Abstract
Objective:
To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants.
Study design:
We used electronic health records (2010–2013) from four neonatal intensive care units to identify infants of ≤28 weeks’ gestational age (GA) exposed to caffeine citrate. Safety outcomes included: death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events.
Results:
Of 410 infants with a median (interquartile range [IQR]) GA of 26 (24–27) weeks, 95% received caffeine citrate for >10 days. Infants received a median (IQR) daily dose of 8 (5–10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were: death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis.
Conclusions:
Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose or therapy duration, was not associated with increased risk of necrotizing enterocolitis.
Keywords: bronchopulmonary dysplasia, necrotizing enterocolitis, apnea
Caffeine citrate is the most common non-antimicrobial medication used in the neonatal intensive care unit (NICU) and is used primarily to treat apnea of prematurity (AOP) (1). Infants with AOP experience frequent episodes of apnea, resulting in hypoxemia and bradycardia, placing the infant at risk for prolonged mechanical ventilation, retinopathy of prematurity, bronchopulmonary dysplasia (BPD), and long-term neurodevelopmental impairment (2–4). Approximately 85% of infants born at <34 weeks gestational age (GA) and almost all infants born at <29 weeks GA develop AOP (5, 6).
The drug label for caffeine citrate was last updated by the U.S. Food and Drug Administration (FDA) in 1999. The label recommends using caffeine citrate for short-term treatment of AOP in infants between 28–33 weeks GA (7). The label dose recommendation includes a single loading dose of 20 mg/kg intravenously followed by maintenance doses of 5 mg/kg administered intravenously or orally every 24 hours (7, 8). However, in clinical practice, caffeine citrate is frequently used off-label among extremely premature infants born as early as 22 weeks GA and is continued at higher doses (>5 mg/kg/day) for several weeks (8, 9).
The caffeine citrate label also includes a warning of a possible association with necrotizing enterocolitis (NEC) based on findings from an older randomized, double-blind, placebo-controlled trial involving 85 premature infants (7, 10). Subsequent studies have examined the safety and efficacy of caffeine citrate in neonatal populations (3, 5, 8, 9, 11). Most notably, in the large, randomized, placebo-controlled, multicenter Caffeine for Apnea of Prematurity (CAP) trial, caffeine citrate exposure in infants with a birth weight (BW) of 500–1250 g was associated with lower rates of BPD and patent ductus arteriosus (PDA) and improved survival without neurodevelopmental impairment (9, 12, 13). The CAP trial demonstrated no difference in the incidence of NEC between the caffeine citrate and control groups (9). However, because the trial was not performed under an investigational new drug application, the resulting data were not available to the FDA to consider a label change.
The current medical literature indicates a significant gap between the caffeine citrate label recommendations and contemporary clinical practice. Therefore, the National Institute of Child Health and Human Development (NICHD) prioritized investigating dosing and safety of caffeine citrate in treating AOP under an investigational new drug application with the FDA. We conducted this study to better characterize safety and exposure-response of caffeine citrate in extremely premature infants receiving the drug off-label, and to provide data to the FDA for consideration of revising the pediatric labeling of caffeine citrate.
Methods
Electronic health records from four NICUs were used to identify premature infants born at ≤28 weeks’ GA who received at least one dose of caffeine citrate prior to day of life 120. We excluded infants with a congenital anomaly. Infants were selected consecutively in reverse chronological order, from 2013–2010. Data collected from electronic health records included basic maternal demographics, infant birth characteristics, laboratory and radiology reports, procedures, medication records, weights, caffeine citrate plasma concentration (when available), and diagnoses. Prior to its start, the study was approved by an institutional review board (IRB) at participating sites, and a waiver of informed consent was granted.
