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With permission from FDLI


Product Safety Update
Report—A Risk
Management Tool for
Everyone by Matthew Weinberg

U nder the International Conference on Harmoniza-
tion (ICH) E2C Guidelines,1 Marketing Authoriza-
tion Holders (MAHs)2 in the European Union (EU), United
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
States, and Japan are to summarize and update available alleged public health risks and it provides a vehicle to
information on the safety and benefit-to-risk ratio of new manage corporate risk—the risk that an inappropriate
drugs at least semi-annually for a minimum of two years analyses of the findings may result in the market loss of
after introduction of the drug. valuable new drugs after massive research and development
The mandated form of communication under the ICH investments. Failure to appreciate the true role of the PSUR
guidelines is the Periodic Safety Update Report (PSUR), but can be one aspect of an improperly organized process that
requirements for PSURs have not been implemented leads to the submission of an incomplete PSUR. Each PSUR
uniformly in all ICH countries. Two recent developments, is considered a stand-alone report that sets the regulator’s
however, may ease the burden of preparing PSURs: the agenda for controls over the use of the drug. Unless PSUR
addendum to the ICH E2C guidelines3 and the U.S. Food submissions are planned properly, the MAH will not be in a
and Drug Administration’s (FDA’s) implementation of the position to protect the public or to promote the drug.
guidelines. These developments should help MAHs shift the Little or no thought seems to be given to the requirements
focus of PSUR preparation from simply collecting and for the PSUR during the development of many drugs, despite
collating pharmacovigilance data, to developing an inte- the fact that the first report is due six months after the
grated program for benefit-to-risk assessment—a vital part of International Birth Date (IBD) (i.e., the date of first market-
the pharmaceutical asset protection plan. ing authorization for a new product). During this key period,
PSURs are the key communication tool concerning safety the MAH and comarketers seek to expand drug registration
and utility between the MAH and regulatory authorities. A and introduction of the product into many new markets. Less
PSUR must serve three purposes. First, it must meet the thought is given to the acquisition of key outcomes data that
regulator’s demand for reporting any alleged side effect will allow for proper characterization of the benefit-risk
associated with administration of the drug. Second, it must ratio.
evaluate the information generated and appropriately frame The operational process of assembling and interpreting
the issues arising from that information that will require PSUR data usually is not addressed until there is some
public health risk management. Third, a PSUR must address indication of a product problem. Less-than-useful PSURs are
requirements for updating and characterizing the benefit-risk produced if they do not properly consider the impact on drug
balance of the drug. The information on all indications, dose availability, image, use, and resultant acceptance. Many
forms, and regimens for an active substance should be PSURs seem to focus on signal events, and are compiled
included in a single PSUR, with a single data lock point for willy-nilly, almost right up to the required submission date.
all aspects of product use. There is great value in a single This flies in the face of the reality that new, successful drugs
document that contains a consistent, broadbased examination will target specific disease entities found among unique—
of the information on an active substance. This permits a
Mr. Weinberg is the Chief Executive Officer of
clear evaluation of the benefit-to-risk profile for a drug
substance that may have many uses and many user profiles.
Washington, D.C.

52 UPDATE July/August 2003 w w w. f d l i . o r g
and often medically-compromised—patients. Without FDA, a specific rapporteur health agency in the EU, or
adequate forethought and preparation, the MAH is in no the appropriate regulatory authorities in Japan. This
position to carry out a number of tasks that must accompany process requires coordination of the knowledge and the
the preparation of useful and effective PSURs. resources of the entire developmental organization.
Operational tasks that are frequently inadequately
planned for in PSUR submissions include: In addition to the operational tasks, thought must be
given to characterization of the disease’s natural history and
• Synchronization of the IBD with the national birth date of the severity of a disease incidence in both the target popula-
the drug to be able to set appropriate data collection cut-off tion and in any potential off-label user populations from
dates to permit efficient collection and analysis of data. which spontaneous report data will be collected. Failure to
The registrant is given the opportunity to do just that. do so leaves little opportunity to differentiate real signals
• Programs for appropriate communications, data collec- from incidents appropriate to and expected in the treated
tion, and collation techniques and interactive analyses populations. In addition, health and economic outcomes
among the MAH and others who, as a result of studies are important to characterize benefit and to portray
comarketing and licensee arrangements, will be collect- the benefit-to-risk analysis properly. This requires identify-
ing data about adverse events and carrying out studies to ing and measuring all of the outcomes that can contribute to
evaluate the utility of the drug. Without these, there are understanding the benefits of the new drug substance and
no assurances that reports will be complete or, more products. Both of these activities require ready access to new
importantly, that the available data will be processed sources of data—large-scale databases such as claims or
homogeneously. electronic medical records—and the early (peri-approval)

