10/17/09 Researchers are urging people with arthritis who take biologic medications that block an inflammatory protein called tumor necrosis factor alpha, or TNF-alpha, to check their skin regularly for signs of cancer.
That advice comes after two new studies found higher rates of both non-melanoma and melanoma skin lesions in those who take these kinds of biologic medications compared to those who take traditional disease-modifying, anti-rheumatic drugs, or DMARDs.
The current studies, which were released Saturday at the annual meeting of the American College of Rheumatology meeting in Philadelphia, are the some of the first to look specifically at the risk of skin cancer in people who take TNF-alpha blockers, and though the findings are provocative, experts say they are not a reason to stop taking biologic medications.
"It’s my opinion that the benefits of these drugs so far outweigh the observed risks," says Kimme Hyrich, MD, PhD, of Manchester University in the U. K. and lead author of one of the papers. "Overall,the risk of skin cancers in the bigger picture remains low."
For the first study, a team of researchers from Washington University in St. Louis and the St. Louis Veterans Affairs Medical Center, analyzed the medical records of nearly 17,000 people with rheumatoid arthritis treated at VA hospitals around the country.
About 3,000 of those patients were on TNF-alpha blockers, and for every 1,000 people treated with TNF-alpha blockers for one year, researchers found about 26 non-melanoma skin cancers and nearly 20 melanomas.
Based on their analysis, the researchers concluded that taking a TNF-alpha blocking drug, including adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), infliximab (Remicade) and golimumab (Simponi), was associated with a nearly 35 percent greater risk of developing non-melanoma skin cancer and about a 50 percent greater risk of developing malignant melanoma compared to treatment with a non-biologic DMARD, such as methotrexate, leflunomide or sulfasalazine.
“The longer people were on these drugs, the higher the risk they had,” says lead author Prabha Ranganathan, MD, a rheumatologist at the Washington University School of Medicine.
Additionally, men seemed to be at greater risk for developing skin cancers, as were those who were older, had a history of cancer or were taking prednisone or other corticosteroids.
For the second study, British researchers analyzed non-melanoma skin cancer cases among those enrolled in the BSRBR, a British registry that tracks the progress of people with rheumatoid arthritis.
For patients with no previous history of skin cancer, taking a TNF-alpha blocking drug appeared to increase the risk of developing a skin lesion by about 70 percent compared to treatment with a traditional DMARD.
When they looked more closely at the numbers, however, the British team found that the biologic drugs did not appear to share the same risk.
In particular, infliximab was associated with a 3-fold increase in skin cancer risk over DMARD treatment.
Dr. Hyrich says she was surprised that the risk jumped so much for infliximab, but she thinks that may be because of something called surveillance bias.
“There are reasons why physicians choose certain drugs for certain patients,” Hyrich says. “It could be that those patients had a higher risk because their disease was more active, or it could be that since people have to go to the hospital to get Remicade, they’re around health care providers more often and therefore it’s more likely that their cancer would be identified.”
Other predictors of skin cancer in the British study were a previous cancer history, male gender, older age and use of corticosteroid medications.
The bottom line, Dr. Hyrich says, is that people on TNF-alpha blockers, or even any kind of immunosuppressive therapy, should be getting regular skin exams and keeping a close eye out for any unusual skin changes - including new moles, firm red bumps or flat scaly crusts that appear on sun exposed areas.
"I think this is an easy and important thing that probably all patients on immunosuppressive therapies should be doing."
This paper analyzes the history of thalidomide and argues that the recent decision to approve the dangerous drug was not only correct but made easy by the approval of another teratogenic drug called isotretinoin (marketed under the brand name Accutane) and by the recent FDA policies supporting inclusion of women in clinical trials. Part I describes thalidomide’s storied past: from European tragedy to American triumph and the direct effect the drug had on FDA’s drug approval process. Part II discusses the recent medical findings of thalidomide’s therapeutic effect on leprosy, cancer, and complications of AIDS, to name only a few. Part III details FDA’s approval of thalidomide, focusing on the S.T.E.P.S.™ Program instituted by Celgene as an effort to prevent as many thalidomide birth defects as possible. Part IV, as stated above, analyzes FDA’s decision itself, and argues that the decision was made uncontroversial by specific events in FDA history.
I. Thalidomide’s Turbulent History
Thalidomide, an off-white, nearly odorless, and crystalline powder,[6] first appeared in Germany in 1953. The discoverer, a West German company called Ciba, discarded the drug after it was found to have no pharmacological effect in animals.[7] A few years later, however, thalidomide experienced a rebirth when another West German company, Chemie Grünenthal, found that it worked as a hypnotic, producing a deep sleep without hangover.[8] Claiming that the drug was “completely non-poisonous” and “completely safe,” the company launched thalidomide under the name Contergan on October 1, 1957.[9]
Contergan soon became the sedative of choice in West Germany. In fact, by the end of the first year, Grünenthal was selling an amazing 90,000 packets of the drug a month.[10] Much of the popularity was due to the availability of the drug (it was inexpensive and available without a prescription) and the drug company’s 1958 advertising campaign.[11] The company intentionally set out to promote the alleged safety of the product. For instance, in an August, 1958 letter to West German general practitioners, Grünenthal promoted the use of Contergan by pregnant mothers: “In pregnancy and during the lactation period, the female organism is under great strain. Sleeplessness, unrest, and tension are constant complaints. The administration of a sedative and hypnotic that will hurt neither mother nor child is often necessary.”[12] Despite the claim that Contergan “[did] not damage either mother or child,” the drug company had never tested thalidomide on any pregnant animals.[13]
Grünenthal exported Contergan to forty-two countries worldwide and negotiated numerous manufacturer licenses to allow for the foreign production of thalidomide.[14] Anxious to exploit the American market, Grünenthal approached both Smith, Kline & French, and Lederle before finally successfully securing Vick Chemical Company (Richardson-Merrell), [15] the parent of William S. Merrell Company known for Vicks VapoRub, as its American licensee.[16] At the time, Richardson-Merrell knew nothing about thalidomide yet they planned to promote the drug as a panacea; the company expected to cure anxiety associated with a panoply of afflictions that included cancer, tuberculosis, menopause, alcoholism, poor school work, and even marital discord.[17]
Thalidomide’s “investigational” period in the United States began on February 11, 1959 when Richardson-Merrell sent the drug to an unsuspecting medical community for human experimental use.[18] The company had not engaged in prior animal testing yet the physicians were assured that the drug was safe.[19] By May, pregnant women were given the drug.[20] Even by the relaxed standards of the time, the “trials” themselves were controversial. The investigational program was operated through Richardson-Merrell’s sales, not medical, division, placebos were distributed only after a participating physician specifically requested them, and no other company had ever relied on more than 5,000 test subjects (whereas 20,000 American subjects took thalidomide).[21] In the months following the tragedy, it was found that a total of 2,528,412 thalidomide tablets had been sent to 1,267 doctors across the country.[22]
Frances Oldham Kelsey arrived at the Food and Drug Administration just one month before Richardson-Merrell’s thalidomide application.[23] Fresh from Vermillion, South Dakota where she had spent three years practicing general medicine, the University of Chicago-trained physician and pharmacology Ph.D. spent her first month in an orientation program learning about the agency’s general practices.[24] Once back in the New Drug Branch of the Bureau of Medicine (now the Center for Drug Evaluation), Kelsey’s superiors decided to assign their newest medical officer what they considered a straightforward application.[25] It was under these auspices that on September 12, 1960, Dr. Kelsey was introduced to Richardson-Merrell’s thalidomide product, Kevadon.[26]
At the time of the application’s submission there had not been any reports of problems pertaining to thalidomide.[27] Although it would be later proved that the first thalidomide baby was born on Christmas day, 1956 in Stolberg, Germany,[28] European doctors had yet to make the connection between the horrible birth defects and thalidomide.
