* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Successes & Challenges In Development Of Drugs For
Survey
Document related concepts
Compounding wikipedia , lookup
Orphan drug wikipedia , lookup
Polysubstance dependence wikipedia , lookup
List of off-label promotion pharmaceutical settlements wikipedia , lookup
Drug design wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Drug discovery wikipedia , lookup
Bevacizumab wikipedia , lookup
Neuropharmacology wikipedia , lookup
Theralizumab wikipedia , lookup
Pharmacognosy wikipedia , lookup
Prescription costs wikipedia , lookup
Transcript
Successes & Challenges In Development Of Drugs For Children Uspesi i izazovi u razvoju lekova za decu Smiljana Milosavljević – Ristić MD PhD Beograd, 28. Oktobar 2011 1 Content • Historical Examples • Current situation – – – – Modern drug development Insufficient pediatric drug research New legislations to stimulate pediatric drug development Specific challenges in pediatric drug development • Examples of Current Pediatric Drug Development – Avastin: identification of pediatric indications in oncology – Mircera: paediatric dose finding and long term safety study • Conclusions -2- Historical example - Soothing syrup 1906 USA advertisement Mrs. Winslow's Soothing Syrup: For children teething. Greatly facilitates the process of teething, by softening the gums, will allay all pain and is sure to regulate the bowels. Contained alcohol and morphine Causing coma, addiction & death 3 Historical experience - Sulfanilamid September 1937 in USA Sulfanilamid compounded with an solvent, diethylene glycol (chemically related to antifreeze) 107 deaths including many children 1938 Food and Drug Act: firms had to prove that any new drug was safe before it could be marketed 4 Historical example - Talidomide • 1960 a New Drug Application in USA, drug approved in Europe • FDA felt data were incomplete to support the safety • 10 000 children in 46 countries born with birth defects (phocomelia) 5 Modern Drug Development and Approval Pediatric Drug Development: Changing Paradigm • • Drug treatment has made progress since 1960 when the regulations requiring intensive testing in animals and human were introduced. However, during the same period limited research performed in children – Inadequate dosing and safety information places children at risk for adverse events and denies them potential therapeutic benefit • • • Children are treated like small adults This has been recently addressed by regulatory authorities, academia and pharmaceutical industry. Today European and USA regulations require and reward pediatric drug development. Old Paradigm Adult Development Pediatric Development New Paradigm Adult and Pediatric Development -7- EU Pediatric Regulation in 2006 REQUIREMENTS INCENTIVES Pediatric Investigation Plan (PIP) to be approved by EU Pediatric Committee – Condition for the submission of the new drug dossier – Compliance check at submission validation For drugs with patent – Six-month patent extension 8 International Recommendations on Timing of Pediatric Drug Development - ICH E 11 • Medicinal products for diseases predominantly affecting children – Development in children only, e.g. lung surfactant • Drugs for serious or life-threatening diseases, occurring in both adults and children with limited therapeutic options – Pediatric development should begin early with initial safety/efficacy evidence. e.g. antibiotics, antivirals • Medicinal products for other diseases and conditions – Less urgent in children, start development in phase IIIb/IV, e.g. osteoporosis, lipid lowering drugs 10 Use Of Pre-clinical (Animal) Research For Pediatric Drug Development • Adult drug development includes reproductive toxicology and carcinogenicity studies • Postnatal developmental toxicity can be addressed in juvenile animal studies Comparing Development Among Species (CNS & Reproductive System Only) From Buelke-Sam, 2003 in Hood: Developmental and Reproductive Toxicology : A Practical Approach , 2006 12 Age related challenges in drug formulation Dose size i.v. Metabolism oral liquid Palatability Flexible dosing flexible dosing Compliance oral solid 13 Challenges in pediatric drug formulation Oral liquid or powder for reconstitution are preferred for children <6 yrs. • may be difficult to develop: stability, taste masking • not preferred for developing countries 14 Clinical trials in children are more difficult and more expensive • Informed Consent – Assent from children 6-13 years and adolescents – Consent from the legal representative • Limited use of placebo – Only if no approved therapies • Limited population – Lower incidence of diseases, need to study different age groups • Specific efficacy and safety measurements – Children not able to perform (spirometry) • Minimal invasiveness of examinations – number & volume of blood samples • Child and family friendly research facilities Avastin: Pediatric drug development in oncology Bernie & Herby studies - 16 - Pediatric Cancer: Still the most common fatal disease in children • Childhood cancer is rare: • High cure rate: 15000/y new cases in Europe Leukemia/Lymphoma – Only 1% of all cancers • In children, cancer is the leading disease killer • Different nature, distribution and prognosis vs. adult cancer – More that 60 diagnoses, varies with the age • 1 of 1000 adults today are childhood cancer survivor – need to follow up long term effects of treatment – – – – ALL 84% AML 48% NHL 84% M. Hodgkin 94% • Low cure rate: Solid Tumors – Soft tissue sarcoma 65% – CNS-Tumours 67% – Osteosarcoma 67% – Neuroblastoma 70% – Ewing-Tumour 70% Avastin (bevacizumab) Development of 2 pediatric indications ADULT INDICATIONS: Metastatic colon, lung, renal cancer SPC expiry end 2019 2008 2009 2010 2011 Start RMS / STS study 2012 2013 2014 Complete RMS / STS study Start HGG study PEDIATRIC INDICATIONS 2015 2016 2017 Pediatric data required 2018 2019 6-month SPC extension Complete HGG study RMS= Rhabdomyosarcoma STS=Soft tissue sarcoma The BERNIE Study Oct 1, 2008 – Avastin PIP approved Open Label, Multi-center, randomized phase II study evaluating the addition of Bevacizumab to chemotherapy in childhood and adolescent patients presenting with metastatic rhabdomyosarcoma (RMSTS) and non-rhabdomyosarcoma soft tissue sarcoma (NRMSTS) CHT + bevacizumab (n=75) Eligible patients with RMSTS and NRMSTS 1:1 CHT (n=75) • Primary endpoints: – Duration of Event-Free Survival – Safety (AE), discontinution or modification of therapy, Duration of response – PK evaluation,epiphyseal maturation, height, weight and head circumference – Rhabdomyosarcoma (high risk metastatic disease) vs. rhabdomyosarcoma (nonhigh risk metastatic disease) vs. non-rhabdomyosarcoma soft tissue sarcoma • Secondary endpoints: • Pediatric Specific Safety endpoints: • Stratification factors: The Herby Study: High Grade Glioma (HGG) Research of Bevacizumab in children&adolescents • 2009: accelerated approval for the treatment in adults with glioblastoma muliforme (GBM) • Pediatric unmet medical need • Applicability to pediatric glial tumors? – Differences in biology between pediatric and adult glial tumors? • Molecular and chromosomal characteristics • Lower frequency of EGFR amplification or overexpression – Effects of bevacizumab on child’s growth/development • Effects on post-natal bone growth and development • Bevacizumab distribution and metabolism The Herby Study Participating countries 14+ countries 77+ sites North America • Canada Europe • Austria • Belgium • Czech Republic • Denmark • Finland • France • Hungary • Italy • Netherlands • Poland • Spain • Sweden • UK 120 patients: 3-18 years 10 patients: 6 months–3 years Asia-Pacific Region • Australia The Herby Study Study population • Children… – – – – – Between the age of 3 and 18 years With newly diagnosed histologically documented HGG Localised supratentorial non-brainstem HGG WHO Grade III or IV Confirmed by an independent reference neuro-pathologist • Before randomization, to avoid inclusion of low grade glioma The Herby Study: Stratification Age ( 3 – < 6 vs 6 – < 13 vs 13 – < 18 years) Grade (Grade III vs Grade IV) Surgery (total/near total resection vs others) The Herby Study Efficacy outcome measures • Primary Endpoint – Event-Free Survival (EFS) • Secondary Endpoints – Overall Survival (OS) and 1-year OS – 6-month and 1-year EFS • Exploratory Endpoints – Health status measured by the health utility index – IQ measured by Wechsler scale adapted to age – Multimodal imaging Mircera: Development of pediatric indication for maintenance treatment of anemia in chronic kidney disease on hemodialysis with long terms safety extension - 25 - Mircera: Pediatric drug development for treatment of anemia in chronic kidney disease on hemodialysis • Children with end-stage renal disease represent small proportion (1.5%) of total ESRD population – Most 60% treated with peritoneal dialyses at home – 20% below age of 6 • Mircera: chemically synthesized continuous erythropoietin receptor activator – Efficacious in correction anemia in ESRD – Toxicology data suggest good safety and tolerability Multiple dose study: to determine starting dose of MIRCERA® for maintenance treatment of anemia in children on hemodialysis Zaključci • Lekovi koji se primenjuju kod dece generalno nisu dovoljno rigorozno ispitani u pedijatrijskoj populaciji • Nove zakonske regulative za odobravanja upotrebe leka zahtevaju da se pedijatrijske studije rade paraleleno sa adultnim studijama • Razvoj lekova za pedijatrijsku primenu je kompleksan proces jer zahteva razvoj pedijatrijske formulacije, odredjivanje optimalne doze sve starosne grupe i dugotrajno pracenje ispitanika • Primena novih zakonskih regulative je povecala broj istrazivanja usmerenih na optimalnu primenu modernih lekova kod dece Best Pharmaceuticals for Children – Oxymoron? Da joj čitam pred spavanje? A šta misliš, da joj damo opet jedan benzedinčić? 29 © New Yorker