Medication Repurposing in Pediatric Patients: Teaching Old Drugs New Tricks

Abstract

OBJECTIVES: Gaps in pediatric therapeutics often result in off-label use and specifically, novel uses for existing medications, termed “drug repurposing.” Drug Information (DI) queries to a Pediatric Medication Resource Center of a large metropolitan pediatric hospital in New York and inherent difficulties in retrieving evidence-based information prompted a review of current medication repurposing for pediatric patients. The objective included characterization of innovative off-label use of medications Food and Drug Administration (FDA)-approved for 1 or more indications to treat a totally different disorder or indication in pediatric patients.

METHODS: A systematic literature review was conducted to retrieve publications describing repurposed medications in pediatric patients. Excluded was FDA-approved indications used off-label in pediatric patients (e.g., different dose), preclinical data, adult use only, and experimental use. Evidence quality was classified using a modified American Academy of Neurology Level of Evidence. Results were analyzed using χ² at p < 0.05.

RESULTS: Over 2000 references were retrieved and reviewed. A total of 101 medications repurposed for novel off-label uses for pediatric patients were identified: 38 for neonates, 74 for children, and 52 for adolescents. Neonates and infants were least likely to receive a medication for a repurposed use. Strong or intermediate evidence existed in 80.2% of cases. The evidence was weak in 19.8%. No significant relationship was observed between the pediatric age group and strength of the literature. Most repurposed uses pertained to generic or widely used medications. Less than 5% of medications were first marketed after 2011.

CONCLUSIONS: While not exhaustive, the present study represents the most comprehensive listing of novel uses exclusive to pediatric patients. Further research is needed to identify the frequency of repurposed uses. The valuable DI role of pharmacists in assessing repurposed uses is of expanding and increasing importance to ensure such uses are evidence-based.

INTRODUCTION

In 1963, Dr Harry C. Shirkey stated, “By an odd twist of fate, infants and children are becoming therapeutic or pharmaceutical orphans.”¹ More than half a century later, most medications used in pediatric patients are not Food and Drug Administration (FDA) approved for use in this patient population. That is, they are used off-label. Off-label use is the mainstay of therapy in pediatric patients. Several studies have shown that between 39% and 79% of children admitted to pediatric hospitals receive 1 or more courses of off-label therapy.^2,3

see Editorial on page 4

Legislative efforts to improve pediatric drug therapy include The Best Pharmaceuticals for Children Act (BPCA)⁴ and the Pediatric Research Equity Act (PREA).⁵ Table 1 lists similarities and differences between BPCA and PREA. Both became permanent in 2012 under the FDA Safety and Innovation Act and have resulted in about 500 pediatric labeling changes.⁶ Despite this success, less than half of all products are labeled with pediatric information.⁷

Table 1.

Provisions of the BPCA and PREA

The FDA does not mandate pediatric ages to be tested, and medications have received exclusivity by testing in 12- to 17-year-olds, extending use to adolescent but not pediatric patients. A recent study of 192 medications that were granted pediatric exclusivity by the FDA reported that studies in support of exclusivity are often not designed to meet pediatric patient needs. For example, hypertension and high cholesterol are the therapeutic category most frequently granted pediatric exclusivity.⁸ Additionally, exclusivity is currently not conditioned upon studies in pediatric patients being either successful or resulting in FDA approval.

No legislation exists to incentivize pediatric research of FDA-approved medications that have no existing patent life, especially where generic versions exist. For such medications or where the medication is inexpensive, manufacturers have little financial incentive to invest in costly pediatric clinical trials. Likewise, there is no incentive to submit Supplemental New Drug Applications (SNDAs), which when approved will allow a company to make changes in a product that already has an approved new drug application (NDA) (e.g., change to FDA-approved indications). Rarely are SNDAs used to obtain FDA approval for repurposed or innovative indications. However, for high cost medications, the incentive to conduct such trials may exist. Regardless, nothing mandates manufacturers to seek FDA approval for new indications as they become established. Even for NDAs, pharmaceutical companies are reluctant to include extra indications that might further complicate their application's approval.⁹

Contributing factors for the extensive lack of pediatric clinical trials include, for example, difficulty recruiting pediatric patients, especially where the risk:benefit ratio is unclear or there is limited pediatric prevalence for the condition. Even with Orphan Drug Act¹⁰ drug development incentives, it still may be financially unattractive to conduct research in the pediatric population where contradictory evidence may be found and the manufacturer is already profiting from a medication's recognized off-label use. For monoclonal antibodies, for example, twice as many off-label uses as FDA-approved indications exist. Under the Federal Food, Drug, and Cosmetic Act, manufacturers are prohibited from directly marketing a medication for a use other than FDA-approved indications.¹¹ However, the FDA does not have the legal authority to regulate the practice of medicine, and prescribers may prescribe a medication off-label.