Before Kevadon could be marketed, the 1938 Food, Drug and Cosmetic Act required Richardson-Merrell to prove to FDA that their drug was safe.[29] FDA had a sixty-day window of time to review the application and to contact the drug company if safety problems or questions arose.[30] If FDA failed to contact the drug sponsor by the sixtieth day, then the New Drug Applications automatically became effective.[31] If FDA found the NDA incomplete, then the applicant manufacturer was notified of the deficiencies and, because technically the application was not accepted for filing, the applicant was allowed to submit supplemental information to correct the application.[32] The NDA was regarded as withdrawn and resubmitted, giving FDA a new sixty-day review period.[33]
This statutory framework played a central role in Dr. Kelsey’s attempt to keep Kevadon off the market. From the beginning, Kelsey was troubled by the application, finding that the “claims were just too glowing—too good to be true,” and that the clinical reports were “really more testimonials than scientific studies.”[34] With these concerns in mind, Kelsey effectively put a halt to the drug’s manufacture by penning a letter to Richardson-Merrell on November 10, 1960, only two days before the end of the sixty-day statutory review period. Had Kelsey not contacted the drug company, Kevadon’s NDA would have automatically become effective pursuant to the provisions of the 1938 Food, Drug and Cosmetic Act.[35] This letter, which found the Kevadon NDA incomplete and outlined it’s inadequacies,[36] in effect gave FDA an additional statutory review period and required Richardson-Merrell to provide FDA with more information if the drug company wanted to market thalidomide. The November 1960 letter, the first of five such “application incomplete” letters that FDA would send over the course of the next year,[37] marked the beginning of the tumultuous relationship between FDA’s most junior medical officer and one of America’s medical giants.[38]
In February 1961, Kelsey discovered a letter by Dr. A. Leslie Florence in the December 31, 1960 issue of the British Medical Journal suggesting that prolonged use of thalidomide resulted in peripheral neuritis.[39] Angered by the fact that Richardson-Merrell had failed to disclose the side effect, Kelsey requested further animal studies, clinical information, and a list of all of the clinical investigators who had been given Kevadon.[40]
Reluctantly, Richardson-Merrell representatives traveled to Germany to meet with Grünenthal about the link between peripheral neuritis and thalidomide.[41] Grünenthal told Richardson-Merrell’s Dr. F.J. Murray that the side effects were reversible: in all of the only thirty-four cases in West Germany, the symptoms faded once the patient stopped taking the drug.[42] This report, like the many others from Richardson-Merrell that crossed Kelsey’s desk, were read with a great deal of suspicion. Later, Kelsey commented that she “had the feeling throughout that [Richardson-Merrell was] at no time being wholly frank with me.”[43] Her skepticism was for good reason: Grünenthal in fact knew of 400 cases of peripheral neuritis, many of which were not reversible.[44]
The situation escalated again in April when Dr. Murray contacted Dr. Kelsey’s supervisor alleging that the company would be contacting the FDA Commissioner because Kelsey was unreasonably avoiding a decision on whether or not the Kevadon NDA was complete.[45] Murray then wrote to Dr. Kelsey demanding a final decision and stating, “I again want to stress that there is actually no proof thalidomide causes peripheral neuritis. The evidence is circumstantial.”[46] Kelsey’s May 5, 1961 response informed Murray once again that the application was incomplete and inadequate and boldly accused the company of deliberately hiding information from FDA:
On the present evidence we cannot regard Kevadon tablets as safe in the sense that its usefulness as a sedative hypnotic outweighs the toxic effects indicated by the cases of peripheral neuritis. . . . The burden of proof that the drug is safe—which must include adequate studies of all the manifestations of toxicity which medical or clinical experience suggest—lies with the applicant. In this connection we are much concerned that apparently evidence with respect to the occurrence of peripheral neuritis in England was known to you but not forthrightly disclosed in the application.[47]
Incensed over what he called a “somewhat libelous” letter,[48] Murray set up another meeting with Dr. Kelsey. There, for the first time, Kelsey requested proof that Kevadon was safe for use during pregnancy.[49]
Peripheral neuritis continued to be Kelsey’s primary concern since the investigator was unaware of the link between thalidomide and the unusual outbreak of birth defects in Europe. Unbeknownst to FDA and Richardson-Merrell, foreign scientists were beginning to draw the connection between the drug and children born with flipper-like limbs and missing fingers, toes, and ears.
Although Australian obstetrician William McBride is credited as one of the first to implicate thalidomide, his thin proof caused the global scientific community to dismiss his message.[50] In June 1961, McBride discovered that of the three malformed babies he had recently delivered all of the mothers had taken Distaval, the thalidomide brand name in Britain.[51] Convinced that Distaval was to blame, the doctor contacted the drug’s Australian manufacturer,[52] sent a paper to Britain’s medical journal The Lancet,[53] and began animal studies to replicate the effects he had witnessed in humans.[54] The next three months proved frustrating for McBride: the manufacturer, DCBAL, refused to believe his claims, he was unable to produce the same deformities in mice and guinea pigs, 23 women who had taken thalidomide during their pregnancy gave birth to normal children, and The Lancet rejected McBride’s paper for publication.[55]
The link between thalidomide and phocomelic birth defects was under investigation in Germany also in June 1961. At that time a young lawyer named Karl Shulte-Hillen contacted Professor Widukind Lenz, the Assistant at the Children’s Clinic at Hamburg University.[56] Both Shulte-Hillen’s wife and sister had recently given birth to babies with shrunken arms and missing fingers and the lawyer theorized that something in his hometown was responsible for the birth defects.[57] Although Lenz discounted Shulte-Hillen’s theory, he began counting the number of phocomelic cases and found that while there had only been one recorded case between 1930 to 1955, there were a record fifty between September 1960 and October 1961.[58] Still missing the common thread, Lenz interviewed the mothers of the affected children hoping that they might provide insight into the causal agent.[59] The Hamburg doctor fortuitously stumbled upon the answer when on November 11, 1961 one of his subjects described an intake of thalidomide before and during her pregnancy, the peripheral neuritis she experienced, and her concern throughout the pregnancy that the drug might be harming her child.[60] The next day four other mothers told Lenz of their thalidomide use, and by November 15 fourteen more cases were recorded.[61] Lenz immediately contacted Grünenthal.
