Friday, December 7, 2007

Off-Label: What Are the Issues?

The Prescription Project blog has several links to recent news coverage of the FDA's proposed rules change that would allow companies to market off-label uses of drugs in very limited ways (Dec. 7 posting):

What I want to do here is to lay out some concerns about the entire "off-label" issue. My worries are that we have been a bit lazy in attacking Pharma's sleazy marketing behavior. Given our natural outrage over the real violations of scientific truth and integrity, we can easily fall into the trap of deciding that anything that places any limits at all on Pharma marketing is a good thing, independent of the actual merits of the proposal. I am afraid that the "off-label" debate has done us the disservice of creating a dichotomy that is not valid--that "on-label"/"off-label" somehow corresponds to good/bad or rational/irrational uses of drugs.

True confession time--in 26 years as a family physician, I probably prescribed a lot of drugs off label. Even truer confession--when I prescribed drugs off label, a good deal of the time, I had no idea that was what I was doing. How could this be?

The basic fact is--how does a practitioner know what is on-label? You have to read the label. How do you do that? The easiest way is to look up the drug in an industry source such as the infamous PDR. There, the label hits you square in the face. Indeed, everything in the PDR is the label and only the label. For that reason we try to teach our med students and residents not to use the PDR as their primary reference source on drugs.

So instead of using the PDR, I look up the treatment for a given disease in a reference that appears to me to be reasonably evidence-based and non-commercial. Now, in so doing, that source might mention which uses of the drug are listed on the label. But my main concern is not that, it is what drug is good for that disease. So I could easily miss noticing the details about the labelling.

All of the above might simply mean that I was a rotten doc. But the following considerations clearly show that "off-label" is hardly synonymous with bad or suspicious prescribing:

  1. The great majority of pediatric prescribing is off-label as many very useful drugs have never gotten formal FDA approval for use in kids.
  2. When an old generic drug is found to be useful for a new disease--such as hydralazine and isosorbide in combo for heart failure, especially in African-Americans--its use will certainly be off-label, as the generic manufacturers will never pay to do the new clinical trials needed to expand the FDA labeling.
  3. Like everything else in Pharma, the decision as to what studies to fund or not by the industry is a marketing decision, not a science decision. The fact that a given indication for the drug was not researched, or that supporting studies were not submitted to the FDA, may have precious little to do with whether that drug is any good or not.
  4. And, finally, we all know examples where the FDA labeling process has simply not kept up with what reasonable medical judgment is aware of. The makers of Neurontin were quite legitimately taken to the woodshed for their off-label marketing of the drug for numerous psychiatric disorders, for which it is probably no good. At the same time, the use of Neurontin as adjunctive treatment of chronic neuropathic pain was probably a reasonable choice, even though equally off-label.
Is it a good or bad idea to allow drug companies to market off-label uses? Knowing how the industry can drive a Mack truck through any tiny opening we allow, maybe the best choice is to keep the strictest limits in place. But I cringe when people get sloppy about "off-label" and suggest that the term has some real, medical (as opposed to regulatory and bureaucratic) significance.


Howard Brody said...

The following comment came to me by e-mail from Eric Jackson, PharmD:

I’ve been reading your blogs (via a link from the Prescription Project) for the past several months. One of the latest addressed the issue of “off label” uses of drugs. I tried to reply (make a comment) to that posting, but stopped because of technical problems. What I wanted to say was that Pfizer uses both sides of the “off label” coin. For many years they unethically promoted (via paid speakers) the use of gabapentin for many off label uses while they held the exclusive rights to Neurontin. As soon as it became generically available they came out with the structurally related pregabalin (Lyrica). In a meeting with a Pfizer rep with several of our family medicine residents earlier this week, we were detailed on Lyrica’s recent FDA approval for fibromyalgia. The rep stressed over and over again that Lyrica was the only drug approved by the FDA for this condition. In a discussion with the residents after the representative left (what I call a debriefing and critique of what just happened) one of the residents indicated that he would now use Lyrica exclusively for this condition because it was the only one shown to be effective for this disorder. I then asked him and the other residents what drug they used for treating early Lyme disease (most of Connecticut is endemic for Lyme disease). They all said in unison, “doxycycline”. I then asked them if they knew the name of the only drug approved by the FDA for this condition. After several seconds of silence I told them that Ceftin was the only drug with an approved label for Lyme disease. We then discussed the economics of seeking an FDA approval for a drug that was already generically available. So for Pfizer, off label use of Neurontin was fine, but that is not the case for gabapentin. Excuse my long windedness thank you for fighting the good fight and speaking truth to power.

Eric has graciously permitted me to post this for him, and I thank him for his comment.--HB

Anonymous said...

Many drug reps, by thier very nature, are compelled to suggest that thier promoted products are beneficial for off label uses. And they very well may be. Yet how a med is prescribed for a provider's treatment regimen should be left to the objective discretion of the provider, as off label prescribing is a frequent occurence.

I'm still in a state of shock at the suggestion of the FDA to allow drug reps to speak off label based on some constructed clinical trial provided by such a rep. The harm is clearly a possiblity, and illustrates the alliance between the FDA and the pharma industry.