Labeling Pediatric Products: BPCA Efforts and Orphan Drug Opportunities

Abstract

OBJECTIVE

Although the Orphan Drug Act (ODA) has substantially increased the number of therapies available for rare diseases, there are still unmet needs for drug development in pediatric patients. The current study represents an exploratory collaborative effort from the National Institutes of Health (NIH) and the US Food and Drug Administration (FDA) to use publicly available data to advance the assessment of orphan products not fully labeled for pediatric use. We first document the efforts to label drugs for pediatric use by the NIH under the Best Pharmaceuticals for Children Act (BPCA). Then, we explore whether publicly available pediatric data exist for orphan drugs previously identified as not fully labeled for pediatric use.

METHODS

The NIH BPCA efforts have labeled 20 drugs for pediatric use. We conducted additional analyses of drugs not fully labeled for pediatric use under the ODA for assessment in the relevant pediatric age range using data from published studies.

RESULTS

Tafenoquine and miltefosine were identified, and noncompartmental analyses were conducted using published data. Tafenoquine exposures of pediatric patients (2–15 years old) with body weight–based dosing were comparable to the approved patient population with 300 mg daily, along with acceptable variability within the observed subjects. High similarity was also found between studied pediatric patients (2–12 years old) and the approved patient population with the same dose of 2.5 mg/kg/day in the miltefosine exposure-response analysis.

CONCLUSION

Tafenoquine tablets and miltefosine capsules could be considered as additional examples of the BPCA effort to fully label drug products for the pediatric patient population.

Introduction

The effort to label drugs for pediatric use dates back several decades.¹ At the time that Dr Harry Shirkey claimed that pediatric patients were “therapeutic orphans,” off-label drug use was approximately 80% of all prescriptions written for pediatric patients.² In 1999, Turner et al³ associated off-label drug use in pediatric patients with a significant number of adverse drug effects. While legislation in the United States and Europe supporting the inclusion of pediatric patients in drug development has decreased the percentage of off-label drug use, there is still significant off-label use remaining in certain pediatric patient populations, such as hospitalized, critically ill, and rare disease patients.

The United States Congress enacted the Orphan Drug Act (ODA) in 1983 to encourage drug development in rare diseases.⁴ This act provides financial incentives to sponsors to develop drugs and biologics for diseases that impact less than 200,000 people in the United States.^1,5,6 These regulatory incentives aim to decrease the cost of drug development while providing new therapies to patients with rare diseases.

Orphan drug development is crucial to children, who are disproportionately affected by rare diseases.⁶ According to the National Organization for Rare Disorders, rare diseases affect around 30 million people in the United States, and approximately 50% of them are children under 18 years of age. Rare diseases have increasingly been discussed over the past several years as the number of new treatments has surged. Many of these diseases are life-threatening or life-limiting. Although the ODA has substantially increased the number of therapies available for rare diseases, there are still many unmet needs for drug development in some subgroups of pediatric patients.¹ For example, neonates and infants have frequently not been included in drug development programs, leading to considerable numbers of drugs that are “not fully labeled for pediatric use.”^1,7 In addition, orphan drugs are exempt from the Pediatric Research Equity Act of 2003, which is an act that allows the US Food and Drug Administration (FDA) to require pediatric studies for certain drugs and biologics. Thus, sponsors are not required to conduct pediatric trials for orphan indications, which has led to some products not being fully labeled for use in all applicable groups of pediatric patients.¹

Orphan drug development has benefited children with rare diseases, mostly by expanding the use of existing drugs.³ In drug development programs where the adult and pediatric diseases are considered sufficiently similar, the FDA can consider extrapolating efficacy from adult populations to support the efficacy in pediatric populations.⁴ Efficacy extrapolation reduces the amount of efficacy data from traditional phase III trials in children and may result in quicker access to effective treatments. It is also possible to use literature data and pharmacometrics tools to evaluate the similarity in exposure-response (ER) between the pediatric and adult patient populations for which the drug is labeled and to extend labeling in the pediatric patient population for which the drug is not fully labeled.⁷

