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Combination products: How to Achieve Compliance Under EU MDR?
Author: Alice KARAM, Medical Writer, ECLEVARDr. MARKUS NILLRONG, Deputy Head of Regulatory department, ECLEVAR.
COMBINATION PRODUCTSINTRODUCTION
Medical devices
Blood
Medicines
Tissues & cells
Combination products
Combination products are composed of acombination of a device, an ancillary drugand/or a biologically active material. Themedical device market currently shows anincreasing pace of innovation and theboundaries between medicines and devicesare becoming blurred. Accordingly, it hasbecome essential to adapt the regulation tothese new complex medicines and strengthentheir safety and efficacy.In this paper, we will discuss theimplementation of the EU MDR in theregulation of the combination products and wewill outline what manufacturers of theseproducts need to know in order to achievecompliance under EU MDR, as well as thechallenges that they will face and how toovercome them.
Pre-filled inhalers Patches for transdermal
drug delivery
Medicinal Product With Integral DeviceComponent
The EU MDR (article 117) introduces a newrequirement for medicines with an integraldevice. Three cumulative conditions wouldrender a medicinal product subject to this newrequirement:
• The device and the medicinal product forma single integral product
• Intended exclusively for use in the givencombination
• not reusable
Such medicinal product shall be governed bythe Medicinal Products Directive (MPD),however, the general safety and performanceof the device part of the single integral productare concerned (Table 1).
Regulation of Products at The Interface
In the European union, combinations productsare regulated depending on which componenthas an ancillary function. Hence, they aregoverned either by:
- The Medical Device legislation, if the integraldrug’s function is ancillary. For example,drug eluting stents and medicated dressingsare regulated as devices since the medicinalcomponent has a secondary purpose to themedical device claims. These products mustbe CE-marked.
- The Pharmaceutical legislation, if the drugcomponent achieves the principal intendedaction and the medical device has anancillary function. For example, the insulininjector pens and the inhalers are prefilleddrug delivery systems, where the medicaldevice has an ancillary function that consistsof the administration of the drug.
If the ancillary substance is derived fromhuman blood or plasma, the notified bodymust seek a scientific opinion from theEuropean Medicines Agency on the qualityand safety of the ancillary substance,before it can issue a CE certificate.
COMBINATION PRODUCTS
Summary of Article 117Amendment to Annex I of Medicinal Products
Directive 2001/83/EC.
This article of EU MDR introduces a newrequirement for notified body involvement in amedicinal product with integral medical device.The marketing authorization dossier for amedicinal product with an integral device isexpected to include:
- The results of the assessment of theconformity of the device part with therelevant general safety and performancerequirements of the Annex I of the MDR.These results are usually found in thedeclaration of conformity and the relevantEU certificate issued by a notified bodyallowing the manufacturer to affix a CEmarking to the medical device.
- If the device is not CE-marked, the applicantshould provide an opinion from a notifiedbody designated under MDR on theconformity of the device in question. Thisopinion should demonstrate the conformitywith relevant requirements of Annex I ofMDR.
This applies to medicinal products that form anintegral product with a medical device, wherethe action of the medicinal product is principaland the medical device is used to administer amedicinal product (Article 1 (8) and 1 (9))
Transition Period to the EU MDR
The transition period for combination productmanufacturers ends on May 26, 2020.
However, CE marked products under thecurrent MDD 93/42/EEC can be extendeduntil their certificate expiry date, but no laterthan May 26, 2024.
Before the 26th of May 2020, if substantialchanges are made, the applicants shouldprovide an new/updated EU certificate,declaration of conformity or an opinion of anotified body as a part of their extension/variation application. These changes can be:
- An addition or full-replacement ofthe device part.
- A substantial design changes to thedevice component.
Changes to the device component areconsidered substantial if they affect theperformance and safety characteristics of thedevice.
If the change does not affect the medicaldevice part then no new /updated certificateor opinion of the Notified body is required.
“Approximately one in four centrally authorized medicines includes a medical device component, and the majority of these involve an integral device. This includes for example
pre-filled syringes and pens, patches for transdermal drug delivery and pre-filled
inhalers.”
European Medicines Agency
Challenges For Pharmaceutical Companies
The Medicinal Product Directive (MPD) doesnot contain any text related to the regulationof the device part of a medicinal product andthe Medical Device Directive (MDD) simplystates that device should comply with therelevant essential requirements of the Annex Ito this directive particularly if the safety andperformance of the device are concerned.
However, nothing is mentioned about how tomeet the requirements of Annex I or thedocumentation needed to show compliance.
Therefore, some medicinal productmanufacturers may not have the internalexpertise for medical device compliance.
This issue has become more urgent with theincreasing pace of innovation of the medicaldevice components of these combinationproducts.Recently, the MDR that entered into force on 25May outlines specific requirements for thedevice component (cf. summary of article117).
Pharmaceutical companies will face a newchallenge to liaise with Notified Bodies for theirdevice components in addition to regulators forthe drug components (Table 1). Nevertheless,their regulatory team might be unfamiliar with thisnew role of interpreting the regulation anddeveloping compliance documentation.
Moreover, with the deadlines for EU MDR fastapproaching and the small number ofdesignated Notified Bodies (NB) under MDR (todate four NB: TÜV SÜD, BSI UK, DEKRA & IMQ),the regulatory system is slow and thecompanies are queuing to apply for conformityassessments under MDR.
