A new opinion (CECP-2022-000222) provided under the Clinical Evaluation Consultation Procedure (CECP) was recently published by the European Commission. Here are some things worth noting, a summary to digest and lessons learnt both for manufacturers and notified bodies alike.
The subject device was a programmable implantable stimulation device intended for adjunctive neurostimulation in reducing the burden of epilepsy in adults over 18 years of age, with focal onset seizures that are refractory to two or more antiepileptic medications. This was a Class III device consisting of an implantable pulse generator and an electrode array and lead body.
The justification for seeking an opinion from the expert panel was sound. The device was novel (including technical stimulation parameters), the procedure was novel (even though the device remained in the extracranial space and therefore carried minimal risk) and it intended to reduce the burden of a health condition (epilepsy) associated with serious consequences and even sudden death.
It was clear from the assessment that there were uncertainties about the patient selection criteria in the two studies provided to support sufficiency of clinical evidence and lack of granularity in the causal adverse events. The expert panel commented on the small number of patients recruited, the extent of the follow-up of the patients, and the lack of clinical details in reported seizures following the use of the device. They also commented on many technical details missing that had to do with stimulation and what the post market investigations set out to do.
I full heartedly agree with the clinicians concerns in this case and the comments made on the device itself shows that they had the required expertise in the subject matter (neurostimulation / neuromodulation) and clinical condition (epilepsy).
Although we were not provided with the device details (all relevant information redacted) I wonder how much clinician input the manufacturers had during the clinical development of this device.
On the assessment of the adequacy of the manufacturer’s CER
The expert panel commented on the lack of assessment of the patient burden that results from repeated surgical events (surgical replacement of the IPG). This is something to keep in mind when making an overall assessment of the benefit-risk determination. Notably, the panel never required a mathematical/ statistical determination as the patient burden is a subjective quality and not quantity unless set to be measured in a quantitative way. So, please consider the patient burden and clinical pathway when the use of a device requires repeated assessments or repeated procedures, whether invasive or not.
This was tied up to the assessment of lifetime of the device. If the device has several components with some remaining permanently implanted, but some having to be removed and replaced, then what is the overall lifetime of the device? The lifetime of the patient using it (or at least when it is elected to be explanted), the lifetime of the materials themselves, or the lifetime of the battery that needs replacing every 40 weeks. And if it is the material themselves which part of the material? The panel suggests more essential questions that should have been asked; for example, what the critical lead component and its lifetime is. This debate is linked to the appropriate follow-up and the manufacturer's PMCF plan. To cut a long story short, the panel proposes a minimum acceptable follow-up period of five years for these patients. That is a long follow-up!
The expert panel commented on the depth of the stimulation. Without becoming too esoteric to reach a certain area in the brain the stimulation must cross many anatomical structures including white and grey matter (brain tissue). This would limit the scope of use in focal and cortical (or superficial) areas. The manufacturer did not provide clarity on this aspect bringing overall doubts to the effectiveness of the delivered stimulation. The manufacturer did not provide salient details on seizures observed. This is then linked with the adverse events observed in the two studies, and this in turn brings doubt to the patient selection and inclusion criteria of the studies.
One can see that a weak link in the clinical development or regulatory submission can wreak havoc to the outcome of that submission and as such this opinion provides an excellent case study for manufacturers and notified bodies alike.
Sufficiency of the clinical evidence provided by the manufacturer
The panel suggests that patients who have experienced "worsening of seizure situation" should be monitored for at least five years for assessment of the duration and frequency of these adverse events. This period may appear quite lengthy for a new manufacturer and even feel unjustified, but it is justifiable based on the lifetime claimed as well as the observed failures. The clinical impact of such failures on individuals must be considered. The panel also introduces the concept of the burden of treatment extending beyond the possible long-term improvement of epileptic seizures and should include assessment of the patient’s quality of life. This highlights that patient outcomes may include a complex instrument or a multidimensional or 360 degrees approach.
Finally, the panel proposes a sham-controlled clinical trial as the ideal clinical strategy. I must agree that this device presents the perfect opportunity for such a trial and the manufacturers should have considered this.
The adequacy of the manufacturer's benefit-risk determination
The expert panel alludes that with the information provided the benefit-risk of the device cannot be adequately evaluated. More information such as the premorbid characteristics of the group that presented with worsening of seizures should be sought. Also, the long-term outcomes of that sub cohort from the two trials are needed. It is clear that what is requested here is more granularity on the patients who did not do well or presented with adverse events. This is important as otherwise it is unclear whether the “failures” were due to the device or due to the natural progression of the condition.
The consistency of the manufacturer's clinical evidence with the intended purpose, including medical indication(s)
Although the clinical indications could have been considered specific enough the expert panel suggests more improvements, with clarification of the phenotype of the seizures. This suggestion extends to the adverse events reported as “worsening of seizures”, such reporting being generic and meaningless in a complex condition. It appears that basic information such as the number of patients suffering from the adverse event is missing!
Consistency of the manufacturer's clinical evidence with the PMCF plan
This last section summarises what was said before. All in all, we do not have access to the technical file, or the clinical reports submitted and evaluated but this case study highlights both the pitfalls of the manufacturer’s submissions and areas where the notified bodies should pay particular attention.
For novel devices, a manufacturer needs to ensure that they:
- Integrate their clinical development plan with the patient pathway.