The Best Pharmaceuticals for Children Act (BPCA) became law in 2002 and has components relating to both the FDA (on-patent drugs) and to the National Institutes of Health (NIH) (off-patent drugs). The BPCA was reauthorized in 2007 under the FDA Amendments Act, in 2012 under the FDA Safety and Innovation Act, and again in 2017 under the FDA Reauthorization Act. The latest renewal of the BPCA legislation occurred in 2022. The primary goal of this act is to improve the safety and efficacy of medication use for children and improve drug label instructions. In addition, the mission and focus of the Eunice Kennedy Shriver National Institute of Child Health and Human Development is to align with the legislation goals to sponsor research and conduct safe and effective clinical trials to “enhance the lives of children and adolescents, and optimize abilities for all.” A major overarching goal of the NIH portion of the BPCA is to prioritize various therapeutic areas that need further study, sponsor clinical trials that close knowledge gaps in pediatric therapeutics, and submit clinical trial data that ultimately lead to FDA labeling of products for pediatric use. From 2003 through 2009, the NIH funded academic centers as Pediatric Off-patent Drug Study Centers to conduct large dosing, safety, and efficacy studies. In 2010, the National Institute of Child Health and Human Development funded the Pediatric Trials Network as the infrastructure for conducting clinical trials that lead to label changes for off-patent medications used in children. The NIH BPCA Program has historically used and currently uses innovative approaches, including combining literature data and pharmacometrics tools, to evaluate ER between the pediatric and adult patient populations and, through these approaches, has been able to extend labeling in the pediatric patient population.

The current study represents an exploratory effort to evaluate the use of existing publicly available data to assess orphan products not fully labeled for pediatric use. This study aimed to 1) document the efforts to label drugs for pediatric use by the NIH under the BPCA and how the work correlates to orphan drug listing and (2) explore whether publicly available pediatric data exist for orphan drugs previously identified as not fully labeled for pediatric use.

Methods

BPCA Labeling Effort.

The National Institute of Child Health and Human Development’s BPCA website provides background on the NIH BPCA program, as well as a listing of the BPCA priorities list and the drugs that the FDA has labeled for pediatric use through studies conducted under BPCA.

Orphan Drug Listing and Examination of Pediatric Labeling Opportunities.

The primary search was conducted by indication, and the data were further narrowed to include only drugs with FDA-labeled indications in the pediatric population. The lists available for drugs that are considered to be “not fully labeled” for pediatric use came from the following 2 sources: the FDA’s Report to Congress on the “Pediatric Labeling of Orphan Drugs”⁷ and a similar published report from the FDA by Park et al.¹ The “not fully labeled” drugs were defined as a disease or indication having an onset and diagnosis in newborn to younger than 2 years but which was not labeled in this age group.

Another publicly available FDA source used was Drugs@FDA to review relevant product labels for the therapies.⁸ Articles were not restricted based on publication date, and on-label drugs were included. Studies were included if 1) there was a measured pharmacokinetic (PK) parameter used in both adult and pediatric studies, 2) the published manuscript characterized treatment response or an ER relationship, and 3) the data in the published study had tables/graphs/figures suitable for digital data extraction.

Data Analysis.

All noncompartmental analyses (NCA) were conducted using Phoenix NLME (V8.3, Certara, Raleigh, NC). The ratio between the calculated values and reported values was computed for each dataset obtained from included studies. In addition, a clearance ratio between pediatric and approved patient populations was calculated using results from NCA. The ER relationship based on model-based estimates was explored by fitting the sigmoid E_max model to an extracted predicted probability of cure curve using Phoenix NLME. Graphical analysis was conducted in Phoenix NLME and Microsoft Excel (Version 2208, Microsoft, Redmond, WA) with box plots to visualize distributions of PK parameters from each studied group and the efficacy similarity between pediatric and approved patient populations. Specific analyses were dependent on the type of publicly available data. The details of data analysis approaches are listed in Supplemental Methods S1.

Results

BPCA Labeling Efforts.

The activities of BPCA have produced 20 label changes to improve pediatric labeling (dosage, safety, and/or efficacy information) (Table 1) (https://www.nichd.nih.gov/research/supported/bpca/accomplishments). Among the 20 label changes, approximately 37% of products were orphan drugs, and 32% of label changes were designed for neonates and infants. Of the 32% of infant label changes, half were related to the orphan products assigned for neonate use. Meanwhile, around 26% of label modifications were approved based on the pharmacokinetic, safety, and efficacy data. Based on BPCA’s current research, 4 additional studies have been submitted to the FDA for label change consideration and are currently pending final review. Among them, 2 cases are related to pediatrics and are fluconazole dosing and safety in preterm neonates and metronidazole for dosing in newborns.

Table 1.

