CLINICAL STUDY PROTOCOL STUDY DRUG: Ixempra ® [Ixabepilone powder for Injection (IV infusion)] STUDY CODE: IXEAC-2012 VERSION NUMBER: 01 DATE: April 15,2012 TITLE AN OPEN LABEL, MULTICENTRE, RANDOMISED STUDY FOR THE SAFETY AND EFFICACY OF IXEMPRA ® (IXABEPILONE POWDER FOR INJECTION) MANUFACTURED BY BAXTER ONCOLOGY GMBH, GERMANY IN PATIENTS WITH CERVICAL CANCER PRINCIPAL INVESTIGATOR Antonio T. Fojo, M.D. PHASE OF DEVELOPMENT Phase II STUDY DESIGN An open label, multicentre, randomised clinical study INDICATION Metastatic or locally advanced Cervical cancer DRUG PRODUCT AND DOSAGE Ixempra ® (Ixabepilone) with loading dose 40 mg/m 2 administered over 3 hours of every 3 weeks. DURATION OF STUDY 32 weeks Treatment period: 27 weeks (10 treatment cycles). SPONSOR National Cancer Institute (NCI) April 15, 2012 Page 1 of 60 Study Code: IXEAC-2012
Transcript
Version No.: 01 Study Code: IXEAC-2012
Study Code: IXEAC-2012
CLINICAL STUDY PROTOCOL
STUDY DRUG: Ixempra® [Ixabepilone powder for Injection (IV infusion)]STUDY CODE: IXEAC-2012
VERSION NUMBER: 01DATE: April 15,2012
TITLE
AN OPEN LABEL, MULTICENTRE, RANDOMISED STUDY FOR THE SAFETY AND EFFICACY OF IXEMPRA® (IXABEPILONE POWDER FOR INJECTION) MANUFACTURED BY BAXTER ONCOLOGY GMBH, GERMANY IN PATIENTS WITH CERVICAL CANCERPRINCIPAL INVESTIGATOR Antonio T. Fojo, M.D. PHASE OF DEVELOPMENT Phase II
STUDY DESIGN An open label, multicentre, randomised clinical study
INDICATION Metastatic or locally advanced Cervical cancer
DRUG PRODUCT AND DOSAGE
Ixempra® (Ixabepilone) with loading dose 40 mg/m2
administered over 3 hours of every 3 weeks.
DURATION OF STUDY 32 weeks
Treatment period: 27 weeks (10 treatment cycles).
SPONSOR National Cancer Institute (NCI)
Confidentiality statement: This document is confidential and is to be distributed for review only to investigators, study staff, and applicable independent ethics committees or institutional review boards. Information contained herein cannot be disclosed, submitted for publication or used for any purpose other than that mentioned above without the sponsor's prior written authorization.
Name :Dr. Robert Wichert Address : National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office1-888-NCI-1937E-mail: [email protected] No.: 031-254632
Medical services Name : Maureen E. EdgerlyAddress : National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office1-888-NCI-1937E-mail: [email protected] No.: 031-254892
Project coordinator Name : Dr. Shubhangi TakeContact No.: 9594326512
Data management
Central Laboratory
Name addressE-mail: Contact No.:
1. For reading of CT scan:Name addressE-mail: Contact No.:
3. For laboratory examinations:Name addressE-mail: Contact No.:
Central Laboratory 3. For reading of CT scan:Name addressE-mail: Contact No.:
2. For IHC/FISHName addressE-mail: Contact No.:
3. For laboratory examinations:Name addressE-mail: Contact No.:
LIST OF INVESTIGATORS
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Site Code Name Address
A Dr. Anand Pathak Cancer Care Clinic, 5th Floor Vasant Sheela Tower, Dhantori, Nagpur-440012
B Dr. N. K. Mohanty VM Medical college & associated Safdar jung Hospital, New Delhi
SPONSOR’S APPROVAL OF THE PROTOCOL
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Version No.: 01 Study Code: IXEAC-2012
Study Code: IXEAC-2012
AN OPEN LABEL, MULTICENTRE, RANDOMISED STUDY FOR THE SAFETY AND EFFICACY OF IXEMPRA® (IXABEPILONE POWDER FOR INJECTION) MANUFACTURED BY BAXTER ONCOLOGY GMBH, GERMANY IN PATIENTS WITH CERVICAL CANCER
The following personnel has reviewed and approved the above mentioned protocol dated Apr 15, 2012.
Sponsor’s Representative
Dr. Robert Wichert National Cancer Institute (NCI)
Sponsor’s medical and safety expert
Maureen E. Edgerly
SIGNATURE PAGE (INVESTIGATOR)Apr 15, 2012 Page 5 of 43
AN OPEN LABEL, MULTICENTRE, RANDOMISED STUDY FOR THE SAFETY AND EFFICACY OF IXEMPRA® (IXABEPILONE POWDER FOR INJECTION) MANUFACTURED BY BAXTER ONCOLOGY GMBH, GERMANY IN PATIENTS WITH CERVICAL CANCER
I agree to implement and conduct this study diligently, in strict compliance with this protocol, Good Clinical Practices and all applicable laws and regulation.
I have read this protocol in its entirety and I agree to all aspects.
Date:Investigator Signature
Investigator name
Address of Institution:________________________________________________
AE : Adverse EventADR : Adverse Drug ReactionCDSCO : Central Drug Standard Control OrganisationCRF : Case Report FormCT : Computerised tomographyCFR : Code of Federal RegulationsECOG : Eastern Cooperative Oncology GroupFISH : Fluorescence In-Situ HybridizationGCP : Good Clinical PracticeHIV : Human Immunodeficiency VirusICH : International Conference on HarmonisationIEC/IRB : Independent Ethics Committee/ Institutional Review BoardIHC : ImmunohistochemistryIMP : Investigational Medicinal ProductLVEF : Left Ventricular Ejection FractionPP : Per ProtocolSAE : Serious Adverse EventSOPs : Standard Operating proceduresNCI : National Cancer Institute
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TABLE OF CONTENTS
ANNEXURE I: Preparation of IMPANNEXURE II: World Medical Association Declaration of Helsinki
1.0 SYNOPSIS
TITLEAn Open Label, Multicentre, Randomised Study For The Safety And Efficacy Of Ixempra® (Ixabepilone Powder For Injection) Manufactured By Baxter Oncology Gmbh, Germany In Patients With Cervical Cancer
PRODUCT IXEMPRA® (Ixabepilone powder for injection) manufactured by Baxter Oncology Gmbh, Germany
DOSE Initial loading dose of Ixabepilone of 40 mg/m2
administered over three hours after every three weeks. Total treatment duration is of 27 weeks (10 treatment cycles).
