ISO TC 194 WG 4 - ISO 14155 Revision - Meeting Minutes
Mishima, Japan. April 24 /25, 2014
Convenor: D. Giroud (CH)
Notes by: M. Tocchi (IT)
Attendees: Sumati Randeo (AHWP), Jennifer Kerr (US), Keith Kinsley (US), Klaus Dermann (DE), AnnCatrin Petersson (SE), Roland Pohl (DE), Koki Ueno (JP), Kazuo Yano (JP), Hwal Suh (Korea), Scott McNamee(US), Alan Hood (US).

OPENING
Introduction: Total 12 (13) attendees (plus J. Tinkler by phone)
Documents received for discussion during the meeting, are distributed to attendees by USBfrom Anneke Hurkens and Klaas
Jeremy Tinkler sent documents on Risk Analysis
Arrangements for telephone connection with members in Europe
Adoption of meeting minutes of the Berlin timelines: agreed by all attendees

TIMELINES OF NEW ISO 14155 REVISION
Danielle commented that European new regulation will be delayed because no consensus was reached,
except for the data protection directive (the latter was adopted).
Meeting with Karl Wenzelewski.
Proposal will be reviewed in 30 days. (Already distribute as WD dated June 6th, 2014) Revision
process can select 24 months or 36 months of 48months.
The process is now CD, DIS, Publication, much faster. The CD stage can be avoided if it is felt thatthe DIS is well done and will be easily approved. The FDIS stage does not exist anymore.
Danielle suggests 36 months as ISO 14155 revision time. We have some quite heavy items toaddress and international discussion is expected. So this revision will be expected to take sometime. The expected change in EU regulation should take longer.
NEXT MEETINGSNext meeting of ISO TC 194 will be in Malmo Sweden (June 2015) of if Sweden cannot host,
Germany Berlin (Sept 2015).
The WG4 will have another meeting week 26th of October 2014, probably in the US (to facilitate
involvement of US representatives). Problem for budget of some companies because 3 meetings in
one year. To be confirmed after receiving news from FDA representative Fabienne Santel.
DHHS/FDA/CDRH/OMPT/CDRH/OC/DBM, MEDICAL OFFICER

1Need to check with AAMI if room is available (28th-29th October, 2014). Jennifer proposed to hostthe group in the company facilities in Indianapolis (2 hours south of Chicago).

REVIEW OF THE ACTION ITEMS FROM THE AGENDA
The following action items from the Berlin meeting (February 6, 2014) were opened for discussion.

TOPIC 1: SPONSOR MEMBERS FOLLOWUP Speaker: D. Giroud
Sumati’s summary: Plan to involve members from India, Singapore, Taiwan and Malaysia. Other country to
involve: Vietnam (they are drafting their MD regulation). Sumati suggests to draft an ISO letter to approach
the prospective countries. Several meetings in May so the letter is needed soon. During plenary meeting,
Danielle was informed an official liaison MOU must be drafted by TC 194 – action items of the plenary
meeting.
EXPAND MEMBERSHIP
Danielle has not been able to connect with the Chinese FDA before this meeting but will do so after to keepthem informed. Jennifer Kerr indicates that new regulation is coming up shortly. Advamed has strong
relationship with China and could aid the liaison. Other possibility is the Department of Commerce. A
further possibility is through their relationship to Taiwan (Danielle to investigate). Other possibilities topursue: Mexico, South America. Jennifer suggests to connect with CRO allegiance in Mexico.

