Think tank: Time to look beyond the gold standard in drug R&D

Print 10 August 2015
Mark McCarty and Mari Serebrov / BioWorld

As technology pulls medical innovation into the 21st century, the burnish may be wearing off randomized, controlled trials (RCTs), the FDA's longtime gold standard for developing new therapies.

The Bipartisan Policy Center (BPC) is among the latest urging the FDA to look past the glitter of RCTs. Rather than relying on them to confirm safety and efficacy, the agency should consider the use of "pragmatic randomized studies" of broader populations under more typical settings in addition to RCTs for the review of drugs, devices and diagnostics, the think tank said in a recent report on advancing medical innovation.

The group's recommendations come as the Senate Health, Education, Labor and Pensions Committee continues to form a narrower, more "practical" response to the sweeping 21st Century Cures Act passed last month by the House.

The BPC report boasts some names with clout in Washington, including former physician and one-time Sen. Bill Frist, as well as Mark McClellan, a senior fellow at the Brookings Institution whose resume includes time at the FDA commissioner's office and as the administrator of the Centers for Medicare & Medicaid Services. (See BioWorld Today, April 29, 2015, and July 13, 2015.)

The proposed modernization of the standard phase III RCT would entail public- and private-sector investment in a national virtual clinical trial infrastructure. The report also recommends developing a program for evaluating and prioritizing the use of real-world evidence for post-approval studies and studies of new indications for existing drugs and devices. The program should include a framework for "improved clinical trials," it said.

The BPC is not the only one challenging the value of RCTs as the sole standard for developing new therapies. Members of FDA advisory committees, especially those who are practicing physicians, are increasingly calling for more real-world data in drug development, noting that RCTs often test products in populations that are not representative of the patients who would get the approved drugs.

The FDA itself seems to be questioning its devotion to the RCT standard. Speaking last week at an FDA/Brookings Institution conference on improving productivity in drug R&D and reducing late-stage failures by advancing early learning, Janet Woodcock, head of the agency's drug center, acknowledged the limitations of RCTs.

Although they're the "triumph of clinical medicine," such trials can only test a single hypothesis, she said. As a result, a vast amount of information from each patient is lost, and that loss could doom a trial. (See BioWorld Today, July 29, 2015.)

The greatest barrier to moving drug development forward, Woodcock said, is the tension that exists between the empirical tradition of RCTs and a mechanistic, scientific approach that seeks to understand the mechanism of action of the disease, the drug and the patient.

BEYOND THE GILDED EDGE

Looking beyond the gilded edge of RCTs is just one of the recommendations the BPC makes in its report on modernizing the development of new treatments. Citing the need for improvements in regulatory clarity and an increased investment in R&D, the report noted that an aggregate investment of $1 billion generated nearly 100 new molecular entities in the 1950s. But today, about $2 billion is needed to develop a single new drug.

Another BPC recommendation that's been discussed at many FDA and industry meetings is a more streamlined qualification process for biomarkers, especially those used as surrogate endpoints. A biomarker program should include a mechanism that gives the FDA and sponsors access to the expertise of "biomedical research consortia or others with expert knowledge and insights," the group advised.

Commercial speech is also on the BPC agenda. The report authors suggested the FDA issue rules dealing with the dissemination of information about off-label uses of drugs and devices and creating a safe harbor for communicating such information to health care professionals. But along with information about emerging new off-label uses, sponsors should have to "share data on safety and efficacy for off-label uses with researchers, regulators and insurers, for the purpose of rapidly validating emerging uses for established therapies," the authors said.

Other items on the BPC list include regulatory harmonization, electronic health record interoperability and greater statutory clarity on the designation of combination products, a hot topic with industry these days. The report called for the FDA centers to tighten their procedures for collaboration on reviewing combo product applications.

Recognizing that the demands for modernization could increase the financial burden on the FDA, the authors suggested boosting the agency's appropriations, possibly by raising user fees. But as it is, innovator and biosimilar drugmakers will be paying $2.374 million come October for new drug and biologic license applications.

That's a 21 percent increase since the latest PDUFA agreement took effect in fiscal 2013. Meanwhile, appropriations of tax dollars for the FDA have barely budged.

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