Peekaboo -- ETASU

  • by: |
  • 11/07/2011

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.

(My complete opening comments on the “responsibility of risk” can be found here and many of the presentations from the Summit can be found here.)

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.


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

Blog Roll

Alliance for Patient Access Alternative Health Practice
Better Health
Biotech Blog
CA Medicine man
Cafe Pharma
Campaign for Modern Medicines
Carlat Psychiatry Blog
Clinical Psychology and Psychiatry: A Closer Look
Conservative's Forum
Club For Growth
Diabetes Mine
Disruptive Women
Doctors For Patient Care
Dr. Gov
Drug Channels
DTC Perspectives
Envisioning 2.0
FDA Law Blog
Fierce Pharma
Fresh Air Fund
Furious Seasons
Gel Health News
Hands Off My Health
Health Business Blog
Health Care BS
Health Care for All
Healthy Skepticism
Hooked: Ethics, Medicine, and Pharma
Hugh Hewitt
In the Pipeline
In Vivo
Internet Drug News
Jaz'd Healthcare
Jaz'd Pharmaceutical Industry
Jim Edwards' NRx
Kaus Files
Laffer Health Care Report
Little Green Footballs
Med Buzz
Media Research Center
More than Medicine
National Review
Neuroethics & Law
Nurses For Reform
Nurses For Reform Blog
Opinion Journal
Orange Book
Peter Rost
Pharm Aid
Pharma Blog Review
Pharma Blogsphere
Pharma Marketing Blog
Pharmacology Corner
Pharmaceutical Business Review
Piper Report
Prescription for a Cure
Public Plan Facts
Real Clear Politics
Shark Report
Shearlings Got Plowed
Taking Back America
Terra Sigillata
The Cycle
The Catalyst
The Lonely Conservative
Town Hall
Washington Monthly
World of DTC Marketing
WSJ Health Blog