Comparison of Unlicensed and Off-Label Use of Antipsychotics Prescribed to Child and Adolescent Psychiatric Outpatients for Treatment of Mental and Behavioral Disorders with Different Guidelines: The China Food and Drug Administration Versus the FDA

Abstract

Objectives:

This study aims to compare the prevalence of unlicensed and off-label use of antipsychotics among child and adolescent psychiatric outpatients with guidelines proposed by the China Food and Drug Administration (CFDA) and the U.S. Food and Drug Administration (FDA), and to identify factors associated with inconsistencies between the two regulations.

Methods:

A retrospective analysis of 29,326 drug prescriptions for child and adolescent outpatients from the Affiliated Brain Hospital of Guangzhou Medical University was conducted. Antipsychotics were classified as “unlicensed” or “off-label use” according to the latest pediatric license information registered by the CFDA and the FDA or the package inserts of antipsychotics authorized by the CFDA or the FDA for the treatment of pediatric mental and behavioral disorders, respectively. Binary logistic regression analysis was performed to assess factors associated with inconsistencies between the two regulations.

Results:

The total unlicensed use, according to the CFDA analysis, was higher than that found in the FDA analysis (74.14% vs. 22.04%, p < 0.001). However, the total off-label use, according to the FDA analysis, was higher than that found in the CFDA analysis (46.53% vs. 15.77%, p < 0.001). Antipsychotic drug classes, age group, number of diagnoses, and diagnosis of schizophrenia and schizotypal and delusional disorders were associated with inconsistent unlicensed use. Antipsychotic drug classes, age group, number of prescribed psychotropic drugs, gender, diagnosis of schizophrenia and schizotypal and delusional disorders, diagnosis of mood [affective] disorders, diagnosis of mental retardation, and diagnosis of psychological development disorders were associated with inconsistent off-label use.

Conclusions:

The difference in prevalence of total unlicensed and off-label use of antipsychotics between the two regulations was statistically significant. This inconsistency could be partly attributed to differences in pediatric license information and package inserts of antipsychotics. The results indicate a need for further clinical pediatric studies and better harmonization between agencies regarding antipsychotic used in pediatrics.

Introduction

The use of antipsychotics in the pediatric population, especially among adolescents, has significantly increased worldwide during the past several decades (Harrison et al. 2012; Ronsley et al. 2013; Song and Guo 2013; Olfson et al. 2015). Meanwhile, unlicensed and off-label use of antipsychotics in pediatrics has also become a common phenomenon. This is due to the fact that antipsychotics approved for pediatric use are limited (Braüner et al. 2016), and there is inadequate pediatric labeling of antipsychotics, which is often attributed to a lack of assessment during the drug development process (Kimland and Odlind 2012). A recent study performed in a Danish child and adolescent psychiatric outpatient clinic showed that 27.6% of psychotropic drug prescriptions were off-label (Nielsen et al. 2016); in Germany, outpatient antipsychotic treatment in the pediatric population appeared to have a substantially larger increase of off-label prescriptions, varying between 61.0% and 69.5% (Schröder et al. 2017).

The findings of studies on the contribution of unlicensed and off-label drug use to adverse drug reactions (ADRs) have been inconsistent. One study found no association between unlicensed or off-label drugs and ADRs (Turner et al. 1999), while another found that the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use (Neubert et al. 2004). Although the use of unlicensed and off-label medicines is not prohibited in most countries, there is accumulating evidence that unlicensed and off-label medicinal use are a potential risk factor for ADRs, and these drugs are more likely to be implicated in an ADR than labeled medicines used in the pediatric population (Bellis et al. 2014; Saiyed et al. 2015).

Currently, data on pediatric psychotropic prescription and use in China are sparse, especially concerning evaluation of unlicensed and off-label antipsychotics (Song and Guo 2013; Hsu et al. 2014). Moreover, China still has significant gaps and weaknesses in regulatory oversight of unlicensed and off-label use of drugs (Ma and Lou 2013). Therefore, it is essential to monitor the prevalence of unlicensed and off-label use of antipsychotics among children and adolescents with mental and behavioral disorders.

Most of the drug manufacturing firms in China, a developing and transitional country, primarily produce generic drugs with little development of originator pharmaceuticals. Originator drugs are imported mainly from the United States, Japan, and European countries. Chinese doctors must prescribe according to official regulations from the China Food and Drug Administration (CFDA), but the U.S. Food and Drug Administration (FDA) offers important alternative reference material for the physician when prescribing a medication, given that the CFDA often makes decisions by referring FDA practices. As the list of unlicensed drugs and authorized product information of approved drugs differ between the CFDA and the FDA, it is more difficult for us to describe the prevalence of use of unlicensed and off-label antipsychotic prescriptions; however, it also presents a unique opportunity to specifically pinpoint the differences between the two regulations in classifying pediatric drug use as unlicensed or off-label, as well as drug prevalence (Berdkan et al. 2016).

