1. Eastman, Peggy

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The annual meeting of the Friends of Cancer Research (FOCR), held in Washington, D.C., featured innovative ways of making new drugs available to cancer patients sooner, while preserving standards of safety and effectiveness.

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FOCR, a nonprofit think tank, convened working groups of contributors who presented three white papers at the meeting, each aimed at a cutting-edge strategy to shrink the time from bench to bedside for effective new cancer drugs. The papers were discussed by invited panelists and meeting participants. The intent is to take next steps with these white papers, not "just put them on the shelf," emphasized FOCR Chairperson and founder Ellen Sigal, PhD.


"We're already thinking about how we can move some of these papers forward," added FOCR President and CEO Jeff Allen, PhD. The organization played a key role in formulating FDA's breakthrough therapy designation, which was implemented in 2012.


In a keynote address at the meeting, Anna Abram, the FDA's Deputy Commissioner for Policy, Planning, Legislation, and Analysis, stressed the organization's openness to new approaches to streamline drug development to help patients. She said that, in the era of precision medicine, agency officials know that as a regulatory body the FDA needs to be "modern, flexible, and able to respond to changing circumstances" while retaining its rigorous standards of safety and efficacy. Abram noted that FDA's breakthrough therapy designation started as a scientific white paper; it has led to some 100 approvals.


"Oncology is leading the precision medicine revolution," stated Abram. She noted that FDA's Oncology Center of Excellence (OCE) is taking the lead in this revolution. As previously reported in Oncology Times, the OCE had its genesis in the 21st Century Cures Act; it is FDA's first intercenter institute focused on a specific disease area rather on a type of product.


Examining Clinical Trials

The first white paper presented at this year's annual meeting, "Case Study in Non-Small Cell Lung Cancer," explored whether a synthetic control arm can be derived from historical clinical trials. The aim is to use historical clinical trial data to match the baseline characteristics and overall survival outcome of a randomized control arm.


The white paper notes that today such a concept makes sense because "patients may be reluctant to enroll in trials where they may be randomized to receive a perceived inferior therapy, or they may discontinue from ongoing clinical trials once the product is accessible through accelerated approval." Thus, data from the randomized control arm may be compromised by early discontinuation or crossover to the investigational therapy.


Indeed, "We have drugs today that are so effective that patients don't want to be randomized," Antoine Yver, MD, MSc, told Oncology Times. "It's a new problem," added Yver, Executive Vice President and Global Head of Oncology Research and Development at Daiichi Sankyo and a contributor to the white paper on NSCLC. In addition to cancer patients' increasing unwillingness to be randomized, the white paper noted that "there are some clinical settings (e.g., rare diseases) where scarcity of patients or ethical concerns have demonstrated that a randomized control is not possible."


The NSCLC white paper presents a statistical case study showing that a synthetic control arm based on historical data from previous clinical trials can mimic the results of a traditional randomized control arm. It contains detailed matching methods and efficacy analyses. The paper concludes that it is possible to produce matched cohorts of patients from historical clinical trials using "propensity scores" derived from observed baseline characteristics to form a synthetic control arm.


"In this NSCLC case study, the synthetic control arm successfully replicated the control arm of the target trial," said white paper contributor Ruthie Davi, PhD, at Medidata Solutions. "Overall we're very pleased with the outcome of this case study."


Speakers emphasized that the idea is not to do away with the traditional clinical trial randomized control arm, but rather to explore a new tool for use in certain carefully selected cases when appropriate.


"I don't want to preside over the death of randomized trials," commented Richard Pazdur, MD, Director of the OCE at FDA. While noting that he is not opposed to the concept of synthetic controls, Pazdur asked, "Who's going to be doing this synthetic control arm? The sponsor? Really?"


During a freewheeling luncheon conversation at the meeting, Pazdur noted that FDA efforts at modernization do have their detractors. "We do have our critics," he said. Some of them ask: how could you not have two randomized trials for new drug approval?


The specifics of synthetic controls need more study, panelists agreed. White paper contributor Andrea Ferris, MBA, President and CEO of the LUNGevity Foundation, said she looks forward to having a meeting next year where this approach has been used in clinical trials. "I hope this is a start at developing a whole body of literature on this topic," said white paper contributor Elizabeth Stuart, PhD, Associate Dean for Education and Professor in the Department of Mental Health at Johns Hopkins Bloomberg School of Public Health.


Circulating Tumor DNA

The second white paper presented at the FOCR meeting was entitled "Exploring the Use of Circulating Tumor DNA as a Monitoring Tool for Drug Development." The paper noted that ctDNA is composed of small fragments of nucleic acid circulating in the bloodstream that are not associated with cells or cell fragments, thus differentiating it from circulating tumor cells.


"The ability to detect small amounts of ctDNA in fluids has given rise to the use of liquid biopsies, a minimally invasive test done on a blood sample, or other fluids, that provide an alternative to surgical biopsies of solid tissues," stated the paper. While the white paper notes that ctDNA could potentially be used for early cancer detection, prognosis determination, and molecular characterization of a patient's tumor, it could also be used as a potential monitoring tool to track the effectiveness of cancer therapies.


