Presentation on theme: "IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting Chemotherapy Adjuvant Study for Women at Advanced Age (CASA) Diana Crivellari, MD Centro di Riferimento."— Presentation transcript:
IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting Chemotherapy Adjuvant Study for Women at Advanced Age (CASA) Diana Crivellari, MD Centro di Riferimento Oncologico, Aviano (PN), Italy Silvia Dellapasqua, MD European Institute of Oncology, Milan, Italy
Annual Incidence by Age US, 1995 http://merck.micromedex.com Sirovich BE, Sox HC Jr. Surg Clin North Am 79: 961-90, 1999
Baseline life expectancy for patients with various ages and comorbidity levels Life expectancy (years) Age (years) Healthy Average Sick 6520.018.59.7 7015.814.88.6 7512.111. 57.3 808.88.45.9 818.104.22.168 Extermann et al, JCO, 2000.
Available information Use of adjuvant chemotherapy for elderly women with breast cancer is controversial. Lack of clear guidelines for patients aged > 70 years. Decreasing use of chemotherapy with age. No age-related differences in drug regimens neither recommended nor preferred by pts. No clinical trials specifically conducted in elderly women with endocrine non-responsive breast cancer. EBCTCG 1998 & 2005 Overview publications: no information (too few women > 70 years).
Patients on IBCSG Trials I-14 according to age > 65 years old at entry TrialTotal ptspts > 65pts >70 I - IV1601320137 V2504537 VI147500 VII121226485 VIII111100 IX166939291 10473446382 1117400 1234410822 13129400 14969 962 Total 12813 1666 (13%) 717 (5.6%)
CHEMOTHERAPY RECURRENCE Age < 50 6901 women 35% N+
CHEMOTHERAPY RECURRENCE Age 50 - 69 18629 women 70% N+
CHEMOTHERAPY RECURRENCE Age < 50 ER Poor No TAM 1673 women 12% N +
CHEMOTHERAPY RECURRENCE Age < 50 ER +/? All with TAM 2254 women 34% N + 87% ER+
CHEMOTHERAPY RECURRENCE Age 50 - 69 ER Poor No TAM 1474 women 29% N +
CHEMOTHERAPY RECURRENCE Age 50 - 69 ER +/? All with TAM 11333 women 73% N + 88% ER+
Approaches: adjuvant CT Advanced age and endocrine non-responsive breast cancer represent a therapeutic dilemma. The physician may decide not to offer a relatively frail patient any treatment for fear of possible subjective or severe toxic effects of chemotherapy. Patients may be treated in a heterogeneous way, by arbitrarily reduced doses or modified schedules of adjuvant CT regimens studied in younger women. Such dilemma does not exist if the patient is biologically (and functionally) young, and a “standard” chemotherapy regimen may be offered with no concern.
Rationale Relapses may occur earlier in patients with endocrine non-responsive disease, even when pN0. The choice of the population (endocrine non-responsive) is advantageous because the magnitude of CT effect for this postmenopausal cohort is likely to be quite large. Avoiding dilution with patients with endocrine responsive tumors maximizes the chance to observe a benefit in the shortest time with the lowest number of patients.
Chemotherapy Adjuvant Study for Women at Advanced Age (CASA) Phase III Trial Evaluating the Role of Adjuvant Pegylated Liposomal Doxorubicin (PLD, Caelyx®, Doxil®) for Women (age 66 years or older) with Endocrine Non-Responsive Breast Cancer Who Are NOT Suitable for Being Offered a “Standard Chemotherapy Regimen” Two Individual Complementary Randomization Options: Option 1: CASA-nil (PLD versus nil) Option 2: CASA-CM (PLD versus CM) Coordinating Group: IBCSG
Tailored Treatment Investigations A phase III study, the CASA Study, with two individual complementary randomization options: Investigate the role of adjuvant cytotoxic CT for postmenopausal women at advanced age with endocrine non-responsive early breast cancer Options tailored to the investigator's decision and/or the patient’s preference about what would constitute an appropriate control treatment group
Tailored Treatment Investigations Choice between options 1 & 2 allows investigators to “personalize” participation according to attitude towards adjuvant CT in a subpopulation of older women with receptor negative disease. Although incidence of breast cancer in elderly women is high, only about 15% will have a receptor negative (no expression of ER and PgR) disease. Thus, a satisfactory accrual can only be reached through an international collaboration and participation around the world.
