Template - Summary Report · Web viewTemplate developed for European Medicines Agency by Fiona Lewis and Vanessa Crookes December 2009 EMA/52099/2013 EMA/PDCO Summary

EMA/52099/2013

EMA/PDCO Summary Reporton an application for a <Paediatric Investigation Plan> <including> <a deferral> <and> <a> <waiver>

UPI Number: <number>

<Active substance> or <INN> (only if this is a recommended INN)

<Trade name> <and associated trade names> (Only in case of existing

products)

<Applicant's name>

<EMEA-xxxxxx-PIPxx-xx>

Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The

An agency of the European Union Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000

Application SummaryTo be included by the applicant in the submission document. This overview is to inform about the main aspects of the proposal for a PIP and / or waiver. Please, do not exceed 750 words. Guidance is included in green italic font.

Active substance(s), class and mechanism of action: <Text> Brief description of mode of action, including expected differences between children and adults.

Product name: <Text> if already authorised in the EEA

MAH / applicant: <Text> Name of applicant

Authorised indication(s): <Text> in children and/or adults

Planned indication(s) in adults: <Text> as mentioned in the PIP scientific application

Condition: <Text> as mentioned in the PIP scientific application should be relevant to the mechanism of action.

Proposed indication(s) in children: <Text> as mentioned in the PIP scientific application

Potential benefit for children: <Text> Outline of potential significant therapeutic benefit for this medicinal product in relation to unmet needs in children. A brief justification for waiver or deferral request may also be included.

Clinical development: <Text> Summary of proposed studies (type, age, numbers), including short justification for proposed study programme (underlying strategy). Make transparent links to paediatric networks and communities. Explain how feasibility of proposed studies is ensured.

Pharmaceutical form: <Text> Identify if there is a need for development (based on proposed age groups and indication). If potentially yes, describe plans including timing of availability of age-appropriate formulation for paediatric studies.

Non-clinical plans: <Text> Brief overview of how proposed non-clinical study programme and / or existing data support studies and use in children. Summarise proposed non-clinical studies or justify absence of proposed studies.

Extrapolation: <Text> If there is a possibility to extrapolate efficacy from adults to children or from older to younger children, this should be elaborated. Data related to extrapolation of safety information from adults to children can also be included. Modelling of PK and/or PD if used for decision-making should be mentioned.

Waiver(s), deferrals: <Text> Provide justification for product-specific waiver or partial waiver in relation to proposed paediatric subsets. Summarise

EMA/PDCO Summary Report EMA/52099/2013 Page 2/43

milestones of proposed paediatric studies, if relevant, in relation to adult development.


Table of contentsApplication Summary..............................................................................2Table of contents....................................................................................4Abbreviations.........................................................................................7Proposed studies....................................................................................8Proposed key elements............................................................................................................8Outline of each of the planned and/or ongoing, studies and steps in the pharmaceutical development............................................................................................................................8Synopsis/outline of protocol of each of the planned and/or ongoing non-clinical studies.........8Synopsis/outline of protocol of each of the planned and/or ongoing clinical studies................8Modelling and simulation study................................................................................................8Extrapolation study..................................................................................................................8Part A Procedure for the assessment of the application..........................9A.1. Details of the medicinal product and overview of the application.....................................9A.1.1. Medicinal product..........................................................................................................9A.1.2. Authorised use.............................................................................................................11A.1.3. Applicant’s proposals...................................................................................................11A.1.4. Discussion of proposed condition(s) (scope of application)..........................................12A.2. Regulatory information on completed clinical trials related to the condition and to the development for the paediatric population............................................................................12A.3. Regulatory status of the product....................................................................................13A.3.1. Marketing authorisation status inside the European Union..........................................13A.3.2. Marketing authorisation status outside the European Union........................................14A.3.3. Refusal / withdrawal / restriction of a marketing or extension authorisation or application (inside or outside EEA).........................................................................................14A.4. Regulatory advice on the development of the product...................................................14Part B Overall development of the medicinal product............................16B.1. Discussion on similarities and differences and pharmacological rationale......................16B.1.1. Similarities and differences of the disease/condition between populations..................16B.1.2. Pharmacological rationale and explanation.................................................................17B.2. Current methods of diagnosis, prevention or treatment in paediatric populations.........18B.3. Significant therapeutic benefit /fulfilment of therapeutic needs.....................................19Part C Applications for product-specific waivers....................................21C.1. Overview of the waiver request(s)..................................................................................21C.2. Grounds for a product-specific waiver............................................................................21C.2.1. Grounds based on lack of efficacy or safety.................................................................21C.2.2. Grounds based on the disease or condition not occurring in the specified paediatric subset(s)................................................................................................................................22C.2.3. Grounds based on lack of significant therapeutic benefit............................................22Part D Paediatric investigation plan.....................................................24D.1. Existing data and overall strategy proposed for the paediatric development.................24D.1.1. Paediatric investigation plan indication.......................................................................24D.1.2. Selected paediatric subset(s)......................................................................................24


