Revision of the Directive 98/79/EC on In Vitro Diagnostic Medical Devices. Response from Cancer Research UK to the Commission August 2010

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1 Revision of the Directive 98/79/EC on In Vitro Diagnostic Medical Devices Response from Cancer Research UK to the Commission August Cancer Research UK (CR-UK) 1 is leading the world in finding new ways to prevent, diagnose and treat cancer. We are the largest independent funder of cancer research in Europe. Over half of all cancer research in the UK is carried out by our doctors and scientists. Cancer Research UK s work is entirely funded by the public and in 2008/09 we spent 355 million on research, supporting the work of more than 4,800 scientists, doctors and nurses. While Cancer Research UK is a British charity, our researchers come from across the world and regularly work with colleagues elsewhere in the EU. 2. CR-UK funds research into all aspects of cancer from exploratory biology to clinical trials of novel and existing drugs as well as population-based studies and prevention research. Our scientists and doctors have made significant contributions to the development of half of the top 30 drugs used to treat cancer patients worldwide today. 3. Advances in the understanding of the molecular pathology of cancer over the past 30 years have allowed the invention of targeted therapy and an increasing number of new treatments are being shown to preferentially benefit sub-populations of patients. Stratified medicine is the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. In the context of cancer this would include the use of shared molecular and genetic abnormalities to characterise a sub-population of tumours suitable for a particular treatment. The adaptation of treatment to individual tumour or host characteristics is often referred to as personalised medicine. 4. These advances mean that we now have the opportunity to target treatments, getting the right therapy to the right patient at the right time. We hope to revolutionise the way that we diagnose and treat cancer. There are already around two dozen individually targeted treatments for cancer, which rely on the clinician knowing about a specific mutation in the tumour. Some of these are already approved by relevant authorities (such as the NICE National Institute for Health and Clinical Excellence in the UK), for example, Cetuximab, which is used to treat metastatic colorectal cancer based on the status of the KRAS gene. 5. Cancer Research UK is leading a partnership to deliver a national programme of stratified medicine. The programme will demonstrate how routine genetic testing at diagnosis to improve treatment choices such as drug therapy could be rolled out across the NHS. The first phase of the programme, running from , will establish the feasibility of setting up a technology platform to prospectively deliver sequence analysis on 5-10 genes (somatic mutation and pharmacogenetic) in certain tumour types. Once the feasibility of delivering this process has been established, the numbers of participating centres involved in the programme will broaden and number of genes analysed will expand with the potential for whole genome scanning to be implemented. 1 Registered charity no

2 6. We welcome the opportunity to respond to the Commission, and have also shared a copy of our response with the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Acknowledgements 7. Our response has been collated following internal staff discussion and wider discussions, with contributions from individuals including: Dr. Rachel Butler, Consultant Clinical Scientist and Head of the All Wales Molecular Genetics Laboratory, Institute of Medical Genetics, University Hospital of Wales Dr. David Gonzalez de Castro, Head of Laboratory, Molecular Diagnostics, The Institute of Cancer Research and Royal Marsden Hospital Dr. Hans Scheffer, President of the Dutch Society of Clinical Laboratories and Associate Professor of Clinical Molecular Genetics, Radboud University Nijmegen Medical Centre Dr. Fiona Hemsley, Head of Strategic Projects, Cancer Research UK James Peach, Director of Stratified Medicines, Cancer Research UK 8. This response does not represent the views of any one individual or organisation listed above, but is the product of collaboration between all listed parties. 9. If you have any queries about this response, or would like to discuss it, please contact Layla Theiner, Public Affairs Manager (EU) (layla.theiner@cancer.org.uk; 0044 (0) ). Classification Question 1: - Would you consider the adoption of a risk-based classification for in vitro diagnostic medical devices as an improvement of the current European regulatory framework? - Are you aware of any consequences for the protection of public health? - Can you provide economic data linked to a change-over to this GHTF classification system? 10. Cancer Research UK considers the proposal to develop a risk-based classification for in vitro diagnostic medical devices could be an appropriate method to ensure the legislation is able to cover unforeseen future developments. 11. However, we are concerned that classification of risk levels for genetic tests should be based not only on the degree of invasiveness of the test and risks associated with this, but also reflect the impact the potential results of the tests could have upon the patient and their family, as well as the likelihood of tests being performed and interpreted correctly. Crucially, it is not just the diagnostic assay that needs to be classified but the whole diagnostic process (i.e. from when a sample is taken to a clinical report being issued) since it is vitally important how the result of the test is interpreted, and therefore the expertise of the people and methods used when undertaking the test. 2

