The views expressed here are of those of the author and do not reflect official policies or positions of any agency

Use It Right Away LING CHIN, MD, MPH President and Medical Director GDU Clinical Trials Consulting, LLC Previous: Head of Safety and Pharmacovigilance, NIAID/DAIDS Chief, Clinical and Translational Research, NIDCD Medical Officer, Division of OTC Products, FDA/CDER The views expressed here are of those of the author and do not reflect official policies or positions of any agency 1

Introduction Data Acquisition CDISC CDASH Model SAE Standard Conclusion Making the Case Drug Causality Information must be robust Complete Comprehensive Adequate detail for review Introduce SAE Standard Model to improve signal detection 2

Introduction Data Acquisition CDISC CDASH Model SAE Standard Conclusion Site Level: SAE Data Capture 3

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6 Introduction Data Acquisition/ Reporting CDISC CDASH Model SAE Standard Conclusion EDC, Electronic Reporting of SAEs Electronic Data Capture Data acquisition forms standardized Safety data: SAE and AE are linked Minimize duplication Efficient reconciliation Utilize data standards Electronic Reporting Site to Sponsor: SAE Form Sponsor to Regulatory Authority: ICH E2B (R2): Specifies data elements for transmission of Individual Case Safety Reports Feb 2001 ICH E2B (R3): Electronic transmission of individual case safety reports (ICSRs) - implementation guide - data elements and message specification Mar 2012 Comments

7 Introduction Data Acquisition/ Reporting CDISC Model SAE Standard Conclusion Clinical Data Interchange Standards Consortium Global, open, multidisciplinary, neutral, non-profit standards developing organization (SDO) [1997] Mission: develop global standards to streamline medical research and ensure a link with healthcare via consensus-based collaborative teams platform-independent, enable information system interoperability CDISC has developed a suite of standards to support medical research of any type from protocol through analysis and reporting of results harmonized through a model that is a CDISC standard, also an HL7 standard on the path to becoming an ISO/CEN standard, thus giving the CDISC standards (harmonized together through BRIDG) international status and accreditation

Global Content Standards for Clinical Research (Protocol-driven Research; Protocol Reporting) Protocol Study Design Eligibility Registration Schedule (PR Model) Harmonized through BRIDG Model** Controlled Terminology (NCI-EVS) Glossary FDA Critical Path Initiative Case Report Forms (CRF) (CDASH) Study Data Lab Data (LAB and PGx) FDA esubmissions Analysis and Reporting Tabulated CRF data (SDTM) Study Data Lab Data Study Design Analysis Datasets (ADaM) * Slide courtesy: CDISC 2013 ** CDISC, ISO, HL7 Standard *Transport: CDISC ODM, SASXPT and/or HL7

Introduction Data Acquisition/ Reporting CDISC CDASH Model SAE Standard Conclusion Clinical Data Acquisition Standards Harmonization Basic Concepts of CDASH: Provide minimal core dataset for clinical research Standardize the questions/fields on CRFs Standardize the variables and harmonize with SDTM (CDASH is a subset of SDTM) Collect data using standard CDISC controlled terminology (maps into SDTM) 9 CDASH-SAE Standard is an enhancement to the current CDASH-AE Domain (within the CDASH Standard) The intent is to provide for the collection of information necessary to describe SAEs (in conformance w E2B format) To facilitate data collection at site Slide courtesy: CDISC 2013

Introduction Data Acquisition/ Reporting CDISC CDASH SAE Tables Model SAE Standard Conclusion Series of tables for all of the data elements necessary to complete SAE Form (E2B message) Question Text Prompt E2B Variable Name What is the sex of the patient? What is the date adverse event/ reaction/ became serious? 10 Patient sex Serious adverse event/ reaction/ start date E2B Data Element SDTM or CDASH Variable Names* patientsex B.1.5 SEX Patient Sex reactionstart date B.2.i.4b SAESTDAT Date the adverse event became serious Definition Controlled Terminology *Use SDTM variable names if exist *Create CDASH variable names if SDTM does not specify {SEX} ISO 8601 SAE Form Completion Instructions Record the appropriate sex (e.g., F (female), M (male) Enter the date the adverse event became serious

