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ASCO Pushes for Cancer Trial Improvements
The Pink Sheet Daily. 2011 Nov 7, E Hayes
Cancer research is in need of an overhaul, the American Society of Clinical Oncology concludes in a new report calling for, among other things, co-development of experimental drugs and innovative trial designs that can make trials smaller and faster, with potentially better outcomes. Barriers to development of therapeutics at a time of significant progress in the understanding of cancer biology were outlined in the organization’s new report, “Accelerating Progress Against Cancer – ASCO’s Blueprint For Transforming Clinical and Translational Cancer Research.”
Issued Nov. 3, the report aims to help establish a new approach to therapeutic development, based on a thorough understanding of cancer biology. To meet the goals outlined in the report, ASCO will be holding workshops on a range of issues with industry, regulatory bodies and other stakeholders to reach consensus on how to remove roadblocks and speed development of new cancer drugs.
One key recommendation is for testing novel drugs in combination, given that in the vast majority of cancers it has become clear that “targeting a single molecular defect is not enough,” because “most cancers are driven by multiple mutations.”
And increasingly, the report notes, new treatments will be pertinent to a patient based on molecular characteristics, rather than location in the body: “There is no single breast cancer or lung cancer or colon cancer, but rather several or even dozens of molecularly distinct cancers of each type that can arise.”
Today, though, there is limited understanding of which molecular pathways should be targeted. A cocktail approach combining multiple drugs is needed, but currently there are legal hurdles that make it “challenging for companies to work together to test promising combinations.”
Performing trials of novel investigative agents is challenging for many reasons, including competitive and intellectual property issues. FDA has issued draft guidance on industry co-development of two or more un-marketed drugs for use in combination, which includes solutions to help address some of the roadblocks.
Despite the challenges, there are a small but growing number of examples of collaboration in trials of unapproved drugs from different sponsors. Merck and AstraZeneca were among the first, with a study of AKT inhibitor MK-2206 and AZ AZD6244, a motiogens-activated protein kinase 1 inhibitor. Other companies, like Genentech and Sanofi, are following suit, with co-development within and between pipelines.
Collaboration by big pharmas is finally beginning to happen out of necessity, in order to improve efficacy, said John Mendelsohn, one of the report’s executive editors and former president of the MD Anderson Cancer Center, during a Nov. 3 press conference. Drug companies have learned that unless patients are preselected for a particular mutation, the response rates for a single drug may be only 5% to 10%, Mendelsohn noted.
“It’s not happening as much as we’d like but it’s happening more, and I see economics driving this,” he said.
Consensus-Building Workshops
Groups assembled by ASCO will look for ways to incentivize collaboration in development. Among other things, they will consider whether changes to intellectual property law are needed to facilitate more collaborative work.
ASCO workshops also will seek to build consensus on research priorities, to help minimize studies that offer only marginal benefits and instead focus on drugs that represent significant advances.
Patient-reported outcomes should be a key part of this assessment of value, according to the ASCO report. Today, parameters for measuring these outcomes is lacking, and the Patient-Centered Outcomes Research Institute has been charged with helping to establish quality measures.
The ASCO report advises that therapeutic developers should be gathering more data on quality of life when testing new therapies in trials: “This will enable greater recognition of value of a treatment based not only on patients’ survival, but on the quality of their survival. The FDA and therapeutic developers will increasingly work together to enable consideration of these factors in approval decisions and to include this information on drug labels.”
FDA nodded to its willingness to consider quality-of-life and patient-reported data during the debate on the potential withdrawal of the breast cancer indication for Genentech’s Avastin. The agency clarified that improvement in QoL would have been acceptable as evidence of a clinically meaningful benefit.
Such measures, however, are lacking in oncology. ASCO will be partnering with patient advocates to develop a consensus on what constitutes a meaningful benefit and aims to work with insurers to help ensure linkage of reimbursement to demonstrated outcomes.
