As negotiations for the fifth incarnation of the Prescription Drug User Fee Act get serious, there seems to be a widening gap between what the U.S. Food and Drug Administration wants (more resources) and what industry wants (more predictability).

After all, as President Obama wrote January 18 in The Wall Street Journal about his ordering a review of federal regulations, “Sometimes, those rules have gotten out of balance, placing unreasonable burdens on business—burdens that have stifled innovation and have had a chilling effect on growth and jobs.”

Nowhere is this more in evidence than in the desire for a more formalized way to determine (and, indeed, predict) the benefit/risk equation.

The FDA is designing a five-item grid as a management tool to explain its risk-benefit decisions in a more concise format. The model that it has created as a working template confirms a truism about its drug approval tendencies that industry has suspected for years: the baseline for FDA approval is a high rating of the severity of the disease being treated and the medical need for the product.

The agency is developing a grid of the five basic factors that need to be addressed in any decision on the commercial availability of a drug. The top two are the seriousness of the condition addressed and the need for a new treatment of the condition. Then comes the traditional heart of the NDA package: analyses of clinical data on the benefits of the drug and the risks associated with its use.

The fifth fundamental factor is explicitly the level of risk management associated with the product. The FDA is going to take it into consideration in every decision; sponsors who ignore or underplay the identification of who should use the product and who might use it will have a gap in their filings.

The grid proposal does not call for a fixed mathematical formula behind each approval. The agency has not tried to reduce the judgments in an approval decision to a rigid calculation.

Judgment? You mean FDA decisions aren’t black and white?
In the words of John Jenkins, director of the Office of New Drugs at the Center for Drug Evaluation and Research, disagreement “happens a lot in the decisions that we have to make. Very few of the decisions that we make on drugs are easy. Very few of the drugs we see have a dramatic overwhelming benefit with relatively no risk. We see that most drugs have marginal to moderate benefits on a population basis and they have general safety but they have the risks of serious toxicities at some low levels." In other words, every decision is very complex.

That’s a good start, but there’s a better way forward.
A new paper in Clinical Pharmacology & Therapeutics, calls for the creation of a Benefit Risk Action Team (BRAT) framework, a set of processes and tools for selecting, organizing, summarizing, and interpreting data that is relevant to decisions based on benefit–risk assessments. The result of a 5-year effort by a team organized and facilitated by the trade group the Pharmaceutical Researcher and Manufacturers of America, the BRAT framework is a move toward an assessment that seeks to incorporate all relevant aspects of benefit and risk. The focus is on both qualitative and quantitative analysis. The current framework can incorporate weighting of outcomes but does not focus on calculation of overall benefit–risk scores.

The authors argue that BRAT provides a standardized yet flexible platform for incorporating study outcomes and preference weights as well as for communicating the rationale for decisions.

“The advantages of developing and adopting such a framework are well recognized. By specifying the essential attributes that both regulators and companies should consider across the life cycle of a drug, the entire process of drug development, review, and approval would be strengthened,” the authors write. “In the development and approval stages, the existence of a risk–benefit assessment framework would improve the quality of the discussion between sponsors and regulators and, as a consequence, between providers and patients, particularly with respect to medicines for which the benefit–risk balance is not straightforward (e.g., because of large and complex efficacy and safety data sets or because of inherent uncertainty regarding the available data).”

A companion paper that discussed how BRAT members collaborated with epidemiologists at RTI International in order to continue development of the framework and applied it to several case studies, concluded that the framework was of value in different settings. “Because benefit–risk assessment for a drug is rarely straightforward, the framework or similar tools for elucidating the relevant data can help facilitate discussions between sponsors and regulatory agencies, help communicate complex information to other stakeholders, enhance the transparency of assumptions and decisions, and provide support for difficult regulatory benefit–risk decisions,” the authors conclude.
It’s time for the FDA to welcome the BRAT Pack to the drug regulatory process.

“Our economy is not a zero-sum game,” president Obama wrote in his piece in The Wall Street Journal. “Regulations do have costs; often, as a country, we have to make tough decisions about whether those costs are necessary. But what is clear is that we can strike the right balance. We can make our economy stronger and more competitive, while meeting our fundamental responsibilities to one another.”

Peter J. Pitts is president of the Center for Medicine in the Public Interest and a former Associate commissioner of the FDA.