- Typical Immunomodulator
Thalidomide summons horrific images of deformed babies. Yet the drug is back in clinical use, helping to treat various diseases. What had been feared for its teratogenic effects is now life-saving. This remarkable transformation of thalidomide from notoriety to respectability testifies to the success of the stronger drug regulations in the U.S. that the tragedy of thalidomide babies engendered.
According to "Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation," by Philip J. Hilts (New York: Alfred A. Knopf, 2003), the German drugmaker Chemie Grünenthal introduced thalidomide--under the brand name Contergan--to the German market on Oct. 1, 1957, as a sedative to treat insomnia as well as to reduce nausea associated with pregnancy. By 1960, the drug was in more than 20 countries in Europe and Africa. On Nov. 18, 1961, the German paper Welt am Sonntag reported on a study finding that pregnant women who had been taking thalidomide were giving birth to babies with gross deformities. "By November 27, Grünenthal had pulled the drug off the market, blaming the sensationalism of the press," Hilts writes.
Thousands of thalidomide babies were born in Europe. Thousands more might have been born in the U.S. were it not for a reviewing medical officer at the Food & Drug Administration named Frances Oldham Kelsey. When she joined FDA in 1960, her first assignment was thalidomide. Her dogged insistence on safety data derailed the drug's approval in the U.S.
On Sept. 12, 1960, Richardson-Merrell Inc. submitted a New Drug Application to market thalidomide in the U.S. under the brand name Kevadon. According to various accounts, the company was aggressively seeking to have the drug approved by early 1961.
Kelsey found the data for the application "extremely inadequate," FDA historian John P. Swann says. At the time, the prevailing law was the 1938 Federal Food, Drug & Cosmetic Act, which required proof of safety to be submitted to FDA before a drug could be approved for marketing. "The application did not establish the drug's safety, so it could not be approved," Swann says.
On the basis of the 1938 law, Kelsey insisted that Richardson-Merrell conduct further studies to establish the drug's safety, Swann says. "It's fascinating to see how many letters and communications went back and forth. She was asking for additional data, and what they were sending was in her eyes insufficient to answer the questions she was raising. She was increasingly pressured by the sponsor to get the drug approved. She didn't back down." On March 8, 1962, Richardson-Merrell withdrew its drug application, after the effects were widely publicized.
BY CURRENT standards, the drug evaluation and regulatory laws in place in the late 1950s were appallingly inadequate. In many European countries, for example, "they were insufficient to control the easy distribution of a product like thalidomide," Swann says.
The U.S. was still operating under the 1938 act, which did not require demonstration of efficacy for a drug to be approved. The law also allowed "experimental" use of drugs while approval was being sought, which, at the time, meant that a drug could be distributed--widely--before it was approved. In Congress, however, questions were beginning to be raised about the practices of the drug industry and the effectiveness of FDA's drug review process.
By the early 1960s, "the drug approval process was under considerable criticism, particularly the quality of the scientific data submitted in New Drug Applications and the lack of an efficacy requirement," according to Kelsey, writing in the 1996 annual report of FDA's Office of Compliance. "The nature and magnitude of the thalidomide disaster," she wrote, spurred the swift passage of legislation addressing the shortcomings of the 1938 law that had been sitting in Congress before the disaster. Known as Kefauver-Harris Drug Amendments, they were signed into law by President John F. Kennedy in October 1962.
FDA thus acquired the power to require proof of both safety and efficacy in New Drug Applications. According to the FDA document "Time Line: Chronology of Drug Regulation in the United States," the 1962 law for the first time required drug manufacturers to prove to FDA the effectiveness of their products before marketing them. The law gave the agency closer control over investigational drug studies and granted FDA inspectors access to additional company records. It also required manufacturers to demonstrate the efficacy of products approved prior to 1962.
The thalidomide disaster also focused attention on the distribution of investigational drugs, Swann says. It turns out that Richardson-Merrell had given thalidomide to thousands of patients, including some hundred pregnant women, under the 1938 law's experimental-use provision, he explains. In light of how widely Richardson-Merrell disseminated an unapproved drug, regulations were promulgated for closer oversight of investigational drugs, including the requirement of informed consent from patients being treated with investigational drugs.
By stubbornly insisting on applying the safety provisions of the 1938 law, Kelsey thwarted the introduction of thalidomide to the U.S. market; as a result, the thalidomide tragedy in the U.S. was of a far smaller magnitude than that in Europe. For that achievement, Kelsey received from President Kennedy in August 1962 the President's Award for Distinguished Federal Civilian Service.
Because of thalidomide, new drug candidates now are tested for the ability to cause birth defects. In general, drug candidates showing such activity in animal models are dropped like hot potatoes. Now, however, thalidomide is showing how compounds with extremely dangerous side effects still can be used therapeutically with the appropriate controls and precautions.
It turns out that thalidomide has potent anti-inflammatory effects that can ease erythema nodosum leprosum, a painful inflammatory condition associated with Hansen's disease, also known as leprosy. In July 1998, FDA approved the application of Celgene to market thalidomide--under the brand name Thalomid--for treatment of that condition. Because of the drug's well-known teratogenicity, FDA also imposed severe restrictions on the drug's distribution.
|FDA HISTORY OFFICE|
SAFETY'S CHAMPION In the 1960s, Kelsey prevented the marketing of thalidomide in the U.S. through her insistence on credible proof of its safety.
