A subgroup of the EU’s Heads of Medicines Agencies issued new recommendations Friday on conducting complex clinical trials.
The HMA’s Clinical Trials Facilitation Group—coordinated by the Danish Medicines Agency—identified eight key recommendations to establish a framework on the initiation and conduct of complex trials for the development of personalized medicine. They were prepared “in recognition of the fact that the development of personalized medicine is gaining ground and clinical trials with trial subjects are becoming more and more complex,” the Danish agency said.
The first four recommendations describe how sponsors should clearly describe and justify the design of a complex trial, maintain scientific integrity, optimize clinical feasibility as well as ensure the quality of trial conduct and the safety of trial subjects. The remaining four recommendations address the areas of data integrity, benefit-risk balance throughout a trial’s duration, validation of companion diagnostics and considerations around data transparency.
Sponsors should read the eight recommendations in conjunction with current EU legislation on clinical trials, CTFG clarified in its new 15-page paper. Specifically, the paper references the EU Clinical Trial Directive 2001/20/EC. It also directs sponsors to recommendations from the European Commission expert group on clinical trials for the implementation of the European Medicines Agency’s 2014 Clinical Trial Regulation for more information. This regulation is set to replace the Clinical Trial Directive next year after being postponed from October 2018 “due to technical difficulties with the development of the IT systems” to launch the clinical trial portal.
The paper also defines common concepts of complex clinical trials, including sub-protocols, master protocols and extensive adaptive features. The guiding definition of a complex clinical trial relates to whether the trial design “has separate parts that could constitute individual clinical trials and/or is characterized by extensive prospective adaptations such as planned additions of new Investigational Medicinal Products (IMPs) or new target populations.”
Information regarding the potential opportunities of and challenges facing complex clinical trials within the context of precision medicine is provided in the CTFG paper as well. The paper argues that “biomarker-driven development is advantageous for both patients and sponsors because it aims to match patients with the expected best available treatment and could streamline clinical development.”
Greater operational complexity as it relates to the need for several adaptions and data transparency are some of the barriers and concerns of complex clinical trials. “There are also concerns regarding the scientific value or outcome of complex clinical trials due to the parallel testing of several IMPs in small numbers of trial subjects, difficulties to control type I error, and challenges created by shared control arms,” HMA’s subgroup said.
CTFG’s recommendations are partly based on the E6 Good Clinical Practice (R2: Integrated Addendum to E6 (R1) guidance developed by the International Council for Harmonization. This coincides with how global regulatory authorities joined forces in recent years to address challenges in effective regulation of precision medicine.
Date: March 13, 2019