Template / Title / Development Safety Update Reporting for IMP Clinical Trials
Scope / Template DSUR form including additional guidance
Version / 2.0 / Date / 120209 / WI ID / CTT55

(Below is the CTT55 template including additional directions for completion for each section listed on the DSUR index.)

Name of IMP(s)
Sponsor / University of Leeds or Leeds Teaching Hospitals NHS Trust
Chief Investigator
Address
Sponsor Address / Leeds Sponsor Office
Research and Development
Leeds Teaching Hospitals and NHS Trust
34 Hyde Terrace
Leeds
LS2 9LN
Date of Report / (This can be up to 30 days after the end of the reporting period)

Signed:………………………………………………..

Name:

Note: This developmental Safety Update Report may contain confidential information, including unblinded adverse event data.

EXECUTIVE SUMMARY

This section should provide to the reviewer a concise summary of the relevant and important information contained in the report as whole. This section of the DSUR will serve as part of your annual report which must also be submitted to the Research Ethics Committee responsible for your study. When you submit this section to the REC is should also include any relevant line listings of Serious Adverse Event (SAEs) and Serious Adverse Reactions (SARs) which can also be added from this report’s appendices.

The executive summary should contain the following information;

  • Brief introduction to the report describing content, report number and report period.
  • Confirmation that this report refers to the trial named and not all the sponsor activity with this IMP
  • Detail on the IMP(s – why are you using this IMP in this patient group?), mode of action, therapeutic class, indication(s), doses used, route of administration (sub-cut, oral etc.), any relevant formulation data.
  • The estimated cumulative exposure of patients to the IMP in the study (is this more or less than normal if the IMP is licensed?)
  • Has the IMP marketing approval? If so where – EU and/or beyond?
  • Summary of safety assessment (this will be detailed in the main report – section 19) to include a brief description of the main risks.
  • Any safety changes to the protocol or Investigator Brochure (IB) – that have resulted in amendments sent to the MHRA or other competent authority to be described briefly here (not REC only amendments)
  • Conclusions – safe to continue, risks seem acceptable as potential benefits still significant in the patient group.

Try and keep this section concise – two sides of A4 should in most cases cover everything. This is a summary section.

Table of Contents

  1. Introduction
  2. World Wide Marketing Approval Status
  3. Actions taken in the Reporting period for Safety Reasons
  4. Change to Reference Safety information (e.g. – IB)
  5. Other Trials On-going with this IMP during this reporting period.
  6. Estimated Cumulative Exposure
  7. Cumulative Subject Exposure in this Trial
  8. Patient Exposure from Previous Marketing Experience
  9. Data in Line Listings and Summary Tabulations
  10. Reference Information
  11. Line Listings of Serious Adverse Reactions (SARs) during Reporting Period.
  12. Cumulative Summary of all Serious Adverse Events (SAEs) during Reporting Period.
  13. Significant Findings from Clinical Trials during reporting period
  14. Completed Trials
  15. Ongoing Trials
  16. Long Term follow-up
  17. Other Therapeutic Uses of IMP
  18. New Safety Data related to any combination therapies using the IMP
  19. Safety findings form non-interventional studies (Safety or PK studies)
  20. Any other Clinical Trial/Safety Study data
  21. Any Safety Issues form Marketing Experience
  22. Any relevant non-clinical data
  23. Literature
  24. Other related DSURs
  25. Lack of Efficacy
  26. Any regional specific information
  27. Late breaking Information
  28. Overall Safety Assessment
  29. Evaluation of Risks
  30. Risk – benefit considerations
  31. Summary of Important risks
  32. Conclusions

Appendices:

  1. Introduction

This section should include the following details of the study:

  • Background information, earlier work and objective
  • Reporting period and sequential number of the report;
  • Brief description of the drug - therapeutic class, mechanism of action, route of

administration, formulation; e.g. a lyophilised powder (x mg/vial) re-constituted in saline prior to infusion.

  • A brief description of the indications and populations being studied;
  • A short summary of the scope of the clinical trials covered by the report (e.g. all trials with the investigational drug, indication-specific trials, trials with combination products);
  • A brief description and explanation of any information that has been excluded

(e.g., when written agreements with a partner company do not provide for exchange of all safety data).

  1. Worldwide Marketing Authorisation

Is the IMP marketed within the EU?

If the IMP is not yet marketed in the EU, please highlight anywhere else worldwide where the IMP is currently marketed. If this information is unknown please clearly state this in the report.

  1. Actions taken in the Reporting Period for Safety Reasons

Within the study have there been any changes to the protocol in response to the events that occurred in the trial?

Examples;

(a) Changes to the inclusion / exclusion criteria to refine groups who recruited to the study?

(b) A series of Adverse Events that in light of other data (possibly received from the IMP manufacturer / provider) indicated that more tests or more frequent testing were needed to monitor a particular side effect.

(c) SAR(s) occurred which caused the safety profile of the study to be re-assessed.

