A Review and Analysis of Key Regulations and Guidelines concerning the Safety Sections of the Investigator's Brochure

Abstract

Recent regulatory initiatives and consensus documents have altered the conventional approach to evaluating and communicating pharmacovigilance information. While these trends may initially seem to provide opportunities to combine certain aspects of the premarketing and postmarketing safety evaluation functions, they also have the potential to obscure the substantial differences between comprehensive risk assessment in investigational and postmarketing settings. Personnel involved in evaluation of safety data from clinical trials (including studies for new indications for currently marketed products) must give special consideration to those regulatory, legal, scientific, and ethical issues that are unique to the premarketing environment. In this paper, we approach this complex topic by contrasting the risk assessment of investigational products, as summarized in the investigator's brochure, with similar, well-described risk evaluation processes that are carried out for marketed products.

Keywords

Adverse events Signaling Premarketing surveillance Investigator's brochure Informed consent

Get full access to this article

View all access options for this article.

References

European Parliament and Council Directive. Clinical Trial Directive: On the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. COM(97) 369:/97/0197(COD). April 26, 1999.

21 Code of Federal Regulations (US). Section 312.32.

21 Code of Federal Regulations (US). Section 314.80.

The European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products. ICH Topic E2A, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting: CPMP/ICH/377/95. London: June 1, 1995.

United States Food and Drug Administration, Center for Drug Evaluation. ODE IV Pilot Targeted Product Information Template. www.fda.gov/ceder/tpi/default.htm. March 8, 1999.

Council for International Organizations of Medical Sciences (CIOMS). Report of CIOMS working Groups III and V (including new proposals for Investigator's Brochures). Guidelines for Preparing Core Clinical Safety Information on Drugs. Second Edition. Geneva, Switzerland: CIOMS; 1999.

ICH E6. Good Clinical Practice: Consolidated Guidelines. International Conference on Harmonization.

Kramer

Lane

Causal propositions in clinical research and practice. J Clin Epidemiol. 1992;45:639–649.

Rothman

Greenland

Causation and Causal Inference. Chapter 2 in: Rothman

Greenland

. Modern Epidemiology. Philadelphia: Lippincott-Raven; 1998. 7–28.

10.

Lane

Kramer

Hutchinson

Jones

Naranjo

The causality assessment of adverse drug reactions using a Bayesian approach. Pharma Med. 1987;2:265–283.

11.

Karch

Lasagna

Towards the operational definitions of adverse drug reactions. Clinical Pharm Ther. 1977;21:247–255.

12.

Blanc

Levenberger

Judgment of trained observers on adverse drug reactions. Clin Pharm Ther. 1979;5:493–498.

13.

Hutchinson

Lane

Assessing methods for causality assessment of suspected adverse drug reactions. J Clin Epidemiol. 1989;42:5–16.

14.

Meyboom

Egberts

Principles of signal detection in pharmacovigilance. Drug Safety. 1997;16:355–365.

15.

Lindquist

Edwards

Bate

From association to alert—a revised approach to international signal analysis. Pharmacoepidemiol Drug Safety. 1999;8(Suppl):S15–S25.

16.

Chuang-Stein

Safety analysis in controlled clinical trials. Drug Inf J. 1998;32(Suppl):S1363–S1372.

17.

Gait

Smith

Brown

Evaluation of safety data from controlled clinical trials: The clinical principles explained. Drug Inf J. 2000;34:273–287.

18.

O'Neill

Biostatistical considerations in pharmacovigilance and pharmacoepidemiology: Linking quantitative risk assessment in pre-market licensure applications, safety data, post-market alert reports and formal epidemiological studies. Stat Med. 1998;17:1851–1858.

19.

McKenzie

Fried

Sallie

Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. New Engl J Med. 1995;333:1099–1105.

20.

The Nuremberg Code. Br Med J. 7070(313):7 December.

21.

The Belmont Report: Ethical Principles and Guidelines for Research Involving Human Subjects. FR Doc. 79–12065 Filed 4–17-79.

22.

Declaration of Helsinki. Adopted by the 18th World Medical Association General Assembly, Helsinki, Finland, June 1964 and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000.

23.

Finney

An international drug safety program. J New Drugs. 1963;3:262–265.