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Another aspect that would need clarification if evidence is to be shared is the

difference in validity of the data that are required by the different assessors.
Whereas regulators prefer the internal validity provided by the RCT, payers are
more interested in the external validity obtained from real-life clinical practice
or observational studies. Though ideally all assessors prefer data obtained
over the longest possible period of time, regulators are more accepting of
shorter time horizons as evidenced in the duration of clinical trials. The payers
are more interested in longer time horizons, for example, through the long-term
follow-up of MS patients in the patient access scheme in the United Kingdom.
It is unclear whether a requirement for RE assessment is likely to streamline
this process.

to provide more evidence on the comparative value of their new products, it


is evident that the actual implementation requires more detailed discussions
around process, methodology, timelines and tasks. IC

Even if all these questions can be answered, many remain on matters of


implementation and methodology, such as how RE will be implemented in
practice and who would be responsible. Current thoughts are that the EMA may
be given responsibility, however, this aspect still remains unclear. Even if such
a requirement were implemented, it is possible that evidence on RE will not be
required for all licensing decisions but could be reserved for cases where there
is a clear comparator or a substantial innovation. As part of any procedure, in
case RE assessment takes place, an appeals/complaints procedure will need
to be established. This is a substantial undertaking. Further thoughts should
be given as to how and to what extent data will be made publicly available. The
RE assessment may include substantial commercial-in-confidence data which
will not be suitable for publication, and so mechanisms will need to be put into
place to ensure the confidentiality of these data, while still sharing results with
the wide public.

3. Backhouse ME, Wonder M, Hornby E, et al. Early dialogue between the developers of
new technologies and pricing and reimbursement agencies: a pilot study. Value Health
2011;14:608-15.

References

1. European Medicines Agency. The European Medicines Agency Road Map to 2015:
The Agencys Contribution to Science, Medicines, Health. 2010. Available from: http://
www.ema.europa.eu/docs/en_GB/document_library/Report/2010/01/WC500067952.
pdf. [Accessed August 10, 2011].
2. Eichler HG, Bloechl-Daum B, Abadie E, et al. Relative efficacy of drugs: an emerging
issue between regulatory agencies and third-party payers. Nat Rev Drug Discov
2010;9:277-91.

4. Jonsson B. Relative effectiveness and the European pharmaceutical market. Eur.J


Health Econ 2011;12:97-102.
5. Hoaglin DC, Hawkins N, Jansen JP, et al. Conducting indirect-treatment-comparison
and network-meta-analysis studies: Report of the ISPOR task force on indirect treatment
comparisons good research practices-Part 2. Value Health 2011;14:429-37.
6. Jansen jp, fleurence r, devine b, et al. interpreting indirect treatment comparisons
and network meta-analysis for health-care decision making: Report of the ISPOR task
force on indirect treatment comparisons good research practices: Part 1. Value Health
2011;14:417-28.
7. European Commission - High Level Pharmaceutical Forum. Core principles on relative
effectiveness. Available from: http://ec.europa.eu/pharmaforum/docs/rea_principles_
en.pdf. [Accessed September 18, 2010].

In conclusion, though the reasoning behind the need for RE assessments


is clear, and even though this type of assessment could result in important
time savings and manufacturers should, regardless of the requirements, aim

policy analysis

A Comparison of US Food and Drug Administration


and European Medicines Agency Regulations for
Pharmaceutical Risk Management: Report of the
International Society for Pharmacoeconomic and Outcomes
Research Risk Management Working Group
Yvonne Lis, PhD, Consultant, PAREXEL International, Uxbridge, UK; Jeff J. Guo, PhD, Professor of Pharmacoeconomics, University of
Cincinnati Medical Center College of Pharmacy, Cincinnati, OH, USA; Melissa H Roberts, MS, Senior Research Associate, LCF Research,
Albuquerque, NM, USA; Shital Kamble, PhD, Duke Clinical Research Institute, Duke University, Durham, NC, USA; Dennis W. Raisch,
PhD, Professor, University of New Mexico, College of Pharmacy, Albuquerque, NM, USA

Introduction

As a response to the withdrawal of high profile drugs over the last few years
such as, VioXX [1], Seldane [2], Rezulin [3], Propulsid [4], Baycol
[5] and Trasylol [6], the US Food and Drug Administration (FDA) and the
European Medicines Agency (EMA) have changed emphasis from the reactive
collection of safety data to a more proactive risk management approach.
Increased public scrutiny has also been driving the focus on drug safety
surveillance, increasing the demand for more refined pharmacovigilance tools.
Both agencies independently have implemented proactive approaches for drug
safety surveillance which have reframed the traditional business model of
the pharmaceutical industry. The purpose of this document is to describe the
current characteristics of the FDA and EMA regulatory guidelines as they have
been implemented and to compare their respective approaches.

