The slippery slope of off-label promotion

When it comes to drugs, there is a huge gulf between off-label prescription and off-label promotion. One is legal, the other is not. For the most part, medical imaging doesn't get involved in either, although there are exceptions. Contrast-enhanced MR angiography is one.

The first MR contrast agents were approved two decades ago, specifically to enhance cancer tumors of the central nervous system. Since then, their use has evolved beyond that narrow indication. In the absence of a commercially available blood pool contrast agent, radiologists began using CNS products to enhance MR angiograms. Their use has become so widespread, and so accepted, that third-party payers reimburse for these applications and equipment manufacturers optimize scanners to perform them.

It has even become the subject of CME courses, such as one advertised on the MedScape site that explains the "tricks of the trade" behind contrast-enhanced MRA, detailing coil selection, bolus timing, the importance of delayed T1-weighted 3D gradient-echo MRI, and postprocessing techniques.

Few would argue that this off-label usage has been anything but positive. Belying the gray area in which it resides is the legal disclaimer that typically accompanies off-label advice. On the MedScape site, for instance, it says that CME materials may discuss off-label uses of approved products and that a "qualified healthcare professional should be consulted." It is a lesson recently exemplified by GE Healthcare.

As part of its 510(k) submission to the FDA for its CT750 HD (high-definition) scanner, GE sought to do more than prove the usual "substantial equivalence" of this scanner to previously marketed products. The company made specific claims, such as spatial resolution of 230 microns as well as contrast improvement of 33% in the body and 47% in the heart. When the FDA cleared the product last spring, it cleared the use of those claims as part of its marketing campaign.

In the runup to the commercial launch of the new CT scanner, a GE executive told me that the company "will set the pace for marketing in the future" by making only claims that are reviewed and cleared by the FDA.

The dependence of established modalities, such as MR, CT, x-ray, nuclear medicine, and even ultrasound, on imaging agents for certain applications underscores the importance of having FDA reviewers sign off on claims involving these agents. The expected growth in molecular imaging and its reliance on smart agents could make it all the more important in the future.

But the path to this future will be anything but easy. The makers of imaging devices that use drugs to enhance or produce images must be careful not to slip into the bad habits of pharma, habits detailed last month in an article in PLoS Medicine by Dr. Adriane Fugh-Berman, an associate professor of physiology and biophysics at Georgetown University Medical Center, and Dr. Douglas Melnick, a preventive medicine physician in the Los Angeles County Department of Public Health. They argue that companies may be tempted to subvert off-label prescription because such usage means "larger revenues from larger user populations, especially for products with narrow indications."

"People think we are against off-label uses of drugs," said Fugh-Berman, who also serves as principal investigator of PharmedOut, a project to educate physicians about the influence of pharmaceutical companies. "But the problem we have is with corporate promotion of off-label for something not proven to have more benefit than risk."

In their article, she and Melnick document ways that drug companies have sought off-label use. In the "decoy indication," the developer of a drug with several possible applications seeks a very narrow indication to get the product on the market. The corporate hope is that information about other possible uses, achieved through research, will convince doctors to use the drug off-label.

Toward that end, companies may encourage off-label promotion, for example, through publication of case studies, presentation of posters at scientific meetings, and word-of-mouth or buzz marketing by influential academic physicians.

Companies select these investigators on the basis of views that reflect their own marketing messages, Fugh-Berman said. They are groomed as opinion leaders, provided with editorial assistance to produce articles, and flown around the country or world to give speeches at medical conferences.

"These physicians will say, ‘Yes, the company pays for me to give speeches, but they don't tell me what to say,'" Fugh-Berman said. "That may be true, but the company wouldn't fly people around to say things not in their interests."

She described this type of off-label campaign as "invisible promotion," because doctors can say anything they want and are not subject to the kinds of regulation placed on companies. In this way, companies launder their marketing messages through physicians, many of whom may be unaware that "they are vectors of marketing messages," she said.

Sometimes off-label promotion even crosses the line between legal and illegal. Drug representatives may overtly promote off-label uses, Fugh-Berman said. In their article, she and Melnick quote a pharmaceutical industry attorney from an article in Medical Marketing and Media: "Before engaging in off-label promotion, companies should ascertain the risk profile, safety, efficacy, and potential commercial benefits of the use -- without committing that last bit to print." In other words, illegal promotion may be judged cost-effective, if potential profits trump potential fines.

Fugh-Berman and Melnick argue that states and other jurisdictions have a duty to protect the health of the public. Allowing off-label promotion of drugs for unproven benefits can increase industry profits at the expense of public health.

How off-label promotion is defined, however, remains to be seen. The PLoS article signals the start of an era of increased scrutiny in which claims made by companies for medical products are put to the test, not only in practice but in the regulatory arena.

GE saw this era coming already months ago, and it bears close attention by all who market medical products.