D.1.3. Information on the existing quality, non-clinical and clinical data...............................25D.2. Quality aspects...............................................................................................................26D.2.1. Strategy in relation to quality aspects.........................................................................27D.2.2. Outline of each of the planned and/or ongoing, studies and steps in the pharmaceutical development................................................................................................28D.3. Non-clinical aspects........................................................................................................29D.3.1. Strategy in relation to non-clinical aspects..................................................................29D.3.2. Overall summary table of all planned and/or ongoing non-clinical studies..................29D.3.3. Synopsis/outline of protocol of each of the planned and/or ongoing non-clinical studies.............................................................................................................................................. 30D.4. Clinical aspects...............................................................................................................30D.4.1. Strategy in relation to clinical aspects.........................................................................30D.4.2. Overall summary table of all planned and/or ongoing clinical studies.........................32D.4.3. Synopsis/outline of protocol of each of the planned and/or ongoing clinical studies....32D.5. Other studies..................................................................................................................33D.5.1. Modelling and simulation study...................................................................................33D.5.2. Extrapolation study......................................................................................................34D.6. Timelines of measures in the paediatric investigation plan............................................35Part E Applications for deferrals...........................................................37Part F References................................................................................38F.1 Initial references..............................................................................................................38F.2 Additional references.......................................................................................................38Paediatric formulation development......................................................................................38<Paediatric Committee discussion at Day 30>........................................40<Comments from CHMP Members and PTL>...........................................40<Paediatric Committee discussion and Request for Modification>...........40<Restart of procedure after submission of answer to the Request for Modification>.......................................................................................41<Paediatric Committee discussion at Day 90>........................................42<Paediatric Committee discussion – conclusions at Day <60> <120>>.................42


General guidance:

When commenting on the different sections on the summary report, the Paediatric Co-ordinator, the Rapporteur and Peer Reviewer should:

Provide scientific argumentation, which would support the request for modification and/or the Opinion. The comments should be both critical and constructive, proposing specific changes requested in the proposed application;

Consider the existing CHMP guidelines/Scientific Advice and issues raised in the assessment of products within the same class/same indication. If the Paediatric Co-ordinator, Rapporteur and Peer Reviewer consider that there is a need to deviate from the existing CHMP guidelines/Scientific Advice, this should be scientifically argued.

In this respect the Paediatric Co-ordinator should draw attention:

to contents of previous applications and questions raised on similar products (while any confidential information on other products/applications should be deleted from the report before sending it to the applicant);

to products for which the evaluation is ongoing at CHMP and specific relevant points raised in their assessment;

to products already authorised centrally for which there may be specific post-marketing issues (e.g. safety issues) which may be of relevance for the assessment of the application;

to written requests issued by the FDA for the same or similar products;

to specific information provided by the FDA on the product during one of the monthly EMA-FDA paediatric teleconferences.


Abbreviations <Text>


Proposed studiesAll studies are generated from Key binding element form

Comment:

<Text>

<Text>

<Text>


Part A Procedure for the assessment of the applicationOn <Date> the applicant submitted to the European Medicines Agency an application for a <Paediatric Investigation Plan> <including> <a deferral> <and> <a> <waiver>.

Name

Paediatric Co-ordinator <name>

Rapporteur <name>

Peer Reviewer <name>

Name Outcome of evaluation of conflict of interest

External Expert(s) <No experts were involved by the PDCO.> <Level 1><Level 2><Level 3>

<Table 1 for full waivers only>

Pre-submission meeting Yes / No <Date>

Start of the procedure Day 1 <Date>

First discussion by the PDCO by Day 30 <Date>

PDCO request to modify the PIP by Day 60 <Date>

<Table 2>

Pre-submission meeting Yes / No <Date>

Start of the procedure Day 1 <Date>

First discussion by the PDCO <and request for supplementary information> by

Day 30 <Date>

Submission of supplementary information <Date>

Adoption of the PDCO Opinion Day 60 <Date>

A.1. Details of the medicinal product and overview of the application

A.1.1. Medicinal product

Applicant <Applicant's name>

Active substance(s) <Active substance>

INN <INN>

Put INN here. Additionally indicate if INN is proposed or recommended.

Invented name Only when authorised <Trade name> <and


associated trade names>

Type of product <Text>

ATC code Only if existing

Therapeutic area(s) <Text>

Treatment / diagnosis / prevention of

Gastroenterology - Hepatology

Neurology

Psychiatry

Haematology - Haemostaseology

Oncology

Immunology - Rheumatology - Transplantation

Dermatology

Ophthalmology

Cardio-vascular Diseases

Pneumology - Allergology

Infectious Diseases - Parasitology

Oto-rhino-laryngology

Uro-nephrology

Endocrinology - Gynaecology - Fertility - Metabolism

Neonatology - Paediatric Intensive Care

Pain

Anaesthesiology

Vaccines

Diagnostics

A.1.2. Authorised use

Condition(s) Adults: <Text>

Children: <Text>

Pharmaceutical formulation(s) authorised <Text>

Strength(s) authorised <Text>

Route(s) of administration authorised <Text>

Indication(s) authorised Adults: <Text>


Children: <Text>

A.1.3. Applicant’s proposals

Condition(s) Adults: <Text>

Children: <Text>

Pharmaceutical formulation(s) proposed <Text>

Strength(s) proposed <Text>

Route(s) of administration proposed <Text>

Indication(s) proposed Adults: <Text>

Children: <Text>

PIP indication proposed <Text>

Comment:

Comment on any regulatory issues.

Applicable only if already authorised: are all authorised indications/form/route covered by the application?

