Implementing a National Cancer Clinical Trials System for the 21st Century

Second Workshop by the American Society of Clinical Oncology and Institute of Medicine

INTRODUCTION

The National Clinical Trials Network (NCTN) supported by the National Cancer Institute (NCI) has played an integral role in cancer research and in establishing the standard of care for cancer patients for more than 50 years. Formerly known as the NCI Clinical Trials Cooperative Group Program, the NCTN is comprised of more than 2,100 institutions and 14,000 investigators, who enroll more than 20,000 cancer patients in clinical trials each year across the United States and internationally.

Monica Bertagnolli, professor of surgery at Harvard Medical School, chair of the Alliance for Clinical Trials in Oncology, and chair of the Institute of Medicine (IOM) workshop planning committee, noted that cancer mortality in the United States is falling. Bertagnolli said that the NCTN has contributed substantially to this reduction in cancer mortality over its 56-year legacy. However, she added that “the world has changed in many, many ways, and it has become incredibly more complex and challenging to do the kind of work that we want to do.” At the same time, the promise of cancer research has never been greater, she said.

John Mendelsohn, chair of the IOM National Cancer Policy Forum (NCPF) and director of the Khalifa Institute for Personalized Cancer Therapy at the University of Texas MD Anderson Cancer Center, opened the workshop with a brief overview of the 2010 IOM consensus report titled A National Cancer Clinical Trials System for the 21st Century: Reinvigorating



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Implementing a National Cancer Clinical Trials System for the 21st Century Second Workshop by the American Society of Clinical Oncology and Institute of Medicine INTRODUCTION The National Clinical Trials Network (NCTN) supported by the National Cancer Institute (NCI) has played an integral role in cancer research and in establishing the standard of care for cancer patients for more than 50 years. Formerly known as the NCI Clinical Trials Cooperative Group Program, the NCTN is comprised of more than 2,100 institutions and 14,000 investigators, who enroll more than 20,000 cancer patients in clinical trials each year across the United States and internationally. Monica Bertagnolli, professor of surgery at Harvard Medical School, chair of the Alliance for Clinical Trials in Oncology, and chair of the Insti- tute of Medicine (IOM) workshop planning committee, noted that cancer mortality in the United States is falling. Bertagnolli said that the NCTN has contributed substantially to this reduction in cancer mortality over its 56-year legacy. However, she added that “the world has changed in many, many ways, and it has become incredibly more complex and challenging to do the kind of work that we want to do.” At the same time, the promise of cancer research has never been greater, she said. John Mendelsohn, chair of the IOM National Cancer Policy Forum (NCPF) and director of the Khalifa Institute for Personalized Cancer Ther- apy at the University of Texas MD Anderson Cancer Center, opened the workshop with a brief overview of the 2010 IOM consensus report titled A National Cancer Clinical Trials System for the 21st Century: Reinvigorating 1

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2 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM the NCI Cooperative Group Program (IOM, 2010b). Recognizing the recent transformative advances in cancer research that necessitate modernization in how cancer clinical trials are run, as well as inefficiencies and other chal- lenges impeding the national cancer clinical trials program, the NCI asked the IOM to develop a set of recommendations (summarized in Appendix B) to improve the federally funded cancer clinical trials system. These recom- mendations were published in the 2010 report. In early 2011, the NCPF and the American Society of Clinical Oncology (ASCO) held a workshop in which stakeholders discussed the changes they planned to implement in response to the IOM goals and recommendations (IOM, 2011). Two years later, on February 11-12, 2013, in Washington, DC, the NCPF and ASCO reconvened stakeholders to report on the changes they have made thus far to address the IOM recommendations.1 At this work- shop, representatives from the NCI, the NCTN, comprehensive cancer c ­enters, patient advocacy groups, the Food and Drug Administration (FDA), industry, and other stakeholders highlighted the progress that has been made in achieving the goals for a reinvigorated national cancer clini- cal trials system, and discussed additional strategies to further improve the system. This report is a summary of that workshop. An overview of key accom- plishments since 2010 is shown in Box 1, and a summary of suggestions from individual participants for further improvements is provided in Box 2. A summary of NCI progress to date toward implementation of the IOM recommendations was presented by James Doroshow, director of the Divi- sion of Cancer Treatment and Diagnosis at the NCI, as shown in Table 1. The workshop agenda and statement of task can be found in Appendix A. The speakers’ biographies and presentations (as PDF and audio files) have been archived at http://www.iom.edu/Activities/Disease/NCPF/2013- FEB-11.aspx. 1 This workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, are not necessarily endorsed or verified by the Institute of Medi- cine, the National Cancer Policy Forum, or the American Society of Clinical Oncology, and should not be construed as reflecting any group consensus.

