Biomarkers: FDA Working To Define 'Reasonably Likely To Predict' Standard
This article was originally published in SRA
The US Food and Drug Administration wants to help expand biomarker use as surrogate endpoints, but is encouraging pharma companies and researchers to create common evidentiary standards and vocabulary for their development.
Agency officials plan to look at potentially publishing their definition of the “reasonably likely to predict clinical benefit” standard for a surrogate endpoint to be used for accelerated approval, said Janet Woodcock, director of FDA's Center for Drug Evaluation and Research.
While there is plenty of literature on the use of surrogate endpoints for efficacy, little has been published on their use in accelerated approval, Woodcock said during her charge to participants at an Aug. 21 conference sponsored by the University of Maryland Center for Excellence in Regulatory Science and Innovation.
“FDA really needs to pick this up and we plan to and work it up in concert with the community,” she said.
“We have a lot of experience doing accelerated approvals. … How much evidence do you have to have? I’ve not articulated that. I’m not sure we actually know.”
So far, FDA has qualified 14 biomarkers for specific contexts of use. The agency announced on Aug. 17 that it had approved an imaging biomarker that can be used for enrichment of clinical trials in autosomal dominant polycystic kidney disease1.
A prognostic biomarker for enrichment of clinical trials in chronic obstructive pulmonary disease was qualified in July2.
Shashi Amur, biomarker qualification scientific coordinator in the CDER Office of Translational Sciences, said the agency also has 24 submissions under review.
Amur said FDA may need 19 to 28 months for it to complete the various stages of the qualification process. Sponsors generating data and responding to FDA questions can further lengthen it, she said.
Woodcock said among the reasons biomarker development has been so slow is regulatory skepticism.
“Companies have come to the FDA with proposals frequently, and they still do, to use this biomarker, rely on this biomarker,” she said. “But also there isn’t enough data and … it’s very difficult to generate enough data about a biomarker.”
Increased biomarker development also would help FDA meet one of its requirements in the 2012 FDA Safety and Innovation Act. Congress said in the PDUFA V prescription drug user fee legislation that FDA should encourage more use of accelerated approval outside the oncology and HIV settings.
FDA Doesn’t Have All The Answers
An FDA guidance further clarifying its surrogate endpoint standards could dramatically push biomarker development forward.
But Woodcock also made it clear that FDA does not have the answer to many of the questions biomarker sponsors are asking.
“I think it’s important to realize that FDA doesn’t inherently know,” she said. “This is something that has to be worked out by the community. We’re participating together.”
Woodcock asked the researchers to try to determine the data needed to consider a biomarker reliable for drug development along with the best ways to generate that evidence.
Much more focus has been placed on growing precision medicine recently, which will require a new generation of reliable biomarkers, she said.
President Obama called for more funding to help advance precision medicine in his State of the Union Speech.
The House of Representatives 21st Century Cures legislation also could help the biomarker qualification process, should it be enacted3.
Among the provisions is a requirement for FDA to issue guidance on biomarker development and the evidence needed to support using surrogate endpoints for accelerated approval.
Those changes are potentially several months down the road however. While the House passed the legislation in July, the Senate continues to work on its own bill.
However, in the past, agency officials have said that biomarkers in many cases likely will have to be evaluated on a case-by-case basis.
Rare disease advocates have asked for general criteria for surrogate endpoint approval in part to help companies gain financing for rare disease drug development.
If all-encompassing criteria are not possible, the agency may be able to better inform industry of its examples of biomarker approvals and how they are interpreted.
PDUFA, Cures To The Rescue?
As more attention falls on biomarker issues, it seems more of the burden is falling on FDA rather than industry and academics to grow the field.
Woodcock said the agency had depended mostly on the community to develop and validate biomarkers and then once they were accepted, FDA officials would endorse them.
During the conference, she said FDA is looking for more funding sources for academic research of biomarkers to further development.
One potentially could come from industry. An official from the National Institutes of Health suggested during the conference that the prescription drug user fee reauthorization designate biomarker development as a foundational activity for FDA. It could allow the agency to put more money toward biomarker research.
Woodcock also said biomarkers could be a PDUFA VI issue.
“The industry I think is realizing that qualification of biomarkers could help move the field along,” she said.
As part of PDUFA V, FDA was supposed to expand its biomarker and pharmacogenomics teams.
An industry source indicated that the agency has not been able to hire some regulatory science personnel, in part for reasons out of FDA’s control.
That may affect how industry officials negotiate the PDUFA reauthorization, especially in light of the pending 21st Century Cures legislation4.
The Cures bill also includes additional funding for FDA biomarker and other activities.
But the agency appears to be seeking more support, perhaps even through a user fee mechanism. FDA estimated that each biomarker qualification package review would cost about the same as a new drug application, between $1.3m and $2.3m.
References
- FDA, Draft Guidance for Industry, Qualification of Biomarker – Total Kidney Volume in Studies for Treatment of Autosomal Dominant Polycystic Kidney Disease, website accessed Sept. 8, 2015, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458483.pdf
- FDA, Draft Guidance for Industry, Qualification of Biomarker – Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality in Patients With Chronic Obstructive Pulmonary Disease, website accessed Sept. 7, 2015, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM453496.pdf
- US 21st Century Cures bill passes House, as more debate waits in the wings, Scrip Regulatory Affairs, July 13, 2015
- Spending User Fees In The US: Biomarker Research, Drug-Device Combos?,Scrip Regulatory Affairs, Sept. 3, 2015
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