Throughout this time, McBride had continued his Australian crusade against thalidomide. After two more babies with phocomelia were born in September 1961 to mothers who had taken Distaval early in their pregnancies, McBride spent another two months pressuring DCBAL.[62] It wasn’t until late November that the drug company finally agreed to meet with the obstetrician.[63] In what proved to be fortunate timing, a report of McBride’s findings arrived in Germany just after Lenz presented his damning research to Grünenthal.[64]
Despite the evidence from across the globe, Grünenthal executives were still reluctant to withdraw their money-making wonder drug. In a weekend meeting, the company leaders opted only to notify doctors and pharmacists of the Lenz data.[65] Their decision was preempted the next day, when on November 26, 1961 the headline of the German newspaper Welt am Sonntag screamed “Malformations from tablets—alarming suspicion of physician’s globally distributed drug.”[66] Grünenthal was forced to withdraw Contergan from the market that same day.[67] News of the German event reached Dr. Kelsey on November 30, 1961 when Richardson-Merrell reported to her the possibility that thalidomide was causing appalling birth defects.[68]
At first, FDA was hesitant to blame thalidomide. Kelsey later claimed: “In any adverse reaction report like this there always is a period of doubt where you’re not sure that this is the real correlation. We were aware that this drug was in the investigational stage. We felt perhaps wrongly . . . that it was well under control of the sponsors.”[69] However, little doubt remained after Kelsey and an FDA colleague met with Dr. Helen Taussig, a Pediatrics professor at the Johns Hopkins University School of Medicine, in April 1962.[70] Dr. Taussig had contacted FDA after returning from Europe to report her firsthand knowledge of the widespread and devastating effects caused by thalidomide.[71] Taussig was the first to describe to Kelsey the “seal limbs” of the European children she encountered and how a number of European researchers felt that thalidomide was to blame.
Armed with this new knowledge, Kelsey wrote to Richardson-Merrell to determine whether Kevadon was still in investigational use.[72] Throughout the Kevadon application’s review, FDA presumed that only thirty-five to sixty clinical investigators had been working with thalidomide.[73] Kelsey was therefore shocked to learn at the end of April that Richardson-Merrell had sent the drug to over 1,000 doctors.[74]
After meeting with Kelsey, Dr. Taussig worked quickly to warn the American medical community. In mid-April 1962 Taussig described the birth defects of the thousands of European children to a meeting of the American College of Physicians.[75] While a New York Times article covering the meeting was largely ignored by the American public, it was embraced by lawmakers in Washington.
Since 1959, Senator Estes Kefauver (D-TN) had been investigating the American drug industry in the hopes of reducing drug prices.[76] The history of drug regulation in this country is a troubled one. The Federal Food and Drugs Act of 1906 allowed companies to market drugs without government examination but permitted what was then the U.S. Department of Agriculture’s Bureau of Chemistry to seize an adulterated or misbranded drug already in the stream of commerce.[77] Comprised of a confusing amalgamation of rules, the archaic statute permitted drug manufacturers to deviate from nationally established purity and quality standards so long as the individual standard was printed on the drug’s label.[78] Following the 1937 “Elixir Sulfanilamide” tragedy which killed 107 people, the Federal Food, Drug, and Cosmetic Act of 1938 was enacted requiring FDA drug safety approval before marketing.[79] The limitations of the 1938 Act soon became apparent. For instance, since the Act only required the drug to be “safe,” any effectiveness claims were the manufacturer’s responsibility.[80] Furthermore, the exemption for new drugs in clinical investigations allowed the manufacturer to proceed virtually unmonitored. The drug sponsor was not required to notify FDA of human testing and the manufacturer was only required to report the trial results if a new drug application was submitted.[81]
Congressional hearings in late 1959 on the pricing and promotional practices of the drug industry produced Sen. Kefauver’s bill, S.1552, which as originally submitted was an attack on high drug prices.[82] After further hearings, the bill was radically amended and resubmitted out of the Subcommittee on Antitrust and Monopoly on March 8, 1962.[83] The focus of the amended S.1552 shifted from curbing exorbitant drug prices to strengthening the Federal Food, Drug and Cosmetic Act of 1938 by requiring, among other things, that a drug manufacturer provide information on a drug’s effectiveness as well as it’s safety.[84] Over the next few years S.1552 sat lame in committee but was given new life by the 1962 New York Times article on Dr. Taussig’s presentation to the American College of Physicians.[85] Soon, Taussig was testifying in front of Congress and a few months later the Washington Post broke the thalidomide story to the American public.[86] Thalidomide, Dr. Kelsey, and the lack of FDA controls over experimental drugs became front-page news.
The popular press’s coverage of the teratogenic drug increased the pressure on FDA to locate all of the samples Richardson-Merrell had distributed during its “investigational” studies. During a nationwide recall, it was discovered that of the more than five tons of thalidomide that Richardson-Merrell had initially received, over two tons were still at large and could not be located through the drug company’s spotty records.[87] Richardson-Merrell and FDA set out to track down the remaining doses of the drug and even President John F. Kennedy became involved when he urged Americans during a press conference to check their medicine cabinets for thalidomide.[88]
Following the completion of the drug’s recall, FDA determined that seventeen thalidomide children had been born in the United States.[89] While seven of the mothers had acquired the drug overseas, the remaining ten had been affected by the Richardson-Merrell distribution.[90] In subsequent years, it was clear that the United States had escaped tragedy. Nations around the globe reported shocking statistics: 3,049 thalidomide births in Germany, more than 300 in Japan, 271 in the United Kingdom, 122 affected Canadian children, and thousands more from other countries.[91]
The thalidomide ordeal was directly responsible for positive change in this country. For one, Sen. Kefauver’s efforts, although originally aimed at reducing drug prices, drew attention to the inadequacies of the drug approval process. Recognizing the need for tighter agency control, Congress passed a greatly amended version of S.1552 in what became known as the Kefauver-Harris Amendments or the Drug Amendments of 1962.[92] In final form, the Amendments changed the approval process, added an effectiveness requirement, and mandated record-keeping. Specifically, by requiring explicit FDA authorization before a manufacturer is allowed to introduce a drug into interstate commerce, the Amendments eradicated the automatic sixty-day approval process that had bound Dr. Kelsey.[93] The new law also permitted FDA to withdraw approval if new evidence not contained in the application was found to be an “imminent hazard to the public health.”[94] Furthermore, manufacturers were required to prove not only the safety of the drug product but also the effectiveness under the stated conditions and uses.[95] Data from clinical trials had to be recorded and the manufacturer was obligated to report immediately any adverse conditions attributable to the drug product.[96] Since many of the Americans taking thalidomide as part of Richardson-Merrell’s clinical trials were unaware of the drug’s investigational status, the Amendments required manufacturers, with limited exceptions, to inform patients of the study and to secure their consent to take an experimental drug.[97]
Thalidomide is also responsible for the development of teratology as a field of study. In the years following the tragedy, researchers were able to pinpoint the critical period of exposure. Phocomelia resulted only if the mother ingested thalidomide thirty-six to fifty days following her last menstrual period, or twenty-two to thirty-six days after conception.[98]
Finally, as for the woman credited with fending off an American drug giant and saving thousands of babies from devastating birth defects, President John F. Kennedy awarded Dr. Kelsey with the Gold Medal Award for Distinguished Federal Civilian Service.[99]
II. Thalidomide’s Resurgence.
In a surprising 1965 article, an Israeli doctor reported the remarkable effects thalidomide had had in alleviating complications of leprosy. Since then, through controlled clinical trials and FDA compassionate-use programs, the drug has been found to be effective in treating a myriad of disorders, including certain mycobacterial and autoimmune diseases, HIV and AIDS-related afflictions, cancer, and miscellaneous skin conditions.