Approved Labeling Changes

Product Name	Labeling Change	Final Approved Label	Docket Info
Acyclovir	Update dosage and administration, clinical pharmacology, and adverse reactions sections of the label with information that dosing for neonatal HSV should be based on PMA at doses higher than those included in the acyclovir label at the time of the study	Final label approved 1/25/2019	Docket FDA-2017-N-3102
Ampicillin	Revise pediatric dosing to include neonatal dosing for meningitis and septicemia based neonatal gestational age at birth and postnasal day of life. Add seizures to adverse reactions	Final label approved 2/15/2018	Docket FDA-2015-N-2342
Bactrim	Add pediatric pharmacokinetic data to the clinical pharmacology section.	Final labels Bactrim tablets approved 7/28/2020 Bactrim pediatric suspension approved 7/28/2020	Docket FDA-2018-N-3833
Caffeine Citrate	Include a broader gestational age range of premature infants and longer treatment durations	Final label approved 3/2/2020	Docket FDA-2019-N-3414
Clindamycin	Add clinical pharmacology and dosage information for obese children (clindamycin should be dosed based on total body weight)	Final labels Cleocin injection 3/4/2020 Cleocin capsules 3/9/2020	Docket FDA-2019-N-4338
Clindamycin	Add clinical pharmacology and dosing information for pediatric patients less than one month of age with intra-abdominal infections	Final labels Cleocin phosphate 12/4/2021 Clindamycin phosphate 9/1/2022	Docket FDA-2021-N-0142
Diazepam	Update dosage and administration, clinical pharmacology data, and adverse reactions sections for patients ages 3 months to 18 years old	Diazepam injection 50 mg/10mL, Multi-Dose vial 11/12/21 Diazepam injection 8/26/21 Diazepam injection 5 mg/mL 9/2/21 Diazepam injection 5 mg/mL and 10 mg/2 mL 11/12/21 Diazepam injection 10 mg/2 mL 11/12/2021 Diazepam injection 50 mg/10 mL Multi-Dose vial 8/10/2021 Diazepam injection 5 mg/mL 3/23/22 Diazepam injection 10 mg/2 mL 3/23/22 Diazepam injection 10 mg/2 mL Single-Dose prefilled syringe 3/23/22 Diazepam injection 5 mg/mL 4/25/23	Docket FDA-2020-N-2359
Doxycycline	Add pediatric data to pharmacokinetics subsection of clinical pharmacology section	Final labels Vibramycin 12/20/19 Acticlate 3/4/2020 Doryx 2/12/2020	Docket FDA-2018-N-3834
Fluconazole	Update pediatric information in the clinical pharmacology, clinical studies, precautions, adverse reactions, and dosage and administration sections including information on preterm and term infants, as well as pediatric patients on extracorporeal membrane oxygenation	Final labels Diflucan oral Diflucan IV approved 2/12/2024	Docket FDA-2019-N-2698
Levetiracetam	Add dosing information in pharmacokinetics section for obese pediatric patients	Final labels Keppra 8/31/2023 Spirtam 8/31/2023	Docket FDA-2022-N-2575
Lithium	Add pediatric use information to the indications and usage, dosage and administration, adverse reactions, use in specific populations, clinical pharmacology, and clinical studies sections of the label, along with updates to the medication guide	Final label approved 10/4/2018	Docket FDA 2018-N-2986
Lisinopril*	Add lisinopril pharmacokinetic data in children with kidney transplant and found to be comparable to children and adults without a kidney transplant	Clinical pharmacology section 12.3. approved April 2016 DailyMed - LISINOPRIL tablet (nih.gov)	The information is available at the NICHD Data and Specimen Hub (DASH)
Lorazepam	Add to the pediatric use section, status epilepticus subsection, information from a randomized, double-blind, superiority-design clinical trial of Ativan versus intravenous diazepam demonstrating a failure to establish the efficacy of Ativan in the treatment of status epilepticus in pediatric patients	Final label approved 5/27/2016	Docket FDA-2015-N-3037
Mercy Tape (children)*	Device study—to evaluate the predictive performance of 2D and 3D Mercy Tape method of weight estimation		The information is available at the NICHD Data and Specimen Hub (DASH)
Mercy Tape (infants)*	Device study—developed to use head and chest circumference measures to predict infant weight		The information is available at the NICHD Data and Specimen Hub (DASH)
Meropenem for Injection	Update dosing recommendations for the use of meropenem in neonates and infants less than 91 days of age for complicated intra-abdominal infections	Final label approved 12/19/2014	FR Vol 80 No. 102 pg 30467 Thursday, May 28, 2015
Metronidazole†	Update the indication for the treatment of serious bacterial infections in neonates	NA	NA
Oxycodone†	Update dosing in breastmilk of lactating mothers	NA	NA
Pralidoxime*	Add existing data on pediatric patient exposure after BPCA prioritization	Final label, approved 9/8/2010
Prophylthiouracil*	NICHD sponsored workshop in October 2008 resulted in data that showed increased risk of liver toxicity	FDA drug safety communication: new boxed warning on severe liver injury with propylthiouracil | FDA
Rifampin	Update clinical pharmacology and adverse reactions sections of the label with information for infants	Rifadin capsules and Rifadin IV for injection 2/17/2023	Docket FDA-2020-N-1675
Sodium Nitroprusside	Update dosing, pharmacokinetics, tolerability, and safety information in pediatric patients from birth to 18 years of age who receive SNP for controlled reduction of blood pressure	Final label approved 11/22/2013	FR Vol 79 No.16 pg 4167 Friday, January 24, 2014

BPCA, Best Pharmaceuticals for Children Act FDA, US Food and Drug Administration, HSV, herpes simplex virus, IV, intravenous, NA, not applied, NICHD, National Institute of Child Health and Human Development, PMA, postmenstrual age, SNP, sodium nitroprusside.

