The Chill in Birth Control Research

Pharmaceutical manufacturers usually wait with bated breath for that happy day when the mysterious and demanding U.S. Food and Drug Administration tells the company: Go ahead. You are free to market your product.

That was hardly the case on Aug. 15, 1996, when the agency told Wyeth-Ayerst Laboratories in Philadelphia that its latest contraceptive device--a second-generation version of the implantable contraceptive Norplant--was deemed safe and effective.

Instead of cranking up the fax to spew out celebratory news releases and alerting its production line, Wyeth took its new product--still unnamed--and shelved it.

Eighteen months later, a Wyeth spokeswoman says researchers are fiddling with the product’s design, even though the FDA didn’t ask for any design changes. But she also admits something else.

The company simply hasn’t decided if it can risk marketing a new contraceptive in the United States.

“We’re evaluating whether to introduce it into the U.S. market,” says Audrey Ashby, a spokeswoman for Wyeth, a division of American Home Products Corp. “Frankly, we have to assess the environment of the U.S. market--including litigation. We’re looking at what has happened.”

The situation Ashby refers to is the legal tempest over the original Norplant, which was introduced in 1990. Hundreds of lawsuits alleging problems with Norplant have led to the near death of the once heralded device, which was the first totally new contraceptive introduced in this country in 20 years.

But the story of Norplant is about more than just one controversial product. It’s symptomatic of a field in trouble. Despite four decades of intense effort in contraceptive research, most products carry too many side effects or often fail. Yet, instead of pursuing something better, pharmaceutical companies increasingly see contraceptives research as too risky--medically and legally.

Part of the risk rests on the fact that some side effects are inevitable among a population of young, healthy women who are using a contraceptive voluntarily and for a long period of time. When problems do occur among this group, they tend to stand out and attract more sympathy from juries, experts say.

But manufacturers also fear the “Norplant syndrome”--the mass filings of product liability lawsuits that, they say, greatly distort or exaggerate problems.

The number of U.S. manufacturers carrying out contraceptives research has plunged from several dozen in the 1960s to just two today. Many companies are nervous about pursuing any product development aimed at young women, says Phyllis Greenberger of the Society for the Advancement of Women’s Health Research.

“We see liability as a major impediment to women’s health research,” says Greenberger, executive director of the Washington, D.C.-based organization, which was created in 1990 to press for more medical studies involving women. “We are trying to get companies interested in doing women’s health research, and often when they do they get attacked.”

Breast implants, intrauterine devices, oral contraceptives, a medication (Bendectin) to treat morning sickness in pregnancy and Norplant have been the targets of widespread lawsuits. More recently, the diet-drug combination known as fen-phen--which was used primarily by women--is the focus of several class-action lawsuits.

To be sure, products for women in their childbearing years carry inherent risks, says Greenberger.

“In the real world, there will always be risks,” she says. “And this is a large population who is young and healthy, who has a choice to use these products, and then uses the products for a long period of time--all conditions that increase the risk of potential problems emerging.”

There is also good reason for women to be fearful, or at least skeptical, of contraceptives. Most contraceptives have at least some side effects. Oral contraceptives, for example, should not be used by women who smoke because of increased risk of cardiovascular problems. One particular IUD popular in the 1970s, the Dalkon Shield, was flawed and harmful.

In the ‘90s, it is Norplant that has been the object of similar concerns. In some cases, the surgical insertion and removal of Norplant has been botched by health professionals who didn’t bother to become trained in the technique.

Norplant also causes myriad side effects--although none of them are considered serious enough to keep it off the market. These include changes in menstrual bleeding for a year or two in 60% of users, headaches in about 16%, and breast tenderness in about 6%. In clinical trials, about 6% of women experienced scarring after the implant’s removal.

Finally, critics say that many patients were not appropriately counseled about the risks associated with Norplant.

Attorney Arthur Sherman of Beverly Hills, who represents a large group of plaintiffs suing over Norplant, puts it this way: “There is a real question as to whether this product is a good one.”

But other products for women, besides contraceptives, have drawn lawsuits as well. These include silicone breast implants and Bendectin--neither of which has been conclusively shown in medical studies to be unsafe.