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 initiation of large, simple outcomes trials or registries.
agility to deal with, report, and analyze the beneficial Key business issues arise in planning the introduction of
outcomes data or alleged adverse events and to put these a new drug. Thought is given to the maintenance of supply
in the overall perspective needed in the PSUR. This should drug acceptance be high; to alternate suppliers of raw
requires integration of many in-house and external materials and packaging; to ways to acquire new data to
supporters beyond the data-gathering function. support new uses and new users; to label improvements to
• Assurances that independent, expert, practitioner/ ensure the broadest possible use of the drug; to the orderly
prescriber, statistical, and regulatory interpretation of the approach to downstream phases of the product lifecycle; and
events, signals, and outcomes data can be made appropri- lately to the potential for vulnerabilities to civil and criminal
ately in the timeframe between data collection and report actions.
submission. This is a necessary step to ensure balance in Until recently, little thought was given to the manage-
communications with FDA and/or a combination of the ment of the risks inherent in reporting findings of various
European Agency for the Evaluation of Medicinal pharmacovigilance programs. In light of discussions gener-
Products (EMEA) and the Committee for Proprietary ated by concept papers on risk management from members
Medical Products (CPMP). of the Organization for Economic Cooperation and Develop-
• Execution of a process in which all of the groups within ment, FDA, and several national regulatory agencies, greater
the corporate organizations pool their knowledge in attention is being given to the development of a formal risk
drawing up and presenting the PSUR, especially the management plan as part of the drug development process.
benefit-risk balance section. This is needed to ensure The necessity for such a risk management plan is akin to the
effective evaluation by the specific organization to which need for a clinical development plan. To date, the suggested
the PSUR is being submitted—be it a specific part of framework for a risk management plan includes processes

FDLI July/August 2003 UPDATE 53
for pre-approval risk assessment, specific postmarketing risk studies to identify benefits of drug uses, they clearly
management programs (interventions), and a formal require that the results of such studies be included with
pharmacovigilance plan. A complete corporate risk manage- the PSUR submission.
ment plan also must include risks of product use. To all of
these plans must be added the development of an operational These are not additional tasks for the MAH in support of
plan for PSUR submission, as part of a coordinated scheme PSUR preparation; rather they are tasks typically conducted
that will evolve during drug development and risk manage- by various parts of the organization that now must become
ment. The operative word is “coordinated.” part of a coordinated risk management plan. The PSUR is
To support the preparation of a useful PSUR under not the sole responsibility of some data acquisition and
difficult circumstances and tight time constraints, the collation organization, nor is it not merely a tool for the
following activities must be incorporated a priori into any identification and management of hazards. It is a key tool for
risk management product planning and support program: managing the dangers inherent in the loss of important new
treatment modalities.
• Anticipation of expected events based on knowledge of The goal of submitting a properly-prepared and well-
the disease’s natural history and the populations most thought-out PSUR involves both the submission of acquired
likely to be affected, in addition to consideration of the information linking alleged association between drug use and
pharmacologic class and product characteristics. adverse events and the proper interpretation of the updated
Knowledge of disease severity, progression, and benefit-risk balance. Producing the most useful PSUR for
comorbidities must be combined with knowledge of the regulatory authorities and for the company itself will be the
effect of concurrent treatment modalities in the specific shared responsibility of the entire drug development and
user population. A strong epidemiologic knowledge base support team and of the outside bodies that provide indepen-
is imperative, not only for assessing risk, but also to dent support and interpretation.
inform the benefit side of drug development through a Pharmacovigilance plans must recognize and deal with
thorough understanding of the interest outcomes. the PSUR process. Operational and reporting plans must be
• Hazard assessment that includes anticipation of how the in place before introduction of the drug. Risk management
product will be used in the “real world,” not only by real plans require that companies break down internal silos and
patients with comorbid conditions and potential compli- those groups such as epidemiology, safety, clinical research,
ance issues, but also by practitioners who may not clearly outcomes research, clinical pharmacology, and marketing
understand or who may ignore labeled recommendations work together in an objective environment that facilitates
for proper use. This also must include knowledge of optimum analysis of all findings. Companies must organize
practitioners making informed choices regarding off- themselves to facilitate communications among groups, but
label use. also must designate leadership for each risk management
• Risk management includes objective and informed component to ensure that submissions are complete, timely,
evaluation of pharmacovigilance data. To determine properly organized, and make efficient use of all of the data
whether or not a signal should be evaluated further or collected by the multidisciplinary team. Without this
pursued with specific studies, careful and thoughtful coordination and forethought, the MAH is in no position to
analysis must take place. The formation of an external carry out the necessary tasks that must be considered in the
advisory body, similar to a data safety monitoring board, preparation of useful and effective PSURs for the protection
may be helpful in teasing apart true signals from con- and benefit of patients and products.
founding by indication or other factors, in an objective
ICH, International Conference on Harmonization of Technical Requirements for
and timely way. There always will be some unexpected Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite
events; these must be reviewed from an objective Guideline. Clinical Safety Data Management: Periodic Safety Update Reports for
Marketed Drugs (1996), available at (last visited
viewpoint. May 29, 2003).
• Development and execution of formal outcomes studies to 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
identify key health and economic outcomes resulting from 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
the use of the new drug to ensure proper presentation of Japanese Ministry of Health, Labor and Welfare. We have used the same
the benefits of the product and of the most current nomenclature in this article.
understanding of the benefit-to-risk balance. While the ICH, ICH Harmonized Tripartite Guideline, Addendum to ICH E2C. Clinical Safety
Data Management. Periodic Safety Update Reports for Marketed Drugs (2003),
ICH E2C Guidelines do not require detailed reporting of available at (last visited May 29,

54 UPDATE July/August 2003 w w w. f d l i . o r g