june 3, 2019 dr. yinghui liu working group chair€¦ · dr. yinghui liu, imdrf june 3, 2019 page 2...

701 Pennsylvania Avenue, NW Suite 800

Washington, D.C. 20004–2654

Tel: 202 783 8700 Fax: 202 783 8750

www.AdvaMed.org

Bringing innovation to patient care worldwide

June 3, 2019

Dr. Yinghui Liu

Working Group Chair

Medical Devices Clinical Evidence Working Group

International Medical Device Regulators Forum (IMDRF)

Dear Dr. Liu:

On behalf of AdvaMed, the Advanced Medical Technology Association, thank you for

the opportunity to review and provide comment on the technical documents which update

the current Global Harmonization Task Force (GHTF) documents on clinical evaluation

including GHTF SG 5 N1, N2 and N3 documents. We greatly appreciate your leadership

and that of the Medical Device Clinical Evaluation (MDCE) Working Group (WG) in

revising and updating the Clinical Evidence – Key Definitions and Concepts, Clinical

Investigation and Clinical Evaluation documents.

AdvaMed is the world’s largest trade association representing medical device and

diagnostics manufacturers. AdvaMed's member companies produce the innovations that

are transforming health care through earlier disease detection, less invasive procedures

and more effective treatments. AdvaMed’s member companies range from the smallest to

the largest medical technology innovators and manufacturers. AdvaMed advocates for a

legal, regulatory and economic environment that advances global health care by assuring

worldwide patient access to the benefits of medical technology. The Association

promotes policies that foster the highest ethical standards, rapid product approvals,

appropriate reimbursement, and access to international markets.

AdvaMed has both general comments and specific comments on the working group

documents below.

General Comments

AdvaMed strongly supports the development of a harmonized approach for clinical

evidence for use by regulatory authorities in regulatory submissions. We believe a

globally harmonized approach will allow for faster introduction of safe and effective

medical technologies for patients while leveraging scientific research from around the

globe. Importantly, such an approach will also limit the number of patients exposed to

experimental products.

http://www.advamed.org/

Dr. Yinghui Liu, IMDRF

June 3, 2019

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We concur with the statement in the Clinical Evidence – Key Definitions and Concepts document

“… that convergence of requirements for clinical evidence, including common data submission,

will lead to better understanding of medical device safety, clinical performance, and/or

effectiveness by all stakeholders” as well as “more efficient use of resources of the clinical

community, medical device regulators and industry, and increased transparency and confidence in

the global regulatory model.” Additionally, as noted in the Clinical Evaluation document, “when

clinical investigations are conducted ethically in accordance with good clinical practice, the

clinical data should be accepted for consideration in any jurisdiction” dependent upon differences

in regulatory requirements or scientifically-based intrinsic or extrinsic factors. We also strongly

support the concept embedded in the Clinical Evaluation document that aspects of the

investigation that do not meet requirements for study conduct in each jurisdiction can be explained

and justified by the sponsor.

We support IMDRF’s efforts to promote efficiency and effectiveness in premarket review by

promoting leverage and evaluation of all sources of available clinical evidence, including

integration of the principles of real-world evidence.

Real-world evidence is becoming an increasingly important source of credible scientific evidence

for regulatory decision-making: ongoing technological advances are enabling improved

generation, aggregation, and analysis of real-world data; and global governments and healthcare

systems are establishing infrastructure and frameworks for collection and use of real-world

evidence for regulatory decision-making and healthcare research, subject to assurance of relevance

and reliability, and compliance with ethical and privacy legislation.

AdvaMed recommends that the three IMDRF MDCE documents help protect and promote

convergence of thought on this subject. As currently drafted, these documents take a step in that

direction by pointing out registries and adverse event databases as acceptable sources of clinical

experience/clinical data. However, we recommend that these documents go even further by

adding:

• Explicit real-world data terminology, and

• Mention of other common real-world data sources

We believe these recommended edits are consistent with the IMDRF MDCE WG’s intent to

integrate the principles of real-world evidence into these documents, ultimately ensuring efficient,

predictable, and timely access to medical technology by patients and society worldwide.

AdvaMed has included a number of editorial recommendations to accomplish this objective in

Specific Comments below.

Dr. Yinghui Liu, IMDRF

June 3, 2019

of 14

Specific Comments

AdvaMed has a number of Specific Comments that are included in the attached Excel Tables.

In closing, thank you for your consideration of AdvaMed’s General and Specific comments and

the IMDRF MDCE WG documents. Please don’t hesitate to contact me if you have any questions.

Sincerely,

/s/

Tara Federici

Vice President

Technology and Regulatory Affairs

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IMDRF MDCE

WG Comment

Form

Document: IMDRF MDCE WG (WD)/Nx (formerly GHTF/SG5/N1R8:2007)

Clinical Evidence – Key Definitions and Concepts

Name Company/

Organization

Email

Address Section

Line

Number

Type of

Comment Comment Proposed Change

Tara Federici

AdvaMed [email protected]

Section 4.1

95 - 103 T We are concerned that safety and clinical performance and effectiveness will potentially be interpreted as three different requirements when under the differing regulatory schemes, they are always treated as two requirements (i.e., either safety and clinical performance or safety and effectiveness. We suggest editing the definition to say safety and clinical performance/effectiveness. This terminology change should be made throughout all of the documents.

