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Submission strategies for combined studies in the EU

Many clinical trials deploy medical devices (MDs) or in-vitro diagnostic devices (IVDs). Assessing the device¡¯s safety or performance is not within the scope of the study, but the device is necessary to conduct the study. Complying with EU regulations in combined studies like these involves additional planning to ensure both efficiency and regulatory approval. 

In this article we look at how an oncology study sponsor managed their submission process which spanned more than 30 countries, many in the EU. Before detailing the study we outline why combined studies have increased regulatory burdens.

Combined studies, increased regulatory burdens

Combined studies involve the simultaneous evaluation of a medicinal product, a medical device and/or an IVD. These studies can entail a significant regulatory compliance burden. The use of a medical or in vitro device implies separate applications via distinct procedures, which impact the efficiency of approval and start-up timelines. They also introduce significant regulatory compliance burdens. Sponsors and CROs must prepare and submit separate applications via very distinct, independent submission pathways. The applications for a clinical trial, a clinical investigation (CI) and a clinical performance study (CPS) are significantly different, but with some overlap with requirements for study documentation. This overlap requires additional strategic considerations, more time, effort and expertise. 

Adding to this is the complexity of the study documentation for both clinical trial and device applications. Dealing with requests for changes from the independent assessment process adds to the burden. The different change requests from the independent assessments must be aligned and captured in the study documentation. A substantial modification might be required to align the updates and ensure that the same final document is authorised under both approval pathways. Inconsistencies in the requirements, submission documents, assessment and approval pathways, and authorisation lifecycle expectations can create confusion and uncertainty. In turn this can lead to variations in interpretation and implementation in the EU countries where the regulations apply.

Combined study with in vitro device investigating an oncology treatment

ÃÛÌÒ´«Ã½ Regulatory Affairs supported a study which was dealing with many of the issues outlined above. The study sponsor was investigating a biological treatment for oncology patients in addition to the standard of care chemotherapy. The study involved more than 30 countries, including many from the EU, with all patients providing a tissue sample as part of the inclusion process. The diagnostic protocol was conducted in association with the main investigational medicinal product (IMP) trial to test tissue samples from patients undergoing screening in the clinical trial.

The study¡¯s objective was to evaluate the safety and efficacy of the treatment plus chemotherapy in patients with this particular cancer. The trial results will provide the basis for evaluating the clinical performance of a companion diagnostic (CDx) assay as a CDx device for biological treatment in combination therapy in the same patient population. The sponsor sought regulatory support from ÃÛÌÒ´«Ã½ due to the study¡¯s complexity, the geographic span and because the IVD was used outside its intended purpose. 

Managing submission packages under IVDR and CTD

Within the EU, the trial was subject to the requirements of IVDR in addition to the Clinical Trials Directive (CTD). The clinical trial and performance submissions took place following the implementation of IVDR. However, not all European countries had implemented IVDR at national level so there was some variation in requirements depending on the site locations. The study start-up timeline was challenging ¨C the IVD performance study was submitted between two and three months after the main IMP clinical trial.

Within the submission packages there were overlapping documents such as IMP protocol, ICF, or insurance. Changes made to one part resulted in modification submissions for other parts. The various regulatory authorities (RAs) raised queries at different points during the submission process. Once the initial approval was granted any changes to the overlapping documents for the IMP clinical trial resulted in change submissions for the IVD performance study. This required more regulatory support throughout the study.

Streamlining a successful submission strategy

ÃÛÌÒ´«Ã½ developed a comprehensive regulatory submission strategy for the study. This considered the different national requirements and processes including parallel RA and CEC submission for the IMP clinical trial. Sequential submissions for the IVD performance study were planned with EC submission, followed by RA. ÃÛÌÒ´«Ã½¡¯s experienced regulatory team engaged at international and national level to optimise the study¡¯s submission strategy. One of the goals of the submission strategy was to avoid potential delays to the study start-up. With this in mind, the team clarified country-specific requirements with each of the regulatory agencies, paying particular attention to the new compliance details of IVDR. Through consultation with the agencies involved, they agreed on the most appropriate way to process the many elements of the study applications.

The study sponsor and IVD manufacturer confirmed the strategy and timeline for conducting the IVD performance aspect of the application process. Roles and responsibilities were agreed with the sponsor and IVD manufacturer for document preparation and process implementation. All requirements were identified at the outset to ensure that no package elements were missing. Following ÃÛÌÒ´«Ã½¡¯s advice, a cover letter was created which connected both parts of the combined project with clear descriptions of the role of the investigational sites and central testing site. The cover letter provided details related to the patient enrolment, tissue sample collection and the central laboratory where the IVD performance study was conducted. This minimised the potential number of validation questions from each RA. The team also put in place a plan for amending the overlapping documents during the project.

Clarifying complex submissions

All of the RA and ECs approved the initial study with no unanticipated delays. There were minimal validation comments or queries in relation to the process flow and responsibilities between the IMP and IVD aspects of the combined study. There were evaluation comments from two authorities seeking clarification on the IVD technical documentation. These were easily addressed by the manufacturer. Collaboration between ÃÛÌÒ´«Ã½, the sponsor and manufacturer ensured that project and product development milestones were achieved.

Conclusion

EU Regulations for combined studies which involve medical devices, in vitro diagnostic devices or medicinal products demand robust submission strategies. We¡¯ve explored some of these issues in previous articles on EU CTR, MDR and IVDR submission pathways and how medical devices, medicinal and combination product are classified. While delays and confusion may seem inevitable, they don¡¯t have to be. With the right supports, planning and collaboration your study¡¯s regulation submissions can be streamlined for success. 

Download our whitepaper to demystify EU CTR, MDR and IVDR regulations.

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