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Recommendations Proposed for Off-Label Cancer Treatments
Elsevier Global Medical News. 2012 Jan 17, E Mechcatie
Prospective clinical studies that evaluate off-label uses of approved oncology drugs for advanced cancers should include patients in community settings and, whenever possible, should use actual survival as the primary outcome, according to recommendations published online Jan. 17 in the Journal of Clinical Oncology.
These and other proposed recommendations are outlined in a document intended "to guide the design of future prospective trials for off-label use of oncology drugs," wrote C. Daniel Mullins, Ph.D., professor of pharmacoeconomics at the University of Maryland, School of Pharmacy, Baltimore, and his coauthors, in the paper, published online (doi:10.1200/JCO.2011.35.5198). The recommendations "address the needs of patients and their clinical providers, compendia, payers, and policy makers," and focus on "the design of clinical studies to support evidence-based clinical and health policy decision making, but do not focus on changing the FDA-approved label of these drugs or resulting in approvals of the indications."
Referring to the "pervasive" use of oncology drugs for nonapproved indications, the authors noted that, in 2005, 50%-75% of cancer drugs were being used off label, an increase from previous years, but clinical evidence was available to support use of the drug for only about 27% of the off-label indications. Sources oncologists turn to when prescribing off-label treatments for patients include Food and Drug Administration-approved drug labels, medical literature, anecdotal information from colleagues, and continuing education programs, which are useful, but "reflect evidentiary gap that make it difficult for end users to gain information sufficient to make informed treatment decisions," they said.
The recommendations are based on the proceedings of a November 2009 meeting hosted by the Center for Medical Technology Policy (CMTP), with input from oncologists, drug manufacturers, the FDA, the National Cancer Institute, Centers for Medicare and Medicaid Services, public and private payers, and other stakeholders. The recommendations apply to studies of drugs for late-stage cancers, "in which there are hypothesized survival benefits for the drugs being examined in new indications," and are most likely relevant to patients who have been pretreated and have gone beyond first-line treatments. (The CMTP is a private, nonprofit organization, which "serves as a neutral forum to promote discussion and development strategies that improve the quality of clinical research for health care decision making," according to its website. (The founder and director, Dr. Sean Tunis, is a coauthor of the paper.)
"In oncology, more so than in any other area of medicine, drugs are used outside of FDA-labeled indications," Dr. Mullins said in an interview. In some cases, there is good evidence of the drug's net health benefit for the indication that has not resulted in approval for that indication or a label change. "But oftentimes, there is very limited evidence, so physicians have to make decisions and talk with patients about important decisions that affect their lives," without adequate evidence, he noted.
To address this gap, the group provided recommendations about the conduct of clinical trials of off-label indications so that the study of a treatment and the data collected in the postapproval setting parallel what takes place in the "preapproval process for a drug being reviewed for an indication being considered for [FDA] approval, where the data are more consistent," said Dr. Mullins, who is also with the School of Pharmacy's Center of Drugs and Public Policy."Our goal is to help patients and their physicians make better informed decisions" by making more consistent data available, so that if, for example, two drug options have been studied in similar trials, "you can compare them more readily," he added.
The recommendations in the document are divided into four categories: trial design and data analysis, patient and site recruitment, comparators, and outcomes.
Recommendations in the section on trial design and data analysis include using a blinded reviewer, incorporating biomarkers, and designing the study protocol to test the drug for the intended therapeutic use and in the way it is expected be used (as monotherapy or as adjuvant therapy, for example). Subpopulations should be described before the study starts, not in a post hoc analysis that may not provide adequate information.
The section on patient and site recruitment includes the recommendation to develop a strategy that addresses the reluctance of patients and physicians to participate in a study of a drug that is available - and to recruit patients from different clinical practice settings, since most patients are treated for cancer in the community, although most trials are available in academic medical centers.
The section on comparators includes the recommendation to use active comparators in studies that are approved by the FDA, are commonly prescribed, and are considered as having the "greatest clinical net benefit," for the indication being evaluated - with clear definitions of other components of treatment, such as surgery radiation or palliative care.
The outcomes section states that actual survival, "whenever feasible," should be used instead of a surrogate for survival as the primary outcome in studies, referring to frustration among decision makers over the common use of surrogate markets for survival in oncology drug studies. When a survival end point is not feasible, disease-free survival or progression-free survival can be used as the primary outcome end point, but in such cases, it is important to provide evidence of a link between one of these end points and actual survival, patient-reported outcomes, or health-related quality of life for the type and stage of cancer and the treatment being studied. Studies should also collect "meaningful" patient data, such as health-related quality of life measures.
In an accompanying editorial, Dr. David Pfister of Memorial Sloan-Kettering Cancer Center, New York, described the framework provided in the paper as "an important and thoughtful start to better understanding and defining the indications for, and appropriate use of, off-label drugs in cancer care." However, more work will be needed to "address potential challenges to the implementation of the recommendations," he added (doi:10.1200/JCO.2011.38.5567).
Dr. Mullins has served as a consultant or in an adviser for Amgen, Bayer Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, and Sanofi-Aventis, for which he received compensation; and has received funding from the CMTP, Bayer, GSK, Novartis, Pfizer, and Sanofi-Aventis. One of the other authors, Stephen Pearson of Massachusetts General Hospital, Boston, has received funding from Merck, Johnson & Johnson, and the National Pharmaceutical Council.
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