Overview of Conclusions and Recommendations

Advances in biomedical research have produced significant opportunities to improve cancer prevention, detection, and treatment. Insights about the genomic and molecular mechanisms of disease have enabled basic scientists to identify new therapeutic targets and develop new agents that are changing the paradigm of cancer research from nonspecific, broadly toxic chemotherapies to highly targeted combinations of therapies. However, the ability to translate biomedical discoveries into advances in care for patients with cancer remains dependent on the clinical trials system. Clinical trials provide an essential link between scientific discovery and clinical practice. These trials are crucial to the translation of new knowledge into tangible benefits for patients, and the knowledge gained in a clinical trial can also inform and guide further research into the biology of the disease.

Many clinical trials are undertaken by the pharmaceutical and biotechnology industries, whose primary objectives are to develop novel therapeutic agents and gain Food and Drug Administration (FDA) approval for clinical use. These research and development efforts entail enormous costs (hundreds of millions of dollars) and are critical to progress in cancer treatment. Publicly funded clinical trials also play a vital role and are complimentary to industry trials in advancing science and patient care, particularly by addressing questions that are important to patients but are less likely to be top priorities of industry. For example, companies may have less incentive to

  • conduct clinical trials to compare the effectiveness of different treatment options that are already approved for clinical use,



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Overview of Conclusions and Recommendations Advances in biomedical research have produced significant opportuni- ties to improve cancer prevention, detection, and treatment. Insights about the genomic and molecular mechanisms of disease have enabled basic sci- entists to identify new therapeutic targets and develop new agents that are changing the paradigm of cancer research from nonspecific, broadly toxic chemotherapies to highly targeted combinations of therapies. However, the ability to translate biomedical discoveries into advances in care for patients with cancer remains dependent on the clinical trials system. Clinical trials provide an essential link between scientific discovery and clinical practice. These trials are crucial to the translation of new knowledge into tangible benefits for patients, and the knowledge gained in a clinical trial can also inform and guide further research into the biology of the disease. Many clinical trials are undertaken by the pharmaceutical and biotech- nology industries, whose primary objectives are to develop novel thera- peutic agents and gain Food and Drug Administration (FDA) approval for clinical use. These research and development efforts entail enormous costs (hundreds of millions of dollars) and are critical to progress in can- cer treatment. Publicly funded clinical trials also play a vital role and are complimentary to industry trials in advancing science and patient care, particularly by addressing questions that are important to patients but are less likely to be top priorities of industry. For example, companies may have less incentive to • conduct clinical trials to compare the effectiveness of different treatment options that are already approved for clinical use, 

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM • combine novel therapies developed by different sponsors, • develop therapies for rare diseases, • determine optimal duration and dose of treatment with drugs in clinical use, • test multimodality therapies, such as radiation therapy, surgery, or devices in combination with drugs, • study screening and prevention strategies, or • focus on rehabilitation and quality of life following therapy. Publication of negative research findings about the therapies used in prac- tice, which are underreported in the literature but which are essential in setting the standard of care, is also an important aspect of publicly funded research. To address these needs, the National Cancer Institute (NCI) supports the largest U.S. network of clinical trials of any type through several dif- ferent funding mechanisms. The largest component of that network is the Clinical Trials Cooperative Group Program (informally known as the Cooperative Group Program), which comprises 10 Groups that involve more than 3,100 institutions and 14,000 investigators who enroll more than 25,000 patients in clinical trials each year. Most Cooperative Group trials are either moderate-scale Phase II or large-scale Phase III clinical trials that may have practice-changing implications directly relevant to patient care. In contrast, many single-institution, investigator-sponsored trials are relatively small, nonrandomized Phase II trials that are less likely to have a major impact on the standard of care. Since its inception in the 1950s, the Clinical Trials Cooperative Group Program has been instrumental in establishing the standards for cancer patient care and clinical research methods. The research undertaken by the Cooperative Groups has contributed to significant advances in cancer treatment and prevention, including the introduction of new treatments or new drug indications that have led to improved survival and increased cure rates, particularly for pediatric cancers and some early-stage cancers in adults. Furthermore, the role of the Cooperative Group Program is growing in importance as industry trials are increasingly being conducted outside of the United States. The Cooperative Group Program provides a primary mechanism by which the value of therapeutic agents can be assessed within the medical milieu of the U.S. health care system. One of the Program’s strengths is the extensive involvement of physi- cians and patients from the community setting. Participation by the diverse patient populations treated in the community setting helps to ensure that the results of clinical trials are meaningful to a broad segment of the U.S. population and provides these patients with access to promising, innova- tive therapies as they are developed and tested. In addition, Cooperative

