Striking the Benefit-Risk Balance

John Ferguson, VP of Pharmacovigilance at Novartis Vaccines and Diagnostics, examines today’s drug safety landscape.

NGP. Can you begin by commenting on the magnitude and importance of the focus on benefit-risk today, looking at current industry initiatives and regulatory focus?
JF. Demonstrating a positive benefit-risk balance is the basis for obtaining and maintaining drug approval. Yet, there is no explicit framework for making a benefit-risk balance. The current process involves unstructured pooling of individual judgments that are subjective, inscrutable and difficult to reproduce.
 
There is increasing recognition of the need for stakeholder consensus about the benefit-risk balance of widely used drugs. Building a benefit-risk balance consensus requires agreement on the facts, for instance, which health states to balance, data on the likelihood of these outcomes and the relative merits of these health states.
While consensus is the goal, informed dialogue is the vehicle to reach the goal. Informed dialogue requires an explicit, logical, standardized and validated framework for choosing and measuring health states of importance, accounting for uncertainty in these measurements, and bridging stakeholders’ health state valuations. To this end, regulators, academics, health care providers, patient groups and payers are currently working together to develop a structured approach to making a benefit-risk balance that can be independently examined, characterized and vetted against accepted standards.

NGP. Can you describe what you see as the fundamental problems underlying the state of drug safety?
JF. In short, the demands on safety organizations are exceeding the capacity to adapt quickly enough to meet societal expectations. The demand for increasingly evidence-based approaches to drug safety is outpacing the capacity to develop new tools and meet the increasing need for safety professionals, who are expert in both evidence-based inference and compliance. Defraying the attendant costs requires rebalancing resource allocation, tilting it more towards safety.
NGP. What are the drivers behind pushing clinical safety earlier into the development process?
JF.  In my opinion, the main driver is the need to identify genuine safety issues earlier in the product life cycle, so as to:

• protect the public health
• identify drugs that will fail as early as possible in development, and thereby, increase efficiency, reduce development costs, eliminate spending on something that is doomed to fail, and reduce litigation-related risk
• identify product-saving risk management opportunities before the occurrence of a crisis that precludes product-saving program changes
• strengthen internal partnerships that accelerate identification of real safety issues and decrease the likelihood of a crisis, for example, non-approval or withdrawal

Perception is reality. If a drug looks dangerous, it will be treated as such. Reliably establishing a positive benefit-risk balance is easier to do when the safety group is ‘hardwired’ into early development.
NGP. What kind of structural realignment of organizations needs to happen to optimize drug safety assessment resources and ultimately improve drug safety?
JF. Optimal handling of safety requires stakeholder alignment. This may require internal re-alignment in some organizations. Two elements of particular interest are the standing and cross-functional interactions of the clinical safety group.
 
Ideally, the safety group has the independence, standing and wherewithal to influence decision-making in early drug development. To this end, it helps to have a Chief Safety Officer operating in peer-to-peer relationships with the heads of Clinical Development, Medical Affairs, Discovery, Preclinical Development and Regulatory Affairs. An effective Chief Safety Officer is necessary but not sufficient. The proposition only works if the Chief Safety officer has the right supporting cast, for instance, safety-physicians with as much clinical and clinical research experience as their counterparts in Clinical Development and Medical Affairs. Emphasizing the strategic role of the safety group helps to attract these physicians to safety. Rebalancing resource allocation helps to keep them there.
 
A safety group’s ability to influence decision-making in development also depends on its cross-functional interactions. In some companies, this may require realignment with internal partners to ensure Safety’s membership on key development and regulatory teams and vice versa, for instance, research, preclinical and clinical development representation on cross-functional signaling teams. Placing Medical Affairs under the Chief Medical Officer may facilitate implementation of evidence-based safety, in studies of marketed product. In addition, product risk management tools may ‘belong’ to the commercial organization, which calls for a rapprochement between the groups.

NGP. How will realignment of an organization enable companies to take a more structured approach to balancing benefit and risk?
JF. Proper alignment can be expected to increase the ability to anticipate and react to issues earlier in development. Greater integration of clinical safety –traditionally focused only on risk – with other stakeholders in development – traditionally focused on efficacy – provides the operational basis for implementation of structured approaches to balancing benefit and risk.

NGP. Can you describe an optimal scenario of a corporate risk management strategy that helps to connect middle management product risk efforts with regulation and compliance bodies’ efforts?
JF. The key questions is: ‘How does the management team know that decision makers will receive the information that they need to make informed decisions about product risk in a timely manner?’
 
In some companies, product risk management may be handled at a level that is several steps removed from the management team. This approach can introduce a potential time lag that could be problematic. The profound corporate impact of recent high-profile product safety issues underscores the advisability of developing comprehensive corporate risk management strategies. Most companies have corporate risk management vehicles, whether they refer to them as such or not. However, these may focus on financial risks, without explicitly and proactively accounting for emerging product risks. If this is the case, it may be advisable for management to develop and communicate a corporate risk philosophy that includes clear procedures for escalating important, potential safety issues to management in real-time.

Dr. John Ferguson is Vice President and Global Head of Pharmacovigilance and Medical Safety at Novartis Vaccines and Diagnostics. He is a board certified cardiologist who received his training in Cardiology and Clinical Epidemiology at McGill University, MacMaster University and Cedars-Sinai Medical Center. Prior to entering the pharmaceutical industry, his research focused on expert systems, risk prediction in coronary artery disease and catheter-based interventions for prevention and treatment of ischemic stroke. Ferguson has dealt with a broad spectrum of safety issues involving biologics and pharmaceuticals. He is an active participant in industry organizations, having served on clinical trial, safety, risk management and benefit-risk management committees.

These are the views of John Ferguson and in no way reflect those of the companies that he works for or has worked for.