Development Safety Update Report (DSUR)

DSUR is the annual clinical trial safety report (for the adverse reactions observed during clinical studies) which is submitted to health authorities among the ICH regions. DSUR is submitted instead of existing annual clinical trial safety reports in US (IND Annual Report) and in the EU (Annual Safety Report).

A DSUR is the pre-marketing equivalent of the post-marketing Periodic Safety Update Report (PSUR)/Periodic Benefit-Risk Evaluation Report (PBRER)

Purpose of DSUR

During the clinical development of an investigational drug, periodic analysis of safety information is crucial to the ongoing assessment of risk to trial subjects.  It is also important to inform regulators and other interested parties (e.g., ethics committees) at regular intervals about the results of such analyses and the evolving safety profile of an investigational drug, and apprise them of actions proposed or being taken to address safety concerns.

This purpose is served by a DSUR. US and EU regulators consider that the DSUR, submitted annually, would meet national and regional requirements currently met by the US IND Annual Report and the EU Annual Safety Report, respectively, and can therefore take the place of these existing reports.

FDA has indicated that it will accept DSURs instead of IND Annual Reports (76 Federal Register 52667 (23-Aug-2011) as long as they have all the requirements of the US Annual Report in the region specific appendices of the DSUR.

Objective:

The main objective of a DSUR is to present an annual review and evaluation of pertinent safety information collected during the reporting period to:

• Summarize the current understanding and management of identified and potential risks.
• Describe new safety issues that could have an impact on the protection of clinical trial subjects.
• Examine whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the product’s safety.
• Provide an update on the status of the clinical investigation/development programme.

A DSUR is drafted based on the available data from the below sources:

1. Interventional clinical trials (CT) (sponsored & supported)
2. Non-Intervention CT, Compassionate programmes, and other solicited studies
3. Significant safety findings from non-clinical studies
4. Significant and relevant articles from the Literature

Frequency and periodicity of DSUR

The first DSUR may be submitted anytime within one year after Developmental International Birth Date (DIBD) for the drug, but not longer than 1 year after the birth date.

DIBD is the ‘first authorization for the conduct of a clinical trial anywhere in the world’. A DSUR should be submitted until the last visit of the last patient in the last study in the country(ies) concerned. The DSUR should be submitted no later than 60 calendar days from the DSUR data lock point (DLP).

A few more important points:

• A single DSUR should be prepared for clinical trials involving a fixed drug combination.
• For clinical trials involving drug combinations (which are not of fixed dose), a stand-alone DSUR can be prepared. Alternatively, information on the multi-drug regimen trials can be included in the DSUR of one or all of the components.
• Drug-Medical Device combination: DSUR need to be prepared if therapeutic effect is achieved either by drug or medical device.
• Reference Safety Information (RSI): Investigation brochure (IB) serves as the RSI for an investigational drug irrespective of its marketing authorisation status (even though the product is having other labelling documents)

DSUR Format [As per ICH-E2F Guideline]

Title page

The following information needs to be included in title page

• DSUR number (the sequential number of the DSUR report)
• Investigational drug(s): Name of the Investigational drug(s) & its DIBD/IBD
• Reporting period: Annual Period covered by the report (Review period from DIBD to DLP)
• Date of the report
• Sponsor(s) name(s) and address(es)
• Statement on the confidentiality of the information included in the DSUR
• A cautionary statement that the DSUR includes unblinded information, if applicable

Executive Summary

It provides a concise summary of the important information presented in the report.

It can serve as “a stand-alone document” together with title page suitable for submission to ethics committees and other stakeholders, if required by national or regional laws or regulations.

The following information should be included in the Executive Summary:

• Introduction — report number and reporting period
• Investigational drug(s) — mode(s) of action, therapeutic class(es), indication(s), dose(s), route(s) of administration, formulation(s)
• Estimated cumulative exposure of clinical trial subjects
• Marketing approval(s)? (yes/no) — If yes, number of countries
• Summary of overall safety assessment (based on section 18 of the DSUR)
• Summary of important risks (based on section 19 of the DSUR)
• Actions taken for safety reasons including significant changes to IB
• Conclusion

Table of Contents

1. Introduction
2. Worldwide Marketing Approval Status
3. Actions Taken in the Reporting Period for Safety Reasons
4. Changes to Reference Safety Information
5. Inventory of Clinical Trials Ongoing and Completed during the Reporting Period
6. Estimated Cumulative Exposure

        6.1 Cumulative Subject Exposure in the Development Program

        6.2 Patient Exposure from Marketing Experience

7. Data in Line Listings and Summary Tabulations

        7.1 Reference Information

        7.2 Line Listings of Serious Adverse Reactions During the Reporting Period

        7.3 Cumulative Summary Tabulations of Serious Adverse Events

8. Significant Findings from Clinical Trials during the Reporting Period

        8.1 Completed Clinical Trials

        8.2 Ongoing Clinical Trials

        8.3 Long-term Follow-up

        8.4 Other Therapeutic Use of Investigational Drug

        8.5 New Safety Data Related to Combination Therapies

9. Safety Findings from Noninterventional Studies
10. Other Clinical Trial/Study Safety Information
11. Safety Findings from Marketing Experience
12. Nonclinical Data
13. Literature
14. Other DSURs
15. Lack of Efficacy
16. Region-Specific Information
17. Late-Breaking Information
18. Overall Safety Assessment

        18.1. Evaluation of the Risks

        18.2 Benefit-risk Considerations

19. Summary of Important Risks
20. Conclusions

Appendices to the DSUR

1. Introduction

Below information need to be included under Introduction section.