Study outcomes
Clinical events of interest included BPD, medical and surgical NEC, spontaneous intestinal perforation, grade II-IV intraventricular hemorrhage (IVH), seizure, arrhythmia, PDA ligation, and death. BPD was defined as the need for supplemental oxygen at 36 weeks postmenstrual age (PMA). NEC was defined by modified Bell’s staging criteria, stage IIA or greater (14). The diagnosis of IVH was based upon head ultrasound results with the highest grade II, III, or IV hemorrhage in either ventricle (15). NEC, spontaneous intestinal perforation, PDA ligation, seizure, and arrhythmia events were included if the event occurred on a day of caffeine citrate dosing. All BPD and IVH events occurring after initiation of caffeine therapy were included in this analysis regardless of whether the infant received caffeine citrate on the day of the event. Death was reported after initiation of caffeine therapy, as well as on the day of caffeine citrate dosing.
Statistical analyses
The planned sample size was 400, which was based on the 95% confidence interval (CI) (exact binomial) for a clinical event of interest of 0.04–8.9%. We used descriptive analysis to examine the frequency of clinical events of interest as well as the mean, median, and range of caffeine citrate exposures. For each participant, we evaluated caffeine exposure regarding loading dose (defined as day 1 of caffeine), average daily maintenance dose (mg/kg) (defined as cumulative caffeine doses excluding loading day 1 divided by number of dose days), the maximum dose of caffeine after loading day 1, and cumulative exposure (including all caffeine doses). Additionally, we evaluated age at start of therapy, duration of exposure, and individual average plasma concentrations when available as part of clinical care. Indications for the use of caffeine citrate or the reason why concentrations were obtained were not available in this cohort. We reported medians (interquartile ranges [IQRs]) of individual caffeine citrate exposures for the cohort.
We evaluated the association between caffeine citrate exposure and select clinical events of interest with a higher event rate at the participant level using logistic regression controlling for site, GA, BW, and concomitant medications (Table 5; available at www.jpeds.com). Specific clinical-event-of-interest outcomes were BPD, NEC, and PDA ligation. Two separate adjusted analyses were performed for each event outcome to evaluate exposure based on either caffeine citrate dose information or serum concentrations, where available, for a total of six models. For analyses with caffeine citrate dose, we considered mean daily caffeine citrate dose (mg/kg/day) and duration of therapy. For regression, the average daily caffeine dose predictor was calculated as the cumulative caffeine dose (including the day 1 loading dosage) divided by the number of dose days until the event day for participants who experienced the clinical event of interest, and over the full study period for participants who did not. For analyses with caffeine citrate plasma concentrations, we used the maximum plasma level for BPD and the most recent plasma level seven days before or after the event for NEC and PDA ligation in the subset of participants with available plasma concentration information. In the BPD analyses, all infants discharged or transferred from the hospital before 36 weeks PMA were not considered at risk of BPD and were excluded.
Table 5:
Concomitant medications
| 1. Furosemide | 12. Fentanyl | 23. Miconazole | 34. Midazolam |
| 2. Bumetanide | 13. Hydromorphone | 24. Nifedipine | 35. Pentobarbital |
| 3. Ethacrynic acid | 14. Methadone | 25. Omeprazole | 36. Phenytoin |
| 4. Hydrochlorothiazide | 15. Amiodarone | 26. Propranolol | 37. Dopamine |
| 5. Chlorothiazide | 16. Amlodipine | 27. Ranitidine | 38. Dobutamine |
| 6. Spironolactone | 17. Dexmedetomidine | 28. Sildenafil | 39. Epinephrine |
| 7. Acetazolamide | 18. Erythromycin | 29. Carbamazepine | 40. Milrinone |
| 8. Indomethacin | 19. Fluconazole | 30. Phenobarbital | 41. Norepinephrine |
| 9. Ibuprofen | 20. Ketoconazole | 31. Rifampin | 42. Phenylephrine |
| 10. Hydrocortisone | 21. Lidocaine | 32. Fosphenytoin | 43. Vasopressin |
| 11. Morphine | 22. Methimazole | 33. Lorazepam | 44. Acetaminophen |
Results
The analysis included 410 infants (Table I) from the following participating sites: Children’s Hospitals and Clinics of Minnesota (n=100), Coastal Carolina Neonatology (n=108), Children’s Hospital of Philadelphia Newborn Care at Pennsylvania Hospital (n=107), and Hackensack University Medical Center (n=95). The studied infants had a BW range of 340–1460 g and a GA range of 22–28 weeks. The median (IQR) first-day loading dose was 20 (19–23) mg/kg/day, and the subsequent median of the individual average daily maintenance caffeine citrate dose for the study cohort was 8 (5–10) mg/kg/day, excluding the first (loading) day of dosing; total duration was 60 (46–75) days (Table 2). Median (IQR) postnatal age at the start of caffeine citrate therapy was 0 (0–1) days, the median (IQR) PMA on the last day of caffeine citrate dosing was 34 (33–36) weeks, and the median (IQR) postnatal age at hospital discharge or transfer was 87 (68–104) days. Overall, 389 (95%) infants started caffeine citrate therapy by 2 days of age, and 390 (95%) infants received caffeine citrate for ≥10 days. Plasma caffeine concentrations were available for 174 infants, with a median (IQR) of 4 (2–10) concentrations recorded per infant. The median (IQR) of the individual average plasma concentration was 18 (15–24) mg/L (Table 2). The postnatal age at first plasma collection varied, with an overall median of 7 (4–20) days.
