REPORTS AND REPORTING - Pharmacovigilance-Material

REPORTS AND REPORTING

1. Expedited Reporting to Competent Authorities

1.1.Timelines for SUSAR Reporting

The Clinical Trials Regulations set time limits for expedited reporting of SUSAR for all IMPs in a clinical trial (including comparators and placebos*): Sponsors should report:

•         Fatal or life threatening SUSARs: No later than 7 calendar days after being made aware of the case**, with any follow-up information to be reported within a further 8 calendar days.

•         All other SUSARs: No later than 15 calendar days after being made aware of the case.

•         *Events associated with placebo will usually not satisfy the criteria for a SUSAR. However, where they do occur, (for example a reaction due to an excipient or impurity) the sponsor should report such cases.

•         **The clock for expedited initial reporting starts as soon as the information containing the minimum reporting criteria (see section 6.1.3) has been received by the sponsor (not when the sponsor first registers that a report has been sent by the local investigator). The definition of what constitutes Day 0 should be clearly described in local sponsor SOPs

•         If significant new information on an already reported case is received by the sponsor, the clock starts again at day zero, i.e. the date of receipt of new information. This information should be reported as a follow-up report within 15 days.

•         Any SUSARs identified after the end of the trial should also be reported

Minimum Reporting Requirements for SUSARs

Information on the final description and evaluation of an adverse reaction report may not be available within the required time frames for reporting. For regulatory purposes, initial expedited reports should be submitted within the time limits when the following minimum criteria are met:

•         A suspected investigational medicinal product;

•         An identifiable subject (e.g. trial number);

•         An adverse event assessed as serious and unexpected, and for which there is a reasonable suspected causal relationship;

•         An identifiable reporting source;

•         And, when available and applicable:

•         A EudraCT number (or, in the case of non-European community trials, the sponsor’s trial protocol code number); and

•         A unique case identification (i.e. sponsor’s case identification number)

•         Treatment assignment after unblinding and validation (or not) of the suspected causes.

The sponsor is responsible for ensuring that all relevant follow-up information is requested and submitted to competent authorities and ethics committees as appropriate. Detail on what would be considered relevant follow-up information can be found in Volume 10 EC Guidance Document: Questions and Answers Specific to Adverse Reaction Reporting in Clinical Trials.

SUSARs from Trials Run in Third Countries (i.e. Countries outside the European Economic Area)

In an international trial, reporting should follow the requirements of the countries in which the trial is taking place. For trials with sites within the EU, the sponsor must ensure that all SUSARs occurring in third countries are reported to the competent authorities of the EU countries in which the trial is taking place. If a sponsor is conducting a trial outside the EU (and has no other trial in the EU with the same active substance), there is no requirement to ensure reporting into the EudraVigilance Clinical Trial Module (EVCTM).

The procedures for notifying events to the sponsor, and of reporting relevant events onwards to competent authorities and ethics committees should be included in any agreements between international groups performing the trial.

Other Safety Issues Requiring Expedited Reporting

Safety issues, which might materially alter the current benefit-risk assessment of the trial but which do not meet the definition of a SUSARs, may occur during a trial.

Examples include new events related to the conduct of the trial or the development of the IMPs and likely to affect the safety of the subjects, such as:

•         A serious adverse event which could be associated with the trial procedures and which could modify the conduct of the trial;

•         A significant hazard to the patient population, such as lack of efficacy of an IMP used for the treatment of a life-threatening disease;

•         A major safety finding from a newly completed animal study (such as carcinogenicity);

•         A temporary halt of a trial for safety reasons and conducted with the same IMP in another country by the same sponsor;

•         Recommendations of the Data Monitoring Committee (DMC), if any, where relevant for the safety of the subject.

These events/observations are not to be reported as SUSARs, but they might require other action, such as urgent safety measures, substantial amendments or early termination. Where such actions are not taken, Commission guidance (CT-3 2011) recommends that the sponsor informs the competent authorities and ethics committees.

2. Expedited Reporting to Ethics Committees

Notification (submission) of an ICSR in a designated format to the appropriate Regulatory Authorities in compliance with the parameters and timelines specified by legislation and local regulatory guidelines. An expedited report would be an ICSR meeting the criteria for rapid transmission to a Competent Authority.

