GDS_0527792_ABT751_v1 1 20July2012 Site Initiation Visit 1Company Confidential © 2012 Abbott Concomitant Medications Abbott Oncology A Randomized Phase

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Site Initiation Visit1Company Confidential

© 2012 Abbott

Concomitant Medications

Abbott OncologyA Randomized Phase 2 Study of the Efficacy and Tolerability of Veliparib in Combination with Temozolomide or Veliparib in Combination with Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Subjects with BRCA1 or BRCA2 Mutation and Metastatic Breast Cancer

Protocol Amendment 1 dated 16/Mar/12

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Site Initiation VisitCompany Confidential© 2012 Abbott

2Company Confidential© 2012 Abbott

2Company Confidential© 2012 Abbott

Abbott Study M12-895 Site Initiation Visit Agenda

• Study Team Members

• Study Design and Population

• Compound Information - Veliparib

• Protocol

• Objectives• Eligibility• Medical History/Concomitant Medications• Study Visit Procedures• Study Medication• Subject Discontinuation and Survival Follow-up

• Safety Reporting

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Abbott Study M12-895 Site Initiation Visit Agenda (Cont.)

• Vendor Training

• Imaging (Perceptive)• Central Laboratory (ICON)

• Barcode Scanner• PD/PG/PK Sampling

• BRCA Testing (Myriad)• IVRS/IWRS (ClinPhone)• EDC (RAVE)

• Good Clinical Practice

• Investigator Responsibilities & General Study/Visit Information

• Q & A Session

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Study Design and Population

• Global study (16 countries)

• Approximately 255 subjects at approximately 85 sites

• Anticipated 13 month enrollment period

• Study population

• Men and women ≥ 18 years of age with measureable metastatic breast cancer and a documented BRCA1 or BRCA2 deleterious germline mutation who have received no more than one prior line of cytotoxic therapy for metastatic disease.

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Overall Study Design

Endpoints

Primary Endpoint

Progression Free SurvivalSecondary Endpoints

Overall SurvivalClinical Benefit Rate

Objective Response RateSafety and Tolerability

CIPN

Patient Population N = 85

N = 85

• Men and women≥ 18 years of age

• Measureable metastatic breast cancer

• Documented BRCA1 or BRCA2 deleterious germline mutation

40 mg Veliparib BID + Temozolomide

Ran

do

miz

atio

n 1

:1:1

Placebo + Carboplatin/Paclitaxel

N = 85

120 mg Veliparib BID + Carboplatin/Paclitaxel

80% power at two-sided = 0.05 assuming true HR 0.58

Primary analysis:150 PFS Events

Interim analyses: Safety: 36 subjects complete Week 18

Futility: 30 subjects on veliparib/TMZ complete Week 27 tumor assessment

Abbott Oncology

Veliparib (ABT-888)

Oral Poly(ADP-Ribose)Polymerase (PARP) Inhibitor

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PARP and DNA Damage Repair

• PARP biology– Activated on DNA damage

– Effects DNA repair

• PARP inhibition in cancer therapy

– Tumors often defective in DNA repair

• More sensitive to DNA damage

• More sensitive to PARP inhibition

– ↑ PARP is resistance mechanism

Adapted from Dawson et. al., (2004) Trends in Pharm Sciences 25, 259-64.

Measured in Biomarker ELISA

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ONH2

NH

N

NH

CH3

Potent Inhibitor

PARP-1, 2 Ki = 5, 3 nM

Cellular EC50 = 2 nM

Orally bioavailable

% Fhuman = > 80%

30% CV

Excellent pharmaceutical properties

BCS class 1

Low molecular weight

Highly soluble

Crosses BBB

Favorable metabolic profile

No Cyp inhibition

No Cyp induction

Not a PgP substrate

In vivo preclinical efficacy with:• Cisplatin• Carboplatin• Cyclophosphamide• Irinotecan• Topotecan• Temozolomide (TMZ)• Radiation

ABT-888: PARP Inhibitor

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PARPi Potentiates TMZ by a pathway not normally exploited by TMZ monotherapy

PARP inhibition restores tumor cell sensitivity to TMZ

(MMR defective, high MGMT expression)

{

MMR proficient + low DNA alkyltransferase{ G-T

mismatch

Adapted from Japtap and Szabo 2005 Nature Reviews/Drug Discovery

M12-895

Protocol Discussion

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Overview

• Objectives

• Eligibility Criteria

• Medical History/Concomitant Medications

• Study Visits and Procedures

• Study Medication

• Study Discontinuation and Survival Follow-up

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Study Objectives

• Primary• Progression Free Survival (PFS)

– Number of days from date of randomization to date of confirmed progression per RECIST 1.1 or date of death (if disease progression is not reached)

• Secondary• Overall Survival (OS)

– All subjects will be followed until the endpoint of death or until lost to follow-up or until study termination by Abbott

• Clinical Benefit Rate (CBR)– The proportion of subjects with at least SD (CR, PR, or SD) through the end of Week 18

• Objective Response Rate (ORR)– Proportion of subjects with confirmed complete or partial response per RECIST 1.1

• Chemotherapy-Induced Peripheral Neuropathy (CIPN)– As assessed by the EORTC QLQ-CIPN 20 questionnaire and NCI-CTCAE 4.0 grading for

peripheral Neuropathy in those subjects randomized to the veliparib/placebo + carboplatin + paclitaxel treatment arms

• Tertiary• Quality of Life (QoL)

– Assessed with subject completed questionnaires: EORTC QLQ-C15/BR23• Eastern Cooperative Oncology Group (ECOG) performance status

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Stratification Factors for Randomization

• Estrogen Receptor positive and/or Progesterone Receptor Positive versus Estrogen Receptor Negative and Progesterone Receptor Negative status

• Prior cytotoxic therapy versus no prior cytotoxic therapy

• ECOG status 0‑1 versus 2


Eligibility Criteria

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Inclusion CriteriaFor Selection of Subject Population with Sufficient Disease Severity

• Males and females ≥ 18 years of age

• Histologically or cytologically confirmed breast cancer with evidence of metastatic disease

• Documented deleterious BRCA1 or BRCA2 germline mutation

• The investigator should ensure that the testing is consistent with local guidelines, and clinical practice, and that the test uses either:

– Direct DNA sequencing/multiplex ligation-dependent probe amplification (MLPA); or– A well-characterized methodology previously validated by sequencing, such as that

used to assess founder mutations.

• If testing has been performed by a laboratory other than Sponsor core laboratory, subjects may be enrolled and must be re-tested by Sponsor core laboratory for confirmation of BRCA1 or BRCA2 germline mutations

• HER2-positive subjects must have progressed on at least one prior standard HER2-directed therapy or be ineligible to receive anti-HER2 therapy.

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Inclusion Criteria For Selection of Subject Population w/Sufficient Disease Severity (Cont.)

• Measurable lesion by RECIST 1.1 in at least 1 site that has not received prior radiotherapy, unless progression has been demonstrated in the lesion

• If only a single measurable lesion exists, it cannot be a bone or cystic lesion;

• Bone-only lymphangitic pulmonary mets & previously irradiated tumors without subsequent progression will be considered non-measurable;

• ECOG Performance status of 0 to 2

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Inclusion CriteriaFor Subject Safety and GCP

Renal FunctionSerum Creatinine OR

≤1.5 x ULN

Creatinine Clearance ≥50 mL/min/1.73m2

Bone MarrowANC ≥1,500/mm3 (1.5 x 109/L)Platelets ≥100,000 (100 x 109/L)

Hemoglobin ≥9.5 g/dL (1.4 mmol/L)

Leukocytes >3,000/mm3

Hepatic FunctionAST and/or ALT ≤2.5 x ULNAST and/or ALT

(subjects with liver mets)

<5 x ULN

Bilirubin ≤1.5 x ULN

Bilirubin

(subjects with Gilbert’s syndrome)

≥ 1.5 x ULN^

CoagulationaPTT* ≤1.5 x ULNINR* <1.5

*Subjects on anticoagulant therapy will have an appropriate activated partial thromboplastin time (aPTT) and INR as determined by the investigator

^If no evidence of biliary obstruction

• Willing to take appropriate measures to prevent pregnancy prior to study entry, during study and for 90 days following completion of study;

• Willing to comply with study and to sign the main IRB/EC informed consent

• Laboratory inclusion criteria:

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Exclusion CriteriaFor Safety of Subject

• Received anticancer agent(s), an investigational agent or radiotherapy, within 21 days prior to C1D1

• Prior treatment with palliative local breast or bone lesion radiation (other than pelvis) can occur, if administered at least 14 days prior to C1D1

• Subjects experiencing a significant adverse effect or toxicity (Grade 3 or 4), causally attributed to previous anticancer treatment that has not recovered to at least Grade 2 are excluded

• Anticancer hormonal therapy must be stopped 7 days before starting C1D1. Subjects receiving bisphosphonates or denosumab are eligible

• More than 1 prior line of cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, capecitabine) for metastatic disease

• Regimens received in the adjuvant/neoadjuvant setting within the past 6 months will also be considered towards the maximum of 1 prior line of therapy

• In order to count as a line of therapy, a cytotoxic agent must have been administered for at least 1 full cycle. Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal transduction agents, (e.g., trastuzumab, lapatinib, erlotinib, gefitinib, bevacizumab) are allowed and are not counted toward the prior line of therapy

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Exclusion CriteriaFor Safety of Subject (Cont.)

• Prior therapy with temozolomide, a platinum agent, or a PARP inhibitor

• Prior taxane therapy for metastatic disease

• Use of taxanes as adjuvant therapy is permitted, if given more than 6 months prior to C1D1

• A history of or evidence of brain metastases or leptomeningeal disease. Subjects with symptoms suggestive of CNS metastases should have a brain MRI within 21 days of enrollment to confirm the absence of CNS metastases. Contrast CT is acceptable for subjects who are unable to undergo a brain MRI

• History of uncontrolled seizure disorder

• Pre-existing neuropathy from any cause in excess of Grade 1

• Known history of allergic reaction to cremophor/paclitaxel

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Exclusion CriteriaFor Safety of Subject (Cont.)

• Clinically significant uncontrolled condition(s), including but not limited to:

• Active infection;• Symptomatic congestive heart failure;• Unstable angina pectoris or cardiac arrhythmia;• Myocardial infarction within last 6 months;• Psychiatric illness/social situations that would limit compliance with study

requirements; or• Any medical condition which in the opinion of the investigator places the

subject at an unacceptably high risk for toxicities

• Pregnant or breastfeeding

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Exclusion CriteriaFor Selection of Appropriate Subject Population

• Previous or concurrent cancer that is distinct in primary site or histology from metastatic breast cancer, except:

– Cervical carcinoma in situ– Non‑melanoma carcinoma of the skin, or– In situ carcinoma of the bladder

• Any cancer curatively treated > 3 years prior to entry is permitted; for these subjects, metastases must be histologically/cytologically confirmed breast cancer

Concomitant MedicationsMedical History and Concomitant Medications

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Key Medical History

• Clinically significant medical conditions

• History of tobacco and alcohol use

• Child bearing status

• Seizure history

• History of neuropathy

• Presence of any preexisting symptoms or recurring complaints

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Key Medical History Detailed Oncology History

• Date of primary cancer diagnosis

• Pathology (histology or cytology) of primary tumor

• Metastasis information (including the location and histological markers, if applicable)

• Prior treatments by line of therapy (including dates)• Cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, capecitabine, etc.)• Hormonal therapy (e.g., tamoxifen, aromatase inhibitors, etc.)• Signal transduction agents (e.g., trastuzumab, lapatinib, erlotinib, gefitinib,

bevacizumab)• Treatment with TMZ, taxanes, platinum agents, or PARP inhibitors

• Surgical history, including tumor resection

• Radiation treatments (including dates, location, and type of modality)

• History or symptoms of brain metastases or leptomeningeal disease

• History of allergic reaction to cremophor/paclitaxel

• Presence and severity of any symptoms/conditions associated with breast cancer

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Prior Therapy

• Antitumor treatment may be defined as, but not limited to, anticancer agents, radiotherapy, and investigational agents

• An investigational agent is any drug or therapy not currently approved for use in humans

Anticancer Agents:

• No more than one prior line of cytotoxic therapy

• Regimens received in the adjuvant/neoadjuvant setting within the past 6 months will also be included towards the maximum of 1 prior line of therapy

• Prior therapy with biologic agents including vaccines and immunostimulants are allowed

• Prior therapy with signal transduction agents such as EGFR/HER2-direct agents, are allowed and will not count toward prior lines of therapy

• Anticancer hormonal therapy is not permitted within 7 days prior to C1D1

Radiation:

• Prior treatment with radiation is allowed as long as the last treatment was at least 28 days prior to C1D1.

• Prior treatment with palliative local breast or bone lesion radiation (other than pelvis) can occur within 14 days of C1D1

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Concomitant Therapy

• Current medications or vaccines (over-the-counter, prescriptions, vitamins, and/or herbal supplements) will be collected at Screening, during study, and up to 30 days following last dose

• The locally approved product label, institutional guidelines, local practice, or applicable SPC for TMZ, carboplatin, and paclitaxel should be referenced for any concomitant therapy guidelines

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Concomitant Therapy - Allowed

Premedication:

• Prophylactic use of a 5-HT3-antagonist is strongly recommended before TMZ administration

• Additional prophylactic antiemetics may be given, as appropriate

• To reduce the severity of hypersensitivity reactions to paclitaxel, manage according to institutional guidelines, the locally approved product label, local practice, or applicable SPC (i.e., premedication with corticosteroids, diphenhydramine, and H2 antagonists)

Growth Factors:• Biologic response modifiers administered for erythropoiesis and

colony‑stimulating factors may be administered according to institutional or clinical practice guidelines – but not to be given prophalactically

Best Supportive Care:

• Should be given as appropriate. Includes antiemetics, antibiotics, transfusions, nutritional support, non-radiation palliative treatment for pain, bisphosphonates

• Prophylactic antimicrobials should be considered in subjects receiving concurrent immunosuppressive therapy and those with lymphopenia and continued until lymphopenia resolves

Surgery: • Surgery required during the study needs to be discussed with the Abbott Medical Monitor

Allowed during study:

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Concomitant Therapy – Not Allowed

Anticancer Agents: • Anticancer agents are not permitted during the treatment portion of the study. All subjects will receive carboplatin/paclitaxel with veliparib/placebo or temozolomide with veliparib during the treatment portion of the study. The locally approved carboplatin, paclitaxel, and temozolomide product labels or SmPCs should be referenced to determine if there are any contraindications associated with concomitant medications.