10 September/October 2011 ISPOR CONNECTIONS

The FDA Approach

The FDA identifies risk management as an iterative process designed to


optimize the benefit-risk balance for regulated medicines throughout the
product life cycle [7]. In March 2005, three guidance documents were
issued which defined the formal basis of risk management. These were:
Premarketing Risk Assessment [8], Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment [9] and the Development and Use of
Risk Minimization Action Plans (RiskMAPs) [10]. These three documents
became the building blocks for the more recent Risk Evaluation and Mitigation
Strategies (REMS) [11].
The FDA Premarketing Risk Assessment Guidance aims at improving the
adequacy of clinical trials for characterizing a products safety profile.

The focus is on the generation, acquisition, analysis and presentation of


premarketing safety data and the document contains a comprehensive set of
recommendations for conducting clinical studies.
The Good Pharmacovigilance Practices and Pharmacoepidemiologic
Assessment Guidance defines pharmacovigilance as, all observational
post-approval scientific and data gathering activities relating to the
detection, assessment and understanding of adverse events with the goals
of identifying and preventing these events to the extent possible. It contains
recommendations for reporting and analytical practices to monitor safety
concerns and risk associated with medical products. The guidance also
recognizes the heterogeneous nature of benefit and risk assessment stating
that, because different products pose different benefit risk considerations
including seriousness of the disease, the nature and frequency of the safety
signal, it is impossible to delineate a universal set of criteria to identify the point
at which a pharmacoepidemiologic safety study should be initiated.
The RiskMAP was defined as a strategic safety program designed to minimize
known risks of a product while preserving its benefits. It described how
industry could address specific risk-related goals and objectives, suggesting
various tools to minimize the risks of drug and biological products. The FDA
recommended that a plan should target at the achievement of particular health
outcomes related to known safety risks and be stated in absolute terms. For
example patients prescribed drug X should not also be prescribed drug Y.
The FDA also recognized that a variety of tools could be used to minimize
risk, including: targeted education and outreach, reminder systems and
performance based systems.
Enacted in March 2008, the Food and Drug Administration Amendments Act of
2007 (FDAAA) [11] provides the FDA with authority to request a REMS at any
point during a products life cycle. The REMS requirement which effectively
replaces the RiskMAP applies to all new drug applications (NDAs), abbreviated
new drug applications (ANDAs), and biologics license applications (BLAs).
Certain products approved prior to March 2008, and those with elements
to assure safe use, were deemed to have an approved REMS but were also
required to submit a proposed REMS within 180 days of the FDAAA.
Currently there are no set rules or direct guidance for when the FDA might
impose a REMS, however, considerations that drive their decision include:
the estimated size of the patient population; the seriousness of a disease or
condition; the expected benefit of the intervention; the anticipated duration of
treatment; the seriousness of known or potential adverse events; and whether
the drug is a new chemical entity. Other considerations after approval may
include new evidence that REMS requirements are needed to ensure that the
benefits of the drug outweigh its risks.
Where required, the REMS is intended to manage known or potentially serious
risks and the REMS elements vary according to the severity of identified risks,
the population likely to be exposed, and other factors. The REMS guidance
provides a general framework for mandated post marketing safety activities
and incorporates many of the principles in the original RiskMAP guidance
[12]. The requirements may include the provision of a medication guide, a
patient package insert, a communication plan or other Elements to Assure
Safe Use (ETASU). ETASUs may include such provisions as dispensing
only by pharmacies or practitioners in health care settings that are specially
certified, the product only being dispensed where there is evidence of safeuse conditions, or monitoring of patients either individually or by enrolment in
a registry. Provision must also be made for monitoring the implementation of
ETASU requirements.
Evaluation of each REMS is conducted by the FDAs Drug Safety and Risk
Management Advisory Committee comprised of various stakeholders including
patients, physicians, pharmacists and other health care professionals who
provide input on implementation requirements and management strategy. After
approval, timings for routine assessment of the program are 18 months, 3 years