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 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS Group trials have contributed high-quality, annotated biospecimens that have aided preclinical and translational research activities, providing critical prognostic and predictive markers of response to therapy. The Cooperative Groups also provide data that support initial or expanded FDA labeling on the basis of clinical trial results supporting new indications for cancer therapeutics. The Cooperative Groups also provide a valuable training ground for clinical investigators, offering opportunities for mentorship, collaboration, and career advancement. However, despite these important contributions and a long record of accomplishments, the public clinical trials system in the United States is at a critical juncture. The Cooperative Group Program in particular is facing numerous challenges that threaten its ability to continue to undertake large- scale, innovative clinical trials that benefit patient care. Funding for the Program has never covered the full cost of the trials that the Groups under- take. Stagnant and declining funding, inefficient processes, extensive and complex government oversight, and a lack of resources to accommodate the new targeted and personalized approach to the development and evaluation of cancer therapy contribute to the Cooperative Group Program’s current difficulties in efficiently and effectively translating research discoveries into timely clinical applications. Recognizing the importance of maintaining an effective publicly funded clinical trials system, the director of NCI, John Niederhuber, requested that the Institute of Medicine (IOM) conduct a consensus study of cancer clinical trials and the Clinical Trials Cooperative Group Program and develop recom- mendations for how to improve the current system. To address the charge, the IOM appointed a 17-member committee with a broad range of expertise and experience, including experts in biomedical and clinical investigations in aca- demia and community practice, statistics, radiology, research and development in the biotechnology and pharmaceutical industries, management research, systems engineering, the health insurance industry, and patient advocacy. Because the environment in which clinical trials are conducted influ- ences the pace of clinical advances, the committee took a broad view of the clinical trials process rather than simply focusing on NCI’s role. The com- mittee concluded that the academic, government, and commercial sectors must join with the public to develop a 21st-century clinical trials system to more effectively leverage scientific advancements and translate them into public health benefits by improving the science; technology; efficiency; and timely creation, launch, and completion of the very best cancer clinical tri- als. The committee began by describing the needs of an ideal cancer clinical trials system of the near future (Box O-1). Then, on the basis of a review of the available published literature along with input from experts in the field and interested individuals, the committee developed a set of goals and

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX O-1 Needs for Cancer Clinical Trials in 2015 Rapid translation of scientific discoveries into public health benefits • Trials that address questions with significant implications for patient care • ollaboration  among  stakeholders,  with  effective  and  timely  communication,  C in developing the most promising treatments • treamlined  procedures  for  the  rapid  planning,  approval,  and  launch  of  tri- S als, with accountability for meeting timelines and the provision of rewards for  productivity • fficient  incorporation  of  new  technologies  and  scientific  questions,  such  as  E the  identification  and  application  of  biomarkers  and  molecular  imaging,  into  clinical trials A strong publicly supported clinical trials system in the United States that comple- ments industry trials to develop drugs and devices •  highly efficient and flexible system for innovative, rigorously prioritized clinical  A trials • Adequate funding for well-designed, high-quality trials • Patient access to promising therapies as they develop • ddresses questions and collects data that are relevant and meaningful to the  A diverse U.S. patient population A robust, standardized, and accessible clinical trials infrastructure • A complete database of active and planned trials • Standardized electronic data capture • ublicly  accessible  tissue  repositories  with  high-quality,  fully  annotated,  and  P inventoried samples collected and stored in a standardized fashion strategies that aim to enhance the value of national Cooperative Group clinical trials in cancer. The committee concluded that a robust, standing cancer clinical trials network is essential to effectively translate discoveries into clinical benefits for patients. Multi-institutional collaborations are necessary to conduct large Phase III trials for indications such as adjuvant therapy, first-line therapy of metastatic disease, and prevention; single institutions are not capable of undertaking such large-scale trials. For research on some other diseases, the National Institutes of Health (NIH) supports large trials on a case-by-case basis, aggregating appropriate institutions for a particular study and then disbanding the group on completion of the study. How- ever, cancer encompasses more than 100 different diseases, the treatment regimens are complex and diverse (and becoming more so), and hundreds of experimental therapies for cancer are in development. Thus, there is a

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 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS • road  use  of  those  samples  in  retrospective  studies  as  new  hypotheses  B evolve •  consistent and dynamic process for rapidly setting national standards and  A unified procedures for new technologies, such as diagnostics, with reproduc- ibility and effective incorporation into clinical trials  Harmonized  and  synchronized  rules  and  guidelines  across  federal  regulatory  agencies  • uidance  grounded  in  an  understanding  of  contemporary  science  as  new  G paradigms in therapeutic approaches as well as in clinical trials methodology  develop Support for clinical investigators • raining and retention of professionals to efficiently and swiftly carry out impor- T tant clinical research • Adequate paid protected research time for active clinical investigators • ecognition  and  appropriate  rewards  for  collaborative  clinical  research  by  R providing advancement in academia and community practice careers • dequate  reimbursement  of  costs  for  actively  participating  institutions  and  A physicians Broad patient involvement in clinical trials  • hird-party payor coverage of the nonexperimental costs of care to ensure that  T patients do not forgo participation in trials because of financial hardship • articipation  in  the  design,  implementation,  and  conduct  of  trials  and  in  the  P communication and dissemination of trial results continuous need for the design and implementation of new trials, and it would be highly inefficient to fund and develop infrastructures and research teams separately for each new clinical trial. If NCI is to achieve the goal of improving outcomes for patients with cancer, it is imperative to preserve and strengthen the unique capabilities of the NCI Clinical Trials Cooperative Group Program as a critical com- ponent of NCI’s translational continuum. Given its long and impressive history of accomplishment, the Cooperative Group Program should ideally provide an established infrastructure for the rapid and efficient translation of scientific knowledge into practical therapeutic solutions that incorporate targeted agents matched to the characteristics of the patient and tumor and routinely achieve change in clinical practice, as well as FDA approval, where appropriate. However, although a strong and adequately funded clinical trials coop-

