Clinical Investigation Protocol Template - Molecular Medicine Ireland

Clinical Investigational Plan- Template
Reference Number:
Title of Clinical Investigation Plan
Product Name:
Sponsor Name:
Sponsor Address:
Version No. :
Date......................................
Revision History
Version Number
Date
___________________________
Principle Investigator
_______________________
Date
___________________________
Chief Executive Officer– Company Name
_______________________
This document contains confidential and proprietary information and may not be copied or
reproduced in whole or part without the written permission of ___________
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Clinical Agreement Signature Log
I, the undersigned, have read and understand the specific Clinical Investigation Plan, and agree
with the contents. The Clinical Investigation Plan, the Investigator’s Agreements and any
additional information provided by the sponsor will serve as a basis for co-operation in the
study.
I agree to conduct in person or to supervise the study.
I agree to ensure that all who assist me in the conduct of the study have access to the study CIP
plus any amendments and are aware of their obligations.
Site Principle Investigator:
_________________________ ________________________ ______________
Name Signature Date
___________________________________________________________________________
Institution
Name and address and professional position of:
Name and address of principal investor
Coordinator Investigator, if appointed
Name and address of other investigation site(s) in which the clinical investigation will be
conducted.
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Clinical Investigation Summary
Title
Investigational Medical
Device
Test and (comparator, if
appropriate):
Study Objectives:
Study Design:
Inclusion/
Exclusion Criteria:
Inclusion Criteria:
Exclusion Criteria:
Primary Performance
Endpoints:
Secondary Performance
Endpoints:
Safety Endpoints:
Duration of
Investigation
Follow-up
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Table of Contents
1.Introduction................................................................................................................................7
2. Identification and description of the investigational device ..................................................... 7
2.1.Summary description of the investigational device…………………………………..7
2.2. Manufacturer of the investigational device……………………………………………...7
2.3. Model/Type……………………………………………………………………………...7
2.4. Traceability……………………………………………………………………………....7
2.5. Intended Purpose………………………………………………………………………...7
2.6. Populations and indications……………………………………………………………..7
2.7. Description of the investigational device……………………………………………….7
2.8. Summary of required experience/training………………………………………………7
2.9. Description of specific procedures involved in the use of the investigational device….8
3. Justification for the design of the clinical investigation………………………………………8
3.1. Justification for the design of the clinical investigation…………………………………8
3.1.1. Prevalence of Disease/condition Background ........................................................... 8
3.1.2 Impact of Disease/condition ........................................................................................ 8
3.1.3 Clinical Evaluation ...................................................................................................... 8
4. Risks and benefits of the investigational device and clinical investigation.............................. 9
4.1. Anticipated Clinical Benefits ............................................................................................. 9
4.2. Anticipated adverse device effects .................................................................................... 9
4.3 Residual risks associated with the investigational device .................................................. 9
4.4. Risks associated with participation in the clinical investigation ....................................... 9
4.5. Possible interactions with concomitant medical treatments .............................................. 9
4.6. Steps to be taken to control or mitigate risks ..................................................................... 9
4.7. Risk to benefit rationale ................................................................................................... 10
5. Objectives and hypothesis of the clinical investigation .......................................................... 10
5.1. Clinical investigation objectives
5.2. Hypothesis ....................................................................................................................... 10
5.3. Claims of performance of the device ............................................................................... 10
5.4. Risks and anticipated adverse device effects that are to be assessed .............................. 10
6. Design of clinical investigation .............................................................................................. 10
6.1. General ............................................................................................................................. 10
6.1.1.Description…………………………………………………………………………..10
6.1.2. Measures to minimise bias ....................................................................................... 10
6.1.3. Primary and Secondary endpoints ............................................................................ 11
6.1.4. Methodology ............................................................................................................. 11
6.1.5. Equipment ................................................................................................................. 11
6.1.6. Replacement of Subjects .......................................................................................... 11
6.2. Investigational devices and comparators……………………………………………….11
6.2.1. Description………………………………………………………………………...11
6.2.2. Justification of comparator………………………………………………………...11
6.2.3. Concomitant therapies……………………………………………………………..11
6.2.4. Number of investigational devices………………………………………………...11
6.3. Subjects…………………………………………………………………………………11
6.3.1. Inclusion criteria…………………………………………………………………...11
6.3.2. Exclusion criteria…………………………………………………………………..11
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6.3.3. Criteria withdrawal or discontinuation…………………………………………….11
6.3.4. Enrolment………………………………………………………………………….12
6.3.5. Duration of clinical investigation………………………………………………….12
6.3.6. Expected subject duration………………………………………………………….12
6.3.7. Expected number of subjects………………………………………………………12
6.3.8. Time to select all subjects………………………………………………………….12
6.4. Procedures……………………………………………………………........…………...12
6.4.1. Clinical investigational procedures……...……………………….........…………..12
6.4.2. Activities performed by Sponsor representative…………………………………..13
6.4.3. Factors that may compromise the outcome of the clinical investigation
/interpretation of the results……………………………………………….……………………13
6.4.4. Follow up…………………………………………………………………………..13
6.4.5. Follow up medical care……………………………………………………………13
6.5. Monitoring plan…………………………………………………………………………13
7. Statistical considerations.........................................................................................................14
7.1. Statistical design...............................................................................................................14
7.2. Sample size.......................................................................................................................14
7.3. The level of significance and power of the clinical investigation....................................14
7.4. Expected drop out rates....................................................................................................14
7.5. Pass/ fail criteria...............................................................................................................14