and 7 years. If considered appropriate the FDA may stipulate shorter or longer
intervals between assessments and can remove the need for assessments
after year 3 if serious risks have been adequately identified, assessed and
managed.
With the introduction of REMS requirements, the FDA also issued a number
of guidance documents relating to specific safety issues which include:
drug-induced liver injury [13], a recommended approach for communicating
important drug safety information to the public [14], pharmacovigilance
planning at the time of license application [15] and quality risk management to
provide regulators and industry with principles and tools for risk management
as a basis for consistent risk-based decisions throughout a products lifecycle
[16]. More recent guidance [17] is focused on detailing the circumstances and
type of post-marketing studies and clinical trials that may be required for safety
evaluation and other agreed upon post marketing commitments.

The EMA Approach

Within the European Union (EU), the focus has also been on a proactive
approach in ensuring patient safety, with continuing efforts to improve
the spontaneous reporting scheme. In 2005, legislation formalised the
introduction of risk management plans [18] and subsequently the European
Medicines Agency (EMA) issued guidelines on risk management systems, a
template for a Risk Management Plan (RMP), and new regulations governing
pharmacovigilance [19].
An RMP is required when routine pharmacovigilance practice for medications
is considered to be insufficient. Products containing a new active substance,
or for which there is a significant change in indication or for which serious or
potentially serious safety risks have been previously identified, generally fall
into this category. An RMP is also required for biological medicinal products
and generic/hybrid medicinal products, for which a safety concern requiring
additional risk minimisation activities has been identified [20].
The process comprises a Safety Specification with a Pharmacovigilance Plan
(Part I) and a Risk Minimisation Plan (Part II). Part I is intended to enable
determination of whether routine post authorisation pharmacovigilance will be
sufficient or whether there is a need for additional pharmacovigilance activities.
It requires a summary of important identified and significant potential risks of a
medicinal product, information on populations potentially at risk together with
any outstanding safety questions which warrant further investigation.
Part II requires details of any additional pharmacovigilance or risk minimisation
activities planned. No precise guidance is given on which activities are to be
used in any given situation as each safety concern has to be considered on a
case-by-case basis. The guidance does, however, recommend early and full
consultation with appropriate experts.
Accurate and timely communication of emerging data on risk is considered an
essential part of pharmacovigilance with risk education, risk management and
any risk minimization activities being essential components. The Summary of
Product Characteristics and Patient Information Leaflets are the prime vehicles
for communicating any potential risks to prescribers and patients. Once the
overall RMP has been approved, updated documents including any reported
adverse event signals and safety evaluations should be submitted along with
the periodic safety update report (PSUR).
In the recent EMA draft, The European Medicines Agency Road Map to
2015 [21], a key strategic area identified for optimization is the safe use of
medicines. Plans include revisions to the overall risk management concept
and enhancements to current pharmacovigilance activities including the
on-going strengthening of post authorisation monitoring. In support of this
EMA strategy, the European Network of Centres of Pharmacoepidemiology
and Pharmacovigilance (ENCePP), set up in 2006, was charged with
conducting independent multi-centre post-authorisation studies focused on
investigating safety and a lack of efficacy [22]. The Road Map to 2015 >
September/October 2011 ISPOR CONNECTIONS 11

also set out several priority challenges, including the development of tools
for the anticipation of potential safety issues and the appropriateness of the
current legal/regulatory framework with regard to benefit/risk evaluation. The
EMA indicates that although the risk management plans are increasing the
knowledge of a medicine in the post-authorization phase, there is also merit
in systematically gaining information on the benefits of a medicinal product
throughout its lifecycle. Evidence of evolution in the EMA approach can be
seen in the recently revised Regulations [23] and Directives [24] effective from
July 2012 which is aimed at improving routine pharmacovigilance activities,
strengthening the EudraVigilance system and harmonizing access across
member states.

