Issues Relating to the Safety of Accutane

Subcommittee on Oversight and Investigations
December 11, 2002
09:30 AM
2123 Rayburn House Office Building 

George B. Abercrombie
President & Chief Executive Officer
Hoffmann-La Roche Inc.
340 Kingsland Street
Nutley, NJ, 07110

Mr. Chairman and Members of the Subcommittee, I am George Abercrombie, President and Chief Executive Officer of Hoffmann-La Roche Inc. ("Roche"), a research-based pharmaceutical company.  I am a registered pharmacist, and I practiced retail pharmacy prior to spending almost 20 years in the pharmaceutical industry, joining Roche in January, 2001.  I am accompanied today by my colleagues Dr. Susan Ackermann, who is the Head of Risk Management in our Department of Drug Safety and Risk Management, and Dr. William Smith, Director of Medical Science.

You have invited us here today to discuss Accutane® (isotretinoin), our pharmaceutical product indicated for the treatment of Severe Recalcitrant Nodular Acne.  In my testimony, I will describe some of the issues we have faced in ensuring the safe and effective use of Accutane, and our scientific and risk management initiatives.

Let me first personally convey our tremendous sympathy for the Stupak family, whose tragedy served as the impetus for the Subcommittee's review of Accutane.  Although I can only imagine how devastating such a tragedy must be, as the father of two teenage sons I know how precious they are to me and my family.  Congressman Stupak, although we may differ on some important points, I hope you know that we have tried to directly and vigorously address the concerns expressed by you and your colleagues.

We also fully appreciate that this hearing is based upon the broader oversight role of this Subcommittee.  It is our hope that this hearing can be a part of the ongoing constructive dialogue on how best to address the complex issues often associated with adverse events and risk management, particularly in the context of a teratogenic drug product.  Moreover, although we may differ as to whether Accutane is associated with psychiatric adverse events, we strongly believe that the broader issue of depression and suicide among young people is a major public health concern that calls for further research and education. 

Accutane and Severe Recalcitrant Nodular Acne 

In considering the issues presented today, it is critical to understand why Accutane is such an important medication.  I have appended to my testimony several photographs of typical cases of Severe Recalcitrant Nodular Acne for your review.  As you can see, unlike in less severe forms of acne, in Severe Recalcitrant Nodular Acne a number of factors combine to cause nodules or inflammatory lesions.  These lesions, typically found on the face, chest and back, can be extremely painful and often result in a lifetime of scars if left untreated. 

As in many other medical conditions, the causes of Severe Recalcitrant Nodular Acne are not fully understood.[1]  However, Accutane is a uniquely effective treatment for this disfiguring condition. Accutane is typically used after patients have failed topical and systemic antibiotic treatments for this severe form of acne, and have no other therapeutic options.  Over 80 percent of patients require only one 4-5 month course of treatment to eliminate the Severe Recalcitrant Nodular Acne and avoid disfiguring scars. 

Over six million U.S. patients have benefited from Accutane since it was first approved by the Food and Drug Administration (FDA) in 1982.  We believe such prescribing is generally appropriate and intended to alleviate the suffering of patients with Severe Recalcitrant Nodular Acne rather than less severe conditions.  In a small number of patients, Accutane is also used in the treatment of a variety of cancers.  Ultimately, we must rely on the physician to use appropriate judgment in the practice of medicine, weighing the risks and benefits of the drug in consultation with patients and their families.

We are quite proud of the benefits of Accutane, and we often receive spontaneous letters and e-mails from patients providing personal testimony as to their dramatic experience with the drug.  These patients often document how Severe Recalcitrant Nodular Acne fundamentally affected their lives -- including complete isolation from social situations and the bleeding and constant pain of acne nodules -- and how Accutane transformed their lives greatly for the better.  We are thus committed to ensuring that the many patients with Severe Recalcitrant Nodular Acne have access to this important medication.

However, Accutane is a very powerful medication, and the profound benefits of the drug are accompanied by serious risks that must be managed by all who are responsible for its manufacture, prescribing, dispensing and use.  Roche takes these responsibilities very seriously.  Since the introduction of Accutane in 1982, we have been committed to continuing to manage the known risks associated with Accutane, as well as to addressing, based upon sound scientific principles and methods, potential safety concerns derived from adverse event reports.  Indeed, because we take our responsibilities so seriously, we have led the industry in developing and implementing innovative risk management programs.  

