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The Implementation of ICH Development Safety Update Report (DSUR) Guidance

Angelo Tinazzi, profile picture
Angelo Tinazzi

The document summarizes a presentation about implementing the ICH Development Safety Update Report (DSUR) guidance. It discusses: - The background and overview of the new ICH DSUR guidance, including its history and key points. - Implications for study sponsors, including streamlining multiple reports into a single DSUR and establishing standardized processes. - Components of DSUR implementation, such as developing a clinical trials inventory, extracting and managing data, and mapping data for analysis outputs.

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Geneva Branch The Implementation of ICH Development Safety Update Report (DSUR) Guidance PhUSE SDE Switzerland Basel 28 / 06 /2013 Angelo Tinazzi Cytel Inc., Wilmington Del. USA Succursale de Meyrin – Geneva – Switzerland angelo.tinazzi@cytel.com
Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided  Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 2 Geneva Branch Geneva Branch
Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Type of Outputs to be provided  Use of CDISC principles Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 3 Geneva Branch Geneva Branch
4 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Geneva Branch Geneva Branch  Regular analysis of safety is crucial for the assessment of risk to trial subjects and to understand the riskbenefit of a medical product  PSUR (Periodic Safety Update Report) is for postmarketing periodic reporting  For medical product under development (IMP), some ICH countries required submission of periodic safety report  Differences in the content  Differences in the format  Differences in the timing (1) US IND Annual Report [21 CFR 312.33] (2) EU Annual Safety Report [2001/20/EC and ENTR/CT3] (3) Japan Investigational Product Serious / Infection Case Priodical Report’ – 6 monthly [PFSB 0229011 Feb 08 and 1001005 Oct 08] The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential 5 Background and Overview of the new ICH Guidance Overview and Benefits of new DSUR ICH Guidance - DSUR History ICH guideline E2F – Note for guidance on development safety update report: September 2010: Final adoption by CHMP September 2011: Date for coming into effect August 2011: FDA Guidance to industry document http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm073109.pdf ICH E2F DSUR EMA/CHMP/ICH/309348/2008 E2F Development Safety Update Reporrt FDA Aug 2011 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
Cytel Inc. - Confidential 6 Background and Overview of the new ICH Guidance Overview and Benefits of new DSUR ICH Guidance Geneva Branch Geneva Branch The DSUR is an annual review and evaluation of pertinent safety information related to an Investigational Medical Product, before and after marketing authorization  Safety information during the current review period  Analysis of new information based on previous knowledge of the product safety  Consistent regulatory terminology  Co-ordinated periodicity of reports  Same scope and content for same trials in different regions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
7 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Overview of new DSUR ICH Guidance – Key points Geneva Branch Geneva Branch The sponsor’s first authorization to conduct a clinical Development International trial in any country worldwide. It is used to determine the start of the annual period for DSUR Birth Date DIBD DLP The last day of the one-year reporting period Data Lock Point Scope Molecule Periodicity Once a year no more than 60 calendar days from DLP Information to be included Any completed and ongoing trials: • All Indications • All strenghts • All formulations • All patients populations PSUR Overlap PSUR and DSUR both needed when Clinical Trials continue after market approval The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
8 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Overview of new DSUR ICH Guidance – By-Period vs Cumulative Outputs (DLP-1yr)+1d DLP By-Period Outputs Only ‘events’ occurred in the reporting period (one year) DIBD DLP All ‘events’ occurred since DIBD up to DLP The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Cumulative Outputs Geneva Branch Geneva Branch
Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 9 Geneva Branch Geneva Branch
Cytel Inc. - Confidential 10 Implications for study sponsors Before DSUR  Multiple reports (e.g. one for FDA one for EMA)  Multiple database cleaning / extract  Multiple outputs programming tasks  Unclear requirements for outputs production  Last minute requests  No central coordination (e.g. from safety dept) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
