PET Research A FRAMEWORK FOR PET RESEARCH IN THE UK. March 2007

Transcription

1 PET Research March 2007 A FRAMEWORK FOR PET RESEARCH IN THE UK

2 National Cancer Research Institute 61 Lincoln s Inn Fields PO Box 123 London WC2A 3PX Images on the page opposite and on page 44 were kindly provided by Dr Sally F. Barrington et al (33) and reproduced by permission of Edward Arnold (Publishers) Ltd info@ncri.org.uk

3 A FRAMEWORK FOR PET RESEARCH IN THE UK Report of the NCRI PET Strategic Planning Group A Framework for PET Research in the UK ii.

4 Contents Executive Summary Introduction The Opportunity for PET The Need for a Strategic Approach to Research Scope Scope for the Analysis The Scope of the Enquiry into PET Research Mode of Working The Current Position of PET in Cancer Management and Research Capabilities and Strengths of PET Use of PET in the Clinical Management of Patients PET Research The Emerging Role for PET in Drug Development Identifying the Research Questions and Priorities Clinical and Cost Effectiveness Developing the Role of PET in Anti-Cancer Drug Development Priorities for Technology Development The Necessary Conditions for PET Research in the UK UK Strengths for PET Research Areas of Uncertainty Barriers to PET Research Developing the UK Research Potential Introduction UK PET Research Steering Committee and Coordination Unit Training Looking to the Future iii. A Framework for PET Research in the UK

5 APPENDICES Appendix I Descriptions of PET and PET/CT Appendix II Members of the PET Strategic Planning Group Appendix III Expert Involvement Appendix IV Analyses of Current PET Research Appendix V UK PET-CT Advisory Board Appendix VI Financing PET Scans for Research Purposes Appendix VII Glossary of Terms and Acronyms Appendix VIII References Appendix IX Current and Planned PET Scanners and Cyclotron Facilities in the UK Appendix X Partners in the National Cancer Research Institute A Framework for PET Research in the UK iv.

6 Executive Summary Introduction Following the launch of the Framework for the Development of PET Services in England by the Department of Health, NCRI Partners agreed to consider the needs and opportunities for research that would flow from its implementation. In doing so, they have looked at the foreseeable applications of PET in cancer research throughout the UK and have also kept in mind the possibilities for application in other diseases. Clinical Applications of PET Positron Emission Tomography (PET) has the potential to provide a major advance in the management of patients with cancer and other diseases. It is used mainly for staging of some cancers, where it can prevent inappropriate use of radical therapy. In future it may be used to guide treatment regimens by providing functional definition of tumours and early assessment of response and such uses may lead to improved outcomes for cancer patients. In spite of the potential, evidence on the benefits and costs of PET scanning is relatively limited. The impact of PET on patient management and patient outcomes, and the health economic aspects of PET all need further assessment. Without action now, there is a risk that interventions which are expensive, yet not fully proven, will become accepted into clinical practice and the opportunity for research will be lost. This is unlikely to be in the best interests of patients, or a cost-effective use of limited NHS resources. As this report shows, the UK is well-placed to make an important contribution to clinical PET research, currently in cancer and then in other areas such as cardiology and neurology, as applications develop in these specialties: The National Cancer Research Network and associated NCRI Clinical Studies Groups and Clinical Trials Units provide an effective mechanism to identify the key questions in cancer and to develop and implement trial protocols. The wider UK Clinical Research Network (UKCRN) will be primed to pick up the research needs in other diseases. Under the Framework for the Development of PET Services in England, the NHS is making substantial investment in facilities for PET, with similar initiatives in the other UK countries. The UK PET-CT Advisory Board is developing a system of national audit and ensuring the quality of clinical scans across the NHS and Independent Sector scan providers. For clinical research to be carried out effectively, it will be necessary that: Arrangements for the provision of the treatment costs of research and service support costs function effectively within NHS Trusts. Research protocols are put in place to evaluate the impact of PET on patient outcomes and cost-effectiveness. Patient-related outcomes need to be defined differently for diagnostic, and for treatment related research. 1. A Framework for PET Research in the UK

