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Protocol Template

VIEWS: 99 PAGES: 29

									                     Clinical Study Protocol – (Protocol Number)
                                        (Drug Name)




          RENAME THIS FILE AND DELETE THIS TEXT BEFORE
                          PROCEEDING!
                           (Protocol Title)




                                   PROTOCOL: (Date)
                                       If applicable:
                                   AMENDMENT 1: (Date)
                                   AMENDMENT 2: (Date)




                                     CONFIDENTIAL




This document is a confidential communication of XXXX. Acceptance of the document
constitutes agreement by the recipient that the contents will not be disclosed to any unauthorized
personnel, without the prior written authorization of XXXX. In event of actual or suspected
breach of this agreement, XXXX will be promptly notified.
[Drug]                                                    Protocol [Protocol Number]


SIGNATURE PAGE

Protocol Number:     (Insert study number)

Title of Protocol:   (Insert full title)

Prepared by:




(Name)                                                 Date
(Title/Position)




(Name)                                                 Date
(Title/Position)


Approved by:




(Name)                                                 Date
(Functional Head of Safety)




(Name)                                                 Date
(Functional Head of Clinical Research)




(Name)                                                 Date
(Functional Head of Regulatory Affairs)




                                             i   (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                          Protocol [Protocol Number]


PROTOCOL SUMMARY

(Provide a brief summary [not to exceed two pages] highlighting the major features of the study.
The sections that should be included in the protocol summary are presented below.)

 Study Number and Number: Title of Study
 Title:
 Clinical Phase:
 Study Objectives:    Present the primary and secondary objectives of the study clearly and
                      succinctly. There should be one defined primary objective.
                      Primary:
                      Secondary:
 Study Design:        State the study type/configuration/level, method of blinding, and level
                      and method of control. Include a brief statement of the sequence and
                      duration of all study periods and follow-up periods.
 Study Population:    Include the intended number of patients (including the number of
                      patients expected to be evaluable) and patient types (main inclusion and
                      exclusion criteria).
 Study Treatment:     Include the treatment type and dose, mode of administration, frequency,
                      regimen, etc.
 Study Variables:     Describe and define the primary and secondary variables.
                      Pharmacokinetic:
                      Efficacy:
                      Safety:
 Study Procedures     Describe how the above variables will be measured or assessed, and any
 and Assessments:     other important study measurements or assessments.
                      Pharmacokinetic:
                      Efficacy:
                      Safety:
 Statistical          Describe sample size calculation and describe how the above stated
 Analyses:            variables will be analyzed.
                      Pharmacokinetic:
                      Efficacy:
                      Safety
 Study Duration:      State the expected start date of study, expected duration of the patient
                      enrolment period, and the defined follow-up period for the primary and
                      confirmatory analyses, if any, as appropriate to the study.




                                               ii      (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                                                        Protocol [Protocol Number]


                                                     TABLE OF CONTENTS

1. INTRODUCTION AND BACKGROUND ......................................................................... 1
1.1 Background of the Disease ....................................................................................... 1
(Discuss disease incidence and other important considerations.) ................................. 1
1.2 Background of Treatment Options ........................................................................... 1
1.3 Summary of Nonclinical and Clinical Data ............................................................... 1
1.4 Risks and Benefits to Human Patients ..................................................................... 1

2. RATIONALE ................................................................................................................... 1
2.1 Rationale for the Study .............................................................................................. 1
2.2 Rationale for Drug Dose Selection............................................................................ 1

3. STUDY OBJECTIVES .................................................................................................... 1
3.1 Primary Objective ....................................................................................................... 1
3.2 Secondary Objective(s) .............................................................................................. 1

4. INVESTIGATIONAL PLAN ............................................................................................. 2
4.1 Overall Study Design ................................................................................................. 2
4.2 Discussion of Study Design ...................................................................................... 2

5. SELECTION AND WITHDRAWAL OF PATIENTS ......................................................... 2
5.1 Number of Patients .................................................................................................... 2
5.2 Inclusion Criteria ........................................................................................................ 2
5.3 Exclusion Criteria ....................................................................................................... 3
5.4 Withdrawal of Patients ............................................................................................... 3

6. RANDOMIZATION AND BLINDING PROCEDURES ..................................................... 3
6.1 Randomization ........................................................................................................... 3
6.2 Blinding ....................................................................................................................... 4

7. STUDY TREATMENTS ................................................................................................... 4
7.1 Supply, Packaging, Labeling and Storage ............................................................... 4
7.1.1 Drug .......................................................................................................................... 4
7.1.2 Comparative Treatment or Placebo ........................................................................... 4
7.1.3 Devices ..................................................................................................................... 4
7.2 Drug Dosage and Administration .............................................................................. 4
7.2.1 Drug .......................................................................................................................... 4
7.2.2 Comparative Treatment or Placebo ........................................................................... 4
7.3 Drug Dose Modification ............................................................................................. 4
7.4 Concomitant Treatment ............................................................................................. 5

8. RISKS/PRECAUTIONS .................................................................................................. 5

9. STUDY PROCEDURES .................................................................................................. 5
9.1 Screening and Baseline Procedures ........................................................................ 5
9.2 Treatment Procedures ............................................................................................... 5
9.3 Follow-up Procedures................................................................................................ 5
9.4 Schedule of Events .................................................................................................... 6