Cytel Inc. - Confidential 11 Implications for study sponsors Detailed Process  Develop cross-functional SOPs / Process Guide  Track of projects requiring DSUR  Development International Birth Date (DIBD)  Countries / Regions requiring submission  Identification of Trials to be included  Clinical Trials Inventory  Outputs  Grouping of studies  Identification of Additional outputs/rules to be provided / followed  Outputs from SAE database  Standard mapping rules / outputs programs The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
12 Cytel Inc. - Confidential Implications for study sponsors The Clinical Trial Inventory Geneva Branch Geneva Branch  All «interventional» studies ph 1 to 4 sponsored by «sponsor XXX»  No observational studies  Corporate and non-corporate from all regions  Non corporate trials can be incorporated but usually provided by Medical Affairs  Planned vs Ongoing vs Completed study  Planned  Ongoing when the study was approved by any Health Authorities in or before the review period  Completed ICH-E2F: defined as “a trial for which a final CTR is available, so locked db and there is no further collection of data  Stratification factors (indication, formulation, etc.)  Key Contacts (CRO, DM, Trial Manager) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
13 Cytel Inc. - Confidential Implications for study sponsors Data Management Geneva Branch Geneva Branch  Retrieving/Extracting data for multiple studies  In-house / CRO / Investigator Trials  Other trials when the medical product is used in combination to other IMP(s)  Data cleaning/reconciliation as much as possible  Demography, Adverse Events, Exposure, Disposition, Deaths  SAE reconciliation  MedDRA version alignment not needed  Complete coding not needed The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
14 Cytel Inc. - Confidential Implications for study sponsors Possible Timeline Geneva Branch Geneva Branch DSUR author specify grouping / additional outputs / blinding List of CTRs DSUR Submission DIBD DLP Additional info from literature search Db Extract Individual Case Safety Report Safety and Stat Outputs Additional inputs and reviews +60d -1Yr -60d -35d -15d -1d 0 +2d Reporting Period 24JAN2012 23JAN2013 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 +7d +32d
Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 15 Geneva Branch Geneva Branch
16 Cytel Inc. - Confidential Implementation in Biostatistics Department Geneva Branch Geneva Branch  Clear process definition e.g. SOP  Technical Guidance  Global Derivation Rules  Standard Mapping  Outputs Templates including SAS Program Templates  Aligning differences in existing SAPs  Definition of Treatment Emergent AEs  Definition of Population e.g. Safety vs ITT Population  Blinding  Application of data cut-off / reporting period  Identification of new information from previous reporting period  Maintaining historical data (e.g. DSUR2012, DSUR2013, etc) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
17 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches Geneva Branch Geneva Branch Option 1 Pooled ADaM SDTM  Available in late stage projects when for example submission effort already occurred  Harmonization already occurred  Trial domains facilitate identification / reporting of trial characteristics The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
18 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches Geneva Branch Geneva Branch Option 2 Pooled ADaM Raw Db Light SDTM  The most common situation of early stage development projects or projects where CDISC investment did not yet occur  Light SDTM can be the start of the CDISC «effort»  TS (Trial Summary Datasets)  DM (Demographics), AE (Adverse Events), EX (Exposure), DSlight (light disposition) for deaths / end of treatment The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
19 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches Geneva Branch Geneva Branch Option 3 Pooled ADaM Raw Db  The most common situation of early stage development projects or projects where CDISC investment did not yet occur  Harmonisation effort directly in the pooled ADaM including Controlled Terminology The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential 20 Implementation in Biostatistics Department Data Mapping Approaches - ADaM Pooling - ASDL ADSL For the purpouse of DSUR:  Demographics  Arms/Treatments Grouping  Study Population  Trial Indication and additional stratification factors  Deaths and Disposition In addition  Compliance / Exposure (Subject Years) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
21 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches - ADaM Pooling - ADAE Geneva Branch Geneva Branch ADAE For the purpouse of DSUR:  Description including coding terms (PT and SOC)  Action Taken, Outcome, SAE, Severity  Drug (IMP) relationship  Treatment Emergent Identification  Imputation of partial start date as per company standard  AE started before first IMP administration and within xx days from last IMP drug administration (follow-up period). E.g. 50 days  Flag of events belonging to the reference period The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
