DEVELOPMENT SAFETY UPDATE REPORT - ICH
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USEICH HARMONISED TRIPARTITE GUIDELINEDEVELOPMENT SAFETY UPDATE REPORTE2FCurrent Step 4 versiondated 17 August 2010This Guideline has been developed by the appropriate ICH Expert Working Group andhas been subject to consultation by the regulatory parties, in accordance with the ICHProcess. At Step 4 of the Process the final draft is recommended for adoption to theregulatory bodies of the European Union, Japan and USA.
E2FDocument HistoryCodeHistoryDateE2FApproval by the Steering Committee under Step 2and release for public consultation.5 June2008Current Step 4 versionE2FApproval by the Steering Committee under Step 4and recommendation for adoption to the threeICH regulatory bodies.17 August2010
DEVELOPMENT SAFETY UPDATE REPORTICH Harmonised Tripartite GuidelineHaving reached Step 4 of the ICH Processon 16 August 2010, this guideline is recommended foradoption to the three regulatory parties to ICHTABLE OF CONTENTS1.INTRODUCTION . 11.1Background. 11.2Objectives. 11.3Scope of the DSUR . 21.4Relation of the DSUR to the Periodic Safety Update Report. 31.5Recipients of the DSUR . 32.GENERAL PRINCIPLES . 32.1Single DSUR for an Active Substance . 32.2Periodicity and DSUR Data Lock Point . 32.3Duration of DSUR Submissions . 42.4Responsibilities for Preparing and Submitting a DSUR . 42.4.1Sponsor’s Responsibilities. 42.4.2Responsibilities of Multiple Parties. 42.5DSURs for Combination Therapies . 52.6Reference Safety Information . 52.7Format and Presentation of DSUR . 62.7.1Format . 62.7.2Presentation. 63.GUIDANCE ON CONTENTS OF DSUR . 73.1Introduction . 73.2Worldwide Marketing Approval Status . 83.3Actions Taken in the Reporting Period for Safety Reasons . 83.4Changes to Reference Safety Information . 93.5Inventory of Clinical Trials Ongoing and Completed during the Reporting Period . 93.6Estimated Cumulative Exposure . 103.73.6.1Cumulative Subject Exposure in the Development Programme. 113.6.2Patient Exposure from Marketing Experience . 11Data in Line Listings and Summary Tabulations. 113.7.1Reference Information . 123.7.2Line Listings of Serious Adverse Reactions during the Reporting Period . 123.7.3Cumulative Summary Tabulations of Serious Adverse Events . 13i
3.8Significant Findings from Clinical Trials during the Reporting Period . 133.8.1Completed Clinical Trials . 133.8.2Ongoing Clinical Trials . 133.8.3Long-term Follow-up . 133.8.4Other Therapeutic Use of Investigational Drug. 143.8.5New Safety Data Related to Combination Therapies . 143.9Safety Findings from Non-interventional Studies . 143.10Other Clinical Trial/Study Safety Information . 143.11Safety Findings from Marketing Experience. 143.12Non-clinical Data . 143.13Literature . 153.14Other DSURs . 153.15Lack of Efficacy . 153.16Region-Specific Information . 153.17Late-Breaking Information. 163.18Overall Safety Assessment . 163.18.1Evaluation of the Risks . 163.18.2Benefit-risk Considerations . 173.19Summary of Important Risks . 183.20Conclusions . 184.APPENDICES TO THIS GUIDELINE . 19APPENDIX A Glossary . 20APPENDIX B Examples of Tables and Table Headings for Clinical Trial Listings . 23APPENDIX C Examples of the Summary of Important Risks . 26ii
DEVELOPMENT SAFETY UPDATE REPORT1.INTRODUCTIONThe Development Safety Update Report (DSUR) proposed in this guideline is intended tobe a common standard for periodic reporting on drugs under development (includingmarketed drugs that are under further study) among the ICH regions. US and EUregulators consider that the DSUR, submitted annually, would meet national andregional requirements currently met by the US IND Annual Report and the EU AnnualSafety Report, respectively, and can therefore take the place of these existing reports. 1This guideline defines the recommended content and format of a DSUR and provides anoutline of points to be considered in its preparation and submission.Definitions of the technical terms used in the guideline are included in a glossary(Appendix A); the first mention of a term in the guideline is identified with an asterisk(*).1.1BackgroundDuring the clinical development of an investigational drug,* 2 periodic analysis of safetyinformation is crucial to the ongoing assessment of risk to trial subjects. 3,4 It is alsoimportant to inform regulators and other interested parties (e.g., ethics committees) atregular intervals about the results of such analyses and the evolving safety profile of aninvestigational drug, and apprise them of actions proposed or being taken to addresssafety concerns. Currently, laws and regulations of some ICH countries and regionsrequire submission of a periodic report to regulatory authorities to provide thisinformation. However, significant differences in the content, format and timing of thesereports highlight the importance of a common standard report in promoting consistencyand enhancing efficiency. Some national and regional laws and regulations also requirea periodic report that describes the status of ongoing individual investigations,manufacturing changes, and overall development status and plans. To be broadly useful,the DSUR should also include this information, in addition to safety-related information.The harmonisation of the content, format, and timing of periodic safety reports will