DSUR (Developmental Safety Update Report)

 DSUR (Developmental Safety Update Report)

DSUR which is prepared while the product is still in development phase, which stands for Developmental Safety Update Report. We can also call it as a pre-marketing equivalent of a PSUR (Periodic Safety Update report).

Before we go to the core of content and format, first let’s understand what a DSUR is?

DSUR is an internationally harmonized, safety document which covers the safety summary of investigation products during their development or clinical trial phase. This means that all new drugs under development that are currently undergoing a clinical trial must submit a DSUR to the regulatory authorities.

Now you might be wondering, why do we come across DSURs for medicines which are already on the market. There will also be instances where a product is already on the market, but the sponsor/MAH (Marketing Authorization Holder/Pharma Company, wants to further evaluate the drug; for example, for a new dose, new formulation or a new indication that is not covered by the drugs approved marketing status. In that case, the sponsor must submit  DSUR until the clinical trials for a marketed drug are ongoing.

What are the objectives of a DSUR? The purpose of a DSUR is to provide a comprehensive annual analysis  of the safety summary collected during the clinical trial. You may consider the document as a communication to the regulators about adequate monitoring and evaluation of a safety profile of a drug under investigation.

What is the scope of products for a DSUR? A DSUR may be required for any of the following

-          Investigational drugs

-          Investigational Biologicals

-          Investigational Vaccines

-          Combination products under investigation.

 Clinical trials using an investigational drug

 Clinical trials conducted to support changes in the manufacturing process of medicinal products

   Clinical trials conducted using marketed drugs in approved indications

  Therapeutic use of an investigational drug

What is DIBD?: - Developmental international Birthdate (DIBD) – it is the date of first authorization from a regulatory agency to the sponsor to conduct any clinical trial for an investigational product anywhere in the world.

How long is it to be submitted?- A DSUR is to be submitted as long as the clinical trial is ongoing. When submission of an annual report is no longer required in an individual country  or region, the sponsor should indicate that the final DSUR serves as the last annual for the investigational drug in that country or region.

What is the frequency of a DSUR submission?- Usually the DSUR is submitted annually (the frequency may vary occasionally as per national or regional regulatory requirement).  

 The first DSUR should have a data lock point which should be within a year of its DIBD.

Also note that the DSUR is to be submitted to the regulatory authorities within 60 calendar days after the DSUR data lock point.

What is the reference safety document for a DSUR? Unlike PSUR, in case of DSUR the IB i.e. the Investigators Brochure stands as a reference document for the DSUR report.  

The Format and Content is described in International Conference on Harmonization (ICH) guideline E2F.

Each section of DSUR is highlighted in the table below, along with a brief overview of what each section entails.

DSUR	PSUR	Comment for ease of understanding
Part I	Title Page	Information about company, author of DSUR, Reviewers , data period etc
Part II	Executive Summary	Snapshot of DSUR , summary of risk-benefit of product
1	Introduction	-          DIBD and Reporting period -          Details of investigational drug- mechanism of action, therapeutic class, dose, route, and formulation, indication etc
2	Worldwide Marketing Authorization Status	-          Date of first approval -          Indication(s), approved dose(s), and countries where approved, if applicable.
3	Actions Taken In the reporting interval for Safety Reasons	-          Significant safety related actions taken during the reporting period along with reasons for each action. e.g. Regulatory authorities requested hold on clinical trials, withdrawal of product etc
4	Changes to Reference Safety Information	Significant safety-related changes to the Investigators Brochure OR USPI or other such RSI documents within the reporting period.
5	Inventory of clinical trials ongoing and completed during the reporting period	-          Overview of the clinical trials ongoing and completed by the sponsor during the reporting period.
6	Estimated Cumulative Exposure 6.1 Cumulative Subject Exposure in the Development Programme 6.2 Patient Exposure from Marketing Experience	-          Sections 6.1 and 6.2 of the DSUR should provide information on cumulative exposure in clinical trials and the marketed setting, respectively.
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	This should present important clinical safety information through line listings (cumulative and reporting period)
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	-          Each sub section should provide a brief summary of clinically important emerging efficacy and safety findings from clinical trial
9	Safety Findings from Non Interventional Studies	-          Relevant safety information from sponsored or co-sponsored non-interventional studies (e.g. observational studies, epidemiological studies, active surveillance programmes)
10	Other Clinical Trial/Study Safety Information	-          Relevant safety information from any other sponsored or co-sponsored clinical trial/study sources (e.g. results from pooled analyses or meta analyses of randomized clinical trials)
11	Safety Findings from Marketing Experience	-          Applicable in case investigational drug has been approved for marketing in any country -          Should provide a summary of key safety findings that have arisen from marketing experience.
12	Nonclinical Data	-          Major safety findings from non-clinical in vivo and in vitro studies (e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the reporting period.
13	Literature	-          New and significant findings, either published in the scientific literature or available as unpublished manuscripts, relevant to the investigational drug during the reporting period.
14	Other DSURs	-          In case, multiple DSURs are to be prepared for a single investigational drug, this section should summarise significant findings from other DSURs. .
15	Lack of Efficacy	-          Data indicating lack of efficacy for investigational drugs intended to treat serious or life-threatening illnesses (e.g. excess cardiovascular adverse events in a trial of a new antiplatelet drug for acute coronary syndromes)
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.
17	Late-Breaking Information	-          Important safety findings that arise after the data lock point but while the DSUR is in preparation.
18	Overall Safety Assessment 18.1. Evaluation of the Risks  18.2 Benefit-risk Considerations	-          Concise, integrated evaluation of all new relevant clinical and non-clinical and epidemiological information obtained during the reporting period relative to the previous knowledge of the investigational drug.
19	Summary of Important Risks	-          Concise, cumulative, issue-by-issue list of important identified and potential risks.
20	Conclusions	-          Changes to the previous knowledge or efficacy and safety since the last DSUR.