22 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches - ADaM Pooling Standard Corporate ADaM requirements for DSUR - Additional Rules Geneva Branch Geneva Branch  Exposure (Subject-years)= sum for all subjects of [(min(last treatment admin date, end of reporting period) – first treatment admin date) +1] / 365.25  Compliance derivation depends on indication/type of therapy e.g. relative dose-intensity in oncology The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
23 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided Geneva Branch Geneva Branch Outputs to be provided from clinical trials database as an appendix 3a. Status of Ongoing and completed trials Cumulative 3b. Estimated cumulative exposure Cumulative 4a. Cumulative subject exposure to IMP by age and gender Cumulative 4b. Cumulative subject exposure to IMP by racial group Cumulative R2a. Tabulation of ongoing trials with number of subject drop out count Cumulative R2b. List of subject who died during the reporting period Period R2c. List of subject dropped out during the reporting period due to AE Period R3. Cumulative tabulation of AEs with frequency higher than 5% Cumulative SAE. Cumulative summary tabulation of serious adverse events Cumulative Compliance. Subject compliance to study drug in the reporting period Period Rxx, are applicable to US only The numeration above is the numeration choosen by one of our customer Study is always used as a ‘stratification’ factor The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential 24 Implementation in Biostatistics Department Type of Outputs to be Provided Depending on the status of the IMP development  Additional Stratifications  By Indication  By Dosage  Type of drug used in combination.  E.g. drugs containing a specific agent  Additional Outputs  Pooled adverse events tables  SMQ and other AEs of «potential» interest The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
25 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Geneva Branch Geneva Branch The table can be automatically created if SDTM is available (e.g from trial domain) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential 26 Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
27 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Geneva Branch Geneva Branch Example from a late stage development program with stratification by indication and type of combination therapy The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
28 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Example of Treatments Grouping in ADSL TRT01PN TRT01P 1 IMP 500 MG 2 IMP 1000 MG 3 IMP 1500 MG 4 IMP 1000 + TREATMENT WITH XX 5 IMP 1500 + TREATMENT WITH YY 6 IMP 2000 + TREATMENT WITH XX Geneva Branch Geneva Branch } Derived from ARMCD Use of standard ADaM ADSL variables TR01PG1/N to pool treatment 1=MONOTHERAPY 2=COMBINATION THERAPY TYPE A 3=COMBINATION THERAPY TYPE B The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential 29 Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Estimated=Blinded studies were allocated to ‘random dummy’ arm The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
Cytel Inc. - Confidential 30 Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
31 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Example / Templates Geneva Branch Geneva Branch Clear definition / rule to identify death if death form is not available e.g. AE with fatal outcome The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
32 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Example / Templates By-Period Outputs - Filtering for new «events» or events not yet in db at the time of previous DSUR (DLP-1yr)+1d DLP Only ‘events’ occurred in the reporting period (one year) • Some «events» (Drop-outs or deaths) may be not in db at the time of db extract • A new «event» is considered new if: • Occurred in the current DSUR reporting period • Not in db at the time of previous DSUR DSUR 2012 DSUR 2013 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 DSUR YYYY Geneva Branch Geneva Branch
33 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Example / Templates Geneva Branch Geneva Branch  Additional outputs for compliance  The way compliance is described depends on the indication and type of therapy  Estimated=Blinded studies were allocated to ‘random dummy’ arm The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
