template protocol for investigational medicinal product(imp)

Created by ICRIN (QM subgroup) . Version XX. Date:………. of 14

Template protocol for Investigational Medicinal product(IMP)

<Trial Acronym>

<Full Protocol Title>

<Version Number and Date>

Main Sponsor or list of co-sponsors : ………………………………………………………..

Trial Coordination Centre:…………………………………………………

EUDRACT Reference Number: …………………….

Protocol authorised by:

Name : ………………………… Date: ……………… Signature: ..………………….

Role: ………………………..

Name : ………………………… Date: ……………… Signature: ..………………….

Role: ………………………..


Trial Management : Coordinating Investigator:………………………….

Co-Investigators:………………………………….......

………………………………………………

………………………………………………

Trial Statistician:…………………………………………………..

Trial Management:……………………………………………….

Trial Coordinating Centre For general enquiries, supply of trial documentation, and collection of data please contact:

Trial Coordinator:……………………….

Address:……………………………………………….

Telephone Number………………………………

Fax Number:…………………………………….

Randomisations:

Email: …………………………………………………

Web address: ……………………………………………

Clinical Queries Clinical queries should be directed to xxxxxxxxx at xxxxxxxxxxx, who will direct the query to

the appropriate person.

Sponsor Xxxxxxxxxxxxxxxxx is the main research sponsor for this trial. For further information, please

contact: Xxxxxxxxxxxxxxxxxxxx at xxxxxxxxxxxxxxxxxxxxxxxxx

Funder <who is funding the trial>


This protocol describes the XXXX trial and provides information regarding procedures for recruiting and enrolling subjects.The protocol

should be used as a guide for the treatment of participating subjects; every care should be taken in its drafting, however, corrections or

amendments may be necessary. Problems relating to this trial should be referred to the trial coordination centre. This trial will adhere to

the International Conference on Harmonisation Good Clinical Practice (ICH GCP)guidelines. It will be conducted in compliance with the

protocol, Data Protection regulations and other regulatory requirements as appropriate.

Table of Contents

1. INTRODUCTION……………………………………………………………………..Page 1.1 Background and Rationale……………………………………………………………………………Page

1.1.1 Prevalence of Disease/Condition…………………………………………………….Page

1.1.2 Impact of Disease/Condition……………………………………..…………………...Page

2. OBJECTIVES OF THE TRIAL……………………………………………………….Page

3. EXPERIMENTAL DESIGN AND METHODS………………………………….Page 3.1 OVERALL STUDY DESIGN……..………………………………………………………………….…..Page

3.2 STUDY OUTCOME MEASURES……………………………………………………………………..Page

3.3 TREATMENT GROUPS……………………………………………………………………………….…Page

3.4 CENTRES……………………………………………………………………………………………………...Page

3.5 NUMBER OF PATIENTS/ ASSIGNMENT TO TREATMENT GROUP………….………Page

3.6 DOSING REGIMEN……………………………………………………………………………..…………Page

3.7 STUDY DURATION…………………………………………………………………………..……………Page

4. PATIENT SELECTION CRITERIA……………………………………………….…Page 4.1 Population Base

4.2 Pre-randomisation evaluations

4.3 Inclusion Criteria

4.4 Exclusion Criteria

4.5 Withdrawal Criteria

4.6 Concomitant Medication and Treatment

5. SCHEDULE OF ASSESSMENTS…………………………………………………..Page

6. RANDOMISATION AND ENROLMENT PROCEDURE…………………..Page

6.1 Randomisation or Registration practicalities

6.2 Unblinding

7. TREATMENTS……………………………………………………………………….…Page 7.1 Treatment Arms

7.2 Dose Modification for Toxicity

7.3 Premedication

7.4 Interaction with other drugs

7.5 Dispensing and accountability

8. DRUG SAFETY (PHARMACOVIGILANCE)………….……………………..Page 8.1 Definitions

8.2 Causality

8.3 Reporting Procedures

9. ASSESSMENTS AND FOLLOW UPS…………………………………….……Page 9.1 Loss to Follow up


9.2 Trial closure

10. STATISTICS AND DATA ANALYSIS…………………………………………..Page 10.1 Primary and secondary Trial Parameters

10.2 Statistical and Analytical Methods

10.3 Statistical Model

10.4 Hypothesis testing

10.5 Types of analysis

10.6 Exclusion of data from analysis

10.7 Safety Data Analysis

10.8 Sample Size

10.9 Independent Safety committee, if applicable

11. MONITORING……………………………………………………………………….Page 11.1 Risk Assessment

11.2 Monitoring at Trial Coordination Centre

11.3 Monitoring at Local Site

12. REGULATORY……………………………………………………………………….Page 12.1 Clinical Trial Application (CTA)

12.2 Ethics Approval

12.3 Consent

12.4 Confidentiality

12.5 Indemnity

12.6 Sponsor

12.7 Funding

12.8 Audits and Inspections

13. TRIAL MANAGEMENT…………………………………………………………….Page

14. PUBLICATION POLICY…………………………………………………………….Page

LIST OF APPENDICES

APPENDIX1: ……………………………………………………………………..…………………………………………...Page

APPENDIX 2: …………………………………………………………………………………………………………..………Page

ETC.

