Guidance for Industry1
Development and Use of Risk Minimization Action Plans
DRAFT GUIDANCE
This guidance
document is being distributed for comment purposes only.
Comments and suggestions regarding this draft
document should be submitted within 60 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers
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identified with the docket number listed in the notice of
availability that publishes in the Federal Register.
For
questions regarding this draft document contact (CDER) Christine
Bechtel at 301-443-5572, or (CBER) Mark Weinstein at 301-827-3518.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2004
Clinical Medical
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I.
INTRODUCTION
III.THE ROLE
OF RISK MINIMIZATION AND RiskMAPs IN RISK MANAGEMENT
This
draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It does
not create or confer any rights for or on any person and does not
operate to bind FDA or the public. You can use an alternative
approach if the approach satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an
alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the
appropriate FDA staff, call the appropriate number listed on the
title page of this guidance.
This document provides guidance to industry on
the development, implementation, and evaluation of risk minimization
action plans for prescription drug products, including biological
drug products.
In particular, it gives guidance on (1) initiating and designing
plans to minimize known risks (i.e., risk minimization action plans
or RiskMAPs), (2) selecting and developing tools to minimize those
risks, (3) evaluating and monitoring tools and RiskMAPs, and (4) the
recommended components of a RiskMAP submission to FDA.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
On June 12, 2002, Congress reauthorized, for
the second time, the Prescription Drug User Fee Act (PDUFA III). In
the context of PDUFA III, FDA agreed to satisfy certain performance
goals. One of those goals was to produce guidance for industry on
risk management activities for drug and biological products. As an
initial step towards satisfying that goal, FDA sought public comment
on risk management. Specifically, FDA issued three concept papers.
Each paper focused on one aspect of risk management, including (1)
conducting premarketing risk assessment, (2) developing and
implementing risk minimization tools, and (3) performing
postmarketing pharmacovigilance and pharmacoepidemiologic
assessments. In addition to receiving numerous written comments
regarding the three concept papers, FDA held a public workshop on
April 9–11, 2003, to discuss the concept papers. FDA considered all
of the comments received in producing three draft guidance documents
on risk management activities:
1. Premarketing Risk Assessment (Premarketing
Guidance)
2. Development and Use of Risk Minimization
Action Plans (RiskMAP Guidance)
3. Good Pharmacovigilance Practices and Pharmacoepidemiologic
Assessment (Pharmacovigilance Guidance)
Like the concept papers that preceded them,
each of the three draft guidance documents focuses on one aspect of
risk management. The Premarketing Guidance and the
Pharmacovigilance Guidance focus on premarketing and
postmarketing risk assessment, respectively. The RiskMAP
Guidance focuses on risk minimization. Together, risk
assessment and risk minimization form what FDA calls risk
management. Specifically, risk management is an iterative
process of
(1) assessing a product’s benefit-risk balance,
(2) developing and implementing tools to minimize its risks while
preserving its benefits, (3) evaluating tool effectiveness and
reassessing the benefit-risk balance, and (4) making adjustments, as
appropriate, to the risk minimization tools to further improve the
benefit-risk balance. This four-part process should be continuous
throughout a product’s lifecycle, with the results of risk
assessment informing the sponsor’s decisions regarding risk
minimization.
When reviewing the recommendations provided in
this guidance, sponsors and applicants should keep the following
points in mind:
·
Many recommendations in this guidance are not
intended to be generally applicable to all products.
Industry already
performs risk assessment and risk minimization activities for
products during development and marketing. The Federal Food, Drug,
and Cosmetic Act (FDCA) and FDA implementing regulations establish
requirements for routine risk assessment and risk
minimization (e.g., FDCA section 503(b) (21 U.S.C. 353(b)), which
provides for limiting drugs to prescription status; FDA regulations
regarding spontaneous adverse event reporting and FDA-approved
professional labeling). As a result, many of the recommendations
presented here focus on situations when a product may pose an
unusual type or level of risk. To the extent possible, we have
specified in the text whether a recommendation is intended to apply
to all products or only this subset of products.
·
It is of critical importance to protect patients and
their privacy during the generation of safety data and the
development of risk minimization action plans.
During all risk
assessment and risk minimization activities, sponsors must comply
with applicable regulatory requirements involving human subjects
research and patient privacy.
FDA recommends that sponsors comply with ethical principles for
patient protection.
·
To the extent possible, this guidance conforms with
FDA’s commitment to harmonize international definitions and
standards as applicable.
The topics covered
in this guidance are being discussed in a variety of international
forums. We are participating in these discussions and believe that,
to the extent possible, the recommendations in this guidance reflect
current thinking on related issues.
·
When planning risk assessment and risk minimization
activities, sponsors should consider stakeholder input (e.g., from
consumers, pharmacists, physicians, third-party payers).
·
There are points of overlap among the three guidances.
We have tried to
note in the text of each guidance when areas of overlap occur and
when referencing one of the other guidances might be useful.