Paediatric Co-ordinator:

Add * to above conditions indications if applicant or delete the following if not applicable:

<*The applicant stated that these conditions or indications (authorised or under development) are covered by the Agency’s decision(s) granting class waivers. They are therefore not discussed in the report. >

<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

A.1.4. Discussion of proposed condition(s) (scope of application)

Comment:

Discuss the proposed condition(s) in the context of current medical practice, paediatric needs and envisaged use, pharmacological properties of the medicine, medical classification systems and relevant orphan medicine designation(s), starting from the indication(s) being developed and / or authorised for use in the adult population (if applicable) and/or proposed as PIP indication.


(1) In which way are the pharmacological properties of the medicine consistent with the proposed condition? Is the medicine intended for treatment or for primary prevention of the condition, taking into account experience from medical practice using this or similar medicines?

(2) What are the unmet paediatric therapeutic needs that could reasonably be met using the medicine based on its properties? Among the needs, what are the priorities, if any?

Is the condition as proposed acceptable or should it be revised to represent the expected activity of the medicine and to address paediatric needs? If yes, which is the appropriate PIP condition?

(3) If classification systems lead to substantially different representations of the condition, which system is appropriate for the therapeutic area? Explain the hierarchical context of the paediatric use, for example by using MedDRA: Which is the relevant organ class (only if more than one) and which is/are the relevant high-level term(s) and high-level group term(s) encompassing the adult and paediatric indication(s)?

(4) Is / are orphan designation(s) identical to the appropriate PIP condition (disregarding editorial differences)? If the scope is different, which paediatric needs (if any) would be covered by the appropriate PIP condition(s), but not by the orphan designation(s)?


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

A.2. Regulatory information on completed clinical trials related to the condition and to the development for the paediatric population

Reference Number

Trial Country

Protocol Number

Protocol Title Trial Status

<Text> <Text> <Text> <Text> <Text>

Comment:

<Text>

<Text>


<Text>

Comment:

Any trials which would suggest another therapeutic interest in children not covered in the application?

In case of trial stopped prematurely, check if impact on the paediatric development is discussed in the application.

<Text>

<Text>

<Text>

A.3. Regulatory status of the product

A.3.1. Marketing authorisation status inside the European Union

Only applications for Article 8, otherwise delete the following table.

EU No. Invented Name

Strength

Pharmaceutical form

Route of administration

Packaging

Content (concen-tration)

Package size

Indication

<Text> <Text> <Text>

<Text> <Text> <Text> <Text> <Text> <Text>

Planned submission date(s) of the marketing authorisation application or variation(s) or line extension(s)

For condition(s) / indication(s)

<Date> <Text>

Date of completion of adult pharmacokinetic studies: <Date> Only applications for Article 7, otherwise write "Not applicable"

Justification when no date for completion of adult pharmacokinetic studies is provided or explanation for PIP / waiver submission date: <Text> Only applications for Article 7, otherwise write "Not applicable"

Orphan drug designation:


<Condition> - Add the EU number for the orphan drug condition. Repeat line if several ODDs.

A.3.2. Marketing authorisation status outside the European Union

Paediatric indications: <Text>

A.3.3. Refusal / withdrawal / restriction of a marketing or extension authorisation or application (inside or outside EEA)

None according to application - Or <Text>

Comment:

In keeping with legislation? If delayed, are justifications acceptable? If justifications acceptable, take into consideration for a deferral.

Discuss and comment on refusal/withdrawal/restriction of either marketing authorisation or extension application or of submitted applications inside or outside the EEA.


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

A.4. Regulatory advice on the development of the product

Advices from any regulatory authority relevant to the development in the paediatrics population.

Advice Status

Advice Date

Advice Number Advice Comment Advice Type

<Text> <Text> <Text> <Text> <Text>

Relevant guidelines:

Name only disease-specific guideline(s) here.

<Text>

Comment:

Specify type of advice, and summarise part of information which is relevant to the development in the paediatric population as per PIP or waiver request.

Were there differences between national and the Agency’s Scientific Advice?


Has the applicant followed the SA given? Are there explanations or justifications why scientific advice has not been adhered to? (Brief, details to be discussed in part D).

Any FDA written request received (or planned)? Was there any the proposed paediatric study request (PPSR), was it refused to issue a Written Request?

Were any waivers granted? Justifications? Scope of development in children?

If guideline(s) explicit and relevant for paediatric development, has guideline been followed?

Note for the reviewers: any advice, CHMP assessment for similar products, previous Opinion of the PDCO related to a competitor should be considered and discussed. However, any confidential information (e.g., advice given for non-authorized product) should be clearly highlighted, preceded by the statement “CONFIDENTIAL INFORMATION:” and deleted before submitting the D30/90 draft Summary Report to Applicants.

<Text>

<Text>

<Text>


Part B Overall development of the medicinal productIn case of several conditions, parts B, C, D and E are repeated in this order per condition.

B.1. Discussion on similarities and differences and pharmacological rationale

B.1.1. Similarities and differences of the disease/condition between populations

Summary of Applicant’s position:

<Text>

Comment:

Populations refer to a comparison of adult versus paediatric and within paediatric subsets.

Agreement with the Applicant’s position? Differences based on e.g. disease pathophysiology, on maturation (which organ, receptors)?

