Transcript Paediatric clinical trials Kyiv2012

Clinical Trials to make medicines
available to Children
A shared responsibility
www.ema.europa.eu
Presented by: Dr Agnes Saint Raymond
Human Medicines Special Areas
An agency of the European Union
© EMA 2012
Acknowledgments
Special thanks to Dr Gunter Egger, Anne-Sophie
Henry-Eude and Ralf Herold, and to the
Paediatric Team at EMA
Data from the FDA Office of Pediatric Therapeutics
(Dr Dianne Murphy, Jean Temeck)
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© EMA 2012
Outline
The European Union and European Medicines
Agency
The EU initiative on paediatrics
The US initiative
Clinical trials in children – Ethics and Science
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© EMA 2012
What is the EMA?
An Agency of the European Union responsible for
the scientific evaluation of medicines for human
and animal use in the European Union:
– Activities pre-approval (help to development, special
medicines)
– Marketing Authorisations (approvals) on quality safety and
efficacy
– Inspections (GCP, GMP, GLP, GVP)
– Referrals from national procedures to European level
– Pharmacovigilance
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© EMA 2012
The EMA coordinates the work of National
Agencies
–
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Scientific Advice
Orphan Designation for human medicines for rare diseases
Paediatric Investigation Plans
Small & Medium Sized businesses
Scientific Support and Projects (biostatistics, toxicology,
innovation...)
Marketing Authorisations (approvals)
Collaboration with WHO (Article 58)
Inspections
Referrals
Pharmacovigilance
London, Canary
Wharf
EMA
© EMA 2012
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© EMA
© EMA 2012
How does EMA work?
• Our priority is public health (and animal health)
• We also have to support innovation and
European industry.
EMA Scientific Committees produce 'scientific
opinions'. Decisions are taken by the European
Commission (except for paediatrics)
600 staff for a budget of about 210 million € (80%
from fees, the rest from European Union budget)
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Different responsibilities (with some overlap)
EMA
MEMBER STATES
- Clinical Trials
-Scientific advice
-Paediatric investigation plans
-Orphan designation
- Scientific advice
-Approval of innovative medicines - Approval in non-mandatory scope
-Mandatory for biologicals,
(in practice, only generics)
oncology, neurodegenerative dis.,
diabetes, HIV, viral, auto-immune
dis., for orphan medicines
-Approval for Advanced Therapies
-Pharmacovigilance
- Pharmacovigilance
-Hosting EU databases
- Pricing Reimbursement
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© EMA 2012
Life cycle of a medicine from EMA
perspective
Clinical
Trials
Research &
Development
MA
Pricing
Orphan
Paed.
Sc.
Investigation
Advice designation
Plan
Advanced
Therapies
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Pharmacovigilance
© EMA 2012
Why do we need to study
medicines for children?
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© EMA 2012
Evidence-based medicines
Studying/assessing medicines for children implies
doing clinical research WITH children
And the evidence shows that children are NOT ‘small
adults’
You will say or hear: “Paediatric studies are
impossible, parents don’t consent”…
“Trials are expensive, trials are slow”…
“there are not enough children (small sample size)”…
“Children should not be ‘Guinea pigs’, We cannot use
placebo with children”
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More challenges to develop paediatric
medicines
Need for
- Age-appropriate formulations and dosage forms
- Paediatric dose(s)
- Validated outcome measures
- Need for safety outcome measures
- Adapted clinical trials facilities, investigations,
assays and trained personnel
- All of this is true to a certain extent, but
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In fact,
Clinical Trials with children are necessary:
- We must prescribe based on evidence
- Prescribing untested medicines is unethical
- Children are not small adults (physiology,
metabolism, growth and maturation)
- Doses in children can be higher, lower or the
same and this cannot be ‘guessed’
- Safety in children is different from adult safety
-13 Children need specific pharmaceutical forms
© EMA 2012
Trials with children are necessary
With robust evaluation of Benefits and Risks
With Special Precautions for vulnerability
With active Ethical oversight
Not using children as commodity (no healthy
volunteer child!)