SPONSOR National Cancer Institute
STUDY CODE IXEAC-2012
CTRI Registry No. NCT00924066
VERSION NO. & DATE
Final Version No. 01 dated April 15, 2012
INDICATION Metastatic or locally advanced Cervical cancer
OBJECTIVES The objective of this study is to monitor the safety and efficacy Ixempra ® (Ixabipilone powder for Injection) of Baxter Oncology Gmbh, Germany in patients with Cervical Cancer administered for 27 weeks (10 treatment cycles) period.
STUDY RATIONALE
Ixempra ® is indicated in metastatic or locally advanced Cervical cancer. Ixabepilone binds directly to β-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixempra ® is a FDA approved drud in treating metastatic Breast Cancer. Safety and efficacy results obtained will be extrapolated to approved indications.
STUDY DESIGN An Open Label, Multicentre, Randomised Study For The Safety And Efficacy Of Ixempra® (Ixabepilone Powder For Injection) Manufactured By Baxter Oncology Gmbh, Germany In Patients With Cervical Cancer.
Visit 1 (Screening visit): Patients will be provided screening number after obtaining written informed consent and screened for eligibility for the study. Medical/Surgical
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history, physical examination, vitals, CT scan, 2D Echocardiography, Histopath, Pathology Laboratory examination including Haematology, Urine routine, Biochemistry, HIV I & II, Hepatitis B & C will be done at this visit. Urine pregnancy test, will also be done at this visit. Immunohistochemistry (IHC) and/or Fluorescence in situ hybridisation (FISH) testing will be performed to confirm Cervical cancer. Blood samples will be collected for immunogenicity testing (for estimation of antibodies to Ixabepilone).
Visit 2(Treatment visit): Patients, who fulfil all the eligibility criteria for the study, will come for the treatment visit, 2 weeks after the screening visit. Eligible Patients will receive their first dose of assigned IMP i.e. Initial loading dose of 40mg/ m2 of Ixabepilone powder for Injection for infusion in this visit.
Visit 3 to Visit 10 (Interim visits): Maintenance dose of assigned IMP will be given in each of these visits.These visits will be carried out every three weeks i.e. at weeks 3, 6, 9, 12, 15, 18, 21, 24 after treatment visit (visit 2).
Visit 11 (End of treatment visit): Last dose of assigned IMP will be given in this visit at week 27 after treatment visit (visit 2). End of study visit: At the end of study visit, safety and efficacy evaluation will be carried out at week 30 after treatment visit (visit 2).Physical Examination and Vitals will be checked at every visit (Visit 2 – End of study visit). ECOG Performance Status check will be done at every visit (Visit 2 – End of study visit).
Efficacy assessments:CT Scan will be performed at Visit 2 (treatment visit), week 12 (visit 6), week 21 (visit 9) after treatment visit and at end of study visit.
Safety Assessments: Immunogenicity testing will be performed for estimation of antibodies to Iixabepilone and Histopath testing at week 15 (visit 7) after treatment visit (visit 2) and at end of study visit.
2D Echocardiography will be performed at week 9 (Visit 5), week 21 (Visit 9) after treatment visit (visit 2) and at
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end of study visit. Lab Investigations (Haematology, Urine routine, Biochemistry) will be performed at end of study visit.
INCLUSION CRITERIA
1. Histologic or cytologic confirmation of cervical carcinoma; either squamous cell or non-squamous consisting of cervical adenocarcinoma, cervical adenosquamous carcinoma or cervical carcinoma, non-squamous type.
2. Subjects with unresectable recurrent cervical cancer are eligible.
3. Written informed consent after being provided with detailed information about the nature, risks, and scope of the clinical trial as well as the expected desirable adverse effects of the drug.
4. Female patients aged ≥18 years.5. At least 1 measurable lesion as defined by Response
Evaluation Criteria in Solid Tumors (RECIST) criteria. 6. Acceptable life expectancy. 7. Patients whose Eastern Cooperative Oncology Group
are within acceptable limits as considered by the Investigator.
9. Patients whose LVEF is within acceptable limits as considered by the Investigator.
10.Urine pregnancy test is negative at the time of screening.
11.Prior therapy with cisplatin or carboplatin is required.
EXCLUSION CRITERIA
1. Patients with history or presence of cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, metabolic, dermatologic, neurological, psychiatric or other immunologic disease which is considered as significant at the discretion of Principal Investigator.
2. Patients who are on vaccinations and monoclonal antibodies.
3. Patients with absolute neutrophil count <1,500/mm3
or platelet count <100,000/mm3, haemoglobin level < 9 g/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >2.5 x upper limit of normal (ULN) (>5 x ULN in patients with liver metastases), or serum (total) bilirubin >1.5 x ULN.
4. Patients who are currently on hormonal therapy for cancer.
5. Known hypersensitivity to Ixabepilone or any of the components of study therapy.
6. Patients with history of alcohol, drug or chemical abuse.
7. Pregnancy, lactation period or females of child-
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bearing age unwilling to take adequate contraceptive precautions.
8. Treatment with any other investigational drug in a clinical trial in the last 3 months before initiation of this trial.
9. Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the study.
10. In the investigator’s opinion, patients unlikely to comply with study procedures.
11. Patients previously enrolled into this study.
STUDY DURATION 2 weeks of screening + 27 weeks of treatment period (10 treatment cycles) Patients will be followed up for 1 month after end of study visit for safety evaluation.
EVALUATION VARIABLES
Efficacy end point:1. Overall response rate (ORR)
Safety End Points: 1. Incidence of all adverse events2. Incidence of drug related adverse events3. Results of laboratory examination: haematology,
biochemistry and urinalysis, 2D echocardiography, Immunogenicity testing (for estimation of antibodies to Iixabepilone).
SAMPLE SIZE Minimum 60 patients will be enrolled in the study.