7 Applications of PET in Experimental Medicine PET is now used as a research tool in drug development aiding the early selection, or elimination, of drug candidates. This application, both in academia and industry, will increase in the future. The principles and requirements of PET in experimental medicine are similar in different disease categories. The major research need is the validation of PET biomarkers to establish that they can be used in decision making with confidence. This type of PET research often requires more sophisticated and expensive equipment to enable on-site production of very short-lived isotopes and will thus be available in fewer locations. The UK s strengths are: A small but strong base for PET developmental research with a number of experienced researchers across industry and academia, and considerable expertise in the development and use of new tracers and instrumentation. Recently increased investment in experimental medicine in the academic sector for both cancer and other diseases. Research will be most effective if: There is close collaboration between industry and Experimental Medicine Centres. UK research is coordinated with international biomarker initiatives. Access to novel radiotracers is facilitated to promote the full potential of the emerging uses of PET in drug development, response monitoring and new uses in radiotherapy planning. Underpinning UK PET Research A number of structural problems must be rectified to underpin UK PET research. The most important are: The serious shortages in many of the professions required to provide both an effective clinical service and research capacity. The challenge of matching the supply and demand for the differing types of PET facility, as the use of PET in both clinical service and research grows. The diverse methods used for the acquisition and analysis of PET data which need to be harmonised to facilitate multi-centre research, increase the value of research and speed the translation of research into practice. The Way Forward The large number of possible research developments using PET, the multi-disciplinary nature of PET research, the number of organisations involved and the cost of equipment and scanning, make it essential that leadership and coordination is provided at national level. This will be provided through a UK PET Research Steering Committee which will act as an enabling body for PET research, facilitating a collaborative approach. It will comprise a small, influential group of the leaders of organisations that reflect the main themes relevant to PET research. The Steering Committee will be supported by a small PET Research Coordination Unit that will bring information and issues to the attention of the Committee and implement agreed actions. In partnership with research funders and the NHS, they will drive and integrate the diverse components of infrastructure, technology and workforce to provide an effective structure for PET research in the UK. Since cancer will be the initial focus, this initiative will be resourced by NCRI Partners in the first instance. A Framework for PET Research in the UK 2.

8 CHAPTER One Introduction 1.1 The Opportunity for PET 1 Positron Emission Tomography (PET) is a powerful functional imaging modality that provides dynamic, quantitative information on the biological characteristics of tumours and other tissues. While PET has mainly found clinical application in oncology, uses in cardiology, neurology and neuropsychiatry are expected to increase in the future. In oncology, scanning with PET can improve the accuracy of staging and thus optimise the treatment of patients with cancer. It also has the potential to improve outcomes from current treatments for cancer and to play an important role in the development of future drug treatments. The UK is well placed to take these opportunities forward. PET using 18 F-fluorodeoxyglucose (FDG) as tracer has been shown to be of clinical benefit by improving the staging of some cancers thereby allowing more appropriate treatment decisions and sometimes avoiding the inappropriate use of radical surgery and radiotherapy. PET is now combined with CT scanning to provide anatomical information. PET/CT scanners are used increasingly for clinical applications and are expected to have higher diagnostic accuracy than PET alone. (1) PET is likely to become an important tool in radiotherapy planning in the future and it may also prove to be of value in monitoring early response to radiotherapy or anti-cancer drugs, enabling treatment regimens to be adapted for those patients whose tumours do not respond to initial treatment. Quantitative PET, often using a range of shorterlived tracers, is being used as a research tool in drug development for a number of diseases, both in industry and in academia. It has the potential for contributing at several stages in the drug development pipeline and is increasingly likely to be used in the early selection, or elimination, of drug candidates. Implementation of the recommendations in the Framework for the Development of PET Services in England, published by the Department of Health in 2005 (2), together with initiatives in the Devolved Administrations for Wales, Scotland and Northern Ireland, will provide a significant increase in the capacity for PET/CT within the NHS from 2007 onwards. (3,4) This provides the initial infrastructure required to implement some of the established uses of PET in clinical practice and to help take forward the research needed to evaluate new indications and approaches. The UK has particular expertise and strength in PET research to support the development of these new applications. There are also strong academic initiatives in anti-cancer drug development and the UK is well-placed to provide an effective environment for commercial drug research using PET. Many countries have had greater access to PET scanning for both clinical and research purposes, and usage has become more widespread than in the UK. An argument may therefore be put forward that the UK has missed the opportunity for PET research and has little to contribute. This is not the case. The following report will demonstrate that much research is required to establish the staging uses of PET and new uses in response monitoring and radiotherapy planning in cancer. The role of PET as an investigative tool to increase confidence, and speed the drug development process, is also likely to expand in the future. PET scanning provides information 1 See Appendix I for descriptions of PET and PET/CT 3. A Framework for PET Research in the UK