To produce high quality results that are
meaningful for the children
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(Nature Reviews, June 2007)
© EMA 2012
Why do we need incentivised paediatric
development?
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The US initiative (in brief)
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Dual system
A voluntary one: BPCA
- Based on Written Request, decided by FDA based
on public health needs, time limits
- 6-month exclusivity reward
A mandatory one: PREA
- No reward, but paediatric development limited to
proposed adult indication, later included time limits,
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The European Initiative
A single system
Law passed in EU end of 2006
“Regulation (EC) No 1901/2006 of the European
Parliament and of the Council on medicinal
products for paediatric use”
= Paediatric Regulation
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Objectives of the Paediatric Regulation
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
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Tools in the Paediatric Regulation
• An expert Paediatric Committee at EMA
• Paediatric Investigation Plans / Waivers
• Obligations and rewards
•For new medicines, as well as authorised &
patented medicines (6-month extension of
patent)
•For orphan medicines (+2 year exclusivity)
•For off-patent medicines (10 y data protection)
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• Other measures (transparency, Network,
publication of old studies, EU Funding for offpatent medicines)
© EMA 2012
Paediatric Investigation Plans
Data on efficacy, safety and quality (formulation, dosage form),
Timelines (ref ICH guideline E11)
In practice, discussion on potential paediatric use and unmet
needs to decide on the development and formulation for each
age group, from birth to 18 years
Formulations
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Safety,
Efficacy
Proof
Toxicology,
concept Dose
Safety
Pharmacology,
finding issues…
Juvenile
PK
Animals studies
© EMA 2012
PIP Waivers/Deferrals
• Waiver of class, or indications or specific
product
– When the medicine is likely to be ineffective
or unsafe
– When the condition does not occur in children
– When the product does not bring Significant
Therapeutic Benefit
• Deferral, of initiation of studies and/or
completion so as not to delay approval in
adults, or for safety reasons
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On request from applicant, or Committee
US BPCA
US PREA
EU
Optional
Mandatory
Mandatory
(Optional for off-patent)
Written Request
-
Paediatric Investigation Plan
Waiver
na
3 grounds
3 grounds
Timing
End of phase 2-3
End of phase 2-3
End of phase 1-2
Reward
6 months
exclusivity
-
6 months patent
Yes
With exclusivity
Yes
No
All
All
(except generics)
Orphan
Included
Excluded
Included
Decision
FDA
FDA
EMA - Paediatric Committee
Development
Instrument
Drugs
(section 505)
Biologicals
(most)
© EMA 2012
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Agencies interactions
© EMA 2012
EC/EMA
Phase Three
Phase Two
PREA*/WR
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FDA
Marketing Approval
Phase One
NDA Submission
Preclinical Phase
PIP (all inclusive) Required for Filing
Postmarketing
Written Request
© EMA 2012
Global Development
Active collaboration with FDA ongoing
Exchange of staff, cooperation on guidelines
Monthly teleconferences discussing PIP and
Written requests and other topics - Japan
and Canada have joined teleconferences as
observers
Collaboration with other regions/countries like
Singapore, Australia.
Collaboration with World Health Organization
(network of regulatory agencies for
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paediatric medicines)
© EMA 2012
Ethics of paediatric medicine development
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Prescribing untested medicines to
children is ethically unacceptable
• Each child is included in an un-controlled trial
• Results are not helpful for other children
• No prior hypothesis set up, and results are
inconclusive (were they obtained by chance or due to
treatment?)
• Potential safety issues (overdose), or loss of chance
for the patient (under-dose)
• A trial that is not scientifically based cannot be
ethical (i.e. need to provide robust answer to a
new question)
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Ethical and legal framework for European
trials
• Ethical principles are shared at international
level
• The main principles such as in Declaration
of Helsinki and other texts (subject
autonomy, beneficence, distributive justice)
• EU Clinical Trials Directive and its
implementing texts (GCP Directive)
• Ethical considerations on clinical trials in the
paediatric population (EU ethics guideline)
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• ICH guidelines (E11, E6)
© EMA 2012
EU Clinical Trials legislation in
minors/children
All medicinal products (authorised or not)
All interventional trials
Follows Good Clinical Practice
Main objective: protection of research
participants
Special protection of vulnerable participants
Full implementation 1 May 2004
Ongoing revision
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Conditions to protect minors (1)
1.