As described above, FDA views risk management
as an iterative process encompassing both risk assessment and risk
minimization. In particular, the premarketing guidance and the
pharmacovigilance guidance discuss how sponsors should engage in
evidence-based risk assessment for all products in development and
on the market. Evidence-based risk assessment will assist the
sponsor in defining the nature and extent of a product’s risks in
relation to its benefits. The goal of risk minimization is to
minimize a product’s risks while preserving its benefits. For the
majority of products, routine risk minimization measures are
sufficient to minimize risks and preserve benefits. Only a few
products are likely to merit consideration for additional risk
minimization efforts (see section III.D.).
The statutory
standard for FDA approval of a product is that the product is safe
and effective for its labeled indications under its labeled
conditions of use (see sections 201(p)(1) and 505(d) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321(p)(1) and 355(d)).
FDA’s determination that a product is safe, however, does not
suggest an absence of risk. Rather, a product is considered to be
safe if the clinical significance and probability of its beneficial
effects outweigh the likelihood and medical importance of its
harmful or undesirable effects. In other words, a product is
considered safe if it has an appropriate benefit-risk balance for
the intended population and use.
Benefit and
risk information emerges continually throughout a product’s
lifecycle (i.e., during the investigational and marketing phases)
and can reflect the results of both labeled and off-label uses.
Benefits and risks can result in a range of corresponding positive
and negative effects on patient outcomes that may (1) be cosmetic,
symptomatic, or curative; (2) alter the course of the disease; or
(3) affect mortality. A major difficulty in relating benefits and
risks is that they are usually measured in different units. Thus,
one often needs to compare a modest benefit that occurs in many
patients with a rare but very serious adverse effect. Benefits as
well as risks are also patient-specific and are influenced by such
factors as the severity of the disease being treated, its outcome if
untreated, existing therapeutic options, and the intended patient
population. Thus, assessment and comparison of a product’s benefits
and risks is a complicated process that is influenced by a wide
range of individualized factors.
To help
ensure safe and effective use of their products, sponsors have
always sought to maximize benefits and minimize risks. FDA believes
that, for most products, routine risk minimization measures are
sufficient. Such measures involve, for example, FDA-approved
professional labeling describing the conditions in which the drug
can be used safely and effectively, updated from time to time to
incorporate information from postmarketing surveillance or studies
revealing new benefits (e.g., new indications or formulations) or
risk concerns. Efforts to make FDA-approved professional labeling
clearer, more concise, and better focused on information of clinical
relevance reflect the Agency’s belief that such labeling is the
cornerstone of risk management efforts for prescription drugs.
For most products, routine risk management will be sufficient and a
RiskMAP need not be considered.
For the small
number of products where a RiskMAP should be considered (see section
III.D.), sponsors are encouraged to consider developing a RiskMAP.
FDA recommends that RiskMAPs be used judiciously to minimize risks
without encumbering drug availability or otherwise interfering with
the delivery of product benefits to patients.
This guidance
focuses on the development, implementation, and evaluation of
RiskMAPs.
As used in this document, the term RiskMAP
means a strategic safety program designed to meet specific goals
and objectives in minimizing known risks of a
product while preserving its benefits. A RiskMAP targets one or
more safety-related health outcomes or goals and uses one or more
tools to achieve those goals.
FDA recommends that RiskMAP goals target the
achievement of particular health outcomes related to known safety
risks. FDA suggests that sponsors state goals in a way that aims to
achieve maximum risk reduction. The following are examples of
RiskMAP goals: “patients on X drug should not also be prescribed Y
drug” or “fetal exposures to Z drug should not occur.” FDA
recommends that goals be stated in absolute terms. Although it might
not be possible to ensure that absolutely no one on X drug receives
Y drug, FDA believes that a goal, as the term implies, should
reflect the ideal outcome of a RiskMAP.
FDA recommends that RiskMAP goals be
translated into pragmatic, specific, and measurable program
objectives that result in processes or behaviors leading to
achievement of the RiskMAP goals. Objectives can be thought of as
intermediate steps to achieving the overall RiskMAP goal. A RiskMAP
goal can be translated into different objectives, depending upon the
frequency, type, and severity of the specific risk or risks being
minimized. For example, objectives to achieve a goal of eliminating
dangerous concomitant prescribing could include guiding physician
prescribing practices and/or pharmacist dispensing practices. As
described in greater detail in section IV., many processes or
systems to minimize known safety risks are available or under
development for use in RiskMAPs. These systems include:
·
targeted education and outreach for health care
practitioners or patients
·
reminder systems, processes, or forms to foster
reduced-risk prescribing and use
·
performance-linked access systems that guide
prescribing, dispensing, and use of the product to target the
population and conditions of use most likely to confer benefits and
to minimize particular risks
As described in the premarketing guidance
and pharmacovigilance guidance, evidence-based risk
identification, assessment, and characterization are processes that
continue throughout a product’s lifecycle. Therefore, a risk
warranting the consideration of a RiskMAP could emerge during
premarketing or postmarketing risk assessment.
The Agency recommends that the appropriate information for
consideration in making such a determination include, as applicable,
(1) data from the clinical development program, postmarketing
surveillance, and phase 4 studies, and (2) the product’s intended
population and use.
FDA may recommend that a sponsor consider a
RiskMAP based on the Agency's own interpretation of risk
information.