Introduction Data Acquisition/ Reporting CDISC CDASH E2B Model Conclusion ICH E2B (R2) Guideline 11

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B.2.i.0 Reaction/event as reported by the primary source B.2.i.1 Reaction/event in MedDRA terminology (Lowest Level Term) B.2.i.2 Reaction/event MedDRA term (Preferred Term) B.2.i.3 Term highlighted by the reporter B.2 Reaction(s)/event(s) B.2.i.4 Date of start of reaction/event B.2.i.5 Date of end of reaction/event B.2.i.6 Duration of reaction/event B.2.i.7 Time intervals between suspect drug administration and start of reaction/event B.2.i.8 Outcome of reaction/event at the time of last observation B.2.i.7.1 Time interval between beginning of suspect drug administration and start of reaction/event B.2.i.7.2 Time interval between last dose and start of reaction/event 13

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B.4.k.1 Characterization of drug role B.4.k.2 Drug identification B.4.k.3 Batch/lot number B.4.k.4 Holder and authorization/application number of drug product name B.4.k.2.2 Active substance name(s) B.4.k.2.3 Identification of the country where the drug was obtained B.4.k.4.1 Authorization/Application Number B.4.k.4.2 Country of authorization/application B.4.k.4.3 Name of holder/applicant 15 B.4 Drug(s) information B.4.k.5 Structured Dosage Information B.4.k.6 Dosage text B.4.k.7 Pharmaceutical form (Dosage form) B.4.k.8 Route of administration B.4.k.9 Parent route of administration (in case of a parent child/fetus report) B.4.k.10 Gestation period at time of exposure B.4.k.11 Indication for use in the case B.4.k.12 Date of start of drug B.4.k.13 Time intervals between drug administration and start of reaction/event B.4.k.14 Date of last administration B.4.k.15 Duration of drug administration B.4.k.16 Action(s) taken with drug B.4.k.17 Effect of rechallenge (or re-exposure), for suspect drug(s) B.4.k.18 Relatedness only of drug to reaction(s)/event(s) (repeat B.4.k.18.1 through B.4.k.18.4 as necessary) B.4.k.19 Additional information on drug B.4.k.5.1 dose (number) B.4.k.5.2 dose (unit) B.4.k.5.3 number of separate dosages B.4.k.5.4 number of units in the interval B.4.k.5.5 definition of the interval unit day B.4.k.5.6 cumulative dose to first reaction (number) B.4.k.5.7 cumulative dose to first reaction (unit) B.4.k.13.1 Time interval between beginning of drug administration and start of reaction/event B.4.k.13.2 Time interval between last dose of drug and start of reaction/event B.4.k.18.1 Reaction assessed B.4.k.18.2 Source of assessment B.4.k.18.3 Method of assessment B.4.k.18.4 Result

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Introduction Data Acquisition/ Reporting CDISC CDASH Model SAE Standard Conclusion Narrative Narrative section aids/tools: Content specification Sample template Include all information that is relevant for a complete understanding of the event/reaction, and allow for a causality assessment of the product 17

