SEP 20 1966
September 19, 1966

Dr. Joshua Lederberg
Stanford University
Palo Alto, Celifornia

Dear Dr. Lederberg:

Your Science and Man column in today's Washington Post
startled and disappointed me. It is a piece of work
unbecoming a man of your ltstrous reputation. It is

marked by an absence of careful factfinding, of precision
and of relevance, I had hardly been prepared for a
complaint in, of all places, The Washington Post, against
"glib" newspaper accounts of the report made oy the Advisory
Committee on Obstetrics and Gynecology of the Food and

Drug Administration, Anyone who attempts a serious
discusston of the safety of the oral contraceptives

does so at considerable peril, but if the é#ondescending

word "glib" should be affixed anywhere I suggest it

might more appropriately be attached to publications sther
than Ehe Washington Post, to Commiszioner James L. Goddard
of FDA, to Alan Guttmacher of Planned Parenthood and,
regrettably, to Joshua Lederberg of Stanford, as well as

to the Advisory Committee itself,

On August 15 the newspaper that publishes your column
devoted more than a full page to sories related to the
Committee report and to exceppts from that report. In
the few days after that we carried a news analysis (Aug. 16),
an editorial and a second, and lengthy, news analysis
(Aug. 28). Perhaps you did not intend that the word "glib"
asply to The Washington Post. Perhaps you did. In any event,
you_tarred everyone indiscriminately. I would think one
could have expected from you some effort to distinguish
between the performance of The Washington Post and that,
say, of the Paltimore Sun, which on Aug. 15 nrinted not
one word about the report; of Newsweek, Time and the ANA News,
all of which carried false headlines asserting that the
birth control pills had been found "safe"; of the New York
Times and the "all Street Journal, both of which seid in
their stories that the Committee hed found no "evidence"
the pills were unsafe (even Yr. Goddard made the same
blooper. Of course there was "evidence"; what wes at
issue was the quantity and qwality of the evidence),

If you intended to brand the coverage ggven this matter
by The Washington Post as "glib," then I invite you to
say what your reasons are.
Joshua Lederberg -~ 2 =

One error in several press accounts was attributeble
not to reporters, but to Dr. Goddard. Newspapers repeated
-~ we did not, I an hapoy to say =~ his assertion, which —
wes in a prepared statement distributed at a press briefing

on August 11, that 20,009 women in the District of

Columbia are in proppective studies sponsored by the
National_Institutes of “ealth in cooperation with D.C.
Planned Parenthood. ‘then I checked I found that such
studies are nonexistent - that NIH has a contract to

see if such studies are feasible, and thet the contract

is not with Planned Parenthood, but with the D.C. YVepartment
of Public “ealth. ‘Who wes being "glib"?

Whatever criticisms may be made of the Comittee and
its reports, no one cun fairly say that there was not
& predominant note of caution. Over and over, in regard
to cancermy clotting, diabetes, effects on the offspring--
over and over the theme was repeated that the data are
insufficient, that more must be learmed. One could not
gether it from your reference to the "amber light," but
the fact is that it was Dr. Hellman himself who, at the
August 11 press briefing, characterized th: report as
“a yellow light of caution." Drug News ‘eekly went further
and said the report was a yellow Tiahe or @ red light.
In a casual, almost flippant way, Dr. Goddard went on
television to give what was, for practical purposes, a green light,
Dr. Guttmacher said the report was "a complete green light."
But in an apnoearance on Aug. 15 on National Educational
Television Dr. Roy Hertz, a member of the Committee, said
that any characterization of the report as a green light
was "totally fallacious." Correct me if I'm wrong, but
i susest that if anyone was being "glib" it was Se
GoddardéGutimacher, not Drs, Hellman & Hertz; and that
if one is going to criticize "glib" newspaper accounts
permeated by "confusion and contradictions", one might
put the blame where it belongs, on sources such as Drs,
Goddard & Guttmacher,

You quoted the conclusion of the report, wherein is the
crucial statement that the Committee "finds no addcuate
scientific data, at this time, proving these compounds
unsafe..." f submit that one might have expected a
scientist to make note of at least one of the following

points:

*A statement of this kind is unscientific in that it
fails to give the necessary counterbalance, that there is
"no adequate scientific data, at this time, proving
these compunnds safe..."

*The Committee did take a scientific approach in the
introduction to its report, when it said that there is
such a paucity of data on severe adverse effects that
"any assumptions"--I repeat, “any ascumptions"--must be
considered "unreliable,"
Joshua Lederberg -—3——

*If the pills should saver be unsafe, which I emphatically
hope they are not, this will never be "proved." ‘There
can be no proof in the legal sense, nor in mattcr o8 the
public he-lth can proof be awaited. You surely know,
for instance, that no ascociation between cigarette
smoking and lung cancer, heart disease and other
afflictions has been "proved." What we have, and what
we may Someday have in connection with the pill, isa
Statistical association, The auzy¥zq probability that
the pills cause clots, strokes, eve damage, or whatever,
may be of a higher or lower order, and at certain rates,
thet is what emr decisions will have to be based on,

in your next paragraph you quote the advice of the
Committee that each physician must evaluate the acventares
and the risks of the pills, and that he "can do this
wisely only when there is presented to him dispassionate
scientific imowledge of the available data." What
you fail to do is to note the meagerness of such data
and of the efforts to expand ziztexme the body of
knowleijige to meaningful proportions.