7.6. Provision for interim analysis...........................................................................................14
7.7. Criteria for stopping clinical investigations.....................................................................14
7.8. Procedures........................................................................................................................14
7.9. Specification of subgroups...............................................................................................14
7.10. Procedures to take into account all subject data.............................................................14
7.11. Treatment of missing, unused, spurious data.................................................................14
7.12. Exclusion of data from hypothesis testing.....................................................................14
7.13. Min/ max number of subjects per centre (multi-centre investigation)...........................15
7.14. Special reasoning............................................................................................................15
8. Data management ................................................................................................................... 15
8.1. Procedures used for data review, database cleaning, and issuing and resolving queries.15
8.2. Procedures for verification, validation and securing electronic data systems.................15
8.3. Procedures for data retention...........................................................................................15
8.4. Specified retention period................................................................................................15
8.5. Other aspects of clinical quality assurance, as appropriate..............................................15
9. Amendments to the clinical investigation plan.......................................................................15
10. Deviations from the clinical investigation plan....................................................................16
10.1. Statement that investigator is not allowed to deviate from the CIP...............................16
10.2. Procedures for recording, reporting and analysing CIP deviations................................16
10.3. Notification requirements and timeframes.....................................................................16
10.4. Corrective and preventative actions (CAPA) and principal investigator disqualification
criteria..........................................................................................................................................16
11. Device accountability............................................................................................................16
12. Statements of compliance......................................................................................................17
12.1. Statement of compliance with the ethics principles that have their origin in the
Declaration of Helsinki...............................................................................................................17
12.2. Statement of compliance with ISO 14155 and national regulations..............................17
12.3. Statement regarding ethical and regulatory approval.....................................................17
12.4. Additional requirements from Ethics Committee and/or regulatory authority..............17
12.5. Statement of insurance cover.........................................................................................17
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13. Informed consent process.....................................................................................................17
13.1. General informed consent..............................................................................................17
13.2. Informed consent, where subject is unable to give informed consent (incapacity
emergency)..................................................................................................................................18
13.2.1. Subjects unable to read or write.............................................................................18
13.2.2. Emergency treatment..............................................................................................18
14. Adverse Events, Adverse device events and device deficiencies ......................................... 19
14.1. Definition: adverse event (AE) ...................................................................................... 19
14.2. Definition of adverse device effect (ADE)....................................................................19
14.3. Definition of device deficiencies...................................................................................19
14.4. Definition of serious adverse event (SAE)....................................................................20
14.5. Definition of serious adverse device effects (SADES)..................................................20
14.6. Definition of unanticipated serious adverse device effects............................................20
14.7. Time period for reporting to Sponsor and, where appropriate, EC and Regulatory
Authority......................................................................................................................................20
14.8. Reporting adverse events................................................................................................21
14.9. Reporting device deficiencies.........................................................................................21
14.10. List of foreseeable adverse events, anticipated adverse device effects........................21
14.11. Emergency contact details for reporting SAEs and SADEs.........................................21
14.12. DMAC..........................................................................................................................21
15. Vulnerable population (if required).......................................................................................21
15.1. Description of the vulnerable population.......................................................................21
15.2. Description of informed consent process.......................................................................21
15.3. Description of EC's specific responsibility....................................................................21
15.4. Description of medical care to be provided after the clinical investigation has been
completed....................................................................................................................................21
16. Suspension or premature termination of the clinical investigation.......................................22
16.1. Criteria for suspension of whole clinical investigation or in one or more sites.............22
16.2 Criteria for unblinding.....................................................................................................22
16.3. Requirements for subject follow up...............................................................................22
17. Publication policy ................................................................................................................. 22
17.1. Commitment to publish results......................................................................................22
17.2. Conditions of publication...............................................................................................22
18. Bibliography ......................................................................................................................... 22
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1. INTRODUCTION
Describe what the study is in brief – single arm, cross over, double blind, single centre, multicentre,
randomised clinical investigation designed to examine the (safety – performance) of
the XXX device in patients with XXX disease/condition.