This is a [Age] year old [Race] [Male/Female] in [Study] who reported [Primary AE] on [Date of AE]. The subject was enrolled into study on [Date Enrolled]. Study medication was started on [Date] at [Dose], which is [Study Day _/Week _], taken for [Duration]. Include all changes in dose and frequency. The event occurred during the [Screening/Treatment/Follow-up] Phase. If fetus: provide [Gestational Age], (or mother s LMP), at time of event. Also, [Gestational Age/Trimester] at first drug exposure and duration of exposure. If birth, provide details of [Infant Status] at birth. If hospital stay is complicated, provide details of hospital stay. Provide details of the [SAE] in chronological order, along with other [Signs/Symptoms]. Start with date (and time, if relevant) and description of signs and symptoms; provide details of [Physical Exam], along with all relevant [Procedures] and [Lab Results]. Specify the diagnosis that was made based on symptoms and test results. Specify the seriousness criteria that apply for the SAE and the dates when the seriousness criteria apply. If hospitalization, provide [Dates Hospitalization], describe relevant [Hospital Course], and any additional [Diagnostic Work-up], [Procedures/Tests and Results]. If lifethreatening, specify the measures that were taken for the immediately life-threatening situation. If death, report date of death and cause of death, including autopsy or post-mortem findings when available. If medically significant, provide a rationale for the medical significance. Provide details of [Treatment] and [Treatment Rationale] on basis of [Findings/Test Result(s)]. Describe [Treatment Response]. Include Dechallenge/Rechallenge information. Provide [Outcome/Discharge Diagnosis], and any [Follow-up Information]. List [Discharge Meds]. If fatal outcome, [Cause of Death] and provide all relevant information and include records, such as autopsy report. Provide pertinent [Past Medical Hx], [Family Hx], [Concomitant Meds], [Alcohol/Tobacco/Substance Use] and any previous similar [AEs]. 18 Provide assessment of causality and rationale for the conclusion.

19 Introduction Data Acquisition/ Reporting CDISC CDASH Narrative Structure Model SAE Standard Conclusion Adverse Event: Intro statement about subject i.e. Age, Sex, AE Term Full focused, factual, and clear description of reaction(s), including body site and severity Description of the reported signs and symptoms Setting (e.g., hospital, out-patient clinic, home, nursing home) Specific diagnosis for the reaction Onset date (and time) of reaction Stop date (and time) or duration of reaction Dechallenge and rechallenge information Evaluation and Investigations: Full description of the workup including history and physical exam All relevant laboratory data All relevant diagnostic tests and results Intervention Regarding the Adverse Event: Treatment provided or required to mitigate medical consequences Did treatment have to be provided in a hospital setting? Response to treatment

Introduction Data Acquisition/ Reporting CDISC CDASH Narrative Structure Model SAE Standard Conclusion Outcome of the Adverse Event Non-Fatal: Did the event resolve Did the subject recover Was there any sequelae Fatal: Stated cause of death Relevant autopsy or post-mortem findings, including coroner s report If unknown, perform due diligence to obtain necessary information to ascertain cause of death Other Information Provide all relevant information that can facilitate the assessment of the case such as medical history including allergies, drug or alcohol abuse; family history, social history; findings from special investigations Provide all concomitant medications. Include dosing details and indications 20

Introduction Data Acquisition/ Reporting CDISC CDASH Narrative Structure Model SAE Standard Conclusion Assessment By the reporter (investigator): Confirm possible diagnos(e)s For each diagnosis, determine the relatedness of the product to the reaction(s)/event(s) By the sender (sponsor): Provide comment or any other issues considered relevant Opportunity to combine signs and symptoms that were reported into a succinct diagnosis; include reasoning Confirm or describe disagreement with reporter s assessment If disagreement, provide alternatives to diagnos(e)s and/or causality conclusion(s) 21

Introduction Data Acquisition/ Reporting CDISC DASH Model SAE Standard Safety Report Illustration: Before Conclusion 22

