Appendix O Nonprofit, Eventual Private/Public Funding Example: United Kingdom National Cancer Tissue Resource Background In 2000, the United Kingdom (UK) developed a National Cancer Plan with the primary aim of improving the quality of cancer care delivered by its National Health System (NHS) and positively impacting the country’s cancer survival rates. One of the plan’s most important initiatives was the establishment of two national cancer research networks, embedded in the NHS and distributed around the country. The first network, the National Cancer Research Network (NCRN), would be an infrastructure for large, multicenter clinical trials. The second network, the National Translational Research Cancer Network (NTRAC), would take the lead on translational research. These research networks are funded by the Department of Health (DH) and are under the strategic oversight of the National Cancer Research Institute (NCRI), whose key partners include DH, the Medical Research Council, and Cancer Research UK (a consortium of medical charities). NTRAC, the translational research arm, hopes to improve the quality of cancer care by creating a national network of cancer research centers that integrates scientific and clinical expertise and ultimately shares knowledge and resources for the benefit of cancer organizations and patients. These aims will be achieved through building research infrastructure and workforce capability within the centers, both to support the development of novel anticancer therapeutics and diagnostics and to test their promise in early clinical trials. Currently, full NTRAC Network Center status and funding have been awarded through a competitive process to 10 centers of scientific and clinical excellence. The funding support may be used with complete flexibility by each of the centers to actualize fast-track research for cancer patients. Like the United States, the UK found that limited access by academic research communities and industry to large-scale, high-quality biological samples linked to clinical information was a primary barrier to the maximization of recent advances in genomic, proteomic, and molecular research. Historically, there has been difficulty in obtaining funding in the UK through existing peer review mechanisms to support local sample acquisition. A shortage of pathologists and an increased demand for their services have negatively affected the acquisition and annotation of high-quality biological samples. Limited personnel and funding for sample collection and a lack of nationally standardized quality control (QC) mechanisms and standard operating procedures (SOPs) for the collection and storage of those samples have resulted in varied tissue collections, which are of limited potential use to emerging technologies. A lack of high-quality clinical outcome data associated with local biological sample collections also limits the ability to support research aimed at identifying novel prognostic markers. Recent misuse of human tissues, widely publicized by the popular press, has created ethical challenges, necessitating the legislative design of an ethical framework for the acquisition and use of human tissue. Faced with these challenges, many researchers are reluctant to share the limited tissue resources they might have with the wider research community. In order to overcome these substantial economic, logistical, and ethical barriers and to meet the current and future needs of the research communities, it was determined that a unified national approach to tissue collection was necessary. In January 2002, NCRI requested that NTRAC produce a strategic framework and blueprint for a National Cancer Tissue Resource (NCTR), including infrastructure requirements and resource implications, for the collection of high-quality biological tissue samples, well annotated with pathological and clinical data. It was necessary that the blueprint be built on principles of inclusion, accessibility, and flexibility and that it be established within a clear ethical framework that balances the interests of society and the rights of patients. Cathy Ratcliffe and Dr. Kirstine Knox of NTRAC assumed this responsibility and, following a series of workshops and consultations with experts (including from the U.S. NCI) as well as stakeholders throughout the country, produced a draft strategic plan in September 2002 for an NCTR in the UK. Goals The proposed strategy for the NCTR includes three key components: The NCTR must maximize benefits from existing high-quality collections of biological samples linked to clinical outcome information, with the aim of realizing the potential of the retrospective NHS paraffin-embedded tissue archive. Paraffin samples are valuable at both the hypothesis validation and clinical stages of the research process. This aim is particularly focused around gathering specimens from patients already enrolled in key clinical trials and will involve central collection of samples, the production of tissue microarrays, distribution to researchers, and collation of research results. The inclusion of this component will allow some work to go forward quickly with little infusion of new resources. The NCTR