helpto ensure that regulators in the three ICH regions receive a uniform, high-quality,comprehensive report.1.2ObjectivesThe main objective of a DSUR is to present a comprehensive, thoughtful annual reviewand evaluation of pertinent safety information collected during the reporting periodrelated to a drug under investigation, whether or not it is marketed, by: (1) examiningwhether the information obtained by the sponsor during the reporting period is in accordwith previous knowledge of the investigational drug’s safety; (2) describing new safetyissues that could have an impact on the protection of clinical trial subjects; (3)summarising the current understanding and management of identified and potentialJapan will consider existing regulations on periodic safety reporting in implementing the DSUR.The term “investigational drug” is used in this guideline to indicate only the experimentalproduct under study or development.3 For detailed discussion see: The Development Safety Update Report (DSUR): Harmonizing theFormat and Content for Periodic Safety Reporting During Clinical Trials: Report of CIOMSWorking Group VII, Geneva 2007.4 ICH Topic E6 (R1). Guideline for Good ClinicalPractice. http://www.ich.org/LOB/media/MEDIA482.pdf121
Development Safety Update Reportrisks;* and (4) providing an update on theinvestigation/development programme and study results.statusoftheclinicalA DSUR should be concise and provide information to assure regulators that sponsorsare adequately monitoring and evaluating the evolving safety profile of theinvestigational drug. All safety issues discovered during the reporting period should bediscussed in the text of the DSUR; however, it should not be used to provide the initialnotification of significant new safety information or provide the means by which newsafety issues are detected.1.3Scope of the DSURThe main focus of the DSUR is data and findings from interventional clinical trials*(hereafter referred to as “clinical trials”) of drugs and biologicals that are underinvestigation, whether or not they have a marketing approval. Because clinicaldevelopment of a drug frequently continues following marketing approval, 5 relevantinformation from post-marketing studies should also be included in the DSUR. TheDSUR should concentrate primarily on the investigational drug, providing informationon comparators only where relevant to the safety of trial subjects.The DSUR should provide safety information from all ongoing clinical trials and otherstudies that the sponsor is conducting or has completed during the review periodincluding: Clinical trials using an investigational drug (i.e., human pharmacology,therapeutic exploratory and therapeutic confirmatory trials [Phase I – III]); 6Clinical trials conducted using marketed drugs in approved indications (i.e.,therapeutic use trials (Phase IV));Therapeutic use of an investigational drug (e.g., expanded access programmes,compassionate use programmes, particular patient use, single patient INDs, andtreatment INDs); andClinical trials conducted to support changes in the manufacturing process ofmedicinal products.The DSUR should also include significant other findings pertinent to the safety of theinvestigational drug, including findings from: Observational or epidemiological studies;Non-clinical studies (toxicological and in vitro studies);Related DSURs, if applicable to the investigational drug;Manufacturing or microbiological changes;Studies recently published in the literature;Clinical trials with results indicating lack of efficacy that could have a directimpact on subject safety (e.g., worsening of the underlying condition if theindication is serious or life-threatening);Any other source of relevant safety findings for products in the same therapeuticclass;For the purposes of this document, we use the term “authorisation/authorised” to refer toapprovals of clinical trials, and “approved/marketing approval” to refer to marketingauthorisations.6 For classification of clinical trials see ICH E8 General Considerations for Clinical Trials.Current Step 5, 17 July 1997. http://www.ich.org/LOB/media/MEDIA484.pdf52
Development Safety Update Report 1.4Clinical trials conducted by a co-development partner, if permitted by thecontractual agreement.Relation of the DSUR to the Periodic Safety Update ReportAt present, some ICH countries and regions accept submission of a Periodic SafetyUpdate Report (PSUR) to fulfil national and regional requirements for periodic reportingon the safety of approved drugs. Although the focus of the DSUR is on investigationaldrugs, there can be overlap between the content of the DSUR and PSUR, and somerepetition is expected. For example, information from marketing experience (reported inthe PSUR) might be relevant to clinical development, and therefore reported in theDSUR. Safety findings from clinical trials conducted using marketed drugs would beincluded in the DSUR, but would also be pertinent to post-marketing safety and wouldbe reported in the PSUR. Both the DSUR and PSUR should be comprehensive and standalone as they focus on different subject matter and have differing periodicities andrecipients.1.5Recipients of the DSURThe DSUR is intended to serve as an annual report to regulatory authorities. Wherenational or regional laws or regulations require