As discussed above, the relationship between
a product’s risks and benefits is complicated and multi-faceted. As
a result, it is not straightforward to assess a product’s risks and
benefits in specific subgroups or circumstances. Decisions to
develop, submit, or implement a RiskMAP are always made on a
case-by-case basis, but several considerations are common to most
determinations of whether development of a RiskMAP may be desirable:
·
Nature and rate of known risks versus benefits:
Comparing the characteristics of the product’s adverse events with
those of the product’s benefits may help clarify whether a RiskMAP
could improve the product’s benefit-risk balance. The
characteristics to be weighed might include the (1) types,
magnitude, and frequency of risks and benefits, (2) populations at
greatest risk and/or those likely to derive the most benefit, (3)
existence of treatment alternatives, and (4) reversibility of
adverse events observed.
- Preventability of the event: Serious and
labeled adverse events that can be minimized or avoided by
preventive measures are the preferred candidates for RiskMAPs.
- Probability of benefit: If factors are
identified that can predict effectiveness, a RiskMAP could help
encourage use accordingly to increase benefits relative to known
risks.
For example, opiate
drug products have important benefits in alleviating pain but are
associated with significant risk of overdose, abuse, and addiction.
The Agency recommends that sponsors of Schedule II controlled
substances, including Schedule II extended release or high
concentration opiate drug products, consider developing RiskMAPs for
these products.
A risk minimization tool is a process or
system intended to minimize known safety risks. When risks are
minimized, the benefit-risk balance is more likely to be favorable.
When the conditions in which a product can be used safely and
effectively are well-defined, use of the product under those
conditions is more likely.
Tools can communicate particular information
regarding optimal product use and can also provide guidance on
prescribing, dispensing, and/or using a product in the most
appropriate situations or patient populations. A number of tools
are available, one or more of which could be used in the
minimization of product risk. FDA encourages and anticipates the
development of additional tools.
Risk minimization tools are designed to help
achieve one or more RiskMAP objectives that serve the overall
RiskMAP goal or goals. One or more tools can be chosen to achieve a
particular objective. For example, a sample goal might be that
patients with condition A should not be exposed to product B. An
objective for achieving this goal might be to communicate to
patients that if they have condition A, they should not take product
B. Depending on the likelihood and severity of the adverse event
associated with product B in a patient with condition A, a variety
of tools could be applied to achieve this objective. One possible
tool would be patient labeling explaining that a patient with
condition A should not take product B. On the other hand, if the
potential harm to a patient with condition A is severe and/or likely
to occur, a more active tool may be appropriate. For example, the
sponsor could choose to develop a patient agreement where the
patient actually acknowledges, before receiving the product, that he
or she knows that product B should not be taken if he or she has
condition A.
A variety of tools are currently used in risk
minimization plans. These fall within three categories: (1)
targeted education and outreach, (2) reminder systems, and (3)
performance-linked access systems. A RiskMAP might include tools
from one or more categories, depending on its risk minimization
goals. FDA notes that a sponsor’s selection of specific categories
of tools for a drug product should not be used in an assessment of
comparative safety to another drug product without a RiskMAP or with
a different RiskMAP.
FDA
recommends that sponsors consider tools in the targeted education
and outreach category (1) when product risks cannot be minimized
with routine risk minimization measures alone or (2) as a component
of RiskMAPs using reminder or performance-linked access systems (see
sections IV.B.2. and 3. below).
Tools in this
category employ specific, targeted education and outreach efforts to
increase appropriate knowledge of key people or groups (e.g., health
care practitioners and consumers) that have the capacity to prevent
or mitigate the product risks of concern.
Examples of tools in this category are as follows:
·
health care practitioner letters
·
training programs for health care practitioners or
patients
·
Continuing Education (CE) for health care
practitioners
·
prominent professional or public notifications
·
patient labeling such as medication guides and patient
package inserts
·
focused or limited promotional techniques such as
product sampling or direct-to-consumer advertising
In addition
to informing health care practitioners and patients about conditions
of use contributing to product risk, educational tools can inform
them of conditions of use that are important to achieve the
product’s benefits. For example, a patient who takes a product
according to labeled instructions is more likely to achieve maximum
product effectiveness. On the other hand, deviations from the
labeled dose, frequency of dosing, storage conditions, or other
labeled conditions of use might compromise the benefit achieved, yet
still expose the patient to product-related risks. Risks and
benefits can have different dose-response relationships. Risks can
persist and even exceed benefits when products are used in ways that
minimize effectiveness. Therefore, educational tools can be used to
explain how to use products in ways that both maximize benefits and
minimize risks.
We recommend
that tools in the reminder systems category be used in addition to
tools in the targeted education and outreach category when targeted
education and outreach tools are insufficient to minimize those
risks.