• DSUR Report sequential number and investigational drug name
• DIBD/IBD of investigational drug
• Reporting period [Review period covering the interval of DIBD/IBD to DLP]
• Investigational drug(s) — Mechanism of action(s), therapeutic class(es), dose(s), route(s) of administration, formulation(s)
• A brief description of the therapeutic indication(s) and population(s) 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)
• Information pertaining to fixed drug combinations.
• A brief description and explanation of any information that has not been included in the DSUR (e.g., when written agreements with a partner company do not provide for exchange of all safety data)
• The rationale for submission of multiple DSURs for the investigational drug, if applicable

Example:

This is the <<sequential number>> Development Safety Update Report (DSUR) for <<investigation drug name>> prepared by <<Name of Sponsor>> (hereinafter referred to as “the Company”) as sponsor of the clinical development program, according to the agreed format in the ICH-E2F Note for guidance on development safety update reports. The International Birth Date (IBD) is XX XXX XXXX.

This report summarizes safety data arising from the <<investigation drug name>> worldwide clinical development program received during the period from <<Reporting Interval>>.

<<Investigation drug name>>, is an <<-brief description of molecule, mechanism of action, drug class, dose, route of administration, formulation, intended therapeutic application and population>>

Brief description of information on fixed-combination products with <<investigation drug name>> [If Applicable]

This DSUR includes safety information concerning <<investigation drug name>> and fixed-dose combination (FDC) products containing <<investigation drug name>> with Drug A, Drug B etc.,

The <<investigation drug name>> monoproduct and the above fixed-combination products are indicated for the treatment of <<intended therapeutic applications>>. This DSUR contains information from studies completed within the reporting period with <<investigation drug name>>, including studies being investigated in combination with other products or for different indications.

2. Worldwide Marketing Approval Status

A brief summary of information pertaining to the date of first approval, indication(s), approved dose(s), and name of country in which it is approved etc., needs to be presented.

Example:

<<Investigation drug name>> was first authorized in <<country name>> on XX XXX XXXX. The IBD of <<Investigation drug name>> has been designated as XX XXX XXXX.

As of the data-lock point (DLP) of this report, XX XXX XXXX, <<Investigation drug name>> is approved to treat <<therapeutic indication>>, as an oral tablet containing XX mg, XX mg in XX countries.

<<Investigation drug name>> and Drug A FDC is approved as an agent to treat <<Therapeutic Indication>> as an oral tablet containing XX mg or XX mg <<Investigation drug name>> with XXX mg, XXX mg or XXX mg Drug A, in 50 countries.

The indications for use of <<Investigation drug name>> and its FDC may vary in different countries.

3. Actions Taken in the Reporting Period for Safety Reasons

A summary of description need to be presented for any significant actions related to safety have been taken during the reporting period by the sponsor, regulators, data monitoring committees (DMC) or ethics committees that had an impact on the conduct of a specific clinical trial(s) or on the overall clinical development program.

The reason(s) for each action should be provided if known. Relevant updates to previous actions should also be summarized in this section (e.g., resumption of a clinical trial after suspension).

Examples of significant actions taken for safety reasons include:

Actions related to investigational drugs:

• Refusal to authorize a clinical trial for ethical or safety reasons
• Partial or complete clinical trial suspension or early termination of an ongoing clinical trial because of safety findings or lack of efficacy
• Recall of investigational drug or comparator
• Failure to obtain marketing approval for a tested indication including voluntary withdrawal of a marketing application
• Risk management activities, including:

1. Protocol modifications due to safety or efficacy concerns (e.g., dosage changes, changes in study inclusion/exclusion criteria, intensification of subject monitoring, limitation in trial duration)
2. Restrictions in study population or indications
3. Changes to the informed consent document relating to safety issues
4. Formulation changes
5. Addition by regulators of a special safety-related reporting requirement
6. Issuance of a communication to investigators or healthcare professionals
7. Plans for new studies to address safety issues

Actions related to marketed drugs:

• Failure to obtain a marketing approval renewal
• Withdrawal or suspension of a marketing approval
• Risk management activities including:

1. Significant restrictions on distribution or introduction of other risk minimization measures
2. Significant safety-related changes in labeling documents that could affect the development program, including restrictions on use or population treated
3. Communications to health care professionals
4. New post marketing study requirement(s) imposed by regulators

 Summarization of information pertaining to below requests from regulatory authorities could be presented in this section.