submission of an annual safety report onan investigational drug to ethics committees/institutional review boards, the DSURExecutive Summary might be appropriate, supplemented with line listings of seriousadverse reactions 7 (SARs) as warranted.2.GENERAL PRINCIPLES2.1Single DSUR for an Active SubstanceIn order to promote a comprehensive analysis and presentation of the safety profile ofthe investigational drug, a sponsor should prepare a single DSUR with data pertinent toall dosage forms and strengths, all indications, and all patient populations under studywith the investigational drug, wherever feasible. If this is not possible (e.g., when thedata are not available to the sponsor), an explanation should be provided in theintroduction section of the DSUR.If more than one sponsor is involved in drug development, particularly in a codevelopment or other contractual agreement, a single DSUR can be submitted (seeSection 2.4.2).2.2Periodicity and DSUR Data Lock Point*The “Development International Birth Date”* (DIBD) is used to determine the start ofthe annual period for the DSUR. This date is the sponsor’s first authorisation to conducta clinical trial in any country worldwide. The start of the annual period for the DSUR isthe month and date of the DIBD.When the sponsor’s first clinical trial is conducted in a country without a formalauthorisation process, the sponsor should designate an appropriate date linked to thecommencement of the first clinical trial. Where clinical trials are ongoing in one countryand are later initiated in another country, the original DIBD should be maintained andused for all countries in preparing the DSUR.“Serious adverse reaction,” “serious adverse event” and “adverse drug reaction” are defined inICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.October 1994. http://www.ich.org/LOB/media/MEDIA436.pdf73
Development Safety Update ReportThe data lock point of the DSUR should be the last day of the one-year reporting period.For administrative convenience, if desired by the sponsor, the data lock point of theDSUR can be designated as the last day of the month prior to the month of the DIBD.When clinical development of a drug continues following a marketing approval in anycountry worldwide, both a PSUR and a DSUR should be submitted as specified bynational or regional laws or regulations. If desired by the sponsor, a DSUR can beprepared based on the PSUR International Birth Date (IBD) so that the DSUR and thePSUR can be synchronised. In synchronising the data lock points for the DSUR andPSUR, the period covered by the next DSUR should be no longer than one year.The DSUR should be submitted to all concerned regulatory authorities no later than 60calendar days after the DSUR data lock point.2.3Duration of DSUR SubmissionsDSURs should continue to be submitted for as long as indicated by national or regionallaws or regulations. 8 When submission of an annual report is no longer required in anindividual country or region, the sponsor should indicate that the final DSUR serves asthe last annual report for the investigational drug in that country or region. The sponsorshould also indicate whether or not clinical trials are continuing elsewhere.2.4Responsibilities for Preparing and Submitting a DSUR2.4.1 Sponsor’s responsibilitiesThe sponsor* of a clinical trial is considered responsible for the preparation, content andsubmission of a DSUR. The sponsor can delegate the preparation of the DSUR to a thirdparty (e.g., a contract research organisation).In situations where the sponsor does not have access to the information to be included inspecific sections (e.g., sponsor-investigators* might not have information onmanufacturing issues, non-clinical data, and marketing status), this should be stated inthe DSUR.2.4.2 Responsibilities of Multiple PartiesWhen there is more than one sponsor of a clinical trial or drug development programme,the parties should arrange to prepare a single DSUR, if possible. This includessituations where a sponsor is in a formal co-development or licensing relationship withone or more partners, or where individual clinical trials or a drug developmentprogramme involve collaboration with public or private institutions, business partners,or other parties. Written agreements should be in place specifying how data will beexchanged and detailing the responsibilities for preparation and submission of theDSUR.When a single DSUR cannot be arranged, multiple sponsors can agree to prepareseparate DSURs for the same investigational drug. This can occur where differentindications, routes of administration, or formulations are being investigated by differentparties. In this situation, the rationale for separate DSURs should be provided in eachreport.For example, in the US, sponsors might keep an IND open even if no clinical trials are ongoingor planned. Annual reports are submitted for as long as the IND remains open.84
Development Safety Update Report2.5DSURs for Combination TherapiesGiven the potential complexities of clinical development involving combinatio
therapeutic use trials (Phase IV)); Therapeutic use of an investigational drug (e.g., expanded access programmes, compassionate use programmes, particular patient use, single patient INDs, and treatment IN
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