Transcript Ravimid laste jaoks

Drugs for children
Irja Lutsar
Tallinn 2007
Pediatrics does not deal with miniature men
and women, with reduced doses the same
class of disease in smaller bodies, but …..
has its own independent range and horizon
Abraham Jacobi rohkem kui 100 aastat tagasi
Problem statement: child vs adult
• The effectiveness and tolerabily is likely to be
different
–
–
–
–
Neonates (premature and full-term) - < 28 days
Infants – 1 mo - < 2years
Children – 2 years – 11 years
Adolescents – 12 years – 16 (-17) years
• Dose cannot be directly extrapolated from adults
– Different pharmacokinetics
• absorption
• distribution
• elimination
• Many agents used in paediatric are never tested
in children
Pharmacokinetics of pencillin G
Premature < 1200 g
30 mg/kg
15 mg/kg
Full-term baby
15 mg/kg
adult
600 mg/dosi
T1/2
Cmax
3,8 h
4,6 h
145,5 mcg/ml
58,9 mcg/ml
3,4 h
22,0 mcg/ml
0,5 h
45 mcg/ml
Metsvaht et al. AAC 2007; 51: 1995-00
Mean voriconazole plasma concentrations
after IV and POS administration
Mean plasma voriconazole
concentration (ng/mL)
BA in adults 96%
upper limit of SD: 19,030
12000
10000
8000
6000
4000
2000
0
0
2
4
6
8
10
12
Time postdose (h)
6 mg/kg IV (120 min infusion)
Walsh et al. AAC 2007
8 mg/kg IV (160 min infusion)
6 mg/kg POS
Formulations not suitable for
children
• IV formulation toxic or too concentrated
– Cyclodextran & nephrotoxic
– Quinolones are reconstituted in acids
– Not suitable presentations (too large or too small vials)
• Oral formulations
– Capsules and film-coated tablets (children cannot
swallow)
– Crushed tablets vs whole tablets
– How to give bitter tablets?
– Solution and suspensions
•
•
•
•
•
Better solubility worse taste
What is a good taste?
Should a medicine have a good taste?
Too large amounts
Bioavailability
Slow release tablet
Crushed tablet
History
• 1937 – 107 people with streptococcal infection
died (mainly children)
– All were treated with a sulphonamide that was diluted in
diethylglycole (antifris)
• 1956 – neonates who received sulphonamides
had more often kernicterus than those receiving
tetracycline
• Chloramphenicol & “gray baby syndrome”
(enzyme immaturity)
• “Gasping syndrome”
– Agents that are reconstituted in benzylalcochol (IV
clindamycin)
• Antidepressants
How common is off-label use
Years
>1 unlicenced or
off-label drug (%)
off-label
(%)
Children
(hospitalised)
1985-99
36-92
7-60
Neonates
(hospitalised)
1998-02
80-97
14-63
Outpatient
1978-01
16-56
9-33
Then younger the child then lower number of studies
Then sicker the child the less studies
Eur J Pediatr 2005; 164: 552-558
Studies in children: statistics
• 1997 – FDA 33 new drugs licenced
– 27 potentially used for children
– 9 had some information on use in children
• Neonates use a lot of medicines
– Detroit (USA) 1997-2004 NICU 3,6/per child
– ELBW - 11,7/per child
– Australia 93% ELBW at least 1 untested drug
will be used
FDA: paediatric studies
• FDAMA Pediatric Exclusivity 1997 (voluntary)
• Pediatric Rule Regulation 1998 (enjoined 2002)
• January 2002
- FDAMA Exclusivity Sunsets
• January 2002 (compulsary)
- Best Pharmaceuticals for Children Act
(BPCA)
• December 2003
- Pediatric Research Equity Act (PREA)
• October 2007: Sunset for BPCA & PREA
FDA: stick (WR) & carrot (PE)
• All new drugs ned to be
tested in children
• Industry initiated (WR)
• waivers
• Patent prodection for 6
months
– Fluconazole 600 mill $
– Sildenafil 1 bill $
– Disease does not exsist
in children
– Drug is too toxic for
children
• Deferral until more data
on adults are available
Priotrity list of medicines
Pediatric Drug Development
Number
120
69
60
98
45
21
24
12
19
15
19
10
22
25
25
14
11
3
12
17
23
20
23
17
15
18
1999
2000
2001
2002
2003
2004
2005
2006
0
Calendar year
Pediatric exclusivity determinations
Written requests issued
Pediatric exclusivity labeling changes
FDA: results (March 2007)
• FDA issued 341 WR
• 150 new medicines were tested in
children
• 128 labelling changes were made
Benefits of WR (FDA)
• 1998- 2004 – 253 studies in children with new
agents
–
–
–
–
125 (50%) – efficacy
51 (20%) – MD PK
34 (13%) – SD PK
43 (17%) – safety & tolerability
• 127 (50%) new information
• 113 (45%) published
• Net economic return - -8,9 mil....507.9 mil $
JAMA 2006; 296: 120-123
JAMA 2007; 297: 480-8
FDA: 127 changes in drug
information
• New dose or changes in exsisting dose (n = 25)
• New data on tolerability (n = 35)
• “No data in children” added into label (n = 28)
• New dosing recommendations for infants or
neonates (n = 83)
We got know what we do not
know
