Tracy E. Macaulay, Aaron M. Cook, Joseph L. Fink, III, Robert P. Rapp and William R. Vincent, III

TRACY E. MACAULAY, PHARM.D., BCPS, is Cardiology Clinical Pharmacy Specialist, Pharmacy Services, UK HealthCare, and Adjunct Assistant Professor, Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky (UK), Lexington. AARON M. COOK, PHARM.D., BCPS, is Neurosurgery/Critical Care Clinical Pharmacy Specialist, Pharmacy Services, UK HealthCare, and Adjunct Assistant Professor, Department of Pharmacy Practice and Science, College of Pharmacy, UK. JOSEPH L. FINK III, BS.PHARM., J.D., is Professor, Colleges of Pharmacy and Public Health, UK. ROBERT P. RAPP, PHARM.D., FCCP, is Professor of Pharmacy and Surgery, Colleges of Pharmacy and Medicine, UK. WILLIAM R. VINCENT III, PHARM.D., is Assistant Professor, Division of Pharmacy Practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, and Clinical Pharmacy Educator, Critical Care, Brooklyn Hospital Center, Brooklyn.

Address correspondence to Dr. Macaulay at Pharmacy Services, UK HealthCare, 800 Rose Street, Room H110, Lexington, KY 40536-0293 ( ).


In the United States, up to 80% of prescription drugs are prescribed for indications not approved by the Food and Drug Administration (FDA).1 Unlabeled use is often the mainstay of therapy in patient populations for whom less conclusive evidence is available, such as pediatric,2 oncology,3 and critical care4 patients, or for whom substantial evidence exists but manufacturers do not pursue FDA approval for new labeled indications. Educating health care providers about unlabeled uses of medications is the subject of a recent guidance for industry5 issued by FDA, which suggests that representatives of drug manufacturers should be permitted to distribute information about unlabeled uses of their company’s products to the prescribers they serve.

Although the guidance only provides recommendations and does not establish legal boundaries, it does provide FDA’s current perspective on the role of representatives of the pharmaceutical industry as educators of health care providers. FDA recognizes that off-label treatment regimens may represent a standard of care and suggests procedures to ensure that references distributed to prescribers are truthful and not misleading. The guidance has sparked commentary in major medical journals by physicians and professional organizations.6,7 Overall, concerns surround the potentially biased promotion of medication use for unlabeled indications and the lack of FDA oversight.

This article provides an overview of legal considerations for the unlabeled use of medications, FDA’s guidance on good reprint practices, the pharmaceutical industry’s involvement in the education of health care professionals, and recent ethical concerns raised about publications of clinical research. It also serves as a call to action of pharmacists to be educators, particularly regarding the unlabeled use of medications. Prescribers frequently identify unlabeled uses and consult clinical pharmacists regarding complex pharmacotherapies.8 In light of the recent FDA guidance, the role of pharmacists as educators and drug information experts is of increasing importance.

Legal and regulatory framework of unlabeled use.

Given the attention FDA pays to the specific wording of the package insert as part of the premarketing approval process for a medication, why does FDA not regulate the unlabeled use of medications? The answer lies in the basic framework of the U.S. system of government. The Founding Fathers were concerned about the concentration of power in a central national government, and this concern was worked into the Constitution of the new country in the form of two provisions. The Commerce Clause gives the federal government the authority to regulate pharmaceuticals moving in interstate commerce,9 while the 10th Amendment reserves to the states the authority known as "police power."10 Police power is the authority of government to make laws related to the public health, safety, and welfare. This includes authorizing states to license health professionals and define practice, including the regulation of prescribing.11

As the state courts have struggled with sorting out legal liability when medication use causes untoward effects for the patient, they have fashioned a rule known as the "learned intermediary" doctrine.12 This approach states that physicians and other prescribers are best positioned to assess the potential benefit and risk with use of a medication in the context of what they know about a patient’s disease and other health conditions. So, when the prescriber decides to use a specific medication for a particular patient, the law looks to that professional to be accountable for that decision. This doctrine was applied in a recent Alabama case in which a physician consulted a pharmacist before prescribing a medication he had not prescribed for nearly 20 years.13,14 The pharmacist provided misinformation that led to patient injury. When the patient attempted to sue the hospital that employed the pharmacist, the court ruled that responsibility for the prescribing decision rested with the physician and that the hospital could not be held liable for the negligence of the pharmacist in making an erroneous recommendation.