TOPIC 2: CIP Content – Changes to annex A Speaker: Kazuo Yano
Kazuo Yano presents Proposal for Changing annex A.
Slide presentation is given (authors Kazuo Yano, Maria Donawa, Jennifer Kerr), that covers the sideby-side gap analysis with SPIRIT Recommendations.
Only 6 items of ISO 14155 may need additional information (trial registration/study setting/allocation/blinding/access to data/dissemination policy).
Various changes are made through ought ISO for protocol clarifications.
Dissemination policy:
Jennifer comments on Dissemination Policy.
Statement to be added to ISO 14155 should focus on making the data publicly available (fortransparency).
Team discussion regarding what extent of data is to be made publicly available.
Trial Registration in public database:It is an important point because it is becoming part of the regulation.
In the US it is already mandatory that it is in the informed consent.
There is a note in the current ISO 14155, section 7.3 (note 2).
Either the protocol or informed consent must state that the study is registered in a database.
Jennifer suggests to follow national regulation.
It could be included in multiple sections
o Section “Sponsor responsibilities”
o Section 5, Planningo also in 4.1 (General ethical consideration); or in 4.7 (Informed consent).
Possibility to create separate section, Section 4.5 where it stands out.
The group agrees to create a separate point, between current points 4.3 and 4.4
New point 4.4. Registration in publicly accessible database.
Danielle drafts the new text into the ISO 14155 with input from the group and other sections were
updated as well.
“Study setting” discussion: new issue for discussion is the debarment of investigators, conflict of interest,
financial compensation issue. The item was added to the “parking lot” (presented at the end of thisdocument).
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Discussion on trial design (including blinding/masking): should this be addressed in details in the ISO? We
will wait for the new information derived from the work on the MEDDEV Guideline for Regulatory Authority
2.7/2 which is being developed. CIE (Computer, Instrumentation, Electric control) will discuss it in May inBrussels, and the publication is expected by the end of the year. Danielle has already sent many comments
because of several areas of concern. She will circulate the summary to the WG4 after the meeting in May.
Access to data: Review of SPIRIT. This relates to trial data publication.

TOPIC 3: Weak Points with regard to Annex A review Speakers: NOT PRESENTKim Oleson is no longer with the WG4. Jennifer will step in as liaison for ADVAMED.
Maya is not in attendance.
This topic is reassigned to Maya and Jennifer, for discussion during next WG4 meeting. This topic will be
combined with the topic of “Study Design”.

TOPIC 4: Report need to adapt ISO 14155 for Registries Speaker: Sumati Randeo
Presented slides on the topic of registries
Refers to Singapore HSA (Health Science Authority) meeting (2013) which discussed the topic and came up
with recommendations.
Roland presents definition and recommendations from MEDDEV on PMCF (Post Market Clinical Follow Up)
Ann-Catrin presents an overview of FDA regulation and guidelines.
All group agrees on the need to provide clarification on postmarket studies and registries, differentiating
the different kinds (sponsored, investigator driven, organized by scientific associations or authorities, etc)
AHRQ (Agency for Healthcare Research and Quality, US Department of Health & Human Service) 2010
User’s Guide can be a source for a gap analysis with ISO 14155.
Action item: team will prepare a proposal for next meeting.
Tasks are to look at post-market studies, which include the category of “registries”. Work in combination
with team assigned to “study design” (Topic 3).
Reference documents: ICH, HRQ, FDA 2013 guideline on pivotal studies.

TOPIC 5: Risk Management Speaker: Jeremy Tinkler (by phone)
Discussion with Jeremy by phone. All agreed on the benefit of adding the flowchart prepared by Jeremy.
Action item: Danielle will insert Jeremy’s flowchart as an annex in ISO Revision and wait for comments.
Monica to share her presentation about the same topic with Jeremy for further elaboration of theflowchart.

TOPIC 6: FDA Feedback on EC guidance Speaker:
Scott McNamee presented some FDA considerations based on US device and drug regulations. Here is an
extract from Fabienne’s email“FDA does not have authority to regulate foreign EC’s and we respect the respective country’s regulatory
authority and their ability to oversee the EC’s that function in that country. However FDA does expect that
foreign EC’s review research in accordance with good clinical practice. Specifically FDA has recognizedboth ISO 14155:2011 and ICH E6 “Guideline for Good Clinical Practice” and encourage foreign EC’s tofollow the international guidelines for EC’s described in these documents – ICH E6 has more
extensive recommendations.
In addition FDA is in the process of amending the device regulations (proposed rule from February 2013)
requiring that foreign data submitted in support of FDA marketing follow good clinical practices.
This will provide further guidance on the role of IEC’s and foreign data. The proposed rule and comments
received are under review.
A similar amendment to the drug regulations was finalized in 2008 - 21 CFR 312.120 and the members of
WG4 can refer to that for reference. It states that foreign clinical studies not conducted under an3