A Comparison of Approaches

The current sets of FDA and EMA guidance are driven by similar objectives
for the identification, monitoring and minimization of risk to patient safety.
As a result, they frequently lead to the generation of similar data needs. In
todays global market environment such similar data requirements facilitate the
exchange of information between the regulators. Although the central concept
for both agencies is assessing risk and determining if it is acceptable, none of
the current guidelines directly define risk acceptability.
Implementation of REMS and RMP requirements initiated new risk management
approaches for pharmacovigilance. When serious safety concerns are
identified, they must be rigorously monitored and action taken to reduce
risk to patients. Modified standards of approval, new label models, patient
inserts, special advertising and mandatory registry monitoring have become
established risk minimization tools.
The authors had not expected to find significant differences in the approaches
to risk management between the FDA and the EMA and a detailed comparison
of respective guidance documents suggests similarity in overall objectives
with respect to the identification, monitoring and minimization of risk. Similarly,
both Agencies allow flexibility in the determination of product specific actions
required, recognizing the dependency on differing potential concerns. From
an enforcement perspective, both agencies have the power to assure that
manufacturers adequately implement approved REMS/RMPs.
Differences in the timing of the approval or revisions to REMS/RMPs for the
same product are also known to occur; however, these are usually driven by
the timing of entry into the different markets and the new information that
becomes available as a result.
There are cases, however, where the two Agencies have made different
decisions in response to the safety issues identified in currently marketed
products. For example, in December 2010 EMA suspended Avandia,
Avandamet and Avaglim on the basis of data suggesting elevated risk of
heart attacks in patients treated with rosiglitzone. The FDA, however, decided
only to restrict access and the REMS was modified accordingly in May 2011.
There are differences in emphasis for the communication of risk to patients
and physicians. In the EU, the Summary of Product Characteristics is the key
communication to physicians, including data on treatment effects, serious
adverse effects, contraindications and special warnings. Communication to
the patient is principally through the Patient Information Leaflet provided as
a package insert with every prescription, supplemented with advice from the
physician at the time of prescribing. In the United States, the Medication Guide
represents the basic vehicle for communicating information on medicinal
risks to patients. A communication plan for ensuring that risks are fully
communicated to health care professionals is not always required.
There are also differences in monitoring implementation of risk minimization
actions and the reporting time requirements which are generally related to
geographic and logistic factors. Where there are known safety concerns,
in its single market, the FDA requires monitoring and measurement to be

12 September/October 2011 ISPOR CONNECTIONS

implemented through the ETASU plan. Given the range of health care systems,
varying medical practice and diversity of cultures among the 27 EU Member
States and 3 EE/EA countries that EMA oversees, implementing a standard
approach to monitoring and measurement is currently both practically and
politically challenging. Therefore, the EMA relies principally on routine adverse
event reporting and regular PSUR submission to detect risk experienced in
clinical practice. Like the FDA it also places emphasis on additional data
collection in the form of prospective studies, such as Registries, to further
characterize known or potential risks and to fill specific safety information
gaps.
One other dimension to consider is that while the EMA has an overarching
role within Europe, national agencies may still take independent action. One
example is the case of pioglitazone, where recently available five year results
indicated a possible increased risk of bladder cancer in some patients. Both
the FDA and EMA are currently reviewing the risks and benefits pending any
decision on the marketing status of the product; however, the French Medicines
Agency (Afssaps) has already suspended its use pending the review of
available evidence.
A summary of conceptually similar FDA REMs and EMA RMP elements are
detailed in Table 1, while components not shared by the two agencies are
shown in Table 2.
Table 1. Conceptually similar components between Food and Drug Administrations (FDA) Risk Evaluation and Mitigation Strategies (REMS) and
European Medicines Agency (EMA) Risk Management Plans (RMPs)
FDA REMS EMA RMPs
Medication guides

Patient alert cards

Patient information sheet

Patient information leaflet

Container labels

Summary of Product Characteristic (SPC)


contraindications SPC special warnings
and precautions for use

Provider communication plan


Provider information sheet
Highlighted information for prescribers
Training of healthcare professionals

