User:AMcMillanPTN/draft main article
The Pediatric Trials Network (PTN) is a consortium of clinical research sites located around the United States that are cooperating in the design and conduct of clinical trials to improve health care for young patients. The network is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).[1]
The work of the PTN addresses a critical lack of information regarding the impact of therapeutic agents on infants and children. Developing organs and changes in metabolism throughout infancy and childhood affect how drugs are processed by immature or maturing bodies[2]; thus, age-dependent adjustments in doses are required to ensure that such therapies are used safely and effectively. Unfortunately, only a small percentage of drugs and devices approved by the Food and Drug Administration (FDA) have actually been studied in children and are labeled for pediatric use. Pediatricians, consequently, are often forced to prescribe medical therapies "off-label," or according to their best guess based on adult studies.[3][4]
To fill this knowledge gap, the PTN is studying the formulation, dosing, efficacy, and safety of drugs, as well as the development of medical devices, used in pediatric patients. In keeping with the goals of the Best Pharmaceuticals for Children Act (BPCA),[5] data collected from PTN trials are helping regulators to revise FDA labels for safer and more effective use in infants and children.
A map of sites currently participating in PTN trials may be viewed on the network's website [1].
Background[edit]
Pediatric clinical research faces unique challenges: low study consent rates among parents of sick children, limited blood volume available for the conduct of pharmacokinetic studies, and a relative lack of pediatric analytical expertise in pharmacokinetics and pharmacodynamics, to name a few.[6] Because of such obstacles, before 1998, pharmaceutical companies were not required by the government to test their drugs in infants and children, even if the drugs were commonly given to those populations.
The Food and Drug Administration Modernization Act (1997) and BPCA (2002, amended in 2007 and renewed in 2012) offer financial incentives in the form of patent extensions for companies that voluntarily test their drugs in pediatric patients.[5][7] BPCA also provides a mechanism by which off-patent therapeutics might be studied through a collaboration between the FDA and National Institutes of Health. The NICHD is responsible for funding these studies from its annual budget.
Since the BPCA was first enacted, the NICHD has awarded numerous projects to organizations and institutions for the purpose of gathering information to improve pediatric drug labeling. One of these projects is the PTN, which is creating a scientific, technical, and administrative infrastructure that, in strategic partnership with the NICHD, is studying critical drugs and diagnostic devices in children to improve labeling for pediatric use.
Current Projects[edit]
The PTN is conducting a number of pediatric trials spanning several therapeutic areas, including cardiovascular diseases, cancer, infectious diseases, gastroenterology, respiratory diseases, neonatology, and medical devices. Below is a summary of PTN projects as of October 2013.
| Trial | ClinicalTrials.gov Identifier | Molecule(s) of Interest | Summary |
|---|---|---|---|
| Safety and pharmacokinetics of multiple-dose metronidazole in premature infants [2] | NCT01222585 [3] | Metronidazole | Studied the safety and pharmacokinetics of intravenous metronidazole in premature infants with suspected serious infection; study completed, dosing recommendations published [4] |
| Taking the guesswork out of pediatric weight estimation (TAPE) [5] | NCT01507090 [6] | N/A | Evaluated the predictive performance and equivalence of the Mercy Method™ weight estimation method in children; study completed, results published [7] |
| An open-label study to describe the pharmacokinetics of acyclovir in premature infants [8] | NCT00942084 [9] | Acyclovir | Evaluating the safety and pharmacokinetics of intravenous acyclovir in premature infants with suspected systemic infection; analysis in progress, results expected in 2013 |
| Hydroxyurea in pediatric patients with sickle cell anemia [10] | NCT01506544 [11] | Hydroxyurea | Examining the pharmacokinetics of hydroxyurea in children with sickle cell anemia; enrollment ongoing |
