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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.
Generally, when you think about President Obama’s “core constituencies,” blue-collar unions are at or near the top of the list.
Consider, then, the following groups and their united position against the President’s plan to impose additional mandatory rebates on the pharmaceutical industry:
(And let’s call it what it is – a tax. More precisely, an excise tax imposed by Uncle Sam on drug sales – and not a single penny goes towards lower costs for a single patient. Not one. The cash goes into the general fund.)
· The International Brotherhood of Electrical Workers
· The International Brotherhood of Boilermakers
· The International Association of Police Associations
· Sheet Metal Workers’ International Association
· International Association of Fire Fighters
· International Association of Bridge, Structural, Ornamental, and Reinforcing Iron Workers
And the soliDarity is for a good reason – according to a new study by the Battelle Technology Partnership Practice, the President’s new tax on Medicare Part D would:
· Increase Medicare prescription drug premiums by up to 40%
· Increase annual out-of-pocket spending for almost 18 million seniors by as much as $208 annually
· Increase yearly total out-of-pocket drug costs for seniors by up to $3.7 billion.
The bottom line is the bottom line: As Yale Economist Fiona Scott Morton plainly states, “Applying the Medicaid rebate rule to Medicare Part D would likely result in higher prices for consumers in the private sector.”
That is not what the union movement signed on for when they supported the passage of the Affordable Care Act.
But wait, it gets worse.
The President’s tax a job killer. According to the Battelle Report, the tax could cause the elimination of between 130,000 and 260,000 jobs – many of them in the construction industry -- and hence the union revolt.
And, to add insult to injury, the President’s tax would also stifle life science innovation.
It’s hugely disappointing that the same man who (as a United States Senator) once said that …
“Realizing the promise of personalized medicine will require continued federal leadership and agency collaboration; expansion and acceleration of genomics research; a capable genomics workforce; incentives to encourage development of genomic tests and therapies; and greater attention to the quality of genetic tests, direct-to-consumer advertising and use of personal genomic information."
… is now advocating a policy that would result in precisely the opposite.
After speaking (during the State of the Union and a widely quoted op-ed in the Wall Street Journal) about the need for America to embrace innovation – President Obama is trying to make it more difficult, specifically when it comes to the desire to invest in pharmaceutical innovation – a sure bet under no circumstances.
If innovation is one of the key answers to our national economic recovery, then the President should abide by what he said, “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.”
As Harvard University health economist (and Obama healthcare advisor) David Cutler has noted: "Virtually every study of medical innovation suggests that changes in the nature of medical care over time are clearly worth the cost."
Let’s keep our eye on the prize. No, not ill-considered budget reduction on the backs of working Americans and seniors – the real prize: better access to smarter healthcare for all Americans. Rather than wasting time on spin, let’s redouble our efforts on innovation. Then, when we succeed through brainpower and teamwork (and, hopefully some civil bipartisanship), the circus surrounding the President’s tax will be but a footnote in the history of American healthcare.
Sent: Thursday, November 03, 2011 11:17 AM
To: CDER-ALL-HANDS
Subject: FY2011 Innovative Drug Approvals
CDER Staff:
You may have seen news reports or statements by industry that we are not “innovative,” or that we make it too hard for companies to get a new product on the market. But these broad-brush statements are, in most cases, inaccurate and unfair. They often lack important context that would explain our intentions and the work we do.
To help correct these misimpressions, CDER recently collaborated with the Commissioner’s Office, CBER, and many others throughout FDA on a report that highlights the innovative products approved by the agency in Fiscal Year 2011.
The report, released today, shows that in FY 2011, for CDER and CBER combined, FDA approved 35 new molecular entities (NMEs). These include innovative therapies for hepatitis C, late-stage prostate cancer, lupus, drug resistant skin infections, pneumonia, and other serious and life-threatening diseases.
The speed and efficiency with which these products were approved speaks directly to our staff and our high-quality reviews. It also demonstrates our willingness to exercise regulatory flexibility and creative approaches to help industry meet our standards—without lowering them.
FDA expedited the approval of many of these products by streamlining clinical trial requirements to permit smaller, shorter, or fewer studies wherever possible.
Here are a few highlights of the report:
FDA approved nearly half -- 16 -- of the innovative drugs under the agency’s “priority review” program for drugs that may offer major advances in treatment; priority reviews carry a six-month target date for review.