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 3 BOX 1 Overview of Key Achievements Since 2010 •  onsolidated and integrated cooperative groups and C operations • Substantially reduced median time to trial activation • Improved information technology systems •  mproved intellectual property terms for collaborative I research • mproved processes and timelines for the two NCI central I institutional review boards • ncreased reimbursement to sites for large phase II studies I and additional funding for select phase III trials based on complexity • New guidance from the FDA on data collection •  ew initiatives and resources to support the development of N precision medicine BOX 2 Overview of Suggestions Made by Individual Participants •  nhance and expand collaborations among stakeholders E (e.g., the NCTN, the pharmaceutical and diagnostics indus- tries, federal agencies, and patients) • Expand use of innovative trial designs • Develop and validate technologies for precision medicine • Define criteria for use of genomic and other biomarker tests •  dequately cover the costs of tumor profiling and rebiopsy A if necessary •  reate a centralized clearinghouse for annotated genetic C profiles of patients’ tumors •  nsure that endpoint measurement is free of bias in trials E assessing tumor response or progression •  ssess quality-of-life issues in cancer clinical trials A •  ngage patients in trial design to enhance participation E •  onduct a pilot study to assess whether reimbursing oncol- C ogists for the time it takes to inform patients about clinical trials increases patient accrual

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4 TABLE 1 NCI Progress Toward Recommendations of the IOM Report A National Cancer Clinical Trials System for the 21st Century (2010) Goal 1: Improve speed and efficiency of the design, launch, and conduct of clinical trials Recommendation NCI Response as of February 2013 1: NCI should facilitate some • New Program with up to 4 adult and 1 pediatric Network Groups consolidation of Cooperative Group • Peer-review focused on overall research strategy, collaboration, and operational efficiency “front office” operations by reviewing • Support for trials designed with integral molecular screening and ranking the Groups with defined • Integrated translational science and Lead Academic Participating Site awards metrics on a similar timetable and by • Core Radiotherapy/Imaging services linking funding to review scores • Strategic planning and trial prioritization at the national level • Adult and pediatric central institutional review boards (IRBs); updated consent template 2: Require or facilitate consolidation • Centralized 24/7 patient registration, regulatory support, and site verification of trial participation by of Group “back office” operations and, the Cancer Trials Support Unit working with extramural community, • Implementation of timelines for study review and development with major time savings for trial make process improvement in the activation operational and organizational • Implementation of a common IT data management system for trial development and conduct management of clinical trials a priority instituted for all new clinical trials activated in 2013 3: The U.S. Department of Health and • Established an interagency agreement with FDA for rapid review of approved Group phase III Human Services (HHS) should lead treatment trials at concept stage a transagency effort to streamline and • Developed coordinated processes for development/review of trials under the FDA Special Protocol harmonize government oversight and Assessment (SPA) regulation of cancer clinical trials • Developed adult and pediatric NCI central IRBs, with major improvement in review timelines and accreditation by the Association for the Accreditation of Human Research Protection Programs • Working with FDA to coordinate early review of investigational devices (biomarker tests)

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4: NCI should take steps to facilitate • Harmonized all guidelines for programs engaged in the conduct of clinical trials so that the more collaboration among the various appropriate incentives are in place for collaboration (Specialized Programs of Research Excellence, stakeholders in cancer clinical trials Cancer Centers, Groups) • In collaboration with the CEO Roundtable on Cancer, developed Standard Terms of Agreement for Research Trials (START) clauses for company and academic collaborations to speed clinical trial negotiations • Revised the intellectual property (IP) option on all Cooperative Research and Development Agreements (CRADAs) in the Cancer Therapy Evaluation Program relating to drug development; for Biomarkers/Tissues—no blocking IP; royalty-free nonexclusive licenses • 6-month absolute deadline for CRADA negotiations with pharmaceutical companies 5: NCI should mandate submission • Revising the Request for Applications for U24 grants (cooperative agreements) for National of annotated biospecimens to Specimen Banks for NCTN Groups to include common operating procedures for samples collected high-quality, standardized central from patients in NCTN and other NCI-supported trials biorepositories when samples are • Developing a common process and procedures for requesting biospecimens banked from NCI collected from patients in the course clinical trials of Group trials and should implement • Developing a shared IT infrastructure to enhance specimen inventories new funding mechanisms and policies to support the management and use of those resources for retrospective correlative science 5 continued

