Transcript Can we???

Relevance and Challenges of
Juvenile Toxicity Studies
Can we? Should we? Will we?
Diane Stannard
Senior Study Manager
Huntingdon Life Sciences
25 February 2013
Contents
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Background
Challenges – can we?
Relevance – should we?
The future – will we?
Summary/Conclusion
References
Background
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Until ~10 years ago, lack of targeted paediatric drug
development – extensive “off-label” use.
Assumed children exhibit similar disease progression and
respond similarly to the intended therapeutic intervention.
Estimated 50% - 90% of drugs never specifically evaluated for
paediatric use.
How can we be sure that adult/paediatric toxicity profiles are
the same?
Inherent differences of mature/immature systems » risk of:
 Unique tox profile in children
 Poor efficacy
 Exaggerated pharmacology
 Unexpected adverse effects (even death)
Background
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2002 – EU consultation paper “Better Medicines for
Children” – proposed new legislation.
FDA issued formal guidance in 2006: “Guidance for Industry
– Nonclinical Safety Evaluation of Pediatric Drug Products”.
EMA guideline issued in 2008: “Guideline on the need for
non-clinical testing in juvenile animals of pharmaceuticals for
paediatric indications”
Oct 2012: Japanese MHLW guideline issued: “Guideline on
the Nonclinical Safety Study in Juvenile Animals for Pediatric
Drugs”
Now, drug dvlpt programs for a paediatric population must
take into consideration possible effects on developmental
processes specific to the relevant age groups.
Why are they needed?
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To obtain information on potentially different safety profiles
from those seen in adults – bridging the gap between
reprotox and repeat dose tox studies.
General tox study – direct dosing
from ~6 weeks of age in rats
Pre and post-natal study
– no direct dosing
When are they needed?
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Situations that would justify toxicity studies in juvenile
animals include, but are not limited to:
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When the indication is specifically targeted for children
Findings in non-clinical studies that indicate target organ or
systemic toxicity relevant for developing systems.
Possible effects on growth and development in the intended
age group.
If a pharmacological effect of the test compound
could/would affect developing organs.
Unique chemical class or unique combination product.
Regulatory involvement
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The original proposal was that the conduct of juvenile toxicity
studies should be considered on a case-by-case basis.
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The emphasis has changed though. Rather than questioning
whether studies need to be conducted, there is now an
assumption that these are required unless you can justify
why they are not!
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Study design/content must be discussed with, and approved
by, the Regulatory Agencies (FDA/EMA).
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In the EU, as part of regulation a Paediatric Investigation
Plan must be submitted and agreed by the Paediatric
Committee (PDCO)
Paediatric Investigation Plan (PIP)
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The PIP facilitates the development, accessibility and safe use
of new drugs in the paediatric population through clinical
studies to provide justification for a waiver/deferral from such
studies. Exemptions include:
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Generics
Biosimilars
Well-established medicinal use
Homeopathics
Herbals
As well as any proposed paediatric studies, the PIP must
include proposals for juvenile toxicity studies. Needs to:
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Highlight what juvenile animal work is planned
What the specific endpoints will be (eg. neurotox assessment)
Outline the study design
Provide timelines for work … be warned, this must be accurate!
Challenges – Can we???
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There are many!!!
Children are not “miniature adults”
Predicting responses in children based on adult data is hard.
Known cases of different sensitivity between children and
adults exist.
Reasons for sensitivity differences
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Post-natal growth and development can affect drug
disposition and action:
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Metabolism (maturation rate of Phase I/II enzyme activities)
Body composition (water and lipid partitions)
Receptor expression and function
Growth rate
Organ functional capacity
These are all susceptible to modification or disruption by
drugs.
Comparative age categories
Structural & functional development
Human
Rat
Nervous system: up to adulthood.
Pulmonary system: up to 2 yrs.
Reproductive system: up to adulthood.
Brain: by ~ 35 days.