^* National Institutes of Health counts as label changes that is not on the FDA website.

^† Potential drug label changes that could occur in this calendar year under review with FDA.

The current BPCA priorities list posted on the internet is from 2020-2021, and lists 17 tables related to therapeutic areas that require studies and labeling in pediatric patients (Table 2). (https://www.nichd.nih.gov/research/supported/bpca/recent-priority-lists).

Table 2.

BPCA Priorities List

Therapeutic Areas	Number of Products	Number of Orphan Products
Infectious disease	13	5
Cardiovascular disease	9	6
Respiratory disease	3	2
Intensive care	7	3
Biodefense research	3	2
Pediatric cancer	5	2
Psychiatric disorder	4	4
Neurological disease	7	5
Neonatal research	21	15
Adolescent research	No specific drugs	NA
Hematologic disease	1	1
Endocrine disease and diseases with limited alternative therapies	2	1
Dermatologic diseases	2	1
Gastrointestinal diseases	3	1
Renal diseases	No specific drugs	NA
Rheumatologic disease	No specific drugs	NA
Special considerations	Multiple therapeutic areas	NA

Abbreviations: NA, not applicable

NA, not applicable

Orphan Drugs.

The current analysis was narrowed from 60 to 30 drugs that were not fully labeled for the infant age group, as cited in Park et al¹ (see Supplemental Table S1 for the complete list). One drug, gemtuzumab ozogamicin, was removed from the list because the label has been extended to 2 years and older. Two anti-infectious orphan drugs were exampled for use as candidates for assessment based on criteria listed in the “Study Eligibility and Selection” of Methods section, which were the tafenoquine (TQ; Krintafel; GSK, Brentford, UK) tablet and the miltefosine (MF; Impavido; Knight Therapeutics, Montreal, Canada) capsule.

Tafenoquine Tablet.

Tafenoquine is an antimalarial drug indicated for the radical cure (prevention of relapse) of Plasmodium vivax malaria and was approved in 2018 for patients 16 years and older.⁹ A single dose of 300 mg administered as two 150-mg tablets taken together is recommended for the approved patient population who are receiving chloroquine therapy for acute P. vivax infection. However, the onset age of the disease can occur at any age and is most deadly for children under 5 years old^10,11 (Supplemental Table S1).

An NCA using Phoenix NLME was conducted to compute the area under the curve (AUC) from day 1 to 60 for both pediatric and approved patient populations. More than 2400 systemic observations from a total of 485 subjects receiving TQ were included in the NCA datasets. These data were collected from 3 clinical studies (a phase II study,¹² a DETECTIVE part 2 study,¹³ and a GATHER study¹³), summarized in Supplemental Table S2. The mean AUC_0–∞ or AUC_0–t was calculated by NCA for each dataset and the calculated values were comparable to the reported ones (Table 3). The calculated C_max was also reported as a mean C_max together with minimum and maximum values (Table 4). The calculated mean AUC_0–∞ and C_max were plotted across all age groups.

Table 3.

Summary of Tafenoquine and Miltefosine AUC_0–∞ Results of the Noncompartmental Analysis

Drug(s)	Study		Age, yr	n		Dose, mg	Reported AUC0–∞, µg.hr/mL		Calculated AUC0–∞, µg.hr/mL		Ratio*
							Mean AUC0–∞	AUC Range	Mean AUC0–∞	AUC Range
TQ	NCT02563496	2–9			14	100	85.10	47.43–116.63	90.16	68.56–140.42		1.06
		3–8			5	150	165.73	107.33–246.47	148.09	161.66–279.49		0.89
		5–12			22	200	109.43	74.06–143.11	107.18	109.92–170.61		0.98
		10–15			19	300	121.29	36.19–181.32	129.14	85.91–159.12		1.06
	TAF112582 (DETECTIVE part 2)	15–79			259	300	134.08	45.68–227.79	122.28	NA†		0.91
	TAF116564(GATHER)	15–79			166	300	104.32	25.42–170.86	107.39	NA†		1.03
						Dose, mg/kg/day	Reported AUC0–∞, µg.day/L		Calculated AUC0–∞, µg.day/L
MF	IP	3–11			39	2.5	667.61	328.60–1144.57	743.77	313.35–1914.04		1.11
	NCT02431143	4–12			30	3.2	582.00	NA‡	556.00	NA§		0.96
	EA	4–12			30	3.2	588.60	NA‡	1056.44	NA§		1.79
	NCT01067443	7–12			21	2.38	550.50	NA‡	859.51	NA§		1.56
	NCT01462500	2–12			29	2.3	688.00	NA‡	948.21	769.56–1039.19		1.38
	EUA	19–49			34	2.5	712.60	412.25–1109.20	1023.55	973.11–1109.20		1.44
	IA	12–50			30	2.5	762.00	412.25–1109.21	1368.06	NA§		1.80
	NCT01462500	21–51			29	2.1	1056.00	NA‡	948.21	769.56–1039.19		0.90

