Pain Acceptance: A Path Forward?

The world apparently needs more opioids, so the FDA approved another one yesterday.  Egalet Corporation's long-acting morphine formulation, Arymo ER, will hit the market here in the US before the close of Q1.  Interesting side note for those interested in the economic value of abuse-deterrence: Egalet stock initially shot up 27% on the approval news.  But when it became clear the Arymo label would only include abuse-deterrence language for dissolution and injection, but not for snorting or chewing it (because another abuse-deterrent opioid has rights to exclusivity for the particular claim), the stock dropped 16% yesterday and another 20% this morning.  By my calculations, that drop erased about $70 million in equity value.  And according to Yahoo Finance, 58% of the share are held by "insiders" (aka company executives) and one officer, Egalet CEO Robert Radie, holds nearly 50% of those insider shares.  So he's $20 million poorer this morning because he can't claim his new drug cannot be snorted or chewed.  If the mix of healthcare and high finance is a little nauseating to you, you're not alone.

In other pain management news, there's a really interesting study in this month's Journal of Pain Research regarding the relationship between "pain acceptance" and outcomes measures such as disability, mental health, and quality of life.  The study also relates this concept of "pain acceptance" to behaviors such as "pain catastrophizing," a phenomenon wherein a person "experiences exaggerated worrying and overestimation of the probability of unpleasant outcomes in response to pain." Notably, the study looks exclusively at a workers' compensation population.

Not surprisingly, higher "pain acceptance" scores were strongly correlated with less disability and greater mental and physical health.  "Pain catastrophizing" appeared to have the opposite effect - increased disability and poorer perceived health.  If you're wondering why you're hearing so much these days about cognitive behavioral therapy, this is why.

The study caused me to contemplate the broader picture of where we stand on the issues of chronic pain and opioid use.  We get lost in the statistics sometimes and fail to see the forest for the trees. Here's the real bottom line: the last quarter century has seen both an explosion in chronic pain and an explosion in opioid use.  The latter does not appear to be mitigating the former.  At all.

From another (highly clinical/technical) study that also crossed my desk last week from the Department of Palliative Care at Geisinger Medical Center, I drew this important insight: "Do not use pain intensity as the primary outcome in the management of chronic pain."  Sounds pretty simple.  But do we use, then?  Perhaps a greater focus on concepts like "pain acceptance" will help us break through the chronic pain conundrum.

Michael
On Twitter @PRIUM1

FDA and Off-Label Drug Use: Danger Ahead

The FDA has scheduled hearings for November (and a public comment period that will extend to January) regarding the agency's current approach to the marketing of off-label uses of FDA-approved medications.  Drug and device manufacturers have been waiting years for this opportunity to change the agency's stance on off-label marketing.  

This is not good news.    

First, a definition: Drugs approved by the FDA are approved only for the specific conditions for which they were tested in clinical trials conducted by the manufacturer.  These approved medications have an FDA "label" which stipulates those conditions for which the drug has been approved.  FDA approval, however, does not govern the practice of medicine.  Doctors are free to prescribe FDA approved drugs for conditions not included on the "label" (thus, off-label use of FDA approved drugs).  While the practice is common among doctors, pharmaceutical and medical device companies are restricted from "marketing" off-label uses of drugs.    The 1938 Food, Drug, and Cosmetic Act gave the FDA the power to regulate promotional materials on medications and to this day, they do. Very closely.  

Second, some basic statistics:

• 1 in 5 medications prescribed today is for off-label use. (Example relevant to you: tricyclic antidepressants do not have FDA approval as a treatment for neuropathic pain, yet this class of drugs is considered by many physicians to be a first-line treatment option.) 
• In recent years, antipsychotic drug use for unapproved FDA indications has increased. One study estimated that the cost of off-label antipsychotic drug use in 2008 was $6.0 billion.
• The fines connected to illegal off-label marketing by pharmaceutical companies appear material (though this is debatable in light of the annual sales of some of these drugs): 
• 2009: Eli Lilly paid $1.4 billion off-label marketing of olanzapine for dementia
• 2009: Pfizer paid $2.3 billion for alleged off-label marketing of 4 of its medications
• 2012: GSK paid $1.3 billion for off label marketing of paroxetine
• 2012: Abbott paid $1.6 billion for off label marketing of valproic acid 

So here's the core question: Should the FDA allow pharmaceutical and medical device companies to market to doctors off-label uses of medications?