Because of the separate designs, at the time of randomization the investigator will be asked to select one of the two Randomization Options: Low-dose, metronomic CM RANDOMRANDOM PLD alone q 2w x 8 No adjuvant therapy (nil) RANDOMRANDOM Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. PLD: 20 mg/m 2 iv x 8 doses delivered every 2 weeks Low-dose, metronomic Cyclophosphamide and Methotrexate (CM): C = cyclophosphamide 50 mg/day orally continuously for 16 weeks; M = methotrexate 2.5 mg/twice a day orally days 1 and 4 of every week for 16 weeks. PLD alone q 2w x 8 Option 1: CASA-nilOption 2: CASA-CM Trial Design
RANDOMRANDOM Caelyx alone q 2w x 8 No adjuvant therapy (nil) Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. Caelyx®: 20 mg/m 2 iv x 8 doses delivered every 2 weeks CASA-nil
Low-dose, metronomic CM RANDOMRANDOM Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. Caelyx®: 20 mg/m 2 iv x 8 doses delivered every 2 weeks Low-dose, metronomic Cyclophosphamide and Methotrexate (CM): C = cyclophosphamide 50 mg/day orally continuously for 16 weeks M = methotrexate 2.5 mg/twice a day orally days 1 and 4 of every week for 16 weeks. Caelyx alone q 2w x 8 CASA-CM
Tailored Treatment Investigations Due to the separate designs, at the time of randomization the investigator will be asked to select one of the two Randomization Options: Option 1, Caelyx versus nil, is designed for patients who, according to the treating physician and/or to the patient's preferences, are candidates to receive no adjuvant therapy. Option 2, Caelyx versus low dose, metronomic cyclophosphamide and methotrexate (CM), is designed for patients who, according to the treating physician and/or to the patient's preferences, should receive some adjuvant treatment.
Patient Population Patient Characteristics 1.Women aged 66 years or older with histologically proven, resected breast cancer. 2.Patients must NOT be candidates for endocrine therapy or standard chemotherapy regimen. 3.Performance status (ECOG) 0-2.
Patient Population Disease Characteristics 1.Patients must have endocrine nonresponsive tumors (ER < 10% by IHC; if PgR done, < 10% by IHC) 2.Tumor must be confined to the breast and axillary nodes without detected metastases elsewhere. 3.Not eligible: locally advanced inoperable BC including inflammatory BC, supraclavicular node involvement, or enlarged internal mammary nodes (unless path. neg.). 4.Patients with synchronous (diagnosed histologically within 2 months) bilateral invasive breast cancer eligible if all tumors are endocrine nonresponsive and above criteria are met.
Patient Population Prior Surgery 1.Patients must have had surgery for primary breast cancer (with or without axillary clearance) with no known clinical residual loco-regional disease. 2.Margins must be negative for invasive breast cancer and DCIS. 3.Patients should be randomized and start treatment as close to definitive surgery as possible; within 6 weeks is recommended and not more than 16 weeks (from last surgery in case of bilateral breast cancer).
Patient Population Prior/Concurrent Disease: Not eligible 1.Prior ipsilateral or contralateral invasive BC. 2.Previous or concomitant malignancy within the past 5 years. Adequately treated basal or squamous cell ca. of the skin, in situ ca. of the cervix or bladder, contra- or ipsilateral in situ breast ca. are eligible regardless of date of diagnosis. 3.Other non-malignant uncontrolled systemic diseases that would preclude trial entry according to PI (e.g. uncontrolled active or chronic infection such as active HBV or HCV). 4. Myocardial infarction, pulmonary embolism or DVT within 6 months prior to randomization. 5.Significant malabsorption sdr or disease affecting GI tract function 6.At least one “geriatric syndrome”: dementia, delirium, depression, recent falls, spontaneous bone fractures, neglect and abuse.
