Download Information on Clinical Investigation Plan (CIP) Template

Sponsor Reference Number:
Date and Version No:
Information on Clinical Investigation Plan (CIP) Template
This template has been designed primarily for device clinical investigations in
accordance with ISO 14155:2011 guidelines. It has been specifically adapted for
non-commercially sponsored studies.
The template is available for use by all investigators who are carrying out device
clinical investigations sponsored by NUH NHS Trust.
All advisory text and quotations from ICH GCP are highlighted in yellow. These
should all be deleted before finalising the document. All sample text is in ‘basic
text’ style. This text of course will be altered or deleted as required while you
produce the draft.
Repetition of information throughout the CIP is not necessary; it may be useful to
cross-reference other sections of the CIP to avoid repetition.
CONFIDENTIAL
Page 1 of 39
Sponsor Reference Number:
Date and Version No:
Clinical Investigation Title:
insert full title including brief reference to the
design, disease or condition being studied, and primary objective
Clinical Investigation Acronym:
Sponsor
Nottingham University Hospitals NHS Trust
Funder
Insert name of funder
Funding Reference
Insert funding reference
Chief Investigator
Insert name of CI
Eudract Number
Insert Eudract number
ISRCTN Number
Insert ISRCTN number
Number
CONFIDENTIAL
Page 2 of 39
Sponsor Reference Number:
Date and Version No:
REC Reference Number
Insert REC reference number
Sponsor Reference
Insert R&I number
Version Number and
Insert version number and date
Number
Date
Confidentiality Statement
This document contains confidential information that must not be disclosed to
anyone other than the Sponsor, the Investigator Team, host NHS Trust (s),
regulatory authorities, and members of the Research Ethics Committee.
CONFIDENTIAL
Page 3 of 39
Sponsor Reference Number:
Date and Version No:
CLINICAL INVESTIGATION PLAN AUTHORISATION
Chief Investigator
Sponsor
Name:
Name:
Title:
Title:
Signature:
Signature:
Date:
Date:
Principal Investigator
Name:
Title:
Signature:
Date:
Site:
CONFIDENTIAL
Page 4 of 39
Sponsor Reference Number:
Date and Version No:
TABLE OF CONTENTS
Insert
CONFIDENTIAL
Page 5 of 39
Sponsor Reference Number:
Date and Version No:
CLINICAL INVESTIGATION MANAGEMENT GROUP
Chief Investigator
Name:
Co Investigators (may not be applicable,
insert additional sections as appropriate)
Address:
Name:
Telephone:
Telephone:
Statistician
Clinical investigation Management
Name:
Name:
Telephone:
Telephone:
Email:
Address:
Email:
Address:
Email:
Address:
Email:
Clinical investigation Coordination Centre (may not be applicable)
For general queries, supply of clinical investigation documentation, and collection of
data, please contact:
Clinical
investigation
Coordinator:
Address:
Telephone:
Fax:
Email:
Clinical Queries
CONFIDENTIAL
Page 6 of 39
Sponsor Reference Number:
Date and Version No:
Clinical queries should be directed to xxx who will direct the query to the
appropriate person
Sponsor
Nottingham University Hospitals NHS Trust is the main research sponsor for this
clinical investigation.
For further information regarding the sponsorship conditions,
please contact the Head of Regulatory Compliance at:
Nottingham University Hospitals NHS Trust
Research & Innovation, Nottingham Health Science Partners
C Floor, South Block
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
Email: [email protected]
Funder
[Who is funding the clinical investigation]
This CIP describes the xxx clinical investigation and provides information about
procedures for entering participants.
corrections
investigators
or
in
amendments
the
clinical
may
be
Every care was taken in its drafting, but
necessary.
investigation.
These
Problems
will
relating
be
to
circulated
this
investigation should be referred, in the first instance, to the Chief Investigator.
to
clinical
This clinical investigation will adhere to the principles outlined in the NHS Research
Governance Framework for Health and Social Care (2nd edition). It will be
conducted in compliance with the CIP, the Data Protection Act and other regulatory
requirements as appropriate.
CONFIDENTIAL
Page 7 of 39
Sponsor Reference Number:
Date and Version No:
1. AMENDMENT HISTORY
Amendment
No.
CIP Version
No.
Date Issued
Author(s) of
Changes
CONFIDENTIAL
Details of Changes
Page 8 of 39
Sponsor Reference Number:
Date and Version No:
List details of all clinical investigation plan amendments here whenever a new
version of the clinical investigation plan is produced.
CONFIDENTIAL
Page 9 of 39
Sponsor Reference Number:
Date and Version No:
2. CLINICAL INVESTIGATION PLAN APPROVAL
Insert clinical investigation title:
______________________
______________________
______________
Chief Investigator
Signature
Date
______________________
______________________
______________
Clinical investigation Statistician
Signature
Date
______________________
______________________
______________
Sponsor Representative
Signature
Date
CONFIDENTIAL
Page 10 of 39
Sponsor Reference Number:
Date and Version No:
CONFIDENTIAL
Page 11 of 39
Sponsor Reference Number:
Date and Version No:
3. ABBREVIATIONS
Add or delete as appropriate.
AE
Adverse Event
CI
Chief Investigator
AR
CIP
CRA
CRF
CRO
CT
CTA
EC
GCP
GP
GTAC
IB
ICF
Adverse Reaction
Clinical Investigation Plan
Clinical Research Associate
Case Report Form
Clinical Research Organisation
Clinical Trial
Clinical Trial Authorisation
Ethics Committee (see REC)
Good Clinical Practise
General Practitioner
Gene Therapy Advisory Committee
Investigator Brochure
Informed Consent Form
ICH
International Conference of Harmonisation
IMP
Investigational Medicinal Products
IEC
IRB
MHRA
NHS
NRES
PI
PIL
R&I
REC
SAE
SAR
SmPC/SPC
SOP
SUSAR
TMF
Independent Ethics Committee
Independent Review Board
Medicinal Health Research Authority
National Health Service
National Research Ethics Service
Principle Investigator
Participant Information Sheet
Research & Innovation
Research Ethics Committee
Serious Adverse Event
Serious Adverse Reaction
Summary of Products Characteristics
Standard Operating Procedure
Suspected Unexpected Serious Adverse Reactions
Clinical investigation Master File
CONFIDENTIAL
Page 12 of 39
Sponsor Reference Number:
Date and Version No:
CONFIDENTIAL
Page 13 of 39
Sponsor Reference Number:
Date and Version No:
4. CLINICAL INVESTIGATION SUMMARY
Clinical Investigation
Title
Sponsor Reference
Number
Clinical Phase
Clinical investigation
Design
Clinical investigation
Participants
Planned Sample Size
Number of
Participants
Follow-up Duration
Planned Clinical
investigation Period
Primary Objective
Secondary Objective
Primary End points
Secondary End points
Device Name
Manufacturer Name
Principle Intended Use
CONFIDENTIAL
Page 14 of 39
Sponsor Reference Number:
Date and Version No:
Length of Time the
Device has been
Used
CONFIDENTIAL
Page 15 of 39
Sponsor Reference Number:
Date and Version No:
5. INTRODUCTION
Include the following



