Fda Periodic Safety Update Reports

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Now that Drug Safety Update Reports (DSURs) are in full force in the EU and elsewhere and, now that they are being accepted by FDA, it is time to take a look at DSURs and the issues and strategies around them. In particular, should a company submit a DSUR or an Annual Safety Report to the FDA?

Periodic Safety Update Reports (PSURs) Submission Frequency Schedule Page Content It is a list of the marketed pharmaceutical products in Saudi Arabia and their dates for submission of PSURs to Saudi Food and Drug Authority (SFDA). The 120 Day Safety Update contains any new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverser reactions in the draft drug labelling. Also know as the Safety Update Report, the report must be received by the FDA within 120 days of drug approval submission.

Although recently coming into force in various regions, the idea of the DSUR is rather old going back to CIOMS VI/VII and ICH E2F in the early and mid 2000’s. It came into effect in the EU about 2 years ago and is accepted (but is not obligatory) by FDA. See the E2F document at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500097061.pdf . This document is a must read if you prepare DSURs.

What is a DSUR?

The DSUR is the pre-marketing equivalent of the post-marketing Periodic Safety Update Report (PSUR). It covers drugs, biological, vaccines and combo products. It is a stand-alone document that is not just a data dump but is an analytical document. It should be “clear and succinct” (as all documents should be but rarely are). Its goal is the assessment of risk and any changes in risk since the previous DSUR. It also notes actions taken to reflect new or ongoing risks. The document is submitted to regulatory agencies and sometimes also to Ethics Committees/IRBs.

There should be only one DSUR for one investigational drug (active moiety) – no matter whether there are different formulations, indications etc. This is different from the US where each IND usually requires an annual report even if it is for the same drug (though FDA sometimes allows combining the several INDs into a single annual report submitted to more than one IND).

There should be only one DSUR used everywhere around the world. This, unfortunately, is not the case. Additional sections may need to be added for particular countries such as the US (see below).

There is a single, harmonized Developmental International Birthdate (DIBD) which is the first authorization from a regulatory agency to the sponsor to do a clinical trial anywhere in the world. This will require the regulatory group in the company to convey this information to all of the involved health agencies so that the birthdate is harmonized. Since there is a known fixed schedule for submission, there will be a fixed, single data lockpoint 60 days before submission for each DSUR.

In most countries the DSUR is submitted annually. Companies that have open INDs and NDAs (or the ex-US equivalents such as CTCs/CTXs and MAs respectively) may also have their regulatory departments harmonize the birthdate for DSURs and PSURs such that there is a single submission date. However, think carefully about this in terms of operational resources. If the DSUR and PSUR are each large documents full of much data and detailed analyses, the company may not be able to write two large documents with the same submission date. A careful analysis of the internal resources needed for a simultaneous DSUR and PSUR should be made before committing to a harmonized submission of both every year.

DSUR Contents

The DSUR contents include:

  • Executive Summary
  • Table of Contents

1. Introduction

2. Worldwide marketing authorisation status

3. Actions taken for safety reasons

4. Changes to the IB (reference document)

5. Status of ongoing and completed interventional trials during reporting period

6. Estimated exposure

  • Clinical trials
  • Marketed exposure

7. Line listings & summary tables

  • General considerations
  • SAR line listing table – for this reporting period
  • SAE line listing table – cumulative
  • Deaths
  • Drop outs due to safety issues

8. Significant findings from clinical trials

  • Completed & interim data
  • Ongoing
  • Other uses
  • Combination therapy if any

9. Relevant findings from non-interventional trials

10. Relevant findings from other sources

11. Safety findings from marketing experience

12. Other information

  • Non-clinical data
  • Long term follow up
  • Literature
  • Other DSURs
  • Significant manufacturing changes (for US)
  • Lack of Efficacy
  • Phase I protocol modifications (for US)
  • Plan for upcoming year (for US)

13. Late breaking news

14. Overall safety evaluation and analysis

  • Evaluation of risks
  • Benefit risk considerations
  • Conclusions

15. Summary of important risks

16. Annexes

The new concepts and pieces of this document compared to the old EU Annual Safety Reports and the current US Annual Reports are primarily in the overall safety evaluation and the summary of important risks sections.