To the best of our knowledge, this is the first study comparing the prevalence of unlicensed and off-label use of antipsychotics among child and adolescent outpatients with mental and behavioral disorders in China with different guidelines proposed by the CFDA and the FDA.

Methods

Data source

A retrospective medication records review of outpatients from January 1, 2013 to 2016, from the outpatient clinics of the Affiliated Brain Hospital of Guangzhou Medical University, a major mental health center in South China, was conducted based on data extracted from an electronic drug prescription system. Before conducting this study, approval was obtained from the ethical committee at the Affiliated Brain Hospital of Guangzhou Medical University, with exemption from the informed consent requirement acquired.

Participants

According to the age classification of pediatric patients in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) harmonized tripartite guideline E11 (ICH 2000), child (2–11 year olds) and adolescent (12–17 year olds) psychiatric outpatients from the outpatient clinics of the Affiliated Brain Hospital of Guangzhou Medical University, who received treatment with antipsychotics classified using the Anatomical Therapeutic Chemical classification system codes, were included in the study.

Electronic medication record collection

The following information of each electronic medication record for prescriptions was extracted for each patient: patient ID card, prescription number, gender, age, diagnoses according to the ICD-10 (International Classification of Diseases, 10th Revision, Classification of Mental and Behavioral Disorders), and drug information (including drug name, dosage, and administration form). Exclusion criteria included the following: (a) prescriptions with unclear or contradictory diagnoses; (b) patients aged less than 2 years or at least 18 years of age; (c) medication records without antipsychotics; (d) prescriptions with organic diseases' diagnoses, excluding symptomatic and mental disorders (including epilepsy, central nervous system infection, and migraine); and (e) medication records with unavailable or incomplete information on dosage, indication, or patient characteristics.

Unlicensed and off-label use identification

Each electronic medication record included in our study corresponds to an antipsychotic drug. The antipsychotics were classified as unlicensed or off-label use according to the latest pediatric license information or the package inserts of antipsychotics authorized by the CFDA or the FDA for treatment of mental and behavioral disorders in pediatrics, respectively. The term “unlicensed use” means the use of a drug without pediatric license information in China or the United States (McD Taylor et al. 2015). FDA-unapproved drug usage was also considered unlicensed use in the FDA analysis. The following categories were used for off-label prescriptions: (a) indication not approved (off-label indication); (b) medicine not approved for age of the patient (off-label age), and (c) dose higher than approved (off-label dose) (Yasinta et al. 2016). As most of the administration forms of antipsychotics for outpatients were oral solid forms, potential off-label use of alternative routes of administration was not assessed.

Assessment

As two different regulatory agencies approve medicines in China and the United States (the CFDA and the FDA, respectively), the number of authorized antipsychotics for pediatric use varies between the two countries. In China, 11 antipsychotics, risperidone, clozapine, perphenazine, fluphenazine, fluphenazine decanoate, haloperidol, haloperidol decanoate, sulpiride, chlorpromazine, tiapride, and penfluridol, are authorized for treatment of mental and behavioral disorders in pediatric populations. However, just eight antipsychotics—aripiprazole, quetiapine, risperidone, olanzapine, paliperidone, perphenazine, haloperidol, and chlorpromazine—are approved for pediatric use in the United States. The latest package inserts of antipsychotics authorized by the CFDA or the FDA for treatment of mental and behavioral disorders in children and adolescents are listed in Table 1.

Table 1.

The Latest Package Inserts of Antipsychotics Authorized by the CFDA or the FDA for Treatment of Mental and Behavioral Disorders in Pediatric Populations