                                                                     iii        (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                                                         Protocol [Protocol Number]

10. EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ................... 6
10.1 Definitions .................................................................................................................. 7
10.1.1 Adverse Event ........................................................................................................... 7
10.1.2 Serious Adverse Event .............................................................................................. 7
10.2 Adverse Event Descriptors ........................................................................................ 7
10.2.1 Intensity ..................................................................................................................... 7
10.2.2 Relationship to Study Treatment ............................................................................... 8
10.3 Reporting and Evaluation of Serious Adverse Events and Other
     Clinically Significant Adverse Events ....................................................................... 9
10.3.1 Serious Adverse Events ............................................................................................ 9

11. STUDY VARIABLES AND STATISTICAL ANALYSIS .................................................. 10
11.1 Sample Size/Power Considerations ........................................................................ 10
11.2 Data Sets to be Analyzed ......................................................................................... 10
11.2.1 Pharmacokinetic/Pharmacodynamic........................................................................ 10
11.2.2 Efficacy ................................................................................................................... 10
11.2.3 Safety ...................................................................................................................... 10
11.3 Analysis of Demographic and Baseline Data ......................................................... 11
11.4 Pharmacokinetic/Efficacy Variables and Analyses ................................................ 11
11.5 Safety Variables and Analyses ................................................................................ 11
11.6 Interim Analysis (if applicable) ................................................................................ 11

12. ESTIMATED DURATION OF THE STUDY ................................................................... 11

13. STUDY ETHICAL CONSIDERATIONS ......................................................................... 11
13.1 Ethical Conduct of the Study .................................................................................. 11
13.2 Informed Consent..................................................................................................... 11
13.3 Institutional Review Board or Ethics Committee ................................................... 12

14. ADMINISTRATIVE PROCEDURES .............................................................................. 12
14.1 Sponsor’s Responsibilities ..................................................................................... 12
14.1.1 Study Supplies ........................................................................................................ 12
14.1.2 Investigator Training ................................................................................................ 12
14.1.3 Study Monitoring ..................................................................................................... 12
14.2 Investigator’s Responsibilities ................................................................................ 13
14.2.1 Reporting and Recording of Study Data .................................................................. 13
14.2.2 Source Documentation ............................................................................................ 13
14.2.3 Study Drugs ............................................................................................................ 14
14.2.4 Records Retention ................................................................................................... 14
14.3 [Other Services] as Applicable ................................................................................ 14

15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA .................................. 14

16. REFERENCES.............................................................................................................. 15

17. APPENDICES ............................................................................................................... 15




                                                                     iv          (Date of Protocol in format dd/mmm/yyyy)
[Drug]                     Protocol [Protocol Number]


APPENDIX 1.
APPENDIX 2.
APPENDIX 3.
APPENDIX 4.




              v   (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                           Protocol [Protocol Number]


ABBREVIATIONS AND DEFINITIONS

(Provide a list of abbreviations and definitions of unusual or specialized terms or measurement
units used in the protocol. At the first appearance in the summary and at the first appearance in
the text, spell out abbreviated terms with the abbreviation indicated in parentheses. The list
should be in alphabetical order. This list includes many commonly used abbreviations. Delete
those that do not apply and add others as needed.)

1o           primary
2o           secondary
%            percent

ABMT         Autologous bone marrow transplant
AE(s)        Adverse event(s)
AIDS         Acquired Immune Deficiency Syndrome
AJC          American Joint Commission for Cancer Staging and End Results Reporting
ALL          Acute Lymphocytic/Lymphoblastic Leukemia
ALT          Alanine transaminase
ANC          Absolute Neutrophil Count
ANCOVA       Analysis of covariance
AST          Aspartate transaminase
AUC          Area under the curve

BCCA         British Columbia Cancer Agency
BID          twice per day
BL           Burkitt’s Lymphoma
BSA          Body Surface Area
BUN          Blood Urea Nitrogen
o
C            degrees Celsius
CAV          Cyclophosphamide, doxorubicin, & vincristine combination chemotherapy
CBC          Complete blood count
CDER         Center for Drug Evaluation and Research
Chol         Cholesterol
CHOP         Cyclophosphamide, doxorubicin, vincristine & prednisone combination
                  chemotherapy
CI           Confidence interval
CFR          Code of Federal Regulations
cm           centimeters
CNS          Central nervous system
CR           Complete Response
CRF(s)       Case Report Form(s)
CRO          Contract research organization
Cru          Complete response unconfirmed


                                               vi      (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                       Protocol [Protocol Number]


CSF      Cerebral spinal fluid
CT       Computerized Tomography
CTC      Common Toxicity Criteria
CXR      Chest X-Ray

DLBCL    Diffuse Large B-Cell Lymphoma
DLCL     Diffuse Large Cell Lymphoma
DLT      Dose-limiting toxicity
DSMB     Data and Safety Monitoring Board
D5W      Dextrose 5% in Water

EC       Ethics Committee
ECG      Electrocardiogram
ECOG     Eastern Cooperative Oncology Group
EU       European Union
o
 F       degrees Fahrenheit
FDA      Food and Drug Administration

GCP      Good Clinical Practice
G-CSF    Granulocyte colony stimulating factor
GGT      Gamma-glutamyl transferase
GLP      Good Laboratory Practice

