Notified Body involvement in
   combination products

                   Gert Bos
                   BSI, UK


 The Organi...
Overview

• Notified Body role

• Consultation procedure

• Working with competent authorities



       The Organisation ...
Notified Body KEY Role

• Notified body reviews dossier, audits
  and might issue certification

• Scientific advise from ...
Purpose consultation procedure


-   Essential Requirement 7.4 (MDD): NB has responsibility
    to address this requiremen...
Steps in process

•   Acceptance review
•   Selection review panel / audit team
•   NoBo review complete dossier
•   Paral...
Acceptance review

– Devices  medicinal product
  • What definition fits best
  • MEDDEV 2.1/3 regulates “borderline” bet...
Team selection

•   Scheme / client manager
•   Expert reviewers
•   Lead auditor + team
•   Drug agency
•   Certification...
NoBo review

•   Preliminary technical review
•   Usefulness review
•   Sections divided over review team
•   Instructions...
NoBo: centre of communication

   -   new device or assumption ?
   -   Pre-application (option selected DA)
   -   Pre-me...
Projected timelines




Most DA’s: 210 days

                            Existing       New substances
                   ...
The process

• Dossier requirements:
  • (Consultation application form)
  • (Provisional decision of the NoBo)

  • Drug ...
Advice drug agency

One or more evaluation reports and a covering letter
including recommendation of report(s):
- positive...
Final stages of approval

Following completion of consultation procedure:


-   Ultimate responsibility for decision belon...
Experiencing Drug Agencies

• Currently active agencies
  –   Dutch MEB
  –   UK MHRA
  –   Irish IMB
  –   Swedish MPA
  ...
Experiences BSI

               MHRA       MEB    MPA      IMB        BfArM      EMEA

Experience     V          V      V ...
Experiences


Consultation process takes 6 -24 months

Time is lost due to the following:
- more requirements
- questions ...
What will help….
• General:
  – Make sure guidelines from EMEA are followed as far
    as possible
    http://ec.europa.eu...
Further help….

–     Ph.Eur. Monographs, CPMP, ICH and EMEA guidance
      documents (even if not directly applicable) sh...
And more…

–     Most recent Certificate of Suitability
–     Animal studies:
    •   number of animals used could statist...
Conclusion

•   NoBo coordinates consultation
•   NoBo takes final decision
•   Good & early preparations pays
•   Look fr...
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Topra Combination Products Gert Bos

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Topra Combination Products Gert Bos

  1. 1. Notified Body involvement in combination products Gert Bos BSI, UK The Organisation for Professionals in Regulatory Affairs 1
  2. 2. Overview • Notified Body role • Consultation procedure • Working with competent authorities The Organisation for Professionals in Regulatory Affairs 2
  3. 3. Notified Body KEY Role • Notified body reviews dossier, audits and might issue certification • Scientific advise from drug agency of choice needed in review • Decision on dossier with NoBo The Organisation for Professionals in Regulatory Affairs 3
  4. 4. Purpose consultation procedure - Essential Requirement 7.4 (MDD): NB has responsibility to address this requirement “by consulting one of the competent bodies established by the Member States in accordance with the Dir. on Medicinal Products before taking a decision”. - Verification of the “safety, quality and usefulness” of the medicinal substance by drug agency.
  5. 5. Steps in process • Acceptance review • Selection review panel / audit team • NoBo review complete dossier • Parallel consultation process • Certification decision • Surveillance / extensions / state of art The Organisation for Professionals in Regulatory Affairs 5
  6. 6. Acceptance review – Devices  medicinal product • What definition fits best • MEDDEV 2.1/3 regulates “borderline” between medical devices and medicinal products • Written rationale manufacturer – Agreement with manufacturer on above – Disagreement: MHRA arbitration – Quotation
  7. 7. Team selection • Scheme / client manager • Expert reviewers • Lead auditor + team • Drug agency • Certification team The Organisation for Professionals in Regulatory Affairs 7
  8. 8. NoBo review • Preliminary technical review • Usefulness review • Sections divided over review team • Instructions to lead auditor • NCs identified • Report issued • Interaction until NCs closed The Organisation for Professionals in Regulatory Affairs 8
  9. 9. NoBo: centre of communication - new device or assumption ? - Pre-application (option selected DA) - Pre-meeting (when available) - NB sends dossier to drug agency - Dossier delayed: initial time schedule may be changed !
  10. 10. Projected timelines Most DA’s: 210 days Existing New substances substances or new indications (established of existing MEB: indications) substances Initial 10 weeks 14 weeks Subsequent 8 weeks 12 weeks Variations 6 weeks 6 weeks
  11. 11. The process • Dossier requirements: • (Consultation application form) • (Provisional decision of the NoBo) • Drug Master File (DMF) from original API mft • Medicinal substance dossier MEDDEV 2.1/3. Notice to applicants for drug registration in Europe, volume 2a and 2b • Changed to be in eCTD pharma format (see http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm)
  12. 12. Advice drug agency One or more evaluation reports and a covering letter including recommendation of report(s): - positive advice - request for further information (*) - negative advice * - sometimes within certain period of time - NB may request extension of this period - IF information is not received: substance is “insufficient”…
  13. 13. Final stages of approval Following completion of consultation procedure: - Ultimate responsibility for decision belongs to NoBo - NoBo requested to inform drug agency on decision made - IF NoBo receives negative advice from drug agency, NoBo requested to consult Competent Authority of MS before issuing a certificate
  14. 14. Experiencing Drug Agencies • Currently active agencies – Dutch MEB – UK MHRA – Irish IMB – Swedish MPA – German Bfarm – (Poland, France, Spain, Luxemburg, ….)
  15. 15. Experiences BSI MHRA MEB MPA IMB BfArM EMEA Experience V V V meetings meetings V Guidance V V - V V V documents on internet Scientific - V V V (V) V advice Review times 210 days V V 210 days - 210 days (4 Mo) Reliability V V ? V - V Feedback V V ? V V (V) 3rd round V V ? ? (V) -
  16. 16. Experiences Consultation process takes 6 -24 months Time is lost due to the following: - more requirements - questions due to inconsistencies in documentation - priorities of reviewer change Review of product by drug authority is not always clear Data provided for combination product are reviewed as data for API
  17. 17. What will help…. • General: – Make sure guidelines from EMEA are followed as far as possible http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev3.htm) – Make sure information on products and packaging is very clear – Make sure description on how medicinal substance is incorporated into medical device is explained in detail – Make sure dossier is complete
  18. 18. Further help…. – Ph.Eur. Monographs, CPMP, ICH and EMEA guidance documents (even if not directly applicable) should be followed. – Other medical components within a kit should be defined – Stability usually is a struggle – Lack of clinical data: a benefit / risk assessment in terms of balancing clinical efficacy and clinical safety is not possible – Give proper justification of excipients used in formulation – Data on interaction between drug and excipients not present: • % active compound • influence of the production process on the active compound
  19. 19. And more… – Most recent Certificate of Suitability – Animal studies: • number of animals used could statistically not lead to valid conclusions • were not backed up by rationale for methodology behind test • no control studies were made to see effects that would happen with absence of medicinal substance
  20. 20. Conclusion • NoBo coordinates consultation • NoBo takes final decision • Good & early preparations pays • Look from pharma and device points • Long process to improve patient safety The Organisation for Professionals in Regulatory Affairs 20

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