A. Microbacterial Diseases
Approximately ten to fifteen million people worldwide suffer from leprosy, or Hansen’s Disease, a chronic disease of the skin and peripheral nervous system.[100] Although more common in Africa, India, Southeast Asia, and Brazil, this greatly misunderstood disease is indigenous to certain parts of the United States and, according to 1992 statistics, affects more than 7,000 Americans.[101]
There are two main forms of leprosy: tuberculoid and lepromatous.[102] The symptoms of the former include an enlarged nerve near a solitary lesion which can arise anywhere on the body whereas the latter manifests itself in dry, cracked skin, numerous lesions all over the body, and eventual hand and feet deformities.[103] Once treatment begins, patients respond to the leprosy antigens by experiencing what are called “lepra reactions,” of which there are two types.[104] In type 1 lepra reaction, commonly associated with tuberculoid leprosy, the skin lesion simply becomes inflamed.[105] However, in type 2, found in lepromatous leprosy sufferers, red nodular lesions appear in clusters all over the body, arms and legs may swell, eyesight worsens, and fever, weight loss, arthritis, and general malaise may occur.[106] This type 2 lepra reaction is called erythema nodosum leprosum, or ENL. Studies report that while between 15 and 50% of lepromatous leprosy patients develop ENL within the first year of treatment, the reaction can develop after the first year and even after treatment has been discontinued.[107]
In 1965 Israeli dermatologist Jacob Sheskin accidentally discovered that thalidomide rapidly alleviated ENL symptoms.[108] Following the ingestion of thalidomide, the lesions of six patients, all of whom suffered from the lepromatous form of leprosy, showed significant clearing after a mere twenty-four to forty-eight hours.[109] The dermatologist then embarked on a fifteen-year worldwide study that included 4522 ENL patients.[110] The results were remarkable: 99% showed improvement with thalidomide treatment.[111] Sheskin also noted the remission of other side effects such as headache, anorexia, and vomiting.[112]
Shortly after the publication of Sheskin’s 1965 study, FDA approved the clinical study of thalidomide at the National Hansen’s Disease Center in Carville, Louisiana and in 1975 the US Public Health Service set up a compassionate use program to distribute the drug to Hansen’s Disease patients.[113] The results of these long-term studies would later facilitate thalidomide’s move from experimental to approved status.[114]
Recently, researchers have begun to test thalidomide’s effectiveness in tuberculosis (TB). The oldest documented infectious disease, TB continues to cause about three million deaths per year and affects an estimated one billion people worldwide.[115] In 1991, a team of Rockefeller University scientists discovered that thalidomide aided the immune system by suppressing a protein responsible for inflammation called tumor necrosis factor-alpha (TNF-alpha).[116] Once researchers determined that increased TNF-alpha was present in patients with TB and ENL, they hypothesized that thalidomide would treat both diseases effectively.[117] Confirming this theory, a 1995 study including thirty tuberculosis-infected men in Thailand and New York reported a decrease in the patients’ adverse blood condition.[118]
B. HIV and AIDS-related disorders
The combination of the Rockefeller findings and the discovery that patients with HIV possessed increased levels of TNF-alpha led researchers to test the efficacy of thalidomide on HIV and AIDS-related disorders. Preliminary success has been found in cachexia (or wasting syndrome), recurrent aphthous ulceration, and Kaposi’s Sarcoma.
Cachexia, or HIV wasting syndrome, is a common manifestation of AIDS involving involuntary weight loss plus either chronic diarrhea or chronic weakness and fever.[119] It is estimated that 50,000 - 100,000 Americans (or 50% of AIDS patients) suffer from cachexia during their battle with AIDS and, because of the patient’s inability to maintain normal body weight, the syndrome can lead to death.[120] The increased frequency of cachexia in recent years is believed to be the result of a longer AIDS survival rate.[121] The exact cause of cachexia is still unknown, although elevated TNF-alpha levels are present and may contribute to the weight loss.[122]
Thalidomide has proven to aid weight gain in small clinical trials. For example, in a trial sponsored by the National Institute of Nutrition in Mexico City, researchers found that in a twelve-week trial of twenty-eight patients, eleven of the fourteen receiving thalidomide either gained weight or remained stable (79% efficacy) compared to four of fourteen in the placebo group (29%).[123] Similarly, another study reported a mean percentage body weight increase of 2.07% after one week and 3.06% after two weeks of thalidomide therapy in a trial of thirteen HIV-infected patients.[124] Presently, FDA has approved an expanded-access program for cachexia patients experiencing an involuntary loss of 20% or more body weight and for whom alternative treatments have failed.[125]
Another complication of AIDS thought to be relieved by thalidomide is recurrent aphthous ulceration. The ulcers, appearing in about 3% of AIDS patients, may present themselves in the mouth, esophagus, or genital area.[126] Oral ulcers inhibit the patient’s ability to eat and take medication, therefore wasting and malnutrition can occur.[127] One troubling aspect of the available corticosteroid treatment is the recurrence of the ulcers.[128]
In 1997, an article in the New England Journal of Medicine reported that thalidomide is an effective treatment for aphthous ulceration of the mouth.[129] As part of a large AIDS Clinical Trials Group study (ACTG #251) the group of researchers found that the ulcers of 55% of the patients taking thalidomide completed healed within four weeks and 90% exhibited either complete or partial healing.[130] These results were compared to healed ulcers in only 7% of the placebo group, with 28% showing complete or partial healing.[131] Furthermore, patients reported that thalidomide alleviated the pain associated with aphthous ulcers and improved their ability to eat.[132]
Despite the promising results described above, The New England Journal of Medicine article disclosed a disturbing result: thalidomide increased the patients’ HIV-viral load.[133] Although earlier studies had found thalidomide to suppress TNF-alpha, the thalidomide-treated patients in this study actually experienced increased and higher levels of TNF-alpha than those in the placebo group.[134] Because increases in TNF-alpha enhance the production of HIV and the strength of the disease, the researchers discouraged the use of thalidomide in HIV-infected patients for longer than a two to four week period of time.[135]
Thalidomide is also under investigation for the treatment of Kaposi’s sarcoma (KS), the cancerous lesions commonly associated with AIDS.[136] Prevalent in HIV-infected homosexual men,[137] the lesions, sometimes over a hundred in number, may appear anywhere on or in the body. While lesions on the skin are most common initially, they later appear in the mouth in approximately one-third of HIV patients and in the gastrointestinal tract in 40%.[138] Social isolation, anguish, and depression are common as a result of the unsightly lesions.[139]
