A Flaw in the System: Page One

Parke-Davis—the Physician—the FDA

A medicine can get overlooked for a million years if no one discovers it. But can the benefits of a discovered medicine get overlooked for decades when thousands of studies have demonstrated its usefulness? The answer is it can. We have a flaw in our system of bringing prescription medicines to the public. That there’s a flaw is no surprise. We’re human and all our systems have flaws. But this particular flaw should be explained. It has acted like a barrier between the American public and a great medicine. From drug company, through FDA, to physician—that’s the route a prescription medicine takes to get to the public. That’s our system. It was not set up by anyone, it just evolved. But we’re used to it; it has become custom. And as Mark Twain said, custom is like iron.

Years ago doctors concocted their own medicines—and leeches outsold aspirins. But for the last century the business of pharmaceuticals has been in the hands of the drug companies. Drug companies, formed for the purpose of making money for shareholders, are not charged with a responsibility to the public that is not consistent with making money. That is not to suggest that drug companies are not interested in public welfare but they are not charged with a responsibility for it.

In 1938 the FDA was empowered to protect us against medical substances more dangerous than therapeutic. Since that time drug companies have been required to get approval as to safety of a new chemical entity and, since 1962, approval as to its effectiveness. Although the neglect of a great drug can be far more deadly than the use of a bad one, correcting such neglect does not appear to be a function of the FDA.

When a drug company synthesizes a compound which it believes to be therapeutic, it’s brought to the FDA. If the drug satisfies that agency’s requirements, the company is awarded a “listed indication-of-use,” which permits it to market the drug. Getting FDA approval is time-consuming and expensive; it has been estimated, on average, to take seven years and to cost $11 million. (Today, the estimate of cost is far greater.)

Drug companies patent their new compounds. Patents give the company exclusive rights for seventeen years. If the FDA approves a drug and it becomes popular, the drug company has a winner since the drug will sell at a high price for the life of the patent. (This is reasonable; a drug that is a winner has to pay for the research that went into it, the expense of getting FDA approval, and for money spent on the many drugs that are not successful.) However, when the patent expires, competition enters the picture and the price of the drug drops dramatically. At that point there is more financial incentive for the drug company to look for a new drug to patent than to look for new uses of an old drug.

FDA approval is the second of the three steps in our system. The third step is to introduce the drug to the physician. This is a function of the drug company and is done through advertisements in trade journals and by visits of their salesmen to physicians.

That is the system—and physicians have come to depend on it. If a doctor doesn’t hear from a drug company about new uses for an old medicine, the doctor infers there aren’t such uses. This is a reasonable inference. But in the case of PHT it’s wrong.

So this is the flaw in the system. When a drug company doesn’t do what is expected of it, and the FDA can’t or doesn’t do anything about it, the physician doesn’t get vital information. And, as in this case, a great drug can get overlooked.

Parke-Davis

Parke-Davis’s research did not discover PHT. The company bought the compound from a chemist in 1909. For twenty-nine years this remarkable drug sat on the shelf doing nobody any good. Then Putnam and Merritt, two physicians outside the company, discovered its first therapeutic use. Parke-Davis paid almost nothing in money for PHT. They paid less in brains for PHT. Still, were it not for Parke-Davis we might not have PHT today. Someone in the company did buy the compound, and someone else in the company did give it to Putnam and Merritt for trial. It should also be said, to its credit, that Parke-Davis has been consistent in manufacturing a good product.

It is not easy to understand how a drug company can overlook its own product. An outline of my own experience with Parke-Davis may help. In 1966, as Secretary Gardner had recommended, I made contact with Parke-Davis. I phoned the company and spoke to the president, Mr. H. W. Burrows. I told him of Secretary Gardner’s recommendation that I speak to Parke-Davis, and supposed that would arouse his interest. But as I talked I didn’t hear the noises one expects from an interested listener. To get his attention I said, “Look, I’ve spent $400,000 on your medicine and I don’t want anything for myself, I just want to tell Parke-Davis about it.” That got Mr. Burrows’ attention. He said, “I wouldn’t know anything about this, I’m just a bookkeeper.”

That startling statement was my introduction to Parke-Davis. President Burrows said he would have someone get in touch with me. Two months later I got a call from Dr. Leon Sweet of Parke-Davis’s research department. He was calling at Mr. Burrows’ suggestion and made a date to meet with me in New York.