X number of patients will be enrolled to undergo the procedures detailed in this Clinical
Investigation Plan using XXX device. - See Schedule of events… Appendix XX
2. IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL
DEVICE
2.1 Summary Description of investigational device
A summary description of the investigational device and its intended purpose.
Design/pictures of device if available would be beneficial to include here.
2.2 Manufacturer of the investigational device
Provide information concerning the manufacturer of the device.
Name:
Address
Etc.
2.3 Model/Type
A summary of the name or number of the model/type, including software version and
accessories, if any to allow full identification of the device.
2.4 Traceability
A description as to how the traceability of the investigative devices will be achieved during and
after the clinical investigation, e.g. assignment of lot numbers, batch numbers or serial
numbers
2.5 Intended Purpose
A description of the intended purpose of the investigational device in the proposed clinical
investigation.
2.6 Populations and Indications
A description of the populations and indications for which the investigational device is
intended.
2.7 Description of the Investigational Device
A description of the medical device, including any materials that will be in contact with
tissues or body fluids (this will include details of any medicinal products, human or animal
tissues or their derivatives, or other biologically active substances).
2.8 Summary of required experience/training
A summary of the necessary training and experience required to use the investigational device
What measurements will be used to ensure compliance Give a detailed description of how the
device is to be used. What processes are there to ensure correct use of the device
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2.9 Description of specific procedures involved in the use of the investigational device
A description of the specific medical or surgical procedures involved in the use the
investigational device
3. JUSTIFICATION FOR THE DESIGN OF THE CLINICAL
INVESTIGATION
3.1. Justification for the design of the clinical investigation
Describe the rationale and justification for the design of the clinical investigation based on the
assessment of the pre-clinical data and the results of the clinical evaluation. It may be useful to
answer the following questions:
What is the rationale of developing the device
What benefit will it bring to the patient population in question
Describe briefly any data previously reported or preliminary data to justify development
What is the plan for the future with the device if known
Summary of any pre-clinical and human data
Clinical data concerning safety or performance of the device.
3.1.1. Prevalence of Disease/condition Background
Brief description of the prevalence of the disease – based on literature search – reference any
detailed information.
3.1.2 Impact of Disease/condition
What is the impact of the disease – burden, cost, outcome etc Again reference any available
information.
3.1.3 Clinical Evaluation
A synopsis of the assessment and analysis of clinical data concerning safety or
performance of the investigational device or similar devices or therapies. The evaluation
must be relevant to the intended purpose of the investigational device and the proposed
method of use using the principles of GHTF clinical evaluation
(http://www.ghtf.org/documents/sg5/sg5_n2r8_2007final.pdf).
The results of the clinical evaluation will be used to justify the optimal design of the
clinical investigation. They shall also help to identify relevant endpoints and confounding
factors to be taken into consideration, and serve to justify the choice of comparator(s).
The clinical investigation will be designed to evaluate whether the investigational device
is suitable for the purpose(s) and population(s) for which it is intended.
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4. RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND
CLINICAL INVESTIGATION
X Company/Researcher has conducted an analysis of the benefits and risks of the X device and
procedure.
X Company/Researcher and the Investigator have determined that this research study is
justified – based on the rationale described in section 3 above.
Risk analysis has been completed following the guidance in ISO14971 and is
available….appendix
Risk Analysis
What risks/complications, if known, about the device may the subjects experience by
participating in this study.
“This is a new device and the likelihood of complications is not known at this time.
Complications that can happen are thought to be similar to using similar devices – if available
on the market – depending on classification the risk will vary.
4.1. Anticipated Clinical Benefits
Describe the clinical benefits to you anticipate from use of your device
Benefits: List the potential benefits your device has to offer.
List what the anticipated clinical benefit of the device/treatment will be, for example:
Flexibility/ease of use
Effectiveness
Benefit to subject
Benefit to user
4.2Anticipated adverse device effects
List the anticipated adverse device effects e.g., Infection, Bleeding, Perforation of artery, Death
etc.
4.3 Residual risks associated with the investigational device
A synopsis from the risk analysis report.
4.4. Risks associated with participation in the clinical investigation
List these from the risk analysis.
4.5 Possible interactions with concomitant medical treatments
List any known or anticipated interactions.
4.6 Steps to be taken to control or mitigate risks
Summary of these steps from the risk analysis.
List what steps are to be completed to reduce any risks to subject prior/during/after
procedure. e.g. will the procedure be performed under sterile conditions/aseptic
technique/controlled environment
What support will be provided if unexpected events occur
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4.7 Risk to benefit rationale
Describe your risk to benefit rationale
5. OBJECTIVES AND HYPOTHESIS OF THE CLINICAL
INVESTIGATION
5.1 Clinical investigation - Objectives
Primary Objective:
The primary objective is to evaluate the safety/efficacy using device X in-patients with X
disease/condition.