• To conduct long-term animal studies before initiating a long-term clinical trial
• Specification of a maximum dose to be evaluated
• Request for specific safety data before initiating trials in paediatric subjects (cumulative listings can be presented in the tabular format).

Example:

Any regulatory/sponsor actions taken for safety reasons needed to be summarized in this section. If there are no specific actions made in the reporting interval, the following information could be presented.

No actions due to safety reasons have been initiated related to <<Investigation drug name>> with regards to:

Failure to obtain or apply for a marketing authorisation renewal

• Withdrawal or suspension of a marketing authorisation
• Suspension of supply by the MAH
• Actions taken due to product defects and quality issues

4. Changes to Reference Safety Information

Summary of significant safety-related changes to the IB or other reference safety information within the reporting period need to be presented in this section.

The change in information pertaining to following sections of IB is required to present here.

• Exclusion criteria
• Contraindications
• Warnings
• Precautions
• Serious Adverse Drug Reactions
• Adverse Events of Special Interest
• Drug Interactions
• Important findings from Non-Clinical Studies (e.g., cardiotoxicity, carcinogenicity studies etc.,).

Example:

The following adverse reactions have been identified for <<Investigation drug name>> during clinical trail study and added under adverse drug reaction section of IB.

Cardiac disorders: QT prolongation

OR

If there are no significant changes, following information might be included.

There are no significant safety-related changes to the RSI (IB) to be submitted to the authorities in parallel to this DSUR.

5. Inventory of Clinical Trials Ongoing and Completed during the Reporting Period

A brief overview of the clinical trials (both ongoing and completed) by the sponsor in the reporting interval need to be included in this section. The information can be presented in the tabular format. However, separate tables can be provided by indication, formulation, and study population, other therapeutic use of an investigational drug in the reporting period.

The table(s) should include the following information for each clinical trial:

• Study ID (e.g., protocol number or other identifiers)
• Phase (I, II, III, or IV)
• Status of clinical trial-

1. Ongoing (clinical trial has begun; has begun but is currently on hold; has concluded but clinical study report has not been finalized)
2. Completed (clinical study report is finalized)

• Countries/regions where there is at least one investigational site for the protocol
• Abbreviated study title
• Design (uncontrolled, controlled, open, single blind, double blind, parallel, cross-over, etc., including treatment arms)
• Dose and regimen of investigational drug and any comparators
• Study population as appropriate (age; sex; indication(s); specific patient groups, e.g., trial subjects with impaired renal function or trial subjects resistant to treatment)
• Date of clinical trial start (as defined by the sponsor, e.g., first visit of first patient (FVFP)) Planned enrollment for study as a whole
• Estimates of cumulative numbers of exposed subjects for each treatment arm, where available. The actual enrollment numbers for open or completed trials, and/or an estimate based on the randomization scheme for blinded trials, should be provided.

 Example:

Study Number: ABCCX

Study title: A double-blind, randomized, placebo-controlled, parallel-group study to ABCCX.

Brief study description: The study was conducted at multiple sites in North America, Europe, and Australia. A total of XX, XXX subjects were screened; XXXX subjects were randomized. (Continued…)

Study Number: ABCDXS

Study title: A blinded, long-term extension study to evaluate the safety and efficacy of <<Investigation drug name>> ABCDXS

Brief study description: This study was conducted at multiple sites in North America, Europe and Australia. A total of XXX subjects were randomized. This study has been terminated due to the results of the efficacy XXXXXX

6. Estimated Cumulative Exposure

The cumulative exposure data in clinical trials and the marketed setting needed to present in the section 6.1 and 6.2, respectively.

An estimation of cumulative subject exposure can help provide context for the cumulative summary tabulations of serious adverse events (SAEs) and the overall assessment of safety.

The accuracy of the estimation of clinical trial exposure might be limited because of a number of factors, including the rapidity of subject enrollment and the number of ongoing trials where treatment assignment remains blinded.

The optimal method of data presentation will depend on a number of factors, and the following general points should be considered in the preparation of the estimated exposure for the DSUR:

• Data should be presented in tabular format.
• When there are important differences among trials in dose, route of administration, or patient population, these differences can be noted in the tables, or separate tables can be considered.
• If the summary tabulations of SAEs are presented by indication, the exposure data should also be presented by indication, when available.
• When there are substantial differences in time of exposure between subjects randomized to the investigational drug and comparator(s), or disparities in length of exposure between clinical trials, it can be useful to express exposure data in subject-time (subject days, -months, or -years).
• Investigational drug exposure in healthy volunteers might be less relevant to the overall safety profile, particularly when volunteers are exposed to only a single dose. Such data can be presented separately with explanation, when appropriate.
• For marketed drugs that are under clinical investigation, it might not be feasible or useful to obtain precise cumulative clinical trial exposure data (e.g., when the drug has been marketed for a number of years and/or has many indications). In these circumstances, the sponsor should provide an explanation.

6.1 Cumulative Subject Exposure in the Development Program

Following information can be presented in the tabular format.