Tools in this category include systems that
prompt, remind, double-check or otherwise guide health care
practitioners and/or patients in prescribing, dispensing, or
receiving a product in ways that minimize risk. Examples of tools
in this category are as follows:
·
patient agreement or acknowledgment forms
·
certification programs for practitioners (i.e., when
physicians complete training and demonstrate knowledge and
understanding)
·
enrollment of physicians, pharmacies, and/or patients
in special educational programs that reinforce appropriate product
use
·
limited amount in any single prescription or refill of
product
·
specialized product packaging to enhance safety
·
specialized systems or records that attest to safety
measures having been satisfied (e.g., prescription stickers,
physician attestation of capabilities)
Performance-linked access systems include systems that link product
access to laboratory testing results or other documentation. FDA
recommends that tools in this category be used when (1) products
have significant or otherwise unique benefits in a particular
patient group or condition, but unusual risks also exist, such as
irreversible disability or death, and (2) routine risk minimization
measures, targeted education and outreach tools, and reminder
systems are insufficient to minimize those risks.
Examples of
tools in this category include:
·
the sponsor's use of compulsory reminder systems, as
described in the previous section (i.e., the product is not made
available unless there is an acknowledgment, certification,
enrollment, or appropriate test records)
·
prescription only by specially certified health care
practitioners
·
product dispensing only by specially certified
pharmacies or practitioners
·
product dispensing only to patients with evidence or
other documentation of safe-use conditions (e.g., lab test results)
FDA plans to develop a RiskMAP Web site that
will include (1) descriptions of tools that are currently used in
RiskMAPs and (2) other information relevant to RiskMAP development
(see section IV.D. below). The information will be made available
consistent with federal law and regulations governing disclosure of
information by FDA to the public. The list of tools will be
intended to assist sponsors in designing a RiskMAP but will not
suggest that the listed tools are FDA-approved or -validated. To
the contrary, FDA does not suggest that the tools listed on the Web
site are the only tools and encourages sponsors to develop tools
that may be optimal for their particular products.
Given the variety of available tools, FDA
recommends that a sponsor carefully consider which tool or tools are
most appropriate, given the goals and objectives of its product’s
RiskMAP. A tool could be developed or selected based on its
individual impact and/or because of its impact when used in
coordination with other tools. Generally, the best tools would be
those that have a high likelihood of achieving their objective based
on positive performance in other RiskMAPs or in similar settings and
populations. Relevant non-RiskMAP evidence and experience can be
found in health care quality initiatives, public health education
and outreach, marketing, and other outcomes-based research (see
section V. for a more detailed discussion of evaluating tools’
effectiveness).
Although FDA suggests that the best tool or
tools be selected on a case-by-case basis, the following are
generally applicable considerations in designing a RiskMAP. In
choosing tools for a RiskMAP, FDA recommends that sponsors:
·
Maintain the widest possible access to the product
with the least burden to the health care system that is compatible
with adequate risk minimization (e.g., a reminder system tool should
not be used if targeted education would likely be sufficient).
·
Identify the key groups who have the capacity to
minimize the product’s risks (such as physicians, pharmacists,
patients, and third-party payers) and define the anticipated role of
each group.
·
Seek input from the aforementioned groups on the
feasibility of implementing and accepting the tool in usual health
care practices, disease conditions, or lifestyles. Examples of
considerations could include (but would not be limited to) patient
and health care practitioner autonomy, time effectiveness, economic
issues, and technological feasibility.
·
Acknowledge the importance of using tools with the
least burdensome effect on health care practitioner-patient,
pharmacist-patient, and/or other health care relationships.
·
Design the RiskMAP to be:
1.
compatible with current technology
2.
applicable to both outpatient and inpatient use, as
appropriate
3.
accessible to patients in diverse locales, including
non-urban settings
4.
consistent with existing tools and programs that have
achieved positive results
·
Select tools based on available evidence of
effectiveness in achieving the specified objective (e.g., tools
effectively used in pregnancy prevention).
·
Consider indirect evidence of tool effectiveness in a
related area that supports the rationale, design, or method of use
(e.g., tools applied in modifying patient or health care
practitioner behaviors in medical care settings).
·
Consider, and seek to avoid, unintended consequences
of tool implementation that obstruct risk minimization and product
benefit.
FDA recognizes that, once it approves a
product for marketing, health care practitioners are the most
important managers of product risks. FDA believes that, by
including in the FDA-approved professional labeling information on
the conditions in which medical products can be used safety and
effectively by their intended population and for their intended use
or uses, the Agency and the sponsor encourage health care
practitioners to prescribe medical products in circumstances that
yield a favorable benefit-risk balance. However, as the Agency has
long recognized, the FDCA and FDA regulations establish requirements
governing the safety and effectiveness of medical products. FDA
does not have authority under these provisions to control decisions
made by qualified health care practitioners to prescribe products
for conditions other than those described in FDA-approved
professional labeling, or to otherwise regulate medical or surgical
practice. FDA believes that, in designing RiskMAPs, sponsors should
recognize the central role played by health care practitioners in
controlling the risks of medical product use and should adopt tools
that facilitate this role.
This guidance focuses on the tools that
industry can incorporate into RiskMAPs. As noted, FDA has a variety
of risk management measures at its disposal under the FDCA and FDA
regulations (e.g., prescription designation, FDA-approved
professional labeling). FDA must occasionally invoke other
mechanisms to minimize the risks from medical products that pose
serious risks to the public health. These tools include:
- FDA-requested product recalls, warning and
untitled letters, and import alerts
Further information on these mechanisms is
available on the Internet at http://www.fda.gov.
