Appendix A
Previous and Ongoing Analyses Undertaken by NCI

In the 50 years of its existence, the Cooperative Group Program has advanced the treatment of cancer and the conduct of clinical research. Despite these successes, the Cooperative Group Program has continued to face a number of challenges that threaten its effectiveness. To further explore the challenges and opportunities confronting the Cooperative Groups, multiple evaluations of the Program have been conducted. Two of the most recent reviews of the Cooperative Group Program include the Armitage report (1997) and a review by the Clinical Trials Working Group (CTWG) in 2005. As a result of the CTWG report, the National Cancer Institute (NCI) established the Operational Efficiency Working Group (OEWG) to provide recommendations for improving the time from concept approval to enrolling patients on a clinical trial. In addition to these specific recommendations aimed at the Cooperative Group Program, the Program has also been influenced by other working group recommendations, including the Translational Research Working Group (TRWG) report recommendations.

REVIEWS OF THE COOPERATIVE GROUP PROGRAM

Armitage Report

In 1996, the NCI director and the chair of the Extramural Board of Scientific Advisors commissioned an external review of the Cooperative Group Program in response to concerns that the clinical trials portfolio had become increasingly inefficient and unresponsive to evolving needs.



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Appendix A Previous and Ongoing Analyses Undertaken by NCI In the 50 years of its existence, the Cooperative Group Program has advanced the treatment of cancer and the conduct of clinical research. Despite these successes, the Cooperative Group Program has continued to face a number of challenges that threaten its effectiveness. To fur- ther explore the challenges and opportunities confronting the Cooperative Groups, multiple evaluations of the Program have been conducted. Two of the most recent reviews of the Cooperative Group Program include the Armitage report (1997) and a review by the Clinical Trials Working Group (CTWG) in 2005. As a result of the CTWG report, the National Cancer Institute (NCI) established the Operational Efficiency Working Group (OEWG) to provide recommendations for improving the time from concept approval to enrolling patients on a clinical trial. In addition to these specific recommendations aimed at the Cooperative Group Program, the Program has also been influenced by other working group recommenda- tions, including the Translational Research Working Group (TRWG) report recommendations. REvIEWS OF THE COOPERATIvE GROuP PROGRAM Armitage Report In 1996, the NCI director and the chair of the Extramural Board of Scientific Advisors commissioned an external review of the Cooperative Group Program in response to concerns that the clinical trials portfolio had become increasingly inefficient and unresponsive to evolving needs. 2

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2 A NATIONAL CANCER CLINICAL TRIALS SySTEM The Clinical Trials Review Group was asked to recommend changes to the current system that would (1) take advantage of the most promising opportunities in therapy and diagnosis; (2) prioritize the most important research questions so that they can be explored in the fastest possible time; (3) improve the organization, funding, review, and cooperation in the Cooperative Group Program; and (4) attract both patients and researchers to participate in clinical trials. The review committee met six times over an 11-month period and included experts from academic research institutions, cancer centers, community oncology practices, cancer patient advocacy groups, and the National Institutes of Health. The committee released its findings, known as the Armitage report, after its chair, James Armitage, in 1997 (NCI, 1997). The report made the recommendations regarding review, funding, design, oversight, and administration of the NCI clinical trials system. A subse- quent implementation committee report was completed in 1998. Clinical Trials Working Group Report In 2004, the NCI director established the CTWG to advise the National Cancer Advisory Board on the development, conduct, infrastructure, sup- port, and coordination of cancer clinical trials across NCI. The CTWG was asked to develop recommendations to (1) optimize the NCI-supported clinical trials system by improving coordination and research infrastructure, (2) remove institutional and regulatory barriers that inhibit collaboration in clinical trials research, and (3) envision how clinical trials should use the tools of contemporary bioinformatics and molecular medicine. The review committee conducted 7 face-to-face meetings and 10 group conference calls over a 16-month period and included experts from aca- demic research institutions, community oncology practices, the pharmaceu- tical and biotechnology industries, cancer patient advocacy groups, NCI, the Food and Drug Administration (FDA), and the Centers for Medicare & Medicaid Services (CMS). The committee released its findings in 2005 (NCI, 2005b). The committee proposed 22 recommendations to achieve four major goals for designing a more efficient national system for clinical trials con- ducted or supported by NCI, as follows: (1) better coordination, (2) prioriti- zation based on solid science and the needs of patients, (3) standardized tools and procedures, and (4) improved operational efficiency (NCI, 2005b). Recommendations While the Armitage report had a broader focus than the CTWG report, including a focus on issues such as organization, prioritization,

