Adjuvant study in Locally Advanced High Risk Prostate … · Web viewDoc. no. AI App 01 Version no 1.0 Version No: 1.0 Confidential Page 1 of 23 Instructions are in red, insert text

RESEARCH PROTOCOLClinical study (interventional or observational)Doc. no. AI App 01

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Instructions are in red, insert text within < >. Suggested text is blue.Delete all coloured text from the completed document or change accepted blue suggested text into black.

Clinical study protocol reference number <institutional reference number or REC number>:

<Clinical study research protocol title>The title must correspond to the project content, should be written in English and consist of max. 150 characters.

Clinical study protocol – <Clinical study interventional or observational, but not pharmaceutical products or medical devices>

Person responsible for research at responsible institutionEntity responsible for research:

Date......................................

Revision history

Version number Date

___________________________ _______________________Project Manager Signature Date

___________________________ _______________________Representative for the research responsible institution DateSignatureThis 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 STUDY AGREEMENT SIGNATURE LOG I, the undersigned, have read and understand the specific research protocol, and agree with the contents.

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 research protocol plus any amendments and are aware of their obligations.

Researcher:

_________________________ ________________________ ______________Name Signature Date

___________________________________________________________________________Institution

Project ManagerNameProfessional positionAddressE-mail addressPhone number

Contact information of other study site(s) in which the clinical study will be conducted.NameProfessional positionAddressE-mail addressPhone number

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CLINICAL STUDY SUMMARY

Title:

Study objectives:

Clinical study design:

Inclusion / exclusion criteria: Inclusion criteria:

Exclusion criteria:

Primary performance endpoints:

Secondary performance endpoints:

Safety endpoints:

Duration of study:Follow-up:

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TABLE OF CONTENTS Clinical study agreement signature log.................................................................................................................................2

Clinical study summary.........................................................................................................................................................3

Table of Contents................................................................................................................................................................. 4

List of abbreviations and definition of terms.........................................................................................................................8

1 Introduction............................................................................................................................................................... 11

2 Study Description..................................................................................................................................................... 11

2.1 Background......................................................................................................................................................11

2.2 Study Rationale................................................................................................................................................11

3 Objectives and hypothesis........................................................................................................................................11

3.1 Clinical study - objectives.................................................................................................................................11

3.1.1 Primary objective....................................................................................................................................11

3.1.2 Secondary objective...............................................................................................................................11

3.1.3 Other study objectives............................................................................................................................12

3.2 Hypothesis....................................................................................................................................................... 12

3.3 Any results expected during the project period................................................................................................12

3.4 Risks and anticipated adverse events that are to be assessed.......................................................................12

4 Project methodology.................................................................................................................................................12

5 Study design.............................................................................................................................................................12

5.1 General............................................................................................................................................................12

5.1.1 Description..............................................................................................................................................12

5.1.2 Primary and secondary endpoints..........................................................................................................12

5.1.3 Equipment...............................................................................................................................................12

5.1.4 Methodology...........................................................................................................................................12

5.1.5 Measures to minimise bias.....................................................................................................................13

5.1.6 Including more subjects to compensate for drop-outs............................................................................13

5.2 Study treatment................................................................................................................................................13

5.2.1 Description..............................................................................................................................................13

5.2.2 Justification comparator..........................................................................................................................13

5.2.3 Concomitant therapy...............................................................................................................................13

6 Risks and benefits....................................................................................................................................................13

6.1 Anticipated clinical benefits..............................................................................................................................13

6.2 Anticipated adverse events..............................................................................................................................13

6.3 Possible interactions with concomitant (medical) treatments...........................................................................13

6.4 Steps to be taken to control or mitigate risks...................................................................................................14

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6.5 Subjects...........................................................................................................................................................14

6.5.1 Inclusion criteria......................................................................................................................................14

6.5.2 Exclusion criteria.....................................................................................................................................14

6.5.3 Criteria for withdrawal or discontinuation................................................................................................14