As FDA and sponsors seek additional knowledge
about the design, effectiveness, burdens, and potential unintended
consequences of RiskMAPs, it is important to collect as much
information as possible on plan performance. Timely evaluation
monitors the effectiveness of RiskMAPs and their component
objectives and tools to identify areas for improvement.
At least two studies have documented poor or
limited implementation and effectiveness of traditional risk
minimization tools. In particular, the studies examined situations
in which labeling changes (with or without Dear Health Care
Practitioner letters) were used to reduce safety problems.
The iterative process of risk assessment, risk minimization, and
reevaluation previously described is intended to avoid repeating
these experiences by identifying poorly performing or ineffective
RiskMAPs or RiskMAP components as soon as possible. Ultimately,
RiskMAP evaluation is intended to ensure that the energy and
resources expended on risk minimization are actually achieving the
desired goals of continued benefits with minimized risks. FDA
considers evaluation of the effectiveness of a RiskMAP to be
important and recommends that every RiskMAP contain a plan for
periodically evaluating its effectiveness after implementation (see
section VII. for a detailed discussion of RiskMAPs).
The evaluation of RiskMAPs can take several
forms. Most critical is determining the performance of the overall
RiskMAP in achieving its targeted health outcomes or goals.
Separate but related assessments can be done for (1) individual tool
performance, (2) acceptability of RiskMAP tools by consumers and
health care practitioners, and (3) compliance with important RiskMAP
processes or procedures.
Generally, FDA anticipates that RiskMAP
evaluations would involve the analysis of observational or
descriptive data. Statistical hypothesis testing in the context of
RiskMAP evaluation would not typically be expected, given the
limitations of the data likely to be available.
FDA recommends that RiskMAP evaluation plans
be tailored to the specific product and designed to assess whether
the RiskMAP’s goals have been achieved through its objectives and
tools. The following are generally applicable guidelines for
sponsors designing RiskMAP evaluation plans.
The Agency recommends that sponsors select
well-defined, evidence-based, and objective performance measures
tailored to the particular RiskMAP to determine whether the
RiskMAP’s goals or objectives are being achieved. An appropriate
measure could be a number, percentage, or rate of an outcome, event,
process, knowledge, or behavior. Ideally, the chosen measure would
directly measure the RiskMAP’s health outcome goal. For example,
for a RiskMAP with a goal of preventing a particular complication of
product use, a sample outcome measure could be to have no more than
a specified number or rate of that complication. However, in some
cases, a health outcome cannot be practically or accurately
measured. In those cases, other measures can be used that are
closely related to the health outcome, such as the following:
·
surrogates for health outcome measures (e.g.,
emergency room visits for an adverse consequence, pregnancy tests
for pregnancy status)
·
process measures that reflect desirable safety
behaviors (e.g., performance of recommended laboratory monitoring,
signatures attesting to knowledge or discussions of risk)
·
assessments of comprehension, knowledge, attitudes,
and/or desired safety behaviors about drug safety risks (e.g.,
provider, pharmacist, or patient surveys)
FDA recommends that the validity of a
measure be judged by how closely it is related to the desired health
outcome goal of the RiskMAP. Simply stated, the more closely
related a measure to the RiskMAP goal, the greater its degree of
validity. For example, if the RiskMAP goal is avoidance of fetal
exposures, then complete ascertainment of pregnancies in the user
population would be a highly valid performance measure. The
frequency of contraceptive counseling in users could be used, but it
is less directly linked to the desired outcome and would be of lower
validity as a measure of successful prevention of pregnancy
exposures.
Most evaluation measures have limitations. FDA
suggests that, in choosing among evaluation methods and measures,
sponsors consider their strengths and limitations. The following
are examples of some of the limitations of evaluation methods:
- Spontaneous adverse event data are a
potentially biased outcome measure because reporting of adverse
events varies due to many factors and represents an unknown and
variable fraction of the adverse outcomes that are actually
occurring. As a result, systematic data collection in defined
populations would be recommended for purposes of evaluation.
- Population-based evaluation methods can use
administrative or claims-based data systems that capture service
or payment claims to measure rates of events, although it is
usually recommended that medical records be examined to validate
the actual occurrence of coded diagnoses and procedures.
Administrative data come from various insurers, purchasing groups,
or networks that are often tied to employment, which may mean that
individuals at higher risk are excluded because of poor health,
advanced age, institutional status, or low socioeconomic status.
Also, unless enrollment in an administrative claims system is
large, the number of patients exposed to any single product is
likely to be limited, as will be the power to detect uncommon
adverse events.
- Active surveillance using sentinel reporting
sites may be useful for evaluating adverse events, but it is
costly and may not detect rare events. Surveys of health care
practitioners or patients using various modes (in-person, mail,
telephone, electronic) can be another useful form of active
surveillance of knowledge, attitudes, policies, and practices of
health care practitioners, institutions, and patients about
recommended RiskMAP tools and their associated processes.
However, issues relating to response rates, representativeness,
and reporting biases may limit the accuracy of survey results.
These examples demonstrate how using only
one method could skew assessment of the performance of a RiskMAP.
