Medical Directorate PHARMACOVIGILANCE STANDARD OPERATING PROCEDURE NO SOP 01 DATE RATIFIED 02/07/2013 NEXT REVIEW DATE 02/07/2014

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1 PHARMACOVIGILANCE STANDARD OPERATING PROCEDURE NO SOP 01 DATE RATIFIED 02/07/2013 NEXT REVIEW DATE 02/07/2014 POLICY STATEMENT/KEY OBJECTIVES: This document outlines the procedure for defining a research incidents severity, identifying, recording and reporting all incidents in a clinical trial. POLICY AUTHOR: Katie Helm; Research & Development Facilitator Page 1 of

2 BACKGROUND In order to meet the requirements of the European Directive (EU) on Clinical Trials (2001/20/EC), Health care commission Core standard C12 and Research Governance (Department of Health, 2001) all NHS Trusts are required to have systems in place to record and report the spectrum of research related clinical incidents for both Trust Sponsored and externally Sponsored clinical trials. This Standard Operating Procedure (SOP) outlines these systems and describes the classification of incidents. Where a clinical trial is Sponsored outside of the Trust, please also refer to the study protocol for Sponsor definitions of adverse events. Adverse Events (AEs) and Serious Adverse Events (SAEs) should be reported in accordance with the Medicines for Human Use (Clinical Trials) Regulations 2004 and also in compliance with the International Conference of Harmonisation Good Clinical Practice (ICH GCP) guidance, and within any other conditions stipulated in the trial protocol or by the host Trust. It is the responsibility of the Sponsor to ensure that events are reported appropriately to the competent authority; in the UK this is the Medicines and Healthcare Regulatory Agency (MHRA) and also the Research Ethics Committee (REC) providing the favourable opinion for the trial. The Regulations distinguish between AEs, Adverse Reactions (ARs), SAEs, Serious Adverse Reactions (SARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs), with differing reporting requirements for each type of event. This clarification is also included in all study protocols that require such reporting. Page 2 of

3 Definitions For Lancashire Care Foundation Trust (LCFT) Sponsored studies the following definitions apply. However, external Sponsors may apply alternative definitions which will be defined in the study protocol: Adverse event (AE): Any untoward medical occurrence in a trial patient which does not necessarily have a causal relationship with the treatment. Serious Adverse Event (SAE): Any untoward medical occurrence that: Results in death Is life-threatening Requires inpatient hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability/incapacity or Is a congenital anomaly or birth defect An untoward medical occurrence that is otherwise considered medically significant to the investigator may also be reported as an SAE. Some Sponsors may specify other events that should be reported as SAE although they do not fulfil any of the above criteria of SAE (this will be specifically identified in the study protocol) Adverse Reaction (AR): All untoward and unintended responses to an investigational medical product related to any dose administered. Any event that could not be determined as definitely not caused by the IMP should be reported as an AR. Serious Adverse Reaction (SAR): An adverse reaction resulting in serious outcomes as listed in SAEs. Seriousness is not the same as severity, as seriousness relates to the outcome of the event and not the intensity of the reaction. Page 3 of

4 Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction is unexpected if its nature and severity are not consistent with the medicinal product information (detailed in the Summary of Product Characteristics if a licensed product or in the Investigators Brochure if not yet licensed). PURPOSE This SOP is designed to describe the process of reporting research Clinical incidents that occur at LCFT Adherence to this will fulfil the Trusts legal obligations under the SI1031 Medicines for human use (clinical trials) regulations PROCEDURE Who? This SOP applies to AE s, SAE s, AR s, SAR s and SUSAR s which occur within the LCFT or research that is being conducted by the Trust s personnel elsewhere. The research team and Principle Investigators (PI) have an obligation to report AE s, SAE s, AR s, SAR s and SUSAR s that they become aware of to the appropriate Sponsor. It is usual that this is Sponsor as soon as possible in accordance with the Sponsor requirements (usually within 48 hours of awareness of the event), by completing an incident form as stipulated in the trial protocol and adhere to any un-blinding procedures that the protocol also requires. Where LCFT is acting as Sponsor the research team will report to the R&D department using the Incident reporting form (Appendix 1) within 72 hours via the R&D generic account; R&D@lancashirecare.nhs.uk. Trust R&D should also be notified of all SAE s, SAR s and SUSAR s for externally Sponsored studies. Page 4 of