Table 1.
Cohort characteristics
| N=410 | |
|---|---|
| Gestational age (weeks) | 26 (24, 27) |
| Birth weight (g) | 800 (660, 950) |
| Male | 55% |
| Singleton birth | 70% |
| Inborn | 83% |
| Cesarean delivery | 72% |
| Hospital stay (days) | 87 (68, 104) |
| White | 50% |
| Antenatal steroids | 90% |
| Surfactant therapy | 95% |
Data presented as % or median (interquartile range).
Table 2.
Summary of caffeine citrate doses and concentration by site
| Site 1 (N=100) |
Site 2 (N=108) |
Site 3 (N=107) |
Site 4 (N=95) |
Total (N=410) |
|
|---|---|---|---|---|---|
| Postnatal age at start of caffeine (days) | 1 (0–1) | 0 (0–0) | 0 (0–1) | 0 (0–1) | 0 (0–1) |
| Loading dose day 1 (mg/kg/day) | 20 (19–22) | 17 (13–25) | 20 (20–25) | 20 (20–20) | 20 (19–23) |
| Daily maintenance dose (mg/kg/day)a | 9 (8–10) | 7 (5–10) | 5 (5–6) | 9 (8–10) | 8 (5–10) |
| Maximum daily dose (mg/kg/day) | 20 (12–24) | 11 (8–19) | 13 (10–15) | 19 (17–20) | 16 (10–20) |
| Cumulative dose (mg/kg) | 666 (584–852) | 380 (295–517) | 263 (201–333) | 538 (412–718) | 455 (292–640) |
| Duration of treatment (days) | 77 (62–97) | 55 (45–65) | 52 (35–64) | 63 (51–80) | 60 (46–75) |
| Site 1 (N=24) |
Site 2 (N=3) |
Site 3 (N=101) |
Site 4 (N=46) |
Total (N=174) |
|
| Average plasma concentration (mg/L)b | 26 (22–30) | 24 (22–26) | 16 (14–18) | 24 (18–29) | 18 (15–24) |
| Maximum plasma concentration (mg/L) | 29 (26–33) | 24 (22–26) | 24 (21–27) | 27 (18–35) | 25 (21–29) |
| Postnatal age at first collection (days) | 21 (15–38) | 40 (38–43) | 4 (3–6) | 22 (17–31) | 7 (4–20) |
Data presented as median (IQR) in cohort; individual variables represent summary statistics per participant.
Multiple doses administered in a calendar day were combined as the daily dose.
For each participant, maintenance dose was defined as the average of all caffeine doses after loading dose day 1.
For each participant, average plasma concentration was defined as the average of all available plasma concentrations.
