Lilly & Co., in an interview recorded last November 6 for "This Hour Has 7 Days," a Canadian Broadcasting Corp. program.

"The effects of birth control pills have been studied possibly more thoroughly and for a longer continuous time on the same persons than any other drug."-G. D. Searle & Co., manufacturer of Enovid, the first oral contraceptive.

Among the critics, there is a growing belief that the confidence of most of the medical profession in the pills is, at least in part, a result of inadequate information, wishful thinking, and questionable scientific and statistical analysis.

In the Searle statement, for example, critics say the word "possibly" automatically raises questions about the quality of the testing.

They also make a more serious objection: because the pill studies have not been controlled, the data is less meaningful than that from scientific investigations made of other drugs in fewer people over shorter periods.

Apart from contraception, the pills are recognized to have purely medical uses for many women, such as treatment for abnormal bleeding not caused by benign or malignant growths. This is one of the reasons why none of the doubters, so far as is known, advocates taking the pills off the market.

In addition, the benefit-risk ratio is variable. It is at one level for a mother who may die if she becomes pregnant again and goes to a planned parenthood clinic, but cannot be relied upon to use a mechanical method of contraception. It is different for a young woman who is willing to use a diaphragm but has been inspired by popular reports to ask her doctor for a prescription for the pill. Frequently, pill advocates meet questions about possible hazards by departing from the purely medical context to assert that the risks are miniscule in the context of the population explosion.

The advocates also say that the incidence of harmful effects is extremely low. But the fact remains that they have not established that the rate is low, or that it is even as low as they say it is, or that it is not actually many times higher than they say it is.

In addition, there is a widespread, resentful "don't rock the boat" attitude in the medical profession.

Recently, one manufacturer said that if warnings about the pills are widely circulated "literally millions of American women could be thrown into panic regarding the safety of all oral contraceptives."

Dr. Gregory Pincus, codeveloper of the pill with Dr. John Rock, says it has yet "to be proved that there is a cause-and-effect relationship" between use of the pill and subsequent ill effects suffered by some.

This is generally conceded. But those who keep speaking of lack of proof of a causal relation in regard to the pills and many other drugs as well, fail to specify just what degree of evidence would, in their eyes, constitute proof. One such is Dr. Joseph F. Sadusk, Jr., Medical Director of the Food and Drug Administration. They imply that proof can be black or white, that it has a finality that all would concede.

Scientists recognize, however, that there is no proof that evidence is in a gray area, that it is relative, that it boils down to sufficient data on relative risks. This is the kind of data on which persons charged with protecting the public health must judge the relative safety of all drugs-with a small chance of being wrong. They must decide whether the occurrence of adverse reactions is significantly more than would have arisen under normal conditions.

To insist upon certainty rather than compelling evidence of lack of safety, is to risk the public health.

Dr. Lerov E. Burney, while Surgeon General of the Public Health Service, said that to wait for "proof" is "to invite disaster, or at least to suffer unnecessarily through long periods of time."

Pointing out that some sensed an association between epidemics and filth long before anyone had seen a germ, Dr. Burney said, "wherever they had sufficient foresight to act on this circumstantial evidence, they made striking_progress. Cleaning up the city filth resulted in better health. Years later they found out why."

In the case of oral contraceptives, it has not been proved, and perhaps never can be, that they can cause, say, painful migraine.

But some women who had never had migraine get it on the pills, lose it when they go off the pills, and get it again when they resume taking the pills. By accepted scientific standards, this kind of challenge (taking a drug a second time) and response (reappearance of a side effect) is overwhelming evidence.

To demand evidence of this quality for such side effects as lung clots or strokes is to risk lifelong disability or life itself.

Inescapably, then, the lack of proof of a causal relation-the standard repeatedly invoked by Dr. Sadusk-requires acceptance of evidence less conclusive than that in the migraine situation.

These questions, then, arise:

SOME QUESTIONS

Has FDA been adequately protecting the public health-has it been reverent of life and scientifically responsible in taking the position that it must wait on such problems as clots and strokes for the kind of proof of a "cause-and-effect relationship" that is available for migraine?

In the labeling of oral contraceptives, has FDA promptly given physicians full information about all of the known factors in the benefit-risk ratio so they can make informed, intelligent decisions about whether to prescribe the pills?