Secondary Objective:
Describe any secondary objectives of the clinical investigation.
Other Investigation Objectives
Describe any other investigation objectives e.g. any long-term safety.
5.2 Hypothesis
Describe the primary and secondary endpoints to be accepted or rejected by analysis of the
clinical data from the clinical investigation.
5.3 Claims of performance of the device
Claims and intended performance of the investigational device that are to be verified
5.4 Risks and anticipated adverse device effects that are to be assessed
As detailed in the clinical investigation Investigator Brochure (IB) and/or the risk analysis
report.
6. DESIGN OF CLINICAL INVESTIGATION
6.1 General
6.1.1 Description
Description of the type of Clinical Investigation to be performed (comparative, double-blind,
parallel design etc, with or without a comparator group) as well as a description of the rationale
for this choice.
6.1.2 Measures to minimise bias
Description of measures to be taken to minimise or avoid bias, including randomisation,
blinding/masking.
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6.1.3 Primary and Secondary endpoints
Description of the primary and secondary endpoints, with rationale for their selection and
measurement.
6.1.4 Methodology
A description of the methods to be employed and the timings for assessing, recording and
analyzing variables.
6.1.5 Equipment
A description of the equipment to be used for assessing the clinical investigation variables and
arrangement for monitoring, maintenance and calibration.
6.1.6 Replacement of Subjects
A description of any procedures for the replacement of subjects that have dropped out of the
investigation.
6.2 Investigational device(s) and Comparator(s)
A summary description of the investigational device and, if applicable comparator(s) and their
intended purpose.
6.2.1 Description
A description of the exposure to the investigational device (s) or comparator(s), if used.
6.2.2. Justification comparator
A justification of the choice of comparator(s).
6.2.3 Concomitant Therapy
A list of any other medical device or medication to be used during the clinical investigation.
6.2.4 Number of investigational devices
A description of the number of devices to be used in the clinical investigation, together with a
justification.
6.3 Subjects
6.3.1 Inclusion criteria
The subject must meet all of the following inclusion criteria- list criteria e.g.
Subject must be >= 18 years or older – or if targeted a specific age profile
Subject muse have documented disease/condition as determined by XX.
6.3.2 Exclusion criteria
The following must not be present at the time of enrolment e.g.
Clinical exclusion criteria specific to the disease/condition.
Specific concomitant treatment with X.
Participation in any other device study within the last year.
6.3.3 Criteria withdrawal or discontinuation
Subjects can withdraw from the clinical investigation at any time without any rationale and
without compromising their future medical care. The subject may also be removed from a
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clinical investigation by their physician if he/she feels that this is in the best interest of the
subject.
6.3.4 Enrolment
Subjects with XX disease/condition are candidates for enrolment into this clinical investigation.
Following review of the inclusion and exclusion criteria, eligible subjects will be invited to
participate in this clinical investigation. Information on the clinical investigation, the fact that it
involves research, the purpose of the clinical investigation, potential risks/benefits, etc (as per
ISO 14155 section 4.7 and section 13 of this CIP) will be given to the subject. All subjects must
give written informed consent prior to any investigation procedures being carried out. Once the
subject has given written informed consent, they can be enrolled into the clinical investigation.
The subject’s participation in this clinical investigation is completely voluntary. If the subject
decides not to participate in the clinical investigation, their decision will have no impact on any
services or treatment the subject are currently receiving and will also not affect their
relationship with their doctor. Subjects are allowed to withdraw their participation at any time
during the course of the investigation without sacrificing their rights as a patient or
compromising their quality of medical care.
6.3.5 Duration Clinical Investigation
Describe the total expected duration of the clinical investigation including start-up, enrolment,
treatment, follow up and reporting time estimate. (from CIP to final report).
6.3.6 Expected subject duration
Describe the treatment period from time of enrolment to final follow up for a subject.
6.3.7 Number of subjects
Detail the number of subjects to be included in the clinical investigation.
6.3.8 Time to select all subjects
Detail the expected recruitment period for the clinical investigation e.g. the investigation will
remain open for enrolment until the planned total number of subjects is reached (add number
planned). Estimated time required to select this number of subjects is XX months.
6.4 Procedures
6.4.1. Clinical Investigation Procedures
The clinical investigation methods are described in this section, for details on the specific use
of X medical device please refer to Appendix X (instructions for use).
Add in investigation schedule of events here or refer to it, if it is in an appendix XX.
e.g. Baseline
At the screening visit the following tests and examination will be carried out to screen eligible
subjects and provide baseline information for those patients that meet the study criteria. All
tests must be completed (specify time period if relevant) within X days prior to undergoing the
investigation procedure, unless otherwise stated.
For emergency studies document basic information required prior to entering into the study.