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2 APPENDIX A participation, and funding, the CTWG report was more narrowly focused and emphasized coordination, collaboration, and the adoption of new technologies (Box A-1). Table A-1 lists the recommendations of both the Armitage and the CTWG reports, divided into several categories: data col- lection, standardization, and management; cooperation; process improve- ment; organizational and structural improvement; accrual; funding; and BOX A-1 Comparison of the Armitage and Clinical Trials Working Group Committee Charges •  Armitage Report (1997) o   s the organization of the Cooperative Group Program (number, member- I ship, trials portfolio) best serving the needs of the field? o    ow  can  the  program  ensure  that  the  most  promising  clinical  research  H opportunities and therapeutic questions are identified and addressed in the  fastest possible time? o  How can the program be organized to ▪  effectively  deal  with  increasing  pressures  to  steer  patients  away  from    academic medical centers, ▪  enhance laboratory-to-clinic and clinic-to-laboratory information, ▪  ensure optimal peer review of Cooperative Group trials, ▪  optimize links between industry and the Cooperative Group Program to    maximize program productivity, and ▪  effectively oversee and support the clinical trials program? o    hat  funding  mechanisms  would  provide  the  most  research  progress  in  W the clinical trials program? o    hat is the best relationship between the clinical trials program and other  W research programs of NCI? o    hat options exist to ensure the continued training of clinical researchers? W o    hat are the incentives/disincentives for participating in clinical trials and  W how can NCI ensure that clinical trials are available to all segments of the  population? •  Clinical Trials Working Group (2005) o    he CTWG was charged with developing recommendations and an imple- T mentation plan to optimize the NCI-supported clinical trials system by ▪  improving coordination and research infrastructure, ▪  removing  institutional  and  regulatory  barriers  that  inhibit  collaboration    in clinical trials research, and ▪  envisioning how clinical trials should be conducted by using the tools of    contemporary bioinformatics and molecular medicine. SOURCES: NCI, 1997, 2005b.

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TAbLE A-1 Comparison of Prior Recommendations for the NCI Cooperative Group Program 2 Armitage Report Clinical Trials Working Group Data collection, • Cooperative Groups and cancer centers should have access to all • Create a comprehensive database that contains standardization, relevant electronic databases and should be primary participants regularly updated information on all NCI-funded and management in the development and testing of the new NCI informatics clinical trials. system. • Create a national cancer clinical trials information • Data collection should be uniform among the groups: technology infrastructure, fully interoperable with o Use the same protocol guidelines, NCI’s Cancer Bioinformatics Grid, to improve the o Simplify the eligibility criteria, cost-effectiveness and comparability of results o Standardize study endpoints, across trials and sites. o Develop a common algorithm for protocol development, • Develop a standards-setting process for o Use the same common data collection forms, measurement, analysis, and reporting of o Develop common toxicity criteria, biomarker data in association with clinical trials o Develop common biostatistical principles, to enhance data comparisons, reduce duplication, o Create a simplified common adverse drug reaction and and facilitate data submission for regulatory adverse event reaction reporting system, and approval. o Simplify informed-consent documents. • In consult with industry and FDA, develop • NCI should enlist industry and the clinical trial and patient standard case report forms incorporating communities to work with FDA to develop uniform standards common data elements to improve information and reporting requirements for clinical trials. sharing among cancer researchers and to optimize • Entry criteria for all studies need to be simplified and broadened: data requirements. a range, rather than absolute, set of parameters should be considered. • Data collection should be reduced to only data pertinent to study endpoints and patient safety. • Large, uncomplicated trials of common cancers with minimal data requirements and accrual goals large enough to see definitive treatment differences should be part of the Program’s portfolio. • Tissue samples and other clinical data from intergroup trials should be stored and maintained.

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Cooperation • NCI should appoint a group to develop legal templates for • Develop commonly accepted clauses for clinical interactions between universities, Cooperative Groups, and trial contracts with industry to reduce the lead industry for material transfer agreements, clinical cooperative time needed to open trials. agreements, and Cooperative Research and Development • Realign NCI and academic incentives to promote Agreements (CRADAs). collaborative team science. Process • Cooperative Groups and the Cancer Therapy Evaluation • Reduce institutional barriers to timely trial improvement Program (CTEP) need well-defined timelines for protocol initiation. development, approval, and activation and need to have clearly • Expand awareness of NCI-FDA expedited stated positive and negative consequences of meeting or not approval process to speed trial initiation. meeting timelines. • Investigate integration of Phase II trials into the • All groups participating in an inter-Group trial should be able to overall prioritization process to further coordinate conduct direct registration and submit forms directly to the the national clinical trials system. coordinating Group. • Develop a funding prioritization process that • Amendments and addenda to trials should become the full ensures that critical correlative science and responsibility of the Group conducting the study and should not quality-of-life studies can be conducted in a require the approval of NCI (although they should be filed with timely manner. NCI). • Build a credentialing system for investigators and • The interval for Cooperative Group renewal should be sites recognized by NCI and industry to allow lengthened to 8 to 10 years for established Groups. faster trial initiation and to keep the investigative • The separate protocol review processes of the Division of Cancer community abreast of legal, safety, and regulatory Treatment, Diagnosis and Centers (DCTDC) and the Division of changes. Cancer Prevention and Control (DCPC) should be combined. • Promote the adoption of an NCI central • Cooperative Groups should be engaged as soon as possible in institutional review board-facilitated review CTEP CRADA negotiations that require Group participation. process to reduce the time and resources needed to open trials at individual sites. 2 continued

