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The new regulations aim to introduce greater consistency and uniformity in the assessment and approval of medical devices and in-vitro diagnostics across the European Union.
The European Union’s two main legislative arms--the European Parliament and the Council, representing EU governments--have finally reached a compromise on two closely related regulations (1, 2) on medical devices and
in-vitro diagnostic (IVD) products. The deal was made four years after the two pieces of legislation were first drafted. But it still leaves a number of key issues unresolved. This is particularly the case with products combining devices and pharmaceuticals, in which the dividing line between a device and a drug is becoming increasingly blurred.
For years, some trade, professional, and patient groups have been calling for high-risk combination devices, such as implanted products, to be assessed and authorized by a central body such as the European Medicines Agency. But the exact responsibility of the EMA in the authorizing of more sophisticated devices is still unclear in the new regulations. Also with combination products, differences in the application of production quality standards will remain. While the pharmaceuticals in the products will be subject to good manufacturing practice (GMP) standards, the manufacturing of a device will be covered by the standards of the Geneva-based International Organization for Standardization (ISO).
The new regulations, which replace three existing items of EU legislation covering devices and in-vitro diagnostics, aim to introduce greater consistency and uniformity in the way the two groups of products are assessed and approved across the EU at a time when the numbers of them on the European market have been rising strongly.
The EU’s medical devices industry now comprises approximately 25,000 companies, most of them small- and medium-sized enterprises (SMEs) and employing 575,000 people, according to figures from the European Commission (3).
Total annual sales currently amount to approximately €100 billion ($115 billion), with much of the increase in value terms coming from the upper end of the market where combination and other innovative technologies are being introduced (3). Some leading pharmaceutical companies are now targeting this section of the market because of its potential for growth and for the development of new treatments.
Although it is becoming a new frontier of medical science, its regulation in Europe will remain relatively fragmented despite the two new pieces of legislation (1, 2). The control of medical devices and IVDs will still be carried out, once the new rules start to be enforced early in the next decade, at different levels with individual EU countries continuing to have the scope to pursue their own policies on product approvals.
The key organizations in ensuring that the main objectives of the new regulations--to raise standards of assessment and monitoring along the regulatory chain--are achieved will be around 80 notified bodies (NBs). Mainly consisting of certification services companies and research institutes, these NBs are designated nationally to evaluate and certify medical and IVD devices.
Under the new regulations, NBs are being given more powers, such as, for example, to make unannounced audits of manufacturers and their sub-contractors sites to check in particular whether they are complying with quality management systems (1, 2). The NBs will continue to have room in which to forge their own strategies for ensuring that device manufacturers are complying with the rules.
In shaping the two new regulations, the legislators have tried to reach a balance between the need for greater patient safety and product quality with the requirement for continued flexibility in the enforcement of rules in order not to stifle innovation. The legislators seem to be aware of the future technological trends that are likely to require authorization and a monitoring system similar to that currently applying to pharmaceuticals in Europe. This system operates on a centralized level through the EMA and on a decentralized basis through mutual recognition of decisions by national medicines agencies. As a result, NBs will be more closely scrutinized by the national agencies, many of them responsible for the controlling of both medicines and devices and to which the NBs are accountable.
When assessing devices, NBs will have to consult, if necessary, specialists at the EU level although they will not be obliged to comply with their opinion. A Medical Device Co-ordination Group (MDCG), composed of experts in medical devices and IVD products, will be set up under the two regulations. It will be able to establish subgroups to provide “in-depth” technical expertise with the support of specialist laboratories. The MDCG will effectively be at the core of a pre-market assessment system that the European Parliament has been demanding.
The European Commission itself will also, under the new legislation, be appointing expert panels and laboratories to advise the Commission, the MDCG, manufacturers, and NBs. “The expert panels should fulfil the tasks of providing an opinion on the clinical evaluation in the case of high-risk implantable devices,” says the approved text of the medical devices regulation (1, 2). It is, however, uncertain from the text of the two regulations what contribution EMA will make to this expert advice. Currently, under the existing regulations (4-6),
EMA is the main central source of specialist advice on combination devices. Its know-how on devices has been expanding considerably as a result of a growing number of marketing applications for combination devices in which pharmaceutical treatment is the principal function so that they have to be authorized by the agency.
Other centralizing measures to be introduced by the regulations, similar to those already being applied in the pharmaceutical sector, include a central database of quality, safety, and performance details of each device on the EU market. Its clinical-trial data will be linked closely to that available centrally on pharmaceutical clinical trials.
