Guidance for Industry
Development and Use of Risk Minimization Action Plans
(PDF
version of this document)
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)
March 2005
Clinical Medical
Guidance for Industry
Development and Use of Risk
Minimization Action Plans
This
guidance represents 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 called risk minimization action plans or RiskMAPs to minimize
identified product risks, (2) selecting and developing tools to
minimize those risks, (3) evaluating RiskMAPs and monitoring tools,
and (4) communicating with FDA about RiskMAPs, and (5) 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 developing the three draft guidance
documents on risk management activities. The draft guidance
documents were published on May 5, 2004, and the public was provided
with an opportunity to comment on them until July 6, 2004. FDA
considered all of the comments received in producing the final
guidance documents:
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 and draft guidances
that preceded them, each of the three final 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 (see e.g., FDA requirements for professional labeling
and adverse event monitoring and reporting). As a result, many of
the recommendations presented here focus on situations
in which a product may pose a
clinically important and unusual type or level of risk. To the
extent possible, we have specified in the text whether a
recommendation is intended for 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.
·
To the extent possible, this guidance reflects FDA’s
commitment to harmonization of international definitions and
standards.
·
When planning risk assessment and risk minimization
activities, sponsors should consider input from healthcare
participants likely to be affected by these activities (e.g., from
consumers, pharmacists and pharmacies, physicians, nurses, and
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 in section II.B, FDA views risk
management as an iterative process encompassing the assessment of
risks and benefits, the minimization of risks, and the maximization
of benefits. Specifically, 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 to define 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). Efforts to maximize
benefits to improve the overall balance of risks and benefits can be
pursued in concert with risk minimization efforts
and can be discussed with FDA.
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. Benefits and risks are difficult to quantify
and compare because they may apply to different individuals and are
usually measured and valued differently. Examples of factors to
weigh are (1) population risks and benefits, (2) individual benefits
from treatment, (3) risks of nontreatment or alternative products,
and (4) modest population benefits in the context of a serious
adverse effect that occurs rarely or unpredictably. Benefits as well
as risks are also patient-specific and are influenced by such
factors as (1) the severity of the disease being treated, (2) the
outcome of the disease if untreated, (3) the probability and
magnitude of any treatment effect, (4) existing therapeutic options,
and (5) the individual’s understanding of risks and benefits and the
value they attach to each of them. Thus, assessment and comparison
of a product’s benefits and risks is a complicated process that is
influenced by a wide range of societal, healthcare, and
individualized patient 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 communication of risks
and benefits through product 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.
There are,
however a small number of products for which a RiskMAP should be
considered (see section III.D). 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.
A RiskMAP could also be
considered as a selectively used type of Safety Action Plan as
defined in the International Conference on Harmonization (ICH)
guidance E2E: Pharmacovigilance Planning (E2E guidance).
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, is a statement of 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, a goal may be the elimination of dangerous
concomitant prescribing. The objectives could include lowering
physician co-prescribing rates and/or pharmacist co-dispensing
rates. 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 to communicate risks
and appropriate safety behaviors to healthcare 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
For certain types of risks (e.g.,
teratogenicity of category X drug products), it may be possible to
develop systems with similar processes and procedures that can be
used industrywide.
The use of these systems can occur outside of
a RiskMAP. For example, while most drugs do not need a RiskMAP,
many would still benefit from a program of physician and patient
education and outreach. At times, communication of potential
product risks may be warranted before a sponsor agrees to do a
RiskMAP or an agreed upon RiskMAP is completed.
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.
Although it is expected and hoped that
sponsors will determine when a RiskMAP would be appropriate, FDA may
recommend a RiskMAP based on the Agency's own interpretation of risk
information.
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 effects and
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
their risks and benefits; and (4) reversibility of adverse events
observed.
- Preventability of adverse effects: Serious
adverse effects that can be minimized or avoided by preventive
measures around drug prescribing are the preferred candidates for
RiskMAPs.
- Probability of benefit: If factors are
identified that can predict effectiveness, a RiskMAP could help
encourage appropriate use to increase benefits relative to known
risks.
Consider the following examples:
·
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.
·
Drugs that provide important benefits, but that are
human teratogens would often be appropriate for a RiskMAP to
minimize in utero exposure.
·
Some drugs may warrant RiskMAP consideration because
safe and effective use call for specialized healthcare skills,
training, or facilities to manage the therapeutic or serious side
effects of the drug.
