Timolol for Infantile Hemangiomas under Review

Since first reported in 2008 that propranolol, a beta blocker, was effective in the treatment of Infantile Hemangiomas (IH)—a birthmark that most commonly appears as a rubbery, bright red nodule of extra blood vessels in the skin, commonly called a “strawberry”—this class of drug has been used as the first line of therapy for infants with IH. Timolol, also a beta blocker, is available in topical formulation, and increasingly used off-label for small, non-complicated IH. The popularity of timolol is likely due to its perceived safety as a topical drug. However, data on timolol efficacy, safety and pharmacokinetics are limited.

Under the protocol thought leadership of Dr. Beth Drolet, Principal Investigator, the PTN’s Timolol study will enroll 100 infants between the ages of ≥32 to <50 weeks postmenstrual age. The infants will be treated with timolol for 28 days then randomized into 2 groups. One group will continue timolol treatment while the other will be withdrawn from treatment. Both groups will remain on the study in their respective groups for up to 120 days. The study will begin to enroll in the early summer of 2016 in approximately 10 US sites, and will end in the fall of 2017. The data received from the study will be presented to the FDA to support the use of timolol for the treatment of IH.

PTN Pantoprazole Study Closes Enrollment

Congratulations to the PTN Pantoprazole Study Team for closing enrollment with 41 subjects. The study goal was to enroll 40 subjects in two age groups. The dedicated team worked hard to keep the study on track and accomplish this goal.

The Pantoprazole Study will evaluate the pharmacokinetics of pantoprazole in obese children and adolescents with gastroesophageal reflux disease (GERD) following administration of an oral dose of pantoprazole.

2015 Best Pharmaceuticals for Children Act Update

Dear Colleagues:

We would like to thank you for your continued interest and past input into the Best Pharmaceuticals for Children Act (BPCA) program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). As stakeholders in this important program, we would like to keep you abreast of current developments:

1. To date, all of our BPCA legacy studies—trials conducted prior to award of the Pediatric Trials Network (PTN) in 2010—have been completed. In September 2014, we submitted the Clinical Study Report (CSR) for the Lorazepam for Status Epilepticus study. A meeting with the FDA division was held in October, and the final CSR incorporating FDA comments was submitted in November 2014. Per FDA request, we recently submitted additional analyses and reports to the agency for a potential label change of this drug.

2. In 2014, we announced one official label change—the use of sodium nitroprusside in children for blood pressure control. This year, we have the privilege to announce the label change for meropenem for intra-abdominal infections. We anticipate that data from at least three additional studies (lithium, acyclovir, and diazepam) will be submitted to the agency by the end of 2015.

3. Between 2014 and to date in 2015, the program has submitted six additional CSRs to the agency. Five of these are PTN-led studies and include: a hydroxyurea bioequivalence study that complements the BABY HUG study; ampicillin for use in preterm neonates to treat infection; lisinopril for use in patients with renal transplant to lower blood pressure; clindamycin-dosing study in patients who are obese; and fluconazole for use in preterm neonates to treat infection. In October 2014, we also submitted a draft CSR for isotretinoin for use in treating neuroblastoma. Our hope is that these submissions will result in label changes in the near future.

4. In addition to the drug studies, the PTN and the BPCA Data Coordinating Center worked closely together to submit our first device study to the agency—the TAPE study, which was approved as of May 2015.

5. The PTN is currently conducting 7 new studies, including an innovative opportunistic study of commonly used medications that more than 1,300 children are receiving for their medical conditions. These new studies on diuretics, caffeine, pediatric opportunistic PK studies (POPs), antibiotics safety, Baby TAPE, sildenafil, and pantoprazole will improve our knowledge of how drugs are used in children.

6. Through the Pediatric Clinical Pharmacology T32 fellowship program, we continue to train new pediatric clinical pharmacologists while stimulating interdisciplinary collaboration among clinical, translational, and basic researchers in pediatric therapeutics.

