A Whole New World… of Regulatory Approvals

Any ophthalmologist who aspires to bring a medical device to market knows that the process is slow and arduous. It’s important for new devices to be thoroughly tested before they can be made commercially available – but historically, the regulatory environment in Europe has meant that this hasn’t always been the case – and clearly, regulatory failures can have significant consequences. To address these issues with device submissions already in their approval pipeline, the European Union are currently in the process of revising their Medical Device Directives (MDDs) in ways that will bring sweeping changes to the medical device industry and change the outlook for companies seeking approval.

Safety and ethics are two key areas where the old regulations fell short. A dramatic example is the 2010 Poly Implant Prothèse (PIP) scandal. PIP, a breast implant manufacturer, had been approved to manufacture and sell implants made with medical-grade silicone gel – but when sales dropped, the company substituted it with cheaper, industrial-grade silicone to continue turning a profit. Considerable harm was done when some of the implants ruptured – not only to the patients, but also to the public’s perception of the EU regulatory process for medical devices (1).

The fallout from that scandal continues today, as the old directives failed to clearly identify the responsibilities and liabilities of each party involved. Indeed, there is even the possibility, following a French court ruling (2), that patients who received PIP implants may have to return compensation payments paid to them by Notified Bodies (organizations accredited to assess medical devices).

Then there’s the 2012 case that revolved around the potential toxicity from metal-on-metal hip implants, in which Notified Bodies were prepared to approve a hip replacement with specifications similar to a banned product. Why was it banned? It was suspected of causing toxic reactions in thousands of patients (3). More recently, European medical device regulators issued a warning statement on contaminated breast, penile, and testicular implants from a Brazilian manufacturer (4).

The proposed revisions to the MDDs are intended to increase the scrutiny of such implants before they enter the European market, and tighten surveillance once they become available. Among other things, new regulations will include a unique identifier (UID) system that makes it easier to recall faulty products and fight counterfeit devices.

Becoming law

Device manufacturers shouldn’t wait to see if the revisions become law before considering the changes – the revisions are making good progress through the legislative processes and are likely to take effect early this year. Some have been skeptical about the European Parliament’s ability to reach a consensus and conclude these discussions, but the timetable for enactment hasn’t slipped so far, and the member state review process did not result in any dilution of the original recommendations – in fact, the vast majority of changes suggested in the most recent round of negotiations were technical corrections, rather than substantive alterations (5,6).

The European Council outlined a general approach to the MDD revisions on October 5, 2015, shortly before discussions started between the European Parliament, Council, and Commission. The first informal Trilogue meeting took place on October 13, and although the minutes have not yet been published, it appears that the new directives will be released as planned in the second quarter of 2016.

Why update?

Any company that develops a medical device within the EU knows of the need for a CE mark, which demonstrates that the product conforms to MDDs. Companies are probably also aware of the need to approach a Notified Body toward the end of their product’s design and development phase. What fewer companies know about, though, is the increasingly stringent regulatory environment, which already includes, for example, unannounced audits of production facilities.

In the aftermath of the PIP scandal, the EU called for immediate action to tighten controls and increase surveillance, especially for high-risk products (9). Several problems were identified: a lack of relevant clinical evidence to support the safety of new and existing devices, inadequate ability to trace risks associated with the use of devices in the market, and inadequate surveillance of products after certification (including the inability to identify and recall problem products).

In response to these issues, the EU proposal called for tighter controls over Notified Bodies, which in turn requires auditors to have both expertise relevant to the device type and the power to conduct surprise audits. Manufacturers will continue to monitor and report adverse events, but now, these reports will be centralized in Eudamed, a European medical device database accessible to all Notified Bodies (10). The application of MDDs will also need to be harmonized across all member states.

An ongoing discussion

Some issues still need to be addressed by both government and industry. One is the scrutiny mechanism, which concerns how closely the Notified Bodies will work across all of the member states. Regulators must determine how to make sure Notified Bodies from different member states apply the standards uniformly, which means there’s a need for experts in the Notified Bodies. However, it’s likely that member states will find locating enough experts challenging, so they’ll need to initiate large training efforts.

Another issue revolves around the reuse of “single-use” medical devices. In the EU, powerful environmental lobbies have succeeded in adding terms to the MDDs stating that, wherever possible, medical devices should be reused. But from a regulatory perspective, it’s unclear how a company can prove that a reused device still meets safety standards – and at what cost. The EU Council is divided on this topic, leaning toward national empowerment for regulation and enforcement. As a result, the healthcare community is justifiably concerned about the potential for double standards or even varying degrees of standards between member states.

Then there’s the issue of unannounced audits. For small companies in particular, unannounced audits may impose a disproportionately heavy burden. Companies that undertake small batch production may not have the capacity to run the manufacturing part of their operation every day, or to have qualified staff available at all times to support the auditors.

The ramifications of revision

The changes to the MDDs will likely have major consequences for medical device companies (11). One significant change involves the use of medical literature reviews to provide clinical data to support device certification. Under the new MDDs, manufacturers must quote all available literature, not just the material that supports their claims.

Perhaps more importantly, if a manufacturer is not using exactly the same manufacturing processes, technical methods, and device materials as an existing product previously described, then a literature review may be considered insufficient to document safety and efficacy. In the new regulatory environment, companies may need to have their own clinical data to back up claims according to their device’s intended use. This may mean setting up and running clinical trials, as well as presenting peer-reviewed data, because internal reports will no longer be sufficient. The financial burden of providing this extra clinical evidence is likely to increase the cost of new devices.

At this point, companies that haven’t already done so should be carefully considering their strategies for responding to these regulatory changes – especially because they’re already having an impact. Some Notified Bodies have advised that they are not accepting new clients for CE marking services, whereas others have quoted lengthy lead times for new clients for this service – and this means that medical device manufacturers who need to recertify their CE marking are also likely be affected. The Notified Bodies’ lack of capacity to take on new clients can be attributed to two key factors: the advent of unannounced Notified Body audits by European regulators (which requires considerable time and resources), and higher rates of staffing changes, affecting the organizations’ ability to audit and certify clients (12).

For medical device companies, the new MDDs will prompt a Darwinian response – “survival of the fittest.” Ignoring the coming changes will leave companies unprepared to react to an altered regulatory environment and put them at risk of losing out to competitors who adapt more quickly.

Mark S. Talary is chief technology officer of IROC Science to Innovation AG in Zürich, Switzerland.