Involving all stakeholders during the initial
phases of considering whether a RiskMAP is appropriate allows input
and buy-in by all parties who will later have roles in implementing
the RiskMAP. If a RiskMAP is appropriate, stakeholders can help
shape the RiskMAP to foster its success in the healthcare delivery
environment. Therefore, we recommend public discussion about the
appropriateness of a RiskMAP through the FDA advisory committee
process. Such public advisory committee meetings can also be used
to address (1) whether a RiskMAP is appropriate, (2) what the goals
and objectives of the RiskMAP could be (see footnote 6), (3) the
circumstances under which a RiskMAP tool might be revised or
terminated, and (4) whether a RiskMAP itself is no longer
appropriate. The FDA advisory committee structure and processes are
well suited to foster such discussions as they arise on a
case-by-case basis.
A risk minimization tool is a process or
system intended to minimize known risks. 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; FDA encourages and anticipates the
development of additional tools.
Risk minimization tools are designed to help
achieve one or more RiskMAP objectives that are directed at the
overall RiskMAP goal or goals. One or more tools can be chosen to
achieve a particular objective. For example, a 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, before
receiving the product, the patient formally acknowledges their
understanding and/or agreement not to take product B 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 the use of tools in different categories does
not imply greater or lesser safety risks, but rather indicates the
particular circumstances put in place to achieve the objectives and
goals.
1.
Targeted Education and Outreach
FDA recommends
that sponsors consider tools in the targeted education and outreach
category (1) when routine risk minimization is known or likely to be
insufficient to minimize product risks 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
about risks to increase appropriate knowledge and behaviors of key
people or groups (e.g., healthcare practitioners and consumers) that
have the capacity to prevent or mitigate the product risks of
concern.
FDA
acknowledges that tools in this category are occasionally used for
products where the benefit/risk balance does not necessarily warrant
a RiskMAP. Educational efforts by sponsors might include one or
more of the tools described below without a RiskMAP being in place.
Sponsors are encouraged to continue using tools, such as education
and outreach, as an extension of their routine risk minimization
efforts even without a RiskMAP.
Examples of
tools in this category are as follows:
·
healthcare practitioner letters
·
training programs for healthcare practitioners or
patients
·
continuing education for healthcare practitioners such
as product-focused programs developed by sponsors and/or
sponsor-supported accredited CE programs
·
prominent professional or public notifications
·
patient labeling such as Medication Guides and patient
package inserts
·
promotional techniques such as direct-to-consumer
advertising highlighting appropriate patient use or product risks
·
patient-sponsor interaction and education systems such
as disease management and patient access programs
In addition to
informing healthcare 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 known or likely to be insufficient
to minimize identified risks.
Tools in this category include systems that
prompt, remind, double-check or otherwise guide healthcare
practitioners and/or patients in prescribing, dispensing, receiving,
or using a product in ways that minimize risk. Examples of tools in
this category are as follows:
·
Patient education that includes acknowledgment of
having read the material and an agreement to follow instructions.
These agreements are sometimes called consent forms.
·
Healthcare provider training programs that include
testing or some other documentation of physicians' knowledge and
understanding.
·
Enrollment of physicians, pharmacies, and/or patients
in special data collection systems that also reinforce appropriate
product use.
·
Limited number of doses in any single prescription or
limitations on refills of the product.
·
Specialized product packaging to enhance safe use of
the product.
·
Specialized systems or records that are used to attest
that safety measures have 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. Tools
in this category, because they are very burdensome and can disrupt
usual patient care, should be considered only 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 known or likely to be 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 (e.g., the product is not made
available unless there is an agreement or acknowledgment, documented
qualifications, enrollment, and/or appropriate testing or laboratory
records)
·
prescription only by specially certified healthcare
practitioners
·
product dispensing limited to pharmacies or
practitioners that elect to be specially certified
·
product dispensing only to patients with evidence or
other documentation of safe-use conditions (e.g., lab test results)
Performance-linked access systems should seek
to avoid unnecessary or unintended restrictions or fragmentation of
healthcare services that may limit access by physicians,
pharmacists, or patients, or that may lead to discontinuities in
medical or pharmacy care.
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. On
the contrary, FDA does not suggest that the tools listed on the Web
site are the only tools that could be useful and encourages sponsors
to develop tools that may be optimal for their particular products.
See also Section V.D on making information from RiskMAP evaluations
available to the public.
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 healthcare 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 healthcare system that is compatible
with adequate risk minimization (e.g., a reminder system tool should
not be used if targeted education and outreach would likely be
sufficient).
·
Identify the key stakeholders who have the capacity to
minimize the product’s risks (such as physicians, pharmacists,
pharmacies, nurses, patients, and third-party payers) and define the
anticipated role of each group.
·
Seek input from the key stakeholders on the
feasibility of implementing and accepting the tool in usual
healthcare practices, disease conditions, or lifestyles, if
possible. Examples of considerations could include (but would not
be limited to) patient and healthcare practitioner autonomy, time
effectiveness, economic issues, and technological feasibility.
·
Acknowledge the importance of using tools with the
least burdensome effect on healthcare practitioner-patient,
pharmacist-patient, and/or other healthcare relationships.
