Thalidomide Prescribers Cannot Assign Survey Responsibility to Pharmacists
Thalidomide became one of the worlds most notorious prescription drug products after being linked to severe birth defects in more than 10,000 people, according to the March of Dimes, which works to prevent birth defects and infant deaths.
Physicians in the late 1950s and early 1960s had prescribed the drug to treat insomnia, anxiety, and morning sickness in pregnant women. At that time, FDA had not approved the drug for use in the United States because of safety concerns.
When thalidomides teratogenic effects became widely recognized in 1961, the drug was pulled from the market in various countries and, by the following year, banned worldwide.
But in 1998, under a restricted distribution program, FDA approved the marketing of thalidomide for the treatment of erythema nodosum leprosum, a complication of leprosy resulting in painful skin lesions. The program does not, however, limit the use of thalidomide to that medical condition.
Five other drug productsalosetron, bosentan, oral transmucosal fentanyl citrate, mifepristone, and sodium oxybate (also known as gamma-hydroxybutyrate)are marketed under the same special regulation that restricts the distribution of thalidomide, according to Ed Cox, lead medical officer in FDAs Office of New Drugs.
F. Hoffmann-La Roche Ltd., under FDAs guidance but not regulation, voluntarily established a similar restricted distribution program for its acne-control medication isotretinoin, a drug known to cause severe birth defects and spontaneous abortion.
What is required? FDA mandated that prescribers of thalidomide, dispensing pharmacists, and patients who receive the drug must register and participate in a risk-management program, known as the System for Thalidomide Education and Prescribing Safety (STEPS).
Prescribers are required to counsel and educate patients about the teratogenic and other potential adverse effects associated with thalidomide use.
To prevent fetal exposure to thalidomide, patients must agree to comply with the mandatory contraceptive measures of the STEPS program. All female patients of childbearing potential must agree to use two reliable forms of contraception for at least one month before taking the first dose of thalidomide, during the therapy, and for one month after discontinuing the drug. Since thalidomide has been detected in sperm, men must agree to wear a latex condom every time they have heterosexual sexual contacteven if they have had a successful vasectomy.
Prescribers must provide inoffice pregnancy testing each month for women of childbearing potential who use the drugeven if continuous abstinence is the chosen method of birth control.
Prescriptions are limited to a 28-day supply of thalidomide, available only as 50-mg capsules. A new prescription must be written for each 28-day supply of the drug, and no prescriptions can be issued over the telephone.
As part of the program, prescribers of the drug must confirm, by completing an automated telephone survey, to thalidomides U.S. manufacturer, Celgene Corporation of Warren, New Jersey, that the patient has been appropriately counseled and that there has been no fetal exposure to the drug. Patients and pharmacists are also required to complete a separate telephone survey.
Who is responsible? One health-system pharmacist, who spoke on the condition of anonymity, reported that his hospitals management has appointed the responsibilities of completing the STEPS prescribers survey and counseling patients about thalidomide use to the pharmacy department.
"As pharmacists, we feel qualified to counsel the patients, but we do not feel comfortable that it is ethical or legal to identify ourselves as the prescriber when completing the survey," he said. "And that is what we are being asked to do."
When completing the monthly survey, Celgene requires prescribers of thalidomide to provide their identification number issued by the Drug Enforcement Administration (DEA), the patients Social Security number, average daily dose prescribed, total number of days for which the drug is supplied, and, if applicable, the date and result of a patients most recent pregnancy test.
After a prescriber has entered his or her identification number and necessary patient and drug-use information by telephone, Celgenes automated system responds with a unique authorization number that the prescriber must write on the thalidomide prescription.
The prescriber must obtain a new authorization number for each thalidomide prescription, according to STEPS program requirements.
According to FDAs Cox, the information provided by the prescribers telephone survey is filed electronically under the prescribers DEA identification number and is information that the prescriber is certifying as accurate.
"Therefore the prescriber survey should be completed by the prescriber," he said.
If a health care provider, patient, or pharmacist does not comply with the provisions of the STEPS program, Cox said, that person can lose the privilege to prescribe, receive, or dispense thalidomide.
Prescribers affirm by signature on the STEPS prescriber-registration form: "I understand that if I fail to comply with all requirements of the STEPS program, my prescriptions for [thalidomide] may not be honored at registered pharmacies."