Overall safety evaluation/Benefit-risk considerations

This section is a succinct statement describing the perceived balance between identified risks and anticipated efficacy/benefits. Any changes in this balance since the previous DSUR should be noted.

Summary of Important Risks

This section is a concise, cumulative issue-by-issue list of identified and potential risks (which are defined as those that might lead to warnings, precautions or contraindications in the labeling). These risks include issues based on a particular molecular structure or drug class, or concerns based on accumulating non-clinical or clinical data. Each risk must be reevaluated annually and addressed in the DSUR as appropriate with new information highlighted. A more detailed review should be done in early development of a drug when risks are less well characterized.

Appendices

After the conclusions section, there are several appendices including:

  • Investigator’s Brochure (if required locally)
  • Cumulative Table of Important Regulatory Requests
  • Status of Ongoing and Completed Clinical Trials
  • Cumulative Summary Tabulations of Demographic Data
  • Line Listings of Serious Adverse Reactions
  • Cumulative Summary Tabulation of Serious Adverse Events
  • Scientific abstracts (if relevant)
  • Regional appendices such as a cumulative table of SARs, subjets who died or dropped out of studies, phase I modifications (US requirement), manufacturing changes, plan for the upcoming year (US requirement) and other IND issues (US requirement).

This is the “official” description covering the DSUR. Further information for the EU is available in an FAQ from the Heads of Medicines Agencies website on DSURs: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2011_12_22_Q___A_DSUR.pdf

These Q&As give very useful information. Some of the key points are summarized here:

Q: When do you start preparing a DSUR?

A: After the first authorization of a clinical trial anywhere in the world. This also creates the Developmental International Birthdate (DIBD) for the drug. The DIBD of an authorized drug is the IBD (International Birth Date), the date when the product was first authorized in any country of the world. The submission dates for DSURs PSURs may also be harmonized. The first DSUR may be submitted anytime within one year after this birthdate but not longer than 1 year after the birthdate.

Q: When do you stop preparing DSURs?
A: The document indicates that there is ambiguity here in the regulations. The Heads of Medicines have concluded in this document that a DSUR should be submitted until the last visit of the last patient in the country(ies) concerned. If the trial has ended in a particular member state the DSUR does not have to be submitted there – only in countries where the study is still actively continuing. If there are several trials going on in that country, the DSUR must be submitted till the last patient’s last visit in the last study.

Q: Is a DSUR required for a trial lasting less than 1 year?
A: No

Q: Is a DSUR required for phase IV clinical trials if these are the only trials being conducted?
A: Yes. For investigator-initiated trials (IITs) a simplified document may be filed. See the Q&A for more details. If several IITs are being run at independent sites one single DSUR should be prepared. Member states may grant waivers to this if it is appropriate that more than one DSUR be submitted.

Q: Is a DSUR required for comparator and placebo products?
A: No a separate DSUR is not required but relevant safety information on the comparators should be addressed in the DSUR of the investigational drug. In certain sections (7.2, 2.7 and 3.7) of the DSUR all SAEs/SARs are required to be noted. The sponsor is encouraged but not obligated to provide relevant safety information to the MAH of the comparator products.

Q: What about the reference safety information if the SmPC is being used and not an IB?
A: The same SmPC should be used in all member states for the DSUR. If the SmPC (or IB) is updated during the period of the DSUR, the document in effect at the beginning of the reporting period should be used for DSUR preparation. Updating of the document(s) is not recommended during this time period however.

Q: Can the Company Core Safety Information (CCSI or CSI) be used as the reference safety information instead of an IB or SmPC?
A: Yes but only if it is part of the Investigator Brochure.

Annual Reports or DSURs to the FDA

Finally, FDA has indicated that it will accept DSURs instead of IND Annual Reports (76 Federal Register 52667 (23Aug2011) as long as they have all the requirements of the US Annual Report in the region specific appendices of the DSUR.