2.
3.
4.
5.
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Legal representative’s consent
Information, appropriate to level of
understanding
Explicit wish to refuse participation or to
withdraw must be ‘considered’
No incentives to participate
‘Direct’ benefit for the group
© EMA 2012
Conditions to protect minors (2)
6.
7.
8.
EMA’s guidelines to be followed
Minimisation of pain and risk: definition
and monitoring
Paediatric expertise for Ethics
Committee
Patient’s interest prevails over science’s
and society’s
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“Ethical considerations …”
European Ethics practical Guideline
for paediatric clinical trials (interventional clinical
trials) since 2008
ftp://ftp.cordis.europa.eu/pub/fp7/docs/ethicalconsiderations-paediatrics_en.pdf
This document was required because the
Paediatric Regulation was going to increase the
number of trials and to protect the children
involved in medicines research
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Assent – for the child and
Consent for parents / legal representatives
Assent: ‘knowing agreement’
Simultaneous process to informed consent
Respect of different opinions
Assent, like consent, is a continuous process, not just
at the beginning
From the age of 3 years on, a child has emergent
capacity to agree. Information in all cases, and
capability to assent should be evaluated
Strong and definite objections by the child should be
respected!
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Example:
Pain, distress and fear minimisation
Personnel and facilities appropriate for childcare
Fear should be prevented, if unavoidable, minimised
Physical and emotional pain should be prevented as
much as possible, and effectively treated when
unavoidable
Separation of child from parents to be avoided
Changes in procedure have to be explained in
advance
React to signs of distress or pain during a procedure:
pause, explain, reassure, allow to feel in control,
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consider to abandon
© EMA 2012
Risk and risk assessment (1)
Potential ‘risk sources’: the medicinal product tested, the lack of dosage
form, the control, withholding active treatment, the disease itself, the
accumulation of research for some individuals
In principle required: Data and Safety Monitoring Board, stopping rules
Harms are: invasiveness, intrusiveness, severity and seriousness of
potential harms, reversibility of adverse effects, and the
preventability
“Levels of risk” can be categorised, or continuous
Categories: Minimal risk; minor increase over minimal risk; greater than
minor increase over minimal risk
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Risk assessment (2)
Not easy in practice (public consultation’s comments)
Levels of risk in paediatrics as evaluation different from adults
Identification and grading of procedures (invasiveness)
Taking into account the repetition of risks
PREVENTION, or minimisation before and during trial,
MONITORING during trial
What is not measured is under-estimated!
Interest of involving patients’ representatives in the
design of trials.
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Considerations on Placebo
Placebo use should be for scientific reasons (equipoise) in adults like
in children.
Placebo can be used on top of ‘standard care’.
Subjects on placebo are protected against serious adverse effects!
As the level of evidence in favour of an effective treatment increases,
the ethical justification for placebo decreases (no more equipoise)
In the protocol, need to minimise exposure to placebo and include
rescue medication and escape procedures
Need for information of participants
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Training of patients’ representatives on clinical trials
© EMA 2012
“Repetitive tests will not be carried
out…” – Transparency & databases
•
EUDRACT database with access to Member
States, EMA and Eur. Commission,
•
but was otherwise confidential
NOW Public access to protocol-related
information and later to results in EU-CTR
(https://www.clinicaltrialsregister.eu/)
•
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EUDRAVIGILANCE for Individual Case Safety
Reports and SUSARs for authorised
medicines and those used in clinical trials –
Public reports on EMA website
© EMA 2012
Practical aspects of Paediatric Clinical Trials
• Issues in Paediatric Investigation Plans
• The outcome of the EU paediatric Regulation after 5 years
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Paediatric Committee Workload
2008
Applications
271
(indications) (395)
2009
2010
2011 2012
Total
273
326
187
138
1195
(395) (403) (220) (165) (1578)
Opinions on
PIP/Waivers
133
202
260
155
100
850
Modification
s
8
51
107
155
126
447
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Sept 2012
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Pharmaceutical forms and formulations?
