OFF LABEL, IN BOUNDS

OFF LABEL, IN BOUNDS

Liebman, Milton

An estimated 25% of drugs are legally prescribed for off-label uses – a significant income for pharma companies. But the regulatory environment surrounding promotion of off-label indications is complex and treacherous. By Milton Liebman.

With a slowing flow from new-drug pipelines and rapidly expiring patent protection on current bestsellers, pharmaceutical companies are under pressure to get the most out of what their drugs have to offer. And that means ensuring that the already increasingly significant proportion of sales from off-label prescriptions is maintained.

According to recent analysis from Knight Ridder, the number of prescriptions written for off-label uses has nearly doubled in the past five years, accounting for almost a quarter of prescriptions, and up to 90% of scripts for certain drugs. The report also estimates that at least 8,000 people became seriously ill last year after taking frequently prescribed drugs for off-label purposes.

But while it is perfectly legal for a doctor to prescribe a drug for any indication, the pathway to off- label drug promotion is lined with government regulation and potential prosecution. It is vital for management to understand the impact that Food & Drug Administration regulations can have on the company. The FDA has initiated enforcement actions against companies for promoting unapproved uses.

Off-label “promotion” is a freely used term, but by FDA definition it means any communication of favorable information by or for a pharmaceutical company about use of a product that is not covered by labeling.

Off-label drug “information” or “education” is specifically the controlled distribution of independently published information about an additional use of an approved product. The FDA has not taken action against companies for distributing peer- reviewed studies of off-label drug use – done right, that’s legal.

The regulatory minefield

However, companies must walk the tightrope between education and promotion to avoid potential punitive action. In addition to meeting complex guidelines from FDA, regulations for educating physicians on drug use are influenced by the Food and Drug Administration Modernization Act (FDAMA), compliance issued by the Office of the Inspector General (OIG) of Health and Human Services, code of ethics from the American Medical Association (AMA) and guidelines for physician/ industry relations from PhRMA.

Every pharmaceutical company has its own view of how well it meets FDA policy. But to avoid tripping over the maze of existing regulations, manufacturers must review, understand, and adopt those policy guidelines for their own use. These rules should form the basis for a company-wide set of guidelines that determines how sales, marketing, public information, and other departments will legally implement an off-label communications effort.

How to handle that legal and regulatory environment was discussed at the Center for Business Intelligence’s (CBI) 5th annual conference on Disseminating Off-Label Information, held in Washington, D.C., in late October. Kathleen Knight, vice president and deputy general counsel for Alcon Laboratories, addressed the audience on the responsibilities of companies.

“Management must be committed to the program and be serious about enforcing the guidelines,” said Knight, pointing out that marketing and sales management participate in drafting the guidelines, and sign off on them. “Guidelines should take the steps that would encourage compliance, while minimizing damage to a company’s own sales and marketing efforts.”

A compliance committee should include legal, research, regulatory department participation in addition to, of course, sales and marketing.

“We send out a very clear message,” Knight added. “Sales representatives can only disseminate data on off-label use when the data itself has been approved by a core group at headquarters.”

FDA scrutiny shifts to detailing

Viewing PDA’s approach to industry today, John Kamp of the Washington law firm Wiley, Rein & Fielding believes the focus is now moving to detailing. In drug promotion, detailing is the biggest area of expenditure. Kamp feels that the controversy about DTC advertising has passed its peak. The FDA has its own studies to show positive results from consumer promotion. “Detailing is where the money is,” says Kamp.

Alcon’s Knight has her own technique for motivating compliance by the sales force, at least on a short-term basis: She instills fear and guilt.

Knight explains to field representatives the consequences of overly aggressive acts. These include a warning letter from FDA that may be used in a court case against the company; prosecution of the company and employees, leading to massive fines; and potential product liability claims, among other offenses.

Some of the new legal risks that companies may face were explained at the conference by William W. Vodra, partner in the Washington law firm Arnold & Porter. For example, Medicaid will not reimburse for a submitted claim for off-label use of a drug, unless that indication is listed in a compendium. (Three such publications are recognized by Medicaid: Drugdex Information Service, AHFS Drug Information and The U.S. Pharmacopeia.)

The company that bills and gets paid for off-label use, or urges others to do so, becomes subject to prosecution under the False Claims Act. The Neurontin case (U.S. Franklin vs. Parke-Davis), now in the courts, raises the possibility of substantial liability for fraudulent off-label promotion. Franklin claims that 50 percent of the prescriptions written for Neurontin and paid for by Medicaid were for off-label indications. Physicians can use an PDA-approved drug for any indication they see fit. But the company is on soft legal ground if it promotes an off-label use which is then submitted to the government for payment.

Liability insurance is based on the regulated conduct of pharmaceutical companies concerning a particular drug. It excludes coverage for “foreseeable” and “intended” events covered in labeling, such as the described side effects. The company takes on the known possibility of risk and warns the doctor of potential negative reactions If sued for a foreseeable event, the company relies on the “learned intermediary” defense, whereby the doctor stands between the patient and the drug company.

Marketing for an off-label use of the drug, however, may create “foreseeable” events not covered by insurance, putting the company at greater risk. Courts have found a legal basis for liability for off-label promotion, particularly when it is false or lacks substantiation.

Distribution requirements

There are no official instructions on what materials may be distributed and how they must be prepared in order to pass muster as an education rather than promotion. But Jack Angel, executive director of the Coalition for Healthcare Communications, reviewed some of the requirements, which appear in detail in a position statement by the Coalition:

* The company holding an approved drug or device “may distribute in any manner to any healthcare professional” textbooks, compendia, peer-reviewed journal article reprints “that includes off-label information about a drug or a device.”

* Companies distributing texts or reprints should include the approved labeling, and must disclose in writing or by sticker that they mention use of a drug or device not approved by FDA. Companies may distribute these printed materials to healthcare professionals but should not promote the off-label uses.

* The material must not be false or misleading. Any financial arrangements among researchers, authors, publishers and companies must be disclosed. Promotional or product material should not be appended.

* Specifically the journal reprints must be unabridged, independently produced articles that have appeared in peer-reviewed journals. Angel pointed out that peer review assures balance and objectivity, independence and scientific rigor. Financial arrangements and conflicts of interest must be revealed.

* Medical texts have somewhat different requirements. The text must be from a bona fide publisher, independent of the company distributing the book. Content should not have been prepared, reviewed or edited by a representative of a drug or device firm.

* Individual, but complete, chapters may be distributed separately. The texts should be generally available for sale at bookstores and not distributed primarily a drug or device company.

Jack Angel says that “these criteria respond to the interests of all parties by allowing free scientific exchange while providing responsible protection for the integrity of the material.”

Copyright CPS Communications Dec 2003

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