AUC, area under the curve; EA, Eastern Africa; EUA, European adults; IA, Indian adults, adolescence patients included as subjects recruited according to label approved age; IP, Indian pediatrics; MF, miltefosine; NA, not applicable, TQ, tafenoquine

^* Ratio was calculated using mean AUC0–∞ values from NCA results and reported in the original publications.

^† The calculated AUC range were not reported for studies TAF112582 and TAF116564 because only mean plasma concentrations at each time point reported in the original publications were qualified for the digitization.

^‡ The information was not reported in original literatures.

^§ The calculated AUC0–∞ range was not reported because only mean plasma concentrations were provided by publications.

Table 4.

Summary of Tafenoquine and Miltefosine Cmax Results of the Noncompartmental Analysis

Drug(s)	Study		Age, yr	n	Dose, mg	Calculated Cmax, ng/mL*
						Mean (Min, Max)
TQ	NCT02563496	2–9		14	100	327.07 (138.19, 458.10)
		3–8		5	150	643.67 (375.99, 860.00)
		5–12		22	200	424.90 (270.56, 729.42)
		10–15		19	300	327.20 (111.61, 540.49)
	TAF112582 (DETECTIVE part 2)	15–79		259	300	472.10 (125.10, 659.49)
	TAF116564(GATHER)	15–79		166	300	333.21 (61.54, 623.59)
					Dose, mg/kg/day
MF	IP	3–11		39	2.5	55.54 (47.20, 72.26)
	NCT02431143	4–12		30	3.2	28.26*
	EA	4–12		30	3.2	33.12*
	NCT01067443	7–12		21	2.38	28.27*
	NCT01462500	2–12		29	2.3	15.79 (11.16, 24.21)
	EUA	19–49		34	2.5	44.92 (39.28, 51.60)
	IA	12–50		29	2.5	34.93 (27.12, 99.75)
	NCT01462500	21–51		29	2.1	29.03 (26.83, 35.07)

EA, Eastern Africa; EUA, European adults; IA, Indian adults; adolescence patients included as subjects recruited according to label approved age; IP, Indian pediatrics; Max, maximum; Min, minimum; MF, miltefosine; NA, not applicable; TQ, tafenoquine

^* The calculated Cmax were reported from NCA, ratios between calculated and reported Cmax were not applicable because some of Cmax values were not reported in original literatures.

There was a high similarity between the approved patient population and children, as indicated by graphic analysis from plots of TQ calculated mean AUC_0–∞ and C_max (Figure 1). High interindividual variability and higher than the label-approved group AUC_0–∞ and C_max were observed for 1 pediatric group (N = 5) aged from 3 to 8 years old with 150 mg daily dose, which suggests the dose is too high for this age group. The remaining pediatric groups were very comparable with the label-approved groups. The overall range of the 2 calculated PK parameters from the 3- to 8-year-old age group was acceptable in comparison to the approved patient population. In addition, AUC_0–∞ ratios and clearance ratios between the approved patient and pediatric populations are summarized in Tables 5 and 6. Figure 2 reports the AUC distribution for the entire studied pediatric population as supplemental supporting evidence for the similarities between the pediatric and label-approved group. Noncompartmental analyses calculated clearance ratios between pediatric and approved patient populations show variability, which suggests clearance is not comparable between the 2 populations and raises a concern about matching the exposures. However, the AUCs are comparable between the 2 groups with the adjusted body weight–based dosing scheme in pediatrics compared with the fixed dosing in 16 years and older. The most frequently reported adverse events for studied subjects aged from 2 to 15 years were vomiting and pyrexia at mild or moderate levels, which is consistent with previous studies. There were no deaths during the study.

Figure 1.

Graphical analysis of tafenoquine exposure for label-approved aged and pediatric populations using (A) calculated mean AUC_0–∞ and (B) C_max by noncompartmental analyses conducted with datasets across multiple clinical studies. Labeled age group recruited patients aged 15 of years and older.

Table 5.