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6 TABLE 1 Continued Goal 2: Incorporate innovative science and trial design Recommendation NCI Response as of February 2013 6: Cooperative Groups should lead • Initiated the Biomarker, Imaging, and Quality of Life Studies Funding Program (BIQSFP) to ensure the development and assessment of that critical correlative studies could be incorporated in a timely manner into phase III and large, innovative designs for clinical trials multi-institutional phase II trials during the process of concept development that evaluate cancer therapeutics and • From mid-2008 thru December 27, 2012, 24 of 88 concepts were submitted incorporating integral biomarkers (including combinations of and integrated BIQSFP-funded studies and Cost Effectiveness Analysis studies have been supported therapies) for a total commitment of $30,538,091 7: NCI, in cooperation with • Under the auspices of the Clinical Trials and Translational Research Advisory Committee (CTAC), other agencies, should establish a developed definitions of integral and integrated studies for biomarkers, imaging, and quality of life consistent, dynamic process to oversee (QOL) investigations associated with NCTN trials development of national unified • Working with the National Library of Medicine and the Association of American Cancer Institutes standards to develop the Cancer Trials Reporting Program (CTRP) database to provide accrual information related to all NCI-supported clinical trials with full accrual reporting to begin in 2013 8: NCI should reevaluate its role in the • CTAC Strategic Planning Working Group was established to evaluate the overall effectiveness of clinical trials system studies conducted by NCTN • Revamped prioritization process for phase 3 and large phase 2 treatment and control trials through disease and modality-specific Steering Committees to ensure most important trials are given highest priority • NCI represents Institute priorities for the public program on the Steering Committees and facilitates implementation of prioritized clinical trials

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Goal 3: Improve prioritization, selection, support, and completion of cancer clinical trials Recommendation NCI Response as of February 2013 9: NCI, Cooperative Groups, and • Modernizing the clinical trials IT infrastructure by implementing a common clinical data physicians should take steps to increase management system to be used across the NCI-supported clinical trials system the speed, volume, and diversity • Enhancing trial participant diversity through support for Minority-based Community Clinical of patient accrual and to ensure Oncology Programs, Patient Navigator Research Program, and other NCI programs high-quality performance at all sites • Working with patient advocates in concept development and accrual planning, along with Groups, participating in Group trials Disease Steering Committees, and Patient Advocate Steering Committee 10: NCI should allocate a larger • Developed targeted initiatives that have increased reimbursement to sites for patients on large portion of its research portfolio to phase II studies and additional funding provided for select phase III trials based on complexity as the Clinical Trials Cooperative Group well as the funding for critical biomarker, imaging, and QOL studies Program to ensure that the Program • Changes in the funding model for the new Funding Opportunity Announcement: has sufficient resources to achieve its o Increased reimbursement for high-performing sites (aimed at 40% accrual) unique mission o Need for additional infrastructure support with proposed budget increased to support better reimbursement but lower total level of accrual o Increase in core resources for genomic correlative studies 7 continued

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8 TABLE 1 Continued Goal 4: Incentivize the participation of patients and physicians in clinical trials Recommendation NCI Response as of February 2013 11: All stakeholders should work to • Created the Clinical Investigator Team Leadership Award to promote collaborative science and ensure that clinical investigators have recognize outstanding clinical investigators; annual awards made since 2009 adequate training and mentoring, paid protected research time, necessary resources, and recognition 12: Health care payment policies • Working with the NIH as well as across HHS agencies and with other federal agencies to help define should value the care provided to and shape national policy on clinical trials and reimbursement as well as to educate patients and patients in clinical trials and adequately payers regarding the benefit of clinical trials compensate that care • Working with FDA to facilitate incorporation of genomic tests into definitive clinical trials and the development of companion diagnostics SOURCE: Doroshow presentation (February 12, 2013).