·
Design the RiskMAP to be:
1.
compatible with current technology
2.
applicable to both outpatient and inpatient use
3.
accessible to patients in diverse locales, including non-urban
settings
4.
consistent with existing tools and programs, or systems that have
been shown to be effective with similar products, indications, or
risks
·
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 healthcare practitioner
behaviors in medical care settings).
·
Consider, and seek to avoid, unintended consequences
of tool implementation that obstruct risk minimization and product
benefit, such as obstructing patient access or driving patients to
seek alternative product sources (e.g., Internet sales, counterfeit
products) or less appropriate products.
FDA recognizes that once it approves a
product for marketing, healthcare practitioners are the most
important managers of product risks. FDA believes that by including
information in the FDA-approved professional labeling on the
conditions in which medical products can be used safely and
effectively by their intended population and for their intended use
or uses, the Agency and the sponsor encourage healthcare
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 healthcare practitioners to prescribe products for
conditions other than those described in FDA-approved professional
labeling, or to otherwise regulate medical or surgical practice.
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 (see e.g., FDA requirements for professional labeling
and adverse event monitoring and reporting).
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. RiskMAPs and their
component objectives and tools should be monitored and evaluated in
a timely manner 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 Healthcare
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 RiskMAP submissions to
FDA).
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
healthcare 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. The specific types of data gathered in a RiskMAP
evaluation will determine whether it would be appropriate to include
a statistical analysis of evaluation results.
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
outcome from product use, a sample performance measure could be the
complication rate. For evaluation purposes, a target for that
measure could be established to be no more than a specified number
or rate of that complication. In some cases, however, 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 test
results for determining if pregnancy occurred). The sensitivity,
specificity, and predictive value of surrogate markers should be
established before their use as a performance measure.
·
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 is to the RiskMAP goal, the greater its degree of
validity. For example, if the RiskMAP goal is avoidance of liver
failure, then ascertainment of the rate of liver failure in the user
population would be a highly valid performance measure.
Hospitalization for severe liver injury would be another, but less
direct, assessment of the RiskMAP goal. The frequency of liver
function monitoring in users could be used to see if RiskMAP
processes to prevent liver failure were being followed, but since
liver function monitoring may not be tightly linked to the
occurrence of liver failure, such process monitoring would have
limited validity as an indicator of successful prevention of liver
failure.
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 or active
surveillance of adverse events in populations with well-defined
exposure to the product would be preferred 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 may come from various insurers, purchasing
groups, or networks that are tied to employment or entitlement
programs, so it is important to determine if an administrative
data system is representative of the general population being
treated with the product. 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.
In addition, there may be data processing time lags of several
months or longer before administrative data can be retrieved and
analyzed.
- 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 healthcare
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
healthcare 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 illustrate how using only one
evaluation 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, surveys of healthcare practitioners may indicate high
compliance with systems for preventing product complications.
However, systematically collected or spontaneous reports might show
that product complications are occurring, thus suggesting that
prevention efforts in actual practice may be ineffective or
incompletely applied. 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.
If RiskMAPs use multiple tools or interventions, it may be useful to
consider using evaluation methods applicable to the program as a
whole. For example, a systematic program evaluation model, such as
Failure Modes and Effect Analysis (FMEA),,
can provide a framework for evaluating the individual RiskMAP
components and the relative importance of each in achieving the
overall RiskMAP goal or goals.
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 achievement of
goals and the performance of 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. Two
important factors that contribute to tool effectiveness are its
acceptability and unintended consequences. Since tool performance
will often depend upon the understanding, cooperation, efforts, and
resources of healthcare providers, pharmacists, and patients,
evaluation of acceptability and unintended consequences for
individual tools may help to improve the use of tools and thus their
performance.
FDA recommends that, to the extent possible,
sponsors evaluate tools for effectiveness before implementation. As
discussed in section IV.D, FDA suggests that in selecting tools to
include in a RiskMAP, a sponsor consider tools that are likely to 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. Application of
computer modeling or simulation techniques may also assist in
projecting potential outcomes of implementation of various
combinations of RiskMAP tools.
Besides using literature evidence and past
RiskMAP experience to identify tools with a known track record of
effectiveness, sponsors can pretest or pilot test a tool before
implementation. Such testing, ideally with a comparison group or
time period, can help to assess comprehension, acceptance,
feasibility, and other factors that influence how readily RiskMAP
tools will fit into patient lifestyles and the everyday practices of
healthcare 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
preventable risk is identified in Phase 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. In such instances, sponsors should
seek to employ tools with a proven track record of effectiveness.
In general, the greater the rate or severity of risks to be
minimized, the more critical it becomes to have compelling evidence
of effectiveness of the tool through some form of testing or prior
use.
