Regulation of Companion Diagnostics

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-09-02-2017, Volume 41, Issue 9

EMA recognizes that a regulatory framework, under which medicines and diagnostics are developed and approved independently, may not be ideal.

The European Union has been overhauling its rules on in-vitro diagnostics (IVD), particularly companion diagnostics, to bring them more into line with internationally agreed standards. But despite the changes, it is still retaining a regulatory system that keeps the approval of IVDs separate from those for pharmaceuticals. The authorization of medicines and diagnostics will continue to be done along different regulatory pathways even though the use of companion diagnostics (CDx) is considered to be crucial to the performance of the drug.

The splitting of regulatory responsibilities could hamper prospects for the co-development of a medicine and its CDx and cause the drug and the diagnostic to reach the market at different times. Co-development, particularly of drugs with assays for pharmacogenomic biomarkers necessary for patient selection, will be an important component of the shift to precision or personalized medicines. The division of responsibilities could also maintain gaps in controls, in the pre-analytical phases of biomarker testing, on the quality of specimens, particularly during their storage and transportation, and in the monitoring of the reproducibility of tests. 

New legislation 

Legislation on IVDs (1) was approved, simultaneously with a regulation on medical devices, by the European Parliament in April 2017. The regulation on diagnostics (1) will come into full force in 2022 and the one on medical devices (2) in 2020. Both replace existing legislation, parts of which date back to the early 1990s. The new rules are more consistent with those developed at the international level for medical devices including IVDs, in particular, with the guidance from the Global Harmonization Task Force (GHTF) and the International Medical Devices Regulators Forum (IMDRF). However, unlike in countries and regions outside Europe, the EU has decided that even new technologies, such as pharmacogenomics testing, whose regulatory requirements are increasingly overlapping with those of pharmaceuticals, should not be brought under the ultimate control of regulators responsible for licensing medicines.

The United States Food and Drug Administration (FDA), for example, has had responsibility for the approval of medical devices since 1975. The EU’s European Medicines Agency (EMA), which runs Europe’s centralized procedure of marketing authorizations of medicines, has responsibility only for pharmaceuticals. Within the EU’s 28 member states, only a minority of national medicines agencies also have responsibility for controls of medical devices and diagnostic products.

“Diagnostics are gaining considerable importance in the effective treatment of patients, especially in oncology, but also other conditions,” Peter Keeling, chief executive of the Irish consultancy Diaceutics, told Pharmaceutical Technology Europe. “It makes sense that the control of diagnostics should be brought under the control of single regulatory bodies. It helps to harmonize standards and benefit/risk assessments.”

One major similarity between the European and US diagnostics sectors is the high proportion of diagnoses carried out with laboratory developed tests (LDTs), which are exempt from the regulations on IVDs. Many of these are administered in the laboratories of hospitals and other healthcare institutes specializing in oncology, cardiology, neurosciences, and other conditions requiring detailed diagnoses.

“In Europe, approximately 50–60% of testing-and only a little bit less in the US-are still conducted through LDTs, with the remainder of the market comprising commercial in-vitro kits,” said Keeling. “These in-house laboratories have demonstrated their excellence in finding evidence, especially in genetics. We don’t want to thwart this innovation.”

The EU’s new IVD legislation states that health institutes, including hospitals, should continue to have the freedom “of manufacturing, modifying, and using devices in-house” outside the regulation, although they may still be subject to national quality rules. The legislation also retains much of its existing regulatory system under which IVD manufacturers are able to self-certify the quality and safety of their diagnostic kits. The higher-risk tests have to be certified by organizations, called notified bodies (NB), which specialize in assessing whether diagnostic products or other medical devices comply with EU standards laid down by the European standards agency.

The role of notified bodies


A big change under the new legislation is that the majority of IVDs, including CDx products, will be certified by NBs, which themselves will be subject to close scrutiny by the national competent authorities within the member states responsible for medical and diagnostic devices. The NBs will also be required to audit and inspect at minimum regular intervals the sites of IVD manufacturers. 