34 Cytel Inc. - Confidential Implementation in Biostatistics Department Case 1 – Late Stage Development Project Geneva Branch Geneva Branch  An oncology IMP with active ph 2/3 Trials  18 ongoing/closed trials  SDTM available for all trials  Because of several SDTM studies managed by the same CRO, cut-off and therefore reporting period was cut by one week  Reports provided by  Indications: NSCLC, Breast, Pancreatic Cancer  Type of Combination: Monotherapy, Combination Therapy 1, Combination Therapy 2  Identification of Adverse Events of Special Interest Data mapping approach option 1 was used The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
35 Cytel Inc. - Confidential Implementation in Biostatistics Department Case 2 – Early Stage Development Project Geneva Branch Geneva Branch  Only ph 1/2 Trials  6 ongoing/closed trials  SDTM not available for all trials  Data Harmonisation entirely performed in ADaM  Healthy volunteers ph 1 not included but reported separately  Reports provided by  Dose level of the sponsor IMP  Blinded studies  A dummy randomisatiom arm was used Data mapping approach option 3 was used The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 36 Geneva Branch Geneva Branch
37 Cytel Inc. - Confidential Conclusions Geneva Branch Geneva Branch  The new DSUR ICH guidance requires more information / effort than its predecessors  The new process can be challenging as it requires involvement of several functions and definition of a clear centrally coordinated process  Use of CDISC principles facilitate harmonisation / dataintegration. The DSUR can be seen as a ‘pilot’ for data integration of a medical product  SDTM delivery may delay / change internal timeline  Once implemented it is «easy» to repeat (subsequent DSURs) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
38 Cytel Inc. - Confidential References & Acknowledgments Geneva Branch Geneva Branch Development Safety Update Report E2F, Step 4 Version 17 August 2010 (http://www.ich.org/products/guidelines/efficacy/efficacysingle/article/development-safety-update-report.html) Adapt and Survive: Implementing the new ICH Development Safety Update Report (DSUR) - P.Gerend R.Sharma – PharmaSUG 2012 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
39 Cytel Inc. - Confidential Questions Geneva Branch Geneva Branch Cytel’s mission is to improve success rates in the development of drugs, biologics and medical devices. We do this by improving clinical trials through innovative application of statistical and data management science. We are leaders in adaptive trial design and implementation. All 25 leading biopharma companies rely on our technology in their clinical studies. www.cytel.com The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential 40 Geneva Branch Geneva Branch Backup Slides The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
41 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Geneva Branch Geneva Branch Background – US IND vs EU Annual Safety Report US-IND EU-ASR  US IND Annual Report [21 CFR 312.33] authorization of a Based on the IND anniversary date Based on the first (DIBD) of the IMP clinical trial of an IMP by authority in [2001/20/EC and ENTR/CT3] any EU member state  EU Annual Safety Report Benefit-risk assessment Progress Report  Japan Investigational Product Serious / Infection Case (Cumulative data from DIBD) Priodical Report’ – Indication (Period under review) monthly [PFSB 0229011 Molecule 6 and Annual 1001005 Oct 08] Feb 08 Annual or on request FDA EU member state authorities Independent Ethics Committees All SAEs All Serious ARs Narrative or Tabular summary of most frequent AEs List of deaths and drop-outs List completed/Non-Completed studies Coincise global analysis All new and relevant findings in the period The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
42 Cytel Inc. - Confidential Implications for data management / biometrics departments Geneva Branch Geneva Branch Use of CDISC Principles – Standard Corporate ADaM requirements for DSUR - ADSL Notes to programmer: • If no Death page is available, but AE/SAE with outcome “fatal” are present in the data base, the DTHDT should be derived based on AE start/end dates • ** If no Death page is available, but AE/SAE with outcome “fatal” are present in the data base, the DTHREAS should be derived as AE MedDRA Preffered Term • Variables STUDYIDN: “Study Identifier (N)”, STRFR1 “Stratification Factor 1”, STRFR1N “Stratification Factor 1 (N)” could be added into data set ADSL if required for programming of outputs The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
Cytel Inc. - Confidential Implications for data management / biometrics departments Use of CDISC Principles – Standard Corporate ADaM requirements for DSUR - ADAE TRTEMFL The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 43 Geneva Branch Geneva Branch

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The Implementation of ICH Development Safety Update Report (DSUR) Guidance