| Pharmacokinetics of understudied drugs administered to children per standard of care (POPS) [12] | NCT01431326 [13] | Amiodarone, Ampicillin, Bumetanide, Clindamycin, Clonidine, Doxycycline, Epinephrine, Fentanyl, Fluconazole, Furosemide, Granisetron, Griseofulvin, Hydrochlorothiazide, Hydroxocobalamin, Ketamine, Meropenem, Methadone, Metoclopramide, Ondansetron, Pravastatin, Simvastatin, Trimethoprim-sulfamethoxazole | Characterizing the pharmacokinetics of understudied drugs that are administered to children regularly by their treating physicians; enrollment ongoing |
| Safety and pharmacokinetics of lisinopril in pediatric kidney transplant recipients [14] | NCT01491919 [15] | Lisinopril | Examining the pharmacokinetics of lisinopril in pediatric kidney transplant recipients; enrollment completed, results expected in 2013 |
| Midazolam for treatment of status epilepticus [16] | N/A | Midazolam | Providing supplemental data to support the change of the current midazolam prescription labeling to include the treatment of seizures; analysis in progress |
| The ampicillin in infants study [17] | N/A | Ampicillin | Evaluating the pharmacokinetics and safety of ampicillin for the treatment of sepsis and/or meningitis in infants at various ages and birth weights; analysis in progress |
| Studying obesity and drug dosing in children [18] | N/A | N/A | Developing a drug database for clinicians and researchers that will provide dosing guidelines for obese children; in progress |
| Pharmacokinetics of anti-staphylococcal antibiotics in infants [19] | NCT01728363 [20] | Clindamycin, Rifampin, Ticarcillin-clavulanate | Studying the pharmacokinetics and safety of 3 anti-staphylococcal antibiotics in term and premature infants; enrollment ongoing |
| Pharmacokinetics of sildenafil in premature infants [21] | NCT01670136 [22] | Sildenafil | Evaluating the pharmacokinetics and safety of sildenafil for the treatment of bronchopulmonary dysplasia in premature infants; enrollment ongoing |
| Safety and pharmacokinetics of multiple-dose intravenous and oral clindamycin in obese children [23] | NCT01744730 [24] | Clindamycin | Determining the pharmacokinetics of intravenous and oral clindamycin in overweight and obese children and adolescents with Staphylococcus aureus infections; enrollment ongoing |
| Safety of fluconazole prophylaxis in infants [25] | N/A | Fluconazole | Examining the safety of fluconazole prophylaxis in premature infants with candidemia; data collection underway |
| Efficacy of antiviral suppression therapy after neonatal HSV infection of the central nervous system | N/A | Acyclovir | Will assess the safety of high-dose acyclovir in infants with herpes simplex virus via retrospective database and chart reviews and secondary data analysis |
| The effect of obesity on the pharmacokinetics of pantoprazole in children and adolescents | N/A | Pantoprazole | Will assess the pharmacokinetics of pantoprazole in obese children and adolescents; protocol in development |
| Safety of drugs used in hospitalized infants | N/A | N/A | Will characterize the safety of drugs used in hospitalized infants using data collected on infants discharged from NICUs managed by the Pediatrix Medical Group; protocol in development |
| Antibiotic safety in infants with complicated intra-abdominal infections (SCAMP) | Pending | Ampicillin, Clindamycin, Metronidazole, Piperacillin-tazobactam | Will evaluate the safety of drug regimens consisting of ampicillin, metronidazole, clindamycin, and piperacillin-tazobactam in infants with complicated intra-abdominal infections |
| Extremely low birth weight infants exposed to furosemide or bumetanide in the neonatal intensive care unit | N/A | Bumetanide, Furosemide | Will estimate incidence of adverse events in infants exposed to furosemide or bumetanide during hospitalization in the NICU; the safety profile of the drugs of interest will be evaluated |
| Pharmacokinetics of multiple-dose methadone in children | Pending | Methadone | Will determine the pharmacokinetics of enteral methadone in children treated for opiate withdrawal |
Published Results[edit]
Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants. [26] Hornik CP, Herring AH, Benjamin DK Jr, Capparelli EV, Kearns GL, van den Anker J, Cohen-Wolkowiez M, Clark RH, Smith PB; Best Pharmaceuticals for Children Act-Pediatric Trials Network. The Pediatric Infectious Diseases Journal • July 2013, volume 32, issue 7, pages 748-53. PMC 3708263 [Free access available on 7/1/2014]
