Promoting Drugs for Unapproved Uses

Author: James C. McAllister III, MS, FASHP


Mr. McAllister is a health-systems consultant based in Chapel Hill, North Carolina.


In January 2009, the FDA issued Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices (FDA.2008.D.0053). The 1997 statute and the implementing regulations for the industry promoting unapproved uses ceased to be effective in September 2006, so new guidelines were issued. After first review, I thought the new recommendations were significantly less stringent and had opened doors for abuse by the industry. A more careful review, however, revealed "nonbinding recommendations" that could maintain the status quo if we hold the manufacturers accountable for compliance.

The use of drugs for unapproved indications has been an issue that has frequently been discussed and sometimes caused great angst in hospitals and health systems. The predominant conundrum has been genuine interest in achieving optimal drug therapy outcomes while ensuring safety and minimizing cost.

The issue is complicated, if not created, by the drug approval process itself. Pharmaceutical manufacturers usually race to drug approval to maximize patent protection as well as generate revenue. To achieve FDA approval as rapidly as possible, the company usually seeks approved indications for use with data that are as robust and least controversial as possible. Thus, although there may be indications that look promising, study data to support this use may be incomplete or questionable at some level. Manufacturers then must decide whether to seek approval for limited indications to bring the product to market as soon as possible or delay overall approval to expand the number of approved indications.

Following the initial approval of the new drug, the manufacturer must then decide whether the investment required in conducting additional trials to achieve approval for new indications will result in an acceptable financial return. As you might imagine, a myriad of factors, including the availability of competitive products and duration of patent protection, and the availability of resources that could be available for other drugs under development are considered, but the dominant factor will always be net profit.

Prior to approval, clinical trials generate a great deal of interest among research physicians who give presentations and publish papers, the results of which generate interest in using a drug, including uses outside those indications that are eventually approved by the FDA. Clinical trials using the drug often continue following FDA approval and sometimes result in reliable data supporting other indications. Some other "trial" results also may be published but without the scientific rigor commonly used in studies submitted in the approval process.

Individual prescribers are not bound by the FDA-approved indications and thus prescribe new drugs for unapproved indications based on their professional judgment. Pharmacy and Therapeutic Committees have struggled to ensure that such uses are substantiated by as much reliable data as possible and to minimize the influence of manufacturers' representatives and any promotional material that were not substantiated by well-controlled clinical trials.

The 1997 FDA Modernization Act began the establishment of conditions under which manufacturers could distribute materials discussing unapproved indications. In 2000, following an Appeals Court decision, the FDA published a notice clarifying a "safe harbor" for manufacturers regarding distributing materials about a drug's unapproved uses. As a result, companies halted their sales force from discussing unapproved uses at all and frequently created a cadre of providers—often pharmacists and dubbed "medical science liaisons" whose compensation was not tied to sales and who were allowed to discuss unapproved uses with providers. From my perspective, this strategy had positive results in terms of limiting inappropriate influence of manufacturers on prescribers who might consider inappropriate uses.

Limiting inappropriate influence of manufacturers over unapproved uses will require vigilance on our part. We must become familiar with the new recommendations and report excesses to the FDA. I think we are up to it. What do you think?