Safety of Accutane 

Although there are a number of well-recognized adverse events associated with Accutane, our central concern throughout this drug's history has been teratogenicity, or the potential for birth defects.  Unlike some of the other adverse events in the Accutane patient population, such as the issue of psychiatric adverse events, there is no scientific doubt that isotretinoin is a potent teratogen.  Since the approval of the drug in 1982, we have worked with FDA to assure that prescribers and patients are aware that Accutane can cause birth defects, and that every effort must be made to prevent pregnancy for one month prior to starting treatment, while taking Accutane, and for one month after concluding therapy.  Indeed, although our patient labeling and risk management measures have evolved significantly over the last 20 years, it is worthwhile noting that Accutane was one of the first drugs to be accompanied by a patient brochure, which communicated the teratogenic risks associated with the drug at the time of introduction.

In the late 1980s, these early efforts evolved into a revolutionary Pregnancy Prevention Program, which was recently enhanced in close coordination with the FDA and is now called the "System to Manage Accutane Related Teratogenicity," or the "S.M.A.R.T." program, which I will describe in detail.

I have appended the physician, pharmacist and patient materials associated with the Accutane Risk Management Program, which I urge you to review, as it represents the most extensive program of its kind for a major prescription pharmaceutical.  It is our hope that this enhanced program will ultimately enable us to reach our public health goals of no woman starting Accutane while pregnant and no woman becoming pregnant while on Accutane.  

Psychiatric Events in the Accutane Patient Population 

We have also addressed adverse events that have not been proven to be associated with Accutane, but serve as signals for further study, analysis and, when appropriate, labeling.  These include psychiatric adverse events reported in the Accutane patient population.

First, let me relate some critical background facts about psychiatric problems among young people.  Simply put, depression and suicide in that population -- a group which is highly represented in the population prescribed Accutane -- is an enormous public health problem.   According to the Surgeon General's 2001 National Strategy for Suicide Prevention:

• For young people 15-24 years old, suicide is the third leading cause of death, behind unintentional injury and homicide. 

• Every 17 minutes, another life is lost to suicide.  Every day, 86 Americans take their own life and over 1500 attempt suicide.  There are now twice as many deaths due to suicide than due to HIV/AIDS.

• For every completed suicide, there are five hospitalizations and 22 Emergency Department visits for suicidal behaviors - over 670,000 visits in a year.

Psychiatric adverse events are not like typical adverse events that have a clear physical manifestation.  Rather, there are a complex range of behavioral, biochemical, genetic and environmental factors implicated in psychiatric disease.  Unfortunately, due to a number of factors, including the unfortunate and unwarranted stigma associated with mental health issues, these problems are often hidden by those who suffer from them.  Thus, suicides often occur without any clear indication of a need to intervene.  Mental disorders are also difficult for even many medical professionals to diagnose accurately, despite the relatively high background rate in the patient population.  In fact, one of the major themes of the National Strategy for Suicide Prevention is integrating suicide prevention into existing health services activities, including clinics and medical offices.

Given the widespread nature of psychiatric events, including suicide, it is unfortunately not surprising to find deaths by suicide in the Accutane patient population.  Indeed, you will find that a broad range of prescription pharmaceutical products have labeling regarding depression, suicidal ideation, and suicide in patients, including products as diverse as oral contraceptive, anti-infective, anti-viral, anti-seizure and anti-fungal medications.  Typically, there is no scientifically proven relationship between the events and the prescription drug product. 

In fact, as a matter of science it is often extremely difficult, if not impossible, to discern whether events of this type are related to a medication.  This Subcommittee may be presented with theories regarding how a relationship could exist between Accutane and psychiatric events.  We can only respond to such theories with the scientific methodologies that form the foundation for drug safety, labeling and risk management.  In addition to the extensive studies conducted for approval of Accutane, and 20 years of drug safety monitoring, Roche has completed several epidemiological studies specifically probing these psychiatric concerns using different methodologies and data sources, and one clinical study that included the evaluation of depression in patients.  The science has not shown that Accutane causes depression, suicide, or other psychiatric events.  Indeed, even using conservative assumptions, the rate of psychiatric events in the Accutane patient population does not appear to deviate from the background incidence of such events in a comparative population.  Thus, we continue to believe the psychiatric conditions reported in temporal association with Accutane therapy are consistent with the multiple risk factors in the population as a whole, as well as the subpopulation of young adults afflicted with the disfiguring disease of Severe Recalcitrant Nodular Acne.