GLOSSARY OF ABBREVIATIONS


KEYWORDS

<Insert a list of Keywords>

TRIAL SUMMARY

TITLE

DESIGN

OBJECTIVES

OUTCOME MEASURES

POPULATION

ELIGIBILITY

TREATMENT

DURATION

REFERENCE DIAGRAM

RANDOMISE

ARM A ARM B


1. INTRODUCTION

1.1 BACKGROUND AND RATIONALE

< Include review of previous studies, disease particulars, incidence, current treatment

options, risks and benefits>

<To include the hypothesis and research question, as well as potential risks and

benefits>

2. OBJECTIVES OF THE TRIAL

<List the primary, secondary and other study objectives>

3. STUDY DESIGN

<Type of study: e.g. randomised double-blind, placebo controlled etc.>

<Duration i.e. what constitutes the treatment phase and the follow up phase of the study>

<Number and type of subjects recruited e.g. 400 participants, 200 of which are healthy>

3.1 STUDY OUTCOME MEASURES

What are the endpoints of the study ¸e.g. disease-free survival, death, toxicity etc.

4. PATIENT SELECTION CRITERIA

4.1 Population Base

< Type of specific subject required in the trial e.g a certain stage of a disease etc.>

4.2 Pre-randomisation evaluations

<what tests need to be performed before a subject can be included in a study e.g. CT

scan LFT, biopsy etc. All screening procedures should be included>

4.3 Inclusion Criteria

< with justifications, if required>

4.4 Exclusion Criteria

< with justifications, if required>

4.5 Withdrawal Criteria


< describe the procedures for stopping the trial early. Describe the procedures for

subjects should they wish to withdraw their consent, i.e. will all data to-date be held,

will all data be destroyed>

4.6 Concomitant Medication and Treatment

<all concomitant medication as well as any diagnostic, therapeutic or surgical

procedure performed during the study period should be recorded as well allowable

rescue medication for predicted events>

5. SCHEDULE OF ASSESSMENT

<A schedule of assessments needs to be included, generally as a figure, for each treatment

arm>

6.RANDOMISATION AND ENROLMENT PROCEDURE

6.1 RANDOMISATION OR REGISTRATION PROCEDURE

<Procedure for enrolling participants and processes that require completion prior to

randomisation. Include telephone numbers to call for randomisation, either through a

central hub, a programmed interactive voice response system (IVRS) or a web address for an

interactive web response system (IWRS)>

6.2 UNBLINDING

<Unblinding is discouraged during the study unless as a response to urgent safety issues or

by drug safety as a requirement for reporting. Details on the process for unbliniding a

subject as a result of a safety concern needs to be described here>

7. TREATMENTS

7.1TREATMENT ARMS

<Dosage, route of administration, labelling, packaging , where the study drug supply will

come from, whether a supply will be delivered to the pharmacy at

randomisation/registration, if the study drug is free, will need to be described

7.2 DOSE MODIFICATION FOR TOXIICITY

<Tables are best for describing what dose reductions should be taken in the event of

toxicity>

7.3 PREMEDICATION

<A list of medications should be included , if they are to be prescribed before or during the

trial e.g. antibiotics>


7.4INTERACTION WITH OTHER DRUGS

<A list of any particular medications that the trial subjects should avoid should be included>

7.5DISPENSING AND ACOUNTABILITY

< Procedures for the pharmacy on dispensing and performing drug accountability should be

included>

8. DRUG SAFETY (Pharmacovigilance)

The sponsor is responsible for the ongoing safety evaluation of the investigational product(s). The

sponsor should promptly notify all concerned investigator(s)/institution(s) and the competent

authorities (CAs) of finding(s) that could affect adversely the safety of subjects, (ICHGCP 5.16). The

Sponsor should also follow ICHE2A (Guideline for Industry, Clinical Safety Data Management,

Definitions and Standards for Expedited Reporting.

8.1. DEFINITIONS (ICH E2A)

Adverse Event or Adverse Experience(AE): Any untoward medical occurrence in a patient or

clinical trial subject administered a pharmaceutical product and which does not necessarily

have a causal relationship with this treatment.