9 on biological processes; as new understanding of disease biology and therapeutic mechanisms develops, so the ways in which PET can be used will continue to evolve. There will therefore be a continuing need for PET research and the UK is well-placed to make a significant contribution. 1.2 The Need for a Strategic Approach to Research A strategic approach to research is required to realise the full capability of PET and prevent its clinical use without validation of its effectiveness. PET scanning is an expensive, complex technology that exposes patients to radiation. The reasons for development of a national strategy to facilitate research are outlined below. The Need to Enhance the Evidence Base for the Clinical Uses of PET While there is significant potential, evidence substantiating the clinical value of PET is relatively limited (see section 3.2.1). Many research questions, particularly relating to the impact of PET on patient management, patient outcomes and health economic considerations remain to be answered. There is a danger that PET scans will be regarded by both clinicians and patients as an important influence on clinical decisions but information from PET may, however, lead to inappropriate decisions and treatment if its use is not properly validated. Research and evaluation is required to prevent de facto use. Commercial Drug Development The UK has much to offer commercial companies that want to use PET as a tool in drug development, both in cancer and in other diseases. There is a strong base for PET developmental research in the UK with a number of experienced researchers and considerable expertise in the development and use of new tracers and instrumentation. These capabilities are not provided by countries that are now offering low cost FDG-PET scans for clinical trials and they provide an opportunity for the UK to develop competitive advantage in attracting industry-sponsored research. The Need for Training There are serious skills shortages in many of the healthcare, scientific and technical professions required to deliver an effective PET clinical service and to support research. The provision of training needs to be closely linked to infrastructure, both in terms of specialised facilities in which to train staff, and in delivering adequate numbers of trained personnel to meet future skill and capacity requirements. A number of academic, clinical and commercial organisations have a role to play in the provision of training and infrastructure. Efforts must be cooperative and will need to be coordinated if they are to be successful. The Need to Standardise PET Methods and Protocols There is considerable variation in the methods used in clinical PET research which inhibits collation of research findings and can also be a barrier to multi-centre research. The lack of standard methods is a particular constraint for research using quantitative methods, on which some emerging uses of PET, such as radiotherapy planning and response monitoring, are dependent. A plan is needed to bring together investigators in the UK to agree common approaches and participate in international initiatives to standardardise methods for clinical PET research. This will increase the general applicability of research findings and speed the translation of research into clinical practice. The Complexity and Expense of PET Infrastructure Requirements The capital cost of a PET facility for clinical use is in the region of 2m and individual scans, using commercially produced FDG, can be purchased for around While provision of PET for routine clinical use in the NHS will carry considerable cost, it is intended that national coverage will be achieved. The additional infrastructure required to deliver this clinical service is largely being developed by the Independent Sector. While clinical and commercial pressures will be the main determinants of the nature and location of facilities, national coordination will help to maximise research opportunities. Research using isotopes with shorter half-lives such as 11 Carbon and 15 Oxygen requires an onsite cyclotron and radiopharmaceutical facilities, and quantitative PET research requires further specialised facilities and expertise. These facilities are substantially more expensive and technically A Framework for PET Research in the UK 4.

10 complex to set up and run than those required for the production and use of FDG in clinical practice or qualitative research. It will not be feasible to have more than a small number of such specialised facilities in the UK in the foreseeable future. Decisions on the placement of any such new facilities should be made strategically, and industry will also have a role to play in providing facilities and expertise for collaborative research. Summary of Main Conclusions PET research involves multidisciplinary working and is a long-term endeavour that requires collaborative working between researchers, research funding organisations, the NHS, Independent Sector scan providers and industry (both the pharmaceutical and medical devices sectors) to ensure that resources are targeted to best effect. Leadership and coordination at national level will be needed to oversee and integrate the diverse components of workforce, infrastructure and technology, to provide an effective platform for PET research in the UK, to avoid unnecessary duplication and to facilitate a collaborative approach. This report explores how this might be achieved. 5. A Framework for PET Research in the UK

11 A Framework for PET Research in the UK 6.

12 CHAPTER TWO SCOPE 2.1 Scope for the Analysis The NCRI Board agreed to set up a Strategic Planning Group (SPG) to consider the research needs for use of PET scanning in cancer and how best to take them forward, in response to the Department of Health s (DH) consultation on a draft framework for PET in the NHS in England. (5) The interests of the NCRI Partners are broader than clinical research and it was, therefore, agreed at the outset that the Group would consider all aspects of PET that were of potential interest to Partners (Appendix X lists the Partners in NCRI). The membership of the NCRI PET SPG is appended (Appendix II). At the first meeting, the scope of the review was delineated in the following terms: PET technology and method development Instrumentation and software Image reconstruction and analysis Radiochemistry and radiotracer supply Kinetic modelling Infrastructure requirements Workforce issues Capacity issues Facility requirements Research on the role of PET in the clinical management of patients Staging of cancer Monitoring response to therapy Radiotherapy planning Health economic assessment Methods for clinical research Use of PET as a developmental research tool Cancer biology and physiology Drug development 2.2 The Scope of the Enquiry into PET Research The SPG placed some limitations on the scope of the enquiry: Cancer The use of PET to investigate cancer biology in model systems was not included as part of the consideration of PET research. Cancer biologists tend to use imaging modalities based on fluorescence or bioluminescence which are high through-put, relatively cheap to run, do not use radioactivity and require little infrastructure. These techniques are a part of modern cancer research, for example many genetically modified cell and animal lines have been established using optical reporter genes, and can be used to visualise processes such as apoptosis and gene expression. 7. A Framework for PET Research in the UK