The question then is whether the sponsor should do an old style annual report or the DSUR. To a certain degree the answer to this is tactical and strategic. On the one hand, the DSUR is more complex and analytical than the old IND annual report which is largely a “data dump”. It requires the company to clearly delineate risks and then to come to a benefit risk conclusion. This requires more thought, time and analysis. This is presumably a good thing. On the other hand this requires more thought, time and analysis and risk description which, at least early in the development cycle, may be too preliminary, too inconclusive and perhaps even misleading and, for a small company with few resources, difficult to do. So what is the best or right thing to do? The narrow answer is that the sponsor will clearly obey the law by doing the old style annual report. The broader (and to my mind better) answer is that the sponsor as an ethical company working to improve the public health should do an analysis of the data and benefit/risk status and report this to the authorities.

Conclusions

The DSUR is a more or less harmonized document now accepted in most of the countries of the world. It is a more complex and analytical document than the old style annual safety reports. It should be harmonized with other documents (PSURs, reference safety information etc.) and there is an international birthdate meaning that only one DSUR needs to be prepared in most cases. It is more complex and arguably preferable than the documents it replaces.

Fda Periodic Safety Update Reports Definition

In this post we shall discuss about Periodic Safety Update reports (PSURs). in this post we will cover the following topics:

Origin

The origin of PSUR stems from the following:

  1. 1992 – “International Reporting of Periodic Drug Safety update summaries” (Council for International organisations of medical sciences [CIOMS] II)
  2. 1996 – “Guidance for Industry E2C Clinical Safety Data Management: Periodic Safety Update reports for Marketed drugs”
  3. 2001 – “Current challenges in Pharmacovigilance: Pragmatic approaches” (CIOMS V)
  4. 2002 – “Draft Consensus Guideline – Addendum to ICH E2C Clinical Safety Data Management Periodic Safety Update Reports for marketed drugs.

Purpose

Periodic Safety Update Report (PSUR) is a stand alone global-standardised document that can be used worldwide for:

  • Identification of new safety signals and also
  • Identification of changes to benefit-risk profile medical product
  • Change in product label
  • Change in product name/package/promotional material
  • “Dear Doctor” letter
  • Need for risk management activities
  • Withdrawal from the market
  • Monitoring effectiveness of risk management initiatives in relation to safety of the product

General Principles

A PSUR is intended to provide an update of the worldwide safety experience of a medicinal product to Competent Authorities at defined time points post-authorization. At these times, marketing authorization (MA) holders are expected to provide succinct summary information together with critical evaluation of the risk-benefit balance of the product in the light of new or changing information. This evaluation should ascertain whether further investigations need to be carried out and whether changes should be made to the marketing authorization and product information.

PSURs must be submitted for all registered products regardless of marketing status. A single report may cover all products containing the same active substance (s) licensed by one MA holder.

General Scope of Information of a PSUR

All relevant clinical and non-clinical safety data should cover only the period of the report (interval data) with the exception of authorization status information for initial and renewal applications, and data on serious, unlisted adverse reactions. This should be provided for both, the period in question and as cumulative summary tabulations starting from the International Birth Date (IBD).

The report will usually include all dosage forms and formulations, as well as indications associated with such an active. Within the PSUR, separate presentations of data for different dosage forms, indications or populations (for example children vs adults) may be appropriate, however an overview of the combined data should also be provided.

For combinations of substances which are also registered individually, safety information for the fixed combination may be reported in a separate PSUR, or be included as a separate presentation the report for one of the separate components, depending on the circumstances. Cross referencing all relevant PSURs is essential.

The main focus of the report should be adverse reactions. Unless indicated otherwise by the reporting healthcare professional, all adverse experiences reported spontaneously should be considered adverse reactions; for clinical study and literature cases, only those judged not related to the medicinal product by both the reporter and MA holder should be excluded.

PSURs should include a scientific evaluation of risk: benefit balance of the product (s)and should be generated according to the ICH E2C guidelines.

Submission of PSURs

PSURs should be submitted according to special MAIL.

Following submission of PSURs an acknowledgement letter is sent, if it is not received within 14 days then submitting authority should contact the Regulatory Information Service (RIS) to ensure the application.

Frequency of PSUR reporting

The following are the requirements of Frequency of PSUR reporting:

Fda Periodic Safety Update Reports Psurs

PSURs should be submitted at the following times from the time of authorization, for all medicinal products unless the marketing authorization makes different provisions:

  • Immediately upon request
  • At least 6 monthly after authorization and until the placing on the market.
  • At least 6 monthly for the first two years after being placed on the market
  • Annually for the subsequent two years
  • Thereafter at three-yearly intervals.