Summary of Product Characteristic


(SPC) contraindications
Educational programmes

Monitoring of patients receiving


medication

Specific adverse event and


pharmacovigilance surveillance reporting
requirements
Prospective observational studies

Prescriber and patient database

Additional trial and study data

Post marketing studies


Registry

Specific adverse event and


pharmacovigilance surveillance
reporting requirements
Registry

Table 2. Requirements not shared between Food and Drug Administrations (FDA) Risk Evaluation and Mitigation Strategies (REMS) and
European Medicines Agency (EMA) Risk Management Plans (RMPs)
FDA REMS EMA RMPs
Monitoring of patients receiving
medication
Specification of distribution or
dispensing locations
Monitoring of distribution
Patient or physician survey to evaluate
understanding of risk
REMS print advertisement
Audit of communication plan
Audit of pharmacies

SPC undesirable effects


Development of diagnostic tests for
adverse event

Although neither agency currently provides specific guidance for risk versus
benefit assessment [25], the need for a more consistent, structured yet flexible
approach by the Regulator to the evaluation of risks versus benefits is being
discussed by both European and United States constituents with ongoing
initiatives to identify acceptable methodologies [26,27]. The EMA reflection
paper issued in 2008 [28] was followed by a benefit risk methodology project
aimed at providing a more consistent and transparent approach for evaluating
the risks and benefits of medicines. The FDA is also working towards developing
a framework for a more structured approach to risk benefit assessment [29].
In summary, both FDA REMS and EMA RMPs currently provide broadly
comparable comprehensive post approval guidance for the identification,
monitoring and minimization of risk to patient safety with some differences
in respective implementation toolkits. There is also an increasing tendency
towards collaborative efforts between the two regulatory agencies in
approaches to monitoring and minimizing risk for patients. IC

References

1. Merck and Company, letter concerning withdrawal of Vioxx. Available from: http://
www.vioxx.com/rofecoxib/vioxx/consumer/index.jsp. [Accessed December 10, 2010].
2. FDA US Food and Drug Administration. Appendix G - Market Withdrawals. Available
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event reporting programme. Propulsid (cisapride) April 2000. Available from: http://www.
fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/
ucm175000.htm. [Accessed December 10, 2010].
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adverse event reporting programme. Baycol August 2001. Available from: http://www.
fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/
ucm172268.htm. [Accessed December 10, 2010].
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adverse event reporting programme. Traysol (aprotinin injection) Nov 2007. Available from:
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7. Bull J. US activities in risk management of pharmaceutical products. Chapter 43 in
Pharmacovigilance (2nd ed.). Eds. Mann R, Andrews E. Wiley, 2007.
8. FDA Guidance for Industry: Premarketing Risk Assessment (Premarketing Guidance).
March 2005. Available from: http://www.fda.gov/downloads/RegulatoryInformation/
Guidances/UCM126958.pdf. [Accessed June 15, 2011].
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Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance) March 2005.
Available
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UCM126834.pdf. [Accessed June 15, 2011].
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(RiskMAP Guidance). March 2005. Available from: http://www.fda.gov/downloads/
RegulatoryInformation/Guidances/UCM126830.pdf. [Accessed June 15, 2011].
11. Food and Drug Administration Amendments Act (FDAAA) of 2007. Available from:
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm. [Accessed June 15, 2011].
12. Leiderman DB. Risk Management of drug products and the US FDA: Evolution and
context. Drug Alcohol Depend 2009;105(Suppl. 1):S9-S13.
13. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation.
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WEB CONNECTIONS
The US Department of Health and Human Services (HHS)
(http://www.hhs.gov/) encourages and facilitates the collection
of national health and other data. The HHS is comprised of 11
operating divisions which are responsible for a wide variety of
tasks and services, including research. HHS and the operating
divisions publish critical disease and/or therapeutic area data.
Given the variety of data, HHS has developed a directory of HHS
data resources. The directory was designed to capture data
resources that are of interest to a wide variety of audiences.
The directory is available on HHSs home page on the Internet
at: http://aspe.hhs.gov/datacncl/datadir.
Do you know of any websites that you would like to share
with the ISPOR community? If so, contact Bonnie M. Korenblat
Donato, PhD, at: bonnie.donato@bms.com.
September/October 2011 ISPOR CONNECTIONS 13