• The cumulative number of subjects from clinical trials (both ongoing and completed); the number exposed to the investigational drug, placebo, and/or active comparator(s) since the DIBD.
• When treatment assignment is blinded, numbers of subjects can be estimated based on the randomization scheme.
• The cumulative number of subjects exposed to the investigational drug from ongoing and completed clinical trials, sub grouped by age range, sex, and racial group for the development program when the data are available
• Demographic characteristics for a single trial if the trial is of particular importance (e.g., a pivotal Phase 3 trial).

Method use for estimating subject exposure-Rationale for selection of particular method and limitations need to be presented.

Example:

Overall, XX, XXX subjects have been enrolled in the Company-sponsored clinical trials with <<Investigation drug name>> of which XX, XXX have received active treatment based on actual exposure data from completed clinical trials.

An estimate of the overall cumulative exposure of <<Investigation drug name>> is presented in the below table based upon the actual exposure from completed studies.

6.2 Patient Exposure from Marketing Experience

If the investigational drug is marketed by the sponsor, the DSUR should include an estimate of the cumulative patient exposure in the marketed setting, based on the information provided in the most recent PSUR or other suitable data source, with an explanation of the method(s) used to determine the estimate.

Example:

Since the first regulatory approval in the <<country name>> on XX XXX XXXX through the DSUR cut-off date of XX XXX XXXX, it is estimated that XXXX patients were exposed to <<Investigation drug name>> worldwide.

7. Data in Line Listings and Summary Tabulations

The significant safety information from clinical is presented in this section received during reporting interval of DSUR and also cumulatively from the DIBD

1. Interval line listings of the serious adverse reactions that were reported to the sponsor during the period covered by the DSUR
2. Cumulative summary tabulations of serious adverse events that have been reported to the sponsor since the DIBD.

Although causality assessment is generally useful for the evaluation of individual rare adverse drug reactions (ADRs) and for making decisions regarding expedited reporting, individual case causality assessment has less value in the analysis of aggregate data, where group comparisons of rates are possible. Therefore, the summary tabulations in a DSUR should include all SAEs and not just SARs for the investigational drug and comparators. The line listings and tabulations should include blinded and unblinded clinical trial data. Unblinded data might originate from completed trials and individual cases that have been unblinded for safety-related reasons (e.g., expedited reporting), if applicable. Sponsors should not unblind data for the specific purpose of preparing the DSUR. At the sponsor’s discretion, graphical displays can be used to illustrate specific aspects of the data when useful to enhance understanding. If the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for coding the adverse event/reaction terms, the Preferred Term level should be presented in the line listings and summary tabulations. In general, the tabulation(s) of SAEs should include only those terms that were used in defining the case as serious; they should not include non serious events. Certain adverse events can be excluded from the line listings and summary tabulations, but such exclusions should be explained in the report. For example, adverse events that have been defined in the protocol as “exempt” from special collection and entry into the safety database, and those that are integral to efficacy endpoints, can be excluded (e.g., deaths reported in a trial of a drug for congestive heart failure where all-cause mortality is the primary efficacy endpoint, disease progression in cancer trials).

7.1 Reference Information:

This subsection is used for inclusion of version of MedDRA and RSI used during preparation of DSUR for adverse event coding and expectedness assessment purposes, respectively.

7.2 Line Listings of Serious Adverse Reactions During the Reporting Period:

**Only Presentation**No Analysis**

This section of the DSUR should summarize how case reports were selected for inclusion in the line listings. This section should not serve to provide analyses or conclusions based on the SARs. The line listings should provide key information on all serious adverse reactions (blinded and unblinded) reported from the sponsor’s clinical studies during the reporting period. The data should be organized by trial and then by System Organ Class (SOC). Where possible the line listing(s) should include each subject only once regardless of how many SAR terms are reported for the case. If there is more than one reaction, they should all be mentioned but the case should be listed under the most serious adverse reaction (sign, symptom, or diagnosis), as judged by the sponsor. It is possible that the same subject could experience different SARs on different occasions (e.g., weeks apart during a clinical trial). Under such circumstances, the SARs can be listed separately, and a single subject can be included in a line listing more than once. The following information should be included in the line listings:

(a) Study identification number and EudraCT number as applicable

(b) Subject clinical trial identification number

(c) Sponsor’s adverse reaction case reference number

(d) Country in which case occurred

(e) Age and sex of trial subject

(f) Treatment group; identified as “blinded” if the blind has not been broken

(g) Dose and dosing interval of investigational drug (and, when relevant, dosage form and route of administration)

(h) Date of onset and/or time to onset of the most serious adverse reaction

(i) Dates of treatment and/or best estimate of treatment duration

(j) Serious adverse reaction(s); when MedDRA is used, the Preferred Term should be presented

(k) Outcome (e.g., resolved, fatal, improved, sequelae, unknown). This field should indicate the consequences of the reaction(s) for the patient, using the worst of the different outcomes for multiple reactions.

(l) Comments, if relevant (e.g., causality assessment if the sponsor disagrees with the reporter; concomitant medications suspected to play a role in the reactions directly or by interaction; indication treated with suspect drug(s); dechallenge/rechallenge results if available) Appendix B, Table 5 of this guidance provides an example of the headings for a line listing.

