Regulation of Medical Devices and Companion Diagnostics

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Pharmaceutical Technology, Pharmaceutical Technology-08-02-2015, Volume 39, Issue 8

The trend towards personalized medicines in Europe requires a more integrated framework that regulates the approval of devices and diagnostics.

In Europe, the regulation of medical devices has traditionally been completely separate from pharmaceuticals. But in recent years, pressure has been mounting for a more integrated approach to the control of medical devices, particularly in-vitro diagnostic (IVD) tests, so that medicines regulators would be much more involved in their approval. Medicines regulators have tended to avoid participating in the assessment of devices, even though at the national level, they work within agencies that are ultimately responsible for authorization of the devices. Nonetheless, health technology assessment (HTA) bodies, which decide on which and often by how much pharmaceuticals and healthcare products should be reimbursed, have started investigating combinations of individual medicines and IVD tests for detecting patients most responsive to them. These HTA evaluations, however, are not comprehensive because they do not cover the design, materials, and manufacturing process that may affect the accuracy and reliability of the IVD equipment.

The impetus behind moves for the combined examination of pharmaceuticals and devices, particularly companion diagnostics specifically intended to select patients for targeted therapy, has come from the trend towards personalized medicines in Europe. Another driver has been the development of electronic digitalized technologies enabling diagnostics and health monitoring to be conducted outside laboratories at points of care (POC) and, increasingly, by lay people with the use of electronic wearable devices, during exercising and other every-day activities.

As a result, the question of whether companion diagnostics and other medical devices that help provide more effective pharmaceutical treatments need to be regulated in ways similar to that for medicines has become a key issue among politicians, regulators, professionals, and healthcare sectors in Europe. Should medicines licensing authorities control devices, particularly with regard to design and manufacturing standards?

New legislation proposed
The European Union’s two legislative arms-the European Parliament and the Council of Ministers representing the EU’s 28 member states-are currently in the later stages of approving a new legislation that attempts to resolve some of these issues. Two new proposed regulations (1, 2), one on medical devices and other IVDs, have been drawn up by the European Commission, the Brussels-based EU executive, to replace existing rules (3–5), the first of which was introduced in 1990.

The objective of the regulations is primarily to achieve greater harmonization and consistency in the way the assessment and certification rules are applied. Initially, the commission aimed to make only a series of incremental improvements. But then a number of scandals took place, which forced the commission to put forward more radical measures.

In the medical devices market, a French company was found to have distributed breast implants made with industrial rather than medical-grade silicone, while across Europe, there was a widespread deterioration in the quality of metal-on-metal hip implants (6). One of the most disturbing occurrences was with IVDs, where an officially approved HIV test providing a high level of false negative results was able to stay on the market for several years (7).

The role of notified bodies
The main aim of the two new regulations is to raise standards of assessment and monitoring along the regulatory chain. The nationally designated organizations-called notified bodies-responsible for evaluating and certifying medical and IVD devices are being given powers to make unannounced audits of sites of manufacturers and their subcontractors to check, in particular, whether they are complying with quality management systems. The notifying bodies, which mainly comprise certification services companies or research institutes, will themselves be subject to much stricter accreditation requirements, which a lot of the existing ones may not be able to meet.

These notifying bodies will be scrutinized more closely by the national agencies, many of them also medicine licensing authorities, to which they are accountable. They will be subject to joint assessments by teams from other member states. Their workload will rise considerably. With IVD devices, the vast majority of products will be switched from a classification needing only self-certification by their manufacturers to one in which they will have to be assessed by a notified body. Similar to medical devices, submissions for approvals of IVD tests will have to be supported by much more clinical evidence than before. In addition, this clinical information will have to regularly updated with data from post-marketing surveillance.

Assessment of diagnostic products
A central Medical Device Coordination Group (MDCG), consisting of experts in medical and IVD devices, will be set up to help in the assessment of high-risk and companion diagnostic products. The evaluation of some high-risk devices is considered to be so complex that it will be carried out at the national level by specially designated notified bodies.

The MDCG will also be involved in drawing up quality standards or common technical specifications (CTS) for companion diagnostic devices. A network of high-calibre laboratories, known as reference laboratories, will be allocated the task of verifying that devices comply with CTS.

When assessing companion diagnostic devices, notified bodies will have to consult with national medicines authorities or the European Medicines Agency (EMA) “regarding the suitability of the device in relation to the medicinal product concerned,” according to the Commission’s draft law (1). The new IVD regulation, however, does not lay down to what extent the notified body has to take account of the opinion of EMA or national agency, except that it must be included in the documentation for the product.

Industry concerns
This centralization of the evaluation process is worrying the medical and IVD devices industry. “We don’t need a centralized component in the assessment procedure,” said Oliver Sude, legal counsel to the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), an association representing SMEs making pharmaceuticals and medical devices. “The present decentralized system is on the whole working relatively well,” he told Pharmaceutical Technology Europe in an interview.