Change to the following: Definition: Any systematic investigation or study in or on one or more human subjects, undertake to assess the safety, and clinical performance/effectiveness, and/or effectiveness of a medical device.

mailto:[email protected]


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IMDRF MDCE

WG Comment

Form


Clinical Evidence – Key Definitions and Concepts

Name Company/

Organization

Email

Address Section

Line

Number

Type of


Tara Federici

AdvaMed [email protected]

Section 6

280-283 T We appreciate that IMDRFs revisions of the Medical Device Clinical Study documents encourages leverage and evaluation of all sources of available clinical evidence, including acceptance of overseas clinical data. Acceptance of overseas clinical data can be an important way to avoid duplicative clinical trials and conserve resources of sponsors and reviewers alike. Before mentioning considerations around multi-regional clinical trial designs, we recommend that the document first mention acceptance of overseas data by including relevant language from Appendix D of IMDRF MDCE WG (PD1)/Nx “Clinical evaluation” This modification is consistent with the IMDRF MDCE WG’s intent.

Add the following text between line 279 and 280: “When clinical investigations are conducted ethically in accordance with applicable good clinical practice, the clinical data should be accepted for consideration in any jurisdiction. The clinical investigation should be conducted in compliance with study conduct regulations in both the jurisdictions where the investigation is performed as well as in those jurisdictions where the investigational device is going to be reviewed for the market approval. If intrinsic or extrinsic factors such as those outlined in Appendix D of “IMDRF MDCE WG (PD1)/Nx “Clinical evaluation” will prevent the acceptance of data in all intended jurisdictions, then multi-regional clinical investigation designs may be considered to facilitate more efficient medical device development, thus providing earlier access to new medical devices worldwide. For multi-regional clinical investigation designs, the potential differences between two or more regions that might affect study results should be carefully considered.”



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IMDRF MDCE

WG Comment

Form

Document: IMDRF MDCE WG (PD1)/Nx (formerly GHTF/SG5/N3:2010)

Clinical Investigation

Name Company/

Organization Email Address Section

Line

Number

Type of


Tara

Federici

AdvaMed [email protected] Introduction 46 T The date stamp on the referenced document is February 2010 (rather than May 2007)

Strike and add the following: May, 2007 February, 2010 (GHTF/SG5/N3:2010

Tara

Federici

AdvaMed [email protected] Scope 67 E Remove GHTF and replace with IMDRF

Future GHTF IMDRF documents will specifically address post-market clinical follow-up studies.

Tara

Federici

AdvaMed [email protected] References 84 E Please update the Labelling reference with the updated version (final expected to be released shortly)

GHTF SG1/N43:2005 Labelling for Medical Devices Update with IMDRF 2019 Principles of Labeling for Medical Devices and IVD Medical Devices document when released




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IMDRF MDCE

WG Comment

Form



Name Company/


Line

Number

Type of


Tara

Federici

AdvaMed [email protected] Section 6 280-283 T We appreciate that IMDRFs revisions of the Medical Device Clinical Study documents encourages leverage and evaluation of all sources of available clinical evidence, including acceptance of overseas clinical data. Acceptance of overseas clinical data can be an important way to avoid duplicative clinical trials and conserve resources of sponsors and reviewers alike. Before mentioning considerations around multi-regional clinical trial designs, we recommend that the document first mention acceptance of overseas data by including relevant language from Appendix D of IMDRF MDCE WG (PD1)/Nx “Clinical evaluation” This modification is consistent with the IMDRF MDCE WG’s intent.

Add the following text between line 279 and 280: “When clinical investigations are conducted ethically in accordance with applicable good clinical practice, the clinical data should be accepted for consideration in any jurisdiction. The clinical investigation should be conducted in compliance with study conduct regulations in both the jurisdictions where the investigation is performed as well as in those jurisdictions where the investigational device is going to be reviewed for the market approval. If intrinsic or extrinsic factors such as those outlined in Appendix D of “IMDRF MDCE WG (PD1)/Nx “Clinical evaluation” will prevent the acceptance of data in all intended jurisdictions, then multi-regional clinical investigation designs may be considered to facilitate more efficient medical device development, thus providing earlier access to new medical devices worldwide. For multi-regional clinical investigation designs, the potential


of 14

IMDRF MDCE

WG Comment

Form



Name Company/


Line

Number

Type of


differences between two or more regions that might affect study results should be carefully considered.”

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IMDRF MDCE

WG Comment

Form


Clinical Evaluation

Name Company/

Organization Email Address Section Line Number

Type of


Tara Federici

AdvaMed [email protected] Section 5 What about in vitro diagnostic devices

line 434-435 Technical The general advice provided in these medical device clinical study documents concerning harmonization in approach and leveraging and evaluating available clinical evidence such as overseas clinical trial data and integrating real-world evidence principles are also relevant to IVD clinical evaluations. However, these important concepts are not emphasized in the older (2012) IVD-specific documents that are still in force. We would like to see recognition of the fact that the advanced thinking on these points also applies to IVDs. To this end, we recommend including wording extending these concepts to IVD studies, while still acknowledging the additional separate considerations brought forth in the 2012 documents cited. This suggestion is consistent with IMDRF’s overall strategic priorities to increase the predictability and efficiency of premarket review.