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 9 IMPROVING SPEED AND EFFICIENCY OF TRIALS The first four consensus recommendations in Appendix B provided strategies to achieve the goal of improving the speed and efficiency of inno- vative clinical trials through reorganization of the system, by enhancing collaboration, and by streamlining and standardizing data collection and analysis. A major focus since 2010 has been on consolidating and integrat- ing the participating cooperative groups and providing more centralized administrative and IT support and data management to improve collabora- tion and operational efficiency. Reorganization of the NCTN The cooperative groups have reorganized themselves into four groups focused on adult cancers, in addition to a preexisting group focused on pedi- atric cancers (see Box 3). This reorganization has been an enormous undertak- ing and is partly due to a new Funding Opportunity Announcement from the NCI that limited funding to five groups. The merged groups submitted proposals in response to that announcement in February 2013, and awards are anticipated in 2014. Thus, the consolidation is still a work in progress. BOX 3 Reconfigured Groups of the NCTN •  lliance for Clinical Trials in Oncology (consolidation of A Cancer and Leukemia Group B, the North Central Cancer Treatment Group, and the American College of Surgeons Oncology Group) •  hildren’s Oncology Group C •  COG-ACRIN Cancer Research Group (consolidation of E the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network) •  RG Oncology (consolidation of the National Surgical N Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) •  WOG (formerly known as Southwest Oncology Group) S SOURCE: Comis presentation (February 11, 2013).

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10 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM The Clinical Trials Strategic Planning Subcommittee, a subgroup of the NCI’s Clinical Trials and Translational Research Advisory Committee (CTAC), is charged with helping to develop a fully integrated Clinical Trials System. However, group leaders stressed the benefits of consolidation. Bertagnolli said, “I think it’s very important to acknowledge the tremen- dous and extremely positive impact that the involvement of the IOM in our enterprise has had. The initial consensus statement and the first work- shop have yielded truly amazing changes that have updated the groups and allowed us to really feel confident as we go forward that the work that we do will be preserved and even strengthened.” Robert Comis, president and chair of the Coalition of Cancer Coopera- tive Groups, group chair of the Eastern Cooperative Oncology Group, and professor of medicine and director of the Clinical Trials Research Center at Drexel University, concurred. He reported that the consolidation of the Eastern Cooperative Oncology Group (ECOG) with the American College of Radiology Imaging Network (ACRIN) will enable an integrated data warehouse that will include case report forms and imaging data, digital pathology, a specimen repository inventory, and “omics” information and resources, adding that the pooling of resources will enable ECOG to take advantage of ACRIN’s tremendous amount of electronic imaging data. “From the inception of the ECOG-ACRIN idea, we had always envisioned this as a great opportunity, not just for us but for the whole system,” he said. NCTN group operations were also reorganized into five major hubs: 1. Statistics and data management centers 2. Radiation therapy and imaging core services centers 3. Integrated translational science centers 4. Lead academic participating sites 5. The Canadian Collaborating Clinical Trials Network All groups will contribute to and use the resources of the newly estab- lished integrated translational science centers, Comis noted. The goal is to develop integrated next-generation sequencing, advanced imaging, immunobiology, biorepositories with clinically annotated specimens, and reference labs. These centers will offer a platform for sustained, cutting-edge scientific effort and enhance interactions across groups and with cancer centers, he stressed. The NCI has also expanded its Cancer Trials Support Unit to enable centralized administrative and regulatory functions for clinical trials. It now

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 11 offers 24/7 centralized Web-based patient registration; provides educational materials for patients, nurses, and physicians; and offers regulatory support, financial management, accrual reimbursement, and protocol coordination, as well as other types of support. Aggressive Timelines Previous studies indicated that a substantial contributor to the inef- ficiency of cancer clinical trials has been the length of time between when a trial concept is first proposed and when it is approved and activated, said Doroshow. Prior to 2008, it often took more than 2 years to activate a phase III trial and nearly that long for early-phase trials as well. However, several changes have substantially reduced the median time to trial activation, with a 30 percent improvement for early-phase trials and a 50 percent improve- ment for phase III trials (see Figure 1) (Abrams et al., 2013). These time-saving changes include setting aggressive timelines for implementing clinical trials that provide not only optimal target dates, but also absolute cutoff dates, after which a trial cannot be activated. The NCI also established a new website that tracks all phases of a protocol’s life cycle, created new positions to manage protocol development, and implemented uniform templates for protocol development and reviewers’ comments. Other major contributors to the shortened trial activation time include improved processes for the two NCI central IRBs—one for adult trials and one for pediatric trials—and updated consent templates. These changes slashed the time from protocol receipt to trial approval by a central IRB from a median of about 4 to 5 months in 2008 to only 3 weeks in 2012. As of 2013, all NCTN trials are required to use the central IRBs (with waiver exemptions possible for sites demonstrating similar local IRB review timelines). “This will decrease a lot of needless busy work that results from hav- ing hundreds of institutions review the same protocols,” Doroshow said. It will also facilitate more clinical trials of rare cancers by enabling rapid approval of a trial as patients with these rare diseases are encountered in the clinic, he added. “Now that we’re going to have these small and molecularly defined populations, it’s rather critical that institutions have the ability to open trials when they find the right patients, because we probably will have many more trials with such small populations,” said Jeffrey Abrams, associ- ate director of CTEP in the Division of Cancer Treatment and Diagnosis at the NCI.

