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While there are those who want combination products to be controlled by a centralized pharmaceutical-type approval system, the majority of the medical technology industry wants to retain a decentralized device-focused approach.
Combination products in the European Union (EU) are currently regulated through two different arrangements. Combinations comprised solely or mainly of pharmaceutical actives are controlled by medicines agencies while those consisting predominantly of devices are approved through a fragmented national-based system based on certification by an expert organization called the Notified Bodies. However, European politicians, non-governmental organizations (NGOs), doctors, and sections of the pharmaceutical sector have been calling for the regulation of combination products to become more centralized. This approach would make it more similar to the system in the United States where FDA approves combination products whether they are pharmaceuticals or devices.
The pressure for a more centralized approach has intensified after the European Commission proposed revisions to the existing EU legislation on medical devices, with the aim of putting more emphasis on patient safety. The Commission suggested that the European Medicines Agency (EMA) take a wider and more active responsibility for the scientific assessment of some in vitro diagnostic devices such as the companion diagnostic tests (CDTs). European Biopharmaceutical Enterprises (EBE) has cautiously welcomed the Commission's proposal that EMA should participate in the assessment of clinical evidence on the scientific validity of companion diagnostics.
"The proposed involvement of EMA in the assessment of companion diagnostics could prove beneficial, provided that the regulatory obligations and research efforts to provide clinical evidence are not duplicated," says Titta Rosvall-Puplett, executive director of EBE.
Members of the European Parliament and some NGOs want the Commission to be much tougher with devices outside the diagnostics category by proposing the introduction of premarketing authorization (PMA) of high-risk or Class III products. This relatively large group of medical devices would then have to undertake an approval procedure similar to that applied to pharmaceuticals. Some EU member states, such as France, have hinted that they might support the idea of PMA for these devices. Inevitably, EMA is seen by PMA supporters as the appropriate body to carry out premarketing approval based on data from pharmaceutical-style preclinical and clinical trials.
"A premarketing authorization system for high-risk devices, such as that run by FDA in the US, is needed in Europe because the safety challenges for these products is similar to those for medicines, and in some cases, the hazards could be even more severe," says Monique Goyens, director general of the European Consumer Organization (BEUC). "You can stop taking a medicine if something goes wrong, but with a deficient medical device, the patient may require surgery," she continues. "EMA has the right infrastructure and experience to do the premarketing assessment work."
The medical devices sector, led by its main trade association Eucomed, has recognized that the legislation needs to be overhauled after a number of scandals. The biggest of these scandals came to light three years ago after a leading French devices manufacturer, Poly Implant Prothese (PIP), used industrial rather than medical grade silicone for making breast implants. The industry supports the Commission's proposed introduction of higher safety and quality standards among the Notified Bodies. It also backs more stringent requirements for clinical evidence to demonstrate the efficacy of higher-grade devices.
However, the medical devices sector is unhappy about the Commission's move to set up a central body of member state representatives—the Medical Device Co-ordinating Group (MDCG)—to conduct an additional "scrutiny" procedure on risky devices. It is even more concerned about any initiative to bring in PMA, especially if it is operated by EMA.
"What we want is a device-specific, effective, and predictable approval system that guarantees the highest safety for patients without necessary delays, (and which is) specifically important for the highest risk class of devices," Serge Bernasconi, Eucomed's chief executive, told a European Parliament workshop on the revised legislation in February 2013. He claimed that a centralized approval system would not work for patients and the industry. He cited research conducted last year by the Boston Consulting Group (BCG) showing that devices have been approved and made available to patients in Europe at least three years before the same devices were approved in the US.
Class III products
The high-risk Class III products incorporate substances that would be classified as medical products if marketed separately but in a combination, they enhance the functioning of the device itself. This group includes intra-uterine contraceptives and devices such as the heparin-coated catheters and bone-cement containing an antibiotic. With improvements in combination technologies, the distinction between what is primarily a device or a medicine has become harder to determine. In Europe, there has been a growing number of Class III combination products in recent years, whereby the drug and device are so closely integrated that one cannot be considered to be clearly ancillary or supplementary to the other. Furthermore, the materials and active ingredients can affect the function of each other.
"Under the present system, this interaction between the drug ingredients and the device materials is not being properly analyzed or assessed," says Goyens. "It needs to be done by an independent body with a public health mission and not by the Notified Bodies without any public health mission."
Although EMA has not been openly touting the EU for a key role in the assessment of devices, the agency's executive director, Guido Rasi, spoke out in an interview with Reuters last year in favor of regulating devices "at the same level of science and attention as with drugs." The agency clearly wants to establish a strong position in the assessment of combination products in areas of innovative medicine, such as advanced therapies and nanomedicines in which drugs and devices are closely integrated.
EMA's committee for advanced therapies (CAT) already has an advisory group that acts as the Notified Body for certifying devices for gene and cell therapies, and tissue engineering. Last year, the agency started issuing public assessment reports (PARs) on pharmaceutical substances combined with biological devices. The reports included details of the safety and quality of the pharmaceutical while looking at the benefits of its integration with the biologics devices such as scaffolding.
Nonetheless, some observers doubt whether EMA has sufficient competence to assess both pharmaceuticals and devices, and the interactions between the two. "In my experience, people from pharmaceutical backgrounds can struggle with medical devices because of different approaches to the interpretation of the data," says Peter Rose, managing director of High Edge Consulting, Nottingham, England. "The device experts are much better at stepping up to the role of medicines assessment whereas with the pharmaceuticals specialist, it is the reverse."
There may have to be a compromise by incorporating elements of both centralization and decentralization without having to bring together expertise in pharmaceuticals and devices within one organization. "Evaluators of the drug and the device need to work more closely together with a sharing of evaluation data at some stage, but the evaluators do not necessarily need to be working in the same entity," says Marielle Fournier, director of Voisin Life Sciences Consulting, London.
Ultimately, the key decisions on the revised or recast legislation on medical devices will be taken by the European Parliament and the Council of Ministers of governments of EU member states. As the changes are unlikely to be approved until next year at the earliest, there is plenty of time for the centralizers and decentralizers to resolve their differences.
Sean Milmo is a freelance writer based in Essex, UK, firstname.lastname@example.org