Modify the second sentence of the paragraph to read as follows: “The basic principles of sourcing, appraisal, and analysis of objective review clinical data will apply as described in this guidance document and its appendices”. However, In addition to these basic principles, …


of 14

IMDRF MDCE

WG Comment

Form


Clinical Evaluation

Name Company/


Type of


Tara Federici

AdvaMed [email protected] Section 6.2 538 (After 4th bullet)

T We appreciate IMDRF’s efforts to promote efficiency and effectiveness in premarket review by promoting leverage and evaluation of all sources of available clinical evidence, including integration of the principles of real-world evidence. Real world evidence is becoming an increasingly important source of credible scientific evidence for regulatory decision-making. ▪Ongoing technological advances are enabling improved generation, aggregation, and analysis of real-world data; and ▪Global governments and healthcare systems are establishing infrastructure and frameworks for collection and use of real-world evidence for regulatory decision making and healthcare research, subject to assurance of relevance and reliability, and compliance with ethical and privacy legislation.

Add a new bullet after the first bullet as follows: ▪Real-world data from

sources such as: registries, electronic health records, claims and billing databases, wearable devices, and smart medical technologies


of 14

IMDRF MDCE

WG Comment

Form


Clinical Evaluation

Name Company/


Type of


The IMDRF documents concerning clinical evaluations should protect and promote convergence of thought on this subject. As currently drafted, this document takes a step in that direction by pointing out the value of clinical experience data in larger populations; and including registries as acceptable sources of clinical experience/ clinical data. We recommend that this document go even further by ▪Adding explicit real-world data terminology ▪Adding mention of other common real-world data sources ▪Mentioning potential use in regulatory-decision making. Such modifications are consistent with the IMDRF MDCE WG’s intent to integrate the principles of real-world evidence into these documents, ultimately ensuring efficient, predictable, and timely access to medical technology by patients and society worldwide.

of 14

IMDRF MDCE

WG Comment

Form


Clinical Evaluation

Name Company/


Type of


Tara Federici

AdvaMed [email protected] Section 6.2 548 End of section

T We appreciate IMDRF’s efforts to promote efficiency and effectiveness in premarket review by promoting leverage and evaluation of all sources of available clinical evidence, including integration of the principles of real-world evidence. Real world evidence is becoming an increasingly important source of credible scientific evidence for regulatory decision-making. ▪Ongoing technological advances are enabling improved generation, aggregation, and analysis of real-world data; and ▪Global governments and healthcare systems are establishing infrastructure and frameworks for collection and use of real-world evidence for regulatory decision making and healthcare research, subject to assurance of relevance and reliability, and compliance with ethical and privacy legislation.

Add a new sentence on line 548 as follows: “Increasingly, such real-world clinical experience data can also be considered for use in regulatory decision- making, subject to assurance of relevance and reliability.”


of 14

IMDRF MDCE

WG Comment

Form


Clinical Evaluation

Name Company/


Type of


The IMDRF documents concerning clinical evaluations should protect and promote convergence of thought on this subject. As currently drafted, this document takes a step in that direction by pointing out the value of clinical experience data in larger populations; and including registries as acceptable sources of clinical experience/ clinical data. We recommend that this document go even further by ▪Adding explicit real-world data terminology ▪Adding mention of other common real-world data sources ▪Mentioning potential use in regulatory-decision making. Such modifications are consistent with the IMDRF MDCE WG’s intent to integrate the principles of real-world evidence into these documents, ultimately ensuring efficient, predictable, and timely access to medical technology by patients and society worldwide.

of 14

IMDRF MDCE

WG Comment

Form


Clinical Evaluation

Name Company/


Type of


Tara Federici

AdvaMed [email protected] Appendix D Section 1

#1, lines 976-982

T In order for foreign data to be accepted by other countries, it must meet their submission requirements as well as Good Clinical Practice (GCP) principles. It will be extremely challenging for a study conducted in one country to meet all other countries’ requirements. For example, data privacy requirements vary significantly from country to country. In addition, many times the sponsor may not know which countries the data will be submitted to in advance. To avoid the potential for misinterpretation which is at cross purposes with the intent of the guidance, we recommend further clarification of the language as suggested.

Modify Section 1 to read as follows: “The clinical investigation should be conducted in compliance with both regulations required in the jurisdictions where the investigation is performed and generally consistent with GCP principles. In addition, the application containing the clinical investigation should meet the submission requirements as well as where the investigational device is going to be reviewed for the market approval. Aspects of the investigation that do not meet the requirements for study conduct in each jurisdiction (e.g., human subject protection, data privacy and ethical review) should be explained and justified.”


june 3, 2019 dr. yinghui liu working group chair€¦ · dr. yinghui liu, imdrf june 3, 2019 page 2...

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