In addition to manufacturers having to conform to quality- and risk-management systems, they will also have to apply post-market surveillance systems as well. An EU-wide unique device identification (UDI) scheme covering each device will be created to boost the effectiveness of post-market surveillance and improve monitoring of device deficiencies by medical agencies. However, critics of the new legislation wanting more centralization of controls on medical devices claim it does not go far enough, particularly with the responsibilities being given to expert groups (1, 2).
The European Consumer Organization (BEUC) said in a statement (7) that “clinical experts should be in charge (of pre-market assessment), not non-experts who merely check if the device works.” Because of the degree of uncertainties in the legislation, “consumers will still be guinea pigs,” BEUC added.
Healthcare providers and health insurance groups, which in Europe are primarily state funded or supported, have been expressing concerns about the lack of strict central controls on devices at a time of rising healthcare costs.
“[We’ve] always asked for a centralized approval procedure at the European Union level for high-risk medical devices, similar to that of the United States Food and Drug Administration (FDA) or what is currently in place for pharmaceuticals in the EU,” said Menno Aarnout, executive director, International Association of Mutual Benefit Societies (AIM), Brussels, in an interview with Pharmaceutical Technology Europe. “These expert panels are only a small step in that direction,” she explained. “After seeking advice from the panels, the notified bodies don’t have to follow that advice. They should only give ‘due consideration’ to the views expressed by the panels. This is not enough for us.”
The major challenge facing medical-device regulators in future is differentiating between combination devices that are primarily devices and those that are basically medicines. This means distinguishing clearly between devices in which the pharmaceutical is an integral part or is supporting the device’s function and those in which the application of medicine is the principal function and must be authorized as a pharmaceutical.
The emergence of new technologies is likely to make this task increasingly difficult, especially the drawing up of quality, safety, and performance standards to go with them.
Among the latest of these new technologies is bioelectronics, the importance of which has been highlighted by the recent announcement of the creation of a United Kingdom-headquartered joint venture in the relatively new sector by GlaxoSmithKline (GSK) and Google’s Alphabet life-sciences unit (8).
Devices controlling electrical signals in the human body have been used in the management of heart conditions and Parkinson’s disease. The new bioelectronics, being pioneered by companies such as GSK, use miniaturized devices that connect to specific groups of neurons or their nerve fibres. They can then modulate electrical signalling patterns so that targeted organs suffering from chronic diseases are restored to health. Some of the devices could both diagnose and treat diseases.
Although GSK has been involved in research into bioelectronics for the past year, it concedes that the regulatory status of its bioelectronics devices is still uncertain. “It’s too early to say what the regulatory position is and we haven’t yet even started to go through the regulatory process yet,” a spokesperson at GSK told Pharmaceutical Technology Europe. The drugmaker does not expect to launch its first bioelectronics product before seven years.
Many of the standards and criteria to be applied by the two regulations, such as those in quality management and pre-market assessment, will be drawn up by the EC in its position as the EU executive. Once the European
Parliament and the Council have formally adopted the new legislation by early 2017, the medical devices regulation will come into effect in 2020 and that for IDV in 2022. The European Commission will need that time to ensure it gets the standards and criteria right.
1. Council of the European Union, Proposal of the European Parliament and the Council on Medical Devices, Document 10617/16 (Brussels, 27 June 2016).
2. Council of the European Union, Proposal for a Regulation of the European Parliament and of the Council on In Vitro
Diagnostic Medical Devices, Document 10618/16 (Brussels,
27 June 2016).
3. European Commission, The Importance of the Medical Devices Sector, accessed 23 Aug. 2016.
4. European Union, Directive Concerning Medical Devices, 93/42/EEC (Brussels, 12 July 1993).
5. European Union, Directive on the Approximation of the Laws of the Member States Relating to Active Implantable Medical Devices, 90/385/EEC (Brussels, 20 June 1990).
6. European Union, Directive on In Vitro Diagnostic Medical Devices, 97/79/EC (Brussels, 7 Dec. 1998).
7. European Consumer Organization, Factsheet--Medical Devices.
medical_devices_factsheet.pdf, accessed 23 Aug. 2016.
8. GlaxoSmithKline, “GSK and Verily to Establish Galvani Bioelectronics--A New Company Dedicated to the Development of Bioelectronic Medicines,” Press Release, 1 Aug. 2016.
Pharmaceutical Technology Europe
Vol. 28, No. 9
When referring to this article, please cite it as S. Milmo, “New Regulations for Combination Products,” Pharmaceutical Technology Europe 28 (9) 2016.