Clinical evaluations and clinical investigations are two of the most critical parts of a medical device’s journey to mass marketing. Despite this being the case, there are frequent, widespread misconceptions of what each means.
In this article, clinical evaluations, clinical investigations, and the processes, along with the requirements for each, will be discussed.
What is Clinical Evaluation?
When discussing clinical evaluation, we are not referring to the type where a patient is evaluated for medical reasons, though the two references do often get mixed up. Instead, we are referring to the clinical evaluation of a medical device. Clinical Evaluations are mandatory and were required starting with the early Active Implantable Medical Device Directive (90/385/EEC 20 JUN1990) and the Medical Device Directive (93/42/EEC 14 JUN1993). It was later incorporated into the first ISO 13485 quality management standard (see the current standard ISO 13485:2016 – Medical Device Quality Management System clause 7.3.7). Now it appears in the European Union (EU) Medical Device Regulation (MDR) 2017/745 May 2017.
Clinical evaluation is the term used to describe a process plan where all of the relevant data regarding a device is collected and then assessed. The review determines whether there’s enough evidence to show that the device conforms to the necessary regulatory requirements and when a clinical investigation might be needed. The EU MDR 2017/745 Article 2 (Definitions) defines clinical evaluation as a systematic and planned process to continuously generate, collect, analyze and assess the clinical data pertaining to a device to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer. In other words, the clinical evaluation is a methodologically sound, ongoing (living) planned procedure to collect, appraise, and analyze ‘clinical data’ relating to a medical device. The manufacturer must answer the question, “Is there sufficient clinical evidence to confirm compliance with the relevant requirements for safety and performance when using the device according to the Instructions For Use (IFU)?”
A document called a Clinical Evaluation Report is where the results of the process plan and analysis are recorded and documented.
How to obtain the clinical data?
There is more than one way to obtain the clinical data needed for the initial clinical evaluation. First, is the relevant scientific literature relating the design, intended purpose, safety, and performance. Here the manufacturer can either use the equivalence pathway or collect new clinical data on their device. If the equivalence route is chosen, the data must demonstrate compliance to or the spirit of the relevant regulatory requirements, e.g., Essential Requirements under the medical device directives or the General Safety and Performance Requirements (Annex I) under the newer medical device regulations. If equivalence is not demonstrated or established, other methods have to be used to collect new clinical data, e.g., surveys, clinical investigations, or if approved in other countries, large, “big data” hospital networks or registries. Some manufacturers may choose a combination of both equivalence and new clinical data for their initial submission.
The whole point of the clinical evaluation is to assess the clinical data to ensure that it conforms to the national requirements and standards. Once this data has been acquired, the clinical evaluation report can written and finalized. The clinical evaluation report is not just a paper exercise to meet requirements. It is an ongoing process of becoming compliant and then staying up-to-date on products being placed on the market.
It is mandated that the clinical evaluation and all of its documentation be updated continuously with any post-market surveillance information that becomes available. If for any reason, the post-market surveillance is found not to be necessary regarding the medical device follow up, there must be an acceptable justification and it must be documented. Current thinking, unlike in the past, among Notified Bodies and regulators is that those justifications for not performing surveillance would be rare. In regards to high-risk medical devices, the final report must include a clinical follow-up report.
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What is Clinical Investigation?
Not to be confused with clinical evaluations, clinical investigations are clinical trials (studies) in at least one human subject, which are performed to assess the performance and, most importantly, the safety of a specific medical device. Recently, an international standard, ISO 14155:2020, was updated. This standard addresses the good clinical practice that is expected for the design, conduct, recording, and reporting of clinical investigations carried out in human subjects to assess the clinical performance or effectiveness as well as the safety of medical devices. Another international standard that also has relevance to performing a clinical investigation is ISO 14971:2019. All medical devices have risks. This standard is intended to help manufacturers of medical devices to:
- Identify the hazards associated with medical devices
- Estimate and evaluate the associated risks
- Control those risks
- Monitor the effectiveness of those controls
As clinical investigations are usually performed on higher risk devices, ISO 14971:2019 highlights three principles that should guide the manufacturer to mitigate or alleviate risks along the approval (and post-approval) pathway. First, they should design medical devices that are inherently safe. Next, protective measures or controls in the actual medical and/or the manufacturing process should be identified and implemented. Finally, safety information, such as found on the product labeling or within the IFU, should be communicated to either:
- those using the device
- coming in contact with the device, or
- caregivers of those requiring the device.