The responsibility of a prescriber is expected to conform to professional practice standards. Therefore, prescribers must have knowledge of standard prescribing practices, taking into consideration comorbidities and concomitant pharmacotherapies when prescribing medications for approved or unapproved uses. For FDA-approved uses, the drug’s package insert represents the applicable standard of care in prescribing activities.

The role of the package insert in a lawsuit alleging damages based on medication use recently came before the U.S. Supreme Court.15 While full consideration of the facts of that case and the basis for the court’s decision is beyond the scope of this discussion, the court ruled that the package insert cannot be used to shield the manufacturer from liability claims filed in state courts.

After the labeling for a drug is approved, new information about the drug’s efficacy and safety may become available from clinical experience and new clinical trials. It is not unusual for unlabeled uses to become widely accepted, but it is unusual for all uses of a medication to be incorporated into the package insert. The addition of a new use into the package insert requires the manufacturer to submit a supplemental new drug application for that use. Submission of this application alone costs over $500,000 and is voluntary. Pharmaceutical companies are not required to request FDA approval for new indications as they become established. As profit-seeking businesses, it behooves major pharmaceutical manufacturers to devote their financial and investigative resources to other research once a product is approved for marketing. Lack of incentives for manufacturers to seek approval for new uses ultimately leads to the omission of potentially useful information about unapproved uses in the package insert.

Thus, in the absence of a mechanism to more frequently update the package insert to reflect current prescribing practices, prescribing for unlabeled uses has become common and accepted.16,17 Such prescribing is also legal. FDA has a long-standing policy statement about the interplay of federal and state laws in this area:

The physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patients, or may otherwise vary from the conditions for use from those approved in the package insert, without informing or obtaining the approval of the Food and Drug Administration.18


Again, the learned intermediary doctrine requires providers to be familiar with the body of evidence surrounding a medication when prescribing it for an unlabeled use.19 Physicians may learn about standard off-label prescribing practices from various sources; therefore, challenges exist to ensure a balanced approach to education and dissemination of new information about unapproved uses of medications, and pharmacists can play a role in overcoming these obstacles. FDA’s role as a mediator in the interactions between health care professionals and the pharmaceutical industry is vital to prevent tipping the scale.

Background on FDA’s guidance to industry.

Section 401 of the FDA Modernization Act describes certain conditions under which industry could disseminate medical and scientific information about unapproved uses of approved devices or drugs. As of September 30, 2006, section 401 ceased to be effective, which prompted creation of the recent FDA guidance to industry. The marketing of approved products for unapproved uses violates the Food, Drug, and Cosmetic Act. However, FDA recognizes that providing information that is truthful and not misleading about unlabeled uses may advance public health. The guidance stresses the importance of peer and editorial reviews, the discussion of reported data, the disclosure of conflicts of interest, and the prevention of undue industry influence (appendix). If manufacturers are not compliant with recommendations in this guidance and unlawfully promote unapproved uses of medical products, enforcement action may result. Despite inherent concerns about manufacturers indirectly promoting their products, FDA clearly sees a role for industry representatives as educators.

Manufacturers and their representatives as educators.

In the absence of a formal, unbiased mechanism for educating health care providers about standard prescribing practices for unlabeled medication use, the distribution of medical and scientific literature by pharmaceutical sales representatives has become a widely used means of education. Currently, the Food, Drug, and Cosmetic Act regulates manufacturers’ representatives for distribution of references related to approved uses and this regulation allows FDA to oversee the dissemination of trials which are only those included in the drug-approval process, deemed to be well-balanced, and of high quality.20 Pharmaceutical sales representatives cannot discuss unapproved uses with providers, even when such uses have undergone clinical trials whose results have been published in peer-reviewed medical journals. The recent guidance to industry suggests that promotional material should not accompany references and that recipients should instead be referred to medical or scientific officers (e.g., medical science liaisons) or other departments (e.g., drug information) for inquiries about disseminated information.5 Also, the recommendations limit interactions between health care professionals and pharmaceutical sales representatives at industry-sponsored events in an attempt to prevent the provision of biased educational programming.

