Regulatory Focus™ > News Articles > FDA Publishes New Benefit-Risk Paradigm Framework, Rejects Quantitative-Only Approach

FDA Publishes New Benefit-Risk Paradigm Framework, Rejects Quantitative-Only Approach

Posted 06 March 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has published a new report calling for a new drug regulatory decision-making paradigm for risk-benefit assessments, rejecting calls for a quantitative-only approach to regulation as counterproductive to its goals to make the decision-making process as clear and predictable as possible.


The plan, published on 5 March 2013, notes that FDA's mission calls for it to approve drugs that are both safe and effective. But the meanings of those terms are not defined by statute or regulation, leaving FDA with wide latitude to make adjustments to its own interpretation as needed. Over time, the agency's understanding of risk and benefit have frequently changed, sometimes oscillating between over-reactions to safety scandals and periods of complacency.

FDA faces perhaps its greatest regulatory challenges when evaluating new drug and biological products, submitted to it in the form of New Drug Applications (NDAs) and Biologics Licensing Applications (BLAs). The products are sometimes the first treatment for a given condition, and might constitute the product's first-ever use in humans. All of this leaves the true safety profile of the product in doubt, even after clinical testing meant to ameliorate regulators' concerns and learn more about the product.

But these risks don't exist in a vacuum, and FDA has taken pains in recent years to say-and indeed show-that its benefit-risk paradigm is flexible and depends on the condition for which the drug would be indicated. Assuming equal safety risks for two drugs, one for a non-lethal condition and the other for a potentially lethal one, FDA will most often assume a greater tolerance for risk for the latter of the two drugs unless the risks for both products are unacceptably high.

Even that understanding, however, leaves open an important question: how does FDA define its own benefit-risk paradigm?

A New Paradigm

FDA's document, entitled "Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making," is an attempt to lay the groundwork to answer that very question. It is, as FDA notes, a constantly evolving paradigm, which can pose problems for drug manufacturers, whose products can take upwards of a decade to bring to market.

"In the past, some FDA stakeholders have indicated that there is room for improvement in the clarity and transparency of FDA's benefit-risk assessment in human drug review," FDA wrote. Those concerns basically state that FDA's regulatory decision-making should be more formulaic and quantitatively defined. Others, FDA notes, have expressed skepticism regarding this approach, observing that the "highly subjective exercise … would add little clarity to regulatory decision-making."

FDA set out to address these concerns in 2009, launching an initiative to develop what it called a "structured approach" to the assessment of the benefits and risks of a product which could serve as a "vehicle for explaining the basis of FDA's regulatory decisions in drug approvals."

This initiative was eventually wrapped up into the PDUFA V discussions, and its deliverables are not a part of FDA's commitment to industry, as found in its PDUFA V commitment letter.

"FDA's commitments include the publication of a draft five-year plan that describes the Agency's approach to further develop and implement structured benefit-risk assessment in the human drug and biological product review process," the agency explained.

A Qualitative Approach

FDA said it supports a qualitative approach to the measure of risk-not quantitative-and has come to the conclusion that, "The best presentation of benefit-risk considerations involves focusing on the individual benefits and risks, their frequency, and weighing them appropriately."

The report explains that a quantitative approach would fall short because it assumes the existence of a binary decision, when in reality most decisions are far more complex and nuanced, and involve numerous competing concerns and benefits. Further, even if these concerns are reduced to a qualitative assessment score, FDA said this would likely result in a highly complex model that would only serve to make the entire process more difficult to understand, and not easier, particularly for the lay public.

Which isn't to say that there isn't room for a more clearly defined qualitative model, the agency wrote.

Certain components can certainly be quantified, FDA said-just not the whole regulatory process. The agency, after interviewing its staff, found that the most important benefit-risk considerations could be grouped into just a few areas, including the demonstrated benefits and risks of the product, ways to mitigate risk, the characteristics of the disease, and other treatments available for the disease.

From those categories, FDA said it then asks two additional questions: How certain can regulators be about the evidence presented (and what is left unknown), and what conclusions can be generated from that evidence.

These considerations are then brought into the post-market setting, where monitoring is used to keep track of potential problems and other unanswered questions that regulators might still have, particularly if a product was approved using an accelerated process.

Future Considerations

Going forward, FDA said it is continuing to refine this framework and working to expand its usefulness.

"There are two areas where we intend to focus efforts beginning in FY 2013," FDA explained. "The first is characterizing the uncertainty in how well the benefit-risk assessment based on pre-market clinical trial data translates to the post-market setting after the drug is approved and used in a much wider patient population."

"The second area," FDA continued, "pertains to our level of uncertainty about a result or finding, particularly a new finding that becomes available in the post-market setting where the basis for the finding comes from sources of varying levels of rigor."

Regulators said a combination of these two approaches would "lead to more explicit communication of regulatory decisions," and that this stage of refinement will continue beyond 2013. By 2014, it said it hopes to be able to apply it to all NDAs and BLAs that are new molecular entities, all efficacy supplements for new and expanded indications by 2016, and all original NDAs by 2017.

FDA said the framework used to approve each product will be published and made available to the public to the extent possible.

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