DATA ANALYSIS Baseline characteristics of the treatment groups will be assessed using descriptive statistics. The efficacy will be evaluated by comparing the efficacy variable values at end-of-study with the treatment visit (V2) values. The results for the efficacy parameter for the will be compared.Safety will be evaluated by comparing the nature, number and severity of incidence of the adverse events in patients
2.0 BACKGROUND INFORMATION
Metastatic cancer is cancer that has spread from the place where it first started to another place in the body. A tumor formed by metastatic cancer cells is called a metastatic tumor or a metastasis. The process by which cancer cells spread to other parts of the body is also called metastasis.
Metastatic cancer has the same name and the same type of cancer cells as the original, or primary, cancer. For example, breast cancer that spreads to the lungs and forms a metastatic tumor is metastatic breast cancer, not lung cancer.
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cancer usually have some molecular features in common, such as the expression of certain changes.
Although some types of metastatic cancer can be cured with current treatments, most cannot. Nevertheless, treatments are available for all patients with metastatic cancer. In general, the primary goal of these treatments is to control the growth of the cancer or to relieve symptoms caused by it. In some cases, metastatic cancer treatments may help prolong life. However, most people who die of cancer die of metastatic disease.
Ixabepilone – Semi synthetic analog of epothilone B.Ixabepilone binds directly to β- tubulin subunits on microtubules. Leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of αβ-II and αβ-III microtubules. Ixabepilone possesses low in vitro susceptibility to multiple tumor resistance mechanisms including efflux transporters, such as MRP-1 and P-glycoprotein. Ixabepilone blocks cells in the mitotic phase of the cell division cycle, leading to cell death.
Benefit Risk Evaluation
When used as directed, Ixabepilone is efficacious and has a defined role to play in the treatment of Cervical Cancer. Common adverse effects include allergic reactions such as rash, hives, itching, flushed face, sudden swelling of face etc; Some most common side effects like tiredness, loss of appetite, disorders of tonsils, hair loss, fever, joint pain and muscle pain, headache, decreased platelets, nausea and vomitting.
3.0 STUDY OBJECTIVE
3.1 Primary Objective
The study aims to establish the safety and efficacy of Ixempra ® (Ixabipilone powder for Injection) of Baxter Oncology Gmbh, Germany in patients with Cervical Cancer
3.2 Secondary Objectives
To assess pharmacodynamic endpoints to determine the extent of tubulinpolymerization and whether or not there has been activation of cellular death pathways distal to the target.Estimate progression-free survival and duration of response.
4.0 STUDY DESIGN
This Is An Open Label, Randomised, Multi-Centre Study In Patients With Cervical Cancer To Evaluate Safety And Efficacy Of Ixabepilone Powder For Injection Baxter Oncology Gmbh, Germany.
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Visit 1 (Screening visit): Patients will be provided screening number after obtaining written informed consent and screened for eligibility for the study. Medical/Surgical history, physical examination, vitals, CT scan, 2D Echocardiography, Histopath, Pathology Laboratory examination including Haematology, Urine routine, Biochemistry, HIV I & II, Hepatitis B & C will be done at this visit. Urine pregnancy test, ECOG performance status check will also be done at this visit. Immunohistochemistry (IHC) and/or Fluorescence in situ hybridisation (FISH) testing will be performed to confirm Cervical cancer. Blood samples will be collected for immunogenicity testing (for estimation of antibodies to Ixabepilone).
Visit 3 to Visit 10 (Interim visits): Maintenance dose of assigned IMP 40mg/m2
will be given in each of these visits. These visits will be carried out every three weeks i.e. at weeks 3, 6, 9, 12, 15, 18, 21, 24 after treatment visit (visit 2).
Visit 11 (End of treatment visit): Last dose of assigned IMP will be given in this visit at week 27 after treatment visit (visit 2).
End of study visit: At the end of study visit, safety and efficacy evaluation will be carried out at week 30 after treatment visit (visit 2).
In case of early withdrawal or drop out, end of study evaluations should be done as soon as possible.
Physical examination and vitals will be checked at every visit (Visit 2 – End of study visit).
ECOG performance status check will be done at every visit (visit 2- End of study visit).
Efficacy assessments:CT scan will be performed at Visit 2 (treatment visit), week 12 (visit 6), week 21 (visit 9) after treatment visit and at end of study visit.
Safety Assessments: Immunogenicity testing will be performed for estimation of antibodies to Ixabepilone and Histopath testing at week 15 (visit 7) after treatment visit (visit 2) and at end of study visit.
2D Echocardiography will be performed at week 9 (Visit 5), week 21 (Visit 9) after treatment visit (visit 2) and at end of study visit. Lab Investigations (Haematology, Urine routine, Biochemistry) will be performed at End of study visit.
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Patients will also be dispensed a diary card after enrolment (Visit- 2) in which the patients have to record their disease condition. Patients will be asked to record their disease condition for the entire duration of the study. Diary cards will be returned at each visit and a new diary will be dispensed (except at End of study visit).
4.1 Study Plan
Eligible patients who fulfil all inclusion and exclusion criteria will receive Ixabepilone in this visit (V-2) + 2 days of window period.
Total treatment duration: 2 weeks of screening + 27 weeks of treatment period (10 treatment cycles)
Refer to figure 1 for study flowchart and table 1 for schedule of activities.
* Female patients of child bearing potential$ Pulse, blood pressure, respiratory rate, body temperature,# Laboratory test includes haematology, biochemistry, urinalysis, liver and kidney function test.@ Window period will be +2 days
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5.0 SELECTION OF PATIENTS
5.1 Number of patients
Total 60 patients will be enrolled for the study of Cervical cancer.
5.2 Inclusion Criteria:
Metastatic Cervical cancer patients1. Written informed consent after being provided with detailed information
about the nature, risks and scope of the clinical trial as well as expected desirable and adverse effects of the drug.
2. Female patient aged ≥ 18 years.3. At least 1 measurable lesion as defined by Response Evaluation
Criteria in Solid Tumors (RECIST). 4. Acceptable life expectancy.5. Patients whose Eastern Cooperative Oncology Group (ECOG)
performance status ≤ 2.6. Patients whose pre-study screening laboratory tests are within
acceptable limits as considered by the investigator.7. Patients whose LVEF is within acceptable limits as considered by the
investigator.8. Female patient’s urine pregnancy test should be negative at the time of
screening.
5.3 Exclusion Criteria
1. Patients with history or presence of cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, metabolic, dermatologic, neurological, psychiatric or other immunologic disease which is considered as significant at the discretion of investigator.
