With permission from FDLI
GLOBAL CORNER
Product Safety Update
Report—A Risk
Management Tool for
Everyone
U nder the International Conference on Harmoniza-
tion (ICH) E2C Guidelines,1 Marketing Authoriza-
tion Holders (MAHs)2 in the European Union (EU), United
States, and Japan are to summarize and update available
information on the safety and benefit-to-risk ratio of new
drugs at least semi-annually for a minimum of two years
after introduction of the drug.
The mandated form of communication under the ICH
guidelines is the Periodic Safety Update Report (PSUR), but
requirements for PSURs have not been implemented
uniformly in all ICH countries. Two recent developments,
however, may ease the burden of preparing PSURs: the
addendum to the ICH E2C guidelines3 and the U.S. Food
and Drug Administration’s (FDA’s) implementation of the
guidelines. These developments should help MAHs shift the
focus of PSUR preparation from simply collecting and
collating pharmacovigilance data, to developing an inte-
grated program for benefit-to-risk assessment—a vital part of
the pharmaceutical asset protection plan.
PSURs are the key communication tool concerning safety
and utility between the MAH and regulatory authorities. A
PSUR must serve three purposes. First, it must meet the
regulator’s demand for reporting any alleged side effect
associated with administration of the drug. Second, it must
evaluate the information generated and appropriately frame
the issues arising from that information that will require
public health risk management. Third, a PSUR must address
requirements for updating and characterizing the benefit-risk
balance of the drug. The information on all indications, dose
forms, and regimens for an active substance should be
included in a single PSUR, with a single data lock point for
all aspects of product use. There is great value in a single
document that contains a consistent, broadbased examination
of the information on an active substance. This permits a
clear evaluation of the benefit-to-risk profile for a drug
substance that may have many uses and many user profiles.
52 UPDATE July/August 2003
www.fdli.org
by Matthew Weinberg
The PSUR plays a complex role in the pharmaceutical
risk management process; an understanding of which appears
to be lacking. The PSUR allows for the examination of any
alleged public health risks and it provides a vehicle to
manage corporate risk—the risk that an inappropriate
analyses of the findings may result in the market loss of
valuable new drugs after massive research and development
investments. Failure to appreciate the true role of the PSUR
can be one aspect of an improperly organized process that
leads to the submission of an incomplete PSUR. Each PSUR
is considered a stand-alone report that sets the regulator’s
agenda for controls over the use of the drug. Unless PSUR
submissions are planned properly, the MAH will not be in a
position to protect the public or to promote the drug.
Little or no thought seems to be given to the requirements
for the PSUR during the development of many drugs, despite
the fact that the first report is due six months after the
International Birth Date (IBD) (i.e., the date of first market-
ing authorization for a new product). During this key period,
the MAH and comarketers seek to expand drug registration
and introduction of the product into many new markets. Less
thought is given to the acquisition of key outcomes data that
will allow for proper characterization of the benefit-risk
ratio.
The operational process of assembling and interpreting
PSUR data usually is not addressed until there is some
indication of a product problem. Less-than-useful PSURs are
produced if they do not properly consider the impact on drug
availability, image, use, and resultant acceptance. Many
PSURs seem to focus on signal events, and are compiled
willy-nilly, almost right up to the required submission date.
This flies in the face of the reality that new, successful drugs
will target specific disease entities found among unique—
Mr. Weinberg is the Chief Executive Officer of
THE WEINBERG GROUP,
Washington, D.C.
w w w. f d l i . o r g
and often medically-compromised—patients. Without
adequate forethought and preparation, the MAH is in no
position to carry out a number of tasks that must accompany
the preparation of useful and effective PSURs.
Operational tasks that are frequently inadequately
planned for in PSUR submissions include:
• Synchronization of the IBD with the national birth date of
the drug to be able to set appropriate data collection cut-off
dates to permit efficient collection and analysis of data.
The registrant is given the opportunity to do just that.
• Programs for appropriate communications, data collec-
tion, and collation techniques and interactive analyses
among the MAH and others who, as a result of
comarketing and licensee arrangements, will be collect-
ing data about adverse events and carrying out studies to
evaluate the utility of the drug. Without these, there are
no assurances that reports will be complete or, more
importantly, that the available data will be processed
homogeneously.
To all of these plans must be added the development of an
operational plan for PSUR submission, as part of a coordinated
scheme that will evolve during drug development and
risk management.
• Commitment of resources to ensure the flexibility and
agility to deal with, report, and analyze the beneficial
outcomes data or alleged adverse events and to put these
in the overall perspective needed in the PSUR. This
requires integration of many in-house and external
supporters beyond the data-gathering function.
• Assurances that independent, expert, practitioner/
prescriber, statistical, and regulatory interpretation of the
events, signals, and outcomes data can be made appropri-
ately in the timeframe between data collection and report
submission. This is a necessary step to ensure balance in
communications with FDA and/or a combination of the
European Agency for the Evaluation of Medicinal
Products (EMEA) and the Committee for Proprietary
Medical Products (CPMP).
• Execution of a process in which all of the groups within
the corporate organizations pool their knowledge in
drawing up and presenting the PSUR, especially the
benefit-risk balance section. This is needed to ensure
effective evaluation by the specific organization to which
the PSUR is being submitted—be it a specific part of
FDLI
FDA, a specific rapporteur health agency in the EU, or
the appropriate regulatory authorities in Japan. This
process requires coordination of the knowledge and the
resources of the entire developmental organization.