Summary description of the investigational device and its intended purpose.
Details concerning the manufacturer of the investigational device.
Name or number of the model/type, including software version and
accessories, if any, to permit full identification.

Description as to how traceability shall be achieved during and after the
clinical investigation, for example by assignment of lot numbers, batch
numbers or serial numbers.

Intended purpose of the investigational device in the proposed clinical
investigation.

The populations and indications for which the investigational device is
intended.

Description of the investigational device including any materials that will be in
contact with tissues or body fluids. (This shall include details of any
medicinal products, human or animal tissues or their derivatives, or other
biologically active substances.)

Summary of the necessary training and experience needed to use the
investigational device.

Description of the specific medical or surgical procedures involved in the use
of the investigational device.

Justification for the design of the clinical investigation and an evaluation of
clinical data that is relevant to the proposed clinical investigation.

Anticipated clinical benefits and risks.
6. CLINICAL INVESTIGATION OBJECTIVES
6.1 OBJECTIVES
There is usually only one primary objective, the rest are secondary objectives.
The wording of the objectives should be clear, unambiguous and as specific as
possible – the clinical investigation will be judged on how and how well the
objectives were satisfied.
6.1.1 Primary objective
CONFIDENTIAL
Page 16 of 39
Sponsor Reference Number:
Date and Version No:
Detail primary objective.
6.1.2 Secondary objective
Detail secondary objective.
6.2 ENDPOINTS
Describe the end-points/outcome measures and how/when they will be measured
during the clinical investigation.
Endpoints/outcome measures should reflect the objectives. It is important that only
one primary endpoint/outcome measure is selected as it will be used to decide the
overall results or ‘successes’ of the clinical investigation. The primary
endpoint/outcome measure should be measurable, clinically relevant to participants
and widely accepted by the scientific and medical community.
6.2.1 Primary endpoint
Detail Primary endpoint
6.2.2 Secondary endpoint
Detail secondary endpoint
7. CLINICAL INVESTIGATION DESIGN
Summary of clinical investigation design

Describe the overall clinical investigation design e.g., double-blind, placebocontrolled, parallel design, open labelled.

Description of the measures to be taken to minimise or avoid bias, including
randomisation and blinding.

Give the expected duration of participant participation, number of visits, and
a description of the sequence and duration of all clinical investigation periods
e.g. screening period, treatment period, post treatment follow up period, and
possibly add a flow chart here or as an appendix.
CONFIDENTIAL
Page 17 of 39
Sponsor Reference Number:
Date and Version No:



Points in the clinical investigation to measure the outcomes.
Detail any stopping rules for the clinical investigation.
Any procedures for the replacement of subjects.
8. CLINICAL INVESTIGATION POPULATION
8.1 NUMBER OF PARTICIPANTS
Include



Number of participants
Number of sites
Length of recruitment period
8.2 INCLUSION CRITERIA
Example criteria (amend as appropriate):

Participant is willing and able to give informed consent for participation in the
clinical investigation.