2. Patients who are on vaccinations and monoclonal antibodies.3. Patients with absolute neutrophil count <1,500/mm3 or platelet count
<100,000/mm3, haemoglobin level < 9 g/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >2.5 x upper limit of normal (ULN) (>5 x ULN in patients with liver metastases), or serum (total) bilirubin >1.5 x ULN.
4. Patients who are currently on hormonal therapy for cancer.5. Known hypersensitivity to Ixabepilone or any of the study components
of study therapy.6. Patients with history of alcohol, drug or chemical abuse.7. Pregnancy, lactation period or females of child-bearing age unwilling to
take adequate contraceptive precautions.8. Treatment with any other investigational drug in a clinical trial in the last
3 months before initiation of this trial. 9. Legal incapacity and/or other circumstances rendering the patient
unable to understand the nature, scope, and possible consequences of the study.
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10. In the investigator’s opinion, patients unlikely to comply with study procedures.
11.Patients previously enrolled into this study.
6.0 STUDY PROCEDURES
6.1 Demography
The following demographic characteristics will be recorded at the screening visit (V1): date of birth, ethnic origin, height and weight.
6.2 Medical/Surgical History
All relevant medical/surgical history will be recorded at the screening visit (V1). This will include all current conditions by diagnosis (where possible) and any concomitant medication, together with significant past conditions, operations and therapeutic or diagnostic procedures.
6.3 Vital Signs
Vital signs will be assessed at every visit during the study. Blood pressure (systolic and diastolic), pulse, respiratory rate and body temperature will be measured after the patient has sat quietly for at least 10 minutes.
6.4 Physical ExaminationPhysical examination will be performed at every visit as follows: general appearance, skin, eyes, ears, nose, throat, abdomen, lymph nodes.
6.5 2D Echocardiography
Cardiac monitoring with 2D echocardiography will be carried out.
A 2D Echo will be recorded at the screening visit (V1), week 9(visit 5), week 21(visit 9) after treatment visit (visit 2) and at end of study visit.
The investigator will review the 2D Echo report, as ‘clinically significant’ or ‘not clinically significant’ and sign and date the report. Patients with clinically significantly abnormal 2D Echocardiography will be excluded from the study at the discretion of investigator.
6.6 CT scanCT scan will be performed at CT scan will be performed at Visit 2 (treatment visit), week 12 (visit 6), week 21 (visit 9) after treatment visit and at end of study visit.
A CT scan will be performed at respective local labs. Reading of CT scans will be performed by centralized laboratory.
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6.7 Immunogenicity testing: Immunogenicity testing will be performed for estimation of antibodies to Ixabepilone at week 15 (visit 7) after treatment visit (visit 2) and at end of study visit.
6.8 Histopath testingHistopath testing will be performed at week 15 (visit 7) after screening visit (visit 1)
Patients with no documented history of IHC3+ or FISH+ results will be screened by immunohistochemistry assay. Patients with IHC3+ results will be enrolled into the study while patients with IHC2+ result can be further screened with FISH assay for confirmation of cervical cancer at the investigators discretion.
6.10 Laboratory Assessments
Haematology, biochemistry and urinalysis assessments will be performed at screening visit and at the end of study visit at specified local labs and/or central lab. Serology will be done at screening visit.
The following haematology, biochemistry, urinalysis and serology parameters will be assessed:
HematologyHaemoglobin Neutrophils (Absolute) Mean Corpuscular
Haemoglobin Concentration (MCHC)
Red Blood Cell (RBC) Count
Eosinophils (Absolute)
White Blood Cell (WBC) Count
Basophils (Absolute) Red Blood Cell Distribution Width (RDW)
(MPV)Basophils HaematocritLymphocytes Mean Corpuscular
Volume (MCV) Monocytes Mean Corpuscular
Haemoglobin (MCH)
BiochemistryCreatinine Aspartate Transaminase
(AST)Total Bilirubin Alkaline PhosphataseDirect Bilirubin Random glucose Alanine Transaminase (ALT)
Triglycerides
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Indirect Bilirubin
UrinanalysisColour Appearance DepositspH Specific gravity AlbuminSugar Ketone bodies Bile saltsBile pigments Urobilinogen NitriteRBCs Pus cells Epithelial cellsCasts Crystals Amorphous materialYeasts Mucus T.vaginalis
SerologyAntibodies to HIV I and II HBsAg (Hepatitis B
Surface Antigen)Anti HCV (Antibodies to Hepatitis C)
All laboratory test results must be reviewed promptly upon receipt. Laboratory values outside the normal range will be classified by the investigator as clinically significant or not clinically significant. Patients with abnormal clinically significant lab value at investigator’s discretion at the screening visit will not be enrolled in the study. All clinically significant abnormal lab values during the study duration will be documented as an adverse event in the CRF and followed-up by the investigator or investigator’s designee at least till stabilization.
6.11 Urine Pregnancy Test
Pregnancy test will be done at screening (visit-1). Women of childbearing potential must have a negative urine pregnancy test at the screening visit (V1) to be eligible for enrolment into the study.
Woman of childbearing potential includes any female who;
a) Has experienced menarche and is not post-menopausal (defined as amenorrhea for more than 12 consecutive months)
b) Has not undergone surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation).
c) Women who are using acceptable contraceptive medications or devices to prevent pregnancy.
Women of child-bearing potential will be asked to take adequate contraceptive control for the duration of the study. Any patient not agreeing to this will not be eligible for the study unless abstinence is considered acceptable in the investigator’s opinion.
Female patients who become pregnant during the study will be discontinued from the study immediately and will be followed up to the birth of the child or the outcome of the pregnancy.
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6.12 ECOG Performance Status13
ECOG performance status will be checked for every patient from screening visit to end of study visit.
Grade ECOG
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 Dead
6.13 Patient’s diary
Patients will be dispensed a diary card after treatment visit (Visit- 2) in which the patients has to record their disease condition. Patients will be asked to record their disease condition for the entire duration of the study. Diary cards will be returned at each visit and a new diary will be dispensed except at end of study visit.
7.0 INVESTIGATIONAL MEDICINAL PRODUCT
7.1 Treatment allocation
Patients will be allocated a unique screening number at the screening visit (V1). As this is an open label, randomised study, patients will receive either test or reference drug Ixabepilone powder for Injection for infusion for the entire duration of the study.