The white paper examines several case studies, and the working group that produced it recommends the establishment of a multi-stakeholder consortium to operationalize the use of ctDNA in drug development. This working group also proposes the creation of a prospective pilot project to evaluate whether changes in ctDNA levels accurately reflect the therapeutic effect of immune checkpoint inhibitors.


In addition, the working group proposes exploration of the establishment of a virtual ctDNA data repository that could "generate broad learnings in a pre-competitive fashion to facilitate our understanding of ctDNA changes as a measure of drug effect." The virtual repository would contain data only from blood samples collected in a uniform, systematic, consistent way, not the actual blood samples.


"This is a tool that could really help in monitoring high-risk patients," said white paper contributor Jean-Charles Soria, MD, PhD, Senior Vice President and Head of Oncology Innovative Medicines at Astra Zeneca/MedImmune. "I think the promise of ctDNA is huge...but it's only going to be a good tool if we do it well," he added, noting that sometimes in early drug development there is a drop in ctDNA indicating seeming efficacy-but this early signal is not durable.


What is needed is solid evidence that the change in ctDNA really does predict outcome, said white paper contributor Julia Beaver, MD, Director of the Division of Oncology Products 1 in the Office of Hematology and Oncology Products at the FDA. To obtain this solid evidence, it may be necessary to start with advanced cancer and then move to earlier disease, said white paper contributor Geoffrey R. Oxnard, MD, Thoracic Oncologist at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School.


Patient acceptance of ctDNA as a monitoring tool is likely to be high, said white paper contributor Jamie Holloway, PhD, a breast cancer survivor who now works as a patient advocate as part of the Breast Cancer Program at Georgetown University's Lombardi Comprehensive Cancer Center. Holloway noted that patients are already going through blood draws on clinical trials, and so "one extra tube is not too much of a burden." She said that when physicians explained to their cancer patients why an extra blood draw was needed, patients would be happy to comply since most want to do something for others from their own difficult cancer experience.


The second FOCR white paper lists these next steps in making ctDNA a useful tool in oncology:


1. FOCR will seek to develop a ctDNA multi-stakeholder consortium.


2. The consortium will meet to discuss the initiatives explored in the white paper, including the pilot study and the virtual ctDNA data repository.


3. The consortium will implement the optimal approach to advance the understanding of ctDNA use in drug development.



Cancer Drug Review Process

The third white paper presented at the FOCR annual meeting, "Real-Time Oncology Review and the Assessment Aid," explored use of the real-time oncology review (RTOR) and the assessment aid (AAid), two new pilot projects initiated by the FDA's OCE. RTOR's goal is to improve the efficiency of the cancer drug review process for supplemental indications through data and analysis standardization and early engagement between the FDA and the drug sponsor. RTOR is intended for oncology supplements for drugs or biologics likely to demonstrate "substantial improvements over available therapies." The RTOR pilot process allows for the submission of key efficacy safety tables and figures and datasets before the complete dossier submission, and it gives FDA an early look at a proposed clinical trial by a product sponsor.


FDA's AAid pilot is for new drug applications and biologic license applications or supplements. It provides a shared document, using an assessment aid template, into which the product's sponsor/applicant can insert its positions on its product, and the FDA review team can then subsequently respond with its assessment reflecting its critical evaluation. The white paper notes that "both pilot programs may ultimately be converted to permanent programs," and that their full value would be realized by expansion beyond their initial limited scope. The white paper makes it clear that with expansion, the ultimate benefit of this new two-pronged regulatory approach would likely be earlier patient access to effective new therapies.


"This is the time to expand it," said white paper contributor Karen Jones, Vice President and Global Head of the Product Development Faster Filing Office at Genentech and Roche. She cited the success of FDA's breakthrough therapy designation as support for expansion of RTOR and AAid sooner rather than later.


The third white paper noted that results from the first two RTOR supplemental approvals (for ribociclib and pembrolizumab) and the first use of the AAid have generated optimism about the use of both. What the pilot projects really show is that early interaction between the FDA and a product's sponsor can be the key to success, said white paper contributor Qi Liu, PhD, a team leader in the FDA's Office of Clinical Pharmacology (OCP), where she serves as Vice Chair of the OCP Biologics Oversight Board.


"I think ultimately at a high level it was a success; we know we can do it now," said white paper contributor Jonathan Cheng, MD, Vice President and Oncology Therapeutic Area Head at Merck Research Laboratories, which sponsored the pembrolizumab supplemental application using RTOR, which was approved.


"It was very innovative from both the FDA side and the sponsor side; I think we were genuinely surprised that it was moving through so quickly," added white paper contributor Jitan Rana, PharmD, Global Program Regulatory Director for Novartis Pharmaceuticals Corp., which sponsored the ribociclib supplemental application using RTOR-the first approval under this pilot program.


From the standpoint of cancer patients, RTOR and AAid are good news, said white paper contributor and breast cancer survivor Katherine Couvillon, who spent 10 years as a health care data analyst for academic centers before becoming a patient advocate following her diagnosis.


"The sooner drugs are approved, the longer patients' lives will be extended," noted Couvillon. She added that the next cancer drug approved "might be the drug I need or that one of my friends might need."


Peggy Eastman is a contributing writer.