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

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