Pediatric Clinical Trials at the National Institutes of Health Anne Zajicek, MD, PharmD Obstetric and Pediatric Pharmacology Branch Center for Research.

Pediatric Clinical Trials at the National Institutes

of Health

Anne Zajicek, MD, PharmDObstetric and Pediatric Pharmacology

BranchCenter for Research for Mothers and

ChildrenNational Institute of Child Health and Human

Development, NIH

Outline

ClinicalTrials.gov listings Pediatric Clinical Trials in the Obstetric and

Pediatric Pharmacology Branch Pediatric Pharmacology Research Units Network Best Pharmaceuticals for Children Act Grants

ClinicalTrials.gov

Industry: 5250 total studies (adults + children), 813 enrolling children (15 %)

Other Federal Agencies: 627 total studies, 151 in children (24 %)

NIH: 4892 total studies, 1400 in children

(29 %)

Pediatric Clinical Trials: ongoing/all trials including closed  Sponsor

PhaseNIH Other Fed FDA Industry Univ/Org

I172/681 14/38 6/12 62/179 286/604

II342/1311 27/57 18/27 209/606 591/1311

III210/637 23/61 6/14 342/1043 406/896

IV36/96 12/35 1/1 169/381 238/447

I - IV685/2548 69/167 26/45 721/2066 1342/2908

All1400/4892 151/356 41/82 813/2341 2391/4610

Break-down by InstituteInstitute Total Trials In children

NCI 1669 414

NHLBI 322 120

NIAID 395 188

NICHD 244 175

NIDDK 270 101

NIMH 367 111

NINDS 240 65

NIDA 229 43

ORD 19 12

Obstetric Pharmacology Research Units

Funded in 2004 Define pharmacokinetic (PK),

pharmacodynamic (PD), pharmacogenomic (PG) changes that occur during pregnancy Opportunistic PK studies PK studies of 17α hydroxyprogesterone caproate

used to prevent of preterm delivery PK/PD/PG studies in glyburide

Pediatric Pharmacology Research Units

First funded in 1994 Purpose: to improve knowledge of PK, PD,

PG in children 13 sites Performs Phase 1, 2, 3 studies in children of

all ages

NIH Rapid Access to Interventional Development (RAID)

Purpose: to make available, on a competitive basis, certain critical resources needed for the development of new small molecule therapeutic agents

Projects associated with NICHD Metastin Friedrich ataxia

More funding available than projects- please apply Contact information

(301) 594-4660 nih-raid@mail.nih.gov

Best Pharmaceuticals for Children Act

Legislation signed into law 2002, sunsets Oct 2007

Purpose: improve pediatric labeling Extends marketing exclusivity for on-patent

drugs if FDA-requested studies (as described in the Written Request) are performed

For off-patent drugs: NIH prioritizes drugs for study, sponsors clinical trials if the Written Request declined

Master List of all Off-Patent Drugs which lack adequate pediatric labeling

N=200

Consultation with experts in pediatric practice and research

Develop, prioritize, publish an Annual List

N=5-15

Consider for prioritizing: Availability of S/E dataAre additional data needed?Will new studies produce health benefits?Reformulation?

Drugs on the Priority List: January 2003

FR 68: 13; Jan 21, 2003

Azithromycin

Baclofen Bumetanide Dobutamine Dopamine Furosemide Heparin

Lithium

Lorazepam Rifampin Sodium nitroprusside Spironolactone

Drugs on the Priority List: August 2003

FR 68: 156; Aug 13, 2003

Ampicillin/sulbactam Diazoxide

Isoflurane Lindane Meropenem

Metoclopramide Piperacillin/

tazobactam Promethazine

Drugs on the Priority List: February 2004

FR 69:30; February 13, 2004

AmpicillinKetamine Vincristine Dactinomycin Metolazone

Drugs on the Priority List: January 2005

FR 70:17; January 27, 2005

Ivermectin Hydrocortisone valerate Hydrochlorothiazide Ethambutol Griseofulvin Methadone Hydroxychloroquine Sevelamer Morphine

Drugs on the Priority List: January 2006 FR 71:79; April 25, 2006

Sickle Cell Disease: Hydroxyurea Oncology: Methotrexate, Daunomycin Poisoning: Pralidoxime Other disease areas of continuing

interest/discussion: ADHD Hypertension Parasitic Diseases Influenza

Off-Patent Written Requests Issued by FDA Lindane Rifampin

Methicillin resistant Staph aureus endocarditis CNS shunt infections

Meropenem Vincristine Actinomycin-D Ampicillin Griseofulvin Methotrexate

Off-Patent Written Requests Issued by FDA

Lorazepam Sedation Status epilepticus

Nitroprusside Azithromycin

for Ureaplasma pneumonia Azithromycin for Chlamydia

Baclofen* Lithium Morphine* Hydroxyurea*

Off-Patent Written Requests Declined by Industry

Rifampin MRSA endocarditis CNS shunt infections

Meropenem Vincristine Dactinomycin Ampicillin Griseofulvin Methotrexate

Off-Patent Written Requests Declined by Industry

Lorazepam Sedation Status epilepticus

Nitroprusside Azithromycin

for Ureaplasma pneumonia Azithromycin for Chlamydia

Baclofen* Lithium Morphine*

On-Patent Written Requests Declined by Industry

Morphine* Bupropion Sevelamer Zonisamide Hydroxyurea Baclofen* Dexrazoxane Eletriptan Metoclopramide*

Pediatric Studies that are on-going under BPCA

Contracts

Contracts awarded Lorazepam for sedation

Is lorazepam more effective than midazolam? How should lorazepam be given, by intermittent bolus

or by continuous infusion? Lorazepam for status epilepticus

What is the correct dose of lorazepam to treat seizures?

Is lorazepam more effective or safer than diazepam for children in status epilepticus?

BPCA Studies on-going

Nitroprusside for controlled hypotension What is the dose-response relationship for nitroprusside? Is there tolerance to the hypotensive effect?

Ketamine (pre-clinical) Does ketamine cause apoptosis?

Lithium for acute mania Is lithium safe and effective for the treatment of acute

mania in children with bipolar disease? Baclofen for spasticity in cerebral palsy

Is oral baclofen safe and effective in children with cerebral palsy?

BPCA Studies On-going

Methylphenidate Replication of cytogenetic studies in children

receiving methylphenidate

Intra-Agency Agreements Vincristine Actinomycin-D

What is the incidence of toxicity in children? What are the toxicities, and is there a relationship to dose,

diagnosis, age, weight? Is there a relationship between systemic exposure and

efficacy/toxicity?

Methotrexate and neurocognition Is the method of dosing MTX related to neurocognitive

changes in children with high-risk acute lymphocytic leukemia?

Daunomycin: relationship of disposition to body size Hydroxyurea in sickle-cell disease

Contracts under Negotiation

Meropenem for complicated intra-abdominal infections

Grant

Morphine To evaluate the relationship of developmental

stage (defined by both gestational and postnatal age) to the disposition of morphine and the clinical response

Coordinating Center

Purpose: Coordinate patient enrollment Coordinate, monitor data collection Report adverse events and other data (usually blinded) to

Data Safety Monitoring Board (DSMB) Analyze, organize results into a supplemental NDA for

submission to FDA

Contract awarded to Premier Research, Philadelphia, Pennsylvania

Summary

NIH is sponsoring clinical studies in children that will produce improvements in pediatric therapeutics