Regulatory Open Forum

Ming,

This is a complex question without much current enforcement precedent to define it.  MDR is complex and requirements are "buried" throughout the document, making a complete tally of requirements difficult in some cases.

It is necessary to look beyond Article 117 for the requirements that apply to the device constituent. 117 requires " the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device." ...
and Article 5;3 requires " Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61."

The device constituent of a combination device must meet all relevant 2017/745 GSPR requirements if placed on the market after 2021/05/26. But as always "It depends" on the device itself and how your company uses it. While the therapeutic agent is "primary" in achieving the intended effect, depending on how the device constituent is used, its design or manufacture could have the potential to affect the therapy's effectiveness and these potential risks should be clearly detailed in the Hazard and Risk Analysis. Clinical evaluation is the process by which a detailed medical understanding of the device's nature, actions and interactions with the therapeutic agent and the user and patient are studied and justified as part of robust Risk Management processes.

If the device is a "standalone" device (like a delivery system that can be used with other therapeutics) and is marketed in EU as MDD or MDR CE marked, then the device must meet all 2017/745 requirements. 

The details in how the device constituent interacts with the drug and the user/patient, and the device's current status or ability to "stand-alone" are key determinants for determining requirements by the NB.



REFERENCES

Recitals:

(33)

The risk management system should be carefully aligned with and reflected in the clinical evaluation for the device, including the clinical risks to be addressed as part of clinical investigations, clinical evaluation and post-market clinical follow up. The risk management and clinical evaluation processes should be inter-dependent and should be regularly updated.

Article 5

1.   A device may be placed on the market or put into service only if it complies with this Regulation when duly supplied and properly installed, maintained and used in accordance with its intended purpose.

2.   A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose.

3.   Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61.

Article 10
3.   Manufacturers shall conduct a clinical evaluation in accordance with the requirements set out in Article 61 and Annex XIV, including a PMCF.

Article 117

(12)

Where, in accordance with the second subparagraph of Article 1(8) or the second subparagraph of Article 1(9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*1), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device. If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question.

------------------------------
Michael Chellson
RAC
------------------------------

Original Message:
Sent: 22-Mar-2021 01:29
From: Ming Aquila
Subject: Question regarding MDR Article 117 and Clinical Evaluation Report

We are developing a combination product with the drug PMOA. The combination product meets the definition per MDR Article 1 Point 9 the second paragraph, therefore, we are following MDR Article 117 requirements. There are directions given by consultants that we need to produce a CER (clinical evaluation report). I wonder if this is indeed a requirement as Article 117 does not dictate such a requirement. Certainly, an executive summary must include that the device constituent part is deemed safe and effective as the combination product as a whole performs as intended; however, from my point of view, a CER is not warranted. as we are evaluating clinical efficacy from a drug (PMOA) perspective, not the device. Can someone who has experience dealing with NB Opinion on a Combination Product with drug PMOA shed some light on this topic? Thank you.

Original Message:
Sent: 3/23/2021 9:31:00 AM
From: Michael Chellson
Subject: RE: Question regarding MDR Article 117 and Clinical Evaluation Report

Ming,

This is a complex question without much current enforcement precedent to define it.  MDR is complex and requirements are "buried" throughout the document, making a complete tally of requirements difficult in some cases.

It is necessary to look beyond Article 117 for the requirements that apply to the device constituent. 117 requires " the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device." ...
and Article 5;3 requires " Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61."

The device constituent of a combination device must meet all relevant 2017/745 GSPR requirements if placed on the market after 2021/05/26. But as always "It depends" on the device itself and how your company uses it. While the therapeutic agent is "primary" in achieving the intended effect, depending on how the device constituent is used, its design or manufacture could have the potential to affect the therapy's effectiveness and these potential risks should be clearly detailed in the Hazard and Risk Analysis. Clinical evaluation is the process by which a detailed medical understanding of the device's nature, actions and interactions with the therapeutic agent and the user and patient are studied and justified as part of robust Risk Management processes.

If the device is a "standalone" device (like a delivery system that can be used with other therapeutics) and is marketed in EU as MDD or MDR CE marked, then the device must meet all 2017/745 requirements. 

The details in how the device constituent interacts with the drug and the user/patient, and the device's current status or ability to "stand-alone" are key determinants for determining requirements by the NB.



REFERENCES

Recitals:

(33)

The risk management system should be carefully aligned with and reflected in the clinical evaluation for the device, including the clinical risks to be addressed as part of clinical investigations, clinical evaluation and post-market clinical follow up. The risk management and clinical evaluation processes should be inter-dependent and should be regularly updated.

Article 5

1.   A device may be placed on the market or put into service only if it complies with this Regulation when duly supplied and properly installed, maintained and used in accordance with its intended purpose.

2.   A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose.

3.   Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61.

Article 10
3.   Manufacturers shall conduct a clinical evaluation in accordance with the requirements set out in Article 61 and Annex XIV, including a PMCF.