13 Other Diseases Although the SPG was largely concerned with the use of PET scanning in cancer, it kept in mind the possibilities for application in other medical fields. It was clear that the main clinical application would be in cancer for the foreseeable future. When opportunities do arise in other diseases, careful consideration of the balance of benefits and risks in relation to radiation exposure is required. Other imaging modalities may sometimes be more appropriate. Nonetheless, the SPG considered that the infrastructure and coordination requirements identified in the proposed framework for PET research in cancer would be readily applicable to other fields of medicine. 2.3 Mode of Working Strategic Planning Groups (SPGs) are joint planning exercises, aimed at developing a coherent approach among NCRI Partners to funding research in specific areas. The Groups consist of senior representatives of NCRI Partner organisations, patient representatives and other interested parties where appropriate. The role of an SPG is to carry out an evidence-based overview of an area to identify gaps and opportunities in research and to recommend and begin to oversee actions which participating Partners may undertake either individually or collectively. harness a wide range of expertise and opinion. The SPG held a series of workshops during late 2005 and early 2006 on PET clinical research and health economic questions, PET technology and method development, the use of PET in translational research and cancer biology, and the use of PET in radiotherapy planning. A list of the experts who assisted the SPG in all these activities is shown in Appendix III and reports from all workshops are available on the NCRI web site. The NCRI Consumer Liaison Group (CLG) also hosted a discussion on PET scanning. Consumer input from the patient representatives on the SPG was broadened by inviting additional representatives from the CLG to the workshops. The SPG has liaised closely with the Royal College of Radiologists and the UK PET-CT Advisory Board which is taking a lead on issues arising from the implementation of PET clinical services (Appendix V). Professor Souhami, who has chaired the NCRI PET SPG, is a member of the UK PET-CT Advisory Board. The SPG has worked closely with UKCRC, with representatives attending meetings and workshops. A wide range of individuals and organisations were also consulted on the report and the proposed developments and are listed in Appendix III. The method of working is to gather evidence from multiple sources, which generally include analyses from the NCRI Cancer Research Database, expert opinion, published data and, where appropriate, specially commissioned reports. The SPG uses this evidence to examine issues such as resources and infrastructure, training and workforce capacity, funding and portfolio balance to identify priority areas, and to identify any barriers to progress in those areas. This evidence-based approach allows the SPG to devise solutions relevant to the obstacles and opportunities in the area under investigation. In the present case, a dossier was compiled by the Secretariat and initial briefings were invited from experts. Analyses were performed from the NCRI Cancer Research Database and other relevant research databases, and an on-site visit to a PET Centre was arranged. However, the bulk of the evidence gathering was via workshops with experts and organisations to A Framework for PET Research in the UK 8.

14 CHAPTER THREE The Current Position of PET in Cancer Management and Research 3.1 Capabilities and Strengths of PET PET is a sensitive method for the quantitative and non-invasive measurement of physiological processes in vivo in man. Biologically relevant molecules are labelled with positron emitting radionuclides to produce socalled radiotracers; a ring of detectors is used to detect positron emission and the location of the radiotracer is ascertained by tomography. There are two main reasons why the major clinical application of PET scanning is in cancer. The most established and widely available radiotracer, FDG, is preferentially taken up and retained by tumour tissue because tumours can have high levels of glucose metabolism. Also, the risk to cancer patients from the radiation dose involved in PET scanning is generally considered to be proportionate to the severity of the disease. This is not necessarily the case for other diseases or younger age groups. In addition to its clinical use, PET has particular strengths when used as a tool to aid drug development. Positron emitting radionuclides can be substituted for naturally occurring isotopes in organic molecules. Many drugs can therefore be labelled without changing their chemical structure or function. PET is highly sensitive and this, together with the biological authenticity of many radiotracers, means that systems can be studied with relatively little unintended perturbation, although attention has to be paid to how the molecule is metabolised in the body. The availability of animal PET scanners also enables inter-species comparative studies to be undertaken during drug development. 3.2 Use of PET in the Clinical Management of Patients The major current use of PET in the clinical management of patients is the staging of cancer. The information is predominantly of value in assigning the appropriate treatment and in sparing patients from radical interventions such as surgery. The evidence base for this use, and related issues, are discussed below. However it is highly probable that PET will also be used to monitor the response of tumours to treatment with drugs or radiation. Information from scans performed during treatment will be used to change and adapt treatment regimens. This is distinct from the use of PET in staging, where scans are done before treatment and the information is used to direct patients between existing treatments. Much research is needed to establish the role of PET in assessing response to therapy before it is applied in clinical practice. This is discussed further in Chapter FDG-PET in Staging International Health Technology Assessment (HTA) reports have consistently concluded that there are few indications where there is convincing evidence of the clinical and cost effectiveness of FDG-PET. There is evidence that FDG-PET changes the management of patients in some settings. This is important, as are other end points of benefit to patients such as more rapid completion of staging but there is little evidence that these changes in staging lead to improved longer-term outcomes such as survival. The Ultra Rapid Review commissioned by the National Coordinating Centre for Health Technology Assessment (NCCHTA) reported strong 9. A Framework for PET Research in the UK