Another major alteration is that, for the first time, a definition of a CDx is included in the text of the IVD legislation, which is similar to that used by FDA in the US. A CDx is defined in the new regulation as a device that is “essential for the safe and effective use” of its corresponding medicine (1). The CDx is used to identify, before or during treatment, patients most likely to benefit from the medicine or those likely to be at increased risk of a serious adverse effect from the drug. As a result of the division of regulatory responsibilities, the NB’s main task is to assess the technical quality and performance of the CDx. Both the NB and the medical agency, either EMA or the national authorities, have to assess, in the light of evidence from clinical trials, whether the CDx has sufficient sensitivity and specificity to be safe and effective.

Under the new legislation, the NB is required to consult EMA or, if necessary, a national medicines licensing agency on its scientific opinion before issuing an EU compliance certificate for a CDx product. EMA or the national agency has to provide an opinion within 60 days. But EMA, under the legislation, does not have the power to veto the NB’s assessment. The NB only has to give “due consideration” to EMA’s or other agency’s opinion. EMA, however, will have the option of deciding, in the light of an NB assessment contrary to its own scientific opinion on a CDx product, that the medicine has a negative benefit/risk balance and cannot be given a marketing authorization. In the five-year transition period between the approval of the IVD regulation and its full implementation, EMA will have plenty of opportunity to lay down requirements in guidelines. These could limit the freedom of NBs to certify CDx products, which do not sufficiently take into account the essential role of CDx technologies in ensuring the effectiveness of its corresponding drug.

Under the legislation, the European Commission in its role as the EU executive is allowed to stipulate common standards in areas where no harmonized standards exist. As an agency of the commission, EMA will have a key role to play in drawing up guidelines on the operation of the regulation.

In an analysis of the new IVD regulation, a group of experts at the German Federal Institute for Drugs and Medical Devices (BfArM), one of the minority of national agencies with combined responsibilities, suggested that EMA should impose requirements on NBs for individual CDx products. The group included Harald Enzmann, head of European and international affairs at the agency, who is also vice chair of EMA’s key committee for medicinal products for human use (CHMP). “The EMA could define in their initial assessment of a new medicine, the minimum requirements for the performance of the CDx,” the study said (3). 

EMA’s views

In a concept paper (4) issued in July 2017, for a planned guideline on the use of predictive biomarkers in the light of the IVD regulation, EMA admitted that a system under which medicines and IVDs are developed independently “may not be ideal as there remain gaps in evidence and validation.” It stressed that it was crucial that any CDx used to select patients for treatment is “sufficiently quality assured.” 

“[The guideline] will address some technical performance requirements used for predictive biomarker assays depending on the stage of development and how the biomarker status may affect patients’ eligibility to participate in a clinical study,” an EMA spokesman told Pharmaceutical Technology Europe. “It is anticipated that feedback on the concept paper received by medical device stakeholders will be used to address various aspects related to the expected quality standards of companion diagnostics,” he added.

EMA is among a number of specialist bodies that will be providing guidance and possibly standards on the implementation of the legislation. Under the new regulation, a Medical Device Co-ordination Group (MDCG), comprising experts in medicine devices including IVDs, is being set up to ensure its uniform implementation.

The commission will also have its own expert advisory panel. There will also be a network of EU reference laboratories that, when necessary, will use their specialist staff and equipment to verify the performance of CDx products and other higher risk IVDs. The role of the MDCG could turn out to be highly important because it will be able to press for amendments to the legislation to make it work more effectively, particularly on quality and reproducibility issues.


  1. EU Regulation 2017/746, In-Vitro Diagnostic Medical Devices (Brussels, 5 April 2017). 
  2. EU Regulation 2017/745, Medical Devices (Brussels, 5 April 2017). 
  3. H. Enzmann, R. Meyer, K. Broich, Biomark. Med. 10 (12) 1261–1268 (2016).
  4. EMA, Concept Paper on Predictive Biomarker-Based Assay Development in the Context of Drug Development and Lifecycle, EMA/CHMP/800914/2016 (London, July 2017). 

Article Details

Pharmaceutical Technology Europe
Volume 29, Number 9
September 2017
Pages: 6–8


When referring to this article, please cite it as S. Milmo, “Regulation of Companion Diagnostics,” Pharmaceutical Technology Europe 29 (9) 2017.