FDA approved all but one of the 35 products on or before the target dates for approval agreed to with industry under the Prescription Drug User Fee Act.
FDA approved the majority of these innovative drugs on the “first cycle,” that is, without requests for additional information that would trigger a second review cycle.
Continuing to enhance our efficiencies remains important, and in the near future I will be sharing with you some ideas on this topic. The positive messages highlighted in this report are a direct result of the combined hard work of all of us at CDER. Thanks to all of you! I am proud and appreciative to be part of the CDER team!
To view today's press release and the report, please visit http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278383.htm
FY2011 Innovative Drug Approvals Page: http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm276385.htm
Please join the Center for Medicine in the Public Interest (www.cmpi.org) and some of the nation’s top experts in PDUFA and FDA reform for an interactive panel discussion of “Defining the Future of the FDA: PDUFA V and Beyond.”
When: 12:00 – 1:30PM, November 29, 2011
Where: RM.2168 Rayburn House Office Building
Who:
Peter J. Pitts (Moderator), Former FDA Associate Commissioner, President of the Center for Medicine in the Public Interest
Vincent J. Ventimiglia, Jr, Former Assistant Secretary for Legislation at the US Department of Health and Human Services, Senior Vice President in the Health and Life Sciences Practice at B&D Consulting, a division of Baker & Daniels LLP.
Paul T. Kim, Former Deputy Staff Director for health policy for Senator Edward M. Kennedy, Partner at Foley Hoag LLP in the Government Strategies practice.
Michele J. Orza, Former Assistant Director of the Health Care Team at the Government Accountability Office, Principal Policy Analyst at the National Health Policy Forum.
Tim Franson, Former Vice President, Global Regulatory Affairs, Eli Lilly & Co., President, USP Convention, Senior Vice President, Health and Life Sciences Sector, B&D Consulting.
RSVP: mcoluccio@cmpi.org
From today’s edition of The Washington Examiner:
Who watches the watchdogs of government prescription detailing?
Misguided political philosophy and tens of millions of taxpayer dollars are behind one of the least transparent aspects of Obamacare, government-funded pharmaceutical "detailing."
Known by those who support it as "academic detailing," it is an effort by Uncle Sam to change the prescribing habits of America's physicians. So what's the problem?
Well, that change is driven by the largest health care insurance company in the country to lower costs rather than improve patient care. And that insurance behemoth is the government of the United States.
Specifically, the verbatim goal is to change prescribing habits that are "not in accord with the recommendations" of studies commissioned by the Agency for Healthcare Research and Quality.
The long and the short of it is that our government is spending tens of millions of tax dollars to tell our doctors how to practice medicine based on studies that are commissioned without any public input or transparency.
And the term "academic detailing" isn't accurate -- because the work isn't being done by academics. The AHRQ hired a firm, Total Therapeutic Management, and is paying it $11,680,060 to recruit and train physicians, pharmacists, nurses and physician assistants.
That's not academic detailing. That's government detailing. And the devil is in the details.
Will physicians be required to be visited by this new battalion of government agents? Will physicians be given incentives to spend time with AHRQ's angels and punished if they do not (via Medicare and Medicaid restrictions)?
And how will Uncle Sam decide which doctors are to be visited? Will "high prescribers" of on-patent medicines be on a priority list? Barry Patel, the CEO of Total Therapeutic Management, said its top priority is "high volume" practices.
Rather than focusing on offices with disproportionately high negative patient outcomes, Uncle Sam is directing its efforts against those doctors who are high prescribers -- which is a pretty good indicator about what government detailing is all about -- decreasing cost rather than improving care.
And what safeguards are in place to certify that physicians are being presented information that is unbiased? Previous government detailing efforts have often focused on demonstrating their own value by highlighting the cost-effectiveness of initiatives through savings generated from the increased utilization of generics and other low-cost therapies.
The repercussions of choosing short-term savings over long-term results, of cost-based choices over patient-centric care, of "fail first" policies over the right treatment for the right patient at the right time -- are pernicious to both the public purse and the public health. Skimping on a more expensive medicine today but paying for an avoidable hospital stay later is a fool's errand.
