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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e318272af1f
Special Feature

Drug Development: The Use of Unlicensed/Off-label Medicines in Pediatrics

Yamashiro, Yuichiro*; Martin, Jennifer; Gazarian, Madlen; Kling, Sharon§; Nakamura, Hidefumi||; Matsui, Akira||; Cucchiara, Salvatore; Aloi, Marina; Wynn, Erica L.#; Mulberg, Andrew E.#

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*Probiotics Research Laboratory, Juntendo University Graduate School of Medicine, Japan

Princess Alexandra Hospital School of Medicine, University of Queensland, Brisbane, Australia

University of New South Wales, Sydney, Australia

§Department of Paediatrics and Child Health, Tygerberg Children's Hospital and Stellenbosch University, Stellenbosch, South Africa

||National Centre for Child Health and Development, Tokyo, Japan

Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy

#Division of Gastroenterology and Inborn Errors Products, Food and Drug Administration, Rockville, MD.

Address correspondence and reprint requests to Yuichiro Yamashiro, MD, PhD, Juntendo University School of Medicine, Tokyo, 113-8421, Japan (e-mail: yamasiro@juntendo.ac.jp).

Received 30 August, 2012

The authors report no conflicts of interest.

Pediatricians now need and our children deserve a more robust and effective system to avoid compromise of children's health from off-label drugs. In 2002 (1), the US Food and Drug Administration (FDA) established a new policy that, although pediatric clinical trials are not necessarily required for all new drugs, market exclusivity will be offered for pharmaceutical companies performing appropriate pediatric studies, mainly with medications that may have the potential to significantly affect children's health. In addition, the World Health Organization adopted the resolution “Better Medicines for Children” in 2007 (2).

We describe recent initiatives for implementing procedures to resolve off-label drug issues. The present situation, however, remains far from satisfactory, especially in developing countries.

As one of several global contributions to the 30th anniversary issue of JPGN, professionals caring for children should view this as a good opportunity to not only collect and disseminate important information worldwide but also encourage a more proactive approach in their professional activities, for example, by establishing international networks for off-label drugs to collaborate and to exchange information about new findings pertaining to standard and innovative drugs for children.

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Prescribing of unapproved medicines (off-label [off-label prescribing refers to prescription of a registered medicine for a use that is not included in or is disclaimed in the regulatory body approved product information {eg, for a different indication, age group, dose, frequency, or route}] or unlicensed [prescribing an unlicensed medicine is when a medicine or dosage form of a medicine has not been evaluated nor approved by regulatory authorities for any purpose {eg, extemporaneous preparation of a formulation for pediatric use}]) is common in the pediatric population worldwide (3), and Australia is no exception (4). Up to 40% to 90% of pediatric inpatients worldwide receive at least 1 unapproved medicine during their hospitalization, with higher rates in younger and sicker patients. Use in community settings is less and most often associated with new medicines, younger ages, specialist treatment, and low-use medicines (3).

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Why Does It Occur and Is It a Problem?

Off-label prescribing is not illegal in Australia nor is it regulated by the Therapeutic Goods Administration. Pediatric prescribers are expected to use their “professional judgment” to determine appropriateness but with often limited data to inform their decisions. This is because of insufficient medicines research conducted in the pediatric population and lack of evidence about actual and comparative efficacy, safety, and cost-effectiveness. Landmark legislative and regulatory reforms in the United States and Europe in recent years have resulted in more pediatric medicines research and improvements in licensing of some medicines for older children (5). It is disappointing that this new information is not well reflected in other parts of the world, including Australia (6), where similar reforms are so far lacking despite recent changes in the regulatory area (7).

Off-label prescribing may sometimes be appropriate but is always associated with important clinical, ethical, and financial consequences, which need to be considered when assessing overall benefits and risks (3,8). There is accumulating evidence that such uses can result in harm, with increased incidence and seriousness of adverse drug reactions associated with unapproved medicines use in this population (3). Furthermore, some long-established and well-accepted off-label uses have been shown to be either ineffective or harmful when prospectively evaluated in randomized controlled trials in the pediatric population (3), for example, proton pump inhibitors. Furthermore, evidence supporting their longer-term safety is still lacking despite widespread use (9). Additional consequences of this behavior can include potential limitation of the needed medicines research agenda and withdrawal of useful (older, approved) medicines from the market because of reduced demand from newer (unapproved, and often unproven) medicines (3).