Radiation Therapy: • If needed to treat symptoms due to underlying breast cancer, the subject will be discontinued from the study

Alternate Therapy: • No anti-cancer Chinese medicine/herbal remedies may be taken concurrently with veliparib (a 14-day washout period must be documented)

Not allowed on study:


Study Visit Procedures

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Study Visit Procedure Timing

• Informed consent must be obtained prior any study procedure;

• Diagnosis of a deleterious BRCA1 or BRCA2 mutation must be documented prior to randomization and genetic risk assessment and counseling should proceed per NCCN guidelines or institutional standard policy;

• Screening procedures must be performed within 28 days prior to C1D1;

• Procedures performed at Screening will serve as baseline unless repeated on C1D1;

• Baseline radiographic assessment performed within 21 days prior to C1D1;

• Post Screening and C1D1 study procedures should be performed within 4 days surrounding the scheduled study visit date except labs

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Adverse Event Collection Period

SAEs occurring after the informed consent is signed but prior to the initial dose of investigational product will only be collected if they are considered by the Investigator to be causally related to study required procedures.

All serious and non-serious adverse events will be collected from time of study drug administration through 30 days post-therapy.

Consent Signed

SAEs SAEs and Non-Serious AEsElicited and/or Spontaneously Reported

Study Drug Start

Study Drug Stopped

30 Days after veliparib/placebo, TMZ, carboplatin or paclitaxel are

stopped

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Study Visit Procedures for Screening

• Medical and oncology history

• Complete physical exam (PE), including height and weight

• Vital signs (heart rate, blood pressure, and body temperature)

• ECOG performance status

• 12-lead ECG

• Routine Laboratory tests

• Hematology, chemistry, aPTT/INR, and urinalysis

• Serum pregnancy test

• CT scan (chest, abdomen and pelvis)

• Full body bone scan

• BRCA1 and BRCA2 germline mutation (unless BRCA germline mutation status is known per previous Sponsor core lab testing)

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Subject Number Assignment

• IVRS/IWRS must be contacted to obtain the subject (screening) number once subject has signed the informed consent AND before a study-specific procedure has been performed

• If the subject does not proceed to randomization, the reason for screen failure will be recorded on the eCRF

• Subjects who complete all screening procedures and meet eligibility criteria will proceed to randomization in the IVRS/IWRS prior to C1D1

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Study Visit Procedures for Cycle 1 Day 1

• Symptom-directed PE, including weight • If a Screening PE was performed within 7 days of C1D1, PE is not required

on C1D1, unless clinically indicated

• Vital signs


• Routine laboratory tests: hematology, chemistry and urinalysis

• Urine pregnancy test• If a urine test is positive on C1D1, it must be confirmed by a serum

pregnancy test, and dosing should be delayed until confirmation of negative results

• 12-lead electrocardiogram• Veliparib/TMZ Arm Only: Approximately 2 hours after the first dose of

veliparib/TMZ

• Quality of life questionnaires

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Study Visit Procedures for Veliparib + TMZ Treatment Arm Only

• Cycle 1 and Cycle 2 Day 15 study procedures:

• Physical exam

• Vital signs


• Laboratory tests: hematology and chemistry

• Cycle 1 and Cycle 2 Day 22 study procedures

• Physical exam

• Vital signs


• Routine Laboratory tests: hematology

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Study Visit Procedures for Veliparib/Placebo + Carboplatin/Paclitaxel Treatment Arms Only

• Cycle 1 Day 3 study procedures:

• Vital signs

• 12-lead ECG approximately 2 hours after the morning dose of veliparib/placebo

• Administer carboplatin/paclitaxel

• Cycle 1 Day 17 study procedures:

• Physical exam

• Vital signs


• Routine Laboratory tests: hematology and chemistry

• Day 3 of every Cycle - study procedures:

• Vital signs

• Administer carboplatin/paclitaxel

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Study Visit Procedures for Cycle 2 Day 1for all treatment arms

• Symptom-directed PE, including weight

• Vital signs


• Routine Laboratory tests: hematology, chemistry, and urinalysis


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Study Visit Procedures for Day 1 of Each Cycle Starting with Cycle 3 for all treatment arms


• Vital signs


• Routine laboratory tests: hematology, chemistry and urinalysis


• Questionnaires are completed every other cycle after C4

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Final Visit Study Visit Procedures


• Vital signs


• Routine laboratory tests: hematology, chemistry, and urinalysis

• 12-lead electrocardiogram

• If not performed within last 4 weeks

• Quality of life assessment

• CT scan (chest, abdomen and pelvis)

• If not performed within last 4 weeks

• AE assessment

• Collect unused study drug

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30-Day Follow-up Study Visit Procedures


• Vital signs


• Routine laboratory tests: hematology and chemistry

• Quality of life assessment

• AE Assessment

• Follow-up Visit does not need to be performed for subjects who have had a Final Visit conducted ≥ 30 days after the last dose of study drug.


Study Procedure Clarifications

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ECG Requirements

• 12-lead ECGs:

• Required approximately 2 hours after morning veliparib dose

• Subjects randomized to TMZ/Veliparib arm will be required to have an ECG at C1D1

• Subjects randomized to Carboplatin/Paclitaxel arm will be required to have a chair side ECG at C1D3 due to the timing of the veliparib dosing

• A qualified Physician (as delegated by the PI) will document any abnormal findings on the report and sign and date it

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Lab Results

• Routine Laboratory Test Results:

• Local lab may be used for immediate subject management– Split or concurrent samples should be drawn and sent to the central lab for analysis

• Qualified medical staff (as delegated by the PI) will review, initial and date all local and central lab results

• Veliparib/TMZ Arm: Day 1 of each cycle after Cycle 2, lab samples may be collected within 48 hours prior to dosing

• Carboplatin/Paclitaxel Arm: Day 1 of each cycle after Cycle 1, lab samples may be collected within 48 hours prior to dosing. If based on these results, the subject is not anticipated to be able to receive carboplatin + paclitaxel on Day 3 of the cycle, then veliparib/placebo on Day 1 should be held until dosing of the entire regimen can resume

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BRCA1/BRCA2 Testing

• Previous diagnosis of a BRCA1 or BRCA2 mutation

• If the diagnostic testing for BRCA1/BRCA2 was not conducted by the Sponsor core laboratory, the investigator should ensure that the testing is consistent with local guidelines and clinical practice and that the test employs either

1. direct DNA sequencing/MLPA or2. a well-characterized methodology previously validated by sequencing, such

as that used to assess founder mutations.

• These subjects must also undergo Sponsor core laboratory BRCA gene sequencing during Screening or on C1D1

NOTE: These subjects may be eligible for randomization prior to receiving results from the Sponsor core laboratory

Documentation of BRCA mutation status must occur by one of the following mechanisms prior to randomization:

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BRCA1/BRCA2 Testing (Cont.)• Subjects considered high risk for BRCA1/BRCA2 mutation are eligible for Sponsor

core BRCA testing during Screening if they meet one of the following criteria:• Breast cancer diagnosed at age ≤ 45 years• Diagnosed at age ≤ 50 years with first-, second-, or third-degree blood relative with

breast cancer diagnosis ≤ 50 years and/or epithelial ovarian/fallopian peritoneal cancer at any age

• Diagnosed at age < 60 years with a triple negative breast cancer• Two breast primaries when first breast cancer diagnosis occurred prior to age 50• Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer• Diagnosed at any age, with ≥ 2 first-, second-, or third-degree relatives with breast and/or

epithelial ovarian/fallopian tube/primary peritoneal cancer at any age• First- or second-degree relative of an individual known to carry a deleterious BRCA1 or

BRCA2 mutation• Ashkenazi Jewish descent• Male breast cancer• First-, second-, or third-degree male relative with breast cancer

• NOTE - Patients who pre-qualify with one or more of these criteria will be eligible to screen for BRCA1/BRCA2 mutation by the Sponsor core laboratory. These subjects may be eligible for randomization upon receipt of a confirmed deleterious germline BRCA1/BRCA2 mutation by the Sponsor core laboratory.

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BRCA1/BRCA2 Testing (Cont.)

• BRCA Bridging Study

• In order to permit future bridging studies to other potential BRCA assays, two tubes of blood must be obtained from all subjects to be tested at a future date. This will be in addition to the sample collected for the Sponsor core laboratory BRCA test.*

*These two tubes will be collected even if no sample for the Sponsor core lab was required for entry into the study.

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Tumor Assessments• CT scan of the chest, abdomen and pelvis

• Non‑contrast CT may be performed if a subject is unable to undergo a CT scan with IV contrast due to allergy or renal insufficiency

• MRI scans can be conducted if local laws or requirements mandate it; sponsor or central imaging center approval is required prior to MR

• Performed every 9 weeks from C1D1

• Tumor assessments may be conducted 8 days prior or 2 days following the scheduled assessment from C1D1

• Scheduled tumor assessments will not be affected by delays in therapy and/or drug holidays

• Scans should be assessed per RECIST, Version 1.1

• Scans will be sent to a central imaging center within 2 days of collection for review • Interpretations from the central imaging center will not be sent to the site• Subject treatment management will be based on review by the local investigator and/or site staff

All events of disease progression must be confirmed by the central imaging center

If progression is not confirmed, the subject should remain on study and continue to undergo the scheduled assessment until objective evidence of progression is obtained

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Tumor Assessments (Cont.)

• A full body bone scan is required at Screening• Subsequent bone scans will be performed as clinically indicated or per the institution’s

standard of care

• If a lesion is identified by PE, or a skin lesion is present, a report including the information below, must be submitted to Abbott. Abbott will, in turn, review and submit for central review

• Location• Size in mm, assessed using calipers• Color (for skin lesions)

– For documentation, a color photograph of the lesion should be taken. This photograph should include a ruler (metric) so that scale can be determined if the photograph is reviewed at a later time. The color photograph will not be forwarded to Abbott or the central imaging vendor

• New lesions will not be considered progressive disease, unless confirmed as increasing destruction/lytic on CT/MRI

• Increasing sclerosis will not be considered PD

• New lesions or increasing sclerosis of existing bone lesions (flare) must be evaluated by CT/MRI

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Disease Progression

• Disease progression will be defined by RECIST, Version 1.1

• Clinical data that support progression will be collected and submitted for central review – monitors may be requested by CPM to obtain copies of individual subject cytology reports for submission to Abbott. Abbott will, in turn, review and submit for central review

• Clinical progression may be characterized, but not limited to,

• An increase of at least 2 points in ECOG performance status attributable to cancer progression

• Requirement for palliative radiation, chemotherapy, or surgery, or death from disease progression

• Every effort will be made to document radiographic or clinical evidence of progression for analysis of the primary endpoint, even after discontinuation of treatment

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Quality of Life Questionnaires

• Subjects will complete paper questionnaire worksheets

EORTC QLQ-C15/BR23• 38-item validated questionnaires (< 15 minutes to complete) to assess health-related

quality of life items, including physical and emotional well-being, and breast symptom-specific questions

• Note: The QlQ-BR23 is a module of the QLQ-C30. The QLQ-C30 (30-item questionnaire) is not being used for this study; therefore, the QLQ-BR23 questionnaire administered to the study subjects will begin with question number 31.

• Subjects randomized to the veliparib/placebo + carboplatin + paclitaxel treatment arms will complete an addition questionnaire worksheet

EORTC QLQ-CIPN20• 20-item validated questionnaire (< 7 minutes to complete) to assess CIPN related

symptoms• Note: The QLQ-CIPN20 is a module of the QLQ-C30. The QLQ-C30 (30-item

questionnaire) is not being administered for this study, therefore the QLQ-CIPN20 questionnaire administered to the study subjects will begin with question number 31.

• Site personnel will check the forms for completion before the subject leaves the clinic;

• If subject is unable to complete, qualified site personnel may administer by interview and complete the forms for the subject

The data from these worksheets will be entered into EDC by the site staff


Study Medication

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Study Medication Overview

• Veliparib/placebo, temozolomide, carboplatin and paclitaxel will be supplied by Abbott

• Bottles/vials will be dispensed by IXRS

• Subjects will be provided self-administration instructions and dosing cards to record the date/time the veliparib/placebo and temozolomide were administered

• Subjects will be instructed to return all veliparib/placebo and temozolomide bottles (empty, partially filled or full) prior to each cycle and the Final Visit

• Drug accountability will be performed via the IXRS

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Site Initiation Visit

Study Medication Overview• Veliparib/placebo will be supplied

in the following capsule strengths:

• 10 mg active

• 20 mg active/placebo

• 40 mg active/placebo

• Temozolomide will be supplied in the following capsules strengths:

• 5 mg

• 20 mg

• 100 mg

• Carboplatin will be supplied in the following strengths:

• 150 mg/15 mL vials

• 450 mg/45 mL vials

• Paclitaxel will be supplied in the following strengths:

• 100 mg/16.7 mL vials

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Study Drug Storage Conditions

• All clinical supplies provided by Abbott must be stored in a secure place at the proper storage conditions, until they are dispensed for subject use, destroyed or returned to Abbott

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Dosing information

• Veliparib/placebo and Temozolomide Dosing Information:

• If less than 6 hours have passed since the scheduled dosing time, recommend taking the dose immediately

• If a subject vomits within 15 minutes of taking veliparib/placebo, another dose should be taken. This can only be repeated once. If more than 15 minutes have passed from time of dosing, no additional doses should be taken

• If a subject vomits within 15 minutes of taking TMZ, another dose should not be taken


Study Medication

Veliparib + Temozolomide

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Veliparib + TMZ Treatment Arm

Days 1 2 3 4 5 6 7 8-28

Veliparib Twice a Day

Twice a Day

Twice a Day

Twice a Day

Twice a Day

Twice a Day

Twice a Day

TMZ*

Once a Day

with a.m. veliparib

Once a Day

with a.m. veliparib

Once a Day

with a.m. veliparib

Once a Day

with a.m. veliparib

Once a Day

with a.m. veliparib

= No drug dosing*Taken under fasting conditions (to reduce the chance of nausea and vomiting per the TMZ label recommendation)

• Veliparib 40 mg BID is administered on Days 1 through 7

• TMZ 150 to 200 mg/m2 QD Days 1 through 5 in each 28-day cycle

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TMZ Dose Escalation after Cycle 1

• The starting dose of TMZ at C1D1 will be 150 mg/m2/day to be given on Days 1 thru 5. The TMZ dose is determined using the body surface area (BSA) calculated from the height obtained at baseline and the weight obtained prior to each cycle. The daily dose may be rounded down to 5% from the calculated dose in order to minimize the number of capsules per dose.