Consequences of discussion of disease/condition:

Are differences justifying a separate development (efficacy, safety) or different endpoints between adults and all paediatric subsets and between paediatric subsets?

Is there a product-related issue with selected clinical endpoints?

Agreement with the earliest age of onset and / or with the figures on prevalence and incidence?

What is the paediatric age range subset concerned by the disease / condition?

If disease does not occur in subsets of paediatric population, potential ground for waiver.

Similarities regarding seriousness of the disease, aetiology, clinical manifestations and prognosis, variability in terms of genetic background (suitability of the referenced literature and own searches).

Does this indicate safety issue, efficacy, and dose issue?

<Text>

<Text>


<Text>

B.1.2. Pharmacological rationale and explanation


<Text>

Comment:

For discussion of available data and knowledge on pharmacological properties related to anticipated similarities and differences between adults and children or within paediatric subsets, the following aspects are relevant:

Absorption: active transport (if any)? Location: intestine, other? Type of transporter mainly involved?

Influence of food (including milk)? Influence of maturation on the absorption: function of age (from birth onwards)? Age at which 90-100 % of adult absorption is reached.

Distribution: binding (red blood cells, plasma proteins)? Influence of maturation on binding (whenever expected to be of clinical relevance)? First-pass effect?

Active transport? Location: intestine, blood-brain barrier, placenta, breast milk, other? Type of transporter mainly involved? Pharmacogenetics of transporters involved?

Influence of maturation on the distribution? Function of age (from birth onwards)? Age 90-100 % of adult distribution?

Metabolism: main routes (studies with labelled compounds in adults, in vitro studies with human liver cell preparations, human microsomes, with recombinant cDNA)? CYP involved? Conjugation enzymes involved? Existence of active metabolites? Pharmacogenetics of metabolism? Influence of maturation on the metabolism? Description as a function of age (from birth onwards) for the main pathway(s)? Age 90-100 % of adult elimination is reached for the main metabolic pathway(s)?

Elimination: main routes of elimination (studies with labelled compounds in adults)? Renal clearance in adults and consequent expected tubular handling (adult renal clearance compared to adult normal GFR)? Influence of maturation on elimination/renal clearance? Description as a function of age (from birth onwards)? Age 90-100 % of adult elimination is reached?

Mechanism of action, as far as known at this stage:

Is it clearly described and understood, how closely is it directed at the disease / condition?

What are the main sites of action, potential expected side effects, and expected pharmacodynamic drug interactions, potential other indications which could be envisaged?


How does this compare to other medicinal products of the same class and same indication?

If applicable, discuss chemical structure and physicochemical properties and importance of enantiomers and interconversion.

Are PK/PD models for this condition available, under development, not feasible for this condition? What would be needed in respect of PK/PD models?

Agreement with the applicant that the product is expected to act in the same or a different way in adults and children and in different subsets of the paediatric population?

Does this require separate development?

Is there a proof of concept?

<Text>

<Text>

<Text>

B.2. Current methods of diagnosis, prevention or treatment in paediatric populations


<Text>

Comment:

Standard of care (authorised products or not), include therapeutic options other than medicinal products.

If highly variable and dependent on the Member state/country, please indicate as this is potential issue for trial design later.

Is treatment similar in adults?

Consequences for any paediatric development.

Potential for active comparator in trial?

<Text>

<Text>


<Text>

B.3. Significant therapeutic benefit /fulfilment of therapeutic needs


<Text>

Comment:

Use conclusions from previous B.2 to identify unmet needs.

Comment on whether the applicant’s position sufficiently argues for the following situations of potential significant therapeutic benefit in the proposed condition:

Reasonable expectation for safety and efficacy to treat a paediatric condition where no authorised paediatric medicinal product is on the market;

Expected improved efficacy in a paediatric population compared to the current standard of care for the treatment, diagnosis or prevention of the condition concerned;

Expected improvement in safety in relation to either adverse events or potential medication errors;

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;

Availability of a new clinically relevant age-appropriate formulation;

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: needs, subsets;

Different mechanism of action with potential advantage for the paediatric population(s) in terms of improved efficacy or safety;

Existing treatments are not satisfactory and alternative methods with an improved expected benefit/risk balance are needed;

Expected improvement in the quality of life of the child.

If unmet needs or presence of significant therapeutic benefit in some or all subsets, then conclude on the need to have a PIP.

Discuss feasibility of performing clinical trials in the condition (lack of feasibility might be a ground for waiver).


Discuss expected therapeutic benefit justifying paediatric trials in the condition.

Discuss whether new data need to be generated when there are existing data/indication (replicating data is of no benefit).

<Text>

<Text>

<Text>


Part C Applications for product-specific waivers(If applicable, if not, delete the whole section.)

C.1. Overview of the waiver request(s)


<Text>

Comment:

Are all indications and age subsets covered by waiver requests, taking into account the complementary PIP indications (and if applicable, the Agency’s class waiver decisions)?

Which is the paediatric population subset that remains or is not covered, if any?

Discussion on the grounds to follow, i.e. not here

<Text>

<Text>

<Text>

C.2. Grounds for a product-specific waiver

C.2.1. Grounds based on lack of efficacy or safety


<Text>

Comment:

State if this ground does not apply, irrespective of the applicant information.

