# April 9-11 Public Workshop on Risk Management, Washington DC

# REF: Docket Number 02N-0528

# Comments of behalf of the International Society of Pharmacoepidemiology (ISPE) -- [www.pharmacoepi.org](http://www.pharmacoepi.org/)

*ISPE speaker: Annette Stemhagen, Chair, ISPE Membership Committee*

It is a pleasure and an honor to provide comments to the concept paper
on RISK ASSESSMENT OF OBSERVATIONAL DATA: GOOD PHARMACOVIGILANCE
PRACTICES AND PHARMACOEPIDEMIOLOGIC ASSESSMENT on behalf of the
International Society for Pharmacoepidemiology, ISPE. ISPE is a
non-profit international professional membership organization dedicated
to promoting the science of applying epidemiologic approaches to
studying the use, effectiveness, value and safety of therapeuticals. The
Society provides an international forum for sharing knowledge and
scientific approaches to foster the science of pharmacoepidemiology.
ISPE has over 700 members representing 45 countries. Our members work in
academic institutions, pharmaceutical industry, and government agencies,
non-profit and for-profit private organizations. Specific backgrounds of
the membership are: epidemiology, biostatistics, medicine, nursing,
pharmacology, pharmacy, law, health economics, and journalism.

The following comments are based on the feedback provided by senior
members of the Society, including Executive Committee, and Board of
Director members and Past-Presidents.

There are several areas of the Concept Paper where, as epidemiologists,
we suggest some clarification.

### The first is a quantitative definition or risk

From an epidemiologic standpoint, we recommend providing a quantitative
definition of risk. Risk is a measure of frequency based on a numerator
AND denominator. The numerator consists of the number of people who
develop an event and the denominator, which represents the amount of
exposure in the population. If the denominator may consist of number of
people exposed then the measure of frequency is referred to as risk. If
the denominator consists of person-years (a measure of \# of people and
duration exposed), then the frequency is referred to as incidence.

### Expansion of Types of Studies to be Considered

We would suggest that epidemiologic assessments of safety endpoints is
important, and should be further emphasized in this document. Also very
important are studies of the natural history of disease, as well as
evaluations of drug use patterns and patient characterization studies.
The latter serve to inform both our understanding of safety endpoints
and spontaneous reports. Natural history of disease and safety studies
among users of available therapeuticals should be initiated early during
development. Drug use and patient characterization studies should be
initiated during the development phase of a new drug, based on the
therapeutic class, and should continue after launch to further
understand drug use in diverse populations and across various countries.
Similarly, evaluations of endpoints among products in the therapeutic
class, and within diverse populations are important. Targeted safety
studies should be initiated shortly post-launch based on the
specifications of the development program and the pharmacovigilance
plan.

### Definition of a registry 

We also suggest making a distinction between a registry and a
pharmacoepidemiologic study. Registries generally involve voluntary
reporting, and as such usually do not allow definition of the source
population (i.e., what is the population the participants represent).
Yet when registries become very large, they are often analyzed in a
similar manner to pharmacoepidemiologic studies.

### Section IV.A. Definition of pharmacoepidemiologic studies

We recommend that in section IV.A. pharmacoepidemiologic SAFETY studies
are differentiated. For clarification purposes, please be aware that
pharmacoepidemiologic studies are not limited to safety studies, but
include all observational studies, which describe the use and effects of
pharmaceuticals in the real world setting. We also recommend that in
section IV.A. the definition of pharmacoepidemiologic studies be
expanded to include prospective data collection in addition to the
already mentioned existing automated claims databases. In several
sections of the concept paper, pharmacoepidemiologic studies seem to
refer only to those studies conducted in databases.

### Section V

The list of 5 examples of safety signals (lines 254 -- 258) is very
useful and probably covers most safety signals. However, we recommend
that the general category of "other risk factors" (factors associated
with the development of the adverse event of interest) be mentioned.
Safety signals regarding specific subgroups of people (age, racial,
genetic, specific co-morbidities) or ways in which the drug is used
(e.g. dose escalation) may also be very important.

We would like to ask for clarification of Line 319. Point #8 regarding
analyses of safety signals. (Analyses of the potential for an excess of
adverse events given the disease being treated, such as might be
observed in advanced cancer or immunocompromised patients) Is it
intended to address analyses to identify the background risk of adverse
events in the disease being treated?

Line 352. Point #2. Relative risk or odds ratios

This point mentions the relative risk or odds ratios from
pharmacoepidemiologic studies to be used to evaluate causality. Although
risk ratios or odds ratios are the very frequently reported as measures
of outcome frequency in pharmacoepidemiologic studies, please be aware
that risk DIFFERENCES, not ratios, are best for evaluating the frequency
in which a drug causes or contributes to an event. In the end the
frequency with which an event occurs because of a drug, along with other
characteristics of the event, must be weighed against the benefit of the
drug. In addition Risk Management should consider the risk associate
with any intervention designed to reduce the risk of a particular event,
e.g., the potential reduction of benefit associated with the use of the
therapeutical.

### Reporting of Safety Signals

Line 374. Paragraph D. appears to combine elements of 1) hypothesis
generation signal detection, 2) providing for hypothesis testing, 3)
placing the signal in perspective of the benefit of the drug and finally
4) risk management. The implication is that the sponsor would initiate
all actions simultaneously. It would appear that the steps should be
addressed in logical temporal fashion, and that all may not be
necessary, depending on the results of the earlier steps.

### Surveys

We would also like to comment on the inclusion of surveys risk
assessment or risk management evaluation tools. Although many of the
examples provided are cross-sectional designs, surveys can also be
conducted as longitudinal cohort studies to evaluate changes in risk
over time. In addition to epidemiologic expertise, it will be important
to include members of other academic disciplines as well, such as social
scientists who bring expertise in areas such as knowledge, attitude and
behaviors surveys.

### Analytic Methods

Our final point is that we believe there is still a great deal of work
to be done in the development and refinement of analytic methods for
evaluating safety signals as well as methods for risk assessment and
risk management evaluation. ISPE is committed to working with the FDA
and others such as the CERTS to further knowledge of the methodological
and statistical techniques required.

ISPE is firmly committed to providing an unbiased scientific forum to
the views of all parties with interests in the safety of therapeuticals,
and as such is deeply committed to the advancement of Risk Management
Sciences.

We welcome the opportunity to work together with the Agency in this
area, and will engage our full membership in the feedback process of
this concept paper.

Our next annual conference will be focused on Risk Management. Several
workshops and sessions are being planned jointly with FDA staff. I take
this opportunity to invite you to join us at the combined 1^st^
International Conference on Therapeutic Risk Management and the 19th
International Conference on Pharmacoepidemiology. This meeting will be
held August 21-24 in Philadelphia.

Thank you