This is an open label study therefore investigators, other clinical and laboratory staff and patients will be aware of the treatment allocated to individual patients.
Patients will also be dispensed a diary card after treatment visit (Visit- 2) in which the patients has to record their disease condition and use of concomitant medications. Patients will be asked to record these details for the entire duration of the study. Diary cards will be returned at each visit and a new diary will be dispensed except at end of study visit. The diaries will be checked at every visit for patient compliance. Since the drug administration will be done at the site, compliance for study medication will be checked at the same time by authorised personnel from investigator.
IMP would be received by the patient at the site. A drug accountability log for recording, dispensing and destruction of IMP will be maintained by the investigator or authorised personnel. Reconciliation between the amounts of medication received from sponsor, dispensed and destroyed must be performed and any discrepancies accounted for. All unused IMP will be requested to be
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destroyed at site or returned back to the sponsor at the end of the study. Partially used IMP should be destroyed at the site.
7.7 Blinding and Randomisation
Patients will be allocated a unique screening number at the screening visit (V1). To minimise bias, patients will be serially allocated a randomisation number in order of reporting to the study site according to a computer-generated randomisation list at the start of visit 3. The randomisation list will be generated by an independent statistician. Patients will be allocated a unique number at randomisation and the treatment the subject receives will be according to the randomization list. This is an open label study therefore investigators, other clinical and laboratory staff and patients will be aware of the treatment schedule allocated to individual patients.
8.0EARLY DISCONTINUATION OF THE STUDY OR INDIVIDUAL PATIENTS
8.1 Early Discontinuation of the Study
If, in the opinion of the sponsor or investigator, the clinical observations in the study suggest that it might not be justifiable to continue, the study may be terminated.
In case of early discontinuation of the study, the safety assessments should be performed for each patient, as far as possible. The sponsor will notify to the investigator, regulatory authorities and ethics committee, including reason(s) regarding early discontinuation study.
8.2 Early Discontinuation of Individual Patients
The Patients are free to withdraw from the study at any time without giving a reason. In addition, the Principle Investigator (PI) may withdraw a patient if he considers that there could be a risk to the health of the patient, or for any of the following reasons (at the discretion of the PI)
Patient experiences an SAE/AE Any abnormal laboratory test considered clinically significant. Patient develops inter-current illness and is unable or unwilling to continue in
the study. Any serious protocol violation. Patient wishes to discontinue from the study on his personal reasons. Patient lost to follow-up (Without informing investigator)
For a subject who is lost to follow-up, every effort should be made to determine the medical status of that subject.
In case of early discontinuation of individual patient, safety assessment should be performed.
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The date of discontinuation/withdrawal from the study and reason for discontinuation/withdrawal will be recorded on the CRF and in the patient’s medical records. Any follow-up data should be recorded in case of withdrawn due to AE/SAE.
8.3 Early Discontinuation of a Centre The sponsor has the right to close the study centre;
• If it becomes apparent that patient enrolment is unsatisfactory with respect to quality and/or quantity
• If data recordings are repeatedly inaccurate and/or incomplete• Because of fraud or misconduct.
8.4 Protocol Violators Protocol violations occurring during a patient’s study participation will be discussed between the investigator and the sponsor. It will be assessed on a case-by-case basis if the patient is to be withdrawn from further participation.
Protocol violators are defined as follows: • Failure to meet the inclusion criteria and pass the exclusion criteria• Use of concomitant drugs that are not allowed according to the protocol • Other severe deviations from the study protocol considered relevant by
the investigator and/or the sponsor.
Major protocol violators will be withdrawn from the per-protocol analysis.
Minor protocol deviations will be assessed case-by-case based on the reasons for the deviation documented in the CRF. The decision whether a visit will be excluded will be made by the sponsor prior to evaluating the study.
9.0 ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP, whether or not related to the IMP.
Baseline signs and symptoms will be recorded. All AEs that occur (whether treatment related or not) will be recorded at each visit, for the duration of the study.
As far as possible, each AE must be described by its duration (start and end dates or ongoing), its frequency (single episode, intermittent, continuous), its severity (mild, moderate, severe - see Section 9.1), a causality assessment (the underlying study indication, coexisting disease, concomitant medication, the IMP, or other cause), its relationship to the IMP (not related, unlikely, possibly,
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probably, definitely – see Section 9.2), whether this influenced the course of the IMP, and whether it required specific action or therapy.
Patients who experience AEs will be followed up until the resolution or stabilisation of the AE.
9.1 Severity
The severity of AEs will be rated as follows:
Mild Symptom barely noticeable to patient; does not influence performance or functioning; prescription drug not normally needed for relief of symptom but may be given because of personality of patient.
Moderate Symptom of sufficient severity to make the patient uncomfortable; performance of daily activities influenced; patient is able to continue in the study; treatment for the symptom may be needed.
Severe Symptom causes severe discomfort; may be of such severity that the patient cannot continue; severity may cause cessation of treatment with IMP; treatment of the symptom may be given and/or the patient hospitalised.
9.2 Relationship to Investigational Medicinal Product
The causal relationship of AEs to the IMP will be rated as follows:
Not related Those AEs which, after careful consideration, are clearly and incontrovertibly due to extraneous causes (disease, environment etc.).
Unlikely Those AEs which, after careful consideration, appear to be unrelated to the IMP. An AE may be considered unlikely to be related if two or more of the following apply: It does not follow a reasonable temporal sequence from
administration of the IMP. It could be reasonably explained by the patient’s clinical state,
environmental or toxic factors, or other modes of therapy administered to the patient.
It does not follow a known pattern of response to the IMP. It does not disappear or decrease on cessation or reduction in
dose of IMP and recur with exposure*.
Possibly Those AEs which, after careful consideration, appear unlikely to be related but which cannot be ruled out with certainty. An AE may be considered possibly related if two or more of the following apply:
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It follows a reasonable temporal sequence from administration of the IMP.
It could not be reasonably explained by the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered to the patient.
It follows a known pattern of response to the IMP. It disappears or decreases on cessation or reduction in dose of
IMP and recurs with exposure*.
Probably Those AEs which, after careful consideration, are judged with a high degree of certainty to be related to the IMP. An AE may be considered probably related if three or more of the following apply: It follows a reasonable temporal sequence from administration
of the IMP. It could not be reasonably explained by the patient’s clinical
state, environmental or toxic factors, or other modes of therapy administered to the patient.
