Notified Body Requirements for Clinical Literature Evaluation

The most recent revisions to the European medical devices directive have underlined the importance of clinical data in demonstrating compliance to the Essential Requirements. The first step in this process is the clinical literature evaluation, for which there are three key sources of guidance: ISO 14155-1 (2009) Annex A, MedDev 2.7.1 and GHTF document SG5/N1R8. However, many manufacturers are still unclear as to Notified Body and Competent Authority expectations, and how much data is required to demonstrate that a clinical investigation is not required.

As the majority of devices are launched on the basis of equivalence to existing devices, and since review of the literature is the first step in any clinical evaluation, this article will focus on issues related to evaluation by literature review rather than clinical trial. The most common problems Notified Body reviewers find in clinical literature evaluations are:

• Poorly established design equivalence
• Insufficient data provided to demonstrate the short to medium term safety and efficacy of the equivalent (and by extension subject) devices.
• Adequacy of postmarket surveillance including postmarket clinical follow-up (PMCF)

Design Equivalence

Whether or not there is any clinical data available for the devices themselves, the literature review should include any available data for similar devices. For this purpose, ‘similar’ can be approached from two perspectives. In terms of establishing baseline performance and relevant risks, equivalence can be considered fairly broadly and might include all devices with similar indications for use. For example, if trying to demonstrate that a particular design of collarless cementless hip stem is of a safe and effective design, the manufacturer might first consider the performance of hip replacements in general, how this performance compares with cementless hip stem performance and any generic risks and complications for these devices.

However, in establishing the adequacy of existing clinical data to demonstrate safety and performance for a specific subject device, more detail is required. For these purposes, the manufacturer should describe all known design differences and provide an evaluation of the potential impact of these differences on anticipated clinical safety and performance. This should include a detailed examination of differences in:

• Bone contacting geometry (e.g., impact on ease and reproducibility of surgical technique; extent of bone resection and therefore options for revision; load transmission and therefore, potential for bone resorption or cement fixation, etc.). Note that even seemingly small differences might affect performance. For example, a change in radius for a taper edge or groove patterning could affect stress in the cement mantle and subsequently, medium to long term fixation, or a slightly longer stem for a hip could result in increased thigh pain. Hence, all differences should be discussed.
• Articulation geometry (e.g., impact on range of motion, kinematics, wear, etc.)
• Surface finish and patterning (e.g., impact on cement fixation, bone ingrowth, subsidence, etc.)
• Coatings (e.g., impact of differences in density, porosity and surface roughness as well as possible differences in material specification)
• Material properties (although normally, devices made from different materials will not be considered equivalent, unless strong justification is provided)

As even small design differences can have a significant impact on clinical results, it would not normally be expected that a manufacturer could claim strong equivalence to several different devices.

Two additional factors should be considered when establishing design equivalence:

• Design evolution of the device with which equivalence is claimed. As a device design may incorporate incremental changes over several years, the manufacturer should establish the specifics of the design for which data is presented, especially if older studies are referenced.
• Design variants within a family. Often manufacturers will have several design variants within a family that have the same name, but would not be considered equivalent to one another. The clinical literature evaluation should demonstrate, as far as practically possible, that the devices for which data are presented are for the specific designs with which equivalence has been established.

As suggested by the above, when a dossier includes more than one distinct design variant, the clinical impact of these design differences on indications as well as safety and performance risks should be discussed.

Adequacy Data Available in the Clinical Literature

Once design equivalence has been established, and a robust rationale provided to support the claim that clinical performance of the subject devices can be predicted on the basis of clinical results for the equivalent devices, the manufacturer must demonstrate that the total volume of clinical data available is sufficient for the subject devices to be placed on the market. If there are insufficient data in the literature for the device or its close equivalents, a pre-market clinical trial may be required. Consideration should be given to the following factors:

• Volume of data. “How much data is enough” will depend in part upon how similar the subject device is to the device(s) with which equivalence is claimed. An evaluation of the adequacy of the volume of data based on number of publications included, number of centers and surgeons involved, number of patients and length of follow up should be provided.
• Quality of data. This will be affected by strength of design equivalence, as well as source of evidence (e.g., peer reviewed journal vs. expert opinion), study design, patient population (i.e., is it representative for the range of patients for which the subject devices are indicated) and relevance to the subject device indications and claims.
• Indices of safety and performance. Typical indices of performance for orthopaedic devices include survivorship, functional performance and patient satisfaction scores. Adequacy of survivorship data should be justified (for example, on the basis of an established benchmark), as well as the length of follow-up. If the length of follow-up is insufficient, it may indicate a requirement for either a pre- or postmarket clinical trial. Similarly, the adequacy of functional performance and patient satisfaction data should be justified, with reference to postmarket follow-up if appropriate. Safety information can be obtained from review of complications reported in the literature and from adverse event reporting anywhere the devices are sold.
• Identified risks. The literature evaluation should include an evaluation of risks for the device type in general, as well as risks associated with design features specific to the subject device. The manufacturer should demonstrate how the available data is sufficient to draw a positive risk-benefit conclusion, with reference to postmarket follow-up as appropriate.

Postmarket Follow-up

Postmarket surveillance activities must be justified in accordance with the risks associated with the device and its intended use. General postmarket surveillance activities might include reactive measures such as complaints and vigilance evaluation, clinical literature and registry reviews and review of experience with similar competitor devices. Further proactive postmarket clinical follow-up (e.g., postmarket trial, internal registries, etc.) may be required for devices for which long-term clinical safety and performance cannot be demonstrated.

Current Medicines and Healthcare products Regulatory Agency (MHRA) guidance states that joint replacement implants may be placed on the market on the basis of short- to medium-term performance data, and that postmarket surveillance mechanisms should include “properly structured postmarket clinical studies designed to confirm the medium and long term performance of the implant, and to ensure that the manufacturer’s claims on performance are justified.” Long term performance is generally accepted to mean “in excess of ten years.” Even in cases where good clinical performance has been demonstrated in excess of ten years, there may be risks related to specific design features or functional requirements requiring PMCF.

The clinical evaluation should include a description of planned postmarket surveillance activities (including frequency of planned activities), and if a “no-PMCF” route is adopted, a justification should be provided. For example, if there is ample data in the literature to support the long-term performance of the device itself, or a device which is essentially identical to the subject device, a manufacturer may justify a no-PMCF route on the basis that the long-term performance of the device is well known, and that continuing compliance with “state of the art” can be demonstrated by reactive means such as literature reviews and complaints evaluation. If long term data is not available, but reasonable performance can be extrapolated on the basis of existing data and anticipated risks, then market launch with appropriate PMCF to confirm the anticipated safety and performance may be justified. And if there is insufficient data to demonstrate the short-to-medium term performance of the device, a pre-market trial will be required.

In summary, to demonstrate adequacy of clinical evidence, manufacturers should ensure that:

Design equivalence has been described and justified in detail

Evidence provided to demonstrate that design differences will not affect the applicability of clinical results

Volume and quality of data is sufficient to demonstrate at least the short-to-medium safety and performance of the devices, and that a long term risk-benefit conclusion can be drawn

Planned postmarket activities are appropriate to ensure that clinical data to demonstrate long term safety and performance of the devices will be available.

Addressing these common issues will facilitate medical device certification in Europe.

Additional Sources of Information

93/42/EEC, Annex X

ISO 14155-1 (2009), Annex A

MedDev 2.7.1, Clinical Evaluation: A Guide for Manufacturers and Notified Bodies

GHTF SG5/N2R8, Clinical Evaluation

MHRA Guidance, Postmarket Surveillance of CE Marked Joint Replacement Implants Including Guidance to Manufacturers on Postmarket Clinical Studies

MedDev 2.12.2, Guidelines of Post Market Clinical Follow Up

Amie Smirthwaite is a Product Technical Specialist with the Orthopaedic and Dental team at British Standards Institution, one of the EU Notified Bodies. She has 20 years of experience in academic and industrial medical devices research and development, and has been working as a Notified Body technical specialist and auditor for the past seven years. She has a Ph.D. in Bioengineering from Strathclyde University and an undergraduate degree in Biomedical Engineering from Tulane University. Ms. Smirthwaite can be reached at Amie.Smirthwaite@bsigroup.com.

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