ISO 14155.pdf

A guideline on medical devices designed internationally for harmonization.
As the site access is unavailable have managed the data for easy access of the details for the Regulatory affairs aspirants of Masters of Pharmacy

1. By:
Zeel Shah
Masters of Regulatory Affairs

3. C
O
N
T
E
N
T
S
History
Amendments
Risk management in practice
Clinical Quality management
Scope
Normative references
Terms and definitions
Summary of GCP
Ethics Committee
Clinical Investigation Planning
Clinical Investigation Conduct
Suspension, termination and closeout of the clinical investigation
Sponsor responsibilities
PI responsibilities
Annexures

4. •Clinical investigation of medical devices for human subjects —
Good clinical practice
ISO 14155:2020
(Current)
•Clinical investigation of medical devices for human subjects —
Good clinical practice
ISO 14155:2011 (Withdrawn)
•Clinical investigation of medical devices for human subjects —
Good clinical practice —Technical Corrigendum 1
ISO 14155:2011/Cor1:2011
(Withdrawn)
•Clinical investigation of medical devices for human subjects —
Part 1: General requirements
ISO 14155-1:2003 (Withdrawn)
•Clinical investigation of medical devices for human subjects —
Part 2: Clinical investigation plans
ISO 14155-2:2003 (Withdrawn)
•Clinical investigation of medical devices
ISO 14155:1996 (Withdrawn)
HISTORY

5. Clinical quality management
Addressing increased statistical requirements by notified bodies
Clinical Investigation audits
Risk based monitoring and related monitoring plan
Ethics Committee
In-vitro diagnostic medical devices (IVD’s)
Increased emphasis on risk management (ISO 14971)
Clinical investigation planning requires inclusion of personnel with relevant medical expertise
Alignment with definitions with current updated GCP guidelines
Emphasis on clinical evidence in European Regulation
AMMENDMENTS in ISO 14155:2020

6. Risk Management in Practice
Implementation of ISO 14971 involves a system for risk
management.
Risk management plan indentifies, evaluates, ranks and
control risks.
-RMP’s can be inclusive of risk from entire product life.
-Risk can be product related or patient related.
-Can be applied to project specific risks (clinical trials)
Formal risk management processes is focus of ISO
14155: 2020

7. Quality management process includes SOP’s , computerized quality system and
personnel training.
Sponsor is responsible for clinical study quality even if study management is
outsourced to third party.
Document control process for study files such as protocol, IDs , and so on
Complete record maintenance
Preparation for audits
Identify, Justify and document expectations to requirements
CLINICAL QUALITY MANAGEMENT

8. 1. SCOPE
Addresses GCP (design,
conduct, recording,
reporting) for clinical
investigations in human
subjects (effectiveness
and safety) of medical
devices
Protect the
rights, safety
and well-being
of human
subjects
Ensure the
scientific conduct
of the clinical
investigation and
the credibility of
the clinical
investigation
results
Defines
responsibilities of
Principal
investigator ,
sponsor and
other parties
Assist sponsors,
investigators, ethics
committees,
regulatory
authorities and other
bodies involved in
the conformity
assessment of
medical devices.

9. 2.
Normative References
The following documents are referred to in the text in
such a way that some or all of their content constitutes
requirements of this document.
For dated references, only the edition cited applies.
For undated references, the latest edition of the
referenced document (including any amendments)
applies.
ISO14971,Medical devices —Application of risk
management to medical devices

10. 3. TERMS AND DEFINITIONS
•Adverse events resulting from insufficient or inadequate instructions for use,
deployment, implantation, installation, or operation, or anymalfunctionof the
investigational medical device.
•Includes any event resulting fromuse erroror from intentional misuse of the
investigational medical device.
Adverse Device
Effect (ADE)
•Set of printed, optical or electronic documents for eachsubjecton
which information to be reported to thesponsoris recorded, as
required by the CIP
Case Report Form
(CRF)
•Document that states the rationale,objectives, design and pre-
specified analysis, methodology, organization,monitoring, conduct and
record-keeping of theclinical investigation
Clinical
Investigation Plan
(CIP)
•Document describing the design, execution, statistical analysis and
results of aclinical investigation
Clinical
Investigation Report