23 Narrative Prompt I. Adverse Event: Intro subject Full description of reaction Signs and symptoms Setting Specific diagnosis Onset reaction Stop date reaction Dechallenge/ rechallenge II. Evaluation: Full workup, including H&P All relevant labs All relevant tests Narrative Text 51 y.o HIV infected Caucasian female, found dead at home on 2/8/12. Enrolled 11/1/10, started on study agents (emtricitabine/tenofovir/ ritonavir-boosted darunavir). On regimen for 1 year. Ritonavir/darunavir switched to raltegravir on 11/15/11 because of side effects. Started on Hep C treatment on 1/15/12 with peg-interferon and ribavirin. On 12/26/11, seen by psychiatrist for sadness, crying, anhedonia, depression, irritability, and hopelessness, diagnosed as mood disorder; started on valproic acid and fluoxetine. On 2/1/12, overdosed on fluoxetine, valproic acid, and amitriptyline. On 2/2/12, taken to the emergency room with complaints of asthenia, dyspnea, and abdominal pain. Admitted with psych suicide monitoring. Given antibiotics and steroids. Deteriorated with worsening dyspnea. Placed on O 2 and monitored closely. At enrollment, HIV viral load was 70,000 copies/ml, CD4 count 475 cells/mm3. 12/26/11: HIV viral load was <40 copies/ml, CD4 count 628 cells/mm3 12/26/11: Hgb: 8.4 g/dl, ALT: 18 U/L, and AST: 18 U/L 2/2/12: Hgb: 2.7 g/dl, ALT: 418 U/L, AST: 483 U/L, and HCO3: 13.7 mmol/l Blood culture, toxicology tests, endoscopy, and EKG were performed. CXR: bilateral, interstitial, and alveolar diffuse infiltrates. Blood culture: unidentified gram-positive cocci. 2/4/12: Hgb of 8.8 g/dl post transfusion. 2/5/12: liver function tests and renal function tests returned to normal.

III. Intervention for AE: Treatment to mitigate medical consequences Hospitalization required? Treatment response IV. Outcome of the AE i. Non-Fatal: AE resolve/sequelae? Subject recover? ii. Fatal: Cause of death? Autopsy? V. Other Information All relevant information to facilitate the assessment, such as: medical history including allergies, drug or alcohol abuse; family history, social history; special investigations Conmeds: Include dosing, indications VI. Assessment i. By the reporter (site): ii. 24 By the sender (sponsor): 2/2/12: Started on IV sulfamethoxasole /trimethoprim, amoxicillin/clavulanate, and prednisone. Transfused with 4 units of packed red blood cells. On 2/4/12, azithromycin added. Respiratory status improved, back to room air On 2/5/12, counseling initiated. On 2/6/12, signed out AMA. On 2/6/12: afebrile, no respiratory distress. Psychiatric status not considered fully stable. Plan was for psych inpatient until stable to return home. 6/15/10: HIV diagnosis July/10: diagnosed with reactive depression, started on amitriptyline. August/10: attempted suicide by taking high doses of amitriptyline. Emphysema GERD Back pain from MVA Alcohol use Cocaine use Social stressors associated with the subject: HIV Infected by former husband Family rejection because of HIV-infection Job loss due to her HIV infection Divorced Con Meds: omeprazole 40 mg BID, oxycontin 20 mg BID, albuterol inhaler prn, peg-interferon 120 mcg SQ injection weekly, ribavirin 600 mg Qam, 400 mg Qpm. i. Site investigator: Suicide attempt NR to study drugs; PMH significant ii. Sponsor in agreement. Multiple risks present.

51 y.o HIV infected Caucasian female enrolled into study on 11/1/10. Started on HAART (emtricitabine/tenofovir/ritonavir -boosted darunavir) and was on this regimen for 1 year. Ritonavir/darunavir was switched to raltegravir on 11/15/11 because of side effects. Started on Hep C treatment on 1/15/12 with peg-interferon and ribavirin. On 2/8/12, found dead at home of unknown cause. 25

