A clinical investigation of medical devices is not always a necessary component in the approval process, which comprises several phases. Most of the time, these trials are time-consuming and cost-intensive, because the regulatory requirements for a clinical investigation are extensive and complex. This article shows which phases a clinical investigation goes through and what needs to be paid particular attention to.
The new ISO 14155:2020 – standard and guide at the same time
An essential building block for the conduct of a clinical investigation is ISO 14155 “Clinical investigation of medical devices for human subjects – Good clinical practice”. The current third edition of ISO 14155-GCP came into force in July 2020 and replaces the last valid version from 2011 without a transition period.
While compliance with ISO 14155 has already ensured a high level of acceptance of clinical results internationally in the past, and the checklist of documents to be provided from Annex E is considered a very helpful verification document, the new version of the standard with further details and three additional annexes now provides a truly practical guide for conducting clinical investigations.
The current version strives for even further consensus with other international standards in order to continue to ensure the worldwide acceptance of ISO 14155. Thus, when ISO 14155 is observed, the requirements of the international guideline of ICH-GCP (Good Clinical Practice) are also fulfilled, which is why ISO 14155 may bear the genteel addition “GCP” in its title. The “Declaration of Helsinki”, which must also be observed in a clinical investigation, as well as internationally applicable data protection requirements are incorporated. Furthermore – and this is particularly advantageous – the requirements of the MDR for clinical investigations have been integrated.
However, national requirements must still be taken into account, especially for clinical investigations outside the EU. For example, different archiving periods for clinical data or special requirements for the recruitment of study participants may apply. The coding system for the mandatory reporting of adverse events (AE) to the authorities may also differ from country to country. In Germany, for example, the BfArM prefers the free IMDRF terminology, while many other countries use the fee-based MedDRA terminology for coding medical information.
In the current version of ISO 14155, the procedure and terminology were aligned with the international guideline ICH-GCP and a separate chapter with a summary of the GCP principles was dedicated to it (Chapter 4). The newly added Annex I should be mentioned here, which deals with the terms and contents of the different types of clinical investigations. These are clearly presented and explained, including post-market studies. The importance and content of the synopsis as a component of the clinical investigation plan (CIP) are emphasised.
While registration of a clinical investigation in a public database was still optional in the 2011 edition, it is now mandatory. This requirement also reflects that of the MDR (§ 44). European studies with medical devices and must be registered in the EUDAMED database and can also be entered in other databases such as the globally valid ClinicalTrials.gov or in national databases.
The consideration of the preceding clinical evaluation with the evaluation of already existing preclinical data clearly moves into focus. Here, ISO 14155:2020 takes into account the increased MDR requirement for clinical evidence.
Requirements for specific medical expertise in the planning of clinical investigations are defined in Chapter 6.
A new emphasis is placed on the clean statistical underpinning of the study objective and the final statistical calculation of the study results (Appendix A).
The significantly increased focus on the risk-based approach should be emphasised. In the previous version of the standard, risk assessment only referred to the trial product itself. In the current standard, risk management is extended to all phases of the clinical investigation, from planning to assessment of results, see Chapter 6.2 and Annex H. Special attention is given to the clinical risk of the trial conduct itself as well as to a risk-based approach to monitoring (Chapter 9.1).
A new addition is the introduction of clinical quality management (Chapter 9.1). This is the responsibility of the sponsor. Accordingly, procedural instructions for the phases of the clinical investigation must be provided and lived. It is advisable that they are part of the sponsor’s QMS. As before, the sponsor can outsource all study-related tasks, but he must at least document the outsourcing and carry out process monitoring. In support of this, Appendix J is now offered, which deals with clinical investigations by the sponsor or its representative.
Also newly added is Annex G, which deals with the tasks of ethics committees.
Clinical investigation according to MDR
Even if the essential standard is ISO 14155, the relevant chapters of the MDR should be consulted.
Article 62 of the MDR describes general requirements for clinical investigations to be used to demonstrate compliance.
These requirements are for identification and verification:
- that a product is designed, manufactured and packaged in such a way that, under normal conditions of use, it is fit for one or more […] specified purposes and achieves the intended performance stated by its manufacturer (intended purpose).
- of the clinical benefit stated by the manufacturer of a product (clinical added value).
- the clinical safety of the device and to determine any undesirable side effects of the device that may occur under normal conditions of use and to assess whether these pose acceptable risks compared to the benefits provided by the device (safety, benefit-risk assessment).
Article 73 describes the Electronic Clinical investigations System in more detail. It includes the following publicly accessible aspects:
- Generation of the unique identification numbers for clinical investigations, e.g. EudraCT or UTN number.
- Submission of any applications or notifications, including for permits, amendments and coordinated assessment procedures.
- Information on the part of the sponsor vis-à-vis the member states concerned within the framework of its duty to provide information pursuant to Article 77
- Reporting of serious adverse events and product defects and related updates
- Handling of non-accessible, personal data as well as confidential business data
Article 78 of the MDR describes the coordinated assessment procedure for clinical investigations, i.e. a clinical investigation in several EU Member States, with the lead usually corresponding to the location of the principal investigator. This means that only one application has to be submitted via the electronic system, which is sent to all member states concerned.
Phases of a clinical investigation
The activities for a clinical investigation can generally be divided into three phases: Planning, conducting and evaluating the trial. All three phases usually involve the sponsor, the monitor, the investigator and the ethics committee or the supervising authority.
Phase 1 – Study planning:
Planning includes the preparation of the study in compliance with the regulatory framework as well as obtaining approvals from the authorities and coordination between sponsor, monitor and investigator. For this purpose, it is important that the sponsor clearly formulates the objectives of the study and that the associated documentation is prepared and continuously managed and maintained. This task can be performed by a CRO (Clinical Research Organisation), which can then also act in a supporting or leading role in the two subsequent phases.
Phase 2 – Study implementation:
During implementation, most of the work is done by the investigators, who conduct the actual study with and on the patients and generate the required data. The monitor oversees the data and study sites during this phase according to the sponsor’s monitoring plan. The sponsor is responsible for ensuring that the monitoring plan is implemented and that the documentation is correctly updated and maintained. If changes or adverse events (AEs) occur during the course of the study, the official authorities must be involved. In serious cases (serious adverse events SAEs), fixed reporting deadlines to the official bodies apply and must be observed.
Phase 3 – Study evaluation:
After completion of the study, all records on the medical device obtained during the study must be checked for completeness and up-to-dateness and be stored. The applicable retention periods must be observed. Finally, a statistical evaluation is required and a study report must be written, which should also be taken up again in the areas of clinical evaluation and risk management within the framework of the conformity assessment procedures. Finally, the competent authorities must be informed of the completion of the study in accordance with the country-specific requirements. This status, as well as any change in status beforehand, must be published in the corresponding clinical investigation register.
Clinical investigations are not only necessary before conformity assessment, as so-called pre-market studies. There are also cases in which studies become necessary despite existing CE marking, for example if the intended purpose is expanded or there is insufficient data from follow-up.
You are not sure whether your data is sufficient for these scenarios? Then you are welcome to contact us. We will assess your data situation and work out a study concept with you.
Please note that all details and listings do not claim to be complete, are without guarantee and are for information purposes only.
