Adaptive Designs for Clinical Trials of Drugs and Biologics Adaptive Designs for Clinical Trials of...

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Adaptive Designs for Clinical Trials of Drugs and Biologics

Adaptive Designs for
Clinical Trials of Drugs
and Biologics
Guidance for Industry

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)

November 2019
Biostatistics
Adaptive Designs for
Clinical Trials of Drugs
and Biologics
Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD XXXXXXXXXX
Phone: XXXXXXXXXXor XXXXXXXXXX; Fax: XXXXXXXXXX
Email: XXXXXXXXXX
https:
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or

Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD XXXXXXXXXX
Phone: XXXXXXXXXXor XXXXXXXXXX
Email: XXXXXXXXXX
https:
www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics
iologics-guidances

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)

November 2019
Biostatistics
https:
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
Contains Nonbinding Recommendations
TABLE OF CONTENTS

I. INTRODUCTION AND SCOPE ................................................................. XXXXXXXXXX1
II. DESCRIPTION OF AND MOTIVATION FOR ADAPTIVE DESIGNS XXXXXXXXXX2
A. Definition ..................................................................................................................... XXXXXXXXXX2
B. Important Concepts .................................................................................................... XXXXXXXXXX2
C. Motivation and Examples........................................................................................... XXXXXXXXXX3
D. Limitations ................................................................................................................... XXXXXXXXXX6
E. Choosing to Adapt ...................................................................................................... XXXXXXXXXX6
III. PRINCIPLES FOR ADAPTIVE DESIGNS ............................................... XXXXXXXXXX7
A. Controlling the Chance of E
oneous Conclusions .................................................. XXXXXXXXXX7
B. Estimating Treatment Effects .................................................................................... XXXXXXXXXX8
C. Trial Planning ............................................................................................................. XXXXXXXXXX8
D. Maintaining Trial Conduct and Integrity ................................................................. XXXXXXXXXX9
IV. ADAPTIVE DESIGNS BASED ON NON-COMPARATIVE DATA..... XXXXXXXXXX10
V. ADAPTIVE DESIGNS BASED ON COMPARATIVE DATA ............... XXXXXXXXXX10
A. Group Sequential Designs ........................................................................................ XXXXXXXXXX11
B. Adaptations to the Sample Size ............................................................................... XXXXXXXXXX13
C. Adaptations to the Patient Population (e.g., Adaptive Enrichment) .................... XXXXXXXXXX14
D. Adaptations to Treatment Arm Selection .........................................

adaptive-trials-guidance-from-fda-1-ymuvreqs.pdf

Dr. Saloni · Accepted Answer

Running Head: Adaptive Trials                                                                                                   4
Adaptive Trials
Introduction
After the trial has commenced, an adaptive design enables certain proactively intended changes to the research design to be implemented while retaining the trial's authenticity and coherence. If done appropriately, the additional flexibility to change specific aspects of the study design might result in more reliable and effective study results. Adaptive trial approaches have been widely employed in the development of medical devices, and the lessons learned are also being extended to drug development. Whereas adaptive trials frequently include adjustments, not all alterations are acceptable for each trial (Bahety et al., 2021).This paper focuses on clinical trials, their benefits, and some of the challenges associated with their use.
An Instance
The INHANCE trial was an adaptive 2-stage confirmatory, randomised clinical trial of inhaling indacaterol, once a prolonged acting beta2-agonist dilator for the management of COPD; the trial included various treatment cohorts, including dose adjustment after phase 1. In phase 1, individuals with COPD were randomly assigned to each of 7 groups to obtain four doses of indacaterol, formoterol, placebo, or tiotropium in a double-dummy, double-blind way; the last 2 schedules were deemed conventional-of-care comparators. In phase two, 2 of the 4 indacaterol dosages, as well as tiotropium and placebo, were to be chosen for further research (Chuang-Stein & Kirby, 2021). The aggregated data from the 2 phases would be utilised in the conclusion. The primary effective goal was to demonstrate that at least 1 dosage of indacaterol outperformed placebo. The statistics and security management committee chose dosages of 300 g and 150 g based on the thorough dose-selection parameters that were pre-specified in the charters, and patient recruiting for the next phase of the trial was subsequently resumed. The dose-choice norm at the intermediate statistical and analysis inference at the conclusion are the 2 key statistical issues for a strategy of this kind. This example illustrates several characteristics that must be met for an adaptive design to be implemented successfully (Mandrola et al., 2021).

Adaptive Designs for Clinical Trials of Drugs and Biologics Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry U.S. Department of Health and Human Services Food and Drug...

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