6.5.4 Enrolment...............................................................................................................................................14

6.5.5 Duration clinical study.............................................................................................................................14

6.5.6 Expected subject duration......................................................................................................................15

6.5.7 Number of subjects.................................................................................................................................15

6.5.8 Time to select all subjects.......................................................................................................................15

6.6 Procedures.......................................................................................................................................................15

6.6.1 Clinical study procedures........................................................................................................................15

6.6.2 Activities performed by representatives for research responsible institution..........................................15

6.6.3 Factors that may compromise the outcome of the clinical study / interpretation of the results...............16

6.6.4 Follow-up................................................................................................................................................16

6.6.5 Follow-up medical care...........................................................................................................................16

7 Statistical considerations..........................................................................................................................................16

7.1 Statistical design..............................................................................................................................................16

7.2 Sample size..................................................................................................................................................... 16

7.3 The level of significance and power of the clinical study..................................................................................16

7.4 Expected drop out rates...................................................................................................................................16

7.5 Pass/fail criteria................................................................................................................................................16

7.6 Provision for interim analyses..........................................................................................................................16

7.7 Criteria for stopping the clinical study..............................................................................................................16

7.8 Specification of subgroups...............................................................................................................................17

7.9 Procedures to take into account all subject data..............................................................................................17

7.10 Treatment of missing, unused, spurious data..................................................................................................17

7.11 Exclusion of data from hypothesis testing........................................................................................................17

7.12 Min/max number of subjects per centre (multi-centre study)...........................................................................17

7.13 Special reasoning............................................................................................................................................17

8 Data management....................................................................................................................................................17

8.1 Procedures for data review, database cleaning, and issuing and resolving queries........................................17

8.2 Procedures for verification, validation and securing electronic data systems <if applicable>..........................17

8.3 Procedures for data retention..........................................................................................................................17

8.4 Specified retention period................................................................................................................................17

9 Amendments to the research protocol......................................................................................................................18

10 Deviations from the research protocol......................................................................................................................18

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10.1 Statement that investigator is not allowed to deviate from the research protocol............................................18

10.2 Procedures for recording, reporting and analyzing protocol deviations...........................................................18

11 Accountability of study treatement............................................................................................................................18

12 Statements of compliance........................................................................................................................................18

12.1 Statement of compliance with ethics principles................................................................................................18

12.2 Statement regarding ethical approval..............................................................................................................18

12.3 Additional requirement from ethics committee.................................................................................................18

12.4 Statement of insurance cover..........................................................................................................................19

13 Informed consent process........................................................................................................................................19

13.1 General informed consent................................................................................................................................19

13.2 Informed consent, where subject is unable to give informed consent (incapacity/emergency)........................19

14 Adverse events.........................................................................................................................................................19

14.1 Definition of adverse event (AE)......................................................................................................................19

14.2 Definition of serious adverse event (SAE).......................................................................................................20

14.3 Reporting adverse events................................................................................................................................20

14.4 List of foreseeable adverse events, anticipated adverse treatment/intervention effects..................................20

14.5 Emergency contact details for reporting SAEs.................................................................................................20

14.6 Data monitoring committee – <if applicable>...................................................................................................20

15 Vulnerable population (if required)...........................................................................................................................20

15.1 Description of the vulnerable population..........................................................................................................20

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 study has been completed.................................21

16 Suspension or premature termination of the clinical study.......................................................................................21

16.1 Criteria for suspension of the whole clinical study or in one or more sites.......................................................21

16.2 Criteria for un-blinding......................................................................................................................................21

16.3 Requirements for subject follow-up..................................................................................................................21

17 Publication policy......................................................................................................................................................21

18 Bibliography..............................................................................................................................................................21

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS If other abbreviations, please add/delete rows and provide information in an alphabetic order.

Abbreviation or special term ExplanationAE (Adverse Event) An unfavorable change in the health of a participant,

including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied.