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10 A NATIONAL CANCER CLINICAL TRIALS SySTEM erative network is essential for addressing questions of national importance, the current structure and operating processes of the entire trials system need to be reevaluated to improve value by reducing redundancy and improv- ing effectiveness and efficiency. Numerous changes, as further delineated throughout this report, are needed to fully achieve that ideal, including an evaluation and justification of the unique role of each Cooperative Group, as well as an evaluation of the key roles that NCI has in administering and overseeing the Cooperative Group Program. Novel, multidisciplinary solu- tions are needed for currently intractable problems in cancer clinical trials. Redesigning a more effective and efficient clinical trials system would likely speed the pace of advances in cancer patient care. The committee’s recommendations are organized under four broad goals: Goal I, improve the speed and efficiency of the design, launch, and conduct of clinical trials; Goal II, incorporate innovative science and trial design into cancer clinical trials; Goal III, improve the prioritization, support, and completion of cancer clinical trials; and Goal IV, incentivize the participation of patients and physicians in clinical trials (Box O-2). Taken together, these recommendations would alter the entire clinical trials system, including the functions of NCI as well as those of the Cooperative Groups. GOAL I. IMPROvE THE SPEED AND EFFICIENCy OF THE DESIGN, LAuNCH, AND CONDuCT OF CLINICAL TRIALS background A clinical trial is a highly complex endeavor. It comprises hundreds of steps that must be taken, numerous decision points, and multilayered and iterative review processes because multiple oversight bodies with different objectives and responsibilities have jurisdiction over clinical trials. Inef- ficiencies in the processes used to develop, launch, and complete cancer clinical trials lead to lengthy delays in each step. Recent studies indicate that the time needed to transit from concept approval to activation of a Phase III Cooperative Group trial often exceeds 2 years. Given the rapid pace at which new scientific findings from basic or preclinical studies accumulate, a trial concept may lose relevance or become outdated in that 2-year time period. Moreover, evidence indicates that trials with lengthy activation times are statistically less likely to accrue the targeted number of patients required to draw valid scientific conclusions. Thus, process improvements are essential to achieve the rapid translation of scientific discoveries into public health benefits. The current structure and organization of the Cooperative Groups did not result from any kind of strategic planning with regard to what might be optimal with respect to trial design and execution. Each Group

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11 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS BOX O-2 Summary of the Committee’s Goals and Recommendations Goal I. Improve the speed and efficiency of the design, launch, and conduct of clinical trials   1.  Review  and  consolidate  some  front  office  operations  of  the  Cooperative  Groups on the basis of peer review   2.  Consolidate  back  office  operations  of  the  Cooperative  Groups  and  improve  processes   3.  Streamline and harmonize government oversight   4.  Improve collaboration among stakeholders Goal II. Incorporate innovative science and trial design into cancer clinical trials   5.  Support and use biorepositories   6.  Develop and evaluate novel trial designs   7.  Develop standards for new technologies Goal III. Improve prioritization, selection, support, and completion of cancer clinical trials   8.  Reevaluate the role of NCI in the clinical trials system    9.  Increase the accrual volume, diversity, and speed of clinical trials 10.  Increase funding for the Cooperative Group Program Goal IV. Incentivize the participation of patients and physicians in clinical trials 11.  Support clinical investigators 12.  Cover the cost of patient care in clinical trials operates independently, with its own administrative structures and operat- ing procedures, committees, and statistical and data management centers. Although the Groups were originally organized by geographic area or, in some cases, by type of disease or therapeutic modality, today there is considerable overlap in the interests of the existing Groups, most of which conduct clinical trials in medical oncology, radiation, and surgery and thus compete for similar trial strategies and funding. Although some overlap generates competition for trial ideas, and some replication is necessary to serve as validation, too much redundancy in the Groups and in individual activities can lead to an unnecessary duplication of efforts, which wastes limited resources. The recent voluntary consolidation of the pediatric oncol- ogy Groups, which was done to pool and conserve limited resources, serves as an informative precedent for how the system could change. Some consolidation of the Cooperative Groups and common activities, along

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12 A NATIONAL CANCER CLINICAL TRIALS SySTEM with a focus on best practices, could increase operational efficiencies and conserve resources, ease the workload of the Cooperative Groups, and lead to more consistency for providers who would like to enroll patients in trials launched by different Cooperative Groups. At the same time, maintaining a robust competition for innovative trial concepts is essential. Large-scale clinical trials also necessitate interactions among numerous stakeholders, including governmental agencies, academic medical centers, community practices, patients, and industry. However, effective communi- cation and collaboration among stakeholders has been challenging. Thus, meaningful change to the cancer clinical trials system will require actions by the numerous stakeholders. Although NCI should play a leading role in instituting the necessary changes, other agencies within the U.S. Department of Health and Human Services (HHS), such as FDA, as well as academic centers, community practices, and others, will need to be actively involved in improving the system. Because of the complexity of the system and the interconnected roles that these stakeholders play, changing only one or a few steps is unlikely to achieve the desired improvements. Recommendations 1 to 4 provide strategies to achieve the goal of improving the efficiency and the average time for the design and launch of innovative clinical trials by consolidating Groups, committees, and func- tions, by enhancing collaboration, and by streamlining and standardizing data collection and analysis. The first two recommendations, in particu- lar, would significantly alter the definition, structure, and operations of Cooperative Groups (Figure O-1). The current system entails 10 indepen- dent Groups that generate ideas for clinical trials and then conduct trials using their own infrastructures for trial operations and data management. Cooperation primarily occurs among the members within each Group. The revised system that would result from implementation of the committee’s recommendations would go beyond cooperation to integration for many functions. Each Cooperative Group would consist of multidisciplinary committees focused on particular disease sites (referred to as disease site committees) and statistical offices that generate trial concepts and provide leadership for the conduct of trials selected as high priorities. The number of Groups and committees should be reduced on the basis of peer review. Most of the infrastructures used to support clinical trial operations and management would be consolidated to achieve greater consistency and efficiency under the new system. The committee’s recommendations also aim to streamline and coordinate the many iterative oversight processes to achieve further gains in the speed and efficiency of trial launch and conduct. NCI’s role would shift from a primary focus on oversight to a greater focus on supporting high-priority trials conducted through the national cancer trials network. Trial sites would be certified to participate in a national trials network and could enroll patients in any high-priority