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 and the other risk management
guidances. At a minimum, FDA and sponsors would discuss their
respective RiskMAP evaluations in a meeting or teleconference. In
cases where risks are frequent and/or severe, or where results are
ambiguous or uncertain, or where there is disagreement between the
sponsor and FDA in the interpretation of the RiskMAP or tool
effectiveness, public and expert input would be sought through the
FDA Advisory Committee process. This will also allow airing and
discussion of important information about effective and ineffective
RiskMAPs and tools.
As discussed in section IV.C, FDA plans to
maintain a RiskMAP Web site that will describe all publicly
available information about implemented RiskMAPs (and their tools).
On the same Web site, FDA intends to make available, in summary
format, information that has been publicly discussed or is otherwise
publicly available (from sponsors or other sources) about the
effectiveness of particular RiskMAP tools in achieving risk
minimization objectives. The summaries may derive from materials
presented and discussed at FDA Advisory Committee meetings where the
effectiveness of a particular RiskMAP has been discussed and
potential modifications have been entertained.
VI.
COMMUNICATING WITH FDA REGARDING RiskMAP DEVELOPMENT AND DESIGN
ISSUES
As discussed in section III.D, because risk and
benefit information emerge continually throughout a product’s
lifecycle, a sponsor could decide, or FDA could recommend, that a
RiskMAP is appropriate at several different times. These times
include:
- before approval, when a risk is identified
from clinical studies, nonclinical studies, or in similar class of
products, 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 review division is the
primary contact for a sponsor. The review division may choose to
consult with other Offices in assisting the sponsor in developing a
RiskMAP. These consulting offices could include CDER’s Office of
Drug Safety (ODS), CBER’s Office of Biostatics and Epidemiology (OBE),
or CDER’s Office of Generic Drugs (OGD), as appropriate. In any
particular case, it is 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 their targets,
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.
Both CDER and CBER will develop internal
Manuals of Policies and Procedures (MaPPs) (or standard operating
procedures (SOPs)) regarding the review of RiskMAPS. The procedures
will define milestone points at which RiskMAP discussion is logical
and will promote consistency in RiskMAP review and design. All
RiskMAPs involving reminder tools or performance-linked access
systems will be considered at the Center level as a secondary method
of ensuring consistency across product classes and across
divisions.
If the sponsor decides to submit a RiskMAP
before marketing approval of the product, most times the RiskMAP
will be submitted to the new drug application (NDA) or biologics
license application (BLA) for the product in question. However, if
a risk is identified early (e.g., the product is a teratogen), and
the sponsor wishes to institute formal risk management activities
during Phases 1 to 3 studies, the sponsor can submit the RiskMAP to
the investigational new drug application (IND). 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.
Additional user fees will only be applicable to a supplement if FDA
determines that new clinical data are required for its approval.
This would be unlikely for a RiskMAP supplement.
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?
These questions are similar in intent to what
the ICH calls a Safety Specification in its E2E guidance.
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 affect 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 healthcare, or sponsor
actions in minimizing the risks of concern for this product.
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. We encourage sponsors to
provide applicable information or evaluations from past experiences
with products or programs that are similar to the proposed RiskMAP.
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 patient or healthcare interests, and if it did, we suggest that
the sponsor describe the feedback that was received regarding the
feasibility of its RiskMAP. FDA plans to maintain a Web site that
will describe publicly available summary information about
effectiveness of RiskMAP tools (see section V.D).
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.,
ascertainment of outcomes, comprehension testing, patient surveys,
process audits). FDA suggests that it describe the evaluation plan,
sources of potential measurement error or bias for the outcome of
interest, and any 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 for detecting differences where appropriate.
To the extent possible, we recommend that the
Data section of a RiskMAP progress report contain data that would
allow FDA to analyze the information and make conclusions
independently.
To the extent possible, we recommend that the
Results section of a RiskMAP progress report contain the primary
data from each evaluation method and analyses of the evaluation
data, statistical estimation if appropriate, and the sponsor's
comparison of tool, objective, and/or goal achievement relative to
targeted performance measures.
FDA recommends that this section describe
whether the RiskMAP has met or is making progress in meeting the
stated measures for each tool, objective, and goal. We suggest that
this discussion take all available data, evaluations, and analyses
into consideration.
Progress
towards achieving RiskMAP goals or performance measures should be
reported. Where appropriate, sponsors are encouraged to propose
modifications to the RiskMAP and discuss them with FDA.
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
This ICH guidance is available on
the Internet at
http://www.fda.gov/cder/guidance/index.htm
under the topic ICH Efficacy. The draft E2E guidance was made
available on March 30, 2004 (69 FR 16579). ICH agreed on the
final version of the E2E guidance in November 2004.
As noted in section III.B,
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 sponsor should consider submitting a formal
evaluation plan.
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Date created: March 24, 2005 |