Specifically: In 1963 the FDA's Wright Committee
Said the data available showed an incidence of fatal
pulmonary embolisms in women taking Enovid of about
12 per million, compared with an incidence in the normal
female populations of about 3 per million. ‘the Committee
sensibly concluded that the difference was statistically
insignifanant. But it also sensibly concludec that the
date on nonfatal clots were hopelessly imprecise, that
the data on fatal clots was shaky, that the pill insofar
as fatal lung cl@ts were concermed had not been demonstrated
to be unsafe (or sefe) and that a controlled, prospective
stucy wee needed. No such study has been done; PDA has
failed to implement the recormendation. The Advisory
Committee now, three years later, bemoans the situation
and says we must have a retrospective study (in recomiending
agcinst a prospective study for clotting while recon ending
fox such a study of concer, it cited "cost", which was not
its business, and complexity). But, in any cace, would it
not have ben ap»oropriate for you to have note) the Leck of
date on clotting that now has been damned by two FDA
Gommittees? Would it not have been appropriate for you to
have noted that the latency period for human cancer is ea decade,
and that a physician does not have the means to detect it
before then? And that the Conmittee emphasizes thet it does
not know whether the pills have, or do not have, @ cercinogenic
potential? ‘Would it not heve been aporopriete for you to
bring out the seme fact--the fect of ignorance-~as to
effects on future offspring (see the special report by
Dr. Hertz that the Committee included), on diabetes,
on strokes, on infarctions, on masculinization of the fetus?
Joshua Lederberg --4——

In column two of your article you engage in sone
statistical discussion tnut I find, frankly, atrocious,
and this after dragging in the abortion chestnut. All
we are (or should beQconcerned with if there is to be
a pretense to a scientific ap roach, it seems to me,
is this auestion: Is there, or is there not, a higher
risk of injury or death--and, if there is, how much
higher--in women who use the pills than in women who
use other forms of contraception? I am concerned about
the problem of abation, too, but I do not think it
relevant to the guestkam need for getting the fects about
the mecical characteristics of the pill. Abortions have
nothing in the world to do with whether the pill cause Cxhage.
strokes, If, let's say, Ralph “ader wants to praise a 4
Rover and condemn the Volkswagen, let him do so without
dragging in the problem of drunken drivers, As to your
statistic. 1 discussion: You wrote that "even today
pregnancy carries a risk of 300 maternal deaths per million
gestations. This number is at least 20 times higher than
for any specific side effects fhat might conceivably be
attributed to the pill by interprepation of the existing
statistics,"

Let us assume that there is indeed a risk of 300
maternal deaths in pregnancy. The maximum risk of
clotting is acknowledged to be in the period innediately
after pregnancy - acknowledged, incidentally, by the
Committee in its report. As you note, the pill induces
a pseudo pregnancy. But you and the Committee fail to
note that a woman on the pill is in effect pregnant and
delivering 13 times a year, She may, therefore, be running
the maximal clotting risk 13 times as often as a nonuser,.
Is this not relevant? let us go on. You said the
300-per-million rate "is at least 20 times higher than
for any specific side effect..." Where is your authority
for that? xzisummyseax2® If--and it's a big if--there is
in fact a 4 per million higher incidence in Enovid users
than nonusers of fatal pulmonary embolisms (12 minus 8),
the pregnancy risk is 80 times higher. But if you know
what the risk may be of strokes, of nonfatal thromoboembohisms,
of infarctions, of migraine, of psychic depression, of
e-neer, of foetal malformations--if you know what the rete
is for any of these things, let along for the sug of then,
then, Sir, myhat:is off to you, because you have
informational sources denieé the Advisory Co mittee, the
PDA, the pill manufacturers, the medical journals end
everyone else I lmow of.

Sut your statistical r-asoning is atrocious fo» yet
another reason. No one, to Liy kmowledge, has sugested that
&@ woman who uses a diaphragm and jelly runs a risk of cancer
or stroke. FDA fores no committees to investigate tha
such a possibility. szwoman Assume that the efficacy of
tne pill is 100 per cent. The efficacy of the
diaphragm, properly used, is about 98 per cent. [It is,
Joshua Lederberg ~-5 me

therefore, a Scientific and statistical fallacy to
lay the deatn rate in pregnancy alongside a wholly
conjectural death rate among users of the pill. vould

ou not agree that for those women who can properly
use & diaphragm (for the sake o simplicity, T an leaving
out the impressively efficacious use of foam alone, and

of other mechanical contraception) the comparison should
be made, if it is to be madé at all, betwemm in terms of
the 2 per cent in whom contraception will fail? To put

it another way: the fatal hazards of pregnancy you deery
will be faced not by 3 million women who use a diaphragm
in preference to a pill, but by 2 per cent of the 14 million,
or 20,000. At the rate you cite, 300 per Million, the
banardy then xextsts for 6 women wee will die--6 per million,
and not, in those women using a diaphragm, the 300 you
imply.