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1 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS FIGuRE O-1 (a) Overview of the current structure and function of the Cancer Clinical Trials Cooperative Group Program. The components within the bold box are unique to each Cooperative Group. Each of the 10 Cooperative Groups has an operations center and a statistical center, scientific committees, and data manage- ment infrastructure. NCI is involved at multiple points throughout the process of trial concept design, protocol development, and trial implementation and conduct. Patient enrollment occurs at sites affiliated with and approved by specific Coopera- tive Groups to carry out clinical trials. The basis of peer review includes the sci- entific accomplishments and future plans of the Group, the organization of Group resources, the organization of data management and statistical centers, overall leadership, the Group’s publication record, and the effectiveness of disease- and modality-specific committees (collectively and, to some extent, individually). All of these factors are reviewed against a general standard for Cooperative Groups. FDA oversight is not required for all trials; FDA is involved any time a trial is conducted under an investigational new drug (IND) application. In general, any trial designed to provide information that may be used to change the drug label is conducted under an IND application, but this is not always the case. Double-sided arrows indicate repetitive interactions between organizations; changes in response to one review can trigger a re-review by another body. (b) Overview of the proposed structure and function of the Cancer Clinical Trials Cooperative Group Program, as described in the committee’s recommendations. The components within the bold box would be unique to each Cooperative Group, while the other components would be consolidated and shared across the Groups. The Cooperative Groups would primarily consist of multidisciplinary disease site committees and statistical offices that generate concepts for clinical trials. These concepts would be prioritized through external peer review, with only high-prior- ity trials being selected for implementation. Patient enrollment would be at sites certified to participate in a National Trials Network that comprises cancer centers, Community Clinical Oncology Programs, and community practices. Most of the infrastructure used to support trial operations and management would be con- solidated to facilitate greater consistency and efficiency, but leadership for each trial would still be provided by the originating cooperative Group and principal investigators. The basis of front office peer review would include the success of the multidisciplinary disease site committee in innovation, winning study approv- als, completing high-impact studies, mentorship of younger clinical investigators, and the publication of findings. Each multidisciplinary disease site committee will be reviewed against others in its peer group (i.e., committees focused on the same disease site will be reviewed against each other at the same time). Back office opera- tions will also be evaluated through the use of new performance metrics and will be funded accordingly. In cases in which NCI is the IND holder in a clinical trial, the type of NCI oversight would be similar to that used for the current Cooperative Group Program. For other studies, NCI’s role would be limited to facilitating the launch and completion of the trial. NOTE: CIRB = central institutional review board; FDA = Food and Drug Adminis- tration; IRB = institutional review board; NCI = National Cancer Institute.

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A Funding to Support 1 A Cooperative Group A Group Operations (Repeat for 10 Groups) Operations Center Statistical Office Trial Concepts Approval by Steering Committee Scientif ic Committees (disease site, modality-specific, Trial Protocol quality of life, etc.) Review by NCI Asynchronous Peer Review of FDA Cooperative Groups NCI Local IRB Patient enrollment at participating trial sites (approved by a specif ic Group) NCI CIRB Data NCI Oversight and Support Data Management Data Analysis Publication Figure O-1a R01707

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B Cooperative Group A (Repeat for each Group) Multidisciplinary Statistical Off ices Disease Site Committees Funding Concurrent New Data Analysis Publication Peer Review of Performance Propose Trial Concepts Front Off ice Metrics Prioritization and Selection via Peer Review Local IRB Funding Consolidated High-priority Clinical Trial Protocols Back Off ice Peer Review with Full Funding from NCI Operations of Back and Data NCI Off ice New FDA Management CIRB Operations Performance Patient enrollment at any trial site Functions Metrics NCI certif ied to participate in a Support National Trials Network Data 1