Members of the European Parliament (MEPs) are, however, opposed to EMA and/or the national medicines agencies being consulted on the evaluation of the performance of companion diagnostics on the grounds they have neither “the necessary competence or mandate” (7). This is in line with the opposition of the industry to medicines regulators being consulted during the approval process of a companion diagnostic. The European Diagnostic Manufacturers Association (EDMA) has suggested a system in reverse, in which the medicines agencies would consult the notified bodies when approving drugs with companion diagnostic tests.


“At the time of approval of a medicinal product that relies on a companion diagnostic, it is to be expected that the medicines agency would want to have an assurance that the companion diagnostic used performs as required,” EDMA says in a position paper (8) on the new IVD regulation. EMA has been assisting in the development of companion diagnostics by issuing draft guidance on the detecting of genomic biomarkers in patients for anticancer drug treatments, while also creating a system for consultation with innovators in the areas. However, while the agency has approved anticancer medicines with the licensed indication based on the selection of patients with certain pharmacogenetic biomarkers, none of the authorizations has referred to the use of a specific companion diagnostic device.

Combined approach
A growing number of HTAs in Europe have been investigating medicines, particularly anticancer ones, with companion diagnostics in the hope that they would be able to recommend the combination of a drug with a specific IVD test. This approach is seen as a way of reducing treatment costs at a time when healthcare funds are being squeezed. But few have been able to make specific recommendations mainly due to the scarcity of evidence showing that one IVD test works better than another in combination with an individual drug.

The National Institute for Health and Clinical Evidence (NICE), the UK’s main HTA, has published approximately 15 studies of pharmaceuticals with companion diagnostics. The vast majority of these publications, however, are appraisals rather than guidance documents with specific recommendations.

In a paper (9) published in 2014 on the assessment of companion diagnostics, a team of NICE researchers described the difficulties they encountered when trying to evaluate tests for epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations prior to anticancer drug treatments. It cited one test with 99% sensitivity and 69% specificity estimates while other tests had sensitivity and specificity estimates ranging from 61% to 84%, respectively.

“A wide variety of different test methods and strategies were being applied across the laboratories (in England) providing EGFR-TK mutation tests services,” the researchers said in the paper published in the Clinical Cancer Research Journal (9). “During the assessment (of the tests), it became clear that for several of the test strategies, there was very limited evidence on which to determine clinical and cost effectiveness,” they added.

With pharmaceutical companies investing more in the co-development of medicines and companion diagnostic devices with their medicines, they will be hoping that medicines authorities in Europe will be able to make “one drug, one test” approvals, or even that HTAs will even be able to make similar recommendations. “Part of the problem is that regulations often lag behind technological progress,” Benjamin Roussel, activity leader at Yole Developpement, Lyons, France, a market research consultancy specializing in the IVD sector, told Pharmaceutical Technology Europe. “With IVD devices, the European regulations could take a long time to catch up,” he added.

Regulating companion diagnostics within the same legislative framework as pharmaceuticals could be a strong platform for sustained market growth in IVD devices. Nevertheless, the creation of such a regulatory structure seems unlikely to happen in the near future.

1.   EC proposed regulation 2012/0266, Medical Devices (Brussels, September 2012).
2.   EC proposed regulation 2012/0267, In Vitro Diagnostic Medical Devices (Brussels, September 2012).
3.   EC Directive 1990/385/EEC, Active Implantable Medical Devices (Brussels, June 1990).
4.   EC Directive 1993/42/EEC, Medical Devices (Brussels, June 1993).
5.   EC Directive 1998/79/EC, In-Vitro Diagnostic Medical Devices (Brussels, October 1998).
6.   UK House of Commons, Science and Technology Committee, “Regulation of medical implants in the EU and UK,” Fifth Report of Session 2012–13, 17 October 2012.
7.   European Parliament, “Text tabled of amendments with explanatory statement on proposed regulation on in vitro diagnostic medical devices,” AT-0327/2013 (Brussels, October 2013).
8.   European Diagnostic Manufacturers Association (EDMA), “A Need for Separate Legislation,” EDMA Analysis of Proposed Regulation on in vitro diagnostic medical devices, accessed 15 July 2015.
9.   S.K. Byron et al., Clin Cancer Res, 20 (6) 1469-1476 (2014).

About the Author
Sean Milmo is a freelance writer based in Essex, UK,


Article DetailsPharmacetical Technology Europe
Vol. 27, No. 8
Pages: 6–8

Citation: When referring to this article, please cite it as S. Milmo, "Regulation of Medical Devices," Pharmaceutical Technology Europe 27 (8) 6–8 (2015).