In addition to the operational tasks, thought must be
given to characterization of the disease’s natural history and
the severity of a disease incidence in both the target popula-
tion and in any potential off-label user populations from
which spontaneous report data will be collected. Failure to
do so leaves little opportunity to differentiate real signals
from incidents appropriate to and expected in the treated
populations. In addition, health and economic outcomes
studies are important to characterize benefit and to portray
the benefit-to-risk analysis properly. This requires identify-
ing and measuring all of the outcomes that can contribute to
understanding the benefits of the new drug substance and
products. Both of these activities require ready access to new
sources of data—large-scale databases such as claims or
electronic medical records—and the early (peri-approval)
initiation of large, simple outcomes trials or registries.
Key business issues arise in planning the introduction of
a new drug. Thought is given to the maintenance of supply
should drug acceptance be high; to alternate suppliers of raw
materials and packaging; to ways to acquire new data to
support new uses and new users; to label improvements to
ensure the broadest possible use of the drug; to the orderly
approach to downstream phases of the product lifecycle; and
lately to the potential for vulnerabilities to civil and criminal
actions.
Until recently, little thought was given to the manage-
ment of the risks inherent in reporting findings of various
pharmacovigilance programs. In light of discussions gener-
ated by concept papers on risk management from members
of the Organization for Economic Cooperation and Develop-
ment, FDA, and several national regulatory agencies, greater
attention is being given to the development of a formal risk
management plan as part of the drug development process.
The necessity for such a risk management plan is akin to the
need for a clinical development plan. To date, the suggested
framework for a risk management plan includes processes
July/August 2003 UPDATE 53
 for pre-approval risk assessment, specific postmarketing risk
management programs (interventions), and a formal
pharmacovigilance plan. A complete corporate risk manage-
ment plan also must include risks of product use. To all of
these plans must be added the development of an operational
plan for PSUR submission, as part of a coordinated scheme
that will evolve during drug development and risk manage-
ment. The operative word is “coordinated.”
To support the preparation of a useful PSUR under
difficult circumstances and tight time constraints, the
following activities must be incorporated a priori into any
risk management product planning and support program:
• Anticipation of expected events based on knowledge of
the disease’s natural history and the populations most
likely to be affected, in addition to consideration of the
pharmacologic class and product characteristics.
Knowledge of disease severity, progression, and
comorbidities must be combined with knowledge of the
effect of concurrent treatment modalities in the specific
user population. A strong epidemiologic knowledge base
is imperative, not only for assessing risk, but also to
inform the benefit side of drug development through a
thorough understanding of the interest outcomes.
• Hazard assessment that includes anticipation of how the
product will be used in the “real world,” not only by real
patients with comorbid conditions and potential compli-
ance issues, but also by practitioners who may not clearly
understand or who may ignore labeled recommendations
for proper use. This also must include knowledge of
practitioners making informed choices regarding off-
label use.
• Risk management includes objective and informed
evaluation of pharmacovigilance data. To determine
whether or not a signal should be evaluated further or
pursued with specific studies, careful and thoughtful
analysis must take place. The formation of an external
advisory body, similar to a data safety monitoring board,
may be helpful in teasing apart true signals from con-
founding by indication or other factors, in an objective
and timely way. There always will be some unexpected
events; these must be reviewed from an objective
viewpoint.
• Development and execution of formal outcomes studies to
identify key health and economic outcomes resulting from
the use of the new drug to ensure proper presentation of
the benefits of the product and of the most current
understanding of the benefit-to-risk balance. While the
ICH E2C Guidelines do not require detailed reporting of
54 UPDATE July/August 2003
studies to identify benefits of drug uses, they clearly
require that the results of such studies be included with
the PSUR submission.
These are not additional tasks for the MAH in support of
PSUR preparation; rather they are tasks typically conducted
by various parts of the organization that now must become
part of a coordinated risk management plan. The PSUR is
not the sole responsibility of some data acquisition and
collation organization, nor is it not merely a tool for the
identification and management of hazards. It is a key tool for
managing the dangers inherent in the loss of important new
treatment modalities.
The goal of submitting a properly-prepared and well-
thought-out PSUR involves both the submission of acquired
information linking alleged association between drug use and
adverse events and the proper interpretation of the updated
benefit-risk balance. Producing the most useful PSUR for
regulatory authorities and for the company itself will be the
shared responsibility of the entire drug development and
support team and of the outside bodies that provide indepen-
dent support and interpretation.
Pharmacovigilance plans must recognize and deal with
the PSUR process. Operational and reporting plans must be
in place before introduction of the drug. Risk management
plans require that companies break down internal silos and
those groups such as epidemiology, safety, clinical research,
outcomes research, clinical pharmacology, and marketing
work together in an objective environment that facilitates
optimum analysis of all findings. Companies must organize
themselves to facilitate communications among groups, but
also must designate leadership for each risk management
component to ensure that submissions are complete, timely,
properly organized, and make efficient use of all of the data
collected by the multidisciplinary team. Without this
coordination and forethought, the MAH is in no position to
carry out the necessary tasks that must be considered in the
preparation of useful and effective PSURs for the protection
and benefit of patients and products.
1
ICH, International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite
Guideline. Clinical Safety Data Management: Periodic Safety Update Reports for
Marketed Drugs (1996), available at http://www.ich.org/pdfICH/e2c.pdf (last visited
May 29, 2003).
2
For the sake of uniformity, the ICH refers to companies that hold authorization to
market medicinal products as Marketing Authorization Holders, be it that the
authorization was granted by the U.S. Food and Drug Administration via the NDA
process, by the European Agency for the Evaluation of Medicinal Products, or by the
Japanese Ministry of Health, Labor and Welfare. We have used the same
nomenclature in this article.
3
ICH, ICH Harmonized Tripartite Guideline, Addendum to ICH E2C. Clinical Safety
Data Management. Periodic Safety Update Reports for Marketed Drugs (2003),
available at http://www.ich.org/pdfICH/E2CaddStep4.pdf (last visited May 29,
2003).
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