Appropriately qualified health care professionals, Cox noted, may be able to provide valuable assistance in the administration of some of the various components of the STEPS program, such as patient education.
But the "ultimate responsibility for the proper administration" of the STEPS program, he said, "rests with the prescriber."
Carmen A. Catizone, executive director of the National Association of Boards of Pharmacy, said he would welcome the opportunity for pharmacists to assume the responsibility of completing the monthly prescriber survey "because they would be best qualified."
But Catizone worried that, if FDA allows prescribers to delegate the responsibility of completing the prescriber survey, prescribers might choose to appoint unqualified staff, such as a customer service representative, to complete the survey.
"And I have an ethical problem with that because [customer service staff] are not going to be able to detect the type of occurrences or clues that were the basis for these monthly surveys," he said, referring to fetal exposure to thalidomide.
Catizone said he sees a clear legal problem for pharmacists who complete the prescribers survey and strongly suggested that pharmacists carry out the STEPS requirements as mandated by FDA.
Celgene spokeswoman Anne Healy said that her company "always adheres to FDAs regulation" that requires prescribers to register with the STEPS program.
"We strongly believe that it is the prescribers responsibility to complete the prescriber survey," she said, adding that she is unaware of any situation in which a prescriber has delegated the responsibility of completing the monthly survey to another health care professional.
Since 1998, when thalidomide was approved to be marketed in the United States, Healy said, there have been "no cases of fetal exposure."
"The program has been very successful," she added.
Prescribers of thalidomide, Healy said, must inform Celgene of the medical condition for which they are prescribing the drug.
Clinical studies. Although thalidomides labeling lists the treatment of erythema nodosum leprosum as the only indication for the drug, many medical institutions, according to Celgene, are conducting clinical studies to test the drugs effectiveness for treating other conditions.
The University of Texas M.D. Anderson Cancer Center in Houston is studying thalidomide use in treating multiple myeloma and prostate cancer, according to William Dana, the institutions pharmacy division director for drug-use policy. Past studies at the center have examined the drugs effectiveness, either as a single agent or in combination therapy, in treating myelodysplastic syndrome, acute myelocytic leukemia, non-Hodgkins lymphoma, astrocytoma, glioma, glioblastoma, and squamous cell, renal cell, biliary tract, endometrial, and uterine cancers.
The Houston center dispenses 90 prescriptions of thalidomide per month, Dana said.
Other uses. "We are really just beginning to study thalidomide in pediatric cancer," said David W. Henry, a board-certified oncology pharmacist and associate professor at University of Kansas School of Pharmacy at Lawrence.
Thalidomide, Henry said, is also being studied for use in treating several other diseases, such as Kaposis sarcoma, systemic lupus erythematosus, graft-versus-host disease, and rheumatoid arthritis.
The drug, he added, is fairly well accepted outside of the clinical trial setting as an off-label treatment for multiple myeloma.
Pharmacist Larry D. Sasich, a health research analyst with consumer-advocate group Public Citizen, said he is concerned that the STEPS program does not go far enough to ensure that patients who are prescribed thalidomide for an off-label use are being properly informed of the potential adverse effects of the drug.
"Part of a clinical trial is to allow a patient to give their informed consent," he said. "Within a clinical trial, somebody is keeping track of the data. You dont have that outside of a clinical trial where the physician is prescribing the drug for other uses."
Sasich suggested that physicians and other prescribers who want to order the drug for an off-label use should submit an investigational new drug application.
Celgene is permitted by FDA to market thalidomide only for use in treating erythema nodosum leprosum, the labeled indication.
FDA admonished the drug maker in April 2000 for marketing the drug for others uses, specifically multiple myeloma.
While there were less than 100 reported occurrences of leprosy in the United States in 2000, according to the Centers for Disease Control and Preventions latest figures, Celgenes reported sales of thalidomide that year were $62 million, with about 92% of those prescriptions written for cancer-related conditions. Total thalidomide sales in 2001 were $82 million, an increase of 32% from the previous year. Thalidomide sales for the first six months of 2002, according to a July 25 company statement, were $54.5 million. Celgene sells thalidomide only in the United States.
According to the companys most recent annual report, thalidomide is in Phase-III studies for the treatment of multiple myeloma, renal cell cancer, and recurrent aphthous stomatitis.