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0 A NATIONAL CANCER CLINICAL TRIALS SySTEM The NCI Clinical Trials Cooperative Group Program has been chroni- cally underfunded for the work that it performs, as noted in a 1997 review of the Program commissioned by the NCI director, and current funding does not cover the cost of the clinical trials undertaken. For the past 3 years, the annual budget for the Program has been held at about $145 million, but in real dollars it has declined to less than the 1999 funding level of $119 million, when the funding is adjusted for inflation. Despite this decrease in funding, the Cooperative Group Program has maintained patient accrual, with sev- eral hundred clinical trials ongoing at any given point. This level of funding, which represents approximately 3 percent of the total NCI budget, is simply not sufficient to support the number of trials that the Groups undertake. As a result, the Cooperative Group Program is highly dependent on the voluntary efforts of participating investigators and on supplemental funding from other sources, such as foundations, the pharmaceutical industry, and the institutional contributions of Cooperative Group members. Especially in light of the new focus on targeted therapy and personalized medicine, which raises the complexity and cost of clinical trials, the Cooperative Group fund- ing process is becoming increasingly unsustainable. Recommendations 8 to 10 aim to improve prioritization, selection, and support for clinical trials that have the greatest possibility of improving survival and quality of life for cancer patients and, along with Recommen- dations 11 and 12, aim to substantially increase the proportion of initiated clinical trials that are completed and published. Recommendation 8: NCI should reevaluate its role in the clinical trials system. For example, NCI should file more investigational new drug applications for • agents to be tested in high-priority trials and provide a leadership role to ensure the success of those studies. In cases in which NCI does not hold the investigational new drug • application, the primary focus of NCI should be on supporting high-priority trials, with less emphasis on oversight of the selection and implementation process and greater focus on facilitating the launch and execution of the trial. The process of peer review for trial concepts should be strength- • ened and streamlined and should entail the evaluation of concise proposals (including the intended statistical design) that are ranked against each other. The emphasis should be on scientific strength and opportunity, innovation, feasibility, and the importance to improving patient outcomes. Steering committees administered by NCI should operate inde- • pendently of NCI staff and should focus on the prioritization of

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1 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS clinical needs and scientific opportunities, selection of trial con- cepts proposed by the Cooperative Group disease site committees, and facilitation of communication and cooperation among the Groups. Since the funding mechanism for the Cooperative Group Program was changed from grants to cooperative agreements in 1980, NCI has exercised oversight of every aspect of the clinical trials process, including trial selec- tion, protocol development, and trial operations. NCI has crucial responsi- bilities in the clinical trials system, for example, by providing a framework for both cooperatively and competitively organized interactions between Groups and their committees and in the management of IND sponsorship. As already noted in Recommendation 2, there are numerous steps that NCI could take to further improve the support and facilitation of high-prior- ity trials. Helping Group investigators gain access to more experimental therapeutic agents for high-priority trials by filing an IND application would reduce the time that the Groups spend in negotiations with industry to acquire agents before a trial is launched and also ensure the availability of the agent during the trial. At the same time, it is necessary to reassess NCI’s role and interaction with the Groups, which has evolved over the past 50 years and has become quite complex. NCI has leadership and legal obligations associated with holding an IND, but in cases in which NCI does not hold the IND, NCI should shift its limited resources from oversight to support of the trials process. A Cooperative Group whose trial concept has scored well in peer review should be able to request assistance from NCI as needed to develop and implement the protocol, but it should have the necessary expertise to develop and run the trial without extensive oversight by NCI, which can delay the process. Specific research projects funded through other grant mechanisms on the basis of peer review (the bulk of NCI extramural fund- ing) are not subjected to such oversight. The role of the steering committees should also be reevaluated. The historical CTEP approval rate for trial concepts before implementation of the steering committees was about 65 percent. As of January 1, 2010, the approval rate under the new system was not substantially different, with 62 percent of the concepts reviewed by these committees being approved. The length of concept proposals has also increased substantially (now about 20 to 25 pages compared with 10 to 12 pages in the past), making the review process more arduous. Moreover, multiple layers of review still slow the process, and trial concepts are still not ranked against each other with consistent criteria, as is usually done in peer review. Steering commit- tees review and vote up or down on trial concepts as they are submitted and NCI staff actively participate in the review process, unlike other NCI

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2 A NATIONAL CANCER CLINICAL TRIALS SySTEM peer review groups. In addition, there is little interaction among the disease- specific steering committees to determine trial priorities across disease categories, nor do they consider how to balance the inclusion of Phase II or Phase III trials in the trial portfolio, although the steering committees are charged with “guiding the development of strategic priorities.” A pos- sible alternative approach might be for the steering committees to identify research priorities and then issue requests for proposals to address them. If the steering committees continue to function as peer-review bodies, then NCI should have a more traditional role of facilitating the review process rather than actively participating in it. In any case, it is imperative to strengthen the process for selecting high- priority trials. Launching only the highest-ranked trials would improve quality, speed advances, and ensure that patients are enrolling in the most meaningful and potentially beneficial trials. Recommendation 9: NCI, Cooperative Groups, and physicians should take steps to increase the speed, volume, and diversity of patient accrual and to ensure high-quality performance at all sites participating in Cooperative Group trials. For example, they should develop electronic tools that cue physicians practicing oncology via • electronic medical record systems about trials for which a particu- lar patient is eligible; encourage patient eligibility criteria that allow the broadest partici- • pation possible; encourage greater enrollment in high-priority trials, regardless of • where the trial originates; establish a centralized credentialing system for participating sites; • eliminate investigators and sites with low rates of accrual or inad- • equate data management skills or quality; strive to make participation in clinical trials a key component of • clinical practice and to achieve the exemplary attributes of the American Society of Clinical Oncology for academic and commu- nity clinical trial sites, including high accrual rates4 of 10 percent or more; and encourage greater participation of patient advocates in trial con- • cept development and accrual planning, and partnerships with patient advocacy organizations to support accrual efforts. 4 The American Society of Clinical Oncology defines “accrual rate” as the number of patients enrolled in trials annually/number of new patients seen annually.