CRF Case Report Form (electronic or paper)

Clinical study A research study using human subjects to evaluate biomedical or health-related outcomes. Two types of clinical studies are Interventional studies (or clinical trials) and Observational studies

Completed The clinical study has ended normally, and participants are no longer being examined or treated (that is, the "last subject, last visit" has occurred).

Controlled trial A type of clinical trial in which observations made during the trial are compared to a standard, called the control. The control may be observations of a group of participants in the same trial or observations from outside the trial (for example, from an earlier trial, which is called a historical control).

EC Ethics Committee, synonymous to Institutional Review Board (IRB) and Independent Ethics Committee (IEC) and Regional Ethics Committee (REC)

Eligibility Criteria The key standards that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility Criteria include both inclusion criteria and exclusion criteria. For example, a study might only accept participants who are above or below certain ages.

Enrollment The number of participants in a clinical study. The "estimated enrollment" is the number of participants that the researchers need for the study.

Exclusion criteria The factors, or reasons, that prevents a person from participating in a clinical study.

Inclusion criteria The factors, or reasons, that allows a person to participate in a clinical study.

Intervention Model (Design) The general design of the strategy for assigning interventions to participants in a clinical study. Types of Intervention Models include Single Group design, Parallel design, Cross-over design, and Factorial design.

Interventional study (or clinical trial) A clinical study in which participants are assigned to

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receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. The assignments are determined by the research protocol. Participants may receive diagnostic, therapeutic, or other types of interventions

Primary Outcome Measure The planned Outcome Measure in the protocol that is the most important for evaluating the effect of an intervention. Most clinical studies have one Primary Outcome Measure, but some may have more than one.

Primary Purpose The main reason for the clinical trial. The types of Primary Purposes are Treatment, Prevention, Diagnostic, Supportive Care, Screening, Health Services Research, Basic Science, and Other.

PRO Patient Reported Outcome

Protocol The written description of a clinical study. It includes the study's objectives, design, and methods. It may also include relevant scientific background and statistical information.

Secondary Outcome Measure A planned Outcome Measure in the protocol that is not as important as the Primary Outcome Measure but is still of interest in evaluating the effect of an intervention. Most clinical studies have more than one Secondary Outcome Measure.

Serious Adverse Event An adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above.

Sham comparator arm A group of participants that receives a procedure or device that is made to be indistinguishable from the actual procedure or device being studied but does not contain active processes or components

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Single group design Describes a clinical trial in which all participants receive the same intervention.

Study completion date The date on which the final data for a clinical study were collected because the last study participant made the final visit to the study location (that is, "last subject, last visit"). The "estimated study completion date" is the date that the researchers think will be the completion date for the study

Study start date The date on which the enrollment of participants for a clinical study began

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1 INTRODUCTION Describe the study in brief

The introduction should provide a focused description of the scientific background for the project and an overview of state-of-the-art and key challenges in the field. The academic originality /novelty relative to the research front should be highlighted. Does the proposed project challenge current clinical practice and knowledge and/or current research?

This is a single arm, cross over, double blind, single centre, multi-centre, randomised clinical study designed to examine the (safety – performance) of XXX in study subjects with XXX disease/condition.

X number of patients will be enrolled in this study. See schedule of events, appendix XX.

2 STUDY DESCRIPTION

2.1 BackgroundBrief description of the prevalence of the disease/condition – based on literature search – reference any detailed information.

2.2 Study RationaleGive details regarding the expected impact/benefit for patient care and/or disease prevention and/or health service organization and quality in the short and/or long term. Describe for whom the proposed research project will have an impact (target group), and how the results of the project may come to use.

In addition, the project description should be used to explain the importance of the proposal for:

obtaining new knowledge for the health services creating potential for improvement of existing services / practice filling knowledge gaps (academic significance) creating other societal benefits creating opportunities for generalization and a broad application of knowledge

Provide a summary description of the study treatement and its intended purpose.