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Quality: main points
•
Chemicals and Biologicals:
• Paediatric-specific route of administration
 Age/maturation and weight-appropriate formulation and
form
• strengths available
• size of tablets, or concentration / volume
• taste  palatability
• convenience of administration
• Toxicity of the excipients in children? (e.g. ethanol /
parabens / preservatives / phtalates / colouring agents)
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Paediatric formulations and forms in PIPs
One review of the initial PIPs
- Paediatric Committee requires more new forms than
proposed by companies:
- Oral dispersible or micro-tablets rather than liquids
- New (lower) strength for younger age groups
- If injectable form, change in concentration for either
tolerability, or volume issues (25 milliliters for preterms!)
- Major issues of unknown safety of excipients (known for
adults but not children, especially newborns)
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Non-clinical development in PIP
⇒ Need for additional juvenile toxicity studies:
• Safety signals in mature animals
• Age and species appropriateness
• Mechanism of action
• Species? Dose?
⇒ Prerequisites for clinical trials with children (ICH)
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Juvenile animal studies in PIPs
• First review Nov 2008- May 2010
Of 97 PIPs: 14% required an amendment of the
studies proposed (new study, change in
species, etc.)
• March 2011- December 2011
Juvenile animal studies proposed in 19% but
required in 25% of 88 PIP opinions
⇒Mostly because the neonates and infants have to
be studied.
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General pharmacology and mechanism of
action in PIP
• Knowledge of the mode of action of the medicine
• Influence of the disease
• Lack of (animal) models for many paediatric
diseases
 Modification of the target related to the
physiological age and maturation
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Kearns et al.,
NEJM 2003;349: 1157-
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© EMA 2012
Clinical development: efficacy in PIP
• Endpoints:
• Relevant and validated outcome measures
• Prospective, comparative data (RCT)
• Comparator in children?
• Role of extrapolation to avoid un-necessary trials:
• Efficacy: Yes under certain conditions,
• No extrapolation of safety
• With scientific hypothesis and statistical demonstration
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Clinical plan: challenges
Clinical trial feasibility:
• Competition for scarce paediatric patients
(hypertension, diabetes, oncology)
• Conflicting research priorities of paediatric networks
• Lack of funding
• Source of data from non-European paediatric
population: genetic or metabolic differences
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© EMA 2012
Clinical development: adaptive designs
• Many requests for Scientific Advice
• Several PIPs agreed with adaptive designs
• Change in endpoints (almost always no)
• Change in sample size (generally OK if initial
uncertainty on e.g. treatment effect)
• Change in number of tested doses (generally
OK) if sufficient power to conclude for the
remaining population
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Endpoint issues in Paediatric Investigation
Plans
•
•
•
•
•
•
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Cardiovascular: Diastolic Blood Pressure rather than
systolic in hypertension? - No endpoint for Heart failure
Diabetes: Glycated haemoglobin or Hypoglycaemia?
Duchene Myodystrophy: survival or muscle strength? - No
use of ‘walking test’ for infants
Pulmonary Hypertension of newborn: vascular resistances
or ultrasonography?
Cystic fibrosis: FEV1?
TIME to endpoint (clinical endpoint may happen 10 years
later)
Endpoints
From G. Pons
VAS for
5-10 years old
Very very painful
TOKENS
Visual Analog Scale
No pain at all
PAIN SCALES FPS-R
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© EMA 2012
Paediatric Trials design in PIPs (March 2011Dec 2011)
Number
Proposed
%
Required
%
Total
Double blind
70
34
+9
15
79
Single blind
86
42
+22
36
101
Placebo
control
55
27
+10
16
65
Active control
38
18
+11
18
50
3
1
+2
1
5
Active and
placebo
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Clinical safety development
• Short and long term (>20 years?) safety
• Impact on organs maturation in each age group
• Appropriate size of safety database?