Male or Female, aged 18 years or above.
Diagnosed with required disease/severity/symptoms, any specific assessment
criteria for these), or, if healthy volunteer clinical investigation: be in good
health.

(alter as required) Stable dose of current regular medication (specify type if
needed) for at least 4 weeks prior to clinical investigation entry. Or (delete one
or other), if healthy volunteer clinical investigation: have had no course of
medication, whether prescribed or over-the-counter, in the four weeks before first
clinical investigation dose and no individual doses in the final two weeks other
than mild analgesia, vitamins and mineral supplements or, for females, oral
contraceptives.

Female participants of child bearing potential and male participants whose
partner is of child bearing potential must be willing to ensure that they or their
partner use effective contraception during the clinical investigation and for 3
months thereafter.

Participants has clinically acceptable laboratory and ECG (specify any other
additional assessments) within <insert duration> of enrolment.

Able (in the Investigators opinion) and willing to comply with all clinical
investigation requirements.
CONFIDENTIAL
Page 18 of 39
Sponsor Reference Number:
Date and Version No:

Willing to allow his or her General Practitioner and consultant, if appropriate, to
be notified of participation in the clinical investigation.

Additional clinical investigation specific criteria as required.
8.3 EXCLUSION CRITERIA
Example criteria (amend as appropriate):
The participant may not enter the clinical investigation if ANY of the following apply:

Female participants who is pregnant, lactating or planning pregnancy during the
course of the clinical investigation.


Significant renal or hepatic impairment.
Scheduled elective surgery or other procedures requiring general anaesthesia
during the clinical investigation.


Participant who is terminally ill or is inappropriate for placebo medication.
Any other significant disease or disorder which, in the opinion of the
Investigator, may either put the participants at risk because of participation in
the clinical investigation, or may influence the result of the clinical investigation,
or the participant’s ability to participate in the clinical investigation.

Donation of blood during the clinical investigation. or, if healthy volunteer PK
clinical investigation within the past 12 weeks.

Participants who have participated in another research clinical investigation
involving an investigational product in the past 12 weeks.

Additional clinical investigation specific criteria as required.
9. PARTICIPANT SELECTION AND ENROLMENT
9.1 IDENTIFYING PARTICIPANTS
Include

How will participants be identified eg, in clinic, database, invitation letters and
posters

Who will be responsible for identifying participants
9.2 CONSENTING PARTICIPANTS
CONFIDENTIAL
Page 19 of 39
Sponsor Reference Number:
Date and Version No:
Specify who will take informed consent, how and when it will be taken. Informed
consent should be obtained prior to any clinical investigation related procedures
being undertaken. Describe the informed consent process in situations of lack of
capacity or emergency situations.
Example:
The participant must personally sign and date the latest approved version of the
informed consent form before any clinical investigation specific procedures are
performed.
Written and verbal versions of the participant information and Informed consent will
be presented to the participants detailing no less than: the exact nature of the
clinical investigation; the implications and constraints of the clinical investigation
plan; the known side effects and any risks involved in taking part. It will be clearly
stated that the participant is free to withdraw from the clinical investigation at any
time for any reason without prejudice to future care, and with no obligation to give
the reason for withdrawal.
The participant will be allowed as much time as wished to consider the information,
and the opportunity to question the Investigator, their GP or other independent
parties to decide whether they will participate in the clinical investigation. Written
Informed Consent will then be obtained by means of participant dated signature and
dated signature of the person who presented and obtained the informed consent.
The person who obtained the consent must be suitably qualified and experienced,
and have been authorised to do so by the Chief/Principal Investigator. A copy of
the signed Informed Consent will be given to the participants. The original signed
form will be retained at the clinical investigation site.
*can be substituted parent/guardian or legally authorised representative, as
appropriate, make sure that the term is consistent throughout the document
9.3 SCREENING FOR ELIGIBLE PARTICIPANTS

Detail how potential participants will be identified, approached, screened and
recruited.



