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EU Paediatric Regulation The experience with PIP submissions from

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					   EU Paediatric Regulation
 The experience with PIP
submissions from the PDCO
       perspective


                    Daniel Brasseur
Adediem Paris
February 2008     PDCO at the EMEA



                                      1
Main Pillars Regulation 1901/1902


 Incentives (Art. 7,8 & 30)

  - 6 months extension SPC

  - 2 additional years exclusivity

  - PUMA

 Paediatric Investigations Plans (PIP)

 Paediatric Committee (PDCO) at EMEA



                                          2
      Paediatric Investigation Plan


 Basis for the development and authorisation
  of a medicinal product for the paediatric population
  subsets
 Include details of the timing and the measures
  proposed to demonstrate
    – Quality
    – Safety         Marketing Authorisation Criteria
    – Efficacy

+ Any proposed adaptation of the medicinal product




                                                         3
4
                        Principles

1.   Same application (form) for PIP/Waiver/Deferral/
     Combination
2.   Applications to cover all subsets of the paediatric population
3.   Applications (Article 8) to cover all existing and new
     indications but in one PIP
4.   All relevant information (+ or – to the product) to be
     included in the dossier, in particular
     incomplete/discontinued pharmaco-toxicological test/CT
5.   The assessment of
     • Significant therapeutic benefit
     • Fulfilment of therapeutic needs
     to be assessed in the light of any other relevant information




                                                                      5
             Overall Development
            Information on Target
             Diseases/Conditions
Part B
1. Discussion on similarities/differences between
   populations (adults versus paediatric [subsets])
2. Discussion on anticipated similarities/differences on
   the effect of the product (adults versus paediatric
   [subsets])
3. Prevalence/incidence in the paediatric population
4. Current methods of diagnosis/prevention/treatment in
   the paediatric population (including [unauthorized]
   standard of care)
5. Significant therapeutic benefit, fulfilment of therapeutic
   need (decision to go for a PIP/waiver)

                                                                6
      Basis for Significant Therapeutic
                   Benefit

a)   Improved efficacy upon the existing
b)   Substantial improved safety profile
c)   Better dosing scheme/method of administration
d)   Availability of relevant age-appropriate formulation
e)   New/relevant clinical knowledge of better use
f)   Different mechanism of action


 At this (early) stage of development, such claims could be
  based on ‘well justified’ and plausible assumptions
 If not, consider waiver/deferral
 Refer to the inventory when appropriate



                                                               7
          Applications for Waivers


Part C
1. Scope
    Age range/subsets
    Pharmaceutical form
    Route of administration

2. Grounds
    Based on efficacy/safety (justify lack of E/S
     risks)
    Based on condition/disease (in adults ‘only’!?)
    Based on lack of significant therapeutic benefit



                                                        8
                       PIP

Part D1
Overall strategy proposed by the applicant:
   Indication
   Selected age groups
   Outline of the quality/(non)-clinical data
   Extrapolation/interrelation between
     adult/paediatric
   Existing paediatric information
   Significant therapeutic/fulfilment of
     therapeutic need




                                                 9
      Strategy in Relation to Quality


Part D2
   Need for a specific formulation/dosage form in
    relation to age group
   Availability/timeframe of the formulation/
    dosage form
   Appropriateness to age subsets (device, food…)
    (suitability)




                                                     10
                        Deferrals

Part E
   Specify indication/route/form
   Specify age group to which it applies
   Justify
         - Conduct in adults prior to the paediatric
           population
         - Longer duration in paediatric populations
         - Need for additional non-clinical data
         - Difficulties to develop timely a relevant
           formulation




                                                       11
                                    ?