11. 3. TERMS AND DEFINITIONS
•Independentcommittee that can be established by thesponsorto assess, at
intervals, the progress of theclinical investigation, the safety data or the
criticalclinical performanceoreffectiveness, endpointsand to recommend to
the sponsor whether to continue, suspend, modify, or stop the clinical
investigation.
Data Monitoring
Committee
(DMC)
•Inadequacy of amedical devicewith respect to its identity, quality, durability,
reliability, usability, safety or performance.
•Includemalfunctions,use errors, and inadequacy in the information supplied by
the manufacturer including labelling.
Device
Deficiency
•Medical devicebeing assessed forclinical performance,effectiveness, or safety in
aclinical investigation
•Includes medical devices already on the market that are being evaluated for new
intended uses, new populations, new materials or design changes.
•includes medical devices already on the market that are being evaluated within
their intended use in a post-market clinical investigation (interventional or non-
interventional).
Investigational
Medical Device

12. 3. TERMS AND DEFINITIONS
Medical Device
Instrument,apparatus,implement,machine,appliance,implant,reagentforinvitrouse,software,materialorothersimilaror
relatedarticle,intendedbythemanufacturertobeused,aloneorincombination,forhumanbeings,foroneormoreofthe
specificpurpose(s)of:
—diagnosis,prevention,monitoring,treatmentoralleviationofdisease;
—diagnosis,monitoring,treatment,alleviationoforcompensationforaninjury;
—investigation,replacement,modification,orsupportoftheanatomyorofaphysiologicalprocess;
—supportingorsustaininglife;
—controlofconception;
—disinfectionofmedicaldevices;
—providinginformationbymeansofinvitroexaminationofspecimensderivedfromthehumanbody;
anddoesnotachieveitsprimaryintendedactionbypharmacological,immunologicalormetabolicmeans,inoronthehuman
body,butwhichmaybeassistedinitsintendedfunctionbysuchmeans
Productswhichmaybeconsideredtobemedicaldevicesinsomejurisdictionsbutnotinothersinclude:
—disinfectionsubstances,aidsforpersonswithdisabilities,devicesincorporatinganimaland/orhumantissues,devicesforin
vitrofertilizationorassistedreproductiontechnologies.

13. 3.TERMS AND DEFINITIONS
•Adverse device effectthat has resulted in any of the consequences
characteristic of aserious adverse event
Serious Adverse
Device Effect (SADE)
•Signal from any adverse event ordevice deficiencythat indicates an imminent risk of
death or a serious deterioration in the health insubjects, users or other persons, and that
requires prompt remedial action for other subjects, users or other persons
•Include events that are of significant and unexpected nature such that they become
alarming as a potential serious health hazard or possibility of multiple deaths occurring at
short intervals.
Serious Health Threat
•Serious adverse device effectwhich by its nature, incidence, severity
or outcome has not been identified in the current risk assessment
Unanticipated Serious
Adverse Device Effect
(USADE)
•Is an effect which by its nature, incidence, severity or outcome has
been identified in the risk assessment.
Anticipated Serious
Adverse Device Effect
(ASADE)

14. 4.
Summary
of GCP
Ethical
Principles
Risk benefit
ratio
Rights, safety,
well-being of
human
subjects
Scientifically
sound
Ethics
Committee
approval
Expert advice
and care
Education or
experience
Privacy,
Confidentiality
Systems
for quality
control

15. Ethical
Considerations
•Principle in clause 4 must be understood,
observed and applied in every step in the
clinical investigation
•Coercion
•Compensation
•Registration and public access
•Responsibilities (all parties)
•Communication with EC (use this document
and record)
•Information from EC (approval documents)
•Informed consent
5. ETHICS COMMITTEE (EC)

