Tuesday, June 10, 2014

An Off-Label Use Hot Spot Comes Up Again


Off-label use was a concept that it took some time to wrap our minds around as young drug and device lawyers.  Manufacturers undertake extensive product development and clinical trials, and they spend months, sometime years developing FDA-approved drug labeling that sets forth the products’ uses and indications.  Then physicians in their medical judgment decide to prescribe the drug in different ways or for different reasons or to different populations. 
This may seem odd to the uninitiated, but it is called the practice of medicine, and there is absolutely nothing wrong with physicians prescribing drugs off-label.  The FDA does not regulate medical practice, and if a physician decides that a drug’s benefits and risks weigh in favor of treating his or her patients in a particular way or for a particular malady, he or she is free to make that treating decision.  In fact, as our faithful readers know, off-label use is sometimes medically necessary, and the standard of care sometimes requires that doctors prescribe drug in ways that do not appear in the labeling. 
Off-label use has found support lately in cases involving the controversial topic of medication abortion.  Several states have attempted to ban or limit medication abortions, including by purporting to prohibit off-label use of prescription drugs used in the process.  We have previously written on such laws here, and another such state is Arizona, which passed a law requiring that “any medication, drug or other substance used to induce an abortion is administered in compliance with the protocol that is authorized by the [FDA] and that is outlined in the final printing labeling for that medication drug or substance.”  Planned Parenthood Arizona, Inc. v. Humble, No. 14-15624, 2014 U.S. App. LEXIS 10260, at **11-12 (9th Cir. June 3, 2014).
In other words, the Arizona law prohibited off-label use, which provoked a legal challenge by Planned Parenthood.  In 2000, the FDA approved the prescription drug mifepristone for use in medication abortions, and under the “on-label” regimen, the drug is administered in a certain dose in combination with another drug, misoprostol.  Id. at **3-4.  Studies, however, have recommended a different regimen—the “evidence-based” regimen—which deviates from mifepristone’s drug labeling, but is now used by “virtually all” medical professionals who provide abortions.  Id. at *4.  According to the evidence presented in the district court, the evidence-based regimen is more effective and presents fewer risks than both the on-label regimen and surgical options, which has made it the standard of care.  Id. at **8-9.
Because Arizona's only claimed state interest was to protect women’s health, the Ninth Circuit enjoined enforcement of the law as an undue burden, but here at the Drug and Device Law Blog we are interested mainly in what the court had to say about drug approval and off-label use.  The court first noted that the FDA approves drugs for marketing and approves labeling providing guidance for use.  The FDA does not, however, authorize drug “protocols,” nor does it set forth binding drug uses.  The court explained as follows: 

According to plaintiffs’ expert . . . , who participated as an FDA official in the approval process for mifepristone, the FDA “does not authorize protocols for drugs . . . .  Rather, approval of [a drug] allows the drug sponsor to advertise and promote the drug for a particular use.”  The drug’s manufacturer also submits a proposed label for approval.  The label “provides physicians with guidance about how to use a drug in accordance with how the drug sponsor requested and received FDA approval for its use.”  The label “does not impose binding obligations on physicians.”

Id. at *9.  That last part captures the essence of the point.  The FDA approves drugs for marketing, but physicians are the gatekeepers, and the labeling neither binds the doctor nor prohibits uses that are outside the four corners.
And to our point that off-label use is sometimes medically necessary, we did not come up with that on our own.  As the court explained further,

According to [plaintiff’s expert], the FDA “neither prohibit[s] nor discourage[s]” off-label use of FDA-approved drugs.  In fact, “the FDA has repeatedly acknowledged that off-label use is common and is sometimes required by good medical practice.”

Id. at *10.  In support, the court quoted extensively from a 1982 FDA Bulletin, where the FDA itself said flat out that once a product has been approved for marketing, “a physician can prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling.”  Id. at *10 (quoting 12 FDA Drug Bulletin 5 (1982)).  As the Bulletin also said,

“[U]nlabeled” uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.  [¶]  Valid new uses for drugs already on the market are often . . . confirmed by well-planning and executed clinical investigations. . . . 

Id.  Something like this apparently has occurred with mifepristone, which is approved “on label” for medication abortion, but for which an “evidence based” alternative regimen has emerged.  We avoid politics, and we are well aware that the topic of abortion involves strongly held convictions.  But it seems that states attempting to regulate medical care by prohibiting “off label” use in the name of promoting health are setting a dangerous precedent.  Prescription drug uses outside the approved labeling may or may not be the best courses of treatment, but there is no telling that merely from calling the treatment “off label.” 

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