It follows a known pattern of response to the IMP. It disappears or decreases on cessation or reduction in dose of
IMP and recurs with exposure*.
Certainly Those AEs which, after careful consideration, are judged to be incontrovertibly related to the IMP. An AE may be considered definitely related if all of the following apply: It follows a reasonable temporal sequence from administration
of the IMP. It could not be reasonably explained by the patient’s clinical
state, environmental or toxic factors, or other modes of therapy administered to the patient.
It follows a known pattern of response to the IMP. It disappears or decreases on cessation or reduction in dose of
IMP and recurs with exposure*.
9.3 Serious Adverse Event
A Serious Adverse Event (SAE) is defined as one of the following:
An event causing the death of the patient A life-threatening* event An event causing hospitalisation** or prolongation of existing hospitalisation An event causing persistent or significant disability or incapacity*** An event causing a congenital anomaly or birth defect Important medical events (i.e., not immediately life-threatening or do not result
in death or hospitalisation but require urgent and intensive intervention to prevent one of the outcomes listed in the definition above, for example, intensive treatment at home or in an emergency room for bronchospasm or convulsion)
Pregnancy will be considered as an important medical event. If any woman becomes pregnant during the course of the study, she will be followed up to the
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birth of the child or the outcome of pregnancy.
* The term ‘life-threatening’ refers to an event in which the patient was at risk of death at the time of event; it does not refer to an event which hypothetically might have caused death if it were more severe.
** A hospitalisation is defined as an overnight stay, including time spent in an emergency room, for an AE. A prolongation of existing hospitalisation is defined as an additional overnight stay. Elective surgery is not classified as a SAE.
*** The term ‘persistent or significant disability or incapacity’ refers to an event which results in a substantial and/or permanent disruption of patient’s ability to carry out normal life functions.
9.4 Reporting Serious Adverse Events
All SAEs occurring during the study or within 30 days following the completion of the study by the patient must be reported to the sponsor by telephone or fax within 24 hours of the investigator becoming aware of the SAE.
Investigators should not wait to receive additional information to fully document the event before notifying the sponsor of a SAE. A full written summary, detailing relevant aspects of the SAE, should follow the initial telephone or fax report. Where applicable, information from relevant hospital case records and post-mortem reports should be obtained.
Principal Investigator Referral Contact For more information:
Antonio T. Fojo, M.D.National Cancer Institute (NCI) National Institutes of HealthBuilding 10Room 12N22610 Center DriveBethesda, Maryland 20892 (301) 496-2831 [email protected]
Maureen E. Edgerly, R.N.National Cancer Institute (NCI) National Institutes of HealthBuilding 10Room 12N22610 Center DriveBethesda, Maryland 20892 (301) 435-5604 [email protected]
NCI Referral OfficeNational Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office1-888-NCI-1937
9.5 Adverse Drug Reaction(s) All noxious and unintended responses to the medicinal product related to any dose should be considered as adverse drug reactions (ADR).The phrase “responses to a medicinal product” means that a causal relationship between the medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out (ICH E6 Guideline for Good Clinical Practice, 1996).
9.6 Unexpected ADR An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. investigator’s brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) is an unexpected ADR (ICH E2A Clinical Safety Data Management – Standards for Expedited Reporting, 1995).
10.0 DATA ANALYSIS AND STATISTICAL METHODS
10.1 Patient to be included in analysis
1. PP population: The per protocol population will constitute all patients who have been enrolled and have completed the study as per protocol.
2. Safety Population -The safety population will constitute all patients who have been enrolled and have received at least one dose of the study medication.
3. Efficacy Population: The efficacy population will constitute all patients who have been enrolled and have completed the study as per protocol.
10.2 Baseline Characteristics
Baseline characteristics will be analyzed descriptively. In addition, treatment effects will be tested by parametric methods. The patient disposition will be summarised. The demographic, background and baseline data will be presented descriptively. Unless and otherwise stated all the continuous variables like age, height, weight will be represented by mean, standard deviation, minimum and maximum. All the categorical variables will be presented as counts and percentages.
10.3 Evaluation variables
Efficacy end point:1. Overall response rate (ORR)
Safety End Points: 1. Incidence of all adverse events2. Incidence of drug related adverse event3. Results of laboratory examination: haematology, biochemistry and
urine analysis.4. Immunogenicity testing (for estimation of antibodies to Ixabepilone).
10.4 Missing, Unused and Spurious Data
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The handling of missing, unused and spurious data will be described in the Statistical Analysis Plan. 10.5 Deviations from the Planned Analysis
Any changes to the planned analysis (as described in the protocol and Statistical Analysis Plan) will be documented in the clinical study report.
11.0 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS
11.1 Declaration of Helsinki
The investigator will ensure that this study is conducted in full conformity with the current revision of the 1964 Declaration of Helsinki.
11.2 Good Clinical Practice
The study will be conducted according to the protocol and to Standard Operating procedures (SOPs) that meet the guidelines laid down by the ICH/GCP and CDSCO in clinical trials.
The investigator must inform, and obtain approval from, the IEC/IRB for the conduct of the study at named site, the protocol and Informed Consent Form, any other written information that will be provided to the patients and any advertisements that will be used. Written approval must be obtained prior to recruitment of patients into the study and shipment of IMP.
Proposed amendments to the protocol and aforementioned documents must be submitted to the IEC. Amendments may be implemented only after a copy of the IEC/IRB approval letter has been transmitted to the sponsor. Amendments that are intended to eliminate an apparent immediate hazard to patients may be implemented prior to receiving IEC/IRB approval. However, in this case, approval must be obtained as soon as possible after implementation.
Serious or unexpected AEs occurring during the study likely to affect the safety of the patients or the conduct of the trial will also be reported to each IEC/IRB.
11.4 Regulatory Authority Approval
The study will be performed in compliance with regulatory requirements. Regulatory authority approval for the clinical trial will be obtained prior to recruitment of patients into the study and shipment of IMP.
11.5 Insurance
Insurance will be taken for each clinical trial site to cover the expenses for AEs/SAEs experienced by the subjects during the study period. If the investigator
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and designates follow the instructions given in the study protocol or in any amendments to it, and in general perform the study scientifically and in keeping with currently acceptable techniques, and provided that the treatments administered to the patients in connection with the study have been supplied by the sponsor or are required by the study protocol, the sponsor assumes liability by law on behalf of the investigator and designates for possible injury to the subject directly or indirectly caused by the investigational product in connection with the study.