(d) Safety related changes to the IB or SPC that meant the study conditions have to be altered.

Any substantial amendment submitted to the MHRA in this reporting period should be described here including detail of the changes to the study documentation.

  1. Changes to Reference safety Information

Please list any new IB or SPC here – if this is not applicable please clearly state.

This section should list any significant safety-related changes to the Information Brochure (IB) or other reference safety information within the reporting period. Such changes might include information relating to exclusion criteria, contraindications, warnings, precautions, serious adverse drug reactions, adverse events of special interest, interactions, and any important findings from non-clinical studies (e.g. carcinogenicity studies).

  1. Inventory of Clinical Trials On-going and Completed During the Reporting Period.

Please state that this DSUR covers a single study; include the full name of the study, the EudraCT number and REC reference number.

Describe whether the study is single site or multi-site (if the latter state how many sites and if they are all in England, EU or worldwide.)

Describe briefly the type of study: Phase, status (ongoing, completed, follow up), design (blinded, open etc), the study regimen including doses in each arm, date of first patient recruited, recruitment to date and estimate of dose for each groups (estimate if blinded).

E.g. Study status: first patient was recruited 21-Jul-2009. As of end of this report date, 18 subjects have been enrolled (enrolment is behind schedule due to change in staffing – now amended).

Group 1 – placebo –n=9

Group 2 – IMP – (10k/kg) n= 9

  1. Estimated Cumulative Exposure

6.1 Cumulative Subject Exposure in the Study.

If your study is blinded you can only estimate this on the basis of the randomisation scheme. A table of exposure can be used. If there are only two arms this will be straightforward – if there are several blinded arms some thought will be needed to describe the possible numbers exposed at each dose. This should be completed for all patients recruited to date.

Explain the method used to estimate subject exposure and the overall number of subjects exposed, if available

.

1.2Patient Exposure from Marketing Experience

It is unlikely that the Trust or University will be marketing the IMP so this is one section than can be answered “Not Applicable”.

  1. Data in line Listings and Summary Tabulations
  2. Reference Information

Describe how you are grading or coding your adverse events – this may be the MedDRA system or you may be using a protocol defined system based on the IB or SPC of the IMP. This influences how you assess expectedness.

7.2Line listing of Serious Adverse Reactions (SARs) during the reporting period.

The MHRA require information on any DRUG related Serious Adverse Events. This section should summarise how case reports were selected for inclusion in the line listings. A brief narrative of the SAE should occur here including whether it is a SAR or SUSAR.

The line listings should be provided in an appendix (this will aid the annual report to ethics who only require the executive summary and line listings from this report).

E.g. Subject 037 is a 39 year old male who presented to A&E at St Mary’s London on 17-Mar-2011 at 3pm (24 hours after receiving medication) with symptoms (describe). He was treated (describe) and kept in overnight. He was diagnosed with acute xxx which is a rare expected side-effect of the IMP in this patient group however the seriousness was not unexpected. The CI determined the reaction to be related to the IMP, it was serous as described in the protocol but was not unexpected. This event has been recorded as a SAR. The treatment was not un-blinded.

Repeat as necessary.

  1. Significant Findings from the Clinical Trial during the Reporting period

E.g. This trial is on-going – the study is monitored by a Trial Steering Committee (TSC) and or Data Monitoring Committee (DMC) – no significant findings have been identified in this period.

8.1 Completed Trials:Should provide a brief summary of clinically important emerging efficacy and safety findingsfrom clinical trials completed during the reporting period.

8.2 Ongoing Trials: Should provide details of clinically important safety information that has arisen from ongoing clinical trials (e.g. learned through interim safety analyses or as a result of unblinding of subjects with adverse events), this section should briefly summarise the issue(s).

8.3 Long Term Follow up: Where applicable, this section should provide information from long-term follow up of subjects from clinical trials of investigational drugs

8.4Other uses of the Drug (therapeutic or combination therapies: Any information that has come to light in the literature that might affect the study if applicable.

8.5New Safety Data Related to Combination Therapies: If this DSUR is for an investigational drug that is also under development as a component of a fixed combination product or a multi-drug regimen, this section should summarise important safety findings from the combination therapy DSUR.

  1. Safety Findings from Non-Interventional Studies

If applicable, describe any observational or epidemiological data that you are aware of that has influenced the safety aspects of the trial in the reporting period.

  1. Other Clinical Trial Study Information

If your study IMP is not licensed/being used in a new indication and is being supplied by a commercial company you will need to request this information from the company in order to complete this section. Please state if not applicable.

  1. Safety Findings from Marketing Experience

As outlined in section 10.

  1. Non- Clinical Data

Any new major safety findings from in vivo or in vitro work that you become aware of should be listed here and can be discussed in the Overall Safety Assessment in section 18.