Drug	Agencies	Indication	Age	Recommended dosage
Typical antipsychotics
Chlorpromazine	CFDA	Schizophrenia; Manic and other psychotic disorders	≥6 years	600 mg/day, po,
	CFDA	Schizophrenia; Manic and other psychotic disorders	Child	200 mg/day, iv or im,
	FDA	Preoperative anxiety	Child	0.25 mg/pound, po or im^a
	FDA	Children behavioral disorders	≥0.5 years	100 mg/day, po, or 40 mg/day, im, <5 years; 200 mg/day, po, or 75 mg/day, im, 5–12 years
Haloperidol	CFDA	Schizophrenia; Mania; Tourette's disorder; Organic mental disorder	≥3 years	40 mg/day
	CFDA	Schizophrenia; Mania; Organic mental disorder	Child	30 mg/day, iv or im
	FDA	Schizophrenia; Tourette's disorder	≥3 years	6 mg/day, 3–12 years; 100 mg/day, >12 years
	FDA	ADHD; Children behavioral disorders	≥3 years	6 mg/day, 3–12 years; 15 mg/day, >12 years
Haloperidol Decanoate	CFDA	Schizophrenia, maintenance therapy	Child	300 mg/day, iv or im
Perphenazine	CFDA	Schizophrenia or other psychotic disorders; Aggressive behavior	≥12 years	60 mg/day
Perphenazine	FDA	Schizophrenia	≥12 years	12 mg/day
Fluphenazine	CFDA	Schizophrenia	≥6 years	30 mg/day
Fluphenazine Decanoate	CFDA	Schizophrenia	≥12 years	25 mg/2–5 week, iv or im
Atypical antipsychotics
Aripiprazole	FDA	Schizophrenia	≥13 years	30 mg/day
		Bipolar I disorder, manic or mixed episodes	≥10 years	10 mg/day
		Bipolar I disorder, as adjunctive therapy to lithium or valproate	≥10 years	30 mg/day
		Irritability associated with autistic disorder	≥6 years	15 mg/day
		Tourette's disorder	≥6 years	20 mg/day
Quetiapine	FDA	Schizophrenia	≥13 years	800 mg/day
Quetiapine	FDA	Bipolar mania, monotherapy	≥10 years	600 mg/day
Risperidone	CFDA	Schizophrenia or other psychotic disorders	≥15 years	10 mg/day, tablets; 16 mg/day, others^b
	FDA	Schizophrenia	≥13 years	6 mg/day
		Bipolar mania	≥10 years	6 mg/day
		Irritability associated with autistic disorder	≥5 years	3 mg/day
Olanzapine	FDA	Schizophrenia; Bipolar I disorder, manic or mixed episodes	≥13 years	20 mg/day
Olanzapine	FDA	Bipolar I disorder, depressive episodes	≥10 years	12 mg/day
Paliperidone	FDA	Schizophrenia	≥12 years	6 mg/day, <51 kg; 12 mg/day, >51 kg^a
Clozapine	CFDA	Schizophrenia; Manic and other psychotic disorders	≥12 years	600 mg/day
Sulpiride	CFDA	Schizophrenia; Depressive symptoms	≥6 years	120 mg/day, po; 800 mg/day, iv or im;
Tiapride	CFDA	Tourette's disorder	≥7 years	100 mg/day, 7–12 years; 600 mg/day, >12 years
Penfluridol	CFDA	Schizophrenia	Child	120 mg/week

In China, 11 antipsychotics, risperidone, clozapine, perphenazine, fluphenazine, fluphenazine decanoate, haloperidol, haloperidol decanoate, sulpiride, chlorpromazine, tiapride, and penfluridol, are authorized for treatment of psychiatric disorders in children. However, just eight antipsychotics—aripiprazole, quetiapine, risperidone, olanzapine, paliperidone, perphenazine, haloperidol, and chlorpromazine—are approved for pediatric use in the United States. Antipsychotics without pediatric license information in China or the United States were not listed in the table.

Only one antipsychotic (paliperidone extended release tablet) in our study was needed to use the patient's body weight to identify its “off-label dose use.” Chlorpromazine was not considered because diagnosis of preoperative anxiety could not be found in the prescriptions.

Others include oral solution, orally disintegrating tablets, and dispersible tablets.

CFDA, China Food and Drug Administration; FDA, U.S Food and Drug Administration; ADHD, attention-deficit/hyperactivity disorder; po, by mouth or orally; iv, intravenous; im, intramuscular.

Each electronic medication record for prescriptions was investigated for unlicensed or off-label use using CFDA and FDA guidelines, respectively, according to the following ranking: (a) pediatric license information, (b) indication, (c) age, and (d) dose. A flowchart of unlicensed and off-label prescribing pattern screening and inconsistency assessments of unlicensed and off-label use of antipsychotics between the two regulations are presented in Figure 1. Each electronic medication record for prescriptions was counted only once.

FIG. 1.

Flowchart of unlicensed and off-label prescribing pattern screening and inconsistency assessment of unlicensed and off-label use of antipsychotics between the two regulations. Each electronic medication record included in our study corresponds to an antipsychotic drug. Use of combined antipsychotics for patients with treatment-resistant schizophrenia is a common practice in psychiatry, which means that there can be more than one medication record for one prescription. A total of 40,528 electronic medication records for 29,326 drug prescriptions were included in our study. Of the total electronic medication records, 4210 met the exclusion criteria and 36,318 were investigated for unlicensed or off-label use using the CFDA and FDA guidelines, respectively, according to the following ranking: (a) pediatric license information, (b) indication, (c) age, and (d) dose. The word “Yes” above the arrowed lines means that the antipsychotics were classified as unlicensed, off-label indication, off-label age, or off-label dose use. The word “No” next to the arrowed lines means that the antipsychotics were classified as off-label indication, off-label age, off-label dose use, or on-label use. The words “Yes” or “No” in the shaded boxes and white boxes were the judgment results of unlicensed, off-label indication, off-label age, and off-label dose use of antipsychotics using the CFDA and FDA guidelines, respectively. The word “Inconsistency” means that the results judged by the CFDA guidelines were not the same as the FDA guidelines. CFDA, China Food and Drug Administration; FDA, Food and Drug Administration.