AT PRESENT, only doctors registered with Celgene's STEPS (System for Thalidomide Education & Prescribing Safety) program can prescribe the drug. Prescriptions are not to be given to female patients without a negative pregnancy test within 24 hours of treatment start; those patients must take pregnancy tests regularly for a prescribed period and must use two reliable forms of contraception while under treatment. Male patients are admonished to use condoms during intercourse because it is unknown whether thalidomide in sperm or semen affects fetal development.
In addition to being anti-inflammatory, thalidomide also is a potent antiangiogenic and immunomodulatory agent and has been shown to be effective against previously untreatable cancers. Celgene is seeking approval for its use against multiple myeloma.
Because of its effectiveness against certain cancers, thalidomide is a pot of gold for Celgene. According to the company's fourth-quarter and full-year 2004 report, Thalomid sales in 2004 were $308.6 million, or almost 82% of Celgene's 2004 revenues of $377.5 million. According to an August 2004 analysis by Merrill Lynch, more than "90% of Thalomid sales are for off-label use in the treatment of multiple myeloma and other hematological (blood) cancers and solid tumors."
Use of thalidomide in cancer therapy has allowed Celgene to raise the price of Thalomid by almost 400%--from $6.00 to $29 per 50-mg capsule--between 1998 and 2004, according to a Nov. 15, 2004, story in the Wall Street Journal. The story points out that a 100-mg capsule can be had for 7 cents in Brazil and for $2.60 in the Netherlands. The story suggests that, used as a cancer drug, thalidomide has room for further growth in price but that patients and doctors alike are beginning to complain.?
As of April 2005, mail-order quotes for 50-mg Thalomid ranged from $21 to $38 per capsule in the U.S. With alternative sources of the drug, prices would not be so out of control.
One company that is hoping to offer competition is Andrulis Pharmaceuticals, Beltsville, Md. According to its president, Peter J. Andrulis Jr., the company supplied thalidomide to the Hansen's Disease Center, Carville, La., in the 1970s when the center was investigating the drug to treat erythema nodosum leprosum. In the 1990s, the company supported Phase II clinical trials of thalidomide against aphthous ulcers that are common in patients with AIDS. In addition, the company has been issued patents for use of thalidomide against neurological diseases and various cancers.
Yet Andrulis Pharmaceuticals has not gotten thalidomide to market. Even as recently as 1998 when Andrulis prepared a business plan, thalidomide had such a bad reputation that he couldn't get financial backing, he explains. Now that the drug's reputation has been rehabilitated, other barriers exist. Any company that wishes to market thalidomide must ensure restricted distribution. Celgene's STEPS program is patented. It could be difficult to design noninfringing alternatives.
Nevertheless, Andrulis is upbeat. He thinks Andrulis Pharmaceuticals has a good chance of bringing thalidomide to market for treatment of AIDS-associated aphthous ulcers if it can raise the money for a New Drug Application. As for restricting distribution, protocols other than STEPS are possible, he says.
Meanwhile, Celgene is seeking approval for Revlimid to treat myelodysplastic syndrome, a malignant disorder of blood cell production. This second-generation analog of thalidomide differs from thalidomide by only one oxygen atom. It has fewer of the older drug's other known side effects, such as somnolence, constipation, and neuropathy. Revlimid is a product for which Celgene would have complete patent protection and, thus, wider latitude in pricing.
A finding that Revlimid is nonteratogenic to humans would be a therapeutic breakthrough and a financial windfall for Celgene. Studies have not demonstrated teratogenicity of the drug in animals, and its teratogenicity to humans is not known. It is up to FDA to determine whether use of Revlimid, if approved, will require strict restrictions such as the STEPS program for thalidomide, according to a Celgene official.
Until a restriction-free, nonteratogenic analog comes to light, patients with difficult-to-treat diseases that are treatable by thalidomide have good reason to turn to the old drug: As dangerous as it is, its dangers are well-known and have proven to be manageable. Especially if other suppliers can break through, the cost of thalidomide would be far less than that of a fully patent-protected analog.
Thalidomide's notoriety has been accompanied by a myth that must be dispelled as the drug continues to gain respectability: that the birth defects the drug caused could have been avoided had it been made available as a single enantiomer rather than a racemate.
According to Israel Agranat, a chemistry professor at Hebrew University of Jerusalem with particular interest in chiral drugs, the popularity of this myth was enhanced after the Nobel Prize in Chemistry was awarded in 2001 for achievements in asymmetric synthesis, when thalidomide was offered as the quintessential example of enantiomers having very different biological activities. That may be true, but in the case of thalidomide, its enantiomers undergo rapid chiral inversion in vivo. The good enantiomer, therefore, will convert to the bad enantiomer anyway, and the birth defects would not have been avoided.
At age 90, Kelsey retired last year, after 45 years at FDA. She declined a face-to-face interview with C&EN. According to her daughter Susan K. Duffield, of Seattle, Wash., Kelsey never talked about what she thinks she accomplished by denying the approval of thalidomide. "She's extremely modest," Duffield says. Nowadays, the woman whose skepticism spared the U.S. from the devastating thalidomide tragedy and strengthened drug evaluation in this country lives at home in a suburb of Washington, D.C., "enjoying her garden and her cat, following the news, and doing the crossword faithfully," Duffield says.