History and physical examination – if special examinations required document here.
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Height and weight if relevant.
Specific tests, e.g. Blood pressure, heart rate, ECG,
Laboratory tests if required.
If female of chid bearing potential, a urine pregnancy test.
Description of other visits and the procedures involved in them from the schedule of events.
Visit 1…… N
Follow Up
6.4.2 Activities performed by Sponsor representatives
Description of the activities to be performed by the Sponsor or delegated to a third party by the
Sponsor e.g. Clinical Investigation Set-up, including development of CIP, IB, labelling, CRF,
Randomisation, if applicable, Site documentation (CV of PI etc.). Ethics and Regulatory
submissions and documentation, Clinical Investigation Agreements, Insurance, Device Supply,
Investigative site selection, Investigative site initiation, subject recruitment, vigilance, data
management, statistics, medical writing.
6.4.3 Factors that may compromise the outcome of the Clinical Investigation/interpretation
of the results.
For example factors include subject baseline characteristics, concomitant medication, the use of
other medical devices and subject related factors such as age, gender, and lifestyle. The
methods for addressing these factors in the clinical investigation, e.g. subject selection, clinical
investigation design (i.e. stratified randomisation) or by statistical analysis will be described.
6.4.4 Follow up
Describe the rationale for follow-up period to permit demonstration of performance over
sufficient period of time to represent a realistic test of the performance of the investigational
device and allow any risks associated with adverse device effects over that period to be
identified and assessed.
Describe follow-up visits and what procedures are involved in these visit(s).
6.4.5 Follow up medical care
Describe the medical care to be provided after the Clinical Investigation is completed.
6.5 Monitoring Plan
An investigator is required to prepare and maintain adequate case histories designed to record
all observations and other data pertinent to the investigations on each individual subject treated
with the investigational product, or comparator, if relevant. Data reported on the (e) CRF, that
are derived from source documents, must be consistent with source documentation or the
discrepancies must be explained.
General outline of the monitoring plan to be followed may include:
Access to source data.
The extent of planned source data verification.
If risk based monitoring is applied to the monitoring plan.
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7. STATISTICAL CONSIDERATIONS
To be completed by the investigation statistician with reference to the sections 5 and 6 above
on the objectives, hypothesis and the design of the clinical investigation and including:
7.1 Statistical design
A description and justification of the statistical design of the clinical investigation, including
method and analytical procedures to be employed.
7.2 Sample size
A description of the sample size rationale and methods of calculation
7.3 The level of significance and power of the clinical investigation
A description of the rationale for the level of significance and power of the analysis for the
clinical investigation to be considered successful.
7.4 Expected drop out rates
The expected drop out rates for the clinical investigation and a rationale regarding the
calculation of these.
7.5 Pass/Fail criteria
A description of the pass/fail criteria that may apply to the analysis of the analysis of the
clinical investigation.
7.6 Provision for interim analyses
A description of any interim analyses that may be included within the clinical investigation,
with a rationale for them, including the timings and data to be included within the interim
analyses.
7.7 Criteria for stopping clinical investigation
A description of any stopping rules on statistical grounds and the rationale for these criteria.
7.8 Procedures for reporting deviations
A description for the reporting of any clinical investigation plan or statistical plan deviations.
7.9 Specification of subgroups
A description of any subgroups of subjects for analysis with a description of the rationale for
the subgroup analyses.
7.10 Procedures to take into account all subject data
A description of analyses to take into account all subject data.
7.11 Treatment of missing, unused, spurious data
A description of any rules for handling any missing, unused or spurious data as well as a
rationale for their use.
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7.12 Exclusion of data from hypothesis testing
A description of any data that may be excluded from the hypothesis testing along with the
rationale for exclusion.
7.13 Min/Max number of subjects per centre ( Multi-centre investigation)
For multi-centre investigations a description of the minimum and maximum number of subjects
to be enrolled per centre.
7.14 Special reasoning
A description of any special statistical reasoning pertaining to the clinical investigation, this
may apply to e.g. sample size calculations for early clinical investigations such as feasibility
clinical investigations.
8 DATA MANAGEMENT
8.1 Procedures used for data review, database cleaning, and issuing and resolving queries.
Describe the process for data review, cleaning after data entry, either from a paper or electronic
CRF. For discrepancies in the data, describe the process for issuing queries to the sites, for
tracking and resolution of these queries.
8.2 Procedures for verification, validation and securing electronic data systems, if
applicable.
If electronic data capture systems are being employed, describe the processes for validating and
securing the data capture systems.
8.3 Procedures for data retention.
Describe the procedures to be followed for the retention and archiving of data on the clinical
investigation for the period(s) specified in 8.4.
8.4 Specified retention period.
Documentation for the clinical investigation must be retained for non-implantable device and
available to the national authorities for inspection for a period of at least five years after the
last product has been manufactured and for implantable devices for at least 15 years after the
last product has been manufactured.