Off-label use can be classified into 2 broad categories: 1) using an FDA-approved medication for 1 or more indications to treat an entirely different disorder or indication, or 2) prescribing a medication for an indication it was FDA-approved for, but outside certain specifications (age, weight, route of administration, doses, or patient populations).¹² In the first instance, the off-label use can be classified as innovative or novel where, for example, the benefit was serendipitously clinically observed. In other cases, these uses have been discovered through mining chemical structure or pharmacogenomics databases, clinical research, or trial and error.

While studies have been conducted in hospitalized pediatric populations to determine incidence of off-label use,^13–15 and to investigate pediatric off-label use of unapproved medications,^6,16 few studies have investigated either the incidence or characterization of repurposed or innovative off-label medication use in pediatric patients. The focus of this article is innovative off-label use of medications approved for 1 or more indications in adult and/or pediatric patients to treat a totally different disorder or indication in pediatric patients.

METHODOLOGY

A literature search was performed to retrieve all publications describing repurposed medications in pediatric patients. Patient ages were categorized as: infant (< 1 year), child (1 to < 12 years), and adolescent (12–18 years). This classification closely follows FDA age categories for exclusivity studies. The search was conducted in PubMed (1966 through January 2015), EMBASE, Ovid, The Cochrane Library, and Google Scholar using the search terms “pediatric,” “off-label,” “repurposed medications,” “repositioning medications,” “drug repositioning,” “drug rediscovery,” and “drug repurposing.” No language or date restrictions were considered. The FDA “Pediatric Labeling Database,”¹⁷ FDA “Rare Disease Repurposing Database,”¹⁸ Off-Label Drug Facts,¹⁹ and Harriet Lane Handbook were also reviewed.²⁰ To ensure the latest prescribing information was reviewed, the FDA Web site (Center for Drug Evaluation and Research) listing of marketed medications was used.

Off-label was defined as an indication not listed in the current prescribing information (i.e., package insert). For the purposes of this study, repurposed uses were defined as those involving different categories of diseases (e.g., asthma and epilepsy), rather than merely different diseases in the same category (i.e., eczema and boils). Both prescription and over-the-counter (OTC) products were included.

Clinical observations of innovative uses from a large metropolitan pediatric hospital were included, and further literature searches were conducted to obtain publications reporting the novel use. Additionally, included were Drug Information requests received at a Pediatric Medication Resource Center pertaining to the need for information about dosing, supporting literature, and administration for innovative uses.²¹

An effort was made to locate the best and most recent evidence (e.g., randomized clinical trials versus anecdotal case reports). Included were randomized controlled trials, cohort and case control studies, professional guidelines or recommendations, case reports, case series, and studies conducted on small numbers of pediatric patients. Preclinical and chemical screening studies, review articles (other than meta-analysis or systematic reviews), letters to the editor, editorials, and commentaries were excluded. Both positive and negative evidence were included. For each repurposed use identified, a second search was conducted both in the databases above as well as by reviewing the bibliography of each article to locate the best evidence possible.

To identify the strength of the evidence and evaluate evidence quality, a modified American Academy of Neurology (AAN) Level of Evidence classification for therapeutic intervention was employed.²² Our modified classification involved a 3-tiered system (i.e., strong, intermediate, weak). Strong evidence involved prospective randomized controlled trials or prospective matched group cohort studies directly relevant yielding positive findings or inclusion in a Pediatric Association Guideline. Intermediate evidence involved conflicting data in randomized clinical trials or cohort studies, case-control studies (including well-defined natural history controls or patients serving as their own controls), some evidence in the form of small or pilot (preliminary) trials or case series, or consensus recommendation in the absence of relevant clinical trials and better evidence than case reports. Weak evidence involved isolated or anecdotal case reports, expert opinion, or where the results of strong or intermediate evidence indicated the medication was not clinically useful for the repurposed usage. Only a few key citations were included in the citation column even where multiple existed. Finally, we reported out the specific ages of the pediatric patient population or subpopulation (e.g., adolescents) for which the novel use was either most likely to be used or was reported as used. Results were analyzed using χ² and significance was set at p < 0.05.