• The TMZ dose will be escalated to 200 mg/m2/day at C2D1 only if during Cycle 1:• Platelets (nadir) are > 100,000/µL and• ANC (nadir) is > 1,500/µL and• No Grade 3 or 4 CTCAE non-hematological toxicities attributable to TMZ are

observed• If the dose was not escalated at Cycle 2, then the dose cannot be

escalated in subsequent cycles.

• For all cycles, dose delays and reductions will be managed according to Section 5.7 of the protocol.

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Daily Dose Calculations by BSA for Temozolomide

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TMZ Dose Modifications Following Cycle 1Hematological Toxicity Attributable to TMZ

150 mg/m2 per day x 5 days (Cycle 1 Dose)

Based on lowest counts at either Day 22 or Day 29

ANC <1000/µLor

Platelets <50,000/µL

ANC 1,000/µL to 1500/µLorPlatelets 50,000/µL to

100,000/µL

ANC >1500/μL and

platelets >100,000/μL, and no Grade 3 or 4 clinically significant toxicities attributable to TMZ

Postpone therapy until ANC >1500/μL and

platelets >100,000/μL

Postpone therapy until ANC >1500/μL and

platelets >100,000/μL Increase dose to

200 mg/m2 per day × 5 days for

subsequent cycleReduce dose by 50 mg/m2 per day

for subsequent cycle

Maintain initial dose of 150 mg/m2 per day

for subsequent cycle

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TMZ Dose Reductions Starting in Cycle 2Non-Hematological Toxicity Attributable to TMZ

150 mg/m2 per day x 5 days (Cycle 1 Dose)

Nausea/VomitingCTC ≥ Grade 3Despite optimal

antiemetic therapy

Fatigue, constipation, anorexia and

headachesCTC ≥ Grade 3

Any other CTC ≥ Grade 3 deemed to

be clinically significant by PI

Hold TMZ + Veliparib Delay cycle until Grade 1(or Grade 2, if present at baseline)

Reduce Veliparib dose by one dose level

Veliparib should be discontinued at the same time as TMZ

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Veliparib + TMZ Dose Reductions

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Veliparib + TMZ Discontinuation

• Subjects may receive veliparib + TMZ for up to 24 cycles, or until reaching a protocol-defined event of disease progression or experiencing unmanageable toxicity

• The investigator and Abbott will develop a plan to continue treatment beyond 24 cycles if a subject has not progressed

• If toxicities have resulted in discontinuation of either veliparib or TMZ, both are to be discontinued

• Subjects who discontinue treatment with veliparib + TMZ prior to an event of disease progression should remain on study and continue to follow the schedule for study visits and procedures until disease progression is experienced


Study Medication

Veliparib + Carboplatin/Paclitaxel and Placebo + Carboplatin/Paclitaxel

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Veliparib/Placebo + Carboplatin/Paclitaxel Treatment Arms

Days 1 2 3 4 5 6 7 8-21Veliparib or

PlaceboTwice a

DayTwice a

DayTwice a

Day*Twice a

DayTwice a

DayTwice a

DayTwice a

Day

Paclitaxel** IV Infusion

Carboplatin IV Infusion

*Morning dose of veliparib/placebo on Day 3 of every cycle should be taken before the carboplatin/paclitaxel infusion**Paclitaxel will be infused before Carboplatin

= No drug dosing

• Veliparib/Placebo 120 mg BID Days 1 through 7 + carboplatin AUC 6 administered on Day 3 and paclitaxel 175 mg/m2 administered on Day 3 of each 21-day cycle

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Veliparib/Placebo + Carboplatin/PaclitaxelDose Reductions (Amendment 1) Carboplatin

Paclitaxel

Dose Level Veliparib/Placebo BID Strength Capsules per Dosing

Starting Dose 120 mg 40 mg 3 BIDDose Level -1 80 mg 40 mg 2 BID

Dose Level -2 40 mg 40 mg 1 BID

Veliparib/Placebo

Dose Level Carboplatin (AUC) Max Dose if Serum Creatinine by IDMS

Starting Dose 6 900 mgDose Level -1 5 750 mgDose Level -2 4 600 mg

Dose Level Paclitaxel (mg/m2)Starting Dose 175 Dose Level -1 135

Dose Level -2 110

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Dose Reductions/Delays

• For all cycles, dose delays and reductions will be managed according to Section 5.7 of the protocol

• The monitor should be contacted for subjects who require more than a 2-week delay in the re-initiation of the next cycle.

• All dose reductions are considered permanent.

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Veliparib/Placebo + Carboplatin/PaclitaxelDiscontinuation

• All subjects will continue on Veliparib/Placebo + Carboplatin/Paclitaxel until:

• A protocol-defined event of disease progression; or

• Experience unmanageable toxicity

• Subjects may continue on the remaining agent in combination with veliparib

• Any veliparib/placebo dose reduction beyond 40 mg BID will result in veliparib/placebo discontinuation

• If toxicities have resulted in discontinuation of both carboplatin and paclitaxel, veliparib will also be discontinued

• At the investigator's discretion, carboplatin and paclitaxel administration may continue after veliparib has been discontinued

• Subjects who discontinue treatment with veliparib/placebo + carboplatin/paclitaxel prior to an event of disease progression should remain on study and continue to follow the schedule for study visits and procedures until disease progression is experienced

Concomitant MedicationsSubject Discontinuation, Status Changes and Survival Follow-up

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Removal of Subjects from Therapy or Assessment

• Each subject has the right to withdraw from study treatment at any time

• If necessary, the investigator may discontinue a subject from study treatment at any time and for any reason, including the occurrence of an AE or noncompliance with the protocol

• Subjects will be withdrawn from the study if any of the following occur:

• Disease progression as defined by RECIST (version 1.1)

• Investigator believes it is in the best interest of the subject

• Clinically significant deterioration of the subject's medical status, as determined by the investigator

• Pregnancy

• Withdrawn consent

• Alternative anti-cancer therapy is indicated

• Any other medical reason that Abbott or the Investigator deems appropriate

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Discontinuation of Individual Subjects

• Abbott should be informed prior to discontinuation of any subject (if discontinuing without reaching a protocol-defined endpoint)

• When a subject discontinues the study, a Final Visit will be conducted (preferably prior to the initiation of another anticancer therapy)

• These procedures should not interfere with the initiation of any new treatments or therapeutic modalities

• The reasons for discontinuation will be recorded

• Final Visit procedures will be performed, as soon as possible after discontinuation from the study

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Discontinuation of Individual Subjects (cont’)

• All subjects will have one Follow-up Visit approximately 30 days after the last dose of study drug

• Follow-up Visit does not need to be performed for subjects who have had a Final Visit conducted ≥ 30 days after the last dose of study drug

• Subjects who discontinue treatment prior to an event of disease progression should remain on study and continue to follow the schedule for study visits and procedures until disease progression is experienced, if possible

• Report subject status changes to the IVRS/IWRS system within 3 days. This should be captured as a “Subject Status Change” in the IVRS/IWRS and noted as “on study – off drug” (temozolomide, carboplatin, paclitaxel, veliparib/placebo)

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Post Study Assessments- IVRS/IWRS

• Report subject discontinuations to the IVRS/IWRS system within 3 days of the subject's discontinuation

• Post Study Assessment data is collected every month or as requested by Abbott to support data analysis for up to 3 years, until the endpoint of death, subject is lost to follow-up or until study termination by Abbott

• Information can be obtained through phone calls, review of medical records, etc.

• Data collected:

• Survival information (date and cause of death)

• If known, post study anti-cancer therapies, dates of initiation, and end dates

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Interim Analyses

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Safety Interim Analyses

• To ensure subject safety, an IDMC will review unblinded safety data (which will include all subjects enrolled in the study) when approximately 36 subjects enrolled under Amendment 1 have met at least one of the following criteria:

• Received 2 cycles of treatment

• Reached an event of disease progression

• Discontinued the study due to toxicity/adverse events

• Subsequent reviews will be based on recommendations from the IDMC

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Futility Interim Analyses

• An interim futility analyses will be conducted and reviewed after the week 27 tumor assessment of the first 30 subjects randomized to the veliparib/TMZ treatment arm

• If futility is declared, at the time of futility analyses any subjects currently receiving veliparib/TMZ will be allowed the option of either:

• Receiving veliparib + carboplatin + paclitaxel, or

• Discontinuing therapy and remain on study and continue to follow the schedule for study visits and procedures until they have reached an event of disease progression


Com

pleting Electronic C

ase Report F

orms (eC

RF

s) +

Non-C

RF

Form

s Related to A

dverse Event R

eporting

Safety Reporting

Completing Electronic Case Report Forms (eCRFs) + Non-CRF Forms Related to Adverse Event Reporting

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Adverse Event Reporting Agenda

• Adverse Event/ Serious Adverse Event Definitions

• Key Elements of Adverse Event Reporting

• Common Problems When Reporting Adverse Events

• Completing SAE-related eCRFs

• Subject Identifying Information

• SAE Collection and Reporting Requirements

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Adverse Event Defined

An adverse event/experience is any untoward medical occurrence in a study subject/patient administered a pharmaceutical product, which does not necessarily include a causal relationship to the study drug.

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What is an Adverse Event?

An adverse event may be:• A sign, symptom, disease or medical diagnosis (not the intervention)

• An abnormal laboratory finding or changes in vital signs if:–It results in premature discontinuation–It necessitates therapeutic medical intervention–The investigator considers it an adverse event–Meets protocol-specific criteria

• Any worsening of a pre-existing condition or illness

• Any change in physical exam findings deemed by the investigator to be clinically significant

Note: Any complications of an event should be reported as separate events

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Adverse Event: Severity

• Seriousness is defined from a regulatory perspective

• “Severe” events are not necessarily serious

• “Severe” is a measure of intensity

–If a reported adverse event increases in severity, the initial adverse event should be given an outcome date and a new adverse event reported to reflect the change in severity.

–For all reported serious adverse events that increase in severity, the supplemental eCRF’s also need to be updated to reflect any changes due to the increase in severity, and the new AE serial number.

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What is a Serious Adverse Event?

• Serious criteria:

• Life-threatening

• Hospitalization or prolonged hospitalization

• Important medical event requiring medical or surgical intervention to prevent serious outcome

• Persistent or significant disability/incapacity

• Death of subject

• Congenital anomaly

• Miscarriage/spontaneous abortion (Abbott specific)

• Elective abortion (Abbott specific)

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Key Elements of AE Reporting

• Onset Date:

• Reflects when the signs and symptoms began, not when the subject reported them or was questioned about them.

• For Serious Adverse Events, this date may or may not reflect the date that the event became serious.

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Key Elements of AE Reporting:

• Event Diagnosis

• Is a single medical concept/condition that encompasses all signs and symptoms of an event

• Must be supported by evidence

• Record diagnosis only (if known)– Example: The subject experienced cough, fever, & shortness of breath and a

diagnosis of pneumonia was made. Record the event diagnosis as Pneumonia

Pneumonia

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Event Diagnosis

• Signs and symptoms not represented by the event diagnosis must be reported as separate events.

– Example: The subject experienced cough, fever, shortness of breath and diarrhea with a diagnosis of pneumonia.

– Pneumonia and diarrhea would be reported as two separate events

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•Event Diagnosis

• If a diagnosis has not been made or is unknown, record the sign/symptom, one per line.

-Example: The subject experienced nausea and vomiting, but no diagnosis (such as gastroenteritis) was made or confirmed.

vomiting

nausea

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• Final DiagnosisIf signs/symptoms were initially recorded and a diagnosis was subsequently made,

change the sign/symptoms to the diagnosis.

Example: The subject experienced nausea and vomiting, but no diagnosis (such as gastroenteritis) was made. The signs/symptoms were recorded. Subsequent follow-up confirmed diagnosis of gastroenteritis.

Nausea

Vomiting

The confirmed diagnosis of gastroenteritis should replace the symptoms of nausea and vomiting

gastroenteritis

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• Confirmed diagnosis should replace the symptoms.

• To change the event term to the final diagnosis:

• Highlight the sign and symptoms

• Hit delete – Do not use backspace bar

• Enter Final Diagnosis

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• End Date

• The end date should reflect the actual date the event resolved; not the date on which the subject was questioned about it

• If the AE has not resolved at the end of the study an “ongoing as of” date should be used and should reflect the date of the last visit

• End date must be documented in the source documents

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• Time Course of Event

• Duration – if less than 24 hours

• Intermittent

– Yes would indicate sporadic– No would indicate continuous

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Key Elements of AE Reporting• Action Taken

• Check all that apply

– none– Medication taken– Diagnostic/Therapeutic procedure– Emergency room/Hospital outpatient <24

hours– Discontinued study- related to

progression– Discontinued study-not related to

progression– Other

• Interruption, discontinuation, dose reduction, delay of study drug as an action taken and must be completed for Veliparib, TMZ, Carboplatin, Paclitaxel

• Actions taken for an AE are found in the source documents

•

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Adverse Event:Other Cause of Event

• Other Cause of the Event is required when the event meets serious criteria and the causality is:

– Possibly related – Probably not related– Not related

• It should not be the same as the event reported.