The study of thalidomide treatment for Kaposi’s sarcoma is still young and researchers continue to recommend conventional available treatments like chemotherapy and radiotherapy.[140] A few researchers report efficacy in individual cases,[141] but others caution that the results may have arisen from mechanisms other than thalidomide.[142]
C. Autoimmune diseases
Thalidomide’s ability to suppress TNF-alpha and affect other cell activity[143] has sparked scientific interest in the drug’s ability to combat certain autoimmune diseases like lupus and rheumatoid arthritis. Currently, clinical trials are testing thalidomide’s usefulness in lupus erythematosus, rheumatoid arthritis, and Crohn’s disease.[144]
Thalidomide’s efficacy has been established in certain forms of lupus. Simply stated, there are two major forms of lupus: discoid lupus erythematosus (DLE), a generally mild, but sometimes chronic, form of the disease manifesting in a red, scaly rash usually located on the face, and systemic lupus erythematosus (SLE), the more common and severe form of lupus that includes rash, swelling of the joints, organ inflammation, and ulcers in the mouth or nose.[145] The effectiveness of thalidomide in DLE patients was established early in the 1980s[146] and the drug has shown similar promise for SLE. For example, a study of 23 SLE patients reported that 90% had complete remission with thalidomide treatment.[147]
The drug has also shown some promise in small rheumatoid arthritis studies. For example, in an open study of seven female patients, thalidomide was found to relieve pain and joint inflammation in all cases.[148] Four of the women even enjoyed remission long after withdrawal of the drug.[149] Similarly, in a later thalidomide study involving seventeen patients, seven experienced complete remission and five partial remission.[150]
D. Cancer and Related Disorders
Aside from suppressing TNF-alpha, thalidomide prevents angiogenesis, the formation of new blood vessels.[151] This property, which was responsible for stunting the uterine limb growth of the 1950s and 60s thalidomide babies, may prove useful in combating breast and prostate cancer by preventing new tumor growth.[152] Preliminary results from the National Cancer Institute’s prostate cancer study showed the drug stabilized the disease and lowered the PSA (or prostate-specific antigen) levels of all eighteen participants.[153] Presently, over 100 individual cancer patients use thalidomide on what FDA calls “an emergency basis.”[154]
Thalidomide’s antiangiogenesis properties have given researchers at Harvard Medical School and the University of Pennsylvania hope of using the drug for macular degeneration, a blinding eye disorder caused by harmful blood vessel growth and retinal bleeding.[155] The two institutions have teamed up to study the early stages of the disease in a small clinical trial.[156]
Chronic graft-versus-host disease (CGvHD) is another area of study. The disease, a complication of leukemia associated with bone marrow transplants, occurs in approximately 40% of patients who survive 100 days following their transplant.[157] Research shows that 52% of all patients with CGvHD do not survive.[158] Like many of the aforementioned disorders, the increased level of TNF-alpha in CGvHD sufferers led researchers to believe thalidomide would be an effective treatment.[159] Several studies have confirmed this hypothesis in chronic cases.[160]
E. Miscellaneous Skin Conditions
One final area of general thalidomide study involves special skin disorders, including Behçet’s syndrome. Numerous individual case studies have found thalidomide useful in treating Behçet’s disease, a multisystem disorder presenting oral and genital ulcers, arthritis, colitis, and painful lesions on the skin and eyes,[161] but not until last year were researchers able to replicate the results in a controlled trial. In that instance, a group from the Behçet’s Syndrome Research Center in Istanbul, Turkey found thalidomide effective in suppressing existing oral and genital ulcers as well as preventing the formation of new ones.[162] Not surprisingly, the ulcers recurred after thalidomide treatment ceased.[163] A disturbing and unique side effect was an increase in the number of ENL lesions during the first eight weeks of the thalidomide treatment.[164]
F. Side Effects
Despite the great strides made with thalidomide, researchers have been unable to prevent the dangerous side effects responsible for its notoriety. Aside from the drug’s teratogenicity,[165] nerve damage, or neuropathy, remains the leading concern of widespread thalidomide use. Since the drug has been tested in such a wide range of diseases, the overall incidence of the condition is difficult to determine. While one retrospective study found thalidomide-induced neuropathy to occur in 21-50% of various dermatologic cases, others focus on specific disorders, citing rates as high as 70%.[166] Early reports that neuropathy does not strike ENL patients taking thalidomide (or occurs in as little as 1% of patients) have recently come into question by those who argue that the distinction between nerve damage caused by the leprosy itself and that caused by thalidomide was not properly made.[167] Furthermore, the use of thalidomide for complications of AIDS has presented special problems since preexisting neuropathy is common in HIV patients and such patients as a whole have been shown to be particularly sensitive to the drug.[168]
While many studies report that the neuropathic symptoms (which include numbness of the arms, hands, legs, or feet as well as general muscle weakness) ceased upon discontinuation of the drug,[169] it is well known that thalidomide-induced nerve damage can be irreversible and can occur when even small doses of the drug are administered.[170]
Aside from neuropathy and birth defects, thalidomide patients have reported, among other things, drowsiness, dizziness, mood swings, nausea, and headaches.
In sum, forty years of research have proven that the reviled drug of the 1950s and 60s can be used to treat life-threatening illnesses like cancer, complications from AIDS, and tuberculosis, but with the high likelihood of severe side effects. Due to specific modes of action, thalidomide has proven effective in some of the most difficult mycobacterial, autoimmune, and angiogenetic challenges facing the medical community today.
III. Approving Thalidomide
Amidst reports of both thalidomide’s efficacy and the burgeoning black market of Brazilian thalidomide imports, FDA in 1995 solicited applications from manufacturers to market the drug.[171] Within a year, the Celgene Corporation, in its first-ever effort to bring a drug to the market, presented the government agency with its New Drug Application for Thalomid™ (thalidomide), which would be used in the treatment of the leprosy complication known as ENL.[172] Throughout the approval process FDA weighed the promising results against the chilling side effects, the possibility of treating life-threatening diseases against the rights of future children born with debilitating deformities, the availability and efficacy of alternative treatments, and the feasibility of instituting a restricted drug monitoring program.