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 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS Rationale Surveys indicate that the most important factor affecting patient accrual in clinical trials is whether a care provider offers participation in a trial to his or her patients. The majority of patients who participate in clinical trials are enrolled by a small percentage of participating sites, while many sites enroll only a few patients in trials to maintain their status as investigators. These circumstances can contribute to the underrepresentation in clinical trials of minority and medically underserved populations. Given the impor- tance of trials in generating the evidence needed to make the best treatment decisions, more physicians should be encouraged to include trial participa- tion in their clinical practice. As noted in Recommendation 10, providing adequate case reimburse- ment would help to align physician and patient incentives and facilitate higher accruals at participating sites. However, another obstacle to increas- ing patient enrollment is that physicians may lack timely and easy-to- access information about clinical trials that would be appropriate for their patients. Some public databases with information about clinical trials exist, but in their current form, they may not adequately serve the information needs of physicians and patients as they are not part of the normal work flow of a busy clinical practice. User-friendly electronic tools, available with the right features for a physician’s work flow, would increase awareness of trials and make it easier for physicians and patients to enroll in the most appropriate studies. Eligibility criteria present another challenge to increasing enrollment. Historically, stringent eligibility criteria have excluded many patients, including, for example, those with prior cancers or certain prior treatments. However, it has been argued that the adoption of less restrictive eligibility criteria for most studies would permit more rapid accrual and would also allow broader generalizations to be made, would better mimic the situa- tion as it occurs in medical practice, and reduce the complexity and costs of clinical trials without compromising patient safety or requiring major increases in sample size. Greater involvement by patient advocates could help facilitate this change. Patient advocates also provide valuable input to study design and procedures, safety and confidentiality issues, feasibil- ity, informed-consent processes, and other factors important to potential research participants to help facilitate the development, implementation, and recruitment processes. Ensuring consistent quality at participating trial sites is also important. Site credentialing requirements vary among the Cooperative Groups, mak- ing the credentialing process onerous for sites that wish to engage with multiple Groups. A centralized credentialing system, perhaps outsourced to an independent entity, would increase consistency and quality across

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM sites and eliminate the burden of recredentialing. Such a system would also facilitate higher levels of enrollment in high-priority trials, regardless of where the trial originates, because sites would be credentialed to partici- pate in any Cooperative Group trial. Moreover, elimination of sites with low rates of accrual would reduce costs and improve the efficiency of the clinical trial system. Recommendation 10: NCI should allocate a larger portion of its research portfolio to the Clinical Trial Cooperative Group Program to ensure that the Program has sufficient resources to achieve its unique mission. NCI should increase the per case reimbursement rate and ade- • quately fund highly ranked trials to cover the costs of the trial, including the costs of biomedical imaging and other biomarker tests that are integral to the trial design. To ensure sufficient funding for high-priority trials, the total • number of NCI-funded trials undertaken by the Cooperative Groups should be reduced to a quantity that can be adequately supported. External advisory boards, such as the National Cancer Advisory • board and the board of Scientific Advisors, should have a greater roles in advising NCI on how it allocates its funds to support a national clinical trials program. Rationale High-priority trials must be adequately funded to efficiently and effec- tively attain results that can move the field forward. Compromising the science to launch more trials than the available funding can support is detrimental to progress. Innovative approaches to leveraging funding from sources other than NCI, as described in Recommendation 4, could also strengthen the Program, but NCI has an obligation to adequately fund trials identified as being of high priority. NCI should increase the total funding allocation for the Cooperative Group Program to ensure the effective trans- lation of discoveries made with public funding to improved clinical care. A first important step will be to raise the per case reimbursement, which has been set at $2,000 since 1999, although the median costs are estimated to be from $3,500 to $6,000 per patient. The many duties required of physicians and other key research staff, such as research nurses and clinical research associates, to participate in clinical trials are costly in terms of both time and resources. For example, before a trial can be opened at a particular site, much work must be done to ensure compliance with federal regulations

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 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS governing human subjects research. Once a trial is opened, a significant amount of time is spent discussing potential trial options with patients. If a patient enrolls, the data collection and documentation requirements are substantially more onerous than they are for patients receiving standard therapy outside of a trial. These voluntary contributions of clinicians who participate in the Cooperative Group Program constitute a substantial value and strength of the Program. However, when the discrepancy between the per case reimbursement and the actual cost of participation is excessive, as it is now, it becomes a major disincentive to participation. A substantial increase in the NCI per case reimbursement rate would constitute a major step toward aligning the incentives of physicians with those of their patients who wish to participate in clinical trials. Even in the absence of a sub- stantial increase in the overall funding of the Program, the funds saved by launching fewer but higher-priority trials could be allocated for increased per case reimbursements to trial sites. The existing system also often does not provide the resources required to thoroughly characterize each patient’s tumor and carefully match that profile to targeted therapeutics. Biomedical imaging and other biomarker tests are commonly becoming integral components of modern cancer clini- cal trials, but supplemental funding for these tests must be obtained by the Cooperative Groups through other support mechanisms. The allocation of NCI funds among the competing needs of its various programs is a major challenge for the NCI director, who must take many factors into consideration. Greater input from the broad expertise and experience of external advisory boards, such as the National Cancer Advi- sory Board and Board of Scientific Advisors, would be helpful to ensure the most rational distribution of funds across the major NCI programs, in light of such factors as scientific opportunity and clinical need. These high- level boards should not be involved in the oversight of individual trials or in concept review, which would further slow the process, but rather, they should have a greater influence on how much funding is allocated to the overall Cooperative Group Program. GOAL Iv. INCENTIvIzE THE PARTICIPATION OF PATIENTS AND PHySICIANS IN CLINICAL TRIALS background A robust clinical trials infrastructure is largely dependent on a criti- cal mass of patients and physicians willing to participate in clinical trials. However, current indications suggest that participation in clinical trials is the exception rather than the rule, both for patients and for physicians. For clinical investigators, concerns about reimbursement, extensive regulatory