SUSARs and other safety issues are reported to the ethics committees which approved the trial in the same timeframes as the reports to competent authorities. However, the UK ethics committee is only required to receive expedited reports of SUSARs occurring in the UK, in the trial.

All safety reports to the UK ethics committee should be accompanied by the covering form provided on the NRES website. The form should be signed by the person submitting the report and submitted on paper. All enclosures should be listed and referenced on the form. Reporting requirements are detailed on the NRES Safety Reporting pages.

3. Annual Safety Report (ASR)

An aggregate Safety Report in the context of clinical trials, taking into account all newly available safety information produced during a defined reporting period. Where several clinical trials are conducted with the same Investigational Medicinal Product (IMP) the reporter should include a concise global analysis of the actual safety profile of the tested IMP based on the experience for all the clinical trials.

An annual report for each trial must be submitted by the sponsor to the competent authorities and the ethics committees of the concerned Member States, taking into account all new available safety information received during the reporting period. It should be in the format of a Developmental Safety Update Report (DSUR). The required format is detailed in the ICH guideline E2F Note for guidance on development safety update reports. The main points are summarised below:

Development Update Safety Reports (DSURs)

The Development Safety Update Report (DSUR) Guidance (ICH E2F) was published in the EU in September 2010 and has been implemented in September 2011 and the one year transition period agreed by the Commission has now ended.

In addition to the expedited reporting required for SUSAR, sponsors are required to submit a safety report to the MHRA and the Ethics Committee, once a year throughout the clinical trial or on request. The annual safety report should take into account all new available safety information received during the reporting period.

DSURs should be provided at yearly intervals from the date of the original exemption, for trials ongoing on 1 May 2004, or the date of the first CTA approval for trials starting after 1 May. For trials with marketed products, the date is the first marketing authorisation granted in the EU.

The aim of the annual safety report is to describe concisely all new safety information relevant for one or several clinical trial(s) and to assess the safety of subjects included in these studies.

The DSUR should include the following:

Part 1: Analysis of the subjects’ safety in the concerned clinical trial(s) with an appraisal of its ongoing risk:benefit

Part 2: A line listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the concerned trial(s), including all serious adverse reactions from third countries

Part 3: An aggregate summary tabulation of suspected serious adverse reactions that occurred in the concerned trial(s).

Content and Format of a DSUR

The aim of the annual safety report is to describe concisely all new safety information relevant to the IMP providing information on comparators where required (separate DSURs for comparators and placebos not required). The DSUR should contain:

•         Safety information obtained by the sponsor during the reporting period

•         Analyses of any new information based on the previous knowledge of the IMP

•         Changes to the safety profile of the IMP and any change in the benefit-risk ratio

To achieve these objectives, it is important to use the format provided in ICH guideline E2F which includes data presented in line listings and summary tabulations:

•         Interval line listings of SARs for the reporting period

•         Cumulative summary tabulations of SAEs since the DIBD

•         Subject exposure to the IMP (number of subjects treated in the reporting period)

The ICH guideline E2F requires the sponsor to produce one DSUR per IMP (covering all trials undertaken by the sponsor with that IMP). Therefore, when an unlicensed IMP is being developed by a non-commercial sponsor, (for example a biomedical unit) one DSUR should be submitted covering the IMP and safety data from all trials being conducted within the reporting period.

For UK trials however, where the sponsor is not the Marketing Authorisation Holder, the MHRA recognize that it may be more appropriate to submit trial specific DSURs. In this instance, the sponsor should submit a covering letter with any justification for the approach taken with a specific point of contact for any queries.

The completion of a DSUR may be shared, for example between the chief investigator and sponsor and in this case, it is important to ensure that responsibilities are defined in any relevant SOP. Generally, the chief investigator completes the majority of sections in the DSUR report however; the sponsor’s input is required in areas such as:

•         Inclusion of any unblinded SUSAR/SARs for submission to competent authorities and ethics committees with a blinded version for the CI to file;

•         Where a trial specific DSUR is completed, a list of all trials with the IMP sponsored by that organisation.