3 OBJECTIVES AND HYPOTHESIS Hypothesis should be presented clearly with regard to primary and secondary objectives. The objectives should be clearly defined, concrete and verifiable.

3.1 Clinical study - objectives

3.1.1 Primary objectiveThe primary objective is to evaluate the safety/efficacy using treatment X in-patients with X disease/condition.

If applicable, give short and long term objectives

3.1.2 Secondary objectiveDescribe any secondary objectives of the clinical study.

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3.1.3 Other study objectivesDescribe any other study objectives e.g. any long-term safety.

3.2 HypothesisDescribe the primary and secondary endpoints to be accepted or rejected by analysis of the clinical data from the clinical study.

3.3 Any results expected during the project periodClaims and intended performance of the study treatment that are to be verified.

3.4 Risks and anticipated adverse events that are to be assessedDescribe these as detailed in the risk analysis report.

4 PROJECT METHODOLOGY Give an overview on the strategy for project implementation and describe how the project will be managed and completed within the given project period.

5 STUDY DESIGN Explain why the specified scientific methods have been chosen. Method choices should be justified, and it should be explained how they are suited to resolving the stated hypotheses and specific issues. Alternatively, provide a description of how suitable methods will be developed during the project.

5.1 GeneralProvide a description of:

5.1.1 DescriptionStudy design (comparative, double-blind, parallel design etc., with or without a comparator group etc.)

5.1.2 Primary and secondary endpointsDescribe the primary and secondary endpoints, with rationale for their selection and measurement.

5.1.3 EquipmentNecessary equipment (and arrangement for monitoring, maintenance and calibration), infrastructure and access to resources

5.1.4 MethodologyMethods and why these represent an innovative approach in the field (if relevant). Describe the timings for assessing, recording and analyzing variables. Describe PROs e.g. will there be a quality of life questionnaire, or health technology assessment? How frequent will the questionnaire be completed and by who (patient or research team)?

5.1.5 Measures to minimise biasThe measures to be taken to minimise or avoid bias, including randomisation, blinding/masking, compliance in the collection of patient reported outcome (PRO), and clinical follow-up data

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5.1.6 Including more subjects to compensate for drop-outsDescribe any procedures for the replacement of subjects that have dropped out of the study by including more subjects. Patients who withdraw or are withdrawn from the study after randomisation cannot be replaced.

5.2 Study treatmentProvide a summary description of the treatment under study, if applicable comparator(s) and their intended purpose.

5.2.1 DescriptionProvide a description of the exposure to the treatment (s) or comparator(s), if used.

5.2.2 Justification comparatorProvide a justification of the choice of comparator(s).

5.2.3 Concomitant therapyProvide a list of any other treatments or medication to be used during the clinical study.

6 RISKS AND BENEFITS <Researcher/company/other as applicable> has conducted an analysis of the benefits and risks of the study

<Researcher/other as applicable> has determined that this research study is justified – based on the rationale described in section 2.

Risk analysis: What risks/complications / side effects, if known, may the subjects experience by participating in this study?

«This is a new interventional procedure and the likelihood of complications is not known at this time….». Complications that can happen are thought to be similar to using similar treatment/procedure – depending on classification the risk will vary.

6.1 Anticipated clinical benefitsDescribe the clinical benefits you anticipate from this study.

Benefits: List the potential benefits.

6.2 Anticipated adverse eventsList the anticipated adverse events e.g., infection, bleeding, perforation of artery, death etc.

