WELCOME and INTRODUCTION WELCOME and INTRODUCTION Workshop on Regulatory and Scientific Issues related to the Workshop on Regulatory and Scientific Issues related to the Investigation of Medicinal Products intended for Neonatal Use Investigation of Medicinal Products intended for Neonatal Use John van den Anker, MD, PhD Children’s National Medical Center, Washington, DC & Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands 11 October 2006
Historical Drug “Development” in Children Historical Drug “Development” in Children Colic, diarrhea, Colic, diarrhea, cholera & teething cholera & teething alcohol (8.5%) alcohol (8.5%) morphine (1/8 grain) morphine (1/8 grain) Teething Teething Deodorized Deodorized tincture of tincture of opium (1.5%) opium (1.5%)
Historical Drug “Development” in Children Historical Drug “Development” in Children
WHAT IS A LICENSED DRUG? • Has a product license or marketing authorisation • issued by the national licensing regulatory bodies • or the European Medicines Evaluation Agency (EMEA) • following detailed review of data presented by the drug company
Why was the licensing system introduced? Origin in ADR’s – 1938 sulfanilamide (107 deaths) – 1959 chloramphenicol (‘grey baby syndrome’) – 1961 thalidomide (phocomelia)
What is a licensed drug? • SAFE • EFFECTIVE • HIGH QUALITY
Examples of unlicensed drugs • Modifications of licensed drugs • New drugs/formulations produced under a ‘specials’ manufacturing license • Drugs which have a license in other countries but not in the UK or France or Germany or the Netherlands or.. • Use of chemicals as drugs
Examples of off label use Use outside the licensed: • Age range • Indications • Dosage recommendations • Route of administration • Contraindications
Unlicensed and off label drug Unlicensed and off label drug use in the neonate use in the neonate • 70 babies • 70 babies • 455 prescription episodes • 455 prescription episodes • Licensed 35% • Licensed 35% • Unlicensed 10% • Unlicensed 10% • Off label 55% • Off label 55% • 90% babies received at least one UL/OL • 90% babies received at least one UL/OL drug drug • Conroy S, McIntyre J, Choonara I. Arch. Dis. Child. Fetal Neonatal Ed. 1999;80:F142-5 • Conroy S, McIntyre J, Choonara I. Arch. Dis. Child. Fetal Neonatal Ed. 1999;80:F142-5
The Knowledge Gap: The Knowledge Gap: Possible Reasons-Still Exist Possible Reasons-Still Exist • Ethical Concerns • Ethical Concerns • Limited populations for certain diseases • Limited populations for certain diseases • Difficulties in conducting trials in neonates: • Difficulties in conducting trials in neonates: logistical to technical reasons logistical to technical reasons • Lack of infrastructure-improving • Lack of infrastructure-improving
The Knowledge Gap: The Knowledge Gap: Possible Reasons-Still Exist Possible Reasons-Still Exist • Belief dosing could be determined by weight • Belief dosing could be determined by weight based calculations (“little children”) based calculations (“little children”) • Lack of accepted endpoints and validated • Lack of accepted endpoints and validated pediatric assessment tools pediatric assessment tools • Limited marketing potential compared to adults • Limited marketing potential compared to adults
BPCA: Pediatric Exclusivity BPCA: Pediatric Exclusivity Stats (As of July 2006) Stats (As of July 2006) • Proposed Pediatric Study Requests 474 • Proposed Pediatric Study Requests 474 • Written Requests issued by FDA 323 • Written Requests issued by FDA 323 • Exclusivity granted for PRODUCT 123 • Exclusivity granted for PRODUCT 123 • Number of Determinations 135 • Number of Determinations 135 • Label changes 114 • Label changes 114 • Number of patients in requested studies 43,427 • Number of patients in requested studies 43,427 • Summaries of Medical/Clinical Pharmacology • Summaries of Medical/Clinical Pharmacology 64 64 – Summaries on fda.gov/cder/pediatrics – Summaries on fda.gov/cder/pediatrics www.fda.gov/cder/pediatric/summaryreview.htm www.fda.gov/cder/pediatric/summaryreview.htm
Scientific Trial Issues Scientific Trial Issues • Scientific Issues • Scientific Issues - Extrapolation - Extrapolation - Bridging Studies - Bridging Studies - Safety Studies: length and type - Safety Studies: length and type - Endpoint & Validation Issues - Endpoint & Validation Issues - Neonatal population still an issue - Neonatal population still an issue - Need for longer term outcomes for - Need for longer term outcomes for studies (18-24 months) studies (18-24 months) • Learning from the trials conducted • Learning from the trials conducted