Excluded were FDA-approved indications used off-label in pediatric patients; innovative uses which were used in both adult and pediatric patients but primarily in adult patients or where the literature pertained solely to adult patients; where the use was only described in adults and the literature pertained only to adults; and where no literature support was located or where the only available literature regarding the novel off-label use pertained to preclinical studies. In such cases, the use would be experimentation requiring informed consent or perhaps submission of an Investigational New Drug Application (IND) to the FDA.

RESULTS

The search retrieved over 2000 references, many of which were excluded as either not pertinent or related to pediatric off-label, but not necessarily repurposed, use of medication FDA approved for the indication in adults. No single source contained all the repurposed indications, but Off Label Drug Facts identified the most. Tables 2 to 4 detail repurposed uses of medications for pediatric patients, and provides the medication name, the repurposed indication, patient age ranges, strength of evidence, and reference(s). Table 2 represents medications for which strong published evidence was retrieved based on a modified AAN Level of Evidence.^23–78 Tables 3 and 4 represent intermediate^79–129 and weak^130–156 evidence, respectively. A total of 101 medications used in a repurposed manner in pediatric patients were identified; 38 medications for neonates and/or infants; 74 for children; and 52 for adolescents. The majority (i.e., 58) involved multiple age categories; thus the total adds up to 164. Medications repurposed for multiple pediatric categories were as follows: 11 infants and children; 42 adolescents and children; and 5 infants, children, and adolescents. Neonates and infants were least likely to receive a medication for an innovative off-label use.

Table 2.

Repurposed Medications for Pediatric Patients With Strong Evidence for Use

Table 3.

Repurposed Medications for Pediatric Patients With Intermediate Evidence for Use

Table 4.

Repurposed Medications for Pediatric Patients With Weak Evidence for Use

Table 2.

Repurposed Medications for Pediatric Patients With Strong Evidence for Use (cont.)

Strong or intermediate evidence existed in a majority of cases (81/101) (80.2%); that is, the use was supported by the published literature. The evidence was strong in 40/101 instances (39.6%); intermediate in 41/101 instances (40.6%); and weak in only 20/101 (19.8%). While only about 20% of the evidence was considered weak, this may have been a result of failure to identify every repurposed usage. Table 5 identifies the strength of the evidence by age group. Using χ² analysis, no significant relationship was observed between the pediatric age group and strength of the literature.

Table 5.

Summary of Strength of the Evidence for the Age Categories

Most references provided the dosages used; most often weight-based, but sometimes fixed dosing was used. In a number of cases, the doses differed for the same repurposed indication. Dosing information was not included in Tables 2 to 4, as it was felt very important for clinicians to retrieve and review the latest primary literature.

Our research also revealed the fact that, in almost every instance, the medical record did not indicate that patients or their guardians/parents were informed that a drug was being prescribed for an unlabeled indication.

DISCUSSION

Due to resource constraints, we did not attempt to produce the most exhaustive list possible. Rather, our list represented the most extensive list of repurposed medications in pediatric patients published to date. A recent study by Blatt and Corey¹⁵⁷ identified 63 repurposed medications used in pediatric patients with emphasis on pediatric hematology/oncology. The authors looked for medications having at least 1 pediatric indication for which a newer use was in hematology/oncology. The present study differed in that it did not focus on hematology/oncology. Additionally, repurposed medications were excluded if the use was also found in adult patients (e.g., aspirin for colon cancer prevention).

Some studies have shown that off-label use is extensive in hospital as well as outpatient settings.^13–15 The present study was limited to the literature and hospital setting and did not seek to answer the question of frequency of off-label prescribing in either inpatients or outpatients. Further research is needed to determine the extent of novel off-label use of medications in pediatric populations.