16. Responsibiliti
es (Annex G)
•Provides guidance on best practices for operation of EC
reviewing clinical investigation of medical devices.
Purpose
•Composed of members who collectively have
experience/qualification to review/evaluate scientific
medical, methodological, statistical and ethical aspects of
proposed clinical investigations.
5. ETHICS COMMITTEE (EC)

17. •All involved with trial design and conduct must be qualified by education, training or
experience.
•Qualification must be documented.
•The sponsor must have access to medical expertise relevant to the trial.
6.1 General
•Balance risk associated with device and related clinical procedure against anticipated
benefits to subjects.
•The sponsor should predefine risk acceptability threshold, if threshold is reached or
exceeded, risk assessment to determine whether/what actions are needed.
6.2 Risk
Management
•It is about risk management of medical devices.
•Risk control effectiveness evaluated by device lifecycle, including during trials.
•Trials provide data to support/refuse acceptability of benefit-risk ratio
6.2 Applications
of ISO 14971
(Annex H)
6. CLINICAL INVESTIGATION PLANNING

18. 6. CLINICAL INVESTIGATION PLANNING
•Design trial to evaluate if device suitable for
intended purpose and population.
•Based on preclinical data and clinical
evaluation, aligned with risk assessment.
•Clinical evaluation includes analysis of clinical
performance, effectiveness and safety data
of investigational device or similar device.
•Use to justify endpoints, confounding factors,
choice of control groups, bias minimization
and subject selection.
6.3 Design
of Clinical
investigation

19. •Identification of CIP, sponsor, principle investigator, co-ordinatinginvestigator and investigation
sites.
•Objectives and hypothesis of clinical trials
•Synopsis of investigation.
•Identification and description of investigational device.
•Design of clinical investigation including: investigation devices & comparator, subjects,
procedures and monitoring plan.
•Justification of designs.
•Statistical design and analysis.
•Data management
•Benefits and risks of investigational device, clinical procedure and clinical investigation.
•Description of procedures to amend CIP
•Deviations from CIP
•Device accountability
•Statements of compliance
•Informed consent process
•Adverse events, adverse device effects, device defeciencies
•Vulnerable population
•Suspension or premature termination of investigation.
•Publication policy
•Bibliography
6.4 Cinical
Investigation
Plan(CIP)
(Annex A)
6. CLINICAL INVESTIGATION PLANNING

20. 6. CLINICAL INVESTIGATION PLANNING
•Purpose:To provide principal investigator and investigation site
team with sufficient safety and performance data to justify
human exposure to investigational device. (Principal investigator
acknowledge receipt in writing and keep confidential).
•Update throughout investigation as new data becomes
available.
•Update if investigational device design changes.
6.5
Investigator
Brochure(IB)
(Annex B)
Components (Annex B)
•Identification of IB
•Sponsor/manufacturing
•Investigational device information
•Preclinical testing
•Existing clinical data
•Risk management of investigational device
•Regulatory and other references

21. 6. CLINICAL INVESTIGATION PLANNING
•Captures data for each enrolled subject: 1) Condition of each subject
at beginning and throughout investigation. 2)Exposure to
investigational device and other therapeutics.
•Format should minimize error.
•CRF completion guidelines provide instructions for accurate
completion, correction and signature of CRFs.
•If CIP amended, CRFs should be reviewed to determine if need
revised.
6.6 Case
Report
Form (CRF)
(Annex C)
•Benefit-risk summary should be disclosed in relevant trial documents.
•Example: Residual risk in IB and Instructions for Use (IFU) , all anticipated AE
device effects in CIP and informed consent form (ICF), rationale for benefit-
risk ratio in CIP
Risk
Disclosure