Neonatal Studies: FDAMA Neonatal Studies: FDAMA 1999-2002: N=11 1999-2002: N=11 • Ranitidine GERD • Ranitidine GERD • Omeprazole • Omeprazole • Famotidine • Famotidine • Remifentanil Anesthesia • Remifentanil Anesthesia • Sevofluran • Sevofluran • Propofol • Propofol • Bisoprolol Hypertension • Bisoprolol Hypertension • Sotolol Arrhythmia • Sotolol Arrhythmia • Didanosine HIV • Didanosine HIV • Stavudine • Stavudine • Lamivudine • Lamivudine
BPCA- Exclusivity BPCA- Exclusivity Neonatal and Infant Studies: Neonatal and Infant Studies: 2002-2005 2002-2005 • Written Requests issued which included • Written Requests issued which included the age range: 0-2 years: the age range: 0-2 years: N= 41 N= 41 • Products with submitted studies for • Products with submitted studies for infants less than 4 months of age: infants less than 4 months of age: N=13 N=13 • Products with submitted studies for • Products with submitted studies for newborns (<1month of age): newborns (<1month of age): N=9 N=9
Neonatal Studies: BPCA Neonatal Studies: BPCA N=9 N=9 • Ciprofloxacin: Ophthalmic • Ciprofloxacin: Ophthalmic • Moxifloxacin: Ophthalmic • Moxifloxacin: Ophthalmic • Ofloxacin: Conjunctivitis • Ofloxacin: Conjunctivitis • Esmolol: Hypertension • Esmolol: Hypertension • Nelfinavir: HIV • Nelfinavir: HIV • Fenoldopam: Blood Pressure • Fenoldopam: Blood Pressure • Linezolid: Pneumonia & skin • Linezolid: Pneumonia & skin infections infections • Nizatidine: GERD • Nizatidine: GERD • Argatroban: Thrombosis • Argatroban: Thrombosis
BPCA-Off Patent: N=9 BPCA-Off Patent: N=9 Requested Studies for Neonates: Requested Studies for Neonates: 2002-2005 2002-2005 • Ampicillin: Sepsis and meningitis • Ampicillin: Sepsis and meningitis • Azithromycin: Chlamydia • Azithromycin: Chlamydia • Azithromycin: U. urealyticum • Azithromycin: U. urealyticum • Dactinomycin: Wilms, rhabdosarcoma • Dactinomycin: Wilms, rhabdosarcoma • Lorazepam: Sedation in ICU • Lorazepam: Sedation in ICU • Meropenem: Complicated abdominal • Meropenem: Complicated abdominal • Morphine: Analgesia in ICU • Morphine: Analgesia in ICU • Nitroprusside: Reduction of BP • Nitroprusside: Reduction of BP • Vincristine: Malignancies • Vincristine: Malignancies
What Pediatric Trials Have What Pediatric Trials Have Taught (what we were doing Taught (what we were doing before we knew better) before we knew better) 1. Unnecessary Exposure to Ineffective 1. Unnecessary Exposure to Ineffective Drugs Drugs 2. Ineffective Dosing of an Effective 2. Ineffective Dosing of an Effective Drug Drug 3. Overdosing of an Effective Drug 3. Overdosing of an Effective Drug 4. Undefined Unique Pediatric AE’s 4. Undefined Unique Pediatric AE’s 5. Effects on Growth and Behavior 5. Effects on Growth and Behavior
ONGOING LESSONS LEARNED ONGOING LESSONS LEARNED 1. PK is more variable, even within the 1. PK is more variable, even within the pediatric population, than pediatric population, than anticipated anticipated 2. Adverse reactions that are pediatric 2. Adverse reactions that are pediatric specific will not be defined without specific will not be defined without pediatric studies pediatric studies 3. Trial designs are being modified as 3. Trial designs are being modified as we learn from submitted studies we learn from submitted studies
ONGOING LESSONS LEARNED ONGOING LESSONS LEARNED 4. Ethical issues have to be 4. Ethical issues have to be reassessed from the pediatric reassessed from the pediatric perspective perspective 5. Safety studies, of sufficient duration 5. Safety studies, of sufficient duration and longer term follow-up studies, and longer term follow-up studies, remain problematic remain problematic 6. The present incentive program still 6. The present incentive program still leaves many subpopulations leaves many subpopulations unstudied unstudied
For the Future: Needs For the Future: Needs • More transparency for all pediatric studies • More transparency for all pediatric studies and the data from those studies and the data from those studies • Continued development of pediatric • Continued development of pediatric endpoints and assessment tools endpoints and assessment tools • Real time inspections of pediatric trials • Real time inspections of pediatric trials
Recommend
More recommend