In a word, no.  But let's dig a little deeper into the argument the pharma companies are making.

Their position is summed up best by the quote in the Bloomberg article (linked above) from Deborah M. Shelton, deputy general counsel for healthcare at the Biotechnology Innovation Organization (BIO):  “Removing current regulatory barriers, and clarifying the ability of companies to share truthful and non-misleading information [emphasis added] about medicines, is essential to our collective ability to realize the full potential of 21st century medicines and helping to ensure that patients are able to get the right medicines at the right time for them,” 

Two key words here: truthful and non-misleading.  Leaving aside that the use of both terms appears redundant, we're still left the the fundamental question of who decides what is truthful and non-misleading.  

We have three choices available to answer that question: the FDA, the drug companies, and broad clinical experience.  

The FDA seems like the most logical answer.  They approved the drug in the first place, why can't they be responsible for approving additional indications (or uses) of that same medication?  The reply from the drug companies to this idea is understandable: it's really expensive.  The FDA requires a similar level of data and similar level of rigor from clinical trials to approve an additional indication as they do to approve the initial indication.  In many cases (though not all), the costs are clearly prohibitive.  

The drug companies cannot be trusted to decide what's truthful.  If you can't see the obvious conflicts of interest here, then you should stop reading.  You're not worth another word.    

Broad clinical experience, or the general body of knowledge developed as a result of actually practicing medicine, is a valuable source of information and the means by which some portion of off-label prescribing comes to occur in the first place.  When such knowledge is documented in well-respected, peer reviewed journals, the medical community gains a trusted and codified source that might prove valuable to other clinicians.  But how to get that information disseminated?  Could the pharma companies do that?  Isn't that what they're asking for here?  To relay "truthful and non-misleading information" to doctors about off-label uses of medications?  

Here's the thing: they can already do that.  From the Mayo Clinic's article by Chistopher Wittich, et al [emphasis added]: "The 1997 FDA Modernization Act allowed manufacturers to distribute to health care providers peer-reviewed journal articles about unapproved uses of medications.  If a given drug company chose to engage in distribution of this type of information, it was required to submit an application for approval of that indication within a rigid and pre-specified period. These requirements were subsequently revised in 2009 with the approval of new FDA guidelines. The new guidelines clarified existing rules and allowed distribution of information on off-label uses by pharmaceutical manufactures if specific regulations were followed.  After 2009, pharmaceutical manufacturers could distribute information, including journal articles and textbook chapters, describing unapproved uses for their medications. The FDA demanded that the information in these... publications be accurate, the relationship between the distribution of information and the sponsoring drug manufacturer be disclosed, and the published material not be edited or presented in an abridged form. In addition, the manufacturer is no longer required to submit an application for approval for that indication."

Sounds reasonable to me.  What do the drug companies want to be able to do beyond this?  Makes me very, very nervous.  

Michael 

On Twitter @PRIUM1

A New Approach to Opioids From FDA?

After we were all inundated with direct-to-consumer advertising from the pharma industry on Sunday evening, I thought I'd share some potentially good news from federal regulators (the same regulators that would do us all a favor by banning DTC advertising from pharma).  The emphasis here is on the word "potentially."

Last week, three physician leaders at the Food and Drug Administration (FDA) published an article in the New England Journal of Medicine that suggests a new approach to how FDA should deal with opioids as a medication class.  The article concisely lays out new steps, clear priorities, and a commitment to better handling issues around pain management.  While the paper is characterized as part of a larger initiative on the part of the Department of Health and Human Services (HHS), those who follow FDA activities closely know that this is also a response to significant criticism over the last several years regarding FDAs unpredictable and haphazard responses to new drug applications in the opioid class.  FDA mandated necessary and positive label changes to all extended release / long acting opioids... and also approved Zohydro and generic Opana ER... Clearly, the agency has suffered from a lack of a clear and comprehensive strategy.