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM burdens, and academic procedures regarding tenure, promotion, and career development can all deter participation in trials. Investigator participation in trials requires substantial resources and staff. Given the limits in funding and capacity of the system, it is unrealistic to expect all or most clinicians to participate in trials, but those who are motivated to do so should be supported and encouraged. Patient access to clinical trials is also an import issue to consider. Even if patients are eligible for trials and are informed about the option by their physicians (as discussed in the section describing Goal III), they may decline because of financial concerns, as coverage of patient care costs in clinical trials by health insurers is not consistent. Recommendations 11 and 12 provide strategies to achieve the goals of increased participation by physicians and patients in Cooperative Group clinical trials. Recommendation 11: All stakeholders, including academic medical centers, community practices, professional societies, and NCI, should work to ensure that clinical investigators have adequate training and mentoring, paid protected research time, the necessary resources, and recognition. For example, NCI should recognize and reward Cooperative Group efforts in • Cancer Center Support Grant (CCSG; P30) site visits, and allow the CCSG research base to include the federal per case funding received by cancer centers that participate in Cooperative Group trials. NCI should provide funding to site and trial principal investigators • to cover the time that they need to develop and oversee approved trials. Academic medical centers should develop policies and evaluation • metrics that recognize and reward clinical and team research in promotion and tenure decisions. NCI should work with a nonprofit foundation to develop a certifi- • cation program and registry, as recommended by the Clinical Trials Working Group. Rationale Multiple stakeholders need to take steps to support the recruitment and retention of clinical investigators both in community practice and in academia. The large-scale, multi-institutional trials that are the hallmark of the Cooperative Group Program require a team approach to research. However, career advancement in the field has traditionally focused on indi- vidual accomplishment. The current system does not adequately recognize,

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 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS reward, or support collaborative work. Furthermore, clinical investigation is often accorded less value than either basic research or patient care. This must change if the goal is to have talented individuals embark on a career that entails active participation in clinical trials for cancer as well as other diseases. Clinical research is a complex endeavor that requires training, mentoring, and paid time set aside for research to master and apply the skills needed to undertake innovative trials. For example, the provision of funds for principal investigators to cover the time that they need to develop and oversee approved trials could improve the speed and quality of those trials. Recognizing the per case reimbursements for Cooperative Group trials in the CCSG assessment of a cancer center’s funding base would acknowledge the importance of patient accrual in these trials and encourage broader participation at those centers. A certification program for all research staff (including physicians, nurses, clinical research associates, pharmacists, etc.) would recognize the valuable contributions that these professionals make to the improvement of patient care and treatment. Ultimately, the inability to recruit, train, and retain a sufficient num- ber of talented clinical investigators will compromise the ability to con- duct clinical trials in the United States, to the detriment of the U.S. biomedical research enterprise and to patients, those who participate in clinical trials as well as those who do not. Clinical trials help to raise the standard of care in the community by setting examples, and they have educational and training value for the oncologists involved, as physicians gain early knowledge of new drugs and gain experience with delivering complex therapies. Recommendation 12: Health care payment policies should value the care provided to patients in clinical trials and adequately compensate that care. For example, the Centers for Medicare & Medicaid Services (via a national coverage decision), federal and state health benefits plans, and private health insurers should establish consistent payment policies to cover all patient care costs • (except for study-related costs, such as study drugs, devices, and tests, which should be paid for by the manufacturer) in clinical tri- als approved through the NCI prioritization mechanism, without having to pay for experimental therapies administered to patients outside of a clinical trial (any such limitation in coverage should not affect off-label use that is backed by evidence from clinical tri- als published in the scientific literature, as evidence-based off-label use constitutes the standard of care for many cancer therapies and is therefore not experimental) and