Therefore, FDA recommends that, whenever feasible, sponsors design
evaluation plans to include at least two different quantitative,
representative, and minimally biased evaluation methods for each
critical RiskMAP goal. By using two methods, one method can
compensate for the limitations of the other. For example,
hospitalization data on an adverse event do not capture deaths that
occurred out of the hospital; however, coupling such data with death
certificate surveillance would offer complementary and more complete
ascertainment of mortality risks. If it is not practical to use two
complementary and representative methods, FDA suggests using other
quantitative methods such as multiple site sampling or audits that
aim for high coverage or response rates by the affected population.
FDA recommends that sponsors periodically
evaluate each RiskMAP tool to ensure it is materially contributing
to the achievement of RiskMAP objectives or goals. Tools that do
not perform well may compromise attainment of RiskMAP goals, add
unnecessary costs or burdens, or limit access to product benefits
without minimizing risks. Tools that are implemented incompletely
or in a substandard fashion could result in additional tools being
adopted unnecessarily. For all these reasons, evaluating tools is
important. Data from such evaluations may make it possible to
improve a tool’s effectiveness or eliminate the use of a tool that
fails to contribute to achieving a RiskMAP goal. By eliminating
ineffective tools, resources can be concentrated on useful tools.
Distinguishing between the evaluation of
RiskMAP goals and tools is important because the performance of
goals and tools may not be linked. For example, the overall goal of
a RiskMAP may be achieved despite individual tools performing
poorly.
The reverse situation may also occur, with component tools
performing well but without appropriate progress in achieving the
RiskMAP goal. This situation may occur if a surrogate objective
correlates poorly to the desired health outcome. The first example
(i.e., the RiskMAP goal may be achieved despite individual tools
performing poorly) may afford an opportunity to discontinue a tool,
whereas its converse may trigger the implementation of new or
improved tools, or even a redesign of the overall RiskMAP.
FDA recommends that, to the extent possible,
sponsors evaluate tools before implementation. As discussed in
section IV.D. above, FDA suggests that in selecting tools to include
in a RiskMAP, a sponsor consider whether the tool will be
effective. For example, the success of potential RiskMAP tools
might be predicted to some extent by evidence in the scientific
literature or from their use in other RiskMAPs.
In addition to considering literature evidence
and past RiskMAP experience, FDA recommends that sponsors test a
tool before implementation. Pretesting (or pilot testing) can help
to assess comprehension, acceptance, feasibility, and other factors
influencing how readily RiskMAP tools will fit into patient
lifestyles and the everyday practices of health care practitioners.
Pretesting can potentially avoid wasted time, expense, and
escalation of RiskMAP tools by discriminating between high- and
low-performing tools. For example, if a risk is identified in Phase
1 or 2 trials, Phase 3 trials could provide an opportunity to
pretest targeted education and outreach tools.
FDA recommends that pretesting methods be
chosen on a case-by-case basis, depending on the product, tool,
objective, and goal. For example, in certain preapproval
situations, large simple safety studies may be a means of generating
useful information about the effectiveness of RiskMAP tools in
conditions close to actual practice.
On the other hand, for certain tools such as targeted education and
outreach, published best practices could be used as
guidelines for implementation. If time is particularly limited,
multiple interviews or focus group testing can assist in determining
acceptance or comprehension of a RiskMAP tool by major stakeholder
groups. This action might be particularly useful in situations
where risks and benefits are closely matched, and RiskMAP goals may
include the making of informed therapeutic choices by patients and
prescribers.
FDA recognizes that, in some cases, tools
cannot be pretested for logistical reasons. Pretesting of tools may
not be practical in situations in which newly recognized adverse
events dictate the importance of rapid implementation of a RiskMAP
after approval and marketing.
FDA recommends that, if a sponsor makes a
RiskMAP submission to the Agency, the submission describe when the
sponsor will send periodic evaluation results to FDA. As discussed
in section VII.B., the Agency recommends that sponsors analyze
evaluation results and requests that sponsors provide FDA with (1)
the data, (2) all analyses, (3) conclusions regarding effectiveness,
and (4) any proposed modifications to the RiskMAP. FDA, in turn,
generally would perform its own assessment of RiskMAP effectiveness
according to the principles of this guidance.
As discussed in section IV.C. above, FDA plans
to maintain a RiskMAP Web site, including a listing of RiskMAP
tools. FDA intends to make available, on the same Web site,
general information FDA receives from sponsors and elsewhere about
the effectiveness of particular RiskMAP tools in achieving risk
minimization objectives. The summaries will not contain information
from which a particular sponsor or product could be identified. FDA
believes this approach to disclosing information from specific
RiskMAP evaluations appropriately balances (1) the Agency's interest
in disclosing information to assist sponsors in designing new
RiskMAPs and selecting tools with the sponsor's interest in
confidentiality, and (2) the Agency's interest in avoiding any
disclosure that would create disincentives to adopt RiskMAPs or to
conduct or submit to FDA results of RiskMAP evaluations.