Pulmonary system: by 28-35 days.
Reproductive system: ~35/45 days (F/M).
Renal system (anatomical): GW35.
Renal system (functional): up to 1 year.
Immune system: up to adulthood.
Renal system (anatomical): 4-6 weeks.
Renal system (functional): ~ 21 days.
Immune system: by ~ 60 days.
Liver: depending on the endpoint:
differences in functioning of drugmetabolising enzymes, transporters,
etc. during the first months 
ca 3years
Liver: adult structure reached by ~28 days.
Enzyme/transporter activity still not
clearly understood, but P450
considered to be ~ 45 days.
US FDA CDER Guidance 2006
Dose route/volume
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Stage of physical development determines feasibility
of dose route:
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SC/IP/Oral (buccal cavity): Day 1.
Oral gavage: Day 14-18.
IV: single dose from ~Day 14; repeat dose from Day 21.
IM: Day 21.
Inhalation: depends on who you ask!
Oral dosing at PND4
Inhalation
administration
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Poses some unique challenges when
compared to other routes:
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Size of animals
 Much smaller than mice (handling issues?)
 No fur to ~Day 11 of age (maintenance of body temp during
exposure?)
Age of start of treatment?
 Is there time for and/or is it practical to
acclimatise to the restraint tubes?
Duration of removal from dam?
 Dose determined by length of exposure due to max. prac.
conc.
 Maternal rejection?
Inhalation administration (cont’d)
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Method of exposure
 Snout only a challenge due to size (pivot ability → turn around
in tubes?; tubes small enough?)
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Whole body → risk of maternal exposure through grooming →
possible “double-hit” exposure through milk?
Stage of respiratory system maturation
Practicality of procedures
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Ophthalmoscopy:
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Urine collection:
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Not practicable prior to weaning; probably not meaningful.
Early post-weaning: individual volumes low – pooled
samples? limited list of parameters?
Behaviour assessments:
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Not possible prior to Day 15, so pre-treatment
assessment often not feasible; can confound data
interpretation.
Essential to tailor to age at testing.
During treatment - conducted prior to dosing.
Ensuring correct identification of pups pre-weaning
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Robust toe marking (or alternative) required.
Practicality of procedures (cont’d)
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Blood sample collection:
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Currently subject to many changes!!
Study design considerations
There is no such thing as a “standard” study design –
each study is uniquely tailored according to the test
material, target population, organ system of interest &
duration of use.
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Age of animals at start of dosing
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To match lowest age of target patient group.
 Pre-weaning: relatively easy for rats, may be possible for
minipigs, but tricky for other species, as difficult to obtain
dams with litters or gestating females.
 Post weaning: equivalent to 2yr old, all species can be used.
Duration of dosing period
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To cover developing organ system(s) of interest.
Link with age that general tox studies started.
Will treatment be life-span?
Will recovery period be necessary?
Study design considerations
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Route of administration
 As intended clinical route, where possible.
 … but not always practical (eg. repeat IV in the rat from Day
4 of age)
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Selection of species
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Must be appropriate for evaluating tox endpoints relevant for
intended pediatric popn
Rats and dogs are traditionally the species of first choice.
Testing in one appropriate species using both sexes will
normally be sufficient (but not always!).
Study design considerations
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Dose selection
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Preliminary study essential
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Numerous and flexible
 Each study has tailor-made design
Numbers per sex per group not standard
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To assess tolerability/dose-range
Inclusion of TK essential
Endpoints
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Exaggerated toxicity not desirable, aim is to detect any
possible increase in sensitivity of young vs adults.
Depends on endpoints
Practical issues!!!
Relevance – Should we?
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So we’ve established that whilst challenging, these studies
are practically and logistically possible, but … should we
be conducting them?
 Are the study results relevant?
 Are we seeing clear new toxicities that would affect
dosing in a paediatric population or just findings related
to exposure/maturation differences?