• When in doubt, include measures in Risk
Management Plan (RMP) post approval
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Outcome of the Paediatric Regulation
after 5 years – THE FACTS
• Report published
http://ec.europa.eu/health/documents/new_en.htm
• Research on medicines for children
• Availability of medicines for children
• Information on medicines for children
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Outcome of the Paediatric Regulation
after 5 years - RESEARCH
• Creation of a network for paediatric research:
European Network of Paediatric Research at EMA
(Enpr-EMA) with membership based on quality
research, expertise, and patient/family involvement
• 18 networks fulfilling all quality requirements
• 20 more on their way…
• Every year a meeting between EMA, networks and
pharmaceutical industry (paediatric medicines)
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Outcome of the Paediatric Regulation
after 5 years - RESEARCH
The trials are registered in the EU database of
trials (mandatory registration of all human
interventional trials with at least one site in EU,
and any paediatric trial if included in a Paediatric
Investigation Plan) – Public access for protocol
related information, work ongoing on results
related information
Limitations: reliability of data not absolute!
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Outcome of the Paediatric Regulation
after 5 years – PAEDIATRIC TRIALS
2005
2006
2007
2008
2009
2010
2011
253
315
351
341
401
379
360
N in PIPs
1
0
1
4
12
22
70
% of PIP
trials/all paed.
trials
-
-
-
1%
3%
6%
19%
All EU TRIALS
3,327
3,951
4,730
4,506
4,411
4,019 3,622
% paed.
trials/all
7.6%
8%
7.4%
7.6%
9.1%
9.4%
N paed. trials
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9.9%
© EMA 2012
Outcome of the Paediatric Regulation
after 5 years – PAEDIATRIC TRIALS
N of subjects
2006
2007
2008
2009
2010
2011
Pre-term
newborns
0
0
0
207
36
2290
Newborns
0
0
0
64
42
1051
330
0
15
54
184
2,465
1,910
150
1,178
940
1,248
9,345
Adolescents
136
85
1,129
1,543
1,600
8,369
N trials�
254
285
305
332
321
272
Infants and
Toddlers
Children
� N excluding ‘vaccines /immunological’ trials
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Outcome of the Paediatric Regulation
after 5 years – PAEDIATRIC TRIALS
N of
discontinued
trials
2004
2005
2006
2007
2008
2009
2010
2011
Any reason
2
10
15
18
27
18
22
1
Quality of the
investigational
medicine
0
0
0
0
0
0
0
0
Lack of
efficacy
0
1
1
0
3
3
2
0
Not started
0
5
3
6
9
4
6
0
Safety
1
0
1
2
1
2
0
0
Other
2
10
15
17
24
13
12
1
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Outcome of the Paediatric Regulation
after 5 years – AVAILABILITY OF MEDICINES
• Initial Marketing authorisations (new active
substances) with a paediatric indication
• New paediatric indication for an authorised product
• New pharmaceutical forms for authorised products
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62 ©EMA
Medicines for children in the EMA
centralised procedure – THE PAST
~10 paediatric
indications per
year
289 active substances, until Jan 2006
© EMA 2012
Outcome of the Paediatric Regulation
after 5 years – AVAILABILITY OF MEDICINES
N centralised/Total
MA
N national
2007
2008
2009
New MA with paed.
indication
10/39
6/25
7/41
2
2/17
0
6/30
1
31/152
34
New paed. indication
7/17
5
6/28
4
8/31
11
3/21
7
15/31
6
39/128
82
Paed. pharmaceutical
form
3/21
1
1/15
1
2/28
2
2/23
3
7/21
2
15/109
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63
2010 2011
Total
Between 30 and 50% of new indications or
pharmaceutical forms are the direct consequence of
the Paediatric Regulation obligations
© EMA 2012
Outcome of the Paediatric Regulation
after 5 years – INFORMATION ON MEDICINES
• Mandatory submission of paediatric data
Information from both
- Old paediatric trials (trials performed before 2007)
- and New paediatric trials within 6 months of
completion (since 2007)
- 18,000 old paediatric reports available on EMA
website (17,506 records)
- Ongoing submission of new trials (EudraCT)
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Outcome of the Paediatric Regulation
after 5 years – INFORMATION
Study
submission
20082011
Old studies
EMA
N
Changes in Product
medicines information
55
61
12
Old studies
National (all)
994
(~18,000)
89*
2175
53
New Studies
EMA
55
68
15
New Studies
national
124
?