While it's been forever and a day, FDA finally appears to be crafting one.  The key quote: "... the United States much deal aggressively with opioid misuse and addiction, and at the same time,... it must protect the well-being of people experiencing the devastating effects of acute or chronic pain.  It is a difficult balancing act, but we believe that the continuing escalation of the negative consequences of opioid use compels us to comprehensively review our portfolio of activities, reassess our strategy, and take aggressive actions when there is good reason to believe that doing so will make a positive difference."

FDA will now reexamine the role of pharmaceuticals in pain management, encourage the development of non-opioid alternatives, focus on abuse-deterrent formulations of new drugs, support the development of evidence-based guidelines for opioid use, and ensure that the approach to pediatric pain management is the right one.

But to me, the most important commitment FDA appears to make in this announcement is a willingness to "balance individual needs for pain control with the risk of addiction, as well as the broader public health consequences of opioid abuse and misuse."  

This the first time, to my knowledge, that FDA has acknowledged public health concerns as part of its mandate related to pain management medications.  Should FDA develop a rational, repeatable, replicable approach to balancing the safety and efficacy to an individual patient with the safety and efficacy to the broader public, this will represent a major step forward in the fight against opioid misuse and abuse.

This is promising.  But now the hard work begins.  FDA actually has to implement this.

Michael
On Twitter @PRIUM1

The Flu, My Inbox, and Opioids

I found myself felled by the flu last week.  I'm glad to be back on my feet and figured it would make my life easier if I caught up on my inbox and blogged about what I found there at the same time... Here's what popped in there while I couldn't stand to stare at a screen:

Vicodin scripts plummeted due to the rescheduling of hydrocodone from SIII to SII.  There were over 26 million fewer scripts (a 22% drop) and over 1 billion fewer tablets (a 16% drop) as a result of the change.  That's a dramatic shift.  But did those scripts disappear?  Or were they replaced by other opioids?  Yeah, that's what I think, too.

US Senator Ed Markey (D-MA) is holding up confirmation of a new FDA Commissioner over some of the practices that appear to have caused the last FDA Commissioner to resign.  Markey wants a reformed approach to opioid approvals and for FDA to rescind its approval of oxycodone for pediatric populations.  These are tough tactics.  Whether or not you agree with him, here's a Senator using the power of his office to shine a light on a major issue and trying to create change in an agency that desperately needs it.

Any high school in the US that wants Narcan on hand in case of a drug overdose can now have it free of charge (thanks to the the drug's manufacturer and the Clinton Foundation).  I'm not supportive of a Narcan script along with every opioid script, but having this drug on hand in high schools as standard operating procedure is good public policy.  Why would a high school turn this down?  Any principal that does so risks being hoist by his own petard... and on the front page of his local paper trying to explain why the poor kid died when he might have been saved.

The US Preventative Services Task Force has recommended that all adults >18 be screened for depression.  Some of you are thinking, "whoa... that's gonna be expensive!"  And you're right, it will be.  But you know what the only thing more expensive than diagnosed depression is?  Undiagnosed, untreated depression.  So let's start getting used to this being a good idea.  Quote to take away on this one is from Dr. Keith Humphreys, a professor of psychiatry at Stanford: "The reality of American healthcare is that mental health has to be done in primary care."

So I guess I didn't miss much.

Michael
On Twitter @PRIUM1

Opana, HIV, and Unintended Consequences

With the exception of a great piece on medical billing from back in March of 2013, Time magazine hasn't managed to publish much worth reading.  But the forthcoming issue of the magazine features a cover story titled "Why America Can't Kick Its Painkiller Problem."  And it's worth 15 minutes of your time, albeit not for the most obvious reasons.

Yes, the article offers a fairly thorough overview of the recent history of pain management in this country.  The usual suspects make their appearances (big pharma, Russell Portenoy, the Joint Commission, etc.) and the standard statistics are rolled out ($8 billion painkiller market, 17,000 annual deaths from overdose, more than 200 million annual prescriptions written for opioids, etc.)  You know most of this and it would be easy to scan the article and think (as I usually do), "If Time Magazine is only now publishing a story about the problem, we must be making progress..."

But this article turns out to shine some important light on three issues we normally miss when we contemplate the epidemic of prescription drug misuse and abuse:  First, that there are incredibly harmful unintended consequences that no one could have foreseen; second, seemingly harsh punitive measures taken against pharma companies haven't put a dent in the problem; third, the FDA isn't helping.

