Introduction
Mr. Chairman and Members of the Committee, I am Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA or the Agency).
I appreciate the opportunity to discuss the Committee’s concerns regarding the prescription drug, Accutane (isotretinoin). Helping to ensure the safe and effective use of Accutane involves challenging scientific and ethical issues for FDA. We have taken our regulatory responsibilities concerning this drug very seriously. Since we last testified before Congress regarding Accutane, on December 5, 2000, we have been involved in many activities regarding this drug. These actions include updated labeling, educational programs for patients and prescribers, implementing an innovative, comprehensive risk management program, and on-going monitoring of both adverse event reports and performance of the risk management program.
FDA approved Accutane in 1982 for use in treatment of severe, recalcitrant nodular acne that is unresponsive to conventional therapy, including antibiotics. In most cases, cystic acne is disfiguring and painful, causing red cysts and deep nodules that can leave deep scars. Accutane is uniquely effective in treating patients with this disease, and in many cases is curative after a single 4 to 5 month treatment course. Accutane can, however, be associated with serious adverse events including birth defects. For these reasons, it continues to be one of FDA’s most difficult challenges in the area of post-approval management.
This testimony will provide the Committee with an update on FDA’s post-marketing activities regarding Accutane.
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 Accutane. We recognize that FDA is but one of many players that can and must improve on the safety of health care in the United States.
During the review of a new drug application, FDA carefully reviews the data from the clinical trials to ensure that products are truthfully and adequately labeled. Approval of a drug product is based on FDA’s assessment that the benefits of the drug outweigh the risks for the intended use and population. 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 also conducts post-marketing 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.
Once a drug is approved, the prescriber assumes primary responsibility for managing the product risks (and benefits) for the individual patient through specific knowledge of the unique circumstances surrounding each patient. In this situation, FDA’s role has been to assist the prescriber by requiring a description of the risks and benefits in the labeling and promotional materials, and to assure, through analysis of reports of potential new safety information, that this new information about risk is relayed promptly to clinicians. To minimize risks, product labels often describe how to select patients, how to select and modify the dose schedule for individual patients, how to avoid interactions with other 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 they need to take medicines as safely as possible. For example, 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, which set forth goals for the distribution of useful prescription drug information to consumers. It 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 the private sector to achieve the MedGuide goals. Consequently, a private sector Action Plan was developed to meet the need. In 1998, FDA published a final rule requiring patient labels (MedGuides) for products that pose “serious and significant” public health concerns, anticipating that five to ten products would be subject to this requirement annually. This rule became effective on June 1, 1999, and provided the framework under which the Accutane MedGuide was developed. For the vast majority of products that will not have MedGuides, patient information distributed with prescriptions is expected to be provided by the private sector’s voluntary efforts.
Following the approval of Accutane in 1982, it became evident that a formal risk management program would be needed due to the drug’s harmful effects in pregnancy. In our testimony before the House Government Reform Committee in December 2000, we outlined the details of our activities up until the most recent advisory committee meeting in 2000.
On September 18 and 19, 2000, FDA convened a meeting of its Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) to re-examine the issues of pregnancy.
Psychiatric Adverse Events
While the advisory committee did not express certainty that a causal relationship exists between Accutane and serious psychiatric events such as severe depression and suicide, they recognized that the potential for adverse psychiatric events is of substantial concern. The advisory committee recommended a number of strategies to help manage this potential risk.
Patient Education
The committee recommended a “Medication Guide” for patients to provide more information in plain language about the possible side effects of Accutane than could be covered in the existing patient information on the actual medication package. The “Medication Guide” for Accutane was approved in January 2001. It must be distributed by the pharmacist to every Accutane patient each time an Accutane prescription is dispensed. The “Medication Guide” was developed in conjunction with FDA to emphasize key safety issues that patients should know about the use of Accutane. It summarizes, in layman’s language, information in the Professional Package Insert, including the approved indication for Accutane and major adverse events reported in the package insert.
The advisory committee also recommended use of a consent form for all Accutane patients addressing possible psychiatric side effects. The Informed Consent form for Accutane is intended to be used by the prescriber after the prescriber has determined that a patient may be a candidate for Accutane, and has explained the proper use of this medication and its possible side effects. Patients then initial each of the items on the form and sign and date the entire form, thereby acknowledging their understanding of the information presented. The prescriber also signs this document. The signed and dated documents can then be placed in the patient’s medical records.
To summarize, both the “Medication Guide” and the “Informed Consent” documents explain in plain language the benefits and risks of taking Accutane. These documents supplement other patient education materials provided by Hoffman LaRoche, such as Important Information Concerning Your Treatment with Accutane®; (isotretinoin) –7th Edition (patient’s brochure). Patient education materials are intended to be used by prescribers in discussions with patients to ensure they have information necessary for safe and effective use of Accutane.