  • 1. Geneva Branch The Implementation of ICH Development Safety Update Report (DSUR) Guidance PhUSE SDE Switzerland Basel 28 / 06 /2013 Angelo Tinazzi Cytel Inc., Wilmington Del. USA Succursale de Meyrin – Geneva – Switzerland angelo.tinazzi@cytel.com
  • 2. Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided  Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 2 Geneva Branch Geneva Branch
  • 3. Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Type of Outputs to be provided  Use of CDISC principles Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 3 Geneva Branch Geneva Branch
  • 4. 4 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Geneva Branch Geneva Branch  Regular analysis of safety is crucial for the assessment of risk to trial subjects and to understand the riskbenefit of a medical product  PSUR (Periodic Safety Update Report) is for postmarketing periodic reporting  For medical product under development (IMP), some ICH countries required submission of periodic safety report  Differences in the content  Differences in the format  Differences in the timing (1) US IND Annual Report [21 CFR 312.33] (2) EU Annual Safety Report [2001/20/EC and ENTR/CT3] (3) Japan Investigational Product Serious / Infection Case Priodical Report’ – 6 monthly [PFSB 0229011 Feb 08 and 1001005 Oct 08] The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 5. Cytel Inc. - Confidential 5 Background and Overview of the new ICH Guidance Overview and Benefits of new DSUR ICH Guidance - DSUR History ICH guideline E2F – Note for guidance on development safety update report: September 2010: Final adoption by CHMP September 2011: Date for coming into effect August 2011: FDA Guidance to industry document http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm073109.pdf ICH E2F DSUR EMA/CHMP/ICH/309348/2008 E2F Development Safety Update Reporrt FDA Aug 2011 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 6. Cytel Inc. - Confidential 6 Background and Overview of the new ICH Guidance Overview and Benefits of new DSUR ICH Guidance Geneva Branch Geneva Branch The DSUR is an annual review and evaluation of pertinent safety information related to an Investigational Medical Product, before and after marketing authorization  Safety information during the current review period  Analysis of new information based on previous knowledge of the product safety  Consistent regulatory terminology  Co-ordinated periodicity of reports  Same scope and content for same trials in different regions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 7. 7 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Overview of new DSUR ICH Guidance – Key points Geneva Branch Geneva Branch The sponsor’s first authorization to conduct a clinical Development International trial in any country worldwide. It is used to determine the start of the annual period for DSUR Birth Date DIBD DLP The last day of the one-year reporting period Data Lock Point Scope Molecule Periodicity Once a year no more than 60 calendar days from DLP Information to be included Any completed and ongoing trials: • All Indications • All strenghts • All formulations • All patients populations PSUR Overlap PSUR and DSUR both needed when Clinical Trials continue after market approval The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 8. 8 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Overview of new DSUR ICH Guidance – By-Period vs Cumulative Outputs (DLP-1yr)+1d DLP By-Period Outputs Only ‘events’ occurred in the reporting period (one year) DIBD DLP All ‘events’ occurred since DIBD up to DLP The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Cumulative Outputs Geneva Branch Geneva Branch
  • 9. Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 9 Geneva Branch Geneva Branch
  • 10. Cytel Inc. - Confidential 10 Implications for study sponsors Before DSUR  Multiple reports (e.g. one for FDA one for EMA)  Multiple database cleaning / extract  Multiple outputs programming tasks  Unclear requirements for outputs production  Last minute requests  No central coordination (e.g. from safety dept) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 11. Cytel Inc. - Confidential 11 Implications for study sponsors Detailed Process  Develop cross-functional SOPs / Process Guide  Track of projects requiring DSUR  Development International Birth Date (DIBD)  Countries / Regions requiring submission  Identification of Trials to be included  Clinical Trials Inventory  Outputs  Grouping of studies  Identification of Additional outputs/rules to be provided / followed  Outputs from SAE database  Standard mapping rules / outputs programs The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 12. 