Likelihood of product to be ineffective?

Does this match the applicant’s claim of efficacy in other populations?

Rationale for inefficacy (e.g. physiopathology, lack of receptor, etc.)?

And/or

Likelihood of product to be unsafe.


Any theoretical safety issue from class effect?

Any specific safety concern from animal studies, or from adult already identified?

Link with B.1 and B.2 conclusions to explain lack of efficacy or safety.

<Text>

<Text>

<Text>

C.2.2. Grounds based on the disease or condition not occurring in the specified paediatric subset(s)


<Text>

Comment:

Which subsets of paediatric population are excluded? Does this match the prevalence/incidence analysed? State if this ground does not apply.

<Text>

<Text>

<Text>

C.2.3. Grounds based on lack of significant therapeutic benefit


<Text>

Comment:

State if this ground does not apply

Significant therapeutic benefit not expected?

All paediatric needs in all subsets and conditions are met, and therefore there is no need for further development?


Does this match B.1.1 and B.3?

<Text>

<Text>

<Text>


Part D Paediatric investigation plan

D.1. Existing data and overall strategy proposed for the paediatric development

D.1.1. Paediatric investigation plan indication

Indication means relevant target use within the condition, for example ”treatment of episodic asthma” whereas the condition is "treatment of asthma".


<Text>

Comment:

Does the application justify the choice and scope of the proposed paediatric investigation plan? Is this in line with assumptions and conclusions in B.3?

Does the proposed PIP indication cover the condition in question?

Are there indications and in the case of article 8 indications left out in the application?

The Regulation considers the need for data in the potential and correspondent paediatric use. This can be based on the mechanism of action of the drug, on the potential for off-label use in children. The Regulation does not require that the PIP is limited to the proposed wording of the adult indication, but it is assumed that there should be some relationship between development in adults and in the paediatric population.

<Text>

<Text>

<Text>

D.1.2. Selected paediatric subset(s)


<Text>

Comment:


Does it cover all potential paediatric subsets? If disease does not occur in some subsets of paediatric population, potential ground for waiver in these subsets.

Is there justification for the selected subsets in the application?

<Text>

<Text>

<Text>

D.1.3. Information on the existing quality, non-clinical and clinical data


<Text>

Comment:

Although the PIP is not intended to include all the elements necessary for drug development, some requirements may have to be included. Is the proposed outline fulfilling the requirements of Annex 1 of Directive 2001/83/EC as amended?

The clinical strategy in adults should be briefly described and commented for its relationship to the planned paediatric development.

Is this a comprehensive and appropriate development plan?

Quality: how adequate are the existing formulations to the paediatric population, their different subsets?

Is the ADME (absorption, distribution, metabolism, excretion) and toxicity well described? Which consequences have the ADME and toxicity for the pharmacological / dosing strategy in children?

Are the main available pharmacokinetic parameters presented and discussed:

linearity of the kinetics, Tmax, Cmax, absolute bio-availability, volume of distribution, plasma clearance, half-lives (T½,terminal T½);

hepatic extraction ratio for medicinal products primarily eliminated through the liver (comparison of plasma clearance to normal liver blood flow)

Are there data on pharmacodynamics (effect of interest and other effects) in animals and/or in adults? How does maturation influence the


PK-PD relationship? Is there data on the age at which 90-100 % of adult maximum PD response as a function of plasma concentration is reached?

Non-clinical: What is known from juvenile models (corresponding approximately to which child age)?

Is there an indication that effects on growth and/or maturation may be a concern?

Are the effects only in juvenile animals or also in adult animals?

Clinical: Is there a proof of concept of the effect of the product or the class?

Are there measures to identify the dose?

Is there a need for demonstration of efficacy, or a justification for the extrapolation of efficacy from other age groups?

Are there safety studies in the appropriate subsets of the paediatric population?

What are the missing studies?

Are there elements of the development that are unnecessary?

Is the Applicant using all available data to avoid unnecessary studies?

Comment on usefulness of existing information in the paediatric population. Quality of the paediatric data available, level of evidence, reliability, age/weight groups or other relevant subsets such as pubertal stages addressed? Conflicting evidence?

<Text>

<Text>

<Text>

D.2. Quality aspects


<Text>

Comment:

<Text>


<Text>

<Text>

D.2.1. Strategy in relation to quality aspects


<Text>

Comment:

This section should be a logical follow-on from D.1.c with regards to existing formulations.

Is there a need for development of paediatric formulation?

If so, has the applicant justified the proposed quality strategy and discussed all various options?

Has the applicant provided with the composition of the proposed formulations both qualitative and quantitative?

Discuss the suitability of the proposed formulations for the subsets of the paediatric population, taking into account the comments on existing formulations in D.III.c.

Were adequate justifications for the need for or lack of development of a new formulation provided?

If applicant declares that a formulation is unfeasible, are there sufficient technical data presented and justifications acceptable?

Discuss formulation in relation to proposed route of administration.

Has the applicant justified the excipients chosen (including the quantities) in relation to age, duration of treatment, and route of administration.

Discuss mixing with food.

Are the taste and palatability acceptable, or are measure to address this acceptable?

Discuss dosing accuracy for all weight ranges and feasibility (e.g. need to deliver 1microL).

Is the therapeutic margin “critical” that requires very high precision?