investigational new drug application (IND) (“non-IND foreign clinical studies”) as support for an IND or a
new drug application (NDA), abbreviated new drug application (ANDA), or a biologics license application(BLA) (collectively known as “marketing applications” or “applications for marketing approval”) be
conducted in accordance with good clinical practice (GCP), including review and approval by anindependent ethics committee (IEC) and informed consent from subjects.
With respect to IEC’s the drug rule defines the IEC as a “a review panel that is responsible for ensuring theprotection of the rights, safety, and well-being of human subjects involved in a clinical investigation, and isadequately constituted to provide assurance of that protection.” The proposed device rule also has thisdefinition. We have received comments on this and they are currently under review. However this issue isaddressed in the March 2012 FDA guidance document on the amended drug regulations entitled “Guidancefor Industry and FDA Staff FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND
Frequently Asked Questions”. The following is from page 9 of the guidancea. What does FDA consider an “adequately constituted” IEC?

Answer: FDA regulations at 21 CFR 312.3(b) define an IEC as a “review panel that is responsible for
ensuring the protections of the rights, safety, and well-being of human subjects involved in a clinicalinvestigation and is adequately constituted to provide assurance of that protection.” FDA believes an“adequately constituted” IEC is one that consists of a reasonable number of members who collectively
have the qualifications and experience to review and evaluate the science, medical aspects and ethicsof the proposed trial. As provided in ICH E6, section 3.2, an IEC includes at least five members,
including at least one member whose primary area is in a nonscientific area and at least one member
who is independent of the institution where the research will be conducted (i.e., not otherwise affiliatedwith the institution and not part of the immediate family of a person who is affiliated with theinstitution).
FDA recommends that every nondiscriminatory effort be made to ensure that the IEC composition is
not limited to only one gender and that it reflects the social and cultural diversity of thecommunity(ies) from which research participants are most likely to be drawn. It is further advised that
only those members who are independent of the investigator and the sponsor of the trial vote on trialrelated matters.
Another issue that came up from the last standards meeting was the requirements for foreign data ofsignificant risk, non-significant and exempt devices. We received many comments on the proposed rule andthis is also under review.”
Action point: Danielle looks at archives and find early proposal of EC requirements which was drafted in thepast by Kimber Richter to be included in an Annex of ISO 14155 in the new Revision and make a cross checkwith ICH 6. Sumati to send recent Indian regulation on EC requirements.

TOPIC 7: Proposal for including Public Health Threat Speaker: Danielle Giroud
Review of proposed definitions and reporting timescales from MEDDEV and GHTF in slide presentation
prepared by Klaas van t’Kooster.
Consensus of the Dutch committee and the WG4 in Mishima agrees to adopt the following definition:
Serious health threat/hazard. Any SAE that indicates an imminent risk of death or a serious
deterioration in the health in subjects, users or other persons and that requires prompt remedialaction for other subjects, users or other persons.
重篤な健康被害の恐れ/ハザード：被験者、使用者あるいは第三者の切迫した死亡のリスク、健康の著しい悪化を示すあらゆる重篤な有害事象で、他の被験者、使用者あるいは第三者に迅速な救済措置が必要である

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ACTIONS FOR NEXT MEETING (assigned to Klaas)
Add some explanations in 6.4.3, 7.1.1 and 8.2.5, and Annex A 14.
Add this entity to the flowchart in annex F
Add the bibliography to refer to the GHTF and MEDDEVTOPIC 8: Overview of EDC Validation Speaker: Monicca
Presentation by M. Tocchi, will be circulated to attendees.
ACTIONS FOR NEXT MEETING
Monica: do a side by side gap analysis of ICH E6 versus ISO 14155; and suggest one paragraph and abibliography
Jennifer: suggests to expand the data protection clause that is a note in 4.7 (d). (Assigned to Jennifer, add
to 6.7)

TOPIC 9: Better link to ISO 13485 & Usability Standard Speaker:
Discussion of interpretation of the following sentence by Quality Assurance in Abbott Vascular (comment
received by Danielle from Glen van Landeghem) creating discordance between clinical department andoverall QA department in that company:
From 8.1 Clinical quality assurance and quality control may be integrated in the sponsor's overall
quality system. NOTE For further information, see ISO 13485[1].
The WG confirms the adequacy of the section.
The rest of this topic has been considered important and assigned to Danielle Giroud and Suzanne
Bloemsma. Points to modify are 6.9 (device accountability) and make a section on device readiness. Also
modify the annex on investigator brochure regarding the need to establish conformance with design
control processes as described in quality system regulation.