6.3 Possible interactions with concomitant (medical) treatmentsList any known or anticipated interactions.

6.4 Steps to be taken to control or mitigate risksGive a summary of these steps from the risk analysis.

6.5 Subjects

6.5.1 Inclusion criteriaThe subject must meet all of the following inclusion criteria – list criteria e.g.

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Subject must be <enter age, e.g. ≥ 18 years, children 10-12 years >

Subject must have documented the disease/condition as determined by XX

Completed quality of life questionnaire

6.5.2 Exclusion criteriaThe 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 clinical study within the last month

inability to comprehend and respond to the quality of life questionnaire

6.5.3 Criteria for withdrawal or discontinuationSubjects can withdraw from the clinical study at any time without any rationale and without compromising their future medical care. The subject may also be removed from the clinical study by their physician if he/she feels that this is in the best interest of the subject. For some studies, patients may withdraw from the PRO-part, but still be included in the rest of the study procedures. Specify whether patients who are withdrawn from study treatment will be followed up or not.

6.5.4 EnrolmentSubjects with XX disease/condition are candidates for enrolment into this clinical study. Following review of the inclusion and exclusion criteria, eligible subjects will be invited to participate in this clinical study. Information on the clinical study, the fact that it involves research, the purpose of the clinical study, potential risks/benefits, etc. will be given to the subject. All subjects (and/or their designee) must give written informed consent prior to any study procedures being carried out. Once the subject has given written informed consent, they can be enrolled into the clinical study.

The subject’s participation in this clinical study is completely voluntary. If the subject decides not to participate in the clinical study, 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 study without sacrificing their rights as a patient or compromising their quality of medical care.

6.5.5 Duration clinical studyDescribe the total expected duration of the clinical study including start-up, enrolment, treatment, follow-up and reporting time estimate (from protocol to last patient last visit).

6.5.6 Expected subject durationDescribe the treatment period from time of enrolment to final follow-up for a subject.

6.5.7 Number of subjectsDetail the number of subjects to be included in the clinical study.

6.5.8 Time to select all subjectsDetail the expected recruitment period for the clinical study e.g. the study 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.

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6.6 Procedures

6.6.1 Clinical study proceduresThe clinical study methods are described in this section.

Add in study 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 study procedure, unless otherwise stated. The first PRO-instruments should be filled in after inclusion, before the first intervention.

Examples of PROs could be

For emergency studies document basic information required prior to entering into the study:

history and physical examination – if special examinations required document here

height and weight if relevant

specific tests, e.g. blood pressure, heart rate, ECG

laboratory tests if required

if female of child bearing potential a urine pregnancy test

Describe other visits and the procedures involved in them from the schedule of events.

Visit 1…… N

Follow-up

6.6.2 Activities performed by representatives for research responsible institutionDescription of the activities to be performed by the research responsible institution or delegated to a third party e.g. clinical study set-up, including development of research protocol, collected documentation for study treatment (e.g. labelling, case report form (CRF), randomisation, if applicable, site documentation (CV of researcher etc.), ethics (EC/REC) application with attachments (and amendments if applicable) and EC/REC approval, clinical study agreements, insurance (if applicable), treatment supply, investigative site selection/training/initiation, subject recruitment, adverse events management, data management, statistics, medical writing.

6.6.3 Factors that may compromise the outcome of the clinical study / interpretation of the results For example factors including subject baseline characteristics, concomitant medication, the use of other treatment and subject related factors such as age, gender, lifestyle and drop-out for PRO-assessments. The methods for addressing these factors in the clinical study, e.g. subject selection, clinical study design (i.e. stratified randomisation) or by statistical analysis will be described.

6.6.4 Follow-upDescribe 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 study treatment and allow any risks associated with adverse treatment effects over that period to be identified and assessed. Describe follow-up visits and what procedures are involved in these visit(s). Describe any postal or internet-based collection of PRO-data.

6.6.5 Follow-up medical care Describe the medical care to be provided after the clinical study is completed.

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7 STATISTICAL CONSIDERATIONS To be completed by the study statistician with reference to the sections 3, 4 and 5 on the objectives, hypothesis and the design of the clinical study and including:

7.1 Statistical designProvide a description and justification of the statistical design of the clinical study, including method and analytical procedures to be employed.

7.2 Sample sizeProvide a description of the sample size rationale and methods of calculation

7.3 The level of significance and power of the clinical studyProvide a description of the rationale for the level of significance and power of the analysis for the clinical study to be considered successful.