  1. Literature

This section should summarise any new safety related information on the IMP that has been published during the reporting period, that the team are aware of. This section can also include unpublished data, perhaps from a scientific meeting, that is relevant to the safe administration of the IMP.

The information included in this section can be from clinical or non-clinical studies

  1. Other DSURs

The investigator should contact the sponsor via the QA team for information on any other DSUR submitted in the period for the same IMP. It is possible although unlikely that related information may need to be included – this might include reports of SUSARs in other trials using the same IMP.

  1. Lack of Efficacy

Any evidence of lack of efficacy, or lack of efficacy relative to established gold standard therapies should be discussed here. E.g. increased incidence of nausea means compliance can be poor, resulting in overall lack of efficacy. Where compliance is good efficacy appears high alongside comparator. This may mean that a change to the dose might need to be considered.

  1. Region Specific Information

Things to be covered for UK submission are;

  • List of subjects who died
  • List of any subjects who drop out of the study due to adverse events
  • Any phase I modifications
  • Any significant manufacturing changes
  • Description of plan for the next year (projected recruitment rates, predicted end of study dates)

The answer to these may all be not applicable.

  1. Late Breaking Information

Any safety related events that have occurred from the end of the reporting period to the submission date of the DSUR that may relate to the safety of the IMP.

  1. Overall Safety Assessment

This section is probably the most important. A coherent argument must be made for continuing the study in its current form. There should be a coherent narrative here describing all new relevant safety data compared to the previous knowledge of the IMP. It should not repeat previous information but should provide an interpretation of the information and its implications for the clinical trial population. You should evaluate the risks and weigh up the benefits taking the following points into consideration.

18.1.Evaluation of the Risks

  • NEW safety issues – possibly related to dose, duration of exposure, new lab or genetic associations
  • Changes in rate or severity of adverse events and in particular adverse reactions to the IMP
  • Study drop outs due to adverse events
  • Manufacturing issues (danger to supply)
  • Evidence of lack of efficacy
  • Evidence of clinically significant medication errors
  • Lack of compliance
  • Evidence of IMP misuse or abuse
  • New safety information from a related drug in the same class

18.2.Risk- benefit Considerations

This section should contain a succinct and clear statement on perceived balance between the risks identified in the reporting period and the anticipated benefits. You should make a clear statement that the potential benefits still outweigh the risks even with the new information taken into account. You should detail how any amendments have mediated risk in the previous year.

  1. Summary of Important Risks

You should outline the main safety risk factors related to the IMP that have been influential in your decision to continue or amend the study in this reporting period. There may be one or several or no such risk factors.

E.g. Hypotension - an increase in hypotension was noted in 12% of patients taking this IMP in a study reported in the BMJ. The IMP was being used in a different patient group, however after taking this into consideration we amended the inclusion / exclusion to exclude patients with confirmed coronary artery disease.

  1. Conclusions

This should be very brief and describe any changes to the previous knowledge or efficacy and safety resulting from information gained since the last DSUR. The conclusions should outline the actions that have been or will be taken to address emerging safety issues

E.g. The risks remain consistent with experience described in previous DSUR (or in our application to the regulator) and we conclude that in the information obtained in this reporting period warrants continuation of the study, with the modifications outlined in this DSUR.

Appendices

Possible appendices:

  1. Investigators Brochure;
  2. Cumulative Table of Important Regulatory Requests;
  3. Cumulative Summary Tabulations of Demographic Data;
  4. Line Listings of Serious Adverse Reactions (mandatory – please see template 1);
  5. Cumulative Summary Tabulation of Serious Adverse Events;
  6. Scientific Abstracts (if relevant).

Template / Title / Development Safety Update Reporting for IMP Clinical Trials
Scope / Template DSUR form including additional guidance
Version / 2.0 / Date / 120209 / WI ID / CTT55

Template 1: ExampleLine Listing of All Serious Adverse Events

Study Subject ID / Country/ gender / diagnosis / Outcome / Time to Onset from administration / Suspected drug / Dose, route of administration and formulation / Date of treatment / Comments
0023* / UK - male / hypotension / resolved / 2 hours / IMP / 10mg/kg, x3, IV / 10-Apr-2011
11-Apr-2011
14-May-2011 / Describe event.
0168 / UK male / Metastatic prostate cancer / ongoing / 3 months / blinded / 10mg/kg, x3 IV or placebo / 21-feb-2011
18-Mar-2011
15-June -2011 / Describe event
0109** / UK female / neutropenia / sequale / 3 days / blinded / 10mg/kg, x3 IV or placebo / 06-May-2011
07-May 2011
12-May-2011 / Describe event
  • * Indicates event suspected to be related to the IMP – a serious adverse reaction (SAR)
  • ** Indicates event reported as a Suspected Unexpected Serious Adverse Reaction (SUSAR).

Template / Title / Development Safety Update Reporting for IMP Clinical Trials
Scope / Template DSUR form including additional guidance
Version / 2.0 / Date / 120209 / WI ID / CTT55