06/14/2022

The European Medicines Agency (EMA) released a Complex Clinical Trials Questions and Answers guidance document in May 2022. Complex clinical trials (CCT) 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.” CCTs can be beneficial for gathering data that support early decisions for how to proceed in clinical development. Recommendations are in line with the EU Clinical Trials Regulation and are aimed to address scientific and operational challenges sponsors face with CCTs. The guidance focuses on considerations for the planning, design, and conduct of CCTs while maintaining robust, quality data and support the safety of study participants. The guidance notes the structure of the results for submissions for CCT marketing authorizations (MAA) may be different from the clinical trial authorizations (CTA), for example, different CTA that are combined into one MAA.

There are seven questions with multiple related sub-questions and answers.

Question 1: Important considerations for the planning and conduct of complex clinical trials
- Q1.1: How to define in the protocol research questions, objectives, endpoints, assumptions, and hypotheses when they are common and/or specific for sub-protocols?
- Q1.2: How to apply risk-proportionate approaches to CCTs?
- Q1.3: Do I need to submit a CCT and its parts as one single trial or as separate clinical trials under the CT Regulation?
- Q1.4: What considerations are important when planning a complex clinical trial as a co-sponsorship?
- Q1.5 What additional considerations, including for benefit-risk reassessment, need to be made during the conduct of CCTs?
- Q1.6: Which specific aspects of CCTs would benefit from seeking advice?
Question 2: Which additional considerations are needed for the design and conduct of master protocol studies?
- Q2.1: How do requirements for clinical trial application and marketing authorization need to be considered?
- Q2.2: What additional information needs to be provided and/or clarified at the time of CTA and MAA submission?
- Q2.3: Where to include the pre-specified statistical analysis for sub-protocols and/or the entire trial?
Question 3: How to describe and explain Bayesian approaches in complex clinical trials?
Question 4: What are the considerations for planning, collection, and use of control data from within a complex clinical trial for regulatory purposes?
Question 5: Which principles apply, and which regulatory pathways should be considered when using biomarkers and biomarker assays in complex clinical trials and consequently applying for marketing authorizations?
- Q5.1 What are specific aspects of relevance for the use of biomarkers and biomarker assays in complex clinical trials?
- Q5.2: How to integrate pre-screening and screening processes for biomarkers within the shared framework of CCTs?
- Q5.3 What are the requirements with regard to the biomarker assays when results of complex clinical trials are submitted to support MAAs?
Question 6: Safety, rights, and well-being of participants
- Q6.1: How to ensure adequate risk-based quality management, sponsor oversight and investigator supervision in support of subjects safety /positive risk benefit?
- Q6.2: How to organize safety monitoring and reporting (including urgent safety measures, unexpected event changing benefit risk, serious breaches, corrective measures), in complex clinical trials with multiple responsible parties involved?
- Q6.3: Do I need to establish a data (safety) monitoring committee in all situations?
Question 7: Transparency (balance with integrity) and communication between regulators, sponsors, and investigators
- Q7.1: What is expected as “end of trial” for a complex clinical trial?
- Q7.2: How and what to communicate around and during the trial submission and conduct between authorities and sponsor, sponsors, and investigators as well as investigators and participants?
- Q7.3: How should I organize the documents to facilitate understanding and communication?
- Q7.4: How to ensure balance between transparency and trial integrity when closing of sub-protocols and communicating the summary of sub-protocol results?

Due to the diverse and complex nature of CCTs, balancing the benefits versus the complexity should be determined early in the process, during the planning stage if possible. It is also suggested to contact regulatory agencies early in the process to ensure CCTs are planned and designed appropriately, and to consult stakeholders such as patients and investigators. This is aligned with ICH E8(R1).