15 evidence of the clinical effectiveness of PET in the staging of non-small cell lung cancer (NSCLC) and in the re-staging of Hodgkin s disease. (6) These applications are generally considered to also be cost- effective. (1) The same review concluded that there is strong evidence of the clinical effectiveness of PET in the initial staging of recurrent colorectal cancer although further economic evaluation in a UK setting is still required. (6) The National Institute for Health and Clinical Excellence (NICE) guidance on lung cancer, issued in February 2005, recommended the use of PET scanning to stage patients who are candidates for surgery or radical radiotherapy and also as part of investigations into solitary pulmonary nodules. (7) The guidance recommended that every cancer network should have a system of rapid access to FDG-PET/CT scanning for eligible patients. There is suggestive, but less strong, evidence of the accuracy and value of PET in the staging of a wide range of other cancers. (1,6) Further research is required to establish these uses. There are several outcomes to be considered: changing management, avoidance of inappropriate treatment, quality of life, survival and economic assessment. These research issues are considered further in section Current Practice There has been little clinical use of PET in the UK to date, in part due to the low number of PET facilities and also the fairly limited evidence base. In some other countries, however, PET is being used much more extensively in clinical practice for a wide range of indications including those where HTA assessments suggest that further evidence of clinical and cost effectiveness in the UK is required. Medicare coverage for PET/CT scanning for cancer in the USA, for example, extends to use for specific indications in NSCLC, colorectal, lymphoma, melanoma, oesophageal, head & neck, breast and thyroid cancers. (8) Such National Coverage Determinations are based on whether PET/CT is considered to be reasonable and necessary for the diagnosis or treatment of illness or injury. The approval mechanisms used by the US Centres for Medicare and Medicaid Services (CMS) do not, however, explicitly cover health economic considerations. In contrast, Canada has a universal healthcare system funded through tax revenue. The Province of Ontario has decided that a higher level of evidence than that currently available is required for almost all indications prior to making a funding decision. PET/CT scans are therefore only available within specific clinical trials designed to establish the evidence base before wider use and within a limited number of indications where data must be entered into a PET registry. (9) CMS have recently taken the unusual step of introducing a new type of coverage, CMS Coverage with Evidence Development (CED), which links coverage with the requirement for prospective data collection. (10) CMS expects to use CED infrequently, for promising technologies that are unproven and where current evidence development is not adequate for National Coverage Determination. Under this policy, CMS coverage is provided for the use of PET/ CT for the diagnosis, staging, re-staging and therapy monitoring in nearly all cancers on the condition that data is entered into the National Oncologic PET Registry. (11,12) This Registry will be used to determine whether and how PET scanning affects treatment plans for patients and to inform future CMS coverage decisions. Reimbursement of scan costs on condition that data is entered into a national registry is also being pursued by other countries as an approach to evaluating less well-established uses of PET Evaluating an Evolving Technology The diversity of approaches to implementing and evaluating PET in clinical practice is one example of the difficulty of evaluating a technology which can change and evolve faster than the evidence supporting its use is developed. This challenge is particularly relevant with PET because of the rapid and widespread introduction of PET/CT since The ability to co-register functional and anatomical images greatly extends the capability of PET scanning and the diagnostic accuracy of PET/CT is generally much better than that of PET. (1) The use of PET/CT in staging cancer is therefore increasing rapidly, ahead of research and publication of data on clinical and cost effectiveness. A Framework for PET Research in the UK 10.

16 3.2.4 Research within the PET Service Framework Cancer Current developments in line with the Service Framework will provide approx. 40,000 scans for cancer patients in England by (2) Of these, it is estimated that 30,000 scans will be used for indications for which there is a high level of evidence to support clinical implementation (so called level A indications). A further 10,000 scans will be available for a number of indications where further evidence development is required (level B or C indications) as summarised in Table 1 below. Data from PET registries, such as those set up in the USA and Australia and currently planned in the UK (see section 4.1.3), will be an important source of information as to whether, and how, patient management is altered by PET scanning. Reliable evidence on patient outcomes, however, cannot be obtained by registry data alone and prospective randomised clinical trials are required where the contribution of PET to patient outcomes can be clearly evaluated. It is therefore important that the scans conducted on level B and C indications within the UK are included in clinical research protocols and that these scans contribute to development of the evidence. Without this, un-validated uses of PET will become established in clinical practice and the opportunity for research will be lost since it will then be impractical to conduct randomised trials. Other Diseases Implementation of the Service Framework will also provide approx. 6,000 scans for use in diseases other than cancer. There is evidence that FDG- PET can be used to assess myocardial viability to identify patients suitable for revascularisation and also evidence of diagnostic accuracy for use in Alzheimer s disease and in the pre-surgical evaluation of refractory epilepsy. (13) Further research is required to establish both these and other uses of PET in cardiology and neurology. Tumour Group Indications / basis for estimate Likely # of scans Lung Lymphoma Colorectal cancer Assessment of suitability of radical therapy (surgery or radiotherapy) Assessment of solitary pulmonary nodule Monitoring for reoccurrence / other 2 3 scans per new patient with Hodgkin s disease or non-hodgkin s lymphoma, for staging, monitoring treatment response and assessing recurrence Assessment of recurrent disease including suitability for resection of liver metastases 10,000 15,000 5,000 Oesophageal cancer Assessment of suitability for radical surgery (level B) 2,000 Other cancers with level B evidence Brain and spinal cord Thyroid Testical Sarcoma Melanoma 5,000 Other cancers with level C evidence Head and neck Breast Unknown primary 3,000 TABLE 1: Estimated demand for cancer-related PET scans in England used to inform the PET Service Framework. (2) 11. A Framework for PET Research in the UK

