Guidance for Industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications

Guidance for Industry

Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications





U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

April 2003

CP
Guidance for Industry
Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications

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http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training and Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research (CBER)

Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

Voice Information: 800-835-4709 or 301-827-1800

http://www.fda.gov/cber/guidelines.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

April 2003

TABLE OF CONTENTS

I. INTRODUCTION
1

II. BACKGROUND 2

III. DRUG DEVELOPMENT AND REGULATORY APPLICATIONS 2

A. Information to Support the Drug Discovery and Development Processes 3

B. Information to Support a Determination of Safety and Efficacy 3

iV. DOSE-CONCENTRATION-RESPONSE RELATIONSHIPS 8

AND EFFECTS OVER TIME 8

A. Dose and Concentration-Time Relationships 8

B. Concentration-Response Relationships: Two Approaches 9

V. DESIGNS OF EXPOSURE-RESPONSE STUDIES 9

A. Population vs. Individual Exposure-Response 10

B. Exposure-Response Study Design 10

C. Measuring Systemic Exposure
12

D. Measuring Response 15

VI. MODELING OF EXPOSURE-RESPONSE RELATIONSHIPS 16

A. General Considerations 17

B. Modeling Strategy 17

VII. SUBMISSION INFORMATION: EXPOSURE-RESPONSE STUDY REPORT 19

REFERENCES 21

APPENDIX A: RELATED GUIDANCES 22

APPENDIX B: PEDIATRIC DECISION TREE INTEGRATION OF PK-PD 25

Guidance for Industry¹
Exposure-Response Relationships: Study Design, Data Analysis,

and Regulatory Applications

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

I. INTRODUCTION

This document provides recommendations for sponsors of investigational new drugs (INDs) and applicants submitting new drug applications (NDAs) or biologics license applications (BLAs) on the use of exposure-response information in the development of drugs, including therapeutic biologics. It can be considered along with the International Conference on Harmonisation (ICH) E4 guidance on Dose-Response Information to Support Drug Registration and other pertinent guidances (see Appendix A).
This guidance describes (1) the uses of exposure-response studies in regulatory decision-making, (2) the important considerations in exposure-response study designs to ensure valid information, (3) the strategy for prospective planning and data analyses in the exposure-response modeling process, (4) the integration of assessment of exposure-response relationships into all phases of drug development, and (5) the format and content for reports of exposure-response studies.
This guidance is not intended to be a comprehensive listing of all of the situations where exposure-response relationships can play an important role, but it does provide a range of examples of where such information may be of value.
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND

Exposure-response information is at the heart of any determination of the safety and effectiveness of drugs. That is, a drug can be determined to be safe and effective only when the relationship of beneficial and adverse effects to a defined exposure is known. There are some situations, generally involving a very well-tolerated drug with little dose-related toxicity, in which the drug can be used effectively and safely at a single dose well onto the plateau part of its exposure-response curve, with little adjustment for pharmacokinetic (PK) or other influences in individuals. In most situations, however, for more toxic drugs, clinical use is based on weighing the favorable and unfavorable effects at a particular dose. Sometimes with such drugs, the doses can be titrated to effect or tolerability. In most cases, however, it is important to develop information on population exposure-response relationships for favorable and unfavorable effects, and information on how, and whether, exposure can be adjusted for various subsets of the population.

Historically, drug developers have been relatively successful at establishing the relationship of dose to blood concentrations in various populations, thus providing a basis for adjustment of dosage for PK differences among demographic subgroups or subgroups with impaired elimination (e.g., hepatic or renal disease), assuming systemic concentration-response relationships are unaltered. Far less attention has been paid to establishing the relationship between blood concentrations and pharmacodynamic (PD) responses and possible differences among population subsets in these concentration-response (often called PK-PD) relationships. These can be critical, as illustrated by the different responses to angiotensin-converting enzyme (ACE) inhibitors in both effectiveness and safety between Black and Caucasian populations.
For the purposes of this guidance, we are using the broad term exposure to refer to dose (drug input to the body) and various measures of acute or integrated drug concentrations in plasma and other biological fluid (e.g., Cmax, Cmin, Css, AUC). Similarly, response refers to a direct measure of the pharmacologic effect of the drug. Response includes a broad range of endpoints or biomarkers ranging from the clinically remote biomarkers (e.g., receptor occupancy) to a presumed mechanistic effect (e.g., ACE inhibition), to a potential or accepted surrogate (e.g., effects on blood pressure, lipids, or cardiac output), and to the full range of short-term or long-term clinical effects related to either efficacy or safety. This exposure-response guidance focuses on human studies, but exposure-response information in animal pharmacology/toxicology studies is also a highly useful component of planning the drug development process (Peck 1994; Lesko 2000).