FDA Willing to Accept Different Endpoints When Assessing Lung Cancer Drugs

Regulatory NewsRegulatory News | 22 April 2015 |  By 

Companies will be permitted to use several types of clinical trial endpoints to show the efficacy of drugs intended to treat non-small cell lung cancer (NSCLC), the US Food and Drug Administration (FDA) confirmed in a new guidance document released this week.

The final guidance document, Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics, is intended to clarify the evidence FDA is willing to accept in the review of new NSCLC drugs.


FDA has approved at least six NSCLC drugs since May 2013, including:

Drug NameManufacturerDate of Approval
Opdivo (nivolumab)Bristol-Myers SquibbMarch 2015
Cyramza (ramucirumab)Eli LillyDecember 2014
Zykadia (ceritinib)NovartisApril 2014
Xalkori (crizotinib)PfizerNovember 2013
Gilotrif (afatinib)Boehringer IngelheimJuly 2013
Tarceva (erlotinib)AstellasMay 2013

Those drugs have been approved based on several types of endpoints, including perhaps the most important endpoint of them all: overall survival (OS). In layman's terms, that's the amount of time a person's life is extended by taking a drug relative to either the current standard of care (e.g. the current best-in-class drug) or a placebo.

For FDA, this is the gold standard of endpoints. If a company's drug can meaningfully extend overall survival in NSCLC patients, it can likely expect full approval, FDA's guidance document states. The measure, FDA wrote, "is accurate, is observed on a daily basis, and provides direct evidence of clinical benefit to the patient."

Other Endpoints FDA Will Accept

But OS isn't the only endpoint FDA has expressed comfort with or a willingness to use. For example, some NSCLC drugs are eligible for FDA's accelerated approval pathway—a review process which aims to allow for the rapid approval of new drugs for serious or life-threatening diseases based on surrogate endpoints.

In NSCLC, a relevant surrogate endpoint might be evidence indicating that a tumor has shrunk, even if it's not yet clear that a patient lives longer. This endpoint is often referred to as the objective tumor response rate (ORR). While FDA notes that this endpoint does not necessarily predict overall survival "reliably," it can nevertheless support accelerated approvals for NSCLC drugs.

Another relevant endpoint is time-to-progression (TTP)—similar to progression-free survival (PFS)—which is an indication of how long a cancer's growth is checked in a patient. "When the observed differences in TTP or PFS are of a substantial magnitude, then TTP or PFS may provide evidence of clinical benefit sufficient to support approval," FDA notes in its guidance. FDA added that PFS surrogate endpoints must be measured as part of a planned interim efficacy analysis. Early or unplanned analyses can "overstate the magnitude of the effect," FDA noted.

And then there are patient-reported outcomes (PROs)—subjective measurements of a patient's quality of life. FDA is still working on the development of these PROs as part of its Patient-Focused Drug Development program. Still, FDA said it "encourage[s] the development of well-defined and reliable PRO instruments that capture the essential treatment benefit concepts in the targeted population."

Companies interested in using a PRO as part of the review process should review another guidance document, Patient-Reported Outcomes Measures: use in Medical Product Development to Support Labeling Claims.


Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics (FR)


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