3 Scope Question 7: - Would it be necessary to maintain the exemption [for in-house test ] provided for by article 1(5) of Directive 98/79/EC and why? 12. Cancer Research UK believes it would be best to maintain the exemption for in-house tests, especially for genetic tests. Many genetic tests are family-specific ( private mutations ) and it would not be possible to have a CE marked test for every such genetic mutation. For example, for inherited breast cancer, many families have private mutations and without the exemption for in-house tests, laboratories would need a CE marking for every individual, family-specific test. These tests are either for pre-natal diagnosis or presymptomatic testing and the results of these tests can have massive implications (including terminated pregnancies and double mastectomy) and have to be turned around very rapidly. It can also be necessary to have tests specific for an individual s (solid) tumour so similarly, it is not possible to use the same test for different people. 13. Furthermore, CE marked tests are only available for the simplest tests but the tests do not offer the required complexities we need. For example, there is a test available for KRAS mutations in codons 12 and 13 but not elsewhere in the gene. This may be because of the scientific data available when the test was first manufactured but developments since then mean that an in-house test is more sensitive and illustrates that CE marking would not be able to keep up with the progress of science. Another example is cystic fibrosis, which is a relatively common rare disease but there are also regional differences in the genetic mutations that cause it. For instance, there are different mutations in Wales or England, which are different again to mutations in other parts of Europe, so one test will not fit everyone, even within a single nation. 14. The necessary costs, in both time and monetary terms, required to develop these tests and obtain a CE marking would be prohibitive. In addition, getting CE marking for all types of tests would mean it was not possible in a reasonable timeframe to test someone quickly since the time taken to get CE marking on a particular test would delay access to a specific test. In the context of cancer, testing in a short timeframe can be crucial. Based on initial analysis undertaken by the All Wales Molecular Genetics Laboratory, Institute of Medical Genetics, University Hospital of Wales, where a CE marked test exists, we believe that it currently costs 10 times as much compared to an in-house genetic test. 15. Currently, CE mark genetic tests are only available for a few genetic conditions, such as cystic fibrosis and Fragile X Syndrome. The majority of routine analysis covers many disorders outside of CE marked tests. According to our research, tests would only be available for 6% of the All Wales Molecular Genetics Laboratory s workload, for example. Molecular genetic tests are available for over 600 different conditions, whereas CE marked tests are only available for only a handful of these 16. The tests that are CE marked are manufactured by companies which are driven by the interests of pharmaceutical companies. As mentioned, these tests might not detect all mutations, just the one(s) the pharmaceutical company wants it to. In addition, they would not have a business interest in developing tests for rare disorders since they could not expect to receive a sufficient return on their investment. If we were to wait for CE marked tests for all 3

