Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov

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Abstract

Objectives

This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials.

Design

Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators’ experiences with adaptive designs.

Results

142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs.

Conclusions

Wider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis.

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Most cited references 32

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Adaptive trial designs: a review of barriers and opportunities

John Kairalla, Christopher S. Coffey, Mitchell Thomann … (2012)

Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies. A broad definition of adaptive designs allows for countless variations, which creates confusion as to the statistical validity and practical feasibility of many designs. Determining properties of a particular adaptive design requires careful consideration of the scientific context and statistical assumptions. We first review several adaptive designs that garner the most current interest. We focus on the design principles and research issues that lead to particular designs being appealing or unappealing in particular applications. We separately discuss exploratory and confirmatory stage designs in order to account for the differences in regulatory concerns. We include adaptive seamless designs, which combine stages in a unified approach. We also highlight a number of applied areas, such as comparative effectiveness research, that would benefit from the use of adaptive designs. Finally, we describe a number of current barriers and provide initial suggestions for overcoming them in order to promote wider use of appropriate adaptive designs. Given the breadth of the coverage all mathematical and most implementation details are omitted for the sake of brevity. However, the interested reader will find that we provide current references to focused reviews and original theoretical sources which lead to details of the current state of the art in theory and practice.

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Adaptive designs in clinical drug development--an Executive Summary of the PhRMA Working Group.

M Krams, Vladimir Dragalin, Christy Chuang-Stein … (2006)

A PhRMA Working Group on adaptive clinical trial designs has been formed to investigate and facilitate opportunities for wider acceptance and usage of adaptive designs and related methodologies. A White Paper summarizing the findings of the group is in preparation; this article is an Executive Summary for that full White Paper, and summarizes the findings and recommendations of the group. Logistic, operational, procedural, and statistical challenges associated with adaptive designs are addressed. Three particular areas where it is felt that adaptive designs can be utilized beneficially are discussed: dose finding, seamless Phase II/III trials designs, and sample size reestimation.

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Funding of US biomedical research, 2003-2008.

E Dorsey (2010)

With the exception of the American Recovery and Reinvestment Act, funding support for biomedical research in the United States has slowed after a decade of doubling. However, the extent and scope of slowing are largely unknown. To quantify funding of biomedical research in the United States from 2003 to 2008. Publicly available data were used to quantify funding from government (federal, state, and local), private, and industry sources. Regression models were used to compare financial trends between 1994-2003 and 2003-2007. The numbers of new drug and device approvals by the US Food and Drug Administration over the same period were also evaluated. Funding and growth rates by source; numbers of US Food and Drug Administration approvals. Biomedical research funding increased from $75.5 billion in 2003 to $101.1 billion in 2007. In 2008, funding from the National Institutes of Health and industry totaled $88.8 billion. In 2007, funding from these sources, adjusted for inflation, was $90.2 billion. Adjusted for inflation, funding from 2003 to 2007 increased by 14%, for a compound annual growth rate of 3.4%. By comparison, funding from 1994 to 2003 increased at an annual rate of 7.8% (P < .001). In 2007, industry (58%) was the largest funder, followed by the federal government (33%). Modest increase in funding was not accompanied by an increase in approvals for drugs or devices. In 2007, the United States spent an estimated 4.5% of its total health expenditures on biomedical research and 0.1% on health services research. After a decade of doubling, the rate of increase in biomedical research funding slowed from 2003 to 2007, and after adjustment for inflation, the absolute level of funding from the National Institutes of Health and industry appears to have decreased by 2% in 2008.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2018

Publication date (Electronic): 10 February 2018

Volume: 8

Issue: 2

Electronic Location Identifier: e018320

Affiliations

[1] departmentProgram on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine , Brigham and Women’s Hospital and Harvard Medical School , Boston, Massachusetts, USA

Author notes

[Correspondence to ] Dr Aaron S Kesselheim; akesselheim@ 123456partners.org

Article

Publisher ID: bmjopen-2017-018320

DOI: 10.1136/bmjopen-2017-018320

PMC ID: 5829673

PubMed ID: 29440155

SO-VID: f08c2539-1129-4f02-a945-19af09cb06a4

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 20 June 2017

Date revision received : 12 October 2017

Date accepted : 02 November 2017

Funding

Funded by: Brigham and Women’s Hospital Innovation Hub;

Funded by: Greenwall Foundation;

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ScienceOpen disciplines: Medicine

Keywords: adaptive design,flexible design,clinical trial,review,history,regulation,policy,fda,ema,data monitoring committee,interim analysis

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ScienceOpen disciplines: Medicine

Keywords: adaptive design, flexible design, clinical trial, review, history, regulation, policy, fda, ema, data monitoring committee, interim analysis

Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov

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Abstract

Objectives

Design

Results

Conclusions

Related collections

Wits Journal of Clinical Medicine

Most cited references 32

Adaptive trial designs: a review of barriers and opportunities

Adaptive designs in clinical drug development--an Executive Summary of the PhRMA Working Group.

Funding of US biomedical research, 2003-2008.

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