Multiples of six-monthly PSURs are acceptable, provided that the MA holder submits a PSUR bridging summary report (BSR). Where multiple reports are being provided, the BSR should be comprehensive.

The data-lock point (DLP) is defined as the cut-off date for data to be included in the PSUR. It may be set according to the European Birth Date (EBD) or IBD of the medicinal product. The MAH should in any case submit the PSUR no later than 60 days after the DLP. For generic products the DLP may be set according to the Eu harmonised birth date (EU HBD) of a medicinal product as published on the Heads of Agencies (HMA) website.

Reports

Each PSUR should cover the period of time since the last update report. A PSUR, and BSR if appropriate, should also be submitted at renewal in line with renewal guidelines. Reports previously submitted for each marketing authorization do no need to be resubmitted and duplicate reports should not be submitted.

If the product is not marketed at approval, then there will be extra 6 monthly PSURs before marketing.

Indian Regulatory Aspect

Schedule Y also recommends that for all new products, PSURs should be submitted every 6 months for the initial 2 years, and thereafter annually for the next 2 years.

It is quire similar to the reporting cycle requirements of European Union (EU), where PSURs are required to be submitted every 6 months for the first 2 years, annually for the three following years and every 3 years, thereafter. In Eu, it is generally acceptable to the regulators that the generic companies skip the 6-monthly cycles of initial 2 years and submit the PSURs every 3 years from the date of marketing approval.

Reporting requirements of the USD FDA are, however, different. The US regulations require quarterly reports during the first 3 years and annual reports, thereafter.

Like other regulatory authorities, DCGI can also extend the total duration for the submission of PSURs if it is considered necessary in the interest of public health.

Contents of PSUR

The following are the Table of contents of a PSUR:

  • Studies
  • Other Information
  • Overall safety evaluation
  • Conclusion
  • Appendix
  • company core data sheet
  • Consumer reports (US)

Introduction

The marketing authorization holder should briefly introduce the product so that the report “stands alone” but is also placed in perspective relative to previous reports and circumstances.

Reference should be made not only to the products covered but also reports and circumstances.

Exclusion should be explained, for example, they may be covered in a separate report (e.g. for a combination product)

If it is know that the PSUR on the same product will be submitted by another marketing authorization holder, some of whose data are included in the report, the possibility of data duplication should be noted.

Worldwide marketing Authorization

This section of the report provides cumulative information.

The following information should be provided, usually as a table, for all countries where a regulatory decision about marketing has been made related to the following:

  • Dates of marketing authorization, and subsequent renewal;
  • Any qualifications surrounding the authorization, such as limits on indications if relevant to safety;
  • Treatment indications and special populations, covered by the marketing authorization, when relevant;
  • Lack of approval, including explanations by regulatory authorities;
  • Withdrawal by the company of an authorization application submission if related to safety or efficacy;
  • Dates of launch;
  • Trade name.

Typically, indications for use, populations treated (e.g. children vs adults) and dosage forms will be the same in many or even most countries, where the product is authorised. However when there are important differences, which would reflect different types of patient exposures, such information should be noted. This is especially true if there are meaningful differences in the newly reported safety information that are related to such different exposures.

If more convenient and useful, separate regulatory status tables for different product uses or forms would be considered appropriate.

Country entries should be listed in chronological order of regulatory authorizations.

Update of Regulatory authorities or MAH actions taken for safety reasons

This section should include details of the following types of actions relating to the safety that were taken during the period covered by the report and between data lock-point and submission.

  • Marketing authorization withdrawal or suspension;
  • Failure to obtain marketing authorization renewal;
  • Restrictions on distribution;
  • Clinical trial suspension;
  • Dosage modification;
  • Changes in target populations or indications;
  • Formulation changes
  • Urgent safety restrictions

The safety related reasons that led to these actions should be described and documentation appended when appropriate; any communication with the healthcare professionals (e.g Dear Doctor letters) as a result of such action should also be described with copies appended.

