Off-Label Drug Use in Pediatric Out-Patient Care: A Multi-Center Observational Study

Abstract

Objective:

Prescribing a drug for a child is not an easy task and requires using the best available evidence as a guide, especially when a drug is used off-label. The practice of prescribing a drug for off-label use is fairly widespread worldwide. The FDA does not regulate prescribing patterns or practices of individual practitioners and, therefore, allows off-label use. The main objective of this study is to evaluate off-label prescribing among the pediatric population in the Kingdom of Saudi Arabia (KSA).

Method:

This is a retrospective, simple random selection observational study of children (≤15 years) who visited pediatric clinics and had at least 1 drug prescribed over a 12-month period (January to December 2018).

Results:

A total of 865 drugs (mean 1 and SD 0.24) were prescribed to 326 children. Off-label was identified in 39.4% of the drugs with a frequency of 512 (as 1 drug may belong to more than 1 off-label category). The most common reason for off-label prescribing was related to doses that were “higher or lower than the recommended use” (48.6%), and the most frequently identified drug class prescribed for off-label use was anti-infective drugs for systemic use (39.9%). The percentage of off-label drug use was found to be higher in girls and in the age group of 1 month to 2 years (P = .001) for both variables. In addition, a significant association was found between off label drug use and the total number of drugs prescribed, P < .001.

Conclusion:

The findings of this study showed a high incidence of off-label prescribing mainly related to dosing and indication. The results of this observational study support the need to establish a unified national pediatric dosing formulary guide to ensure safe drug use in pediatrics.

Background

The United States’ Food and Drug Administration (FDA) is a federal agency of the Department of Health and Human Services (DHHS) responsible for regulating market entry and approval of 3 main medication product types (new drugs, generic drugs, and over-the-counter drugs) after a clear demonstration of drug safety and efficacy for specific indications. ¹ Off-label drug use is defined as the “prescribing of a licensed product for use in an unauthorized way.” ² Off-label use among children is a common occurrence and represents an important health concern, especially as information regarding the safety and efficacy of pediatric patients is either insufficient or absent. ¹ Unfortunately, only 12% of clinical trials have focused on treatment of diseases that are overrepresented in children. ³ This can increase the risk of adverse events and pose legal and ethical dilemmas. ⁴

The FDA does not regulate the prescribing patterns or practices of individual practitioners and, therefore, allows off-label use. Off-label use refers to prescribing a registered medicine for a use that is not included in the medicinal information approved by the regulatory body of the country for the benefit of an individual patient. The term “off-label” does not mean an illegal, contraindicated, improper or investigational use. ⁵ Rather, off-label prescribing is the use of a drug contrary to the label by indication, route, dose, dosing regimen, or age range. ⁶ Although some drugs are prescribed for use in an indication not listed in the approved labeling, their use generally stems from rational and sound medical advice. However, the lack of FDA approval means that the product has not been formally evaluated, and that differences in the physiology of children may result in unexpected pharmacokinetic and pharmacodynamics effects. ⁷ Therefore, the practice of off-label prescribing can be challenging, raise risk concerns, and potentially increase costs to the health care system. ⁸ According to a cross-sectional study published in 2006, there were an estimated 150 million off-label prescriptions written in that year (21% of total use). Of those, 27% were for indications supported by scientific evidence, and 73% had little or no corroborated evidence. ⁹

Off-label drug usage is a widespread phenomenon worldwide. ⁸ Several studies have assessed the prevalence of off-label and unlicensed drug use in pediatric patients and reported that up to 47% % of medications in the US were for off-label indications.^10-12 Conroy and colleagues performed a multicenter cross-sectional study across various European countries focusing on pediatric wards and found that nearly 50% of the prescribed drugs were used for an off-label or unlicensed indication, with off-label use representing the highest percentage. ¹³

The off-label prevalence rate among children was reported to be around 40.2%. ¹⁴ A recently published retrospective cross sectional study in a French pediatric hospital found that 36.5% of the prescribed medicines were for off-label indications and 3.2% were for unlicensed use. ¹⁵

A prospective study conducted in Finland over 2 weeks in pediatric wards showed a significantly high prescribing of unlicensed drugs to children aged less than 2 years. ¹⁶

Saiyed and colleagues conducted a prospective study to quantify the pattern of off-label drugs used in hospitalized pediatric patients in India using the National Formulary of India. The authors found that more than 90% of the included subjects received at least 1 off-label drug, while 70% of uses were prescribed based on 14 possible off-label categories. The majority of off-label prescribing was due to dose differences and use in a restricted age category. Higher rates of off-label use were found with respiratory medicine (82%), anti-infectives (73%), and nervous system medicines (53%). ¹⁷