Patient Population Prior Treatment 1.No prior neoadjuvant or adjuvant therapy for BC. Note: Radiotherapy is allowed prior to randomization. 2.Raloxifene, tamoxifen, or other SERM must be discontinued at least 4 weeks before randomization.
Patient Population Concurrent Treatment (at the time of randomization pts should not be receiving these treatments) 1.No hormone replacement therapy (HRT). 2.No hormonal therapy, except steroids for adrenal failure, hormones for non-breast cancer related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic. 3.No treatment with bisphosphonates, except for the treatment of osteoporosis.
Patient Population Organ function at the time of randomization (within 2 months before randomization) 1. Adequate bone marrow, renal, and hepatic function. Values must meet the following criteria: WBC 3.0 x 109/L Granulocyte count 1.500 x 109/L Platelet count 100 x 109/L Serum creatinine < 120 mol/L (< 1.35 mg/dl) Calculated creatinine clearance at least 50 mL/min Serum bilirubin within normal/reference range AST/ALT within 1.5 x upper normal limit
Patient Population Organ function at the time of randomization (within 2 months before randomization) 2. Adequate cardiovascular function defined as the following: LVEF 50% by echocardiography, radionuclide ventriculography or Multigated Angiography (MUGA) No ECG evidence of acute ischemia No evidence of medically relevant conduction system abnormalities, which in the opinion of the PI would preclude trial entry No myocardial infarction within the past 6 months No NYHA class III or IV congestive heart failure
Patient Population Protocol Requirements BEFORE Randomization 1.Written Informed Consent (IC) signed and dated by patient and investigator prior to completing QL Forms and prior to randomization. 2.Baseline QL assessment: Quality of Life Questionnaire Form QL Mini-Cog test (cognitive functioning) Vulnerable Elders Survey [VES-13] test (physical functioning) Only exceptions: physical impairment that interferes with QL assessment, inability to read any of the languages available.
Patient Population Protocol Requirements BEFORE Randomization 3.Pathology material should be available for submission for central review as part of the quality control measures for this protocol. 4.Patients must be accessible for follow-up. 5.Patients must be informed of and agree to data and tissue material transfer and handling, in accordance with national data protection guidelines. 6.Patients should have no psychiatric, addictive, or cognitive disorder that would prevent compliance with protocol requirements.
Endpoints Primary:Breast cancer free interval (events are reappearance of invasive breast cancer at any site including contralateral disease) Secondary:Tolerability (treatment completion) Adverse events Quality of life DFS (incl. 2 nd malignancies and deaths) Sites of failure Second (non-breast) malignancy OS Causes of death
Primary objective: investigate role of PLD as adjuvant chemotherapy for older postmenopausal women Stratified (pooled) analysis combining the results of both randomization options to assess the primary evidence on effectiveness of PLD (PLD versus non-PLD-containing control groups, either nil or CM) Separate analyses for each of the 2 randomization options to assess each of the individual pair-wise contributions to the overall result 1296 patients (432 per year for 3 yrs with 1.76 years of additional follow up – total study duration of 4.76 years) Statistical considerations, sample size and anticipated study duration
CASA Trial… Is about to start accrual. Additional background for PLD or metronomic CT is available.
Background: PLD in metastatic breast cancer Anthracyclines, most widely used in all settings Conventional doxorubicin = low therapeutic index due to myelosuppression, alopecia, nausea & vomiting, mucositis & cumulative cardiotoxicity Elderly = increased cardiotoxicity PLD developed to improve therapeutic index of conventional anthracyclines by maintaining antitumor efficacy while improving the safety profile
Background: PLD in metastatic breast cancer PLD = doxorubicin in polyethylene glycol-coated liposomes (retain drug in circulation, accumulating preferentially in tissues with microvascular permeability, as is the case of tumors) Lower toxicity in comparison to free doxorubicin (cardiotoxicity, vesicant effects, nausea, vomiting, alopecia and myelotoxicity) Typical toxicities (acute infusion reaction) = mucositis and PPE (especially at higher doses or short dosing intervals) PLD is commonly administered in 4-weeks intervals. Studies in pts with KS indicate that 2-week dosing is better tolerated.