22. 6. CLINICAL INVESTIGATION PLANNING
•Determine appropriate monitoring based on risk
assessment.
•Monitoring methods can differ between countries
and should comply with national/regional
regulations regarding personal data protection.
6.7
Monitoring
Plan
DESCRIBES:
Risksandriskcontrolmeasures
Monitoringmethods
Methodsfordocumentingandcommunicatingmonitoringresults
Escalationprocessifcontinuousoregregiousnon-compliance
Aspectsofinvestigationneedingspecialattention
Processestobemonitoredanddatatobeverifiedinsource
documents

23. 6. CLINICAL INVESTIGATION PLANNING
•Identify criteria necessary for conduct of clinical investigation prior to start of site
qualification.
•Eg: Facilities required, principal investigators qualification, type of environment.
•Principal investigators qualification and investigation site adequacy verified and
documented in investigation site selection report.
6.8
Investigational
Site Selection
•Written agreements between sponsor and principal investigator/investigation site
and other relevant parties should be signed and dated by all parties.
•Agreement should detail responsibilities of each party.
•Agreement should identify instances where parties share regulatory responsibilities
with sponsor.
6.9
Agreements
•The device, IFU and packaging should state device is exclusively for use in clinical
investigation.
•In US, investigational label as per 21 CFR 812.5
•Caution: Investigational device limited by Federal (or United States) law to
investigational use.
6.10 Labeling

24. 7. Clinical Investigation Conduct
7.1 General
•Conducted in
accordance with CIP
•Not to commence until
EC and/or regulatory
approvals are obtained
7.2 Investigational Site Initiation
•Initiation visit or meeting shall be
conducted and documented by
sponsor/monitor at start of clinical
investigation
•Log with names, initials, signatures,
functions and designated authorizations for
principal investigator and members of
investigation site team
•Can be done by telephone or other means
7.3 Investigation
site monitoring
•Conduct of clinical
investigation
monitored according to
monitoring plan
•All monitoring activities
documented

25. 7. Clinical Investigation Conduct
7.4 Adverse events and device deficiencies
7.4.1
AEordevicedeficiency
potentiallyindicatingaserious
healththreatareevaluatedby
sponsor.
Mayrequireaspecific
reportingprocessaccordingto
regulatoryrequirements.
7.4.2
AllAEandanynewinformation
aredocumentedinatimely
mannerandreportedas
specified.
AllAEarereportedininterim
andfinalreports.
7.4.3
Devicedeficienciesdocumented
throughoutclinicalinvestigation
andmanagedbysponsoras
specifiedforcontrolofnon-
conformingproduct.
Alldeficientdevicesarereturned
forevaluationandreports
submittedevenifdeficiencydidn’t
causeAEbutcouldhavecaused
seriousAE.

26. 7. Clinical Investigation Conduct
7.4 Adverse events and device deficiencies
(Continue..)
7.4.4
Arising risk during clinical investigation:
a)Anypersonidentifyingriskpotentiallyimpactingsafetyinformsprincipalinvestigatorandsponsor.
b)SponsorshallperformriskanalysiswithPItodetermineifinformationisreflectedincurrentriskassessmentand
riskremainsacceptable.Ifunacceptable,andserioushealththreatisidentified,sponsorshallsuspendtrial
immediately.
c)Ifapossibleunacceptablerisk,sponsorshallconductriskassessmentincompliancewithISO14971with
possibilityof:
1)Risksremainsacceptable
2)Correctiveactionsfoundnotaffectingvalidityofinvestigationwithrevisedbenefit-riskmaycontinueinvestigation
3)Ifcorrectiveactionsaffectvalidityoftrial,trialistobeterminated
4)Ifnocorrectiveactionsmaybeapplied,investigationistobeterminated

