Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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