Most clinicians perceive off-label prescribing as appropriate and that benefits outweigh risks; however, recent research indicates that their awareness and consideration of consequences appear suboptimal, with worrisome low level of concern about risks, unevaluated efficacy, and issues surrounding informed consent (3). Enthusiastic marketing of new medicines by the pharmaceutical industry is likely to further exacerbate the situation (10). A recent analysis of national prescribing trends for anticonvulsants in Australian children suggests that some of these factors may underlie the decrease in prescribing of older anticonvulsants, with a concurrent increase in prescribing newer anticonvulsants including off-label uses in younger children (11).

In pediatric gastroenterology, monoclonal antibodies are used in Crohn disease (CD) based on demonstrated efficacy in induction and maintenance of remission; however, the safety profile is less well established, especially in the longer term. Antitumor necrosis factor (TNF) treatment is associated with a number of serious adverse reactions including infusion reactions, serious infections, tuberculosis reactivation, lymphomas, and other malignancies (12,13). These need careful consideration when making judgments about appropriate “place in therapy” for children. Such potential risks may be justifiable in refractory cases but not necessarily in early disease in which other agents with less serious toxicity may be effective.

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What Can We Do About It?

A combination of strategies needs to be pursued concurrently (14). These strategies include more (and better) pediatric medicines research to address priority child health needs, including drug regulatory reforms, substantial commitment of public funding and dedicated infrastructure, (5,14) more systematic evaluation of the outcomes (especially safety) of unapproved medicines use, improved availability of up-to-date, objective, balanced medicines information to optimally inform prescribers about benefits and risks of unapproved medicines use, and a more systematic approach by pediatric prescribers to evaluate the appropriateness of proposed unapproved uses of new medicines.

Despite many years of professional advocacy, Australia still lacks any legislative or regulatory reforms addressing pediatric medicines (5), with no dedicated resources for national infrastructure and capacity building specifically for pediatric medicines research; however there are subtle recent improvements with a pediatric prescribing information resource under development and nationally standardized decision-making framework and guiding principles for off-label use of medicines in the consultation stage (14). Furthermore, an independent national body with responsibility for implementing Quality Use of Medicines (judicious selection of management options, including choice between drug, nondrug and no treatment; appropriate choice of medicine if a medicine is considered necessary; and safe and efficacious use of medicines (http://www.health.gov.au/internet/main/publishing.nsf/content/nmp-quality.htm)) has been set up and can be supported to prioritize integration of pediatric-specific Quality Use of Medicines issues into existing and new national medicines programs.

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Licensing of drugs is essential to ensure safety and quality assurance. Off-label prescribing refers to licensed or registered medications being prescribed outside their license, for example, for a different indication, in a different age range, different dose or dosing regimen, or via a different route (15) An unregistered or unlicensed medicine has not been assessed or approved by the medicine registering authority of that country (15).

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Approximately 30% of hospitalized children receive off-label or unlicensed drugs; the figure may be up to 90% in neonatal units (16). All of the specialities are affected. In a pediatric gastroenterology unit in London, 49% of prescriptions were unlicensed or off-label (17). Proton pump inhibitors are commonly used off-label (in young children) or unlicensed (altered formulation) (17,18).

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Ethical Issues in Off-label Prescribing

Off-label prescribing is not illegal and may in fact be appropriate in certain situations, provided there is no alternative and the likely benefits outweigh the potential risks. The main ethical issue in off-label prescribing relates to concerns of harm to patients (nonmalfeasance), with concerns about safety and adverse drug reactions (15).

Before an unlicensed drug may be prescribed, written consent must be obtained, but this does not apply to off-label drug use. Should parents give fully informed consent for off-label medicine use in their children? Is verbal consent sufficient or should it be in writing? The majority of pediatricians in a UK study did not obtain informed consent nor did they inform the parents that they were prescribing off-label medicine (16). Informed consent demonstrates respect for parental autonomy and may protect the doctor in the case of an adverse reaction.

The potential advantages of off-label prescribing include benefit to the individual patient and discovery of new therapeutic uses and collection of efficacy and safety data for medicines being used in new settings (19).

Disadvantages of off-label prescribing include potential risks for both the patient (harm) and the doctor (litigation) because both the types and rates of adverse events may be different for the off-label drug. Crushing tablets may lead to potentially incorrect drug dosages. The doses of drugs licensed only for adults have to be extrapolated from adult data, with resultant incorrect dosing for children. Additionally, safety data for off-label drugs are not available when the medicine is used in different patient populations and in situations where drug–disease interactions may result (19).

