A Tale of Propecia That Could Induce Alopecia!

Sherman Frankel, University of Pennsylvania

In April, 1998 I was contacted by NBC for a possible appearance on a Dateline segment about

Propecia, which is the new name for the drug, finasteride, which had been marketed as Proscar as a cure

for benign prostatic hyperplasia. Proscar had been prescribed for older men with urinary problems on the

supposition that the cause of them is an enlarged prostate. Propecia, I was told, was being marketed for

younger men who wish to grow hair. Because I had never studied this particular use of finasteride, I

declined the invitation to Dateline, but because I knew that finasteride, because of its ability to suppress

the conversion of testosterone to dihydrotestosterone, could promote growth of hair, I thought it would

be interesting to pursue the subject further.

Legal approval of a drug for a new use of it is based on data submitted by the manufacturer to the FDA.

Not finding the approval request for Propecia on the FDA web site, although the data submitted on behalf

of drugs sanctioned at a later date were already there, I decided to obtain knowledge of the Propecia

submission using the Freedom of Information Act. After some months, the fiches appeared and Dateline

was helpful in printing them out and sending the three pounds of pages for me to study. I discovered

beautiful data on the conversion of testosterone to dihydrotestosterone, which is the physical basis for hair

growth. Because I have considerable experience searching the medical literature (I had found 45 articles

in my web search of finasteride, as is described in one of my earlier papers)1 , I was puzzled. I initiated

phone and fax communications relating to Propecia with Keith D. Kaufmann of Merck. He affirmed that

the data about testosterone had, in fact, not been published. I asked why not, despite its having been sent

to the FDA. Surely, he said, I must know how difficult it is to get articles published these days.

That response convinced me to take time off from my other research endeavors for the purpose of

investigating this bizarre circumstance. I diligently studied the huge amount of data, wrote up my results,

and sent a prepublication copy to the ombudsman of the FDA for transmission to the persons at the FDA

responsible for approval of the drug.

In August, 1998 I submitted a manuscript titled, "Study of the Food and Drug Administration Files on

Propecia," to the The Archives of Dermatology. It was assigned to three peer reviewers, all of whom

responded to it favorably. The essay was put into the format of a Commentary, and after minor revisions

were made, was accepted for publication. About a year after submission, it appeared in the March 1999

issue of the Archives.

I am not a physician, but a physicist with over a half century of experience in analysis of data, so I was

pleased by the many e-mails that supported my assessment of that data as it appeared in print. I was

concerned, nonetheless, that the FDA had not appraised appropriately the most quantitative data in the

submission to it by Merck.

My purpose was not to criticize Merck (and I did not), but to raise questions about the FDA's approval.

Toward that end, I traveled to Washington to speak with the director of the FDA, Jonathan Wilkin, and

the chief physician responsible for the approval of Propecia, Hon-Sum Ko. I was troubled that not a

single referee for the FDA had commented on the following key pieces of data: a) Conversion of

testosterone to dihydrotestosterone fell to a low level at 0.05 milligrams and stayed the same up to 5.0

milligrams. b) Efficacy had not been established below a dosage of 1.0 milligram. Although side effects

did not occur often at 1.0 milligram, effects of finasteride on both the volume of ejaculate of semen and a

big depression of the prostate specific antigen (PSA) score (a test for prostate cancer) were included in

the data submitted to the FDA.

Through the ombudsman for the FDA I had communications with the FDA and finally made the trip to

Washington to ask why they had approved Propecia at the 1.0 mg dose. I will return to this later in this

article.

I now returned to my other interests in physics until a dermatologist friend asked me, in December 1999,

whether I had seen three denigrating articles about my Commentary from Merck associates that appeared

in the ``Letters to the Editor'' of The Archives of Dermatology.

It is customary in scientific journals that, if the editors who read the article judge it to be of interest to their

readers, it is then refereed. The editors play a crucial role, especially because they may reject an article

they have read without sending it to referees. My article on the finasteride data was read by either

Kenneth Arndt or Robert Stern, the senior editors of The Archives of Dermatology. It was deemed

sufficiently interesting by them that it was sent to three referees, all of whom approved it for publication.

The same editors, who presumably also read the three negative Merck inspired Letters to the Editor, are

expected to have enough competence to judge their scientific merit. They chose not to have any of those

letters refereed, nor did they follow the usual process of informing me of the fact they were going to

publish the unrefereed Merck responses.

My detailed responses to the Merck letters are technical in nature and are not repeated in this article. The

interested physician can read them however on my web page:

www.physics.upenn.edu/facultyinfo/frankel.html It is listed under ``Medical Research'' and entitled:

``Responses to Merck Comments in Archives of Dermatology''. They will provide some insight into the

logic and science in the drug field.

