Patients and prescribers expect approved medicines to be "safe and effective." The goal of those who produce and regulate proprietary medicinal products is to ensure that this expectation is met. This requires that clinical trials be planned and performed to provide good evidence that tested medicines are effective and that patients can be reassured that the benefits outweigh the risks, both during the development process and in general use.
 
This report has implications for all stakeholders in clinical medicinal research;

          1) patients and other volunteers
                   investigators and their site staff
                   ethics review committees
                   data and safety monitoring boards
                   drug regulatory authorities and the public health community
                   pharmaceutical companies and other clinical research sponsors

The vision of the CIOMS VI Working Group is that this report will enhance awareness of the ethical and technical issues associated with safety in clinical trials and point out the need for increased care and scrutiny in the conduct of research. It is also hoped that this work will advance the methodology for collecting, analysing, evaluating and reporting information on product safety ascertained in clinical trials, and help to set standards in these areas. Establishing and maintaining standards by all involved groups will benefit all participants in trials and improve public health for those who take medicines.

Pharmacovigilance has traditionally focused on detection and evaluation of signals in the post-approval environment in order to secure early detection of new adverse reactions or patient subgroups of exceptional sensitivity, and to introduce measures to manage those risks.

However, we believe that there is a need not only to incorporate newer approaches for managing safety information in the clinical trial setting, but also to adapt the methods and tools used in post-approval pharmacovigilance to the early and late stages of pre-approval development of medicinal products. It is our vision that the practical approaches provided in this report will aid these processes and will enable a more seamless transition in conducting high quality pharmacovigilance from the development stage to the post-approval period. We also hope that this work will stimulate research in several unresolved areas.

Finally, we recognize that new regulations have recently been enacted in the EU and are pending elsewhere, such as in the US. It is hoped that this book will stimulate the regulators to reconsider aspects of regulations pertaining to our proposals; we believe that our suggestions can help to improve the ability to generate and analyze useful safety data and to protect trial participants.

VISION


PREFACE


1. INTRODUCTION AND OVERVIEW

     a.   Rationale for the CIOMS VI Project
           Results of the CIOMS VI Survey on Company Practices
          Areas Covered by the CIOMS Project

• Terminology and definitions
• Ethical aspects of clinical trials
• Overall pharmacovigilance/risk management system
• Collection and proper management of safety data
• Evaluation of safety data
• Statistical analysis of safety data
• Regulatory reporting and communication to others of safety information
• during clinical trials
  

     d.   Limitations of Clinical Trials for Understanding Safety
           Scope of the Project

2. ETHICAL CONSIDERATIONS FOR CLINICAL TRIAL SAFETY MANAGEMENT

     a.  Background
          The Stakeholders  

• Patients
• Regulatory Authorities and the Public Health Community
• Investigators
• IECs and IRBs
• Data and Safety Monitoring Boards
• Pharmaceutical Companies and Their Representatives

      c. Evolving Regulatory and Societal Demands

• Privacy and Confidentiality of Personal Data
• Informed Consent
• Transparency in Availability of Clinical Trial Results
• Other Issues

3. GOOD PHARMACOVIGILANCE AND RISK MANAGEMENT PRACTICES: SYSTEMATIC APPROACH TO MANAGING SAFETY DURING CLINICAL DEVELOPMENT

a.   Introduction
      Principles of a Systematic Approach

• Begin early
• Establish a procedure
• Establish a Multidisciplinary Safety Management Team (SMT)
• Establish a project management function
• Determine background data
• Ensure accessibility of data
• Develop a proactive approach
• Establish timeframes and milestones
• Decision Making
• Advisory Bodies

c.   Components of a Development Risk Management Plan (DRMP)
      Role of Epidemiology
      Specific Issues that Should Always be Considered

• Cardiac electrophysiology
• Hepatotoxicity
• Drug-Drug interactions
• Immunogenicity
• Bone marrow toxicity
• Potential for reactive metabolite formation and hypersensitivity

 f.   Conclusion

4. COLLECTION AND MANAGEMENT OF SAFETY DATA DURING CLINICAL TRIALS

a.    Introduction
       Who?
       What?