5 Additionally researchers are required to report any such incidents to the REC and in the event of a SUSAR or a drug or device being involved and /or if the event is deemed fatal or life threatening, the MHRA must be notified no later than 7 days of becoming aware of the event. An event that is not fatal or life threatening, but remains a SUSAR must be reported to the MHRA no later than 15 days from being made aware of the reaction. Life-threatening in the definition of a serious adverse event refers to an event in which the subject 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 or were left untreated. The Sponsor is responsible for ensuring all events are reported to the MHRA and the REC, however in many cases, this responsibility is delegated to the trials Chief Investigator (CI) or a Contract Research Organisation. The clinical trial PI s are responsible for ensuring that all events occurring at their site are reported appropriately to the Sponsor or their delegate. All staff and clinicians involved with managing trial patients should note adverse events (AE s) that are reported by the patient and make them known to the appropriate study staff. Patients entered into clinical trials must be encouraged as part of the consent process to contact their clinician or research practitioner, e.g. research nurse at the time of an event occurring. Additionally, appropriate assessments should be conducted by the study team to identify AE s; these must be documented in the patient records. To aide identification of Clinical Trial participants, details of a participant s involvement must be clearly documented in the electronic case records. This should include a scanned copy of the patient information leaflet and consent form, the consent process (see SOP ), study number, randomisation codes, changes to patient care or treatment as a result of participation, details of trial medications prescribed, all adverse incidents (AE s, SAE s, AR s, SAR s and Page 5 of

6 SUSAR s), copies of research related patient care communications (i.e. to letters to patients General Practitioner) and end of study involvement. Where allergies is listed at the top of the electronic case records, a comment should be inserted to state that This patient is taking part in a clinical drug trial, please refer to the Trust SOP (number) on Pharmacovigilance for further guidance in the event of a patient admission, death, or other Serious Adverse Event. In the event that a clinical trial participant is admitted to a LCFT ward area, the research team must be informed by the clinical team of the hospital admission as soon as possible. Details of an emergency research contact should be provided in a location on the electronic case records that can be easily accessed. Additionally, information making services aware of their responsibility to inform the study team as soon as an AE occurs (in line with the study protocol requirements), should also be easily accessible. All sites that are responsible for the care of participants involved in clinical trials are also responsible for the formulation of their own site specific SOP on the out of hour s emergency contact processes for their staff and participants. The processes listed in the out of hours SOP should be explained to all clinical trial staff and participants and their potential carers at the start of a clinical trial so that in the event of an emergency, or the need to contact the research team out of working hours, a Physician is available to contact. A copy of the out of hours SOP developed by the team should be made available to R&D. It is the responsibility of the individual research teams to ensure that they follow the site specific SOP requirements governed by each location in which they work and there may be study specific requirements that impact this SOP. It is therefore advised that each clinical trial protocol is also cross referenced Page 6 of

7 for any requirements that may impact reporting of information during out of hours contact. When? At each visit or study assessment, AE s that have occurred since the previous patient contact should be discussed with the patient. For source documentation verification, these events need to be detailed in the patient s medical notes including the start dates, if known; of the onset of the event as well as the date the event stopped or changed, if applicable. Adverse events on-going on completion of the study should be followed up as required by the protocol and as clinically indicated. For some studies, telephone contact may be used between visits to ensure accurate and timely reporting of such events. How? Adequate pharmacovigilance procedures should be clearly documented in the study protocol. All procedures and requirements outlined in the protocol should be followed. Awareness of procedures and documentation should form part of initiation to the study for staff involved. Categorising events This is summarised in Appendix 2. Individual adverse events should only be categorised by a medically qualified person integrally involved in the study i.e. the PI or delegated other and if applicable they should be reported to the Sponsor or delegate for evaluation/clarification. Categorisation of the event should include determination of: 1. Causality: Is there a possible causal relationship between the investigational medicinal product(s) (IMP) and/or concomitant therapy and the adverse event? Page 7 of

