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BEFORE THE
COMMITTEE ON GOVERNMENT REFORM
U.S. HOUSE OF REPRESENTATIVES

DECEMBER 5, 2000

Introduction

Mr. Chairman and Members of the Committee, I am Jonca Bull, M.D., Deputy Director of the Office of Drug Evaluation V, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA or the Agency). I appreciate the opportunity to discuss the Committee�s concerns regarding the drug Accutane. Helping to ensure the safe and effective use of Accutane has involved difficult scientific and ethical issues for FDA. We have taken our regulatory responsibilities concerning this drug very seriously.

FDA approved Accutane in 1982 for use in the treatment of severe, recalcitrant cystic acne that is unresponsive to conventional therapy, including antibiotics. In most cases, cystic acne is severely disfiguring, causing red cysts and nodules, which can leave deep scars. Accutane is uniquely effective in treating patients with this disease, but is associated with serious adverse events including birth defects. For this reason, it continues to be one of FDA�s most difficult challenges in the area of post-approval risk management.

FDA must constantly balance the public need for access to effective therapies against the risks associated with their use. FDA has been proactive in addressing the issue of risk management. For example, as one of her first initiatives as Commissioner, Dr. Jane E. Henney established a Task Force to evaluate the system for managing risks of FDA-approved medical products, focusing particularly on FDA�s part in the system. We recognize that FDA is but one of many players that can and must have an impact on the safety of health care in the United States.

One of FDA�s primary responsibilities is in the premarket phase. A major goal of the premarketing review of a drug is to help ensure by the careful review of the data collected in the clinical trials that products are truthfully and adequately labeled for their intended use and target population. Approval of a drug product is based on FDA�s acceptance and review of data collected during the course of the drug�s development, including the results of clinical trials demonstrating that the drug is safe and effective for its intended use. No drug, however, is 100 percent safe; no pharmacologically active medicine exists that does not have side effects. FDA realizes that when an approved new drug becomes widely used in clinical practice, health care professionals may observe differences from clinical trial results in both the incidence and/or types of adverse drug experiences. For this reason, FDA's other primary responsibility is postmarketing surveillance--to monitor rare, serious, unexpected adverse drug events (i.e., serious or unexpected adverse reactions not described in the approved labeling). The Agency monitors reports from manufacturers, consumers, and health professionals to determine if any safety problems or trends can be identified and takes action accordingly.

After a drug is approved, the prescriber assumes primary responsibility for managing the product risks (and benefits) for the individual patient because of his/her specific knowledge of the unique circumstances surrounding each individual patient. In this situation, FDA�s role has been to assist the prescriber by requiring that risks and benefits are described in the labeling and promotional materials, and to assure, through postmarketing surveillance of reports of potential new safety information, that this new information about risks is relayed promptly to clinicians. To minimize risks, product labeling often describes how to select patients, how to select and modify the dose schedule for individual patients, how to avoid interacting treatments, how to monitor for drug toxicity, and what measures to use to avoid or mitigate drug toxicity. FDA and manufacturers rely on practitioners to prescribe products with full knowledge of the prescribing information and limitations detailed in the product labeling. Likewise, practitioners presume their patients will use their medications according to directions given. We know, however, that this does not always happen.

Because all drugs have risks, it is critical that patients are fully informed about potential side effects as well as benefits before deciding to take a particular medicine. Once the choice to take a product is made, patients need to understand how to take the medicine properly, the precautions they should observe, and the signs of possible side effects. FDA has worked for over two decades to help ensure that patients get the full information that they need to take medicines as safely as possible. In 1980, the Agency published a rule requiring FDA approved patient labeling for ten drugs/drug classes, with the expectation that this would be extended to all prescription drugs. In 1982, the rule was revoked in favor of private sector efforts to provide patient information that FDA would monitor.

By 1994, FDA surveys showed that only 58 percent of patients were receiving some sort of information with prescriptions. Therefore, in 1995, FDA published a proposed rule, commonly called MedGuide, that set forth goals for the distribution of useful prescription drug information to consumers, and would have required manufacturers to include drug information for the patient when a product posed a serious and significant public health concern. In August 1996, Congress passed legislation that provided another opportunity for private achievement of the MedGuide goals. Consequently, a private sector Action Plan was developed to meet the need. In 1998, FDA published a final rule requiring patient labeling (MedGuides) for products that pose "serious and significant" public health concerns, anticipating an average of no more than five to ten products annually. This rule became effective on June 1, 1999, and provides the framework under which the proposed Accutane MedGuide is being developed. For the vast majority of products that will not have MedGuides, patient information given out with prescriptions is expected to be provided by the voluntary private sector effort.