51 y.o HIV infected Caucasian female, found dead at home on 2/8/12E. Enrolled 11/1/10, started on study agents (emtricitabine/tenofovir/ritonavir-boosted darunavir). On regimen for 1 year. Ritonavir/darunavir switched to raltegravir on 11/15/11 because of side effects. Started on Hep C treatment on 1/15/12 with peg-interferon and ribavirin. On 12/26/11, seen by psychiatrist for sadness, crying, anhedonia, depression, irritability, and hopelessness, diagnosed as mood disorder; started on valproic acid and fluoxetine. On 2/1/12, overdosed on fluoxetine, valproic acid, and amitriptyline. On 2/2/12, taken to the emergency room with complaints of asthenia, dyspnea, and abdominal pain. Admitted with psych suicide monitoring. 2/2/12: Started on IV sulfamethoxasole /trimethoprim, amoxicillin/clavulanate, and prednisone. Deteriorated with worsening dyspnea. Placed on O2 and monitored closely. Transfused with 4 units of packed red blood cells. On 2/4/12, azithromycin added. Respiratory status improved, back to room air On 2/5/12, counseling initiated, but subject was unwilling to participate. On 2/6/12: afebrile, no respiratory distress. Psychiatric status not considered fully stable. Plan was for psych inpatient until stable to return home. Signed out AMA on 2/6/12 26

Labs and Investigations: At enrollment, HIV viral load was 70,000 copies/ml, CD4 count 475 cells/mm3. 12/26/11: HIV viral load was <40 copies/ml, CD4 count 628 cells/mm3 12/26/11: Hgb: 8.4 g/dl, ALT: 18 U/L, and AST: 18 U/L 2/2/12: Hgb: 2.7 g/dl, ALT: 418 U/L, AST: 483 U/L, and HCO3: 13.7 mmol/l Blood culture, toxicology tests, endoscopy, and EKG were performed. CXR: bilateral, interstitial, and alveolar diffuse infiltrates. Blood culture: unidentified gram-positive cocci. 2/4/12: Hgb of 8.8 g/dl post transfusion. 2/5/12: liver function tests and renal function tests returned to normal. PMH: 6/15/10: HIV diagnosis 1/15/12: Chronic Hep C diagnosis July/10: diagnosed with reactive depression, started on amitriptyline. August/10: attempted suicide by taking high doses of amitriptyline. Emphysema GERD Back pain from MVA Alcohol use since 1972 Powder Cocaine use in 70 s Social stressors associated with the subject: HIV Infected by former husband Family rejection Job loss Divorced Con Meds: omeprazole 40 mg BID, oxycontin 20 mg BID, albuterol inhaler prn, peg-interferon 120 mcg SQ injection weekly, ribavirin 600 mg Qam, 400 mg Qpm Assessments: i.site investigator: Suicide attempt NR to study drugs; PMH significant ii.sponsor in agreement. Multiple risks present. 27

Introduction B1 Data Acquisition/ Reporting CDISC CDASH E2B Model SAE Standard SAE Standard Model for DILI Patient characteristics e.g. pre-existing liver disease Conclusion B2 Reaction(s)/event(s) e.g. time course of the liver injury B3 B4 Tests and Investigations: Critical labs to indicate hepatocellular injury, altered liver function. Other labs to rule in alternate etiology e.g. hepatitis A, B, or C, biliary tract disorders, etc Drug(s) information: accurate extent of exposure to drug, dose, interval, total dose, etc 28 B5 Narrative case summary and further information: Detailed description of the course of the adverse event, labs/investigations to inform about the extent of the injury or to rule out DILI; i.e. explore differential diagnosis possibilities Other information: Significant PMH, other drugs/hepatotoxins

Introduction Data Acquisition/ Reporting CDISC CDASH E2B Model SAE Standard Conclusion Can and should expect Safety Reports of this caliber Incorporate SAE Standard into study development, planning, and implementation, to facilitate better data collection Expect qualified person to perform structured, systematic, clinical review of the SAE proper diagnosis, work up and evaluation differential diagnosis for causality necessary: either establish drug causality or substantiate an alternate etiology Upgrade safety training beyond filling out a form: investigators should have better understanding of rules and regulations for HSP, safety reporting considerations, SAE data standards 29

The End Thank You for Listening 30