 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
Issues Relating to the Safety of Accutane
Subcommittee on Oversight and Investigations
Janet Woodcock M.D.
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 AccutaneŽ (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.
|
|||||||||||
|