Article 117

(12)

Where, in accordance with the second subparagraph of Article 1(8) or the second subparagraph of Article 1(9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*1), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device. If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question.

------------------------------
Michael Chellson
RAC
------------------------------

Original Message:
Sent: 22-Mar-2021 01:29
From: Ming Aquila
Subject: Question regarding MDR Article 117 and Clinical Evaluation Report

We are developing a combination product with the drug PMOA. The combination product meets the definition per MDR Article 1 Point 9 the second paragraph, therefore, we are following MDR Article 117 requirements. There are directions given by consultants that we need to produce a CER (clinical evaluation report). I wonder if this is indeed a requirement as Article 117 does not dictate such a requirement. Certainly, an executive summary must include that the device constituent part is deemed safe and effective as the combination product as a whole performs as intended; however, from my point of view, a CER is not warranted. as we are evaluating clinical efficacy from a drug (PMOA) perspective, not the device. Can someone who has experience dealing with NB Opinion on a Combination Product with drug PMOA shed some light on this topic? Thank you.

Hello Ming,

The question being asked has been asked ... often.  I am not sure anyone really knows because there is no guidance on this topic nor any type of guidance on Article 117s myriad of unanswered questions.  The requirement is General Safety and Performance Requirements from Annex I are reviewed by the Notified Body providing an opinion.  Indeed your logic thinking is correct because this is required for Annex I and not the overall Technical Documentation - it should be limited to the applicable parts of Annex I for safety and performance.  Since Clinical Evaluation can be part of Technical Documentation and there is no specific clinical evaluation requirement in Annex I, then you could assume this is true.  However, if you read through the first few parts of Annex I there is information related to risk-benefit which is related to clinical evaluation (some would argue or make that connection).  What has been seen is drug delivery systems expecting technical documentation including clinical evaluation to support the whole General Safety and Performance Requirements.  Because this unfortunately will probably vary between Notified Bodies a recommended approach is discussion with a Notified Body, preferably the one you would be working with, to understand their expectations in this regard.  Without further guidance from MDCG or EC, this will remain an elusive question to answer.

------------------------------
Richard Vincins RAC
Vice President Global Regulatory Affairs
------------------------------

Original Message:
Sent: 22-Mar-2021 01:29
From: Ming Aquila
Subject: Question regarding MDR Article 117 and Clinical Evaluation Report

We are developing a combination product with the drug PMOA. The combination product meets the definition per MDR Article 1 Point 9 the second paragraph, therefore, we are following MDR Article 117 requirements. There are directions given by consultants that we need to produce a CER (clinical evaluation report). I wonder if this is indeed a requirement as Article 117 does not dictate such a requirement. Certainly, an executive summary must include that the device constituent part is deemed safe and effective as the combination product as a whole performs as intended; however, from my point of view, a CER is not warranted. as we are evaluating clinical efficacy from a drug (PMOA) perspective, not the device. Can someone who has experience dealing with NB Opinion on a Combination Product with drug PMOA shed some light on this topic? Thank you.

Hello Ming,

I completely agree with your conclusion that a Clinical Evaluation Report (CER) is not required for the type of combination product being developed.

The basic requirement for drug delivery combination products is described in the second paragraph of MDR Article 1(9), which requires: ". . . the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned."

However, under certain circumstances, there are additional special requirements that need to be met, and these are described in MDR Article 117, which offers two possibilities for meeting the regulatory requirements applicable to such drug delivery combination products.

The first paragraph of Article 117 addresses the special situation where the device part is a CE marked medical device in its own right. If this is the case, then this CE marked device must meet the entire MDR, including the requirement for a CER. This does not, however, appear to be the case for the combination product you are describing.

The second paragraph of Article 117 addresses the situation where the device part of a drug delivery combination product is not CE marked in its own right. It does, however, meet the applicable GSPRs for the device part being used in the combination product. Under this circumstance, which I believe is the situation described in your question, no CER is required, because a CER is not included within the MDR GSPRs (as it was under the MDD).

In fact, in the second paragraph of Article 117, there are two routes to follow, depending on what would be the classification of the device part, were it to be assessed as a stand-alone medical device.

If the device part would fall under an MDR classification that required notified body involvement, the applicant (your company) would need to obtain a written opinion from a notified body designated for that type of device under the MDR to confirm its compliance with the applicable GSPRs and submit that opinion with the combination product application to the drug authority.

However, Article 117 of the MDR does not address the circumstance where the device part, if used separately, would be classified as Class I, so based on the language of the Article, a confirmation of compliance with the applicable GSPRs, such as a completed and signed GSPR Checklist, without the involvement of a notified body, should be sufficient to meet the requirement of MDR Article 1(9).

Finally, attention has been called by earlier responders to MDR Article 5.3 and Article 61; however, these MDR articles apply to an item that is regulated solely as a medical device and not as a medicinal product.

