How the EU trial and device regulations compare
The EU regulation on clinical trials of medicines and the EU regulation on medical devices differ in scope and in who implements them, but they define a clinical study and its conduct, registration and disclosure in very similar terms. Their similar requirements weighed very differently on the two industries, which started from different baselines.
Whether medicines and devices live in separate universes
A device regulatory consultant has warned that medicinal products and devices are different species living in parallel universes, and that carelessly switching between them may be deadly. The view that a drug is a drug and a device is a device is relatively widespread. Two regulatory writers who work for both industries challenged the consultant's view by comparing the two regulations on the conduct and disclosure of clinical studies, which are often called trials for medicines and investigations for devices. The regulations were written three years apart, and on a first reading of the device regulation the two universes seemed to them to be coming together, especially in study conduct, reporting and disclosure.
Where the two regulations differ in scope and ownership
The two regulations differ most obviously in scope, and also in who mainly implements them. The trial regulation covers interventional trials of medicines and aims to add clarity to the previous laws and to simplify and harmonise the administrative processes for clinical trials in the EU and the European Economic Area, while marketing authorisation and pharmacovigilance are covered by Directive 2001/83/EC and Regulation 726/2004. According to two regulatory writers, it supersedes Directive 2001/20/EC and Paediatric Regulation (EC) No. 1901/2006. The device regulation is much broader: it covers clinical investigations but also manufacturing, market access and post-market vigilance, and it supersedes Directive 90/385/EEC on active implantable devices and Directive 93/42/EEC on other devices. It aims at a robust, transparent, predictable and sustainable framework that ensures a high level of safety and health while supporting innovation, and at the smooth functioning of the internal market for devices. The European Medicines Agency carries the main responsibility for implementing the trial regulation, supported by the European Commission and the member states. For the device regulation that responsibility lies with the Commission, working with the competent authorities of the member states.
The trial regulation focuses mainly on investigational medicinal products, such as drugs and biologics, and mentions devices only in the context of the administration and delivery systems of medicinal products. The device regulation, which postdates it by three years, refers to the trial regulation three times and recognises that medicinal products and devices may occur together as combined products, a topic the trial regulation does not address.
Where their definitions and duties align
The two regulations are relatively aligned in how they define a clinical trial and a clinical investigation and the key people involved in them. Each defines its study, its investigational product or device, its protocol or clinical investigation plan, the sponsor, the subject, the investigator and informed consent; in some cases the terms differ slightly while the definitions are almost identical. Their requirements compare as follows.
| Requirement | Trial regulation 536/2014 | Device regulation 2017/745 |
|---|---|---|
| Conduct of a study | Required for all investigational medicinal products | Required for device classes II to III that have no CE mark |
| Registration | Obligatory for every trial with at least one EU site, through the EU portal into the EU database, with a unique EU trial number (Article 81) | Obligatory for every investigation with at least one EU site, in the clinical investigation system of Eudamed (Article 73), with a unique number (Article 62); an application made in parallel with a trial application refers to the trial's official registration number |
| Databases | The EU portal as single entry point (Article 80) and the EU database (Article 81), avoiding duplication with the existing databases; partial public access; the European Medicines Agency is controller | Eudamed integrating several electronic systems (Article 33), its clinical investigation system the entry point for applications and notifications; partial public access in a user-friendly, searchable format; the Commission is controller; to be interoperable with the trials database (recital 67) |
| Public disclosure of the application | Protocol, investigator's brochure, parts of the product dossier and the summary of product characteristics, with the protocol describing the publication policy; potentially all public | The application dossier, clinical investigation plan and investigator's brochure, with the plan stating the policy on the report and publication of results; potentially all public |
| Results | A summary of results irrespective of outcome within one year (Article 37, Annex IV); a layperson's summary (Annex V); the clinical study report within 30 days of the marketing authorisation decision | The clinical investigation report within one year of the end of the investigation, or three months after early termination or a temporary halt, irrespective of outcome (Article 77); a summary easily understandable by the user |
| Ethical guidance cited | The 2008 Declaration of Helsinki and ICH good clinical practice | The latest Declaration of Helsinki and ISO 14155:2011 |
| Personal data | Regulation (EC) No 45/2001, since replaced by the General Data Protection Regulation; the protocol should describe compliance, confidentiality and breach mitigation | The same, with the clinical investigation plan to describe compliance, confidentiality and breach mitigation |
| Commercially confidential information | Protected unless an overriding public interest favours disclosure (Article 81(4)(a)) | Commercially confidential information, trade secrets and intellectual property protected unless disclosure is in the public interest (Article 109(1)(b)) |
How registration and the databases line up
Both regulations require each clinical study to be registered in a publicly accessible registry under a unique number, which the earlier legislation already required for medicines but the device directives did not. The device regulation states that its electronic system for clinical investigations should be interoperable with the EU database for clinical trials of medicines, to ensure synergies between the two areas. This is presumably part of the EU initiative for standardised and interoperable electronic health systems. The interoperability will allow a more comprehensive record of the clinical studies conducted in the EU, whatever the product type, similar to what ClinicalTrials.gov offers.