Discuss medical devices in relation to dosage accuracy and precision.

Discuss ease of administration by parents, carers, schools and older children themselves as appropriate.


Discuss use by healthcare professionals or relevance of different healthcare settings.

If the PDCO formulation working group was involved, include discussion and outcome.

<Text>

<Text>

<Text>

D.2.2. Outline of each of the planned and/or ongoing, studies and steps in the pharmaceutical development


<Text>

Other information about the key elements, for example justification for the proposed pharmaceutical form and objectives for pharmaceutical development. Do not repeat information presented in the key elements table.

Comment:

Discuss measures and proposed timeframe for the development of the formulation in relation to paediatric clinical trials and to placing on the market.

In case of studies on formulation prototypes (including enabling formulations), how do they relate to the clinical studies and final pharmaceutical development?

If the PDCO formulation working group was involved, include discussion and outcome.

<Text>

<Text>

<Text>


D.3. Non-clinical aspects

D.3.1. Strategy in relation to non-clinical aspects


<Text>

Comment:

Has the applicant justified the proposed non-clinical strategy?

Does the applicant cover for instance the need of repro-toxicity, genotoxicity, carcinogenicity, and juvenile animal studies? If not, are the justifications acceptable?

Discuss pre-requisites to human administration and in particular paediatric administration. Is the product considered ‘high-risk’ (refer to guideline for ‘first in man’)?

Are studies missing? Are studies unnecessary?

If studies in juvenile animals are proposed, is the species and age of animals appropriate?

If animal models, are they appropriate to study the effect of the product and to extrapolate the results?

Is the development requiring a first in children administration?

Is there a need to study local tolerance (e.g. trans-cutaneous route of administration)?

Is there a need to study immunogenicity?

Need for mechanistic studies if particular safety issue identified from non-clinical development?

Are there any signals (safety) which would have an impact on the development in children?

<Text>

<Text>

<Text>

D.3.2. Overall summary table of all planned and/or ongoing non-clinical studies


<Text>


Non-clinical studies

Study identifier Objective(s) Outcome measure

Test system / species (age)

Dosing, route

D.3.3. Synopsis/outline of protocol of each of the planned and/or ongoing non-clinical studies


<Text>

Other information about the key elements, for example justification for the proposed test system, objectives and duration. Do not repeat information presented in the key elements table.

Comment:

Discuss species, age of the animals and duration for juvenile animals in the proposed studies. Discuss any proposed studies not meeting standard toxicology or non-clinical requirements.

<Text>

<Text>

<Text>

D.4. Clinical aspects

D.4.1. Strategy in relation to clinical aspects


<Text>

Comment:

Discuss first-in-children administration (prerequisites in non-clinical strategy).

Is there a need for proof-of-concept in humans?

Define subsets relevant for PK. Discuss the need for PK data in subsets. Discuss use of population PK, sparse sampling?

Discuss dose-finding strategy. Discuss proposed dosing regimen (according to weight, body surface area?)


Discuss product’s role in light of standard of care (refer to B.2).

Discuss need for demonstration of efficacy in subsets of paediatric population, or extrapolation from adult or older age groups data? Is the Applicant extrapolating data from the adult population? Which ones? Does this match the conclusions of B.1?

Are efficacy studies necessary, and in which subsets?

Refer to specific guideline(s) (see A.4.2) if available and discuss their recommendation (if appropriate to paediatric development).

Are there any issues regarding the efficacy which would have an impact for the development in children?

Are there feasibility issues at this level of the development program?

Has the applicant justified the clinical strategy and the overall approach to the paediatric development?

In case of “small trials’, any adaptive design proposed?

Are there elements of the development that are unnecessary? Is the applicant using all available data to avoid unnecessary studies?

Are there safety studies in the appropriate subsets of the paediatric population?

Is the proposed duration relevant? Are there any signals (safety) which would have an impact for the development in children?

Specify for follow-up studies the time periods and specify whether patients are treated or not, during the follow-up.

Are there measures for studying the long-term follow-up of safety and efficacy proposed? Over which period? Should it be part of the PIP or post-authorisation measures?

What are the missing studies?

Has the applicant followed the SA given? If not, are there explanations or justifications why scientific advice has not been followed and are they acceptable?

In case of previous assessment of by the CHMP were there issues which would have an impact for the development in children?

Please do not discuss here the individual studies. This part is about the approach to and rationale for development.

If common issue to several studies:

Discuss comparator: Placebo as control, or active comparator (authorised, not authorised/standard of care) in phase 3 trials?

Discuss endpoint if common to several studies (validated scales? non-invasive measures?).

Discuss duration (active treatment).


Discuss duration (long term follow-up).

Discuss stopping rules for patients.

Discuss setting (standard of care comparable to EU?).

Location of the proposed study and comparability to the EU population?

Discuss measures to minimise pain and distress.

<Text>

<Text>

<Text>

D.4.2. Overall summary table of all planned and/or ongoing clinical studies


Study identifier Type of study/design features

Study population

Dosage, regimen

Primary endpoint(s)

D.4.3. Synopsis/outline of protocol of each of the planned and/or ongoing clinical studies


<Text>

Other information about the key elements, for example justification for the proposed objectives, primary endpoint and sample size. Do not repeat information presented in the key elements table.