------------------------------
Maria E Donawa, M.D.
President, Donawa Lifescience
Rome, Italy
medonawa@donawa.com
+39 06 578 2665
------------------------------

Original Message:
Sent: 22-Mar-2021 01:29
From: Ming Aquila
Subject: Question regarding MDR Article 117 and Clinical Evaluation Report

We are developing a combination product with the drug PMOA. The combination product meets the definition per MDR Article 1 Point 9 the second paragraph, therefore, we are following MDR Article 117 requirements. There are directions given by consultants that we need to produce a CER (clinical evaluation report). I wonder if this is indeed a requirement as Article 117 does not dictate such a requirement. Certainly, an executive summary must include that the device constituent part is deemed safe and effective as the combination product as a whole performs as intended; however, from my point of view, a CER is not warranted. as we are evaluating clinical efficacy from a drug (PMOA) perspective, not the device. Can someone who has experience dealing with NB Opinion on a Combination Product with drug PMOA shed some light on this topic? Thank you.

Original Message:
Sent: 3/24/2021 1:16:00 PM
From: Maria Donawa
Subject: RE: Question regarding MDR Article 117 and Clinical Evaluation Report

Hello Ming,

I completely agree with your conclusion that a Clinical Evaluation Report (CER) is not required for the type of combination product being developed.

The basic requirement for drug delivery combination products is described in the second paragraph of MDR Article 1(9), which requires: ". . . the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned."

However, under certain circumstances, there are additional special requirements that need to be met, and these are described in MDR Article 117, which offers two possibilities for meeting the regulatory requirements applicable to such drug delivery combination products.

The first paragraph of Article 117 addresses the special situation where the device part is a CE marked medical device in its own right. If this is the case, then this CE marked device must meet the entire MDR, including the requirement for a CER. This does not, however, appear to be the case for the combination product you are describing.

The second paragraph of Article 117 addresses the situation where the device part of a drug delivery combination product is not CE marked in its own right. It does, however, meet the applicable GSPRs for the device part being used in the combination product. Under this circumstance, which I believe is the situation described in your question, no CER is required, because a CER is not included within the MDR GSPRs (as it was under the MDD).

In fact, in the second paragraph of Article 117, there are two routes to follow, depending on what would be the classification of the device part, were it to be assessed as a stand-alone medical device.

If the device part would fall under an MDR classification that required notified body involvement, the applicant (your company) would need to obtain a written opinion from a notified body designated for that type of device under the MDR to confirm its compliance with the applicable GSPRs and submit that opinion with the combination product application to the drug authority.

However, Article 117 of the MDR does not address the circumstance where the device part, if used separately, would be classified as Class I, so based on the language of the Article, a confirmation of compliance with the applicable GSPRs, such as a completed and signed GSPR Checklist, without the involvement of a notified body, should be sufficient to meet the requirement of MDR Article 1(9).

Finally, attention has been called by earlier responders to MDR Article 5.3 and Article 61; however, these MDR articles apply to an item that is regulated solely as a medical device and not as a medicinal product.

------------------------------
Maria E Donawa, M.D.
President, Donawa Lifescience
Rome, Italy
medonawa@donawa.com
+39 06 578 2665
------------------------------

Original Message:
Sent: 22-Mar-2021 01:29
From: Ming Aquila
Subject: Question regarding MDR Article 117 and Clinical Evaluation Report

We are developing a combination product with the drug PMOA. The combination product meets the definition per MDR Article 1 Point 9 the second paragraph, therefore, we are following MDR Article 117 requirements. There are directions given by consultants that we need to produce a CER (clinical evaluation report). I wonder if this is indeed a requirement as Article 117 does not dictate such a requirement. Certainly, an executive summary must include that the device constituent part is deemed safe and effective as the combination product as a whole performs as intended; however, from my point of view, a CER is not warranted. as we are evaluating clinical efficacy from a drug (PMOA) perspective, not the device. Can someone who has experience dealing with NB Opinion on a Combination Product with drug PMOA shed some light on this topic? Thank you.

Dear Ming,
Please refer to this Team-NB's document, it clearly guide you on what documents you need to obtain a positive notified body opinion following article 117:
Team NB position paper on Template for NBOp_V4 (team-nb.org)

Best regards,
Marlon

------------------------------
Marlon Luca Machal
------------------------------

Original Message:
Sent: 22-Mar-2021 01:29
From: Ming Aquila
Subject: Question regarding MDR Article 117 and Clinical Evaluation Report

We are developing a combination product with the drug PMOA. The combination product meets the definition per MDR Article 1 Point 9 the second paragraph, therefore, we are following MDR Article 117 requirements. There are directions given by consultants that we need to produce a CER (clinical evaluation report). I wonder if this is indeed a requirement as Article 117 does not dictate such a requirement. Certainly, an executive summary must include that the device constituent part is deemed safe and effective as the combination product as a whole performs as intended; however, from my point of view, a CER is not warranted. as we are evaluating clinical efficacy from a drug (PMOA) perspective, not the device. Can someone who has experience dealing with NB Opinion on a Combination Product with drug PMOA shed some light on this topic? Thank you.