Iowent to tum nov to some other ppints. The Washington
Post's news coverage referred to the Advisory Tommittes

neit as distinguishe: nor as undistinguished, Each of
those adjectives is a loaded, judgmental word, You chose

to call the Comittee "distinguished," You would say,
Clearly, that "Loyt Hellman is "distinguished," because

you praise "his temper and wisdom," I would, I suppose,

Say that Dr. Hertz could claim to be distinguished, because
he is the former chief of endocrinokogy of the Vational
Cancer Institute and, more recently, the former Scientific
director of the National Institute of Child “ealth ang

Human Development. But I would anoreciete hearing from you
what thea makes the Committee, in your eyes, "distinguished,"
I was kind enough not to point out what should be apparent

to a scientist, that the very name of the Advisory Committee
on Obstetrics and Gynecology distinguishes the groupxfxun

it from the balanced group one might expect--a group
including tepresentatives of the other Specialities deeply
involved in the questions presented by the pill, hematologists,
to name but @ne, Another bit of imowledge counseling
restraint in describing the Committee, but one you mey be
uneware of, is that some of the members were in the FDA.
convened group that voted against a proposal to add a
Warning against use in women of childbezrinz age to the
labels of over-the-counter products containing one of three
antihistamines \eycligzine, chloreyclizine and meclBzine)
suspected of Oaustngxbirth a capability to cause foetal
malformations, “or reasons given in the foregoing, I did

not find the conclusion of the Committee report distinguished
in scientific terms. I found it troubling that the Committee
could say that the pills require obscrvance of an "yn.
precedented standard of Safety," but recommend against a
prospective clotting study on the grounds of cost and
complexity; that it could recommend a Letrospective t¢piex
trial thet its chier advocate, Dr. Surtwell, concedes would
not, even if full implemented, detect one nonfatal clot

in 4000 (or fewer pill takers; that i+ could say that the
Joshua Lederberg -~6--

meximum clotting risk is im:.ediatehy after pregnancy,

but fail to say that pill users are takkng pregnant

13 times a year; that it could publish a report from

its task force on thromboembolic phenomena that omits

a bibliography, while including a letter sent out in 1962
by GoD. Searle & Co., the manufacturer of Enovid, in

the number of 275,000 copies,

Youiwrote that FDA's initial approval was given au
"on the basis of experience with some few hundred or
thousand women..." I will be precise if you will not,
At the time Enovid was aporoved for birth control use
by FDA the number of women in whom it had been tested
for 12 to 21 consecutive menstrual cycles was 66; the
number in whom it had been te-ted for 24 to a maximum of
33 consecutive menstrual cycles was another 66, for
& grand total of 132, and the number of cases it had
in hand, "properly documented with laboratory studies,"
as _to cancer was 400. In the Xfyet@d sete? literature
today the number of women under 40 who have used the pill
for a long time, and who have been adequately studied and
reported is, according to Dr. Hertz, 85. I trust these
figures shock you. They are shocking to, for exumple,
Dr. Raymond Holden gt Washingtoh. He headed the AliA's
Comittee on Human eproduction and Fertility. After the
AMA Committee's report on contraception apoeared in the
Journal of the AMA last October I discussed with Dr. Holden
the striking lack of emphasis in the report on the pill on
safety, the question being dismissed there with the
statement that safety had been assured by FDA. He
was Shocked to learn that only 132 women had received
Enovid for a maximum of 38 consecutive menstrual cycles.
His Committee - a professional source of information for
physicians - did not know of the 132 figure,w which was
sublished by a Senate subcommittee early in 1963 and was
cited in, among other places, my book, The “herapeutic
MWishtmere. Referring to the figure of 132, Drv Holden
sold to me, "You know that's not enough." I know it. Do ypu?

   

I do not understend why you think the prime need now
is to "scrutinize the available data..." The tvouble
with the available data is clearly that it is full of
holes, and that it does not lend itself? to fine analysis,
Are you joining in opposition to a prospective clotting
study, even though the FDA's Vright Committee (wis it
less "distinguished" than Dr. Hellman's Committee?) urged
such a gtudy, end even though uit has been urged anew
by Dr. “ert2?

I am sure that if I had taken more time 7 would have
been more pointed and more coherent, But 7 thought it
important to deal with tuis at once. T have, regrettably,

ae

vincerely yours
m Te . 1 7 r Tra ,
The Vashington Fost Morton Mintz, ational Te

>

& tendency to react strongly to nonscience proferred
by @ scientist with credentials as distinguished as yours, } *
porter