7.3 Cumulative Summary Tabulations of Serious Adverse Events:

This section should refer to an appendix that provides a cumulative summary tabulation of SAEs reported in the sponsor’s clinical trials, from the DIBD to the data lock point of the current DSUR. The sponsor should explain any omission of data (e.g., clinical trial data might not be available for products marketed for many years or for products acquired through a business merger). The tabulation(s) should be organized by SOC, for the investigational drug, as well as for the comparator arm(s) (active comparators, placebo, and treatment unknown due to blinding) used in the program. Data can be integrated across the program. Alternatively, when useful and feasible, tabulations of SAEs can be presented by protocol, indication, route of administration, or other variables. This section should not serve to provide analyses or conclusions based on the SAEs.

Example:

The following table presents a cumulative number of SAEs that have been reported during the clinical development program, from development international birth date (DIBD) to the DLP (XX XXX XXXX), presented by SOC.

8. Significant Findings from Clinical Trials during the Reporting Period

8.1 Completed Clinical Trials:

A brief summary of clinically important emerging efficacy and safety findings obtained from clinical trials completed during the reporting period need to be presented in this section. This information can be presented in narrative format or as a synopsis.

It could include information that supports or refutes previously identified safety issues, as well as evidence of new safety signals.

8.2 Ongoing Clinical Trials:

From an ongoing clinical trial (s), If the sponsor is aware of clinically significant information that has arisen (e.g., learned through interim safety analyses or as a result of unblinding of subjects with adverse events), this section should briefly summarize the issue(s). It could include information that supports or refutes previously identified safety issues, as well as evidence of new safety signals.

8.3 Long-term Follow-up:

Usually, for some advanced therapy products like gene therapy, cell therapy products, and tissue engineered products which require long term evaluations. This section is dedicated to present information availed from the long-term follow-up of subjects from the clinical trials involving these advanced therapy products.

When the development program is completed and long-term follow-up is the only ongoing activity generating data for the DSUR, this could be the only section where new information is presented.

8.4 Other Therapeutic Use of Investigational Drug:

This section of the DSUR should include clinically important safety information from other programs conducted by the sponsor that follow a specific protocol, with solicited reporting as per ICH E2D (e.g., expanded access programs, compassionate use programs, particular patient use, single patient INDs, and treatment INDs).

8.5 New Safety Data Related to Combination Therapies:

If the 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 summarize important safety findings from the combination therapy DSUR. Conversely, if this DSUR is for a multi-drug therapy or fixed combination product, this section should summarize important safety information arising from trials on the individual components. Alternatively, the information specific to the combination can be incorporated into a separate section(s) of the DSUR for one or all of the individual components of the combination.

Example:

Study Number: XXX-XXXXXXX

Study Title: A double-blind, randomized, placebo-controlled, parallel-group study to simultaneously (Continued…)

Summary: This was a Phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study conducted worldwide. The primary objective of the study was to (Continued…)

[Brief description of significant information]

9. Safety Findings from Non-Interventional Studies

The summarization of relevant safety information from non-interventional studies that became available to the sponsor during the reporting interval period need to be presented in this section.

Some of examples of Non-interventional studies (NIS) conducted by sponsor are observational studies, epidemiological studies, registries, and active surveillance programs.

Example:

Non-Interventional Study:

Study number: XXXXXX

Study Title: A prospective, non-interventional study of the use of XXXXX.

This observational, non-interventional, prospective, multicentre study was conducted in China to observe <<drug name>> utilization patterns, as well as clinical response to treatment with <<Investigational drug>> FDCs, in standard clinical practice.

A total of XXX subjects from 15 study sites in China were screened and included in the all subjects screened (ASS) population in the study (Brief description of significant information]

Patient Support Programmes:

There have been one Patient support Program (PSP) with enrollment during the current reporting period. In this program, free product is provided to patients with financial need that meet eligibility criteria, the summary is mentioned below:

This program was intended to make <<company product name>> more affordable to <<targeted therapy>> patients who are indicated for [continued…]

This program was intended to provide free product to patients with financial need that meet eligibility criteria in US. The Program started on XX XXX XXXX.

As of DLP for this report, no new significant safety findings have been identified from these programs.

10. Other Clinical Trial/Study Safety Information

The summarization of relevant safety information from any other clinical trial/study sources that became available to the sponsor during the reporting interval period.

For example, the results from a pooled analysis of randomized clinical trials or the data from meta‑analyses of randomized clinical trials, the safety information provided by co-development partners or from investigator-initiated trials.

Example:

During this reporting period, there was one clinical trial involving <<investigational/company product>> that was co-sponsored by <name of partner company>>.

Clinical trial XXXXXX is an ongoing Phase 3, randomized, double-blind placebo-controlled efficacy and safety study of <<investigational/company product>> for the adjuvant treatment of <<Intended indication>>.