We met at my home. Dr. Sweet brought Dr. E. C. Vonder Heide with him. Dr. Turner was with me. Dr. Sweet said that Parke-Davis’s recent head of research, Dr. Alain Sanseigne, had left the company a few months earlier to go to Squibb, and Dr. Vonder Heide, a former head of research now retired, had come along to be helpful. Dr. Turner and I talked at length about the overlooked uses of PHT. Dr. Vonder Heide said it didn’t surprise him that PHT was more than an anticonvulsant. In fact Parke-Davis had had numerous reports that Dilantin helped with alcohol and drug addiction. He said that he had tried to get doctors to conduct studies in this field without success. He was rather critical of the doctors. I remember thinking, “What’s going on here?” The doctors depend on Parke-Davis to do something, and Parke-Davis depends on the doctors to do something. This is an interesting game of tag, and the public is “it.”

I didn’t realize till years later what a poor excuse Dr. Vonder Heide had given. Many research-minded doctors had already done a great deal, and at that time, 1966, Parke-Davis’s files were stocked with a variety of clinical studies on PHT. Yet apparently neither Dr. Vonder Heide nor Dr. Sweet had heard of them. It seemed Parke-Davis’s research department and its filing department were not acquainted with each other.

Our next contact with Parke-Davis came a few weeks later when we had a visit from a friendly gentleman, Dr. Charles F. Weiss. Dr. Weiss explained that he was a pediatrician and didn’t know anything about PHT, but had come to see us because he’d been asked to. He offered the opinion that Parke-Davis was a little disorganized. He said he wished some company would take them over. Well, he got his wish—but not for six years. Today the company is a subsidiary of Warner Lambert. When Warner Lambert took over in 1971, Mr. J. D. Williams became president of the Parke-Davis division. I felt I should bring the matter of PHT to the attention of the new management, and had several discussions on the telephone with Mr. Williams. The talks were friendly but not useful in furthering the PHT cause. On one occasion Mr. Williams expressed a thought I’d heard from Parke-Davis before, that since we were working on their product, it might be better if we stayed apart—some notion that the FDA might like it better. I couldn’t understand this—I was sure the FDA would want a drug company to know all it could about its own product.

But such is life. An item in the Arizona Republic (at the time I retired from Wall Street in 1970) will give the picture. The paper reported Dr. Joseph Sadusk, vice-president for Medical and Scientific Research of Parke-Davis, to have said that the Dreyfus Medical Foundation is doing “an excellent job” in investigating PHT. As a result he said Parke-Davis has made only “a minimal effort” in this area of research. “Results from an unbiased third party like Dreyfus,” he said, “would mean more to the Food and Drug Administration.”

I appreciate compliments. But the division of labor seemed uneven. The Dreyfus Medical Foundation should do the research, influence the FDA—and Parke-Davis should make the profits. There appears to have been only one person who, while passing through Parke-Davis, got a good grasp of PHT. That was Dr. Alain Sanseigne, head of research before Dr. Sweet. Dr. Turner brought PHT to Dr. Sanseigne’s attention. Dr. Sanseigne graciously acknowledged this in a letter to Dr. Turner in which he said, “Your very thorough knowledge of Dilantin put me to shame.” Once his attention had been directed to PHT, Dr. Sanseigne, in 1965, reviewed its pharmacology, site of activity, and therapeutic activity. It’s an impressive review, and it refers only to information on PHT available over twenty years ago. There are no signs that this review stirred Parke-Davis.

From Dr. Sanseigne’s review:

The Parke-Davis Medical Brochure includes as indications of Dilantin the following:

Epilepsy 
Chorea 
Parkinson syndrome 

Migraine

Trigeminal neuralgia

Psychosis

                                                                             

The following indications...have been studied and seem to show considerable therapeutic response to treatment with PHT:

Cardiac arrhythmia

Wound-healing acceleration

Neurosis

Polyneuritis of pregnancy

Adolescent behavioral disorders

Tabetic lancinating pain
Myotonia
Pruritus ani
Diabetes insipidus
Asthma

The following are indications on which the possibility of favorable response to PHT should be investigated:

Prophylaxis and treatment of cerebral anoxia (carbon monoxide poisoning and other asphyxiation, precardiac and pulmonary surgery)

Wilson’s disease

Poorly controlled diabetes

Cicatrization of oral surgery

Osteogenesis imperfecta

Conditions related to hypothalamus

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