 To summarize, DSUR is a complex and analytical document that should be utilized to analyze risk and safety profile of product in an ongoing manner.

References:

 1. FDA

2. EMA

Written by:

Dr.Shraddha Bhange.

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Periodic Adverse Drug Experience Report (PADER)

What is PADER?

 Periodic Adverse Drug Experience Report (PADER/PAER) is aggregate safety reports required from MAH to be submitted consisting of ICSR submission and their analysis by FDA as per guidance 314.80 (c) and 600.80 (c) (2). 

Why is it needed?

 PADER serves the purpose of collating, updating, evaluating, and providing a summary of post-approval information of a product along with its benefit-risk profile evaluation.

 The key difference is a detailed analysis is not required as per PBRER/PSUR format. Only mention about labelling changes already performed are added. But the actual analysis done during the current PADER and if this data led to changes in labeling of product or if additional investigations are required for any of the new/existing risks mentioned for products is dealt separately and not mentioned. 

When is it needed?

 For the first three years, the company needs to submit the report quarterly and, thereafter, annually upon obtaining approval from the FDA.

 MAH must submit Quarterly PADER within 30 days of the close of the quarter beginning from first quarter from date of approval.

MAH must submit Annual report within 60 days of the anniversary date of approval of the application.

 Waiver not to submit PADER

 An MAH can take waiver from FDA and update the NDA listing and submit PBRER/PSUR instead of PADER in ICH regions.

 Key points for drafting PADER

 1.Ensure all the ICSR are already submitted during the review period (15 day reports), and their submission dates are entered in safety database. If any ICSR not submitted then MAH need to submit it ASAP and initiate CAPA as per internal process.

 2. The cases/ICSR that are going to be submitted as part of PADER are closed in safety database to generate their XML’s.

 3. The ICSR that needs description should be 15 day expedited cases along with their clinical significance. Narrative should be brief, with emphasis on data only about serious and unlisted event, hence avoid copy and paste of narratives. Company comments explaining MAH causality of case should be retained.

 4. Explain the 15 day expedited and other cases in brief manner and corelate their significance in terms of impact on benefit-risk profile of product.

 5. Attaching the recent USPI and describing a very briefly what were the changes in USPI made during review period. Adding any postmarking studies, regulatory actions and any new safety measures implemented in respective sections.

 References:

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=314.80

 

Written by:

Dr.Shraddha Bhange.

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PSUR/PBRER (Periodic Benefit Risk Evaluation Report)-Aggregate report in PV

PSUR/PBRER (Periodic Benefit Risk Evaluation Report)

If you ask anyone what they want to do next in PV? Most certainly if they have just started PV career and /or in ICSR the answer is aggregate reports.  

PBRER/PSUR is one important aggregate report. Let’s look at template of PSUR in this blog and sections. PBRER (Periodic Benefit Risk Evaluation Report) and PSUR (Periodic Safety Update Report) are interchangeably used, but the both are different. PSUR is simple template than PBRER accepted by many health authorities and especially for established products.