The magnitude of prescribing off-label and unlicensed drugs in pediatric patients has been extensively studied and discussed worldwide.^14,18-24 In Saudi Arabia, the Saudi Food and Drug Authority (SFDA) is the competent regulatory body. According to Saudi national laws and regulations, a pharmaceutical product must not be promoted for sale or supply before a marketing authorization license is issued. Furthermore, all advertising and promotional materials regarding a pharmaceutical product must first be approved and certified by SFDA. ²⁵ The main objective of this study is to evaluate off-label prescribing among the pediatric population in the Kingdom of Saudi Arabia (KSA) with the aim of determining the prevalence rate and extent of off-label prescribing in the pediatric population at multiple centers under the Ministry of National Guard Health Affairs (MNGHA).

Methods

This is a retrospective, simple random selection observational study of children (≤15 years) who visited pediatric units/clinics (excluding cancer units/clinics) and had at least 1 drug prescribed at MNGHA medical cities (King Abdulaziz Medical City [KAMC]-Jeddah, Western Region; National Guard Specialized Poly Clinic [NGSPC]-Jeddah, Western Region and Imam Abdulrahman Bin Faisal Hospital-Dammam, Eastern Region) over a 12-month period (January-December 2018) with the aim of determining the rate of off-label drug use in pediatric patients. Data were obtained from the patients’ medical records by 5 of the researchers using a predefined data collection format. They recorded details of all the patients seen and reported patients with any identified off-label drug use to the study’s principal investigator. To avoid discrepancy in terms of methodology, the researchers were trained in order to conduct this study using a predefined standardized data collection format, and to use standardized international terminologies: the Anatomic Therapeutic Chemical (ATC) classification (WHO-ATC) for medication class, and we also used a validated drug reference for pediatric as each data collector had to specify the source of the off-label (Micromedex, Harriet Lane, and Lexicomp), which we used as per FDA regulations for off-label drug categories or reasons, while a chart review was used as the main methodology.

All identified off-labels detected by each researcher were peer-reviewed for validation by 1 consultant pediatric physician, 1 clinical pharmacist, and the researcher (Pharmacist/Physician). A final decision regarding the validation of off-labels was made by consensus after discussion within the group. Off-label incidence was calculated as the number of patients with at least 1 off-label drug use divided by the total number of patients in the total study cohort, and then multiplied by 100.

Children were grouped into 5 age-groups modified from the International Conference of Harmonization Guideline E11 ²⁶ as follows: ≤1 month; >1 month to ≤2 years; >2 to ≤6 years; >6 to ≤12 years; and >12 (we used ≤15 years as the cut-off age to align with our institution’s guidelines). Data includes demographic (sex, age, body weight, and height), diagnosis, and the number of medications prescribed per prescription visit. Medicines will be further classified as off-label based on the study’s definition and the number and details of identified off-labels (drug class, dose, frequency, indication, route of administration, formulation, and duration).^20,21 Off-label use was identified using Micromedex, Harriet Lane, and Lexicomp. The use of a medicine considered as off-label was determined based on the following categories or reasons as per FDA regulations. The same drug may be included in more than 1 category.^5,8,27,28

1. Dose: dose prescribed higher or lower than the recommended use (Category 1)

2. Indication: drug prescribed for indications outside the approved references (Category 2)

3. Age: drug prescribed for age outside the approved references (Category 3)

   Patients’ ages are classified into 5 age-groups:

   ≤1 month

   >1 month to ≤2 years

   >2 years to ≤6 years

   >6 years to ≤12 years

   >12 years to 15 years

4. Route of administration: drug prescribed for route outside the approved references (Category 4)

All drugs are classified according to the Anatomical Therapeutic Chemical (ATC) Classification System (WHO-ATC). ²⁹

Exclusion criteria: blood products, contrast, intravenous fluids, and electrolyte replacements.

Statistical Analysis

A descriptive analysis was performed to describe and summarize the details of the study population such as age, gender, and ATC drug class. Data are presented as numbers and percentages when appropriate. The rates of off-label drug use were calculated by dividing the number of patients who received at least 1 off-label drug by the total number of study participants. We then examined the association using the independent samples t test. The Chi square test was conducted to examine the association between off-label drug use by gender and age of study cases. A P value of less than .05 was considered as statistically significant. All data were analyzed using the SPSS software.