These two international standards, along with the EU MDR, provide confidence that manufacturers are designing safe and effective medical products. Regulators and Notified Bodies will independently confirm this as well.
Clinical Investigation for Class III and Implantable Devices
Clinical investigations were first required in 1990 for all active implantable medical devices, virtually the highest risk medical devices at that time. That thinking has evolved, and authorities are taking a risk-based approach EU MDR 2017.745, Article 61(4). The current thinking is that for implantable devices and class III devices, clinical investigations shall be performed. There are some exceptions, three are described here although others exist:
- The device has been designed by modifications of a device already marketed by the same manufacturer,
- The modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body, and
- The clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements.
In these cases, the notified body shall check that the Post-Market Clinical Follow-up plan is appropriate and includes post-market studies to demonstrate or confirm the safety and performance of the device.
Decisions to perform a clinical investigation under the EU MDR can be complicated and complex, but distill down to an active interaction between data obtained during the risk management and clinical evaluation processes and whether that data allows conformity to Annex I, “General Safety and Performance Requirements” (GSPR). The figure below illustrates this interaction.
In general, a medical device requiring a clinical investigation is ready to enter the market once a successful clinical investigation has taken place. It’s the results from the clinical investigation that will be included within the clinical evaluation which will be used, in part, for product approval. The results (assuming satisfactory) show that the medical device complies with the regulatory requirements of performance and safety. Thus, clinical investigations hold considerable weight.
What is The Clinical Investigation plan?
There are many plans created to bring a medical device to the market. There is even a plan for clinical investigations. The clinical investigation plan involves, among other things:
- Statistical power
- Patient population
- Clear and measurable objectives
- Criteria for stopping the trial
- Ethical consideration and informed consent
‘What is The Manufacturer’s Responsibility?
In a situation where the sponsor of a clinical investigation is outside the EU or is not Union-established, it’s the manufacturer’s or sponsor’s responsibility to make sure that a legal or natural person is Union-established and acting as their legal representative.
In any regard, this said sponsor/manufacturer is responsible for taking care of a large part of this operation. They are responsible for:
- Insurance
- Design of the study
- Principal investigator designation
- Applications with the ethical committee
- Keeping documentation available and up-to-date. Also, incorporating the clinical investigation reports (data) into the technical documentation that’s legally mandated to be kept available by the manufacturer
- Incident reporting
What is The Role of The Competent Authority?
Once clinical investigation registration has taken place, competent authorities and saddled with the responsibility of providing the authorization for a clinical investigation to begin. According to the Medical Device Regulation (MDR), approval could take less than a month. The commission may engage in delegated acts to fine-tune the procedure. Each clinical investigation receives one single registration number or SRN for short. This is to maintain a more efficient and reliable exchange of data between member-states, the Commission, the public, and others.
Related: Mythical Medical and The Unsolvable Equation: Benefit-to-risk analyses
What is The Role of The Notified Body?
The Notified Body is a conformity assessment organization. They review the clinical evaluation and, if required, the clinical investigation. These documents, and others, are part of the technical documentation review that occurs before granting a CE certificate. There are many processes, reports, and personnel that undergo inspection or scrutiny prior to approval which includes, in part:
- A benefit-to-risk analysis
- An inspection or discussion of how the device fits into current clinical practice by evaluating state-of-the-art information
- An assessment of the clinical safety and performance
- Auditing the manufacturer and its personnel
- Evaluation of post-marketing or post-approval processes and plans
Conclusion
Due to the massively impactful nature of medical devices, it is of the utmost ethical and business importance to carefully consider which aspects of safety and performance can be supported by not only pre-clinical evidence, but also clinical evidence from evaluation in humans. It is only through a thorough clinical evaluation of all the available data that regulators and Notified Bodies approve medical devices. There are other requirements, such as post-market surveillance, once a device is on the market. That will be the topic of a future article.
The EU MDR is basically a fascinating and highly intriguing story about redemption within the medical device sector or business. It’s about having a final chance to make a change before it’s too late. If done correctly, clinical evaluations, along with clinical investigations, are steps being taken now to ensure a bright, innovative future for medical device development that meets unmet medical needs.
Get expert guidance through the medical device approval process with Global Strategic Solutions. Learn more here!