Centre for International Organizations of

Medical Sciences (CIOMS) Working Groups

Presented by,
Mr. G. Narayana
Associate Professor
Dept. of Pharmacy Practice
RIPER, Anantapur
 Contents

 Introduction and History

 CIOMS Groups

 CIOMS Form
 Introduction and History

WHO UNESCO

CIOMS
Centre for International Organizations
of Medical Sciences (CIOMS) 1949

Collection and Social

New Developments (Opinions) dissemination Moral
Biology Administrative
Medicine Exploring Legal
 In 1977
CIOMS

National Regulatory Authorities Pharmaceutical Companies

Policy Matter

Independent Forum
In 1986

1st Pharmacovigilance working Group

End of 2005

Six working groups

 CIOMS Six Working Groups

CIOMS I Expedited reporting of individual ADRs (1990)

CIOMS IA Harmonization of data elements and fields for

electronic reporting of ADRS (1995)

CIOMS II Periodic Safety Updates (1992)

CIOMS III Core Clinical Safety Information (1995, 1999)

CIOMS IV Benefit-Risk Evaluation (1998)

CIOMS V Good Case Management and Reporting

Practices (2001)

CIOMS VI Management of safety information from clinical

trial (2005)
 CIOMS Initiatives and Uptakes by ICH

CIOMS I Expedited reporting of individual ADRs (1990) ICH E2A

CIOMS IA Harmonization of data elements and fields for

electronic reporting of ADRS (1995)
ICH E2B

CIOMS II Periodic Safety Updates (1992) ICH E2C

CIOMS III Core Clinical Safety Information (1995, 1999)

CIOMS IV Benefit-Risk Evaluation (1998) ICH E2E

CIOMS V Good Case Management and Reporting ICH E2D

Practices (2001)

CIOMS VI Management of safety information from clinical

trial (2005)
Regulatory Pharmaceutical
Agency Manufacturers

CIOMS DS WG

WHO IFPMA
 Process of ICH in incorporating CIOMS guidelines
into regulatory or legislative network

Step 1 – Technical discussion by the Expert Working Group who

produce a preliminary draft document;

Step 2 – The consensus text is released for a 6-month period of

consultation;

Step 3 – Formal consultation outside ICH;

Step 4 – Sign off of finalized text;

Step 5 – Implementation.
 CIOMS I – EXPEDITED REPORTING OF
INDIVIDUAL ADRS

Rationale

• Importance of continuous ADR surveillance

• Prior 1984; Regulatory authorities were restricted the

requirements that individual ADRs reports should be
domestic only

• Between 1984 and 1987 the United Kingdom, France, the

United States, Italy and Germany introduced regulatory
requirements that submission of foreign reports

• Reporting of ADRs occurring in one country to the

regulatory authorities in other countries where the drug
was also marketed.
 • Regulatory requirements of each regulatory agency will
be different

• CIOMS I Working group developed Internationally

acceptable ADRs reporting system

The CIOMS recommendations for the case criteria for expedited

reporting of a foreign ADR were defined as follows:
• Serious;
• Medically substantiated;
• Unlabeled (unexpected);
• Suspected to be product-related;
• Occurring with a marketed product; and
• in an identifiable patient.
• With in 15 working days

• 15 Working days were reduced to 7 days (LT or Serious)

• Adverse event reporting system was encouraged

Minimum four elements:

These are an identifiable report source; a patient (even if

not precisely identified by name and date of birth); a

suspect drug; and a suspect reaction.

Regulation

Although ICH E2A focused on pre-approval clinical trials, its

definitions and other criteria have been applied by regulators to

expedited reporting of both pre- and post-marketed products.

CIOMS IA – HARMONISATION OF DATA ELEMENTS
AND FIELDS FOR ELECTRONIC REPORTING OF
INDIVIDUAL ADRS (1995)

• Reduces paper work

• Single shared database
• Only one entry by manufacturer and
regulatory agency
• Speed the process
• Follow-up easy
• Signal detection made accurate

ICH E2B – Regulation 1997

 CIOMS II – PERIODIC SAFETY UPDATES

Rationale

In 1989, Several countries had requirements of PSU

Each country
• Different inclusion criteria
• Different Formats
• CIOMS II Working Group
Different time intervals
• developing a harmonized
Different due dates (depends on
approach in preparing PSU
national licensing approval date)
• Even varies with same drug and
different formulation
Manufacturers
Significant administrative burden in preparing summary of safety
updates
Procedure

CIOMS II WG (Survey)

• Existing requirements
• Diversity
• ? to be addressed
• Essential elements

Scope and content (Debate and compromise)

Draft proposals (Pilot phase)

 Procedure (cont..)
Draft proposals (Pilot phase)

Manufacturer representative (Individual)

Single prototype summary report (one
drug)

Regulator
Critical Evaluation of Pilot
Working group report
• Feasibility (Data availability)
• Resources required in
Other Manufacturer representative compilation
Sanitized version • Utility to the regulators

Model Report Final Report

Recommendations:

• PSU should be prepared in standard criteria

• Reassure the regulator

• Narrative report (10 pages)

• All formulations in single report

Scope:

• This proposal guidelines were applied to all chemical entities

licensed in 1992 (to prepare safety summaries)

• Subsequent updated after six months (safety information)

• International Birth Day (IBD)

