was also proposed. This group had no official
authority, but it was hoped that the members
would influence their respective government agen-
cies to enact regulations which would improve
safety reporting, based on the CIOMS initiative.
The CIOMS I working party’s efforts were
highly effective. Today, every regulatory authority
in the developed world has endorsed expedited
SAE reporting, usually within 15 working days
of receipt by the company. The CIOMS form, in
its later editions, is also now ubiquitous.
In 1989, the CIOMS II ‘working group’ took up
the matter of a uniform approach to aggregate
periodic safety update reporting (CIOMS Working
Group II, 1992). Like CIOMS I, the second work-
ing party consisted of representatives from regula-
tory agencies and multinational pharmaceutical
companies, again without authority to mandate
changes in national regulations. The CIOMS II
Working Group (1992) developed a standardized
periodic safety update report template which could
be used by all countries with periodic reporting
requirements. The International Conference on
Harmonization (1994; ICH E2C, see below) later
adopted the CIOMS II report format with minor
modifications and proposed that it be used globally.
Athird CIOMS‘working group’was established
to propose guidelines for preparing core clinical
safety information on drugs (CIOMS Working
Group III, 1995). The Core Data Sheet (CDS)
was defined as:
A document prepared by the pharmaceutical manu-
facturer, containing [among other things] all relevant
safety information, such as adverse drug reactions,
which the manufacturer requires to be listed for the
drug in all countries where the drug is marketed. It is
the reference document by which ‘labeled’ and ‘unla-
beled’ are determined [for the purpose of interna-
tional ADR reporting]...Safety information was noted to be described in
various sections of a CDS, including ADRs (unde-
sirable effects), warnings, precautions and contra-
indications. As there were questions pertaining to
what information should be included in a CDS, and
how the information should be updated, along with
no internationally agreed standards for preparing
this information, the CIOMS III working party
proposed several guidelines for production of the
safety section of the CDS (also termed ‘core safety
information’). Topics such as the first core safety
information, frequency of updates, together with
the anticipated national differencies in product
presentation, use, excipients and package inserts
were also described.Benefit–risk evaluation
No drug is 100% safe in 100% of patients. Com-
parative evaluation, or benefit–risk balancing of
pharmaceutical products is inevitable. Further-
more, there are no absolute or arithmetical stan-
dards for this; it is part of the art of practicing
medicine, if at a large than usual scale of conduct-
ing what is essentially ann¼1 clinical trial every
time a prescription is written. Thus, the definitions
and terms chosen depend entirely on the context in
which they are used, and on the user, in a case-by-
case manner. These complexities are not always
obvious to information users, such as patients and
their lawyers. But again, the factors influencing
benefit–risk assessments includethe audience of the information;the nature of the clinical hazard;the drug, its indication and population under
treatment, and, to be realisticeconomic issues.The CIOMSIV ‘working group’discussed benefit–
risk evaluations under circumstances when there is
aknown,significant clinical hazard associated with
a particular drug (CIOMS Working Group IV,
1999). Benefit should be assessed when compared
with alternative therapies (medical and surgical) or
no treatment at all. Analogously, risks should be
compared between the subject drug and alternative
or no therapy. Methods are suggested by the
CIOMS IV working group for balancing the ben-
efits against the risks for each of these therapies,
and for identifying subsets of patients at relatively39.2 COUNCIL FOR INTERNATIONAL ORGANIZATIONS OF MEDICAL SCIENCES (CIOMS) INITIATIVES 537