If applicable, specify pre-screening procedures.
What is the maximum duration allowed between screening and randomisation?
Specify the recruitment procedures e.g. referral by GPs, screening medical
notes, using advertisements.
CONFIDENTIAL
Page 20 of 39
Sponsor Reference Number:
Date and Version No:
Describe the screening procedures in detail.
These are some of the headings and texts you may want to include. Alter or add
as necessary:
Demographics
The date of birth, gender, race, smoking and drinking habits (add as required)… will
be recorded.
Medical History
Details of any history of disease or surgical interventions in the following systems
will be recorded: Provide details as appropriate.
Concomitant Medication
All over-the-counter or prescription medication, vitamins, and/or herbal supplements
will be recorded on CRFs. Describe what information will be recorded.
Physical Examination
Height, weight and oral temperature will be recorded.
Resting pulse and blood pressure (BP) measurements will be measured after the
participant has sat for at least five minutes. Provide details as appropriate.
ECG Test
A 12-lead ECG will be taken for each participant. At least the following ECG
parameters will be recorded: heart rate (HR), PR, QT and QRS intervals and QTC.
The report will be signed by the Investigator who will record in the CRF whether it
is normal, abnormal but not clinically significant, or abnormal AND clinically
significant. In the latter case the eligibility of the participants will be reviewed.
Laboratory Tests
Describe any laboratory tests e.g. biochemistry, urinalysis and pregnancy tests.
Sample text:
CONFIDENTIAL
Page 21 of 39
Sponsor Reference Number:
Date and Version No:
All laboratory results will be reviewed and the reports signed by the Investigator
who will record in the CRF whether they are normal, abnormal but not clinically
significant, or abnormal AND clinically significant. In the latter case the eligibility of
the participants will be reviewed.
9.4 RANDOMISATION (if applicable)
Describe how randomisation is going to be carried out, and who will provide the
randomisation codes. Will randomisation be done at the same visit as the baseline
visit, or must participants return for a randomisation visit? Will there be a run in
period?
Who will design the randomisation schedule (statistician, CRO), and who will hold it
(Pharmacy, independent organisation).
If the clinical condition of a participant necessitates breaking the code, who will do
this and how?
Will individual envelopes per participant per period be supplied so
that the code may be broken for a single participant without unblinding the whole
clinical investigation? Or will the pharmacist access the randomisation schedule if
required by the Investigator and supply the needed information? Please refer to
NUH SOP 9 on Unblinding.
State that if randomisation of a participant is unblinded during the clinical
investigation then data for that participants will not be admitted to analysis.
Example
Subject numbers will be assigned sequentially as each subject enters the clinical
investigation. The subjects will be assigned clinical investigation drug through a
randomisation schedule based on the randomisation plan. The clinical investigation
drug will be labelled with the clinical investigation number and unique identification
number. The two treatments x and y will be indistinguishable. In the event of an
emergency, the investigator is to decide the necessity of unblinding the subject’s
treatment assignment. The blinded treatment assignments will be accessible to the
investigator should a subject need to be unblinded in an emergency using the
unblinding envelopes provided to the hospital pharmacy and X Toxicology Service.
If unblinding occurs, the investigator or clinical investigation pharmacist must record
CONFIDENTIAL
Page 22 of 39
Sponsor Reference Number:
Date and Version No:
the reason for unblinding, as well as the date and time of the event. Corresponding
information will be recorded on the CRF by the investigator.
Or
A contract research organisation will be commissioned to implement the
randomisation process and provide the medication packs. Both the clinical
investigation drug X and placebo will be formulated and supplied in identical
capsules sealed in identical medication packs. The allocation to placebo/X will be
randomly assigned and the medication packs will be consecutively numbered with
the clinical investigation PIN. Sealed randomisation envelopes will be kept unopened
and in a secure place by the pharmacy at Nottingham University Hospitals and the
Investigators. The medication packs will be kept in the hospital pharmacy which will
dispense them to clinical investigation participants. Participants will be enrolled and
assigned a PIN consecutively, and issued with the medication pack corresponding
to the PIN. Both clinical investigation participants and investigators will be blinded
to the nature of the clinical investigation medication dispensed and all image and
spectroscopic analysis will be conducted while blinded to clinical investigation
treatment. Once all collected data has been analysed, the randomisation code will
be broken by the clinical investigation investigators and the medication data entered
into the analysis. Should urgent un-blinding of a clinical investigation participant’s
medication be required (when requested by a clinician treating the participant), this
will be provided by the pharmacy at the Nottingham University Hospitals. This is
normally a working-hours service, but in exceptional circumstances could operate at
any time. The clinical investigation investigators have reviewed the clinical safety of
the clinical investigation and do not feel that a 24-hour un-blinding service would be
required for the appropriate treatment of participants, either within the Nottingham
University Hospitals or elsewhere.
9.5 WITHDRAWAL OF PARTICIPANTS
Detail criteria for participant withdrawal, discontinuation or replacement, and
subsequent follow up if they are withdrawn or the clinical investigation terminates
prematurely.
10. MEDICAL DEVICE
10.1 DEVICE DETAILS
CONFIDENTIAL
Page 23 of 39
Sponsor Reference Number:
Date and Version No:
Detail



