The Hill: How the FDA can settle the off-label use vs. off-label promotion conflict by Joseph Gulfo

Both the U.S. Court of Appeals for the Second Circuit and district courts have ruled against the Food and Drug Administration (FDA) in two widely publicized cases involving the agency’s enforcement of misbranding policies to prohibit off-label drug promotion, the intention (encouragement of physicians and advertising) of a drug manufacturer to have its drug used in a manner that is not explicitly supported in the FDA-approved labeling.

The FDA attempted to exercise its misbranding provisions as a means of prohibiting drug representative Alfred Caronia from promoting Xyrem for insomnia and fibromyalgia, and against Amarin Pharmaceuticals from promoting Vascepa for persistently high triglyceride levels. The courts ruled that the First Amendment protects drug manufacturers provided that their communications are truthful and not misleading, whether or not the use has been approved by the FDA.The Amarin decision states “[w]here the speech at issue consists of truthful and non-misleading speech promoting the off-label use of an FDA approved drug, such speech, under Caronia, cannot be the act upon which an action for misbranding is based.” Several have argued that these decisions have the potential to undermine the Federal Food, Drug, and Cosmetic Act’s (FDCA) requirement that drugs must be proven safe and effective.

How the FDA will respond to these cases is unknown. On Sept. 8, 2015, citing the Amarin decision, Pacira Pharmaceuticals sought a court order to prevent the FDA from blocking the promotion of its post-surgical pain product for more types of surgeries than the FDA-approved label. Will any statement about off-label uses be acceptable, thereby undermining the safety and effectiveness standard for drug approvals? Or will the FDA simply prohibit off-label use, itself, to end the conflict? Then, of course, the lawfulness of off-label promotion would be irrelevant.

According to the FDA, good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgement. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well-informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.

Off-label use is not without its critics, who argue that it is not as rigorously studied as on-label uses. As such, the level of evidence is not as robust as for labeled claims, which require substantial evidence of effectiveness for FDA approval. In a 2001 study to define prescribing patterns by diagnosis for 160 commonly prescribed drugs, 73 percent of off-label drug mentions had little or no scientific support. One of the most unfortunate outcomes associated with off-label use involved the fen-phen diet drugs, which were prescribed in combination for long-term use contrary to their labels.

However, off-label use is firmly entrenched in medical practice, and very important to doctors and patients:

1. In the same 2001 study cited above, there were an estimated 150 million off-label mentions, which represented 21 percent of the overall use of 160 medications. Off-label use was most common among cardiac medications (46 percent, excluding antihyperlipidemic and antihypertensive agents) and anticonvulsants (46 percent).

2. A 2008 study found that eight out of 10 cancer doctors surveyed had prescribed drugs off-label. Use of the most commonly prescribed anticancer drugs (chemotherapies) that were patent-protected and administered intravenously to patients in 2010 was examined: on-label use amounted to 70 percent and off-label use amounted to 30 percent — $2.5 billion of the total $12 billion in spending was for uses that were neither approved by the FDA nor supported by the National Comprehensive Care Network (NCCN). The National Cancer Institute (NCI) has stated that “Frequently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs.”

3. Off-label treatments were ordered for 96 percent of all pediatric patients, and 100 percent of patients ages 13 to 17, in the intensive care unit of Primary Children’s Medical Center (PCMC) in Salt Lake City from October 2002 to February 2003.

4. A 2011 study of medication orders for 414 patients in 37 intensive care units across nation showed that more than 35 percent were for an off-label purpose and that 97 percent of patients received at least one off-label medication.

For doctors, one of the biggest problems related to widespread off-label use is the lack of information about how to best use the drug other than for what it was approved. The drug label is one of the most reliable and easy-to-find sources of information available to health professionals, caregivers and patients. But the label can only contain the information that’s been approved by the FDA, and it does not cover off-label uses. The medical literature reports clinical trials, including those that are not part of the FDA approval process. This is the main source of off-label use information. Some professional health organizations develop treatment guidelines that may offer options including off-label drug uses.

Clearly, the FDA needs to do something. Rather than continuing to maintain that it alone is the sole arbiter of what scientific evidence is true based on its substantial evidence standard, in our fifth “Medical Innovation Impact Index (MI3) Alert,” we encourage the FDA to enact a policy for off-label uses based on the Federal Trade Commission’s (FTC) “competent and reliable scientific evidence” approach.

We believe that this is an appropriate middle ground. Once a drug receives FDA approval, the ability for it to be safely administered to patients has been established, and substantial evidence of effectiveness has been determined for the indication contained in the label. Off-label use, especially in the context of the existence of clinical studies or clinical experience for the off-label use, is rational. Applying an FTC-like standard means that the advertiser must possess at least the level of substantiation expressly or impliedly claimed in the advertisement: “Tests prove …, “Doctors recommend …,” “Studies show … ” The level of substantiation depends on the nature of what is being claimed. This is very rational, and balanced, especially for a product that has already undergone FDA scrutiny and been formally approved for at least one claim.

We support a model based on the off-label use of the drug Vascepa, for which Amarin followed FDA policies on the dissemination of reprints and other medical communications (outside of the package insert):

1. A statement that the use has not been approved by the FDA.

2. If the FDA has rejected an application for approval of the use, a summary of the basis of the rejection. (This criteria was mandated by the court.)

3. A statement/summary about ongoing studies with the drug in the off-label use.

4. Reprints of peer-reviewed studies of the drug in the off-label use and a summary of the results of these studies.

5. A statement about the eligibility of the use of the drug for reimbursement.

6. Dosing information based on peer-reviewed papers and protocols of ongoing studies. (We have added this criteria in order to assist physicians who are interested in prescribing the drug off-label).

We believe this to be a practical middle-of-the-road proposal that limits the disseminated information to that which is truthful and non-misleading. It is consistent with the concept of “competent and reliable scientific evidence” while providing a warning to doctors that the FDA’s substantial evidentiary standard of effectiveness has not (yet) been met. It also provides critical information that doctors need to administer the off-label use appropriately to ensure an added measure of safety.

Gulfo is the executive director of the Rothman Institute of Innovation and Entrepreneurship at Fairleigh Dickinson University and author of Innovation Breakdown: How the FDA and Wall Street Cripple Medical Advances (Post Hill Press). He has more than 25 years of experience in the biopharmaceutical and medical-device industries and is the former CEO of Mela Sciences. Follow him on Twitter @josephgulfo.

This article originally appeared on on October 5, 2015.

Posted on October 5, 2015 in Dr. Joseph Gulfo, Opinion

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