For the purpose of this document, the nomenclature follows the EU CTR, relevant ICH guidance, CTFG Recommendation Paper on the Initiation and Conduct of Complex Clinical Trials (2019) and international common use as appropriate. Additional non-binding terminology conventions are described in the glossary to facilitate alignment between different sources of information and ensure consistent meaning.
This document aims to address challenges sponsors may face as regards scientific and operational aspects of CCTs and to encourage considering choices in development and implementation as early as possible, in order to generate useful evidence and inform clinical and regulatory decisionmaking. This document also refers to additional resources providing guidance for CCTs throughout the medicinal product lifecycle. The document is planned to be updated with evolving experience. Operational aspects related to the Clinical Trials Information System (CTIS) are not addressed in this Q&A.
The scope of this document is to provide guidance and support for complex clinical trials which are defined as being non-conventional in the sense that they have elements, features, methods or combination thereof, including novel approaches, that confer complexity of their designs, conduct, analyses or reporting.
There can be a scientific rationale and motivation for a complex clinical trial in any phase of clinical development. Complex clinical trials add value to clinical development, including early decisions on further development, and are of particular interest where they have a potential to allow for more efficient and accelerated evidence generation for clinical development to advance public health and to support a marketing authorisation application. Complex clinical trials so far have been rather diverse, so that the balance of their value with their scientific and operational complexities needs to be considered starting from the planning stage. The robustness of data generated in a clinical trial, together with the rights, safety, dignity and well-being of participants, are the foremost principles stipulated in the EU CTR and they also apply to CCTs.
This Q&A document is not restricted to specific types of CCTs and applies also to other designs intended to address multiple research questions. This operational definition does not imply a legal categorisation or a need for sponsors or NCAs to demonstrate that parts of a CCT could in fact be handled as individual trials. This Q&A document recognises that CCTs can also include ATMPs as IMPs (see Q1).
Aspects of the modus operandi for clinical trial authorisation in the EU have consequences that sponsors and regulators have to be aware of and to accommodate. For a complex clinical trial, the structure of its results in a submission for marketing authorisation (MAA) may differ from that of its submission(s) for clinical trial authorisation (CTA). An example is a MAA submission that is based on an active and a control arm which had been submitted as different CTAs yet were part of a shared scientific framework. A CCT builds on a scientific rationale at the level of a shared scientific framework across CTAs and thus across EUCT numbers. Regulators may have to handle an MAA with results of a CCT focusing on its scientific rationale and taking into account the necessities for choosing a submission approach that applied at the time of CTA. A complex clinical trial can thus refer to a trial with a single EUCT number (such as having a master protocol and sub-protocols within a common protocol structure, as one single protocol) or to several trials with different EUCT numbers linked by a common (master protocol) part. Choices for the submission approach for authorisation of CCTs are driven by the rule set for clinical trials in the EU. Since the shared framework of CCTs can span regions beyond the EU, consequences may affect the paradigm of corresponding identifiers in public trial registries between the EU and other regions and the MAA dossier in the EU.
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