4 uses, some would be delayed by a significant amount of time while research (particularly in cancer) is moving at a fast pace, with more and more useful information becoming available which would benefits patients if they were able to access more suitable treatment, and some tests (particularly for rare conditions) would never be manufactured. 17. There is not a case of unfair competition since in-house tests are developed and used by skilled professionals in health institutions to benefit patients. 18. In the UK, all genetic tests for medical purposes are evaluated by the UK Genetic Testing Network (UKGTN) and there is a total of 498 genes for which tests have been authorised. There is a further 113 genes for which tests are undergoing assessment for authorisation, a number which reflects the likely growth of IVDs in the genetic testing field. The vast majority of these tests are developed in NHS genetic laboratories for use by the NHS, fitting the definition of an in-house test. The likely usage rate of the majority of these tests is extremely small. It is vital that such tests continue to be available for use by health services in Europe and worldwide. 19. The result of removing the exemption for in-house tests would be a severe drop in the availability of genetic tests. A continuation of the exemption in some form or another is therefore essential. Genetic testing provides invaluable information to health practitioners and patients; allows the planning of the management and treatment of conditions; enables valuable advice regarding family planning; delivers the relief to the patient that comes with a diagnosis; and furthers our knowledge regarding the incidence and natural history of the disease in question. 20. Any over burdensome regulation of in-house in vitro diagnostics would harm research and treatment in the area of personalised / stratified medicines for other conditions and rare diseases in Europe. We are concerned that possible changes to in-house tests could significantly increase the cost of research into personalised medicine and make it difficult for non-commercial research in this area to proceed, such as the programme Cancer Research UK is leading. Question 8: If the exemption provided for by article 1(5) of Directive 98/79/EC should be clarified or limited, which of the following items you would consider as appropriate in order to clarify the scope of this exemption and ensure a high level of safety: Item 1: Better define the concepts of "in-house test", "health institution", premises of a manufacture or premises in the immediate vicinity. Could you suggest an appropriate definition for these terms? 21. We believe that these definitions are clear but it could be helpful to better define these concepts in order to maintain the exemption and ensure it only applies where it is needed. For example, we could further define a health institution as a hospital or academic site used for the treatment and research of health. However, it could be difficult to further specify what is regarded as a health institution beyond this, across Europe. 4

5 Item 2: Require that all "in-house tests" fulfil the essential requirements of the Directive 98/79/EC, without being subject to a CE marking? 22. While Cancer Research UK believes that the exemption should remain, we believe that it would be possible to fulfil many of the essential requirements without going as far as CE marking. 23. For example, in the UK, the UKGTN ensures the provision of high quality equitable genetic testing services within the National Health Service (NHS). These laboratories offer molecular genetic analysis, clinical interpretation and reporting. These laboratories conform to clinical governance standards and will have clinical accreditation such as the Clinical Pathology Association (CPA). All diagnostic tests are required to undertake a recorded validation process and any subsequent modifications to the protocol as subjected to the same validation process. 24. The network is a collaborative group of all stakeholders with an interest in the regulation of genetic testing, including laboratories, clinicians, commissioners of genetic services and patient support groups. 25. The UKGTN provides regulation of genetic testing in the UK in a proportionate, costeffective manner. UKGTN accredited laboratory members have to comply with CPA (or other relevant) accreditation. Any measures to oversee quality, efficacy and safety of IVDs exempt from this directive should follow a similar pattern to the UKGTN. Tests cannot be used prior to validation. 26. This process complies with ISO norms and is a system that could apply across Europe since a similar process is undertaken in the Netherlands, for example. 27. This process could be formalised and would ensure a risk assessment is undertaken without subjecting all genetic tests to an expensive and lengthy CE marking process. 28. Such a process should allow flexibility to improve tests as more data becomes available, such as being able to include more codons to the KRAS test. In addition, laboratories in the UK and elsewhere already have a lot of the information needed for such an accreditation process (including evaluation, data and a list of reagents) so it would make the introduction of this process less painful than CE marking. 29. Cancer Research UK believes that if a formalised accreditation process was implemented in a sensible manner, it could have additional benefits. It would standardise the procedure across Europe and create a framework for the development of tests (rather than the ad-hoc manner in which they are often currently developed) and would encourage the sharing of protocols. 30. Furthermore, this accreditation process does not just assess the test (unlike CE marking) but the whole diagnostic process including the way the results are governed, and given that it is important how the result of the test is interpreted, an accreditation process would be more effective since it would assess the whole process. 5

