Transcript Successes & Challenges In Development Of Drugs For

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
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Content
• Historical Examples
• Current situation
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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
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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
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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
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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)
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Modern Drug Development and Approval
Pediatric Drug Development:
Changing Paradigm
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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
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Inadequate dosing and safety information places children at risk for adverse events and
denies them potential therapeutic benefit
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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
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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
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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
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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
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Age related challenges in drug formulation
Dose size
i.v.
Metabolism
oral liquid
Palatability
Flexible
dosing
flexible dosing
Compliance
oral solid
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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
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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
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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
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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:
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Duration of Event-Free Survival
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Safety (AE), discontinution or modification of therapy, Duration of response
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PK evaluation,epiphyseal maturation, height, weight and head circumference
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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
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Children…
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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
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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?
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