Summary of Tafenoquine Calculated AUC_0–∞ Ratios in Pediatric and Label-Approved Aged Populations

Study	Age, yr	n	Dose, mg	Calculated AUC*0–∞ Ratio (Pediatrics/Labeled age)
				Min	Q1	Median	Q3	Max	Mean
NCT02563496	2–9	14	100	0.60	0.85	0.93	1.05	1.22	0.93
	3–8	5	150	1.29	1.32	1.47	2.21	2.43	1.67
	5–12	22	200	0.93	1.01	1.11	1.26	2.43	1.14
	10–15	19	300	0.75	0.99	1.19	1.27	1.39	1.13
TAF112582 (DETECTIVE part 2)	15–79	259	300	NA*
TAF116564(GATHER)	15–79	166	300

Q1, the first quartile; Q3, the third quartile; Max, maximum; Min, minimum; NA, not applicable

^* Mean AUC0–∞ values were calculated for subjects enrolled in studies TAF112582 and TAF116564. AUC0–∞ of label-approved aged populations were used in calculations of ratios between these 2 populations for each pediatrics group. Labeled age group recruited patients aged 15 of years and older.

Table 6.

Summary of Tafenoquine Calculated Clearance Ratios in Pediatric and Label-Approved Aged Populations

Study	Age, yr	n	Dose, mg	Calculated Clearance* Ratio (Pediatrics/Labeled age)
				Min	Q1	Median	Q3	Max	Mean
NCT02563496	2–9	14	100	3.28	4.56	5.15	7.18	10.88	6.02
	3–8	5	150	0.20	0.20	0.32	0.35	0.35	0.29
	5–12	22	200	0.45	0.51	0.60	0.64	0.69	0.59
	10–15	19	300	0.72	0.79	0.83	1.04	1.33	0.91
TAF112582 (DETECTIVE part 2)	15–79	259	300	NA*
TAF116564(GATHER)	15–79	166	300

Q1, the first quartile; Q3, the third quartile; Max, maximum; Min, minimum; NA, not applicable

^* Clearance values of labeled age group were calculated from noncompartmental analyses for subjects enrolled in studies TAF112582 and TAF116564. Clearances of labeled age were used in calculations of clearance ratios for each pediatrics group. Labeled age group recruited patients aged 15 of years and older.

Figure 2.

Graphical analysis of tafenoquine safety and efficacy concerns using (A) an AUC_0–∞ and (B) clearance ratios between label-approved aged and pediatric populations with datasets across multiple clinical studies. Labeled age group recruited patients aged 15 of years and older.

Ped, pediatrics.

Miltefosine Capsule.

Miltefosine is an antileishmanial drug indicated in adults and pediatric patients 12 years of age and older weighing greater than or equal to 30 kg (66 lbs).¹⁴ Miltefosine was initially approved in 2014 for the treatment of 1) visceral leishmaniasis due to Leishmania donovani, 2) cutaneous leishmaniasis due to L. braziliensis, L. guyanensis, and L. panamensis, and 3) mucosal leishmaniasis due to L. braziliensis. The disease can occur at any age, while visceral disease affects patients aged from 5 to 15 years old in India and patients aged from 1 to 4 years old from the Mediterranean Basin¹⁵ (see details of included studies in Supplement 1: Examples of products with published data-MF included studies).

Phoenix NLME was used to determine the MF AUC from day 1 to infinity for both the pediatric and approved patient populations. Systemic observations from a total of 241 subjects receiving MF were included in the NCA datasets. These data were collected from four publications that enrolled patients from Asia to Europe as well as South America to Eastern Africa. Supplemental Table S2 summarizes the 7 clinical studies included in this study. Similarly, the NCA calculated mean AUC_0–∞ of each dataset was comparable to those reported (Table 3). Regarding the safety concerns, Table 4 reports the calculated C_max that shows a similar distribution between the studied pediatric and label-approved groups. The calculated mean AUC_0–∞ and C_max across all age groups were plotted for 2 populations (Figure 3A and B).

Figure 3.

Graphical analysis of miltefosine exposure-response between label-approved aged and pediatric populations using (A) calculated mean AUC_0–∞ and (B) C_max from noncompartmental analyses (NCA) conducted with datasets across multiple clinical studies. Regarding the 7- to 12-year group, only mean plasma concentrations at each time point were reported in the original publication. (C) Calculated mean AUC_0–∞ reported by NCA where pediatric patients from different age ranges across multiple clinical studies were grouped together. (D) Calculated mean AUC_D0-D28 vs predicted probability of cure in pediatrics and label-approved aged populations. The predicted probability of cure was simulated using E_max model and extracted data from Kip AE et al¹⁸ Labeled age group recruited patients aged 12 years and older.