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There are few unique indications for medicines in children, the quantities of medication required are small, and thus the financial incentives to develop medicines for children are lacking (15,16). This has led to the description of children as “therapeutic orphans” (20). Developing world diseases are called “neglected diseases” because they do not attract pharmaceutical clinical trials. Only 1% of new drugs developed during the last 30 years are aimed at these diseases (21). Developing world diseases contributing to the high under-5 mortality rate include pediatric tuberculosis, HIV/AIDS, and malaria. In these settings, the requirements are for child-friendly drug formulations as well as formulations that can be safely stored in hot climates (21).

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Ethical Issues Affecting Clinical Trials in Children

Trialing drugs for use in children is hampered by potential risks to the individual child and perceived exploitation of children as vulnerable subjects (22,23). Practical considerations involve different age ranges and the effects of growth and changing physiology on drug handling by child patients (23); however, giving drugs to a population of children in whom they have not been tested is potentially more harmful because the risks are totally unknown (20). Children need to be protected, but they also have the right to participate in research that has the potential to be of benefit to them. To quote Rocchi, “it is clearly preferable to test medicines in children, in a safe and controlled pediatric clinical trial environment, where the individual child is protected” (23).

In conclusion, off-label prescribing of drugs in children is common, often necessary, and may well be appropriate. Every off-label prescription should be carefully assessed regarding the indications, alternative drugs, benefit-versus-risk considerations, and available evidence. If a drug is being used off-label, inform the patient and parents and, where appropriate, obtain informed consent. Clinical trials to license drugs for use in children should be regarded as an ethical imperative, and should be enforced by the regulatory authorities.

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In Asia, many drugs for children are used off-label or unlicensed as is the case in many other countries. Of 2032 drugs prescribed on 531,137 occasions in 1 year at 5 major hospitals in Japan, only 495 drugs (24.4%) for children had sufficient information for pediatric dosage (24). Forty percent of these drugs had the description “safety is not established in children.” Two percent were either “contraindicated” or “not recommended in children” for certain age groups. There were also ambiguous statements “the dose can be adjusted accordingly for age” or no clear guidance on usage in children in 20%. Off-label use is reported in other countries, including China (25) and Korea (26). Patients or physicians may have to import drugs that are unlicensed in their countries. Especially for oncology and genetic diseases, the cost can be more than US$10,000 annually for a person.

Few drugs exist in formulations specifically for children. Extemporaneous use of drugs is common. In 32 Japanese institutions, including 18 children's hospitals, during the 4-week period in 2005, there were 1666 incidences of dosage form changes (27). In 1227 incidences, appropriate powders were made either by crushing tablets and/or adding sucrose to make different strengths. In many occasions, Japanese children take powders orally as they are or after adding a small amount of water to make them paste-like. This obviously is the reason why the dosage form changes to powder are so common. Most Japanese pharmacies have machines to automatically divide powder evenly and to pack it in sachets.

In 176 incidences, tablets were divided into ≥2 sections, and in 50 incidences, syrups/suspensions were made from other forms, including IV solutions (eg, midazolam for sedation). In 40 incidences, the suppositories were cut for appropriate dosages, and in 23 incidences, inhalation solutions were made from other forms, including IV solutions. The top 10 drugs for dosage form changes on prescription number basis were warfarin potassium, methyl digoxin, enalapril maleate, dantrolene sodium, lisinopril, beraprost sodium, hydrocortisone, baclofen, chloral hydrate, and propranolol hydrochloride.

Although the World Health Organization adopted the resolution “Better Medicines for Children” (2) in 2007, there is no harmonized effort among Asian countries. Some countries have started to move forward to facilitate drug development in children. In Korea, the Off-label Use Evaluation Task Force was established inside the Korean FDA in 2010, and there is continuing discussion among industries, academia, and government to solve the problems. In China, a pediatric clinical pharmacology subgroup was organized under the Chinese Pediatric Association in 2011. There is also an effort to set up a pediatric clinical trial network.