This study was approved by the King Abdullah International Medical Research Center (KAIMRC) with protocol number RJ18/080/J.

Results

Characteristics of the Study Population

A 12-month retrospective study was conducted using the electronic health records (EHRs) of pediatric patients, randomly selected from a total population of 39 900 patient encounters at the outpatient clinics of the 3 sites of MNGHA [KAMC-Jeddah (n = 15 700); Specialized Polyclinic (SPC)-Jeddah (n = 14 500); and Imam Abdulrahman Bin Faisal Hospital-Dammam (n = 9700)].

Two thousand, one hundred and ninety-five patients [Jeddah (KAMC 735 patients, SPC 611 patients) and Dammam 849 patients] received 11 058 medications (mean 5.1 and SD 5.4). (see online supplement).

The majority were male (54.7%), aged from 2 to 6 years (61.5%).

Table 1, summary of the basic characteristics of the study population.

Table 1.

Basic Characteristics of All Included Children With Persecution.

Variable	N = 2195	%
Gender
Female	995	45.3
Male	1200	54.7
Age class
<1 month	269	12.3
1 month-2 years	220	10
2-6 years	1351	61.5
6-12 years	284	12.9
>12-15 years	71	3.2
Total drugs prescribed	Mean 5.1	SD 5.4
Off label drug use
Yes	326	14.9
No	1869	85.1

Note. SD = standard deviation.

Nature and Frequency of Off-Label Prescribing

A total of 326 (14.9%) patients were identified as having received 865 drugs (mean 1 and SD 0.24). Table 2 provides details of the basic characteristics of included cases with off-label drug use

Table 2.

Basic Characteristics of Off Label Drug Use Per Cases (N = 326).

Variable	N = 326	%
Gender
Female	176	54
Male	150	46
Age class
<1 month	13	4
1 month-2 years	62	19
2-6 years	202	62
6-12 years	45	13.8
>12-15 years	4	1.2
Off label drugs per patient	Mean 1	SD 0.24
Hospital
KAMC	22	6.7
SPC	239	73.3
Dammam	65	19.9

Note. KAMC = King Abdulaziz Medical City-Jeddah; SPC = specialized poly clinic; SD = standard deviation.

More than one-third (341 out of 865, 39.4%) was prescribed for off-label use, having been validated with either Lexicomp, Micromedex, or Harriett Lane for the 4 off-label categories. Worthy of note is that 1 drug may have been prescribed for more than 1 off-label category. The most common reason for off-label prescribing was related to category 1 “dose prescribed higher or lower than the recommended use” (48.6%), followed by category 2 “indication” (19.9%), category 3 “age” (17%), and then category 4 “route of administration” (14.5%). Table 3 provides the frequency for the identified category (reason) of prescribed off-label drugs.

Table 3.

Frequency of Identified Category (Reason) of Prescribed Off-Label Drugs.

Off label drug categories	Frequencies (N = 512)	% (n/N)
Category 1	n = 249
1	176	48.6
1 and 2	15
1 and 3	8
1 and 4	2
1 and 2 and 3 and 4	30
1 and 3 and 4	12
1 and 2 and 3 and 4	6
Category 2	n = 102
2	35	19.9
2 and 3	9
2 and 4	9
2 and 3 and 4	4
1 and 2	15
1 and 2 and 3 and 4	30
Category 3	n = 87
3	29	17
1 and 3	8
1 and 2 and 3 and 4	30
1 and 3 and 4	12
3 and 4	8
Category 4	n = 74
4	9	14.5
1 and 4	2
1 and 2 and 3 and 4	30
1 and 3 and 4	12
2 and 4	9
2 and 3 and 4	4
3 and 4	8

Note. Category 1 = dose: dose prescribed higher or lower than recommended use; Category 2 = indication: drug prescribed for indications outside the approved references; Category 3 = age: drug prescribed for age outside the approved references; Category 4 = route of administration: drug prescribed for route outside the approved references.

Using the WHO-ATC classification system for medication classes, a total of 10-drug classes were recorded. The most frequently identified drug classes prescribed for off-label use were anti-infective drugs for systemic use (39.9%), followed by respiratory system drugs (28.7%). Medications were mostly prescribed by oral route (69%), followed by the topical inhalation route (10.5%). Table 4 provides a summary of the ATC drug codes.

Table 4.

ATC for Identified Off-Label Drug (n = 341 Off Label Drugs Prescribed).