Last March, Dr. Lasagna of Johns Hopkins disclosed that 2 of his colleagues, Dr. David B. Clark and Dr. Frank B. Walsh, had collected data on about 20 young women who had suffered strokes some of them fatal-after using birth control pills.

An autopsy on one showed clotting in "practically every artery and vein in her body," Dr. Lasagna said.

Yet, he noted, most of these cases had not been reported in American medical literature—although there have been reports of similar episodes in the British Medical Journal since 1962. Thus, many physicians were ignorant of possible serious and sometimes fatal hazards.

Last October 25, the Journal of the American Medical Association published a report on all methods for “the control of fertility" by the AMA's eight-member committee on human reproduction. The report was bound to be highly influential because of who wrote it and where it was published.

None of the authors was an endocrinologist, although the oral contraceptives involve the endocrine system. And the article makes no clear, specific mention of the possiblity of strokes in pill users.

CLOTS

Dr. Lasagna, asked for comment, said he believed the article, "in its concern for the benefits to be obtained from effective contraception, neglects what I consider to be all too definite warning signals on the horizon in regard to the ability of the oral contraceptives to cause vascular catastrophe."

Vascular catastrophe includes serious or fatal clots in the bloodways. Those that block brain arteries are called strokes. Those that reach the lungs are called pulmonary embolisms.

In a recent interview, the chairman of the AMA committee, Dr. Raymond T. Holden, of Washington, D.C., said frankly of the article, "Maybe it wasn't strong enough ***. It's possible we didn't stress the side effects," although "we thought we were being emphatic."

Relying on the theory that the safety of the pills, if used as directed under medical supervision, has been assured by FDA, the article emphasizes their effectiveness, "virtually 100 percent" and says that their acceptability is "of prime importance.

Yet, on November 16, FDA said that "several months ago"-that is, before the article was submitted to the AMA Journal-it had had a copy in hand of a report of 61 injuries involving blood clotting, including strokes and eye damage. That report, which was published in the November issue of Archives of Ophthalmology, included only those cases disclosed by ophthalmologists responding to an invitation to do so, and was therefore an obvious and large understatement of the reality.

Only when asked for comment on the archives report did FDA disclose that30 days after deciding to do so-it was just then in the process of asking manufacturers to include an eye-hazard warning in the labeling for the pills. The agency had had the report in hand "several months ago.'

Despite the great reliance the medical profession would place on Dr. Holden's committee and its report, the committee had been told nothing of these things by FDA.

Nor, according to Dr. Holden, had the committee been aware that FDA had approved inconsistent labeling for different brands of identical pill formulations. This permitted a physician to believe one brand was safer than another, although both brands were chemically the same.

TESTING

About 3 years ago, a Senate subcommittee headed by then Senator Hubert H. Humphrey published a revealing FDA document, of which Dr. Holden wasand other members of his committee apparently were unaware.

The document disclosed the situation in 1960, when FDA released Enovid, the first oral contraceptive, for birth control purposes in possibly millions of women. At that time, when the agency recommended a maximum consecutive use limit of 2 years, the grand total of patients on whom Enovid had been tested for safety for from 12 to a maximum of 38 consecutive mentrual cycles was 132. Dr. Holden said the 132 were "not enough."

The number of Enovid tests has greatly increased since 1960, but similarly small numbers were involved last spring when FDA released the first sequential oral contraceptives, which employ a different concept of action, with a recommended maximum consecutive use limit of 18 months.

The number of women who as of last spring had taken Mead Johnson's sequential product, Oracon, for 18 consecutive cycles was 174; for 24 cycles it was 148; and for 36 cycles it was 16.

For Eli Lilly & Co.'s C-Quens the total for 18 cycles was 445, for 24 cycles it was 180, and for 30 cycles it was 4.

While the kind of faith put in FDA by the AMA committee has been commonplace in organized medicine, it has not been held by the chairmen of congressional committees that have investigated the agency's performance.

In 1962, for example, Senator Humphrey said he had uncovered practices "so lax that there was, in effect, no real regulation at all."

Last summer, Representative L. H. Fountain, democrat of North Carolina, was so disturbed by the findings turned up during his inquiries that he felt impelled to remind top FDA officials that their responsibility is "not to the drug companies, not to the doctors, but to the consuming public that may live or die as a result of your decisions."

The AMA committee report dealt with the troubling question of thromboembolism. (A clot that forms in a blood vessel is the thrombus. An embolus is a piece of a thrombus that has broken off and traveled to another site, where it can cause lifelong disability or death by blocking the flow of blood.)