The development system needs to move away from testing large patient populations that include many patients who are unlikely to benefit, and toward small trials of patients apt to respond based on molecular characteristics of their disease, the report says. Participants in studies should be screened based on molecular characteristics and there should be less reliance on criteria that are no longer as important, such as prior cancers.
“We need to revise criteria to focus on those most likely to benefit and enrich studies to include as many of these patients as possible,” said Neal Meropol, Case Western Reserve University, another executive editor on the report.
FDA is working on a guidance on enriching patient populations, as well as an expedited drug development pathway to facilitate approval on earlier evidence.
Innovative trial designs, such as adaptive trials, allow testing in smaller subpopulations and enable adjustment of populations during the course of a trial based on biomarkers, the report noted. But for enrichment to work, biomarkers need to be identified early on in clinical development.
Running smaller trials of molecularly-selected patients will require new investments in screening populations and in pathology. As trials get smaller and smarter, therapies might need to be twice as good as a prior therapy to make the investment worthwhile, Meropol said. Me-too drugs shouldn’t make the cut.
“We can no longer be focused on finding a few percent benefit from a new therapy,” Meropol said. “If the community agrees we need to set the bar higher, that will create incentives for the folks who develop and produce drugs to set their bar higher in terms of moving products forward in clinical development.”
Another prerequisite for enriched trials is a national infrastructure to facilitate access to tissue samples that can be interrogated for molecular properties, Meropol said. Access to tissue samples is essential for identification of therapeutic targets, but is out of reach for many researchers today.
Wanted: Regulatory Reforms
ASCO is interested in changes to trial design, and regulatory policy, to speed development of and access to molecularly targeted drugs. It currently takes up to five years to develop and initiate a clinical trial in cancer and the time needed to complete trials has increased steadily due to overlapping regulatory requirements and complex data reporting, the ASCO report notes.
“Risk aversion” is one of the chief regulatory barriers to clinical development, in Mendelsohn’s view. Patients with advanced cancer should be able to decide what risks to accept for new therapies, he argued during the press briefing.
The small number of accepted measures for efficacy – typically overall survival and progression-free survival – also presents a hurdle for performing faster trials, the group said. Stakeholders have been slow to reach consensus on other endpoints that could help sponsors reach conclusions about the value of a therapy faster. FDA does have an ongoing effort to craft disease-specific guidances on cancer drug development; it released a draft guidance on lung cancer.
The ASCO report also highlighted ways to cut down on regulatory requirements for new uses of existing treatments. Currently, applications for new indications require collection of data on low-grade safety risks and complete records of other medications taken by individual study participants. These data “do not routinely inform regulatory or clinical practice decisions and consume significant time and resources,” according to the report.
Embracing Health IT
Looking forward, the ASCO report concluded, advances in health IT are “urgently needed” to facilitate development of molecularly targeted therapies in cancer.
Health systems are only beginning to develop capability to process large amounts of data and use it effectively. In ASCO’s view, it should be possible in the future to securely link electronic health records with biospecimens to allow researchers to explore molecular characteristics of an individual patient’s cancer. Future research will be guided by routine collection of patient-reported data – including real-time reports of symptoms and other patient experiences – combined with more complete information about the genetic make-up of their cancers, according to the report. In theory, information systems could be used to track side effects and other outcomes of various therapies.
Linkage of biospecimens with the electronic record also could help identify and alert patients for the most appropriate clinical trials. In some disease areas, such as breast cancer, online registries have been successfully used to dramatically accelerate trial enrollment.
ASCO is developing a “Rapid Learning System For Cancer Care,” an IT system that will connect patients, providers and researchers to a secure database that is updated in real time.
Within the next decade, health information will help dramatically improve patient care, the ASCO report concludes. “For researchers, there will be an unparalleled, high quality dataset to track real-world outcomes of cancer therapy and identify new areas of research,” Meropol said.
Hopeful
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