However, we have by no means abandoned our effort to discern any potential link between Accutane and psychiatric events.  Last year, we convened an expert panel, to which we invited both FDA and the National Institutes of Mental Health, to provide input on the design of a prospective clinical study.  We then submitted an extensive draft protocol to FDA, engaged in a series of discussions with the Agency, and produced multiple iterations of the protocol.  Ultimately, FDA found that the revised protocol could not overcome the daunting methodological problems associated with addressing this issue.  For example, although we made extensive efforts to ensure that the study would be blinded - i.e., patients would not know whether they were on Accutane or placebo - FDA remained concerned that patients who were on the drug would recognize its dermatologic effects and avoid disclosing psychological symptoms.  We will continue to evaluate other sound methodological approaches to the issue.

FDA also asked the National Institute of Mental Health to screen isotretinoin and its metabolites for biochemical activity, and Roche provided the research material for those studies.  It is our understanding that these studies, like others in the past, were inconclusive.  However, studies of this type could conceivably help us arrive at new hypotheses to explore. 

Accutane Labeling and Risk Management 

As noted, our efforts to ensure safe and effective use of Accutane treatment are not limited to scientific study.  We have broken new ground in programs that both manage known risks and address the psychiatric events that occur in the patient population.  Nonetheless, although more and more labeling information is now directed to patients, the success of pharmaceutical risk management has historically been, and remains, dependent upon the physician as the learned intermediary.  We must continue to rely upon the physician to make an informed judgment as to the need for a given treatment, and to communicate critical information to patients. 

Beginning in 1983, Roche began receiving occasional reports of psychiatric adverse events in patients who were taking Accutane or had taken Accutane sometime in the past.  We submitted these reports to FDA, and in December of 1984 we approached FDA to request that the professional labeling information for Accutane be revised to include the reports of depression and emotional instability in the Accutane patient population.

In 1985, and again in 1986, we sent letters to the medical community describing the changes to the Accutane professional labeling relating to the small number of reports Roche had received regarding depression in some patients who were taking Accutane.  During this time, the patient brochure, and later the patient blister packaging, specifically alerted patients to be aware of potential changes in mood during Accutane treatment, and counseled patients experiencing such symptoms to discontinue taking the product and to check with their physician as soon as possible.  These materials also instructed patients to inform their physicians of any personal or family history of depression prior to beginning treatment with Accutane.  Over the years, we actively monitored spontaneous psychiatric adverse event reports along with all other adverse event reports in the Accutane patient population.  Notably, although the exposure to Accutane increased over time, the reporting of psychiatric events remained steady and well below incidence levels in the overall population.

As a result of ongoing discussions with FDA, in 1997 FDA asked Roche to take a closer look at the adverse psychiatric event reports in patients who were taking Accutane.  Roche conducted a cumulative safety review and engaged various outside independent experts to study this issue.  We met with FDA in February 1998 to review the spontaneous adverse event reports and consider labeling changes.  Although the scientific evidence does not establish a causal link between Accutane and psychiatric events, in light of the seriousness of the issues raised, we nonetheless implemented a highly precautionary labeling change.  Roche distributed a Dear Doctor letter to prescribers pointing out the addition of new language on depression and suicide to the package insert.  Our representatives called on dermatologists across the country, and the letter was sent to 210,000 physicians in the United States with specialties in dermatology, psychiatry, general practice, internal medicine, family practice, osteopathy and emergency room care.

The 1998 package insert that was the subject of this broad, precautionary communication to prescribers stated as follows: 

WARNINGS:  

"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)." 

Adverse Reaction language on central nervous system effects and depression was also amended as follows: 

ADVERSE REACTIONS: 

"In the post-marketing period, a number of patients treated with Accutane have reported depression, psychosis and, rarely, suicidal ideation, suicide attempts and suicide.  Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy (see WARNINGS)." 

During this period, Roche commissioned or sponsored a number of epidemiological studies and reviews to further explore any potential causal connection between ingestion of Accutane and psychiatric events.  These analyses, using a variety of methodological approaches and data sets, found no association between Accutane and certain psychiatric events. 