Adverse Effects Associated with Accutane

When Accutane was approved, the most common adverse reaction reported was severe drying and chapping of the lips, which occurred in about 90 percent of patients. In addition, 25 percent of patients treated had an elevation of serum triglycerides (fatty substances in the blood), and elevated cholesterol levels. The labeling of the drug, therefore, suggested that physicians closely monitor these levels during treatment. Also, the approved labeling also informed physicians that about 40 percent of patients developed conjunctivitis, 16 percent developed musculoskeletal symptoms, less than 10 percent of patients experienced rash or thinning of hair, and about five percent experienced peeling of palms and soles, skin infections, nonspecific urogenital findings, nonspecific gastrointestinal symptoms, fatigue, and increased susceptibility to sunburn. Because teratogenicity was observed in animals, Accutane was contraindicated in patients who were pregnant or planning to become pregnant, or in nursing mothers.

During the first ten years after the initial marketing of Accutane, the primary focus of concern was managing the established risk of birth defects, a risk initially suspected and noted in the labeling. FDA�s staff held numerous meetings with the company, analyzed adverse event reports, and convened at least seven Advisory Committee meetings.

Because Accutane is the only currently available product that can potentially cure cystic acne, FDA permitted the continued marketing of the product in spite of the known risk of birth defects and other serious reactions. FDA has proceeded to periodically reassess the risk/benefit equation. From 1983 through 1988, FDA and the company stepped up efforts to communicate the significant risks to women of child-bearing age. These efforts included:
1) physician labeling changes; 2) repeated mailings of special letters to doctors and pharmacists detailing proper use and emphasizing the risks; 3) two articles in FDA�s Drug Bulletin, which reached more than a million health professionals, emphasizing proper prescribing of Accutane; 4) distribution to patients through doctors of a patient information leaflet highlighting the risks; 5) distribution to pharmacists of red warning stickers to be placed on each prescription bottle; and 6) issuance of press releases and background papers to the general news media for use in warning the public about the risks associated with Accutane.

Despite these efforts, there was evidence that the drug was being used in thousands of women of child-bearing age with less severe acne than that for which the drug was approved, i.e., for severe recalcitrant cystic acne which does not respond to conventional therapy. In 1988, the Centers for Disease Control and Prevention (CDC) published an article describing four cases of multiple, serious birth defects occurring from 1983 to 1987, and cited additional cases previously reported. Consequently, FDA convened another Dermatologic Drugs Advisory Committee (the Committee) meeting to consider various options for dealing with the problem. The Committee listened to presentations from experts in several medical specialties, as well as scientists from CDC, FDA, Hoffman La-Roche, Public Citizen�s Health Research Group, the American Academy of Pediatrics, and the American Academy of Dermatology. At FDA�s request, additional experts participated in the deliberations, including doctors specializing in obstetrics, birth defects, genetic diseases, reproductive sciences, clinical pharmacology, and epidemiology.

At the end of the day-long session, the Committee unanimously recommended continued sale of Accutane with revised labeling for physicians and patients and further restrictions in connection with distribution of the drug including: 1) increased prominence and strength of warnings and contraindications through new packaging, and more explicit information about the degree of risk; 2) recommended use only in women who have had a negative pregnancy test (if they are able to bear children); and 3) written acknowledgement from patients taking the drug that they have been informed of the risk of birth defects. In a split vote, the Committee recommended that the drug�s use be restricted by one or more of the following: 1) dispensing only by certain physicians, 2) special restrictions for high risk patients, 3) requiring a second opinion for high risk female patients, or 4) requiring an educational program for certification of physicians to dispense the drug. The Committee also asked for continued monitoring of use and reports of all adverse events.

After the Committee made its recommendations, in May 1988, FDA issued a letter to Hoffman-La Roche outlining actions designed to limit or prevent misuse of the drug. The May l988 letter provided in part: 1) that Accutane be dispensed in a blister pack with the patient warnings (including pictures showing the severity of birth defects) and other information as part of the package itself (this information was provided in addition to the pamphlets physicians provide to patients); and 2) physicians and women patients be asked to sign a form acknowledging their understanding of the very great likelihood of serious birth defects if the drug was taken during pregnancy. More detailed physician and patient labeling was also mandated. FDA�s letter also called for extensive educational campaigns aimed at physicians, pharmacists, and patients and encouraged publication of advertisements on the teratogenic effects of the drug.