Statistical analysis

To compare the prevalence of unlicensed and off-label use of antipsychotics with different guidelines, the McNemar–Bowker test was used. Binary logistic regression analysis was performed to assess factors associated with the consistency (yes/no) of unlicensed and off-label use of antipsychotics between two regulations. Based on the information available, variables included antipsychotic drug classes (atypical vs. typical antipsychotics), age group (adolescent vs. child), gender (female vs. male), number of diagnoses, number of prescribed psychotropic drugs, and different diagnostic categories: organic, including symptomatic, mental disorders (ICD-10 F00–F09) (yes/no); mental and behavioral disorders due to psychoactive substance use (ICD-10 F10–F19) (yes/no); schizophrenia and schizotypal and delusional disorders (ICD-10 F20–F29) (yes/no); mood [affective] disorders (ICD-10 F30–F39), neurotic, stress-related, and somatoform disorders (ICD-10 F40–F48) (yes/no); behavioral syndromes associated with physiological disturbances and physical factors (ICD-10 F50–F59) (yes/no); disorders of adult personality and behavior (ICD-10 F60–F69) (yes/no); mental retardation (ICD-10 F70–F79) (yes/no); psychological development disorders (ICD-10 F80–F89) (yes/no); and behavioral and emotional disorders with onset usually occurring in childhood and adolescence (ICD-10 F90–F98) (yes/no). The odds ratios (OR) and two-sided 95% confidence intervals (CI) were used to describe the observed associations. The results were considered statistically significant if they reached p < 0.05. Statistical analysis was conducted using SPSS version 20.0 (IBM Corporation, Armonk, NY).

Results

Study population

A total of 29,326 drug prescriptions from 28,734 outpatients were included in the study and out of these patients, 16,914 (58.9%) were male. The mean age for all patients was 14.39 (±2.88) years with a range between 2 and 17 years old. The majority, 17,785, of the patients were adolescents (61.9%), ranging in age from 15 to 17 years. Single-diagnosis patients were preponderant (86.0%), and of those patients, mood [affective] disorders (30.7%), schizophrenia and schizotypal and delusional disorders (27.6%), and behavioral and emotional disorders with onset usually occurring in childhood and adolescence (15.8%) were the most commonly diagnostic categories (Table 2).

Table 2.

Characteristics of the 28,734 Patients who Received Antipsychotics

Characteristic	No.	%
Gender
Male	16,914	58.9
Female	11,820	41.1
Age (years)^a
2–6	579	2.0
7–11	3711	12.9
12–14	6659	23.2
15–17	17,785	61.9
Number of diagnoses^b
1	24,702	86.0
2	3548	12.3
3–4	484	1.7
Diagnoses^c
Mood [affective] disorders	9721	30.7
Schizophrenia and schizotypal and delusional disorders	7133	27.6
Behavioral and emotional disorders with onset usually occurring in childhood and adolescence	3381	15.8
Mental retardation	2420	9.9
Neurotic, stress-related and somatoform disorders	1347	8.8
Psychological development disorders	876	5.3
Others^d	3856	13.4

The mean age for all patients was 14.39 (±2.88) years with a range between 2 and 17 years.

Single-diagnosis patients were preponderant.

Detailed diagnoses according to the ICD-10 (International Classification of Diseases, 10th Revision, Classification of Mental and Behavioral Disorders) were included: mood [affective] disorders (F 30, F 31, F 32, F 33, F 34.0, F 34.1, and F 39), schizophrenia and schizotypal and delusional disorders (F 20, F 21, F 25, and F 28), behavioral and emotional disorders with onset usually occurring in childhood and adolescence (F 90, F 91, F 92, F 93, F 94, F 95, and F 98), mental retardation (F 79), neurotic, stress-related, and somatoform disorders (F 40, F 41.0, F 41.1, F 41.2, F 42, F 43, F 44, F 45, and F 48), and psychological development disorders (F 80, F 81, F 84, and F 85.5).

Others include all remaining ICD-10 F-diagnoses (F00–F09, F10–F19, F50–F59, F60–F69, and F70–F79) and comorbid diagnoses from different categories (e.g., comorbid bipolar affective disorder [F31] and tic disorders [F95]).

Total antipsychotic use

A total of 36,318 electronic medication records with antipsychotics for drug prescriptions were assessed (Fig. 1). The average number of antipsychotics prescribed per prescription was ∼1.24. Of the cohort patients, 23,640 had more than one antipsychotic in their prescriptions. The most commonly prescribed antipsychotics were ranked as follows: olanzapine (24.42%), quetiapine (15.93%), risperidone (15.20%), and aripiprazole (13.56%), according to numbers of electronic medication records (Table 3). Atypical antipsychotics accounted for 96.92% of the total antipsychotic use.

Table 3.