12 Cytel Inc. - Confidential Implications for study sponsors The Clinical Trial Inventory Geneva Branch Geneva Branch  All «interventional» studies ph 1 to 4 sponsored by «sponsor XXX»  No observational studies  Corporate and non-corporate from all regions  Non corporate trials can be incorporated but usually provided by Medical Affairs  Planned vs Ongoing vs Completed study  Planned  Ongoing when the study was approved by any Health Authorities in or before the review period  Completed ICH-E2F: defined as “a trial for which a final CTR is available, so locked db and there is no further collection of data  Stratification factors (indication, formulation, etc.)  Key Contacts (CRO, DM, Trial Manager) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 13. 13 Cytel Inc. - Confidential Implications for study sponsors Data Management Geneva Branch Geneva Branch  Retrieving/Extracting data for multiple studies  In-house / CRO / Investigator Trials  Other trials when the medical product is used in combination to other IMP(s)  Data cleaning/reconciliation as much as possible  Demography, Adverse Events, Exposure, Disposition, Deaths  SAE reconciliation  MedDRA version alignment not needed  Complete coding not needed The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 14. 14 Cytel Inc. - Confidential Implications for study sponsors Possible Timeline Geneva Branch Geneva Branch DSUR author specify grouping / additional outputs / blinding List of CTRs DSUR Submission DIBD DLP Additional info from literature search Db Extract Individual Case Safety Report Safety and Stat Outputs Additional inputs and reviews +60d -1Yr -60d -35d -15d -1d 0 +2d Reporting Period 24JAN2012 23JAN2013 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 +7d +32d
  • 15. Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 15 Geneva Branch Geneva Branch
  • 16. 16 Cytel Inc. - Confidential Implementation in Biostatistics Department Geneva Branch Geneva Branch  Clear process definition e.g. SOP  Technical Guidance  Global Derivation Rules  Standard Mapping  Outputs Templates including SAS Program Templates  Aligning differences in existing SAPs  Definition of Treatment Emergent AEs  Definition of Population e.g. Safety vs ITT Population  Blinding  Application of data cut-off / reporting period  Identification of new information from previous reporting period  Maintaining historical data (e.g. DSUR2012, DSUR2013, etc) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 17. 17 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches Geneva Branch Geneva Branch Option 1 Pooled ADaM SDTM  Available in late stage projects when for example submission effort already occurred  Harmonization already occurred  Trial domains facilitate identification / reporting of trial characteristics The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 18. 18 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches Geneva Branch Geneva Branch Option 2 Pooled ADaM Raw Db Light SDTM  The most common situation of early stage development projects or projects where CDISC investment did not yet occur  Light SDTM can be the start of the CDISC «effort»  TS (Trial Summary Datasets)  DM (Demographics), AE (Adverse Events), EX (Exposure), DSlight (light disposition) for deaths / end of treatment The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 19. 19 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches Geneva Branch Geneva Branch Option 3 Pooled ADaM Raw Db  The most common situation of early stage development projects or projects where CDISC investment did not yet occur  Harmonisation effort directly in the pooled ADaM including Controlled Terminology The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 20. Cytel Inc. - Confidential 20 Implementation in Biostatistics Department Data Mapping Approaches - ADaM Pooling - ASDL ADSL For the purpouse of DSUR:  Demographics  Arms/Treatments Grouping  Study Population  Trial Indication and additional stratification factors  Deaths and Disposition In addition  Compliance / Exposure (Subject Years) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 21. 21 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches - ADaM Pooling - ADAE Geneva Branch Geneva Branch ADAE For the purpouse of DSUR:  Description including coding terms (PT and SOC)  Action Taken, Outcome, SAE, Severity  Drug (IMP) relationship  Treatment Emergent Identification  Imputation of partial start date as per company standard  AE started before first IMP administration and within xx days from last IMP drug administration (follow-up period). E.g. 50 days  Flag of events belonging to the reference period The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 22. 22 Cytel Inc. - Confidential Implementation in Biostatistics Department Data Mapping Approaches - ADaM Pooling Standard Corporate ADaM requirements for DSUR - Additional Rules Geneva Branch Geneva Branch  Exposure (Subject-years)= sum for all subjects of [(min(last treatment admin date, end of reporting period) – first treatment admin date) +1] / 365.25  Compliance derivation depends on indication/type of therapy e.g. relative dose-intensity in oncology The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 23. 