It is astonishing to basic scientists that medical journals take paid advertisements from drug companies. It

puts the editors into compromising situations that must, on occasion, cause a twinge of conscience. I have

written about it in an article that appeared in Urology2 and that related to an interaction between me and

The New England Journal of Medicine. The editor of that journal rejected one of my articles about

finasteride, and gave as the reason that it would have been published had it been submitted when the

original Merck data about finasteride was published. One can only infer that the reasoning is used that if a

published claim about research is found to be flawed, it cannot be refuted by the discovery of the error

made at a later time! (My conclusions on Proscar were later verified in a double-blind comparison of

Proscar, Hytrin, and Cardura carried out by Dr. Lepor at New York University.)

The primary author routinely has the opportunity to respond in the same issue. The editors of the Archives

of Dermatology must have understood the special status of representatives of Merck and that their

responses might not be exclusively scientific. Most scientific journals allow an author to respond to critics,

but The Archives of Dermatology did not invite me to do that. When I discovered the negative letters

related to my study of the data submitted by March to the FDA, I called and wrote the editors of the

Archives to discuss the matter with them. My letter of December 5, 1999, and subsequent phone calls

went unanswered, so on January 5, 2000, I again wrote asking that an editor call me. That letter also was

ignored. I decided to Fed Ex an earlier larger and detailed version of this article, including my detailed

response to the Merck criticisms, In February, I received a letter of rejection of that piece. I attempted

again to reach Robert Stern by phone. After many attempts, he called me and we had an interesting

conversation, some of which I record below.

Stern responded to my questions about his unusual decision to neither inform me of the Merck Letters to

the Editor nor give me a chance to respond by asserting that he does not send letters to referees. But

because he had to have approved of publication of those three letters, he must have known of their

content. He apparently decided that the Merck letters had validity and made no effort to find out whether

or not that was correct. Stern said he had taken the time to read my prior articles on finasteride and that

he had examined my work on the frequency of prostate cancer caused by finasteride. But I have never

published any article saying that finasteride caused prostate cancer. This remark seemed to be a mere

invention in order to justify his rejection of my new article. He communicated that the article was actually

rejected by Dr. Arndt but that he concurred in the decision. The reason stated was, ënough is enough,"

thereby setting a new standard for worthiness of publication. He also averred that one reason for rejection

was the journal had ``a limited number of pages.'' Stern ended by saying that ``The problem is between

you and the FDA and Merck, and is not between you and the Archives of Dermatology.''

While my article preceded my discussions with the FDA it seems useful to report now on comments I

received about it in writing from the FDA:

a) The FDA dismissed the data on the T to DHT measurements as ``surrogate'' even though there were

no low dosage measurements on efficacy. That beautiful data cannot be ignored to justify the FDA

dosage approval. Surrogate can only be applied to physical data if the efficacy data are done over the

same dosage range. Otherwise ``surrogate'' has no scientific meaning. But the efficacy studies were not

done below 0.2 mg and the 0.2 and 1.0 mg efficacy studies showed no advantage in the higher dose.

b) ``Dr. Frankel is minimizing this trial by saying the number of participants was only 100. In fact 466

patients were enrolled and 382 completed (92-98 patients completing in each arm).'' Can it be true that

the director of the FDA does not know that the number of patients receiving zero or .01 mg is irrelevant

to the comparison of the patients receiving 1.0 and 0.2 mg. They have nothing to do with the statistics of

the 1.0 and 0.2 comparison, each with 100 participants.

By the way, the submitted Propecia data is still, a half year after my written request, not on the FDA web.

Selling Drugs: There was a time when drug stores had druggists who ``filled prescriptions'' supplied by

physicians. Now the huge conglomerates, like RiteAid, send their customers materials obtained from drug

companies and suggest that they buy that company's drug. There may be a better drug on the market; the

buyer is being provided information that is biased. I received a pitch for Proscar, but there are other drugs

used for treating benign prostatic hyperplasia.

Conclusions: I have examined the responses to my article on Propecia by persons representing Merck, as

well as some who represent the FDA. I believe my responses will be compelling to an unbiased reader.

Physicians recognize that the drug companies are driven by a motive for profit. They are aware of the

underfunding and mediocre performance of the FDA in the process of approval of drugs. Very few

articles by physicians appear about this subject. I will soon submit a citizen's request to the FDA in order

to have it reconsider its approval of the dosage of Propecia, and I plan to ask the many dermatologists

from whom I have received e-mail letters to join in this request. But what is really needed is for

physicians, not physicists, to make the effort to improve medical practices. Organizations like the Institute

of Medicine of the National Academy of Sciences need to engage meaningfully in a study of how to make

the FDA a model of what a federal agency should be.

propackedit printed May 2, 2000

Footnotes:

1 Neurourology and Urodynamics, 14:619-24 (1995)

2 ``Annals of Medicine'', Urology 50(3) 319-20 (1997)