Background: PLD in metastatic breast cancer Treatment = Caelyx® 20 mg/m 2 iv every 2 weeks Characteristics of eligible patients Accrual period: January 2005 – September 2005 Entered/eligible28/25 Median age (Range)53 (31–69) Postmenopausal at entry 21 Pretreated with CT All Advanced disease 24 2 previous regimens 19 EIO experience, data not published
Background: PLD in metastatic breast cancer EIO experience, data not published Tumor Characteristics Endocrine responsiveness ER+ or PgR+16 ER & PgR - 8 Receptors not available1 c-erbB2 some overexpression5 no overexpression 9 not determined11
Background: PLD in metastatic breast cancer EIO experience, data not published Toxicity Hematologic toxicitymax grade 2 leucopenia Not Hematologic side effectsmax grade 2 Nausea/Vomiting 5% HFS9% Asthenia 5% Skin9%
Background: PLD in metastatic breast cancer EIO experience, data not published Response (18 pts evaluable) CR0 (0%) PR2 (11%) SD7 (33%) Early PD (within 1 month)3 (17%) PD 7 (39%) TTPmedian 2 months (1-6+)
Background: low dose CM in metastatic breast cancer Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents, including Cyclophosphamide and Methotrexate, postulating an antiangiogenic activity
Background: low dose CM in metastatic breast cancer Colleoni M, et al. Ann Oncol. 13: 73-80, 2002 DrugDose Day 1 2 3 4 5 6 7 MTX2,5 mg x 2 oral CTX50 mg oral
Background: low dose CM in metastatic breast cancer Characteristics of eligible patients Entered/eligible64/63 Median age (range)57 (36–80) Nr of pts 70 years old 10 Menopausal status pre/post12/51 PD at study entry51 ER and/or PgR positive31 Nr of involved sites 1/2/>213/23/27 Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM in metastatic breast cancer Characteristics of eligible patients Tumor sites Lung16 Liver24 Soft Tissues38 Bone34 Other14 Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM in metastatic breast cancer Characteristics of eligible patients Previously untreated11 Chemotherapy Adjuvant - Neoadjuvant41 For metastatic disease52 1 line32 2 lines11 3 lines 9 Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM in metastatic breast cancer Results2 CR + 10 PR + 8 SD 24 weeks Overall response rate (CR + PR): 19% Overall clinical benefit (CR + PR + SD): 31.7% Median time to response: 2.7 mos Median duration of response (in responders): 6.8 mos Median time to progression: 2.8 mos Median administration time per pt: 2.5 mos Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM in metastatic breast cancer Colleoni M, et al. Ann Oncol. 13: 73-80, 2002 Side EffectsNCIC-CTC Grade 01234 Leukopenia28 (44%)22 (35%)12 (19%)01 (2%) Neutropenia42 (66%)14 (22%)6 (10%)01 (2%) Thrombocytopenia60 (95%)3 (5%)000 Anemia54 (86%)8 (12%)01 (2%)0 Alopecia58 (92%)4 (6%)1 (2%)00 Nausea/Vomiting47 (75%)13 (20%)3 (5%)00 Gastric pain61 (97%)2 (3%)000 Mucositis60 (95%)3 (5%)000 Transaminases31 (49%)11 (17%)12 (19%)9 (15%)0
Background: low dose CM TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 DrugDose Day 1 2 3 4 5 6 7 Arm A MTX2,5 mg x 2 oral CTX50 mg oral Arm B MTX2,5 mg x 2 oral CTX50 mg oral TLM200 mgoral x x x x x x x
Background: low dose CM TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 Patients Characteristics (Total entered: 178) Tumor sites Liver74 Lung40 Soft tissues71 Bone79 Other30 Chemotherapy for metastatic disease109 1 line63 2 lines28 >3 lines18
Background: low dose CM TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 Results (n = 171) Arm AArm B CR3 (3.5%)3 (3.5%) PR15 (18%)7 (8%) SD35 (41%)38 (44%) SD 24 weeks18 (21%)25 (29%) PD33 (38%)37 (44%) Overall RR18 (21%)10 (12%)(p = 0.11) Clinical Benefit36 (42%)35 (41%)(p = 0.19)
Background: low dose CM TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 Hematologic toxicity: arm A (n = 87) Side EffectsNCIC-CTC Grade 1234 Leukopenia23 (26%)16 (18%)2 (2%)1 (1%) Neutropenia17 (20%)6 (7%)3 (3%)1 (1%) Thrombocyto- penia 4 (5%)1 (1%) 0 Anemia10 (11%)2 (2%) 0
We expect significant participation. Thank You. With a significant aid of
IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting A global trial: Challenges and opportunities Rudolf Maibach, PhD Executive Officer for International Trial Activities IBCSG Coordinating Center, Berne
IBCSG: Worldwide cooperation Patients and investigators from five continents cooperate by participating in large IBCSG clinical trials in the adjuvant breast cancer setting