Perhaps the scariest among many unintended consequences is the one highlighted in this article - the rise of Hepatitis C and HIV infections among intravenous drug users addicted to opioids.  In January, Scott County reported an alarming jump in new HIV cases: eight new HIV-positive patients in a small, rural community.  By March, there were 81 new cases.  As of June 2, there were 166 HIV cases in Scott County.  Of those patients interviewed by the CDC, 96% reported injecting Opana intravenously.  I wonder if there are any injured workers among them.  And this is being driven by a formulation that Endo claims is abuse-deterrent.  Turns out the supposed abuse-deterrence makes it much harder, if not impossible, to crush and snort the drug.  As for cooking it down to liquid form and injecting it?  Endo hasn't figured that out yet.    

The federal government has taken aim at big pharma's painkiller marketing tactics.  Purdue Pharma, makers of Oxycontin, paid a $635 million fine in 2007 in connection with a guilty plea for misleading doctors about the abuse potential of the drug.  The next year, Cephalon, makers of Actiq, paid a $425 million fine for misleading marketing.  That's more than $1 billion in fines in an $8 billion industry... and it just keeps rolling.  What do you imagine the gross margin per pill is for Opana (which does $1.16 billion in annual sales)?

Finally, the FDA has proven to be a misguided and inconsistent ally in the fight against prescription drug misuse and abuse.  In the midst of an epidemic, they've not hesitated to add new opioids to the market (Zoyhdro and Hysingla come to mind).  They've also focused a lot of energy on "abuse-deterrent" formulations of extended release opioids.  While they did not grant Opana ER that distinction, I've held the view for some time that abuse-deterrence is necessary, but by itself, entirely insufficient to stem the tide of misuse and abuse of opioids.  

We have a long way to go.

Michael
On Twitter @PRIUM1

Free Speech, FDA, and Short Selling

I was entertained by an article this morning on workcompcentral regarding a drug manufacturer that is suing the FDA for infringing its right to free speech.  Amarin Pharma is upset that it cannot market its fish oil drug for "off-label" uses.  You can't make this stuff up.

A quick refresher (admittedly oversimplified) on the FDA's role as a regulatory body:  A drug manufacturer discovers (or purchases) a chemical entity which they believe has a therapeutic benefit for a particular disease state.  The drug manufacturer runs studies (typically across three phases) to test both the safety and efficacy of the chemical entity for that specified disease state.  Application is made to the FDA and the FDA evaluates all of the evidence.  If the application is approved, the FDA mandates that the drug only be marketed to doctors, patients, and other stakeholders for the specified disease state on which the research and development were conducted.  The FDA does this through the drug's "label" and any marketing for uses not contained on the label (or "off-label" uses) is a violation of federal law.  

So... if you come up with a drug to manage, say, prostate enlargement... and you conduct years worth of studies on the safety and efficacy of the drug for prostate enlargement... and it turns out, after all that, the drug is also causing men with male pattern baldness to grow new hair... you can't simply change your mind and market the drug for male pattern baldness instead of prostate enlargement.  You have to go back through the phase I, II, and III development process (or, at least, recast the data drawn from those studies) to create sufficient evidence for FDA approval to allow you to market the drug for that purpose.  (This actually happened, by the way.  Ever heard of Propecia?)

The argument being made by Amarin is a great example of unintentional comedy: they feel their free speech rights are being infringed because the off-label uses which they'd like to communicate are "truthful" and "non-misleading."  They should be able to market fish oil for off-label usage... because it really works... trust them.

This comes down to a fundamental question of regulatory oversight:  "Truthful" and "non-misleading" according to whom?  

This is why the FDA exists.  I have been a vociferous critic of the agency for its lack of consistency, its approval of questionable medications, and its lack of emphasis on the public health effects of its approval process.  But I have never questioned the necessity of a third party regulatory agency intended to protect Americans from potentially delusional and dangerous claims of safety and efficacy from the pharmaceutical industry.

By the way, Amarin is publicly traded (NASDAQ: AMRN.)  My investment advice is worth exactly what you're paying for it... but I might think about a short position on any company willing to waste money on this kind of frivolous lawsuit.

Michael