Ultimately, in consultation with FDA, and in connection with a significant restructuring of Accutane labeling, we issued a revised patient brochure in May 2000 that specifically noted the rare cases of suicide attempts and suicide that have been reported in the Accutane patient population.  In 2002, in consultation with FDA, we made a series of labeling changes, including adding similar precautionary labeling information regarding violent and aggressive behaviors.  Information regarding this labeling change was also sent to physicians and pharmacists across the country.

We have also implemented precautionary measures relating to psychiatric events as part of our broader Accutane risk management program.  The elements of this program include: 

• A revised informed consent form is provided to all patients who may be prescribed Accutane.  This form ensures that patients have been told and understand essential information.  Notwithstanding the absence of proof of causation, the informed consent form clearly states that some patients have reported that they became depressed or developed serious mental problems, including suicidal ideation, while taking Accutane, and that some people have ended their lives.  This informed consent document is signed and dated by both the prescriber and the patient.  For minors, a parent or guardian must sign the form and consent to treatment.  Only a handful of pharmaceutical products have implemented a broad, mandatory requirement of this type.

• An Accutane Medication Guide developed by FDA in consultation with Roche is also dispensed with each prescription.  This Medication Guide serves as a reminder of the proper use of the drug, its risks, and some warning signs to be aware of during treatment.  In addition to being glued into the product package, since January 25, 2001, pharmacists dispensing Accutane have also provided every patient with this plain language summary of the product labeling.  The Medication Guide specifically states as follows:

"Mental problems and suicide.  Some patients, while taking Accutane or soon after stopping Accutane, have become depressed or developed other serious mental problems.  Signs of these problems include feelings of sadness, irritability, unusual tiredness, trouble concentrating, and loss of appetite.  Some patients taking Accutane have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts).  Some people tried to end their own lives.  And some people ended their own lives.  There were reports that some of these people did not appear depressed.  No one knows if Accutane caused these behaviors or if they would have happened even if the person did not take Accutane." 

The revised informed consent and Medication Guide went to over 350,000 physicians, 130,000 pharmacists and 55,000 pharmacies.

·        For many young people, physicians treating acne are one of the few health care professionals they see on a regular basis.  Thus, consistent with the recommendations of the Surgeon General, we have created a unique brochure intended to educate physicians on recognizing the signs of depression and suicidal ideation, and intervening before a tragedy occurs.  We believe this brochure will have benefits well beyond the isotretinoin patient population.

·        Finally, through an unrestricted grant, we funded a major National Mental Health Awareness Campaign program focusing on psychiatric concerns, and suicide specifically, in the teenage population.  This general public health program was designed to have broad benefits in helping teenagers overcome the unwarranted stigma associated with mental health problems so they seek prompt medical attention.

Overall, the steps we have taken to address the psychiatric events in the Accutane patient population are highly precautionary and unprecedented in scope.

As noted, we have also instituted the S.M.A.R.T. program to further address Accutane teratogenicity concerns.  Although many elements of S.M.A.R.T. are intended for patients, the role of the physician and pharmacist remain critical to success under this program.  Under the S.M.A.R.T. program -- 

• Detailed informed consent language for female patients confirms awareness of the risks of pregnancy during treatment with Accutane, the necessity of avoiding pregnancy before beginning therapy, during treatment, and for one month after treatment, and the recommendation that two effective forms of contraception be used simultaneously. 

• Prescribers must study the S.M.A.R.T. "Guide to Best Practices" provided by Roche, and then sign and return to Roche a Letter of Understanding, certifying their knowledge of Severe Recalcitrant Nodular Acne and of measures to be taken to minimize fetal exposures to Accutane.  We have also developed and presented a Continuing Medical Education (CME) course throughout the country for prescribers that includes specific, practical information about pregnancy prevention.

• Prescribers receive special self-adhesive Accutane Qualification Stickers.  All prescriptions for Accutane should have the special yellow sticker attached to the prescriber's regular prescription form.  This sticker indicates to the pharmacist that the patient is "qualified" according to the new package insert, which means that the female patient has had negative pregnancy tests, has committed to the use of two safe and effective forms of contraception, has signed her informed consent, and has been offered the opportunity to join the Accutane Survey as well as receive education and counseling about pregnancy prevention.  The pregnancy test is repeated every month throughout the Accutane treatment course.

