Writing the clinical evaluation plan
The clinical evaluation plan is the scoping document against which a device's clinical evaluation is run, and the EU Medical Device Regulation sets out what it must contain. Writing one draws on the regulation's list of contents, the scoping topics of the older guidance, the clinical development plan within it, the people and documents that supply its content, its readers beyond the manufacturer, and keeping it current.
Purpose and timing
The plan is the starting point of a device's clinical evaluation. Its purpose is to define the scope of the clinical evaluation and to lay out the systematic process by which it is conducted, so that the manufacturer has in place the plans needed to evaluate the device's performance and safety, in a process that eventually results in a clinical evaluation report. The plan should ideally be prepared early in a device's development, to identify the clinical data that need to be generated for market access, and it may also be used after market entry to keep assessing whether new clinical evidence is needed.
Required contents and guidance
The regulation requires a well-defined plan showing that the manufacturer has thorough procedures in place to confirm compliance with the relevant general safety and performance requirements of its Annex I. To plan, continuously conduct and document a clinical evaluation, manufacturers must establish and update a clinical evaluation plan, and Annex XIV Part A sets out point by point what it must include at least:
- an identification of the general safety and performance requirements that need support from relevant clinical data
- a specification of the intended purpose of the device
- a clear specification of the intended target groups, with clear indications and contraindications
- a detailed description of the intended clinical benefits to patients, with relevant and specified clinical outcome parameters
- a specification of the methods to be used to examine the qualitative and quantitative aspects of clinical safety, with clear reference to the determination of residual risks and side-effects
- an indicative list and specification of the parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the device's intended purpose or purposes
- an indication of how benefit-risk issues relating to specific components, such as pharmaceutical substances or non-viable animal or human tissues, are to be addressed
- a clinical development plan
Guidance issued under the Medical Device Directives that preceded the regulation still bears on the plan. Chapter 7 of MEDDEV 2.7/1 revision 4 defines the topics to be considered during the scoping stage of a clinical evaluation, and a well-compiled plan should carry elements from both the regulation and that guidance.
As of 2020, the Medical Device Coordination Group (MDCG), through which the European Commission provides a range of guidance documents to help stakeholders implement the medical device regulations, had issued none on preparing a clinical evaluation plan, and the topic was not among its planned guidance documents.
The clinical development plan
The regulation names the clinical development plan only twice, both times in Annex XIV. The annex first lists it among the contents of the clinical evaluation plan, as a plan indicating progression from exploratory investigations, such as first-in-man, feasibility and pilot studies, to confirmatory ones, such as pivotal clinical investigations, and a post-market clinical follow-up as referred to in Part B of the annex, with an indication of milestones and a description of potential acceptance criteria. Its second mention requires properly designed clinical investigations, run in accordance with that plan, to generate any new or additional clinical data needed to address outstanding issues. The development plan has no official definition, but it can be described simply as an overview of all the clinical investigations already performed, ongoing or planned for the near future, presented within the clinical evaluation plan.
The development plan is the subset of the clinical evaluation plan concerned with the device's clinical investigations, while the clinical evaluation plan as a whole sets out the clinical strategy the manufacturer is to follow to justify the device's safety and performance against the general safety and performance requirements. It covers investigations already conducted, preferably with a full investigation report available; those under way, with a full protocol available; and those planned, which could include pilot, pivotal or post-market follow-up studies and for which a synopsis should preferably be included. It may be written as paragraphs or presented as a table. Annex I of ISO 14155:2020 explains the differences between pilot, pivotal and post-market investigations in detail and is an excellent reference for it.
