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Many new cancer drugs lack evidence of survival or QoL benefit

 

Key clinical point: Even after several years on the market, only about half of cancer drug indications recently approved by the European Medicines Agency (EMA) lacked conclusive evidence that they can extend or improve quality of life.

Major finding: With a median of 5.4 years of follow-up, significant improvements in overall survival or quality of life had been published for 35 of 68 (51%) cancer drug indications approved by the EMA.

Data source: Retrospective cohort study of regulatory and scientific reports on 48 cancer drugs approved for 68 indications by the EMA between 2009-2013.

Disclosures: The study was supported by Health Action International, which did not have a role in study design or data collection, analysis, or interpretation.

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Fix the broken regulatory system

 

The expense and toxicity of cancer drugs mean we have an obligation to expose patients to treatment only when they can reasonably expect an improvement in survival or quality of life. The study by Davis and colleagues suggests we may be falling far short of this important benchmark.

Few cancer drugs come to market with good evidence that they improve patient centered outcomes. If they do, they often offer marginal benefits that may be lost in the heterogeneous patients of the real world. Most approvals of cancer drugs are based on flimsy or untested surrogate endpoints, and postmarketing studies rarely validate the efficacy and safety of these drugs on patient centered endpoints.

In the United States, this broken system means huge expenditures on cancer drugs with certain toxicity but uncertain benefit. In Europe, payers yield the stick left unused by lax regulatoers. The National Institute for Health and Care Excellence (NICE) excludes from reimbursement drugs that provide only marginal or uncertain benefits at high cost. Their decisions are continually subjected to political scrutiny and public criticism.

What can be done? The default path to market for all cancer drugs should include rigorous testing against the best standard of care in randomized trials powered to rule in or rule out a clinically meaningful difference in patient centered outcomes in a representative population. The use of uncontrolled study designs or surrogate endpoints should be the exception, not the rule.
 

Vinay Prasad, MD, MPH, is assistant professor of medicine at Oregon Health and Science University, Portland. He declared a competing interest (royalties from his book Ending Medical Reversal). These comments are from his editorial (BMJ 2017 Oct 5. doi: 10.1136/bmj.j4528 )


 

From BMJ

 

Even after several years on the market, only about half of cancer drug indications recently approved by the European Medicines Agency (EMA) had conclusive evidence that they can extend or improve quality of life, according to results of a retrospective cohort study.

With a median of 5.4 years of follow-up, significant improvements in overall survival or quality of life had been published for 35 of 68 (51%) cancer drug indications approved by the EMA, according to the report by Courtney Davis, MD, senior lecturer in the department of global health and social medicine, King’s College London, United Kingdom, and colleagues.

Furthermore, not all survival benefits were clinically meaningful, according to an analysis published in the report.

The dearth of evidence for survival or quality-of-life benefits has “negative implications” for both patients and public health, Dr. Davis and colleagues said in their article (BMJ 2017 Oct 5. doi:10.1136/bmj.j4530).

“When expensive drugs that lack clinically meaningful benefits are approved and paid for within publicly funded healthcare systems, individual patients can be harmed, important societal resources wasted, and the delivery of equitable and affordable care undermined,” they wrote.

Dr. Davis and associates systematically evaluated the evidence base for regulatory and scientific reports on 48 cancer drugs approved for 68 indications by the EMA between 2009-2013. Of those indications, 17 were for hematologic malignancies and 51 were for solid tumors.

Only 18 of 68 indications (26%) were supported by pivotal studies that had a primary outcome of overall survival, according to the investigators. That was an important finding for the investigators, who wrote that that EMA commonly accepts use of surrogate measures of drug benefit despite their own statements that overall survival is the “most persuasive outcome” in studies of new oncology drugs.

“To a large extent, regulatory evidence standards determine the clinical value of … new oncology drugs,” Dr. Davis and co-authors wrote. “Our study suggests these standards are failing to incentivize drug development that best meets the needs of patients, clinicians, and healthcare systems.”

The investigators also assessed the clinical value of reported improvements using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). According to investigators, only 11 of the 23 drugs used to treat solid tumors (48%) reached the threshold for a meaningful survival benefit.

This report in BMJ echoes findings of an earlier study by Chul Kim, MD, and colleagues looking at cancer drugs approved by the U.S. Food and Drug Administration (FDA) between 2008 and 2012 (JAMA Intern Med. 2015;175(12):1992-4).

Dr. Kim, of the medical oncology service, National Cancer Institute, National Institutes of Health, Bethesda, Md., and colleagues found that 36 of 54 FDA approvals (67%) occurred with no evidence of survival or quality of life benefit. After a median of 4.4 years of follow-up, only 5 of those 36 (14%) had additional randomized study data that showed an improvement in overall survival, according to the published report.

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