8 The causality assessment given by the PI should not be downgraded by the Sponsor and if the Sponsor disagrees with the PI s assessment, then the opinion of both the PI and Sponsor should be provided in the report. 2. Seriousness, is it: fatal life-threatening requiring inpatient hospitalisation or prolongation of existing hospitalisation resulting in persistent or significant disability/incapacity a congenital anomaly or birth defect another event specified in the protocol to be reported as an SAE 3. Expectedness: Is its nature and severity not consistent with the medicinal product information- detailed in the Summary of Product Characteristics if a licensed product or in the Investigators Brochure if not. Information on expectedness may also be detailed in the protocol An event is a SUSAR if it is unexpected, serious and is possibly related to the trial treatment. Reporting events AEs are reported via a data collection tool usually provided by the Sponsor e.g. Case Report Form or electronic case Report Form. Completed forms will be sent to the Sponsor, or collected by them. AE reports may be submitted to the MHRA and the REC by the Sponsor or their delegate. The Trust incident report form, seen in appendix one, must be completed when informing Trust R&D of incidents and submitted via the generic R&D address R&D@lancashirecare.nhs.uk and reported within 72 hours of site notification. Page 8 of

9 All SAEs must be reported by the site as soon as they are notified by the participant, to the Sponsor, except where the protocol does not stipulate this. The immediate report to the Sponsor can be brief, but must be followed up by a more detailed report. SAE reporting forms should be provided by the Sponsor at study set up and all staff need to be familiar with the study specific requirements and documentation as part of their induction to the study. The procedure for how to report to the Sponsor should be outlined in the protocol. If a Sponsor does not provide a sample incident reporting form, sites must utilise the Trust incident report form. SAEs should be reported by the Sponsor in quarterly annual safety reports to the MHRA and REC and presented regularly at the trial safety monitoring committee if applicable. These reports should be maintained in the site file. All SUSARs should be reported by the site to the Sponsor according in accordance with time frames stipulated in the protocol. The Sponsor must also report such events as per protocol and Clinical Trials Regulations to the MHRA and the REC. The Sponsor must also immediately inform all PIs involved in the trial of relevant information about SUSARs that could adversely affect the safety of their trial patients. Any such notifications should be signed and dated by the PI as acknowledgement of the information, the research team informed of these and the documentation file in the safety reporting section of the site file. The following should be documented as clearly as possible in accordance with the protocol when reporting events: Time and date of start and stop of event (if the patient cannot remember, then as near as possible) Severity of event, this may be graded by using the toxicity criteria in the protocol. This is often mild, moderate or severe (guidance as to what defines each of these may be in the protocol) Page 9 of

10 Action taken regarding study drug (if any) these may include stopping study drug temporarily or permanently. Any treatment/medication given for the event, including the dates the treatment/medication was commenced and the date it was stopped/changed, if applicable. The event outcome Complete collection of the necessary data relating to adverse events will ensure that source data is available to ensure complete and accurate Case Report Form completion and reporting of the adverse event adhering to the study protocol, GCP and appropriate regulations. Reporting SUSARs All SAEs that are SUSARs are subject to expedited reporting to the MHRA and the REC (by the Sponsor) and there are strict timelines set out in the Trials Regulations. Therefore, PIs must report events to the Sponsor or delegate immediately so as to satisfy these requirements. These are: 1. A SUSAR which is fatal or life-threatening must be reported as soon as possible within 7 days after the site became aware of the event. All follow-up information must be reported within 8 days of sending the first report. 2. A SUSAR which is not fatal or life-threatening must be reported as soon as possible and in any event within 15 days after the site became aware of the event. All SUSARs associated with a comparator product in the clinical trial should be reported, even if this product is approved. Generally treatment codes should be broken before reporting a SUSAR to the MHRA and the REC, although the blind could potentially be broken by the Sponsor/CI and not made known to the PI if there is no danger in this to the patient. Page 10 of