Full name, generic name and UK trade name
Is it CE marked
Any other device to be used in the clinical investigation.
10.2 DEVICE MANUFACTURER
Detail the name and address of the company that will supply the Medical Device.
10.3 MARKETING AUTHORISATION HOLDER
Detail the name, address and MA number of the company manufacturing the
device.
10.4 DEVICE ACCOUNTABILITY
Describe.
10.5 STORAGE CONDITIONS
Describe the storage arrangement and any required storage conditions, for the
device. If applicable describe how the device is cleaned/re-sterilise. Describe any
maintenance issues for the device.
10.5 OTHER MEDICATIONS
10.5.1 Permitted medications
Detail drugs that maybe taken during the clinical investigation.
10.5.2 Prohibited medication
Detail other drugs that are not allowed during the clinical investigation due to
interaction with the medical device or an effect on the clinical investigation
outcomes.
CONFIDENTIAL
Page 24 of 39
Sponsor Reference Number:
Date and Version No:
Example:
Throughout the clinical investigation Investigators may prescribe any concomitant
medications or treatments deemed necessary to provide adequate supportive care
except for those listed in the exclusion criteria.
will be withdrawn.
If these are required, the participant
Any medication, other than the clinical investigation medication taken during the
clinical investigation will be recorded in the CRF.
List any contraindicated medications and check that they correspond with the
exclusion and withdrawal criteria.
11. CLINICAL INVESTIGATION ASSESSMENTS
11.1 SAFETY ASSESSMENTS
Detail any specific safety assessment required for the clinical investigation
11.2 CLINICAL INVESTIGATION ASSESSMENTS
Detail specific clinical investigation assessments to be performed and split them into
the visit names. Refer to a schedule of events table in the appendices.
12. DATA COLLECTION
Define what will comprise source documents.
Example:
Source documents are original documents, data, and records from which
participants’ CRF data are obtained. These include, but are not limited to, hospital
records (from which medical history and previous and concurrent medication may
be summarised into the CRF), clinical and office charts, laboratory and pharmacy
records, diaries, microfiches, radiographs, and correspondence.
CRF entries will be considered source data if the CRF is the site of the original
recording (e.g., there is no other written or electronic record of data). In this clinical
investigation the CRF will be used as the source document for …<<add as
required>>
CONFIDENTIAL
Page 25 of 39
Sponsor Reference Number:
Date and Version No:
All documents will be stored safely in confidential conditions. On all clinical
investigation-specific documents, other than the signed consent, the participant will
be referred to by the clinical investigation participant number/code, not by name.
13. STATISTICS
Where possible the statistician should write this section.
The sub-headings given below are suggestions. However, if a Statistical Analysis
Plan is to be produced separately, state this here and condense the most relevant
information from the sub sections here. You should give justification for:











statistical design, method and analytical procedures,
sample size,
the level of significance and the power of the clinical investigation,
expected drop-out rates,
pass/fail criteria to be applied to the results of the clinical investigation,
the provision for an interim analysis, where applicable,
criteria for the termination of the clinical investigation on statistical grounds,
procedures for reporting any deviation(s) from the original statistical plan,
the specification of subgroups for analysis,
procedures that take into account all the data,
the treatment of missing, unused or spurious data, including drop-outs and
withdrawals,

the exclusion of particular information from the testing of the hypothesis, if
relevant, and in multicentre clinical investigations,

the minimum and maximum number of subjects to be included for each
centre.
Special reasoning and sample size(s) may apply for the early clinical
investigation(s), e.g. feasibility clinical investigation(s).
13.1 DESCRIPTION OF STATISTICAL METHODS
Describe the statistical methods to be employed, including timing of any planned
interim analysis.
13.2 THE NUMBER OF PARTICIPANTS
CONFIDENTIAL
Page 26 of 39
Sponsor Reference Number:
Date and Version No:
State the approximate number of participants required to complete (commence).
Justify choice of sample size, including reflections on (or calculations of) the power
of the clinical investigation and clinical justification.
13.3 THE LEVEL OF STATISTICAL SIGNIFICANCE
State the level of significance to be used.
13.4 CRITERIA FOR THE TERMINATION OF THE CLINICAL
INVESTIGATION
Describe.
13.5 PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED AND
SPURIOUS DATA
Describe.
13.6 PROCEDURES FOR REPORTING ANY DEVIATIONS(S) FROM THE
ORIGINAL STATISTICAL PLAN
Procedures for reporting any deviation(s) from the original statistical plan (any
deviation(s) from the original statistical plan should be described and justified in
clinical investigation plan and/or in the final report, as appropriate).
13.7 INCLUSION IN ANALYSIS
The selection of participants to be included in the analyses (e.g., all randomised
participants, all dosed participants, all eligible participants, evaluable participants).
14. SAFETY REPORTING
14.1 DEFINITIONS
14.1.1 Adverse Event (AE)
CONFIDENTIAL
Page 27 of 39
Sponsor Reference Number:
Date and Version No:
An AE or adverse event is:
Any untoward medical occurrence in a patient or other clinical investigation
participant taking part in a clinical investigation of a medical device, which does not
necessarily have to have a causal relationship with the device under investigation.
An AE can therefore be any unfavourable and unintended sign (including an
abnormal laboratory finding), symptom or disease temporally associated with the
use of the device, whether or not considered related to the device.
14.1.2 Adverse Device Effect (ADE)
All untoward and unintended responses to the medical device.
The phrase "responses to a medical device" means that a causal relationship
between the device under investigation and an AE is at least a reasonable
possibility, i.e., the relationship cannot be ruled out.
All cases judged by either the reporting medically qualified professional or the
sponsor as having a reasonable suspected causal relationship to the device
qualifies as a device effect.
This also includes any event resulting from insufficiencies or inadequacies in the
instruction for use or deployment of the device and includes any event that is a
result of a user error.
14.1.3 Serious Adverse Event (SAE)
SAE is an adverse event that