8.5 Other aspects of clinical quality assurance, as appropriate.
All validation checks and other quality assurance checks of the data are documented in a Data
Validation Plan pertinent to the Clinical Investigation it includes the quality control and quality
assurance steps applied to the data and any database systems employed for the clinical
investigation.
9. AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN
The Clinical Investigation Plan may require to be amended during the conduct of a clinical
investigation. Any amendment to the clinical investigation plan will be agreed upon between
the Sponsor and the Principal Investigator. The amendments will be notified (in the case of
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non-substantial amendments) to, or approved by (in the case of substantial amendments) the
EC and Regulatory Authority.
10. DEVIATIONS FROM CLINICAL INVESTIGATION PLAN
10.1 Statement that investigator not allowed to deviate from the CIP
The Clinical Investigation will be performed in accordance with this Clinical Investigational
Plan.
10.2 Procedures for recording, reporting and analysing CIP deviations
Describe the process for recording deviations for the clinical investigation plan, for reporting of
the deviations, development of Corrective and Preventative Actions (CAPA) and analysis of
deviations.
A Clinical Investigation plan deviation is a failure to comply with the information specified in
the Investigational Plan. All clinical investigation related procedures must be complete as
outlined in the Clinical Investigational Plan.
All clinical investigation deviations will be reviewed by the Sponsor for impact on subject’s
participation in the clinical investigation. The Sponsor will notify the Investigator of deviations.
All deviations will be reported to the appropriate regulatory bodies as required.
10.3 Notification requirements and timeframes
Describe the process for requesting deviations from the CIP to the EC, if the deviation affects
the rights, safety or well being of the subjects or the scientific integrity of the clinical
investigation.
Under emergency circumstances deviations from the CIP to protect the rights, safety or wellbeing
of subjects may be implemented without prior approval of the sponsor and EC, but will
be documented and notified to the sponsor and EC as soon possible.
Describe the process for producing and submitting progress reports including safety summary
and deviations to the EC.
10.4 Corrective and preventative actions (CAPA) and Principal Investigator
disqualification criteria
Describe the process for developing and analysing CAPAs in response to CIP deviations as
well as the analysis and further actions required for correction of consistent deviations.
Describe the criteria for disqualification of the Principal Investigator from the Clinical
Investigation.
11. DEVICE ACCOUNTABILITY
Describe how the access to the investigational device will be controlled. Include a statement
that the investigational devices shall only be used in the clinical investigation and according to
the clinical investigation plan.
Describe the process and documentation to be used to record the physical location of all
investigational devices from shipment to the investigation sites until return or disposal
including, if applicable; amount received and placed in storage area, amount currently in
storage area. The devices and detachable components must be identified, in terms of batches
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and serial numbers, to allow all appropriate action to detect any potential risk posed by the
devices and detachable components.
Describe the packaging and labelling requirements that the device be labelled “For Clinical
Investigation Use Only”.
12. STATEMENTS OF COMPLIANCE
12.1 Statement of compliance with the ethics principles that have their origin in the
Declaration of Helsinki
The investigational study will be performed in accordance with the ethical requirements
defined in the Declaration of Helsinki.
12.2 Statement compliance ISO 14155 and national regulations
The investigation will be performed to the standards set out in the ISO 14155 standard and
with national regulations.
12.3 Statement regarding ethical and regulatory approval
The clinical investigation shall not commence until written approval/favourable opinion from
the EC and, if required, the relevant regulatory authorities has been received.
12.4 Additional requirement from Ethics Committee and/or regulatory authority
The clinical investigation performance will include any additional requirements
requested/mandated by the EC and/or Regulatory Authority.
12.5 Statement of insurance cover
Describe the insurance in place for subjects, if appropriate.
13. INFORMED CONSENT PROCESS
13.1 General Informed Consent
Describe the process for gaining Informed consent from competent adults e.g.
Informed consent shall be obtained in writing from the subject prior to any procedures specific
to the clinical investigation being applied to the subject.
Describe the process for preparation of Subject Information Leaflet (SIL) and Informed
Consent form, include all elements required by ISO 14155:2011 and applicable regulatory
requirements. The process must adhere to the ethical principles that have their origin in the
Declaration of Helsinki. Prior to the beginning of the clinical investigation, the Investigator
must have EC approval/favourable opinion of the written informed consent form and any other
information intended to be provided to the subjects.
The Investigator and/or his/her authorised representative will conduct the informed consent
process of explaining the clinical investigation to the subject as well as providing the subject
with a copy of a Subject Information Leaflet (SIL). The consent information will include all
aspects of the clinical investigation that are relevant to the subject’s decision to participate in
the language in which the subject is most proficient. The language will be non-technical and
easily understood.