• Data Lock Point (after six months)

• 45 calendar days of DLP (Manufacturer should submit the

safety)
Content

The working group proposed that the periodic safety

update was presented in nine sections as follows:
1. Introduction
2. Core data sheet – the reference document for determining
‘expectedness’
3. The drug’s licensed status
4. Update on regulatory or manufacturer actions taken
for safety reasons
5. Patient exposure
6. Individual case histories (CIOMS line listing)
7. Studies
• Newly analyzed studies containing important safety
information
• Targeted new safety studies
• Published safety studies
8. Overall safety evaluation
9. Important information received after the DLP.
The criteria for case inclusion were as follows:
• Unlabeled, serious attributable cases from studies
(published or unpublished);
• All serious and non-serious unlabeled spontaneous
reports (including relevant medically unconfirmed
consumer reports);
• Serious published case histories;
• Serious cases from other sources (e.g. from regulatory
authorities).
The CIOMS line listing should consist of:
• Company reference number
• Country of origin of report
• Source of report (e.g. physician, literature)
• Age of patient
• Sex of patient
• Dose of drug
• Duration of treatment prior to event (time to onset)
• Description of reaction (as reported)
• Outcome.
The overall safety evaluation should be a concise
critical analysis and opinion explicitly including:
• increased frequency of known toxicity;
• drug interactions;
• overdose and its treatment;
• drug abuse;
• positive and negative experiences during pregnancy
and lactation;
• effects of long-term treatment;
• any specific safety issues relating to the treatment
of special patient groups (e.g. elderly, children).

ICH E2C GUIDELINES

 CIOMS III – CORE CLINICAL SAFETY
INFORMATION

CIOMS II WG:

Core Data Sheet :

• Minimal safety information
• All countries
• Labeled/Unlabeled determine

Rational clinical decision making Harmonize safety statements

• Public health
• Regulatory purpose
CIOMS III WG:

Develops principles and guidelines

• Content of CCS
• Definitions
• Standard terms
• Standard formats

• 1st edition of CIOMS III report – 1995

• 2nd edition of CIOMS III report – 1999
• CIOMS V proposed CCS information in Drug development
Process:

Development of guidelines and principles for CCSI:

SPC and official document of European union was used as model
• Evidence – decision on inclusion, exclusion or removal adverse
experience in CSI
• Point of threshold crossed – inclusion or change in CSI
• Good safety labelling and class labelling practices
• Sections of CSI – defined, location
What?
• The CSI should be determined by the needs of healthcare
professionals in the context of a regulatory and legal environment.
• Include what is practical and important to enable the prescriber
to balance risks against benefit and to act accordingly.
• Avoid including events, especially minor events, that have no well-
established relationship to therapy.
• There is a legal duty to warn but this must be balanced against the
need to include only substantiated conclusions in the CSI.
• The CSI should include important information which physicians are
not generally expected to know.
When?
• As soon as relevant safety information becomes sufficiently well
established it should be included in the CSI.

How?
• Keep ADRs identified in the initial CSI (premarketing experience)
separate from those identified subsequently.
• ADRs should be listed by frequency in body system order.
• Whenever possible, an estimate of frequency should be provided,
expressed in a standard category of frequency.
CIOMS IV WG: BENEFIT AND RISK EVALUATION

CIOMS II
CIOMS IV
CIOMS III

• Guidance to manufacturer and regulators

regarding B&R Assessment
 Recommendations:

• Different form case specific ADR evaluation in PV

• Consider all pre-clinical, clinical and post-marketing experience
• Not only signal, it also responsible to give overall safety profile in
comparison with comparator
• Not only evaluate benefit and risk and also overall net benefit to
individual and society
 Standard format
and content of a benefit–risk evaluation report:

Introduction
• Brief description of the drug and where marketed.
• Indications for use, by country if there are differences.
• Alternative therapies, including surgery.
• Very brief description of the major safety problem.

Benefit Evaluation
• Epidemiology and natural history of the target
disease(s).
• Purpose of treatment (e.g. cure, prophylaxis).
• Summary of efficacy and general toleration data
compared with other treatments or no treatment
Risk Evaluation
• Introduction.
• Weight of evidence for the suspected risk.
• Detailed presentations and analyses of data on the new suspected
risk.
• Probable and possible explanations.
• Preventability, predictability and reversibility of the new risk
• The issue as it relates to alternative therapies and no therapy.
• Provide similar profiles for alternative drugs.
• When possible, estimate the excess incidence of
• any adverse reactions known to be common to the
• alternatives
Benefit–Risk Evaluation
• Summarize the benefits as related to the seriousness of the target
disease and the purpose and effectiveness of treatment.
• Summarize the dominant risks (seriousness/severity, duration,
incidence).
• Summarize the benefit–risk relationship, quantitatively and
• Provide a summary assessment and conclusion

ICH E2E Regulation

 CIOMS V – GOOD CASE MANAGEMENT
AND REPORTING PRACTICES

1. Sources of individual case reports.

2. Good case management practices.
3. Good summary reporting practices – periodic safety update
reports (PSURs) reconsidered.
4. Population exposure data.
5. Worldwide clinical safety reporting regulations.

ICH E2E
CIOMS VI – MANAGEMENT OF SAFETY
INFORMATION FROM CLINICAL TRIALS

ICH Guideline E6