The development plan summarises the clinical investigations planned, ongoing or already performed, based on the device's risk class and CE-mark status. Adding it to the clinical evaluation plan helps reinforce and demonstrate the regulatory and clinical strategy, with standards such as ISO 14155:2020 and the MDCG guidance documents as supporting references for appropriate methods and wording. Through a well-presented development plan, a manufacturer may demonstrate, early in the clinical evaluation, its safety and performance claims and its strategy for gathering the clinical evidence to justify them. So although the regulation mentions the development plan only sparsely, it can enhance the quality of a manufacturer's technical and regulatory documentation. The medical writer's role in drafting it is particularly important, because the writer foresees the whole of the clinical evaluation from the early planning stage and can offer early support to the regulatory, marketing, research and development, and clinical departments to harmonise their language and work towards regulatory approval of the device. This bird's-eye view of a complex clinical evaluation is a strength of the medical writer, which manufacturers should use to ensure high-quality deliverables.
The questions to ask in drafting a development plan may include these:
- Given the literature review and the device's CE-mark status, what kind of clinical investigation is in view: pilot, pivotal or post-market follow-up?
- Has a statistically sound non-randomised investigation been considered instead of a randomised one? Randomised studies are not always essential for the regulatory approval of a device, depending on the case and on the type and class of device, but the study should comply with ISO 14155:2020 whatever its design.
- Are the inclusion and exclusion criteria of the investigations outlined?
- What endpoints and acceptance criteria did earlier investigations use, and are they clearly presented in the development plan? Based on their results, is something new to be tested or more robust safety information to be gathered? If so, the design of the upcoming investigation may include these new parameters as primary or secondary endpoints.
- Does the design fit the regulatory strategy and the business plan for market access?
- Might a high-quality publication come of it?
- Are off-label investigations to extend the device's indications planned? If so, they may also be included in the development plan.
Two MDCG documents bear on the development plan. The clinical evaluation assessment report template, MDCG 2020-13, tells the notified body to ensure that the development plan is outlined as Part B of Annex XIV sets out, but also says that a detailed description of it is not required for the template unless there are specific concerns. That may be read as meaning that a notified body need not scrutinise its detail at that stage unless something in the clinical development strategy is inherently questionable, and on that reading one may assume that a well-presented development plan within the evaluation plan is enough for the notified body's review. The same template's section K covers the voluntary consultation of an expert panel on the clinical development strategy under Article 61(2): whether the manufacturer gave the panel's views due consideration and included this in the clinical evaluation report, and whether any divergence between the manufacturer's clinical development strategy and the panel's views is justified and acceptable.
The MDCG guidance on clinical evaluation of medical device software, published in March 2020, lists developing the claims in the clinical development plan or in future releases among the uses of real-world performance data. That guidance is written for software, but it shows how real-world data may be used to develop the claims in the development plan, which matters because some manufacturers seldom think their safety and performance claims through at the clinical evaluation stage. Using the data gathered from clinical investigations and from post-market surveillance, a manufacturer may revisit those claims and take them into the development plan and the design of upcoming clinical investigations.
Contributors and input documents
Writing the plan is a team effort, because its information comes from many sources. Besides the medical writer, the people involved come mainly from clinical and medical affairs, regulatory affairs, the vigilance or post-market surveillance team (such as device safety specialists), research and development (such as product development or maintenance engineers) and marketing (such as product managers), along with clinical experts. The input documents the writer needs include parts of the design history file, the instructions for use and other accompanying documents such as surgical techniques or product brochures, verification and validation plans, the post-market surveillance and post-market clinical follow-up plans, clinical investigation protocols where investigations are needed, and the risk management plan.
Readers beyond the manufacturer
The plan matters to several parties across the product life cycle, among them the manufacturer, the notified body and its experts, the European competent authorities, and regulators generally, such as delegates of the European Commission carrying out a joint audit of a notified body. Outside Europe, submissions to health authorities that rely on the CE-mark technical documentation may also use it, as on the Australian regulatory submission pathway or in some countries in Latin America.
Updating the plan
The plan is a living document that has to be updated proactively and regularly. Neither the regulation nor the MEDDEV guidance says how often, but the plan should be reviewed whenever the clinical evaluation report is updated, to decide whether it needs changing.