Furthermore, FDA�s 1988 letter stated that the blister pack should include a tear-off postcard addressed to the company requesting the patient�s name, telephone number, address, and permission to be contacted by the company for studies requested by FDA. FDA requested a follow-up study to ascertain patient awareness, disease status, contraception use, information regarding any pregnancy, and the outcome of that pregnancy. The letter also requested reporting of all pregnancy exposures and an effort to find out why patients, despite warnings, became pregnant or used the drug when already pregnant. The company was asked to do further clinical trials using lower doses of the drug, or higher doses for a shorter period of time.

In mid-1989, the company fully implemented its "Pregnancy Prevention Program for Women on Accutane." This program included the unprecedented educational efforts and restrictions requested by the May 1988 letter from FDA. Consequently, in May 1990, Accutane underwent review by FDA�s Dermatologic Drugs Advisory Committee. FDA asked the Committee to evaluate the effectiveness of the company�s efforts to curb drug/pregnancy exposures and birth defects, and whether additional measures were necessary. The Committee concluded that the manufacturer made a very strong effort to inform patients and physicians of the risk associated with Accutane but that the data on recent efforts was limited. Data included one infant reported with defect in 1990, four in 1989, and three in 1988, compared to ten for 1987 and 12 for 1986. The Committee recommended: 1) that educational materials emphasize the importance of the initial pregnancy test before beginning treatment with Accutane; 2) that physicians stress to patients the importance of the informed consent forms and that such forms be available in numerous languages; 3) pregnancy prevention counseling be made available and emphasized; and 4) that the manufacturer design a program to ensure that patients returned all leftover medications so they would not take Accutane without a dermatologist�s supervision.

Warnings Regarding Accutane and Depression and Suicidal Behavior

The original New Drug Application (NDA) safety database for Accutane did not contain reports of depression or mood disorders. In the mid-1980s, however, due to postmarketing reports of depression, a labeling revision was done to include depression as part of the adverse reactions section. The labeling provided: "Depression has been reported in some patients on Accutane therapy. In some of these patients, this has subsided with discontinuation of therapy, and recurred with reinstitution of therapy." In addition, the adverse reactions section stated: "The following CNS reactions have been reported and may bear no relationship to therapy: seizures, emotional instability, dizziness, nervousness, drowsiness, malaise, weakness, insomnia, lethargy, and paresthesias."

FDA began a re-evaluation of the psychiatric illness reports in 1996, when a physician in the reviewing division noted two cases of suicide in a routine listing of recent adverse events associated with Accutane. Reports such as this do not necessarily mean that the event has any relationship to the drug. Accutane, however, had previously been associated with depression as already noted in the Accutane labeling. Because suicide is the most serious consequence of depression, the FDA reviewing division enlisted the help of specialists in the FDA epidemiology division to try to determine whether the cases could possibly be related to Accutane use. The division undertook a systematic analysis of the published literature, previously reported cases entered into databases, and incoming safety reports.

These reports were not numerous relative to the rate of depression and suicide expected to be seen in the population likely to receive Accutane, namely teens and young adults (sometimes referred to as the "background" rate). Some of the reports, however, included important details that did suggest the possible involvement of Accutane. Some reports described a consistent pattern of symptoms in patients with no previous history of such symptoms and no other identifiable reason for their occurrence. Other cases were described in which the symptoms began during the Accutane treatment and then resolved soon after the medicine was stopped. In a subset of these cases, Accutane was then restarted and the same symptoms returned. While these findings do not prove that Accutane causes psychiatric illness, they are suggestive of a possible link.

In May 1997, when an association appeared possible, FDA began working with the company to fully evaluate the data and determine appropriate next steps. In February 1998, a labeling change included psychiatric adverse events in the professional labeling�s Warnings section, stating: "Psychiatric Disorders: Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts, and suicide. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary. No mechanism of action has been established for these events (see Adverse Reactions: Psychiatric)." The Adverse Reactions section stated "psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis (see warnings: Psychiatric Disorders), emotional instability." While Accutane labeling had previously included depression in the adverse reactions section, it was believed that the addition of wording that called attention to possible suicidal behavior would help to ensure that prescribers would take appropriate actions if patients developed mood changes. Even though a causal relationship between Accutane and suicidal behavior still had not been scientifically established, this action was thought prudent given the available information.

In addition, a letter was sent to doctors who might prescribe Accutane, as well as those likely to see patients who develop psychiatric disturbance. FDA also posted a special notice about Accutane on its public website and released a Talk Paper to the press to help ensure wide attention and dissemination of this warning. FDA also instructed the company to discontinue promotional claims regarding the psychosocial benefits of Accutane treatment for acne.