Collaboration with B.I.G. the Breast International Group (B.I.G) actively supports the trial
IBCSG: a reliable structure The network is supported by: Coordinating Center in Berne Data Management Center in Amherst Statistical Center in Boston Independent scientific review by Data Safety and Monitoring Committee (DSMC)
Communication…... is always a challenge! Participants are in contact with IBCSG through www.ibcsg.org E-mail: email@example.com@ibcsg.org newsletters
IBCSG annual meeting Featuring Personal contacts Lively discussions General assembly Scientific Committee meeting open to all IBCSG members Nice, France, March 25-26, 2006 (5th European Breast Cancer Conference)
Documentation: CRFs CRFs are complete yet user-friendly Data manager manual: careful explanation Extent of data collection: Allows many additional evaluations from database at very little cost
IBCSG publications IBCSG has published 164 publications, among them –only 12 main trial publications, PLUS –publications from database –publications on quality of life –publications on biological params –reviews and commentaries Opportunity for all participants!
Quality of life Continuous commitment to evaluation of patient reported quality of life since 1986 Core module and trial related modules available in many languages
IBCSG biobank (1) IBCSG has collected paraffin blocks since 1981 for Central pathology review Translational research Submission of block is currently rewarded with $ 50.-
IBCSG biobank (2) The IBCSG Biological Protocol Working Group (BPWG) carefully examines all applications for (retrospective) evaluations All participants are welcome to submit project proposals!
Regulatory issues Major headache for any academic research The IBCSG Safety and Regulatory Office offers competent support
How to participate As a current member of IBCSG As a member of a cooperative group participating in the trial As an individual non-IBCSG center As an individual center wishing to become an IBCSG center
IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting Quality of Life Study Karin Ribi IBCSG Quality of Life Office Coordinating Center, Bern
Background Tolerance of cancer treatment and life expectancy are limited for breast cancer patients at advanced age Quality of life (QL) of particular importance Patients at advanced age are underrepresented in cancer treatment trials Very few studies have focused on QL
Methodological Considerations Potential confounding of co-morbidities with real impact of cancer symptoms and treatment on QL Higher frequency of reading and understanding impairment in older patients
Consequences for QL Assessment Short and simple assessment tools Inclusion of baseline assessment of physical and cognitive functioning
Primary Objective Comparing PLD-containing regimens versus non PLD-containing regimens regarding –Patient rated QL –Physician-documented physical functioning –Physician-documented cognitive functioning during and after adjuvant treatment
Longitudinal QL Study Design 03612 Months from Randomization Adjuvant phase = QL Assessments: QL Form, Mini-Cog, VES-13 PLD for 16 weeks vs. no adj. treatment PLD for 16 weeks vs. CM for 16 weeks
QL Study: Instruments To be filled in by patients: Adapted version of the IBCSG QL Core Form (Form QL) To be conducted by physicians: Cognitive Functioning: Mini-Cog (Form MC) Physical Functioning: VES-13 (Form VES) Assessment Checklist (Form AC)
Quality of Life 5 global LASA scales: physical wellbeing, mood, coping, functional performance, overall disease/treatment burden 6 symptom-specific LASA scales: tiredness, appetite, nausea/vomiting, hair loss, stomatitis, restrictions in arm movement Example: How have you been within the last two weeks? None Good Appetite
Cognitive Functioning Mini-Cog: A brief cognitive screening test and composite of: –3-item registration-recall task (taken from MMSE) –Clock-drawing test (CDT) Requires 3 minutes for administration Includes CDT scoring sheet
Physical Functioning Vulnerable Elders Survey (VES-13) –Screening tool to identify older persons at risk for health deterioration –Functioned-based considering age, self- rated health, functional disabilities –Needs less than 5 minutes for completion –Score range 0-10: a score >3 pointing to a 4x higher risk of functional decline or death
