CDG Whitepapers

European Medical Device Update

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.

[1] 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 cdginc@clinicaldevice.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.

Observations
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.

[3] 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.

Distinctions
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.

Got feedback?
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
cdginc@clinicaldevice.com

 

 

CDRH's 510k Working Group Preliminary Report: Finding 5

A GLIMPSE AT THE FUTURE?
A Cycle of 510(k) Whitepapers by Nancy J Stark and Kathleen Johnson

In August 2010, CDRH's 510(k) Working Group published a preliminary report consisting of more than 60 recommendations grouped under seven findings aimed at improving the Center's effectiveness in implementing its missions. Will the recommendations work? Do they comprise a forward-thinking strategic plan for the device industry? Herein you'll find CDG's summation of Finding 3 and part of Finding 4, along with our opinions of their worth.

Finding 5: CDRH's knowledge management infrastructure is limited

Neither Center staff nor 510(k) submitters have access to meaningful information
The only comprehensive electronic source of non-public information on prior 510(k) reviews available to Center staff is a database of archived image files. The database is searchable only by 510(k) number. To find information within each file, staff must conduct a labor-intensive, file-by-file text search. Without looking through each file individually, it is impossible to determine what predicate(s) the reviewer used as the basis for a substantial equivalence determination, and what the rationale for the decision was. Moreover, archived files contain varied levels of detail. Older 510(k) submissions and review memoranda are inconsistent in format and content, and many of them are handwritten.

[1] Enhanced 510k database needed
The Working Group recommends that both internal and public information systems be enhanced.

CDG agrees and further suggests the databases be made available through PubMed, Embase, or even Google where the ability to limit date ranges, use 'not' operators, turn on keyword explosion, use fuzzy logic, and use sophisticated text-search tools are available. Furthermore, the database in its entirety should be downloadable to Excel. The Summaries of Safety and Effectiveness or 510(k)s themselves should be keyworded by K number, product code, predicates, generic and brand names to allow for 'family trees' or 510k pedigrees to be constructed. The information should be available all the way back to 1976, and not stop at 2002.

CDG can write your 510(k)
CDG's extensive Network Staff has expertise in writing 510(k)s in a wide variety of therapeutic, management, or diagnostic areas. My co-author, Kathleen Johnson is a regulatory consultant with more than 10 years experience in medical devices. CDG has capabilities in regulatory submissions, clinical research, toxicology, biostatistics, information research, medical writing, design control—we focus exclusively on medical device pre-approval issues.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

[2] Product Codes, also known as classification numbers
Product codes are the underpinning for CDRH’s information management systems. They are the primary tool for organizing medical device information in CDRH’s databases, and staff across the Center rely on product codes in their day-to-day work. Product codes are used for tracking and analysis of medical device data across a device’s total product life cycle, including information from premarket submissions, adverse event reports, device recalls, inspections, and compliance actions. Review staff and 510(k) submitters use product code searches to identify and obtain information about potential predicate devices. Product codes were intended to provide more granular distinctions than the general descriptive language provided in the classification regulations. However, inconsistencies in the way product codes are assigned make it difficult to access meaningful device information.

The origin of "product codes" is so old even the Working Group could not give it an accurate reference; a day of research revealed the term "classification number" on FDA Form 2892, which was introduced in 1977 in 21 CFR 807.26, somehow transformed itself into the term "product code" (for a three letter, non-numeric code) at some point in time.

Working Group Recommendations
The Working Group recommends that the agency develop procedures for assigning product codes consistently and that special attention be given to IVD multiplex devices.

CDG agrees and suggests the search engine for product codes be improved. At this time, in order to find a predicate device you can: 1) search keywords in the classification database (simple search) to get a list of product codes and regulation numbers that match your keywords, 2) then search on the product code in the 510(k) database to find possible predicates for your new device. But this method is laborious, time-consuming, and the list that results may not contain good matches for your device. Furthermore, if your device is made of multiple components you will have to do a separate search for each component. And the list does not go back to 1976, so a comprehensive search is not possible. We also suggest that the device listing Form FDA 2892 ask for a product code rather than a classification number to dispel confusion, and that a history of the relationship between the two terms be clarified.

[3] 510(k) Databases
The 510(k) database is not easily searchable for either reviewers or submitters. Lacking a reliable source of accurate information, 510(k) submitters may be forced to look at how the predicate is advertised, which does not necessarily reflect the intended use for which it was cleared. Once cleared, device 510(k) are not accompanied by a revewer-prepared Decision Summary or a reviewer-prepared Summary Basis of Approval, as are IVD 510(k)s or pharmaceuticals. These Summaries are written by the FDA reviewer and capture the thought process and rationale for clearance.

 The data are from page 39 of the Working Group Preliminary Report

 
Working Group Recommendations
The Working Group recommends that CDRH develop a publicly available, easily searchable database that includes, for each cleared device, a verified 510(k) summary, photographs and schematics of the device (to the extent that they do not contain proprietary information), and information showing how cleared 510(k)s relate to each other and identifying the premarket submission that provided the original data or validation for a particular product type.

CDG believes that if a decently searchable 510(k) database were made available to submitters, the quality of submissions and appropriateness of predicates would improve automatically and the time to clearance would decrease. The database should go as far back as 1976 to facilate comprehensive searches. No further changes or requirements should be made until a functional seach engine is developed.

CDG further recommends that a reviewer-prepared Decision Summary be prepared for every cleared 510(k) as an enhancement to the 510(k) Quality Review Program (I96-1). It should be made available to the public, along with the company-prepared 510(k) Statement or Summary. This would enhance quality in 510(k) submissions and consistency in 510(k) clearances.

[4] Final Device Labeling
One frustration for FDA is that final device labeling and updates to labeling are not routinely reviewed; hence labeling may be inconsistent with, or over-interpret, cleared indications.

Working Group Recommendatons
The Working Group recommended the agency explore the requiring manufacturers to submit final device labeling to FDA by the time of clearance or within a reasonable period of time after clearance, and also to provide regular, periodic updates to device labeling.

CDG's concern is that requiring final labeling before a 510(k) is cleared would merely add to the timeframe for clearance. Annually updating device labeling—when taken together with the previous recommendations for annual updates for device modifications and the recommendation that all scientific information be included in the original submission, regardless of whether or not it supports an argument of substantial equivalence—is tantamount to requiring an annual 510(k) supplement similar to that required for PMAs. It is unduly burdensome for manufacturers of 510(k) devices and an already overburdened FDA staff could not handle the additional data.

We suggest that FDA update the 1997 guidance document "Deciding When to Submit a 510(k) for a Change to an Existing Device" and make available an online webcast to educate manufacturers about its contents.

[5] 510(k) Ownership
CDRH’s databases rarely reflect changes in 510(k) ownership that occur after clearance, largely because the Center is not typically notified of transfers of ownership.

Working Group Recommendations
The Working Group recommends the agency develop guidance and regulations regarding appropriate documentation of transfers of 510(k) ownership. The Center should update its 510(k) database in a timely manner when a transfer of ownership occurs. CDG, as well as a majority of public comments, support the recommendation.

CDRH Missions
The Center for Devices and Regulatory Health has two important missions: 1) to protect the public health, and 2) to foster medical device innovation. Their difficult job is to keep these missions in balance, never compromising one in favor of the other. Do you have the original citation for fostering medical innovation?

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc