Problems in the U.S.

Last October 26, a United States Food and Drug Administration (FDA) panel recommended that Depo-Provera, which is approved in the U.S. only for use as a cancer palliative, should continue to he denied approval for contraceptive use. The recommendation came after a three year review of data on Depo-Provera by the FDA Public Board of Inquiry, which described most of the Upjohn-sponsored studies required for approval of the drug as "uncoordinated" and "haphazard," and said that the data offered no clue as to the drug's long-term effects. The board's major concern was with unanswered questions regarding cancer and cardio-vascular complications-questions that remain despite the fact that Upjohn has been "testing" the drug for over 25 years.

Effects and side effects

Depo-Provera is believed to work in several ways. It inhibits ovulation by suppressing production of certain hormones by the pituitary gland. In addition, it thickens the cervical mucous and causes thinning of the endometrial lining, both of which further reduce chances of an egg's fertilization and implantation.

Although it is hailed for its effectiveness as a contraceptive, the drug has been associated in animal tests with cancer, and in human use with a host of negative side effects. The FDA board found that the drug "does not appear to pose any immediate irreversible serious side effects," although it was concerned about the lack of data on how long the effects could last.

Other groups, like the National Women's Health Network, a non-profit advocacy organization in Washington, are more concerned about Depo-Provera's side effects. The Network's work has focused on women in the U.S. who have been prescribed Depo-Provera as a contraceptive through a loophole in the FDA drug approval process (see Contraceptive Us of Depo-Provera in the U.S.). In 1979 the organization established a registry and encouraged women who had used Depo-Provera to supply information on their experience with the drug. Although not a scientific study (women who had problems were more likely to respond), the registry has indicated a number of problems. Women reported sterility, irregular bleeding, decreased libido, depression, high blood pressure, excessive weight gain, breast tenderness, vaginal infections, hair loss, stomach pains, blurred vision, joint pain, growth of facial hair, acne, cramps, diarrhea, skin rash, tiredness, and swelling of limbs.

"As many women lose weight on DepoProvera as gain it," testified one independent witness, Gena Corea, before the FDA board. "To thin, undernourished women in the Third World, weight loss can be an extremely serious health threat. And it's doubtful that a male contraceptive that entailed such a side effect as loss of libido would be acceptable to men."

In animal testing of Depo-Provera, the effects have been even more serious; required testing found breast tumors in beagle dogs and endometrial cancer in monkeys. Upjoin dismissed these test results, claiming that animal test findings are not good predictors of effects in humans. Former FDA Commissioner Donald Kennedy disagreed, however. "Humans share most basic biological mechanisms with other animals," he said, "and ... among these mechanisms is that responsible for susceptibility to cancer. With the possible exceptions of arsenic and benzene, all known human carcinogens cause cancer in lab animals." Kennedy also disputed claims that animal testing induces cancer through excess use of drugs, pointing out that in such animal experiments most compounds do not turn out to be carcinogenic. In addition, as an Ad-Hoc Committee on Evaluation of Environmental Carcinogens reported to the Surgeon General in 1970, "Any substance which is shown to conclusively cause tumors in animals should be considered carcinogenic and therefore a potential cancer hazard for man."

Background: The U.S. drug approval process

The federal Food, Drug and Cosmetic Act of 1938 requires that a drug be tested and proven safe before it can be marketed. A 1963 amendment to the law specifies that the drug must also be proven effective. Congress later required refinement of the testing procedure for drugs, which currently consists of a series of animal and human testing.

Before testing of a drug on humans can begin, rodent tests have to be conducted to ensure that the drug will not pose an unreasonable risk to humans. After this, a "Notice of Claimed Investigational Exemption for a New Drug" is filed with the FDA. In this Investigational New Drug (IND) application, the applicant company must submit the results of the preliminary animal studies as well as a comprehensive outline of plans for human clinical trials.

The first phase of human testing involves from 20 to 80 paid volunteers, and is aimed at determining safe dose ranges. In the second phase, up to 200 subjects may participate, and at this stage, efficacy and safety are closely monitored. For the entire experimental period on humans, subjects must be given informed consent forms that describe what is known about the drug based on the most current findings in human and animal testing.

Simultaneously with the second phase of the clinical trials, long term animal studies are begun. The animal studies are conducted either in-house or at commercial laboratories under contract with the applicant company. Testing guidelines passed in 1967 stipulate that for all new steroid contraceptive drugs, seven-year studies in beagles and ten-year studies in monkeys must be conducted.

In the third and final phase of human testing before approval, the company offers contracts to doctors to participate in safety and efficacy tests of the drug. From these tests, knowledge about long and short term side effects is refined and the most effective dosage is determined. Once the clinical and animal data are complete, the company files a New Drug Application (NDA). Then, based on these studies and the experience with patients, the FDA decides whether or not-and for whom and for what indications-the drug should be marketed.

The Depo-Provera Experience

The history of the development of DepoProvera is intertwined with this evolving drug approval process in the U.S. In the mid- 1950s an Upjohn scientist was experimenting with various compounds of the hormone progesterone, and synthesized depot medroxyprogesterone acetate, later brand named Depo-Provera.

The Upjohn Company originally applied for, and in 1960 received, FDA approval of the drug for treatment of endometriosis and threatened or habitual miscarriage. The serendipitous discovery, during testing in Brazil, of the drug's long-term contraceptive effects led Upjohn to begin the long application and experimentation process required by the FDA for approval of a drug for contraceptive use.

In 1963, after Upjohn submitted the requisite rodent studies, along with plans for further animal and clinical trials, DepoProvera was granted Investigative New Drug status. Meanwhile, the drug was already being prescribed as a contraceptive in Jamaica and Los Angeles, California.