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Ensuring Quality Safety Data

• Adverse Events

• Recorded events must:

• Be sufficiently descriptive and clear

• Convey a recognized medical concept/condition

• Avoid abbreviations

• Avoid use of provisional terms such as possible, probable, rule out

• If a reported adverse event increases in severity the initial adverse event should be given an outcome date and a new adverse event reported to reflect the change in severity. For all reported serious adverse events that increase in severity, the supplemental eCRFs also need to be updated to reflect any changes due to the increase in severity.

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Common Problems: Vague or Ambiguous Terms

• The event description is vague or ambiguous

• Example: Congestion– Problem: the symptom “congestion” is ambiguous– Resolution: clarify the term by adding the type of congestion

• Chest congestion• Nasal congestion• Sinus congestion

• Example: Cramps– Problem: the event description of cramps is vague or ambiguous.– Resolution: clarify the term by adding the type of cramps

• Menstrual cramps• Abdominal cramps• Leg cramps

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Common Problems: Provisional Terms

• The event description is an unconfirmed diagnosis, such as “possible”, “questionable”, “rule out”

• If no confirmed diagnosis is available, then the signs/symptoms should be provided

• Example: Possible MI– Problem: Provisional term is reported– Resolution: Provide Signs/symptoms

• Cardiac chest pain• Dyspnea

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Common Problems: Unrecognized Medical Concepts

• The event term is an unrecognized medical concept, spelling error, or reported in a foreign language

• Example: Inestability

– Problem: event term provided in a foreign language– Resolution: event terms must be reported in English

• Inestability = Dizziness

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Common Problems: Abbreviations

• An abbreviation is used in the event term

• Problem: An abbreviation may have multiple meanings

• Resolution: Abbreviations should not be used, except for standard laboratory abbreviations such as ALT

Example: Increased BSReport as: Increased Blood sugar

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Common Problems: Reporting Procedures

• A procedure is reported as an adverse event

• Example: Hysterectomy

• Problem: Hysterectomy is a surgical procedure

• Resolution: Report the underlining condition: Uterine Fibroids

• Procedures should be reported as the “action taken/other specify”

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Common Problems: Abnormal Laboratory Values

• When reporting abnormal lab values as adverse events

• Specify the result as: increased, decreased, elevated, etc.– Example: “Elevated AST”

• Avoid reporting the actual results of lab tests.– Don’t report: “Platelets 78,000”– Report: “Thrombocytopenia”

• Indicate the specimen source: blood, urine, cerebrospinal fluid, etc. – Don’t report : “Increased creatinine”– Report: “Increased serum creatinine ”

• Report the condition instead of the abnormal lab value – Don’t report : “Decreased Sodium”– Report: “Hyponatremia”

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Reporting Pregnancy

• Pregnancy is not an adverse event.

• If a subject becomes pregnant:

• Notify Abbott within one working day of becoming aware of the pregnancy• The subject must be discontinued from the study• Pregnancy information will be collected on pregnancy specific CRFs, including

outcome of the pregnancy

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Reporting Adverse Events of Cancer• New primary (secondary) malignancies should be reported as

adverse events. The investigator determines if event also meets SAE criteria.

• Treatment of new primary malignancies may involve multiple, planned hospitalizations for chemotherapy and/or radiation• Recurring hospitalizations for the same malignancy will be considered

as follow-up and should be documented in the narrative portion (Form 752NC) of the initial event

• Complications or other coincidental adverse events occurring during subsequent hospitalizations should be captured as separate adverse events

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SAE-Related Electronic Case Report Forms• Required eCRFs:

• Adverse Event • Investigator SAE Supplemental • SAE Study Drug Information• SAE Supplemental Trigger

If applicable:• SAE Supplemental Microbiology • SAE Supplemental Laboratory • SAE Supplemental Procedures

• The following eCRFs must also be completed when reporting an initial SAE:

• Other Medications and Supplements• Demographics• Medical/Surgical History• Tobacco and Alcohol Use

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Adverse Event eCRF

• Additional AE eCRFs may be necessary for reporting multiple SAEs at once.

• Each AE eCRF has an unique serial number that is specific to that adverse event.

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SAE Supplemental Trigger

SAE Supplemental Trigger needs to be completed to populate the SAE Supplemental pages

#1- Enter Adverse event number(s)

#2- Always Check Investigator SAE Supplemental and SAE Study Drug Information pages

#3- Select SAE Supplemental Laboratory, Microbiology and Procedure as applicable to SAE

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SAE Study Drug Information

SAE Study Drug Information page was created to capture drug dosing information at the time of the SAE.

#1- Enter AE numbers

#2- Enter dose, route and frequency

#3- Enter drug start date

#4- Answer: Has study drug been interrupted for this event?

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SAE Study Drug Information (cont)

# 5a-Provide date last dose taken prior to interruption (if applicable)

#5b-Answer if study drug was re-introduced (if applicable)

#5c-Provide date re-introduced (if applicable)

#5d- Answer Did event reappear?

#5e- Provide which event's) reappeared

#6- Answer if study drug has been permanently discontinued

#7- Provide date of last dose if permanently discontinued

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Investigator SAE Supplemental

• #1 Enter adverse event serial number(s)

• #2 Dates of hospitalization; admission date and discharge date (if applicable)

• #3 Transcribe the relevant admission history and physical- do not fax a copy of the H&P

• #4 Weight at time of event

• #5 Provide any risk factors relevant to events

• #6 Any family history relevant to events

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Investigator SAE Supplemental (con’t)

• #7 Signs and symptoms associated with current serious adverse events

• #8 If the subject experienced the event before

• #9 Clinical course of event

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Investigator SAE Supplemental

• Clinical Course of event should include:– What lead up to the event– Admitting diagnosis– Relevant clinical course– Diagnostic and/or therapeutic interventions and results– Treatment and outcomes– Final diagnosis as related to the event– Resolution i.e. discharged from hospital, transferred to extend care facility

• The Clinical Course of event should be documented similar to hospital record progress note

• All relevant information found on the discharge summary should be transcribed onto the SAE eCRFs. The discharge summary should not be faxed in unless specifically requested by Abbott.

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Additional SAE-related Data

• Lab and Procedure Data– SAE supplemental Laboratory – SAE supplemental Microbiology – SAE supplemental Diagnostic/Therapeutic Procedures

• These pages should be completed with relevant SAE-related results.– Transcribe test/procedure results from source documents to the eCRFs. Do not

send the hospital lab reports or diagnostic reports.– Only include tests performed specifically for the SAE(s) being reported.

• Relevant discharge summary data (laboratory and diagnostic tests and results) should be recorded on the appropriate page. Do not send in the discharge summary.

• If lab data or diagnostic test results are not available at the time of the SAE, they should be provided as follow-up.

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SAE-related Documents

• If specifically requested by Abbott death certificates and autopsy reports should be faxed to Abbott

• The subject’s identifying information must be obscured and replaced with the subject’s unique number and protocol number.

• The designated Cover memo (750NC paper CRF) should be used when faxing these documents

• Discharge Summaries should not be faxed to Abbott unless specifically requested by Abbott.

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Documents Containing Subject Identifying Information

• The subject’s identifying information must be obscured and replaced with the subject’s unique number and protocol number (if applicable)

• Case Report Forms (e.g. SAE supplemental narrative)

• Adverse Event Reporting Forms

• Local lab reports

• ECG/Echo reports

• X-rays/radiology reports

• Hospital discharge summaries (if requested)

• Admission notes

• History & physical

• Consultation reports

• Subject diaries

• Photos

• Autopsy reports/ Discharge summaries

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Subject Identifying Information

• Subject name/initials

• Subject hospital identifying number

• US social security number or equivalent for other countries

• Laboratory assigned identifying numbers

• Subject contact information (e.g. addresses, phone numbers, e-mail addresses)

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SAE Reporting Non-CRF Process

• Transcribe the SAE information on the 500 AE CRF, 750 NC through the 755NC CRFs

• Once access to Rave is available the most current data will need to be entered into the Rave system

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SAE Reporting Non-CRF Process

• If the AE meets criteria for an SAE, and the Rave system is not accessible complete the following SAE Non-CRF forms for the initial SAE:

• SAE Cover Memo (Investigator to Abbott) 750NC

• Adverse Event CRF (Form 500AE)

• Subject Information (751NC)

• Narrative Description (752NC)

• Other Medications/Subject Medical History (753NC)

• Laboratory/Diagnostic/Therapeutic Procedures form (754NC) only if applicable to the SAE being reported.

• Investigator Serious Adverse Event Non-CRF Supplemental Change Form (Form 755NC) if applicable

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Cover Memo (750 NC)

• A new cover memo should be used with each faxed report (initial or follow-up) – Remember to check whether initial or follow-up

• Collect required documents and check the boxes on the SAE Cover Memo to indicate which items are being sent

• It is recommend photocopies of this form be made so the supply is adequate

• It must be signed by the principal investigator

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Adverse Event (Form 500AE)• Report the event diagnosis if known.

If the event diagnosis is unknown report the signs and symptoms. One sign/ symptom per line.

• Signs and Symptoms vs. Event Diagnosis:

• If the subject’s signs and symptoms are characteristic components of a single, confirmed, event diagnosis, a single AE CRF should be completed.

• Enter the diagnosis in the event diagnosis field (Box #2).

• If, however, the subject has additional signs/symptoms that are not components of this final diagnosis, those signs/symptoms should be collected on separate AE CRFs.

• A separate AE CRF should be completed for a medical complication of a diagnosis.

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Adverse Event (Form 500AE) (con’t)

• AE page continuation.

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Investigator SAE Supplemental (751NC)

• Subject’s birth date, gender, race, weight, drug start date, study drug administration schedule at the time of the SAE, drug interruption and permanent discontinuation information should be provided, as well as information regarding previous episodes, tobacco and alcohol use.

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• Dates of hospitalization; admission date and discharge date (if applicable)

• Transcribe the relevant admission history and physical- do not fax a copy of the H&P

• Provide the signs and symptoms associated with the current serious adverse event(s)

• Provide clinical course

• By no means should the sites’ inability to sign these documents hold up SAE reporting. The principal investigator may delegate signature of these forms, as appropriate, during periods of absence from site. However, his/her signature will still be required

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Investigator SAE Supplemental (752NC)(cont.)

• The clinical course of the event should include:

• What preceded the event

• Signs and symptoms

• Admitting diagnosis and date of hospitalization

• Admitting History & Physical

• Relevant clinical course

• Diagnostic and/or therapeutic interventions and results

• Treatment and outcomes

• Final diagnosis as related to the event

• Resolution i.e. discharged from hospital, transferred to extend care facility

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Other Medications + Supplements/Medical History (753NC)

• Record the name (trade name preferred)

• start and end date

• dose including units

• frequency

• reason for use

• Medical history:

• Record any relevant past medical history including onset date

• Family history

• Pregnancy history

• Risk factors and occupation.

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SAE Relevant Non-CRF Laboratory and Diagnostic/Therapeutic Procedures (754NC)

• Record any laboratory and/or microbiology results pertaining to the diagnosis or management of the SAE. The laboratory test may have been collected in the hospital or elsewhere. Include pertinent negative as well as positive values

• Include the reference range for the lab test being reported

• Record the results of any diagnostic or therapeutic procedure performed to

• Laboratory/Diagnostic/Therapeutic Procedures (754NC) should be faxed to Abbott only if it is applicable to the SAE being reported.

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• This narrative is very important to the understanding and proper assessment of the SAE by Abbott, and should be clearly and concisely written, accurately describing the course of the SAE, signed and dated by the principal investigator

• The clinical course should be continued on the 756 NC if needed

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Collection Timeframe

.

All serious and non-serious adverse events will be collected from time of study drug administration through 30 days post-therapy.

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SAE Reporting Requirements• Once the subject is randomized their

data will be entered into EDC and both non-serious and serious adverse events will be collected.

• SAEs must be reported within 24 hours of site awareness by entering the data into EDC

Completed by Required eCRF forms Additional required eCRF forms

Investigative Site

• Adverse Event Form• Subject Demographics • Subject Medical History • Tobacco and Alcohol • Other Medications

• SAE Supplemental Form

(SAESUPP1) (micro, labs,

diagnostic data, if applicable)• SAE Supplemental Form

(SAESUPP2)

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SAE Reporting Requirements

• Screening SAEs

• Since subject data will not be entered into EDC until randomization, SAEs that occur during screening will be reported using paper SAE forms (Non-CRF Process packet).

• Abbott Safety must be notified within 24 hours of site awareness, via fax.