11 For trials in high morbidity and/or high mortality disease, where efficacy endpoints could also be SUSARs or when a fatal or other "serious" outcome is the primary endpoint in a trial, the integrity of the trial may be compromised if the blind is broken. Under these and similar circumstances, it may be appropriate to reach agreement with the MHRA in advance concerning serious events that would be treated as disease-related and not subject to systematic un-blinding and expedited reporting. This agreed procedure will be outlined in the protocol Other expedited reporting Other safety issues qualify for expedited reporting by the Sponsor: Single case reports of an expected SARs with an unexpected outcome An increase in the rate of occurrence of an expected SAR, judged to be clinically important Post-study SUSARs that occur after the patient has completed a trial (the length of time after completion of the trial may be specified in the protocol) A new event, related to the conduct of the trial or the development of the investigational medicinal product, that is likely to affect the safety of subjects, e.g. an SAE which could be associated with the trial procedures and which could modify the conduct of the trial or a significant hazard to the subject population such as lack of efficacy of a product used for the treatment of a life-threatening disease A major safety finding from a newly completed animal study Sending a report The Investigator Brochure usually outlines the format for event reporting and this should be followed. Reports of SUSARs will normally be in the CIOMS-1 format (available at that is widely accepted as the standard within the pharmaceutical industry. Information on the final description and evaluation of an adverse reaction report may not be available within the required time frames for reporting. For Page 11 of

12 regulatory purposes, initial expedited reports should be submitted within the time limits and must contain the following minimum information: 1. A suspected investigational medicinal product 2. An identifiable subject (e.g. study subject code number) 3. An adverse event assessed as serious and unexpected, and for which there is a reasonable suspected causal relationship 4. An identifiable reporting source 5. Where applicable, EudraCT number or in case of non EU trials the Sponsor's trial protocol code number 6. A unique case identification, i.e. Sponsor's case identification number Where there is incomplete information at the time of initial reporting, all the appropriate information for an adequate analysis of causality should be actively sought. The Sponsor or delegate should report further relevant information after receipt as follow-up reports. Guidance on research adverse event forms The research protocol number requested on the form refers to the number used by the Trust to identify Trust research on the National research register and will be written on your Trust approval letter. Do not delay sending the form if this number is not available, provide the full title and version number instead. Document events in a clear way as far as possible. For example, the patient may say that they felt sick. This can be interpreted in many ways: either they felt nauseated or they may have felt unwell, or they may even have been vomiting. If possible ask patient the date and start and stop time of event. If the patient cannot remember, then as near as possible. Document the action taken regarding the intervention if any. For example was the treatment dose reduced, or was study drug/treatment delayed etc. Page 12 of

13 Document any treatment/medication given for the event, including the dates the treatment/medication was commenced and the date it was stopped/changed, if applicable. Document the event outcome. If all data is not available at initial assessment send what you can to keep within the 24-hour deadline and provide follow-up information within 5 days. This shortened deadline is provided to enable the safety committee time to adjudicate on the incident with 15 days. Events on-going at study completion should be followed up as detailed in the protocol and as clinically indicated. Note Pregnancy in either a patient or the partner of the patient in a trial taking trial medication should be reported as an SAE. Verification of all these events need to be detailed in the patient s medical notes including the start dates (if known) of the onset of the event as well as the date the event stopped or changed, if applicable. Adverse events should also be documented in the patient s research case report form. Adverse events on-going on completion of the study should be followed up as required by the protocol and as clinically indicated. These guidelines have been adapted from ICH/GCP (1996) to use in line with Sponsor incident reporting forms to initially inform research governance personnel of an adverse event. This has been utilized to assist with compliance and implementation within the Trust. The Research department are responsible for approving this standard operating procedure for use and adherence to this procedure will be monitored as part of research Governance audits. The Chief or Principal Investigator of individual projects are responsible for monitoring the adverse events that occur and have a duty to report events as appropriate to their seriousness (see appendix 2 for definition of adverse and serious adverse events). Managers have a responsibility to ensure staff have read and understood the procedure. Subsequent audit results demonstrating (lack of) Page 13 of