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TAbLE A-1 Continued 20 Armitage Report Clinical Trials Working Group Organizational • NCI should urge FDA to form a single oncology advisory • Create an Investigative Drug Steering Committee and structural committee with provision for obtaining the necessary expertise to work with the NCI to enhance design and improvement for ad hoc review. prioritization of early-phase drug development • Inter-Group trials should be harmonized and simplified. trials. • The Decision Network needs to be publicized and would benefit • Create a network of scientific steering committees from external input. CTEP must clarify its role in reviewing leveraging inter-Group, Cooperative Group, novel drugs with questionable patent status to better move Specialized Programs of Research Excellence agents toward clinical trials. (SPOREs), and cancer center structures to work • CTEP’s role should depend on the type of agent studied: with NCI in the design and prioritization of Phase o For Phase II and III studies not involving new agents, CTEP III trials to better allocate resources, increase should approve study concepts and collaboratively establish scientific quality, and reduce duplication. research priorities; CTEP’s authority should otherwise be • Create a clinical trials oversight subcommittee of limited to regulatory and safety issues and prevention of the National Cancer Advisory Board to advise the unnecessary duplication. NCI director on the conduct of clinical trials o For studies with investigational new agents, CTEP should across the Institute. retain its current legislated authority and responsibility, in • Develop a coordinated NCI organizational partnership with industry and the Cooperative Groups. structure to manage the entire clinical trials • For most prevention and control studies, the Groups should be enterprise supported by the NCI. provided with the authority to establish priorities and conduct studies. For large-scale cancer prevention and controlled Phase III studies, the DCPC or a combined DCTDC and DCPC review process should actively participate in concept approval and priority setting. • Treatment trials conducted through the Community Clinical Oncology Program (CCOP) mechanism should be transferred to DCTDC; cancer prevention studies conducted across the NCI clinical trials system should be the responsibility of the newly configured DCPC. Accrual • High-quality patient-oriented public awareness campaigns • Increase patient and public awareness and presenting the value of clinical trials should be a priority. understanding of clinical trials.

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• The public should have access to all information about ongoing • Increase minority patient access to clinical trials clinical trials. to improve the participation of underserved and • NCI should continue to improve efforts to recruit and retain underrepresented populations. members of minority groups, medically underserved populations, • Increase community oncologist and patient and elderly individuals in clinical trials and to tailor recruitment advocate involvement in clinical trial design and and retention approaches to address linguistic and cultural prioritization, which will increase patient accrual differences. and better address the practical and quality-of-life • Representatives of patient and high-risk communities need to be concerns in clinical trials. integrated into the clinical trials decision-making process. • NCI-designated cancer centers should be encouraged to participate in Cooperative Group research and participation should be reviewed favorably in the cancer center review process. • NCI should develop strategies to convince payors that clinical trials are the preferred way to manage patients. • The informed-consent process must be modified and simplified, and NCI should work with the Office for Protection from Research Risks (now the Office for Human Research Protection) to develop a template for informed-consent forms for distribution to clinical scientists and the patient community. Funding • NCI should work with other governmental agencies and private • NCI should work with CMS to identify clinical organizations, including third-party payors, to determine costs studies that address the objectives of both the associated with Phase I to IV clinical trials and should develop a NCI and CMS for which CMS may provide plan for funding the research required to determine these costs. reimbursement for routine costs in investigational • NCI should increase funding to Cooperative Groups to fully trials. recommended levels. • Restructure Phase III funding model to promote • NCI should provide extra funds to the coordinating Group of an rapid patient accrual rates and cost-effectiveness. intergroup trial to cover additional expenses. • Funding should be based on costs of performing as a headquarters office, proportional to CCOP membership. • Systems for awarding credit and funding to institutions 21 participating in intergroup studies must be developed. continued

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TAbLE A-1 Continued 22 Armitage Report Clinical Trials Working Group Investigator • Awards to midcareer and senior scientists should emphasize • No recommendations on investigator recruitment. recruitment salary to ensure protected time for clinical investigation. • Clinical investigator salary lines should be available on cancer center’s core grants and should be for a 3- to 5-year duration. • K12 and T32 awards should be expanded, and K08 awards should be directed to patient-oriented research.a NCI should create new awards and salary support for junior faculty. • NCI should fund at least 10 fellowship programs that provide a formalized academic degree program for clinical scientists. • Cooperative Group grants should include a salary commitment to responsible committee chairs to ensure that time and effort are matched by salary support in planning, implementation, and review of trials. aK12 awards support newly trained clinicians appointed by an institution for development of independent research skills and experience in a fundamental science within the framework of an interdisciplinary research and development program. T32 awards enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. K08 awards provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas. SOURCES: NCI, 1997, 2005b.

