The majority of new oncology drugs that were approved by the European Medicines Agency (EMA) from 2009 to 2013 entered the market without clear evidence that they improved survival or quality of life, according to a new report published onlineOctober 4 in the BMJ.
During this period, the EMA approved the use of 48 cancer drugs for 68 indications.
Of these 68 indications, 39 (57%) approvals were made on the basis of a surrogate endpoint in the absence of evidence of a survival benefit or an improvement in quality of life.
At a median of follow-up of 5.4 years in the postmarketing period, only 35 (51%) drugs showed a significant improvement in survival or quality of life, as compared with other therapeutic options, placebo, or as add-on treatment.
For 33 (49%) of the drugs, there continues to be uncertainty as to whether they extend survival or improve quality of life.
"When expensive drugs that lack clinically meaningful benefits are approved and reimbursed within publicly funded healthcare systems, individual patients may be harmed, important resources wasted, and the delivery of equitable and affordable care is undermined," write the authors, led by Courtney Davis, PhD, a senior lecturer from the Department of Global Health and Social Medicine, King's College London, United Kingdom.
Rigorous Testing, Patient Centered Endpoints
In an accompanying editorial, Vinay Prasad, MD, an assistant professor of medicine at Oregon Health and Science University, Portland, points to his own recent research, in which similar findings were reported for cancer drugs approved by the US Food and Drug Administration (FDA).
His study found that the FDA is now heavily relying on surrogate markers of effectiveness. Between 2008 and 2012, the FDA approved most uses of cancer drugs without evidence of survival or improved quality of life (67%, 36/54).
During a median follow-up period of 4.4 years, only five of those 36 drugs were found to improve overall survival in randomized trials.
Dr Prasad, who has established a reputation as something of a whistle-blower, has spoken out about physicians with financial conflicts of interest, as well as escalating drug prices and approved therapies that have been overly hyped or that offer very modest benefits.
He emphasizes three important factors that have helped to characterize the current regulatory climate.
The first is that when drugs do offer survival advantages, the gains are often marginal.
Second is that the small benefits that are seen often occur in trials that are conducted in unrepresentative patient populations ― patients who are younger and who have fewer comorbidities than physicians would generally be treating in real-world clinical practice.
The third factor is that many of the surrogate outcomes currently used for drug approvals are poorly correlated with survival, and for others, the correlation is largely untested.
"Taken together, these facts paint a sobering picture," says Dr Prasad. "Although we are approving cancer drugs at a rapid pace, few 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, therefore, "are based on flimsy or untested surrogate endpoints, and postmarketing studies rarely validate the efficacy and safety of these drugs on patient centered endpoints," Dr Prasad notes.
Given the fact that the average cost of new drugs is in excess of $100,000 (£75,000, €85,000) per year, the "conclusion seems that the regulatory system is broken," he says.
The conclusion seems that the regulatory system is broken. Dr Vinay Prasad
To help fix this system, he says that the default path for approval should include rigorous testing against the best standard of care in sufficiently powered randomized trials that can "rule in or rule out a clinically meaningful difference in patient centered outcomes in a representative population" and that "the use of uncontrolled study designs or surrogate endpoints should be the exception not the rule."
Survival Benefit Lacking
In the current article, Dr Davis and her colleagues sought to determine the availability of data on overall survival and quality-of-life benefits of cancer drugs that were approved during the past decade in Europe.
They used publicly accessible regulatory and scientific reports on cancer drug approvals by the EMA from 2009 to 2013 and allowed for at least 3.3 years for the completion and publication of clinical studies in the postmarketing period (median, 5.4 years; maximum 8.1 years).
The European Society for Medical Oncology's Magnitude of Clinical Benefit Scale was used to assess the clinical value of gains reported in published studies for drugs associated with an overall survival gain at the time of approval or in the postmarketing period.
For the authorized indications, 33 were first-marketing authorizations, and 35 were extensions. Conditional marketing authorization was granted regarding 10 uses, and 11 (16%) drugs received orphan designation.
A total of 72 clinical trials supported approvals for 68 indications, but only 18 drugs (26%) were supported by a pivotal study that was powered to evaluate overall survival as the primary endpoint.
Overall survival was not evaluated as the primary study endpoint in any of the 10 uses for which drugs received conditional approval, and it was an endpoint for only one of the 11 (9%) drugs that had orphan designation.
The authors note that overall survival was "evaluated as a primary study endpoint in less than a third (18/58, 31%) of all drug indications granted regular marketing authorization."
A significant prolongation of survival was seen in just 35% (24/68) of all drug indications at the time of approval. The benefit ranged from 1.0 to 5.8 months (median, 2.7 months). For the remaining 44 (65%) indications, conclusive evidence was lacking at the time of market authorization that the drugs offered any survival advantage.
With respect to quality of life, a significant improvement over the control arm was observed in only seven (10%) indications; five were for indications without a survival gain.
In the postmarketing period, in only three (7%) of 44 indications for which the drug failed to show a survival benefit at time of approval (following a median of 5.4 years) was the drug subsequently observed to increase overall survival, and for only five (11%) indications was the drug associated with some type of improvement in quality of life.
"This situation has negative implications for patients and public health," conclude Dr Davis and her coauthors.
Surrogate Endpoints, Unrealistic Goals
In an accompanying feature article, BMJ associate editor Deborah Cohen noted that this report comes at a time when European governments "are starting to seriously challenge the high cost of drugs.
"While it's hard to know how much healthcare systems are paying for cancer drugs because prices are often negotiated behind closed doors, the total amount spent on cancer care is growing, partly because of the cost of drugs," she writes.
Cohen points out that the current article shows that many EMA approval decisions are based on uncontrolled studies or studies with surrogate endpoints, and that these do not always translate into outcomes that are meaningful to patients. In addition, some of these drugs received conditional marketing authorizations, with the understanding that overall survival and/or effects on quality of life will be evaluated once the drug had been on the market.
But such evaluations do not always occur. In this study, for 10 drugs that were approved under fast-track arrangements, there was no strong evidence that the drugs provided a survival or quality-of-life benefit after being in the marketplace for 4 years.
Cohen highlights examples of methodologic problems with trials that the EMA had either failed to identify or had overlooked, including problems regarding trial design, conduct, analysis, and reporting. Flawed clinical trials can lead to bias and make it increasingly difficult to identify a drug's true effectiveness.
The imprimatur of regulatory approval may cause patients and doctors to have unrealistic expectations about their benefits and harm. Deborah Cohen
But perhaps most important, she notes, is "the fact the drugs have been given the imprimatur of regulatory approval may cause patients and doctors to have unrealistic expectations about their benefits and harm."
This study was supported by funding from Health Action International. The authors, Dr Prasad, and Deborah Cohen have disclosed no relevant financial relationships.
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