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64 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM reporting. He noted that given the new mechanisms of action of many new cancer drugs, “I’m a little bit hesitant to have guidances that even for supplemental indications are going to reduce the surveillance on even Grade 1 and 2 toxicities.” He added that although collecting less safety data for clinical trials testing new indications for well-known cancer drugs may be appropriate, large companies that sponsor such trials have general SOPs for all types of therapeutic areas. “Unless the FDA and EMA come up with very clear guidances that separate oncology clinical trials from the rest, we will continue to see collection of safety data that may look to you as being superfluous and overcautious,” he said. Schilsky acknowledged concerns about some drugs moving into clini- cal use with limited safety data assessment. “The sponsor and the regulatory agencies should sit down and decide what is sensible data collection given the patient population being studied, the pharmacological class of agent, the known safety profile of the drug and the objectives of the trial,” he said. Progression-Free Survival Endpoints and Bias Speakers and participants also explored how to avoid bias in assess- ing response to therapies in clinical trials, and whether there is a need for independent central review of imaging results when PFS is used as an endpoint. Dodd noted that the use of PFS is an area of active debate, and that in general PFS does not measure clinical benefit, nor is it a surrogate for overall survival. A trial with PFS as a primary endpoint requires strong evidence that the treatment effect is large, she said—greater evidence than would be required when overall survival is the endpoint. Dodd pointed out that progression assessments vary by reader, with discrepancy rates in the timing and presence of progression typically greater than 30 percent. This has led to concern that there is potential for reader bias in unblinded trials due to local evaluators knowing the treatment assignment, prompting the requirement for blinded independent central review. But Dodd’s study, published in 2008, showed that treatment effects were similar when estimated using central review or local evaluations (Dodd et al., 2008). Two more recent reviews of cancer clinical trials found more than 90 percent correlation in the hazard ratios between blinded independent central reviews and local assessments of progression of solid tumors (Amit et al., 2011; Zhang et al., 2013). “Given this, we have to ask ourselves, what is the value of central review?” Dodd said. As an alternative

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 65 to central review, she suggested using overall survival as an endpoint instead of PFS, but recognized that this is often not feasible. Dodd proposed that central review should also not be required in double-blinded studies in which the radiologists did not know the treatment assignment. Another alternative would be to audit for bias by doing blinded, independent central review on a small subset of cases. In July 2012, an FDA advisory committee considered this issue and all committee members agreed that a prospectively defined audit approach should be considered. They advised against complete elimination of blinded independent central review, Dodd reported. She added that the EMA has some guidelines that suggest it is also open to an audit approach. “Moving forward, we need to just make sure that any method we come up with is able to identify bias,” Dodd said. “An audit using central review may be the best strategy today, but technological advances may offer alternative solutions in the future,” she stated. “We should think about ways to ensure that local reviews are blinded because the true effect of a drug on PFS may be best estimated in a double blind trial,” Dodd concluded. But Sledge questioned the value of independent reviews. He noted that in one ECOG clinical trial, two radiologists reading the images disagreed almost half the time. “Does anyone seriously believe adding a third radiolo- gist’s readings will be of statistical benefit?” he asked. “Why are we still even contemplating blinded independent review given that this is an experiment that’s been tried and failed?” Dodd responded, It’s true that the discrepancy rates are shockingly high if you just look at the discordancy raw numbers, but what’s most important is the hazard ratios, which are estimates of treatment effect. What studies show is that in spite of those high discrepancy rates, the hazard ratios are in general agreement. Looking at the discrepancy rates alone is not really the answer we’re looking for. Adding another radiologist doesn’t solve the problem, but if you have two radiologists’ assessments and the treatment effects as estimated by those reads are in general agreement, that makes us feel more comfortable that there wasn’t a lot of systematic bias. Pazdur added, “We have a regulatory obligation to make sure there isn’t bias. If the trial is truly blinded, you don’t need independent review. But most trials in oncology are unblinded because of the differential toxicity between the control and treatment arms of the trial, so one has to have some comfort that there is a true finding. That’s why we’re looking at these alternative mechanisms to ensure there is no bias.” Pazdur gave an example of a trial of a treatment for carcinoid in which