"The possible association of thromboembolic phenomena with the use of oral contraceptives has been reviewed by several committees, including one appointed by the FDA," the report said, thus invoking the FDA as a ground for assuming safety.

The "several committees" were identified by Dr. Holden as two-the British committee on the safety of drugs and the special FDA advisory committee headed by Dr. Irving S. Wright of Cornell Medical College.

WRIGHT COMMITTEE

The Wright committee was convened after FDA and the manufacturer of Enovid had received, by late December 1962, reports of thrombophlebitis-an inflammatory vein-clotting condition-in 172 women who had taken the pills. Thirty died after pieces of the clots broke loose and reached the lungs. By July 1963, the reported total had increased to 400 cases, with 40 deaths.

For the moment, the major point about the Wright committee is that it did not eliminate the possibility of a relation between the use of Enovid and the occurrence of clots in the legs, pelvis, and lungs.

The committee felt that the data it had to work with required it to be cautious in drawing conclusions. In the 27 months since the committee made its report, its restraint has not always been mirrored by others, who have tended to assume that there is no reason for worry about a possible relation. Such an assumption has been nurtured in many places.

In March 1964, for example, Dr. Robert Kistner, a Harvard gynecologist and coworker of Dr. John Rock, codiscoverer of the birth control bill, said that "scrutiny of the available data by experts *** has completely exonerated the drug" as the causative factor.

This defies an axiom followed by expert statisticians: that no data ever warrant a declaration that a drug has been "completely exonerated." They say that the most that can ever properly be said is that the data permit a cautious conclusionthat there is a high or low probability of a causal relation.

Thirteen months after the Kistner exoneration, the FDA's Dr. Sadusk joined in, in a two-step progression.

First, he said that it "seemed reasonable to conclude at this time that there is no evidence of a cause-and-effect relationship between strokes *** and the oral contraceptive drug." His undocumented contention that there is "no evidence" is disputed in several reputable quarters, although no one claims that the evidence is conclusive.

Then Dr. Sadusk went on to declare that the "information at hand is to the contrary."

But numerous reported cases of stroke found since 1962 in Britain and later at Johns Hopkins, at the University of Miami (Fla.) School of Medicine and elsewhere do suggest the possibility of a causal relation with the pills. They do not prove it, but they are hardly evidence "to the contrary."

There are

Mr. FOGARTY: Many people are concerned about this. two articles here "Reassurance-and Warning" is the second article from my local paper.

[From the Providence Journal-Bulletin, Dec. 20, 1965]

ON POSSIBLE PERIL IN BIRTH CONTROL PILLS REASSURANCE AND WARNING (By Morton Mintz, Special to the Journal-Bulletin)

Within days of a statement by Dr. Joseph F. Sadusk Jr., medical director of the Food and Drug Administration, that "there is no evidence of a cause-andeffect relationship between strokes *** and the oral contraceptive drug," and that "information at hand is to the contrary," a preliminary report on women pill users who had strokes was made by Dr. Sherif S. Shafey at Jackson Memorial Hospital in Miami.

Last October, a full-dress version of the report was made before the American Heart Association by Dr. Shafey, who heads the cerebral vascular disease clinical research center at the University of Miami School of Medicine.

He and Dr. Peritz Scheinberg, chairman of the school's neurology department, said that "there is a strong suggestion of an increase in the number of young females suffering from vascular occlusions during the last 2 years. All the cases diagnosed as such were on the oral contraceptives except one."

Instead of the relaxed attitude suggested by Dr. Sadusk, they urged "awareness of the possible existence of a causal relationship.'

Among 4 stroke patients, 20 to 29 who had been referred by private practitioners, there had been no previous symptoms or predisposing conditions. A fifth, 39, had had mildly high blood pressure for 23 years. All had been taking oral contraceptives for between 6 months and 3 years.

A sixth woman, age 29, who had been taking the pills for a year, developed a fatal clot in a major vein in the brain, although "without a precipitating factor." This condition "is rare," the researchers said.

A group of 28 women who had never had migraine a possible indicator of more serious trouble in the bloodwaves-developed the painful headaches after starting the pills. In another group that had had migraine, the headaches worsened while its members were on the pills.

In both groups, the problem was relieved when the women stopped taking oral contraceptives. For all of these women, Drs. Shafey and Scheinberg considered the "existence of a definite relation *** most convincing."