Completed by Required Non-CRF forms If applicable

Investigative Site • SAE Cover Memo (750NC)• AE form (500AE)• Supplemental forms:

– Subject Information (751NC)– Narrative Description (752NC)– Medications/Med Hx (753NC)

• Laboratory/Diagnostic/

Procedure form (754NC)

• Documentation of any

changes to initial SAE

(755NC)

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SAE Reporting Requirements

• SAEs must be reported within 24 hours of site awareness by entering the data into EDC

• Within 24 hours of receiving additional relevant information about the SAE (lab data, diagnostic test results, etc.) the site must enter the updated SAE data into EDC or Fax reports (death certificates and autopsy reports only) to Abbott

• A phone call is NOT a report and does not meet your reporting obligations

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Contact Information

• Medical Monitor

• Stacie Shepherd MD, PhD

• Office: 847-938-6875

• Fax: 847-937-8460

• Cell: 847-505-9348

• Email: [email protected]

• Safety Management Team

• Sharon Bolster-Mills, RN, Lead CSA

• Telephone: 847-938-0741

• Nida Martinez, RN, Sr. CSA (Back-up)

• Telephone: 847-937-3427

• SAFETY TEAM PHONE: 847-935-2609

• SAFETY TEAM FAX: 847-785-8224

• SAFETY MANAGEMENT EMAIL:

[email protected]

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Concomitant MedicationsPerceptive Imaging

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General Guidance

• Please adhere to Perceptive’s Imaging acquisition guidelines

• Please remove all confidential patient/site information and any tumor markings from the images

• Spiral/helical CT scanners strongly preferred

• CT images acquired on PET/CT scanner are acceptable as long as they are of diagnostic quality and adhere to the guidelines

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General Guidance: Consistency

• Baseline and subsequent scans should be performed using identical techniques, including:

• Timing of contrast administration

• Brand, dosage and timing of contrast agent

• Scanner

• Axial slices

• Same method, radiological or physical, should be employed at each tumor assessment visit

• Same individual should assess on each occasion

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Imaging Requirements

Modality

• CT (MRI)

Anatomy

• CT Chest-Abdomen-Pelvis with i.v. Contrast

– MRI can be conducted in cases where local laws or requirements mandate, prior sponsor or central imaging center approval is required

• If iodine contrast is medically contraindicated:– Chest, Abdomen, Pelvis CT without i.v. contrast

• Other areas if clinically indicated

Schedule

• at every timepoint

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CT Oral Contrast Options

Please make sure, whenever possible, to administer oral contrast

• In decreasing order of preference are:– Radio opaque agents (examples include iodine and barium based agents)– Radio-lucent agents (Whole Milk, VoLumen®, Water)


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Modality Bone scan – with correlative

imaging (CT/MRI)

Schedule Required at baseline Subsequently if clinically

indicated

Imaging Requirements

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Image Transfer to Perceptive Informatics

Digital Transfer

AGMednet (preferred)• all images uncompressed DICOM

Shipment of digital media• Digital Media will be provided by Perceptive• If using optical disc, submission shall be limited to 2 studies per

disc at a maximum (1 patient / study on each disc side)• Remove/Mask patient identifiers

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Image Transfer to Perceptive Informatics

Hardcopy Film (if digital is not possible)

• Duplicate original (laser-printed) hard copies films should be obtained at imaging (one tol be sent to Perceptive)

• Number of images per film and display FOV must be kept constant.

• Each hardcopy should include no more than 20 images per film

• Mark the RIGHT side with a point source on each projection

• Circle the marker on the film

• Note the site of injection on the film

For all methods

Keep imaging data (including raw/original data if possible) digitally archived until Perceptive has provided feedback to the quality of the images

Send ALL images acquired to Perceptive until instructed otherwise


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Perceptive Contacts• Patrick Raleigh

Project Manager

[email protected]

Tel.: 978.313.3809

• Julissa Pina

Imaging Operations Lead

[email protected]

Tel.: 978.313.3796

Marvin Carlos

Medical Research Scientist

Marvin. [email protected]

978.313.1513

Annette Schmid, PhD

Medical Director

[email protected]

978.313.3830

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ICON Central Laboratories

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Overview

• Laboratory Manual

• Laboratory Kits and expiration

• Specimen Collection/Preparations

• Barcodes and Requisition forms

• Packaging and Shipping

• Reporting

• Query Process

• Communication

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Laboratory Investigator Manual

• Site Services’ Contact Information

• Study Summary Guide

• Detailed instructions:

• Collection

• Preparation

• Packaging & shipping

• Reference Ranges

• Copy of all requisition forms

• Additional forms:

• Supply Re-Order Form

• CVs, Accreditations and Licenses

www.iconplc.com

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Laboratory Kit

• Contains:• Barcode Labels• 3 part requisition form• Transport and Collection Tubes• Packaging supplies for sample

shipment

• Protocol specific

• Site specific

• Kit Type specific

• Expiration Date Stamped

• Only use one kit per subject per visit

• 10 business days required for all initial supply requests

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Kit Expiration

• Each kit is stamped with an expiration date. This date is approximately 6 months of dating.

• If samples are received from an expired kit visit results will automatically be locked, a query will be issued to the site.

• ICON faxes or emails expiration reports to sites. Initial notification is sent two months before the kits will expire and second time - one month before the kits will expire.

• It is the site’s responsibility to review their inventory, discard expired supplies and reorder if necessary. Supplies are ordered by faxing or emailing the Supply Reorder Form to ICON

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Example of Supply Re-Order Form

All Lab Kits Beginning with Cycle 3 Day 1 –

will be Universal Lab Kit

All Lab Kits Beginning with Cycle 3 Day 1 –

will be Universal Lab Kit

“B” kits are for the Carboplatin/Paclitaxel

Arm

“B” kits are for the Carboplatin/Paclitaxel

Arm

“A” kits are for the TMZ arm

“A” kits are for the TMZ arm

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ICON Lab Manual

• Contains detailed instructions for all sample collections

• Specimen Collection – Quick Reference Guide includes:

• Test/Panel

• Bar Code Label

• Collection Container

• Transport Container

• Shipping Temperature

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Research Blood Tests

Procedure Visit ScheduleBefore Drug

Administration

Sample Plan

Sample MatrixPD Blood Sampling

Plasma Markersa,b

Day 1 of every cycle Pre-dose

Final Visit At the time of clinic visit Frozen -70°C or colder

Serum MarkersDay 1 of every cycle Pre-dose

Final Visit At the time of clinic visit Frozen -70°C or colder

BRCA Sequencing:Bridging Study

C1D1Blood

Frozen -20°C or colder

Circulating Tumor CellsC:US Sites Only

C1D1, C2D1 and D1 of every other cycle there after (C4, C6,

etc.)

Pre-dose Blood Shipped Fresh

on the day of collection(must be kept refrigerated at

2 to 8°C until shipped)C1D15d/C1D17e

and Final VisitAt the time of clinic visit

Blood Plasma

Blood Serum

a. An additional sample may be collected at the time of discontinuation due to an adverse event.b. Based on a discussion between Abbott and the investigator, samples for an individual subject may be collected at an alternate time point.c. CTC/DNA repair collection should not be the first tube drawn. d. For subjects randomized to the veliparib + TMZ treatment arm.e. For subjects randomized to the veliparib/placebo + carboplatin/paclitaxel treatment arm.

Burnske

US sites only - should be removed for RoW

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Research Tissue and Biopsy Samples

Procedure Visit ScheduleBefore Drug

Administration

Sampling Plan

Specimen MatrixOptional with Consent

Serial Biopsies

C1D1 Pre-dose Flash Frozen -70°C and FPPE -20°C Final Visit At the time of clinic visit

Optional with Consent

IHC/FISH FFPE tissue blocksDiagnostic, formalin fixed, paraffin embedded (FFPE)

tissue blocks Optional w/Consent

PG Blood Sampling

Genetic (DNA)

C1D1 BloodFrozen -20°C or colder

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Collection Instructions: Blood Samples for Pharmacodynamics -PD (Plasma Markers)

The process given below should be completed in less than 1 hour from blood draw.

• Collect the blood sample into appropriately labeled 6-mL EDTA (S-PLS) purple top tubes (use 2 tubes for C1D1)

• Immediately invert the collection tube 8 to 10 times to reduce the likelihood of clot formation

• Centrifuge the blood samples at 1100 to 1300 x g for 15 minutes using a refrigerated centrifuge at 2ºC to 8ºC

• Within 15 minutes, transfer the plasma sample into labeled 2-mL cryovials

• total of four 2-mL cryovials for C1D1

• total of two 2-mL cryovials for all subsequent cycles

• Barcode labels are included in the lab kit

• Store the samples immobile and upright at –700C or colder until shipped frozen to ICON Central laboratory.

↺

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Collection Instructions: Blood Samples for PD (Serum Markers)

The complete process should be accomplished in less than 90 minutes from blood draw.

• Collect the blood sample into a 5-mL SST (SER-1)gold top tube

• Immediately invert the collection tube 5 times

• Allow blood to clot for a minimum of 30 minutes in a vertical position, until a dense clot is observed.

• Centrifuge the blood samples at 1100 to 1300 x g for 15 minutes at room temperature to ensure adequate separation of the serum.

• Within 15 minutes, transfer the serum sample into two separate 2-mL labeled cryovials and freeze at -70°C or colder.

• Store the samples at –70°C or colder until they are shipped to the ICON Central laboratory on dry ice sufficient for 3 days.

↺

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Collection Instructions: Blood Samples for BRCA Sequencing Sample (BRCA Bridging)

↺

• Collect approximately 4 mL of blood into 2 appropriately labeled EDTA (WBDNA1 and WBDNA2) tubes.

• Immediately invert the collection tube 8 to 10 times to reduce the likelihood of clot formation.

• Store samples at –20ºC or colder within 30 minutes of the blood draw, until shipped/transported on dry ice sufficient to last for 3 days during shipment/transport to ICON central lab.

In order to permit future bridging studies to other potential BRCA assays, in addition to the sample collected for the Myriad BRCA test, two 4-mL whole blood samples for DNA isolation will be collected from all subjects at C1D1 visit.

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Circulating Tumor Cell Collection (U.S. Sites Only)

Circulating Tumor Cells (CTC) may be examined for the tumor-specific alteration of cellular proteins/peptides and/or nucleic acids. CTC sample will be collected for US patients only and shipped directly to Abbott. Collection procedure follows as:

• Collect 10 mL whole blood into appropriately labeled 10 mL Lavender/Yellow CellSave preservative tube

• Remove tube from ziploc bag and invert it 8 times to mix and prevent clotting (inadequate or delayed mixing may result in inaccurate test results)

• Following collection, the specimen must be kept refrigerated at 2-8°C, if needed, prior to shipping to Abbott on the day of collection

• Specimen should be packed with a frozen gel pack and shipped in a styrofoam container overnight to Abbott

• Notify Abbott of shipment via email to [email protected] and/or [email protected] and fax the completed requisition form to 847-935-1969

↺

delucam

Consider removing this slide for Ex-US SIV's

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Collection Instructions: Blood Samples for PG (Optional)

One 4 mL whole blood sample for DNA isolation will be collected at C1D1 from each subject who consents to provide samples for PG analysis.

• Collect approximately 4mL of blood into an 4 mL EDTA – purple top tube (DNA)

• Ensure that appropriate barcode label is used

• Immediately invert the collection tube 8 to 10 times

• Store samples at -20ºC or colder within 30 minutes of the blood draw until shipped to ICON Central laboratory on dry ice sufficient for 3 days. ↺

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Tissue Sample Collection (Optional)

Fixed Samples (IHC and FISH, qPCR) – optional with consent; can be submitted as an archive tissue block or cut tissue on slides.

• From each representative FFPE tumor tissue, the local pathology laboratory should apply 10 slices of tissue with a thickness of approximately 4 to 6 microns to positively charged slides;

• 5 slices of tissue with a thickness of approximately 10 microns to positively charged slides.

• Minimum of 15 slices of tissue sections should be collected from each subject block.

• Two (2) quality control slides must also be prepared by the pathology laboratory and included in the shipment of slides to the ICON lab.

• Copy of Pathology report should be included

If a site requires their paraffin block returned, please contact Brenda Chyla at 847-937-0020 or via email ([email protected]) at the time the block is shipped to ICON

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Serial Biopsies Collection (Optional)

Serial Biopsies – will be obtained at the C1D1 visit prior to therapy and at the Final Visit, when feasible, for all subject who consent.

• At least 2 core biopsies to be obtained. Biopsies must be at least 18 gauge in diameter and 1 cm in length.

• If needle biopsy cannot be performed, the alternative would be to obtain the tissue via excisional or punch method

– A single specimen is adequate provided it can be bisected into 2 adequate samples

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Core Needle Biopsy: Formalin Fixed Paraffin Embedded Preparation

• Obtain core needle biopsy from patient (at least 18 gauge in diameter / 1 cm in length)

• Place biopsy in formalin for between 8-24 hours

• Embed fixed biopsy in paraffin

• Biopsy should be appropriately labeled

• Store at 4°C until shipment at ambient temperature to ICON Central laboratory

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Core Needle Biopsy: Flash Frozen Preparation

• Complete and place the label for cryovial

• Wrap label with scotch tape to prevent label from becoming displaced during the drop into liquid nitrogen

• Obtain second core needle biopsy (at least 18 gauge in diameter / 1 cm in length)

• Immediately after collection place this tissue sample in properly labeled cryovial

• Flash Freeze the cryovial in liquid nitrogen (alternatively, a dry ice bath with ethanol or methanol may be used)

• Store frozen at –70°C until shipment to ICON Central Lab on dry ice sufficient for 3 days

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Pharmacokinetic (PK) Analysis

• Pharmacokinetic samples confirm drug levels over time

• Typically, a set of samples is collected from an individual at set times after dosing

• Once the drug levels are measured, the absorption, distribution, metabolism, and elimination of the drug can be evaluated

• Accurate recording of the time between dosing and each sample collection is of key importance

• Keeping to the planned dosing and collection schedule is highly desirable

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Veliparib/TMZ ArmPK collection

ProcedureVisit

ScheduleBefore Drug

AdministrationAfter Veliparib

AM Dose

Sampling Plan

Specimen Matrix

Veliparib PK Samplinga C1D1 -- 0.5, 1, 2, 3 hBlood Plasma

a. All samples should be drawn in conjunction with clinical lab blood draws.Note: The date and time of sample collection and the date and time of the morning dose of veliparib will be captured on the eCRF.