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66 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM the data safety monitoring committee recommended closure of the study for early demonstration of efficacy, based on the PFS rate, while another group reviewing the same study recommended it should be closed for futility. “That demonstrated to us that bias crept into the study,” he said, although Dodd added that carcinoids are particularly difficult cancers on which to assess progression via imaging. Dodd’s statement led Comis to suggest some studies may pose more risk of bias than others, and should have a different bias-monitoring strategy imposed on them. Schilsky said that “if there’s any bias introduced to a study, it’s not at the level of the reading radiologist,” because it is uncommon for radiologists “to be aware of or to care about what the treatment is that’s being tested. The risk of bias comes from how the oncologist interprets that information that comes from those radiology reads.” But he added that in large clinical trials, the bias contribution of a single oncologist would be minor and wouldn’t be likely to influence the outcomes. “If all the participating physicians in the trial have a systematic bias, then that trial was doomed from the start. It’s a bigger issue than just reading the films,” he said. Sherman stated that bias in “single trials [used to gain FDA approval] is the most concern to us because we’re making a very major decision based on a study whose findings were not replicated. Unblinded trials introduce more uncertainty, and simply hoping there isn’t bias isn’t the same thing as assessing whether or not there is.” In response to a participant who asked what industry can expect in this regard, Sherman answered, “The end of a phase II trial is the time to have that discussion about bias and monitoring with the FDA. One type of monitoring is appropriate for one study design, but in another situation it may not be. It’s never going to be a one size fits all.” Pazdur agreed, adding, We’re dealing here with a subjective endpoint that is much different than overall survival, so we have to make certain there is no bias. You would have to guarantee that there was training on the sites of radiologists, and that there wasn’t communication between the radiologists and the treating physicians, because as we all know a doctor may go down to a radiologist to read the images. Due to discussions between the physician and the radiologist, there can be changes in interpretations and which metastatic disease sites are mea- sured, depending on if a doctor wants the patients to continue on a particular treatment because he thinks it’s benefiting them. Pazdur said that the FDA welcomes sponsors to suggest the least bur- densome way to ensure there is no bias in their studies that use PFS as an endpoint. Francesco Pignatti, head of oncology, hematology, and diagnos-

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 67 tics in the Safety and Efficacy Sector at the EMA, said that the EMA is also open to approaches for demonstrating lack of bias. “Blinding the local eval- uation is an excellent proposal. I’m also confident that the audit approach will evolve quickly as soon as we gain experience on how and when to use it. We’re trying to simplify things, so in the training and monitoring of the local evaluation, and the firewalls between radiology and clinical oncology, let’s be careful that this doesn’t result in inefficiencies,” he said. Roychowdhury noted that some inefficiencies in clinical trials are due to excessive procedures instituted not only because of regulatory needs, but also because of paranoia on the part of sponsors about what the regulatory authorities want to see. “We cannot solve that by guidances, so how can we have more discussions between the regulatory agencies and the sponsors, especially for those on breakthrough therapies, so we can reduce the time- line of the trial?” he asked. Pignatti agreed that there can be excessive data collection for unimportant aspects due to sponsors’ lack of understanding that regulatory guidelines have flexibility and are not one size fits all. Sherman responded that as a general rule, when in doubt, sponsors should “consult with FDA early and often to make sure [they are] collecting what’s important.” She agreed that often investigators collect an excessive amount of data or the wrong type of data because they believe such data are needed to garner an FDA approval for the treatment being tested. “Why is there this compulsion to collect every piece of data and check every box? Please come talk to us and think about how to make sure we’re making every dollar, and more importantly, every patient, count in clinical trials,” she said. Global Regulation Pignatti from the EMA spoke about global regulation, including Euro- pean regulation of clinical trials, how it differs from U.S. regulation, and efforts to harmonize international regulations. He noted that in Europe, the EMA is responsible for premarket evaluation of drugs as well as supervision of drugs once they reach the market. The European Union (EU) recently reviewed and revised its clinical trials legislation to take a more risk-based approach, and the EMA is trying to foster earlier and more continuous com- munications between regulators and sponsors. But he added that although the EMA will give advice to sponsors about trial design and conduct, that advice is optional and not binding; individual countries have not given the agency authority over design, approval, and conduct of clinical trials.

