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 conclusion— that 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.

"But such figures prove nothing," he said. "It would be a great help if an authoritative body would carry out a valid trial.”

Mr. FOGARTY. Look it over and give us an answer for the record. (The information requested follows:)

FOOD AND DRUG ADMINISTRATION STATEMENT ON JOURNAL-BULLETIN (PROVIDENCE, R.I.) ARTICLE ON ORAL CONTRACEPTIVE PILLS BY MORTON MINTZ The articles by Mr. Morton Mintz, a reporter for the Washington Post, recently were published in the Journal-Bulletin (Providence, R.I.). They are on the subject of the oral contraceptive drugs and discuss the position of the Food and Drug Administration which has permitted these drugs to remain on the market. The articles contain a number of statements and quotations, all designed to imply that substantial dangers will result from the taking of these pills.

The oral contraceptive drugs consist of a combination of an estrogen and a progestogen in varying proportions and dosages, and were admitted to the U.S. market for contraceptive use in 1960. But it would be a mistake to consider that the therapeutic use of these compounds was only of relatively recent introduction; on the contrary, synthetic estrogens and one progestogen have been in clinical use since 1938, although some of the newer drugs in the oral contraceptives have been used only since the early 1950's.

These oral contraceptive drugs have been widely used in the United States and elsewhere in the world. The estimated number of users of such drugs in the United States has been as follows:

Yet, such widespread use has not led to gross public danger, as implied by Mr. Mintz.

Indeed, these combinations have also been used rather extensively for certain gynecological purposes; and, while there is not general agreement as to the rationale for such use, no unusual substantial hazards have been reported. The Bureau of Medicine has and is continuing to review this matter and has presented the subject to an Advisory Committee on Obstetrics and Gynecology. The oral contraceptive drugs produce certain side effects, although none of of these have been demonstrated to be of serious impact:

1. Nausea, sometimes with vomiting, is the most common side effect, though the incidence of this appears to be lower than reported in past years and generally clears after use of the drug following the first several cycles. 2. Headache may occur, especially with patients having migraine.

3. Certain psychological changes have been reported in some patients, but the small number of well-controlled studies in this field makes it impossible to arrive at a conclusive opinion on the matter.

4. The pill user's weight may either increase or decrease. The mechanism of this weight gain is complex and is yet not clearly understood. Certain other systematic effects are seen:

1. The excretion of BSP (bromsulf thallin sodium) may be decreased during the taking of the oral contraceptives, as it is in late pregnancy. However, this abnormality in BSP excretion is reversible, transient, and indeed may disappear with the continued taking of the pill. There has been no conclusive evidence of liver injury in the normal human female without preexisting liver disease.

2. The oral contraceptive pills appear to produce changes in the blood clotting mechanism but the differences in the reports of different observers make it difficult to link these changes with thromboembolic disease.

3. Some authorities have found changes in carbohydrate metabolism, but there does not yet appear to be evidence that these changes produce diabetes. Indeed, evidence in birth control clinics is to the contrary.

4. Studies have indicated that functional changes are seen in certain endocrine glands during the taking of oral contraceptive drugs, but there has appeared no evidence that these changes are irreversible or produce damage to the woman.

There has been brought forward repeatedly the assertion that the taking of oral contraceptives will produce carcinoma of the cervix, body of the uterus, and the breast. Despite such claims, there still remains no conclusive evidence that this occurs in the human. With certain of these drugs and under certain conditions (such as an excessively high dosage and in certain species and strains of animals), cancer of the breast and other organs has been produced and is cause related; but similar evidence for the human female simply is lacking. There should also be kept in mind the fact that 1960 data from Vital Statistics in the United States show that death from cancer of the breast is the leading cause of death in the white female from age 40 through 49; consequently, it would not be surprising to find cases of breast cancer among oral contraceptive drug users.

Assertions have repeatedly been made that thromboembolic disease is related to the taking of oral contraceptive drugs. While the incidence of thrombophlebitis among all women in the childbearing age is not known with certainty, it is estimated from studies in the literature that from one to three women per thousand in this age group develop thrombophlebitis each year. Consequently, it is not surprising that thrombophlebitis is found in women taking oral contraceptive pills, just as this disease is found among the nonusers. It is not surprising that doctors report the occurrence of thrombophlebitis in women on the pill when one remembers that 5 million women are taking such pills and that the rate of this disease each year is from 1 to 3 per 1,000 women. Vital Statistics in the United States show that female deaths from thrombophlebitis have increased in the United States during the 1950–64 period but so, also, has the rate increased for the male in similar fashion.

Much the same can be said for the arterial thromboembolic diseases, such as cerebrovascular accidents. Here, the death rate for females in the United States from this cause has not significantly changed in the 1950-64 period. And it should be noted that death from stroke in the female of childbearing age is not an uncommon form of death. For instance in 1960-well before the oral contraceptives came into common use-stroke as a cause of death ranked fourth to sixth place among white females from age 25 to 39 and as first and second cause of death in nonwhite females of the same age group.

The Food and Drug Administration is continuing to evaluate the hazardsboth real and theoretical-and is interested in the continuing of research in this matter.

Many thousands of patients on these drugs have been studied in detail in birth control clinics and elsewhere and thousands continue to be studied under experimental conditions. The Agency's NDA files are filled with these reports. The funds expended in such research are very substantial. The i DA has studied and continues to study the medical literature, scientific reports, and adverse experiences which are funneled into the Pureau of Medicine. It has studied the report of the Wright committee, which it convened in 1963, and it has placed the matter of oral contraceptives before an Advisory Committee on Obstetrics and Gynecology which it convened in late 1965. It has noted the recent findings of the United Kingdom Committee on Drug Safety. In early 1965, when the United Kingdom Committee on Drug Safety began to study the matter of thromboembolic phenomena, the Medical Director of FDA assembled a group of experts from the National Institutes of Health, the President's Office of Science and Technology, the American Medical Association, industry, and the Bureau of Medicine of FDA to consider the possible relationship of the oral contraceptive drugs and cerebral vascular accidents. The report of this meeting was forwarded through channels to the Secretary of Health, Education, and Welfare.

The Food and Drug Administration is also sponsoring studies to evaluate the hazards of oral contraceptive drugs. The Subcommittee on Thromboembolism of the FDA Advisory Committee on Obstetrics and Gynecology presently is assisting the Medical Director with an initial pilot study of retrospective type for thromboembolic phenomena which should lead to a large retrospective study, and possibly to prospective studies, throughout the United States.

Consequently, the FDA is active in this field. While it realizes the need for continuing evaluation of the subject of oral contraceptive drugs, it concludes that the use of these products presently on the market is relatively safe when balanced off against the usefulness of these products.

The FDA continues to support the need for further studies on the oral contraceptives and indeed states that these drugs compare with the antibiotics and adrenocorticosteroids on the number of experimental studies which have already been carried out.

The FDA also realizes that there always will be differences of opinion among physicians in the use of any drug and promotes such scientific controversy on