must provide infrastructure and workforce capability for prospective collection of population-based, high-quality samples linked to clinical information that would meet the needs of the academic research community and industry in a timely fashion. Frozen samples collected prospectively are the key to innovation at the hypothesis-generation stage of research. This requires dedicated personnel in surgical and pathology environments to collect, process, annotate, and store samples in a standardized, routine manner and to enter information into a clinical information system. The NCTR must ensure the compatibility of approach with international partners (Europe, the United States, Canada, and Australia) to maximize benefits for cancer researchers and patients. Standardization of systems that communicate globally could benefit cancer research around the world. As a result of its work in the UK, NTRAC has been charged with developing the SOPs for the collection of biological samples in Europe (ETRAC). Structural Overview NCTR will take the form of a managed, distributed network. NTRAC will be responsible for the implementation and operation of the resource. A competitive application process will be used to select a network of tissue acquisition resource centers for prospective collection of frozen tissue. Key existing clinical trials will provide paraffin-archived samples, with the process coordinated through NCRN and the Clinical Trials Office. Both frozen and paraffin-embedded tissues will feed into a second network of tissue processing centers. It is possible that some tissue processing centers and some tissue acquisition centers will reside in the same locale. The processing centers will process raw tissue into bioproducts including RNA, DNA, and tissue microarrays. A central bioinformatics hub will form the core of the NCTR. Initial plans are underway to use components developed with the UK e-Science program to develop a powerful, scalable, and secure infrastructure within 2 years. The hub will receive the results of the genomic and proteomic research in addition to standardized, site-specific histopathological data, and it will be responsible for tracking collection, storage, and analysis of deidentified samples. New procedures will be developed to access clinical and outcome information that currently is being collected by clinical trials. Additionally, clinical and outcome information from across the care pathway, including cancer registries, eventually will feed into the bioinformatics hub. Finally, the results of the analysis of samples will be integrated into the system. The ultimate aim is to build an information grid that automatically and seamlessly can incorporate all relevant data from each new patient into the appropriate database, input that patient’s data into existing predictive models, and transmit the resulting information back to the patient’s physician in the clinical environment. As envisioned, this bioinformatics platform also has the potential to serve as a model for other diseases and may facilitate international collaboration. Access to both tissue and data will be available to the academic research community and to industry through an equitable and transparent review mechanism. Initially, the NCTR plans to collect malignant and normal tissue, together with blood, from the five most common cancers in the UK: Breast, colorectal, lung, ovarian, and prostate. This initial limitation of scope increased the ease of obtaining funding for the resource. Expansion to collecting other (especially rarer) forms of cancer will occur as soon as is reasonably possible. Existing Systems The UK NCTR will incorporate existing systems, and in fact, base their new system on the contributions of various tissue collection protocols in existing clinical trials programs. In the UK, participation in the NCTR is linked to payment for services (National Health). Additionally, standards can be mandated by the Royal College of Pathologists and can be a requirement to receive National Health compensation. However, it is critical to the success of the UK system that it be established in a way that correlates with and is complementary to related national tissue bank initiatives. Governance/Organization The NCTR governance/organizational structure will comprise five key component parts: A Coordinating Unit, located within the NTRAC Coordinating Centre, will implement and operate the NCTR. A linked network of tissue acquisition resource centers (TARCs) will be selected through a tendering process and will be contracted to adhere to standard operating protocols for prospective collection of biological samples and outcome clinical information. A linked network of tissue processing resource centers (PRCs) for production of DNA, RNA, and tissue microarrays also will be selected through a tendering process and contracted to adhere to standard operating protocols. Tissue samples will be collected from key established and future clinical trials and will be coordinated through clinical trials offices and the NCRN. Finally, a central information system and bioinformatics hub will link: (1) Tracking of collection, processing, distribution, and