7
*completed assessment only
More than 2000 active substances with paediatric data never
submitted to EU Regulatory authorities
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© EMA 2012
Outcome of the Paediatric Regulation
after 5 years – PRODUCT INFORMATION
Changes
following
review
66
2007
2008 2009 2010 2011
Total
Dosing EMA
Dosing national
14
15
14
12
16
14
15
8
20
26
79
75
Study results
EMA
11
12
11
23
20
77
Safety
EMA
8
11
20
-
28
-
Other
information*
7
13
17
36
50
127
Negative studies
-
0
1
2
2
5
*including mention of waivers and deferrals
© EMA 2012
CONCLUSIONS
• Evidence-based medicine requires studies in
children, with children
• We have a shared responsibility to perform
ethical paediatric studies, and an ethical
duty to progress science
• High quality ethical research means
scientifically robust studies, meaningful for
children
• Respect of ethical principles and appropriate
protection of the vulnerability of children
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CONCLUSIONS
• Sharing of information prevents
unnecessary studies
• Incentivised paediatric development is
necessary and does deliver results:
• More and better research, more medicines
available with appropriate information and
pharmaceutical forms and formulations
• For the children of the world…
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©EMA 2012
© EMA 2012
References/ Back-up slides
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EU Member States
Austria, Belgium, Bulgaria, Cyprus, Czech
Republic, Denmark, Estonia, Germany, Greece,
Hungary, Ireland, Italy, Finland, France, Latvia,
Lithuania, Luxemburg, Malta, Poland, Portugal,
Romania, Slovakia, Slovenia, Spain, Sweden,
The Netherlands, United Kingdom
EEA-EFTA countries (associated): Norway, Iceland,
Liechtenstein
Accessing country: Croatia in 2013
Candidate:, Turkey, Former Yugoslavian Republic of Macedonia,
Montenegro, Iceland
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Paediatric Committee
27 Members (with
alternates)
including 5 from Approval Committee
(CHMP)
3 Health
Professionals
3 Patients’
representatives
2 members from Norway,
Iceland
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1 Chair elected
© EMA 2012
•Neonatology, paediatric
cardiovascular diseases,
immunology, transplantation,
respiratory, ICU, vaccines,
pharmacology, PK, haematology,
oncology, endocrinology and
diabetes, adolescent medicine,
pharmacovigilance,, infectious
diseases, gastroenterology and
nutrition, general paediatrics,
ethics, methodology
• Formulations (plus group of
experts)
•Non-clinical toxicology (plus
group of experts)
• other (adult) physicians
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© EMA 2012
Structure of the PIP application
(industry part)
• Section A: Regulatory with condition/indication
• Section B : Targeted conditions / indications and needs
• General pharmacology
• Clinical need by age groups/subsets (with prevalence)
• Benefit of the product versus alternatives
• Section C : Waiver request
• Section D: Summary of existing data and Development plan
• Quality
• Non-clinical
• Clinical (± Risk management Plan outline)
• Section E: Timelines, deferral request
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Significant therapeutic benefit - EU (1/2)
(a) reasonable expectation for safety and efficacy for a marketed or new
medication to treat a paediatric condition where no authorised
paediatric medicinal product is on the market;
(b) expected improved efficacy in a paediatric population compared to
the current standard of care for the treatment, diagnosis or
prevention of the condition concerned;
(c) expected improvement in safety in relation to either adverse
reactions or potential medication errors in a paediatric population
compared to the current standard of care for the treatment,
diagnosis or prevention of the condition concerned;
(d) improved dosing scheme or method of administration (number of
doses per day, oral compared to intravenous administration, reduced
treatment duration) leading to improved safety, efficacy or
compliance;
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© EMA 2012
Significant therapeutic benefit EU (2/2)
(e) availability of a new clinically relevant age-appropriate
pharmaceutical form;
(f) availability of clinically relevant and new therapeutic knowledge
for the use of the medicinal product in the paediatric population
leading to improved efficacy or safety of the medicinal product
in the paediatric population;
(g) different mechanism of action with potential advantage for the
paediatric population(s) in terms of improved efficacy or safety;
(h) existing treatments are not satisfactory and alternative
methods with an improved expected benefit-risk balance are
needed;
(i) expected improvement in the quality of life of the child.