On September 5, 1997, FDA’s ten-person Dermatologic and Dental Drugs Advisory Committee recommended approval of the drug by voting 8-1 (with 1 abstention) that the benefits of Thalomid™ outweighed the risks in the treatment of ENL.[173] FDA accepted the committee’s endorsement and alerted the manufacturer that the drug would be approved once Celgene submitted plans for a satisfactory distribution system and agreeable labeling.[174] Over the next few months, Celgene worked with FDA, the Centers for Disease Control and Prevention, the Canadian Thalidomide Victims Association and numerous professional health organizations to craft the most restrictive distribution and monitoring program in the history of FDA.[175] With the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.™) Program in place, on July 16, 1998, FDA approved Thalomid™ for ENL.[176]
The S.T.E.P.S.™ Program consists of five general components: 1) Registration of patients, participating physicians and pharmacies; 2) Required pregnancy testing before and throughout thalidomide treatment; 3) Counseling in effective contraception; 4) Comprehensive physician, pharmacist, and patient education; and 5) Patient informed consent.[177]
Thalomid™ may only be administered by pharmacies and physicians who participate in the mandatory registration system, a nationwide program operated by Boston University School of Medicine’s Slone Epidemiology Unit.[178] To register, a pharmacy must agree to comply with the S.T.E.P.S.™ requirements: to confirm that the prescribing physician is in fact registered with Slone, verify the legitimacy of the patient’s informed consent form, record the prescription information, and fill no more than a four-week dosage of the drug.[179] Automatic refills are expressly prohibited by the Program and the new prescription must have been written within the previous fourteen days.[180] Finally, pharmacists are not permitted to repackage the drug.[181]
Similarly, a physician seeking to prescribe Thalomid™ must register and agree to educate the patient about the dangers of the drug, provide contraceptive counseling, comply with the informed consent form requirements, and conduct acceptable pregnancy tests prior to and throughout the thalidomide treatment.[182]
To be eligible for such treatment, a patient first must be capable of carrying out instructions and complying with the requirements of mandatory contraception, pregnancy testing, registration, and surveying.[183] Second, the patient must acknowledge in writing that he or she has received counseling on contraception and fetal defects and assert that he or she will comply with the contraceptive guidelines.[184] Third, if the patient is a minor, a parent or legal guardian must read and comply with the patient requirements.[185]
Because Thalomid™ is contraindicated in women of childbearing potential, the S.T.E.P.S.™ Program’s primary goal is to admit only those unable to become pregnant while on the drug. To this end, the Program requires proof of a negative pregnancy test conducted within the twenty-four hours before starting therapy.[186] Once therapy commences, additional pregnancy tests are to be conducted every week during the first month of Thalomid™ intake and then every month in women with regular menstrual cycles (or bi-monthly in women with irregular cycles).[187] If a woman taking Thalomid™ becomes pregnant, the therapy must end immediately and evaluation and counseling by a toxicology specialist is recommended.[188]
Patients of both genders must receive contraception counseling. Female patients are required either to abstain from sexual intercourse or to utilize two forms of reliable birth control for one month prior to, throughout, and one month after thalidomide therapy.[189] The only patients exempted from this requirement are those who are infertile for reasons of menopause (for two years or longer) or hysterectomy; a general history of infertility is insufficient.[190] If a female patient decides to have sexual intercourse, her contraceptives must include at least one “highly effective method” (such as an IUD, birth control pill, tubal ligation, or partner’s vasectomy) and one “effective method” (a latex condom, diaphragm, or cervical cap).[191] Because it is currently unknown whether thalidomide is present in ejaculate, male patients must agree to use a latex condom when engaging in sexual intercourse with a woman of childbearing potential, even if the patient has had a successful vasectomy.[192]
The fourth component of the S.T.E.P.S.™ Program requires all participating parties to be educated on the dangers of thalidomide. For example, health care professionals receive the twenty-two page package insert that outlines, among other things, the physician and pharmacist requirements, clinical study results, precautions, and adverse effects.[193] Patients are required to receive a videotape featuring a member of the Canadian Thalidomide Victim Association, a brochure with pictures of thalidomide-affected babies, and a letter detailing the likely effects on the fetus of a pregnant woman taking thalidomide.[194]
Lastly, S.T.E.P.S.™ requires a patient’s informed consent. The agreement’s text must be read aloud to the patient, in the language of his or her choice, and the patient must initial each of the statements on the gender-specific form.[195] Both male and female forms require the patient to participate in the national registry and to agree never to share the drug with others.[196] In addition, both men and women must verify that the prescribing physician has answered all of their questions and that they have viewed the videotape or read the brochure included in the patient educational packet.[197]
After this, the two forms differ in their emphases on sex-specific risks. The female form, for example, goes on to specify the requirements of the pregnancy test regime, the forms of acceptable birth control, and the actions to take if a patient misses her menstrual period.[198] In addition, a consenting female must pledge not to try to become pregnant and must agree that “I have been warned by my doctor that my unborn baby will almost certainly have serious birth defects or may even die if I am pregnant or become pregnant while taking THALOMID™ (thalidomide).”[199] Conversely, the male form focuses on the dangers of unprotected sexual intercourse with a woman.[200]
In addition to the five components of S.T.E.P.S.™, the program also requires that Celgene notify FDA within fifteen days of receiving a report that a fetal exposure to thalidomide has occurred.[201] Upon the report of a single case, FDA has stated it will reevaluate the entire Program and consider withdrawing the drug’s approval.[202]
The demand for Thalomid™ is greater than was anticipated. The 1998 figures indicate that the drug’s gross sales were over $3.5 million[203] and while only 2000 physicians and 2000 pharmacists were originally expected to participate in the S.T.E.P.S.™ Program in the first year of marketing,[204] the numbers are currently at 4000 and 6000, respectively.[205] It is estimated that at least 6000 patients are enrolled in the Program.[206]
While the S.T.E.P.S.™ Program has been lauded as the greatest balance between individual and fetal rights, it isn’t without its problems. The approval of this teratogenic drug inevitably will result in the births of babies with severe defects; as the medical community is fond of saying, there is no such thing as zero risk. At its base, then, the Program was created not as cure to the thalidomide problem but as a prophylactic measure meant to prevent as many birth defects as possible. The next part of this paper discusses the inherent loopholes of the S.T.E.P.S.™ Program.
For one, patients simply might not comply with the Program requirements. One area in which FDA has no control is the continuous abstinence exception to the two-contraception rule. To qualify for this exemption, female patients need only state their intention to abstain from sexual intercourse throughout their treatment and for one month following discontinuance of the drug. A sexually active woman experiencing general infertility problems (not due to hysterectomy or menopause) may not want to trouble herself with the contraception requirements and therefore may declare a false promise to abstain, honestly believing that she will never become pregnant. Her continued sexual activity without contraceptives could result in a thalidomide-affected pregnancy.
Just as likely, patients may not adhere to the contraceptive plan. If a female patient’s “highly effective” method choice is hormonal, deviation from the instructions (for example, forgetting to take a birth control pill or choosing not to take the pills at the same time every day) and failure of the “effective method” (for instance, a tear in a latex condom or improper positioning of a diaphragm) could result in pregnancy. Likewise, a male patient may not use a latex condom in every instance of sexual intercourse with a woman of child-bearing potential and fertilization may result.
