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Template for scientific document (part B-F)for an application for a <Paediatric Investigation Plan> <including> <a deferral> <and> <a> <waiver>

<Active substance> or <INN>- (Only when INN is at least recommended)

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

authorised products)

<Applicant's name>

<EMEA-xxxxxx-PIPxx-xx>

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30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom

An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555Send a question via our website www.ema.europa.eu/contact

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.

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. Refer to the policy. State whether it is “treatment”, “prevention” or “diagnosis”.

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.

Route of administration: <Text> Use EDQM standard terminology

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.

Template for scientific document (part B-F) EMA/427403/2012 /27

Waiver(s), deferrals: <Text> Justification for product-specific waiver or partial waiver in relation to proposed paediatric subsets. Summarise milestones of proposed paediatric studies, if relevant, in relation to adult development.


Table of contentsApplication Summary 2Table of contents 4Abbreviations 6Part B - Overall development of the medicinal product 7B.1. Discussion on similarities and differences in the condition between populations, and pharmacological rationale 7B.2. Current methods of diagnosis, prevention or treatment in paediatric populations 8B.3. Significant therapeutic benefit and/or fulfilment of therapeutic needs 9Part C - Applications for product-specific waivers 11C.1. Overview of the waiver request 11C.2. Justification for a product-specific waiver 11C.2.1. Applications based on a likely lack of safety or efficacy in part or all of the paediatric population 11C.2.2. Applications based on the disease or condition not occurring in the specified paediatric subset 12C.2.3. Applications based on lack of significant therapeutic benefit 12Part D - Proposed paediatric investigation plan 14D.1. Existing data and overall strategy proposed for the paediatric development 14D.1.1. Paediatric investigation plan indication 14D.1.2. Selected paediatric subsets 14D.1.3. Information on quality, non-clinical and clinical data 15D.2. Paediatric formulation development 17D.2.1. General strategy 17D.2.2. Summary of all planned and/or ongoing, measures in the pharmaceutical development

18Quality-related studies 18D.3. Non-clinical studies 19D.3.1. General strategy 19D.3.2. Summary of all planned and/or ongoing non-clinical studies 19D.4. Paediatric clinical studies 20D.4.1. General strategy 20D.4.2. Paediatric pharmaco-kinetic/pharmaco-dynamic studies 21D.4.3. Clinical efficacy and safety studies 22D.4.4. Summary of all planned and/or ongoing clinical studies 23D.4.5. Details of the planned and/or ongoing paediatric clinical studies 23D.5. Other studies 24D.5.1. Modelling and simulation studies 24D.5.2. Extrapolation studies 25Part E - Request for deferrals 26E.1. Timelines of measures in the paediatric investigation plan 26


Part F - References 27


Abbreviations <Text>Any synonymous names of the product should be included here. Abbreviations for dosing should not be used (rather, dosing should be explicit e.g., once daily).


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

B.1. Discussion on similarities and differences in the condition between populations, and pharmacological rationale

Summary of applicant’s position<Text>

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

The proposed condition(s) should be discussed in the context of current medical practice, paediatric needs and potential use, the mechanism of action of medicine, MedDRA classification system and relevant orphan medicine designation(s), starting from the indication(s) being developed and / or authorised for use in the adult population if applicable.

Diagnosis, prevention and treatment of a disease will be considered as separate conditions.

Description of the aetiology of disease/condition, clinical manifestations, prognosis, epidemiology, and prevalence/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.

What are the similarities regarding seriousness of the disease, aetiology, clinical manifestations and prognosis, variability in terms of genetic background? These should be discussed with a view to extrapolating efficacy and/or pharmacokinetics between adults and children, and the various paediatric subsets.

Differences based on e.g. disease pathophysiology on maturation (which organ, receptors)?

The following pharmacological aspects are relevant:

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

The main sites of action, potential expected side effects and pharmacodynamic drug interactions;

Is the product 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?