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2 APPENDIX A investigator recruitment. Interestingly, the Armitage report gave several recommendations on the retention and recruitment of clinical scientists, whereas the CTWG report’s 22 recommendations did not address recruit- ment and retention issues. Despite the time lapse between the release of the two reports, several themes emerged from both reports, including the importance of data standardization, the need for a comprehensive database of NCI trials, improved public awareness of clinical trials, and the need to reduce the time it takes to initiate a clinical trial. RESPONSE TO THE CTWG REPORT NCI has launched several initiatives in response to the CTWG report, as delineated in Box A-2. In addition, NCI has launched an evaluation plan in response to the CTWG recommendation for a quantitative and qualita- tive, evidence-based evaluation to assess measures of the program manage- ment process, the system performance process, and system outcomes.1 The evaluation plan consists of a baseline feasibility analysis, an interim evalu- ation of specific initiatives related to these measures, and final evaluations at specified intervals after implementation of the initiatives. A goal is to develop a structured framework for continuous monitoring and feedback to accommodate midcourse corrections. The evaluation aims to compare the baseline to the future on the basis of system outcome measures (overall output) and system performance mea- sures (performance of individual CTWG initiatives). The system outcome measures are intended to gauge the quality and impact of clinical trials and the efficiency of both trial development and initiation and trial conduct. NCI has engaged evaluation specialists to assist with development of the definitions, survey instruments, statistical adjustments, and other tools; to conduct the evaluations; and to determine the appropriate timing for exam- ining the various measures in the context of the implementation timelines and the nature of the impacts envisioned. The baseline evaluation of the current system was completed in 2008 to provide a basis for ascertaining the value of the restructuring effort. The results of that baseline evaluation are being analyzed by a Working Group of the Clinical Trials and Translational Research Advisory Commit- tee (formerly the Clinical Trials Advisory Committee [CTAC]), which will propose which elements of the recommended evaluation system should be implemented and establish a timeline for follow-up evaluations. 1 See http://restructuringtrials.cancer.gov/initiatives/evaluation.

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2 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX A-2 NCI Initiatives in Response to the CTWG Report NCI  has  launched  initiatives  in  six  categories  in  response  to  the  CTWG  report.  The objectives and current status of those initiatives are briefly described below.  Many of these activities are also described in Chapter 3. Enterprise-wide initiatives aim to enhance coordinated leadership of the clinical  trials enterprise by addressing ongoing National Cancer Advisory Board oversight  of  clinical  trials  and  an  integrated  NCI  organizational  structure  for  clinical  trials  management.  NCI  established  the  Clinical  Trials  Advisory  Committee  (CTAC;  since  renamed  the  Clinical Trials  and Translational  Research  Advisory  Commit- tee)  so  that  a  broad  range  of  stakeholders  could  provide  advice  on  NCI-sup- ported national clinical trials (both extramural and intramural) to the NCI director,  deputy  directors,  and  division  directors.  NCI  also  established  the  Clinical Trials  and Translational Research Operations Committee (CTROC) as an internal NCI  advisory committee responsible for review of ongoing clinical trials and prioritiza- tion of proposed NCI-supported clinical trials, correlative science programs, and  translational research. CTROC members include the directors of all NCI divisions,  offices, and centers that have clinical trials or translational science portfolios. The  Coordinating Center for Clinical Trials was established to oversee implementation  of the 22 initiatives recommended by the CTWG in 2005, as well as 15 initiatives  recommended by the TRWG in 2007. The center, which resides within the NCI’s  Office of the Director, facilitates and manages the operations of CTAC and CTROC  in conjunction with all NCI divisions, offices, and centers. Coordination initiatives aim to improve coordination and cooperation among the  functionally diverse components of the current system, including industry and fed- eral regulatory agencies. Currently, NCI is working to establish a comprehensive  database  containing  regularly  updated  information  on  all  NCI-funded  interven- tional clinical trials. Grantees will be requested to enter specific information about  each clinical trial into the database.  Prioritization and scientific initiatives aim to improve prioritization and scientific  quality  by  developing  a  more  open  and  transparent  process  for  the  design  and  prioritization of clinical trials that are science driven and that meet the needs of  patient care. NCI has established an Investigational Drug Steering Committee and  several disease-specific steering committees, as described in Chapter 3. Standardization initiatives  aim  to  improve  standardization  of  the  tools  and  procedures used for trial design, data capture, data sharing, and administrative  functions to minimize duplication of effort and to facilitate the development of a  shared infrastructure to support an integrated national cancer clinical trials net- work. Working with the CEO Roundtable on Cancer, NCI developed the Standard  Terms  of  Agreement  for  Research Trials  clauses  to  help  cut  the  time  spent  on  contract  negotiations  between  pharmaceutical  or  biotechnology  companies  and  academic medical centers.