17 3.2.5 Development of the PET Service Infrastructure The UK currently has relatively few PET scanners and there has been pressure to increase the clinical use of PET, particularly for lung cancer staging where NICE guidance has now been issued. Implementation of the Service Framework for England, issued for consultation in July 2004 and published in October 2005, will provide a very rapid and substantive development in what is a complex, multi-disciplinary technology. To achieve this step change in such a short period of time, much of the increase in capacity will be delivered by the Independent Sector. While it is clear that implementation of the Service Framework, together with initiatives in the Devolved Administrations, will provide reasonable geographic coverage of the UK there is some uncertainty at present as to the precise nature of the facilities and their location. The service will be delivered by a combination of both static and mobile PET/CT scanners but the number of fixed sites, extent to which mobiles will be used and how frequently they will move remains to be seen. The location of current PET and PET/ CT scanners for service delivery and research, together with expected developments in the UK at the time of writing are shown in Figure 1. Contracts for the provision of PET/CT scans from the Independent Sector are being negotiated by DH. The invitation to negotiate has been issued, detailed bids received and contracts are now being negotiated; greater clarity on the precise nature and location of all facilities in the UK should be available once the contracts are agreed. Arrangements for access to FDG are not being negotiated centrally by DH but will instead be made directly by the Independent Sector on a commercial basis. Supply is likely to be from a combination of existing and new commercial cyclotron facilities and also partnership arrangements with academic facilities. The location of current and expected cyclotron facilities in the UK at the time of writing is also shown in Figure 1. These infrastructure issues are considered further in section Summary of Main Conclusions The Clinical Use of PET The main clinical use for PET scanning is the staging of cancer where the information is predominantly used to avoid inappropriate radical therapy. There is evidence that the use of PET leads to changes in patient management for some cancers but as yet there is little evidence that PET scanning leads to improved patient outcomes in terms of survival, morbidity or quality of life. There will be a significant increase in the capacity for PET scanning in the UK from 2007 onwards, including provision for studies to obtain further evidence of its value. Clinical scans within the Service Framework should contribute to research where the contribution of PET to patient outcomes can be evaluated. Without this, un-validated uses of PET will become incorporated into clinical practice and the opportunity for research will be lost. Much of the increase in capacity for PET scanning in the UK will be delivered by Independent Sector providers using mobile scanners. There is some uncertainty at present as to the precise nature and location of scanners and cyclotron facilities in the UK. A Framework for PET Research in the UK 12.

18 FIGURE 1: The location of PET/CT (and PET) scanners for NHS clinical and/or research use together with cyclotron facilities. Both current and planned developments are shown. Further details are provided in Appendix IX. Note: The figure does not include scans that will be provided by the contracts currently being negotiated with the Independent Sector. 13. A Framework for PET Research in the UK

19 3.3 PET Research PET Research Activity in the UK The SPG analysed the NCRI Cancer Research Database and other research databases to build a profile of PET research activity in the UK. NCRI Cancer Research Database The NCRI Cancer Research Database (CRD) contains the research funded by NCRI Partners that can be directly attributed to a set of clearly defined research objectives. The CRD is updated annually and can be searched to identify research spend as at 1st April in each year since The 2004 and 2005 CRDs were searched using key words to identify research grants awarded by NCRI Partners for research involving PET. A total of 15 grants, with an annual research spend of approx. 2.9m, were active as at 1st April This increased to 20 grants, with an annual research spend of approx. 3.1m, active as at 1st April This increase in spend on PET research is in line with the increase in the total spend with the CRD, with PET-related spend representing approx 0.9% in both 2004 and The data are summarised in Table 2 below. Research in the CRD is coded using the Common Scientific Outline that categorises research into the specific areas of Biology, Aetiology, Prevention, Early Detection, Diagnosis & Prognosis, Treatment, Cancer Control and Scientific Model Systems. Over 90% of PET related research within the CRD in 2004 and 2005 was categorised as either Early Detection, Diagnosis & Prognosis or Treatment research, reflecting the clear role of PET in the staging of cancer, clinical treatment and drug development. Results are summarised in Figure 2 below and further details of these analyses can be found in Appendix IV CRD 2005 CRD Number of Grants PET Research Spend 2,857,314 3,105,650 Total CRD Spend 302.7m 342.9m PET spend as % of CRD 0.94% 0.91% TABLE 2: Grants and research spend involving PET FIGURE 2: Spend on PET related research grants by Common Scientific Outline A Framework for PET Research in the UK 14.