In Japan, a premium for innovative drugs and for eliminating off-label use was introduced in 2009 (28). This is considered to be a strong incentive for the industries. The Study Group (Expert Panel) on Unapproved and Off-label Drugs of High Medical Need of the Ministry of Health, Labour, and Welfare are responsible for evaluating the medical need for off-label or unlicensed drugs since 2010. There is major involvement of the representatives of pediatric subspecialty societies to the activity of this study group. This was made possible because there has been a close collaboration between the Committee on Drugs of the Japan Pediatric Society and the associated subspecialty societies, including the Japanese Society for Pediatric Gastroenterology, Hepatology, and Nutrition (JSPGHAN) (29). One example of the systematic effort of academia was the approval of roxatidine, the first H2-antagonist ever approved for children in the country in 2012. The representatives of JSPGHAN contacted the company, discussed the needs, and helped them to design the clinical trials, to conduct pharmacokinetic and pharmacodynamic studies, and to determine the proper dosage. The Japan Pediatric Society and JSPGHAN continue to discuss with government and industry representatives to eliminate off-label and unlicensed drugs. One major discussion is the introduction of legislation similar to that in the Europe and United States (28) that mandates pediatric drug development to industry. Pediatric clinical trial networks are also set up in certain subspecialties, including neonatology, nephrology, and hematology/oncology, as well as in Japanese Association of Children's Hospitals and related institutions.

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Management of pediatric disease may be difficult because of a lack of properly formulated or approved medications (30). In Europe and elsewhere, many drugs are not approved for use in children and are often used outside the terms of the product's approval (off-label use). A study from United Kingdom has shown that up to 50% of medications prescribed in a pediatric gastroenterology unit are off-label (17). One of the most debated fields on this topic is the use of biologic therapies in children with inflammatory bowel disease (IBD). Indeed, during the last decade, the advent of anti-TNF agents has revolutionized the management of IBD. What is disappointing, because of a lack of prospective, controlled trials in children with IBD, is that pediatricians and pediatric gastroenterologists are facing a challenging task when they treat their patients because therapeutic strategies are mainly extrapolated from adult studies. Presently, there are 3 anti-TNF drugs licensed by the US FDA to treat CD in adults: infliximab (IFX), adalimumab (ADA), and certolizumab pegol. IFX is also registered for use in adults with ulcerative colitis (UC). In pediatric IBD, IFX is the only anti-TNF drug that has been approved by the FDA and by the European Medicines Agency, and only for use in refractory CD (31); however, all of the anti-TNF drugs have been used off-label to treat refractory pediatric IBD. Recently, long-term evidence on IFX use, data on ADA efficacy in pediatric CD, and increasing information on IFX use in pediatric UC have become available. IFX has proven to be effective in inducing and maintaining remission, achieving mucosal healing, inducing perianal fistula closure, reducing corticosteroid use, promoting growth, and improving quality of life (32). IFX also has a role in the management of refractory pediatric UC (33). Recent data suggest the effectiveness of ADA in pediatric CD (34). The role of certolizumab in pediatric IBD has yet to be determined.

Nevertheless, the literature on biological therapy in pediatric IBD remains frustrating because most of the published articles are retrospective and often uncontrolled studies with small patient populations. Indeed, there is an emotional resistance by pediatricians to use new pharmacological agents in children before they have been used successfully and safely in adults. Moreover, the pharmaceutical industry does not support studies in children and infants because of concerns about safety and efficacy and, not least, because of an economic concern based on the fact that children can be only a small portion of the potential market for a new drug. The failure of governmental regulatory bodies to ensure that appropriately designed and conducted studies occur in children has contributed to this situation. The failure to conduct clinical trials in children remains a major roadblock to reduce the use of off-label medications. It also represents a significant obstacle to providing appropriate medical care to our children. With limited data on which to base the risk assessment, the pediatrician is at disadvantage when discussing with patients and their families the potential risks of therapy; however, legal impediments to conduct trials in children are going to be removed. In 1998, the Department of Health and Human Services and the FDA issued a guidance document enclosing remarks and suggestions for pediatric pharmacokinetic studies for drugs and encouraging drug testing in children. In 2000, the European Agency for the Evaluation of Medicinal Products published an article for guidance on clinical investigation of medicinal products in children. More recently, the FDA has stated that pediatric trials are not necessarily required for all new drugs, but it will provide market exclusivity for those firms performing adequate studies, mainly medications with a strong potential effect in children (1).

In conclusion, we are now able to effectively treat children with IBD with IFX and, in an off-label manner, with other anti-TNF agents; however, compelling questions arise from the use of biological therapy in pediatric IBD: is early use of biologics as first-line strategy a curative therapy that can alter the natural history of the disease? Are there any genetic and/or phenotypic markers useful for selecting patients who more likely benefit from biological therapy? These issues warrant future prospective, large-scale, pediatric controlled trials. This can be realized only through collaboration among worldwide pediatric IBD centers.

