis management might appreciate the opportunity. I called my new acquaintance, the research officer, and asked him about it. It didn’t surprise me that I was told no. It did surprise me how quickly I got the answer, on the phone, without consideration of the matter. The senior officer explained that Parke-Davis was spending its research moneys on a new medicine the company hoped to patent. I thought there will be snow on the Devil’s roof before they came up with as good a medicine as Dilantin. But I got the point—patents on Dilantin had expired.

Well, to sum up, Parke-Davis got Dilantin by luck. They didn’t understand their own product, have done little to try to understand it, and haven’t spent a bean in furthering its understanding. This has contributed to the overlooking of PHT.

But let’s see Parke-Davis in perspective. There’s no Mr. Parke, no Mr. Davis—just an entity with those names. Since Parke-Davis did not get PHT by the sweat of its research there was none of the interest in the drug that would be found in a company that had developed its own product. As a result, new uses for PHT was a job never assigned to anyone and no one took it upon himself. It has been easy to cuss Parke-Davis, the entity, but not the people. In fact I’ve never met anyone at the company I didn’t like.

About Parke-Davis’s Dilantin package insert.

I was weaned on the Securities Exchange Commission. The SEC is a fiend for full disclosure—the positive as well as the negative. If Parke-Davis operated under SEC regulations the SEC would have the company in court for the rest of the century because of the great amount of positive data that’s not disclosed in its package insert. But Parke-Davis operates under FDA regulations. Apparently full disclosure is required on the negative side, but no disclosure is permitted when the evidence is positive, unless it has an FDA listed indication-of-use. No matter how flimsy the evidence for the negative, it must be disclosed. No matter how solid the positive evidence, it may not be mentioned. It seems a poor way to run a railroad.

An example of inexplicable illogic. For some years prior to 1972, Parke-Davis’s package insert made reference to a number of the uses of PHT other than epilepsy. In 1971 the insert stated: “Dilantin is also useful in the treatment of conditions such as chorea and Parkinson’s syndrome and is employed in the treatment of migraine, trigeminal neuralgia and certain psychoses.” In 1972 reference to these uses was deleted, although the evidence for their use had been substantially increased. Unfathomable. I don’t know whether this was the fault of Parke-Davis or the FDA. But an innocent public has suffered.

The Physician

 

I had taken PHT for about a year when I started talking to doctors about it. These were informal talks and occurred when chance brought me together with physicians, as at a dinner or in a locker room. I must have spoken to more than twenty doctors during that early period. None of them had heard of PHT being used for anything other than epilepsy. The discussions were friendly, but it was almost impossible to get a physician interested in the subject of PHT. I thought this was because, as a Wall Street man, I was an improbable source of medical fact.

But my lack of credentials was the smallest part of the communication problem. In the physicians’ minds there was the fixed notion that PHT was just an anticonvulsant. They had been taught this in school, the “knowledge” had been in their heads for a long time, and had calcified. Don’t pick on the physician. Calcification of ideas is a human trait not special to him.

There was an even bigger obstacle—the sure knowledge the physician had that if Dilantin had as many uses as I said it had, they would have heard about them from Parke-Davis. After all, Dilantin was their product, wasn’t it? And they wanted to make money, didn’t they? This “irrefutable logic” always defeated me. If I tried to explain, time would run out before we could get back to PHT.

There’s been a recent trend to knock the doctor. I think it’s a reaction to the pedestal position we had him in a decade ago. We learned from “Dr. Kildare” and “Marcus Welby, M.D.” that there are two physicians to every patient. In real life this isn’t so. Doctors rarely make house calls anymore. They can see three patients in the office for one in the home—and still it’s hard to get an appointment. Don’t blame the doctor. It’s the ecologists’ fault—they’ve allowed the spread of Homo sapiens to get out of hand.

When you are giving a member of the medical profession a hard time (in your head of course—who would dare do it in person), consider that the doctor’s day never ends. Sick people don’t care what time it is, and the doctor has to go around with a beeper attached to him or be in constant touch with his telephone service. This means twenty-four hours’ tension. We complain about what the doctor doesn’t do. But do we appreciate the things he does that we wouldn’t do?

We come to an important subject: medical literature. Medical studies are called literature (Shakespeare might demur) when they’re published in a medical journal or as part of the record of a medical conference. There is a great deal of this literature. You could wallpaper the world with it and have enough left over to do your kitchen. The notion that physicians know what’s contained in the literature is bizarre. But some of them sound like they half believe they do. If you ask a physician a question he can’t answer, don’t be surprised if he responds, “Nobody knows.” Which seems to suggest he has read all the literature and has total recall.