HIV      Human Immunodeficiency Virus
HPLC     High Performance Liquid Chromatography

ICH      International Conference on Harmonisation
IND      Investigational New Drug Application
INR      International Normalized Ratio
IRB      Institutional Review Board
ITT      Intent-to-treat
IU       International units
IV       Intravenous
IVCI     Intravenous (central infusion)
IVPB     Intravenous (piggy-back)

kg       Kilogram
KPS      Karnofsky Performance Status

L        Litre
LDH      Lactic dehydrogenase
LVEF     Left ventricular ejection fraction

m2       metre squared
MCH      Mean corpuscular hemoglobin


                                              vii   (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                       Protocol [Protocol Number]


MCHC     Mean corpuscular hemoglobin concentration
MCV      Mean corpuscular volume
MedDRA   Medical Dictionary for Drug Regulatory Activities
mg       milligrams
min      minutes
mL       milliliter
MR       Minor Response
MRI      Magnetic Resonance Imaging
MTD      Maximum Tolerated Dose

NCI      National Cancer Institute
NCIC     National Cancer Institute of Canada
NHL      Non-Hodgkin’s Lymphoma

OD       once daily

PD       Progressive Disease
PI       Principal Investigator
PK       Pharmacokinetics
PO       by mouth (orally)
PR       Partial Response

RBC      Red blood cells
RD       Recommended Dose
REAL     Revised European American Lymphoma

SAE(s)   Serious adverse events
SD       Stable disease
SE       Standard error
SGOT     Serum glutamic oxaloacetic transaminase
SGPT     Serum glutamic pyruvic transaminase
SIADH    Syndrome of Inappropriate Antidiuretic Hormone
SM       Sphingomyelin
SPD      Sum of the products of the greatest diameters
STD      Standard deviation

t1/2     elimination half-life
TID      three times per day
TTP      Time to progression

ULN      Upper limit of normal
USP      United States Pharmacopeia

VSLI     Vincristine Sulfate Liposomes Injection 0.16 mg/mL

WBC      White blood cells


                                          viii    (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                             Protocol [Protocol Number]


WHO      World Health Organization

XRT      Radiation therapy




                                     ix   (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                             Protocol [Protocol Number]


1. INTRODUCTION AND BACKGROUND
   (The introduction should include background information for the study. The introduction
   should place the study in the context of the investigational product’s clinical development.
   Provide all references [published and unpublished] used to support the material presented in
   the introduction. Where appropriate, include the subsections below.)
   1.1 Background of the Disease
         (Discuss disease incidence and other important considerations.)
   1.2 Background of Treatment Options
         (Discuss the standard medicines or other therapies used to treat the disease and the
         limitations of these standard medicines or other therapies)
   1.3 Summary of Nonclinical and Clinical Data
         (Refer to the CIB or Package Insert and discuss the nonclinical studies with potential
         clinical significance and clinical studies with relevance to the current trial.)
   1.4 Risks and Benefits to Human Patients
         (Refer to the CIB or Package Insert)

2. RATIONALE
   2.1 Rationale for the Study
         (Briefly explain why the investigational product may be of benefit.)
   2.2 Rationale for Drug Dose Selection
         (Explain how dose to be used was determined from prior preclinical or clinical studies.)


3. STUDY OBJECTIVES
   (State the primary and secondary objectives of the study as specifically and succinctly as
   possible. One primary objective should be defined. The objectives should be consistent with
   the primary and secondary variables.)
   3.1 Primary Objective


   3.2 Secondary Objective(s)




                                                  1       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                             Protocol [Protocol Number]


4. INVESTIGATIONAL PLAN
   4.1 Overall Study Design
         (Briefly and clearly describe the overall study design using a flow chart or diagram if
         needed. The following information should be included:
             A description of the study type/configuration/level and method of blinding [e.g.,
                open, single- or double-blind, parallel groups]
Level of control [e.g., observational, uncontrolled, controlled]
Method of control [e.g., placebo, active, historical]
Method of assignment to treatment
A specific statement of the primary variable to be measured during the study
             Patient population and number of patients to be included and number of planned
                 centers
             A description of the trial treatment[s] including both investigational product[s],
                placebo and/or comparator[s]
             The expected duration of patient participation, and a description of the sequence and
                duration of all trial periods, including follow-up, if any.)
   4.2 Discussion of Study Design
         (Discuss the critical design features of the study, as necessary. Examples of design issues
         meriting discussion include the following: specific control chosen, choice of comparative
         treatment regimen, use of a crossover design, presence or absence of washout periods,
         selection of patients, and rationale for dose and dose-interval selection. If randomization
         was not used, it is important to explain how other techniques, if any, guarded against
         systematic selection bias.)


5. SELECTION AND WITHDRAWAL OF PATIENTS
   5.1 Number of Patients
         (Standard text; ensure that it is correct for your protocol) A total of XX patients will be
         enrolled in this study.
   5.2 Inclusion Criteria
         (Standard text; ensure that it is correct for your protocol and use the terms “patient” or
         “subject” as appropriate) To be eligible for the study, patients must fulfill all of the
         following criteria:
                Patients are men or women between XX and XX years of age (inclusive).
                Female patients of childbearing potential must not be pregnant or lactating, must
                      have a negative pregnancy test at screening and must be practicing an
                      adequate method of birth control. Acceptable methods of birth control



                                                  2      (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                               Protocol [Protocol Number]


                        include use of an intrauterine device (IUD), oral, implanted or injected
                        contraceptives, and barrier methods with spermicide.
                Patients must sign an informed consent that complies with US Regulations (US 21
                        CFR 50) and the International Conference on Harmonization (ICH)
                        guidelines prior to undergoing any study-related procedures.


