Premarket Evaluation of High Risk Medical Devices in the EU

Recently the EU has come under heavy scrutiny for failing to produce adequate premarket clinical evidence that demonstrates efficacy and safety of innovative, higher – risk medical devices.

Medtech experts from around Europe have collaborated to produce a report in which they argue that it is time to introduce randomised clinical trials (RCTs) in the EU for high risk medical devices (these are defined as innovative Class III medical devices and innovative implantable medical devices).The authors also propose centralising the evaluation process of these products.

The authors are aware that the timing of this report’s publication, allows it to be taken into account by those involved in the ongoing rework of the EU Medical Device Directives and that the proposal in the document may dictate the future regulatory outlook for high risk-medical devices.

In the report, the authors note that in the experimental phase after early market introduction, outside the context of trial, there are no laws pacifically targeting the topic of patients rights and states that the device industry should be made aware of the growing importance of generating clinical evidence and the specific expertise this requires.

They authors continued to criticise Europe for allowing earlier market introduction compared with the US, “at a time when the exploratory clinical development phase is not yet completed and the confirmatory phase has not yet been initiated.”

In contrast, in the US, innovative high-risk devices (Class III) typically undergo a thorough pre-market approval (PMA) process and devices are put through a far more demanding clinical trial scrutiny before being allowed on the market. That said, the US system is currently the subject of an internal review by the FDA and the Institute of Medicine (IOM) assessing whether the FDA 510(k) clearance process protects patients as well as it can without limiting improvements in medical devices. This review of the medical devices regulatory systems in the US might widen the gap, the authors suggested.

A critical factor, they note, is the European system is based on the demonstration of safety and performance, whereas the US system requires the pre-market demonstration of safety and efficacy/effectiveness.

“This leads to entirely different clinical trials,” the report says. For the demonstration of device performance, an RCT is neither necessary nor appropriate, whereas it is an essential for the demonstration of clinical safety and efficacy in a controlled way. The level of study evidence required in Europe is much less specified compared with the FDA requirements for a PMA application, they add

They also point out that only one in five of the 8,500 medical devices companies in Europe (probably fewer if companies belonging to a US group are excluded) has approached the US market.

Unfortunately, negative trials are rarely made public. Also, the report continues, final negative decisions on PMA dossiers are not made public on the FDA website. Therefore, it cannot be excluded that devices continue to be marketed in Europe while having failed in the demonstration of efficacy in the RCT required in the context of PNA in the US, as illustrated by a negative FDA panel vote for an endobronchial valve system in 2008.

The authors in this report do not believe the revision, 2007/47/EC, is enough to improve regulations.

“Despite the increase in clinical  trial activity induced by the EU Directive 2007/47/EC, the remaining variation in the stringency of clinical review both at the level of notified bodies and the competent authority level is not optimal to guarantee patient safety in a uniform way for EU citizens,” the authors state. They are also critical for weak wording of the directives and guidance documents when it come to clinical investigation requirements.

They add the argument that conducting clinical trials is too high a hurdle for small companies lacking clinical expertise and financial support is insufficient when confronted with patients’ safety and expectations for effective treatments.

The authors state that for innovative high-risk devices, the future of EU Medical Device Directives should move away from requiring “device performance” data only to also require pre-market data that demonstrate “clinical efficacy or effectiveness.”

Authors are even sceptical about the risk-benefit argument. “The current requirement in the regulation to evaluate ratio already seems to be in consideration with the current absence of controlled assessment of clinical benefit (efficacy) and clinical safety,” they say.

The authors would like to see the following points included in the recast:

• The new pre-market procedure should result in an approved indication for the device and a publicly available product documentation including the full result of the trials. This transparency is required to allow physicians to practice evidence-based medicine, patients to an informed decision and HTA agencies to produce the correct assessment;
• Guidance documents for pre-market clinical trials by type of high-risk device need to be developed. HTA agencies should also be involved in this activity; and
• Payer in Europe should consider, as is the case in the US, co-financing of innovative high-risk devices used in pre-market clinical trials.

The authors also offer transient solutions at member state level. They suggest the while awaiting a reworked Medical Device Directive, patient risk should be minimised at the member state level by improving transparency with regard to the available clinical data and by limiting the market introduction of novel high-risk devices with minimal clinical data to centres with necessary expertise.

Preferably, this should be done under an appropriate protocol (RCT if possible), they say, and requires the commitment of the competent authorities, the marketing company, the physicians and the hospitals.

They also propose that the ethical issues associated with the early market introduction of innovative high-risk devices should be studied further by the commissions and organisations that provide ethical guidance to the physicians and hospitals.

The European Commission, as it considers this document in the context of its work on the recast of the medical device directives, will probably wish that it had the opportunity to consider the text at more length. Will the arguments be convincing enough to result in the centralized pre-market evaluation of high-risk devices? Given that there has already been considerable debate in this area, this report could well be the final weight needed to tip the scale in the balance of such an outcome.