PHARMACOEPIDEMIOLOGY AND DRUG SAFETY 7: 289±291 (1998)
ISPE COMMUNICATION
The Impact of the International Conference on
Harmonization (ICH) on Pharmacoepidemiology
and Pharmacovigilance
DAVID I. GOLDSMITH MD*
Sano® Pharmaceuticals, 90 Park Avenue, New York NY, 10016, USA
The purpose of this short paper is to highlight how
new global cooperation between regulators and
pharmaceutical manufacturers will in¯uence the
science of pharmacoepidemiology in general, and
more speci®cally the process of pharmacovigilance.
The paper brie¯y reviews the ICH participants and
processes, considers the major topics of concern
to the safety aspects of pharmacoepidemiology,
and concludes with some discussion concerning
anticipated potential e€ects on our research and/or
the bene®ts to patients.
The International Conference on Harmonization
(ICH) is a joint endeavour of pharmaceutical
regulatory agencies and the Pharmaceutical Manu-
facturers Associations in Europe, Japan and the
US, which has the goals of reducing redundancy
and costs of drug development while hastening the
delivery of proven new therapeutic agents to
patients. Many aspects of the drug development
process were considered in three major areas of
quality (designated as Q topics), pre-clinical safety
(S) and clinical ecacy (E) to streamline the
process, and through the development of consensus
expert documents, which if followed, would allow
registration of a new product in all three of these
global areas. In addition to these three major areas,
a fourth was formed after the second conference,
which could be applied to all three areas and was
designated as the mixed (M) topics. One of the
clinical ecacy topics relates to clinical safety and
is the subject of the second section of the paper. In
addition to the regulators from the EU, Japan and
* Correspondence to David I. Goldsmith, Senior Medical
Director, Sano® Pharmaceuticals, 90 Park Avenue, New York
NY, 10016, USA. Tel: (212) 551-4100. Fax: (212) 551-4907.
E-mail: david.goldsmith@us.sano®.com.
CCC 1053±8569/98/040289±03$17.50
# 1998 John Wiley & Sons, Ltd.
the US, there are ocial observers from other
organizations or countries such as the WHO and
Canada, and their representation is expected to
facilitate a wider acceptance of the expert working
group documents.
The ICH process is accomplished in ®ve steps.
A proposal to harmonize some aspect of the drug
developmental process is submitted and approved
by the Steering Committee (step 1) and an Expert
Working Group (EWG), usually consisting of one
representative from each of the six parties involved
in ICH, is formed. The EWG (also known as six-
pack) meets and writes a formal proposal for an
ICH guidance including all details for implementa-
tion. When completely signed o€ by the six-pack
and the Steering Committee, the document (now
at step 2) is published by the regulatory agencies
for comments (step 3). After receipt of comments,
the EWG reconvenes to make changes deemed
necessary and a new document is signed o€ by the
regulators on the Steering Committee and pub-
lished (step 4). Regulations are then amended and
the guidance is implemented at step 5. Since
amending regulations are both a legal and a
political process, step 5 occurs outside the ICH
process.
There are three ecacy and two mixed step-4
documents which relate to Clinical Safety
Surveillance. The E2A document entitled `Clinical
Safety Data Management: De®nitions and Stand-
ards for Expedited Reporting' provides for the
harmonization of the ways to gather, and if
necessary, to take action on important clinical
safety information arising in clinical development.
However, because drug development does not
occur at the same pace in all countries or regions,
the guidance recognizes that drugs may be
Accepted 3 June 1998
290 D. I. GOLDSMITH
marketed in some areas of the world while still in
clinical development in others. Thus, the de®nitions
and procedures were harmonized for all drugs
being tested or used in humans. Thus, both pre-
and post-marketing phases are covered. It should
be recognized that the post-marketing phase is of
particular importance to the area of pharmaco-
epidemiology due to the limited sample size in the
pre-marketing controlled clinical trials and the non-
representative nature of the population included in
these trials. Thus, although the E2A document
provides enhancement to Good Clinical Practices
(another E topic), the scope of E2A is potentially
much wider.
The guidance makes provisions for expedited
reporting of adverse reactions that are both serious
and unexpected. Speci®c criteria for being a serious
event are that it results in death, is life-threatening,
requires or prolongs hospitalization, results in
disability, is a congenital anomaly, or jeopardizes
the patient according to medical judgment, or
requires intervention to prevent one of the other
outcomes. In order for the reaction to be subject to
expedited reporting rules, it would also need to be
`unexpected', i.e. not be described in the informa-
tion provided to the researchers or practitioners,
and have a reasonable possibility of being related
to the drug (the distinction between an adverse
event and an adverse reaction). By de®nition, all
spontaneous reports are considered to ful®l this last
criterion.