The Investigator will avoid coercion ,will not appear to waive the subject’s legal rights in any
way, will allow sufficient time for the subject to inquire about the details of the clinical
investigation ask any questions and make the decision to participate or not in the clinical
investigation.
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Should the subject decide to participate in the clinical investigation, the informed consent form
will be signed and personally dated by the subject and by the authorised person who conducted
the informed consent discussion. A copy will be given to the subject. Any new information
that arises during the course of the clinical investigation will be provided to the subject and
their consent to continue will be sought.
13.2 Informed Consent, where subject is unable to give informed consent (incapacity
emergency)
Special circumstances may include: infants, children, juveniles, seriously ill or unconscious
subjects, mentally ill persons, mentally disabled persons. In such cases, legally authorised
representatives and subjects will be informed about the clinical investigation within their ability
to understand.
12.2.1 Subjects unable to read or write:
Informed consent will be obtained through a supervised oral process if a subject or legally
authorised representative is unable to read or write. An independent witness shall be present
throughout the process where the information will be read to the subject/subject’s authorised
representative. Signatures will be obtained if possible from their legally authorised
representative and witness whenever possible.
12.2.2 Emergency treatment:
For clinical investigations involving emergency treatments, when informed consent of the
subject is not possible because of the subject’s medical condition, the informed consent of the
subject’s legally authorised representative, if present shall be requested. When it is not possible
to obtain informed consent from the subject, and/or the subject’s legally authorized
representative, the subject may still be enrolled. The process needs to be described here in the
Clinical Investigation Plan when any of the conditions a-e (below) is met.
The principle investigator may enrol a subject without obtaining the informed consent of the
subject or his/her legally authorised representative only when the following conditions are
fulfilled:
a) The prospective subject fulfils the emergency conditions and is obviously in a lifethreatening
situation;
b) No sufficient clinical benefits are anticipated from the currently available treatment;
c) There is a fair possibility that the life-threatening risk to the prospective subject can be
avoided if the investigational device is used;
d) Anticipated risks are outweighed by the potential benefits of applying the
investigational device;
e) The legally authorised representative cannot be promptly reached and informed.
Arrangements shall be made to inform the subject and the legally authorised representative, as
soon as possible:
a) About the subject’s inclusion in the clinical investigation
b) About all aspects of the clinical investigation
The subject shall be asked to provide informed consent for continued participation as soon as
his/her medical condition allows.
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14. ADVERSE EVENTS, ADVERSE DEVICE EVENTS AND DEVICE
DEFICIENCIES
14.1 Definition: adverse event (AE)
An Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or
injury, or any untoward clinical signs (including abnormal laboratory findings) in subjects,
users or other persons, whether or not related to the investigational medical device.
This includes:
Events related to the investigational medical device or the comparator,
Events related to procedures involved ( any procedure in the clinical investigation plan,
For users and other persons is restricted to events related to investigational medical devices.
14.2 Definitions adverse device effect (ADE)
An Adverse Device Effect (ADE) is defined as an adverse event related to the use of an
investigational medical device resulting from insufficient or inadequate instructions for use,
deployment, implantation, installation, or operation, or any malfunction, user error, intentional
misuse of the investigational medical device.
14.3 Definition of device deficiencies
A Device Deficiency is an inadequacy of a medical device with respect to its identity, quality,
durability, reliability, safety or performance.
Device deficiencies include;
malfunctions,
use errors,
inadequate labelling.
14.4 Definition of Serious Adverse Event (SAE)
Serious Adverse Event (SAE) is any event (whether or not associated with the investigational
device) that:
1. Results in death
2. Led to serious deterioration in the health of the subject , that either resulted in
i. life threatening illness or injury, or
ii. a permanent impairment of a body structure or a body function, or
iii. in-patient or prolonged hospitalization, or
iv. medical or surgical intervention to prevent life threatening illness
or injury or permanent impairment to a body structure or body
function.
3. Led to foetal distress, foetal death or a congenital abnormality or birth defect
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NOTE: This includes device deficiencies that might have led to a serious adverse event if a)
suitable action had not been taken or b) intervention had not been made or, c) if the
circumstances had been less fortunate. These are handled under the SAE reporting system
NOTE: Planned hospitalisation for a pre-existing condition, or a procedure required by the CIP,
without serious deterioration in health, is not considered a serious adverse event.
14.5 Definition of a Serious Adverse Device Effects (SADE)
A Serious Adverse Device Event (SADE) is an adverse device effect that has resulted in any of
the consequences characteristic of a serious adverse event.
14.6 Definition of an Unanticipated Serious Device Effects (USADE)
An Unanticipated Adverse Device Effect (UADE) is a serious adverse device effect which by
it’s nature, incidence, severity or outcome has not been identified in the current version of the
risk analysis report. A SUADE is a USADE who has been deemed to be related to the
investigational device.