An AE therefore can be any unfavourable and unintended sign, symptom( including an

abnormal laboratory finding), symptom, or disease temporally associated with the use of an

Investigational Medicinal Product (IMP), whether or not considered related to the IMP.

Adverse Drug Reaction (ADR): In the pre-approval clinical experience with a new medicinal

product or its new usages, particularly as the therapeutic dose(s) may need to be

established.

All noxious and unintended responses to a medicinal product related to any dose should be

considered adverse drug reactions.

The phrase “responses to a medicinal products” means a causal relationship between a

medicinal product and an adverse event is at least a reasonable possibility i.e. the

relationship cannot be ruled out. All AEs judged by either the reporting investigator or the

sponsor as having a reasonable causal relationship to a medicinal product qualify as adverse

drug reactions. The expression reasonable causal relationship means to convey in general

that there is evidence or argument to support a causal relationship.

Unexpected Adverse Drug Reaction (UAR): An adverse drug reaction , the nature and

severity of which is not consistent with the applicable product information (e.g.IB or SmPC)

or is more severe than described in the IB or SmPC then this should be considered as

unexpected e.g (a) acute renal failure in the IB/SmPC with a subsequent report of

interstitial nephritis, (b) hepatitis with a first report of fulminant hepatitis.

Serious Adverse Event (SAE) or Serious Adverse Reaction: Any untoward medical

occurrence or effect that at any dose:


Results in Death

Is Life-threatening

( Note: The term life-threatening in the definition of serious refers to an event in

which the patient 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 was more severe)

Requires hospitalisation or prolongation of hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Medical judgement should be exercised in deciding whether expedited reporting is required

in other situations, such as important medical events that may not be immediately life-

threatening or result in death or hospitalisation but may jeopardise the patient or may

require intervention to prevent the other outcomes listed in the definition above. These

should also be considered serious.

Examples of such events are internsive treatment in an emergency room or at home for

allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalisation;

or development of drug dependency or drug abuse.

Suspected Unexpected Serious Adverse Reaction (SUSAR): Any suspected adverse reaction

related to an IMP that is both unexpected and serious. All require expedited reporting.

8.2 CAUSALITY

Causality assessment is required for clinical investigational cases, it is assumed in the case of

adverse event reports associated with marketed drugs.

The causality assessment and assignment should be made by the investigator responsible for

the care of the subject using the definitions indicated below.

Relationship Description

Unrelated There is no evidence of a causal relationship

Unlikely There is little evidence to suggest there is a causal relationship

( e.g the event did not occur within a reasonable time after

administration of trial medication). There is another

reasonable explanation for the event (e.g. concomitant

medications, clinical condition)

Possible There is some evidence to suggest a causal relationship (e.g.

event occurs a reasonable time after administration of trial


medication, temporal relationship). However, the influence of

other factors may have contributed to the event (e.g.

concomitant medications, clinical condition)

Probable There is evidence to suggest a causal relationship and the

influence of other factors is unlikely.

Definitely There is clear evidence to suggest a causal relationship and

other contributing factors cannot be ruled out.

Not assessable There is insufficient or incomplete evidence to make a clinical

judgement of the causal relationship.

8.3 REPORTING PROCEDURES

All adverse event require reporting. Different reporting procedures are appropriate for

differing types of adverse events.

1. Non serious AR/AE

All such events should be captured in the AE section of the CRF and sent to the Data

Management coordinating centre on a regular basis for entry into the Clinical Database

and inclusion in the Annual Safety Reports.

2. SAEs

Events which fulfil the seriousness criteria, or are medically significant should be both

entered into the CRF and a signed SAE form should also be completed and faxed to the

coordinating centre for Drug safety within 24 hours. However, hospitalisations for

elective treatment of a pre-existing condition do not require reporting as an SAE

3. SUSARs

All Serious Adverse Events that are unexpected as per the IB or SmPC are SUSARs and

require expedited reporting.

The information for SUSARs should be entered into the Clinical database, and a signed

SAE form should also be completed and faxed to the coordinating centre for Drug safety

within 24 hours or alternatively the information can be provided by phone and a

completed and signed SAE form sent within 24 hours as above.

The drug safety coordinating centre will report to relevant CA, REC and EMEA and the Sponsor of all

SUSARs occurring in the trial to the following timelines


Fatal and Life Threatening SAEs within 7 calendar days with a follow up complete report within a

further 8 calendar days.

Non- Fatal or life threatening SUSARs within 15 calendar days

All investigators will be informed of all SUSARs occurring throughout the study, in a blinded fashion,

for blinded trial designs.

9. ASSESSMENTS AND FOLLOW UP

< How long will the subject be followed up for? When and what will their assessments consist of>

9.1 Loss to follow up

<List procedures for subjects lost to follow up>

9.2 Trial Closure

<include definition of “end of trial”, include a list of the procedures for closing a trial,

whether early of after recruitment.