20 Clinical Research Databases Clinical trials using PET are not fully represented in the CRD, because it does not include the funding provided by DH for own account research undertaken by NHS Trusts, and studies funded by organisations outside NCRI, such as local charities. Specific UK clinical research databases (the National Research Register and NCRN portfolio database) were therefore searched to develop a profile of PET clinical research within the UK. A total of 31 trials were identified as in progress in June The majority of these trials were small scale, single centre trials with only two trials having accrual targets of over 100 patients and one of these trials has subsequently terminated prematurely. This leaves the trial in Hodgkin s Disease (Randomised Phase III trial to determine the role of FDG-PET Imaging in Clinical Stages IA/IIA Hodgkin s Disease) as the only active PET trial in the NCRN portfolio. The fragmented clinical trial activity probably reflects the limited capacity and infrastructure for PET scanning in the UK. Further details of this analysis can be found in Appendix IV. Similar findings, i.e. small-scale studies with little multi-centre research, are to be reported in the forthcoming HTA Monograph on the Clinical Effectiveness of PET Imaging. (1) One of the major funding sources for these trials was the own account element of DH R&D NHS Support Funding. This funding stream is gradually being withdrawn and replaced with specific initiatives as the DH R&D Strategy for England (Best Research for Best Health) is implemented. (14,15) International Perspective Clinical trials databases were searched to build an international profile of clinical trials involving PET. All databases that comply with the registry standards set by the International Committee of Medical Journal Editors (ICMJE) were searched; the ICMJE require that all trials are registered in an approved registry if trial results are to be published in ICMJE journals. A total of 24 trials, either open or in development were identified; the PET research question was the primary outcome in half of these trials. The major disease site was lung, with 8 trials, followed by lymphoma and colorectal cancer which each had 3 trials and sarcoma which had 2 trials Eight other tumour types were the subject of a single clinical trial. The major location for clinical trials involving PET was Northern America with 8 trials taking place in the United States and 3 trials in Canada. European trials activity was found in France, Germany, the Netherlands, Switzerland and the UK with 1 2 trials in each country. A similar level of activity was also seen in Australia, Japan and Taiwan. Further details of this analysis can be found in Appendix IV. Summary of Main Conclusions UK PET Research There is currently a relatively low level of spending on PET research by NCRI Partners. Clinical research into PET scanning in the UK is small scale and fragmented with only one, major, randomised controlled trial currently in progress. 15. A Framework for PET Research in the UK

21 3.4 The Emerging Role for PET in Drug Development Structural imaging using CT or MRI has a major role in assessing tumour shrinkage and progression in all phases of drug development including registration. The role of the novel imaging technologies has been principally in assessing pharmacodynamic end points e.g. blood flow, proliferation and metabolism with an increasing focus on making effective stop decisions earlier in the development process and prioritising star performers. An example is provided in Box 1. Many uses of PET in pharmacodynamic and pharmacokinetic research require use of short-lived isotopes and can only be carried out in facilities with an on-site cyclotron Pharmacokinetic Research Candidate drugs can be labelled with positron emitters to determine the distribution within the body, whether the drug reaches the tumour, intra-tumoural distribution and what level of drug is achieved (i.e. pharmacokinetic studies). This can provide valuable information to help decide which candidate drugs should proceed through the development process and can also inform decisions on dosing regimens and the route of drug administration. PET has been shown to have value in assessing drug biodistribution in the context of neurology where it can provide information on whether or not drugs pass through the blood-brain barrier. This use of PET is less well-established in oncology and further research is required to establish its value Pharmacodynamic Research Drugs are often targeted against specific receptors. By radio-labelling receptor ligands, PET can be used to determine whether a candidate drug interacts with the target receptor and can also provide information on target occupancy which is helpful for dose planning. As well as reporting on individual proteins in isolation, one of the strengths of PET is that it can report on biological processes within cells, representing the combined effect of many proteins and/or interactions. Radiotracers have been, and are being, developed to image processes such as apoptosis, proliferation, angiogenesis, perfusion and to provide information on the hypoxic status of tissues. These can help determine whether a drug is affecting tumour biology and whether this is consistent with what is known about the downstream action(s) of a particular molecular target. This helps inform decisions on whether to proceed with further development of the drug in question and the information is also valuable in validating drug targets for further research. PET radiotracers such as those used in pharmacodynamic research are essentially biomarkers in that they act as indicators of biological processes and can be used to report on how these processes change during tumour development or in response to drug treatment. If they are to be used with confidence, such biomarkers must be fully validated and evidence obtained to confirm that they report accurately on the biological characteristic under study. This validation process can be time-consuming, resource intensive and technically challenging and collaborative approaches are generally required to build sufficiently large data-sets. It is a long-term process and the degree of confidence in each particular biomarker will develop over time. Use of the term validation is gradually being superseded by qualification to reflect the fact that evidence to support each particular use of a biomarker has to be established rather than a biomarker being validated for all uses i.e. validation is a qualified process. PET scanning also has a role to play in the pharmacodynamic assessment of drugs for other diseases. For example, the use of PET in the development of drugs to treat cardiovascular disease may increase in the future. Atherosclerotic plaques are asymptomatic until the lesion is large enough to limit blood flow, causing ischaemia, or it ruptures, potentially leading to the formation of a thrombus and myocardial infarction or stroke. Plaque inflammation is one of the major determinants of rupture and can be imaged using FDG-PET. (16) Early Assessment of Tumour Response FDG-PET is being used to provide early assessment of whether tumour growth is inhibited, regardless of the molecular mechanism of the drug. This can increase the speed of early phase clinical trials and may be particularly helpful in assessing A Framework for PET Research in the UK 16.