11.6 Informed Consent
It is the investigators responsibility to ensure that prior to being enrolled into the study; the subject has given written consent to participate. The subject should be given a complete written and verbal explanation of the nature, scope and possible consequences of the study by a physician in a form understandable to him/her. The subjects must be able to understand the full implications of their decision.
The subject information leaflet will explain the nature of the study, its objectives and potential risks and will be translated into local languages as appropriate. In addition, the following points must also be covered:
• A description of the aims of the study and how it will be organized• Any negative effect possibly attributable to the study treatments• The freedom to ask for further information at any time• The patient's right to withdraw from the study at any time without giving
reasons and without jeopardizing the further course of treatment• The existence of subject insurance cover• Personal information will be treated as strictly confidential and not be
publicly available.• Subject authorizes in written form that the patient’s original medical
records may be validated by the monitor(s), the auditor(s), and the regulatory authorities by direct access in accordance with the applicable laws and regulations.
Informed consent should be given by means of a standard written statement, written in non-technical language. The subject should read and consider the statement and be allowed to ask any questions before signing and dating it. The subject information and the informed consent will be provided as a single document with one photocopy. One personally signed and dated version of the informed consent will be left at the investigator’ site, the copy will be given to the patient. No patient can enter the study and no study-related procedures can be performed before written informed consent has been obtained.
The investigator must submit the informed consent document with the study protocol for IRB/IEC approval.
11.7 Patient’s Confidentiality
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The investigator must ensure that the patient’s privacy is maintained. On the CRF or other documents submitted to the sponsor, patients will be identified by a screening and/or enrolment number only. Documents that are not submitted to the sponsor e.g., signed and dated Informed Consent Forms should be kept in a strictly confidential file by the investigator.
The investigator shall permit authorised representatives of the sponsor, regulatory authorities and IEC/IRB to review that portion of the patient’s medical record that is directly related to the study. As part of the required content of informed consent, the patient must be informed that his/her records will be reviewed in this manner.
11.8 Data Protection
The study will be performed in compliance with Indian Council of Medical Research guidelines, ICH-GCP guidelines and CDSCO guidelines.
11.9 End of Study
The end of the study is defined as Last Patient Last Visit.
11.10 Publication Policy
NIC may publish the results of the study in a scientific journal or publication. Any information published will not reveal the identity of the study patients and confidentiality will be maintained. The investigator may submit study data for publication and/or presentation after finalisation of the clinical study report, subject to prior approval by the sponsor.
12 ADMINISTRATIVE OBLIGATIONS
12.1 Data Collection and Management
Filling in electronic Case Report Forms (eCRF):
Data required for the study in accordance with the protocol will be recorded on specially designed CRF formats called electronic case report forms. An electronic Case Report Form is a computer based system to capture clinical trial data. The Investigator site would be provided with a web link to the e-CRF. Investigator and designees will be provided with individual log-in IDs and passwords so that they can log on to the web page and enter the data into the CRF pages.
21 CFR part 11 compliant Oracle Clintrial platform will be used for this study. Data review and approval will be done by Principal Investigator or authorized study personnel. Track of modifications will be made through software and can be retrieved whenever required.
Sponsor monitors will approve completed CRFs which will be further submitted for data processing.
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12.2 Source Data
All relevant study data will be recorded in the case report form (CRF). Where relevant data already exists on other source documents such as laboratory reports, 2D Echocardiography reports or CT scan reports, the information required will be transcribed into CRF. All other data will be directly written into the CRF.
The investigator/institution will permit trial-related monitoring, audits, IEC/ IRB review and regulatory inspection providing direct access to source documents.
12.3 Source Data Verification
It is the responsibility of the investigator to ensure that the study is conducted in accordance with the protocol, ICH-GCP, local laws and, and that valid data are entered into the CRF. The investigator will permit representatives of the sponsor to monitor the study as frequently as necessary for the purpose of verifying adherence to the protocol and the completeness and exactness of the data entered on the case report forms. Data verification is legally required and will be done by direct comparison of the CRF with those portions of the patient’s source documents which directly concern this study, such as medical/surgical history/concomitant diseases, date of study enrolment, visit dates, results of examinations, administrations of medication and adverse events. Due consideration to data protection and medical confidentiality will always be maintained.
The Sponsor will affirm and uphold the principle of the patient's right to protection against the invasion of privacy. Throughout the study, all study data will only be identified by patient number and patient initials.
All obtained data will be checked for plausibility and completeness by the monitor and in-house by qualified staff of the Sponsor.
12.4 Quality Control and Quality Assurance
Quality control will be performed according to Sponsors internal procedures.
Appropriately qualified and trained staff will be involved in this study. Staff at investigational sites will be instructed in the conduct of the study according to this protocol.
In order to check the performance of the study regarding GCP, audits may be carried out by a quality assurance representative of the sponsor. The investigator will provide access to authorised persons during regulatory authority inspections or sponsor audits.
12.5 Investigator’s File
The investigator will be provided with a study file where the following documents will be stored under lock and key:
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• Signed protocol and all amendments signed by the investigator • Standard operating procedures for the investigator and study personnel. • Approval of the ethics committee (EC), list of members/correspondence
with EC • Announcement of the trial to the authorities/drug import
permission/correspondence with authorities • Sample of informed consent and the signed and dated originals; samples
of patients information leaflet/instructions/diary/questionnaire/translation(s) • Patient insurance/insurance conditions • Patient screening log/enrolment log/identification code list • Sample serious adverse event report form/copies of all SAE reports/safety
information • Sample case report form • Investigator’s brochure/expert information • Documentation about receipt/retrieval and destruction (if applicable) of the
study medication and other study supplies • Drug accountability form • Monitoring log/conventions/trial initiation visit report • Laboratory reference ranges and laboratory certificates and shipment
instructions to the central laboratory • Curricula vitae of the coordinating investigator, principal investigator and
other investigators; Coordinators, study nurse(s) • Signature sheet/study personnel assignment list • Other correspondence concerning the study • Agreements between involved parties (e.g. financial aspects) • List of essential documents for archiving at investigational site • Ethical and legal information on clinical trials (Declaration of Helsinki, ICH-
GCP etc.) • Summary of clinical study report
12.6 Qualification of the InvestigatorsThe investigator(s) should be qualified by education, training and experience to assume responsibility for the proper conduct of the trial. He/she should meet all qualifications specified by the applicable regulatory requirements and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation.
