Summary and Wrap-Up

After Dr. Newcomer’s talk, the workshop finished with a general discussion and wrap-up session. Ms. Denicoff opened the discussion by asking if the IOM could work with stakeholders to determine minimum data and accrual standards as well as reporting requirements for both the NCI and industry trials, since sites often do both kinds of trials.

Dr. Mendelsohn responded by suggesting that the NCI take the lead on developing the criteria she suggested. He agreed that cooperative groups are going to be turning more and more to industry for financial support, and he noted a number of advantages that the cooperative groups offer industry, including diversity of subjects, numerous sites, and tissue banks that enable the genetic studies underlying personalized medicine. He suggested that the leaders of cooperative groups and large pharmaceutical companies come together to decide what studies are best run by cooperative groups and what studies are best run by industry. “That way we might be able to cut down the number of trials that the cooperative groups do and let them focus where they can provide the greatest value,” he said.

Dr. Canetta suggested that cooperative groups conduct more Phase II trials, which are in great demand given the current era of targeted therapy, time to progression endpoints, and new toxicities linked to these novel molecules being tested.

Dr. Louis Weiner, director of the Lombardi Comprehensive Cancer Center, chair of the Department of Oncology, associate vice president of Georgetown University Medical Center, and clinical director of cancer



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Summary and Wrap-Up After Dr. Newcomer’s talk, the workshop finished with a general discussion and wrap-up session. Ms. Denicoff opened the discussion by asking if the IOM could work with stakeholders to determine minimum data and accrual standards as well as reporting requirements for both the NCI and industry trials, since sites often do both kinds of trials. Dr. Mendelsohn responded by suggesting that the NCI take the lead on developing the criteria she suggested. He agreed that cooperative groups are going to be turning more and more to industry for finan- cial support, and he noted a number of advantages that the cooperative groups offer industry, including diversity of subjects, numerous sites, and tissue banks that enable the genetic studies underlying personalized medicine. He suggested that the leaders of cooperative groups and large pharmaceutical companies come together to decide what studies are best run by cooperative groups and what studies are best run by industry. “That way we might be able to cut down the number of trials that the cooperative groups do and let them focus where they can provide the greatest value,” he said. Dr. Canetta suggested that cooperative groups conduct more Phase II trials, which are in great demand given the current era of targeted therapy, time to progression endpoints, and new toxicities linked to these novel molecules being tested. Dr. Louis Weiner, director of the Lombardi Comprehensive Cancer Center, chair of the Department of Oncology, associate vice president of Georgetown University Medical Center, and clinical director of cancer 

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 MULTI-CENTER PHASE III CLINICAL TRIALS services at Georgetown University Hospital, brought up the clinical meth- ods training workshops run by ASCO and the American Association for Cancer Research (AACR). In these workshops, a fellow or junior faculty member with no or limited experience writing clinical trials develops, within a week, a completed protocol after receiving feedback from bio- statisticians and faculty. The protocols that emerge are generally high quality, he said, and most are ultimately executed. “For some of the high- priority Phase III types of studies that we are trying to do, a similar type of approach could be used where you actually bring together all the relevant stakeholders, including empowered representatives from the relevant sponsor, cooperative group setting, biostatistics, and regulatory agencies, and craft the protocol within a compressed timeline,” he suggested. “I believe it could be done if the various stakeholders were empowered to actually make decisions on behalf of their relevant agencies within pre- defined parameters.” Dr. Baker responded that the idea should be examined further and is worth developing. Dr. Mendelsohn said, however, that traditionally the cooperative groups take pride in being the training ground for young investigators, and Dr. Weiner’s idea “pushes them aside and pulls in the super-pros to do the job quickly. There are losses there, and we have to balance what the goals of the cooperative group are.” Dr. Canetta repeated the need for standardized case-report forms that can be used by the entire research community. “We need to sit around the table and reach an agreement,” he said, adding that the FDA’s participa- tion in this process would be valuable. Dr. Doroshow responded that there has been progress in the devel- opment of electronic case-report forms. These have been developed by the NCI with input from the FDA and industry. Currently there are 10 different modules in various stages of being vetted. “There is hope that over the next year that development, plus the electronic data-capture modules, will be helpful to everyone trying to unify what we do,” Dr. Doroshow said. Dr. Aisner brought up what he views as examples of wasted resources in clinical trials. Trials that compare an agent known to be toxic and inef- fective with a treatment arm in which this relatively worthless treatment is added to another agent are one example of such wasted resources, he said. Non-inferiority trials, “where the object of the trial really is how little can we do to do as badly as we have done,” are another example. Another participant raised the concern that cooperative group trials would be limited to sites with the highest accruals, as this would elimi- nate a number of sites that accrue minorities or patients in rural areas.