It’s estimated that there are 3,300 medical journals in the world. A poll in seventeen counties of upstate New York (not exactly the boondocks) showed that the average physician subscribed to 4.1 of these journals. Double this figure if you like. Even if he or she reads the 8.2 journals cover to cover, he or she would still be 3,291.8 journals short. You can see it’s impossible to expect the physician to read the medical literature to determine which drugs he or she should use. That’s why, in this day of specialization, this is left to the drug companies and the FDA.

However, when a physician gets a new idea about an approved drug, he or she may apply it. (Former FDA Commissioner Charles C. Edwards states: “Once the new drug is in a local pharmacy, the physician may, as part of the practice of medicine…vary the conditions of use from those approved in the package insert, without obtaining approval of the FDA.” The Federal Register, Vol. 37, No. 158, Aug. 15, 1972. This was clearly restated in the April, 1982, FDA Drug Bulletin.) But the opportunity doesn’t come up often. Usually new uses of a drug are well explored by the drug company that introduced it. PHT has been a marked exception, and a rare opportunity was presented to the physicians.

The medical profession did not fail us. The work of thousands of physicians has given us a rich literature on PHT. This literature, international in scope, covers a wide variety of medical disciplines. Published in many languages over a period of years, it is spread far and wide. But intermingled with millions of other studies, this literature is almost lost unless someone seeks it out.

The science fiction writer Robert Heinlein calls it the Crisis of the Librarian: “The greatest crisis facing us is not Russia, not the Atom Bomb...It is a crisis in the organization and accessibility of human knowledge. We own an enormous ‘encyclopedia’ which isn’t even arranged alphabetically. Our ‘file cards’ are spilled on the floor, nor were they ever in order. The answers we want may be buried somewhere in the heap....”

Let me give you an example of how difficult it would be, even in a single field, for a physician to be acquainted with the literature on PHT. Disorders in the field have many names. A general description of the field is uncontrolled muscle movement, or continuous muscle fiber activity. To illustrate the point, we made up a table of twenty-one published studies on this subject in 1975. (Since then many more studies have been published. See The Broad Range of Clinical Use of PHT.) These studies show dramatic recovery in intractable patients when given PHT. In many of the cases myogram readings (electrical muscle recordings) confirmed the clinical observations. The difficulty an individual physician would have in becoming acquainted with this work is shown by the following:

The studies were published in eight different countries, in sixteen different journals—Journal of Neurology, Neurosurgery and Psychiatry, Lancet, The Practitioner, South African Medical Journal, Klinische Wochenschrift, Arquivos de Neuro-Psiquiatria, Acta Neurologica, Proceedings of the Australian Association of Neurologists, Ceskolovenska Neurologie, Connecticut Medicine, Neurology, Archives of Neurology, New York State Journal of Medicine, California Medicine, and New England Journal of Medicine.

In only two of the twenty-one studies was the word phenytoin used in the title. The other studies were published under such dissimilar titles that Scotland Yard couldn’t have found them, without the key word phenytoin. Some members of the medical profession have prescribed PHT for a variety of purposes for many years. The breadth of its use has been more than might be imagined. IMS America Ltd. surveys the use of thousands of drugs. For their estimate of the many clinical conditions for which physicians are using PHT, see The Broad Range of Clinical Use of PHT.

One might draw the conclusion from the IMS America survey that the medical profession knows all about PHT. But this is not the case. Many physicians know of one or several uses of PHT. Few have an overall picture of the drug. Thus we have a strange situation. Dr. Jones prescribes PHT for depression. Dr. Smith uses it for migraine. Dr. Hemplewaith for trigeminal neuralgia. But, if a patient asks Dr. Snodgrass if he could try PHT for any of these purposes, he may get ushered from the office with the admonishment that PHT is only for epilepsy.

The right of a physician to prescribe whatever drug he wants is fundamental. But in making his decision he should have a reasonable amount of evidence on which to base his judgment. A reasonable amount of information has not been available to the physician, at least not from the expected source, the drug company. The informsation has been there, but it’s been hidden in millions of medical papers, like trees in a forest.

When physicians know more about PHT they will realize they have been imposed on by the system and deprived of a remarkable therapeutic tool.

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