Led to death
Led to fetal distress, fetal death or congenital abnormality or birth defect.
Led to serious deterioration in the health of the subject that
o
Resulted in a life-threatening illness or injury
CONFIDENTIAL
Page 28 of 39
Sponsor Reference Number:
Date and Version No:
NOTE: The term "life-threatening" in the definition of "serious" refers to an
event in which the participant was at risk of death at the time of the event;
it does not refer to an event which hypothetically might have caused death if
it were more severe.
o
Resulted in a permanent impairment of a body structure or a body function
o
Required in-patient hospitalisation or prolongation of existing hospitalisation
o
Resulted in medical or surgical intervention to prevent permanent impairment
to a body structure or a body function
o
Other important medical events*
*Other events that may not result in death, are not life threatening, or do
not require hospitalisation, may be considered a serious adverse event when,
based upon appropriate medical judgement, the event may jeopardise the
patient and may require medical or surgical intervention to prevent one of
the outcomes listed above
To ensure no confusion or misunderstanding of the difference between the terms
"serious" and "severe", which are not synonymous, the following note of clarification
is provided:
The term "severe" is often used to describe the intensity (severity) of a specific
event (as in mild, moderate, or severe myocardial infarction); the event itself,
however, may be of relatively minor medical significance (such as severe
headache). This is not the same as "serious," which is based on patient/event
outcome or action criteria usually associated with events that pose a threat to a
participant's life or functioning. Seriousness (not severity) serves as a guide for
defining regulatory reporting obligations.
14.1.4 Serious Adverse Device Effects (SADE)
A serious adverse device effect (SADE) is any untoward medical occurrence seen
in a patient that can be attributed wholly or partly to the device which resulted in
any of the characteristics or led to characteristics of a serious adverse event.
CONFIDENTIAL
Page 29 of 39
Sponsor Reference Number:
Date and Version No:
SADE is also any event that may have led to these consequences if suitable action
had not been taken or intervention had not been made or if circumstances have
been less opportune.
All cases judged by either the reporting medically qualified professional or the
sponsor.
14.1.5 Unanticipated Serious Adverse Device Effect (USADE)
Any serious adverse device effect on health or safety or any life-threatening
problem or death caused by, or associated with a device, if that effect, problem, or
death was not previously identified in nature, severity or degree of incidence in the
investigational plan or application (including a supplementary plan or application), or
any other unanticipated serious problem associated with a device that related to the
rights, safety or welfare of the subject.
14.2 REPORTING OF AEs
All AEs occurring during the clinical investigation observed by the investigator or
reported by the participant, whether or not attributed to the device under
investigation will be recorded on the CRF as specified in the clinical investigation
plan. All ADEs will be recorded in the CRF.
The following information will be recorded: description, date of onset and end date,
severity, assessment of relatedness to device, other suspect drug or device and
action taken. Follow-up information should be provided as necessary.
The relationship of AEs to the device will be assessed by a medically qualified
investigator or the sponsor/manufacturer and will be followed up until resolution or
the event is considered stable.
All ADE that result in a participant’s withdrawal from the clinical investigation or are
present at the end of the clinical investigation, should be followed up until a
satisfactory resolution occurs.
CONFIDENTIAL
Page 30 of 39
Sponsor Reference Number:
Date and Version No:
Where relevant, any pregnancy occurring during the clinical investigation and the
outcome of the pregnancy should be recorded and followed up for congenital
abnormality or birth defect.
14.3 REPORTING PROCEDURES FOR ALL SAEs/ SADEs/ USADEs
(Please delete the section which is not relevant for your clinical investigation)
For Non CE marked device clinical investigation: All SAE/SADE/USADEs need to
be reported to the sponsor/legal representative and manufacture and NUH R&I
immediately; regardless of relationship to the device.
For studies of CE marked devices: All SAE/SADE/USADEs need to be reported to
the sponsor/legal representative and manufacture and NUH R&I within one working
day of the investigator team becoming aware of them.
All SAEs, except those expected ones defined in section 14.1.4 (remove if not
applicable) that do not require immediate reporting must be reported to R&I within
one working day of discovery or notification of the event. As Sponsor R&I at NUH
will report all SUSARs to the Competent Authorities MHRA and the Research
Ethics Committee concerned. Fatal or life-threatening SUSARs must be reported
within 7 days and all other SUSARs within 15 days. The CI will inform all
investigators concerned of relevant information about SUSARs that could adversely
affect the safety of participants.
If the University of Nottingham Clinical Trials Unit (CTU) is responsible for the
Clinical investigation, it is the CTUs responsibility to report to the MHRA, Ethics
and then notify the R&I.
Reporting to the MHRA will be done in liaison with the Chief Investigator and the
Manufacturer.
The Manufacturer has a legal obligation to report all events that need to be
reported to the Nominated Competent Authority immediately (without any
unjustifiable delay) after a link is established between the event and the device, but
no more than:
CONFIDENTIAL
Page 31 of 39
Sponsor Reference Number:
Date and Version No:


2 days following the awareness of the event for Serious Public Health Threat.
10 days following awareness of the event for Death or unanticipated serious
deterioration in health.

30 days following the awareness of the event for all other event meeting the
SAE criteria.
14.4 ANNUAL REPORTS
In addition to the expedited reporting above, the CI shall submit once a year
throughout the clinical investigation or on request a Safety Report to R&I, the
Competent Authority MHRA and Ethics Committee.
15. CLINICAL INVESTIGATION MANAGEMENT
15.1 CLINICAL INVESTIGATION MANAGEMENT GROUP
Detail who will form part of the clinical investigation management group what their
role will be and what they will be responsible for.
15.2 CLINICAL INVESTIGATION STEERING COMMITTEE
Detail who will form part of the clinical investigation steering committee what their
role will be and what they will be responsible for. If a TSC is not being set up
then this will need to be justified in this section.
15.3 DATA MONITORING COMMITTEE
Detail who will form part of the data monitoring committee what their role will be
and what they will be responsible for. If a DMC is not being set up then this will
need to be justified in this section.
15.4 INSPECTION OF RECORDS
Investigators and institutions involved in the clinical investigation will permit clinical
investigation related monitoring and audits on behalf of the sponsor and regulatory
inspection(s).
In the event of an audit or monitoring, the Investigator agrees to
CONFIDENTIAL
Page 32 of 39
Sponsor Reference Number:
Date and Version No:
allow the representatives of the sponsor direct access to all clinical investigation
records and source documentation. In the event of regulatory inspection, the
Investigator agrees to allow inspectors direct access to all clinical investigation
records and source documentation
15.5 RISK ASSESSMENT
A risk assessment will be performed by the Sponsor to determine if monitoring is
required and if so, at what level.
15.6 CLINICAL INVESTIGATION MONITORING
A Research Project Manager will visit the Investigator site prior to the start of the
clinical investigation and during the course of the clinical investigation if required, in
accordance with the monitoring plan. Monitoring will be performed according to ICH
GCP. Data will be evaluated for compliance with the clinical investigation plan and
accuracy in relation to source documents. Following written standard operating
procedures, the monitors will verify that the clinical investigation is conducted and
data are generated, documented and reported in compliance with the clinical
investigation plan, GCP and the applicable regulatory requirements.
16. GOOD CLINICAL PRACTICE
Describe ethical considerations relating to the clinical investigation. Include general
and clinical investigation specific ethical considerations.
16.1 DECLARATION OF HELSINKI
The Investigator will ensure that this clinical investigation is conducted in full
conformity with the current revision of the Declaration of Helsinki (last amended
October 2000, with additional footnotes added 2002 and 2004).
16.2 ICH GUIDELINES FOR GCP
The Investigator will ensure that this clinical investigation is conducted in full
conformity with relevant regulations and with the ICH Guidelines for Good Clinical
Practice (CPMP/ICH/135/95) July 1996.
CONFIDENTIAL
Page 33 of 39
Sponsor Reference Number:
Date and Version No:
16.3 APPROVALS
Consider the following text:
The clinical investigation plan, informed consent form, participant information sheet
and any proposed advertising material will be submitted to an appropriate Research
Ethics Committee (REC), regulatory authorities (MHRA in the UK), and host
institution(s) for written approval.
The Investigator will submit and, where necessary, obtain approval from the above
parties for all substantial amendments to the original approved documents.
16.4 PARTICIPANT CONFIDENTIALITY
The clinical investigation staff will ensure that the participants’ anonymity is
maintained. The participants will be identified only by initials and a participants ID
number on the CRF and any electronic database. All documents will be stored
securely and only accessible by clinical investigation staff and authorised personnel.
The clinical investigation will comply with the Data Protection Act which requires
data to be anonymised as soon as it is practical to do so.
16.5 OTHER ETHICAL CONSIDERATIONS
Include any other ethical considerations specific to the clinical investigation e.g. use
of placebo, involvement of vulnerable participants.
16.6 DATA HANDLING AND RECORD KEEPING
Describe method of data entry/management.
Describe how data will be reviewed, cleansed and data queries will be resolved.
Describe how data will be verified and validated.
Example:
All clinical investigation data will be entered on a <<quote software and validation
procedure>>. Note that ICH GCP (Section 5.5) requires that electronic data entry