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Ethical Considerations outline (1/3)
Ethical principles and fundamental rights
Legal context, definitions and glossary
The process of informed consent and assent from children*
Ethics Committee’s composition for paediatric trials
Paediatric clinical trial design
Pain, distress, and fear minimisation*
Risk assessment and monitoring*
Benefit and measures of benefit
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Ethical Considerations outline (2/3)
Assays in relation to age/bodyweight, blood sampling
Studies with healthy children, vaccines
Placebo*
Paediatric formulations to be used in paediatric trials
Individual data protection
Unnecessary replication of trials
Adverse reactions and reporting
Inducements versus compensation for children
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Ethical Considerations outline (3/3)
Insurance
Trials in children in non-EU countries
Ethical violations and non-compliance with GCP
Annex 1: Member States’ responses to questionnaire
Annex 2: List of issues for trials with the paediatric population
Annex 3: Information for informed consent
Annex 4: Examples of levels of risk
References by topic
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Comparative
Developmental
Rat
Schedules
© EMA 2012
0 9 10
0 2
4
Dog 0 0.5 3
6
mini-pig
Nonhuman
primate
Human
0
0
6
28*
2
Infant/
toddler
From B. Silva-Lima, EMA
90
Days
26
14
0.5
pre-term term
neonate neonate
80
21 45
20
36
12
child
Weeks
Weeks
29
48
Months
16 *D/Years
adolescent
Abbreviations
© EMA 2012
AAP: American Academy of Pediatrics
BPCA: Best Pharmaceutical Act for Children (US)
CHMP: Committee on Medicinal Products for Human Use (EU)
(I)EC: (Independent) Ethics Committee (equivalent to US IRB)
EMA: European Medicines Agency (formerly EMEA)
EUDRACT: European Database of Clinical Trials
EUDRAVIGILANCE: Database of Adverse Reactions (Clinical trials and post
authorisation)
FDAAA: FDA Amendment Acts 2008
FDAMA: FDA Modernization Act 1997
FDASIA: FDA Safety and Innovation Act 2012
GCP: Good Clinical Practice
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Abbreviations
© EMA 2012
ICH: International Conference on Harmonization (EU, US, Japan)
MA(A): Marketing Authorisation (Application) EU
MS: Member State
NDA: New Drug Application (US)
NRA: National Regulatory Authority
PeRC: Pediatric Review Committee (US)
PD: pharmacodynamics
PIP: Paediatric Investigation Plan (EU)
PK: pharmacokinetics
PREA: Pediatric Research Equity Act
R&D: Research and Development
SA: Sc. Advice, Scientific Advice
WR: Written Request (US)
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References
Paediatric Ethics
FDA:http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?C
FRPart=50&showFR=1&subpartNode=21:1.0.1.1.19.4
EMA:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/
general_content_000302.jsp&murl=menus/special_topics/special_topics.jsp&mi
d=WC0b01ac058002d4ea
Canada: Best Practices for Research involving children and Adolescents - Genetic,
Pharmaceutical, Longitudinal and Palliative Care Research. Julie SAMUËL, Lee
BLACK, Denicse AVARD, Bartha Maria KNOPPERS. 2009
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References
EMA WEBSITE: WWW.EMA.EUROPA.EU (Medicines for Children webpage)
‘Old’ studies database (article 45 submission):
http://art45-paediatric-studies.ema.europa.eu/clinicaltrials/search.php
Clinical trials database:
https://www.clinicaltrialsregister.eu/
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