When completing a DSUR, a non-commercial sponsor who is not the Marketing Authorisation Holder for the IMP, may not have access to information relevant for the completion of some parts of the report (such manufacturing issues, non-clinical data, and marketing status). This should be made clear in the DSUR.

Where trial specific DSURs are completed, it would be good practice to ensure that all other investigators working with that IMP within the sponsor’s organisation, are provided with appropriate information (e.g. The DSUR Executive Summary). General communication between investigators working with the same IMP can help advance understanding of the use and safetyprofile of that IMP. Any relevant safety information should also be provided to the Marketing Authorisation Holder, where applicable.

Timelines for Reporting DSURs and the Data Lock Point

•         For IMPs without a marketing authorisation, (unlicensed), the Development International Birth Date (DIBD) is the date of the first authorisation by the sponsor of a clinical trial in any country (worldwide) for the investigational product.

•         For IMPs with a marketing authorisation (licensed), the DIBD is the (International Birth Date (IBD) which is the date when the product was first given a marketing authorisation in any country worldwide.

•         For non-commercial trials in the UK, where the sponsor is not the Marketing Authorisation Holder, the formal IBD may not be known and it is usually acceptable for the DIBD to be defined as the date of MHRA approval or, for trials submitted through the clinical trial notification scheme, the date of the confirmation of receipt of the CTA by the MHRA.

•         The DIBD must be indicated within the DSUR or in the covering letter.

•         The Data Lock Point (DLP) of the DSUR is the last day of the one-year reporting period. The DSUR should be submitted to all concerned competent authorities and ethics committees, no later than 60 calendar days after the data lock point.

•         If a trial has not started by the DSUR reporting date then only a covering letter stating this, is required. A DSUR must be submitted during every 12 month reporting period until the End of Trial. If a clinical trial is completed within a time period shorter than 1 year, (for example a Phase I trial) a DSUR does not have to be produced.

DSURs for Combination Therapies

In general, a single DSUR should be prepared for clinical trials involving a fixed combination product (i.e., a product consisting of at least two active ingredients in a fixed dose that is administered in a single dosage form). For trials involving multi-drug therapy, i.e., combinations of drugs that are not fixed, the sponsor can prepare either:

(1) A DSUR for the multi-drug therapy, or

(2) DSUR(s) for one or more of the individual components; in this case information on the multidrug therapy trials can be included in the DSURs of one or all of the components.

The following table provides examples of strategies for preparation of DSURs for multi-drug therapies

Changes in the Reference Safety Information during the Reporting Period

The Reference Safety Information (IB or SmPC) in place at the start of DSUR reporting period should be appended to the DSUR, and should serve as the Reference Safety Information throughout the reporting period. The DSUR should the include date and version number of the IB or SmPC. For SUSAR reporting, expectedness should be assessed in line with the current approved IB or SmPC. When the IB or SmPC has been revised during the DSUR reporting period, the sponsor should also submit the current version with the DSUR.

Pregnancy Notification and Follow-Up (Foetal Exposure to an IMP)

Pregnancies that occur while a subject is on a clinical trial should be notified to the sponsor as specified in the protocol. The local investigator must also ensure that any pregnancy is followed-up until outcome. This follow-up ensures the detection of any congenital anomalies or birth defects that may occur when:

•         Females participating in trials become pregnant; or

•         The female partners of males participating in trials become pregnant.

Any events (including congenital anomalies/birth defects) that meet the definition of a SAE/R would need to be notified in accordance with the Clinical Trials Regulations. In addition, if evidence exists to suggest foetal exposure to a particular IMP may cause a longer term safety issue, (for example, learning difficulties caused by exposure to methotrexate), then the follow up period should be defined appropriately and these timeframes and any follow-up requirements, made clear in the protocol.

A congenital anomaly would only need to be expedited to competent authorities and ethics committees if it met the definition of a SUSAR or if the requirement to report specific safety information is specified in the protocol (usually if it was known that the IMP posed a specific risk). If it was suspected that a pregnancy occurred due to a drug interaction that reduced the efficacy of hormonal contraception (resulted in a healthy pregnancy and baby), this would be a drug interaction of note that should be considered in all future trials. Such information would also be relevant to report in the annual safety report (DSUR) for that trial/IMP.