Number and Percentage of Unlicensed and Off-Label Use of Major Antipsychotics Prescribed to Child and Adolescent Psychiatric Outpatients According to the CFDA and the FDA [n, % (CFDA-FDA)]

Drug ^a	Total (n, %)^b	Unlicensed	Off-label indication	Off-label age	Off-label dose
Olanzapine (A)	8868, 24.42	8868-0, 100-0	0-3783, 0-42.66	0-470, 0-5.30	0-92, 0-1.04
Quetiapine (A)	5785, 15.93	5785-0, 100-0	0-3269, 0-56.51	0-396, 0-6.85	0-230, 0-3.98
Risperidone (A)	5520, 15.20	0-0, 0-0	2963-2845, 53.68-51.54	985-260, 17.84-4.71	63-1160, 1.14-21.01
Aripiprazole (A)	4926, 13.56	4926-0, 100-0	0-1689, 0-34.29	0-468, 0-9.50	0-587, 0-11.92
Amisulpride (A)	2696, 7.40	2696-2696, 100-100	0-0, 0-0	0-0, 0-0	0-0, 0-0
Paliperidone (A)	2107, 5.80	2107-0, 100-0	0-975, 0-46.27	0-85, 0-4.03	0-3, 0-0.14
Ziprasidone (A)	1822, 5.02	1822-1822, 100-100	0-0, 0-0	0-0, 0-0	0-0, 0-0
Clozapine (A)	1180, 3.25	0-1180, 0-100	267-0, 22.63-0	57-0, 4.83-0	13-0, 1.10-0
Sulpiride (A)	948, 2.61	0-948, 0-100	538-0, 56.75-0	5-0, 0.53-0	88-0, 9.28-0
Perospirone (A)	722, 1.99	722-722, 100-100	0-0, 0-0	0-0, 0-0	0-0, 0-0
Tiapride (A)	574, 1.58	0-574, 0-100	120-0, 20.91-0	32-0, 5.58-0	233-0, 40.59-0
Haloperidol (T)	572, 1.57	0-0, 0-0	109-64, 19.06-11.19	0-11, 0-1.92	5-36, 0.87-6.29
Perphenazine (T)	528, 1.45	0-0, 0-0	204-219, 38.64-41.48	28-28, 5.30-5.30	0-224, 0-42.42
Penfluridol (A)	50, 0.14	0-50, 0-100	9-0, 18.00-0	0-0, 0-0	0-0, 0-0

The phrasing “CFDA-FDA” means “CFDA versus FDA,” that is, the comparisons of the prevalence of unlicensed, off-label indication, off-label age, or off-label dose use between these two regulations.

The top 14 antipsychotics prescribed are listed in the table.

A total of 36,318 electronic medication records with antipsychotic information for drug prescriptions were assessed. Atypical antipsychotics accounted for 96.92% of the total antipsychotic use.

A, atypical antipsychotic; T, typical antipsychotic.

Prevalence of unlicensed and off-label use

According to CFDA regulations, the percentage of prescribed unlicensed antipsychotic use among children and adolescents was ranked in the following order: olanzapine (24.42%), quetiapine (15.93%), aripiprazole (13.56%), amisulpride (7.40%), paliperidone (5.80%), ziprasidone (5.02%), and perospirone (1.99%). When FDA regulations were used as a reference, the percentage of unlicensed antipsychotics prescribed to children and adolescents was found to be in the following order: amisulpride (7.40%), ziprasidone (5.02%), clozapine (3.25%), sulpiride (2.61%), perospirone (1.99%), tiapride (1.58%), and penfluridol (0.14%) (Table 3). The prevalence of off-label indication, off-label age, and off-label dose use of major antipsychotics prescribed to child and adolescent outpatients according to CFDA and FDA regulations, respectively, are shown in Table 3.

Comparison of total unlicensed and off-label use

Total unlicensed, off-label indication, off-label age, and off-label dose use of antipsychotics were assessed according to both guidelines (Table 4). The total use of unlicensed antipsychotics, according to the CFDA analysis, was higher than that found in the FDA analysis (74.14% vs. 22.04%, p < 0.001). However, the total off-label use of antipsychotics, according to the FDA analysis, was higher than that found in the CFDA analysis (46.53% vs. 15.77%, p < 0.001), as well as off-label indication (35.37% vs. 11.59%, p < 0.001), off-label age (4.75% vs. 3.06%, p < 0.001), and off-label dose (6.42% vs. 1.12%, p < 0.001).

Table 4.

Comparison of the Total Unlicensed and Off-Label Use of Antipsychotics with Different Guidelines

Classification of use	CFDA [n, (%)]	FDA [n, (%)]	p
Unlicensed use	26,926 (74.14)	8006 (22.04)	<0.001
Off-label use	5729 (15.77)	16,900 (46.53)	<0.001
Off-label indication use	4210 (11.59)	12,844 (35.37)	<0.001
Off-label age use	1111 (3.06)	1724 (4.75)	<0.001
Off-label dose use	408 (1.12)	2332 (6.42)	<0.001

The McNemar–Bowker test was performed to compare the prevalence of total unlicensed and off-label use of antipsychotics with different guidelines.