22 drugs that have a cytostatic, rather than cytotoxic, action since changes in tumour metabolism can be visualised rather than relying on tumour shrinkage. As well as being used as biomarkers to reduce risk and increase confidence in the drug development process, PET may also be used as a surrogate end point in clinical trials to speed up drug approval. A surrogate end point is a biomarker that acts as a substitute for a clinical end point, i.e. it reports on how a patient feels, functions or survives. Surrogate markers will often share a causal mechanism with the clinical end point in question. Again, extensive research is required to validate such markers although FDG-PET is close to being qualified for use in lymphoma. Summary of Main Conclusions The Role of PET in Drug Development There are an increasing number of molecular targets available for the development of anti-cancer drugs and new methods such as PET are needed to validate these targets and rapidly evaluate candidate drugs. PET has the potential to influence decisions on the development of drugs by determining whether they affect tumour biology and by enabling early assessment of anti-tumour effect in clinical trials. This information also helps to validate drug targets for future research. BOX 1: Early assessment of drug activity using FDG-PET CT PET FDG-PET can provide evidence that drugs alter tumour biology ahead of tumour shrinkage. The panel shows CT and PET images of thyroid cancer before (upper panel) and after treatment (lower panel) with ZACTIMA TM. This information, along with other clinical data, supported the decision to conduct further trials in medullary thyroid cancer. [Reproduced with kind permission of the AstraZeneca Zactima team (31) ] 17. A Framework for PET Research in the UK

23 A Framework for PET Research in the UK 18.

24 CHAPTER FOUR Identifying the Research Questions and Priorities The preceding Chapter identified considerable scope for PET research, both in the management of cancer patients and opportunities for innovative approaches to anti-cancer drug development. This Chapter explores the research needs and opportunities in more detail and indicates how research questions may be defined and prioritised. 4.1 Clinical and Cost Effectiveness Introduction In a resource-limited environment, both evidence of clinical effectiveness and economic evaluation of the benefits and costs are required to ensure that services represent value for money. The hierarchy of evidence for diagnostic technology, developed by Fryback and Thornbury, provides a useful framework to consider the development of evidence to support the clinical use of PET. (17) The model extends from basic technology development through to clinical application where diagnostic accuracy, impact on thinking about diagnosis or treatment options, patient outcomes and health economic issues are progressively important considerations (see Table 3). An important aspect of this framework is that increased efficacy at lower levels, such as diagnostic accuracy, does not guarantee increased efficacy at higher levels such as improved patient outcomes and cost effectiveness Areas of Research Need Staging Much PET research has been focused on establishing its diagnostic accuracy but, as outlined in section 3.2.1, there are only a small number of indications where there is firm evidence that this improved diagnostic accuracy leads to changes in the management of patients, and even fewer where such changes have been shown to improve patient outcome. Greater emphasis on research at the higher levels of the diagnostic hierarchy is required to identify where PET can usefully change management and how this can benefit patients. Level Description 1. Technical Technical imaging quality 2. Diagnostic accuracy Sensitivity, specificity, positive and negative predictive values 3. Diagnostic thinking Extent to which the image is helpful in making the diagnosis 4. Therapeutic Degree to which helpful in planning the management of patients, procedures avoided or therapy changed 5. Patient outcome Improvement in survival, disease free-progression, morbidity or quality of life 6. Societal Cost-benefit analysis TABLE 3: The hierarchy of evidence for diagnostic technology proposed by Fryback and Thornbury. (17) 19. A Framework for PET Research in the UK