During this reporting period, there were XX cases that reported X serious adverse reactions of which SARs were considered possibly related to <<investigational/company product>> single agent or to blinded therapy by the investigator and/or the Sponsor; the remaining SARs were considered related to placebo. The serious adverse reactions considered related to <<investigational/company product>> or to blinded therapy encoded to the following MedDRA PTs: PT1, PT2. Of these XX serious adverse reactions, one event was considered to be unexpected (a SUSAR) that encoded to the MedDRA PT PT1, and is reported from a case (Case number#).

11. Safety Findings from Marketing Experience

This section is used for inclusion of a concise summary of important/significant safety findings that have arisen from marketing experience and that became available to the sponsor during the reporting period (If the investigational drug has been approved for marketing in any country).

Some of important safety findings that resulted in changes/updates to the product labeling document, IB, or informed consent document or amendments to the product’s risk management plan. This includes not only safety findings relating to approved use but also off-label use, administration to special populations (e.g., pregnant women), medication errors, overdose, and abuse.

Example:

“Summarized information of changes/updates to the product’s labelling documents, RMP and other relevant documents would be presented here.”

The marketing experience identified no new safety information contributing significantly to the risk of <<investigational/company product>>. The important risks associated with the use of <<investigational/company product>> are minimized through provision of relevant information in the RSI to support safe use of the product. Risks have been evaluated in the context of the enumerated benefits of the product. Based on the available safety and efficacy data for <<investigational/company product>>, the overall benefit risk profile of the drug remains favourable. No additional risk minimization activities are warranted.

12. Nonclinical Data

The summarization of major safety findings from nonclinical in vivo and in vitro studies either ongoing or completed during the reporting interval period need to be presented in this section.

Implications of these non-clinical findings should be discussed in the Overall Safety Assessment section.

Some of examples of non-clinical studies conducted by sponsor are carcinogenicity, reproduction, or immunotoxicity studies etc.,

Example:

During the reporting period, new safety findings were identified in one study.

A X-week mouse toxicity study was conducted with <<investigational/company product>> (Study XXXXX). In males administered XX mg/kg/day <<investigational/company product>>, statistically significant, [[brief description of study].

The data from the current study, in addition to the data from previous studies, indicate that the observed decreases in heart weight are likely <<investigational/company product>>-related. As the non-adverse finding of lower heart weights occurred at systemic exposures in mice at [XX] x higher than the efficacious exposure at the clinically recommended dose, this finding does not impact the clinical risk/benefit profile of <<investigational/company product>>.

13. Literature

The summarized information of new and significant safety findings either published in the scientific literature or available as unpublished manuscripts, relevant to the investigational drug that the sponsor became aware of during the reporting period need to be presented in this section.

This section should include information from nonclinical and clinical studies and, if relevant and applicable, information on drugs of the same therapeutic class. It should also summarize significant new safety information presented at a scientific meeting and published as an abstract; the sponsor should provide a copy of the abstract, if possible.

Example

Non-Clinical (Published)

A search of the Medline and Embase databases identified no nonclinical studies that presented important new safety findings for <<investigational/company product>>.

Clinical (Published)

A search of the Medline and Embase databases identified no clinical trials that presented important new safety findings for <<investigational/company product>>.

Unpublished manuscripts/abstracts/scientific meeting findings

During the reporting period, no new safety findings were identified.

OR

<<If some literature abstracts/articles identified which are having significant safety information relevant for <<investigational/company product>>, abstracts/articles could be summarized in below format.>>

Title: Association of XXXXX with Increased Risk of XX Cancer and XX Cancer: A Functional Network Study [Citation]

XX, et al conducted a study to evaluate the relationships of XXX with X cancer [summarized abstract/article].

Company comment:  The safety topic of higher risk for XX associated with XXX is an unlisted safety concern as per the reference safety information (RSI) for the product XXX. Cardiotoxic profile [company’s assessment/conclusion on the abstract/article]

14. Other DSURs

A sponsor should prepare a single DSUR for a single investigational drug. However, if a sponsor prepares multiple DSURs for a single investigational drug (e.g., covering different indications, development programs, or formulations), this section should summarize significant findings from the other DSURs if they are not presented elsewhere within this report. When available, the sponsor should summarize significant findings from DSURs provided by other sponsors conducting clinical trials with the same investigational drug during the reporting period.

Example

Data for <<Investigational/company product>> is also presented in the <<other investigational/company product>> DSUR, the most recent report had a DLP of XX XXX XXXX.

The significant safety findings observed in the report presented here [Summarized significant safety information]

[OR]

During the reporting period, the Sponsor did not submit another DSUR for <<Investigational/company product>>

15. Lack of Efficacy

In this section, the safety information pertaining to lack of efficacy which is has potential risk to life of subjects is presented.

Lack of investigational drug efficacy which are intended to treat serious or life-threatening illnesses (e.g., excess cardiovascular adverse events in a trial of a new anti-platelet drug for acute coronary syndromes) could reflect a significant risk to clinical trial subjects and should be summarized in this section.

Example:

<<Brief summarization of significant safety information (with or without serious adverse reactions) associated with lack of investigational drug efficacy>>

“If there is no relevant information received pertaining to lack of investigational drug efficacy. The below statement might be appropriate to present.”

