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Drug-device products - and the impact of MDR
CASSS, Strategy Forum EU, DDC SessionNoordwijk, 15th-16th May, 2018
14/06/2018 1© 2018, Corvus Device Limited
Contents
14/06/2018 2
• Types of DDCs and configurations• Different ‘concepts’ at play• Other challenges when combining• Development considerations• MDR (!)• Summary
© 2018, Corvus Device Limited
Some DDC products
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Combining products
Medicinal Device, CE-mark
‘Fixed dose’ Combination Product Medicinal Product orMedicinal Products Drug*Drug*
Convenience Kit 510(k)/PMA Medical Devices
Procedure / System Pack of CE-marked Medical DevicesDeviceDevice
Combination Product †††
(Cross-labelled), CD/BER + CDRH
Medicinal Product
Combination Product (Packaged together), CDRH
(+CD/BER)
Medical Device, CE-markDeviceDrug*
Combination Product (Packaged together), CD/BER
(+CDRH)
Medicinal Product DeviceDrug*
Combination Product (Single-entity), CDRH (+CD/BER)
Medical Device with ancillary substance, NB††, Class III, CE-markDeviceDrug*
Combination Product (Single-entity), CD/BER (+CDRH)
Medicinal Product (single integral-combined-
nonreusable), CA†, No CE-markDeviceDrug*
DeviceDrug*
1
2
3
4
5
6
7
Medical Device, CE-mark
Medicinal Product
Drug* = Drug or Biologic, for the purposes of this image† = Opinion from Notified Body (under MDR), Confirmation by Applicant (under MDD)†† = Scientific Opinion from Competent Authority††† = Note, where a device refers to a drug, the FDA consider this a Device Referencing Drug
(DRD), which may (or may not) also meet the current definition of a Combination Product.
Primary MOA
Legend: Package
+
+
Combining products
Medicinal Device, CE-mark
Medicinal Product
Medical Device, CE-markDeviceDrug*
Medicinal Product DeviceDrug*
Medical Device with ancillary substance, NB††, Class III, CE-markDeviceDrug*
Medicinal Product (single integral-combined-
nonreusable), CA†, No CE-markDeviceDrug*
DeviceDrug*
1
2
3
4
5
Medical Device, CE-mark
Medicinal Product
Combination Product †††
(Cross-labelled), CD/BER + CDRH
Combination Product (Packaged together), CDRH
(+CD/BER)
Combination Product (Packaged together), CD/BER
(+CDRH)
Combination Product (Single-entity), CDRH (+CD/BER)
Combination Product (Single-entity), CD/BER (+CDRH)
+
+
US-FDA Device Risk Classes
I II III EU
Device Risk Classes
Device Constituent: I Is Im Ir IIa IIb III
Combining products brings different concepts into playDrug Combi Delivery Device
Target Disease(Clinical development)
User(HFE, IEC 62366)
‘Focus’ Safety & Efficacy Safety, Reliability & Usability
Development model
ICH Q8 Pharma Development “Non-GMP”
Design Control“Pre-production GMP”
Quality System requirements ICH Q10 PQS ISO 13485
Risk Management ICH Q9 QRM ISO 14971
Laboratory evaluation
Ph.Eur. Testing Monographs /Analytical (chemical) methods
Normative Standards / Verification (physical) methods
Accelerated Stability/Shelf-life ICH Q1 Arrhenius / ASTM F1980
Human evaluation
Phase 1, 2, 3 Clinical Studies [Some exemptions]
Clinical EvaluationClinical Investigation
HF Simulated-use DValidation
Submission IMPD, MAA, CTD STED, Technical Documentation
Review & Approval
(medicine) Competent Authority Notified Body
!
…and several other ‘challenges’ of integration across the organisation, product development and documentation
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• Terminology, vocabulary• Disciplines• Competences• Intellectual Property• Planning ‘touchpoints’
– Trigger for a delivery device vs. Readiness for Phase III– Final formulation vs. Design Inputs for the delivery device
• Different services, contributors, suppliers• Homogenous vs non-homogenous manufacturing• ‘Reluctance’ to change vs continuous improvement
© 2018, Corvus Device Limited
Products may be developed in many different ways… with significant implications for the developer
Drug Device PMOA Configuration Other Considerations
Approved
Approved
DrugCo-packed …
Integrated …
DeviceCo-packed
Integrated
Investigational
DrugCo-packed
Integrated
DeviceCo-packed
Integrated
Investigational
Approved
DrugCo-packed
Integrated
DeviceCo-packed
Integrated
Investigational
DrugCo-packed
Integrated
DeviceCo-packed
Integrated
• Originator, biosimilar, generic, orphan/rare• Hospital, Emergency or Home-use• HCP, Non-professional, Self-admin• Reusable or disposable• Fixed- or variable-dose, Single- or multi-dose• Off-the-shelf, customised, new• Single product, family, platform• Int/external, accountability, oversight• Quality Management System• Applicability of MD and/or MP regs• Drug-device interaction• DC, RM, HFE implications• Characteris’n of originator, competitor, own• Engineering effort and activity• Verification strategy• Manufacturing strategy & supply chain• Control strategy and plan• Clinical vs commercial considerations• Requirement for DMR, DHR• Approval pathway, CE or NB opinion• Submission documentation• Reviewing authority• PAI, cGMP, Surveillance inspections
Medical Device Regulation – Some hot topic areas…
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• Quality System• How much does a Pharma need to conform with ISO 13485 or similar? For which areas?
