Cancer drugs receiving accelerated approval from the U.S. Food and Drug Administration (FDA) commonly fail to prolong overall survival in later "confirmatory" trials, researchers report.
"Only 20% of cancer drugs approved using the accelerated approval (AA) pathway have proven benefits in overall survival (OS) in a confirmatory trial," Dr. Bishal Gyawali from Brigham and Women's Hospital in Boston told Reuters Health by email. "Even when the trials are called confirmatory, usually they just confirm the effect on surrogate measures and do not confirm actual clinical benefit."
Drugs in the AA pathway can be approved by demonstrating an effect on a surrogate measure or intermediate clinical endpoint that is reasonably likely to predict a real clinical endpoint. Manufacturers must then conduct postapproval studies to confirm a drug's clinical benefit and risk profile. Approval can be revoked if the confirmatory trial is never done or if it shows the drug's risks outweigh its benefits.
Dr. Gyawali's team reviewed endpoints used in preapproval trials for granting accelerated approval and compared them with endpoints in confirmatory trials.
Overall, 51 of 93 indications (55%) were classified as having positively confirmed benefit in confirmatory trials, but only 15 (16%) showed improvement in overall survival in those trials.
The other 36 indications had changes in surrogate measures. But for 19 of these indications, the same surrogate measure was used in the confirmatory trials as was used in the pivotal trial that led to accelerated approval, the researchers report in JAMA Internal Medicine, online May 28.
Of 37 indications for which postapproval evaluations were incomplete as of May 2017, nine evaluations were ongoing, 10 were pending, five were delayed, one was terminated and in one case, studies to assess safety outcomes were required but efficacy trials were not.
Among the 10 indications with completed postapproval studies in the year after May 2017, six had confirmatory trials reporting positive results, but three of these showed no improvement in the primary endpoint of overall survival.
"The success of AA pathway lies in the fact that confirmatory studies are duly conducted in time and use clinical endpoints, such as overall survival or quality of life, to actually confirm benefit rather than test another surrogate measure," Dr. Gyawali said. "When drugs fail in confirmatory studies, quick and decisive steps must be taken to withdraw the drug from the market to prevent undue harm from unhelpful drugs. That is how AA pathway is supposed to function, keeping patient benefits at the center of the agenda."
In a related paper, Dr. Emerson Y. Chen and colleagues from Oregon Health and Science University, in Portland, review 59 cancer drugs with 85 unique marketing authorizations approved by the FDA based on the surrogate endpoint of response rate.
The median response rate for all 85 indications was 41%, and the median complete-response rate for the available 81 drug indications was 6%.
Overall, 16% of indications had response rates <20 33="" 47="" and="" had="" p="" rates="" response="">
Most indications (63%) had complete-response rates of <10 74="" 78="" 86="" and="" of="" p="">
Among the 24 drug indications that have not yet received regular approval, only 12 specifically required randomized clinical trials and overall survival as the efficacy endpoint in the postmarketing requirements.
Dr. Chen said by email, "It is always important to look back at our portfolio of cancer drugs and the pathways that have led to their use in order to re-assess if how things are done has matched the vision/goals to which that pathway was intended and then see what we can change for the future. For example, do we really want to rapidly approve drugs with low response rates without definite survival benefit or definite patient-reported benefit?"
"We are currently allowing pharmaceutical companies to widely market (by allowing FDA approval) cancer drugs that have low response rates without definite survival benefit or definite patient-reported benefit, some of which have also failed in post-marketing randomized controlled trials," he said. "It is important to collectively decide what criteria we can agree on that is not too high to achieve (preventing useful drugs to market) but also not too low (allowing drugs with marginal benefit to market) when response rate is used. This study starts that conversation."
Dr. Ezekiel J. Emanuel from Perelman School of Medicine at the University of Pennsylvania, in Philadelphia, who co-authored an editorial accompanying the new findings, told Reuters Health by email, "I (consider) the rate at which the follow-up studies used the same exact intermediate outcome variable the most disturbing. Why use the same exact intermediate outcome when you know it is an intermediate outcome and not something that is intrinsically valuable?"
"And data suggest using overall survival can be done with most of these patients," he said. "This is a real failure of FDA and very worrisome that ineffective treatments are being kept on the market because they are not being rigorously evaluated with valid endpoints."
Dr. Huseyin Naci from London School of Economics and Political Science, who earlier reviewed the characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the FDA, told Reuters Health by email that the new work "is a hugely important analysis. I find it remarkable that only a fifth of cancer drugs that were fast tracked to market through the FDA's accelerated approval pathway have led to overall survival improvements."
"Greater regulatory oversight is needed to ensure that future studies on cancer drugs evaluate outcomes that matter to patients - gains in survival and quality of life," he said.
Dr. Talal Hilal from Mayo Clinic, Phoenix, Arizona recently analyzed control arm quality in trials leading to anticancer drug approvals by the FDA. He told Reuters Health by email, "The goal of the accelerated pathway is to allow early access to drugs which may provide a reasonable benefit to patients. As it stands, 40% of postapproval, confirmatory trials are not measuring clinically meaningful endpoints. That should not be the case. The drug is on the market; manufacturers should ensure that continued existence of these agents is based on solid evidence when conducting postapproval studies."
"The number of postapproval trials that are testing clinically meaningful endpoints to patients should be higher," he said. "Early access to drugs should not be an excuse to not use these endpoints (e.g., overall survival and quality of life) in confirmatory studies of drugs used in metastatic cancers in which survival is generally not very long."
Amanda Turney from FDA's Office of Media Affairs, in Silver Spring, Maryland, told Reuters Health by email, "The FDA only approves drugs when the data received in a drug application demonstrate a favorable risk-benefit profile. Patients with refractory diseases often have few or no therapeutic options and we take that into account when examining the risk-benefit profile of these drugs."
"We have had multiple discussions over a number of years within the global scientific and patient community, including with the Oncologic Drugs Advisory Committee, regarding the use of progression-free survival, response rate, and other endpoints to support approval of drugs that treat cancer," she added. "It has been widely accepted that benefit can be demonstrated by a number of endpoints, not just overall survival."
She pointed to a 2017 FDA commentary on oncology drug approvals (https://bit.ly/2XfLRRC) and a related editorial (https://bit.ly/2KdBWIG) for further discussion of endpoints and evidence in cancer-drug approvals.
SOURCE: https://bit.ly/2MhI84Y, https://bit.ly/2JLJovc, https://bit.ly/30PsxwZ and https://bit.ly/2wutM6E
JAMA Intern Med 2019.
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