7.4 Expected drop out ratesEstimate the expected drop out rates for the clinical study and a rationale regarding the calculation of these.

7.5 Pass/fail criteria Provide a description of the pass/fail criteria that may apply to the analysis of the clinical study.

7.6 Provision for interim analysesProvide a description of any interim analyses that may be included within the clinical study, with a rationale for them, including the timings and data to be included within the interim analyses.

7.7 Criteria for stopping the clinical studyProvide a description of any stopping rules on statistical grounds and the rationale for these criteria.

7.8 Specification of subgroupsProvide a description of any subgroups of subjects for analysis with a description of the rationale for the subgroup analyses.

7.9 Procedures to take into account all subject dataProvide a description of analyses to take into account all subject data (intention-to-treat analysis).

7.10 Treatment of missing, unused, spurious dataProvide a description of any rules for handling any missing, unused or spurious data as well as a rationale for their use. This is also applicable for the PRO-data, both with regard to missing forms and missing values within a form. If not clear at time of protocol, include in separate statistical analysis plan that is finalised prior to database lock.

7.11 Exclusion of data from hypothesis testingProvide a description of any data that may be excluded from the hypothesis testing along with the rationale for exclusion (per-protocol analysis).

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7.12 Min/max number of subjects per centre (multi-centre study)For multi-centre studies: a description of the minimum and maximum number of subjects to be enrolled per centre.

7.13 Special reasoning Provide a description of any special statistical reasoning pertaining to the clinical study.

8 DATA MANAGEMENT

8.1 Procedures for data review, database cleaning, and issuing and resolving queriesDescribe 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 retentionDescribe the procedures to be followed for the retention and archiving of data on the clinical study for the period(s) specified in 8.4.

8.4 Specified retention periodDocumentation for the clinical study must be retained for a period decided by the EC/REC, usually five years after final study report/publication (Norway).

9 AMENDMENTS TO THE RESEARCH PROTOCOL The Research Protocol may require to be amended during the conduct of a clinical study. Any amendment to the Research Protocol will be agreed upon between the representative for the research responsible institution and the principal investigator. The amendments will be approved by the ethics committee (EC/REC).

10 DEVIATIONS FROM THE RESEARCH PROTOCOL

10.1 Statement that investigator is not allowed to deviate from the research protocolThe study will be performed in accordance with this research protocol.

10.2 Procedures for recording, reporting and analyzing protocol deviationsDescribe the process for recording deviations for the research protocol, for reporting of the deviations and analysis of deviations.

All research protocol deviations will be reviewed by the representative for the research responsible institution for impact on subject’s participation in the clinical study. The representative for the research responsible institution will notify the project manager of deviations. All deviations will be reported to the appropriate regulatory bodies as required.

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11 ACCOUNTABILITY OF STUDY TREATEMENT If the treatment in the study is a product where strict control is required, describe how the access to the study treatment will be controlled. Include a statement that the study treatment shall only be used in the clinical study and according to the research protocol.

<If applicable> Describe the process and documentation to be used to record the physical location of all study treatment from shipment to the study site until return or disposal including, if applicable; amount received and placed in storage area, amount currently in storage area, and temperature logging. The study treatment must be identified, in terms of batch- and serial numbers and expiry dates to allow all appropriate action to detect any potential risks to the products.

Describe the packaging and labelling requirements if applicable.

12 STATEMENTS OF COMPLIANCE

12.1 Statement of compliance with ethics principles The study will be performed in accordance with the ethical requirements defined in the Declaration of Helsinki.