Contraceptives, however, seem to be viewed by pharmaceutical manufacturers as especially risky. And, Greenberger says, all of these cases--including Norplant--have been magnets for excessive litigation in which the potential dangers of the devices have been fabricated or dramatically blown out of proportion by trial attorneys looking for big monetary settlements. She points out that Norplant is still used by 1 million U.S. women (2.5 million worldwide).

The rush to sue, she says, has long-term consequences for women’s health.

“The situation is bad enough that we have lost a few products. But what we really fear is the chilling effect on other companies. If you’re looking at spending $600 million [research and development] on something, you’re not going to invest that kind of money unless you think you’re going to get a return,” Greenberger says. “These decisions [on product liability] need to be based on science. There needs to be a faster and fairer resolution to these problems.”

Americans do need more contraceptive choices, according to virtually every opinion poll conducted in recent years. But the future of new contraceptives is resting on several shaky factors, including the success of a fledgling coalition formed to encourage contraceptives research. Others are advocating for the reform of tort laws that might limit the kinds of sweeping awards plaintiffs are now seeking in the Norplant and breast implant cases.

In the short term, the outcome of the Norplant lawsuits may serve as a bellwether.

“Essentially, Norplant provides a case study that offers important insights into why contraceptive research in this country is now plummeting,” said a Wyeth executive, Carrie Smith Cox, in a 1995 speech to health professionals.

Enthusiasm, Then Trouble

In the beginning, Norplant had lots of appeal.

There were hopes that a new choice might help reduce the embarrassingly high rate of unintended pregnancy in the United States (about 60% of all births) and the teenage pregnancy rate (four out of every 10 teenage girls becomes pregnant).

Moreover, Norplant was developed by the nonprofit Population Council, an international organization focusing on voluntary family planning and expanding contraceptive choices. The product was tested for 20 years, in studies involving about 50,000 insertions, and was already highly popular in other countries before being introduced here.

Medically, it looked good. The FDA had not found--and still has not found--flaws that would make the product unmarketable. Norplant consists of six matchstick-size silicone rods containing the hormone levonorgestrel. After being inserted in the underside of the upper arm in a 10-minute surgical procedure, the device provides a 99% guarantee against pregnancy. It lasts five years, is reversible and requires no daily attention.

Initially, about 800 insertions were being done a day in the United States. Soon, however, the troubles began.

Wyeth was sensitive to criticism about Norplant’s high up-front cost--about $500. But the company pointed out that, over lifetime use, the cost is about average among contraceptives options. There were charges that young or poor women might be coerced by the courts into getting the device, even though no such cases have been documented. But the coup de grace was the lawsuits.

When silicone gel breast implants were removed from the market in 1992, Norplant became guilty by association, according to some women’s health advocates. Its rods were made of silicone, although not silicone gel. Moreover, some women had begun to complain that the insertion and removal of the device had caused scarring. Still others were upset with the side effects, including excessive menstrual bleeding, headaches and weight gain.

At Wyeth and the Population Council, there was surprise and dismay. Wyeth says it made extensive efforts to train health professionals in the proper insertion and removal of Norplant. (Today, about 20,000 people have been trained.) As for the side effects, they were spelled out in patient literature, and patients were to have been thoroughly counseled before receiving Norplant.

Nevertheless, consumer anxieties over Norplant soared because of the fears about silicone, the risk of side effects and the possibility of scarring. Sales fell to fewer than 60 a day by 1995.

Plaintiffs’ attorneys, however, say the lawsuits over Norplant are centered on the lack of information given to patients.

“This is a warnings case. We have experts who believe the warnings that were given to women were inappropriate,” says Sherman, the Beverly Hills lawyer and a member of the plaintiff’s steering committee. “You are dealing with a group of people who must be warned properly to understand.”

The intent is not to undermine contraceptives research, he says, adding that women should have received more explicit verbal counseling about Norplant’s risks.

“This isn’t a political thing. We’re not an organization based on a philosophical view. We just think the warnings were inappropriate.”

The Norplant lawsuits now number about 200, representing about 50,000 women. A mistrial was declared last month in the first suit to reach the courts.

“We were sort of disappointed it was declared a mistrial, because it prolongs the agony,” says Population Council spokeswoman Sandra Waldman. “The longer this drags on, the more this method is up in the air.”

Still, says Dr. Anita Nelson, director of the Women’s Health Care Clinic at Harbor-UCLA Medical Center: “Very few private practitioners are offering Norplant even though we don’t have any other reversible method that is as effective.”