Many questions were answered but many
mopre questions raised
Deficiencies in the FDA
regulations
• Industry might not be interested
– Pediatric market is small
– Studies in children are complicated
– Long-lasting negotiations
• No procedure to study off patent drugs
• No paediatric trial registry
European Union
The same issues
Paediatric regulation:
entered into force 26 January 2007
• Improve the health of children
– Increase high quality, ethical research into
medicines for children
– Increase availability of authorised medicines for
children
– Increase information on medicines
• Achieve the above
– Without unnecessary studies in children
– Without delaying authorisation for adults
Main pillars of the Regulation
• New EMEA Committee: the Paediatric
Committee
• An agreed (evolutive) paediatric
development: the Paediatric Investigation
Plan (PIP)
• A mix of rewards and incentives
– For on-patent products
– For off-patent products
• A series of other tools for information,
transparency, and stimulation of research
Paediatric Committee (PDCO)
to be established by 26 July 2007
+ alternates
Paediatric committe: objectives
• Paediatric scientific advice
– Free of charge
– Not binding
• Review of PIPs (+waivers & deferrals)
• Member States Survey of all existing
uses of medicinal products in children,
including off-label within 2 years, final
EMEA inventory in third year (2009)
• Update of Paediatric needs by Paediatric
Committee on basis of inventory
Currently unauthorised products
18 months after entry into force of the Regulation, 26.07 2008
• Stick
– Obligation to submit results of agreed PIP at
time of marketing authorisation application
– If not: Invalid application for MA
– Results reported in SmPC
– Authorisation in all Member States
• Carrot
– 6-month extension of the Supplementary
Protection Certificate
Patent-protected authorised
products
24 months after entry into force of the Regulation, 26.01 2009
• Stick
– Obligation to submit results of agreed PIP at time
of change (variation/extension) for new indication,
route of administration, or pharmaceutical form
– Results reported in SmPC
– Authorisation in all Member States
• Carrot
– 6-month extension of the Supplementary
Protection Certificate
For off-patent products
• Paediatric Use Marketing Authorisation
(PUMA)
New type of MA
• Covers exclusively paediatric indication(s) and
formulation(s)
• Optional but need for PIP and compliance
• No need for MA in all Member States
• Brand name may be retained
Carrot
• 10 years of data protection: (8+2) +1
Paediatric Investigation Plan
• General strategy of paediatric studies
– Epidemiology, pathophysiology, indications,
target population, doses
• New formulations (needs & technology)
• Preclinical studies (toxicity, effect on
pregnancy, young animals)
• Clinical studies (PK studies, efficacy/safety
studies, strategy, time-table)
• Waivers and deferrals
Time-table for paediatric studies
CHMP
NCA
Scientific advice
Non-clin
Phase 1
Phase 2
Phase 3
MA
Post approval
1
Paediatric invest. plan
(PIP)
Amendments
PDCO
Compliance
Deferral (annual
report on
progress)
Waiver
Waivers
• Product likely to be ineffective or
unsafe in all or part of the paediatric
population
• Disease occurs only in adults
• No significant therapeutic benefit
over existing treatments for children
→ for one or more subgroups of the
paediatric population
→ for one or more specified indications
Deferrals
• Request to defer initiation or completion
of some or all the measures set out in the
PIP
• On initiative from applicant or Committee
• For all or part of Paediatric Investigation
Plan
• Annual report to monitor deferred studies
A European Network
EMEA paediatric research network
• To link together existing networks,
investigators and centres with
specific paediatric expertise
• Build up competences at a European
level
• Facilitate the conduct of studies
• Avoid duplication of studies
Preparatory work at EMEA over 2005-6
Paediatric studies are not the
private business of the
pharmaceutical industry
Types of paediatric studies
• Direct clinical studies
– PK studies
– Efficacy and toleration studies
– Preclinical and non-clinical studies
• Indirect studies
– Assessment of paediatric standards
• Growth and development
– Epidemiological studies
• Prevalence of the disease in children
• Pathomechanism of the disease
– Investigations on growth, development &
maturation
Who should conduct studies in
children
• Pharmaceutical industry
• Universities, research institutes, medical
schools
• All paediatricians – why not?