27. 7. Clinical Investigation Conduct
7.5 Clinical Investigation Documents
•Amendments are made as needed
throughout investigation following written
procedures with documentation reviewed
and approved as specified.
•Subject identification log maintained at each
investigation site with an identification code
linked to their private information.
•Source documents are maintained by
investigation site team throughout clinical
investigation
7.6 Additional
members of the
investigation site
team
•New members added
to investigational site
teams will only start
their assignment
after receiving
adequate training
and training is
documented
7.7 Subject privacy
and confidentiality of
data
•Confidentiality observed
by all involved parties
and data is secured
against unauthorized
access.
•Privacy of subjects is
preserved in all reports
and publiction

28. 7. Clinical Investigation Conduct
7.8 Document and Data control
1) Traceability of documents and data:
All documents produced and maintained ensuring reliability, integrity, control and traceability including all
versions of document.
Source documents are verified and signed.
2) Recording data:
Data on CRFs from source documents and discrepancies explained in writing.
All CRFs are signed and dated.
3) Electronic Clinical data system:
Written procedures are used to describe system validation, data collection, security, backup and recovery.
Ensured no deletion of entered data and changes can be followed via an audit trial.

29. 7. Clinical Investigation Conduct
7.9 Investigational device
accountability
•Access to device is controlled and
only used in clinical investigation
following CIP.
•Physical location of all devices
documented.
•Records shall be kept on: a) name
of person received, used, returned
or disposed of device; b) date of
receipt, identification and quality of
device ; c) date of use ; d) subject
identification ; e) expiry date if
applicable ; f) date device returned
; g) return date of unused, expired
or malfunctioning device.
7.10 Accounting for subjects
•All subjects accounted for
are documented
•If subjects discontinued,
the reason shall be
recorded.
•Investigator should use
exciting data on the
subject and may ask for
permission to obtain
follow-up information
7.11 Auditing (Annex J)
•Audits may be conducted to
evaluate compliance to CIP,
ISO 14155 and applicable
regulatory requirements.
•It may cover all involved
parties and are separate from
quality control or routine
monitoring functions.
•Auditors shall be independent
of the clinical investigation.

30. 8. Suspension, termination and close-out of the clinical investigation
8.1 Completion of clinical
investigation
May be pre-specified by the plan or
terminated early
Completion coincides with :
1) Last visit of last subject
2) When follow up is completed
8.2 Suspension/Premature
termination
May suspend entire investigation/single site
May be suspended/terminated by: sponsor, PI, EC
or regulatory authority
Justify in writing and inform all parties
Sponsor is responsible for obligations to
participants
Reasons: Suspicion of unacceptable risk, Suspend
for risk assessment (terminate if risk is
unacceptable), Serious or repeated

31. 8. Suspension, termination and close-out of the clinical investigation
8.2.2 Resuming after
temporary suspension
After problem analysis and corrective actions in
place:
-Inform PI, EC and regulatory authority (as and
when required), provide with reasoning and
support data.
-EC & regulatory authority must concur before
clinical investigation resumes
8.3 Routine close-out
activities
PI records and sponsor file complete and up to date
CRF complete , AE status to be documented
Record retention and archival in place
Disposal of remaining material : devices, samples
and other materials
All identified issues resolved and all parties
should be notified

32. 8. Suspension, termination and close-out of the clinical investigation
8.4 Clinical investigation
report (Annex D)
Include: device information, methodology, clinical
investigation design, CIP deviations, data analysis,
result compared to investigation objectives.
Reports cover all participants at all sites
No identifiable participant information
Sponsor and PI or co-ordinatinginvestigator sign off
–report provided to all parties involved
Results updated in clinical investigation database and
published
Annex D outlines a detail format for the clinical
investigation report to follow and specifies the
content required for the report
8.5 Risk assessment and
conclusions
Risk information should be formally
reviewed; data and conclusions should be
updated in risk analysis and clinical
evaluation documents