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2 APPENDIX A BOX A-2 Continued Operational efficiency initiatives  aim  to  improve  operational  efficiency  by  increasing the rate of patient accrual and reducing operational barriers so that tri- als can be initiated and executed in a timely, cost-effective manner. NCI funded a  study to identify institutional barriers to the initiation of clinical trials by document- ing and analyzing the steps needed to activate clinical trials (Dilts and Sandler,  2006;  Dilts  et  al.,  2006,  2008).  In  addition,  since  2006,  selected  grantees  have  received  administrative  supplements  to  increase  funding  for  the  recruitment  of  minority  and  medically  underserved  patients  to  NCI  clinical  trials.  In  2008,  nine  continuation  supplements  totaling  $830,000  and  four  new  supplements  totaling  $399,000 were awarded. Informatics initiatives aim to define, design, build, and deliver a comprehensive  clinical trials informatics infrastructure that will serve all of the critical stakehold- ers.  NCI  plans  to  rely  on  the  NCI  Center  for  Bioinformatics  to  provide  program  management and infrastructure through caBIG to achieve these aims. SOURCE: See http://restructuringtrials.cancer.gov/initiatives/overview. Results of the baseline Feasibility Study The baseline measures of system performance for the CTWG initia- tives included incentives for collaboration among investigators, the extent of multisite Phase II and multi-Cooperative Group Phase III trials, the extent of collaboration between industry and NCI, the nature and qual- ity of clinical trial prioritization processes, and the distribution and cost- effectiveness of accrual across sites (Doroshow, 2008). The baseline measures did not consider initiatives in which there was little or no activity ongoing prior to the CTWG report, such as a comprehensive clinical trials database, the level of caBIG (cancer Biomedical Informatics Grid)-compatible clini- cal information technology, the value added by the Investigational Disease Steering Committee and Scientific Steering Committee processes, the impact of correlative science funding and standardization, the value and use of standardized clinical trial tools, and the cost savings achieved by shifting patient accrual to highly accruing, more efficient sites. Multiple sources of data were used for the baseline feasibility analysis, including interviews, database analyses, and reviews of factual information in documents. Baseline interviews were held in 2007 with 81 stakeholders (investigators conducting Phase I, II, and III trials; principal investigators of the Community Clinical Oncology Program, investigators conducting

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2 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX A-3 Operational Efficiency Working Group Recommendations Cooperative Group Process Improvement •    ecommendation 1: Group-specific action plan to achieve OEWG target R timeline o  Potential staffing changes ▪  Physician senior protocol officers ▪  Nonphysician trial development managers ▪  Specialist medical writers o  Performance of trial development steps in parallel o  Direct, coordinated interactions to resolve issues o  Project management and protocol tracking tools •  Recommendation 2: CTEP action plan to achieve OEWG target timeline o  Project managers ▪  Manage overall protocol review, revision, and approval process ▪  Facilitate interactions between CTEP and the Cooperative Groups o    oordinated  NCI  scientific  review  to  identify  all  issues  at  time  of  initial  C concept review o    rompt  communication  of  critical  issues  in  advance  of  formal  written  P reviews o  Streamlined methods for communicating comments o  Differentiation of advisory comments from those requiring a response o  Project management and protocol tracking tool •    ecommendation 3: Collaborative Group-CTEP process for concept and R protocol revision o  Direct, coordinated interactions to resolve issues o  High priority for devotion of time to issue resolution o  Resolution of fundamental aspects of study design at concept stage o    ocus  of  interactions  at  protocol  stage  on  mechanics  of  completion  of  F protocol embodying an agreed-upon concept ▪  Prompt communication and resolution of major differences ▪  Minimization of time discussing noncritical differences of opinion ▪  Minimization of time and effort for routine or pro forma revisions o  Rapid arbitration for any issues not resolved quickly •    ecommendation 4: Development of approaches to reward performance R against timelines o    stablish  a  comprehensive,  reliable  system  for  reporting  timeline  perfor- E mance for each step in trial activation process o    ollect timeline performance data for at least 1 year and assess accuracy  C and value of the data and reports o    nalyze  performance  data  by  individual  Cooperative  Groups  and  across  A the Group system in comparison with target timelines o  Joint Cooperative Group-NCI deliberations concerning ▪  Linking incentives to Group-specific timeline performance ▪  Incorporating performance against timeline targets  o    TEP  inclusion  of  timeline  performance  in  its  annual  staff  performance  C evaluations