Altogether, 209 (51%) infants experienced at least one clinical event of interest, and their incidence varied across sites (Table 3). We identified 10 infants (2%) who experienced a clinical event of interest (other than BPD or IVH) on a day without caffeine and, per study design, were not included in this analysis. Death occurred in 28 infants (6.8%), of whom nine (2%) died on a day of caffeine citrate exposure. The median (IQR) GAs for the deceased (on a caffeine dose date) and surviving infants were 24 (23–24) weeks and 26 (25–27) weeks, respectively. The median (IQR) BWs for the deceased and surviving infants were 595 (510–710) g and 810 (670–950) g, respectively. The median (IQR) durations of therapy for the deceased and surviving infants were 9 (3–12) days and 60 (47–76) days, respectively. Overall, the most common clinical events of interest included BPD (37%), grade III-IV IVH (13%), and PDA ligation (12%). NEC (medical or surgical) occurred in 35 (9%) infants. Seizures were reported in 13 infants (3%), all of whom received phenobarbital. No arrhythmias were reported.
Table 3.
Summary of clinical events of interest diagnosed on a day of caffeine citrate exposure by site
| Site 1 (N=100) |
Site 2 (N=108) |
Site 3 (N=107) |
Site 4 (N=95) |
Total (N=410) |
|
|---|---|---|---|---|---|
| Death | 0% | 2% | 4% | 3% | 2% |
| BPDa, b | 49% | 27% | 29% | 40% | 37% |
| Medical NEC | 1% | 8% | 4% | 5% | 5% |
| Surgical NEC | 4% | 3% | 8% | 3% | 4% |
| SIP | 5% | 7% | 5% | 2% | 5% |
| Grade II IVHb | 7% | 7% | 8% | 7% | 7% |
| Grade III or IV IVHb | 17% | 9% | 14% | 11% | 13% |
| PDA ligation | 14% | 19% | 8% | 6% | 12% |
| Seizures | 2% | 8% | 2% | 0% | 3% |
| Arrhythmia | 0% | 0% | 0% | 0% | 0% |
Per BPD definition, participants discharged or transferred from hospital before 36 weeks of PMA are excluded from this analysis.
All BPD and IVH (grade II, III, or IV) are included in this analysis regardless of whether the infant was receiving caffeine on the day of the event.
BPD: bronchopulmonary dysplasia; IVH: intraventricular hemorrhage; NEC: necrotizing enterocolitis; PDA: patent ductus arteriosus; SIP: spontaneous intestinal perforation.
Controlling for BW, GA, site, and concomitant medications, increased average caffeine citrate daily dose was associated with reduced odds of NEC and PDA ligation, with adjusted odds ratios (95% CIs) of 0.78 (0.63–0.92) and 0.74 (0.61–0.86), respectively. There was no significant association between dose and BPD (P = .33). In addition, increasing the duration of therapy was not associated with increased odds of BPD, NEC, or PDA ligation. In the subset of infants with plasma concentrations and adjusting as possible for site, GA, BW, and concomitant medications, increasing plasma concentrations of caffeine citrate were not associated with BPD, NEC, or PDA ligation.
Discussion
Our study demonstrated that caffeine citrate is administered to neonates born at younger GA (22–28 weeks GA) at higher doses and for longer durations than recommended by the FDA-approved drug label. Increasing caffeine citrate dose in this population is associated with decreased rates of NEC and PDA ligation. Most infants in this study received doses that were higher than recommended by the drug label; however, plasma concentrations remained in the therapeutic window. The CAP trial also supported higher dosing in these infants, with a daily maintenance dose of up to 10 mg/kg (9).
No clinical trials have definitively determined when to discontinue caffeine citrate therapy in preterm infants. However, because AOP is uncommon beyond 34 weeks GA, caffeine citrate therapy is often continued until preterm infants are 34–36 weeks corrected GA and free of any apnea episodes for at least 8 days (16). In the CAP trial, the median PMA at discontinuation of caffeine citrate was 34 weeks and the median duration of therapy was 37 days (9). The data in our study align with the CAP trial, as caffeine citrate was used for a median of 60 days, which is six times longer than recommended in the FDA-approved label, and the median PMA on the last day of caffeine citrate dosing was 34 weeks.
This study shows that increasing the duration of therapy with caffeine citrate was not associated with increased odds of BPD. Other studies have demonstrated the important role of duration of therapy with caffeine citrate in decreasing the risk of BPD (17–19). In the CAP trial, there was a significant reduction of BPD incidence in infants who received caffeine citrate (36% vs 47% in the placebo group). The authors attributed the decrement of BPD rates to a shorter duration of endotracheal intubation and positive pressure ventilation in the caffeine citrate-treated patients compared with the controls (9).
