Responses to Merck Comments in Archives of Dermatology
In August of 1998 I submitted the paper ``Study of the Food
and Drug Administration Files on Propecia
'' to the Archives of Dermatology. It was given three peer
reviews, all positive, re-formatted as a
Commentary, and accepted after minor revisions. It finally
appeared about a year after submission, in the
March 1999 issue. Subsequently, and without my being
informed by the editors, comments from three
Merck associates were published without peer review, in
their journal. These authors not only showed a
lack of understanding of statistics, simple logic, and some
medical matters but were very personally
denigrating. The reader can find their letters in the August
and November 1999 issues. The following
material is my technical response to these comments.
A. Keith D. Kaufman Comments ( AOD August 1999 )
1) Kaufman is correct in noting that my conclusions were
``based on serum and scalp DHT
measurements we made on balding men treated with finasteride
...''. Those were the data supplied by
Merck to the FDA and on which the approval was based. The
data showed the percent change in
testosterone (T) to dihydrotestosterone (DHT), was 46% going
from zero dosage to .05 mg and staying
flat to 5 mg. Any physician who has taken a pre-med course
on elementary physics, especially one with a
laboratory component, who examines the error bars on the FDA
plots that I published, would come to
the same conclusion.
2) Kaufman disputes the FDA data by referring to a paper
(his ref 3) which is ``in press'', so neither I nor
the FDA could possibly have known about it in April of 1998.
He quotes the difference in T to DHT
conversion for 1.0 and 0.2 mg samples as 68.5 +/- 1.4% and
61.2 +/- 1.7%, (a difference of 7.3). These
are not the data given to the FDA. Nor did I get a preprint
of these results from Kaufman although he
knew about my interest as the result of our phone calls.
3) Kaufman further makes claims that the efficacy was better
for the 1.0 mg than for the 0.2 mg dosage
quoting his ref. 4, also ``in press''. That is not data on
which the FDA acted.
4) The hair count study: The number of persons in the sample
were only 101 (1 mg) and 99 (0.2 mg). If
Kaufman bothered to read the material that had been
submitted by his company to the FDA, page 23 of
NDA 20-788, he would see that Merck had properly given the
data as mean change from baseline: 68.7
+/- 17.3 and 54.9 +/- 17.3. These are the widths of the
distributions at the 95% confidence interval. At
the risk of boring the reader, we present in Appendix 1 the
standard statistical analysis of the data. Yet
Kaufman suggests in his letter in the Archives ( March 1999
issue) (his references 6 and 7) that a
physicist with over 50 years of publishing data in refereed
journals, complete with both ``statistical''' and
``systematic errors'', 1 needs to read a book on statistics.
5) Kaufman argues that I should have known that he claimed
to have data that proved that 1.0 mg was
superior to .2 mg in hair growth. To show this he gives his
reference3 (3 and 4) which he lists as ``in
press''. There is very remarkable use of the calendar in his
remarks, a kind of new time-reversal
invariance concept.
B. Janet L. Roberts Comments ( AOD August 1999 issue)
1) Roberts says ``commentaries are not held to the same
rigorous scrutiny and high scientific standard as
peer-reviewed articles" This does injustice to the
editors of the AOD since the article was peer-reviewed
by three physicians. The Roberts letter was not
peer-reviewed.
2) Roberts tries to sell the superiority of the 1mg dose by
referring to her reference (1) That reference is
also ``in press''. I do not claim clairvoyance.
3) Conclusion: Roberts has introduced a free advertisment
for Propecia in the Comments Section. My
article never said Propecia did not grow hair.
C. Diane Thiboutot Comments (AOD Nov. 1999)
1) Thiboutot says: ``Dr. Frankel insinuates that
collaboration occurred between physicians and subjects
as regards questionaires and global assessments.''
Absolutely nothing in my paper does so. The placebo
effect is a remarkable effect connecting mind and body.
Although it is routinely used in double blind
studies, the effect is rarely understood in its complexity.
It is recommended that interested readers study
the recent book The Placebo Effect edited by Anne Harrington
of Harvard Medical School.2
Roberts is apparently not familiar with the huge literature
on placebo effects or she would be able to
distinguish patient and physician assessments based on a
``Patient Hair Growth Questionaire'' or a
physician ``Investigator Assessment'' vs. real data based on
the counting of hairs from photographs. The
former are qualitative opinion polls and are usually only
used when real measurements of hair counts are
not available. This was not the case here. What Roberts has
not understood is that one placebo effect
arises because the patient would like to see the treatment
grow hair. So would the physician. To deny this
effect for physicians makes an unflattering statement
suggesting that physicians, unlike their patients, do
not have the same human responses. I thought it was worth
mentioning, from my examination of the data,
that there was nice evidence here for the placebo-like
overestimate of the hair growth for both types of
observers. None of the FDA referees commented on this
result.
2) Roberts goes into well known conditions on pricing that
are irrelevant to the drug dosage approval and
which are well known. I should not have made the remark
about solubility in ethanol since the FDA
actually blacked-out, i.e. censored, the actual solubility.
I apologize for not telling the dermatologist
readers that there is a trivial way to subdivide the pill:
Crush it between two spoons and transfer the very
fine powder to a small clear glass bottle of water. (The
containing coating is easy to remove.) An
extremely fine suspension is obtained. Shaking the bottle
and removing a tablespoon of liquid is the simple
way to reduce the dose.
I cannot understand why saving money ``cannot be condoned''
when the cost is approximately $1000 per
year, not covered by insurance, and the drug must be taken
forever in order to preserve any hair growth.
There are no data proving that the lower dosages are
ineffective while the physical T to DHT conversion
measurements are flat from .05 to 5 mg. Considering the cost
to take the drug for the rest of one's life and
that the drug is too expensive for most young men, an
intelligent user might want to do a few month trial at
lower dosage. Nothing to lose but some fuzz.
A popular article dealing with my interactions with the FDA,
Merck, and medical journals concerning the
finasteride, will appear shortly.
propcrapmerck printed May 2, 2000
Footnotes:
1 Apparently the medical profession almost never assigns
systematic errors in their presentations and
conclusions, yet in many experiments the systematic errors
are larger than the statistical errors.
2 ``The Placebo Effect'', Harvard University Press, second printing, 1999