medical device combination products

1. Notified Body involvement in
combination products
Gert Bos
BSI, UK
The Organisation for Professionals in Regulatory Affairs 1

2. Overview
• Notified Body role
• Consultation procedure
• Working with competent authorities
The Organisation for Professionals in Regulatory Affairs 2

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
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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. Steps in process
• Acceptance review
• Selection review panel / audit team
• NoBo review complete dossier
• Parallel consultation process
• Certification decision
• Surveillance / extensions / state of art
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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. Team selection
• Scheme / client manager
• Expert reviewers
• Lead auditor + team
• Drug agency
• Certification team
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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
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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. 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. 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. 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. 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. Experiencing Drug Agencies
• Currently active agencies
– Dutch MEB
– UK MHRA
– Irish IMB
– Swedish MPA
– German Bfarm
– (Poland, France, Spain, Luxemburg, ….)

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. 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. 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. 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. 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. Conclusion
• NoBo coordinates consultation
• NoBo takes final decision
• Good & early preparations pays
• Look from pharma and device points
• Long process to improve patient safety
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