Comment:

Paediatric Co-ordinator:

<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

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

Summary of applicant’s position

<Text>

Discussion of diagnosis, prevention and treatment interventions that are available in the EU, including unauthorised treatment methods if they represent the standard of care (e.g. if mentioned in internationally recognised treatment guidelines).

The list of available treatments, including those authorised by the national authorities or via the centralised procedure should be put in the table below.

The invented name and the approved use of medical devices marketed in the EU should be provided if applicable.

Use this table for not authorised or off label medicinal products.

Active substance or INN Indication Source of recommendation (e.g.: treatment guideline)


Use this table for authorised medicinal products.

Invented name and active substance or INN

Type of authorisation (e.g.: centralised, national, mutual recognition)

Indication and age groups

Are methods for diagnosis, prevention or treatment of the condition in question included in the inventory of therapeutic needs established pursuant to Article 43 of the Paediatric Regulation?

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000096.jsp&mid=WC0b01ac05800260a1

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

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


<Text>

Conclusions from previous B.2 to identify unmet needs. Consideration of 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 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; and

expected improvement in the quality of life of the child.

If unmet needs or presence of significant therapeutic benefit are identified in some or all subsets, then conclude on the need to have a PIP.Discussion of feasibility of performing clinical trials in the condition (lack of feasibility might be a ground for waiver). Discussion of expected therapeutic benefit justifying paediatric trials in the condition.Discussion of whether new data need to be generated when there are existing data/indication (replicating data is of no benefit).

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>


Part C - Applications for product-specific waivers(Complete this part if applicable.)

B.1. Overview of the waiver request


<Text>

Summary of the waiver request. All subsets of the paediatric population should be covered either by a waiver request or a PIP proposal unless the PIP application intends to support a future paediatric use marketing authorisation (PUMA).

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

B.2. Justification for a product-specific waiver

C.1.1. Applications based on a likely lack of safety or efficacy in part or all of the paediatric population


<Text>

Is there a likelihood of product to be ineffective based on B1 and B2 conclusions?

What is the rationale for lack of efficacy (e.g. pathophysiology, lack of receptors, etc.)?

And/or

What is the likelihood of product to be unsafe?

Are there any theoretical safety issue from class effect?

Are there any specific safety concerns from animal studies, or from adult population already identified?

Comment:



<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

C.1.2. Applications based on the disease or condition not occurring in the specified paediatric subset


<Text>

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

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

C.1.3. Applications based on lack of significant therapeutic benefit


<Text>

Is significant therapeutic benefit not expected?

Are all paediatric needs in all subsets and conditions met implying there is no need for further development?

Does this match B.1.1 and B.3?

Comment:


<Text>

Rapporteur:


<Text>

Peer Reviewer:

<Text>


Part D - Proposed paediatric investigation plan

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

D.1.1. Paediatric investigation plan indication


<Text>

This is the proposed indication in the paediatric population for the purpose of a PIP, and at the time of submission of the PIP, within a specific condition, for example, “treatment of acute asthma episodes”, whereas the condition is simply “treatment of asthma”.

The Regulation considers the need for data on 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.

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

D.1.2. Selected paediatric subsets


<Text>

All subsets of the paediatric population should be covered either by a waiver (Section C) or a PIP (section D) unless the PIP application intends to support a future paediatric use marketing authorisation (PUMA). In this case the application may be limited to certain paediatric subsets without a requirement to cover all subsets.

In addition to age, the selected paediatric subsets may be based on other variables, such as gestational age, pubertal stages and gender.


Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

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

Although the PIP is not intended to include all the elements necessary for drug development, some requirements may have to be included.

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

Quality: Existing formulations with regards to their relevance to the paediatric population or subsets of the paediatric population. Discussion of the suitability of the existing formulations for the subsets of the paediatric population.

Summary of ADME (absorption, distribution, metabolism, excretion) and toxicity data. Are there consequences of the ADME and toxicity data for the pharmacological/dosing strategy in children?

Describe the main available pharmacokinetic parameters:

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?