Order of QL Forms Administration Sequence of form administration is standardized as follows: 1. IBCSG CASA QL Form (Form QL) 2. Mini-Cog Test (Form MC) 3. VES-13 Test (Form VES) 4. Assessment Checklist (Form AC)
General Considerations QL assessments should be done prior to any relevant diagnostic procedures communication of diagnostic information any treatment application exception: previous information about diagnosis at baseline
Data Management Issues Compliance: Good acceptance by patients and staff (problem of missing data) Timing: Crucial to detect the effects of disease and treatment on QL Completeness: Crucial to investigate changes, i.e.we need a reference value = baseline
Please Consider Instruct patient carefully at the first assessment Check for completeness while patient is still present Check that the header is filled out properly before faxing it to the DMC Fax the forms in proper time
In case of questions… … you are very welcome to contact the Quality of Life Office! firstname.lastname@example.org + 41 31 389 93 88
IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting How to participate Gerda Egli, MD Head Quality Assurance & Audits IBCSG Coordinating Center, Berne
How to participate: Current IBCSG members you have already received the complete documentation! Refer to the “activation letter” for all steps to be taken Do not hesitate to contact the CASA trial coordinator at email@example.com firstname.lastname@example.org
How to participate: New member/Non-member Contact the CASA Trial coordinator at email@example.com firstname.lastname@example.org Return completed application form Prepare for Initial visit by QA team Receive approval for participation
How to participate: As a Cooperative Group Contact the CASA trial coordinator at email@example.com firstname.lastname@example.org Specify group coordinator/coordinating office for your group Return completed Application forms (1 for each participating center) Act as gateway to your member institutions Clarify logistics : Adapt the template „Appendix VII participating group specific logistical information“
How to participate: Next steps Collect necessary documents as specified in the IBCSG activation letter Adapt PIS/IC – submit to IBCSG CC Contact the CASA trial coordinator before submission to EC or regulatory authorities Submit documents to local Ethics committee Submit all documents to IBCSG CC Prepare Investigator folder Drug supply - Activation – first patient
Investigator folder (1) TOC provided by IBCSG CC Binder containing all general documents available from CC Add copy of all center-specific documents needed for activation (see previous slide)
Investigator folder (2) Add additional required documents: - Patient identification log - Drug accountability log - Copy of signed informed consents Keep updated - SAE-reports - Amendments - Correspondence with EC and sponsor
Quality control / Quality assurance Initial site visits Data manager review Medical review Quality control reports Audits No on-site monitoring
IBCSG audits (1) Long-standing IBCSG tradition Performed according to IBCSG Audit SOPs For members and non-members Not for participating Collaborative Groups Needed to ensure data Quality and Patient Safety No “police action” But a good opportunity to…
IBCSG audits (2) Establish personal contacts Improve Communication and Collaboration Exchange information Present new trials Receive feed-back from investigators
Audit intervals Initial site visit 1-year audit 3-year audit Special audits (rapid accrual/for cause)
Audit case selection Random selection At least 10% of cases Relapses included
Audit procedures Evaluation of QC reports Source data verification (10%) Signed informed consents (100%) Investigator folder Drug accountability Discussion with investigator/DM’s
Audit follow-up: QA-team General audit report Patient case reports Corrective action plan
Audit follow-up: Investigator Discuss and correct any deficiencies noted Provide requested additional information Provide information on corrective actions taken Return signed audit report (general & case reports) to CC File copy of audit report
IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting Regulatory Issues Barbara Ruepp Head Safety & Regulatory Office IBCSG Coordinating Center, Bern