14 adherence may require the author to develop local strategies for further dissemination. Compliance will be measured by annual audit of completed incident forms against source documentation for research trials held at the Lancashire Care NHS Foundation Trust. If 100% compliance is not observed, the staff involved will be offered further GCP training. Page 14 of

15 OTHER RELATED PROCEDURES, POLICIES, LEGISLATION OR GUIDANCE International Conference on Harmonisation of Good Clinical Practice 1996 Medicines for Human Use (Clinical Trials) Regulations 2004 Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 GLOSSARY Adverse Event (AE) Adverse Reaction (AR) Case Report Form (CRF) Chief Investigator (CI) Electronic Case Report Form (ecrf) Medicines and Healthcare products Regulatory Agency (MHRA) Research Ethics Committee (REC) Principal Investigator (PI) Serious Adverse Event (SAE) Serious Adverse Reaction (SAR) Standard Operating Procedure (SOP) Suspected Unexpected Serious Adverse Reaction (SUSAR) APPENDICES Appendix 1: Incident Reporting Form Appendix 2: Distinguishing event categories Page 15 of

16 Appendix 1: Incident Reporting Form LCFT Research Incident Report Form Patient hospital number: DOB: Patient Initials: Study protocol Version and research number: (as provided by the Clinical Governance department on Trust approval) Patient study number: Principle investigator name: Adverse event number: (Consecutive numbers for each study) Type of Adverse event: (see appendix 2 for categorisation) Is this a Serious Adverse Reaction? Yes/No Is this a Suspected Unexpected Serious Adverse Reaction? Yes/No Researcher contact details: Name: Number: Brief description of event (200 words max) including action taken Definition of an SAE/SUSAR Is fatal results in death (NOTE: death is an outcome, not an event) Is life-threatening Requires inpatient hospitalisation or prolongation of existing hospitalisation (standard length of stay should be stated in the protocol) Results in persistent or significant disability/incapacity Or Is a congenital anomaly/birth defect A Suspected, Unexpected Serious Adverse Reaction (SUSAR) Is an unexpected SAE that is related to the intervention under investigation. Page 16 of

17 Medication 24hours prior and after event: (please continue on further page if necessary) Causality Unlikely to be due to research intervention Possibly due to research intervention Probably due to research intervention Definitely due to research intervention Outcome Recovered Recovered still under treatment Recovered with sequalae Permanent disability or disease Death date date date date date date Signature: Date: Page 17 of

18 Assess Seriousness Appendix 2: Distinguishing event categories Not Serious Serious Adverse Event (AE) record/report Assess Causality According to Protocol Unrelated to Drug/Device Related to Drug/Device Definition of Serious Is fatal results in death (NOTE: death is an outcome, not an event) Is life-threatening Requires inpatient hospitalisation or prolongation of existing hospitalisation (standard length of stay should be stated in the protocol) Results in persistent or Serious Adverse Event (SAE) Record/report According to Protocol Expected Serious Adverse Reaction (SAR) (Declared in Protocol) Page 18 of Record/report Draft V1.0 According to Protocol Assess expectedness Unexpected Suspected Unexpected Serious Adverse Reaction (SUSAR) Record/report According to Protocol and Trials Legislation