Factors associated with inconsistencies

Table 5 presents results from the binary logistic regression analysis. In this analysis, antipsychotic drug classes (atypical vs. typical antipsychotics, OR 166.467, 95% CI 98.148–282.343), age group (adolescent vs. child, OR 1.293, 95% CI 1.199–1.395), number of diagnoses (OR 2.161, 95% CI 1.891–2.468), and diagnosis of schizophrenia and schizotypal and delusional disorders (OR 0.412, 95% CI 0.356–0.476), were found to be statistically significant factors associated with inconsistency of unlicensed use of antipsychotics between the two agencies (p < 0.001). Antipsychotic drug classes (atypical vs. typical antipsychotics, OR 1.248, 95% CI 1.050–1.483), age group (adolescent vs. child, OR 2.271, 95% CI 1.853–2.782), number of prescribed psychotropic drugs (OR 1.172, 95% CI 1.106–1.241), gender (female vs. male, OR 0.801, 95% CI 0.702–0.913), diagnosis of schizophrenia and schizotypal and delusional disorders (OR 37.445, 95% CI 28.790–48.702), diagnosis of mood [affective] disorders (OR 21.110, 95% CI 15.892–28.041), diagnosis of mental retardation (OR 1.648, 95% CI 1.279–2.125), and diagnosis of psychological development disorders (OR 17.865, 95% CI 13.512–23.621), were identified as factors associated with inconsistency of off-label use between the two regulations, showing a statistically significant correlation (p < 0.05).

Table 5.

Results of Factors Associated with Inconsistent Unlicensed and Off-Label Use Between the CFDA and THE FDA

	Variables ^a	B	Wald	OR	95% CI	p
Unlicensed use^b	Antipsychotic drug classes (atypical vs. typical antipsychotics)	5.115	360.041	166.467	98.148–282.343	<0.001
	Age group (adolescent vs. child)	0.257	44.385	1.293	1.199–1.395	<0.001
	Number of diagnoses	0.770	128.607	2.161	1.891–2.468	<0.001
	Diagnosis of schizophrenia and schizotypal and delusional disorders	−0.887	144.093	0.412	0.356–0.476	<0.001
Off-label use^c	Antipsychotic drug classes (atypical vs. typical antipsychotics)	0.222	6.317	1.248	1.050–1.483	0.012
	Age group (adolescent vs. child)	0.820	62.578	2.271	1.853–2.782	<0.001
	Number of prescribed psychotropic drugs	0.159	29.065	1.172	1.106–1.241	<0.001
	Gender (female vs. male)	−0.223	11.041	0.801	0.702–0.913	0.001
	Diagnosis of schizophrenia and schizotypal and delusional disorders	3.623	729.827	37.445	28.790–48.702	<0.001
	Diagnosis of mood [affective] disorders	3.050	443.146	21.110	15.892–28.041	<0.001
	Diagnosis of mental retardation	0.500	14.875	1.648	1.279–2.125	<0.001
	Diagnosis of psychological development disorders	2.883	409.350	17.865	13.512–23.621	<0.001

Statistically significant variables associated with inconsistent unlicensed or off-label use between the CFDA and the FDA are listed in the table.

Binary logistic regression analysis was performed to assess factors associated with inconsistent unlicensed use of antipsychotics between the two regulations. −2 Log likelihood = 42580.584, Cox & Snell R Square = 0.087, Nagelkerke R Square = 0.122.

Binary logistic regression analysis was performed to assess factors associated with inconsistent off-label use of antipsychotics between the two regulations. −2 Log likelihood = 5961.547, Cox & Snell R Square = 0.287, Nagelkerke R Square = 0.404.

CI, confidence intervals; OR, odds ratios.

Discussion

The majority of antipsychotics prescribed to outpatient children and adolescents from the Affiliated Brain Hospital of Guangzhou Medical University were atypical antipsychotics. The prevalence of use of atypical antipsychotics among child and adolescent outpatients was much greater than a previous study that reported 80.2% use among Chinese inpatient children and adolescents in 2010 (Song and Guo 2013). These results may be due to the presence of few extrapyramidal syndromes or sedation adverse effects of atypical antipsychotics and a discrepancy in diagnostic categories of pediatric patients (Chen et al. 2015), as most of the major psychiatric disorders of outpatients in our study were mood [affective] disorders (30.7%) and schizophrenia and schizotypal and delusional disorders (27.6%).