   5.3 Exclusion Criteria
         (Standard text; ensure that it is correct for your protocol and use the terms “patient” or
         “subject” as appropriate.) Patients meeting any of the following criteria will be excluded
         from the study:
                1.
                2.
   5.4 Withdrawal of Patients
         (Standard text; ensure that it is correct for your protocol and use the terms “patient” or
         “subject” as appropriate.) Patients may voluntarily withdraw for any reason. Patients
         may be withdrawn because of the appearance of a new health condition suspected to
         require appropriate care or require medications prohibited by the protocol, unacceptable
         adverse events, refusal to continue treatment, or at the Investigator’s discretion if it is in
         the patient’s best interest according to the Investigator’s clinical judgment.
         If a patient withdraws from the study at any time either at his or her request or at the
         Investigator’s discretion, the reason(s) for withdrawal must be recorded on the relevant
         page of the patient’s Case Report Form (CRF). Patients discontinuing treatment will be
         followed for survival. Patients who withdraw from the study prematurely should undergo
         all end-of-study assessments, if possible.
         It is vital to obtain follow-up data on any patient withdrawn because of an adverse event.
         In any case, every effort must be made to undertake protocol-specified safety follow-up
         procedures. If a patient is discontinued due to an adverse event, the event will be followed
         until resolution or until the event becomes chronic. If a patient refuses to continue study
         procedures, the reason for refusal should be fully documented in the patient’s source
         document and recorded in the study specific CRF.
         (Include a description of the withdrawal criteria for individual patients specifying type
         and timing of data to be collected for withdrawn patients and whether and how patients
         are to be replaced.)


6. RANDOMIZATION AND BLINDING PROCEDURES
   6.1 Randomization
         (Include a detailed description of the randomization method and how it will be executed.
         Explain the method of generating random numbers. Include the randomization ratio and



                                                   3       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                                Protocol [Protocol Number]


         when the randomization will be carried out. If there will be no randomization, this should
         be stated.)
   6.2 Blinding
         (Describe specific procedures that will be used to carry out blinding of site personnel,
         patient and Sponsor. Describe circumstances in which the blind would be broken for an
         individual or for all patients [e.g., for serious adverse events]. Mention the procedures
         that will be used for breaking the blind and a list of the individual[s] who will have
         access to patient codes. Describe the measures taken to ensure that investigational
         treatment and placebo will be indistinguishable. Sometimes blinding is attempted, but is
         known to be imperfect because of obvious drug effects in at least some of the patients.
         Identify such problems or potential problems and, if there will be any attempts to assess
         the magnitude of the problem or manage it, describe the action that will be taken.)


7. STUDY TREATMENTS
   7.1 Supply, Packaging, Labeling and Storage
         (Specify the type of package, content, identification, and labeling as well as specific
         instructions regarding the special precautions on how to store the investigational
         product[s] and/or comparative treatment. Also include information on the packaging and
         content for all devices available or supplied for use in the study. Include information on
         the proper handling and storage of these devices.)
         7.1.1   Drug
         7.1.2   Comparative Treatment or Placebo
         7.1.3   Devices
   7.2 Drug Dosage and Administration
         (Describe the treatments to be administered to each arm of the study [each arm described
         in a separate subsection] including name[s] of all product[s], dose[s], dosing
         schedule[s], route/mode[s] of administration, and the treatment period[s] including
         follow-up period for each individual patient. This information could be presented in one
         section if the trial is not controlled. If the trial is controlled use separate subsections for
         the investigational product[s] and/or comparative treatment.)
         7.2.1   Drug
                 (Describe the intended drug dose, dosing regimen, route of administration, and
                 duration of treatment.)
         7.2.2   Comparative Treatment or Placebo
                 (If the trial is comparative, describe the comparative treatment [placebo or active
                 control].)
   7.3 Drug Dose Modification
         (State any criteria for drug dose modification if applicable to your protocol.)


                                                    4       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                             Protocol [Protocol Number]


   7.4 Concomitant Treatment
         (Standard text) Any concomitant treatment given for any reason must be recorded on the
         Case Report Form (CRF), including dosage, start and stop dates and reason for use.
         (Also state any medication[s]/treatment[s] permitted [including rescue medications] or
         prohibited before and/or during the study.)


8. RISKS/PRECAUTIONS
   (Include information regarding procedures to follow in case of overdose, extravasation, or
   hypersensitivity. Also include known adverse effects to the study drug and/or the class of
   study drug, and information on drug interactions using the package insert, CIB or other
   safety information if available. This section should contain identical information to the
   risks/precautions section of the package insert if the drug is approved.)