Patient information is intended to remind patients about important things they discussed about their treatment with their prescriber. It is often not identical to the wording of professional labeling. Prior to the 1998 change in the professional labeling, there were five "signs" of potentially serious problems listed as bullets for patients, with all capital letter instructions to stop Accutane and call their doctor immediately. All of these "bullets" except mood changes reflected serious adverse events in the Warning section of the professional labeling. Thus, when psychiatric problems were upgraded in 1998 to the Warning section of the professional labeling, it was already in the proper list in the patient information. As with other "symptoms" of possible serious or fatal problems, the patient information on mood changes did not include specific information about the possible outcome (suicide), instead being followed by the advice to stop the drug and call the doctor immediately due to the possibility of serious consequences. For example, the patient information said to watch out for yellow skin or abdominal pain. This reflects professional labeling about hepatotoxicity or pancreatitis, which can be fatal.

After the 1998 change regarding psychiatric disorders, FDA embarked on a very comprehensive re-assessment of the overall labeling and risk management for Accutane. This comprehensive re-evaluation included the following: 1) ways to improve methods to prevent birth defects; 2) possible interactions with drugs not on the market in 1982 when Accutane was approved (e.g., new contraceptive therapies); 3) epidemiologic study of accumulating reports of adverse events not in the labeling to decide on inclusion; 4) safety issues specific to young growing patients; 5) re-organization of the information to make it more useable for prescribers; and 6) re-design of the patient information to improve visibility of items not related to pregnancy prevention, adding new information, and providing specific information about possible outcomes for serious events. The revised patient information resulting from this work was implemented on an interim basis with a commitment by the manufacturer to conduct patient comprehension testing and to pursue further revisions. The interim revision, implemented in the summer of 2000 captures the possible outcome for mood disorder (suicide) but did not accomplish this goal for all of the bulleted serious adverse events.

FDA and the company also began to address the need for further research into the potential link between Accutane and psychiatric events soon after the 1998 labeling change. Roche began a number of studies. The company and FDA had frequent working meetings and some results were submitted to FDA beginning in late 1999. Some of these studies were discussed at the September 2000 meeting of FDA�s Dermatologic and Ophthalmic Drugs Advisory Committee, at least one has been published, and the results of another are expected soon. To date, these studies do not provide a definitive answer. It is very likely that a controlled masked clinical study would not be feasible for ethical and technical reasons and a major goal of seeking outside expert advice in September 2000 was to explore other approaches.

September 2000

As noted previously, in September 2000, the Dermatologic and Ophthalmic Drugs Advisory Committee again discussed Accutane. The two major topics were prevention of fetal exposures and risk management strategies for the uncertain risk of psychiatric effects associated with the use of Accutane. On the pregnancy prevention issue, the Committee agreed on the following three goals or principles: 1) no one should begin Accutane therapy if pregnant; 2) no pregnancies should occur while on Accutane therapy; and 3) a monitoring program should be implemented to assess progress toward these goals. FDA presented five designs to achieve these goals, and the majority of the Committee voted on a design that included: 1) education and informed consent; 2) complete participation including registration of patients and physicians; and 3) tracking of pregnancy exposures including a pregnancy registry, surveys, and external data. The Committee did not want restricted distribution.

On the issue of psychiatric events, the Committee unanimously agreed that there was sufficient concern about Accutane to justify exploring additional risk management strategies even though the risk was uncertain. The Committee recommended that the manufacturer: 1) add the information about the adverse events to the informed consent document signed by patients and/or their parents or guardians prior to receipt of Accutane; 2) develop and distribute an enhanced prescriber educational program about the psychiatric events; and 3) develop and distribute a Medication Guide for Accutane. The Committee also was asked whether further studies to help clarify the relationship between Accutane use and psychiatric events were needed and if so, what kind of studies. The Committee discussed the many ethical and technical problems with a controlled clinical trial and offered ideas for other types of studies with an emphasis on basic science research, particularly focused on the adolescent central nervous system, as well as epidemiologic studies in addition to those already underway. The Agency is working with the manufacturer to implement the Committee�s recommendations.

Conclusion

Accutane continues to be one of the more challenging products FDA regulates. We think the record demonstrates the Agency�s continued concern regarding this product and our efforts to manage the associated risks. We hope that the future will bring a product effective for severe recalcitrant cystic acne without the risk of birth defects or other possible serious adverse events. We are also hopeful that research will establish whether or not the psychiatric events associated with the use of Accutane are truly caused by the drug. We will continue to work with the manufacturer to keep health professionals and consumers aware of the risks associated with Accutane and the circumstances under which it should be used and prescribed. Thank you for the opportunity to discuss this important matter.