Comment:

Discuss the justification for the proposed design of the trial.

Discuss endpoints if not yet discussed in overall strategy. (Validated scales? Non-invasive measures?)

Discuss main primary and secondary endpoints including the number of secondary endpoints.

Discuss inclusion and exclusion criteria (Study population in line with proposed PIP indication?).


Discuss representation of relevant age groups or subsets.

Discuss stratification, power.

Discuss recruitment strategy.

Discuss design, including adaptive design if appropriate.

Discuss statistical analysis. Any interim analysis? Description and appropriateness of the analysis population (e.g. ITT vs. per-protocol).

Discuss time for recruitment and completion.

Discuss systematically DSMB.

Discuss stopping rules for individuals, part or entire trial.

Discuss setting (standard of care comparable / extrapolation to EU).

Discuss measures to minimise pain and distress.

Discuss placebo as control, or active comparator (authorised, not authorised/standard of care).

Discuss total duration (recruitment plan realistic?).

Discuss duration of active treatment and long term follow-up.

Discuss dose chosen, start dose and maximum, escalation (if appropriate).

If applicable, does the trial follow the SA given for this study?

Consider adding a third column for comments on individual key elements.

<Text>

<Text>

<Text>

D.5. Other studies

D.5.1. Modelling and simulation study


<Text>

Other information about the key elements, for example justification for the assumption that the outcome of treatment is likely to be similar in paediatric subsets and adults. Do not repeat information presented in the key elements table.


Comment:

Discuss model objective/s specification, e.g. study optimisation, data analysis, dose finding and decision making.

Discuss type of model specification, e.g. population PK (/PD) model, physiologically based PK (/PD) model, mechanistic model or exposure response model.

Discuss data used to build the model, e.g. literature, in vitro, non-clinical, adult, and paediatric data.

Discuss the approach used to build model, e.g. step-up (physiologically based), step-down (population based) and software used.

Discuss covariates, e.g. age, body surface area, and weight.

Discuss both the internal and external qualification used to validate the model assumptions and to make adjustments.

Discuss the initiation / completion timelines and deferral if requested.


<Text>

<Text>

<Text>

D.5.2. Extrapolation study


<Text>

Other information about the key elements, for example justification for the assumption that the outcome of treatment is likely to be similar in paediatric subsets and adults. Do not repeat information presented in the key elements table.

Comments:

Discuss the existing in house and literature data on medicine / mechanism of action / class of medicines and on concerned conditions.

Comment on disease / population description, studies done, registries, data sources in adults and children in case any paediatric data are used. Discuss the "quantity" of data in adults, number of patients etc.


Consider the maturational profile of pharmacokinetic, pharmacodynamic, response and efficacy parameters in children.

Is the assumption that the outcome of treatment is likely to be similar in paediatric subsets by age and by any other relevant characteristics compared to adults plausible?

Discuss the initiation / completion timelines and deferral if requested.


<Text>

<Text>

<Text>

D.6. Timelines of measures in the paediatric investigation plan


Study identifier

Description Area

(quality, non-clinical, clinical)

Date of initiation1 and deferral requested (Y/N)

Date of completion2 and deferral requested (Y/N)

Other dependency

Comment:

Refer to ICH E11.

Discuss proposed timelines in relation to adult development.

Discuss proposed timelines in relation to recruitment and study duration.

Are timelines realistic (too long and leading to open-ended studies, too short and unrealistic as quality may be at stake)?

Is continuous follow-up of safety necessary?

<Text>

1 First patient included in trial.2 Last patient, last visit.


<Text>

<Text>


Part E Applications for deferralsSummary of Applicant’s position:

<Text>

Comment:

Use ICH E11 strategy and discussion in D.5 as basis for discussing deferral.

<Text>

<Text>

<Text>


Part F References

F.1 Initial references

References submitted by applicant.

<Text>

F.2 Additional references

Any references from Paediatric Co-ordinator, Rapporteur or Peer Reviewer.

<Text>

Paediatric formulation development

Proposed pharmaceutical form: <text>

Length of treatment: <Single dose / Short term / Long term>

Dosages

Active Substance Min foreseen dose Max foreseen dose Unit

<text> <text> <text> <text>

New drug delivery system: <Yes / No>

Multi particulate: <Yes / No>

Type of formulation proposed

New paediatric formulation developed <Yes / No>

Extemporaneous formulation <Yes / No>

Adapted from adult formulation <Yes / No>

Industry verified <Yes / No>

Same as adult formulation <Yes / No>

Composition

Strength 1: <Active substance, Quantity>

Active Substance Excipient Name

Quantity Unit Specification (per body weight kg / per intake, per body surface area / per intake)

<Text> <Text> <Text> <Text>

<Text> <Text> <Text> <Text>


General category for route of administration: <Parenteral / Oral / Rectal / Transdermal / Inhalation / Other>

Exact route of administration: <Text>

Administration concentration: <Text>

Dimensions (max) mm: <Text>

Comment: <Text>

Volume per intake (in ml): Min: <Text> Max: <Text>

Container: <Text>

Manipulation: <Reconstitution [Yes/No]>

<Further dilution [Yes/No]>

Administration device: <Text>

pH: <Text>

Diluent: <Text>

Scoring: <Yes / No>

Enteric tube administration: <Yes / No>

Release: <Immediate Release, Modified Release>


<Paediatric Committee discussion at Day 30>Day 30 (If Opinion is reached at D 60 delete this comment box and use conclusions)

PDCO discussion:

<Text>

Outcome of discussion at day 90 required to identify trend in PDCO and issues to be discussed in Oral Explanation.

