FDARA: Changing Drug Development in the Guise of Safety Controls

The Food & Drug Administration Revitalization Act is famously the “drug safety law”—the once-in-forty-years major overhaul of FDA authority to bring the agency’s drug safety activities back up to par with the agency’s focus on drug efficacy.

But don’t overlook the fundamental changes that the new law will impose on the drug development process. It is likely to change drastically how companies seek FDA approval and how they support marketed products with further research. Some previous analysis of incentives in FDARA can be found here.

The separate versions of the law passed overwhelmingly in the Senate (S1082) and House (HR2900) over the last four months are being forged into one bill in active pre-conference discussions.

Two former FDA commissioners see fundamental changes stemming from the FDARA tools. They pointed out two of the major changes during a September 12 briefing on drug safety in Washington, DC, hosted by American University.

Phase IV--no longer the unchallenged province of drug sponsors: Mark McClellan, MD, says Phase IV, strategic research will never be the same again. The new public-private post-marketing surveillance project that is featured in FDARA will change the dominance of Phase IV by drug sponsors.

The “post-marketing period will move out of the control of the pharmaceutical industry,” McClellan declared. McClellan was the first FDA commissioner in the George W. Bush Administration (2002-2004). He currently heads the Engelberg Center for Health Care Reform at the Brookings Institution.

Faster NDA/BLA approvals for narrow, precise indications: David Kessler, MD, stresses the need for the agency and drug sponsors to act more creatively in the initial approval process.

Kessler sees an opening for FDA to encourage sponsors to study smaller patient populations in return for faster approvals and FDARA may provide the right tool for making that implicit deal occur. FDARA offers a form of tighter safety controls through risk management plans and post-marketing surveillance that could represent a new version of conditional approval. Kessler, vice chancellor of medical affairs at the University of California-San Francisco was FDA commissioner under George H. W. Bush and Bill Clinton (1990-1997).

The impact of FDARA on Phase IV cannot be under-estimated. For over two decades, pharma has lavished resources onto Phase IV to support extended indications, improving ties to medical thought leaders, generating cost data and justifications and gaining access to large user groups. The industry has also made commitments to FDA to carry on work on issues raised by FDA during premarket review.

After the American University event, McClellan was asked by Alicia Mundy (author of Dispensing with the Truth, a book on the Fen-Phen drug interactions) about the likelihood that FDARA would increase corporate compliance with FDA Phase IV requests. Asking whether the industry would still be able to use “stall tactics” to delay Phase IV regulatory commitments, Mundy expressed the general skepticism that has grown around the FDA-agreed Phase IV work.

McClellan chose to answer the question from a broader perspective: looking more at who controls Phase IV rather than whether companies meet or don’t meet FDA commitments. He noted that the new law will jump-start a big effort in post-market surveillance and increase that amount of research on commercially marketed products. The law’s encouragement of a public-private partnership and the $25 million initial funding for the program will start a separate effort—beyond the funding and control of pharma.

McClellan looks to other stakeholders in drug treatments to provide competing funding for post-marketing research: primarily health insurers, academic centers and employers. If those groups feel that post-marketing surveillance will help to cut down unsafe or unnecessary drug use, they clearly would have an economic and quality stake in supporting studies.

While pharma’s dominance of Phase IV appears to face a FDARA challenge, another part of the new law appears to provide a surprising boost to the effort to shorten drug trials and achieve faster initial approvals.

Kessler stated the opportunity for changing drug development in a call for a deal between industry and FDA to adopt smaller trials based on genotyping and a target of smaller patient populations. “The industry is in a conundrum,” Kessler said, is it “willing to narrow the number of patients it sells the drug to?” He believes FDA may soon be in a position to create incentives to get sponsors to aim at the smaller populations.

FDA could tell sponsors, for example, that one, redesigned trial incorporating genotyping information could suffice, Kessler suggested.

Kessler, who still frequently slips into the first person pronoun when describing FDA options, said: “Let’s say we are going to allow you to do one trial and we are going to ask you to genotype everybody in that trial.” The sponsor could use data from the first half of the trial to identify a predictive gene panel. The sponsor could then apply that genetic profile to the second half of the trial to determine whether the drug has a “high degree of effectiveness.” That type of development trial could be used toward a conditional or tightly controlled approval.

FDA is already moving in that direction, asking for information on very specific patient populations and then turning that information into very tight risk management plans.

That tailored market approach, in essence, is an updated version of a conditional approval. It is likely to be used more frequently following FDARA when the agency explicitly receives authority to create risk management plans for each approved product through the REMS (Risk Evaluation & Mitigation Strategies) provisions of the law. Kessler recognizes the potential larger role for REMS.

Risk management plans under the REMS procedures “could be no more than what the agency does now or it could be a drastic change in the way the agency controls drugs,” the former commissioner said. But he predicted that FDA will use the authority expansively and REMS will be applied to a “wide array” of products.

Sponsors will be required to submit information on the level of REMS program that they believe fits their product. A clear definition of the target audience will be an important part of those submissions and are likely to become a fulcrum for future FDA approval decisions. If a sponsor can show a well-defined population and a way to make sure that the product is used on that population, the route to approval will be much faster.

(Originally posted at The RPM Report.)