EMA/229147/2007 Paediatric Committee (PDCO) and Human Medicines Development and Evaluation
EMA/PDCO Summary Report on an application for a
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Abbreviations used...... 5 Part A - Procedure for the assessment of the application...... 6 A.1 Details of the medicinal product and overview of the application...... 8 A.2 Regulatory information on completed clinical trials related to the condition and to the development for the paediatric population...... 10 A.3 Regulatory status of the product...... 10 A.3.1 Marketing authorisation status inside the European Union...... 10 A.3.2 Marketing authorisation status outside the European Union...... 11 A.3.3 Refusal / withdrawal / restriction of a marketing or extension authorisation or application (inside or outside EEA)...... 11 A.4 Regulatory advice on the development of the product...... 11 Part B - Overall development of the medicinal product including information on the target diseases / conditions...... 13 B.1. Discussion on similarities and differences and pharmacological rationale...... 13 B.1.1 Similarities and differences of the disease/condition between populations...... 13 B.1.2 Pharmacological rationale and explanation...... 14 B.2 Current methods of diagnosis, prevention or treatment in paediatric populations...... 15 B.3 Significant therapeutic benefit /fulfilment of therapeutic needs...... 16 Part C - Applications for product-specific waivers...... 18 C.1 Overview waiver request(s)...... 18 C.2 Grounds for a product-specific waiver...... 18 C.2.1 Grounds based on lack of efficacy or safety...... 18 C.2.2 Grounds based on the disease or condition not occurring in the specified paediatric subset(s)...... 19 C.2.3 Grounds based on lack of significant therapeutic benefit...... 19 Part D - Paediatric investigation plan...... 21 D.I Existing data and overall strategy proposed for the paediatric development...... 21 D.I.a Paediatric Investigation Plan indication...... 21 D.I.b Selected paediatric subset(s)...... 21 D.I.c Information on the existing quality, non-clinical and clinical data...... 22 D.II Quality aspects...... 23 D.II.a Strategy in relation to quality aspects...... 23 D.II.b Outline of each of the planned and/or ongoing, studies and steps in the pharmaceutical development...... 25 D.III Non-clinical aspects...... 25 D.III.a Strategy in relation to non-clinical aspects...... 25 D.III.b Overall summary table of all planned and/or ongoing non-clinical studies...... 26 D.III.c Synopsis/outline of protocol of each of the planned and/or ongoing non-clinical studies 26 D.IV Clinical aspects...... 27 D.IV.a Strategy in relation to clinical aspects...... 27 D.IV.b Overall summary table of all planned and/or ongoing clinical studies...... 29 D.IV.c Synopsis/outline of protocol of each of the planned and/or ongoing clinical studies29
EMA/PDCO Summary Report EMA/229147/2007 Page 2/45 D.V Timelines of measures in the paediatric investigation plan...... 36 Part E - Applications for deferrals...... 38 Part F - References...... 39 F.1 Initial references...... 39 F.2 Additional references...... 39
EMA/PDCO Summary Report EMA/229147/2007 Page 3/45 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.
EMA/PDCO Summary Report EMA/229147/2007 Page 4/45 Abbreviations
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).
EMA/PDCO Summary Report EMA/229147/2007 Page 5/45 Part A - Procedure for the assessment of the application
On
Name Highest declared Declaration that no Comments2 level of risk1 interest exists for this product
Paediatric Co- Delete as Delete as Filled in by ordinator appropriate appropriate by Paediatric Co- by Paediatric Co- ordinator Assistants. ordinator
Name Outcome of evaluation of conflict of interest
External Expert(s) 1 Level 1 (Lowest risk level), Level 2 (Intermediate risk level), Level 3 (Highest risk level) Please refer to the Agency’s policy on the handling of conflicts of interests at http://www.ema.europa.eu/pdfs/general/direct/conflicts/3165303en.pdf 2 Please comment e.g. for clarification or in case there is a mismatch between the highest declared level of risk and level of interest for this specific product. No further comments are needed for Level 1. EMA/PDCO Summary Report EMA/229147/2007 Page 6/45 Repeat row if involved by the needed PDCO.> Pre-submission meeting No Date(s) Start of the procedure D 1 Pre-submission meeting Yes / No Date(s) Start of the procedure D 1 Only in case of a re-examination On Name Highest declared Declaration that no Comments4 level of risk3 interest exists for this product Paediatric Co- Delete as Delete as Filled in by ordinator appropriate appropriate by Paediatric Co- by Paediatric Co- ordinator Assistants ordinator 3 Level 1 (Lowest risk level), Level 2 (Intermediate risk level), Level 3 (Highest risk level) Please refer to the Agency’s policy on the handling of conflicts of interests at http://www.ema.europa.eu/pdfs/general/direct/conflicts/3165303en.pdf 4 Please comment e.g. for clarification or in case there is a mismatch between the highest declared level of risk and level of interest for this specific product. No further comments are needed for Level 1. EMA/PDCO Summary Report EMA/229147/2007 Page 7/45 Name Outcome of evaluation of conflict of interest External Expert(s) Receipt of the grounds for re-examination No Date(s) Start of the procedure D 1 A.1 Details of the medicinal product and overview of the application Application to meet the paediatric Article <7> <8> <30> of the Paediatric Regulation requirements under At the time of PIP/Waiver application Applicant Active substance(s) INN Indicate if proposed or recommended Invented name Only when authorised Type of product ATC code Only if existing Therapeutic area(s) Treatment / diagnosis / prevention of Select the relevant one(s), delete others Gastroenterology - Hepatology Neurology Psychiatry EMA/PDCO Summary Report EMA/229147/2007 Page 8/45 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 Authorised use Condition(s) Adults: Children: Pharmaceutical formulation(s) authorised Strength(s) authorised Route(s) of administration authorised Indication(s) authorised Adults: Children: Applicant’s proposals Condition(s) Adults: Children: Pharmaceutical formulation(s) proposed Strength(s) proposed Route(s) of administration proposed Indication(s) proposed Adults: Children: PIP indication proposed <***The applicant stated that these indications (authorised or under development) are covered by the Agency’s decisions on condition class waiver lists. They are therefore not discussed in the report. > - Delete if not applicable or put *** after the class waiver indication. Comment: Comment on any regulatory issues. EMA/PDCO Summary Report EMA/229147/2007 Page 9/45 Applicable only if already authorised: are all authorised indications/form/route covered by the application? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: A.2 Regulatory information on completed clinical trials related to the condition and to the development for the paediatric population Reference Trial Protocol Protocol Title Trial Status Number Country Number 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. Paediatric Co-ordinator: Rapporteur: Peer Reviewer: A.3 Regulatory status of the product A.3.1 Marketing authorisation status inside the European Union Only applications for Article 8, otherwise, delete first table. EU Invented Strengt Pharmace Route of Packa- Content Package Indication No. Name h utical administr (concen- size ging form ation tration) EMA/PDCO Summary Report EMA/229147/2007 Page 10/45 Planned submission date of the For condition / indication marketing authorisation application or variation or line extension Date of completion of adult pharmacokinetic studies: Orphan drug designation: A.3.2 Marketing authorisation status outside the European Union Paediatric indications: A.3.3 Refusal / withdrawal / restriction of a marketing or extension authorisation or application (inside or outside EEA) Comment: In keeping with legislation? If delayed, are justifications acceptable? If justifications acceptable, this may lead to 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. Paediatric Co-ordinator: Rapporteur: Peer Reviewer: A.4 Regulatory advice on the development of the product Advices from any regulatory authority relevant to the development in the paediatrics population. Advice Advice Date Advice Number Advice Comment Advice Type Status Relevant guidelines Name only disease-specific guideline(s) here. EMA/PDCO Summary Report EMA/229147/2007 Page 11/45 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 should be clearly highlighted, preceded by the statement “CONFIDENTIAL INFORMATION:” and deleted before submitting the D30/90 draft Summary Report to Applicants. Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 12/45 Part B - Overall development of the medicinal product including information on the target diseases/conditions In 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: 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 patho-physiology, on maturation (which organ, receptors)? 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 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, dose issue? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 13/45 B.1.2 Pharmacological rationale and explanation Summary of Applicant’s position: Comment: For discussion of available data on pharmacological properties, 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, expected pharmacodynamic drug interactions, potential other indications which could be envisaged? EMA/PDCO Summary Report EMA/229147/2007 Page 14/45 How does this compare to other medicinal products of the same class and same indication? If applicable, discuss chemical structure and physico-chemical 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? Agreement with the applicant that the product is expected to act in the same or a different way in different subset? Does this require separate development? What is the experience in adults? Is there a proof of concept? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: B.2 Current methods of diagnosis, prevention or treatment in paediatric populations Summary of Applicant’s position: 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? Potential for active comparator in trial? Paediatric Co-ordinator: Rapporteur: EMA/PDCO Summary Report EMA/229147/2007 Page 15/45 Peer Reviewer: B.3 Significant therapeutic benefit /fulfilment of therapeutic needs Summary of Applicant’s position: 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). EMA/PDCO Summary Report EMA/229147/2007 Page 16/45 Discuss whether new data need to be generated when there are existing data/indication (replicating data is of no benefit). Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 17/45 Part C - Applications for product-specific waivers (If applicable, if not, delete the whole section.) C.1 Overview waiver request(s) 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 Paediatric Co-ordinator: Rapporteur: Peer Reviewer: C.2 Grounds for a product-specific waiver C.2.1 Grounds based on lack of efficacy or safety Summary of Applicant’s position: Comment: Likelihood of product to be ineffective? Please link with B1 and B2 conclusions. Does this match the applicant’s claim of efficacy in other populations? EMA/PDCO Summary Report EMA/229147/2007 Page 18/45 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? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: C.2.2 Grounds based on the disease or condition not occurring in the specified paediatric subset(s) Summary of Applicant’s position: Comment: Which subsets of paediatric population are excluded? Does this match the prevalence/incidence analysed? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: C.2.3 Grounds based on lack of significant therapeutic benefit Summary of Applicant’s position: Comment: Significant therapeutic benefit not expected? EMA/PDCO Summary Report EMA/229147/2007 Page 19/45 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? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 20/45 Part D - Paediatric investigation plan D.I Existing data and overall strategy proposed for the paediatric development D.I.a Paediatric Investigation Plan indication Indication means for example, ”treatment of episodic asthma”, whereas the condition is simply asthma. Summary of Applicant’s position: Comment: The Regulation considers the need for data in the paediatric use. This can be based 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. Does the PIP indication cover the condition in question? Are there conditions and in the case of article 8 indications left out in the application? Does the application justify the choice and scope of the proposed paediatric investigation plan? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: D.I.b Selected paediatric subset(s) Summary of Applicant’s position: 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? Paediatric Co-ordinator: EMA/PDCO Summary Report EMA/229147/2007 Page 21/45 Rapporteur: Peer Reviewer: D.I.c Information on the existing quality, non-clinical and clinical data Summary of Applicant’s position: 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? Is this a comprehensive and appropriate development plan? Is the ADME (absorption, distribution, metabolism, excretion) and toxicity well described? Which consequences has 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? 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? Is there a proof of concept of the effect of the product or the class? Are there measures to identify the dose? EMA/PDCO Summary Report EMA/229147/2007 Page 22/45 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? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: D.IIQuality aspects D.II.a Strategy in relation to quality aspects Summary of Applicant’s position: Composition/formulation Quantitative and qualitative - As far as known at this stage of the development Authorised Proposed5 Proposed Proposed product formulation 1 formulation 2 formulation 3 Identifier Excipients Preservatives Solubilisers Antioxidants Colours Flavours Adjuvants Container Others 5 If the application includes several new formulations EMA/PDCO Summary Report EMA/229147/2007 Page 23/45 Comment: 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 existing and proposed formulations for the subsets of the paediatric population. 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 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. Discuss the proposed timeframe for the development of the formulation in relation to clinical trials and to placing on the market. In case of studies on formulation prototypes, how do they relate to the clinical studies and final pharmaceutical development? If the PDCO formulation working group was involved, include discussion and outcome. Paediatric Co-ordinator: Rapporteur: EMA/PDCO Summary Report EMA/229147/2007 Page 24/45 Peer Reviewer: D.II.b Outline of each of the planned and/or ongoing, studies and steps in the pharmaceutical development Repeat as per application Summary of Applicant’s position: Comment: Discuss measures and timelines Paediatric Co-ordinator: Rapporteur: Peer Reviewer: D.III Non-clinical aspects D.III.a Strategy in relation to non-clinical aspects Summary of Applicant’s position: 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? EMA/PDCO Summary Report EMA/229147/2007 Page 25/45 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? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: D.III.b Overall summary table of all planned and/or ongoing non-clinical studies Summary of Applicant’s position: Non-clinical studies Study identifier Objective(s) Outcome measure Test system / Dosing, route species (age) D.III.c Synopsis/outline of protocol of each of the planned and/or ongoing non-clinical studies Summary of Applicant’s position: Type of study Copy and paste the sequential number and the description from the summary table and add (Including Study details if necessary. identifier(s) and Study design features) Objectives and outcome Outcome if specific: e.g., histopathology of measure brain. Test system/species (age of Age of the animals at study start should be EMA/PDCO Summary Report EMA/229147/2007 Page 26/45 the animal) Number of animals No need to include number of animals in Opinion but include it in summary report if the data is available. Route of administration and Include the dose only as appropriate. doses Duration of dosing Results observed N/A If not applicable. Date of Initiation By The initiation of this study is Date of completion (final study By 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. Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 27/45 D.IV Clinical aspects D.IV.a Strategy in relation to clinical aspects Summary of Applicant’s position: 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? EMA/PDCO Summary Report EMA/229147/2007 Page 28/45 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. Paediatric Co-ordinator: Rapporteur: Peer Reviewer: D.IV.bOverall summary table of all planned and/or ongoing clinical studies Summary of Applicant’s position: Clinical trials Study identifier Type of Study population Dosage, regimen Primary study/design endpoint(s) features EMA/PDCO Summary Report EMA/229147/2007 Page 29/45 D.IV.c Synopsis/outline of protocol of each of the planned and/or ongoing clinical studies Summary of Applicant’s position: Study identifier(s) Study identifier Copy and paste from the summary table starting with the serial number. Company protocol number or code to be included in the end in brackets. EUDRACT number if available. Do not include features which should be below. Study design features Add design feature or the following categories as relevant. If different design features in different study periods, repeat by period. Sequential recruitment by Background (rationale) It is not needed in the Opinion. Main objective(s) Always use verb: “to evaluate”, “to determine” etc. EMA/PDCO Summary Report EMA/229147/2007 Page 30/45 E.g. efficacy, safety components, acceptability of formulation. DON’T include population, dosing, age range or condition. Mention “superiority” or “non-inferiority” not here, but in study design features. Key or main objective(s) only; don’t copy all that were proposed if not relevant. Specify which is primary, if possible. Normally each objective should be linked to an endpoint. Study population and subset Here only high level information. definition Include gender, age range and condition: “Male and female children from birth to less than 6 years of age with XYZ condition”. Do not include inclusion criteria or treatment. Include description of a staggered subset approach if applicable. For those studies mixing paediatric and adults, mention it in brackets e.g.: “(and in adults)”. Number of study participants ALWAYS BE SPECIFIC and use “At least xx”. by paediatric subset (e.g., age, Consider if a maximum is needed. sex, severity or stage) Define what counts: evaluable for the primary endpoint? (this should be the default option, as the study is designed and powered for this; note that missing data value handling does not make a participant non-evaluable); and if necessary add enrolled?; randomised?; treated? (at least one dose); completer?; etc. Overall number and by subset. Sample size: EMA/PDCO Summary Report EMA/229147/2007 Page 31/45 population to European paediatric population for generalisation of study results, include the agreed indicator(s) for similarity that is to be document in the full study report. Could be based on current scales and measurements indicating e.g., lifestyle, activity, other relevant factors). Should be required for a relevant portion of study participants. Main inclusion criteria List the main criteria, but don’t include the obvious, e.g. informed written consent, ability to cooperate, etc. Only include the condition again if more specific than stated in the study population, e.g., minimum severity, diagnostic criteria, etc Avoid negative wording e.g., “patients not having x disease” (that should be an exclusion criterion). Avoid criteria that undermine the objective, e.g narrowing a paediatric subset of insufficient severity. Main exclusion criteria List the main criteria but don’t include the obvious, e.g., allergy to compound, participation in a trial within 2 months, etc. Check that the exclusion criteria do not undermine the objective: e.g., excluding some comorbidities. Think risk of pregnancy in adolescent girls where relevant (need for contraception). Study duration for participants Use bullet points for each study period. Always specify the active treatment period (time point of the primary outcome). Specify if appropriate. run-in, active treatment and follow-up WITHIN this study. Be careful with extensions, long-term follow- ups, which might need to be in “2. Specific measures for long-term …” if they are optional or part of potential RMP. If data must be available, the completion date must take account of the extension. Dosage, treatment regimen, Make sure it doesn’t differ from the route route of administration specified on the front page. Describe per treatment arm: 10 mg X or 5 mg Y or EMA/PDCO Summary Report EMA/229147/2007 Page 32/45 placebo taken orally twice daily. Describe relevant details for each phase separately including wash-out, dose titration, taper down etc. To avoid too many details dose ranges (3-6 mg) may be adequate. ALWAYS make it VERY clear whether it is the single dose to be taken multiplied by the number of daily intakes OR the total daily dose to be taken divided by the number of daily intakes. NEVER use acronyms like “b.i.d”, always spell out (twice daily). Don’t include trivia like “after meals, or with a glass of water” unless very important. Randomisation strategy Locations (e.g. regions) It is not needed in the