A final and serious deviation from the Program requirements involves drug sharing. Although explicitly instructed not to give the drug to others, including those who experience the patient’s same symptoms, patients may nevertheless do so. The threat of exposing an unborn child to thalidomide greatly increases with drug sharing since the second recipient has not been instructed in any of the risks thus negating any possibility of informed consent.
A second broad issue is that the Program operates in an environment where off-label uses are the norm. When prescribing drugs, physicians are not limited by the drug’s specifically approved purpose; rather, FDA policy states that physicians are free to prescribe a drug for the treatment of any disease.[207] For instance, a participating doctor may prescribe Thalomid™ for cachexia and breast cancer as well as for the approved ENL use. One commentator believes that the availability of off-label usage will make thalidomide one of the most prescribed drugs of the 21st century.[208]
This physician discretion could be extremely detrimental to the health of the patient. Implicit in any drug’s approval is a finding by FDA that the drug is safe and effective for it’s stated purpose. Once the physician ventures into unproven territory by deviating from the drug’s labeled use, she is in effect conducting her own investigational research. While it could be argued that modern medicine is dependent upon this case-by-case experimentation, it is clear that all physicians should not be engaging in such conduct. Misinformed or poorly trained physicians could cause more harm than good. In the case of thalidomide, for example, a prescribing physician would more likely than not educate himself as part of the S.T.E.P.S.™ requirement for registration, but if he were inadequately trained in electrophysiological measuring or other methods of testing for peripheral neuropathy, his patient may suffer irreversible nerve damage. Similarly, a physician may decide to prescribe thalidomide in the hopes of treating the newly-studied Kaposi’s sarcoma and instead increase the HIV-viral load, putting the patient in greater danger of succumbing to the disease.
The problem of physician discretion is exacerbated by pressure from uninformed patients. Results of an FDA study show that two-thirds of those surveyed under the age of forty-five could not define the word “thalidomide.”[209] Without the perspective of history, young people may learn of thalidomide’s positive results, demand it from their physicians, and undaunted by their first refusal, go in search of a physician who will prescribe it to them. By way of comparison, Dr. Gail J. Povar, of the George Washington University School of Medicine, has said that “[e]very week I have a teenager ask for Accutane inappropriately. We have to accept the fact that this will happen with thalidomide and be prepared.”[210]
Finally, while the tensions of the S.T.E.P.S.™ Program discussed above focus on the leniency of certain provisions, an argument can be made that the strictness of the Program as a whole will drive some Americans to secure access to thalidomide through other, illegal channels and therefore increase the risk to unborn children. While suppressing the unlawful distribution of thalidomide was originally one incentive for FDA to approve the drug, the decision itself did not automatically shut down the preexisting black market. The increased availability due to approval in this country combined with the already developed markets in approximately thirty-nine other countries[211] makes it more likely that thalidomide will be obtainable outside of the S.T.E.P.S.™ Program. Supporting this proposition is an example from a 1993 British documentary, Thalidomide: the drug that came back, which focused on the state of the Brazilian leprosy program.[212] Despite government officials’ assertions that the drug was not available to women of childbearing age and could only be distributed from government-controlled facilities, the documentary producers were able to catch on hidden camera a pharmacy dispensing thalidomide to a young woman.[213]
It also has been suggested that developing counties will take their cue from the United States’ approval of thalidomide and will begin issuing the drug without implementing a restricted distribution plan similar to S.T.E.P.S.™.[214] Scholars have noted that in countries like Brazil, where there is a high percentage of leprosy and where Catholicism is the predominant religion, women of child-bearing age will not adhere to the contraception requirements so as not to contradict a central teaching of their faith and will bear children with severe birth defects.[215]
As evidenced by the above, there are strong indications that human behavior is mainly responsible for failings of the S.T.E.P.S.™ Program. The regime is not error-free but, as will be argued in the following two sections, the Program contains the best set of requirements for protecting both a possible fetus and a woman’s right to choose treatment.
IV. Precedent for the FDA Decision
While shocking to an American public who remember the pictures of the thalidomide babies of the 1950s and 1960s, the decision to approve the drug, or in stark terms the subordination of protecting a possible fetus to individual choice, is supported by events of FDA recent history. For one, FDA policy in the clinical trial context has evolved from a position of overprotecting fetal rights to one where a delicate balance is struck in favor of the informed woman. As will be described below, the agency shifted from what was, for all intents and purposes, a ban on all women of childbearing potential from clinical trials to a position of strong encouragement for the inclusion of such subjects. Second, FDA approved the known teratogen isotretinoin, or Accutane, and despite continuing reports of numerous drug-induced birth defects, the drug remains on the market. Combined, these two examples provide a background for the approval of thalidomide and support the striking of the balance in favor of informed, individual choice.
The debate over gender in clinical trials has been very active in recent years. Due to efficiency-minded drug manufacturers and a fetal-protective FDA, the white male historically occupied the clinical trial field, foreclosing women’s opportunities for the advanced techniques, better care, and psychological optimism that accompany trial participation. Over the years, however, the shortcomings of this regime have become apparent and FDA has reoriented it’s position. Demonstrating its new policy choice of an individual’s informed consent over possible or even actual fetal rights, FDA now encourages researchers to include women, even some pregnant women, in clinical trials.[216]
Women were traditionally excluded from clinical trials for a myriad of reasons. For one, menstruation, pregnancy, and menopause worked against the homogeneity drug manufacturers sought in test subjects.[217] Second, accounting for the additional complexities women added to the calculus would be expensive.[218] Third, the manufacturers feared the liability that would attach if a female test subject became pregnant and gave birth to a child with drug-induced defects.[219]
Early FDA policy on female inclusion, designed in the wake of the thalidomide tragedy, eased these manufacturer concerns. Under the agency’s 1977 Guideline, entitled “General Considerations for the Clinical Evaluation of Drugs,” researchers were able to continue their male-dominated research. The Guideline stated in part:
In general, women of childbearing potential should be excluded from the earliest dose ranging studies. If adequate information on efficacy and relative safety has been amassed during Phase II, women of childbearing potential may be included in further studies provided Segment II and the female part of Segment I of the FDA Animal Reproduction Guidelines have been completed. All three segments should be completed before large-scale clinical trials are initiated in women of childbearing potential.[220]
The 1977 Guideline went on to define a woman of childbearing potential as a “premenopausal female capable of becoming pregnant.”[221] This included women using oral, injectable, and mechanical forms of birth control, lesbians, and married women whose husbands had been vasectomized.[222] In an effort to “protect” women, FDA was doing more harm than good: the government agency was approving drugs for women based on proof of efficacy and safety from male-only trials.[223]