9. STUDY PROCEDURES
   (Include the schedule of study procedures. Do not describe the efficacy and safety variables
   in detail, as they will be defined in Section 11.)
   9.1 Screening and Baseline Procedures
         (Standard text–ensure that it is correct for your protocol.) After signing the informed
         consent and within XX days of initial treatment administration, the following data will be
         collected and study procedures will be performed:
         Date informed consent form signed
         Demographic data including date of birth, gender and race
         Significant medical and surgical history
         Disease history including date of diagnosis, histological type, prior treatment(s) (Include
                other details as required by the protocol. Examples of these include relapse
                history and prognostic indicators.)
         Physical examination
         Vital signs, including blood pressure, temperature, pulse and respiration
         Laboratory assessments (include specifics)
         Concomitant medications
         (other baseline or screening assessments as applicable to your study)
   9.2 Treatment Procedures
         (Describe treatment and procedures, incorporating schedule/timing of assessments and
         evaluations as needed.)
   9.3 Follow-up Procedures
         (Describe follow up assessments and evaluations, including the timing.)

                                                    5     (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                             Protocol [Protocol Number]



   9.4 Schedule of Events
         (Include a table representing the schedule of procedures/assessments in this section. See
         example below.)
                               TABLE 1: Schedule of Assessments
    Assessment          Screening /       Initial      Follow Up to     Subsequent       Follow Up
                         Baseline       Treatment         Initial       Treatments         Post-
                                                        Treatment                        Treatment
Informed Consent             X
Inclusion/Exclusion          X
Criteria
Demographics                 X
Medical / Surgical           X
History
Disease History              X
Physical Exam                X               X               X               X              X
Vital Signs                  X               X               X               X              X
Laboratory                   X               X               X               X              X
Assessments
Concomitant                  X               X               X               X              X
Medications
Adverse Events                               X               X               X              X
Treatment                                    X                               X              X
Administration
(Place any required explanations or exceptions as footnotes directly under the table.)


10. EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS
   (Standard text–ensure that it is correct for your protocol and use the terms “patient” or
   “subject” as appropriate.) Inex Pharmaceuticals’ Standard Operating Procedures will be
   followed with regard to the evaluation, recording, and reporting of adverse events.
   All adverse events either observed by the Investigator or one of his/her medical collaborators,
   or reported by the patient spontaneously, or in response to a direct question, will be noted in
   the adverse events section of the patient's Case Report Form (CRF) and source document.
   If any adverse event is reported, the date of onset, National Cancer Institute (NCI) toxicity
   grade, relationship to study medication or treatment, any action taken, date of resolution (or
   the fact that it is still continuing or has become chronic), outcome, and whether the adverse


                                                 6       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                                 Protocol [Protocol Number]


   event is serious or not will be recorded. The different options for these categories are defined
   in Section 10.2.
   (Include a statement regarding when the adverse event reporting period begins and ends [ie
   begins at time the consent form is signed or after first treatment, ends at completion of all
   follow up assessments or 30 days following last treatment, etc.]. The Investigator will
   follow all adverse events until they have resolved or it is determined that they have become
   chronic.
   10.1 Definitions
         10.1.1 Adverse Event
                An adverse event (AE) is any unfavorable and unintended sign (including
                an abnormal laboratory finding), symptom, or disease temporally
                associated with the administration, at any dose, of a medicinal or
                therapeutic product whether or not considered related to that product.
         10.1.2 Serious Adverse Event
                A Serious Adverse Event (SAE) is defined as any untoward medical occurrence
                that (at any dose):

                •       results in death.
                is life-threatening (i.e. the patient was at risk of death at the time of the event).
                requires inpatient hospitalization [suggested clarification: hospitalization of  24
                       hours, exception is hospitalization scheduled before a patient enrolls in
                       the study] or prolongs existing hospitalization.
                results in persistent or significant disability / incapacity.
                results in a congenital anomaly / birth defect.
                is medically significant and may jeopardize the patient or may require intervention
                       to prevent one of the outcomes listed above (examples of such events are
                       intensive treatment for allergic bronchospasm; blood dyscrasias or
                       convulsions that do not result in hospitalization; or development of drug
                       dependency or drug abuse).
   10.2 Adverse Event Descriptors
         10.2.1 Intensity
                The intensity of adverse events will be characterized according to NCI toxicity
                grades (refer to appropriate appendix)




                                                    7       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                              Protocol [Protocol Number]


         10.2.2 Relationship to Study Treatment
                The causal relationship to study drug or treatment will be determined by the
                responsible Investigator according to best medical judgment, as follows:


                 None           The event is definitely not associated with the study drug or
                                treatment.

                 Unlikely       The temporal association, patient history and/or circumstances
                                are such that the study drug or treatment is not likely to have
                                had an association with the observed event.

                 Possible       The event follows a reasonable temporal sequence from study
                                drug or treatment but could have been produced by the patient’s
                                clinical state or other therapies administered to the patient.
                 Probable       The event follows a reasonable temporal sequence from the
                                study drug or treatment, abates upon discontinuation of the
                                study drug or treatment, and cannot be reasonably explained by
                                known characteristics of the patient’s clinical state.

                 Definite       The event follows a reasonable temporal sequence from the
                                study drug or treatment, abates upon discontinuation, cannot be
                                explained by known characteristics of the patient’s clinical
                                state, and is confirmed by reappearance of the vent on repeat
                                exposure to the study drug or treatment (rechallenge).

                 Unknown        Events for which some information exists, but no firm
                                evaluation of relationship to study drug or treatment can be
                                made.