A recent study revealed that few drug-labeling changes made under pediatric legislation include neonates.¹⁵⁸ Previous research has revealed that hospitalized neonates and infants receive the greatest proportion of off-label use of medications.¹² Although this may be true for all off-label use (e.g., age, dose, weight, and route of administration), the present study reveals that this pediatric subpopulation is actually least likely to receive an off-label use for a repurposed indication. Our results reflect other literature that has found neonates to be less likely to receive medications off-label and attributed this to the scarcity of reliable dosing information, as well as a more conservative approach in this pediatric subpopulation.¹⁵⁹

Results presented in this paper validate that the majority of the literature pertained to studies in small numbers of children and that several therapeutic categories had multiple repurposed medications. For example, medications were repurposed more than several times for cerebral palsy, muscular dystrophy, insomnia, cystic fibrosis, migraine, apnea, and stuttering. Our data also revealed that research may be needed on older medications. Most innovative uses pertained to medications that had been on the market for years; that is, older generic medications or widely used medications for which little evidence exists of harm to children. Few new medications were used for innovative uses. In fact, depending upon the definition of a new medication, less than 5% of the medications in Tables 2 to 4 were first marketed after 2011 and could be considered new medications (i.e., exenatide, letrozole, and tocilizumab). Possible reasons for this may include lack of experience on the part of clinicians even in adult patients to use new medications, fear of liability, and/or the fact that novel uses often emerge from postmarketing experience.

In some cases, promising novel uses reported by clinicians to the manufacturer may prompt a clinical trial with subsequent FDA approval. For example, while conducting this research, propranolol, used for pediatric hemangioma, received FDA approval for this indication. Similarly, imipramine is now FDA-approved for nocturnal enuresis in pediatric patients and does not appear in Tables 2 to 4. However, in other cases uses identified decades ago in the literature were not followed up upon and more recent studies could not be located. In a number of cases, the early literature was strong but FDA approval was never sought nor were later clinical studies conducted.

This paper highlights the difficulty in locating information on medications repurposed for pediatric patients. There are few resources that enable a clinician to locate drug information on prescribing, dosing, and dispensing of approved medications for unlabeled repurposed pediatric indications. Such uses can no longer be discussed at symposia or professional meetings. Most of the uses noted in Tables 2 to 4 did not appear in the Harriet Lane Handbook or other pediatric textbooks (e.g., Nelson's Textbook of Pediatrics). Prescribers frequently consult pharmacists regarding complex pediatric pharmacotherapies and the role of pharmacists as drug information experts in facilitating evidence-based prescribing for unlabeled pediatric use of medications is of increasing importance.¹⁶⁰ Pediatric Drug Information practice today entails more and more requests for information about off-label uses. In a recent study of drug information queries to a Pediatric Medication Resource Center conducted by the author, safety and efficacy of off–label uses, dosages, and regimens constituted a large number of requests.²¹ Pharmacy clinicians need to be knowledgeable as to where to locate information. Table 6 provides a listing of drug information resources that include unlabeled pediatric indications.

Table 6.

Drug Information Resources Which Include Unlabeled Pediatric Indications

This study underscores the need for clinical trials. A number of specific repurposed medications did not appear on the FDA list of medications requiring further study in children. It is hoped that our results will assist in further prioritizing certain medications for additional pediatric study. Where evidence is weak, perhaps IND applications would be needed or clinicians could not obtain institutional review board approval to conduct a study in the first place. Repositioned medications do not require the typical 7 to 9 years required for new drug development but go directly to preclinical testing and clinical trials thus reducing risks and costs.¹⁶¹

The BPCA and PREA have increased the study of drugs in children. Prior to these laws, more than 80% of drugs approved for adult use were being used in children, even though safety and efficacy had not been established in children. The FDA estimates that today that number is about 50%. The FDA often requests that manufacturers conduct pediatric studies and it gives the manufacturers a deadline for them. In some cases (e.g., prostate cancer drug), the FDA will waive pediatric study requirements. In other cases, if the manufacturer does not perform the studies, the FDA can grant extensions. But, if a company does not conduct the study or ask for extensions, since August 2013, the FDA has published the non-compliance letters it issues together with the company's response on its Web site…a type of public humiliation.

The BPCA Priority List of Needs in Pediatric Therapeutics is an important initiative to promote pediatric research. The BPCA requires that the National Institutes of Health, and specifically the National Institute of Child Health and Human Development (NICHD), identify drug needs in pediatric therapeutics. The NICHD sponsors relevant clinical trials and is responsible for submission of resulting clinical trial data to the FDA for pediatric labeling changes. Although progress has been made, revisions to the BPCA and the PREA are essential for these laws to achieve their original intent. Clinical studies in pediatric patients should actually be required to include pediatric patients (as opposed to adolescents), be meaningful, and successful to result in exclusivity.