Below is template of PBRER as per E2C (R2) step 3 Guideline:

Section in PSUR	Name of section
Part I	Title Page
Part II	Executive Summary
Part II	Executive Summary
Part II	Executive Summary
Part II	Executive Summary
1	Introduction
2	Worldwide Marketing Authorization Status
3	Actions Taken In the reporting interval for Safety Reasons
4	Changes to Reference Safety Information
5	Estimated Exposure and Use Patterns
5.1	Cumulative Subject Exposure in Clinical Trials
5.2	Cumulative and Interval Patient Exposure from Marketing Experience
5.3	Post  Approval use in Special Population
5.3	Other post approval use
6	Data in Summary Tabulations
6.1	Reference information
6.2	Cumulative summary tabulations of serious adverse events from clinical trials
6.3	Cumulative and interval summary tabulations from post-marketing data sources
7	Summaries of significant findings from clinical trials during the reporting interval
7.1	Completed clinical trials
7.2	Ongoing clinical trials
7.3	Long-term follow-up
7.4	Other therapeutic use of medicinal product
7.5	New safety data related to fixed combination therapies
8	Findings from non-interventional studies
9	Information from other clinical trials and sources
9.1	Other clinical trials
9.2	Medication errors
10	Non-clinical Data
11	Literature
12	“Other periodic reports”
13	“Lack of efficacy in controlled clinical trials
14	PSUR section “Late-breaking information”
15	“Overview of signals: new, ongoing, or closed
16	Signal and risk evaluation
16.1	Summary of safety concerns
16.2	Signal evaluation
16.3	Evaluation of risks and new information
16.4	Characterisation of risks
16.5	Effectiveness of risk minimisation
17	Benefit evaluation
17.1	Important baseline efficacy and effectiveness information
17.2	Newly identified information on efficacy and effectiveness
17.3	Characterisation of benefits
18	“Integrated benefit-risk analysis for authorised indications
18.1	Benefit-risk context - medical need and important alternatives
18.2	Benefit-risk analysis evaluation
19	Conclusions and actions
20	Appendices to the PSUR

Introduction covers the products details (content, date of first marketing authorisation, formulation etc)

The section regarding worldwide market authorisation status is usually available with regulatory affairs or marketing department. It is regarding the status of approval of the product in different countries. This ensures that there is dialog between PV and regulatory affairs and consequently other affiliates in each country where the product is approved regarding its status. If there was any change in authorisation etc ,PSUR stands as a good check periodically in knowing such changes.

In the next section, there is section wherein such changes in the regulatory status due to actions taken by MAH or actions directed by regulatory authority due to safety reasons are enlisted. One example would be if the product labelling was updated due to safety reasons then this will be included herein.

Changes to safety information section would talk about the changes in the reference safety information section of CCDS,USPI,SmPC or IB.

Patient exposure data is generally available with sales team/marketing department. This data is important to understand the age group (pregnancy/breastfeeding etc) and the total product distributed.

The section 6 is about ICSR, and should provide only summary tabulation. If presenting a case is required usually this are SUSARs (Serious unlisted cases) and Fatal cases in section 16. In case of low volume a decision to include short narrative of all cases can be taken. Overall, good idea is to present only relevant cases of that review period. Presentation of cases is usually in a form of short narrative with only information that is relevant to medical assessment of case.

In the section about studies, data regarding ongoing, completed ,company sponsored or non sponsored studies is evaluated and presented.

The sections about overall safety evaluation is summary of all safety information presented in PSUR and how it affects the safety profile of product. 

The most time consuming section is section of risk and benefit. Characterizing risk is very important step which should be derived from RMP or USPI/SmPC when writing for first time. Usually the idea is to only describe risk that are important identified, potential risk and missing information. The risks definitions and signal definition can be referred in GVP modules. One good starting point is the risks that are mentioned in contraindications, warnings and precautions, and important adverse reactions  ,class actions in potential risk. Not all risk qualify as important, those that have higher severity, impact, risk minimization measures are loosely considered as identified. Writing benefits section will depend on current approved indications and usage and should summaries the current profile of product.

Conclusion will give an presentation regarding if the data in PSUR will led to any action in terms of changing label of product, change in RMP etc.

Generally this PSUR template which is more concise is accepted by rest of the world authorities (Non-EU) E.g. DCGI, Russia ,Malaysia etc and generally for generic products.

Frequency of PSUR: Each regulatory authority has different requirements with respect to timelines of PSUR. As an example for CDSCO -India's regulatory authority below is standard:

 PSURs shall be submitted every six months for the first two years from the approval of product and annually for the subsequent two years, and it must be submitted within 30 calendar days of the last day of the reporting period.

If you are author, compiler or reviewer, in addition to PSUR you need to be aware of baseline safety profile of product, competitors USPI/CCDS, Regulatory status on signals or any communications. You should also have other skills and tool to manage this document- word, time management, project management etc.

I hope, I could summarize key points regarding PSUR in this blog.

Reference:

E2C R2

RMP GVP V

PSUR GVP VII

Written by:

Dr.Shraddha Bhange.

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Support the cause of better rural education with me:ThinkSharp Foundation http://thinksharpfoundation.org/#home