Ped, pediatrics; PL, plasma.

Exposure-response analysis is used to explore possible dose selection by characterizing the relationship between drug concentrations and efficacy. In this study, the ER relationship was depicted by the probability of clinical cure as a function of AUC_0–t, where the response was converted to the probability of clinical cure (the equation used in the model fitting is listed in the “Data Analysis” of the Methods section) with data extracted from literature.¹⁸ The probability of clinical cure was less than 95% when AUC_0-t exceeded 535 mg·day/L.¹⁸ The extracted probability of cure curve was well described by a sigmoid E_max model with E_max= 0.99, EAUC₅₀= 475.509 mg·day/L, E₀= 2.02*10⁻⁶ mg·day/L, and γ= 23.81. Figure 3D demonstrates that similar exposures were achieved based on the simulations in pediatric patients compared with the group represented in labeling. However, patients from 3 to 11 years old showed a wider range in AUC_0–∞ compared with the rest of the pediatric groups. The overall ER, in terms of the predicted probability of cure, as well as the primary PK parameters, C_max and AUC_0–∞, with 2.5 mg/kg/day dose in children aged from 2 to 12 years old, were comparable to the label-approved group (12 years and older). In addition, the AUC_0–∞ (which grouped all pediatric subjects together and was plotted in comparison to the label-approved group) is supporting evidence for the similarity found between the 2 populations (Figure 3C). No special adverse events were observed in the above pediatric studies other than those reported for approved patient populations, such as abdominal pain and chills.

Discussion

Both BPCA and the ODA have been successful at achieving the appropriate studies to label pediatric drug products. While the goal of fully labeling the drug products for all age groups affected has fallen short in some ODA programs, the overall success in labeling products for rare diseases in pediatric patients is notable. Similarly, although the BPCA pediatric labeling effort is notable, the BPCA priorities list contains an additional 80 drugs for consideration for additional pediatric studies.

Pediatric orphan drug indications have maintained a consistent percentage of orphan drug programs since Congress passed the ODA of 1983 to stimulate the development of drugs for rare diseases. The overall number of orphan drug designations has increased dramatically in the past 10 years, and a recent report to Congress evaluating the pediatric labeling of orphan drugs illustrated a lack of comprehensive pediatric information in the labeling for orphan therapies for the youngest pediatric patient group.^1,7 Because orphan drugs are exempt from the requirements of the Pediatric Research Equity Act,¹⁶ and written requests under the BPCA are voluntary, sponsors conduct pediatric trials for orphan drugs for those pediatric age groups that are most available or are easiest to study. Consequently, some orphan products are not studied and labeled in the youngest pediatric age groups, and safety and effectiveness are not established for this group of pediatric patients. This creates a clinical situation where there is an increased potential for off-label use of the product without adequate dosing, efficacy, and safety information in this age range of affected pediatric patients. Therefore, exploring strategies to include infants and neonates in orphan drug development programs (i.e., extending labeling down to the onset age of a rare disease with supporting data) would help bridge the knowledge gap and expand the benefits to pediatric patients across all ages.¹ Sponsors should consider and are encouraged to do studies to extend the label in this age group to address the unmet patients’ needs, such as conducting BPCA research.

The situation was observed for the 2 exampled drugs included in this study. Tafenoquine is an antimalarial drug indicated for the radical cure (prevention of relapse) of P. vivax malaria. The onset age of the disease can occur at any age but is most deadly for children under 5 years old.¹⁰ However, the FDA approved TQ for patients aged 16 years and older in 2018. According to the literature search of this study, TQ was studied in pediatric patients aged 2 to 15 years old and administered by a reduced dosage regimen compared with the labeled dose recommended for approved patient populations. Plasma concentrations were extracted from 60 pediatric patients and used for the NCA to compute the AUC_0–∞ and C_max values, which are the major PK parameters evaluated in the analyses. Tables 3 and 4 demonstrate good matching ratios between the calculated mean AUC_0–∞ and C_max from NCA and reported values across all age groups. Also, Figures 1 and 2 indicate the high similarity in the ER between label-approved and pediatric patients based on the plots of these 2 calculated PK parameters. Although higher than approved age and high interindividual variability was observed from 5 subjects in the 3- to 8-year-old group, the high dose (150 mg daily) and the resulting adverse events could be a potential cause. Likewise, a wide range of AUC_0–∞ was also reported by the original publication, which indicated that this was consistent with the NCA. While the dose was assigned based on body weight, the 3- to 8-year-old group had the lowest body mass index and clearance group among all 3 pediatric groups. Therefore, a higher dose may have been given to the 3- to 8-year-old group, which could potentially have led to higher AUC_0–∞ observations. Overall, the major PK parameters for TQ administration in young pediatric patients were supported by similar exposures between the studied pediatric and approved patient populations. Additionally, the Australian Therapeutic Goods Administration recently approved TQ for patients 2 years and older in 2022. A body weight–based dose recommendation (> 10 kg to ≤ 20 kg: 100 mg daily; > 20 kg to ≤ 35 kg: 200 mg daily) was selected to achieve plasma drug levels comparable to those in adults and adolescents at the approved clinical dose of 300 mg daily. However, the 50-mg dispersible tablet used in younger pediatric patients in Australia has not yet been manufactured in the United States, making it difficult to implement the body weight–based dosing scheme.