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its nature,
incidence, severity or outcome has been identified in the risk analysis report
14.7 Time period for Reporting to Sponsor and where appropriate, EC and Regulatory
Authority
Any device deficiencies shall be documented in writing as to whether they could have led to a
serious adverse device effect; in case of disagreement between the sponsor and the principal
investigator(s), the sponsor shall communicate both opinions to concerned parties, as defined in
a) and b) below.
a) report to the EC by the principal investigator(s), of all serious adverse events and
device deficiencies that could have led to a serious adverse device effect, as required
by national regulations or the CIP or by the EC.
b) report to regulatory authorities, within the required time period, all serious adverse
events and device deficiencies that could have led to a serious adverse device effect, as
required by national regulations or the CIP.
Time frame for reporting all adverse events, device deficiencies, serious adverse events and
serious device events to the sponsor
The principal investigator shall report all adverse events and device deficiencies to the sponsor
within 24 hours of the event.
The Principal Investigator shall send an expedited copy of any Suspected Unanticipated Serious
Adverse Device Effects (SUADEs) to the Irish Medicines Board and the relevant IRB/IEC.
The Sponsor shall send safety reports to the Irish Medicines Board and the relevant IRB/IEC.
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A vigilance report should be made as soon as possible to the Vigilance and Compliance Section
of the Human Products Safety Monitoring Department of the IMB. Notification from the
manufacturer to the IMB should occur within:
a) 2 days for a serious public health threat
b) 10 days for death or unanticipated serious deterioration in the state of health
c) 30 days for others
Reportable events occurring in Third countries, in which the clinical investigation is performed
under the same CIP, have to be reported in accordance with this guidance
14.8 Reporting adverse events
Describe process for capturing adverse event data occurring during a clinical investigation,
categorization of the event data, follow up and reporting where the category of the event
requires it.
14.9 Reporting device deficiencies
Describe process for capturing device deficiencies occurring during a clinical investigation,
categorization of the data, follow up and reporting where the category of the deficiency
requires it.
14.10 List of foreseeable adverse events, anticipated adverse device effects.
List of anticipated adverse device effects as from the risk analysis and the IB.
14.11 Emergency contact details for reporting SAEs and SADEs
Contact details for vigilance reporting.
14.12 DMC
Describe the Data Monitoring Committee (DMC) structure, operational objectives and
responsibilities.
15. Vulnerable Population, (if required)
15.1 Description of the vulnerable population
Describe the vulnerable population to be included in the clinical investigation, e.g. mentally
incompetent, emergency etc.
15.2 Description of Informed Consent Process
Describe in detail the Informed consent process with the legally responsible and assent, if
possible for the subject.
15.3 Description of EC’s specific responsibility
Describe the ethics committee’s responsibility to look after the rights, safety and well-being of
subjects.
15.4 Description of medical care to be provided after the clinical investigation has been
completed.
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Describe the medical care to be provided after completion of the clinical investigation.
16. SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL
INVESTIGATION
16.1 Criteria for suspension of whole clinical investigation or in one or more sites
Describe the criteria for suspension nor premature termination of the whole clinical
investigation or for closing sites active in the clinical investigation.
The study may be terminated by the Sponsor or the Investigator at any time. However,
scheduled follow-up, as described in treatment schedule in appendix X, should be continued for
all subjects who were treated prior to termination of the study.
16.2 Criteria for unblinding
Describe the criteria and process for unblinding the clinical investigation, on a subject level or
for the clinical investigation as a whole.
16.3 Requirements for subject follow up
Describe the process and obligation on the Sponsor for subject follow up.
17. PUBLICATION POLICY
17.1 Commitment to publish results
Statement indicating whether the results of the clinical investigation will be submitted for
publication.
17.2 Conditions of publication
Statement indicating the conditions under which the results will be submitted for publication.
18. BIBLIOGRAPHY
List of some bibliographic references pertaining to the clinical investigation .
1. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices.
2. Irish Medicines Board, Guidance Note 6 Glossary of Terms for medical Devices:
Revision 2; Published: 26/03/2004
3. ISO 14155:2011 Clinical investigation of medical devices for human subjects – Good
clinical practice
4. www.wma.net/e/policy/b3.htm
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5. Guidelines on Medical Devices – Clinical Investigations: Serious Adverse Event
Reporting under Directive 90/385/EEC and 93/42/EEC
Other Items worth considering when designing a Clinical Investigation Plan
Recording analyses
If there is a recording or software component to the device how will it be evaluated
What measurements will be used
How will the device be evaluated
Patient Reported Outcome
Will there be a quality of life questionnaire
Will there be a Health Technology Assessment
Describe how frequent the questionnaire will be completed and by who (patient or
research team)
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