6 Item 3: Require that all high risk (i.e. class D according to GHTF classification) "in-house tests" are excluded from the exemption provided for by article 1(5) of Directive 98/79/EC and then have to fulfil the essential requirements of the Directive 98/79/EC including the involvement of a notified body? 31. We do not agree with this proposal as it would be difficult to manage. The definition of high risk would need to also take into account the environment of the testing laboratory, the training of the operators as well as the robustness of the test. In addition, a test can be low risk but the test is undertaken a great number of times so it is more likely that someone will get one wrong. In addition, high risk (in terms of the potential impact) disease tests can be the most valuable. Item 4: Submit the health institutions and premises referred to in Article 1(5) of Directive 98/79/EC that manufacture "in-house tests" to accreditation, based on ISO 15189, or equivalent regulation at national level? 32. We would consider such an option as the method outlined in our response to Question 8, item 2 involves adherence to ISO Question 9: If the exemption provided for by article 1(5) of Directive 98/79/EC should not be maintained, would you consider it necessary to exempt in vitro diagnostic medical devices intended for diagnosis and monitoring of diseases or conditions affecting not more than 5 in 10,000 persons in the European Union from the scope of the IVD Directive and, if yes, why? 33. If the exemption is not maintained, it is reasonable that we have a cut-off point and this would be for rare diseases (based on the EU definition of a rare condition). However, this would therefore exempt all genetic tests for the vast majority of inherited genetic conditions but would not cover tests for stratified medicines, which is a growing area. 34. For example, should only diseases or conditions affecting fewer than 5 in 10,000 people, it may be difficult to assess how to define a test for EGFR in non-small cell lung carcinoma (NSCLC), since the incidence of the disease is higher, but the research is developing and the incidence of specific EGFR mutations in NSCLC is not as high as the incidence of the disease. Genetic tests In addition to the above there are increasing concerns regarding genetic tests (e.g. direct to consumer genetic tests, predictive tests), including genetic tests without a clear medical purpose. These concerns relate to, among other things, the lack of quality, lack of scientific evidence and lack of clinical validity or clinical utility of these tests. Question 10: Do you see a need for a clarification of the scope of Directive 98/79/EC to make clear that it covers all genetic tests that have a direct or indirect medical purpose while clarifying that tests without any direct or indirect medical purpose remain outside the scope of the Directive 98/79/EC. 6

7 If you consider that there is a need to clarify the scope of Directive 98/79/EC as regards genetic tests, which of the following items would you consider as appropriate: Item 1: Extend the scope to all genetic tests by adding a specific indent in the definition of in vitro diagnostic medical devices regarding devices which pursue the purpose of providing information concerning results obtained by analysis of the genome. Should, in this case, an exclusion be introduced in the Directive 98/79/EC as regards some categories of tests (negative list) e.g. paternity, DNA comparison? Item 2: Clarify that tests, including genetic tests, with a direct or indirect medical purpose are included within the scope of Directive 98/79/EC. 35. We have responded to these two items together to prevent repetition. While we acknowledge that there are concerns with genetic testing (as outlined in the questionnaire), we are of the opinion that it would be difficult to include certain categories of tests, such as paternity tests, in a negative list or another method since in some instances, these tests do not have a direct medical purpose, but in other circumstances, they do. 36. In addition, there may come a time when tests which do not have a clear medical purpose, such as eye colour or height, may have a medical purpose. As with our earlier comments, we believe that what is important here is governance of the whole diagnostic process and not just the molecular test. A molecular test may be perfectly adequate in the hands of an accredited diagnostic laboratory, but wholly inappropriate as a direct to consumer test. We therefore believe ongoing guidance at the national (from NICE, for instance) and international levels would be more appropriate than a negative list. Question 11: Do you see a need to create additional requirements or restrictions for direct-to consumer genetic tests in order to ensure a better level of health protection? If yes, on which aspects? 37. Cancer Research UK believes direct-to-consumer tests should undergo the same stringent assessment as diagnostic tests in a laboratory or related healthcare setting, including ensuring the quality of the tests and providers. In addition, we believe that consumers need legislation on the information and quality of services provided, and not just an assurance that the tests are safe, in order to sufficiently minimise risk. Conclusion 38. We thank you again for the opportunity to respond to this consultation. We would be willing to provide further information or meet to discuss the issues raised in our response, such as the exemption for in-house tests, should that be of interest to you. 7