Our results indicate that despite evidence of the benefits of off-label usage, many off-label indications lack scientific support or literature of efficacy or safety. Some have only anecdotal or case report data. Although the vast majority of re-purposed indications were for older medications, research for safety and efficacy is, nevertheless, required. Prescribers are often unaware that the medication does not have FDA approval for a use when they prescribe it. Even worse, off-label use can have no therapeutic effect resulting in wasteful medication use and worst-case scenario the off-label use can harm the patient (Figure). For example, codeine for postoperative analgesia after pediatric tonsillectomy and/or adenoidectomy was used for years before it was discovered that cytochrome P4502D6 ultrarapid metabolizers were at risk of life-threatening or fatal adverse effects from normal doses. Similarly, promethazine, commonly used previously in pediatric patients, received a black box warning in 2005 for children less than 2 years due to respiratory depression and death. Therefore, a procedure that yields information on safety and pharmacovigilance on off-label uses remains imperative to avoid therapeutic roulette.

Figure.

Benefit-to-risk spectrum for off-label use: patient benefit or therapeutic roulette.

Moreover, legal implications of prescribing and dispensing a medication for non-approved uses will be minimized if the prescriber and pharmacist, in the exercise of sound professional judgment conclude the use is rationale, safe, and reasonable.¹⁶²

Some hospitals have policies and procedures for innovative use of medications. Table 7 provides an example of possible elements to include in such a policy. When the use of a medication is experimental, then the patient (or guardian) should be informed of its experimental status. According to the American Academy of Pediatrics Policy Statement, off-label use is neither incorrect nor investigational if based on sound scientific evidence, expert medical judgment, or published literature; when use is truly investigational, or when the prescriber proposes to treat a group of patients rather than a single patient, the use should be performed in conjunction with well-controlled clinical trials.¹⁶³

Table 7.

Policy Title: Innovative Use of Medications

Guidelines for appropriate off-label prescribing would help to inform clinical practitioners. In February 2013, the FDA issued a guidance entitled “Pediatric Information Incorporated Into Human Prescription Drug and Biological Products Labeling,” which provides recommendations for placement and content of pediatric information in prescription drug labeling when available data support a pediatric indication and when data do not support a pediatric indication (i.e., data are negative or inconclusive). This is a step in the right direction but does not address repurposed uses.

The fact remains that there is no central repository for comprehensive data on pediatric off-label uses for policy makers, regulators, payers, and clinicians. Recently, it has been suggested that an online forum be developed to share novel uses of medications for pediatric patients.

It is apparent that an enormous research agenda exists that begs to be addressed to permit more repurposed uses with strong evidence on the product label. Further research should also focus on determining the circumstances of off-label prescribing and its appropriateness. The FDA has perceived its role with regard to identification of important supplemental indications to be somewhat passive. There is a growing recognition that the FDA should adopt a much more active role, facilitating research, evaluation, and labeling revisions for off-label uses. Perhaps preliminarily assessing the available data or providing some other regulatory mechanism for accelerated approval for pediatric indications should be considered. The use of an application similar to an Orphan Drug Act (ODA) request or actually providing ODA designation for all pediatric SN-DAs might be beneficial to accelerate approval for pediatric indications. Ideally, an FDA-mandated efficacy assessment of innovative off-label uses could be established to collect data on clinical effectiveness and adverse events (AEs).¹⁶⁴ This would involve the FDA systematically collecting postmarketing data to quantify the risk:benefit of innovative off-label uses; synthesizing evidence regarding these uses and disseminating requests. Grant funding would assure proper study and monitoring. Such a model has been applied to clinical/surgical registries, AE reporting, and medical device failures. Alternatively, manufacturers could be made responsible for collecting efficacy data and develop pharmacovigilance plans to detect and report AE associated with innovative off-label use. Importantly, however, all this must be accomplished without compromising rigorous efficacy or safety standards.

The use of medications for repurposed uses plays an important role in pediatric pharmacotherapy. When package inserts lag behind clinical practice, clinicians must critically evaluate the entire body of evidence available, become familiar with the strength of the literature on the proposed use, and carefully weigh the potential therapeutic benefits against the risks. Rigorous literature evaluation by pharmacists is of increasing importance to ensure that innovative uses are evidence-based. The valuable role of pediatric clinical pharmacists in assessing novel off-label uses continues to expand and is established in most of the approximately 175 US children's hospitals.

By describing drug repurposing in pediatric patients, the hope is clinicians, industry, academia, and government will continue to cooperate so that Dr Shirkey's phrase pediatric “therapeutic orphan” becomes a colloquialism.