TOPIC 10: Clarification on Clinical Evidence – review evidence Speaker: Danielle
No work done on this yet. Remains in Parking Lot.
Review February email from Isabel Scuntaro (Swissmedic) on good practices for handling patients lost tofollowup. She suggests addressing this point in ISO 14155. Relevant changes are made to ISO to cover theissue of tracing and documenting of subjects lost to follow-up. This task is completed.

TOPIC 10 (11): Outline on annex for inspections/audit Speaker: Danielle
Requested by authorities in Asia. No work done on this yet. Assigned to Sumati but bigger group needed.
Remains in Parking Lot.

TOPIC 11 (12): Clarify Annex E regarding Source Documents Speaker: Ann-Catrin
Add a reference to where source documents are kept.
Changes are made in ISO 14155, sections 8.2.4.4, E1, E2 and other sections. This task is completed.

PARKING LOT & ACTION ITEMS
Items to be addressed before the closure of the ISO Revised document. Agreed timelines for addressing theissues are specified.
TOPIC Actions Timeline SG Members
TOPIC Actions
1
Membership expansion in Asia. Danielle to draft invite
letter from ISO and Sumari to distribute to India, Singapore,
Taiwan, Malaisia, Vietnam.
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Organization of next meeting. Arrange and communicate
dates to the group5Timeline
ASAP

SG Members
Sumati,Danielle

ASAP

DanielleTOPIC
2

Actions
Debarrment of Clinical Investigators. Elaborate on conflictof Interest, Compensation review by Authorities. Asia and US

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Trial design: specify better in the protocol Annex A? Discussagain after May CIE meeting to discuss new MEDDEV 2.7/2 needs
to be circulated
Weak Points with regard to Annex A review. Topic to be
combined with “Trial design”
Adapt ISO for registries. prepare a proposal for ISO
integration /clarification on postmarket surveillance, studies andregistries. Draft to be submitted to Danielle at the end of
September
Risk Management. Danielle will insert Jeremy’s flowchart as anannex in ISO Revision and wait for comments. Monica to liaise
with Jeremy to improve flow chart.
EC Guidance. Action point: Danielle look at archives and findearly proposal of EC requirements to be included in an Annex.
Serious health threat/hazard. Action items: Add some
explanations in 6.4.3, 7.1.1 and 8.2.5, and Annex A 14. Add thisentity to the flowchart in annex F. Add the bibliography to referto the GHTF and MEDDEVElectronic Records/Data Privacy. Monica: do a side by side
gap analysis of ICH E6 versus ISO 14155; and suggest one
paragraph and a bibliography
Jennifer: expand the data protection clause (add to 6.7)
Better link to ISO 13485 & Useability Standard. This topic
will be left on the parking lot.
Sumati and Danielle to review 13485 and send comment to TC
210 regarding the use of terminology regarding clinical evaluationand investigation.
Outline on annex for inspections/audit. Identify more WG
members to work on this task.

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Timeline
End of ISO
revision (2years)
May-June2014

SG Members
Danielle,
SumatiNext WG4
Meeting30
September2
014

Jennifer Kerr,
Maya
Roland,Sumati, AnnCatrin

Next WG4
Meeting

Jeremy,Monica,Danielle
Danielle(done)
Klaas

Next WG4
Meeting
Next WG4
Meeting

Danielle

Next WG4
Meeting

MonicaJennifer

Next WG4
Meeting

Danielle
SusanneNext WG4
Meeting

Sumati

Meeting closing
Danielle shows her meeting summary notes
During the dinner of TC 194, Danielle made a small public note requesting to change the name of
the TC 194 from biological evaluation for medical devices to Biological and Clinical evaluation for
medical devices. This was received very positively immediately and adopted at the plenary meetingon Saturday 26th. The name will change and it will likely also be adopted by the CEN mirror
committee
Greetings from Mount Fuji

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