And how can an "academic detailing" program funded by our nation's largest payer (Uncle Sam) be considered neutral? Just like detailing programs run by pharmaceutical companies, there is an inherent "interest."
And that's OK -- as long as that "interest" is transparent. Who will be the arbiters of transparency? Who will decide what these detailers can say or not say? Will these government "reps" have to play by the same rules as their pharmaceutical counterparts?
And, importantly, what is the oversight mechanism? If academic detailers stray into off-label conversations, to whom does the FDA complain? Whom does the Department of Justice investigate? Who pays the fine? Quis custodiet ipsos custodes?
As currently designed, government detailing is a tool to increase government control over the practice of medicine and is a slippery slope towards the introduction of health care rationing and price controls.
Congressional oversight must be required for the $42.3 million that AHRQ has already awarded for public and physician outreach.
As Rudyard Kipling said to the Royal College of Surgeons in London in 1923, "Words are, of course, the most powerful drug used by mankind. ... They enter into and colour the minutest cells of the brain."
We allow them to be usurped and corrupted at our own peril.
Peter J. Pitts, a former Food and Drug Administration associate commissioner, is president of the Center for Medicine in the Public Interest.
I had the honor and pleasure of chairing the 4th Annual Risk Management and Drug Safety Summit. Here are my opening remarks from Day One (today):
Risk management cannot exist without a more holistic understanding and acceptance of the Responsibility of Risk.
Risk management means more than REMS strategies and tactics, more than validated methodologies and therapeutic registries. It’s not about the management of risk -- it’s about assuming the mantle of responsibility.
Risk management can’t just be about doing what’s necessary to get a product approved and abiding by prehistoric adverse event reporting mechanisms. It’s got to be more than MedWatch and MedGuides. Accepting the responsibility of risk means that we must stop being translucent and start being transparent. It’s more than just doing what we’re told, of being in compliance. Because we know better.
The responsibility of risk a shared responsibility. It must be more than what the FDA expects from industry and more than what industry expects from the FDA. It’s what all parties to the public health conversation must expect from themselves. And that goes 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 fault, dear Brutus, is not in our stars, but in ourselves.”
Let me repeat -- the responsibility of risk means doing more than what is in compliance. The responsibility of risk 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. When we allow either profit or politics to trump what’s in the best interest of the public health – we might as well be selling air conditioners.
Principles, as my father taught me, don’t count until they hurt.
Abraham Lincoln said that patents “add the fuel of interest to the passion of genius.” Well, 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’s important, but its tactical – and very 20th Century. In the 21st Century we have to invent new strategies. And that starts with embracing risk just as we embrace benefit. There should be a journal dedicated to the science of risk – a medical Kabala of Contingency. Otherwise all we’re left with is the anemic and feeble compost of early safety signal communications.
And the responsibility of risk is global. Acknowledging the responsibility of risk means embracing the urgency for harmonized global pharmacovigilence.
Other than that, it’s pretty easy and straightforward.
Thank you.
Letter Urging Rejection of Florbetapir F18 Injection (Amyvid), Experimental Procedure for Diagnosing Alzheimer’s Disease
Letter Opposing Approval of Rivaroxaban (Xarelto) for Anticoagulation Therapy in Patients With Atrial Fibrillation
The ABC News stories ignore context. But so do the press releases and studies from the CDCP triggering this anxiety. The CDC fails to note that the increase is concentrated among young adults in rural areas who are also abusing other prescription painkillers and medications in combination with cocaine. That's not a good thing but it's not an epidemic affecting everyone.
The Wolfe inspired panic is par for the course. For instance, Sid Wolfe opposed the approval of every oral diabetes drugs since the 1970s.
And speaking of scares: Remember when Steve Nissen spread fear about the cardiovascular risks of using meds for ADHD. The cardiologist who knows next to nothing about treating ADHD said he wants doctor's pen to quiver before the write a scrip for a drug Nissen believes is overprescribed. He continued the assault earlier this year when an observational study that Nissen (who specializes in running small observational studies for money) trashed as too small showed no CV risk. http://www.cbsnews.com/8301-504763_162-20063572-10391704.html
Now a large FDA sponsored study finds no risk.