Variable	N = 341 drugs	%
Anti-infective for systemic use	136	39.9
Respiratory system	98	28.7
Alimentary tract and metabolism	36	10.6
Dermatologicals	20	5.9
Musculo-skeletal system	12	3.5
Nervous system	10	2.9
Others	29	8.5

Note. ATC = Anatomic Therapeutic Chemical Classification.

Off-Label Prescribing in Relation to Age and Gender

A Chi square test was performed to examine the association between off label drug use according to gender and age. A significant association was found for both variables. The percentage of off-label drug use was found to be higher in girls and in the age group of 1 month to 2 years (P = .001) for both variables. Table 4 shows the association between off label drug use with gender and age of the study population.

The results of the independent samples t test revealed a significant difference in off-label drug use according to the total number of drugs prescribed, P < .001. Table 5, correlation of off-label drug use with gender and age of respondents.

Table 5.

Correlation of Off Label Drug Use by Percentage of Patients in Relation to Gender and Age (N = 326).

Variable	Off label drug use		P value
	% Yes	% No
Gender
Female (n = 176)	17.7	82.3	.001
Male (n = 150)	12.5	87.5
Age class
<1 month (n = 13)	4.8	95.2	.001
1 month-2 years (n = 62)	28.2	71.8
2-6 years (n = 202)	15	85
6-12 years (n = 45)	15.8	84.2
>12-15 years (n = 4)	5.96	94.4

Discussion

The findings of our study showed that a significant number of drugs were newly prescribed in an off-label fashion. The number of patients who received at least 1 new off-label drug was 326, wherein 341 drugs were prescribed as off-label. In the current study, the overall incidence of off-label drug use was 39.4%, and the majority (61.5%) of our study patients were in the age group of 2 to 6 years. Off-label drug use was found to be significant (P = .001) in girls and in children aged 1 to 2 years, which is considered comparable to other published international data. For example, in the United States, off-label drug use has been reported to range from 36% to 47%, being more common in girls and in neonates.^30,31 In European countries, off-label drug use has been reported at more than 30%.^32,33

In contrast to the majority of published studies,^34-43 we examined all drugs prescribed for off-label use. At the national level, 1 cross-sectional study was conducted in the Eastern Province of Saudi Arabia which found that the majority of physicians are aware of the concept of off-label prescribing and have concerns about the lack of safety data. ³⁵ In another study conducted over 2 years among adults and pediatrics in 6 Saudi tertiary hospitals, the authors concluded that off-label drug use was common among the adult population; however, they only included 26 pediatric patients where off-label use was evaluated for 4 drugs (sildenafil, spironolactone, folic acid, and montelukast). ³⁶

In the current study, we have identified that anti-infective drugs are the most frequently prescribed ATC drug class (39.9%), where nearly half (48.6%) of the prescribed off-label drugs were related to a category 1 reason. Our findings showed a high number of off-label prescribing occurrences mainly related to drug dosing.

Previously, we reported a high incidence of drug-related problems (DRP), and our findings showed that dosing errors (78%) were common, about which we highlighted that using different drug-dosing references could be major contributing factors. One of our previous recommendations was to use a standardized pediatric specific drug-dosing guide. ⁴⁴

Off-label was defined as the use of a licensed drug in a patient population, dosage, or dosage form outside the Food and Drug Administration (FDA) approval. ⁸ Unlicensed drug was defined as using a drug for which no marketing authorization has been granted by an authoritative body. ² While many other studies considered both terms as interchangeable,^45,46 for this study, we opted to use the off-label term to avoid confusion between the 2 terms.

The off-label use of a drug among children is not an uncommon practice worldwide despite the increased awareness. This is of special concern, especially in the context of the pandemic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2, COVID-19) where there are no FDA-approved drugs against it ⁴⁷ other than supportive care with a majority of used off-label drugs that are not recommended for children aged less than 12, as they may cause serious adverse effects.^48,49

This study provides another perspective on off-label drug use in a pediatric-specific population. There are a couple of limitations to be considered when interpreting the study results. We did not assess the outcome of using a drug in an off-label pattern or address safety concerns with the current practice or among hospitalized children.

Prescribing a drug for a child is no easy task and requires using the best available evidence as a guide, especially when a drug is used off-label. Future studies may consider assessing the knowledge and awareness of prescribers and pharmacists about label indications for commonly used drugs in children, assessing off-label use treatment outcomes and any related adverse effects, and conducting age-specific studies to adequately examine the issue of safety among children.

Conclusion

The findings of this study showed a high incidence of off-label prescribing mainly related to dosing and indication. The results of this observational study support the need to establish a unified national pediatric dosing formulary guide to ensure safe drug use in pediatrics.