         10.2.3 Additional Reporting Guidelines
                Adverse events include the following:
                   Events arising from overdose, abuse, withdrawal, sensitivity or toxicity. (For
                    studies in which it would be appropriate, also add “failure of the medication’s
                    expected pharmacologic action” to this sentence.)
                   Apparently unrelated illnesses, including worsening of a preexisting illness. A
                    preexisting illness is defined as a disorder present before the adverse event
                    reporting period starts and is noted as such on the pretreatment medical
                    history, physical examination, or baseline signs and symptoms Case Report
                    Form page. Any worsening of the condition, including an increase in
                    frequency, will be reported as an adverse event.
                   Injury or accidents. Note that if a medical condition is known to have caused
                    the injury or accident (eg, a fall secondary to dizziness), the medical condition


                                                  8       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                             Protocol [Protocol Number]


                   (dizziness) and the accident (fall) should be reported as two separate events.
                   The outcome of the accident (eg hip fracture secondary to fall) should be
                   recorded as part of the event description, but not as a separate event.
                  Abnormalities in physiological testing or physical examination. These are
                   usually only reported as adverse events when the finding requires intervention
                   or investigation beyond a repeat confirmatory test. For any change in, for
                   example, vital signs or ECG measurements that arises after treatment, the
                   Investigator will decide if the value is clinically significant. If so, the
                   evaluation should be repeated. If the result is still clinically significant after
                   being repeated, the abnormality must be recorded as an adverse event.
                  Laboratory abnormalities requiring clinical intervention or further
                   investigation beyond a repeat confirmatory test, unless associated with an
                   already reported clinical event. Laboratory abnormalities associated with a
                   clinical event (eg elevated liver enzymes in a patient with jaundice) should be
                   described as part of the clinical event and not as a separate adverse event.
                   Laboratory values that are outside of normal limits should be repeated as
                   appropriate. Treatment-emergent laboratory abnormalities that the Investigator
                   determines are clinically significant and/or require treatment or a change in the
                   patient’s treatment will be recorded as an adverse event.
                  Diagnostic and therapeutic non-invasive and invasive procedures such as
                   surgery should not be reported as adverse events. However, the medical
                   condition for which the procedure was performed should be reported if it
                   meets the definition of an adverse event (eg an acute appendicitis is
                   considered to be an adverse event, and the resulting appendectomy is the
                   action taken).
                  Symptoms of baseline disease will be captured on the adverse event pages of
                   the patient’s Case Report Form along with their intensity. A worsening of
                   baseline symptoms will result in a new entry on the Case Report Form.
   10.3 Reporting and Evaluation of Serious Adverse Events and Other
        Clinically Significant Adverse Events
         10.3.1 Serious Adverse Events
               (Standard text) Any Serious Adverse Event (SAE) occurring in this study must
               immediately (within 24 hours) be reported by facsimile (fax) to the Sponsor safety
               contacts listed below, using the SAE Reporting Form (CIOMS) provided by the
               Sponsor.
                David Saltman, MD, Ph.D.                  Daphne Middelaer, RRT
                Director, Medical Affairs                 Medical Affairs Associate
                Inex Pharmaceuticals Corporation          Inex Pharmaceuticals Corporation
                100-8900 Glenlyon Parkway                 100-8900 Glenlyon Parkway
                Burnaby, British Columbia                 Burnaby, British Columbia
                Canada V5J 5J8                            Canada V5J 5J8



                                                 9       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                             Protocol [Protocol Number]


                 Toll Free Phone: 1-866-419-3255          Toll Free Phone: 1-866-419-3255
                 Toll Free Fax: 1-866-430-8347            Toll Free Fax: 1-866-430-8347


                The facsimile should include the initial SAE Report completed in capital letters in
                medical terms and in English to the best extent possible given the time
                constraints. The Investigator must also inform the local Institutional Review
                Board (IRB) or Ethics Committee (EC) of any SAEs that occur at the site within
                15 days (or earlier if warranted by local requirements) of the occurrence. The
                Investigator should provide conventional medical treatment if necessary and
                monitor the patient's condition until resolution or until the event becomes chronic.
                An adequate SAE Report, for Inex purposes, includes the following minimum
                information:
                Study name or number,
                Patient number and initials,
                Event description (including date of the event onset, outcome and reason for it
                       being considered serious),
                Name of the investigational product (including drug dose and administration
                     dates),
                Causality (none, unlikely, possible, probable, definite, unknown),
                Person reporting event (include site name or number), and
                Dated signature of the Investigator or Sub-/Co-Investigator.


11. STUDY VARIABLES AND STATISTICAL ANALYSIS
   (Include a description of the statistical methods to be employed, including the timing of
   analyses.)
   11.1 Sample Size/Power Considerations
          (State the number of patients to be enrolled. In multicenter trials, specify the number of
          enrolled patients projected for each study site. Describe how the sample size was
          calculated or estimated.)
   11.2 Data Sets to be Analyzed
         11.2.1 Pharmacokinetic/Pharmacodynamic


         11.2.2 Efficacy


         11.2.3 Safety



                                                 10      (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                           Protocol [Protocol Number]


   11.3 Analysis of Demographic and Baseline Data


   11.4 Pharmacokinetic/Efficacy Variables and Analyses
         (Efficacy variables should be designated as primary and secondary variables. If there
         is more than one primary variable, describe adjustment of the p-value for multiple
         comparisons.)
   11.5 Safety Variables and Analyses