• All female patients must have two negative urine or serum pregnancy tests, provided by Roche at no cost, before the initial Accutane prescription is written, and for each month of therapy they must have a negative pregnancy test result before receiving their next prescription, regardless of whether they are sexually active.  Female patients who are, or might become, sexually active must also select and use two forms of effective contraception simultaneously for at least one month prior to initiation of Accutane therapy, during therapy, and for one month following discontinuation of therapy.  As noted, women must sign a Patient Information/Consent form about Accutane and birth defects, as well as the general Consent Form addressing other risks and drug information that all Accutane patients - including men -- sign.

• Female patients are given the opportunity to enroll in the Accutane Survey.  This confidential, voluntary survey has been in place since 1989 and is designed to collect data to help Roche and FDA determine if the pregnancy prevention program is effective.  We relied upon this survey information to build the current S.M.A.R.T. program, and patients who agree to participate in the survey make a major contribution to the public health by helping to identify aspects of S.M.A.R.T. that could be improved.

• Pharmacists dispense Accutane only upon presentation of a prescription with the special Accutane Qualification Sticker.  Pharmacists dispense a maximum 30-day 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 Accutane without a new prescription) and electronic and phoned-in prescriptions cannot be filled.

• To measure the effectiveness of the S.M.A.R.T. program, Roche is using several independent outcome assessment approaches.  These include the Accutane Survey and an independent audit of pharmacies to assess the proper use and verification of Accutane Qualification Stickers by prescribers and pharmacists.  Prescribers, patients, and pharmacists all must participate fully in these critically important measures to ensure that fetal exposure to Accutane does not occur.

• The Accutane package also continues to serve as a risk management tool, including a blister package bearing written and symbolic pregnancy warnings.

• We also provide toll-free telephone counseling in thirteen languages, as well as a free referral to a health care professional who can provide contraceptive and pregnancy counseling.  The S.M.A.R.T. program materials also include informational videos and story boards.

We have structured our risk management implementation efforts to ensure that we have the most current information - specific to Roche - on progress toward our goals.  We believe it is equally important for generic isotretinoin programs to produce data permitting identification of subtle but important differences between risk management programs. 

We share the Subcommittee's concerns regarding unlawful Internet prescribing and dispensing.  Such practices, while representing what we believe is an extremely small number of isotretinoin prescriptions, could endanger patients by confounding risk management efforts.  Thus, isotretinoin labeling specifically precludes electronic transmittal of prescriptions, and over the last several years we have notified FDA of a number of websites purporting to offer Accutane.  We recently submitted to the Agency information on Accutane from a more comprehensive Internet survey, and we strongly support vigorous enforcement action against such sites by FDA, the states and foreign health authorities.  To this end, Roche will continue to monitor Internet prescribing of Accutane and will alert FDA of activity.

Finally, I would like to note that Roche has not engaged in direct-to-consumer advertising that specifically mentions or promotes the Accutane brand.  We have engaged in non-branded educational efforts that focused on dispelling acne myths.  Few public resources are available for acne education, and we believe such messages play an important role in helping parents and patients understand the causes of acne and the existence of effective dermatological treatments. 

Conclusion 

The issues I have addressed are complex, and I would like to close by emphasizing some important points for the Subcommittee -

• First, we are extremely proud of the dramatic positive benefits provided to patients over this medication's 20-year history.

• Second, as is the case with any prescription medication, every stakeholder in pharmaceutical treatment plays an important role in ensuring safety and efficacy.  We need the active involvement of physicians, pharmacists, patients and their families to ensure the safe and effective use of isotretinoin.

• Third, we have acted in a responsible manner by adopting precautionary measures to communicate psychiatric information to prescribers and patients, and we have engaged in a very significant scientific effort to address this extremely difficult issue.

• Finally, we have also acted responsibly in addressing the risks known to be associated with isotretinoin, including its teratogenicity.  Although we constantly seek improvement, our risk management program is highly innovative and a model for other drug products.

I fully recognize the depth of this Subcommittee's interest in Accutane, and hope that today's hearing clarifies many of the issues that have been raised.  I know that our common goal is to ensure that Accutane is used safely and effectively.

Thank you for the opportunity to present our views on this issue, and I look forward to your questions.

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