If completed clinical studies in adults are available, summarise the results.

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

Is there a need for safety studies in the appropriate subsets of the paediatric population?

Quality data


<Text>

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

Non-clinical data


<Text>

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

Clinical data


<Text>

Comment:



<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

B.2. Paediatric formulation development

D.1.4. General strategy


<Text>

This section should be a logical follow-on from D.1.3 with regards to existing formulations. The discussion should focus on the existing or proposed pharmaceutical development of the product and address critical issues, such as:

the need for specific formulation, pharmaceutical form, strength or route of administration in relation to the chosen paediatric subsets/age groups and the benefit of the chosen formulation, pharmaceutical form, strength or route of administration;

potential issues in relation to excipients and their (anticipated) exposure levels to be used in the paediatric population;

administration of the medicine to paediatric subsets (e.g. acceptability, use of specific administration devices, ability to mix with food);

precision of dose delivery and/or dose accuracy for any pharmaceutical form, with regard to the anticipated paediatric dose and indicated age range;

timeframe for the development of an age-appropriate formulation/pharmaceutical form, where required; and

discuss (if applicable) medical devices in relation to dosage accuracy and precision. Discuss ease of administration by parents, carers, schools and older children themselves as appropriate.

If it is not possible, based on scientific justifications, to develop a formulation/pharmaceutical form which is relevant and acceptable for paediatric use on an i9ndustrial scale, the applicant should state how it intends to facilitate the industry-verified or extemporaneous preparation of an individual ready-for-use paediatric formulation.


Refer to guidelines on pharmaceutical development, including Guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 Rev. 2.

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

D.1.5. Summary of all planned and/or ongoing, measures in the pharmaceutical development

Quality-related studies

This section will contain the Quality-related studies provided in the Key element form Pdf file.

Full study synopses (if available) can be attached as a separate document.

Furthermore if the strategy is to create age-appropriate pharmaceutical form, formulation, strength or new route of administration, the necessary pharmaceutical development studies may need to be more extensive. Proposed measures of particular relevance to the development of paediatric products include:

compatibility with paediatric administration systems, e.g. medical devices; and

taste-making and acceptability (including palatability).


<Text>

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:


<Text>

B.3. Non-clinical studies



<Text>

Description of the proposed non-clinical strategy to support paediatric use in addition to classical non-clinical development.

Discussion of the need of reproductive toxicity and juvenile animal studies.

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

If studies in juvenile animals are proposed, justification of the selected species and age of animals should be put.

Do animal models exist? Are they appropriate to study the effect of the product and to extrapolate the results?

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?

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>


D.1.7. Summary of all planned and/or ongoing non-clinical studies

Non-clinical studies

This section will contain the Non-clinical studies provided in the Key element form Pdf file.



<Text>

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

B.3. Paediatric clinical studies



<Text>

Discussion of the overall strategy for the clinical paediatric development.

This should be in relation to the development in adults where applicable and in relation to existing data and the potential to extrapolate. The discussion should focus on:

possible complete or partial extrapolation from adult data to paediatric patients and between paediatric subsets;

the interrelation, in terms of common studies, data and timelines, between development in adults and paediatric populations; and

where necessary, a discussion on how dosing in very young and young children is determined and verified.

Was a SA given? If so, was it followed? If not, justify why scientific advice has not been followed.

In case of a previous assessment 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.

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

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

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

D.1.9. Paediatric pharmaco-kinetic/pharmaco-dynamic studies


<Text>

Define the relevant subsets for PK studies and the need for PK data in different subsets. Discuss the use of sparse sampling, PK modelling and population PK if relevant.

Is there a need for PD modelling and clinical trial simulations? Discuss any biomarkers for PK / PD.