As for the second-generation, smaller Norplant, many family planning experts don’t have much hope of ever seeing it.

“It’s equally effective, and it’s even better because it’s easier to insert and remove,” Nelson says. “But if there is a litigation risk, those of us in clinical situations are more apt to offer something else.”

Companies Call It Quits

Winning the lawsuits probably won’t keep pharmaceutical companies interested in research, observers suggest. Although the birth control pill is one of the most popular, effective and safe contraceptives available today and has been highly profitable for its manufacturers, many of the drug companies that made the pill have fled the field of contraceptives research, says Roderick Mackenzie, a veteran developer of contraceptives. There were pervasive fears, and accusations, in the early years of the pill that it caused stroke and other vascular problems.

“In the 1970s, anyone in the oral contraceptive business was on the wrong end of adverse publicity,” he says. “It was, quite literally, a lawsuit a day in the 1970s. And even when the lawsuits were won--I think only about 12 lawsuits on oral contraceptives have been lost and thousands have been defended--manufacturers didn’t like their reputation dragged through the mud. It made companies fear litigation. And, now that we’re in the era of class-action lawsuits, the risk is even harder to take.”

Although a dozen major American companies were pursuing contraceptives research in the 1970s, only Wyeth and Ortho Pharmaceuticals and two European companies are among large manufacturers actively involved in innovative research today, according to the Population Council.

Academic centers and nonprofit groups like the Population Council continue to study new methods, but funding is hard to come by, and there is a startling lack of partners among the U.S. pharmaceutical industry willing to bring new products to market.

For example, the National Institute of Child Health and Human Development, has identified some promising agents for use in a spermicide-microbicide, a chemical substance that would kill both sperm and microbes that cause some sexually transmitted diseases, such as HIV. But, so far, only one industrial partner has taken up the research.

“For the most part, the large drug companies have not picked up on the development of microbicide-spermicides,” says Dr. Robert Spiertas, chief of the institute’s contraception and reproductive health branch. “Most of the work is being funded by government or small venture capitalists. It’s theoretically possible that a smaller organization could bring a project through FDA trials. But, as for marketing [a new product], it would be very difficult for a small group to do that.”

Meanwhile, an Arlington, Va., research organization called CONRAD (Contraceptive Research and Development) is pursuing a new barrier method but twice has had companies that supply materials drop out of the project.

At the Population Council, an agreement was reached with a small Florida firm, Sano, that manufactures transdermal patches to pursue work on a contraceptive skin patch. And the council has turned to two German companies to test other products. But the search for partners is consistently difficult, Waldman says.

“We can only go so far, then we need partners to continue the product development; to do the Phase 3 clinical trials, to file the new drug application. But it has to be a good business decision for them.”

One attempt to lure manufacturers back to contraceptives development centers on a project called the Consortium for Industrial Collaboration in Contraceptives Research. Founded in 1995, the consortium solicits money from philanthropic groups like the Rockefeller and Mellon foundations and turns the grants over to nonprofit and academic researchers. Pharmaceutical firms are then encouraged to identify projects they are interested in, match the grants, supply materials and eventually take over product development.

“The women of America desperately want new contraceptive choices,” Mackenzie says. “They are not happy with what’s available.”

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Unintended Consequences

The rate of unintended pregnancies in the United States has ranked among the highest of developed countries, as these statistics from 1987 and 1988 illustrate. Nevertheless, contraceptives research has slowed to a crawl because pharmaceutical manufacturers fear they will face lawsuits once their products reach the market. A case in point: Sales of the implantable device Norplant fell from a high of 800 units per day in 1992 to fewer than 60 per day by 1995 because of negative publicity generated by lawsuits.

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% of unintended % of unintended pregnancies in which % of pregnancies pregnancies nonsurgical that were ending in contraception, other than Age unintended abortion rhythm method, was used 15-19 81.7% 51.0% 13.6% 20-24 60.6% 51.0% 24.5% 25-29 45.2% 47.3% 25.3% 30-34 42.1% 50.1% 18.8% 35-39 55.9% 55.1% 11.2% 40-44 76.9% 59.3% 6.6%

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Sources: National Center for Health Statistics; American Journal of Obstetrics and Gynecology