Everything we worry about, especially when it's a risk hyped by those who are anti-innovation like Wolfe and Nissen , has to be placed in the context of previous studies, other risks, variations unique to individuals or groups. If a risk is not discussed with such parameters in place, it is not a risk..it's a false alarm.
"The order offers drug manufacturers and wholesalers both a helping hand and a gloved fist in efforts to prevent or resolve shortages that have worsened greatly in recent years, endangering thousands of lives."
(A gloved fist? Ouch. I hope that this isn't the President's low cost alternative to PSA screening...)
It instructs the F.D.A. to do three things: broaden reporting of potential shortages of certain prescription drugs; speed reviews of applications to begin or alter production of these drugs; and provide more information to the Justice Department about possible instances of collusion or price gouging.
Price gouging? Harris may have overlooked some of the findings of the administration's own report on the economics of drug shortages? Economic Analysis of the Causes of Drug Shortages (HHS) http://aspe.hhs.gov/sp/reports/2011/DrugShortages/ib.shtml
Harris summarizes the study: "the administration will release two government reports that mostly blame a dysfunctional marketplace for drug shortages, directly contradicting assertions by some commentators that government rules are to blame."
In fact the HHS report does more than blame a 'dysfunctional market', it explains what is behind the problem:
"...drugs that subsequently experienced a shortage are those in which the volume of sales was declining in the 2006-2008 period prior to the shortages."
It goes on to note in AppendixB : "Analysis of average sales prices shows that shows that oncology sterile injectable drugs that experienced shortages since 2008 decreased in price from $56.17 per unit in Q1 2006 to $37.88 per unit in Q1 2011. Oncology sterile injectable drugs that have not experienced shortages have had relatively stable prices over this period."
In plain English: artificially low prices caused the decline in the drugs that are now in shortage.
Ezekiel Emanuel zeroed in on the cause of the low prices in a NY Times oped back in August:
"The Medicare Prescription Drug, Improvement and Modernization Act of 2003...required Medicare to pay the physicians who prescribed the drugs based on a drug’s actual average selling price, plus 6 percent for handling. And indirectly — because of the time it takes drug companies to compile actual sales data and the government to revise the average selling price — it restricted the price from increasing by more than 6 percent every six months.
The act had an unintended consequence. In the first two or three years after a cancer drug goes generic, its price can drop by as much as 90 percent as manufacturers compete for market share. But if a shortage develops, the drug’s price should be able to increase again to attract more manufacturers. Because the 2003 act effectively limits drug price increases, it prevents this from happening. The low profit margins mean that manufacturers face a hard choice: lose money producing a lifesaving drug or switch limited production capacity to a more lucrative drug."
The result is clear: in 2004 there were 58 new drug shortages, but by 2010 the number had steadily increased to 211. (These numbers include noncancer drugs as well.)
http://www.nytimes.com/2011/08/07/opinion/sunday/ezekiel-emanuel-cancer-patients.html
For some reason Harris extolls the public spiritedness of generic drug companies who will pay about $300 million in one time user fees to break the logjam of approvals at the FDA's Office of Generic Drugs:
"The (generic) industry recently agreed to provide the F.D.A. with nearly $300 million annually to bolster inspections and speed drug applications. That amounts to about 1 percent of the industry’s revenues and about 5 percent of its profits in the United States, an extraordinary vote of confidence in the government’s ability to improve the situation. "
If the point is to show how this agreement will be used to resolve the current shortages, Harris is in error. The user fee agreement is designed to start accelerating approval of both new and backlogged generic drug applications by 2017. It has no bearing on the current shortage. But mentioning it is a nice way to divert our attention from the price controls that have lead to an underproduction of injectible cancer drugs and anti-biotics as well as a reluctance to invest in new facilities or production lines. As Emanuel notes:
"You don’t have to be a cynical capitalist to see that the long-term solution is to make the production of generic cancer drugs more profitable. Most of Europe, where brand-name drugs are cheaper than in the United States, while generics are slightly more expensive, has no shortage of these cancer drugs. " (Though it would be interesting to see if that is also a function of treatment patterns in Europe.
The administration's proposal to launch an attack on 'price gouging' will make companies reluctant to even attempt to raise prices. At the same time Team Obama is seeking to impose price controls on all Part B injectible drugs and Part D Medicare drugs. If you like shortages, just wait till these controls kick in.
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.