Although narrow exceptions to the ban on women in clinical trials did exist,[224] manufacturers interpreted the 1977 Guideline as requiring the exclusion of women.[225] Inevitably, this led to a slower understanding of female reactions to drugs and, in essence, fewer advances in women’s health. After an audit by the General Accounting Office concluded the obvious that the 1977 Guideline contributed to the underrepresentation of women in drug trials,[226] FDA in 1993 promulgated the “Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs.”[227] The Supplementary Information to the 1993 Guideline states in part:
The agency has reconsidered the 1977 guideline and has concluded that it should be revised. This does not reflect a lack of concern for potential fetal exposure or indifference to potential fetal damage, but rather the agency’s opinion that (1) exclusion of women from early trials is not medically necessary because the risk to fetal exposure can be minimized by patient behavior and laboratory testing, and (2) initial determinations about whether that risk is adequately addressed are properly left to patients, physicians, local IRB’s, and sponsors, with appropriate review and guidance by FDA, as are all other aspects of the safety of proposed investigations. The agency is, therefore, withdrawing the restriction on the participation of women of childbearing potential in early clinical trials . . . .[228]
Because FDA never codified the 1993 standard as a regulation, the Guideline remains a policy statement without the force of law. Academic disagreement focuses not on the deference to be afforded the promulgation but on its importance. For some scholars, the 1993 Guideline is seen as the product of a weak FDA who, in an attempt both to appease women in their demand for equal access to clinical trials and pacify the manufacturing powerhouses, protected itself with unenforceable and meaningless precatory language.[229] However, the better view is one that sees the Guideline as a positive move toward equality.[230]
At the heart of the 1993 promulgation lies the explicit elimination of the 1977 Guideline’s prohibition of women of childbearing potential in early stages of clinical trials.[231] The agency baldly admits that its 1977 Guideline not only perpetuated the male subject paradigm, but was responsible for the medical community’s lag in understanding gendered reactions to different drugs.[232] FDA dedicates an entire section of the 1993 Guideline to discussing the inclusion of both genders in clinical studies, stating that studies should “reflect the population that will receive the drug when it is marketed” and therefore, “representatives of both genders should be included in . . . numbers adequate to allow detection of clinically significant gender-related differences in drug response.”[233]
Despite the shift in policy, the 1993 Guideline continues to protect the fetus by outlining the measures to be taken to minimize “inadvertent exposure of fetuses to potentially toxic agents . . . .”[234] The manufacturer is required to obtain informed consent and is permitted to require pregnancy testing and abstinence or contraception protocols.[235]
In the end, however, the 1993 Guideline represents a striking of the balance in favor of informed consent. As one scholar notes, it is “an acknowledgment that women, even if they are fertile, are competent to give informed consent to their participation in research trials, and that this informed consent provides the necessary insulation to protect researcher and manufacturer from suit by mother or possible child for all but negligent enrollment practices.”[236]
This shift in policy was confirmed when, in 1997, FDA proposed a new regulation involving the use of clinical holds.[237] According to the proposal, FDA could place a clinical hold on a study upon a finding that men or women of childbearing potential with life-threatening diseases were being excluded because of a researcher’s perceived risk that reproductive or developmental harm would result.[238] While the proposed rule encompasses both genders, “the primary goal of this proposed amendment is to ensure that women with reproductive potential who have a life-threatening disease are not automatically excluded in the future. . . .”[239] In support of the policy, FDA argues that the ethical principle of justice requires that “the burdens and benefits of participation in clinical research be equitably distributed across the entire population in the place or region where the clinical research is conducted.”[240]
Today, even pregnant women are included in clinical trials. Admittedly, the 1997 policy shied away from advocating for their blanket inclusion, but researchers can no longer ignore the societal benefits of doing so.[241] For example, in admitting pregnant women to clinical trials of AZT, researchers have confirmed the reduction in maternal-fetal transmission of HIV when the drug is administered to the mother during pregnancy and to the infant for six weeks following birth.[242]
From the overprotection of the fetus to deference given to the choice of a woman who has been educated on all of the risks, the evolution in FDA policy provides overwhelming support for the agency’s approval of thalidomide. In a sense, the thalidomide policy debate had already been acted out under the hot lights of the clinical trial stage. The desire to protect potential unborn children. The possibly life-saving benefits to admitted women. The importance of informed consent. And in the end, the decision not only to allow a woman to make her own reproductive choices but to permit her access to a possibly life-saving drug.
These and similar policy debates also took place over the drug isotretinoin, another teratogenic drug that greatly influenced the approval of thalidomide. The drug, more commonly called by its generic name Accutane, was first developed in Europe in the 1950s but never marketed because of the protest the teratogen was certain to meet in the wake of the thalidomide devastation.[243] It is somewhat surprising then that in 1982, FDA approved the Roche Pharmaceuticals drug application for the treatment of severe recalcitrant cystic acne, an unsightly disease resulting in deep scars on the face, neck, back, chest, and groin.[244] Because of the drug’s early test results, Accutane’s original labeling included information about birth defects in animals but was silent about any human consequences.
The proliferation of off-label usage soon made Accutane the drug of choice for treating all types of acne. Heralded as a medical breakthrough, as many as 90% of dermatologists prescribed the drug in its first year on the market.[245] It was later reported that in its first five years, only 53,000 women between the ages of fifteen and forty-four had cystic acne but that between 270,000 - 390,000 women had actually received the drug.[246]
Reports of the first Accutane-induced birth defects arrived at FDA within the first year of the drug’s approval. With what would later be termed “isotretinoin syndrome,” babies were born with a combination of heart and central nervous system problems, malformed or absent ears, wide-set eyes, a smaller mouth and jaw, and sometimes a cleft palate.[247] The company responded with a series of labeling changes, “Dear Doctor” letters, and even a warning campaign featuring a “Medical Director’s Page” in industry journals, yet the number of Accutane babies continued to rise.[248]
In February 1988, a division of FDA, the Office of Epidemiology and Biostatistics, recommended that Accutane be withdrawn from the market.[249] Another report in April of that year opined that the warnings and campaigns undertaken by Roche had failed.[250] While only sixty-two cases of Accutane-related birth defects had been reported to FDA by the early months of 1988,[251] the agency estimated that the total number of affected births was between 900 and 1,300.[252] The agency also believed that the drug had caused 700 to 1,000 spontaneous abortions while another 5,500 to 12,500 women had terminated their pregnancies because of a fear of birth defects.[253] It was discovered that a woman exposed to Accutane in her first trimester of pregnancy has a 40% chance of miscarriage and a 25% chance of delivering a malformed child.[254]
In April 1988, FDA’s Dermatologic Drugs Advisory Committee convened to consider, among other things, the recommendation by the Office of Epidemiology and Biostatistics to withdraw agency approval of the drug.[255] The seven-member panel, many members of which were self-interested dermatologists, not surprisingly rejected the proposal but, in a bold move, proposed a novel program of limited distribution (an approach only seen in Europe), education, and written informed consent.[256] In the end, FDA adopted neither the Committee’s limited distribution proposal nor the Epidemiology recommendation for withdrawal. Instead, the agency built upon the Comm
Leave a Comment