Prescription of drugs for unapproved uses : what public policy to control it?, par Marc Rodwin

Marc Rodwin – copyright Christophe Delory

Marc Rodwin, titulaire de la Chaire en cancérologie intégrée IMéRA-SIRIC, est professeur de droit à l’université de Suffolk à Boston, et chercheur au sein du Edmond J. Safra Center for Ethics de l’université d’Harvard. Ses recherches portent sur le droit de la santé, les questions pharmaceutiques et leur politique. Professeur invité dans de nombreuses structures, il a également travaillé pour des commissions gouvernementales et a participé à des comités consultatifs, dont la Food and Drug Administration. Il a notamment publié « Les conflits d’intérêts en médecine : quel avenir pour la santé ? France, États-Unis, Japon» aux presses de L’EHESP (2014).

Article paru dans Fellows#37 “Industrie pharmaceutique : soigner ou vendre”, revue du RFIEA.

It is a widespread practice in the U.S.A. and Europe for pharmaceutical firms to market drugs off-label, that is, for purposes that the authority granting marketing approval has not found to be safe and effective. Sometimes they do so explicitly and illegally because ­the expected revenue exceeds potential penalties, while other times they employ marketing strategies that fail to take precautions to avoid off-label sales. In recent years, U.S. pharmaceutical firm settlement agreements for illegal off-label promotion have included Johnson and Johnson ($2.2 billion for off-label promotion of Risperdal, Invega and Natrecor); Pfizer ($2.3 billion for off-label promotion of Bextra); and GlaxoSmith Kline ($3 billion for off-label promotion of Avandia).  However, the problem is more complex than it appears.

In the United States and many European countries, physicians may prescribe drugs off-label: for a different therapeutic purpose, using a different dose or for a different category of patients than that on which the drug was tested to obtain marketing authorization. Physicians—with the manufacturer’s encouragement—prescribe off-label much more frequently than is justifiable and risk harming their patients. Off-label prescribing makes clinical sense if reasonable evidence suggests that the benefit will outweigh the risks, that declining to treat the condition poses even greater dangers than the off-label prescription does, and that there is no adequate alternative therapy. In fact, 70 percent of off-label uses lack significant scientific support. Physicians value the right to prescribe off-label, but it is pharmaceutical firms’ incentive to increase sales that drives this practice. More sales means increased profits, so manufacturers have financial incentives to promote off-label use.

In principle, France discourages off-label promotion through contracts that the Comité économique des produits de santé (CEPS) signs with pharmaceutical firms. Those negotiated agreements set reimbursement prices for the national health insurance system and also limit the volume of sales to the number of patients who have the medical indication for which the CEPS authorized reimbursement. Those contracts require that manufacturers pay rebates when their total sales exceed the authorized volume of sales . However, these rebates only reduce the manufacture’s rate of return; it is still profitable to sell products off-label; the rebate requirement has not prevented significant off-label sales. In the U.S., the problem is even worse because there is no regulatory authority that can set prices and reduce reimbursement when sales volumes indicates sales clearly are off-label.  Moreover, the First Amendment to the Constitution protects certain off-label promotion as commercial free speech.

Today, public policy does not manage off-label prescribing well, and that compromises good medical practice and the ability of the Food & Drug Administration (FDA) / European Medicines Agency (EMA) ability to protect consumers from unsafe and ineffective drugs. Yet typical reform proposals, such as stronger sanctions for illegal promotion, don’t eliminate the problem.

How public policy should manage the off-label drug issue ?

Public policy has three leverages: tracking off-label prescribing, removing economic incentives to sell off-label, evaluating the safety and effectiveness of off-label uses.

To track off-label prescribing, physicians should be required to indicate on each prescription the purpose for which the drug is prescribed, recording the patient’s principal diagnostic and symptom codes, gender and age. Third-party payers should condition physician reimbursement on reporting this information. This prescribing data would identify the therapeutic goals of off-label uses and the affected populations. Researchers could then obtain anonymized data from treating physicians to evaluate the safety and effectiveness of these uses. The data also could signal when the FDA/ EMA should investigate possible illegal off-label promotion.

Prohibitions on illegal off-label marketing alone are ineffective, because off-label sales are in the drug firms’ economic interests; monitoring compliance is difficult; and fines or rebates are too small given that off-label sales can generate billions of dollars in profits. Far more effective would be to change the economic incentives through new payment rules. Manufacturers would cease promoting and would even discourage off-label prescribing if it increased their costs but not their revenue. The FDA/ EMA grants market exclusivity for new drugs—with resulting monopoly profits—only for approved uses. Allowing firms to earn monopoly profits from off-label prescribing undermines the whole point of FDA/ EMA regulation. Therefore, health insurers should reimburse drug firms only for the marginal cost of manufacturing a drug when it is prescribed for off-label uses. Implementing this policy would require verifying the manufacturers’ production costs. The U.S. Medicare program, which requires hospitals to report cost data to determine reimbursement rates, provides a working model.

Yet when manufacturers sell drugs in bulk to wholesalers, it is uncertain how much will be prescribed off-label. Therefore, it will be necessary to adjust their compensation after the prescription is filled in order to reduce their income from off-label sale. The legislature should require manufacturers to deposit their excess payments into a government-supervised fund dedicated to the evaluation of off-label drug use and drug safety.

When a drug’s off-label sales exceed a significant threshold, it makes sense to evaluate the safety and efficacy of these unapproved uses. Requiring that manufacturers finance these evaluations is a logical extension of their obligations to monitor the safety of drugs they sell. Money generated from the proposed claw-back of off-label sales revenue could fund the evaluation. Until that reform is adopted, the evaluation should be financed by taxing manufacturers. A national health authority should select and oversee independent researchers to conduct these evaluations.

Economic incentives for firms to sell drugs off-label without controls on physician prescribing are a recipe—nay, a prescription—for trouble. To promote sound medical practice and public health the legislature should remove financial incentives to sell off-label, track off-label prescribing, and evaluate the safety and efficacy of off-label prescriptions.

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