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How to Succeed in Modernizing Clinical Trials

Eastman, Peggy

doi: 10.1097/01.COT.0000512066.51409.cd
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At a time of major advances in understanding the biology of cancer, there is an increased emphasis on bringing safe and effective new therapies to cancer patients as rapidly as possible. At its annual meeting in Washington, D.C., the Friends of Cancer Research (FOCR) highlighted three ways of improving and updating the traditional cancer clinical trials process: modernization of eligibility criteria, examining the feasibility of real-world evidence through pilot studies, and optimization of exploratory randomized trials.

Three new white papers from three panels were presented at the meeting, which was supported by the American Association for Cancer Research, ASCO, and Susan G. Komen.

“We cannot afford to do trials the way they're currently being done; we've got to really revolutionize the way we do clinical trials,” said FDA Commissioner Robert M. Califf, MD, MACC, in a keynote address. “Probably the ultimate goal is randomization within the real world.” Califf said the next scientific revolution will be data sharing, which will help to speed findings that will produce major benefits for patients.

Modernization of clinical trials is already in process. In a second keynote address, acting NCI Director Douglas R. Lowy, MD, cited the innovative NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial, which has been “tremendously successful,” accruing about 500 patients per month at multiple sites. NCI-MATCH uses a unique trial design that links targeted cancer drugs to patients' actionable mutations. Treatment with the matched drug continues as long as the tumor shrinks or remains stable.

ASCO is also sponsoring a study targeting therapies to mutations, the Targeted Agent and Profiling Utilization Registry (TAPUR). That study is also proving popular, said ASCO Chief Medical Officer Richard L. Schilsky, MD: “Clinical sites and patients are clearly eager to be a part of this study and are enrolling more quickly than we had anticipated.”

Lowy noted that NCI is developing a formulary, which could be especially useful for studies on combination therapies and preclinical testing. Lowy said there are three major areas where innovative studies “could really make a difference in accelerating the pace of cancer research.” They include the following:

1. going beyond the Cancer Genome Atlas to understand cancer at the molecular level with a tumor cell atlas, which could provide a “cinematic view” of how cancerous tumors develop and how they interact with their microenvironment;

2. full implementation of existing standards of care, including smoking cessation initiatives, colorectal cancer screening, and increasing the uptake of the HPV vaccine; and

3. an increased emphasis on pediatric cancer research, with a focus on reducing the incidence of childhood cancers and reducing the long-term side effects of treatment.

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Clinical Trial Eligibility

Modernization of eligibility criteria could have beneficial effects on improving clinical trial enrollment, said speakers representing the first panel at the FOCR meeting. “It's been a struggle to put patients on trials,” said Edward S. Kim, MD, a co-author of the first white paper, Chair of Solid Tumor Oncology and Investigational Therapeutics and holder of the Donald S. Kim Distinguished Chair for Cancer Research at the Levine Cancer Institute, Carolinas HealthCare System in Charlotte, N.C.

Authors of the first white paper concluded there is a need for a re-evaluation of clinical trial eligibility, including the exclusion of patients with prior cancers. They noted that data have shown “prior malignancies did not impact survival outcomes in patients with stage IV lung cancer or locally advanced lung cancer, suggesting clinical trial outcomes would not be adversely impacted by inclusion of patients with a history of prior cancer.” The first panel concluded patients should not be routinely excluded from clinical trial participation because of brain metastases, minimum age, HIV/AIDS, and organ dysfunction.

In 2016, the FDA, ASCO, and FOCR began an initiative to re-assess the current approach to determining clinical trial eligibility. Benefits could include faster trial accrual, earlier access by patients to investigational agents, more complete safety data, and availability of efficacy results that could inform decision-making on commercially viable treatment options. On the other hand, risks of expanded eligibility could include: limited data from small cohorts, the fact that sicker patients might have a higher likelihood of experiencing an adverse event, complication of attribution of adverse events, and more variability in outcomes.

“We have to challenge ourselves...culture change has to start somewhere,” said Kim. He added that, in 5 years time, researchers should be able to answer affirmatively to the following questions: Have we begun to change trial protocols? Are protocols enrolling more patients? Is industry conducting studies with broader eligibility? Are young investigators writing trial designs with broader eligibility criteria?