   11.6 Interim Analysis (if applicable)
         (Describe the following information regarding the interim analysis: time and purpose,
         who would perform and review the analysis, the decisions that will be made based on
         the analysis, how blinding will be maintained, and any statistical penalty that will
         result from the analysis.)
12. ESTIMATED DURATION OF THE STUDY
   (Include the estimated duration of patient enrollment period and the defined follow-up
   period.)
13. STUDY ETHICAL CONSIDERATIONS
   13.1 Ethical Conduct of the Study
         (Standard text–ensure that it is correct for your protocol.) The study will be conducted
         according to the principles of the Declaration of Helsinki and its most recent updates
         (Scotland, 2000), and the ICH guidelines for Good Clinical Practice. The Sponsor will
         ensure that the study complies with all local, federal or country regulatory requirements
         as applicable, such as US 21 CFR Parts 50, 56, and 312.
   13.2 Informed Consent
         (Standard text–ensure that it is correct for your protocol and use “patient” or
         “subject” as appropriate.) The informed consent forms used for the study must comply
         with the Declaration of Helsinki, federal regulations (US 21 CFR 312, and International
         Conference on Harmonization [ICH] guidelines) and must have been approved by the
         Sponsor (prior to review by the Institutional Review Board [IRB]/ Ethics Committee
         [EC]) and the Investigator's IRB. A sample informed consent form is provided in
         Appendix XX. The Investigator or an authorized associate, who must be a physician,
         must explain orally and in writing the nature of the study and the treatment in such a
         manner that the patient is aware of potential benefits and risks. Patients must also be
         informed that participation is voluntary and that they may withdraw from the study at
         any time, without prejudice. Documentation of the discussion and the date of informed
         consent must be recorded in the source documentation. Patients must give informed
         consent in writing.



                                               11      (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                              Protocol [Protocol Number]


   13.3 Institutional Review Board or Ethics Committee
          (Standard text–ensure that it is correct for your protocol.) The protocol, any protocol
          amendments and consent form for the proposed clinical study and any other documents
          required by the local Institutional Review Board (IRB) or Ethics Committee (EC) must be
          submitted by the Investigator for review and approval. The Investigator must also ensure
          that the IRB/EC reviews the progress of the study on a regular basis and, if necessary,
          renews its approval of the study on an annual basis. A copy of the approval letter must be
          forwarded to the Sponsor before the study is implemented.
14. ADMINISTRATIVE PROCEDURES
   14.1 Sponsor’s Responsibilities
         14.1.1 Study Supplies
                (List supplies to be provided by Sponsor.)
         14.1.2 Investigator Training
                (Describe the specific information that will be communicated during training and
                when training will take place.)
                (Standard text–ensure that it is correct for your protocol and use the terms
                “patient” or “subject” as appropriate.) All Investigators and their study
                personnel will receive training regarding the study procedures. This training will
                take place prior to enrollment of the first patient at each study center. Each study
                center will be provided with information regarding Good Clinical Practices and
                regulations specific to the conduct of clinical trials.
         14.1.3 Study Monitoring
                (Standard text–ensure that it is correct for your protocol and use the terms
                “patient” or “subject” as appropriate.) The study will be monitored by
                representatives of Inex and/or (if appropriate include the contract research
                organization (CRO) and/or partner company). Routine monitoring visits will be
                conducted to:
                Assure compliance with the study protocol.
                Review the patient CRFs and source documents to ensure that reported study data
                      are accurate, complete, and verifiable from source documents.
                Ensure that adequate records of clinical trial supplies are maintained.
                Verify that the Investigator and study site personnel are adequately qualified
                       throughout the study.
                Verify that the research facilities, including laboratories and equipment, are
                       adequate to safely and properly conduct the study.
                Verify that the investigational product[s] are stored properly and under the proper
                        conditions, are in sufficient supply, and that receipt, use, and return of




                                                 12       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                              Protocol [Protocol Number]


                       investigational product[s] at the study sites are controlled and documented
                       adequately.
                Verify that written informed consent was obtained before initiation of any
                       screening procedures that are performed solely for the purpose of
                       determining eligibility for the clinical study and/or prior to the provision of
                       study medication.
                Verify that the safety information and amendments are submitted to the IRBs.


   14.2 Investigator’s Responsibilities
         14.2.1 Reporting and Recording of Study Data
                (Standard text–ensure that it is correct for your protocol and use the terms
                “patient” or “subject” as appropriate.) All requested study data must be recorded
                legibly on the Case Report Forms (CRFs) provided for the study. An explanation
                should be provided for all missing data. Correction of data on the CRF will be
                made by crossing out the incorrect entry with a single stroke and entering the
                correct data beside it with the initials of the individual making the correction and
                date of the correction. Only individuals who are identified on the Authorized
                Signature Page may correct data in the CRF. For those patients who withdraw
                before completion of their specified treatment regimen, all available efficacy and
                safety data must be entered in the CRF. The reason for withdrawal must be
                specified. Incomplete or inconsistent data on the CRFs will result in data queries
                that will be returned to the Investigator for resolution.
         14.2.2 Source Documentation
                (Standard text–ensure that it is correct for your protocol and use the terms
                “patient” or “subject” as appropriate.) The Investigator must maintain adequate
                and accurate source documents upon which case reports for each patient are
                based. They are to be separate and distinct from CRFs, except for cases in which
                the Sponsor has predetermined that direct data entry into specified pages of the
                patient’s CRF is appropriate. These records should include detailed notes on:
                The medical history prior to participation in the study.
                The basic identifying information, such as demographics, that link the patient’s
                      source documents with the CRFs.
                The results of all diagnostic tests performed, diagnoses made, therapy provided
                       and any other data on the condition of the patient.
                The patient’s exposure to study treatment.
                All adverse events.
                The patient’s exposure to any concomitant therapy (including date and quantity
                      dispensed).