12.2 Statement regarding ethical approvalThe clinical study shall not commence until written approval/favourable opinion from the REC

12.3 Additional requirement from ethics committee The clinical study performance will include any additional requirements requested/mandated by the EC/REC

12.4 Statement of insurance coverDescribe the insurance in place for subjects, if appropriate.In Norway patients are covered by “Norsk Pasientskadeerstatning”

13 INFORMED CONSENT PROCESS

13.1 General informed consentDescribe the process for gaining informed consent from competent adult’s e.g.

Informed consent shall be obtained in writing from the subject prior to any procedures specific to the clinical study being applied to the subject. The template provided by REC is to be used in Norway.

The process must adhere to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the clinical study, the investigator must have EC/REC 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 study to the subject as well as providing the subject with a copy of the subject information sheet. The consent information will include all aspects of the clinical study 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 study, ask any questions and make the decision to participate or not in the clinical study.

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Should the subject decide to participate in the clinical study, the informed consent form will be signed and personally dated by the subject and/or when appropriate also by the authorised person who conducted the informed consent discussion. A copy will be given to the subject. Any significant relevant new information that arises during the course of the clinical study will be provided to the subject and their consent to continue will be sought. As judged by EC/REC/regulatory authority.

13.2 Informed consent, where subject is unable to give informed consent (incapacity/emergency)If subjects are to be included that cannot give informed consent themselves this need to be described in the research protocol. The EC/REC will have to approve whether independent witness or legally authorized representative can consent on behalf of the subjects.

14 ADVERSE EVENTS

14.1 Definition of 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 study treatment.

This includes:

Events related to the study treatment or the comparator

Events related to procedures involved (any procedure in the research protocol)

14.2 Definition of serious adverse event (SAE)Serious adverse event (SAE) is any event (whether or not associated with the study treatment) that:

1. Results in death

2. Led to serious deterioration in the health of the subject , that either resulted in

a) life threatening illness or injury, or

b) a permanent impairment of a body structure or a body function, or

c) in-patient or prolonged hospitalization, or

d) need of 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

NOTE: This includes events 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) 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 research protocol, without serious deterioration in health, is not considered a serious adverse event.

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14.3 Reporting adverse eventsDescribe process for capturing adverse event data occurring during a clinical study, categorization of the event data, follow-up and reporting where the category of the event requires it.

14.4 List of foreseeable adverse events, anticipated adverse treatment/intervention effects.Provide a list of anticipated adverse treatment/intervention effects as from the risk analysis and available documentation for the intervention.

14.5 Emergency contact details for reporting SAEs Provide contact details for reporting of serious adverse events.

14.6 Data monitoring committee – <if applicable>Describe the data monitoring committee (DMC) structure, operational objectives and responsibilities.

15 VULNERABLE POPULATION (IF REQUIRED)

15.1 Description of the vulnerable populationDescribe the vulnerable population to be included in the clinical study, e.g. mentally incompetent, children, emergency etc.

15.2 Description of informed consent processDescribe in detail the informed consent process with the legally responsible and assent, if possible for the subject.

15.3 Description of EC’s specific responsibilityDescribe 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 study has been completedDescribe the medical care to be provided after completion of the clinical study.

16 SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL STUDY

16.1 Criteria for suspension of the whole clinical study or in one or more sitesDescribe the criteria for suspension or premature termination of the whole clinical study or for closing sites active in the clinical study.

The study may be terminated by the representative for the research responsible institution 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 un-blindingDescribe the criteria and process for un-blinding the clinical study, on a subject level or for the clinical study as a whole.

16.3 Requirements for subject follow-upDescribe the process and obligation on the representative for the research responsible institution for subject follow-up.

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17 PUBLICATION POLICY Upon study completion the results of this study will either be submitted for publication and/or posted in a publicly assessable database of clinical study results.

The results of this study will also be submitted to the Ethics Committee according to national regulations.

All personnel who have contributed significantly with the planning and performance of the study (Vancouver convention 1988) may be included in the list of authors.

18 BIBLIOGRAPHY List of some bibliographic references pertaining to the clinical study:

1. World Medical Association Declaration of Helsinki – Ethical principles for medical research involving human subjects

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http://www.wma.net/en/30publications/10policies/b3/

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