33. 8. Suspension, termination and close-out of the clinical investigation
8.6 Document retention
Both sponsor and PI are responsible for maintaining
clinical investigation documents.
Custody may be formlytransferred if necessary
CIP, IB, CRF and final reports should be kept in the
manufacturers Quality management system and
incorporated in the device technical document
Essential clinical investigation
documents (Annex E)
Table E.1 –E.3 contains list of documents to be
maintained
Includes document names, purposes, who needs to
keep them, where to find in ISO 14155
Regulatory bodies may require a list of all documents:
-Record location of essential documents
-Version history required
-Easy to search and retrieve

34. 9. Sponsor Responsibility
Ensure quality, planning, conduct, monitoring, management and regulatory approval of studies
•Create and maintain quality procedure documents
•Maintain compliance records
•If applicable, ensure auditing requirements are met per ISO 14155
•Document and justify significant exceptions to ISO 14155 requirements
9.1 Clinical
Quality
Management
•Selection and training of clinical personnel
•Preparation of documents and materials according to clauses 5-7
•Conduct of clinical investigation
•Monitoring –should be documented and recorded
•Safety evaluation and reporting
•Clinical investigation close-out
9.2 Clinical
investigation
planning and
conduct

35. 9. Sponsor Responsibility
•Sponsor may transfer duties and functions to external
organization
•Sponsor responsible for verifying external organization
adheres to written procedures
9.3 Outsourcing
of duties and
functions
•Obtain regulatory authority approval/non-objection
•Report process and status of investigation
•Perform safety reporting
•Report of investigational device withdrawn from site due to
safety or performance issue
9.4
Communication
with regulatory
authorities

36. 10. Responsibilities of Principal Investigator
PI is responsible for patient safety and oversight of all site activities
10.1 General
•PI ensures investigation site team adequately
trained and qualified
•Maintains oversight of team activities
•Ensure data integrity
•Protect subject right’s, safety and well being
•May delegate task to team members but
retains responsibility
10.2 Qualification of principal
investigator
•Have the necessary education, training &
experience
•Experience in the field and trained in use of
investigational device
•Disclose financial and other potential conflicts of
interest
•Understand method of obtaining informed consent

37. 10. Responsibilities of Principal Investigator
10.3 Qualification of
investigation site
•Enough eligible subjects
•Investigation site teams
•Adequate facilities
10.4 Communication with the EC
•Provide copies of communications with
EC to sponsor
•Obtain written EC approval prior to study
beginning
•Perform safety reporting
•Notify EC of the deviations from the CIP,
study suspension/premature termination
and routine close-out of clinical
investigation
10.5 Informed
consent process
•Ensure informed consent
process is compliant with
ethical principles
•Ensure authorized
designees conducting
informed consent process
are trained with training
document

38. 10. Responsibilities of Principal Investigator
10.6 Compliance with CIP
•Written PI acceptance of CIP
•Trial is conducted according to CIP
•Ensure proper documentation processes.
•Ensure CRF reports and data sent to sponsor are accurate, complete and timely.
•Maintain device accountability record.
•Facilitate monitoring and auditing activities performed by the sponsor.
•Investigation instances of non-compliance and implement appropriate corrective and
preventative actions.
•Ensure retention of all records.
•Sign final clinical investigation report.

39. 10. Responsibilities of Principal Investigator
10.7 Medical care of subjects
•Responsible for subject medical care of adverse
events during and after study.
•Inform subjects of significant study findings and
nature and possible causes of adverse event.
•Provide subjects with procedure for potential
emergency situation
•For subjects withdrawing prematurely, make
reasonable efforts to determine reason while
respecting the subjects rights.
10.8 Safety reporting
•Every adverse event and device
deficiency should be recorded and
accessed.
•All serious adverse events and device
deficiencies reported to the sponsor
immediately as per the CIP if may have
lead to serious adverse device effect.
•Additional safety information should be
provided to sponsor upon request.

40. Annexures
Annex A: Clinical investigation plan (CIP)
Annex B: Investigation Brochure (IB)
Annex C: Case Report Forms (CRFs)
Annex D: Clinical Investigation Reports
Annex E: Essential clinical investigation documents
Annex F: Adverse event categorization