FDA also established an Accutane Drug Information webpage on FDA’s website and FDA Consumer Magazine published an article in March 2001 discussing the risks and benefits of Accutane in layman’s language.
Research
The advisory committee recommended research to explore possible mechanisms, risk factors, and management options for psychiatric complications. FDA’s Office of Pharmaceutical Sciences and the National Center for Toxicologic Research (NCTR) are conducting animal studies to identify possible experimental models to further these goals. Presently, NCTR is in the final stage of review for approval of their proposed research. Due to the nature and priority of this work, the experimental design took an unprecedented amount of planning and review.
FDA also began collaboration with the National Institute of Mental Health (NIMH) to address the need for independent research. Subsequently, NIMH held a workshop on November 19, 2002, to discuss basic scientific research into the effects of retinoids on the central nervous system. Retinoids are chemical compounds that act on the vitamin A recognition sites in the body. Accutane (isotretinoin), is a retinoid compound. Neuroscientists presented preliminary research results from animal and in-vitro studies. At the conclusion of the workshop the participants concluded that there was a need for additional basic research in this important area and the NIMH expressed interest in providing funding. We hope that this basic research into possible pathophysiologic mechanisms will generate specific, clinically relevant hypotheses. These hypotheses, in turn, can guide design of future clinical studies aimed at identification of risk factors and management options to allow the greatest number of patients who need isotretinoin to use it with maximal safety. This groundwork is of particular importance in the case of research on isotretinoin and psychiatric adverse events because there are a number of very significant technical and ethical problems with the type of trial usually conducted to settle causality questions (i.e., a large randomized controlled trial). These problems arise because the drug is already on the market and recruitment of patients with scarring acne for a controlled trial would be very difficult and poses ethical questions. In addition, the mucocutaneous side effects of the drug would make it impossible to do the study in a “masked” fashion, which is very important to avoid bias and false results. Obviously, we cannot do a study where suicide is the endpoint; the less objective, but related, psychiatric endpoint, depression, is a problem because patients already know this drug works, and patients in the study would ethically have to need the treatment. Thus, there would be a large incentive to hide psychiatric symptoms in order to avoid being discontinued from the study, again greatly increasing the chance of a false negative result. This is particularly worrisome because such a result could likely seriously undermine the progress made to date in education and awareness.
Prescriber Education
FDA has worked to improve prescriber awareness by a variety of avenues. These include:
Since our last testimony on this issue in December of 2000, Hoffman-LaRoche has issued three “Dear Accutane Prescriber and Dear Pharmacist” letters advising of changes made to the Accutane Package Insert regarding psychiatric events. The first (January 2001) notified prescribers about the availability of the two new communication tools, the Medication Guide and the informed consent forms for all Accutane patients. The documents themselves were also sent, as have been tear-off pads with copies of each update. Now that the major Accutane label revisions have been completed, the Medication Guide has been affixed by manufacturers onto the actual package dispensed to patients to help ensure that the most current version is dispensed. The manufacturer of Accutane plans a voluntary package exchange at the pharmacy retail level in December 2002. The second Letter advised of the new diagnostic brochure noted above. The third (June 2002) noted updated label information concerning reported aggressive and/or violent behaviors based on post-marketing safety reports. This information was also added to appropriate sections of the patient Medication Guide and Informed Consent form and is on FDA’s Medwatch website.
Adverse Event Reports
The Adverse Event Reporting System (AERS)
AERS is a computerized database of post-marketing adverse events for all approved
drug and therapeutic biologic products. It was designed to support FDA’s
post-marketing safety surveillance program. FDA receives adverse drug reaction
reports from manufacturers as required by regulation. Health care professionals
and consumers voluntarily report either to the manufacturer or directly to FDA
(direct reports) through the MedWatch program. Presently, all manufacturer reports
of serious events and all direct reports are entered into the AERS database.
Non-serious manufacturer reports are not usually entered into AERS. Each report
may contain numerous coded adverse events that are both serious and non-serious.
Any serious event renders the entire report serious. The reports in AERS are
evaluated by clinical reviewers in the Center for Drug Evaluation and Research
(CDER) and the Center for Biologics Evaluation and Research (CBER) to detect
safety signals and to monitor drug safety.
AERS contains almost 23,000 reports for Accutane (isotretinoin) from approval in 1982 to December 2002. Approximately 90 percent of these reports are from the U.S. Among these reports the five most frequently reported reactions are, in descending order, alopecia, depression, headache, dry skin, and induced abortion. For 2002 thus far, AERS contains just over 1,100 adverse event reports of which 82 percent are from the U.S. During 2002, the five most frequently reported reactions are, in descending order, depression, pregnancy, induced abortion, suicidal ideation, and headache.