According to both CFDA and FDA regulations, medications approved for pediatric use in China and the United States include risperidone, perphenazine, haloperidol, and chlorpromazine (Table 1). Differences between CFDA and FDA in the classification of off-label use of antipsychotics with pediatric approval were found in this study. The example of risperidone should be highlighted. In China, risperidone was only approved for treatment of schizophrenia or other psychotic disorders in adolescents aged 15–17 years (maximum dose = 10 mg per day for tablets and maximum dose = 16 mg per day for other dosage forms, respectively) (Xian Janssen, China 2014, 2015). However, FDA approved risperidone for treatment of schizophrenia in adolescents aged 13–17 years (maximum dose = 6 mg per day), bipolar mania in the pediatric population aged 10–17 years (maximum dose = 6 mg per day), and irritability and aggression in autistic children and adolescents aged 5–17 years (maximum dose = 3 mg per day), respectively (Drugs@FDA 2016a, 2016b). Thus, the number of CFDA-approved indications was lower compared with FDA-approved indications, while the CFDA-approved minimum age and maximum dose were higher than those of the FDA. Regarding risperidone, we found that the percentage of off-label indication according to the CFDA approval was higher compared with the FDA (53.68% vs. 51.54%), as well as for off-label age (17.84% vs. 4.71%), while the percentage of off-label dose according to the CFDA approval was significantly lower compared with the FDA (1.14% vs. 21.01%). The differences in prevalence of off-label use could be attributed to the differences between CFDA and FDA regulations (Berdkan et al. 2016).

Our results showed that the difference between CFDA and FDA regarding the prevalence of total unlicensed and off-label use of antipsychotics was statistically significant. In this study, our findings suggested that unlicensed antipsychotic use assessed according to the CFDA regulations was common, probably because many atypical antipsychotics (including olanzapine and quetiapine), which were most commonly prescribed to children and adolescents in our study, were classified as unlicensed use according to the CFDA regulations. The difference between the two agencies regarding the prevalence of total unlicensed antipsychotic use seems to suggest that there is greater strictness in antipsychotic drug registration for pediatric use by the CFDA. However, at least in part, this phenomenon could be more attributed to the lack of pediatric clinical research in China (Zhang et al. 2013). The total number of antipsychotics classified as off-label indication, as well as off-label age and off-label dose use, according to the FDA analysis, was higher than that found in the CFDA analysis, suggesting that the FDA has stricter pediatric labeling requirements. This may be due to the fact that, a series of initiatives had been implemented by FDA and the U.S. Congress to improve pediatric labeling, including the 1994 Pediatric Rule, the 1997 FDA Modernization Act (FDAMA), the 1998 Pediatric Rule, the 2002 Best Pharmaceuticals for Children Act (BPCA), and the 2003 Pediatric Research Equity Act (PREA) (Ren and Zajicek 2015). In particular, PREA, made permanent in 2012, ruled that pharmaceutical enterprises must complete pediatric clinical research of new drugs and biological products before marketing them (PREA 2003). The results indicate a need for further clinical pediatric studies to improve knowledge on the efficacy and safety of antipsychotic use in pediatrics and better harmonization between agencies regarding antipsychotic use.

Binary logistic regression analysis was carried out to explore factors associated with inconsistencies of unlicensed and off-label use between the two regulations. In our study, the inconsistency of unlicensed use was prominent with the increase of atypical versus typical antipsychotics. The possible explanation for our findings is that the most common antipsychotics prescribed to children and adolescents in our study were atypical antipsychotics approved for pediatric use, such as olanzapine and quetiapine, by the FDA, but not the CFDA. Thus, this inconsistency could be partly attributed to differences in pediatric license information registered by the CFDA and the FDA. Similar explanations could be used in relation to the diagnosis of schizophrenia and schizotypal and delusional disorders, diagnosis of mood [affective] disorders, diagnosis of mental retardation, and diagnosis of psychological development disorders, which were all identified as positive factors associated with inconsistency in off-label use. The inconsistencies of both unlicensed and off-label use were also obvious with the increase of adolescent versus child, and the inconsistency of off-label use was obvious with the decrease of female versus male. This outcome may be due to the demographic characteristics of the child and adolescent outpatients in our study. The number of diagnoses and prescribed psychotropic drugs were associated with inconsistencies of unlicensed and off-label use, respectively. The positive associations between them were readily comprehensible. Overall, our results suggested that inconsistencies of unlicensed and off-label use between the two agencies could be partly attributed to the differences in pediatric license information and package inserts of antipsychotics, respectively.