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68 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM The main divergence between EU and U.S. regulation is in the area of early approval mechanisms, Pignatti said. The FDA will grant accelerated approval for a treatment for a serious or life-threatening disease based on a surrogate endpoint likely to predict clinical benefit, with confirmation of benefit in postmarketing monitoring. The new agent for an accelerated approval has to be more effective than available therapy. The European Union, in contrast, will grant a conditional marketing authorization for a treatment that fulfills an unmet medical need for a seri- ous, life-threatening, or orphan disease or in response to emergency threats. Even if the clinical data are not complete, authorization will be granted if researchers can show a positive benefit–risk balance, and if that benefit is confirmed with monitoring after the treatment has entered the market. “The critical difference is that in Europe, the benefit–risk must be as posi- tive as for any other type of approval,” Pignatti explained. In 2004, the EMA and the FDA forged a confidentiality agreement to improve dialogue between the two agencies, recognizing that both share the same fundamental public health mission. This agreement has resulted in regular and ad hoc discussions and shared activities between the two agencies “that have been very successful,” Pignatti said. “There are few dif- ferences now in our general guidances. The more difficult part is when we come to applying them, because regulators have to make decisions in the presence of uncertainty,” he concluded. In situations with the most uncertainty (e.g., in the review of small, single-arm studies, studies done on heterogeneous populations, or early- approval applications), the two agencies can differ in their decisions, he noted. “In areas of very high uncertainty or situations where the benefit–risk balance is very close, you can continue to expect to see differences, because even having the best intentions and processes in place does not guarantee full harmonization,” Pignatti said. For example, the FDA revoked approval of bevacizumab for breast cancer treatment because new studies did not show improvement in overall survival, but the EMA found that the benefits of bevacizumab in combi- nation with paclitaxel outweighed its risks and approved the combination (Burstein, 2011; EMA, 2010). One study found that for 42 anticancer drugs approved by the EMA between 1995 and 2008, there were substan- tial differences between EMA and FDA decisions. Nearly half (47 out of 100) of the indications for these drugs had differences in approval; for 19 indications, approval was granted by only 1 agency, and 28 indications were approved by both the EMA and FDA but with different restrictions

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 69 (Trotta et al., 2011). Sixty-nine of the indications were approved first in the United States, although the time lag between FDA and EMA approvals is decreasing, Pignatti said. According to Pignatti, another major discrepancy between FDA and EMA oversight is how the two agencies view the use of PFS as an endpoint in registration trials. Although both agencies agree that overall survival is a more clinically relevant endpoint than PFS, the EMA accepts PFS if it measures a clinical benefit, whereas the FDA tends to view it as a surrogate for overall survival. “Even within our community and our committees, this is a hotly debated issue,” Pignatti noted. This is problematic given that PFS is increasingly being used as an endpoint; one study found that between 1995 and 2000, only 21 percent of pivotal confirmatory trials used PFS as the primary endpoint, but the rate increased to 49 percent between 2006 and 2010. “The different understanding of the clinical relevance of PFS is something we definitely want to work on,” Pignatti said. New Models for Regulation of Drug Development Eichler, also from the EMA, described the New Drug Develop- ment Paradigms (NEWDIGS), a collaborative effort that began at the M ­ assachusetts Institute of Technology and includes representatives from drug regulators, drug companies, payers, patient organizations, and aca- demic institutions. NEWDIGS’s objective is to reliably and sustainably deliver new, better, and affordable drugs to the right patients faster, and to counter “Pharmageddon,” as Eichler described the current situation. “The innovation engine, particularly in the biopharmaceutical industry, isn’t humming along as it should be. Everybody is a bit disgruntled and dissatisfied, whether you’re a patient, in pharma, a provider, a payer, or a regulator,” he said. The goals of NEWDIGS are to provide a unique, collaborative environ- ment for innovation and learning that is creative and nonbureaucratic, to tap the entrepreneurship and collective intelligence of its participants, and to have a collaborative impact similar to what the SEMATECH collabora- tion had on the semiconductor industry in the 1980s.9 “NEWDIGS calls itself not just a ‘think tank’ but also a ‘do tank.’ They want to catalyze pilot 9  SEMATECH is a global collaboration with the objective of accelerating the commer- cialization of technology innovations into manufacturing solutions (see http://www.sematech. org/corporate/index.htm [accessed May 14, 2013]).