In the current study, caffeine citrate therapy was initiated early, as is consistent with previous studies (20). In a large multicenter cohort study using data from 62,056 very low birth weight infants, the use of early caffeine citrate therapy within the first three days of life was associated with a lower odds of BPD in survivors compared with later use (23% vs 31%; odds ratio 0.68 [95% CI: 0.63–0.73]) (21). In our study, the median start day was zero, suggesting that many clinicians are using caffeine citrate shortly after birth to prevent apnea, effectively maintain non-invasive support, or decrease risk of BPD rather than waiting for apnea to occur. In a pilot trial, infants of <29 weeks GA were randomized to early prophylactic use of caffeine before two hours of age or caffeine initiation at 12 hours of age (22). The study reported that fewer infants in the early caffeine treatment group required intubation by 12 hours of age, compared with those receiving caffeine at 12 hours of age (27% vs 70%; P=0 .08).
Other benefits of caffeine citrate include decreased need for treatment (medical and surgical) of PDA (21, 23, 24). This association could be explained by different primary or secondary mechanisms, including a diuretic effect, vasoconstrictor effect, adenosine antagonism, reduction in duration of invasive ventilation, or improvement in cardiac output and blood pressure (25). The decreased need for respiratory or cardiac support may reduce the likelihood of a clinician evaluating the patency of a PDA or choosing to treat a PDA. In our cohort, increased mean caffeine citrate dose was significantly associated with a reduction in surgical treatment for PDA. However, the indications for ligation of a PDA were not evaluated in this study and are controversial in the literature (26). In the CAP trial, the post-hoc analysis revealed that infants in the caffeine citrate group were significantly less likely to require pharmacological treatment or surgical ligation compared with infants in the control group (9). Other retrospective studies also found that early caffeine citrate therapy within the first three days of age was associated with a significant reduction of incidence of PDA requiring treatment compared with later initiation of therapy (16, 20, 21).
NEC is a devastating complication of prematurity (27). The FDA’s label warning for caffeine citrate’s potential association with NEC (7) is based on post-hoc analysis of an older randomized, double-blind, placebo-controlled trial of 85 premature infants (caffeine citrate=46, placebo=39) in whom the incidence of NEC was not significantly different between the caffeine group (4.3%) and the placebo group (2.6%) (10). In contrast, our results as well as those from other large cohorts and the pivotal CAP trial did not demonstrate any association between caffeine citrate exposure and NEC (Table 4) (28, 29). The primary data from CAP were not made available to the FDA, and in general, published studies alone are insufficient for the FDA to make decisions.
Table 4.
Comparison of prior studies of caffeine citrate reporting necrotizing enterocolitis frequency. No studies have shown a significant caffeine-related increase in NEC.
| N caffeine | Sites | Population | NEC, n/N (%) | Median duration of therapy (days) | |
|---|---|---|---|---|---|
| FDA labela | 46 | 9 | 28 to <33 wk GA | 2/46 (4.3%) | 10 |
| CAP trialb | 1006 | 35 | 500–1250 g | 63/1006 (6.3%)c | 37 |
| NICHD NRNd | 9575 | 20 | 22–28 wk GA, BW 401–1500 g |
11% | Not reported |
| VONd | 38,017 | 669 | BW 501–1500 g | 2015/38,017 (5.3%) | Not reported |
| Current studyd | 410 | 4 | 22–28 wk GA | 35/410 (8.5%) | 60 |
BW: body weight; CAP trial: Caffeine for Apnea of Prematurity Trial (9); FDA: U.S. Food and Drug Administration (10); GA: gestational age; NICHD NRN: The National Institute of Child Health and Human Development Neonatal Research Network study from 2003 to 2007 (28); VON: The Vermont Oxford Network study from 2009 (29).
Randomized controlled trial, post-hoc analysis with no significant increase in NEC with caffeine treatment compared with placebo;
Randomized controlled trial with no significant increase in NEC with caffeine treatment compared with placebo (p=0.63);
Placebo group reported NEC in 67/1000 (6.7%);
Retrospective analysis.