The Office of Drug Safety (ODS) within CDER maintains a quarterly cumulative count of reports of Accutane-exposed pregnancies and outcome, if known, based on the Hoffman LaRoche quarterly submission. The latest update as of June 2002 shows a total of 2,350 Accutane-exposed pregnancies and 172 babies born with a congenital defect or anomaly in the U.S. since the product was approved in 1982.
ODS has also kept a monthly cumulative count of psychiatric adverse event reports in AERS. As of November 30, 2002, AERS contains 3104 reports (U.S. and foreign) with at least one reported psychiatric event. FDA is aware of 173 reports of suicide in association with Accutane (includes U.S. and foreign, but excludes duplicates). FDA has requested quarterly summaries of psychiatric events from Hoffman LaRoche. The most recent summary through August 2002 indicates approximately 6000 additional reports that include psychiatric events. A subset of these reports have been sent to FDA as required under the regulations, but are not in AERS because they are not coded as “serious.” The remaining reports (labeled, non-serious) are excluded from submission under FDA’s Waiver Program. Under the Waiver Program, the following conditions are imposed: (1) the sponsor is to hold in their corporate drug product safety files the individual case reports of adverse experiences that are non-serious and labeled; (2) submit these individual case reports to FDA within five-calendar days after receipt of a request by FDA to do so; and (3) continue to include the non-serious, labeled adverse experiences in each periodic adverse drug experience report submitted to FDA for the NDA. The sponsor must include the non-serious reports in the section that includes a summary tabulation by body system of all adverse experience terms and counts of occurrences submitted during the reporting period.
Birth Defects: the S.M.A.R.T. Program
Following the September 2000 advisory committee meeting, FDA and the manufacturer initiated an extensive series of meetings to implement a workable program aimed at meeting the two principal goals articulated by that committee: no woman should begin Accutane therapy if she is pregnant and no pregnancies should occur while a woman is taking Accutane. FDA acknowledges that the second goal may never be 100 percent achievable but expects that the program developed will be highly effective because it involves Accutane prescribers, patients, and pharmacists in a partnership to prevent fetal exposure, while minimizing perceived threats to patient privacy and access to needed therapy. This is of critical importance, since a risk management program unacceptable to stakeholders might well drive significant numbers of patients into alternative sources of drugs.
S.M.A.R.T. stands for the System to Manage Accutane Related Teratogenicity. It replaces the previous Accutane Pregnancy Prevention Program that was implemented in 1989. While S.M.A.R.T. is the prototype program, it is important to note that any approved brand of isotretinoin will have a program alike in all material respects in content to S.M.A.R.T.
Under the S.M.A.R.T. program, pharmacists dispense isotretinoin only upon presentation of a prescription with the special yellow isotretinoin Qualification Sticker. Pharmacists dispense a maximum one-month supply of Accutane, fill prescriptions within seven days from the date of “qualification,” and provide a Medication Guide for patients with each Accutane prescription. Requests for refills (i.e. more without a new prescription) and phoned-in prescriptions are not filled. The risk management components are described fully within the boxed Contraindications and Warnings (Black Box) and the Precautions sections of the Accutane package insert, which provides detailed conditions for prescribing isotretinoin to women of child-bearing potential. By affixing the special yellow Sticker to the prescription, the prescriber asserts that the conditions in the labeling have been met and that the patient is thus “qualified.” In essence, this means that a female patient has a negative pregnancy test each month, has received repeat counseling about pregnancy avoidance and birth defects, has chosen and agreed to use two effective forms of contraception or abstinence, and has been encouraged to join the follow-up survey to help monitor program performance. In order for prescribers to obtain the special yellow Stickers, they must attest to their cooperation with the program and to their competence to treat acne and manage a teratogenic drug. Patient educational materials inform the patient of what the special Sticker means. This innovative program, based as it is on a 3-fold partnership, should enhance the program’s effectiveness, since failure at 3 levels is less likely and liability in the event of failure should be clear.
S.M.A.R.T. includes a number of practical tools to help patients, prescribers, and pharmacists manage the risk of birth defects. These include an updated second informed consent form for female patients, information in the Medication Guide, a patient video, separate patient education kits for men and women, a Guide to Best Practices for prescribers, a pharmacist Dispensing Guide, and carton instructions.
Prescribers receive a Letter of Understanding from the manufacturers to which they apply for the special Stickers. At the time of S.M.A.R.T. introduction, FDA sent a letter to all state boards of pharmacy and is involved in on-going leveraging with pharmacy and prescriber professional organizations to enhance the likelihood of program success. Both of these important stakeholder groups have expressed enthusiastic support for working toward full participation by their memberships and achievement of program goals.