How disclosure runs in parallel
For both regulations, the public application material includes information on the sponsor, the protocol or plan and their amendments, the investigator's brochure and, for medicines, parts of the product dossier, with exceptions for protected personal data and commercially confidential information. Decisions on publishing and sharing results are expected to be described in the protocol or plan, although the legislation does not say so clearly.
Both regulations require full disclosure of a results summary based on the clinical study report or the clinical investigation report. For medicines, the trial regulation requires a technical summary and a layperson's summary, available to the public through the EU database. The device regulation requires a full clinical investigation report and a summary the intended user can understand, similar to the layperson's summary, and both are submitted to Eudamed and made public. Unlike the trial regulation, the device regulation seems to have no intermediate step of posting a results summary, and the report is expected within one year of the end of the investigation.
The device regulation requires every step of a clinical investigation, from considering the need for it to publishing its results, to follow recognised ethical principles, namely ISO 14155:2011 and the most recent Declaration of Helsinki, which in 2019 was the version of 2013. The trial regulation refers instead to the ICH guidelines on good clinical practice and the 2008 Declaration. Both versions of the Declaration recommend registering clinical studies and publishing their results on publicly accessible platforms.
Both regulations require the personal data of study participants to be protected in publicly accessible documents, citing Regulation (EC) No 45/2001, since superseded by the General Data Protection Regulation. Both regulations allow companies to protect commercially confidential information, trade secrets and intellectual property, but in both the protection can be overruled where disclosure is in the public interest. The redaction principles that apply to documents disclosed under EMA Policy 0070 are expected to apply also to the documents the device regulation requires to be disclosed.
Why similar requirements weighed differently on the two industries
The detailed requirements and documentation of the trial regulation of 2014 were nothing new for the pharmaceutical industry; its major changes were a centralised trial application, increased disclosure requirements and a new EU portal and database to replace the existing ones. The device regulation of 2017 met a medical technology industry left to its own devices until then, which struggled with the drastically increased and unfamiliar requirements. To regulatory writers working in both industries, it felt as if aliens had invaded the device universe.
The two regulations are similar in content but differ greatly in their impact on their industries, for two reasons. In 2019 there were around 500,000 medical technology products in Europe, and their number and diversity may have hindered earlier efforts to harmonise their regulation. Under the earlier legislation, the regulatory pathways for the two kinds of product were also very different, and the requirements were clearly less stringent for devices than for medicines. The new regulations bring the requirements for both to the same level of stringency, so the difference in impact comes from the different baselines, the directives, and from the change in requirements the new regulations brought.
Two regulatory writers assessed the change from each baseline and rated its impact as low, moderate or high, arbitrarily by their own account, from the size of the change and their experience with the previous and new requirements. For medicines, the changes to study conduct and documents were small, with low to moderate impact, mainly on timelines for conduct; registration changed little, with low impact; and results disclosure moved from partial to full, a large change with moderate to high impact. For devices, study conduct went from not clearly required under the equivalence route to mandatory for most classes, registration and full results disclosure went from not required to mandatory, all large changes with high impact; documents went from required but not clearly structured to requirements like pharma's, a small change that still had high impact.
What medicines and devices have in common
Medicines and devices differ in appearance, mechanism of action, development and life cycle, but both are medical interventions with a medical purpose whose effectiveness and safety need to be shown in clinical studies. Both industries have had efficacy scandals and safety mishaps, and the lessons learned from them have been used to refine the regulatory requirements. In the view of the two writers, in an era of patient centricity the benefits and risks to the patient matter more than whether the product is a medicine or a device. Merging the two universes is likely to take some time, but the alignment of the two regulations' requirements points towards a single universe.