Evaluation of the Mercy TAPE: performance against the standard for pediatric weight estimation. [27] Abdel-Rahman SM, Paul IM, James LP, Lewandowski A; Best Pharmaceuticals for Children Act-Pediatric Trials Network. Annals of Emergency Medicine • April 17, 2013 [Epub ahead of print]
Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants. [28] Cohen-Wolkowiez M, Sampson M, Bloom BT, Arrieta A, Wynn JL, Martz K, Harper B, Kearns GL, Capparelli EV, Siegel D, Benjamin DK Jr, Smith PB; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network. The Pediatric Infectious Diseases Journal • April 12, 2013 [Epub ahead of print]
Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections. [29] Cohen-Wolkowiez M, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Randolph DA, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Rich W, Brozanski BS, van den Anker J, Blumer J, Laughon M, Watt KM, Kearns GL, Capparelli EV, Martz K, Berezny K, Benjamin DK Jr, Smith PB; on behalf of the Meropenem Study Team. Clinical Infectious Diseases • December 2012, volume 55, number 11, pages 1495-1502. PubMed Central (PMC) ID: PMC3491861. [Free access available on 12/1/2013]
Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections. [30] Smith PB, Cohen-Wolkowiez M, Castro LM, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Bhatt-Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Brozanski BS, Sanchez P, van den Anker J, Blumer J, Kearns GL, Capparelli EV, Anand R, Benjamin DK Jr; Meropenem Study Team. The Pediatric Infectious Disease Journal • October 2011, volume 30, number 10, pages 844-849. PMC 3173561 [Free PMC article]
Innovative clinical trial design for pediatric therapeutics. [31] Laughon MM, Benjamin DK Jr, Capparelli EV, Kearns GL, Berezny K, Paul IM, Wade K, Barrett J, Smith PB, Cohen-Wolkowiez M. Expert Review of Clinical Pharmacology • September 2011, volume 4, number 5, pages 643-652. PMC 3184526 [Free PMC article]
PTN Core Leadership[edit]
- PTN Program Management and Clinical Operations Core; Mentorship Core: Daniel K. Benjamin Jr., Duke Clinical Research Institute [32], Durham, NC
- Clinical Pharmacology Core: Gregory L. Kearns, Children's Mercy Hospital [33], Kansas City, MO
- Pharmacometrics Core: Edmund Capparelli, University of California–San Diego [34], San Diego, CA
- Safety and Ethics Core: Ross McKinney, Duke University Medical Center [35], Durham, NC
- Devices Core: Andre Muelenaer, Virginia Tech Carilion School of Medicine [36], Roanoke, VA
PTN Administrative Core Committee[edit]
- Jeffrey Barrett, Children's Hospital of Philadelphia [37], Philadelphia, PA
- Michael Cohen-Wolkowiez, Duke Clinical Research Institute [38], Durham, NC
- Matthew Laughon, University of North Carolina at Chapel Hill [39], Chapel Hill, NC
- T. Michael O'Shea, Wake Forest Baptist Medical Center [40], Winston Salem, NC
- Ian M. Paul, Penn State College of Medicine [41], Hershey, PA
- P. Brian Smith, Duke Clinical Research Institute [42], Durham, NC
- John van den Anker, George Washington University School of Medicine and Health [43], Washington, DC
- Kelly Wade, Children's Hospital of Philadelphia [44], Philadelphia, PA
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development [45]: David Siegel, Perdita Taylor-Zapata, Anne Zajicek
- The EMMES Corporation (data coordinating center) [46]: Ravinder Anand, Traci Clemons
References[edit]
- ^ Eunice Kennedy Shriver National Institute of Child Health and Human Development website. Available at: http://www.nichd.nih.gov/Pages/index.aspx. Accessed September 4, 2013.
- ^ Kearns, GL, Abdel-Rahman, SM, Alander, SW, Blowey, DL, Leeder, JS, Kauffman, RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–1167.
- ^ Shah SS, et al. Off-label drug use in hospitalized children. Arch Pediatr Adolesc Med. 2007;161:282–290.
- ^ Bazzano AT, et al. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9:81–88.
- ^ a b Best Pharmaceuticals for Children Act website. Available at: http://bpca.nichd.nih.gov/. Accessed September 4, 2013.
- ^ Laughon MM, Benjamin DK Jr, Capparelli EV, Kearns GL, Berezny K, Paul IM, Wade K, Barrett J, Smith PB, Cohen-Wolkowiez M. Innovative clinical trial design for pediatric therapeutics. Expert Rev Clin Pharmacol. 2011;4:643–652.
- ^ Food and Drug Administration Modernization Act. Available at: http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDAMA/FullTextofFDAMAlaw/default.htm. Accessed September 19, 2013.
External Links[edit]
Pediatric Trials Network website. Available at: https://www.pediatrictrials.org/. Accessed September 4, 2013.