Veliparib dose is taken

0.5 h (PK 30M) Sample

1 h (PK 1 HR) Sample



Cycle 1

Day 1

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Veliparib +TMZ ArmVeliparib PK processing

Collected only at C1D1• Approximately 4mL of blood will be collected into one 4 mL

potassium EDTA (PK) purple top tube at each time point

• Immediately invert tube 8-10 times to reduce the likelihood of clot formation


• Using plastic pipette, transfer plasma into a labeled screw-capped polypropylene tubes (cryovial)

• Freeze at –20°C or colder within 2 hours of blood collection

• Store samples at –20°C or colder until shipped to ICON Central Lab. Please, make sure there is sufficient amount of dry ice for at least 3 days for the shipment

↺

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Carboplatin and Paclitaxel ArmPK Collection

ProcedureVisit

ScheduleBefore Drug

AdministrationAfter Veliparib AM

Dose

Sampling Plan

Specimen Matrix

Veliparib PK Samplinga C1D3 0 ha 0.5, 1, 2, 3 hFrozen -20°C or colder

Veliparib PK Samplinga C2D3 0 ha --Frozen -20°C or colder

Paclitaxel PK Sampling C1D3 --2 h 55 min after start of

Paclitaxel infusionb Frozen -20°C or colder

Free Platinum (for Carboplatin) PK Sampling

C1D3 --25 min after start of the

carboplatin infusionc Frozen -80°C or coldera. Before the administration of the morning dose of veliparib.b. Approximately 3 hours after the morning veliparib dose.c. Approximately 3.5 hours after the morning veliparib dose.Note: The date and time of the sample collection and the date and time of the last two doses of veliparib will be captured on the eCRF

Blood Plasma

Blood Plasma

Blood Plasma

Blood Plasma

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Carboplatin and Paclitaxel ArmPK collection (cont.)

Veliparib PK before the morning dose of

Veliparib (PK 0H)

0 H

0.5H Post Dose (PK

30M)

1H Post Dose (PK 1 HR)



Paclitaxel PK (PKPAC) 2h55min

after start of Paclitaxel infusion, approximately 3 h after the morning

veliparib dose

Free Platinum (PKLPA) 3h30min after the morning veliparib dose, 25 min after start of the carboplatin

infusion

- Paclitaxel infusion start time

- Carboplatin infusion start time

Cycle 1

Day 3

- ECG to be performed at approximately 2 hours after the morning dose of veliparib

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Carboplatin/Paclitaxel ArmPK Collection (cont.)

Veliparib PK Sampling before the

morning dose of Veliparib (PK 0H)

0 H

- Paclitaxel infusion start time approximately over 3 hours

- Carboplatin infusion start time, immediately following paclitaxel infusion

Cycle 2

Day 3

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Carboplatin and Paclitaxel ArmVeliparib PK processing

• Approximately 4mL of blood will be collected into one 4 mL potassium EDTA (PK) purple top tube





• Store samples at –20°C or colder until shipped to ICON Central Labs on dry ice sufficient for 3 days

↺One 4mL whole blood sample will be collected at each protocol specified time point at C1D3 and C2D3. Collection procedures follow:

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Carboplatin and Paclitaxel ArmPaclitaxel PK processing

• Approximately 4mL of blood will be collected into one 4 mL potassium EDTA (PK) purple top tube





• Store samples at –20°C or colder until shipped to ICON Central Labs on dry ice sufficient for 3 days

↺One 4mL whole blood sample will be collected at the C1D3 visit approximately 3 hours after veliparib morning dose.

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Carboplatin and Paclitaxel ArmFree Platinum processing

One 4mL whole blood sample will be collected at the C1D3 visit approximately 25 min after start of the carboplatin infusion.

↺

• Collect the sample into one 4 mL potassium EDTA (PKPLA) purple top tube

• Immediately invert the collection tube 8 to 10 times



• Samples for free platinum analysis must be shipped on dry ice to ICON Central Laboratories on the same day of draw. Samples will freeze when placed upright in the dry ice.

• If sample cannot be shipped the same day of draw, then sample must be frozen upright at –80ºC or colder within 1 hour after collection and must be shipped frozen to ICON Central Laboratories within 5 calendar days.

• If courier cannot pick the sample up on the day of the draw - place the sample upright in dry ice overnight and re-pack the dry ice when courier arrives in the morning to pick up sample. Sample cannot sit in dry ice at the site for more than 24 hours waiting for courier. This option is only to be used when the courier cannot arrive same-day but will absolutely arrive the next morning.

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Sample Collection OverviewAll Arms

Visit Time Point Samples

Screening Clinical Labs (chem, hem, urin); Tissue samples (Block or Slides + Pathology Report)

FINAL Clinical Labs (chem, hem, urin); CTC; PD; Serial Biopsies (optional)

30DayFU Clinical Labs (chem, hem)

Unscheduled Clinical Labs (chem, hem, urin)

Cycle 3 Day 1 (and every odd cycle there after –

C5D1, C7D1..)

Clinical Labs (chem, hem, urin); PD

Cycle 4 Day 1 (and every even cycle there after

C6D1, C8D1..)

Clinical Labs (chem, hem, urin); PD; CTC

Burnske

Remove CTCs for SIV's conducted outside of US.

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Sample Collection OverviewVeliparib +TMZ Arm

Visit Time Point Sample

C1D1 Clinical Labs (chem, hem, urin); CTC; BRCA Bridging; PD; PG (optional), PK; Serial Biopsies (optional)

C1D15 Clinical Labs (chem, hem), CTC

C1D22 Clinical Labs (hem)

C2D1 Clinical Labs (chem, hem, urin); CTC; PD

C2D15 Clinical Labs (chem, hem)

C2D22 Clinical Labs (hem)

Burnske

Remove CTC for SIV's outside of US.

Burnske


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Sample Collection OverviewCarboplatin + Paclitaxel Arm

Visit Time Point Sample

C1D1 Clinical Labs (chem, hem, urin); CTC; BRCA Bridging; PD; PG (optional), Serial Biopsies (optional)

C1D3 PK (per protocol)

C1D17 Clinical Labs (chem, hem,); CTC

C2D1 Clinical Labs (chem, hem, urin); CTC; PD

C2D3 PK (per protocol)

Burnske


Burnske

remove CTC for SIV's outside of US.

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Barcode Labels – PK / PD / PG Samples

• CTC

• BRCA Bridging

• PG

• PK

• PD

• Archive Tissue

• Serial Biopsies

These labels will have just one barcode on the left side.

The clinical lab samples (Chemistry, CoAg, Hem, Urine, Slides) will have 2 barcodes. These DO NOT get scanned into EDC.

Burnske

Remove CTC for site's oustide of US.

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Lab Barcode Source worksheet example

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Scanning Device Instructions and Troubleshooting

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Scanning Device Instructions – Connecting the Scanner

• Connect the scanning device to your computer’s USB port.

– Note: USB port must be on your computer (not on your keyboard or monitor).

• Scanner will beep 3 times once plugged in.

USB Port on computer

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Scanning Device Instructions – Re-programming the Scanner

• The bar code scanner is programmed and ready to enter data.

• Scan the barcode below if your scanner requires re-programming (see troubleshooting guide).

– Note: You cannot scan the below bar code directly from your computer screen, only from a paper print-out.

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Scanning Device Instructions – Correct Scanning Methods

• The illustration below outlines correct and incorrect scanner positions.

Correct alignment

Incorrect alignment (off-

center)

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Scanning Device Indicators

• Beep Indicators

– Low/Medium/High beep = Power up

– Short medium beep = Bar code decoded

– 4 long low beeps = Data transmission error detected; data has not been successfully entered

• LED Indicators

– Off = Scanner is on and ready to scan or no power to scanner

– Green = Bar code is successfully decoded

– Red = Data transmission error

• Please refer to reference manual that was included with the barcode scanner for help with troubleshooting

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Scanning Device Troubleshooting

No power to scanner• Check computer system power; ensure power cord to computer is connected to power source; ensure

scanner cord is plugged into computer.

Incorrect interface cable• Contact your Field Monitor.

Interface/Power cables are loose• Ensure all cable connections are secure.

Scanner is not decoding barcode• Scanner must be re-programmed to read type of barcode being scanned. See scanner re-programming

instructions.• Move scanner closer to or further from barcode. Note scanner should not physically be touching the

barcode (scan from approximately 10-15 cm away from the barcode).

Barcode is unreadable• Ensure barcode is not defaced. If so, contact your Field Monitor.

Scanner is decoding barcode, but data is not transmitting to the data field• Ensure your curser is in the correct data field.• Ensure all cable connections are secure.

Scanned data displays incorrectly in data field• Scanner must be re-programmed to read type of barcode being scanned. See scanner re-programming

instructions.

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PK - PD - PG (electronic scanning)

• Barcode label must match the subject number, the visit, and the time point

• PK samples must be entered in chronological order, relative to dose

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PD - PG - PK (electronic scanning) (cont.)

Steps for scanning barcodes:1. Plug barcode scanner into USB port on the computer used for data entry into EDC. Scanner

will beep 3 times once plugged in.

2. If your scanner does not decode a bar code follow the instructions in your troubleshooting guide.

Note: barcode numbers will not be accepted until this step is completed. Scanner is now ready to accept barcodes for data entry purposes.

3. Log into the EDC study for M12-895 and access the PG, PD or PK eCRF.

4. Enter date and time of collection into the appropriate eCRF fields for the PG, PD or PK sample.

5. Place the curser in the barcode data entry field labelled ‘Bar code (14-digit number)’ for the corresponding sample.

6. Scan the barcode label from the source document worksheet, associated to the appropriate timepoint. The scanner will beep once the 14-digit barcode number has been successfully scanned. The number will then appear in the data entry field that was previously selected.

7. Repeat (above) steps 4 through 6 for subsequent barcode entries. NOTE: It is important that barcodes be scanned in chronological order with relation to the timepoints.

8. Please save your data every 5 minutes. Queries will fire upon saving data, but repeated saving of your data will prevent potential data loss due to system security time-out.

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Attaching labels to tubes

•Label samples with sample label as per Lab Manual and Summary Collection Guide

•Please write Subject Number on all labels

•Labels placed lengthwise on the collection and transport tubes before collection

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Requisition Form

Subject info

**Missing or inconsistent Subject demographics, collection date and time will result in a Data Clarification Form (DCF) being sent to the site and a delay in reporting**

Test Panels

Collection Info

Collection Information

Shipping Details

Transport Info

Barcode

This barcode not to be scanned

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Completing the Laboratory Requisition

Each specimen collection kit contains its own requisition form. The requisition form is visit and protocol specific.

Please, follow instruction on completing the Laboratory Requisition Forms in Laboratory Manual.

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Visit Specific Supplies and Packaging

• Each sealed package contains all laboratory supplies for specimen collection for an individual patient at a specific visit.

• Please, refer to Laboratory Manual for packaging instructions specific to each type of specimen

• Please make sure you are sending:

–White copy of requisition form with Ambient Samples –Yellow copy of requisition form with Frozen Samples–Pink copy of requisition form stays with the site

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Shipping via FedEx (US & Canada)

FEDERAL EXPRESS Shipping supplies and preprinted airbills will be furnished by ICON Laboratory with your initial lab supply shipment.

Instructions for completing the airbill will be in your lab manual.

For Ambient shipments only the Date & Weight need to be entered, along with the Shipper’s signature.

Remember to mark airbill Saturday delivery, if applicable. Also when shipping on a Friday, the Saturday delivery box on the airbill should be checked and Saturday Stickers must be applied to the package.

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FedEx International Air Waybill (Canada)

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Laboratory Reporting

The lab report will contain the following:

• Site/Subject Demographics

• Test results

• Accession number

• Exclusion Flagging – “E”

• Panic Values –

• Sites will be contacted with panic values via phone and email.

• Site receipt confirmation required.

• 3 attempts will be made to confirm the receipt at the site before it is escalated to the sponsor

• An email alert will be sent to the appropriate sponsor team.

• Sponsor modified alerts

• Reports can be faxed or emailed to sites

• Exclusions, alerts & panics will be flagged on lab reports

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Lab Report Example

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Lab Report Example (cont.)

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Lab Reporting – Testing Times

Test name Shipping Conditions Testing Time*

Chemistry, HCG-Qualitative Ambient 1 Day

Hematology Ambient 1 Day

PT, INR, APTT Frozen 2 Days

Urinalysis Ambient 1 Day

*Note: Once received at ICON

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Delays in Reporting-Queries

• Missing information on Requisition Form• Missing Collection Date/Time• Illegible documentation (hand written)

• Different demographic information between visits• Please ensure demographic info is the same for all visits

• Missing Requisition Form• Please ensure a requisition form is included with all samples

• Samples• Incorrectly labeled samples

• Expired Kits• Please ensure that sites do not use expired kits

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Key Points to Take Away• Use one kit per visit

• Do not mix barcodes from different kits

• Send all required samples labeled correctly

• Write subject identifier on labels

• Complete Requisition Forms fully and clearly

• Ship ambient samples on day of collection

• Contact courier in advance

• For subjects randomized to carboplatin/paclitaxel – the free platinum PK samples should ship to ICON same day on dry ice

• Ensure dry ice has been ordered in advance of the visit (i.e. order on C1D1 for C1D3 draw)

• If samples cannot be shipped same day as draw, then they must be frozen upright at -80oC within 1 hour after collection and shipped frozen within 5 calendar days.

• Contact ICON Central Laboratories or your monitor if you have any questions

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Contact Details

US Client Services

Toll Free Tel: 877-797-4422

8 AM – 8PM EST/EDT, M-F

8 AM – 5 PM EST/EDT, Sat

Global email address:

[email protected]

Please visit our website:

www.iconplc.com/labsitehelp

delucam

Client Services should be updated for any sites ex-US. Please see labmanual for details.

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Myriad BRCA Test Processing Instructions

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Myriad Supplies

• Each kits contains:

• Protective case for vacutainer tube

• 10 mL EDTA (lavender top) tube

• Plastic seal top bag

• Pre-addressed overnight envelope and prepaid air bill

• Specimen handling, collection and shipping instructions

• A test request form/requisition form

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Test Request Form/Requisition Form

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Test Request Form/Requisition Form instructions

• Enter the “Specimen Collection Date” at the top center of the form.

• Complete the “Ordering Healthcare Provider” section of the test request form with name of the physician at your site.

• Provide patient information below –

• Study # • Subject # • Gender

Please, note, the same information should be indicated on the label on top right corner. This label will be affixed to the tube.