Therefore, when legitimate new uses of previously marketed drugs are established through the published, peer-reviewed literature, education about new indications could be considered a public service, as the guidelines suggest.5 However, one study found that physicians who met with pharmaceutical sales representatives were more likely to prescribe brand-name products and to respond to the requests of patients for a specific therapy with a corresponding prescription for that agent.21 Therefore, this direct interaction between prescribers and pharmaceutical sales representatives may influence the prescriber’s decision-making.22 This perception is exacerbated by manufacturers’ provision of gifts to prescribers, as addressed by the recently released Pharmaceutical Research and Manufacturers of America (PhRMA) marketing code on the ethical interactions between manufacturers and health care professionals.23 Although PhRMA does not require adherence by manufacturers to the marketing code, manufacturers have adopted this strict position on noneducational items sooner than have other professional organizations.24

The FDA guidance suggests practices to ensure that disseminated materials are unbiased; however, it lacks a mechanism to hold manufacturers accountable. To mitigate this concern, FDA has proposed that it be given the authority to screen materials (e.g., peer-reviewed journal articles) and approve only those that it deems "fair." Such FDA-approved literature could then be distributed by pharmaceutical sales representatives without concerns of bias. Of course, FDA would need adequate financial support to provide this service.25 Alternatively, academic detailing by a federally funded agency has been successfully implemented in Australia and Canada and is being discussed in the United States.26,27 Under the Independent Drug Education and Outreach Act of 2008, unbiased educators, such as pharmacists, would visit prescribers and distribute medical and drug information.28 This is an excellent and innovative role for pharmacists, as demonstrated by the South Carolina Offering Prescribing Excellence program.29 At present, given the industry’s inherent bias in promoting its products, concerns regarding the integrity and fairness of industry-distributed educational materials are valid.30

Another issue of concern is the expertise of pharmaceutical sales representatives in the fields of medicine and pharmacotherapy. Typically, they have limited medical training and undergo rapid training about the medications they promote and their approved indications. They become conversant in the pharmacology, results of pivotal clinical trials, and specific aspects of the disease for which the medication is approved. Often, they are equipped to answer common questions regarding the medication’s labeled indications; however, it should be anticipated that questions concerning pharmacology, clinical trial design, and the reporting of data, especially vital to discussions of unlabeled uses, are often beyond their knowledge base. This need is currently filled by medical science liaisons, hired with a specific medical background and given authority by FDA to have these discussions. This distinction is important, as health care providers should be particularly cautious of pharmaceutical sales representatives who discuss unlabeled uses of medications. If FDA decided to expand the role of pharmaceutical sales representatives, not only would training need to be more intensive, but baseline job credentials should also be addressed.

Aside from self-conducted research and office visits by pharmaceutical sales representatives (including distribution of new literature), continuing education (CE) for health care professionals is often obtained through live CE presentations. Currently, the pharmaceutical industry funds the majority of live CE, and concerns exist regarding the validity and balance of these educational sessions.31 In response, standards for continuing pharmacy education have been updated to require providers of CE programs to maintain independence from commercial interests in the planning and delivery of educational activities.32 It is vital that CE opportunities focus on data derived from well-designed clinical trials rather than anecdotal commentary and opinion statements from experts and are without industry involvement. This includes expanding CE to therapeutic areas where unlabeled medication use is necessary, thereby increasing provider awareness to promote research and to facilitate better medication use. Such education can be provided through educational symposia, nonprofit organizations, and industry grants, as long as content control is relinquished to a reputable educator. Therefore, increasing funding of nonprofit educational programs as an alternative means for providing impartial, balanced education is greatly needed, and pharmacist-provided academic detailing is an effective solution. Furthermore, continued support of accrediting bodies such as the Accreditation Council for Pharmacy Education is needed to maintain quality programming.

Lessons learned about the drug-approval process and postapproval marketing.

Past examples of new drug approvals and subsequent marketing by manufacturers demonstrate the pitfalls of the promotion of unlabeled uses, as well as the role of the pharmaceutical industry in clinical trials, the publication of biomedical literature, and the dissemination of this information. Nesiritide and ezetimibe offer two insightful case studies into the need for critical review of published clinical trials.

After falling short with a first attempt at FDA approval, nesiritide’s manufacturer, Scios (Mountain View, CA), conducted the FDA-mandated trial that led to the product’s approval.33 After approval, Scios hired 180 pharmaceutical sales representatives and launched an aggressive marketing campaign, including the publication of potentially misleading advertisements overestimating the benefit of nesiritide. Reports have also indicated that Scios sponsored publication of journal articles about unlabeled uses, such as outpatient infusions and home infusions as bridge therapy to heart transplantation.34 Dissemination of such information resulted in sustained and widespread use of nesiritide. Recently, safeguards have been put in place to disclose sponsorship, delineate the roles of authors, and improve overall transparency of published clinical trials.35 However, despite peer-review processes, studies with these inherent flaws are still published, so the need for critical evaluation of published clinical trials remains.

