Analysis of integrated clinical trial protocols in early phases of medicinal product development

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Abstract

Purpose

While in the past, most clinical trial applications (CTAs) following non-integrated (standard) protocols were used to investigate one primary objective concerning a (new) drug, nowadays, the use of integrated protocols investigating multiple objectives within the same CTA becomes more and more popular. The aims of the present study were to investigate the usage and the impact of integrated protocols on regulatory activities and to find the motivation for their increasing use.

Methods

Two thousand nine hundred sixty-nine phase I and I/II CTAs submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) during the time period from August 1, 2004, until August 31, 2014, were analysed with regard to protocol and sponsor status, duration until initial authorisation and the number of substantial amendments and their respective approval times. Additionally, applicants who submitted integrated protocols to BfArM were interviewed with respect to their opinion on integrated protocols in an online survey.

Results

The percentage of integrated protocols has constantly increased by approximately 10% within the last 10 years from 17.9% in 2004 to 28.2% in 2014. It could be shown that authorisation procedures with single integrated protocols take significantly longer until initial authorisation (58 vs. 53 days) requires more substantial amendments (1.9 vs. 1.2 amendments per CTA) and the approval of the entirety of amendments takes longer to process as compared to standard protocols (22 vs. 14 days). Nevertheless, applicants prefer the use of integrated protocols due to higher time and cost economy for the entire phase I development process.

Conclusion

Although clinical trials (CTs) following integrated protocols are partly more time-consuming and costly, still, time and/or money may be saved during drug development due to the fact that overall, fewer CTs are needed than with standard protocols. Hence, the main reason for the increasing use of integrated protocols is improved time and cost efficiencies when conducting CTs.

Electronic supplementary material

The online version of this article (10.1007/s00228-017-2335-y) contains supplementary material, which is available to authorized users.

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Most cited references 6

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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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The future of drug development: advancing clinical trial design.

Helen M. Branson, Jamal Sabir, Shrenik Mehta … (2009)

Declining pharmaceutical industry productivity is well recognized by drug developers, regulatory authorities and patient groups. A key part of the problem is that clinical studies are increasingly expensive, driven by the rising costs of conducting Phase II and III trials. It is therefore crucial to ensure that these phases of drug development are conducted more efficiently and cost-effectively, and that attrition rates are reduced. In this article, we argue that moving from the traditional clinical development approach based on sequential, distinct phases towards a more integrated view that uses adaptive design tools to increase flexibility and maximize the use of accumulated knowledge could have an important role in achieving these goals. Applications and examples of the use of these tools--such as Bayesian methodologies--in early- and late-stage drug development are discussed, as well as the advantages, challenges and barriers to their more widespread implementation.

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Is Open Access

Benefits, challenges and obstacles of adaptive clinical trial designs

Shein-Chung Chow, Ralph Corey (2011)

In recent years, the use of adaptive design methods in pharmaceutical/clinical research and development has become popular due to its flexibility and efficiency for identifying potential signals of clinical benefit of the test treatment under investigation. The flexibility and efficiency, however, increase the risk of operational biases with resulting decrease in the accuracy and reliability for assessing the treatment effect of the test treatment under investigation. In its recent draft guidance, the United States Food and Drug Administration (FDA) expresses regulatory concern of controlling the overall type I error rate at a pre-specified level of significance for a clinical trial utilizing adaptive design. The FDA classifies adaptive designs into categories of well-understood and less well-understood designs. For those less well-understood adaptive designs such as adaptive dose finding designs and two-stage phase I/II (or phase II/III) seamless adaptive designs, statistical methods are not well established and hence should be used with caution. In practice, misuse of adaptive design methods in clinical trials is a concern to both clinical scientists and regulatory agencies. It is suggested that the escalating momentum for the use of adaptive design methods in clinical trials be slowed in order to allow time for development of appropriate statistical methodologies.

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Author and article information

Contributors

Kevin Fruhner: kevin.fruhner@uni-bonn.de

Gunther Hartmann: gunther.hartmann@ukb.uni-bonn.de

Thomas Sudhop:

ORCID: http://orcid.org/0000-0002-6780-587X

thomas.sudhop@bfarm.de

Journal

Journal ID (nlm-ta): Eur J Clin Pharmacol

Journal ID (iso-abbrev): Eur. J. Clin. Pharmacol

Title: European Journal of Clinical Pharmacology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0031-6970

ISSN (Electronic): 1432-1041

Publication date (Electronic): 18 September 2017

Publication date PMC-release: 18 September 2017

Publication date (Print): 2017

Volume: 73

Issue: 12

Pages: 1565-1577

Affiliations

[1 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Institute of Clinical Chemistry and Clinical Pharmacology, , University Hospital, University of Bonn, ; Sigmund-Freud-Straße 25, 53127 Bonn, Germany

[2 ]ISNI 0000 0000 9599 0422, GRID grid.414802.b, Federal Institute for Drugs and Medical Devices (BfArM), ; Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany

Author information

Thomas Sudhop http://orcid.org/0000-0002-6780-587X

Article

Publisher ID: 2335

DOI: 10.1007/s00228-017-2335-y

PMC ID: 5684304

PubMed ID: 28921395

SO-VID: 6dff8203-2cf7-466c-9fbe-79ba166b18b6

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 7 June 2017

Date accepted : 6 September 2017

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: early-phase clinical trials,integrated protocol,non-integrated (standard) protocol,substantial amendment,federal institute for drugs and medical devices (bfarm)

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: early-phase clinical trials, integrated protocol, non-integrated (standard) protocol, substantial amendment, federal institute for drugs and medical devices (bfarm)

Analysis of integrated clinical trial protocols in early phases of medicinal product development

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Most cited references 6

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

The future of drug development: advancing clinical trial design.

Benefits, challenges and obstacles of adaptive clinical trial designs

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