Citing similar evidence, Dr. Frank B. Walsh, professor emeritus of ophthalmology at Johns Hopkins, and three colleagues said in the Archives of Ophthalmology article:

"It is our impression that the relationship between oral contraceptives and migraine has not received the consideration it deserves."

CRASH PROGRAM

A few weeks ago, FDA, said that a computer was memorizing more than 10,000 instances of adverse experiences with oral contraceptives. The agency said it had a crash program to catalog every scrap if information connected with the pills.

Perhaps inadvertently, the agency thus acknowledged that, despite the gravity of the problems involved, its surveillance of adverse effects had to be strengthened by a crash program.

In explaining the program, FDA said it was about to convene a special advisory committee on obstetrics and gynecology "to look at broad, overall problems of adverse experiences with all contraceptive drugs," including discrepancies in label

ing of identical and similar products that the committee is expected to ask be made uniform.

In its initial meeting November 22-23, the committee said that its preliminary review "finds no evidence of a cause-effect relationship" between the pills and report of eye damage, strokes, and other injuries associated with blood clotting. The committee did not include in its statement the usually expected counterbalance: that it has no evidence that a causal relation does not exist. Yet by adopting a resolution endorsing FDA's request for an interim eye-damage warning in the labeling, the committee clearly indicated that a causal relation might indeed exist.

The committee is scheduled to meet again January 20-21 and to issue its final report after a third meeting next March. Its chairman is Dr. Louis M. Hellman of the State University of New York College of Medicine.

Although certain consultants have been enlisted, Dr. Hellman and the six other committee members are all obstetricians and gynecologists. Such relevant specialties as endocrinology, hematology and cardiovascular and blood-clotting diseases are not members.

STUDIES

One crucial problem area in the committee's deliberations is the significance of the 10,000 instances of adverse experiences and the worth of such studies as have been made about the safety of the pills.

The 10,000 reactionss are a potpourri of often sketchy reports in medical literature, of cases from manufacturers' files, of cases reported with uneven precision by private physicians, or cases from a small proportion of hospitals.

On November 29, Drug News Weekly said that the committee "reportedly found the data useless-at least in its present form." Another warning, this one about assumptions that computers can provide magic answers, came recently from Dr. John T. Litchfield, Jr., a drug industry scientist who spoke at the dedication ceremonies for FDA's new building.

In trying to enlist computers, he said, many people in industry are "learning a few hard facts of life. 'GIGO' is the word-garbage in, garbage out. Computers cannot improve data."

The real fear of some competent, knowledgeable scientists and statisticians is of "garbage results" as a basis for making judgments about the safety of the pills, in addition to being dubious as a sampling of reality, the 10,000 reactions almost certainly understate the reality.

Under reporting of adverse reactions is a fact of life about drugs recognized almost universally by persons familiar with the situation, including officials by FDA. Especially among private practioners, underreporting is tremendous, even when drug reactions are recognized for what they are--and often they are not.

The magnitude of underreporting has probably never been more dramatically illustrated than it was last year at Johns Hopkins, a top-rank teaching hospital where there is a reporting system of extraordinary quality. It has been made easy to follow by providing staff physicians with reporting cards attached to the patients' charts.

Dr. Leighton Cluff, professor of medicine at Johns Hopkins, and three Public Health Service epidemiologists made daily inquiries of doctors and nurses about drug reactions in a 120-bed medical service. They found that those supposed to fill out the cards failed so often that fewer cards were filled out for reactions in the entire hospital than the survey found had actually occurred in a 10-percent sample of the hospital.

In short, the indication was that possibly 9 out of 10 reactions were not being reported, under highly favorable conditions for reporting.

If the 10,000 adverse reactions are a shaky foundation for judgments on safety, so are the uncontrolled studies upon which so much reliance has been placed to date. The studies have troubled even such exuberent boosters of the pills as Dr. Joseph Goldzieher: "I can think of no condition in which these pills would not be safe to take."

A TRIAL ASKED

Citing the "deficiencies in published trials" in an article in the Medical Journal of Australia last June, he said that much of the current discussion of the incidence of side effects is an exercise in futility.

In the British Medical Journal, Dr. Geoffrey Rivett said he had found no circulatory disorders in between 50 and 100 patients on the pills, even though some of them had had a history of such afflictions.