• General Principles
• Causality Assessment
• Diagnoses vs Signs and Symptoms
• Adverse Events of Special Interest
• Laboratory Chemistry Measurements
• Morbidity and Mortality as Efficacy Endpoints
• Special Situations

d.   How?

• General considerations
• Serious and Other Important Adverse Events

e.   When?
       Safety Data Management Considerations

• Clinical Description of Adverse Events
• Coding Procedures
• Dealing with Unblinded Data
• Data Processing Issues

5. IDENTIFICATION AND EVALUATION OF RISK FROM CLINICAL TRIAL DATA

a.   Introduction
b.   Expectations and Limitations in the Identification and Evaluation of Safety Information from Clinical Trials
c.   Points to Consider During Analysis and Evaluation of Safety Information

• Patient Population Characteristics, Including Natural History of Disease
• Current Therapeutic Standards

d.   Timing of Safety Evaluation
e.   Safety Signal Detection and Evaluation
f.    Consistent Causality Assessment – Adverse Events vs Adverse Drug Reactions
g.   Important Types of Analyses
h.   Review of Individual Cases
i.    Considerations for Periodic Review and Evaluations of Case Reports in Aggregate
j.    Pooling of Data
k.   Evaluation of Clinical Laboratory Data
l.    General Benefit-Risk Considerations
m.  Aggregate Analysis and The DCSI

6. STATISTICAL ANALYSIS OF SAFETY DATA IN CLINICAL TRIALS

a.   Introduction
b.   Uses of Statistics for Clinical Safety Data
c.   Principle of Intention to Treat
d    Some Key Problems in Safety analyses
e.   Useful Approaches to Statistical Analysis of Continuous Measurements: Laboratory Chemistries
f.    Statistical Treatment of Binary Data

• Power considerations
• One-sided vs two-sided testing
• The consequences of multiplicity
• General measures using binary data
• Confidence intervals
• Accounting for time on or off treatment
• Statistical tests using time since start of treatment

g.   Combining Data from Several Trials: The Role of Meta-analytical Techniques
h.   Analysis of Rare Events
i.    Measuring and Expressing Effects in Ways Relevant to Public Health
j.    Comments on ICH Guidelines E3 and E9: Discussion of Statistical Aspects of Clinical Safety Data


7. REGULATORY REPROTING AND OTHER COMMUNICATION OF SAFETY INFORMATION FROM CLINICAL TRIALS

a.   Introduction
b.   Expedited Reporting from Clinical Trials

• Expedited Reporting to Regulatory Authorities
• Expedited Reporting: Causality
• Expedited Reporting: Expectedness
• Expedited Reporting: Unblinding
• Expedited Reporting: Comparators
• Expedited Reporting: Spontaneous Reports
• Prompt Reporting Other than Case Reports
• Expedited Reporting: Investigators and IECs/IRBs

c.   Periodic Communication of Safety Information from Clinical Trials

• Development Safety Update Report (DSUR)
• Investigator Brochure and DCSI Updates
• Other Periodic and Ad Hoc Communications to Investigators and IECs/IRBs
• Safety Management Process

d.   Other Reporting Considerations
e.    Informed consent
f.     Other Communications Considerations
g.    Conclusion


8. SUMMARY OF CONCEPTS AND PROPOSALS

APPENDICES

1. Glossary and Abbreviations
2. Membership and Process of CIOMS Working Group VI
3. CIOMS VI Working Group Survey o Pharmaceutical Company Safety-Management Practices During Clinical Trials
4. World Medical Association Declaration of Helsinki
5. Data and Safety Monitoring Boards (DSMBs)
6. Data Elements that Should Be Considered for Individual Adverse Event Reports
7. Causality Criteria and Threshold Considerations for Inclusion of Safety Data in Development Core Safety Information (DCSI)
8. Sample Serious AE Report Data Collection Form for Investigators
9. Databases for Epidemiology and Pharmacoepidemiology
   

INDEX

The report Management of Safety Information from Clinical Trials - Report of CIOMS Working Group VI (ISBN 92 9036 079 8), Price: Swiss Francs, 40.- can be ordered from:

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