The NIH Contribution to Clinical Trials in the US

Pediatric Clinical Trials at the National Institutes of Health Anne Zajicek, MD, PharmD Obstetric and Pediatric Pharmacology Branch Center for Research for Mothers and Children National 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 Phase NIH I Other Fed FDA Industry Univ/Org 172/681 II 14/38 27/57 23/61 12/35 6/12 18/27 6/14 1/1 62/179 209/606 342/1043 169/381 286/604 591/1311 406/896 238/447 342/1311 III 210/637 IV 36/96 I - IV 685/2548 All 1400/4892 69/167 151/356 26/45 41/82 721/2066 813/2341 1342/2908 2391/4610 Break-down by Institute Institute NCI Total Trials 1669 In children 414 NHLBI NIAID 322 395 120 188 NICHD NIDDK NIMH 244 270 367 175 101 111 NINDS NIDA 240 229 65 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 Consider for prioritizing: Availability of S/E data Are additional data needed? Will new studies produce health benefits? Reformulation? Consultation with experts in pediatric practice and research Develop, prioritize, publish an Annual List N=5-15 Drugs on the Priority List: January 2003 FR 68: 13; Jan 21, 2003  Azithromycin  Lithium       Baclofen Bumetanide Dobutamine Dopamine Furosemide Heparin     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  Ampicillin     Ketamine 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 ongoing 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 intraabdominal 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