23 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided Geneva Branch Geneva Branch Outputs to be provided from clinical trials database as an appendix 3a. Status of Ongoing and completed trials Cumulative 3b. Estimated cumulative exposure Cumulative 4a. Cumulative subject exposure to IMP by age and gender Cumulative 4b. Cumulative subject exposure to IMP by racial group Cumulative R2a. Tabulation of ongoing trials with number of subject drop out count Cumulative R2b. List of subject who died during the reporting period Period R2c. List of subject dropped out during the reporting period due to AE Period R3. Cumulative tabulation of AEs with frequency higher than 5% Cumulative SAE. Cumulative summary tabulation of serious adverse events Cumulative Compliance. Subject compliance to study drug in the reporting period Period Rxx, are applicable to US only The numeration above is the numeration choosen by one of our customer Study is always used as a ‘stratification’ factor The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 24. Cytel Inc. - Confidential 24 Implementation in Biostatistics Department Type of Outputs to be Provided Depending on the status of the IMP development  Additional Stratifications  By Indication  By Dosage  Type of drug used in combination.  E.g. drugs containing a specific agent  Additional Outputs  Pooled adverse events tables  SMQ and other AEs of «potential» interest The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 25. 25 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Geneva Branch Geneva Branch The table can be automatically created if SDTM is available (e.g from trial domain) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 26. Cytel Inc. - Confidential 26 Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 27. 27 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Geneva Branch Geneva Branch Example from a late stage development program with stratification by indication and type of combination therapy The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 28. 28 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Example of Treatments Grouping in ADSL TRT01PN TRT01P 1 IMP 500 MG 2 IMP 1000 MG 3 IMP 1500 MG 4 IMP 1000 + TREATMENT WITH XX 5 IMP 1500 + TREATMENT WITH YY 6 IMP 2000 + TREATMENT WITH XX Geneva Branch Geneva Branch } Derived from ARMCD Use of standard ADaM ADSL variables TR01PG1/N to pool treatment 1=MONOTHERAPY 2=COMBINATION THERAPY TYPE A 3=COMBINATION THERAPY TYPE B The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 29. Cytel Inc. - Confidential 29 Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates Estimated=Blinded studies were allocated to ‘random dummy’ arm The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 30. Cytel Inc. - Confidential 30 Implementation in Biostatistics Department Type of Outputs to be Provided – Examples / Templates The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 Geneva Branch Geneva Branch
  • 31. 31 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Example / Templates Geneva Branch Geneva Branch Clear definition / rule to identify death if death form is not available e.g. AE with fatal outcome The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 32. 32 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Example / Templates By-Period Outputs - Filtering for new «events» or events not yet in db at the time of previous DSUR (DLP-1yr)+1d DLP Only ‘events’ occurred in the reporting period (one year) • Some «events» (Drop-outs or deaths) may be not in db at the time of db extract • A new «event» is considered new if: • Occurred in the current DSUR reporting period • Not in db at the time of previous DSUR DSUR 2012 DSUR 2013 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 DSUR YYYY Geneva Branch Geneva Branch
  • 33. 33 Cytel Inc. - Confidential Implementation in Biostatistics Department Type of Outputs to be Provided – Example / Templates Geneva Branch Geneva Branch  Additional outputs for compliance  The way compliance is described depends on the indication and type of therapy  Estimated=Blinded studies were allocated to ‘random dummy’ arm The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 34. 34 Cytel Inc. - Confidential Implementation in Biostatistics Department Case 1 – Late Stage Development Project Geneva Branch Geneva Branch  An oncology IMP with active ph 2/3 Trials  18 ongoing/closed trials  SDTM available for all trials  Because of several SDTM studies managed by the same CRO, cut-off and therefore reporting period was cut by one week  Reports provided by  Indications: NSCLC, Breast, Pancreatic Cancer  Type of Combination: Monotherapy, Combination Therapy 1, Combination Therapy 2  Identification of Adverse Events of Special Interest Data mapping approach option 1 was used The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 35. 