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 SUMMARY AND WRAP-UP POSSIBLE PATHS FORWARD Throughout the workshop, whether the topic discussed was related to the cooperative groups or another infrastructure for clinical trials, or rel- evant to physicians, academics, or patients, the same themes arose again and again, as Dr. Mendelsohn noted in his summary remarks. In these remarks he recognized that the NCI-sponsored cooperative groups have made important contributions to improving treatment of cancer through trials that have led to new drug approvals and supplemental approvals for use of drugs off of the original label, that have established the efficacy of various combinations of agents and modalities, and that have led to various other achievements as well. On the other hand, he also observed that, during the workshop, representatives of cooperative group leader- ship, the NCI, academic institutions, the CCOPs, industry, and insurance payors all expressed concern that cooperative group clinical trials are often inefficient, slow, and wasteful of clinical researchers’ time. Many participants also stressed the inadequacy of funding for the Cooperative Group Program. Dr. Mendelsohn noted that there was general agreement among the participants that the problems with the Cooperative Group Program had reached crisis proportions and that all stakeholders would need to participate in corrective measures. “Each of the participating sec- tors can make changes that will improve these deficiencies,” he said. He then reviewed many of the potential action items suggested by speakers over the course of the workshop (Box 6). In addition, he said, there were a number of areas in which the view- points of workshop participants clearly varied. These areas included the need to ensure adequate numbers of trials, collaboration with indus- try, IRB issues, and globalization of the clinical trials enterprise. While many participants saw a need to decrease the number of clinical trials in the pipeline in order to focus resources on the most important trials, others argued that decreasing the number of trials could further exac- erbate problems of accrual if it meant that fewer types of cancer would be addressed, including rare cancers. There was general agreement that collaboration with industry helps stretch the modest resources of the Cooperative Group Program, but many expressed concern that such col- laboration results in restrictions on the publication of data. There was little agreement on how to address problems with IRBs, especially in light of the different types of IRBs engaged in the process: locally based IRBs, the NCI-based central IRB, and private, commercial IRBs. Finally, in an era of increasing globalization, clinical research institutions face loss of industry collaboration as more clinical trials are conducted overseas, and, for cooperative groups collaborating with industry, streamlining the data

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 MULTI-CENTER PHASE III CLINICAL TRIALS BOX 6 Potential Action Points Suggested by Speakers The following were suggested as potential action points by speakers, as sum- marized by the conference planning committee chair, Dr. John Mendelsohn, and the chair of the National Cancer Policy Forum, Dr. Harold Moses. Conference participants suggested many different ideas, but the ones listed here appeared to garner significant support from participants across various stakeholder types, according to the chairs. The action points are organized according to the organiza- tions that would undertake them. Cooperative Groups • educe the number of trials. “Just say no” to trials that are not excellent or R that undergo excessive debate and revision. • Stop “tweaking” and recycling revisions of trials. • Seek increased industrial support of trials exploring a new agent. • liminate outdated criteria for eligibility for a clinical trial (previous treatment, E previous malignancy). • Eliminate sites that enroll few patients. • onsider increasing randomized Phase II trials and reducing Phase III C trials. National Cancer Institute • educe CTEP-sponsored reviews of clinical trials, especially when they do R not involve a new unapproved agent. There are too many reviewers with veto power in developing a protocol. • Reduce overlapping audits of clinical research units. collected is made even more difficult by the need to satisfy the regulatory requirements of multiple regulatory agencies around the world. Dr. Moses concluded the workshop by noting that the proceedings will serve as an input to an IOM committee that will examine the role of the NCI cooperative groups in the conduct of cancer clinical trials and generate consensus conclusions and recommendations.

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 SUMMARY AND WRAP-UP • xpect that recipients of payment for participation in cooperative group E trials meet metrics for accruals and data reporting, and reward those who surpass the metrics with larger payments. • Standardize data collection using an electronic format. • nclude credit for cooperative group trials in the review of Cancer Center I Support Grants. Federal Government • ass laws that provide reimbursement for the standard-of-care costs of P clinical trials by CMS and by ERISA plans. • or new, marginally active drugs and drugs approved based on response or F time to progression, consider a policy that requires participation in a clinical trial in order to receive reimbursement for the cost of care, akin to what is done in the United Kingdom. • educe requirements for collecting and reporting data on clinical trials to R those essential for evaluating safety and efficacy. • educe the requirements for review involving triple readings of all imaging R studies used as endpoints in clinical trials. Academic Medical Centers • ecognize the scholarship and research accomplishments of clinical inves- R tigators in the promotion and tenure process. • ecognize collaborative and team research in the promotion and tenure R process. • rovide clinical investigators with resources and time protected for research, P in a manner parallel to that provided to laboratory researchers. This list represents the observations of Dr. John Mendelsohn and Dr. Harold Moses; it does not represent the opinion of the IOM.

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