Two years later Upjohn initiated field studies in seventy foreign countries, and in 1967 the company contracted with Grady Memorial Family Planning Clinic in Atlanta, Georgia to conduct a large-scale clinical trial of 1,000 women. At the same time, Upjohn submitted a New Drug Application for approval of Depo-Provera for contraceptive use-although based on new application guidelines which passed in 1967, it's unclear how the application could be considered before the results of the animal studies were in. The monkey and beagle studies were begun in 1968, a year after the large-scale human study at Grady was initiated.

While testing of the drug as a contraceptive continued, in 1970 the FDA revoked approval of Depo-Provera as a treatment for endometriosis and miscarriage, due to lack of substantial evidence of effectiveness for treating those indications. In the case of miscarriages, according to FDA findings, approval was also revoked on the grounds of a "possible association between pre-natal hormonal treatment in mothers and congenital heart defects in offspring."

In 1972, Depo-Provera was approved as a palliative for endometrial cancer. But by 1973, progress reports in the beagles study required for a contraceptive approval revealed higher than normal rates of breast tumors, prompting a debate in the scientific community over whether beagle dogs are overly sensitive to artificial progesterones. As a result of the beagle finding Promone, a veterinary drug containing medroxyprogesterone acetate, was removed from the market by Upjohn. ("They stopped giving it to dogs," says Sybil Shainwald, a lawyer with the National Women's Health Network, "but they kept giving it to women. ")

In February 1973, an OB-GYN Expert Advisory Committee to the FDA recommended limited approval of Depo-Provera as a contraceptive-only with patient consent and information for patients describing the drug's hazards. Then in September 1974, the FDA announced in the Federal Register its intention to approve use of Depo-Provera as a contraceptive. The Health Research Group, a Washington based non-profit consumer organization, quickly contacted the FDA to protest the approval, and U.S. Representative L.H. Fountain, then chair of the House Intergovernmental Relations Subcommittee, objected in a memo to then Secretary of Health, Education and Welfare Caspar Weinberger. Shortly afterwards. Fountain's subcommittee held hearings which revealed that the OB-GYN Expert Advisory Committee had based its recommendation on Upjohn's interpretation of Depo-Provera data and testimony from population control groups, without even considering the FDA's own staff analysis, which disagreed with the comp-'s. The FDA did not approve the application that year.

In 1975, the OB-GYN committee again recommended limited approval, but the FDA did not act on the recommendation. Instead, in 1977 it asked Upjohn to withdraw its application. In early 1978 after Upjohn refused, then-FDA Commissioner Donald Kennedy denied Upjohn's application for contraceptive use of Depo-Provera, citing the following reasons:

• the beagle studies showed an increased rate of breast cancer
• fetal exposure could mean increased chance of birth defects
• if estrogen supplements were given to counter menstrual irregularities, Depo-Provera would lose its advantage as a progesterone-only compound
• a significant patient population needing the drug had not been demonstrated

In denying approval of Depo-Provera for contraceptive use, Kennedy gave Upjohn an avenue of appeal: the company could either plead its case before an administrative law judge - the traditional appeal route - or before a three-physician Board of Inquiry, a new option which had never been used by the FDA. Upjohn chose the board.

The Board of Inquiry heard testimony for five days in January 1983, and announced its decision in October 1984, recommending that Devo-Provera continue to be denied approval for contraceptive use in the U.S. It is now up to FDA Commissioner Frank Young to make a final decision

See the Findings of Fact by the FDA Board of Inquiry.

Who are the "experts"? The Obstetrics-Gynecology Expert Advisory Committee to the FDA has recommended twice that the FDA approve Depo-Provera for use as a contraceptive by a limited U.S. population. Established in the late 1960s, the committee's purpose is to offer outside expertise to the FDA on difficult public policy questions. But it's informative to note how the "experts" on this committee are chosen. For instance, one criterion for determining an individual's expertise is published articles in the field. The articles, however, are often based on studies of drugs financed by the drug companies themselves. In addition, although members of the OB-GYN committee rotate (thus, as DepoProvera proponents point out, the committee which recommended approval of the drug the second time wasn't made up of the same members who had previously recommended approval), new committee members are often recommended by old members, so the same ideological slant is likely to be perpetuated. And population control is a highly politicized field. "When it comes to contraception and abortion," says one FDA medical officer, "people refuse to be scientific and objective." As a past director of the FDA's Bureau of Drugs, Dr. J. Krout, said several years ago, "Most of the members of that [OB-GYN] committee are in the population control business."

Consequences of Depo-Provera approval in the U.S. If the FDA commissioner approves of contraceptive use of DepoProvera in the U.S., it will have the effect around the world of once and for all "legitimizing" the drug. In addition, as Judith Weisz, the chair of the FDA Board of Inquiry has pointed out, approval of the drug would have other implications that go beyond the drug itself. "If science is going to contribute to solutions of problems, it has to be the best possible science," she says. "This drug cannot be approved on the basis of scientific evidence. I will regret if it is said to be approved on that basis, because that would simply be a disservice to science and the use of science in the drug regulatory process. I believe in a woman's right to control her own destiny, but contraception deserves honest and thorough treatment; it cannot be an excuse for bad science." Finally, if Depo-Provera is approved, any glossing over of its potential risks will spill over into new areas of contraceptives research and approval. For instance, the drug industry is now testing a new injectable contraceptive, norithindrone enanthate (Net-en) and another contraceptive, "Norplant," a hormonal capsule implanted under the skin of a woman's arm to prevent conception for five years. Norplant, which is manufactured only by Leiras Pharmaceuticals of Finland, is currently being tested in 19 countries, and approval is expected in at least 40 countries in the next two years. The concern with Norplant, as with DepoProvera, is that progesterone-only contraceptives haven't been adequately tested in humans.