               PIP…          is a plan


• including formulations, preclinical safety, clinical
  efficacy, and some pharmacovigilance
• describing the drug development
  -Timing of studies: start, duration and end, with respect
  to submission of Marketing Authorisation applications
  -Population (age groups) to be studied



                                                              12
         Request for Waiver


                         *
                Full
         YES   Waiver


                                        PIP
 Full
Waiver         PDCO                   Deferral
                                       Partial
                                       Waiver
         NO                  YES
               REFUSAL




                 * Full waiver = no Reward       13
                 Request of PIP

                     PIP
                       
                    deferral

                                         PIP
                    Partial
 PIP
           YES      Waiver
                                            
                                        deferral
deferral
                    PDCO       YES         
                                        Partial
Partial                                  Waiver
Waiver
           NO      REFUSAL

                                          Full
                                                    *
                               NO        Waiver




                               * Full waiver = no Reward   14
Expertise and Efficiency
           OVERVIEW PIP PROCEDURE

                  Adoption of                              Adoption
                   Opinion,                                    of
                      or                                   Opinion
                  Request for                                  &
                  Modification                           Final Report




Start                            Stop    ReStart
        60 DAYS                           Clock       60 DAYS           Decision
Clock                            Clock




                             Expertise & Efficiency                            16
              OVERVIEW PIP PROCEDURE

                     Adoption of                                  Adoption
                      Opinion,                                        of
                         or                                       Opinion
                     Request for                                      &
                     Modification                               Final Report




Start                               Stop     ReStart
           60 DAYS                            Clock          60 DAYS           Decision
Clock                               Clock




        Understand Plan
        Detect Problems
        Identify Experts
        Propose Modifications



                                    Expertise & Efficiency                            17
           OVERVIEW PIP PROCEDURE

                  Adoption of                              Adoption
                   Opinion,                                    of
                      or                                   Opinion
                  Request for                                  &
                  Modification                           Final Report




Start                            Stop    ReStart
        60 DAYS                           Clock       60 DAYS           Decision
Clock                            Clock



                                              Evaluate Changes
                                              Find Agreement
                                              Finalize Plan
                                              Publish Decision



                             Expertise & Efficiency                            18
        Plan


•   PIP submissions
•   PDCO assessment
•   Achievements
•   Challenges




                      19
      Plan


• PIP submissions
•     assessment
• Achievements
• Challenges




                    20
21
              PIP Procedure ‘Intention’ Phase


       Day -60                 EMEA               Day 0
     Rapp/PeerR              Validation           Start
     designations             Period            Procedure




                                                       Start
             40 DAYS            30 DAYS
                                                       Clock
                                                               First Wave 60 DAYS




 Day –70        Day –30         Preparation
Company’s      Company’s         EMEA SmR
 Letter of        PIP                 &
  intent       Application     List of Issues




                                     Expertise & Efficiency                         22
         PIP Validation & Summary Report


       Day -60                                    Day 0
     Rapp/PeerR                                   Start
     designations                               Procedure




                                EMEA                     Start
             40 DAYS          Validation
                                                         Clock
                                                                 First Wave 60 DAYS
                               Period




 Day –70         Day –30        Preparation
Company’s       Company’s        EMEA SmR
 Letter of         PIP                &
  intent        Application    List of Issues    List
                                                  of
                                                Issues




                                     Expertise & Efficiency                           23
         PIP Validation & Summary Report


       Day -60                                    Day 0
     Rapp/PeerR                                   Start
     designations                               Procedure




                                EMEA                     Start
             40 DAYS          Validation
                                                         Clock
                                                                 First Wave 60 DAYS
                               Period




 Day –70         Day –30        Preparation
Company’s       Company’s        EMEA SmR
 Letter of         PIP                &
  intent        Application    List of Issues    List
                                                  of
                                                Issues




                                     Expertise & Efficiency                           24
        Plan


•   PIP submissions
•   PDCO assessment
•   Achievements
•   Challenges




                      25
Access the Meeting Documents System




                   Expertise & Efficiency   26
   Working Method


• Team construct involving

  -   EMEA assessor(s)
  -   Rapporteur/National Assessors
  -   Peer Reviewer
  -   General Meeting




           Expertise & Efficiency     27
             Overview of the PIP Procedure

             1st            1st                                 2nd               3rd
        Presentation    Discussion                          Discussion        Discussion
           PDCO           PDCO                                PDCO              PDCO
           Day 30         Day 60                              Day 90           Day 120




Start                                 Stop        ReStart
Clock       60 DAYS                   Clock        Clock           60 DAYS            Opinion
                                               ~3
                                              month