Changes in reference safety information

The version of the “Company Core Data Sheet (CCDS) with its “Company Core Safety Information” (CCSI) in effect at the beginning of the period covered by the report should be used as a reference. It should be numbered, dated and appended to the PSUR and include the date of the last revision.

Changes to the CCSI, such as new contraindications, precautions, warnings, ADRs, or interactions, already made during the period covered by the report, should be clearly described, with presentation of the modified sections. The revised CCSI should be used as a reference for the next report and the next period.

With the exception of emergency situations, it may be sometime before the intended modifications are introduced in the product-information materials [provided to the prescribers, pharmacists and consumers. Therefore during that period the amended reference document (CCDS) may contain more “listed” information than the existing product information in many countries.

When meaningful differences exists between the CCSI and the safety information in the EU SPC (or the official data sheets/product information documents approved in a country), a brief comment should be prepared by the marketing authorization holder, describing the local differences and their consequences on the overall safety evaluation and on the actions proposed or initiated. The commentary may be provided in the cover letter or other addendum accompanying the local submission of the PSUR.

Patient Exposure

Where possible, an estimate of patient exposure should cover the same period as the interim safety data. While it is recognised that it is usually difficult to obtain and validate accurate exposure data, and estimate of the number of patients exposed should be provided along with the method used to derive the estimate.

An explanation and justification should be presented, if the number of patients is impossible to estimate. In its place, other measures of exposure, such as patient-days, number of prescriptions or number of dosage units are considered appropriate; the method used should be explained. If these or other more precise measures are not available, bulk sales (tonnage) may be used.

The concept of defined daily dose may be used in arriving at patient exposure estimates. When possible and relevant, data broken down by sex and age (especially paediatric vs adult) should be provided.

When pattern of reports indicates a potential problem, details by country (with locally recommended daily dose) or other breakdown (e.g. indication, dosage form) should be presented if available.

When ADR data from clinical studies are included in the PSUR, the relevant denominator(s) should be provided for ongoing and/or blinded studies, an estimation of patient exposure may be made.

Presentation of Individual case Histories

  • General considerations
  • Cases presented as Line listings
  • Presentation of the line listing
  • Summary tabulations
  • Marketing authorisation holders analysis of individual case histories

Table of Contents of the PSUR

Coming back to the contents of the PSUR, the following are the Table of contents of a PSUR:

  • Studies
  • Other Information
  • Overall safety evaluation
  • Conclusion
  • Appendix
  • company core data sheet
  • Consumer reports (US)

Let us have a look at these one by one.

Studies

All completed studies (non-clinical, clinical and epidemiological) yielding safety information with potential impact on product information, studies specifically planned or in progress, and published studies that address safety issues, should be discussed. This includes:

  • Newly analysed studies
  • Targeted new safety studies
  • Published studies
Other Information
Efficacy Related Information

For a product used in prevention or to treat serious or life threatening diseases, medically relevant lack of efficacy reporting, which might represent a significant hazard to the treated population, should be described and explained.

Late Breaking Information

Any important, new information received after the database was frozen for review and report preparation may be presented in this section. Examples include significant new cases or important follow-up data. These new data should be taken into account in the overall safety evaluation.

Overall Safety Evaluation

The marketing authorization holder should provide a concise analysis of the data presented, taking into account any late-breaking information, and followed by the marketing authorization holder’s assessment of the significance of the data collected during the period. The marketing authorization holder should also review the cumulative experience and highlight any new information on:

  • A change in characteristics of listed reactions, e.g. severity, outcome, target population
  • Serious unlisted reactions, placing into perspective the cumulative reports
  • Non-serious unlisted reactions
  • An increased reporting frequency of listed reactions, including comments on whether it is believed the data reflect a meaningful change in ADR occurrence
Conclusion

PSURs should indicate the safety findings that are different than that found in the current reference safety information. It should indicate what actions were or will be taken such as Change in CSI, Risk management initiatives etc.

Appendix

This should include:

  • Company Core Data Sheet
  • Consumer Report (US)
  • Aggregate data – to better identify new safety signals especially rare adverse events
  • Worldwide data – safety signal strengthened is seen in more than one country
  • Multiple sources of information – also strengthens the safety signal
    • Spontaneous reports
    • Healthcare professionals, Consumers (US)
    • Literature
    • Studies
    • Animal findings

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