The organizations released a new report suggesting strategies for dealing with those challenges, “A Blueprint for Drug/Diagnostic Co-Development: Next-Generation Sequencing (NGS) in Oncology.”Speakers at the forum, known as the NGS Working Group, helped develop the report; they include representatives of academia, industry and government. FOCR, an advocacy organization for cancer patients, played a key role in helping to develop the Breakthrough Therapy designation for promising new drugs signed into law in July 2012. FOCR issued a previous related report, “A Risk-based Approach for In Vitro Companion Diagnostics Device FDA Approval Process Associated with Therapies that Have Breakthrough Designation” (OT 10/25/13 issue).
“This is a very complicated topic; I call this a geek conference,” said FOCR’s Chair, Ellen Sigal. PhD. “What we’re trying to do is get this right for patients… that’s our north star, and that’s what this is about.”
Another Working Group member, Karen Gutekunst, PhD, Vice President for Diagnostic Development at Illumina, Inc., said, “Anyone who’s been in the field of oncology for the last five years knows how important sequencing is becoming. … It’s already being used in many cancer centers. It’s a critical tool.”
Currently, for example, the Lung-MAP clinical trial is using a multi-drug, multi-arm, biomarker-driven approach for patients with advanced squamous cell lung cancer.
The report sets forth five proposals to address the complexity and advance the science of next-generation sequencing in cancer care:
1. Define a regulatory pathway for multi-marker cancer panels intended to identify actionable oncogenic alterations that allows flexibility in the appropriate Food and Drug Administration medical device pathway;
2. Approaches for performing validation studies should be based on the types of alterations measured by the assay, rather than every alteration individually;
3. Determine the contents of a cancer panel by classifying potential markers based on current utility in clinical care and clinical trials;
4. Promote the standardization of multi-marker cancer panels through the use of a common set of samples to ensure reproducibility on each platform; and
5. Establish a framework for determining the appropriate reference method rather than relying on any single reference method for all studies.
Speakers described a next-generation sequencing landscape lacking standardization of tools, with little validation data and a broad diversity of specimen quality. There is also a lack of agreement on what is “actionable” – for example, some markers are very specific, such as BRAF, while others are broader, such as EGFR.
“What is actionable?” asked Elizabeth Mansfield, PhD, Director of the Personalized Medicine Staff of the FDA’s Office of In Vitro Diagnostics and Radiological Health. She pointed out that even though there may not be a lot of data on a marker, it may still be useful in terms of referring a cancer patient to a clinical trial. She said FDA is “very receptive” to the concept of companion diagnostics based on next-generation sequencing, and “we want to move it forward.”
Also a member of the Working Group, Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research, said, “In cancer what we’re doing is unfolding complexities.” Because setting up a clinical trial for every subset of cancer patients is not feasible, what is needed are standing clinical trials with standardized procedures and processes in order to “build a picture out of complexity, and not just chaos.” Next-generation sequencing is a tool to help accomplish that goal.
The new report also notes that currently all of the marketed oncology panels have been developed by laboratories and do not require FDA approval. The FDA recently issued a guidance for companion diagnostics, which proposes a risk-based oversight framework for laboratory-developed tests (LDTs), especially genomic tests used to guide treatments for cancer patients. LDTs are currently regulated by the Clinical Laboratory Improvement Amendments (CLIA), but CLIA regulations do not assess the safety and effectiveness of LDTs offered by laboratories, nor do they evaluate the clinical utility of LDTs. Instead, CLIA regulations establish quality standards for laboratory testing in order to determine that the laboratory is in compliance with standards for good laboratory practices [see OT’s 10/10/14 issue for reactions to the FDA actions from ASCO, NCCN, AACR, and ACS].
As cutting-edge technology, next-generation sequencing is “the wild west… the question is, how do different labs see this assay?” commented Mickey Williams, PhD, Director of the National Cancer Institute’s Molecular Characterization Laboratory. “We need to think about the intended use before we move into analytical testing.” Thus, he said, a next-generation sequencing test must be evaluated, for example, according to whether it is intended as a research tool or for clinical use.
“This is a new clinical paradigm: simultaneous assessment of all of the driver mechanisms,” said Roman Yelensky, PhD, Senior Director for Biomarker and Companion Diagnostics Development at Foundation Medicine, Inc. “Clearly we need to account for the fact that the science is changing rapidly.”
Given that the great majority of cancer patients receive care in the community setting, next-generation sequencing is a particular challenge for community oncologists, speakers said. “Patients are logging onto the web and a lot of patients are having their tumors sequenced. How does an oncologist interpret these data?” Williams said in an interview. “I’ve heard that patients sometimes show up with a disk with raw data and give it to their oncologist and say, ‘How would you treat me?’ Oncologists need education, guidelines, and maybe tumor boards.”
Others agreed on the need for more education for practicing oncologists. “If we’re ever going to have accountable care in cancer, we have to stop thinking that all patients have to come to academic centers for a second opinion,” said Keith T. Flaherty, MD, Director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital and a lecturer at Harvard Medical School. But he noted, “It’s a lot to hand next-gen sequencing to a community oncologist.”
As to who has the responsibility for educating community oncologists about next-generation sequencing, he said, “It’s incumbent on us as academic centers to offer guidance to the community.”
Another speaker, Steven D. Averbuch, MD, Vice President for Translational Clinical Development & Pharmacodiagnostics at Bristol-Myers Squibb, said that professional societies such as ASCO also have a responsibility to promulgate guidelines and standards for community oncologists on clinical use of next-generation sequencing. He noted that ASCO is now working on defining standards and criteria for what is an “actionable” genetic alteration.
At the forum, reimbursement for laboratory-developed tests based on next-generation sequencing loomed as an important but unclear issue for oncologists and cancer patients. “From our point of view, we really care about patient access; if it is not reimbursed, patients don’t have access to a technology,” said Jeffrey E. Shuren, MD, JD, Director of FDA’s Center for Devices and Radiological Health.
Clearly, if an insurer does not believe there are enough valid data to support a test, it will not pay for it. When Medicare approves a test, other payors often follow; indeed, if a test is approved by Medicare, payors are obliged to reimburse for it, noted Bryan Loy, MD, MBA, Humana’s Physician Lead for Cancer and Vice President and Market Medical Officer. Asked if he is comfortable following Medicare’s lead on the validity of a Medicare-approved test, Loy said, “We would do our own assessment.”
The reimbursement issue becomes murkier because next-generation sequencing in oncology is such a rapidly moving field. The new report states, “One final issue to consider in the development of a regulatory pathway for an FDA cleared or approved cancer panel are the ongoing improvements in technology and changes in content. FDA-cleared panels may quickly become obsolete based on the rapid evolution and discovery in the oncology field.”
Thus, the report points out, there must be a mechanism for quickly ensuring the inclusion of new marker performance data for genomic alterations so that oncologists have the latest and best information needed to make treatment decisions for their patients.