“We need to continually balance the issue of patient safety against completing trials in a timely manner,” said Paul J. Hesketh, MD, a co-author of the first white paper, Chair of the Lahey Health Cancer Institute, Director of the Sophia Gordon Cancer Center, and Director of Thoracic Oncology at Lahey Hospital & Medical Center in Burlington, Mass. He noted that 20 years ago brain metastases were absolutely forbidden in clinical trial enrollment. But today, he said, new cancer therapies have a magnitude of benefit that is better than chemotherapy regimens of the past, and toxicity profiles that are better tolerated.

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Real-World Evidence

The second panel at the meeting discussed the feasibility of using real-world evidence through pilot studies. Real-world evidence includes that which is gathered through electronic health records (EHRs), patient registries, pragmatic trials that leverage the existing clinical infrastructure to test interventions in everyday clinical settings, administrative claims, surveys, pre-approval access programs, and mobile health-generated data (e.g., smartphones, wearables, and social media).

The panel concluded that as real-world evidence is increasingly used to support drug development, the focus should be on improving data capture, quality, and analytics. Real-world data are especially useful in incorporating patient experiences and outcomes from routine clinical care into drug development processes. “The challenge for studies utilizing-evidence will be to balance the need to ease access to new promising therapies and at the same time provide strong convincing evidence of clinical benefit,” stated the paper.

“Dr. Califf is passionate about real-world data,” said Gideon M. Blumenthal, MD, co-author of the white paper on real-world evidence, Clinical Team Leader for lung and head and neck cancers, and Scientific Liaison for lung cancer in the FDA's Office of Hematology Oncology Products. Blumenthal noted that, in addition to currently available sources, “we're on the verge of new technologies that allow the collection of real-world data.” He stressed the need for good data curation, and said a potential use of real-world evidence might be as observational post-marketing data in rare cancers.

ASCO's Schilsky said it is important to think about how to adapt EHR platforms on the front end and get physicians to collect EHR data in a structured way “so we don't have to spend a lot of time cleaning it up on the back end.”

“I think we really want to do things that can impact patients,” said Jane Perlmutter, PhD, MBA, a co-author of the second white paper, a 30-year plus cancer survivor, a consultant, and patient advocate. She noted that, as with traditional trial designs, new trial designs are never going to please everyone. “There is no perfect trial; there are always going to be tradeoffs,” she said. She praised ASCO's TAPUR study as a “great test case” that will generate useful data.

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Exploratory Randomized Trials

The third panel and their white paper addressed exploratory randomized trials, which are often single-arm studies. Such trials may be undertaken when unexpectedly large improvements in overall survival occur in early phase randomized studies. Exploratory trials, which usually have small numbers of participants, are often initiated to guide go/no-go decisions about drug development, and “they are typically not designed with the necessary statistical rigor for definitive assessments of clinical benefit,” stated the panel.

This panel suggested the following innovative approaches to promising exploratory randomized trials that show marked survival benefits:

* expand the exploratory randomized trial, and if the survival benefit is maintained, seek regulatory approval; or

* for exceptional survival data in an exploratory randomized trial, submit for regulatory approval and potentially initiate a phase III confirmatory study at the same time.

The white paper on exploratory trials cites as one of its case studies olaratumab, a platelet-derived growth factor receptor alpha blocking antibody that received FDA fast track and breakthrough therapy designation, priority review status, and accelerated approval for its use in soft tissue sarcoma. This drug is an example of an investigational therapy in an early phase study that showed a significant improvement in overall survival outcomes, a secondary endpoint; progression-free survival was the primary endpoint in this study. While this study was not designed to be a pivotal trial, it did lead to the approval of olaratumab.

The white paper on exploratory trials notes that, as research techniques better identify patient populations for specific clinical trials, unexpectedly large improvements in overall survival are becoming more frequent. Therefore, “new therapies have necessitated the need for innovative clinical trial designs and expedient pathways for drug approval.”

Peggy Eastman is a contributing writer.

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