Miltefosine is an antileishmanial drug for the treatment of visceral disease, which affects pediatric patients aged from 5 to 15 years in India and patients aged from 1 to 4 years old from the Mediterranean Basin.¹⁵ Even though the onset of the disease can occur at any age, MF was approved in 2014 by the FDA for adult and pediatric patients 12 years of age and older. According to the latest label updated in May 2021, the age range was the same as the initial approval while the additional study was in progress. Based on the literature identified, MF was reported in clinical studies with patients aged from 2 to up to 12 years old to test a conventional dose (2.5 mg/kg/day) in the pediatric population. Systematic observations from 149 pediatric patients were extracted from 7 clinical trials and used for the NCA to determine the AUC_0–∞ and C_max values, which were further evaluated in ER analyses. Similarly, the ratios between the calculated mean AUC_0–∞ and C_max from NCA and reported values for each involved group are summarized in Tables 3 and 4. Figure 3 illustrated a high similarity in the ER between the 2 populations, whereas the entire population of pediatric patients was highly comparable to the approved patient population. The pediatric patients 3 to 11 years old showed a wider range of AUC_0–∞ compared with the rest of the pediatric groups. However, weight differences may have explained why higher exposures were observed in these pediatric patients with the same dosage regimens. Overall, a comparable probability of cure rate was found between 2 tested populations as demonstrated by the AUC_0–t versus the probability of cure plot (Figure 3D). In addition, according to the NCA results of 2 primary PK parameters, the C_max and AUC_0–∞ of patients aged from 2 to 12 years old were well within the acceptable range. These findings can be used to support the prospect that the MF label could be considered for an extension down to the onset age for the disease.

One limitation of the present study was the limited access to the publication datasets. This study focused on 30 drugs (50% of the total) that were found to be not fully labeled in the under 2-year-old age group. However, only 2 drugs were considered as examples for consideration by the BPCA program. The limited access to the data with median plasma concentration profiles prevented the type of pharmacometrics analysis that might be conducted in prospective clinical protocols.

Conclusions

The BPCA program has resulted in the FDA relabeling 20 products for pediatric use. While the relabeling effort is notable, many other products on the BPCA prioritization list still require further pediatric studies.

This analysis provides 2 orphan drugs as examples of opportunities for consideration by the BPCA pediatric labeling program. These 2 drugs were from 1 of the top 5 therapeutic areas pediatric orphan indications fall into, infectious disease.¹ Tafenoquine exposures in studied pediatric patients from 2 to 15 years old were comparable to exposures from an approved patient population with acceptable variability. Therefore, TQ could potentially be evaluated for a labeling extension from the current 16 years of age down to 2 years old for pediatric patients. Likewise, reasonable similarity was found between studied pediatric patients aged from 2 to 12 years old and the approved patient population in MF ER analyses in this study. Therefore, MF could also potentially be considered for label extension from the current 12 years old down to 2 years old for pediatric patients.

The current study represents an example of the collaborative effort from BPCA and FDA to advance the assessment of orphan products not fully labeled for pediatric use. Further efforts from all sponsors, BPCA, and the FDA are needed to label drug products for pediatric patients in the United States whose disease onset age is younger than the product labeling age. Such efforts could include but are not limited to identifying orphan drugs with data that might support efficacy/safety analysis, making age-appropriate pediatric drug formulations available to United States patients, and effective communication between sponsors and the FDA to address these unmet medical needs. Optimally, discussions related to the age groups at risk should take place during orphan drug development among the above 3 parties. The goal of these programs should be to have each product fully labeled for pediatric use. Until that time, the availability of published and real-world data provides opportunities to expand the experience with orphan drugs in the youngest pediatric patients, as this analysis has demonstrated.

ABBREVIATIONS

AUC

area under the curve;

BPCA

Best Pharmaceuticals for Children Act;

ER

exposure-response;

FDA

US Food and Drug Administration;

MF

miltefosine capsule;

NCA

noncompartmental analyses;

NIH

National Institutes of Health;

ODA

Orphan Drug Act;

PK

pharmacokinetic;

TQ

tafenoquine tablet