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM work with health care providers to educate patients more effec- • tively about the availability, payment coverage, and value of clini- cal trials. In addition, The American Medical Association should establish new Cur- • rent Procedural Terminology codes, reimbursed by the Centers for Medicare & Medicaid Services, private insurers, and other third-party payors, to pay an enhanced reimbursement for offering, enrolling, managing, and following a patient in a clinical trial. The u.S. Congress should amend the Employee Retirement Income • Security Act of 1974 to prohibit health plans from denying (or from limiting or imposing additional conditions on) coverage for the routine care associated with clinical trial participation.5 Rationale Inadequate health care coverage is a major deterrent to participation in clinical trials for patients as well as physicians. Health care insurers tra- ditionally have not paid for experimental therapies. However, much of the care provided to cancer patients is similar regardless of whether the patient is receiving a standard of care or an experimental drug. Some insurers and states acknowledge this and provide reimbursement for the routine clinical care of patients enrolled in trials, whereas others do not. The policies of the Centers for Medicare & Medicaid Services (CMS) regarding coverage of care in clinical trials have recently been in flux and, absent national coverage 5 After the committee had completed its report, the Patient Protection and Affordable Care Act (H.R. 3590) was signed into law by President Barack Obama on March 23, 2010, which provides coverage of routine care costs for individuals participating in approved clinical tri- als. According to this Act, a group health plan or a health insurance issuer “may not deny (or limit or impose additional conditions on) the coverage of routine patient costs for items and services furnished in connection with participation in the trial.” As stipulated by the leg- islation, routine patient care costs include all items and services consistent with the coverage provided in the plan (or coverage) that is typically covered for a qualified individual who is not enrolled in a clinical trial. Approved clinical trials include Phase I–IV studies relating to the prevention, detection, or treatment of cancer or other life-threatening diseases or condi- tions that are either (a) federally funded; (b) a study or investigation conducted under an investigational new drug application reviewed by FDA; or (c) a drug trial that is exempt from having such an investigational new drug application. This provision will go into effect in 2014 and is intended to apply to both types of ERISA plans as well as plans offered by the Federal Employees Health Benefits Program. The Patient Protection and Affordable Care Act, H.R. 3590, 111th Cong., 2nd sess., Coverage for Individuals Participating in Approved Clinical Trials, § 2709 (March 23, 2010).

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 OVERVIEW OF CONCLUSIONS AND RECOMMENDATIONS decisions, may not be nationally uniform because fiscal intermediaries and carriers have some discretion on coverage, which can cause variations and inconsistencies by geographical region. Furthermore, the provisions of the Employee Retirement Income Security Act of 1974 (ERISA), which places the regulation of employee benefit plans (including health plans) primarily under federal jurisdiction for about 131 million people, preempts state laws governing such things as access to care and mandated coverage. Thus, coverage of care in clinical trials is variable and may be uncer- tain, and patients who are interested and willing to enroll in a trial may decline because of an inability to pay for care that is not or may not be covered. Others might still enroll but may then experience significant finan- cial hardship as a result. If such patients drop out of the trial, the scientific integrity of the trial can be compromised because of inferential problems that result from missing data. If cancer care is to be evidence based and relevant to the diverse population of patients with cancer, it is important for coverage policies to encourage rather than deter patient enrollment in trials. However, as a quid pro quo for improved coverage of care in clinical tri- als, insurers should be able to eliminate coverage of experimental therapies delivered outside of the clinical trial setting. Currently, many patients who are not enrolled in trials receive experimental therapy and expect coverage for it. The committee’s recommended approach is analogous to the “cov- erage with evidence development” mechanism that CMS has occasionally used, in which coverage is provided only within the context of a clinical trial. However, any such limitation in coverage should not affect off-label indications backed by evidence from clinical trials published in the scientific literature, as off-label use constitutes the standard of care for many cancer therapies and is therefore not experimental. For physicians, even in cases in which routine patient care in a clinical trial is covered by health insurers, the current payment policies do not reflect the additional time needed to enroll and follow patients in a trial. For exam- ple, if a patient receiving off-protocol chemotherapy reports an adverse event or unanticipated problem, the physician can respond however he or she thinks is clinically the most appropriate. However, if a patient on a protocol who receives the same therapy reports the same adverse event, the physician must grade the severity, assess the attribution, document the event, consult the protocol, and make treatment modifications as required by the protocol. New codes in the Current Procedural Terminology, with higher reimburse- ment rates that acknowledge the additional time and resources needed to counsel and care for a patient in a clinical trial would address an important deterrent to physician participation in clinical trials. With a proper definition of eligible trials, use of such a code could easily be audited. However, taking steps to align the incentives of patients and providers to participate in clinical trials may not be effective unless more is done to

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0 A NATIONAL CANCER CLINICAL TRIALS SySTEM educate patients about the availability and value of clinical trials. Educa- tional efforts should focus on making the general population more aware of clinical trials. One reason is that it can be difficult for patients to sort through a large volume of new information and make complex decisions just after they have received a diagnosis of a life-threatening illness. Patients often lack comprehensive and reliable information about clinical trials and may not be able to identify the trials for which they might be eligible. Patients value reliable information from trusted sources, including family members, so appropriate education efforts could provide useful information that would allow patients to make informed choices about participation in a clinical trial. In addition, as noted in more detail in Recommendation 9, user-friendly electronic tools would increase awareness of clinical trials and make it easier for physicians and patients to enroll in the most appropriate studies. SuMMARy Collectively, the implementation of these recommendations would reinvigorate the Clinical Trials Cooperative Group Program for the 21st century and strengthen its position as a critical component of the transla- tional pathway from scientific discovery to improved treatment outcomes for patients with cancer. Modifying any particular element of the Program or the clinical trials process will not suffice; changes across the board are urgently needed. All participants and stakeholders, including physicians, patients, and health care insurers, as well as NCI, other federal agencies, academia, foundations, and industry, must reevaluate their current roles and responsibilities in cancer clinical trials and work together to develop a more effective and efficient multidisciplinary trials system. The Cooperative Group Program is beset by serious problems, but they are not intractable. The committee envisions a system that retains the cur- rent strengths, but moves beyond collaboration to integration, with reor- ganized structures and operations in a truly national clinical trials network and with sufficient funding and support to enable the rapid completion of well-designed, high-priority cancer clinical trials that advance patient care.