analysis of samples to (2) histopathological datasets in line with The Royal College of Pathologists recommendations to (3) clinical/outcome information to (4) results of research. Oversight Oversight of the strategic direction and management of and access to the NCTR will be implemented and operated by NTRAC. Because the governance of the NCTR exists within the ethical framework mandated by the legal structure for England and Wales, the system of governance for the NCTR is the responsibility of the DH. Locating the NCTR within NTRAC means that the NCTR Chief Operating Officer is accountable to the Director of NTRAC and, through established accountability lines, to the DH as well as to the NCRI Board. The NCRI Board will provide strategic oversight, possibly through establishment of an NCRI Management Committee made up of representatives of the contributing funding bodies. An NCTR Steering Committee comprised of independent experts from the UK and other countries, together with representatives from the contributing funding bodies, will oversee access to tissue/information. It has been suggested that this committee be chaired by an international expert, possibly Dr. Stephen Hewitt, Director of the Tissue Array Research and Production Laboratory, NCI, or Dr. Peter Riegman, head of the European Union Framework V initiative on establishing a European human frozen tumor bank. Operational policies and procedures for the NCTR will ensure that: The NCTR operates within an ethical framework Standard contractual agreement that tissue acquisition and processing resource centers contribute to the activities of the NCTR Appropriate guidance and support are provided to all NCTR personnel through a training, education, and communications program as well as through ongoing advice NCTR equipment is adequately maintained A disaster management program is in place A succession planning program is in place Standards and Quality Control NCTR operational policies will include delineated SOPs for the TARCs. These SOPs will have guidelines for (1) obtaining explicit, written consent from well-informed candidate patients, using a standard national consent form and (2) collecting, handling, storing, and processing frozen tissues (including minimizing risk of tissue hypoxia and ensuring that patient diagnosis is never compromised by the sample harvesting process). Tissue manipulation SOPs will cover: Fixation, preparation, storage, and processing of paraffin-embedded tissue Collection, processing, and storage of blood samples Coding of samples and mapping storage locations at each TARC Obtaining complete histopathological datasets and systematic clinical and outcome information Distribution of NCTR samples to processing centers and/or directly to research communities Tissue sample processing for the production of bioproducts A QC policy will be implemented by the NCTR Coordinating Centre to ensure optimal standards of: Tissue sample quality and associated histopathological description—pathological review of representative hematoxylin and eosin sections Frozen tissues and bioproduct quality—extract and assess RNA Paraffin-embedded samples—assess fixation quality Sample location mapping and tracking Interrogation/validation of the information technology (IT) tracking system Sample Acquisition A fully operational NCTR will incorporate up to six geographically distributed TARCs. National Health Service units will be selected and contracted as TARCs by a tender selection process (i.e., through Requests for Proposals [RFPs]). A pilot phase will involve establishment of two or three TARCs functioning under SOPs and linked by an NCTR information system. Each TARC will guarantee Royal College of Pathologists-recommended minimum dataset histopathological assessment of every sample collected for the NCTR. Quality assurance (QA) mechanisms will be enforced by the NCTR Coordinating Centre. Tendering submissions will outline predicted sample accrual during Year 1 for breast, colorectal, lung, bladder, and ovarian tumor types. It is anticipated that each TARC will collect samples from up to 1,000 cases per year. Each TARC will be contractually obliged to fulfill sample and data collection criteria. The NCTR will implement a four-site pilot phase, which will allow assessment of sample collection rates across two or three TARCs and will inform the necessary scale of NCTR to meet the needs of the research community. It is envisioned that the approach will be scaled up during full operation of the NCTR, to include the acquisition, storage, and processing of rarer cancers such as pancreatic, head and neck, bladder, melanoma, and renal cell carcinoma. Sample Processing One or more PRCs will be selected to provide tissue microarray facilities for clinical trialassociated paraffin-embedded sample collections. Up to four PRCs will be selected to provide tissue processing facilities for frozen and paraffin-embedded, population-based TARC collections. It is possible that some PRCs may be synonymous with the TARCs. PRCs will be selected by a tendering process and will be contracted to process samples stored at the TARCs, as well as those associated with key clinical trials, according