The European Commission is proposing that clinical evidence should be a key factor in the forthcoming EU Regulation of IVDs and be required for all but the lowest-risk, Class A products, Clinica has learnt.

This Regulation, which is likely to be implemented across the EU in 2015/16, marks a big change from the current IVD Directive where there are no requirements for clinical evaluation, except for some specific, listed high-risk devices. The only clinical evaluation requirements that exist at present in this respect are within the context of the common technical specifications which must be used for the performance evaluation and re-evaluation of selected IVDs, notably for the safety of blood supply and organ donation.

If the proposals go ahead, IVD companies, in the future, would need to provide the following information in a clinical evidence report that supports :

• the scientific validity of the analyte, meaning evidence of the association of an analyte to a clinical condition or physiological state;
• the analytical performance of the device, referring to the technical test performance of the product;
• the intended purpose of the device; and
• the clinical performance of the device (which, Clinica notes, encompasses those areas that have previously has been referred to as the clinical validity). This performance refers to the relationship between the testing result and the clinical condition of the patients, and may be characterised by:

1) the diagnostic specificity and sensitivity;

2) the positive and negative predictive values;

3) the likelihood ratio; and

4) the expected values in normal and affected populations.

The clinical evidence report containing all this information would form part of technical documentation

The commission is envisaging that clinical performance studies should be required for all products except those in the lowest-risk Class A category, unless it is duly justified and substantiated (including through risk-management) to rely on other sources of clinical performance data or other clinical evidence.

These studies, the commission suggests, should be performed on the basis of an appropriate investigation plan reflecting the latest scientific and technical knowledge and defined in such a way as to confirm or refute the manufacturer’s claims for the device.

The proposal is for the manufacturer to actively update the clinical evidence report with data obtained from post-market surveillance, which will be part of the clinical performance review, unless duly justified and documented.

All manufacturers would need to have a post-market clinical follow-up plan consisting of documented methods and procedures to pro-actively collect clinical evidence data from actual use of the device. And they would be expected to take into account the PMCF evaluation report conclusions for clinical evaluation and risk management purposes.

The new requirements would impact the majority of IVD manufacturers and mean that they would need to invest a significant amount of time and resources to conform to the regulation. Companies currently active or planning to become active in this field would therefore do well to pay close attention to developments in this area now, to enable them to plan as necessary to meet these new requirements in time, as well as to adjust to the likely forthcoming changes in risk classes and related conformity assessment (www.clinica.co.uk, 16 February 2012).

Likely reactions

The European Commission is still open to contributions from stakeholders on its proposals (the latest version put forward as working documents) for the revision of the IVD Directive and the Medical Devices Directive, Clinica has learnt. So it is entirely possible that these proposals could change.

It does not seem likely, however, that there will be a large body of opposition to its proposed measures.

A total of 88% of respondents to the European Commission’s June 2010 public consultation on the proposed revision of the IVD Directive had argued for clarification of demonstration of clinical evidence requirements

In addition, 81% had agreed that the requirements on the demonstration of the clinical validity (now encompassed in the concept of “clinical performance”, should be extended at least to the demonstration of negative predictive value and positive predictive value.

There was, however, no support from manufacturers on this point on clinical validity in contrast with the large support from competent authorities, notified bodies and users. It remains to be seen whether industry will now feel strongly enough on this point to mount an opposition.

It seems likely that manufacturers will be over-ridden here, unless they can create a significant swing in opinion among other stakeholders

Among the respondents to the consultation, there was the proposal that the requirements on clinical validity should be proportionate to the risk linked to the use of the IVD and adapted to the risk-based classification.

Contentious element taken out

The concept of "clinical utility", the most contentious element of the European Commission’s proposals around clinical evidence that were in the 2010 consultation, is not mentioned by the commission in these latest working document proposals.

This concept had been that if a test had utility, the results provided valuable information for making decisions about effective treatment or preventive strategies. The introduction of clinical utility requirements had been opposed by 67% of respondents, with many arguing that it was a “moving concept” and that it should remain outside the premarket assessment process and be something that was assessed by the user.

The concept of “scientific validity”, however, goes some way towards replacing this notion as this refers to the association of an analyte to a clinical condition or physiological state.

GHTF on clinical evidence and performance

Much of the EU work has been carried out in close collaboration with the study group 5 of the Global Harmonization Task Force which has been involved in drafting documents on clinical evidence.

If EU clinical evidence developments continues in parallel with the global work, this should greatly help the European industry in that its forthcoming regulations should be aligned with the regulatory structure that is likely to be adopted in a large number of other regions of the world.

The Global Harmonization Task Force is currently seeking feedback on a draft guideline that explains the factors that IVD manufacturers should consider when conducting clinical performance studies for their products (www.clinica.co.uk, 21 February 2012) .

The deadline for comments on this document, which aims to provide guidance in relation to the selection of clinical performance study design based on the types and intended use of the IVD medical device and considerations to be made when undertaking clinical performance studies, is 2 June.

The GHTF has also posted a document ,in September 2011,on scientific validity determination and performance evaluation in the clinical evidence for IVDs.

For access to these GHTF documents, see: http://www.ghtf.org/sg5/sg5-proposed.html