Hence, combination product manufacturerswith a non-CE marked device should quickly:
- Familiarize and meet the MDR requirements
- Identify the NB that will be accredited for thetype of device in question
- Adjust compliance timelines to incorporateNB liaison and procedures.
Medical Devices with Ancillary Substances
The evaluation of a combination product withmedicinal ancillary substances by the notifiedbody must include an opinion of a competentauthority (CA) designated by an EU Memberstate and / or the EMA. This process can take upto 210 days to complete. It is therefore crucial todevelop an effective regulatory strategy as earlyas possible in the development process for newcombination products.
Manufacturers should seek advice fromregulators, authorities and competent third-parties regarding the documentation requiredto support CE mark approval applications. Thismay reduce the risk of unexpected challengesand setbacks that can prolong or jeopardizeproduct approval.
In most cases, the drug substances are oftenprocured from external pharmaceuticalsuppliers and it may be challenging for devicemanufacturer to verify the integrity and thequality of their clinical data.
Drug-eluting stent Medicated dressings
Clinical Evaluation
Pharmaceutical companies may be undergoingthe clinical evaluation under EU MDR for thefirst time. They may be lacking the required datato demonstrate the clinical safety, performanceand clinical benefits of the device part. In thiscase, they might need to carry out additionalefficient tests and clinical evaluation to be ableto achieve compliance of their device as swiftlyas possible without affecting its placement onthe market.
In order to determine the device classification,manufacturers should first refer to annex VIII ofthe MDR and to define the associated classtaking into account the intended purpose of thedevice and their inherent risks.
All devices should have their technicaldocumentation which demonstrate that theirsafety, performance and clinical benefit meetsthe relevant general safety and performancerequirements of Annex I of the MDR.
COMBINATION PRODUCTS
COMBINATION PRODUCTS
Clinical Evaluation Reports (CER)
CER should demonstrate that:
o the device part achieves its intendedpurpose;
o the known and foreseeable risks, and anyadverse events, are minimized andacceptable when weighed against thebenefits of the device’s intended use;
o any claims made about the device’sperformance, safety and clinical benefitare supported by suitable evidence.
Previously, evaluators were allowed to rely onscientific literature and results of clinical datafrom equivalent devices. Under the MDR, therequirements are more demanding, and it willbe harder to evaluate a given device based onequivalence.
Manufacturers are therefore encouraged toinvest time and resources to get efficient firstCERs that should facilitate the conformityassessments by the Notified body.
Manufacturers of medicinal products with anintegral device should set up a standardizedprocedure that allows regular update of therequired information of the device part andfacilitates its easy access.
Clinical evaluation is not a punctual process andonly when the device is in use, the company cangain a complete understanding of the devicesafety by assessing real world use,
rare complications and adverse events.Ongoing post-market surveillance activities aretherefore crucial and must be conducted inconjunction with risk management and clinicalevaluation.
In ECLEVAR, our medical writers have critical review skills and the suitable expertise to help you to quickly spot the areas of non-
compliance and show you how to overcome them.
Class of the medical Device in the integral medicinal product (s)
NON CE marked device (s) CE marked device (s)
Class I (sterile, measuring or reusable surgical instrument)Class IIa,Class IIb,Class III
- Demonstrate the compliance with the general safety and performance requirements of Annex I of the MDR 2017/745
- An opinion from a notified body must be provided for the medical device component
- Demonstrate the compliance with the general safety and performance requirements of Annex I of the MDR 2017/745
- Declaration of conformity and EU notified body certificate is expected to be provided for the medical device component, if available.
- If the above mentioned documentation is not available then an opinion from a notified body must be provided for the medical device component
Class I (non sterile, non-measuring, or non-reusable surgical instrument)
- Demonstrate that the Medical device meets the relevant general safety and performance requirements of Annex I of the medical devices Regulation 2017/745.
- Demonstrate that the Medical device meets the relevant general safety and performance requirements of Annex I of the medical devices Regulation 2017/745.
- In addition a Declaration of Conformity is expected to be provided for the medical device component, if available.
Table 1 Summary of changes for Marketing Authorization Applications involving medicinal products with integral medical devices (modified from the Q&A of the European Medicines Agency)
COMBINATION PRODUCTS
ABOUT THE AUTHOR
Alice KARAM holds a doctorate in Neurobiology from the Institute ofGenetics and Molecular and Cellular Biology (IGBMC), University ofStrasbourg. She lead different postdoctoral projects in neurology at theInstitute of Biology Paris – Seine (IBPS). After a training on clinical research,Alice made the leap to ECLEVAR to bring her expertise in clinicalevaluation and medical writing.
Alice KARAM, PhD, Medical writer, ECLEVAR
MARKUS NILLRONG has worked in the field of medical device for over 20years. Passionate about medical device technology and optimizingdecision-making in complex environments, Markus has spent most of hiscareer as an Auditor and Operations Lead/Manager in various notified
bodies.Currently leading internal and external training for MDD, AIMD & IVD.Continuing to conduct Technical Documentation and Quality System auditsfor CE marking and ISO 13485 in addition to some aspects of compliancein Canada, USA, Japan, Taiwan and Australia.
MARKUS NILLRONG, Deputy Head of Regulatory department for MedicalDevices MDR, ECLEVAR
CONTACT US+33 01 45 01 61 60
www.eclevar.com
LOCATION33 Rue de Berri
ParisFrance
COMBINATION PRODUCTS
