Pubdate: Fri, 17 Jul 1998 Source: San Jose Mercury News (CA) Section: Page 1 Contact: Website: http://www.sjmercury.com/ Author: Sheryl Gay Stolberg, New York Times THALIDOMIDE GETS STRICT FDA APPROVAL Risky drug offers promise for variety of ills WASHINGTON -- Thalidomide, a sedative whose use produced thousands of babies with flipperlike limbs and other deformities, was approved for use in the United States for the first time Thursday, nearly four decades after it was stripped from pharmacy shelves around the globe. The decision by the Food and Drug Administration marked a major reversal for the agency, which rejected thalidomide in 1960 as it was being promoted worldwide as a harmless cure for morning sickness. That initial rejection spared countless American infants and sealed the FDA's reputation as the finest consumer-safety authority in the world. Today, thalidomide is showing promise for treating maladies as diverse as AIDS, blindness, cancer and autoimmune disease. Technically, the FDA has approved it to treat a complication of leprosy, but the majority of prescriptions are expected to be written for ``off-label'' uses, particularly the severe mouth ulcers and wasting that occur in the late stages of AIDS. ``This is monumental,'' said Dr. Norman Fost, professor of pediatrics at the University of Wisconsin who has been a close observer of the thalidomide controversy. ``It is one of the most interesting and important drugs that the FDA has ever and will ever be asked to approve.'' The FDA first announced its intention to approve thalidomide in September. But it took 10 months for the government -- working with drug manufacturer Celgene Corp. of Warren, N.J. -- to iron out a complex distribution plan that is intended to prevent birth defects. The resulting system will make thalidomide the most strictly regulated medicine in the nation's history. Pharmacists will be required to register with Celgene to dispense the drug, and doctors must register to prescribe it. Patients must fill out detailed surveys that will be submitted to a team of Boston University researchers, who will track the use of thalidomide. Women of childbearing age who want to take thalidomide will be required to use two forms of birth control. They will undergo weekly pregnancy tests in the first month, during which time prescriptions will be filled for seven days at a time. In subsequent months, pregnancy tests will be conducted and prescriptions filled every 30 days. ``This is more rigorous than anything I am aware of in the world,'' said Dr. Allen Mitchell, director of the Slone Epidemiology Unit at the Boston University School of Public Health, which will run the thalidomide-monitoring system. For Celgene, a tiny biotechnology company that has never before brought a drug to market, the FDA's approval was the culmination of five years of work. Bruce Williams, the company's director of marketing, said the drug could reach pharmacy shelves in four to six weeks. The drug will not be cheap; Williams estimated it would cost patients an average of $12 a day, but said it would probably be used for only several months at a time. ``We are somewhat sobered by the fact that now, all the responsibility that we know we are taking on is real,'' Williams said. ``Even with that, this feels great. It's been a long haul.'' But for the original victims of thalidomide, Thursday's approval was no cause for celebration. Of the estimated 12,000 thalidomide babies, about 5,000 survive. ``We're somber,'' said Randy Warren, the founder of the Thalidomide Victims Association of Canada. Warren, 36, was born with deformed hands and stumps for legs after his mother took just two teaspoons of the drug early in her pregnancy. ``We remember all the people that were lost.'' Warren's group helped design the safety rules, reasoning that FDA-regulated thalidomide was preferable to no oversight. ``We hope that history won't repeat itself, but it will,'' he said with a sigh. In designing the plan to prevent birth defects, FDA officials had to strike a delicate balance that would weigh safety against the prospect that severe restrictions would drive the drug underground. It was the black-market trade in thalidomide, which was being imported from Brazil and sold over the Internet several years ago, that prompted the FDA to consider approving the drug in the first place. ``We need to strike a balance between regulation and overregulation,'' said Dr. Debra Birnkrant, deputy director of the FDA's Division of Antiviral Products. ``We do this feeling comfortable that we have a strong safety-monitoring program and that the data support the safety and efficacy of this product.'' The issue of whether, or if, more deformed babies will be born has been a contentious one. While both Celgene and FDA officials say they believe they can achieve their goal of no new birth defects, others, including Warren and Fost, are skeptical. ``It is certainly not achievable,'' Fost said. ``There is nothing in the world that has zero risk. Not water, not air, not cars, not anything. The question is what are reasonable measures to come as close to that goal as possible.'' Should birth defects -- the agency calls them ``adverse events'' -- occur, Birnkrant said, the FDA and Celgene would investigate. If it turns out that a doctor or pharmacist is refusing to comply with the rules of the distribution system, privileges to prescribe or dispense the drug might be revoked. Most experts expect doctors to react cautiously to the drug's approval, in part because they fear lawsuits and in part because of the cumbersome bureaucracy that goes along with prescribing it. Celgene's Williams predicted that fewer than 10,000 patients would use thalidomide in its first year on the market. Originally manufactured by a German company, thalidomide was banned from drugstores in 1962 but never disappeared from use. In the mid-1960s, an Israeli doctor gave it to leprosy patients who had trouble sleeping. To his surprise, their skin lesions cleared up almost overnight. By 1975, the U.S. Public Health Service had set up a special ``compassionate use'' program to distribute thalidomide to patients with erythema nodosum leprosum, or ENL, a complication of leprosy that causes skin lesions, fever and other symptoms. By the late 1980s, Brazil and Mexico had approved thalidomide for sale. Then, in 1991, Gilla Kaplan, a scientist at Rockefeller University, discovered that thalidomide helps regulate the immune response by suppressing a crucial protein called tumor necrosis factor alpha. She teamed up with Celgene, whose scientists began investigating the drug's use for AIDS. Other companies began investigating thalidomide for other ailments, including brain cancer and macular degeneration, which causes blindness. Three years ago, after reports that drug buyers' clubs in New York and San Francisco had been purchasing thalidomide illegally in Brazil and distributing it to AIDS patients, the FDA issued invitations to Celgene and the other companies to submit applications to market thalidomide. - --- Checked-by: Melodi Cornett