systems are validated and that Standard Operating Procedures are maintained.
CONFIDENTIAL
Page 34 of 39
Sponsor Reference Number:
Date and Version No:
The participants will be identified by a clinical investigation specific participant
number and/or code in any database. The name and any other identifying detail will
NOT be included in any clinical investigation data electronic file.
17. CLINICAL INVESTIGATION CONDUCT
RESPONSIBILITITES
17.1 CLINICAL INVESTIGATION PLAN AMENDMENTS
Amendments to the clinical investigation plan must be submitted to the Sponsor for
review before submitting to the appropriate REC, Regulatory Authority and local
R&D for approval.
17.2 CLINICAL INVESTIGATION PLAN VIOLATIONS, DEVIATIONS AND
SERIOUS BREACHES
The CI will not implement any deviation from the clinical investigation plan without
agreement from the Sponsor, except where necessary to eliminate an immediate
hazard to clinical investigation participants.
In the event that the CI needs to deviate from the clinical investigation plan, the
nature of and reasons for the deviation will be recorded in the CRF and notified to
the Sponsor. If this necessitates a subsequent clinical investigation plan
amendment, this will be submitted to the Sponsor for approval and then to the
appropriate REC, Regulatory Authority and local NHS R&I for review and approvals
as appropriate. It is Sponsor policy that waivers to the clinical investigation plan will
not be approved.
In the event that a serious breach of GCP is suspected, this will be reported to the
Sponsor immediately. Refer to SOP-RES-017 “Non-Compliance and Serious Breach
Reporting”.
17.3 CLINICAL INVESTIGATION RECORD RETENTION
All clinical investigation documentation will be kept for 10 years from the clinical
investigation plan defined end of clinical investigation point. When the minimum
CONFIDENTIAL
Page 35 of 39
Sponsor Reference Number:
Date and Version No:
retention period has elapsed, clinical investigation documentation will not be
destroyed without permission from the sponsor.
17.4 END OF CLINICAL INVESTIGATION
The end of clinical investigation is defined as the last participant’s last visit.
The Investigators and/or the clinical investigation steering committee and/or the cosponsor(s) have the right at any time to terminate the clinical investigation for
clinical or administrative reasons.
The end of the clinical investigation will be reported to the REC and Regulatory
Authority within 90 days, or 15 days if the clinical investigation is terminated
prematurely. The Investigators will inform participants of the premature clinical
investigation closure and ensure that the appropriate follow up is arranged for all
participants involved.
A summary report of the clinical investigation will be provided to the REC and
Regulatory Authority within 1 year of the end of the clinical investigation.
17.5 INSURANCE AND INDEMNITY
NHS bodies are legally liable for the negligent acts and omissions of their
employees. If you are harmed whilst taking part in a clinical clinical investigation as
a result of negligence on the part of a member of the clinical investigation team
this liability cover would apply.
Non-negligent harm is not covered by the NHS indemnity scheme. The Nottingham
University Hospitals NHS Trust, therefore, cannot agree in advance to pay
compensation in these circumstances. In exceptional circumstances an ex-gratia
payment may be offered.
17.6 FUNDING
Describe funding arrangements
18. REPORTING, PUBLICATIONS AND NOTIFICATIONS OF
RESULTS
CONFIDENTIAL
Page 36 of 39
Sponsor Reference Number:
Date and Version No:
18.1 AUTHORSHIP POLICY
Ownership of the data arising from this clinical investigation resides with the clinical
investigation team. On completion of the clinical investigation, the clinical
investigation data will be analysed and tabulated, and a clinical clinical investigation
report will be prepared in accordance with ICH guidelines.
18.2 PUBLICATION
The publication policy should cover authorship, acknowledgements, and review
procedures for scientific publications. If there is a department or institution policy, or
agreement, the clinical investigation plan can refer to it.
18.3 PEER REVIEW
Detail procedures for peer review – these may be funder specific or involve an
internal department.
19. REFERENCES
Insert references used in text.
APPENDIX 1. CLINICAL INVESTIGATION FLOW CHART
Optional
CONFIDENTIAL
Page 37 of 39
Sponsor Reference Number:
Date and Version No:
CONFIDENTIAL
Page 38 of 39
Sponsor Reference Number:
Date and Version No:
APPENDIX 2. SCHEDULE OF PROCEDURES
Optional Alter as required, delete if not wanted
Procedures
Visits (insert visit numbers as appropriate)
Screening Baseline
Informed consent
Demographics
Medical history
Concomitant medications
Physical examination
ECG
Laboratory tests
Eligibility assessment
Randomisation
Assessment 1 (describe)
Assessment 2 (describe)
Assessment 3 (describe)
Assessment 4 (describe)
Adverse event
assessments
CONFIDENTIAL
Page 39 of 39