Measuring Program Performance
To measure the effectiveness of the S.M.A.R.T. program, isotretinoin manufacturers are using two independent outcome assessment approaches. These are the isotretinoin patient survey, and an independent audit of pharmacies to assess the use of Accutane Qualification Stickers by prescribers. Prescribers, patients, and pharmacists have all been asked to participate fully in these critically important measures because valid data to assess program effectiveness depends upon a representative sample of the population at risk.
One way to ensure a representative “sample” would be to include all women who take isotretinoin. To this end, development of a mandatory patient registry for Accutane was presented as an option at the September 2000 advisory committee meeting. Detailed plans were not discussed, but the committee advised, in a general way, complete patient registration. They did not advise registration of pharmacies. Mandatory patient registration, in and of itself, does not manage risk, rather, it is a risk assessment tool that might provide a improved understanding of the S.M.A.R.T. program performance due to elimination of bias. However, when contemplating any program elements, unintended consequences need to be evaluated. CDER has encountered such unintended consequences in other risk management programs we have implemented.
In working with the sponsor to design a detailed risk management program, we found that there are a number of significant complications in this case. The medical community has not been supportive of the idea of a mandatory registry for patients. Almost all Accutane precribers are dermatologists. The main dermatologic professional organization, the American Academy of Dermatologists, as well as the American Medical Association, have contacted FDA and expressed their views, that a mandatory registration or burdensome restrictions in the risk management program would not be receptive to the majority of their members. There are also significant perceived patient privacy concerns, and as noted earlier, very real concerns that risk management tools unacceptable to patients might drive them into alternative medication sources on the Internet. This is a very dangerous option for a drug with numerous potentially serious side effects in addition to birth defects. The alternative of seeking high voluntary patient participation was thus selected.
The metrics described above for S.M.A.R.T. were included in the official approval action for the program. In addition, specific performance goals have been prospectively stipulated. Hoffman LaRoche committed to 90 percent compliance with the prescription Sticker program and 60 percent participation in the patient survey within the first year of S.M.A.R.T. implementation. Assessment by FDA of program effectiveness will address a global review of S.M.A.R.T. performance metrics, including compliance with the sticker program, participation in the patient survey, and any other pertinent data.
If FDA concludes that the program has failed or that the collected data from the voluntary metrics are insufficient to determine program performance, manufacturers, prescribers, pharmacists, and patients are already on notice that more stringent and rigorous options designed to increase effectiveness will need to be explored. FDA and the innovator will develop back-up plans, but the hope is that education and awareness will lead to success of the S.M.A.R.T. program now in place, a program that is “owned and operated” by the partnership of patients, prescribers, and pharmacists, rather than by government
Generic accutane
FDA approved the first generic version of isotretinoin, Amnesteem, on November 8, 2002. The generic product will be marketed by Bertek Pharmaceuticals of Research Triangle Park, NC, the branded arm of Mylan Laboratories. All generic brands of isotretinoin will utilize the labeling that is alike in all material respects to the name brand, educational tools, distribution requirements, and follow-up metrics in place under S.M.A.R.T. Like the innovator, generic manufacturers are on notice that failure of the risk management plan, or failure to collect valid data, will obligate consideration of more burdensome measures.
Internet sales and Imports
As already mentioned, Internet sales of Accutane present a significant public health risk. Obtaining Accutane (Isotretinoin) on foreign websites can allow patients to bypass the risk management requirements for Accutane. Moreover, Accutane obtained through foreign websites is generally an unapproved version of the drug. The Agency has posted a special alert on its home page warning consumers that certain restricted distribution drugs, including Accutane, should not be purchased over the Internet. FDA has also put these restricted distribution drugs on Import Alert, informing the Agency’s import inspectors that shipments of these drug are not appropriate for admission into this country under FDA’s Personal Importation Policy. We have also specifically informed Customs about the fact that these dangerous drugs should not be admitted.
Nonetheless, Internet purchases of Accutane will not be eliminated by these efforts. The Agency has identified a number of websites, primarily in foreign countries, which sell Accutane, either with no prescription, with only an on-line questionnaire, or based on a faxed prescription. Hoffman LaRoche sent a letter to FDA, dated November 26, 2002, which also identified Internet websites selling Accutane. FDA takes this problem very seriously and is in the process of actively investigating websites selling Accutane and evaluating options for enforcement action.
Conclusion
FDA has worked diligently with the manufacturers and the medical and scientific communities to assure that patients have access to Accutane under conditions that make its use as safe as possible. FDA will continue its vigilance and keep health professionals and consumers aware of the risks associated with isotretinoin and the circumstances under which it should be used and prescribed. We will vigorously evaluate the S.M.A.R.T. program, and, if it is not performing as expected, consider additional risk management interventions. Thank you for the opportunity to discuss this important issue.
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