• Healthcare provider must sign and date the form in the section labeled Informed Consent and Statement of Medical Necessity in order for the test to be completed

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Sample Collection Instructions:

Collect and Label Sample:

• Draw at least a 7mL sample of blood using the supplied 10mL purple-top EDTA tube.

• Peel off the bar code label found on the upper right-hand corner of the Test Request Form and place lengthwise on the sample tube.

• Write the Site # and Subject ID# on the sample tube. These identifiers must match exactly to the information on the test request form. Do not write patient name on the test request form or sample tube.

• DO NOT centrifuge, refrigerate, or freeze the sample. Room temperature is preferred.

• Ship this sample ambient same day.

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Packaging and Shipping Instructions:Prepare for Shipping:

• Place the blood tube into the foam-lined box and seal the box in the small plastic biohazard bag.

• Place the following items in the Specimen Collection and Transportation Kit:

- Labeled patient sample tube of blood enclosed in the foam-lined box and plastic biohazard bag.

- Completed Test Request Form

• Place the Specimen Collection and Transportation Kit into the FedEx Clinical Pak plastic bag.

Shipping Instructions:

• Affix the prepaid airbill to the outside of the Federal Express mailer. Keep the Federal Express customer receipt for your records / reference.

• If you don’t already have a Federal Express pick-up, call Federal Express at 1-800-GO-FEDEX (1-800-463-3339) for package pick-up. Specify that you are shipping with a prepaid airbill (also called a prepaid billable stamp).

• If you are outside of the United States, go to www.fedex.com and choose your country from the drop-down list.

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Myriad test results

• Sites should set up an account with Myriad to receive the results electronically

• Authorized site personnel will receive results within 14 days of receipt of sample via email after creating account at Myriad website

• Test results will also be provided to the Abbott medical monitor at the same time

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Frequently Asked Questions

How do I sign-up for this new process?

• You can sign up for electronic delivery of test results on-line by going to https://resultsnow.myriad.com

• You will need your Myriad Account Number which is: 2222-5555-6666 and your last name, in order to create your on-line profile.

What other information will I need to provide?

• You will be asked to provide an email address where alerts will be sent. You will select a password and provide a security question and answer for password resets. The email alert will be sent with a hyperlink to the ResultsNow website when test results are ready to be viewed.

If I have more than one Myriad Account Number (address location), can I have all of my account number results (address locations) sent to the same email address?

• All active Myriad Account Numbers (address locations) for which you have received test results will be displayed during the sign-up.

• Please indicate for which Myriad Account(s) you would like email notification sent. For example, if you check both accounts below—

x Account # 452320, 320 Wakara Way, Salt Lake City, Utah

x Account # 55555, 123 State Street, Salt Lake City, Utah

—email notifications for both accounts will be sent to the email address specified in your set-up profile.

• If you have multiple Myriad Account Numbers (address locations), you may choose to have more than one profile (email address). Repeat the steps above for each separate account number (address location) that needs a different email address.

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Frequently Asked Questions (cont.)

What if I want my office manager or nurse to sign-up and receive the results for me?

• An authorized delegate for the Healthcare Provider may sign up. There is a statement in the sign-up process that states, “I am an authorized delegate of the Healthcare Provider registering, not the actual Healthcare Provider.” The delegate will be asked to provide their name and title.

Will I still receive a paper copy?

• No. When you sign up for ResultsNow you WILL NOT receive paper copies of test results. You will be viewing your patient’s test results via a PDF file and will have the ability to print and save a copy.

How do I view the test results?

• Your patient’s test results will be in PDF format and appear the same as the results you now get in printed form via express delivery. You can sort the list of your patient results in many ways to quickly find the one you need. Please remember to change your spam filter settings to accept email from myriad.com. We suggest that you log on to https://resultsnow.myriad.com monthly.

How long will my test results be available electronically?

• Test results will be available for 90 days from the date that you receive the email alert. If you need access to test results after 90 days, please contact our Customer Service Department.

What other documents will be viewable via ResultsNow?

• All of the documents that you currently receive in paper form will be viewable and downloadable for each case, including:

- Patient Test Results (file and patient copies)

- “Understanding Your Genetic Test Results” which may be given to your patient

- Test specifications

- Additional documents, depending on the specific test and test results.

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Myriad Supplies

• Each site will receive 2-4 kits initially

• For additional kits, submit email to:• Stephanie Hamilton: [email protected]• Reference M12-895 study • Allow 14 days for receipt of additional kits

• Questions:• Stephanie Hamilton

Clinical Research AssociateMyriad Genetic Laboratories320 Wakara WaySalt Lake City, UT 84108Phone: 800-469-7423 x 5102Fax: 801-584-3099

OR• Customer Service 800-469-7423

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Introduction to the ClinPhone IWR/IVR for Abbott (M12-895)

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Agenda

• Access to System

• IWR Overview

• IWR Account Set Up

• Web Session Types

• Reports and Alerts

• Support

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Accessing the IWR system

• Make sure you have:

–Access to the Internet

–An access code envelope

–A worksheet and your manual for guidance.

–Read all instructions on the Web page

–Complete the web form

–Fill in appropriate spaces on worksheet during call

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Account Creation/Envelope Activation• Account Creation:• If you do not have an existing ClinPhone account…• Create an account using the Create My ClinPhone

Account link.• Enter all requested details (username, email, password).

After the account is created a link will be sent to your email which must be utilized to register the account within 30 days.

• Envelope Activation:• Select “Activate a New TIN”.• Enter the 16-digit TIN (Temporary Identification Number)

from your envelope. • You will be prompted to enter study specific information,

e.g. site name/number.• Enter a 4-digit PIN of your choice (confidential)• System will now display your 8-digit permanent access

code. Please record this number somewhere safe and confidential as it will be used in all subsequent sessions.

• NOTE: If you already have an access code for another study, you may link that code to your new envelope.

• Your account set-up is now complete! Document on your Envelope Activation worksheet

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To set up a new Clinphone Account log onto: www.clinphone.com/signin and select ‘Create new account’. Fill in the form and select ‘Continue’.

New ClinPhone Account

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Confirmation email is received by the user. This link MUST be clicked on to activate the account.

New ClinPhone Account

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SUL Login www.clinphone.com/signin

Select “Enter My Clinphone Online”

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Activate New Envelope

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Accessing the IWR system – Security Envelopes

Abbott Protocol: M12-895

ClinPhone Reference: ABB240User Type: Investigator

Envelope Number: XXXXX

TIN: XXXX-XXXX-XXXX-XXXX

Your ClinPhone Temporary Identification Number for the protocol printed on the front of this envelope is shown above.

Please refer to your User Manual for instructions on how to use it.

Outside of envelope

Inside of envelope

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Activate New Envelope

After entering your TIN and following the prompts, IWR will display your 8-digit access code

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Log On

• You can now enter your username and password to access M12-895.

• This is not your PIN!!

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General Navigation

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Support

• You can contact support via the following contacts:

• You will be given a ticket number.

• When emailing, please provide the unique

study code: ABB240

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User Call/Web Options

• Investigator/Site Personnel

• Screening – Used to screen a subject

• Screen Failure – Used to register a subject as having failed screening

• Randomization – Used to randomize a subject and assign initial supply of drug.

• Scheduled Medication Resupply – Used to assign medication to subjects at scheduled visits.

• Emergency Resupply – Used to replace damaged or lost medication assigned to a subject during a scheduled resupply.

• Subject Status Change – Used to register a subject as on-study/off-drug(s), or off-study

• Emergency Code Break – Used to unblind a subject in the case of a medical emergency (PI only)

• Medication Arrival – Used to make drug shipped to the site available in the system

• Confirmation report will be triggered once any option is complete

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Medication Arrival

• Medication Arrival Call:

• Site User enters – Shipment Number– confirms whether any medication should be marked as lost or damaged,

• User given the option to register additional medication shipments as arrived.

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Change Medication Status

• Change Medication Status Call:

• Allows the Site User to update the status of medication already acknowledged as received at their site

• Site User provides information about medication:– Damaged or Lost

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Change Medication Status

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Screening

• Screening Call:

• Site User enters – Screening Date– Date of Birth (Month/Year)– Gender

• Once the site user confirms to proceed the system will generate the subject number.

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Screening

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Screen Failure

• Screen Failure Call:

• Site User enters – Subject number – Confirmation of Date of Birth and Gender (each provided)– Screen Failure Date

• Once the site user confirms to proceed the system will screen fail the subject

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Screen Failure

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Randomization

• Randomization Call:• Site User enters

– Subject Number – Confirmation of Date of Birth and Gender (each provided)– The subjects Estrogen receptor and progesterone receptor status– If the subject’s received prior cytotoxic therapy– The subject’s ECOG performance status grade– The subject’s BSA value – The following daily dose questions will be asked in case the subject is randomized to required

treatment arm• Subject’s daily dose for TMZ (should be 150 mg/m2/day)• Subject’s daily dose for Carboplatin (should be AUC 6)• Subject’s daily dose for Paclitaxel (should be 175 mg/m2)

• System announces the randomization number and medication to be dispensed to subject.

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Randomization

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Randomization

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Randomization

Your password will be required to proceed.

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Scheduled Visit

• Scheduled visit Call:

• Site User enters – Subject Number – Confirmation of Date of Birth and Gender (each provided)– Confirmation of next (current) visit– User will be asked if a change subject status is needed

– Subject’s BSA value– Opportunity change doses for each pack type (Specific to treatment arm)

• System announces Subject Number and medication to be dispensed to patient

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Medication Replacement

• Emergency Re-supply:

• Site User enters – Subject Number – Confirmation of Date of Birth and Gender (each provided)– Confirmation of last visit and that replacement is needed– Kit number to be replaced

• System announces replacement medication to be dispensed to patient

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Change Subject Status

• Change Subject Status Call:

• Site User enters – Subject Number – Confirmation of Date of Birth and Gender (each provided)– Confirmation of subject status– Option to change subject status– User will be asked if a change subject status as needed

• Please use work sheets as a guide to assist through the call

• System announces Subject new status

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Change Subject Status

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Survival Assessment

• Survival Assessment:

• Site User enters – Subject Number – Confirmation of Date of Birth and Gender (each provided)– Confirmation of subject status

– Subject survival assessment status – Enter the date of death (if needed)

• If the subject's death due to metastatic breast – Last known alive date – If the subject receive any new cancer therapy

• Please use work sheets as a guide to assist through the call

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Survival Assessment

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Survival Assessment

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Blind Break (PI only)

• Functionality only available to the Investigator role.• Abbott must be notified before the blind is broken unless identification

of the study drug is required for medical emergency, i.e., a situation in which the knowledge of the specific blinded treatment will affect the immediate management of the subject/patient’s conditions. Abbott must then be notified within 24 hours of the blind being broken.

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Abbott Temperature Excursion Management System(ATEMS)

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Temperature Excursion Paper Form

• Complete the paper Temperature Excursion Form located in the Investigator Site File if ATEMs in not available

• Once ATEMs is available, Abbott GDSM will enter the information into ATEMs to ensure all historical information is captured

– No updates to ATEMs by site if paper form is utilized!

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ClinPhone Drug Accountability

• Web-based solution that enables study sites, sponsors and depots to fully track and manage the drug accountability, reconciliation, returns and destruction process

• Developed based upon market research with Trial Directors, CRAs, Depot personnel, Study Site Coordinators and Site Pharmacy personnel

• Hosted by Perceptive Informatics (via ClinPhone IVRS)

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An extension of IVRS Trial Supply Management

Distribution Depot to depot | Depot to site

Dispensation Subject randomization

& pack allocation

AccountabilitySubject dispensing & Return documentation

ReconciliationReview & confirmation of accountability data

DestructionDestruction confirmation

ReturnsManage return of shipments

IVRS Trial Supply Management

• Manages shipment of medication from depot to site

• Manages allocation of medication packs to subjects

• ClinPhone Drug Accountability

• Records site dispensation

• Records medication return and

• reconciliation

• Manages return shipments

• Records depot reconciliation activities

• (if required)

• Records destruction information

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Web-Based Functionality

Electronic signature

Ability to add and respond to comments

Error checking

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List of Kits at Site•Search and Filter functionality

•Allows you to view kit status, reconciliation status and date dispensed

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Lost or Damaged Kits

To identify kit either perform a search or select from the Kit list:

•Enter the lost or damaged date

•Enter comment to explain

•Enter PIN/Save

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Site Accountability

•Returned Date (date returned by subject)

•Accounted Date (date of site accountability)

•Returned/Unused (# of capsules returned)

•Used (# of capsules not returned)

•Comments should be utilized to denote any discrepancies

•Enter PIN/Save

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Kit Destruction

If a discrepancy is noted during monitor reconciliation:

•Enter comments explaining the discrepancy

•Site will be alerted to these comments at the next time they access the system

•Enter PIN/Save

•Once saved – Comments will remain in audit log

If a site has an approved on-site destruction SOP:

•Site can enter destruction date if a kit is destroyed on-site (on-site forms should be utilized)

•Enter PIN/Save

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End of Session Summary

Summary page will display at the end of a session and allow you to view your transaction

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Monitor Reconciliation

•Reconciled Date (date of monitor reconciliation)

•Returned/Unused (# of capsules returned)

•Used (# of capsules not returned)

•Enter comments to denote SDV or any reconciliation discrepancies

•Enter PIN/Save

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Reconciliation Discrepancies

If a discrepancy is noted during monitor reconciliation:

•A comment will be entered explaining the discrepancy

•Sites will be alerted to these comments at the next time they access the system

•Comments will remain in audit log

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Reports and Notifications

• Following each transaction, a notification will be sent

• Notifications can be sent via email or fax

• Documents information entered during the transaction– Site number– Screening or Subject number– Date of session– Etc.

