The 4th Annual Risk Management and Drug Safety Summit is over. But the reverberations will be felt for some time to come.
After event chair (me) opened with a challenge for industry and regulators to step up to the challenge of “the responsibility of risk, the esteemed presenters were, to put it mildly – feisty.
The first keynote presenter at the summit was Janet Woodcock, who said that “advancing the science of safety is a shared effort.” She also shared the agency’s relief (shared by the majority of summiteers) that MedGuides shall now exist outside of a REMS context.
When MedGuides were in safety’s land. Let my REMS plans go.
Janet also made it clear that the outcomes data bases 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) or a benefit/risk assessment tool. Specifically, Janet laid out five “key considerations”: (1) analysis of condition, (2) unmet medical need, (3) clinical benefit, (4) risk and (5) risk management.
Sounds like a plan. Well – almost.
Dr. Woodcock then discussed a pilot program that most in the room (myself included) had never heard of before. Janet shared that CDER has begun a pilot program (with six unnamed NMEs) wherein the various sectors of review teams will fill out their own benefit/risk assessments (based on the five criteria mentioned above) to explain how they arrived at their relative positions. She didn’t mention whether or not these findings would be made public.
(Did somebody say, “transparency?”)
Janet also talked about the agency’s continuing and crucial struggle to advance PMI (patient medical information). The goal of CDER’s current initiative 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.
A noble effort – but the devil is certainly in the details. 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, based on what social science? 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? Janet didn’t have all of the answers – but it’s certainly a provocative topic worth pursuing.
Next up was 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.”
Sir Alasdair 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 mandarins 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?
Brussels sprouts. Alasdair doubts.
He also cited an interesting study (Golder, S., et al, PLoS Medicine, May 2011) on the issue of adverse effects data derived from RCTs as compared to 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.”
This opens up a big can of worms relative to the considered value of observation studies. But, as Alexandre Dumas said, “All generalizations are dangerous – even this one.”
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 a smart question, should we be talking about risk at all – or about benefit risk? shared a timely quote from Edward Tenner’s treatise, Why Things Bite Back: Technology and the Revenge of Unintended Consequences, “Any technology powerful enough to improve life radically is also capable of abuse and prone to serious unanticipated side effects. Mix new technologies with the wide variations in how organizations and individuals behave and you often have a recipe for explosion.”
That passage deals with nuclear power. Discuss.
Dr. Franson concluded his remarks reminding the audience that, when it comes to global benefit/risk management, “We all share in the responsibility.”
Day Two of the summit featured a keynote address by John Lechleiter, Chairman, President and CEO of Eli Lilly and Co. who commented:
“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.”
(John’s compete remarks can be found here.)
The theme of shared responsibility ran through the entire event. But talk is cheap. And if we all believe that to be true – then it must also instruct our rhetoric. For example – should ETASU (Elements to Assure Safe Use) be changed to ETASU (Elements to Assist Safe Use)? After all, (and to brutally frank here) nothing can ever assure safe use, but if we all assist in the endeavor, well, there’s a much higher chance for success.
Shared responsibility. If you can’t say it, you can’t do it.
Which brings us back to where we started – risk as a shared responsibility facilitated relationships built on trust. Trust between regulator and regulated. Trust between physician and patient. Trust enhances perception and, as the saying goes, perception is reality.