In 2011, a survey (on behalf of ILSI/HESI DART technical
committee) was conducted to clarify what has been
learned for the safety assessment of paediatrics.
24 pharma companies contributed, with a combined total
of 241 juvenile studies (range-finding, mechanistic and
definitive) revealed the following:
2011 Survey (Bailey & Marien)
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84% of studies conducted in rats, 14% in dogs and
remaining 2% in other species
15% of programs – existing adult pre-clinical & clinical data
considered sufficient to support paediatric trials.
Majority of studies showed findings comparable to adults,
yielding no new information.
Quantitatively, a general trend for increased sensitivity in
terms of general toxicity was observed in rats but not dogs
Novel toxicity (finding in an organ system not previously
seen in adult animals) was only seen in 14 rat studies and 2
dog studies, and in many cases these could have been
predicted from either known pharmacology or adult data
Concluded that a targeted study design on a case-by-case
basis rather than a prescriptive “standard” toxicology study
design should be the norm.
Are the studies assisting labelling?
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Strattera (atomoxetine): treatment for ADHD (www.rxlist.com)
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Growth, neurobehaviour, sexual dvlpt assessed in rats from
Day 10 of age to adulthood at doses ~8-fold higher than max.
human dose
Slight delays on sexual maturation, ↓ epididymal weight and
sperm numbers, ↓ corpora lutea, ↑ locomotor activity
But, no effects on fertility, reproductive performance or learning
and memory
Product label states that significance of these findings to
humans is unknown & safety/efficacy/PK in paediatric patients
under 6yrs has not been established (Day 10 = 1 month old
child!)
So did this juvenile animal work really add to the risk
assessment process???
Are the studies assisting labelling?
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Tamiflu (oseltamivir): treatment for influenza infection
(www.rxlist.com)
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A single dose of 1000 mg/kg to 7-day old rats resulted in death,
although no deaths occurred at 2000 mg/kg in 14-day old rats
Found that drug concentration in brain was ~1500-fold higher in
7-day old versus adult (plasma levels ~10-fold higher)
Brain levels of drug decrease with increasing age – due to
maturation of blood-brain-barrier
No adverse effects at 500 mg/kg/day from Day 7-21 of age –
exposure ~800-fold higher that expected in 1yr old child
Product label states drug is not indicated for paediatric patients
under 1 year old.
Important finding for human infant safety but all due to kinetics,
not toxicology, so was juvenile work useful???
Regulatory thinking (Carleer & Karres)
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EU (EMA/PDCO) view on juvenile animal studies given in
paper of 97 approved/ongoing PIPs (Nov ‘08-May ‘10):
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Studies proposed by Applicant company for 32/97 (33%) drugs
For these drugs, PDCO requested revisions/further justification
on design for 14 of them (endpoints; duration; timing versus
clinical studies; species; route of admin)
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Studies were required for a further 26/97 (26%) drugs due to:
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Stressed that scientifically based justifications must be provided
when no juvenile animals studies are proposed.
Change in clinical plan (lower paediatric age); lack of knowledge
of maturation of pharmacological target; toxicity signals; lack of
sufficient nonclinical information
Concluded it is too early to ascertain the actual value of
juvenile studies in these PIPs but should be able to establish if
new or unexpected (developmental) toxicities and different
sensitivities are seen and if they are reversible.
Regulatory thinking (Tassinari et al)
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FDA publication on use of juvenile animal data for labeling
purposes.
Data in label for 39 marketed products (1998-2009) reported
as:
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Contributing to overall safety assessment
Giving better characterisation of possible risks
Aiding dosing considerations especially in cases where the
developing animal is more sensitive than adults
Detecting unique toxicities not seen in fully grown adult animals
BUT … pointed out that the value of design specifics and
endpoints used in these juvenile animal studies remains
unanswered
Regulatory differences (Cappon)
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Evidence of a trend towards FDA requesting 2 juvenile
studies per drug in some divisions:
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To support paediatric programme for anidulafungin (to
treat invasive fungal infection)
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Neurology division wants rat for behaviour assessment
but dog for CNS maturation
FDA did not require a juvenile animal study; PDCO did!