How to participate: Regulatory Issues Preparation of center-specific documents Regulatory procedures: obtaining Ethics Committee (EC) and Health Authority (HA) approvals
Preparation of Center-specific Documents Adapt patient information and informed consent according local requirements Summary in national language (if requested) Collect information, signatures for –Protocol signature page –Authorization log –CVs –Obvious correction document signature page
Patient Information/Informed Consent (1) Template in 7 languages available Information to be added –Name of Ethics Committee responsible for evaluation of clinical trial application –Contact persons (Principle Inv., Co-Inv.) –Date, version number, place or name of institution
Patient Information/Informed Consent (2) Necessary modifications –Insurance paragraph (provided by IBCSG with national policy) Modifications only recommended if required by local regulations –Highlighted sections in particular Confidentiality Collection of biological material
Regulatory Procedures: obtaining EC/HA approvals in EU Submission of Clinical Trial Application (CTA) by coordinating investigator/institution or group to –leading Ethics Committee (EC) –Competent Authority (usually Health Authority, HA) All participating centers should be included in application Parallel submission to EC and HA possible Local EC may adopt positive opinion of leading EC and can request modifications of PIS/IC
Information and Documents to be included with CTA Trial related (Protocol including appendices, CRFs, patient information and informed consent) Trial Drug related (Investigators Brochure, Summary of Product Characteristics, labels) Staff/Facility related (CVs of Investigators) Finance related (Insurance policy, contract)
Regulatory Support offered by IBCSG CC For EU countries XML-file of CTA Documents to be enclosed with CTA (eg Investigators Brochure, labels) Information of approvals from other countries
Navigating Regulatory Hurdles Coordination of centers within one country is crucial For specific requests and questions contact us at email@example.com competent and prompt assistance is our firstname.lastname@example.org
Randomization (1) Web-based randomization system Patient enrolment: directly from participating center OR through your Group’s randomization center Each participating Group chooses it’s way before starting with the trial
Randomization (2) After successful randomization the randomization system issues: –Confirmation of randomization and treatment arm –Projected Idealized Schedule for visits and CRF submission
IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting CRFs / Data Submission Karen Price IBCSG Director of Scientific Administration IBCSG Statistical Center, Boston, MA IBCSG Data Management Center, Amherst, NY
CASA CRFs Available in patient packets on IBCSG website Packets for –All CRFs and English QL (A4 or Letter) –Other languages QL Packets are in PDF format
General Tips for Completing CRFs Refer to the Data Managers' Manual Record -1 for any unknown answers Be sure to submit required reports – i.e. Pathology and Hormone receptor Remember to black out patient's names and write the Patient ID on each page of the reports Refer to the Circular Letter
CASA CRFs: Bilateral Patients with bilateral breast cancer –All pts must submit 32-C (Surgery), 32-F (Hormone Receptor), 32-P (Pathology), and 32-R (Radiotherapy, if given) –Patients with bilateral breast cancer must submit additional forms for the opposite breast/side: 32-BC, 32-BF, 32-BP, 32-BR All are due at baseline (32-R and 32-BR after radiotherapy)
CASA CRFs: Chemotherapy Not required if randomized to Nil Total of 4 forms due at 4 timepoints Form NameSubmission #Treatment PeriodCycle Form 32-CT Week 4001 Weeks 1–21 Weeks 3–42 Form 32-CT Week 8002 Weeks 5–63 Weeks 7–84 Form 32-CT Week 12003 Weeks 9–105 Weeks 11–126 Form 32-CT Week 16004 Weeks 13–147 Weeks 15–168
DataFax Data Flow Participating Center 1: Faxes CRFs DataFax System 2. Data Entry Personnel verify data System generates quality checks (QC) Data Manager reviews CRFs & adds queries 3. E-mails QCs 4. Faxes QC ans
Fax/User Support Direct fax numbers Toll-free numbers (with country-specific access codes) User support by phone or e-mail –Business Hours: 7:30 – 18:00 US Eastern Time –Telephone: +1-716-898-7400 –E-mail: email@example.com