During the reporting period, no relevant lack of efficacy information was identified that could constitute a significant risk to clinical trial subjects.

16. Region-Specific Information

The information in this section can be used to comply with national or regional requirements and can be provided in appendices to the DSUR.

Sponsors should refer to national or regional requirements to determine which of the following sections should be included, as well as the scope of clinical trials that should be covered by these sections. Below are some examples included:

1. Cumulative summary tabulation of serious adverse reactions (SAR):

 This cumulative summary tabulation of all SARs should specify the number of SARs by:

(a) SOC

(b) adverse reaction term and

(c) treatment arm (if applicable)

Unexpected adverse reaction terms (SUSARs) should be identified.

Example:

2. List of subjects who died during the reporting period

The list of subjects who died during participation in the clinical trials should include the following information at a minimum: case number, assigned treatment (could still be blinded), and cause of death of each subject. Any safety issues identified from a review of these deaths should be addressed in section 18 of the DSUR as appropriate.

Example:

AER # XX              Subject ID: XXXXXX         Country: China                  EudraCT Number: XXXXXXXX

3. List of subjects who dropped out of clinical trials in association with an adverse event during the reporting period

This list should include all subjects who dropped out of clinical trials in association with adverse events during the reporting period, whether or not thought to be drug-related. Any safety issues identified from a review of these withdrawals should be addressed in section 18 of the DSUR as appropriate.

Example:

4. Significant Phase 1 protocol modifications

This section should describe significant Phase 1 protocol modifications made during the reporting period, if not previously submitted as a protocol amendment, as described in the U.S. Code of Federal Regulations.

<<Brief description of modification/changes to protocol>> or

During the reporting period, there were no significant phase 1 protocol modifications.

5. Significant manufacturing changes

This section should include a summary of significant manufacturing or microbiological changes during the reporting period and discuss potential safety issues arising from these changes in section 18 of the DSUR, if applicable.

<<Brief description of manufacturing changes>> or

During the reporting period, there were no significant manufacturing changes.

6. Description of the general investigation plan for the coming year

This section should outline an investigational plan to replace that submitted for the previous year.

7. Log of outstanding business with respect to the U.S. IND

If desired by the sponsor, this section can provide a log of any outstanding business with respect to the U.S. IND for which the sponsor requests or expects a reply, comment, or meeting.

17. Late-Breaking Information

The summarized information on potentially important safety findings that arise after the data lock point but while the DSUR is in preparation.

Examples include clinically significant new case reports, important follow-up data, clinically relevant toxicological findings, and any action that the sponsor, a data monitoring committee, or a regulatory authority has taken for safety reasons. The Overall Safety Assessment should also take these new data into account.

Example:

Information has been reviewed for potentially important safety, efficacy and effectiveness findings that have been received after the DLP of XX XXX XXXX and during the period of preparation of this DSUR for <<investigational product>> and its Fixed dose combinations.

<<Brief description of important safety information>>

If no potential safety information identified while preparation/drafting of DSUR the below statement might be added.

No late breaking information has been received after the DLP that impacts the safety profile of <<investigational product>> and its FDCs.

18. Overall Safety Assessment

This section provides an integrated evaluation of all new relevant clinical, nonclinical, and epidemiologic information obtained during the reporting period relative to previous knowledge of the investigational drug.

Key points:

• Cumulative experience from DIBD
• New information received in the reporting interval period covered by the DSUR
• Clinically significant post marketing data (for investigational drugs with a marketing approval)
• The information presented in this section should be concise and provide an interpretation of the information and its implications for the clinical trial population and the development program.
• The information presented in previous sections of the DSUR should not be summarized or repeated.
• If appropriate, separate assessments can be provided by therapeutic area, route of administration, formulation and/or indication.

Example:

<<Brief description of overall safety profile (new and changes to previously identified would be presented>>

Across all studies (clinical, nonclinical, and epidemiologic), the most commonly reported <<investigational product>> -related SAEs were diarrhoea, cough, dizziness, asthenia, pulmonary embolism, decreased appetite, atrial fibrillation, and myocardial infarction. As of XXX XXXX, SAEs considered to be treatment-related serious adverse events are presented in Section 6.2.6 (Serious Adverse Events) of the <<investigational product>> IB dated XXX XXXX.

18.1. Evaluation of the Risks

In evaluating the risks, particular emphasis should be placed on interpretation of data related to newly identified safety concerns or providing significant new information relative to previously identified safety concerns.