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2 APPENDIX A Early Drug Development Phase II Trial Activation Process Improvement •  Recommendation 5: CTEP action plan to achieve OEWG target timeline o  Project managers ▪  Management of overall protocol review, revision, and approval process ▪  Facilitation  of  interactions  among  CTEP,  principal  investigators,  and    industry o  Teleconferences to resolve issues for LOIs on hold  o  Prompt communication of disapprovals in advance of review letter o  Streamlined methods for communicating comments o  Differentiation of advisory comments from those requiring response o  Project management and protocol tracking tools •    ecommendation 6: Collaborative Group, N01 research and development R contracts, CTEP process for LOI and protocol revision o    irect,  coordinated  interactions  to  resolve  issues  (within  14  days  of  LOI  D review) o  High priority on devoting time to issue resolution o  Resolution of fundamental aspects of study design at LOI stage o    ocus of interactions at protocol stage on mechanics of completing a pro- F tocol embodying an agreed-upon LOI ▪  Prompt communication and resolution of major differences ▪  Minimization of time spent discussing noncritical differences of opinion ▪  Minimization of time and effort for routine or pro forma revisions o  Rapid arbitration for any issues not resolved quickly Cancer Center Process Improvement •    ecommendation 7: Cancer center-specific action plan to achieve R OEWG target timeline o  Potential action plan elements ▪  Specialist medical writers ▪  Direct, coordinated interactions to resolve differences ▪  Project management and protocol tracking tool o  Center-specific timeline targets ▪    odification of OEWG target to reflect specific cancer center  M environment ▪  Analysis of targets for reasonableness by cancer center directors and    NCI ▪  Reporting of timeline data against target on an annual basis ▪  Annual report on actions taken against centers performing below    expectations  o  Funding sources ▪  Allowance  for  explicit  use  of  Cancer  Center  Support  Grant  (CCSG)    funds for protocol development ▪  Provision of supplemental funds to implement action plan •    ecommendation 8: Streamline university contracting and financial R review processes o  System-level activities continued

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20 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX A-3 Continued ▪  Education of universities on NCI Standardized Clauses for Clinical Trial    Agreements ▪  Development of standardized clauses for other types of agreements ▪  Collaboration with Clinical and Translational Science Awards program    to streamline processes o  Institution-level activities ▪  Education  of  stakeholders  on  NCI  Standardized  Clauses  for  Clinical    Trial Agreements ▪  Establishment of master agreements with individual companies ▪  Consideration of use of nonfederal funds for university legal and con-   tracting staff devoted to cancer center trials ▪  Direct interactions among cancer center, university, and hospital staff to    resolve issues Standardization of Tools and Templates •    ecommendation 9: Form a working group involving the NCI, R Cooperative Group, and cancer center staff to coordinate standardization efforts o    ompilation of inventory of protocol templates, data elements, case report  C form  modules,  etc.,  from  Cooperative  Groups,  cancer  centers,  and  the  NCI o    nalysis of inventory to identify current standards, best-in-class products,  A redundant development efforts, and unmet needs o  Analysis of status and output of existing standardization efforts o   dentification of tools and templates for which standardization is mandatory  I versus recommended or optional o  Identification of standards needed for interoperability o  Development of a coordinated process for implementing standards Recommendations In developing its recommendations, the TRWG outlined the current challenges confronting early translational research at the NCI (Box A-4). To address these challenges, the TRWG developed 15 recommendations in three categories: coordinated management, tailored funding programs, and operational effectiveness (Table A-2). In addition, the TRWG constructed six developmental pathways to describe the decision-making points and processes along which translational research occurs for six domains: bio- specimen-based risk assessment devices, image-based risk assessment agents

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21 APPENDIX A Enhanced Biomarker Funding and Capabilities •    ecommendation 10: Enhancement of funding and capabilities for use R of biomarkers in NCI-funded clinical trials o    xpansion of the Biomarker, Imaging, and Quality of Life Studies Funding  E Program to large randomized Phase II trials o  Support biomarker studies for early-phase trials o    equirement  for  clinical  trial  concepts  and  LOIs  to  describe  proposed  R integral or integrated biomarker studies o    rovision  of  funding  for  development,  validation,  and  conduct  of  clinical- P grade assays o    evelopment of standards for qualifying sites to conduct imaging studies  D associated with clinical trials Cancer Center Trial Prioritization •    ecommendation 11: Performance of rigorous review of clinical trial R concepts in advance of protocol development o  Specification of concept review process in CCSG guidelines ▪  Approval  or  disapproval  by  disease  group  or  throughout  the  cancer    center ▪  Uniformity of reviews across diseases ▪  Content of a concept document ▪  Criteria by which concepts are reviewed o  NCI should mandate the specific process or criteria o    pplicable to all trials: investigator-initiated, Cooperative Group, and N01  A trials SOURCE: Doroshow and Hortobagyi, 2010. and techniques, anticancer agents (drugs or biologics), immune response modifiers, interventive devices, and lifestyle alterations (Cheever et al., 2008; Dorfman et al., 2008a,b; Hawk et al., 2008a,b; Schilsky et al., 2008; Srivastava et al., 2008). Some TRWG recommendations are outgrowths of the CTWG initia- tives, such as the Clinical and Translational Advisory Committee (CTAC; previously the Clinical Trials Advisory Committee, created in response to the CTWG recommendations). The TRWG report expanded the scope of the CTAC committee to include translational research, noting that CTAC