10. Statistics and Data Analysis

< include details on the statistical plan for the study including; sample size calculation, trial

parameters for analysis, the statistical methods and models to be employed, any rules for data

exclusion, any interim analyses, interaction with any safety committees, data management etc.>

< Data and all appropriate documentation for the trial will be held for a minimum of xx years after

completion of the trial, including follow up>

11. Monitoring

11.1 RISK ASSESSMENT

< Describe the level of risk associated with the trial i.e. low,med,high, a level of monitoring

and a justification of the proposed level of monitoring>

11.2 MONITORING AT THE TRIAL COORDINATION CENTRE

<Details of the Data Management of the data>

11.3 MONITORING AT THE LOCAL SITE

<Based on the risk assessment, the frequency ( number) of site monitoring visit and the %

Source Document Verification (SDV)>


12 REGULATORY

12.1 CTA

<This trial has/is pending a Clinical Trials Authorisation from the Irish Competent Authority

IMB Reference XXXXXXXXX, may require updating depending on whether or not is an

international trial>

12.2 ETHICS APPROVAL

<The trial coordination centre has received/expect to receive approval from XXX Research

Ethics Committee. The trial must be submitted for Site Specific Assessment (SSA) at each

participating site and signed before recruiting subjects into the trial.>

<This trial will be conducted in accordance with the recommendations for physicians in the

Declaration of Helsinki 1964 and later revisions>

12.3 CONSENT

<Consent to enter a trial must be sought from each subject only after a full explanation of

the trial, its objectives, the risks and potential benefits, the assessments and timing of these

assessments etc has been given, an information leaflet given and time allowed for

consideration. Signed subject consent forms must be obtained. The right of the subject to

refuse to participate without giving reasons must be respected. See INSTITUTION Patient

Information Leaflet Template>

12.4 CONFIDENTIALITY

<Patients identification data will be required for the recruitment process. The data

generated and the Trial coordination centre will preserve the confidentiality of subjects

taking part in the Trial and follow all procedures detailed in the Data Protection Act>

12.5 INDEMNITY

<XXXXXX holds Public Liability(“negligent harm”) and Clinical Trial (“non-negligent harm”)

insurance policies which apply to this trial.>

12.6 SPONSOR

<XXXXXXXXXXXXXXX will act as the main Sponsor for this trial. Delegated responsibilities will

be assigned to XXXXXXXXXXXXXX taking part in this trial.>

12.7 FUNDING

<Xxxx is funding this trial.>

< Any per patient payments, investigator payments should be detailed here>


12.8 AUDITS AND INSPECTIONS

<This trial may be subject to an audit by XXXXXXXXXXXX under its remit as Sponsor, the Trial

Coordination Centre and other Regulatory bodies to ensure adherence to GCP.>

13 TRIAL MANAGEMENT

< A trial management group (TMG) will be appointed and will be responsible for overseeing the

progress on the trial. The day to day management of the trial will be coordinated through the XXXX

Trial Coordination Centre>

<Include if a Trial Steering Committee or Independent Data Monoting Committee will be convened

for this trial>

14 PUBLICATION POLICY

< The trials publication policy should be described in full. E.g. All publications and presentations

relating to the trial will be authorised by the Trial Management Group. The first publication of the

trial results will be in the name of the Trial Management Group, if this does not conflict with the

Journal’s policy. If there are named authors, these will include at least the trials Chief Investigator,

Statistician and Trial Coordinator. Members of the TMG and the Data Monitoring Committee will be

listed and contributors will be cited by name if published in a journal where this does not conflict

with the journal’s policy. Authorship of parallel trials initiated outside the Trial Management Group

will be according to the individuals involved in the trial but must acknowledge the contribution of

the Trial Management Group and the Trial Coordination Centre>

15 REFERENCES

<List of useful references for the trial>

EXAMPLE APPENDICES

< Appendices should be additional information to the protocol and can consist of:

Drug information from SmPC

PIS, Consent form, GP letter

Performance Scales

Criteria definitions

Detail on processes

Common Terminology

Summary of Dose Modifications

Expected side effects


Schedule of events table

Copy of the Declaration of Helsinki

EXAM VISITS

Screening Randomisation Visit 1 Visit 2 Visit3 Visit 4 Visit 5 Visit n

ECG X X X X X X X

MRI X X X X

X-Ray X

Medical

History

X

Informed

Consent

X

Laboratory

samples

X X X X X X X X

Performance

Status

X X X X X X X X

Efficacy

scales

X X X X X X X

Safety

measures

X X X X X X X X

template protocol for investigational medicinal product(imp)

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