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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© 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

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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© EMA 2012

– 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 2012

© EMA

EMA

London, Canary Wharf

6 © EMA 2012

• 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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© EMA 2012

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

© EMA 2012

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

© EMA 2012

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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

© EMA 2012

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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

On request from applicant, or Committee 22

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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

minor increase over minimal risk 35

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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

© 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/)

• 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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© EMA40

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-

47 © 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: 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

© EMA 2012

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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)

© EMA 2012

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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!

© EMA 2012

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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%

© EMA 2012

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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

© EMA 2012

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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

©EMA

© EMA 2012

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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)

© EMA 2012

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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

© EMA 2012

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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

© 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

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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