Abstract
I had the honor and pleasure of chairing the 4th Annual Risk Management and Drug Safety Summit, held at the National Press Club in Washington, DC, November 1-2, 2011. Here are my opening remarks from Day 1: Risk management cannot exist without a more holistic understanding and acceptance of the “Responsibility of Risk.” Risk management means more than Risk Evaluation and Mitigation Strategies (REMS) and tactics, and more than validated methodologies and therapeutic registries. It is not about the management of risk, but assuming the mantle of responsibility. Risk management cannot solely be about doing what is necessary to get a product approved and abiding by outdated adverse event reporting mechanisms. We need more than MedWatch and MedGuides. Accepting the responsibility of risk means that we must stop being translucent and start being transparent. Risk management is more than just doing what we’re told, of being in compliance. We know better. The responsibility of risk is a shared responsibility. It must be more than what the FDA expects from industry and more than what industry expects from the FDA. It is what all parties to the public health conversation must expect from themselves, which means going far beyond anything to do with marketing or sales or stock price or legislative authority. It means doing what’s right in addition to what is required. The responsibility of risk, therefore, means doing what’s in the best interest of the patient fully and completely and beyond what is required—even when it is contrary (or viewed as such) to short-term sales and marketing objectives. If we allow either profit or politics to trump the best interests of the public health, we should change jobs. Abraham Lincoln said that patents “add the fuel of interest to the passion of genius.” To paraphrase, accepting the responsibility of risk adds the fuel of interest to the passion for serving the public health. The responsibility of risk means appreciating and actualizing the philosophy of the safe use of drugs. For example, the responsibility of risk means not just detailing—but detailing the label. Traditional risk management means finding ways to avoid risk, to mitigate it. That is certainly important, but it's tactical—and very 20th Century. In the 21st Century we have to invent new strategies, which starts with embracing risk just as we embrace benefit. Otherwise all we are left with is an inadequate system of early safety signal communications. The responsibility of risk is global. Acknowledging the responsibility of risk means embracing the urgency for harmonized global pharmacovigilance. Other than that, it’s pretty easy and straightforward.
She also made it clear that the outcomes databases now available to the agency’s Sentinel program will not be used for comparative effectiveness purposes. She then addressed the issue (also part of the PDUVA V discussion) of a benefit/risk assessment tool. Specifically, Dr Woodcock laid out 5 “key considerations”: (1) analysis of condition, (2) unmet medical need, (3) clinical benefit, (4) risk, and (5) risk management. She then discussed a pilot program that most in the room (myself included) had never heard of before, sharing that CDER has begun a pilot program (with 6 unnamed NMEs) wherein the various sectors of review teams will fill out their own benefit/risk assessments (based on the 5 criteria mentioned above) to explain how they arrived at their relative positions. At this time we do not know whether or not these findings will be made public.
Dr Woodcock also talked about the agency’s continuing and crucial struggle to advance patient medical information (PMI). The goal of CDER’s current initiative is to create a one-pager for Rx products more akin to the Nutrition Facts Panel (aka, “the food label”) or an OTC “drug facts” box. This is certainly a noble effort, but the details will need addressing carefully. For example, would this document be progressive, or would existing products need to create them as well? If progressive, would this single sheet be part of the initial label negotiation process? And, if retroactive, can the agency use its FDAAA directive labeling authority to create the page itself—and if so, what social science would the content be based on? Where would the boundaries be between product education and promotion? How would this document be distributed (hard copy, websites, social media, etc)? Would generics use the same information and, if so, what about narrow therapeutic index products? She did not have all of the answers, but this is certainly a provocative topic worth pursuing.
The next talk was given by Sir Alasdair Breckenridge (Chairman, MHRA), who turned heads by saying that “we need to stop talking about safety. Safety should be removed from our lexicon. We must focus on benefits and harms.” He also discussed the difficulties of regulating in an environment where EU-level directives add additional burdens to national level regulatory authority. Specifically, he shared that the regulations writers in Brussels have altered the definition of “adverse reaction.” The new definition includes “noxious and unintended effects resulting not only from the authorized use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorization, including misuse and abuse of the medicinal product.”
How, Sir Alasdair, asked, can any agency address adverse reactions based on medical errors and product abuse? Are they signals or noise? He also cited an interesting study, Golder et al, 2011,
1
on the issue of adverse effects data derived from randomized clinical trials (RCTs) as compared with observational studies. The conclusion of this paper is that empirical evidence indicates that there is no difference, on average, in the risk estimate of adverse effects of an intervention derived from meta-analyses of RCTs and meta-analyses of observational studies. This suggests that systemic reviews of adverse effects should not be restricted to specific study types.
Picking up on Sir Alasdair’s point about “benefits and harms,” Dr Tim Franson (former regulatory chief at Eli Lilly & Co, current President of the USP Convention, and an SVP at B&D Consulting) asked an interesting question: Should we be talking about risk at all—or about benefit/risk? He concluded his remarks by reminding the audience that, when it comes to global benefit/risk management, “We all share in the responsibility.”
Day 2 of the summit featured a keynote address by John Lechleiter, Chairman, President and CEO of Eli Lilly, who commented as follows: We’d like to see the FDA adopt systematic, transparent Benefit/Risk assessment methods consistently across review divisions and the Office of Surveillance and Epidemiology. This would support more balanced regulatory decision-making ... and enable the Agency to clearly communicate the rationale for its decisions to industry, providers and the public at large. I note here FDA’s support for medication adherence in 2011—which we applaud. But a more balanced approach to communicating both the benefits and risks of a drug would also aid in the effort to improve adherence. FDA should accelerate efforts to adopt and apply the best scientific methods and also incorporate the perspectives of affected patients—which can form the basis of consistent, transparent, reproducible decision-making. Here are some things that I believe FDA could do right now to accelerate the benefit-risk agreement outlined in PDUFA: Identify external benefit-risk experts as key consultants. FDA has acknowledged the need for systematic benefit-risk assessment tools ... and has engaged external experts sporadically over the past several years. To accelerate progress, FDA should identify and pull together the leading academicians, clinicians, and thought leaders in the field now to augment their internal practical experiences in drug review. Engage other major regulators in this effort. For example, FDA could advance discussions with EMA and other agencies to develop a harmonized approach to benefit risk assessment that would enrich decision-making and enable effective communications. This is important, as there’s potential for discord as regulators globally develop different tools and approaches. Adopting globally harmonized assessment of benefits and risk could alleviate regulatory confusion and uncertainty and help advance the public health.”
—Peter J. Pitts
Former FDA Associate Commissioner, President, Center for Medicine in the Public Interest