Strengths of this study include that the data are recent (2010–2013), representing current care of extremely preterm infants from four large NICUs, and the availability of caffeine citrate dosing data. This study was performed under an investigational new drug application and with primary data sources available to the FDA.
As with all retrospective analyses of electronic medical records, weaknesses include an absence of data regarding indication for use and variation in the administration of caffeine citrate per local standard NICU practices (i.e., not as a study drug). There was no placebo group involved because nearly all infants in this GA group received caffeine citrate. Because caffeine citrate treatment was administered via standard of care, potential modeling biases were inherent in the selection of dosage and treatment duration based on participant response and changes in condition. Given the study design, clinical events of interest (except for BPD and IVH) were included only if they occurred on the day of caffeine citrate dosing. Characterization of infant death was limited to birth characteristics and exposure to caffeine. Changes in clinical practice over the study period could not be taken into consideration.
In summary, caffeine citrate was routinely administered off-label to extremely premature infants during their first two months after birth. Duration of therapy was not associated with increased odds of BPD. Furthermore, the dose and duration of therapy were not associated with increased odds of PDA ligation or NEC. This study (and the CAP trial) does not support an association between caffeine citrate exposure and NEC. Additional studies are necessary to optimize the timing of caffeine citrate initiation, dose, and the duration of therapy. Given differences between the FDA-approved label and the published literature, results from this research are being submitted to the FDA for review.
Acknowledgments
Funded under National Institute of Child Health and Human Development (NICHD) contract HHSN275201000003I for the Pediatric Trials Network (principal investigator [PI] Danny Benjamin). M.P-D. received salary support from the National Institutes of Health (T32 HD 43029–13 and T32 HD 43029–14, PI: Benjamin). M.L. received support from the US government for work in pediatric pharmacology and trials (FDA R01FD005101, PI Laughon; NHLBI 1R34HL124038, PI: Laughon; NICHD Pediatric Trials Network HHS27500033, PI: Benjamin), for trial design and coordination (ECHO NIH Office of the Director, 1UC2-OD023375; PI: Smith), and as the satellite site PI for the NICHD Neonatal Research Network (NICHD 2UG1HD040492, PI: Cotten). E.P. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The other authors declare no conflicts of interest.
Abbreviations:
- AOP
apnea of prematurity
- BPD
bronchopulmonary dysplasia
- BW
birth weight
- CAP trial
Caffeine for Apnea of Prematurity trial
- FDA
U.S. Food and Drug Administration
- GA
gestational age
- IVH
intraventricular hemorrhage
- NEC
necrotizing enterocolitis
- NICHD
National Institute of Child Health and Human Development
- NICU
neonatal intensive care unit
- OR
odds ratio
- PDA
patent ductus arteriosus
- PMA
postmenstrual age
- VLBW
very low birth weight
Additional members of the Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee
Gary Furda, Duke Clinical Research Institute, Durham, NC; Danny Benjamin, Duke Clinical Research Institute, Durham, NC; Edmund Capparelli, University of California San Diego, San Diego, CA; Gregory L. Kearns, Arkansas Children’s Hospital Research Institute, Little Rock, AR; Ian M. Paul, Penn State College of Medicine, Hershey, PA; Christoph Hornik, Duke Clinical Research Institute, Durham, NC.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development:
Perdita Taylor-Zapata.
The Emmes Corporation (Data Coordinating Center):
Ravinder Anand and Gina Simone.
Pediatric Trials Network Caffeine Study Team and Study Coordinators (SCs):
Duke Clinical Research Institute: Tedryl Bumpass (lead Clinical Research Associate). Children’s Hospital and Clinics of Minnesota: Alissa Jorgenson, Samantha Zimmerman.
New Hanover Regional Medical Center: Danielle Kurtz, Arielle Lapid, Daniel Moya. Hackensack University Medical Center: Gina Dovi, Mary Ellen Riordan.
Footnotes
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List of additional members of the Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee available at www.jpeds.com (Appendix)
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