     Day 1             Adoption of                    Day 61 Re-            Adoption
     After              Opinion,                      Submission                of
   Validation              or                            EMEA               Opinion
   EMEA Sm             Request for                      Update                  &
    Report             Modification                   Sm Report           Final Report


                                                       OE= oral explanation

                                  Expertise & Efficiency                                        28
Mille feuilles




                 Expertise & Efficiency   29
Expertise & Efficiency   30
Worload




          Expertise & Efficiency   31
        Plan


•   PIP submissions
•   PDCO expert assessment
•   Achievements
•   Challenges




     Expertise & Efficiency   32
            Working Groups



General meeting to split in break-out sessions
  to discuss core matters

•   Principles & Understanding
•   Attitudes & Strategic approach
•   Internal Consistency
•   Need for future Guidance?




                Expertise & Efficiency           33
             Working Groups

General meeting to split in break-out sessions
  to discuss core matters


•   Paediatric Formulations
•   Neonatal Vaccination
•   Bone diseases in children/adults?
•   Immuno-compromised children and AB studies?
•   Monitor pubertal development?
•   Place of of new anti-HIV therapies?
•   Anti-epileptic drugs studies, in Neonates?




                 Expertise & Efficiency           34
      Plan


• PIP submissions
•     assessment
• Achievements
• Challenges




                    35
Adopted Nov. 23 2007




                   36
                 PIP applications

EMEA received after 6 months of activities
(by submission deadline 22.112007)

PIP applications*                                     71

corresponding to

Number of indications covered
in the requests for PIPs or waivers:                  182
   including full waivers
   for the paediatric development
   for the whole indication                           11

   * ‘Application’ covers one or more indication(s)


                         Expertise & Efficiency             37
             PIP Distribution

Article 7
New medicinal products not yet authorised 27 38%

Article 8
Medicinal product under patent                43 61%

Article 30
Off-patent medicines developed specifically
for paediatric use
with an appropriate formulation                1   1%




                   Expertise & Efficiency               38
Areas covered by PIPs /waivers    %


•   Neurology                     12
•   Gastroenterology-Hepatology   10
•   Pneumology – Allergology       8
•   Infectious Diseases           11
•   Cardiovascular Diseases       14
•   Endocrinology-Gynaecology     18
•   Immunology–Rheumatology        4
•   Oncology                      11
•   Vaccines                       3


                                       39
       Plan


• PIP submissions
•     assessment
• Achievements
• Challenges
  - Communication
  - Work ▪ load/▪ sharing




                            40
Start              Stop          ~3       ReStart
        60 DAYS
         60 DAYS                                     60 DAYS   Opinion
Clock              Clock        month      Clock



                            Interactions
                           PIP Procedure




                            Expertise & Efficiency                       41
                Two Steps PIP Procedure

 Company’s         EMEA         2nd Rapp     & 2nd PDCO           3rd
                                                                           OE?
                                                                        PDCO
   PIP Re-       Sm Report        Oral       Discussion           Discussion
 Submission       Update        Present.                         Final Report
   Day 61         Day 71             Day     90     .              Day 120




Re-Start                                                                      PDCO      EMEA
                           2d Wave Days 61-120                               Opinion   Decision
 Clock




           Rapporteur’s       PReviewer’s         Members’        Update
           Comments on       Comments on       Final Comments   EMEA/PDCO
           Modifications     Modifications         to EMEA       Sm Report
             Day 80             Day 88             Day 105        Day 110




                                                                OE= oral explanation

                                     Expertise & Efficiency                                       42
      What can we take on board?




Expertise & Efficiency             43
…in terms of workload ?

                          44
Expertise & Efficiency   45
           Conclusion message

•   The PDCO is in place & motivated Members at work
•   ..whilst the anticipated Workload has proven true
•   The PDCO members, EMEA staff are still learning
•   But organizing Evaluation of PIPs,
•   Setting procedures, tools and exploring new
    avenues to settle a dialogue
•   To meet the goals of the Regulation
•   In a fair and acceptable way
•   But really meeting the expectations of all Parties,
•   Neonates, infants, children and families coming
    first...



                     Expertise & Efficiency               46
47

				
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