• Clinical• Implications of including the device in Clinical Studies of the product• Clinical Evaluation of device constituent – when, why and how?• Clinical Investigation of device constituent – when, why and how?• Who reviews what? Who is best advised to guide through advice meetings?
• Documentation• MAA - How much info on the associated medical device is needed in the dossier for the
particular combination to demonstrate safety and efficacy?• STED/TD - How much info on the associated medicinal product is needed for the
particular combination to demonstrate safety, reliability and usability? • Can a line be drawn between drug and device data? • Who reviews what? How much is duplicated? Potential for misinterpretation?
• Change management• How should a device-change be notified ? Who reviews?
• Post-Market Reporting • Should we use the mechanism associated with the original approval (PMOA, as for US)?• In all cases?
© 2018, Corvus Device Limited
Medical Device Regulation – Article 117
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• Art.117 ONLY applies to a:– single integral product, that IS…– intended exclusively for use in the given combination… AND that is…– not reusable
• All other combined drug delivery products fall into Medical Device or Medicinal Product
• Many open questions…– How is Device Risk Classification to be used to define requirements?– How are attributes such as measuring, sterile, active, implantable, to be
used to define the applicability of MDR and other requirements.– Who is the NB opinion applicant - the device developer or the MAA
applicant?– When is review needed relative to MAA submission?– How is the review of the product as a ‘system’ ensured?– When does a change prompt revisiting the NB opinion?– What are the ongoing ‘maintenance’ requirements for an NB opinion?– etc
© 2018, Corvus Device Limited
Summary
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• It’s not always as simple as “Is it a Medicine, or is it a Device?”
• Notified Body review, conformity assessment and CE-marking remain appropriate for standalone medical devices.
• There is huge diversity of combination configurations, and a sliding scale of drug-device interaction.
• MDR applicability to any form of combined product needs further clarification…– The role the delivery device plays should be more carefully considered and the
application of regulation, the review process and the approval co-ordinated appropriately
– The less ‘standalone’ the device, the more clarification is needed• A more integrated approach is needed for more integrated products.
– … to recognise the complexities, permutations, configurations, and challenges …– … both for the developer and the reviewer.
• It is proposed that a formal review of industry concerns is performed and these be gathered, grouped and used to drive specific guidance appropriate to the different types and groups of products.
© 2018, Corvus Device Limited
Q&A
14/06/2018 12
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Different combinations – different models & interactions
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• Co-packed products - Interact at point of use– Drug (MPD, PQS, cGMPs) + ‘off-the-shelf’ device (MDD/MDR, ISO) – most common
• Pharma purchases and confirms suitability of selected device with drug. Studies interactions.• CE-mark independent of drug, Device manufacturer sells CE-marked devices to any buyer.
– Drug (MPD, PQS, cGMPs) + ‘customised’ device (MDD/MDR, ISO)• Pharma defines changes, purchases, confirms suitability of selected device with drug.• Device producer/CMO customises and sells/provides specific versions to several Pharma.• CE-mark in/dependent of drug, CE-marking may be taken up by either.
– Drug (MPD, PQS, cGMPs) + developed device (MDD/MDR, ISO) – least common• Pharma ‘designs’ (may outsource), confirms suitability of selected device with drug.• CMO manufactures and provides specifically to Pharma customer.• CE-mark in/dependent of drug, CE-mark may be taken up by either.
• Integrated products - Interact through life– Drug (MPD, PQS, cGMPs) + ‘off the shelf’ device – least common exc. container components e.g. PFS
• Pharma purchases and confirms suitability of selected device with drug, Studies interactions.• Device manufacturer sells. No development or approval role responsibility. Approved WITH drug.
– Drug (MPD, PQS, cGMPs) + ‘customised’ device – most common, often leveraging external platforms• Pharma defines changes, purchases, confirms suitability of selected device with drug.• Device producer/CMO customises and sells/provides. No development or approval responsibility. Approved WITH
drug.– Drug (MPD, PQS, cGMPs) + developed device
• Pharma ‘designs’ (may outsource), confirms suitability of selected device with drug.• CMO manufactures and provides. No development or approval responsibility. Approved WITH drug.
© 2018, Corvus Device Limited