The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, the current investigator’s brochure, the product information and other information sources provided by the sponsor. The investigator should be aware of and should comply with GCP and the applicable regulatory requirements.
The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial related duties.
12.7 Trial Documentation and archival
The investigator/institution should maintain the trial documents in a comprehensive and centralised filing system that is suitable for inspection by
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representatives of the sponsor and regulatory authorities. The investigator/institution should take measures to prevent accidental or premature destruction of these documents.
The investigator shall retain all the study related documents (like Investigator Site File, including Case Report Forms, raw data, and reports of the Study) and material for a period of at least fifteen (15) years after the completion of the study or submission of the data to the regulatory authority (ies) whichever is later. In the event the Investigator lacks archiving facility, the sponsor, can make archiving arrangements of all documentation except the subject identification list after the end of the study. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained. The sponsor should be informed immediately by the investigator/institution of any change concerning archiving facilities.
12.8 Monitoring
It is the responsibility of the investigator to ensure that the study is conducted in accordance with the protocol, ICH-GCP and that valid data are entered into the CRF.
Monitoring and auditing of this study will be performed by standard operating procedures developed by the sponsor in order to comply with GCP. Therefore the investigator will make all the study related documents available to the sponsor monitor upon request within reasonable time. Case report forms will be checked for correctness and clarity with the source data.
Monitoring visits will be made by the monitors designated by the sponsor to check compliance with the protocol, the completeness, accuracy and consistency of the data, and adherence to GCP.
12.9 Audit
In order to guarantee that the performance of the study is in accordance with GCP and all relevant regulatory and formal stipulations, on-site audits may be carried out.
The investigator agrees to give the auditor access to all relevant documents for review and support the sponsor to solve possible audit findings concerning the study conduct at the respective site. The same applies in case of an inspection by local or international authorities.
After every on-site audit the investigator will receive an audit confirmation by the auditor. This document has to be filed together with the study documentation and
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made available to the authorities in case of inspection. At the end of the study, a copy of the audit certificate(s) will be included in the final report.
Ixebepilone powder for Injection contains two vials, a vial labeled Ixabepilone powder for Injection which contains Ixabepilone powder and a vial containing Diluent for Ixabeplione. It must be stored in refrigerator at 2 – 80C. Prior constituting Ixabepilone powder for Injection, the kit should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes. When the vials are first removed from refrigerator, a white precipitate may be observed in the diluent vial. This precipitate will dissolve to form a clear solution once the diluent warms to room temperature. To constitute :
1. with a suitable syringe, aseptically withdraw the diluent and slowly inject it into the Ixabepilone powder for Injection vial. The 15 mg Ixabepilone powder for Injection is constituted with 8 ml of diluent.
2. Gently swirl and invert the vial until the powder in Ixabepilone is completely dissolved.
To dilute:Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below: The Ixabepilone powder for Injection is administerd by infusion which should be prepared in DEHP [ di-(2-etylhexyl) Phthalate] free bag.
The following infusion fluids have been qualified for use in the dilution of Ixabepilone powder for Injection.- Lactated Ringers Injection, USP- Plasma- Lyte A Injection pH 7.4
ANNEXURE II
World Medical Association Declaration of HelsinkiEthical Principles for Medical Research Involving Human Subjects
October 2000WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human SubjectsAdopted by the 18th WMA General Assembly
Helsinki, Finland, June 1964and amended by the
29th WMA General Assembly, Tokyo, Japan, October 197535th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 198948th WMA General Assembly, Somerset West, Republic of South Africa,
October 1996and the
52nd WMA General Assembly, Edinburgh, Scotland, October 2000.Note of Clarification on Paragraph 29 added by the WMA General
Assembly, Washington 2002Note of Clarification on Paragraph 30 added by the WMA General
Assembly, Tokyo 2004
A. INTRODUCTION1. The World Medical Association has developed the Declaration of Helsinki
as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data.
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2. It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge and conscience are dedicated to the fulfilment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health of my subject, will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the subject's interest when providing medical care which might have the effect of weakening the physical and mental condition of the subject."
4. Medical progress is based on research, which ultimately must rest in part on experimentation involving human subjects.
5. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society.
6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best-proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality.
7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens.
8. Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care.
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.
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11.Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.
12.Appropriate caution must be exercised in the conduct of research, which may affect the environment, and the welfare of animals used for research must be respected.
13.The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol. This protocol should be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the Investigator, the sponsor or any other kind of undue influence. This independent committee should be in conformity with the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events. The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.
14.The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the principles enunciated in this declaration.
15.Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent.
16.Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available. Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results.
17.Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results.
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18.Medical research involving human subjects should only be conducted if the importance of the objective outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects are healthy volunteers.
19.Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.
20.The subjects must be volunteers and informed participants in the research project.
21.The right of research subjects to safeguard their integrity must always be respected. Every precaution should be taken to respect the privacy of the subject, the confidentiality of the subject's information and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.
22. In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject's freely given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed.
23.When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship with the physician or may consent under duress. In that case the informed consent should be obtained by a well-informed physician who is not engaged in the investigation and who is completely independent of this relationship.
24.For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the Investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons.
25.When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the Investigator must obtain that assent in addition to the consent of the legally authorized representative.
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26.Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee. The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legally authorized surrogate.
27.Both authors and publishers have ethical obligations. In publication of the results of research, the Investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.
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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED
WITH
MEDICAL CARE
28.The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the subjects who are research subjects.
29.The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.
30.At the conclusion of the study, every subject entered into the study should be assured of access to the best-proven prophylactic, diagnostic and therapeutic methods identified by the study.
31.The physician should fully inform the subject which aspects of the care are related to the research. The refusal of a subject to participate in a study must never interfere with the subject physician relationship.
32. In the treatment of a subject, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the subject, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed.
Note: Note of clarification on paragraph 29 of the WMA Declaration of Helsinki
The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:
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- Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.
Note: Note of clarification on paragraph 30 of the WMA Declaration of Helsinki
The WMA hereby reaffirms its position that it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care. Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.
![Protocol Ppt[1]](https://static.documents.pub/doc/80x56/555bcdf5d8b42adf478b4b60/protocol-ppt1.jpg)