35 Cytel Inc. - Confidential Implementation in Biostatistics Department Case 2 – Early Stage Development Project Geneva Branch Geneva Branch  Only ph 1/2 Trials  6 ongoing/closed trials  SDTM not available for all trials  Data Harmonisation entirely performed in ADaM  Healthy volunteers ph 1 not included but reported separately  Reports provided by  Dose level of the sponsor IMP  Blinded studies  A dummy randomisatiom arm was used Data mapping approach option 3 was used The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 36. Cytel Inc. - Confidential Agenda  Background and Overview of the new ICH Guidance  Implications for study sponsors  Detailed process  Timeline  The Clinical Trials Inventory  Data-Management  Implementation in Biostatistics Department  Data Mapping Approaches  Type of Outputs to be provided Conclusions The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 36 Geneva Branch Geneva Branch
  • 37. 37 Cytel Inc. - Confidential Conclusions Geneva Branch Geneva Branch  The new DSUR ICH guidance requires more information / effort than its predecessors  The new process can be challenging as it requires involvement of several functions and definition of a clear centrally coordinated process  Use of CDISC principles facilitate harmonisation / dataintegration. The DSUR can be seen as a ‘pilot’ for data integration of a medical product  SDTM delivery may delay / change internal timeline  Once implemented it is «easy» to repeat (subsequent DSURs) The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 38. 38 Cytel Inc. - Confidential References & Acknowledgments Geneva Branch Geneva Branch Development Safety Update Report E2F, Step 4 Version 17 August 2010 (http://www.ich.org/products/guidelines/efficacy/efficacysingle/article/development-safety-update-report.html) Adapt and Survive: Implementing the new ICH Development Safety Update Report (DSUR) - P.Gerend R.Sharma – PharmaSUG 2012 The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 39. 39 Cytel Inc. - Confidential Questions Geneva Branch Geneva Branch Cytel’s mission is to improve success rates in the development of drugs, biologics and medical devices. We do this by improving clinical trials through innovative application of statistical and data management science. We are leaders in adaptive trial design and implementation. All 25 leading biopharma companies rely on our technology in their clinical studies. www.cytel.com The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 40. Cytel Inc. - Confidential 40 Geneva Branch Geneva Branch Backup Slides The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 41. 41 Cytel Inc. - Confidential Background and Overview of the new ICH Guidance Geneva Branch Geneva Branch Background – US IND vs EU Annual Safety Report US-IND EU-ASR  US IND Annual Report [21 CFR 312.33] authorization of a Based on the IND anniversary date Based on the first (DIBD) of the IMP clinical trial of an IMP by authority in [2001/20/EC and ENTR/CT3] any EU member state  EU Annual Safety Report Benefit-risk assessment Progress Report  Japan Investigational Product Serious / Infection Case (Cumulative data from DIBD) Priodical Report’ – Indication (Period under review) monthly [PFSB 0229011 Molecule 6 and Annual 1001005 Oct 08] Feb 08 Annual or on request FDA EU member state authorities Independent Ethics Committees All SAEs All Serious ARs Narrative or Tabular summary of most frequent AEs List of deaths and drop-outs List completed/Non-Completed studies Coincise global analysis All new and relevant findings in the period The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 42. 42 Cytel Inc. - Confidential Implications for data management / biometrics departments Geneva Branch Geneva Branch Use of CDISC Principles – Standard Corporate ADaM requirements for DSUR - ADSL Notes to programmer: • If no Death page is available, but AE/SAE with outcome “fatal” are present in the data base, the DTHDT should be derived based on AE start/end dates • ** If no Death page is available, but AE/SAE with outcome “fatal” are present in the data base, the DTHREAS should be derived as AE MedDRA Preffered Term • Variables STUDYIDN: “Study Identifier (N)”, STRFR1 “Stratification Factor 1”, STRFR1N “Stratification Factor 1 (N)” could be added into data set ADSL if required for programming of outputs The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013
  • 43. Cytel Inc. - Confidential Implications for data management / biometrics departments Use of CDISC Principles – Standard Corporate ADaM requirements for DSUR - ADAE TRTEMFL The Implementation of ICH Development Safety Update Report (DSUR) Guidance– A. Tinazzi – PhUSE SDE Switzerland – Basel 28/06/2013 43 Geneva Branch Geneva Branch