We would also like for you to Save the date December 9, 2015, for our Annual BPCA Stakeholders Meeting. Held on the NIH campus in Bethesda, MD, the meeting will be conducted via webinar for all non-local attendees. You will be hearing from our logistics contractor soon with further details. We hope you can participate.

Finally, we would like to express our sincere appreciation to each of you for your interest in this important program. We look forward to working with you in the 2016 calendar year on our continuing areas of interest. Please feel free to contact me with any questions or concerns.

Best regards,

Perdita Taylor-Zapata, M.D.
Pediatric Medical Officer
Obstetric and Pediatric Pharmacology and Therapeutics Branch (OPPTB)
NICHD/NIH
Bethesda, MD
Phone: 301-496-9584
Email: taylorpe@mail.nih.gov

PTN meropenem study published in the Federal Register

The PTN marks another milestone as the Food and Drug Administration (FDA) has published a summary report of its pediatric study of meropenem in the Federal Register.

Meropenem is a broad-spectrum anti-microbial drug often used to treat intra-abdominal infections in infants. The purpose of the PTN study, which began in the summer of 2008, was to determine the optimal dosing regimen for meropenem in infants younger than 90 days old. Researchers were also interested in determining how safe the drug is for very young infants, especially when compared with imipenem, another broad-spectrum anti-microbial drug closely related to meropenem.

The trial included 200 infants at 24 neonatal intensive care units across the United States. Findings suggested that meropenem as dosed in the study is a safe alternative for young infants with intra-abdominal infections. The FDA recently changed the label for meropenem to reflect these findings, which were published in the Pediatric Infectious Disease Journal.

In accordance with the Public Health Service Act, the FDA is making available the labeling changes for meropenem in the Federal Register.

Mercy TAPE moves closer to market

The FDA has approved the 510(k) application for the Mercy TAPE—an anthropometric-based device developed by Dr. Susan Abdel-Rahman at Children’s Mercy Hospital in Kansas City that predicts weight in children 2 months through 16 years of age. The results from the PTN study validating this device appeared in the Annals of Emergency Medicine in 2013.

Section 510(k) of the Food, Drug, and Cosmetic Act requires device manufacturers to notify the FDA of their intent to market a medical device at least 90 days in advance. This is known as Premarket Notification—also called PMN or 510(k). This step allows the FDA to review the scientific evidence generated related to safety and efficacy and determine whether the device is equivalent to an existing device. Because the Mercy TAPE is the first weight estimation device to be submitted to the FDA, the agency examined it against a standard medical scale and subsequently generated a brand new product code to classify such devices.

The 501(k) approval clears the way for the Mercy TAPE to be marketed and distributed once the commercial partner registers with the FDA. In the meantime, the ongoing Baby TAPE study is collecting the necessary anthropometric data on children under the age of 3 months, with the eventual goal of developing, designing, and validating a similar weight estimation tool for newborns and young infants. Results from this study are expected in 2016.

PTN hosts an investigator gathering at PAS 2015

The PTN hosted an informational, informal gathering during the Pediatric Academic Society meeting in San Diego in late April, giving investigators and study personnel a chance to meet face to face. Thanks to all who participated!

From left to right: Jamie Gao (Duke), Adrienne Tremoulet (UCSD), Micky Cohen-Wolkowiez (Duke), Kristy Rica (University of Florida), Ashley Maddox (University of of Florida), Caroline Ludwig (Wake Forest University), Matt Laughon (UNC), Danny Gonzalez (UNC), Brian Smith (Duke), and Barrie Harper (Duke).
From left to right:
Jamie Gao (Duke), Adrienne Tremoulet (UCSD), Micky Cohen-Wolkowiez (Duke), Kristy Rica (University of Florida), Ashley Maddox (University of of Florida), Caroline Ludwig (Wake Forest University), Matt Laughon (UNC), Danny Gonzalez (UNC), Brian Smith (Duke), and Barrie Harper (Duke).