As discussed above, because risk and benefit
information emerge continually throughout a product’s lifecycle, a
sponsor could decide that a RiskMAP is warranted at several
different times. These times include:
- before approval, when a risk is identified
from clinical studies, and risk minimization is appropriate as the
product is introduced into the marketplace
- after marketing, if pharmacovigilance
efforts identify a new serious risk, and minimization of the risk
will contribute to a favorable benefit-risk balance
- when marketing a generic product that
references an innovator drug with a RiskMAP
If a sponsor would like to initiate a dialogue
with FDA to benefit from the Agency’s experience in reviewing
previously implemented plans, the Agency recommends that the sponsor
contact the product's review division. The division may choose to
establish a working group to assist the sponsor in developing a
RiskMAP. This group could also include representatives from CDER’s
Office of Drug Safety (ODS), CBER’s Office of Biostatics and
Epidemiology (Division of Epidemiology), or CDER’s Office of Generic
Drugs (OGD), as appropriate. In any particular case, it may be
helpful if the sponsor and FDA:
- share information and analyses regarding the
product’s risks and benefits
- discuss the choice of RiskMAP goals,
objectives, and tools
·
discuss the evaluation plan, including (1) times for
evaluation, (2) performance measures, and (3) analyses
Sponsors may wish to discuss RiskMAP issues
with FDA at pre-defined meeting times (e.g., end-of-phase-2
meetings), if appropriate, or request meetings where RiskMAPs can be
specifically considered. To maximize the value of their discussions
with FDA, we recommend that sponsors who seek the Agency’s guidance
apprise reviewers of the rationale for and data underlying RiskMAPs
under consideration. FDA requests that sponsors also share relevant
background information and questions for discussion before their
meetings with FDA.
If the sponsor decides to submit a RiskMAP
before marketing approval of the product, FDA recommends that the
RiskMAP be submitted to the investigational new drug application (IND),
new drug application (NDA), or biologics license application (BLA)
for the product in question. If a RiskMAP is being considered in a
product’s postmarket phase, FDA recommends that it be submitted as a
supplement to the relevant NDA or BLA.
FDA encourages early and open discussion of
safety concerns and whether such concerns may merit a RiskMAP.
Early discussion of RiskMAPs could provide the opportunity to
pretest risk minimization tools.
FDA suggests that a RiskMAP submission to
FDA include the following sections, as well as a table of contents:
·
Background
·
Goals and Objectives
·
Strategy and Tools
·
Evaluation Plan
FDA suggests that the Background section
explain why a RiskMAP is being considered and created. We recommend
that it describe the risks to be minimized and the benefits that
would be preserved by implementation of a RiskMAP. Further, we
suggest that this section describe, to the extent possible, the
type, severity, frequency, and duration of the product's risks, with
particular attention to the risk or risks addressed by the RiskMAP.
The following are sample questions regarding
risk characterization that we recommend be addressed in the
Background section:
·
What is the rationale for the RiskMAP?
·
What is the risk the RiskMAP addresses? Is there more
than one risk to be minimized? If there is, how do they relate to
each other with regard to the following bulleted items?
·
What is the magnitude and severity of the risk?
·
Who is at highest risk?
·
Are particular populations at risk (e.g., children,
pregnant women, the elderly)?
·
Is the risk predictable?
·
Is the risk preventable?
·
Is the risk reversible?
·
Is the risk time-limited, continuous, or cumulative?
FDA recommends that this section include a
discussion that considers the product’s risks in the context of its
benefits. The following are sample questions that address benefit
characterization.
·
What is the overall nature or extent of benefit and
what are the expected benefits over time (i.e., long-term benefits)?
·
How do the populations most likely to benefit from
this product compare to those that may be at highest risk?
·
How would implementation of a RiskMAP affect
individual and population benefits? Will it increase the likelihood
that benefits will exceed risks in patients using the product? Will
the RiskMAP preserve access to the product by patients who benefit
from it?
·
Could certain individuals and/or populations likely to
benefit from the product potentially have less access to the product
because of the tools in the RiskMAP?
We suggest that the Background section include
a discussion, if pertinent, about the successes and failures of
other regulatory authorities, systems of health care, or sponsor
actions in minimizing the risks of concern. Information provided by
the sponsor regarding relevant past experiences, domestically or in
other countries, will assist in harmonizing plans as well as
avoiding the cost of implementing RiskMAP tools already deemed
unsuccessful.
FDA suggests that the Goals and Objectives
section describe the goals and objectives of the RiskMAP.
In addition, we recommend that this section describe how the stated
objectives will individually and collectively contribute to
achieving the goal or goals.
FDA suggests that the Strategy and Tools
section define the overall strategy and tools to be used to minimize
the risk or risks targeted by the RiskMAP. We recommend that the
sponsor provide a rationale for choosing the overall strategy. We
suggest that the sponsor describe how each tool fits into the
overall RiskMAP and its relationship to the other tools. FDA
suggests that the sponsor also provide the rationale for choosing
each tool (see section IV.D. for a discussion of considerations in
choosing tools). In particular, we recommend that the sponsor
describe the available evidence regarding the tool’s effectiveness
and, where applicable, provide results from pretesting. In
addition, we suggest that the sponsor state whether it sought input
from key groups, and if it did, we suggest that the sponsor describe
the feedback that was received regarding the feasibility of its
RiskMAP.
