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US Perspective on Off-label Use in Pediatrics

Karesh, Alyson*; Mulberg, Andrew E.

Journal of Pediatric Gastroenterology and Nutrition: February 2013 - Volume 56 - Issue 2 - p 113–114
doi: 10.1097/MPG.0b013e3182824ccb
Invited Commentaries

*The Pediatric and Maternal Health Staff

Division of Gastroenterology and Inborn Errors Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.

Address correspondence and reprint requests to Andrew E. Mulberg, MD, 10903 New Hampshire Ave, Building 22, Room 5114, Silver Spring, MD 20993 (e-mail:

Received 11 October, 2012

Accepted 10 December, 2012

The views expressed in this article are those of the authors. No official endorsement by the US Food and Drug Administration is provided or should be inferred.

The authors report no conflicts of interest.

See “Drug Utilization and Off-Label Drug Use in Spanish Pediatric Gastroenterology Outpatients” by Ruíz-Antorán et al on page 173.

The evaluation of off-label use published by Ruiz-Antorán et al (1) in this issue of the Journal of Pediatric Gastroenterology and Nutrition provides an opportunity to discuss evolving US legislative measures to improve available clinical trial–derived pediatric data and provide coherent labeling for pediatric providers in dosing of drugs for children. Dr Ruiz-Antorán et al present findings of frequent off-label use of drugs in a Spanish outpatient pediatric gastroenterology clinic, which appear generally consistent with the use of off-label drugs in the United States (1–4).

There are multiple reasons why providers may prescribe drugs off-label. Providers may not be aware that they are prescribing off-label, or may intentionally choose off-label treatments that are supported by widely accepted recommendations or treatment guidelines (1). Providers may also prescribe drugs off-label because other on-label treatments have been ineffective, or because there is an established effect from that class of medications (5). Also, off-label prescribing may be necessary to provide a product in a pediatric-appropriate strength and formulation (6).

The potential negative effect of off-label prescribing in pediatric patients has been evaluated, but the direct relation between off-label prescribing and adverse events has not been definitively established, as noted by Ruiz-Antorán et al (1,7). The potential for adverse reactions associated with off-label drug use exists and steps, such as regulation, clinical practice guidelines, and local initiatives, to decrease adverse reactions associated with off-label use of products are described (1).

Given the breadth of potential reasons for off-label prescribing, no one approach appears likely to address all the reasons providers may choose off-label prescribing (2,5,8). In the United States, legislation designed to encourage the appropriate use of drugs in pediatric patients may decrease the frequency of adverse reactions associated with off-label use. The Pediatric Research Equity Act (PL 108-155) and the Best Pharmaceuticals for Children Act (PL 107-109) provide the Food and Drug Administration (FDA) with specific tools to promote trials of pharmaceutical products in pediatric patients. First, pediatric data submitted in response to these acts must be described in labeling, regardless of whether the findings are positive, negative, or inconclusive (9). By including all pediatric trial results in labeling, the providers and patients have access to valuable information, which may decrease inappropriate off-label prescribing. For example, providers now may be able to determine whether a pediatric approval does not exist for a particular drug simply because pediatric trials have not been conducted with that product, or whether trials were done that failed to establish efficacy or revealed safety issues. That information, in turn, can inform prescribing. Second, if pediatric trials are not required because the drug would be ineffective or unsafe in a pediatric population(s), that information must go into the product's labeling (9). Third, current US legislation requires public internet posting of certain FDA pediatric reviews regardless of whether the trials led to an approval (9). Providers can use these public data to more clearly understand the risks and benefits involved in off-label use of a specific product for their patients.

Although pediatric trial data published in the scientific literature may be informative, that data may not present a complete picture of the benefits and risks of using a drug off-label. Only 48% of trials of products that had pediatric safety information added to the product's labeling were reported in the peer-reviewed literature (10), and approximately half of the published articles did not emphasize the same information as did FDA labeling and drug reviews (10). Therefore, published literature alone appears insufficient to inform fully prescribing decisions, and including pediatric trial data in labeling appears crucial.

Despite the potential value of FDA publically reporting pediatric trial data, simply improving that transparency appears unlikely to completely address all off-label prescribing. For example, lansoprazole is not approved for use in patients younger than 1 year, and labeling describes a negative trial in that age group (11). Nonetheless, a recent analysis of outpatient prescription drug use in the United States revealed substantial off-label use for lansoprazole in infants; approximately 358,000 prescriptions were dispensed in 2010 for infants younger than 1 year (12). The potential disconnect between information in labeling and prescribing practices remains a problem to consider for future intervention, including educational efforts for providers and patients. Potentially, this responsibility to educate could be shared among drug companies, regulatory authorities, and providers.

Presently in the United States, providers may prescribe an approved product for any indication, and drug companies can profit from off-label use. Therefore, the drug companies have potential financial incentives from the practice of medicine that permits off-label use. In comparison to the US approach, in France, a law (law number 2011–2012, December 29, 2011) and a decree on the “Temporary Recommendations for Use” (decree number 2012–743, May 9, 2012) attempt to regulate off-label drug use (13). In France, drug companies are responsible for monitoring the reasons for which their product is prescribed, reporting off-label use, and educating health care providers to avoid off-label use. Additionally, an observation period may be created to assess the risks and benefits of an approved drug's off-label uses (13).

Off-label prescribing for pediatric patients appears widespread despite concerns, including for the potential for serious adverse reactions, and there are many approaches to addressing these potential adverse reactions. US legislation designed to promote pediatric trials and increase the transparency of those trial results may ultimately help to decrease the potential risks associated with off-label drug use in pediatric patients. Further evaluation into pediatric provider prescribing practices, and adverse reactions related to off-label use of drugs, may reveal which measures have been most successful at decreasing adverse reactions secondary to off-label use. Therefore, the stakeholders ought to discuss whether drug companies in the United States akin to France should take a more active role in educating providers, monitoring physicians practice and reasons for off-label drug use, and discouraging off-label prescribing. These issues remain unresolved in the current US environment.

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