Safety of Paediatric CTs. A view of the PDCO

Transcription

1 The role of Regulatory Agencies on Vaccine Safety Safety of Paediatric CTs A view of the PDCO Les Pensières, Fondation Mérieux Veyrier du Lac, March 2010 Dr Daniel Brasseur Belgian & European Agencies

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3 EU Registration of Safe Paediatric Vaccines 1. EU Paediatric Regulation 2. Paediatric Investigation Plans 3. Guidance for Vaccines 4. PDCO evaluation of Vaccines 5. Risk Management Plan 6. Perspectives 02/05/2011 3

4 EU Registration of Safe Paediatric Vaccines 1. EU Paediatric Regulation 2. Paediatric Investigation Plans 3. Guidance for Vaccines 4. PDCO evaluation of Vaccines 5. Risk Management Plan 6. Perspectives 02/05/2011 4

5 Paediatric Regulation

6 Main Pillars Regulation 1901/1902 Incentives (Art. 7,8 & 30) - 6 months extension SPC (Patent) Obligations of an agreed PIP - from , for all new products (not yet in the EU) - from , for variations of protected product new indication route of administration pharmaceutical form

7 An Early Process! EMEA End Adult PK data

8 Vaccine Development Identify Antigen Produce Antigen Preclinical testing Concept validation Phase I Phase Phase III Dossier Registration II Research Preclinical Development End Adult PK data? Clinical Development Process Transfer - Manufacturing Plant building 6 Years 2 Yrs 3 Yrs 1 Yrs

9 EU Registration of Safe Paediatric Vaccines 1. EU Paediatric Regulation 2. Paediatric Investigation Plans 3. Guidance for Vaccines 4. PDCO evaluation of Vaccines 5. Risk Management Plan 6. Perspectives 02/05/2011 9

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11 PIP Includes timing of planned studies for all the paediatric population subsets applicable to Pharmaceutical development (paediatric forms) Pre-clinical studies (such as juvenile toxicity) Clinical studies in children Subsets of population to be considered (neonates, infants, children, adolescents)

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15 D.I.c Information on the existing quality, non-clinical and clinical data 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? Are there safety studies in the appropriate subsets of the paediatric population?

16 D.III.a Strategy in relation to non-clinical aspects 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 )? 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? Are there any signals (safety) which would have an impact on thedevelopment in children?

17 D.IV.a Strategy in relation to clinical aspects 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?

18 EU Registration of Safe Paediatric Vaccines 1. EU Paediatric Regulation 2. Paediatric Investigation Plans 3. Guidance for Vaccines 4. PDCO evaluation of Vaccines 5. Risk Management Plan 6. Perspectives 02/05/

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22 Adjuvants

23 Squalene-based emulsions as adjuvants OIL AS03 Squalene DL-a-tocopherol Tween 80 SURFACTANT MF-59 Squalene Tween 80 Span 85 Na-Citrate buffer

24 Perspectives - Mechanism of action of squalene-based adjuvants at the molecular level is not completely elucidated - Studies are needed to define how preclinical data on MOA can be translated to the human situation - Possibility to dissociate reactogenicity from adjuvanticity? - Adjuvant MOA is a complex field requiring involvement of mutiple investigators, including academic institutions

25 EU Registration of Safe Paediatric Vaccines 1. EU Paediatric Regulation 2. Paediatric Investigation Plans 3. Guidance for Vaccines 4. PDCO evaluation of Vaccines 5. Risk Management Plan 6. Perspectives 02/05/

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29 Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Prymula R, Siegrist CA, Chlibek R, Zemlickova H, Vackova M,Smetana J, Lommel P, Kaliskova E, Borys D, Schuerman L.

30 EU Registration of Safe Paediatric Vaccines 1. EU Paediatric Regulation 2. Paediatric Investigation Plans 3. Guidance for Vaccines 4. PDCO evaluation of Vaccines 5. Risk Management Plan 6. Perspectives 02/05/

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32 Rotavirus Vaccines Age (Months) and Intussusception 10 Protocol 006 (REST) Placebo RotaTeq Number of Cases New York State Data

33 EU Registration of Safe Paediatric Vaccines 1. EU Paediatric Regulation 2. Paediatric Investigation Plans 3. Guidance for Vaccines 4. PDCO evaluation of Vaccines 5. Risk Management Plan 6. Perspectives 02/05/

34 Infants and Children Application for deferrals of results at D121 and post-ma Age Description, Schedule MAA D121 Post- MA Men B 2mo S&I, Booster, Sched.: 2, 4, mo 6mo S&I, Sched.: 6, 8, 12 2mo S&I, lot consistency, Sched.: 2, 4, 6 mo 2mo S&I, Schedule finding, Sched.: 2, 4, 6 mo; 2, 4, 6 mo (MenB alone); 2, 3, 4 mo 12mo S&I of booster schedule: booster (4th) dose at 12 mo; one or twocatch-up doses starting at 12 or 13 mo for original control group. Complete immunogenicity data for booster (4th) dose and two catch-up doses Safety data collected up to 1 mo after the subject s final injection of MenB (post booster dose, or post one or two catch-up doses) m 12mo 6-month safety follow-up data post subject s final dose of MenB 12mo S&I of booster (4 th ) dose at 12 mo, 18 mo or 24 mo; two catch-up doses starting at 12 mo for original control group and 2 catch-up doses for new, naive subjects starting at 18 or 24 mo. Safety (1 mo fu) and Imm. for booster (4th) dose at 12 mo after2, 3, 4 mo schedule

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36 Safety considerations What is known about the vector? - target tissues / biodistribution - pathogenicity - neurovirulence Vector is pre-existing attenuated vaccine - e.g., MVA, yellow fever - maintenance of attenuation Vector is known human pathogen, e.g. adenovirus Vector is known non-human pathogen, VSV

37 Safety evaluation non-clinical studies highly important comparison of construct with wt vector in vitro replication in range of cells in vivo relevant animal model(s) - tissue tropism - neurovirulence clinical evaluation

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