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70 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM studies in real life, not just sit and think,” Eichler explained. NEWDIGS takes a systems approach to catalyzing change by exploring the co-evolution of processes, technologies, policies, and people, he added. NEWDIGS has developed the concept of adaptive licensing (Eichler et al., 2012) to counter some of the problems currently experienced with the regulation of new drugs. According to Eichler, these problems stem in part from the binary nature of that regulation. There is gradual learning about the effects of new drugs in a limited number of animals and people that occurs preclinically and during clinical testing. But “the next morning after that ‘magic moment’ when the new drug is approved, it’s out the door and anyone can have it and we have no idea what happens to these patients. Is that wise?” Eichler asked. Another problem is that some patient groups are frustrated that new drugs are not offered sooner to them, while some consumer advocates maintain that more needs to be known about drugs before they enter the market. As FDA Commissioner Margaret Hamburg has noted, it has been said that the FDA has just “two speeds of approvals—too fast and too slow” (Hamburg, 2010). To counter both problems, NEWDIGS has proposed “doing away with the magic moment and creating a number of milestones where we look at the data on the drug repeatedly over time and align the way a drug becomes available with the growing knowledge as uncertainty is progressively reduced. We can broaden the access of the drug this way,” Eichler explained. He noted that in the current regulation scheme, during post-licensing of a drug, the treatment population grows rapidly but the treatment experi- ence does not contribute to evidence generation. With adaptive licensing, in contrast, after initial license of the drug, the number of treated patients grows more slowly due to restrictions on use, and the patient experience is captured, contributing real-world information about the safety and effec- tiveness of the drug (see Figure 5). Eichler explained that adaptive licensing is a prospectively planned, adaptive approach to the regulation of drugs that has iterative phases of evidence gathering followed by regulatory evaluation and license adapta- tion, which can specify that the drug be withdrawn from the market or continue to be offered to patients. Adaptive licensing seeks to maximize the positive impact of new drugs on public health by balancing timely access for patients with the need to provide evolving information on benefits and harms. “Adaptive licensing is basically the tradeoff between access and knowledge,” he said.

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 71 A License Patients treated, no active surveillance Patients in observational studies, registries, etc. Patients in RCTs (or other interventional studies) Number of patients treated Time (years) Initial “Full” License License B “ObservaƟonal” Phase Number of patients treated Time (years) FIGURE 5  Adaptive licensing captures more of the patient experience, contributing more real-world information about the safety and effectiveness of drugs. NOTE: A = traditional licensing; B = adaptive licensing; RCT = randomized controlled trial. R02456 SOURCE: Eichler presentation (February 12, 2013). Figure 5 type replaced as vectors colored chart is raster

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72 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM Eichler noted that similar licensing already occurs with the FDA’s accelerated approval licensing and with EMA’s Conditional Marketing Authorisation, and can be aided by pharmacovigilance tools that detect adverse reactions to drugs. He added that to achieve the full potential of adaptive licensing, licensing decisions should be aligned with coverage and prescribers’ decisions. Adaptive licensing will require not only randomized controlled trials, but also observational studies. Although some experts are hesitant to rely on such studies, which are considered lower in the hierarchy of evidence-based research, “many regulatory decisions are already based on case studies,” Eichler pointed out. For example, the FDA may decide to withdraw a drug from the market or alter its label based on adverse event reports, which are essentially case reports, he noted. Unlike clinical trials, which have strict conditions for patient partici- pation, observational studies have the advantage of better detecting drug effects in the “real world,” when they are combined with other medications or influenced by concomitant conditions, Eichler added. He stressed, “We have to have the full spectrum of evidence-generation methodologies at our disposal, and you especially will need rapid learning systems in oncology where you probably have more variables than you have patients. The more information you can gather from the real world, the faster the learning experience will be.” The needs and potential benefits of a rapid learning system for cancer were described in a past NCPF workshop (IOM, 2010a). WRAP-UP After a day and a half of presentations, speakers and participants agreed that much has been accomplished since the publication of the IOM consensus report to improve the efficiency, innovation, oversight, and col- laboration potential of the NCTN. But due to the rapidly changing nature of cancer research, challenges still remain. “There has been an enormous amount of change in just 2 years that has been in a very positive direction,” Doroshow said. Looking forward, the NCI aims to foster an NCTN “that’s not just for treatment, screening, and diagnosis, but for control and prevention as well,” he stressed. He added, “I hope as we fund our new system, we will have a very functional platform that allows us to screen and find the patients we need for the molecular trials that are the trials of the future.” Comis added that although there are still major challenges with biomarker screening, there is a real “opportunity

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IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 73 to position the NCTN groups to play a critical role in the development of more targeted therapies.” Doroshow concluded that “it’s remarkable that we can, in a financially tight time, come together to understand where the most important science is and what critical infrastructures we need to allow that science to go for- ward. We have done our job to modernize the system.”

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