Who should fund paediatric studies
• Pharmaceutical industry
• Pharmaceutical industry + private funds
• EU governmental funds (research councils,
science boards)
• EU grants
– EU 7FP specific call for paediatric studies for offpatent used drugs
– Priority list
• Paediatric Societies
• Charities
– Bill & Melinda Gates foundation
Other Measures:
Funding of studies into off-patent
medicines for children
• Community funding
• Liaison with EC (DG Research) for calls for
proposals under the 7th framework programme
(special programme for off-patent drugs)
• Priority list of off-patent medicinal products for
paediatric studies
(published in December 2006 for comments till 31 January
2007- Finalisation at the March Paediatric Working Party)
Paediatric studies – how to start?
Questions to answer first?
• Does the disease occur in paediatrics?
• How common is the disease in paediatrics?
– Common → continue
– Rare → ???
• Is there an unmet medical need?
– Yes → continue
• Which are the potential paediatric indications?
– Similar to adults
– Different of adults
• Is the disaese process in children and adults similar?
–
–
–
–
Infections – yes
Fever – yes
Seizures – unknown
HIV - no
Planning is the key
• Which studies when and how
• Non-clinical studies (toxicity, juvenile animals)
• Formulation issues –child friendly
– suspension, solution
– Taste and amount
– IV formulation (concentration??)
• Veins are narrow
• Limited amount of fluid could be given
– Bioavailability
• Safety/efficacy in all paediatric populations
Pediatric Study Decision Tree
Reasonable to assume (pediatrics vs adults)
 similar disease progression?
 similar response to intervention?
NO
YES TO BOTH
Reasonable to assume similar
concentration-response (C-R)
in pediatrics and adults?
•Conduct PK studies
•Conduct safety/efficacy trials*
NO
NO
Is there a PD measurement**
that can be use to predict
efficacy?
YES
•Conduct PK studies to achieve levels
similar to adults
•Conduct safety trials
YES
•Conduct PK/PD studies to get
C-R for PD measurement
•Conduct PK studies to achieve
target concentrations based on C-R
•Conduct safety trials
An ideal drug
• PK established in all
paediatric populations
• Safety well described
• Efficacy can be
extrapolated from adults
• Child-friendly
formulation available
• Post-marketing
experience
• No need for further
paediatric studies
• Studies with new
formulation could be
performed in adults
Unmet medical need & some
paediatric data
• Pharmacokinetic studies
– Linear pharmacokinetics – SD studies
– Non-linear pharmacokinetics – MD studies
– Target concentration
• Safety studies if efficacy can be extrapolated from
adults
• Efficacy studies if efficacy cannot be extrapolated
from adults
• Step-down timing
– Studies in adults and in older children first
• Do not forget neonates, if there is a need
PK Exposures in Paediatrics and
Adults
1.33 fold dose inc.
Medians
Cave (ng/ml)
AUC (ngh /ml)
3mg/kg
*Paed.
**Adults
889
1155
10, 670
13, 855
1.33 fold
* 35 subjects from SD and MD PK studies
** 236 healthy volunteers from SD and MD PK studies
4mg/kg
*Paed.
**Adults
1186
3217
14, 227
38, 605
2.78 fold
Ethical issues
• Is it ethical to conduct studies in children?
• Is it ethical not to conduct studies in children?
• Points to consider
–
–
–
–
–
–
–
Sample size
Pain and dyscomfort
Informed consent and assent
Blood loss
No investigations for study purposes only
Effect on growth and development
Is there a benefit (for this child, for the group of
children with similar disease)
– Healthy volunteers are not accepted
Kuidas Eesti saaks osaleda laste
uuringutes
• Kui palju Eestis kasutatavaid ravimeid omab
andmeid kõigi eagruppide kohta?
