A Few Items of Note about Device Regulation in the European Union
Life keeps moving along in Europe in spite of the snow and closed airports. Here are three important medical device regulatory issues you'll want to address in the new year.
 No phase in period for ISO 14155 "Clinical investigation of medical devices in human subjects—good clinical practices"
If the stars align, Jupiter stays in the heavens, and my cat stops catching birds, ISO 14155 may be published in the first quarter of 2011. But don't wait around for the big event. Implementation will be immediate and there is no phase in period!
The convener recommends all sponsors start updating their clinical investigation procedures now. However, updating your procedures is a little bit difficult because the final draft of the standard is not available for purchase on the www.iso.org website. ISO.org lists the standard as being under publication (stage 60.00) but provides no means to add it to your shopping cart.
The same is true for the Association for the Advancement of Medical Instrumentation at www.aami.org, which has inexplicably truncated the title to "Clinical investigation of medical devices for human subjects" and left off the declaration of "good clinical practices". AAMI claims identical equivalency to ISO 14155/Ed.3 (edition 3?), and states the draft is not available 'outside of committee'.
CDG can update your clinical procedures to ISO/FDIS 14155
Clinical Device Group is a corporate member of AAMI, a member of ISO TC 194, and has access to the final draft versions of ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practices". While we can't provide you with a copy of the unreleased document, we can review your existing procedures and make recommendations to bring them into conformance. Our style is to work collaboratively with point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5706 or email@example.com.
If you don't work for one of the thirty or so firms who pay corporate dues to AAMI, are members of TC 194, and have access to the final draft standard, you will have to figure out another game plan. You might consider hiring a CRO with access to the final draft to update your procedures for you.
2] MEDDEV 2.7/3 Serious adverse event reporting under the amended Directives
The European Commission published MEDDEV 2.7/3 "Serious Adverse Event Reporting under 90/385/EEC and 93/42/EEC" in December 2010. Although the guidance is voluntary, you are strongly urged to follow it. The guidance uses the ISO/FDIS 14155 definitions of adverse events and effects, and recommends that all serious adverse events (SAEs), device deficiencies that might lead to SAEs, and any new findings regarding existing SAEs, be reported to every National Competent Authority (NCA) in which the investigation is being conducted.
Two categories of SAEs
The guidance takes the odd approach of dividing SAEs into two categories: a) those that require prompt remedial action, and b) those that do not.
SAEs that require prompt remedial action to mitigate an imminent risk of death, serious injury, or serious illness should be reported immediately but no more than 2 (two) calendar days to the NCAs using the Reporting Form provided in the guidance Appendix. SAEs that do not require prompt remedial action should be reported no more than 7 (seven) calendar days. The MEDDEV 2.7/3 guidance and an Excel spreadsheet of the Reporting Form are provided on CDG's website.
A serious adverse event that occurs at a US site should be reported to every European NCA in which the investigation is also being conducted. CDG recommends that investigations in the US and EU be administered and managed as separate studies because: 1) it is difficult to meet the reporting requirements of two different regulatory entities in the same investigation, and 2) it is difficult to justify pooling data given the differences in medical practice. Patients in countries with socialized medicine tend to be farther along in the disease process before receiving medical care than patients from countries with for-profit medical care.
The guidance makes no mention of reporting serious adverse events to Ethical Committees. It doesn't discuss sharing of data between National Competent Authorities. It doesn't address setting up a European database of serious adverse events. And it doesn't address making the SAE reports available to the public. As much as we have complained about a lack of transparency and organization at FDA in recent whitepapers, Europe has a long way to go before it catches up.
 MEDDEV 2.7/4 Clinical investigations: A guide for manufacturers and Notified Bodies
The European Commission also published MEDDEV 2.7/4 "Guidelines on Clinical Investigation: A Guide for Manufacturers and Notified Bodies" in December 2010. Again the guideline is not legally binding, but it reflects the thinking of the European Commission and what manufacturers can reasonably expect from their Notified Bodies.
The guideline tries to clarify the European distinctions between clinical data, clinical evaluation [reports], and clinical evidence. The logic is not obvious, so I've designed a graphic to help sort it out.
Clinical data are numbers, values, measurements, and the like, taken from the literature, sponsored clinical investigations, and other reports such as complaint history files and risk management systems.
Clinical data are assessed, analyzed, and written up in clinical evaluation reports.
Clinical evidence is both the original clinical data (numbers and values) and the clinical evaluation report.
If the clinical evidence is sufficient to establish the safety and performance of a device for its intended use, then the manufacturer may declare conformity to the essential requirements and proceed to market the device. If the clinical evidence is insufficient to establish safety and performance, the manufacturer may withdraw the claim or proceed to a new clinical trial in an effort to generate data to substantiate the claim.
Differences between US and EU
The fundamentals of good clinical practices haven't changed and are not much different between the US and EU. The new ISO 14155 standard was written to harmonize as close as possible with the existing ICH-GCPs; so if you are an experienced clinical research professional there will be no surprises. But there are some differences in implementation.
The first difference is the heavy level of adverse event reporting in Europe. Even for European Class I and IIa devices, all adverse events are reportable to sponsors, Ethics Committees, and NCAs; and all serious adverse events—device related or not—are reportable to NCAs within 2-7 days. In the States, for significant risk devices, only adverse device effects are reportable to sponsors, IRBs, and FDA (unless FDA requires more for a particular investigation); and for non-significant risk devices, adverse device effects are only reportable to sponsors and IRBs.
The second difference will be the increased emphasis on risk management in the clinical investigation process and figuring out how to apply ISO 14971 "Application of risk management to medical devices" to clinical investigations.
If you have comments, disagreements, or additional information, please post them below. I look forward to hearing from you.
Happy New Year,
Nancy J Stark, PhD
President, Clinical Device Group Inc