European Commission Issues New Guidelines For Literature Reviews

By Ron Sills, Nerac Analyst

Clinical data, a critical component of a pre-market approval submission for medical devices, generally can be handled two ways. The manufacturer can conduct clinical trials and publish the results, or it can review the literature from previously published trials of equivalent devices. Obviously, the literature review route is preferable because it avoids lengthy and costly trials, but more stringent approval guidelines in Europe will make that route more challenging.

How The Guidelines Came About
In 2005, the European Commission published a draft proposal to amend Medical Device Directive (MDD) 93/42/EEC, following a two-year commenting period. This is the key governing document for regulating medical devices in Europe, covering all required phases for device manufacturers from pre-market approval through post-market vigilance. Notified bodies will use the MDD to assess whether a manufacturer meets the requirements for European market approval or CE Mark approval.

Similar to FDA requirements in the United States, the MDD considers patient safety and device efficacy as the primary factors for approval decisions. Because the European Commission includes many member countries, it is critical that the MDD is practical and compatible with the regulations of those countries’ health authorities. The updated MDD looks to achieve that harmony without drastically changing the original document, which was first published in 1993.

Several sections of the MDD have been modified, including those addressing device classification, combination products, software in medical devices, and conformity assessments. While none of the changes are drastic, the document clarifies and strengthens its requirements and allows for more effective implementation by member state health authorities and notified bodies.

Evaluating Clinical Data
Perhaps the most significant modification, however, is how clinical data is evaluated. This is a critical area when reviewing a device for market approval, as it presents actual clinical experiences to monitor a device for its risks and benefits in meeting the stated claims.

Clinical data requirements will vary based on the device classification, with an increased emphasis on clinical trial investigations for Class II and III devices. In the past, a literature review was often an adequate means to summarize clinical performances of the device being reviewed or for devices demonstrated to substantially equivalent. The literature review can stand alone or supplement clinical trial investigations of a device. When used as the primary source of information, the literature review must clearly prove the equivalence of the cited devices to the manufacturer’s device. While this has long been supported by both the MDD and FDA, the amended MDD will be more specific in defining the level of acceptance of a literature review alone.

Approval of Class I devices, the lowest level in both the European Union and the U.S., must now include documentation of clinical data through a literature review, at a minimum. European Commission document, MEDDEV 2.7.1 Guidelines on Medical Device, Evaluation of Clinical Data: A Guide for Manufacturers and Notified Bodies, published in April 2003, stands as the outline for using clinical data, whether by a literature review or by conducting clinical trial investigations. The FDA document, Guidance for Industry – Supplements to Approved Applications for Class III Medical Devices: Use of Published Literature, Use of Previously Submitted Materials, and Priority, issued in 1998, is similar in scope, except that it covers Class III approvals only (PMA’s). Device manufacturers as well as FDA reviewers or notified bodies will refer to the EC and FDA documents to assess compliance with clinical data evaluation.

Establishing Equivalency Is Key
It is natural to assume that manufacturers will go the literature review route as much as possible to avoid lengthy and costly clinical trial investigations. But when presenting a literature review, it is critical to demonstrate that the device up for approval is equivalent to the devices described in the literature. However, many clinical articles do not contain detailed descriptions of the device design. Rather, the literature usually focuses on the device’s novel characteristics such as size, unique materials, or the diagnostic and therapeutic applications.

Whoever conducts the literature review must clearly demonstrate equivalence in design and performance in a specified application. The summary must include a description of the search strategy, databases accessed, and the criteria for selecting the articles cited.

A meta-analysis is a more comprehensive literature review in which several clinical trial investigations are evaluated, and data is analyzed both quantitatively and qualitatively.

Statistical analysis is used to quantify and interpret data such as study group size and demographics, data measurement methods and results, and patient outcomes. A qualitative summary will use the data analysis to assess the clinical performance of the devices.

Consider Positive & Negative Outcomes
Whether conducting a standard clinical literature review or a meta-analysis it is important to consider both positive and adverse outcomes as a fair documentation of safety, risk, and efficacy in achieving the intended diagnostic or therapeutic application. There can often be a bias in not presenting adverse data.

Even within an individual clinical study there can be an absence of adverse data reported. Most clinical trial investigations are sponsored by companies with established physician relationships, many of whom are co-developing a device. Both EC and FDA reviewers will continue to be more sensitive to accuracy and bias in data reporting.

The amended MDD will provide more detail on the use of clinical data and the documentation of a literature review, so that notified body reviewers can effectively assess that manufacturers have fully met the requirements.