We recommend this section also include an
implementation scheme that describes how and when each RiskMAP tool
would be implemented and coordinated. FDA suggests that sponsors
specify overall timelines and milestones. For example, this section
could address whether targeted education and outreach tools would be
implemented before, or concurrently with, other tools.
FDA suggests that the Evaluation Plan section
describe the evaluation measurements or measures that will be used
to periodically assess the effectiveness of the RiskMAP’s goals,
objectives, and tools. For a detailed discussion of RiskMAP
evaluation, see section V.
We recommend that this section include:
·
The proposed evaluation methods for assessing RiskMAP
effectiveness (e.g., claims-based data systems, surveys, registries)
and the rationales for the sponsor’s chosen measures.
·
Targeted values for each measure and the time frame
for achieving them. FDA recommends the sponsor include
interpretations of expected results under best- and worst-case
scenarios. In addition, we suggest the sponsor specify what values
of measures at specific time points will trigger consideration of
RiskMAP modification.
·
The nature and timing of data collection, analyses,
and audits or monitoring that will be used to assess the performance
of each individual tool in achieving the RiskMAP’s objectives and
goals. Again, we suggest specifying target values for
measures.
·
A schedule for submitting progress reports to FDA
regarding the evaluation results for the RiskMAP’s individual tools,
objectives, and goals (see section VII.B. for a discussion of
progress reports). We recommend that the timing and frequency of
progress reports be based primarily on the nature of the risk, tools
used, and outcomes under consideration. FDA recommends that
progress reports be included in periodic safety update reports or
traditional periodic reports.
Where applicable and possible, we recommend
that the Evaluation Plan section discuss potential unintended and
untoward consequences of the RiskMAP. Such a discussion would be
particularly valuable if there are therapeutic alternatives with
similar benefits and risks. We suggest that sponsors discuss how
unintended consequences would be assessed after RiskMAP
implementation. The goal of the assessment would be to ensure that
overall population risks are minimized and specific product
benefits, including access, are preserved.
FDA recommends that a RiskMAP progress report
contain the following sections, accompanied by a table of contents:
·
Summary of the RiskMAP
·
Methodology
·
Data
·
Results
·
Discussion and Conclusions
We suggest that the Summary section briefly
provide background on and an overview of the RiskMAP, and describe
the overall RiskMAP goals and objectives, as well as its strategy
and tools. We recommend that this section also summarize (1) the
evaluation methods used and (2) the relevant measures and time
frames for achieving targeted values.
We recommend that the Methodology section
provide a brief overview of the evaluation methods used (e.g.,
comprehension testing, patient surveys, process audits). FDA
suggests that it describe the evaluation plan, sources of potential
measurement error or bias, and the analytical methods used to
account for them. Since RiskMAP evaluations will often rely upon
observational data, we recommend that the analytical plan address
issues such as measurement errors, sensitivity, and specificity of
the measures, as well as power and confidence intervals where
appropriate.
To the extent possible, we recommend that the
Data section of a RiskMAP progress report contain the primary data
from each evaluation method.
FDA suggests that the Results section contain
analyses of the evaluation data, statistical estimation, and the
sponsor's comparison of tool, objective, and/or goal performance
relative to targeted measures.
FDA recommends that this section describe
whether the RiskMAP is meeting or has met the stated measures for
each tool, objective, and goal. We suggest that this discussion
take all available data, evaluations, and analyses into
consideration.
In some
cases, the sponsor may choose to propose modifications to the
RiskMAP if the RiskMAP goals were not achieved.
See 45 CFR part 46 and 21 CFR
parts 50 and 56. See also the Health Insurance Portability and
Accountability Act of 1996 (HIPAA) (Public Law 104-191) and the
Standards for Privacy of
Individually Identifiable Health Information (the Privacy
Rule) (45 CFR part 160 and subparts A and E of part 164).
The Privacy Rule specifically permits covered entities to report
adverse events and other information related to the quality,
effectiveness, and safety of FDA-regulated products both to
manufacturers and directly to FDA (45 CFR 164.512(b)(1)(i) and
(iii) and 45 CFR 164.512(a)(1)). For additional guidance on
patient privacy protection, see http://www.hhs.gov/ocr/hipaa.
Smalley W, D Shatin, D Wysowski, J Gurwitz, S Andrade et al.,
2000,
Contraindicated Use of Cisapride: Impact of Food and Drug
Administration Regulatory Action.
JAMA
284(23):3036-3039; Weatherby LB, BL Nordstrom, D
Fife,
and AM Walker, 2002,
The
Impact Of Wording in “Dear Doctor” Letters and In Black Box
Labels.
Clin Pharmacol Ther 72:735-742.
As noted above, sponsors should
not develop a RiskMAP for a product for which routine risk
minimization measures are sufficient. Similarly, formal
evaluation plans and performance measures should not be
developed for these products. Instead, evaluation by routine
postmarketing surveillance should be sufficient, although some
products may also have a Pharmacovigilance Plan as described in
the Pharmacovigilance Guidance. If a RiskMAP is later
developed for this type of product based on new risk
information, then a formal evaluation plan may be submitted.
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Date created: June 6, 2004 |