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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
• Objectives• Eligibility• Medical History/Concomitant Medications• Study Visit Procedures• Study Medication• Subject Discontinuation and Survival Follow-up
• 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.
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.
• 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
• 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
• 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
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
• 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
• 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
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)
• 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
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
• 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
• 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
• 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:
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.
• 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.
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
• 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
• 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
• 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
• 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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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
• 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
• 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.
• 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
Concomitant Medications
Study Medication
Veliparib + Carboplatin/Paclitaxel and Placebo + Carboplatin/Paclitaxel
*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
• 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
• 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
• 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)
• 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
Concomitant Medications
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
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.
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
• 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.
• 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
• 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
• 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.
• 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
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
• 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.
• 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.
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.
• 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.
• 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
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.
• 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
• 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)
• 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
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)
• 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
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
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.
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
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
2 h (PK 2 HR) Sample
3 h (PK 3 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
• Centrifuge the blood samples at 1100 to 1300 x g for 10 minutes using a refrigerated centrifuge at 2ºC to 8ºC
• 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)
2H Post Dose (PK 2 HR)
3H Post Dose (PK 3 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
• Immediately invert tube 8-10 times to reduce the likelihood of clot formation
• Centrifuge the blood samples at 1100 to 1300 x g for 10 minutes using a refrigerated centrifuge at 2ºC to 8ºC
• 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 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
• Immediately invert tube 8-10 times to reduce the likelihood of clot formation
• Centrifuge the blood samples at 1100 to 1300 x g for 10 minutes using a refrigerated centrifuge at 2ºC to 8ºC
• 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 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
• Centrifuge the blood samples at 1100 to 1300 x g for 10 minutes using a refrigerated centrifuge at 2ºC to 8ºC
• Using plastic pipette, transfer plasma into a labeled screw-capped polypropylene tubes (cryovial)
• 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
Remove CTC for SIV's outside of US.
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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
Remove CTC for SIV's outside of US.
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.
• 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
• 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
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
– 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.
• 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
• 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
• 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
• 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.
• 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)
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
• 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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Informed Consent of Trial Subjects
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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Informed Consent of Trial Subjects
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:
• 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
• 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.
• 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
• 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.
• 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
• 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)
• 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)