Adverse reactions that qualify for expedited
reporting must be provided to regulatory agencies
within 15 calendar days, and if the reaction is either
life-threatening or fatal a preliminary communi-
cation must be made within 7 days. As a result of
the new guidance, it is anticipated that there will be
uniform early submission of information which
should permit more rapid recognition of potential
signals. In the early stages of development a clinical
hold can be implemented until the signal can be
evaluated more completely, and in later stages the
hypotheses generated can then be tested with
formal epidemiological studies.
Closely related to the E2A topic is the E2B
guidance entitled `Data Elements for Transmission
of Individual Case Safety Reports'. This guidance
standardizes the data elements for case safety
reports and is expected to serve as the basis for
electronic data interchange. It will facilitate trans-
ferring information from one database to another
allowing for a more ecient process by eliminating
duplicate data entry. The standards for the
# 1998 John Wiley & Sons, Ltd.
electronic data interchange required some structur-
ing of the clinical history and adverse event
information as well as a mechanism to ensure
accuracy of the data transmission process. The sub-
topics were handled by the M1 and M2 expert
working groups. Medical Terminology (M1) is a
terminology designed to support the classi®cation,
retrieval, presentation and communication of
medical information, especially as it relates to
pharmaceuticals. It includes terminology from
ICD-9, the World Health Organization's Adverse
Reaction Thesaurus, and the FDA COSTART
developed for their adverse event database. In
addition, it includes nomenclature for standard
laboratory tests and terms for social history.
The implementation of this terminology, which is
expected to begin later this year or in early 1999,
should be a substantial help in retrieval of
information from databases and facilitate
pharmacoepidemiological research.
The M2 expert working group for `Electronic
Standards for the Transfer of Regulatory Infor-
mation and Data' has developed the procedures
needed to ensure data integrity and security when
transmitted electronically. In addition, they have
developed the ®le format needed to accommodate
the information provided in the single E2B case
transmission. The FDA and some European
regulators are already pilot testing the E2B/M2
transmission of information.
Finally, the E2C document entitled `Periodic
Safety Updates Reports' provides guidance on the
content, format and frequency of reports to
regulators which summarize the safety experience
with pharmaceuticals. A description of the scope
and nature of these reports is beyond this paper,
but it can be indicated that they consist of narrative
summaries and line listings of adverse events
reported to be associated with drug administration.
The implementation of this guidance is likely to
ensure that all pharmaceutical companies will be
routinely conducting a high level of pharmaco-
vigilance and using the basic principles and some
advanced methods of pharmacoepidemiology.
Each of the ICH documents discussed above has
reached step 4 in the ICH process. Implementation
of E2A has been formally adopted in the US by
FDA regulations. E2C periodic reports are com-
monly used currently in Europe and it is expected
that the FDA will propose new regulations this year
which will require submission of these reports. As
indicated above, the FDA and some European
countries have on-going pilot projects testing
Pharmacoepidemiology and Drug Safety, 7: 289±291 (1998)
 THE IMPACT OF THE ICH ON PHARMACOEPIDEMIOLOGY 291

the E2B standard using M2 guidance's for trans-
mission ®les and security. Full implementation
awaits selection of a maintenance organization for
the medical terminology, and the completion of the
speci®cations for the transmission ®le. In the US,
an advanced notice of proposed rule making is
expected this year. This will serve as the basis for
regulating electronic submission of adverse event
data.
The ICH process has already made signi®cant
advances in the area of clinical safety which taken
together should improve our ability to detect
signals rapidly and to conduct pharmacoepidemio-
logical studies to con®rm or refute the hypotheses
generated by these signals. Of particular interest to
professionals in this area are the development of
large databases with drug-related adverse event
information and the standardization of terminol-
ogy used to describe these reactions. While much of
the data that will be transmitted and stored in the
database will be skewed by the factors in¯uencing
spontaneous reports, it should also be possible to
analyse separately the data captured from con-
trolled clinical trials and this information may help
to provide a better source for descriptive pharma-
coepidemiology. Finally the process of developing
guidelines and their implementation has served to
heighten awareness of the principles and methods
for conducting pharmacoepidemiology and has
expanded signi®cantly the activities of pharmaceu-
tical manufacturers and the amount of research
they conduct in this ®eld.

# 1998 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 7: 289±291 (1998)