to SOP and subject to QA assessment. Funding NCRI partners and other government departments initially will fund NCTR. In particular, the Department of Trade and Industry will provide funding for informatics support. Eventually, private investment (as public/private partnerships) will be instituted in a regulated manner. Informed Consent The DH currently is reviewing the UK law on the removal, retention, and use of human organs and tissues. NTRAC is working to convey the feelings and wishes of researchers to the department. A new bill is being written for introduction in Parliament in late 2003 and for enactment in 2004. The key principle of the legislation is valid consent in a standard paragraph that is nationally agreed upon. Patients would consent (opt-in) to the use of their tissue and associated data for research. Eventually, as the level of public awareness is raised through national educational campaigns, an opt-out system (consent would be assumed unless patients opt-out of donating their tissues) might be considered. Access to Tissue and Data The ultimate goal of the NCTR is to automatically incorporate all relevant data from each new patient into the appropriate database, input that patient’s data into existing predictive models, and transmit that information to the clinician in the clinical environment to assist in treatment decision making. Access to both tissue and data will be available to the academic research community and to industry through an equitable and transparent review mechanism. It is envisaged that academic research communities will have access to tissue on a cost-recovery basis only and to bioproducts at a subsidized cost. It also is envisaged that industry will have access to bioproducts only at full cost of processing and delivery. Arguments for allowing access to industry include the following: Industry is a key player in drug development—on its own and increasingly in partnership with the academic research community; patients and society benefit from drug development advances Access to the NCTR will provide incentives for industry investment in the UK and thereby will help to improve the competitiveness of the UK cancer research base NCRI is a partnership among government, charities, and industry Expanded Services The NCTR expects to collect 6,000 samples per year. Initial testing will include DNA; RNA, supported by laser-capture microdissection; cryostat sections; microarray preparations for highthroughput screening; and blood components. A future rollout will encompass a variety of testing options including: Longitudinal—the NCTR plans to maximize benefits from existing high-quality collections of biological samples linked to clinical outcome information using the retrospective NHS paraffin-embedded tissue archive (which may limit its usefulness). This aim is focused particularly on gathering specimens from patients who are already enrolled in key clinical trials, where procedures for collection of outcome information are in place. Digital image analysis—molecular imaging; image acquisition; image analysis and archiving; quantitation tissue/cell microarray; and expression profile analysis Genomics—custom cDNA/genomic library services; DNA isolation/purification/ characterization; RNA isolation/purification/characterization; recombinant DNA plasmid construction; probe synthesis/labeling; mutagenesis services; transfection services; DNA sequencing; custom oligonucleotide synthesis; peptide synthesis Proteomics—target identification (cDNA cloning technologies); target validation (i.e., cell cycle, apoptosis, tumor suppressors); expression profiling using microarray technologies; protein expression target validation services (i.e., immunocytochemistry interpretation in relation to underlying pathology) Telepathology and reference laboratory services—special, molecular-based classification of human cancer (database linked with above—i.e., localization of gene and gene products in a range of normal and diseased tissues by in situ hybridization and immunocytochemistry); molecular therapies during clinical trials; contract services (i.e., therapeutic monoclonal antibody [cross reactivity]), other Food and Drug Administrationregulated, therapeutic-related studies (i.e., Herceptin, etc.); and clinical trials (i.e., automated DNA ploidy clinical trial; Good Laboratory Practice-compliant kinetic imaging Komet system) designed for use in regulated drug approval studies. Demonstration Project The NTRAC Strategic Plan was met with widespread acceptance and has been approved by the NCRI board. Final funding approval is expected shortly and will include expenditures of one million pounds per year over the next 5 years, with a review at 3 years. The NCTR will be implemented in a two-stage process that includes clear milestones and measures of performance. The first, a demonstration project stage, will involve four linked pilot programs to evaluate and refine operational models; the demonstration project will inform the second stage—widespread implementation. An oversight committee will ensure that the NCTR meets the ongoing needs of all its stakeholders.

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