If a drug has been approved, physicians can legally prescribe the drug for any purpose (Czaja and Valuck 2012; Maher and Theodore 2012). However, if these unapproved, or “off-label,” uses of drugs lack adequate evidence, physicians tend to make prescriptions to children and adolescents more conservatively (Mack 2003). Nevertheless, physicians still probably tend to aggressively prescribe unlicensed and off-label antipsychotics to children and adolescents under the scarcity of drug safety data (Rodday et al. 2014). More clinical research into antipsychotics for pediatric populations is needed to update drug descriptions. During the process, some compulsory measures could be taken, or guideline principles regarding the approval of drugs for pediatric use could be proposed by the government. For example, in the European Union (EU), the EU published European regulation on medicines for pediatric use in 2007, which requires pharmaceutical enterprises to submit the Pediatric Investigation Plan (PIP) to the Pediatric Committee no later than upon completion of the pharmacokinetic studies in adults (Dunne et al. 2007). In addition, the European Medicines Agency (EMA) proposed a framework in 2016 for extrapolation of data from adults to children, which could serve as a basis for regulatory decision-making for PIP (EMA 2016). The Chinese government regulators' guideline principles of pediatric clinical trials as part of the process of the approval of new drugs by referring to other regulators' management experience reflect the harmonization between agencies regarding antipsychotics used in pediatrics. CFDA recently (2016) published guidelines for clinical trials of pediatric population (CFDA 2016) and a similar framework was proposed by CFDA's Center for Drug Evaluation (CFDA CDE), thus providing the basis for an explicit and systematic approach for the extrapolation of data from adults to support pediatric medicine authorization (CFDA CDE 2016).

Limitations and Strengths

There were some limitations of this study. First, only outpatients were enrolled in our study; thus, the impact of excluding inpatients on the overall findings was uncertain. Second, the body weights of outpatients were not available in our database; thus, we estimated body weight according to patients' gender and age, based on Chinese pediatric population normative data (Li et al. 2009). However, the prevalence of underweight and overweight children and adolescents in our study area was not available, which may have led to an underestimation or overestimation of the body weight among some outpatients. The underestimation or overestimation of body weight could increase or decrease the actual prevalence of off-label dose when the dosage of paliperidone was 6–12 mg per day. Third, all data were collected at one hospital (in one region). Thus, the results may not be representative. The study of the prevalence of unlicensed and off-label use of antipsychotics prescribed to the entire pediatric outpatient population is restricted because of the limited sample size of prescriptions of antipsychotic drugs prescribed to patients younger than 2 years of age. Finally, we classified antipsychotics as unlicensed or off-label according to the latest (2016) pediatric license information or package inserts of antipsychotics authorized by the CFDA or the FDA for treatment of mental and behavioral disorders in pediatrics, respectively. Thus, despite few changes with respect to the pediatric license information or the package inserts of antipsychotics authorized by the CFDA or the FDA during the 3 years in which this study took place, there are still inevitable deviations associated with the evaluation of unlicensed and off-label use of antipsychotics (O'Brien et al. 2017).

Similar studies from other countries with respect to the comparison of antipsychotic drug utilization by using different regulations were sparse. This study is the first study, to the best of our knowledge, describing the prevalence of unlicensed and off-label use of antipsychotics prescribed to children and adolescents in China. Moreover, unlike previous published studies that used data from two worldwide official regulatory agencies to determine whether a medicine was considered unlicensed or off-label (Borges et al. 2013; Berdkan et al. 2016), we listed detailed criteria for on-label status based on the authorized product information for antipsychotics with pediatric approval for treatment of mental and behavioral disorders. Furthermore, we innovatively proposed the differences and factors associated with these inconsistencies between the CFDA and the FDA with respect to the prevalence of unlicensed and off-label use of antipsychotics, and a need for better harmonization between the agencies regarding antipsychotics used in pediatrics. Another strength of this study was that it incorporated the largest number of outpatients among similar single-center studies associated with antipsychotic use in children and adolescents.

Conclusions

In conclusion, most atypical antipsychotics commonly prescribed to children and adolescents in China were classified as unlicensed use according to the CFDA regulations. There were significant differences between the CFDA and the FDA regarding the prevalence of unlicensed and off-label use of antipsychotics. The inconsistencies of unlicensed and off-label use between the two agencies could be partly attributed to the differences in pediatric license information and package inserts of antipsychotics, respectively.

Clinical Significance

Unlicensed and off-label use of antipsychotics prescribed to pediatric patients has become a common phenomenon, but prevalence information is still lacking in China. This study is the first evaluation of the prevalence of unlicensed and off-label use of antipsychotics prescribed to child and adolescent outpatients with mental and behavioral disorders in China using the CFDA and FDA guidelines. The results indicate a need for further clinical pediatric studies to optimize the content of package inserts authorized by the CFDA when necessary and better harmonization between the agencies regarding antipsychotics used in pediatric populations.

Footnotes

Acknowledgments

We would like to thank the directors of the hospital information department of the Affiliated Brain Hospital of Guangzhou Medical University for their assistance in data collection.

Funding

This research received the grant from Guangzhou municipal key discipline in medicine for Guangzhou Brain Hospital (Grant Nos. GBH2014-QN06), Guangzhou municipal science and technology project for medicine and healthcare (Grant Nos. 20171A010281, Grant Nos. 20171A010276), and Guangzhou municipal key discipline in medicine (2017–2019). The findings and conclusions are those of the authors and do not necessarily represent the views of the authors' affiliated institutions.

Disclosures

No competing financial interests exist.

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