- Leverage the device's unique features to obtain clinical evidence that will not be disputed later on.
- Involve an experienced specialist clinical team that will advise in writing pre-market clinical reports in a way that imparts the essential details to a reviewer.
- Consider and involve the patients in offering their perspective of their outcomes; this alone may be a deciding factor for your submission.
- Understand and pay attention to what happens to patients with adverse events and the factors that contributed to those.
About the Expert Panel Process
Expert Panels for the EU MDR and IVDR conformity assessment process have been established to provide scientific, technical and clinical assistance to the Commission, the Medical Device Coordination Group (MDCG), Member States, notified bodies and manufacturers in relation to the implementation of Regulation (EU) 2017/745 and in order to provide views in accordance with Article 48(6) of Regulation (EU) 2017/746 of the European Parliament and of the Council. In particular, notified bodies are required to carry out consultations of expert panels on clinical evaluations of certain high-risk medical devices in the context of Regulation (EU) 2017/745 and on performance evaluations of certain high-risk in vitro diagnostic medical devices in the context of Regulation (EU) 2017/746. The expert panel members will base their opinion on documents received from notified bodies and manufacturers, besides their own expert knowledge and experience.
The role of the Expert Panels differs for medical devices and IVDs as described below. Put simply, for medical devices, the Expert Panel review the output of the notified body's review of the Manufacturer's Clinical Evaluation Report. Whereas for IVDs, the Expert Panel are to review the Manufacturer's Performance Evaluation Report prior to the notified body's review. So far, the number of IVD reviews outweigh those for medical devices. In part this is probably due to the difference in the timing of the review within the overall conformity assessment process, and the different criteria used for seeking the opinion of the Expert Panels.
IVDs under IVDR (EU) 2017/746
According to Article 48(6) of IVDR 2017/746, views produced by the expert panel on IVDs cover Performance Evaluation Consultation Procedures (PECP) for certain high-risk IVDs, where no common specifications are available and when it is the first certification of that type of device.
Medical Devices under MDR (EU) 2017/745
According to Article 54 of MDR 2017/745, certain high-risk medical devices, namely class III implantable devices and class IIb actives devices which are intended to administer and/or remove a medicinal product, will require the involvement of the expert panels. For these devices, a Clinical Evaluation Consultation Procedure (CECP) is needed, unless
- there is renewal of certificate issued under the Regulation
- there are relevant common specifications are available
- there is a modification of a device already on the market, with certain conditions
High-risk devices that qualify for the procedure shall be assessed by the Screening panel, which will decide if an opinion by a thematic expert panel is needed. The following criteria shall be considered
- the novelty of the device or of the clinical procedure involved have possible major clinical or health impacts (See below)
- valid health concerns lead to a significant adverse change in the benefit/risk profile of a relevant category or group of devices
- significant increase in the rate of serious incidents for a relevant category or group of devices
As laid out in the Commission's guidance, the novelty of the device is assessed when considering both the device and the procedure:
A) Procedure-related dimensions
Novel clinical procedure or surgical procedure related to, inter alia, a novelty or a change in:
- the mode of use or treatment option;
- device-patient interface (including maintenance and adjustment);
- interaction and control (existing technologies with a new interface or usage context, new way of device application);
- deployment methods.
B) Device-related dimensions
- Novel medical purpose, including a new intended purpose of the device with regard to the clinical setting, severity and stage of disease, site in the body, target population (age, anatomy, physiology, sex) with a particular attention to devices used in paediatrics.
- Novel design, including new/modified specifications and properties such as physicochemical properties (e.g. mechanical properties, viscosity, surface characteristics, wavelength, type and intensity of energy), shape, size as well as software algorithms where these constitute an integral part of the functioning of the device;
- Novel mechanism of action. In case of a combination product, new pharmacological, immunological, metabolic properties of the medicinal substance need to be taken into account;
- Novel materials, including notably new/modified materials or substances in contact with human tissues or body fluids, changes in duration of contact, or in the release characteristics of substances, including degradation products and leachables.
- Novel site of application for an established material, leading to new/modified contact with and/or mechanical loading of the same or different tissues;
- Novel components including parts, pieces or software that constitute an integral part required for the functioning of the device;
- Novel manufacturing process, including for example additive manufacturing, bio-printing, sterilisation processes, in relation to the state of the art.
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- Expert Panel Home Page: https://health.ec.europa.eu/medical-devices-expert-panels/work-expert-panels_en
- Medical Devices CECP Page: https://health.ec.europa.eu/medical-devices-expert-panels/experts/list-opinions-provided-under-cecp_en
- IVDs PECP page: https://health.ec.europa.eu/medical-devices-expert-panels/experts/list-views-provided-and-ongoing-consultations-under-pecp_en
- Commission Implementing Decision (EU) 2019/1396 of 10 September 2019 laying down the rules for the application of Regulation (EU) 2017/745 of the European Parliament and of the Council as regards the designation of expert panels in the field of medical devices: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2019.234.01.0023.01.ENG
- Commission guidance for the medical devices expert panels on the consistent interpretation of the decision criteria in the clinical evaluation consultation procedure: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv%3AOJ.C_.2020.259.01.0002.01.ENG&toc=OJ%3AC%3A2020%3A259%3AFULL