Comments of Larry D. Sasich, Pharm.D., M.P.H, FASHP, Public Citizen’s Health Research Group
Before the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee meeting on isotretinoin (Accutane)
Public Citizen’s apprehension over the safety of Accutane began shortly after its approval in May 1982, when we petitioned the Food and Drug Administration (FDA) to take immediate action to warn patients and physicians about the serious adverse effects associated with the use of this drug in September 1983. The thrust of our petition was a request for a boxed warning on the possibility of birth defects, spontaneous abortions, pseudotumor cerebri, impaired vision, and regional ileitis (Crohn’s Disease) caused by Accutane. In addition, we asked for the mandatory distribution by pharmacists of labeling written for patients, then called Patient Package Inserts, explaining the risks of this drug in non-technical language.
A final rule that became effective on June 1, 1999 gave the FDA the authority to require patient labeling, now known as Medication Guides, for drugs that present a serious risk to the public’s health. Accutane is a drug that clearly meets this standard.
An Accutane Medication Guide would inform patients not only about the risk of birth defects and the other adverse effects mentioned above, but also of the possibility of depression, psychosis, and suicidal ideation; erratic bone growth and premature closure of the growth plates; inflammation of the pancreas; elevations of particular blood fats (triglycerides); hearing impairment; decreased night vision and corneal opacities; anaphylactic and other allergic reactions; and drug interactions all now in the drug’s professional product labeling.
On April 26, 1988 the FDA’s Dermatologic Drugs Advisory Committee recommended, without specifying a method, that the prescribing of Accutane be restricted. Shortly thereafter, we again petitioned the FDA on May 17, 1988 to limit the prescribing of the drug to board-certified or board-eligible dermatologists. Dermatologists would have been required to register with the FDA and be assigned a prescriber number. To prevent the “off-label” use of Accutane, dermatologists would have been required to certify by affidavit that they had read and would follow the regulations and the drug’s approved labeling. Pharmacists would have been prohibited from knowingly filling prescriptions from physicians who were not dermatologists and registered with the FDA. Both physicians and pharmacists would have been subject to criminal penalties for violating the regulations. A copy of our 1988 petition is attached to these comments for reference.
We believe that the legal theory outlined in our 1988 petition shows that the FDA then had the authority to require the restrictions outlined above and that this theory is as sound today as it was 12 years ago. In fact, since our 1988 petition there have been several recent examples of the “creative” use of the Food, Drug and Cosmetic Act to place limitations on the use of certain drugs in a manner consistent with our petition.
- To reduce the chance of potentially life-threatening agranulocytosis the original labeling for the atypical antipsychotic drug clozapine (Clozaril), required ” a baseline white blood cell (WBC) and differential count before initiation of treatment and a WBC count every week throughout treatment” and that “The distribution of Clozaril is contingent upon performance of the required blood tests.” Clozapine was approved on September 26, 1989.
- The approved labeling for thalidomide (Thalomid), a drug cleared for marketing on July 16, 1998, requires that only prescribers and pharmacists registered with the System for Thalidomide Education and Prescribing Safety (STEPS) program are allowed to prescribe and dispense the drug. Also, “patients must be advised of, agree to, and comply with the requirements of the (STEPS) program in order to receive product.” Thalidomide and Accutane are drugs that may have similar risks in causing birth defects.
- The use of trovafloxacin (Trovan), a fluoroquinolone antibiotic approved in 1997, was restricted to hospital or long-term nursing care facilities on June 9, 1999 after reports of serious liver injury.
- The labeling for the anti-arrhythmic agent dofetilide (Tikosyn), approved on October 1, 1999, states it is ” available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education.”
In addition to requiring a Medication Guide for Accutane and the restriction of the drug’s prescribing to FDA-registered dermatologists and its labeled use, the FDA must require a postmarketing study to determine if these interventions will have met the agency’s goals as stated in the questions to this committee: no patients beginning the drug if they are pregnant and no pregnancies occurring while on Accutane treatment. This study protocol should be approved by the FDA’s Office of Postmarketing Drug Risk Assessment (OPDRA). At a minimum, the study should last one year and include evaluation of the requirements that only a limited supply of Accutane is provided to women and that the drug is not provided without proof of a negative pregnancy test. The precedent for this latter requirement is the clozaril “no blood, no drug” policy mentioned above.
Public Citizen believes that Accutane is a beneficial drug when it is used for its approved indication: severe recalcitrant nodular acne. However, if the combination of a Medication Guide and the prescribing and dispensing restrictions mentioned above cannot be shown in a postmarketing study to meet the FDA’s no-pregnancy goals after one year, the drug should be immediately removed from the market.
Continuing Medical Education programs, professional product labeling changes, and optional patient information brochures have been the Pavlovian responses to drug safety issues by manufacturers and the FDA for years. It is time to admit that this is a failed paradigm and recognize that rigorously enforced regulation may be the only way to ensure that patients are informed and that drugs are prescribed appropriately.
Where industry interests have been at stake, the FDA has been innovative in interpreting the Food, Drug and Cosmetic Act to get drugs such as clozapine, thalidomide and dofetilide on the market. It is time for the agency use the same creativity to protect the public’s safety.
We hope that it will not be necessary to return to this committee in the future to discuss how to reduce Accutane’s risks to patients.
 Department of Health and Human Services, Food and Drug Administration. Prescription Drug Product Labeling; Medication Guide Requirements Final Rule. Federal Register December 1, 1998, Volume 63, Number 230, pages 66377 to 66400.
 Professional Product Labeling for Accutane (isotretinoin) accessed at www.rocheusa.com/products/accutane/pi.html on September 16, 2000.
 Professional Product Labeling for dofetilide (Tikosyn) accessed at www.tikosyn.com on September 16, 2000.