FDA seem to have little need for juvenile animal
studies to support use of drugs in adolescent patients,
but EU PDCO have requested studies to support
adolescent indications.
Concerns
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The questions remain:
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Do juvenile animal studies investigate findings that
cannot be adequately/ethically/safely assessed in
paediatric clinical trials?
Do juvenile animal studies examine development not
covered in adult tox studies (CNS; sexual maturation;
bone growth)?
Do juvenile animal studies result in added parameters
for safety evaluation in paediatric work?
Do juvenile animal studies really help with product
labelling/prescribing?
And what do the results mean?
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CNS effects (eg ↓ motor activity) at small margin of
clinical dose
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Effect on long bone growth (not likely to be seen in
adults as growth complete)
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Real potential for neurological effect in children?
Concern for children?
Altered/delayed sexual maturation in rats (not likely to
be seen in adults as sexually mature)
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Concern for children?
The future – Will we?
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Ultimately, yes we will!!
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We know we can conduct these studies, although limited
information database
Regulators are asking for more and more studies based on a
scientific need rationale
Juvenile animal data are included in product labels to assist
informed decisions for drug use
But we must be clear that if juvenile studies are conducted that
they are actually useful in supporting paediatric clinical trials
and/or identify a specific safety concern for the paediatric
population and NOT just a “box ticking” exercise.
The future – Will we?
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It could be that the majority of different toxicities between
adults and juveniles are purely due to an immature state
and/or kinetics
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Currently there is a lack of substantive proof of cases where
juvenile animals have predicted novel human toxicities
How do we really interpret the study findings (especially if
different from adult data)
Therefore, the challenge for the future is to convince fellow
scientists/regulators that toxicology studies in juvenile
animals should only be performed if strictly needed.
References
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Bailey G, Mariën D, The value of juvenile animal studies “What have we learned from preclinical
juvenile toxicity studies? II” Birth Defects Research, Developmental and Reproductive Toxicology
2011; 92;273-291
Baldrick P, Juvenile animal testing in drug development – Is it useful? Regulatory Toxicology and
Pharmacology 57 (2010) 291-299
Baldrick P, Developing drugs for pediatric use: a role for juvenile animal studies? Regulatory
Toxicology and Pharmacology 39 (2004) 381-380
Cappon et al. Juvenile animal toxicity study designs to support paediatric drug development.
Birth Defects Research, Developmental and Reproductive Toxicology 2011; 92;269-272.
Carleer J, Karres J, Juvenile animal studies and pediatric drug development: a European
regulatory perspective Birth Defects Research, Developmental and Reproductive Toxicology
2011; 92;254-260
Clark JB, Bates TE, Cullingford T, Land JM. Development of enzymes of energy metabolism in
the neonatal mammalian brain. Dev Neurosci 1993;15:174-180.
Costa LG, Aschner M, Vitalone A, Syversen T, and Soldin OP. Developmental neuropathology
of environmental agents. Ann Rev Pharmacol Toxicol. 2004;44:87-110.
Myers DP, Bottomley AM, Willoughby CR et al. Juvenile toxicity studies : key issues in study
design. Reproductive Toxicology. 2005;20:475-6.
Tassinari MS et al, Juvenile animal studies and pediatric drug development retrospective review:
use in regulatory decisions and labelling Birth Defects Research, Developmental and
Reproductive Toxicology 2011; 92;261-5
CDER pediatric. In CDER website : http://www.fda.gov/cder/foi/label/2006/021087s033lbl.pdf
EMEA/CHMP/SWP/169215/2005 in EMA website: http://www.ema.europa.eu/ema/index
Thank you for listening 