Relevant points to consider include (where applicable):

• Newly identified safety issues: Detailed description of adverse events or reactions; associated laboratory values; risk factors; relationship to dose, duration, time course of the treatment; reversibility; factors that could be useful in predicting or preventing reactions.
• Previously identified adverse reactions: changes to nature of SAR, increased frequency or severity, change in outcome, having specific risk at special populations.
• Symptoms, signs, and laboratory evidence of newly and previously identified clinically significant toxicities, for example:

1. Hepatotoxicity
2. Cardiovascular effects, including QT interval prolongation and results from thorough QT/QTc studies
3. Bone marrow toxicity
4. Pulmonary toxicity
5. Renal toxicity
6. Central nervous system toxicity
7. Immunogenicity and hypersensitivity

• Deaths that are an outcome of an adverse event
• Study drug discontinuations because of adverse events, including abnormal laboratory values or investigations
• Drug–drug and other interactions
• Important nonclinical safety findings
• Manufacturing issues that could affect risk
• Lack of efficacy where this would place trial participants at risk
• Any specific safety issues related to special populations, such as the elderly, children, patients with hepatic or renal impairment, or any other at-risk groups (e.g., slow, or fast metabolizers)
• Pregnancy and lactation exposure and outcomes
• Long-term treatment: Safety findings arising from experience with long-term treatment
• Medication errors: Evidence of clinically significant medication errors
• Patient compliance: Evidence of lack of patient compliance
• Drug Overdose: Experience with overdose and its treatment
• Drug misuse and abuse: Occurrences of drug misuse and abuse
• Protocol Procedures: Any safety issues resulting from procedures required by the protocol (e.g., bronchoscopy, biopsy, central line insertion) or associated with the conduct or design of a particular study (e.g., inadequate subject monitoring schedule, excessive period without active treatment) and
• Drug Class Effects: Potential impact of significant new safety issues identified with another drug in the same class

The information pertaining to each of the above the specified topic need to be presented.

The list of important potential risks and important identified risks would be presented in this section.

18.2 Benefit-risk Considerations

This section should provide a succinct statement on the perceived balance between risks that have been identified from cumulative safety data and anticipated efficacy/benefits and should note whether there have been any changes in this balance since the previous DSUR. This section is not intended to be a full benefit-risk assessment of the investigational drug.

Example:

There is no new safety information identified for the previously recognized safety concerns during the reporting period. <<that means no change in the nature, severity, frequency, outcome, or exposure data to special populations>>

Review of data available from completed studies has shown that administration of <<investigational product>> was well tolerated.

No data were obtained from interventional clinical trials during this DSUR reporting period suggesting a lack of efficacy relative to established therapies.

New information which has become available from non-interventional studies has not raised any new safety concerns.

Based on the review of the information presented in this DSUR, the overall benefit-risk profile is acceptable for <<investigational product>> and its fixed dose combinations (if applicable)

19. Summary of Important Risks:

This section should provide a concise, cumulative, issue-by-issue list of important identified and potential risks (e.g., those that might lead to warnings, precautions, or contraindications in labeling).

Such risks might include, for example, toxicities known to be associated with a particular molecular structure or drug class, or concerns based on accumulating nonclinical or clinical data.

Each risk should be re-evaluated annually and re-summarized as appropriate, based on the current state of knowledge. New information should be highlighted.

The appropriate level of detail is likely to be dependent on the stage of drug development. For example, summaries covering drugs in early development might include information on individual cases, whereas in later development, as more knowledge and perspective are gained, the information on each risk might be less detailed.

The information in this section could provide the basis for the safety specification of a risk management plan (ICH E2E Pharmacovigilance Planning).

Risks that have been fully addressed or resolved should remain in the summary and be briefly described, e.g., findings from toxicology studies or early clinical trials that were not borne out by later clinical data. The information can be provided in either narrative or tabular format.

Example:

The important potential risks and important identified risk are summarised in this section in the below table.

20. Conclusions

The brief description of any significant changes to the previous knowledge of efficacy and safety resulting from information gained since the last DSUR. The conclusion should outline actions that have been or will be taken to address emerging safety issues in the clinical development program.

Example:

As a result of analysis of data for the current reporting interval, there are no new adverse drug reactions or new potential risks identified for <<investigational product>>.

These important risks will continue to be closely monitored as the development program progresses. The Sponsor will continue to monitor all clinical trial safety information received from worldwide sources and will revise the protocols, consent forms, and/or product documents if an evaluation of surveillance data yields significant new information.

As such there is no change to the benefit-risk profile for <<investigational product>>, it continues to remain favourable and further development of <<investigational product>> is justified by the anticipated benefits expected for patients with <<Intended therapeutic indication>>.

Appendices to the DSUR

The DSUR should be accompanied by the following appendices, as appropriate, numbered as follows:

1. Investigator’s Brochure (if required by national or regional laws or requirements)
2. Cumulative Table of Important Regulatory Requests
3. Status of Ongoing and Completed Clinical Trials
4. Cumulative Summary Tabulations of Demographic Data
5. Line Listings of Serious Adverse Reactions
6. Cumulative Summary Tabulation of Serious Adverse Events
7. Scientific Abstracts (if relevant)

Regional Appendices

1. Cumulative summary tabulation of serious adverse reactions
2. List of subjects who died during the reporting period
3. List of subjects who dropped out of studies during the reporting period
4. Significant Phase 1 protocol modifications with respect to a U.S. IND
5. Significant manufacturing changes
6. Description of the general investigation plan for the coming year with respect to a U.S. IND
7. Log of outstanding business with respect to a U.S. IND