Another potential problem is the inherent selection bias of information that will be distributed to providers by pharmaceutical sales representatives. This can be taken a step further, by the bias inserted into trial design, in presentation of the results in medical journals and the timing of publication. This point can be illustrated with ezetimibe and the combination medication ezetimibe–simvastatin, originally approved to reduce low-density-lipoprotein (LDL) cholesterol levels. Use of ezetimibe and ezetimibe–simvastatin is prevalent, likely because of the assumption made that superior LDL lowering would result in improved outcomes. The results of the ENHANCE trial,36 conducted with patients with familial hypercholesterolemia—an unlabeled indication—found that lowering LDL cholesterol may not be a clinically meaningful predictor of outcome, as evident by the reduction in LDL cholesterol without regression of atherosclerotic plaques. Although concerns exist that ezetimibe may have no clinically meaningful effect, more alarming is the fact that the results of this industry-sponsored, postmarketing trial were known for almost two years. With the manufacturer controlling the release of study data, the delay was undoubtedly questionable.

In light of this information, pharmacists must continue to scrutinize the literature and be aware that even misinformation can be published in peer-reviewed journals, especially for industry-sponsored clinical trials and for unlabeled uses of approved medications. After all, outside of formal FDA review, no one gets to see all of the data or perform a full statistical analysis. Only federally funded research comes close to achieving these high standards. In this era of potentially more "permissive" distribution of literature containing off-label uses, the pharmacist’s role is a crucial one.

Call to action.

The use of medications for unapproved uses continues to play an important role in pharmacotherapy. A package insert may lag behind current practices and standards of care and may not reflect established clinical practice, endorsed by authoritative organizations. Prescribers face difficult decisions regarding the use of medications for both approved and unapproved uses and must critically evaluate the entire body of evidence available. This must include attempts to further decrease our reliance on industry-funded education by finding alternative methods to provide well-balanced and responsible drug information. Therefore, pharmacists are needed to ensure that education provided in the form of reprints is balanced and that any literature received is examined critically. Our discussion of nesiritide and ezetimibe demonstrated that there are negative consequences, with potential safety concerns, that may result from extrapolation of data derived from a poorly designed clinical trial or when the release of results is incomplete, misleading, or untimely. Even if a trial is randomized, if there are serious study flaws (e.g., endpoints not carried out to their prespecified time frame, inadequately powered, high dropout rate with no explanation), the results must be extrapolated with caution. The importance of rigorous drug literature evaluations by pharmacists is of increasing importance to ensure that labeled and unlabeled uses are evidence based.37

All participants in the clinical trial process should demand high ethical conduct of these studies, from trial inception to the analysis and final reporting of the data. In addition, it may be mutually beneficial to offer better incentives in the form of patent extensions to manufacturers to perform both postmarketing evaluation of drug use and additional clinical studies to seek supplemental indications. An important step in the postmarketing environment is the gathering of data at the institutional and national levels (e.g., as part of medication-use evaluation or registry) to identify appropriate and inappropriate unlabeled prescribing. FDA-provided safeguards are also needed, including institutional advisory panels and the employment of counter detailers to aid in the provision of well-balanced information.

The controversies surrounding unlabeled medication use are many. As experts in medication use, pharmacists must always strive to facilitate evidence-based prescribing of medications for safe and effective use by patients.

Appendix—Summary of recent guidance by the Food and Drug Administration (FDA) for industry5

Recommendations for types of reprints  

  • Scientific or medical journal articles should be peer-reviewed, be published by organizations with an editorial board of experts in the related subject matter, and include full disclosures of conflicts of interest.
  • Publications should not be primarily distributed by a manufacturer and should not be edited or influenced by the manufacturer or individuals having a financial relationship with the manufacturer.
  • Information disseminated should not be false or misleading and should not be in the form of letters to the editor, abstracts, or reports of Phase I studies. Publications should contain substantive discussion of the relevant investigation and data.

Recommendations for disseminating reprints  

  • Reprints should not be altered by the manufacturer, directly attached to promotional materials, or distributed in promotional exhibit halls at conferences.
  • Reprints should be accompanied by approved labeling, a comprehensive bibliography of publications of clinical studies investigating the use of the drug or device discussed in the reprint, and a representative publication of contrary conclusions (if applicable).
  • Reprints should be accompanied by a statement disclosing that the information provided describes a use that has not been approved by FDA, conflicts of interest of authors, sources of funding for the study, and all significant risks or safety concerns known to the manufacturer.


The authors have declared no potential conflicts of interest.



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