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Requirements to conduct clinical trials under the Pediatric Research Equity Act (PREA), coupled with incentives from the Best Pharmaceuticals for Children Act (BPCA) to investigate and develop therapeutic classes of molecules in children, are responsible for steady increases in drug development and clinical trial programs involving pediatric patients. Following the codification of PREA and BPCA, 335 written requests were issued between 1998 and 2011; 323 marketing applications were approved with postmarketing requirements through May 2011; and 415 labels were changed between 1998 and 2011 (35); however, both the PREA and the BPCA are set to expire in 2012.

Off-label use of pharmaceutical agents in the management of pediatric illnesses has long been recognized as a problem. In 1975, work by Wilson (36) reported that only 22% of all of the medications listed in the Physician's Desk Reference (PDR) contained adequate pediatric labeling information. Efforts promulgated by legislation and global regulatory agencies, including the FDA, have encouraged the conduct of pediatric clinical trials and increased the critical role of these trials to accelerate the appropriate and informative labeling for drugs in all diseases and in all populations. It has been reported that pediatric labeling for drugs has improved since 1975. Despite the reported advances, only 46% of products in the 2009 ePDR contained information on pediatric use in labeling, suggesting that there is still much work to be done (37).

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There is a need for renewed commitments to identifying appropriate drug candidates and planning a process toward the approval of the candidate products in children. Drugs with pediatric gastrointestinal labeling account for only 8.6% (n = 11) of all the products studied and labeled under US pediatric research incentive legislation. Among the drug classes studied are treatments for hypercholesterolemia, IBD, vomiting, obesity, and hepatitis B and C, and acid-suppression therapy. Based on the paucity or absence of available treatments, notable areas for the potential of new drug development include eosinophilic esophagitis (EoE) and related disorders; motility disorders including gastroesophageal reflux disease in infants and gastroparesis; and irritable bowel syndrome, to name a few (35).

The results of a retrospective cohort study published in 2007 by Shah et al concluded that, “Most patients hospitalized at tertiary care pediatric institutions receive at least 1 medication outside the terms of the FDA product license” (38). Shah et al also observed that there was substantial variability in the occurrence of off-label product use (based solely on age criteria) within and across different diagnostic categories and therapeutic classes. Off-label drug use was particularly noticeable with drugs targeting the central and autonomic nervous systems and those drugs related to fluids, nutrients, and gastrointestinal tract. Specifically, a disproportionately high percentage of patients received off-label treatment with metoclopramide, polyethylene glycol electrolyte solution, docusate, and ondansetron (38). Similarly, off-label use of drugs in pediatric patients in the outpatient setting has been reported in that 80% of drugs used for gastrointestinal indications are used off-label. Much of this off-label use was associated with Miralax (39).

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EoE is a disorder that has become increasingly recognized in the medical community during the last decade (40). Consequently, there has been an increase in the reported prevalence of the condition and EoE appears to affect a significant percentage of the pediatric population (41). EoE is a clinicopathologic condition characterized by varying symptomatic presentations among different age groups (9). Whereas adults and adolescents are most likely to present with dysphagia and food impaction, infants and toddlers usually present with feeding difficulties and failure to thrive, while school-age children present with vomiting and abdominal pain (40,41). In addition to the nonspecific nature of EoE symptoms, symptom frequency can vary from daily to every couple of months (42). Presently, there are no FDA-approved pharmacologic therapies for children with EoE.

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With respect to EoE, collaborations between professional academic societies such as the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the international gastrointestinal eosinophilic researchers, patients, industry, and other stakeholders have been critical to identifying pathway(s) for development of clinical trial endpoints. As a result of these collaborations, evaluation of clinically meaningful endpoint(s), which measure changes in clinical symptoms, as well as assessment of intraepithelial mucosal eosinophilia and potentially other putative biomarkers, is important during the conduct of EoE registration trials for the approval of new therapies. In addition, the development and use of biomarkers, particularly in early-phase drug development, may provide important tools for drug development for diseases such as EoE. The further identification, exploration, and development of biomarkers offer marked potential benefits for diseases, such as EoE, which presently require serial invasive monitoring. All of the stakeholders involved in the drug development process including but not limited to academia, industry, patient and disease advocacy groups, and regulatory agencies must work collaboratively to promote efficient, scientifically sound clinical development programs to address off-label use of drugs through the drug approval regulatory pathway.

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Copyright 2012 by ESPGHAN and NASPGHAN


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