• Uuringute register lastearstide seltsi juures
– Farmaatsiatööstuse poolt läbiviidavad uuringud pole
ainukesed kliinilised uuringud lastel
•
•
•
•
EU grandid koos kolleegidega Euroopast
EV valitsus - ETF, sihtfinatseerimine
Heategevuslikud fondid (nt. Lastefond jne)
Rahva teavitamine
– Miks ja kuidas teostatakse uuringuid lastel
Summary
• Political decision - there is a need for
more paeditaric data
• Each day new paediatric data will be
released
• Future - All medicines used in children
should have paediatric data
Pediaatrilised uuringud on
globaalsed
• Luua sidemed 3-ndate riikide
andmebaasidega
• Lasteuuringute andmebaas kõigile
veebis kättesaadavaks
PIP
Decision
Compliance check:
Possible scenarios (newWaiver
Completion of
Measures at MAA
products)
Deferral
MA
validation
Partial deferral
MA
Completion
measures
Annual reports
on deferral
Partial
completion
measures
Compliance check
Annual reports
on deferral
Completion
measures
Reward : If compliant
+ Results in SPC
+ Authorisation in all MSs
•
Other Measures:
Paediatric Scientific
Free of charge fromAdvice
entry into force
• Prior to submission of a PIP or during PIP
implementation process
• Including advice on pharmacovigilance and risk
management systems
• Not binding on Paediatric Committee
• Link Paediatric Committee / Scientific Advice
Working Party
Other Measures: Provision of
Information
Paediatric clinical trials requiring EUDRACT
Modification
 To include third countries trials linked to a PIP
 To include results of all trials and of other trials
‘submitted to competent authorities’
 Paediatric information to be made public
Proposal made by EMEA to EC on the data fields to be
included in EudraCT and those to be published on
paediatric medicines
For discussion at the Ad Hoc Group for the development of
implementing guidelines for Directive 2001/20/EC
Followed by Release for consultation
Public access to paediatric information for authorised
New EMEA Committee: the
Paediatric
Committee
• An agreed (evolutive) paediatric
development: the Paediatric
Investigation
Plan (PIP)
• A mix of rewards and incentives
– For on-patent products
– For off-patent products
• A series of other tools for
information,
transparency, and stimulation of
research
•
•
•
•
•
•
•
•
•
•
New EMEA Committee: the Paediatric
Committee
• An agreed (evolutive) paediatric
development: the Paediatric Investigation
Plan (PIP)
• A mix of rewards and incentives
– For on-patent products
– For off-patent products
• A series of other tools for information,
transparency, and stimulation of research
BPCA: Pediatric Exclusivity Stats
(As of December 2006)
• Number of patients requested for studies
N= 45,700
• Products with Safety Reviews Presented to PAC
N= 65
http://www.fda.gov/oc/opt/pediatricsafety.html
• Summaries of Medical/Clinical Pharmacology
– Summaries on fda.gov/cder/pediatrics
N=73
– www.fda.gov/cder/pediatric/summaryreview.htm
BPCA: Pediatric Exclusivity Stats
(As of December 2006)
• 65 products had safety reviews
presented to Pediatric Advisory Comm.
• 73 summaries of Medical/Clinical
Pharmacology posted on web.
• 56 products placed on the BPCA offpatent priority list
BPCA vs. PREA
•
•
•
•
•
•
•
•
BPCA
Studies are voluntary
Includes orphan drugs and
orphan drug indications
Drugs only
Studies on whole moiety
1 year safety reviews
Summary posted on Web
Central review=PDIT
10-1-07 Sunset
•
•
•
•
•
•
•
PREA
Studies are required
Orphan drugs
designated exempt
Biologics and Drugs
Studies limited to
drug/indication under
development
No focused postmarketing safety review
No central review
10-1-07 Sunset
BPCA: Before a Written Request
(WR) is issued, we answer these
questions.
• Public Health Benefit – yes
• Risk/Benefit appropriate -- yes
Then we ask …
• What information do we need?
• In what age groups do we need the
information?
• What studies are needed to obtain this
information
Process: BPCA
1. Sponsor makes proposal for WR. Division
rejects, accepts, or modifies. OR
2. Division develops WR independent of sponsor
3. Division presents WR to PDIT(Pediatric Team)
4. Office Director signs off on WR to sponsor
5. Sponsor accepts or declines.
6. If sponsor declines, may be sent to FNIH
7. There is tracking of applications submitted for
an exclusivity determination
8. A summary of the studies is posted for all
studies
9. There is a 1 year post exclusivity safety review
Process: PREA
1. Sponsor submits an IND for an adult indication
2. Division must decide if pediatric studies are
needed and if they can be deferred or if
pediatric studies can be waived.
3. If studies are required the time table and
general outline are decided before an action is
taken on the application.
4. There may or may not be involvement of the
pediatric staff. There is no central process.
5. There is no tracking of outcomes except as
Phase 4
6. Only approved applications have studies
posted
7. There is no mandatory post approval safety
Selected Pediatric Ethics Activities
• Pediatric Ethical Consults
– Sept 2003 – July 2006: approx. 80 consults
– Topics: pediatric safety, compliance with Subpart D,
parental permission and child assent, exception from
informed consent applied to parents, use of “healthy”
children, international studies
• Subpart D (additional protections for children)
Referrals under 21CFR§50.54
– Pediatric Ethics Subcommittee of Pediatric AC:
FACA review of protocols referred by local IRBs for
approval by FDA Commissioner and/or HHS
Secretary
– Since 2004: 3 reviews (prior OHRP non-FACA
reviews=14)
Subpart D Pediatric Advisory Committee
and Ethics Subcommittee meetings
• September 2004: Effects of single dose
Dextroamphetamine in ADHD and functional
imaging
• June 2005: Precursor Preference in Surfactant
Synthesis of Newborns
• November 2005: Gonadotropin Releasing Hormone
Agonist Test in Disorders of Puberty