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22 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX A-4 Translational Research Working Group Assessment of Current Challenges in Translational Research •   nsufficient coordination and integration results in a fragmented translational  I research effort that risks duplication and missed opportunities. •    he absence of clearly designated funding and adequate incentives for  T researchers threatens the perceived importance of translational research  within the NCI enterprise. •    he absence of structured, consistent review and prioritization processes tai- T lored to the characteristics and goals of translational research makes it difficult  to direct resources to critical needs and opportunities. •    he multidisciplinary nature of translational research and the need to integrate  T sequential steps in complex developmental pathways warrant dedicated proj- ect management resources. •    ranslational  research  core  services  can  be  duplicative  and  inconsistently  T standardized, with capacity being poorly matched to the need. •  Collaboration with industry delays appropriate developmental handoffs. •    xtended negotiation on intellectual property issues delays or prevents poten- E tially productive collaborations. •   nsufficient  collaboration  and  communication  between  basic  and  clinical  sci- I entists  and  the  paucity  of  effective  training  opportunities  limit  the  supply  of  experienced translational researchers.  SOURCE: NCI, 2007. was already responsible for early-stage trials and correlative science studies. The TRWG report also indicated that integrated oversight would facilitate the coordination and prioritization process for both early- and late-stage translational research. Other report recommendations focused on priori- tizing translational research activities at NCI, providing better project management of translational research activities, establishing enhanced bio- specimen repositories and analytical methods, and ensuring the provision of training and career incentives for early translational research.

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TAbLE A-2 Summary of TRWG Recommendations and Implementation Status Category Specific Recommendations Implementation Status Coordinated • Establish a flexible, integrated organizational • Expansion of CTAC to include translational research expertise; management approach that coordinates early translational research expansion of the Clinical Trials Operations Committee (and across NCI. name change to Clinical Trials and Translational Research Operations Committee) to include translational research responsibilities; expansion of Coordinating Center for Clinical Trials to include Translational Research Support Team • Designate a specific portion of the NCI budget for early translational research. • Develop a set of award codes that accurately capture • Pilot project with NCI’s Division of Extramural Activities to the nature and scope of the early translational code grants for translational research on the basis of the research portfolio. TRWG pathways; comparison with principal investigator’s assessment of projects to look for consistency and interpretation of pathways • Establish a distinctive prioritization process for early • Two-day NCI translational science meeting (NCI Translates) translational research. held in November 2008 and 2009 to explore potential of translational research prioritization and acceleration, as recommended by the TRWG report • Pilot project to prioritize cancer antigens within the immune response modifier pathway; project expanded to prioritize translational research opportunities within the immune response modifier pathway 2 continued

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TAbLE A-2 Continued 2 Category Specific Recommendations Implementation Status Tailored • Modify multiproject collaborative award guidelines, as • CTAC Coordination Subcommittee Guideline Harmonization funding appropriate, to facilitate early translational research. Working Group mission: promote collaborative team science programs and ensure that guidelines for different clinical trials funding mechanisms are aligned, eliminate redundancy and duplication while proactively encouraging collaboration, harmonize program guidelines and develop incentives to foster collaboration among all components of the clinical trials infrastructure, including cancer centers, Specialized Programs of Research Excellence, and Cooperative Groups • Improve processes and mechanisms for funding investigator-initiated early translational research. • Establish a special translational research acceleration • Pilot project to establish a STRAP for the immune response project (STRAP) to advance prioritized early modifier pathway translational research opportunities. • Establish a funding program for early translational research that requires academia and industry collaboration involving resource sharing or cofunding. • Integrate access to manufacturing and other preclinical • Development of the NCI Experimental Therapeutics Program, a development services according to good manufacturing new drug discovery and development pipeline that can partner practices and good laboratory practices more with researchers to bring new cancer treatments to patients effectively with milestone-driven early translational research projects.

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Operational • Establish a formal project management system for • New Project Management Office established within the NCI effectiveness early translational research. Division of Cancer Treatment and Diagnosis • Establish a system to coordinate core services essential • CTAC Coordination Subcommittee is developing criteria for for early translational research. regional cores and guidelines to encourage sharing and reduce redundancy • Enhance quality and accessibility of annotated biospecimen • Enhancement of NCI’s Office of Biorepositories and repositories and associated analytical methods. Biospecimen Research • Develop enhanced approaches for negotiation of • NCI and the Life Sciences Consortium of the CEO Roundtable intellectual property agreements and agent access. on Cancer have jointly developed a set of common clauses, the Standard Terms of Agreement for Research Trial clauses, that are accessible for use by any party initiating a trial. These standard clauses provide common language for use as a starting point in the contract agreements that govern clinical trials. • Enhance interactions and collaborations with foundations and advocacy groups to advance early translational research. • Enhance training and career incentives for early translational research. SOURCES: Cheever et al., 2009; Clinical Trials Advisory Committee, 2008; Hawk et al., 2008b; NCI, 2007. 2