Useful DM Documents Data Managers’ Manual for Trial 32-05 Patient Packets for Trial 32-05 Obvious Corrections for Trial 32-05 QL Manuel for Trial 32-05 Randomization Manual Instructions for Using the DataFax System Toll-Free Numbers Test DataFax Forms Printing PDF www.ibcsg.org
Supply Chain of PLD (Caelyx®/Doxil®) Activities/ResponsibilitiesWho Manufactering & Vial FillingSchering-Plough/Ben Venue Laboratories Ohio USA Labeling for Clinical Trial use Final release Shipment to Schering-Plough Country Offices Distributor: Fisher Clinical Services, UK Distribution to centersSP Country Offices
Requirements for Release of Drug Supply from Distributor All regulatory documents must be in place –country specific authorizations (Health Authority/EC approvals) –EU countries only: copy of section on trial drug (IMPD section) of clinical trial application
Center Supply Not patient specific SP country office ships starter supply of 4 vials to center/local pharmacy once all regulatory requirements are met Following randomization of a patient 16 vials will be sent automatically from SP country office to center/local pharmacy
Drug Shipment and Storage: Points to Consider Cool chain must be maintained during shipment → PLD only shipped Mo – Wed in order to guarantee delivery to the sites until Friday → provide IBCSG CC with exact name of shipment address where proper storage (refrigerator 2-4°C) is guaranteed
Drug Accountability Drug accountability is mandatory for PLD Already existing forms at your institution may be used Alternatively download Drug Accountability Form from www.ibcsg.org File Drug Accountability Form in Investigator‘s Folder
Drug Destruction Expired vials can be destroyed on site according to local guidelines Complete Study Destruction Certificate and file in Investigators Folder Record drug destruction on Drug Accountability Form In case of expiration or breakage: re- supply will be provided
Coordination of Drug Supply All drug supply-related activities are coordinated by IBCSG CC in Berne, Switzerland Questions, requests? firstname.lastname@example.org
Serious Adverse Event Reporting Obligations of the Investigators Collect, record, assess and report SAEs during and until ≤ 4 weeks after trial treatment stop → all adverse events qualifying as serious ≥ 4 weeks after trial treatment stop → all deaths and other SAEs at least possibly related to trial treatment → all 2nd non-breast malignancies → all congenital abnormalities
Serious Adverse Event Reporting How to report SAEs Submit (datafax) initial SAE-report within 24 hours after occurrence of the event → use Form 32 SAE-A Upon resolution of the event or within 15 days after initial report complete and submit Follow-up report → use Form 32 SAE-B
Processing of SAE-Reports Responsibilities of IBCSG CC Medical review including seriousness and causality Assessment of expectedness Distribution of the SAE-reports to appropriate persons and parties Notification of investigators and regulatory authorities if expedited reporting is required (unexpected serious adverse reactions) Preparation of periodic reports (monthly, annual)
Insurance (1) IBCSG provides clinical trial insurance according to local laws IBCSG CC centrally organizes policies in individual countries – please refer to IBCSG CC for assistance (no direct contacts between centers and local insurance affiliates)
Insurance (2) Requested information to issue policy: estimated accrual per year per country / list of centers per country Patient information/Informed consent: insurance paragraph to reflect local policy and country laws please submit to IBCSG CC for approval
Funding (1) Trial supported by Schering- Plough/ITGI Per patient fee 1’700 € (700 € upon randomization, 500 € after 3 years, 500 € after 5 years, payment twice a year)
Funding (2) Support available for coordinating groups with ACTIVE involvement Up to 1’000 € per patient Payment upon randomization
Contracts (1) Main contract Schering-Plough/ITGI with IBCSG Subcontracts IBCSG with groups/centers Contract template is based on main contract
Contracts (2) Contract discussions between lawyers can cause serious delay contract discussions with your hospital administration to start asap Signed contract needed for activation
Administrative Issues Bureaucracy – hopefully as much as necessary and as few as possible !