                                                  13      (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                               Protocol [Protocol Number]


               All relevant observations and data on the condition of the patient throughout the
                       study.
               The oral and written communication with the patient regarding the study treatment
                      (including the risks and benefits of the study). The date of informed
                      consent must be recorded in the source documentation.
         14.2.3 Study Drugs
               (Standard text–ensure that it is correct for your protocol and use the terms
               “patient” or “subject” as appropriate.) The Investigator is responsible for
               ensuring the study drugs are administered or dispensed only to patients enrolled in
               the study. An accurate accounting of the study drugs must be maintained using a
               separate form (Accountability Record Forms). These records must show dates, lot
               numbers, quantities received and dispensed. The Investigator will return any
               unused study drug and other study material to the Sponsor at the completion of the
               study.
         14.2.4 Records Retention
               (Standard text–ensure that it is correct for your protocol and use the terms
               “patient” or “subject” as appropriate.) The Investigator must arrange for the
               retention of all study documentation (such as CRFs, research files, and master
               files) for at least 15 years after the completion or discontinuation of the study.
               Patient files and other source data must be kept for the maximum period of time
               permitted by the hospital, institution or private practice, but not less than 15 years.
               The Sponsor must retain all other documentation pertaining to the study for the
               lifetime of the product. Archived data may be held on microfiche or electronic
               record, provided that a back-up copy exists and that a hard copy can be generated
               if required.
               The Investigator must inform the Sponsor immediately if any documents are to be
               destroyed, to be transferred to a different facility, or to be transferred to a different
               owner.
   14.3 [Other Services] as Applicable
          (Specify information regarding the use of any other study management group such as a
          a Study Advisory Group, or Data Safety Monitoring Board.)
15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA
   (Standard text–ensure that it is correct for your protocol.) The Sponsor encourages the
   scientific publication of data from clinical research trials. However, Investigators may not
   present or publish partial or complete study results individually. The Principal Investigators
   and the Sponsor may propose appropriate scientific manuscripts or abstracts from the study
   data. Any manuscript or abstract proposed by the Investigators must be reviewed and
   approved in writing by the Sponsor before submission for publication. Names of all
   investigators participating in the study will be included in the publication.




                                                  14       (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                             Protocol [Protocol Number]


16. REFERENCES
(References must appear as endnotes and be electronically inserted, cross-referenced, and
numbered within the text of the protocol. List references in order of their appearance in the text
and use the standard format published in the American Medical Association Manual of Style, 9th
ed.)

Journal articles: [cite 6 authors. If the number of authors exceeds 6, cite 3 plus “et al”]
1        Lastname CH, Lastname DJ. A study of … Journal name. 1980;9(vol):311-314.
Book chapter:
2      Lastname S, Lastname HT. Chapter name. In: Lastname WA, Lastname M, eds. Book
       name. Philadelphia, PA: Saunders; 1974:457-472.

17. APPENDICES
    (Include supplemental information in the appendices as appropriate for your protocol.
    Examples are listed below and in the following pages.)
APPENDIX 1. Investigator Signature Page
APPENDIX 2. Package Insert
APPENDIX 3. Drug Infusion and Constitution Procedures
APPENDIX 4. Sample Informed Consent Form




                                                 15      (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                                           Protocol [Protocol Number]


                                          APPENDIX 1
                                 Investigator Signature Page
Protocol Number:             (Insert study number)
Title of Protocol:           (Insert full title)
Date of the Protocol:        (Insert date of final protocol)
                                         AGREEMENT
This document is a confidential communication of Inex Pharmaceuticals Corporation. The
recipient agrees that no unpublished information contained herein will be published or disclosed
without the prior written approval of Inex Pharmaceuticals Corporation. However, this document
may be disclosed to appropriate Institutional Review Boards, Ethics Committees, or authorized
representatives of the Investigator or of Boards of Health under the condition that they are
requested to respect the confidentiality of the document.
The signature of the Investigator below constitutes his/her agreement to comply with the contents
of this protocol.


                           INVESTIGATOR’S NAME AND TITLE


                               INVESTIGATOR’S SIGNATURE


                                            ADDRESS


                                               DATE




                                                   16   (Date of Protocol in format dd/mmm/yyyy)
[Drug]                         Protocol [Protocol Number]


         APPENDIX 2
         Package Insert




               17     (Date of Protocol in format dd/mmm/yyyy)
[Drug]                                      Protocol [Protocol Number]


                       APPENDIX 3
         Drug Infusion and Constitution Procedures




                            18     (Date of Protocol in format dd/mmm/yyyy)
[Drug]                               Protocol [Protocol Number]


                 APPENDIX 4
         Sample Informed Consent Form




                      19    (Date of Protocol in format dd/mmm/yyyy)

								
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