Combined Clinical Studies

Combination products

Combination products are progressively integrating cutting edge, novel technologies that hold great promise for advancing patient care. Such innovative drug, biological product, device combinations have the potential to make treatments safer, more effective, or more convenient to patients. For example, drug-eluting stents may reduce the need for repeated surgery by preventing restenosis after implantation; or proteins incorporated into novel orthopedic implants may facilitate the regeneration of bone needed to permanently stabilize the implants; or genomic-based diagnostic devices may better determine whether certain patients are suitable candidates for a drug or biological product.

Combination of regulations

This interface between clinical trials of medicinal products, medical devices and in vitro diagnostics (IVDs) creates a mix of regulations that needs to be applied together to develop innovative treatments that combine medicinal products with medical devices or IVDs. In this context, combined studies can involve: (i) a clinical trial of a medicinal product in parallel with a performance study of an in vitro diagnostic; and/or (ii) clinical trial of a medicinal product in parallel with a clinical investigation of a medical device.

Combined clinical studies

Since there are a number of challenges to progress from a novel concept in product development to an innovative marketed product combination, a question that arises is what types of clinical investigation designs are appropriate? Because although a combination product may contain an already approved drug and an already approved device, new scientific and technical issues may arise when these are merged together. As such, clinical development questions frequently appear around trial design, sample size, statistical methods, clinical endpoints, appropriate number of clinical studies, and appropriate indications/claims for the new combined product.

Evaluation of Human factors

For certain combination products that include a device part, it may be necessary to evaluate the human factors of the device. Such studies need to evaluate how users operate the combined system in real world conditions, including an assessment of all components and accessories necessary to operate and properly maintain the device (e.g., controls, displays, labels, instructions, analysis of critical tasks). Such evaluations should take place early in developmentto identify design features that may need modification before conducting the key studies to establish the safety and effectiveness of the combination product.

COMBINE

While the USA Food and Drug Administration has well-established processes guidance on developmental considerations for innovative combination products, in the European Union (EU), the COMBINE project is currently on its second phase to identify possible solutions to the challenges found in the interface of Regulation (EU) 536/2014 on clinical trials of medicinal products for human use (CTR), Regulation (EU) 2017/745 on medical devices (MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR). The COMBINE project involves representatives of competent authorities, the European Commission, medical research ethics committees, the European Medicines Agency and relevant medicinal product and medical device sector stakeholders, and results are expected by the end of the year.

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