As negotiations for PDUFA V get serious, there seems to be a widening gap between what FDA wants (more resources) and what industry wants (more predictability).
After all, as President Obama wrote today in the Wall Street Journal, “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.”
And 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. 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, 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, “Development of a Framework for Enhancing the Transparency, Reproducibility and Communication of the Benefit-Risk Balance of Medicines," calls for the creation of 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 authors argue (and quite persuasively) that BRAT provides a standardized yet flexible platform for incorporating study outcomes and preference weights as well as for communicating the rationales for decisions.
Some selected segments:
Assessing the benefit–risk balance of medicines is a prominent challenge facing all sectors of health care, from pharmaceutical manufacturers and regulators to prescribers to patients seeking to make more informed treatment decisions.
However, although benefit–risk assessments are at the center of decision-making, the current process relies primarily on expert judgment. Indeed, the Institute of Medicine (IOM) recently noted that “in both the pre-approval and the post-marketing setting, the risk–benefit analysis that currently goes into FDA decisions appears to be ad hoc, informal, and qualitative.Despite calls for a more consistent and robust process, a suitable framework for benefit–risk assessment of medicines has yet to emerge.
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. In the development and approval stages, the existence of a risk–benefit assessment 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).
In the post approval stage, the framework could ensure a more balanced assessment and communication of both benefits and risks, particularly as new safety issues emerge. Finally, the use of a framework would allow decision makers (DMs) to incorporate the views of other important stakeholders, such as patients and healthcare professionals. All of these improvements would result in decision-making processes that are more transparent, rational, and defensible. The Pharmaceutical Research and Manufacturers of America (PhRMA) have addressed the need for improved benefit–risk assessment by developing a structured, systematic, and transparent framework. The result of a 5-year effort by a team organized and facilitated by PhRMA, the Benefit Risk Action Team (BRAT) Framework is a progressive move toward benefit–risk assessment that seeks to incorporate all relevant aspects of benefit and risk. The focus is on both qualitative and quantitative analysis of benefit and risk outcomes. The current framework can incorporate weighting of outcomes but does not focus on calculation of overall benefit–risk scores. This paper reports on the design and rationale of the BRAT Framework.
The Brat Framework
Suitable for use by all stakeholders, the BRAT framework is a general platform for benefit–risk assessment. It facilitates the selection, organization, summarization, and interpretation of data and preferences relevant to the benefit–risk decision and also serves as a tool with which to broadly communicate the rationale for the decision.
Six steps represent the current process that structures and assists DMs, without constraining them. The actual decision is depicted outside the framework’s steps, to emphasize that, while the framework aids decision making, it does not replace clinical expertise and judgment.
1. Define the decision context. Define drug, dose, formulation, indication, patient population, comparator(s), and time horizon for outcomes, perspective of the decision makers (regulator, sponsor, patient, or physician).
2. Identify outcomes. Select all important outcomes and create the initial value tree. Define a preliminary set of outcome measures/end points for each. Document rationale for outcomes included/excluded.
3. Identify and extract source data. Determine and document all data sources (e.g., clinical trials, observational studies) Extract all relevant data for the data source table, including detailed references and any annotations, to help the subsequent interpretations create summary measures.
4. Customize the framework. Modify the value tree on the basis of further review of the data and clinical expertise. Refine the outcome measures/end points. May include tuning of outcomes not considered relevant to a particular benefit–risk assessment or that vary in relevance by stakeholder group.
5. Assess outcome importance. Apply or assess any ranking or weighting of outcome importance to decision makers or other stakeholders.
6. Display and interpret key benefit–risk metrics. Summarize source data in tabular and graphical displays to aid review and interpretation, challenge summary metrics, review source data, and identify and fill any information gaps.Interpret summary information.
The paper concludes:
As discussed in the seminal 1998 report by the Council for International Organizations of Medical Sciences, benefit–risk assessment is the “heart” of determining the overall value of a medicine. But although a number of benefit-risk assessment approaches have been proposed, none has been widely adopted.
The lack of uptake may be attributable, in part, to the focus on developing quantitative tools before turning to the development of a fundamental, principled approach to benefit–risk decision making. The BRAT framework is designed as such a fundamental, principled approach. There is evident need for consensus on methods of conducting benefit–risk assessments, tools and processes to better design and evaluate drug development programs, methods to enhance regulatory discussions throughout a product’s life cycle, and tools to improve communication of benefit–risk assessments to clinicians and patients. The BRAT framework facilitates structured, systematic decision making via customizable tools and processes. The adoption and use of the framework will advance the rigor, transparency, and communication of the rationale behind benefit–risk decisions.
A companion paper, “Application of the BRAT Framework to Case Studies: Observations and Insights,” discusses how, during 2008 and 2009, BRAT members collaborated with epidemiologists at RTI International in order to continue development of the framework and arrive at insights that would help enhance it. The framework was applied to three mock, or “constructed,” drugs in five patient populations. RTI and BRAT members organized feedback from selected regulatory and clinical stakeholders at three stages during the Framework applications. This article describes observations from these case studies and the insights gained by applying the Framework to them.
The author’s conclude:
The BRAT Framework appears to be of value in the different settings and case studies considered. As the Framework is further developed, we continue to seek feedback to facilitate improvement and adoption of its principles and processes by both companies and health authorities for regulatory review.
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 Framework processes and associated documentation of all decisions, rationale, and data could also provide an audit trail for past decisions and can inform the design of future clinical trials. Coupled or integrated with other tools, the Framework can …be an important factor in improving evidence-driven decisions on whether and under what circumstances therapeutic benefits outweigh associated risks.
Industry seeks clarity. They want bright lines. They want to know the rules. They want predictability. This may sound simple and fair, but inside the FDA it has proven to be a fractious bureaucratic kulturkampf. “Change is not required,” as management guru W. Edwards Deming once said. “Survival is not mandatory.” And that doesn’t mean change for show, for politics – it means thoughtful, timely, strategic change that enhances the public health. And that kind of change requires not walking on egg shells – but breaking them.
It’s time for the FDA to welcome the BRAT Pack to the drug regulatory process.
As the President writes, “Our economy is not a zero-sum game. 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.”