Opinion. Control(s) E.g., placebo For active, use INN unless too complex e.g. vaccine where exceptionally brand names can be used. If external control, describe the source (patient-level data, publication only) and method. If different by period, repeat per period. Primary endpoint(s) with time Wording should generally be like a measure and a point(s) of assessment time point: EMA/PDCO Summary Report EMA/229147/2007 Page 33/45 observations, define what counts as an event and what is censored. Any comparisons to be made should be detailed in the statistical plan. In case of a primary PK objective: Main secondary endpoint(s) Use bullet points. with time(s) of assessment Only the main (in any case, should not be a too long list). If no specific safety endpoints, include as a minimum. Safety Always to be specified: Intention to treat / Per protocol, defined as Test: Method for controlling alpha: EMA/PDCO Summary Report EMA/229147/2007 Page 34/45 Interim analysis(es): Sensitivity analysis(es): Handling of missing data: Stopping rule(s) for Criteria that would lead to discontinue study discontinuing treatment in treatment in a given participant, if necessary. individual participant Clarify that treatment discontinuation should permit further follow-up and not necessarily result in withdrawal. Rescue treatment Treatments identified in the protocol are those that may be administered to participants when the efficacy of the investigational medicinal product is not satisfactory, or the effect of the investigational medicinal product is too great and is likely to cause a hazard to the patient, or to manage an emergency situation. Rescue medication allows patients to continue in the clinical trial (no drop out). Sample size calculation (incl. It is not needed in the Opinion. estimated effect size) Measures to minimise pain and Only if specific, for example: Maximum amount of distress blood or number of samples in the clinical trial; usage of a micro assay; limits on invasive procedures. Plan for specific follow-up E.g. open label extension of the study. Attention, specify whether an extension is part of the PIP or part of the measures post approval. External Data Safety EMA/PDCO Summary Report EMA/229147/2007 Page 35/45 in safety/efficacy studies in other age groups. No need to mention tasks, mention only a specific decision to be taken after e.g. interim analysis. Date of initiation (inclusion of Check opinion template for guidance. first patient in the study, e.g. date of first visit of the first patient, or date of informed consent) Date of completion (last There must be a date. Never delete or leave patient, last visit) blank. Check opinion template for guidance. By 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?) Main primary endpoints and secondary endpoints including 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 e.g. adaptive 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?). EMA/PDCO Summary Report EMA/229147/2007 Page 36/45 Discuss duration (active treatment). Discuss duration (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? Paediatric Co-ordinator: Rapporteur: Peer Reviewer: D.V Timelines of measures in the paediatric investigation plan Summary of Applicant’s position: Study Description Area Date of Date of Other identifier initiation and completion* dependency deferral and deferral requested requested (Y/N) (Y/N) * last patient, last visit 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? Paediatric Co-ordinator: Rapporteur: EMA/PDCO Summary Report EMA/229147/2007 Page 37/45 Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 38/45 Part E - Applications for deferrals Summary of Applicant’s position: Comment: Use ICH E11 strategy and discussion in D.5 as basis for deferral. Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 39/45 Part F - References F.1 Initial references References submitted by applicant. F.2 Additional references Any references from Paediatric Co-ordinator, Rapporteur or Peer Reviewer. EMA/PDCO Summary Report EMA/229147/2007 Page 40/45 Day 30 (If Opinion is reached at D 60 delete this comment box and use conclusions) PDCO discussion: If applicable. Comment: CHMP Member: Comment: PTL: 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: EMA/PDCO Summary Report EMA/229147/2007 Page 41/45 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. PIP Quality 2. Non-clinical 3. Clinical 4. 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: Comments on the responses and modifications: Focus on elements necessary to answer the request for modifications Paediatric Co-ordinator: Rapporteur: EMA/PDCO Summary Report EMA/229147/2007 Page 42/45 Peer Reviewer: Day 90 (If Opinion is reached at D 60 delete this comment box and use conclusions) PDCO discussion: Opinion at Day 60 / 120 PDCO discussion: 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 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. EMA/PDCO Summary Report EMA/229147/2007 Page 43/45 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 to grant a waiver for 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 Overview of the grounds and the request for re-examination: Paediatric Co-ordinator: Rapporteur: Peer Reviewer: Repeat as needed: Summary of the Applicant’s detailed grounds for re-examination: Comments on the grounds: Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 44/45 Comments on the revised proposals: Paediatric Co-ordinator: Rapporteur: Peer Reviewer: EMA/PDCO Summary Report EMA/229147/2007 Page 45/45