Consider the following aspects where relevant:

pharmaco-dynamic studies:

pharmaco-dynamic differences between adult and paediatric populations (e.g. influence of maturation of receptors and/or systems);

use of pharmaco-dynamic modelling and clinical trial simulations;

discussion of any biomarkers for pharmaco-kinetics/pharmaco-dynamics; and

use of the pharmaco-dynamic approach, particularly where pharmacokinetics cannot be measured; and

pharmaco-kinetic studies:

possibility of using sparse pharmaco-kinetic sampling;

use of pharmaco-kinetic modelling and clinical trial simulations;

use of population pharmaco-kinetics;


discussion of age groups where more extensive studies are needed, e.g. due to expected high kinetic variability; and

pharmacogenetics.

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

D.1.10. Clinical efficacy and safety studies


<Text>

Consider the following aspects where relevant:

the need for specific dose-finding studies;

the selected efficacy and/or safety endpoints (primary or secondary), in each of the relevant paediatric subsets;

issues of relevance across the proposed studies, such as use of placebo or active control, age appropriateness of endpoints, use of surrogate markers, use of alternative study design and analysis, potential need for short-term and long-term safety studies and differential risks by age group;

issues related to the feasibility of the proposed studies (e.g. recruitment capacity);

any potential concern as to long-term safety or efficacy in the paediatric population; and

specific measures proposed to protect the paediatric population involved in development, e.g. the use of less invasive methods.

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

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

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

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


Describe the proposed safety studies in the appropriate subsets of the paediatric population. Are there any signals (safety) which would have an impact for the development in children?

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

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

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(s) if common to several studies (validated scales, non-invasive measures).

Discuss duration of active treatment.

Discuss duration of long term follow-up.

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

D.1.11. Summary of all planned and/or ongoing clinical studies

Clinical studies

This section will contain the Clinical studies provided in the Key element form Pdf file.



<Text>

D.1.12. Details of the planned and/or ongoing paediatric clinical studies


<Text>


Further information, if available and appropriate to the stage of product development, should be provided on the following:

justification of type of study, study design and methodology;

justification of the dose of the proposed product and its regimen, and of the type of control (e.g. placebo or active control, with dose to be used;

description of the sample size/power calculation (as appropriate; with expected effect size in children) used to determine the proposed number of subjects (male/female). This discussion should include, where possible, a sensitivity analysis (a tabulation with varying assumptions and statistical parameters, and the resulting sample sizes);

justification of the relevant age groups or subsets included in the study (and of staggered inclusion where applicable);

justification of the proposed duration of treatment (and duration of post-treatment observation if included in the study);

justification of main inclusion/exclusion criteria;

justification of the choice of outcome parameters/endpoints (primary, secondary);

justification and, if needed, a more detailed description of statistical methods than that contained in the key elements; and

discussion of options in the event of recruitment issues.

Do not duplicate information already present in the key element form.

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

B.4. Other studies

A.1.1. Modelling and simulation studies

This section will also contain the Modelling and simulation studies provided in the Key element form Pdf file.



<Text>

If modelling and simulation studies are planned as a substantial (or exclusive) part of the PIP, justification should be put here for the proposed objective, data to be used and methodology. Do not duplicate information already present in the key elements form.

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

A.1.2. Extrapolation studies

This section will also contain the Extrapolation studies provided in the Key element form Pdf file.


<Text>

If an extrapolation study is planned as a substantial (or exclusive) part of the PIP, justification should be put here for the proposed objectives, methodology and study population. Do not duplicate information already present in the key elements form.

Comments:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>


Part E - Request for deferrals

B.5. Timelines of measures in the paediatric investigation plan

Proposed timelines.

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


<Text>

Requests for deferral should be justified on scientific and technical grounds or on grounds related to public health.

A deferral could be granted if it is appropriate to conduct studies in adults prior to initiating studies in the paediatric population or the studies in the paediatric population will take longer to conduct than studies in adults.

Reminder: A clinical study report is required for the PDCO to perform the compliance check. This should be taken into account in the final timelines of submission.

Comment:


<Text>

Rapporteur:

<Text>

Peer Reviewer:

<Text>

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


Part F - ReferencesList all literature references, articles, bibliography, etc. related to the scientific discussion.


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