An agency of the European Union
Presented by: Dr Agnes Saint RaymondHuman Medicines Special Areas
Clinical Trials to make medicines available to Children A shared responsibility
www.ema.europa.eu
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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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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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
What is the EMA?
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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
The EMA coordinates the work of National Agencies
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© EMA
EMA
London, Canary Wharf
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• 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)
How does EMA work?
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Different responsibilities (with some overlap)
EMA MEMBER STATES
- Clinical Trials
-Scientific advice-Paediatric investigation plans-Orphan designation
-Approval of innovative medicines-Mandatory for biologicals, oncology, neurodegenerative dis., diabetes, HIV, viral, auto-immune dis., for orphan medicines-Approval for Advanced Therapies-Pharmacovigilance
- Scientific advice
- Approval in non-mandatory scope (in practice, only generics)
- Pharmacovigilance
-Hosting EU databases
- Pricing Reimbursement8
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Life cycle of a medicine from EMA perspective
Research & Development
Paed. Investigation
Plan
Sc.
Advice
Orphan
designation
MA
Pharmacovigilance
Pricing
Advanced Therapies
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Clinical Trials
Why do we need to study medicines for children?
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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 medicinesNeed 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
- Children need specific pharmaceutical forms
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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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Why do we need incentivised paediatric development?
(Nature Reviews, June 2007)
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The US initiative (in brief)
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Dual systemA 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)
• Other measures (transparency, Network, publication of old studies, EU Funding for off-patent medicines)
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Paediatric Investigation PlansData 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
Form-ulations
Toxicology,Pharmacology,
Juvenile Animals studies
Safety, Proof
concept Dosefinding -
PK
Efficacy
Safety issues…
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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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US BPCA US PREA EU
Development Optional Mandatory Mandatory (Optional for off-patent)
Instrument 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
Drugs (section 505)
YesWith exclusivity
YesAll
(except generics)Biologicals (most)
No All
Orphan Included Excluded Included
Decision FDA FDA EMA - Paediatric Committee
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Agencies interactions
Pre
clin
ica
l Ph
ase
Phase One
Phase Two
Phase Three
ND
A S
ubm
issi
on
Ma
rke
ting
Ap
pro
val
Postmarketing
FDA
Written RequestPREA*/WR
EC/EMA
PIP (all inclusive) Required for Filing
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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 paediatric medicines)25
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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)
• ICH guidelines (E11, E6)28
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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 revision29
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Conditions to protect minors (1)
1. Legal representative’s consent2. Information, appropriate to level of
understanding3. Explicit wish to refuse participation or to
withdraw must be ‘considered’4. No incentives to participate5. ‘Direct’ benefit for the group
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Conditions to protect minors (2)
6. EMA’s guidelines to be followed7. Minimisation of pain and risk: definition
and monitoring8. 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/ethical-considerations-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 andConsent 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, consider to abandon
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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
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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 PlaceboPlacebo 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
Training of patients’ representatives on clinical trials37
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“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/)
• EUDRAVIGILANCE for Individual Case Safety Reports and SUSARs for authorised medicines and those used in clinical trials – Public reports on EMA website
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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 2009 2010 2011 2012 Total
Applications(indications)
271(395)
273(395)
326(403)
187(220)
138(165)
1195(1578)
Opinions on PIP/Waivers
133 202 260 155 100 850
Modifications
8 51 107 155 126 447
Sept 2012
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 PIPsOne 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 2010Of 97 PIPs: 14% required an amendment of the studies proposed (new study, change in species, etc.)
• March 2011- December 2011Juvenile 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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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: challengesClinical 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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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
• 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)
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PAIN SCALES FPS-R
TOKENSVery very painful
No pain at all
VAS for5-10 years old
Visual Analog Scale
From G. Pons
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Endpoints© EMA 2012
Paediatric Trials design in PIPs (March 2011- Dec
2011)
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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
Active and placebo
3 1 +2 1 5
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
N paed. trials 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% 9.9%
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Outcome of the Paediatric Regulation after 5 years – PAEDIATRIC TRIALSN of subjects 2006 2007 2008 2009 2010 2011
Pre-term newborns 0 0 0 207 36 2290
Newborns 0 0 0 64 42 1051
Infants and Toddlers
330 0 15 54 184 2,465
Children 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
� 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
Medicines for children in the EMA centralised procedure – THE PAST
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289 active substances, until Jan 2006
~10 paediatric indications per year
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Outcome of the Paediatric Regulation after 5 years – AVAILABILITY OF MEDICINES
Between 30 and 50% of new indications or pharmaceutical forms are the direct consequence of the Paediatric Regulation obligations
N centralised/Total MAN national
2007 2008 2009 2010 2011 Total
New MA with paed. indication
10/39 6/25 7/412
2/170
6/301
31/15234
New paed. indication 7/175
6/284
8/3111
3/217
15/316
39/12882
Paed. pharmaceutical form
3/211
1/151
2/282
2/233
7/212
15/10926
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Outcome of the Paediatric Regulation after 5 years – INFORMATION ON MEDICINES
• Mandatory submission of paediatric dataInformation 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
More than 2000 active substances with paediatric data never submitted to EU Regulatory authorities
Study submission
2008-2011 N medicines
Changes in Product information
Old studies EMA
55 61 12
Old studies National (all)
994(~18,000)
89*2175
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New Studies EMA
55 68 15
New Studies national
124 ? 7
*completed assessment only
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Outcome of the Paediatric Regulation after 5 years – PRODUCT INFORMATION
Changes following review
2007 2008 2009 2010 2011 Total
Dosing EMADosing national
1415
1412
1614
158
2026
7975
Study resultsEMA
11 12 11 23 20 77
SafetyEMA
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
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
Thank you!
References/ Back-up slides
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EU Member StatesAustria, 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, Iceland71
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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, Iceland72
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1 Chair elected
•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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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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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.76
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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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ComparativeComparative Developmental Developmental SchedulesSchedules RatRat
DogDog
NonhumanNonhumanprimateprimate
HumanHuman
99 1010 2121 45454545 9090
mini-pigmini-pigmini-pigmini-pig 22 44 14141414 2626 WeeksWeeks
DaysDays
0.50.5 33 66 20202020 2929 WeeksWeeks
0.50.5 66 36363636 4848
28*28* 22 12121212 1616
MonthsMonths
*D/Years*D/Years
pre-termpre-termneonateneonate
termtermneonateneonate
Infant/Infant/toddlertoddler childchild adolescentadolescent
00
00
00
00
00
From B. Silva-Lima, EMA80
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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
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Abbreviations
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)82
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References
Paediatric Ethics
FDA:http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
CFRPart=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/ge
neral_content_000302.jsp&murl=menus/special_topics/special_topics.jsp&mid=
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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