<Comments from CHMP Members and PTL>If applicable.

Comment:

CHMP Member:

<Text>

Comment:

PTL:

<Text>

<Paediatric Committee discussion and Request for Modification>Day 60 (If Opinion is reached at D 60 delete this comment box and use conclusions)

Use for Request for modification. If Opinion use next page

Include outcome of discussions at Committee level:

Include general considerations and contributions relevant to the development that were not part of the application.

If request for modification, identify which part, which studies, and which element should be modified, e.g.

Need for age- appropriate formulation?

Acceptability of the proposed formulation (from PDCO point of view).

Need for juvenile toxicity studies or modification of proposed (e.g. species).

Agreement and consistence with SA received?

PDCO discussion:

<Text>


If applicable, provide information on discussion in EMA FDA PMDA HC paediatric cluster and other international or regulatory interaction.

To be drafted after the day 30 discussion, for preparation of the day 60 outcome. Also to be used as contribution to the meeting minutes. Indicate which waiver requests, if any, may be acceptable.

Request for modification:

Based on the assessment of the application, as reflected in the relevant sections of this summary report and according to the discussions held by the PDCO, the PDCO requests modifications by the applicant, to address the following issues.

When responding to this request for modification and amending the PIP, the applicant only needs to address the issues identified below. It is not necessary to address each individual comment identified in this Summary Report, as these do not necessarily reflect the PDCO position agreed on Day 60.

The Paediatric Regulation accommodates a single clock stop period, in order to enable applicants to modify their plans or to submit supplementary information in response to the request for modification. The PDCO will adopt the final Opinion on the basis of this supplementary information, without an additional clock stop period.

Waiver

1. <Text>

PIP

Quality

2. <Text>

Non-clinical

3. <Text>

Clinical

4. <Text>

<RESTART OF PROCEDURE AFTER SUBMISSION OF ANSWER TO THE REQUEST FOR MODIFICATION>

Name

Paediatric Co-ordinator <name>

Rapporteur <name>

Peer Reviewer <name>

Submission answers to the request for modification <Date>

Re-start of procedure for modified PIP Day 61 <Date>

Meeting of PDCO and applicant <Date>

Adoption of the PDCO Opinion Day 120 <Date>


Repeat both title and comment box for each of the issues of the request for modification.

Summary of the Applicant’s position and the modified paediatric investigation plan:

<Text>

Comments on the responses and modifications:

Focus on elements necessary to answer the request for modifications

<Text>

<Text>

<Text>

<Paediatric Committee discussion at Day 90>Day 90 (If Opinion is reached at D 60 delete this comment box and use conclusions)

PDCO discussion:

<Text>

Outcome of discussion at day 90 required to identify trend in PDCO and issues to be discussed in Oral Explanation.

<Paediatric Committee discussion – conclusions at Day <60> <120>>Opinion at Day 60 / 120

PDCO discussion:

<Text>

Only applications for Article 7.

Same as contribution to the meeting minutes.

Explain the discussion (summary, no protocol) and how final outcome was determined, e.g., summarising the weighting of arguments presented, summarising the rationale for conclusion, e.g., from paediatric therapeutic needs to waiver to PIP contents.

Specifically provide reasoning and conclusions

when a requested waiver is refused, when a proposed PIP is not at


all agreed, and when a requested deferral in an otherwise agreed PIP is not granted;

when a waiver is granted ex officio or a deferral is granted ex officio.

Provide special scientific rationale for significant changes to key binding elements as concluded by the PDCO, if the changes are not yet covered in the summary report.

If applicable, provide information on discussion in EMA FDA PMDA HC paediatric cluster and other international or regulatory interaction.

If relevant, mention oral explanation (presentation / data presented by applicant and discussion of applicant with PDCO) and subsequent PDCO discussion and impact on conclusion.

General conclusion on the PIP and Waiver.

<Text>

Waiver example

Based on the assessment of this application and further discussions at the Paediatric Committee including contributions of external expert(s), the PDCO agrees with the applicant's request for a waiver. The PDCO recommends granting a waiver for <Active substance or INN or Trade name> for all subsets of the paediatric population (0 to 18 years of age) in the condition of <Condition>.

The PDCO emphasises that the granting of a waiver for the condition mentioned above should not prevent the applicant from considering a development in the paediatric population in indications where there is a paediatric need. The PDCO identified <Text> as an unmet need. In principle according to the Paediatric Regulation, incentives for the development for use in the paediatric population are available even if a waiver has been granted in another condition.

If applicant withdrew between D90 and D120, AND a trend towards a negative Opinion was present in the PDCO:

<The applicant withdrew the present application in the month before adoption of the Opinion, after a trend towards a negative Opinion within the PDCO was communicated to the applicant.> - Delete if not applicable.


Documents

Template - Summary Report · Web viewTemplate developed for European Medicines Agency by Fiona Lewis and Vanessa Crookes December 2009 EMA/52099/2013 EMA/PDCO Summary