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2 A NATIONAL CANCER CLINICAL TRIALS SySTEM REFERENCES Cheever, M. A., J. Schlom, L. M. Weiner, K. H. Lyerly, M. L. Disis, A. Greenwood, O. Grad, and W. G. Nelson. 2008. Translational Research Working Group developmental pathway for immune response modifiers. Clinical Cancer Research 14(18):5692–5699. Cheever, M. A., J. P. Allison, A. S. Ferris, O. J. Finn, B. M. Hastings, T. T. Hecht, I. Mellman, S. A. Prindiville, J. L. Viner, L. M. Weiner, and L. M. Matrisian. 2009. The prioritiza- tion of cancer antigens: A National Cancer Institute pilot project for the acceleration of translational research. Clinical Cancer Research 15(17):5323–5337. Clinical Trials Advisory Committee. 2008. CTAC minutes, June 2. http://deainfo.nci.nih. gov/advisory/ctac/0608/25jun08mins.pdf. Dilts, D. M., and A. B. Sandler. 2006. Invisible barriers to clinical trials: The impact of struc- tural, infrastructural, and procedural barriers to opening oncology clinical trials. Journal of Clinical Oncology 24(28):4545–4552. Dilts, D. M., A. B. Sandler, M. Baker, S. K. Cheung, S. L. George, K. S. Karas, S. McGuire, G. S. Menon, J. Reusch, D. Sawyer, M. Scoggins, A. Wu, K. Zhou, and R. L. Schilsky. 2006. Processes to activate Phase III clinical trials in a cooperative oncology group: The case of Cancer and Leukemia Group B. Journal of Clinical Oncology 24(28):4553–4557. Dilts, D. M., A. B. Sandler, S. Cheng, J. Crites, L. Ferranti, A. Wu, R. Gray, J. MacDonald, D. Marinucci, and R. Comis. 2008. Development of clinical trials in a cooperative group setting: The Eastern Cooperative Oncology Group. Clinical Cancer Research 14:3427–3433. Dorfman, G. S., T. S. Lawrence, and L. M. Matrisian. 2008a. The Translational Research Working Group developmental pathway for interventive devices. Clinical Cancer Re- search 14(18):5700–5706. Dorfman, G. S., D. C. Sullivan, M. D. Schnall, and L. M. Matrisian. 2008b. The Translational Research Working Group developmental pathway for image-based assessment modalities. Clinical Cancer Research 14(18):5678–5684. Doroshow, J. 2008. CTWG Evaluation Plan: Results of Baseline Feasibility Analysis. Presented at the National Cancer Advisory Board Meeting, February 2008, Bethesda, MD. Doroshow, J. H., and G. Hortobagyi. 2010. Compressing the Timeline for Cancer Clinical Trial Activation. Operational Efficiency Working Group Final Report. Presented to the Clinical and Translational Research Advisory Committee, March 2010, Bethesda, MD. Hawk, E. T., A. Greenwood, E. R. Gritz, A. McTiernan, T. Sellers, S. D. Hursting, S. Leischow, and O. Grad. 2008a. The Translational Research Working Group developmental path- way for lifestyle alterations. Clinical Cancer Research 14(18):5707–5714. Hawk, E. T., L. M. Matrisian, W. G. Nelson, G. S. Dorfman, L. Stevens, J. Kwok, J. Viner, J. Hautala, and O. Grad. 2008b. The Translation Research Working Group developmental pathways: Introduction and overview. Clinical Cancer Research 14(18):5664–5671. NCI (National Cancer Institute). 1997. Report of the National Cancer Institute Clinical Trials Program Review Group. http://deainfo.nci.nih.gov/ADVISORY/bsa/bsa_program/bsact- prgmin.htm#8a (accessed November 19, 2008). NCI. 2005a. President’s Cancer Panel 200–200 Annual Report: Translating research into cancer care: Delivering on the promise. Bethesda, MD: National Cancer Institute. NCI. 2005b. Restructuring the National Cancer Clinical Trials Enterprise. Report of the Clinical Trials Working Group of the National Cancer Advisory Board. Bethesda, MD: National Cancer Institute. NCI. 2007. Transforming Translation—Harnessing Discovery for Patient And Public Benefit. Report of the Translational Research Working Group of the National Cancer Advisory Board. Bethesda, MD: National Cancer Institute.

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2 APPENDIX A Schilsky, R. L., G. Gordon, T. M. Gilmer, S. A. Courtneidge, L. M. Matrisian, O. Grad, and W. G. Nelson. 2008. The Translational Research Working Group developmental pathway for anticancer agents (drugs or biologics). Clinical Cancer Research 14(18):5685–5691. Srivastava, S., J. W. Gray, B. J. Reid, O. Grad, A. Greenwood, and E. T. Hawk. 2008. Trans- lational Research Working Group developmental pathway for biospecimen-based assess- ment modalities. Clinical Cancer Research 14(18):5672–5677.

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