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Help and Advice

• User Guides Provide:

• FAQs

• Links to Customer Care phone and fax numbers

• User Worksheets Provide:

• All the necessary information to complete the session

• Space to record information provided by the IWRS

• Copy all worksheets prior to use to have extras available for future sessions

• Once you have activated your account, practice on the training system prior to making your first IWR transaction

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Help and Advice

• Support is available 24/7/365 via:

• Telephone

• Fax

• Email

• Provide the following information when contacting Support:

• Study Reference – ABB240

• Protocol Number – M12-895

• Complete contact details - Site ID Number, Name, Fax, Phone Number, and/or Email Address

• Be specific regarding your query and include date/time of call, what you heard, subject/screening number, etc.

• Some manual updates/changes will require authorization from Abbott

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M12-895 Good Clinical Practice for Clinical Investigators and Study Sites

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Good Clinical Practice (GCP)

What is GCP?

• An international ethical and scientific quality standard for designing, conducting, monitoring, auditing, recording, and reporting trials that involve the participation of human subjects

Why is GCP important?

• Provides assurance that the rights, integrity, and confidentiality of trial subjects are protected

• Provides assurance that the clinical trial data and reported results are credible and accurate

GCP references:

• International Conference on Harmonization (ICH) E6 Good Clinical Practice

• Country specific regulations

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Why is Abbott putting emphasis on GCP?

• To ensure ethical conduct and protection of subjects participating in Abbott clinical trials

• As a sponsor, Abbott must comply with its obligations for regulatory standards at global level

• Abbott can use data from the clinical trials only if compliance is ensured also by clinical sites. Loss of data from non-compliant clinical sites is a serious consequence for Abbott.

• In case of non-compliance, Abbott is obligated to take prompt action to secure compliance, including but not limited to inspection by the Sponsor, termination of the investigator’s participation in the study and notification to regulatory authorities

• Upon notification of regulatory agencies, further inspections and regulatory actions are possible, including Warning Letters, Disqualification/Restriction of investigator or staff

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Working together…to ensure a successful trial in compliance to GCP

Trial SubjectParticipates in the

clinical trial

InvestigatorResponsible for the

conduct of the clinical trial

Sponsor Takes responsiblity for initiating, managing

and/or financing the clinical trial

Monitor Oversees the progress of the clinical trial, ensures it is conducted,recorded

and reported as per requirements

IRB/ECSafeguards the rights, the

safety and the well being of trial subjects

Obtains informed consent, ensures adequate medical care, collect data

Provides data

Interacts with the

investigator and advises

him

Reports progress of the clinical

trial

Regulatory Agency

InspectionOfficial review of

documents, facilities, records and

resources related to the clinical trial

Sponsor AuditSystematic and

independent examination of trial-related activities and

documents

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Implementation of the Trial

You have agreed to participate in the trial

Per GCP, this means the Principal Investigator (PI) has taken responsibility for ensuring and is able to demonstrate:

• there is a potential for recruiting the required number of suitable subjects within agreed timelines

• there is an adequate number of qualified staff and compatibility of the workload for the planned duration of the study

• there are adequate facilities to conduct the trial properly and safely

• monitoring, Sponsor auditing and Regulatory inspections are permitted (and facilitated)

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Investigator Oversight

The Principal Investigator (PI) must personally supervise study activities and individuals who assist him in order to conduct the study efficiently, safely and in a timely manner

• Be familiar with protocol, investigational product & GCP requirements

• Provide adequate information about the trial to other involved parties at the trial site (lab, pharmacy, etc)

• Use only EC/IRB-approved documents

• Document study activities as required

• Train your personnel on the study

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Investigator Oversight

The Principal Investigator (PI) must personally supervise study activities and individuals who assist him in order to conduct the study efficiently, safely and in a timely manner

• Supervise study progress

• Schedule sufficient time to review subject medical charts and complete CRFs

• Timely review of lab reports/records and report AE as required by protocol

• Oversee drug administration, data handling and source documentation completion when delegated to your staff

• Be present at Monitoring Visits: meet with monitor and review study progress

The monitor is here to help you in conducting a successful trial!

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Qualifications, Delegation and Training

• The Principal Investigator must be qualified by education, training and experience to assume responsibility for the proper conduct of the study

• Other individuals at study site must be qualified and trained to perform (delegated) study-related duties

• Delegation of Activities is OK but Study Conduct remains the PIs responsibility

• Delegation is to a qualified individual for a specific activity and in agreement with the protocol requirements

• Delegation is approved by the PI (via signature on a Delegation Log)

• Maintain a Delegation of Responsibilities Log and Signature Log

• Update when personnel changes occur

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Qualifications, Delegation and Training

Training records

must match with

delegated duties

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Medical Care of Trial subjects

Study related medical decisions must be made by a physician who is the investigator or a sub-investigator

• Study procedures (i.e physical examination, laboratory results review, etc.) to determine subject eligibility and continued participation in the trial

• Inclusion/exclusion criteria/removal from trial

• if subject agrees, inform his/her primary physician about subject’s study participation

• ascertain reason(s) for subject’s premature withdrawal, fully respecting his/her rights

• Adverse event assessment

The review should be documented (sign/date) and should be evident throughout the study.

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Ethics Committee / Institutional Review Boards

Ensure IRB/EC approval/favourable opinion:- was obtained before starting the trial and implementing any amendments- is signed/ dated and clearly identifies the trial, the investigator, the documents reviewed and their versions.

Maintain copies of :- reports submitted to the EC- reports of all actions or modifications requiring prior approval/favourable opinion and other notifications.

All IRB/EC (central and/or local) and Regulatory Authority requirements must be met for approvals and notifications of:

• Protocols and all amendments

• Informed consents and information provided to subjects

• Investigator’s Brochure

• Expedited safety reports (IND safety reports/SUSARS)

• Protocol deviations

• Premature Termination or Suspension of the Trial

• Study reports and results if required

• New information and requests for information

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• Conduct study according to the EC/IRB approved protocol

• Sign the protocol (and any amendment) to confirm your agreement

• Do not implement any protocol deviation prior to Abbott agreement and review by the Ethics Committee, except when necessary to eliminate an immediate hazard to study subjects

– Submit any protocol deviation implemented to eliminate an immediate hazard to study subjects as soon as possible to the Ethics Committee, to Abbott and to the Regulatory Authorities, as applicable

– Contact your Abbott monitor or the Abbott Medical Monitor with any questions

• Any deviation should be documented and explained

Protocol Compliance

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Informed Consent of Trial Subjects

Approvals

• Prior to screening subjects, the ICF(s) and any written information given to the subject (e.g., dosing instructions, subject diaries) must be approved by the EC

• Ensure the EC Approval is obtained for the ICF/other written information in the language in which it will be provided to the subject

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Administration• Ensure the most current, approved version of the ICF is

administered and signed by the subject before any study procedures are done

• The investigator or person designated should provide the subject ample time and opportunity to inquire about details of the trial and to decide whether or not to participate

• Ensure the subject dates his/her own signature• Must be Ensure the ICF is written in a language understandable

to the subject (e.g., English, Spanish, etc.)• If administration of the ICF is delegated to a non-physician,

make certain a process is in place where a physician is available to answer questions when needed

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Documentation

• Review ICF to ensure it is fully completed by the subject. Ensure all signature(s) are complete

• Document in the source that informed consent was obtained prior to any study-related procedures and that the subject received a copy of the signed/dated ICF/other written information (including amended informed consents)

• Place the original signed/dated ICF in the site records

Re-Consent:

• The ICF and other written information should be revised whenever important new information becomes available or as required by the EC

• Subjects should be informed in a timely manner if new information becomes available that may be relevant to their willingness to continue in the trial.

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Investigational Product

• Review and understand the Investigator’s Brochure

• Maintain accurate records of study drug accountability (quantity received, dispensed to each subject, returned)

• Drug accountability duties may be assigned to the pharmacist or other appropriate individual who is under the supervision of the Investigator

• Only dispense to subjects in accordance to the approved protocol

• Explain the study drug correct use to each subject and ensure they are following instructions

• Subject needs to return used/unused supplies at scheduled visits.

• All unused supplies are returned to Abbott or destroyed on-site per agreement with Abbott

• If applicable, manage randomization process and blind breaking as per protocol

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Investigational Product Storage

• Store drug in a secure location

• Store drug at required temperature

• Monitor temperature using a calibrated thermometer

• Notify Abbott immediately of any temperature excursions

• Do Not dispense drug exposed to temperatures outside the identified range until confirmed by Abbott

• Do Not dispense drug that has expired or is expected to expire while the subject is dosing

• Quarantine drug such that no accidental dispensing errors occur

• Contact your monitor in case of expired drug on-site

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Records and Reports

• All data must first be documented in a source record then later transcribed onto the CRF (unless protocol indicates data may be entered directly on the CRF)

• Source records are defined as original documents, data and records of clinical findings, observations and study visit procedures. Examples include:

• Medical charts, source worksheets, hospital records, physician’s notes, lab reports, subject diaries;

• Data from automated instruments, x-rays;

• Electronic medical records

• Source documents are both current and historical records

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Records and Reports

• Regulatory Agencies can review “all” source records

• Ensure source records also contain information pertinent to protocol compliance and PI oversight (e.g., counseling on non-compliance to study drug, AE and concomitant medication assessment at each visit, follow-up calls)

• Do not use a pencil to record source data

• CRF data should be consistent with source documentation

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Records and Confidentiality

Records

• All study related records must be maintained for the period of time specified by Abbott.

• Allow access to study records upon request for Monitoring, audits and inspections (e.g., Regulatory Authorities, Abbott, IRB/IEC)

Subject Confidentiality

• Obscure subject identifying information on all documents sent to Abbott (e.g., discharge summaries, ECG tracings, local lab reports)

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Good Documentation Practices

• Keep Site Trial Master File up-to-date

• Follow Good Documentation Practices and review documents to ensure they are:

•Complete

• Are all the required documents present?

• Site staff listed on signature delegation log are not listed on Site Initiation Statement or training documentation

• Are all the pages present in each document?

•Legible

• Can handwritten entries be read?

• Check scan quality, is the print dark enough so that it can be read easily?

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Good Documentation Practices

• Follow Good Documentation Practices and review documents to ensure they are:

•Accurate

• Is all information entered correct and consistent?

• Address is complete, including country

•Current

• Are documents that have time bound limits within the required parameters?

• lab certification, last version of informed consent

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Safety Reporting

• Be aware of risks and side effects described in Investigational Brochure

• Adverse Events

• Investigate and report adverse events

• Follow adverse events until resolved

• Serious Adverse Events (SAEs)

• Report serious adverse events to Abbott, IRB/EC and Regulatory Bodies as required

• Report all SAEs to Abbott within 24 hours of site awareness

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Working Together,

We can achieve…

• Ethical conduct and protection of subjects

• Compliance with sponsor and regulatory requirements

• Compliance that allows for use of clinical data from your site

We can avoid…

• Non-compliance and the need for corrective action

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© 2012 Abbott

Concomitant MedicationsInvestigator Responsibilities & General Study/Visit Information

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Investigator Responsibilities

•Review of ICH/GCP Guidelines

•Accessibility of study staff and study documentation

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Investigator Responsibilities-US and Canada

• From FDA 1572

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Accessibility of Study Staff and Study Documents

• First monitoring visit will occur within 14 days of first subject randomization

• Monitoring visits to be conducted at approximately ≥ 10 week intervals

• PI is expected to be present (or available by phone during or shortly after) each visit.

• Study Coordinators should be available at every visit.

• Study will utilize Remote Monitoring, therefore, data must be entered into EDC within 5 business days. Queries should also be resolved within 5 business days.

• Source documents should be maintained and the Essential Documents Binder updated on an ongoing basis throughout the study.

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GCP Training

• Principal Investigator and Primary Study Coordinator to be instructed of his/her responsibility to comply with GCP/ICH before initiating screening activities

• CBTs must be completed before sites start screening subjects

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Ongoing Training

• All study staff who were not in attendance at the Site Initiation Visit must receive training on the protocol before they may perform any study activities

• Ongoing training may be conducted via on-site visits and/or teleconferences

• All training should be documented via training logs and filed in the Essential Documents Binder.

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Record Retention

• All study documents should be retained for at least two years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or until at least two years have elapsed since the formal discontinuation of clinical development of the investigational product

• Abbott will inform the Investigator/Institution as to when trial documents no longer need to be retained

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Informed Consent

• Informed Consent Process

• More than just a signature on a form

• Ongoing process throughout duration of study

• Process of obtaining consent should be documented in source documents

• Informed Consent Documentation

• All pages signed and dated (as appropriate) by:– Subject– Person who conducts the Informed consent discussion– Principal Investigator (per IRB/EC/CA requirements)

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Informed Consent Reminders

• Subjects must sign consent prior to conducting any study specific procedures

• Medication Washouts

• Subject must sign consent prior to washing out of a medication

• Review date of consent to compare the medication stop dates in EDC

– The date the subject signs consent is recorded as the screening visit date• No screening procedures can be done until consent is signed.

• Site personnel providing consent should have documented delegation to do so

• Ensure subjects have been consented on current version of consent and re-consenting has been completed in a timely manner (at the next subject visit)

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Site Supplies

• Regulatory Binder

• CTC 4.0 (version 4.03)

• RECIST quick references guides

• Subject dosing cards (Veliparib + TMZ)

• Subject dosing cards (Veliparib/Placebo + Carb + Taxel)

• Barcode scanner (1 per site)

• IVR/IWR access code envelopes

• 1 assigned for PI, maximum of 5 for study site

• IVR/IWR short user guides

• QoL (10 copies) – Data entered into EDC by site staff

• CIPN (10 copies) – Data entered into EDC by site staff

• BRCA source worksheets

• Lab barcode source worksheets

• Mini Protocols

• Procedure Cards

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Study Forms

• Site Initiation Statement

• Supplemental Training (training provided after the SIV)

• Site Signature/Initial/Delegation of Responsibility Log

• Monitoring Visit Log

• Study Drug Temperature Log(s) – 1 for each drug used in the study

• On-Site Drug Destruction Form(s) – 1 for each drug used in the study

• Storage Temperature Excursion Form (ATEMs)

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Questions & Answers