Clinical Protocol

CytoPRO

CLINICAL STUDY PROTOCOLPhase IIAB

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Clinical Protocol Title: A Phase IIAB, Randomized, Blinded. Controlled Study of the Efficacy of CytoPRO Compared to Silvadene Cream 1% in Patients with Partial and Full Thickness 2nd and 3rd

Degree Burns

Version number and date: #3, August 22-10

Phase of clinical investigation: Phase IIAB Clinical Study

Investigational Treatment: CytoPRO Cream

Sponsor: CytoPRO153 Cahaba Valley ParkwayPelham, AL 35124

Authorized Signatories: TBD

Study Monitor: TBD

Medical Director: Mark Finneran, M.D.

Sponsor-Investigator: CytoPRO153 Cababa Valley ParkwayPelham, AL 35124

Clinical Laboratory, Technical Department and Institution Providing Clinical Study Services:

Mario Catarino Rivas Hospital, San Pedro Sula, Honduras

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SYNOPSIS

Sponsor: CytoPRO, LLC, Pelham AL

Name of Study Therapy: CytoPRO Cream

Title of Study: A Phase IIAB, Randomized, Controlled Study of the Efficacy of CytoPRO Cream Compared to Silvadene Cream 1% in Patients With Partial and Full Thickness 2nd and 3rd Degree Burns

Study Centers: Mario Catarino Rivas Hospital, San Pedro Sula, Honduras

Phase of Development: Phase IIAB

Objectives: Primary: To demonstrate the safety of CytoPRO Burn Cream in healing partial and full-thickness 2 nd and 3rd

degree burns.Secondary: To demonstrate the efficacy of CytoPRO Burn Cream in healing partial and full-thickness 2 nd

and 3rd degree burns.

Design and Investigational Plan: Twenty (20) patients with partial or full-thickness 2nd or 3rd degree burns meeting all inclusion/exclusion criteria will be evaluated at baseline. Patients will be randomized to either CytoPRO or Silvadene treatment groups:

1) CytoPRO Cream applied to burn wounds with dressings and removed and reapplied every 12 hours until complete wound healing

2) Silvadene Cream 1% applied to burn wounds with dressings and removed and reapplied every 12 hours until complete wound healing

Patients will be randomized prior to treatments using permuted blocks to one of the two arms in a 1:1 ratio (CytoPRO, Silvadene, respectively), providing a projected distribution of 50:50 patients among the groups.

Patient Population: Twenty (20) patients with partial and full-thickness 2nd and 3rd degree burns.

Diagnosis and Main Criteria for Inclusion/Enrollment:

Major Inclusion Criteria

The area of the burn injury is at least 200cm2 (1% TBSA in adults) if a contiguous wound, or at least 100cm2 for each of 2 non-contiguous wounds

The area of total burn injury is 1-20% TBSA The study treatment area is a second degree or third degree burn injury The subject is between 2-65 years of age The subject is willing to complete all follow-up evaluations required by the study protocol The subject is to abstain from any other treatment of the wound(s) for the duration of the study

unless medically necessary The subject agrees to abstain from enrollment in any other clinical trial for the duration of the

study The subject and/or guardian are able to read and understand instructions and give informed,

voluntary, written consent

The subject is able and willing to follow the protocol requirements

Major Exclusion Criteria The subject's burn injuries were caused by chemicals, electricity, and/or radioactive substances The total subject burn injury is less than 1% or more than 20% TBSA The subject has a microbiologically proven pre-existing local or systemic bacterial infection The subject is known to have a pre-existing condition that may interfere with wound healing ( e.g.

malignancy, diabetes, or autoimmune disease) The subject is unable to follow the protocol The subject is taking medication known to have an effect on wound healing or skin pigmentation

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( e.g. systemic corticosteroids, retinoids, etc)

The subject has other concurrent conditions that in the opinion of the investigator may compromise patient safety or study objectives

Definition of Endpoints: Safety (Primary): No or minor adverse effects

Efficacy (Secondary): Time to 75% re-epithelialization: subjective pain: Need for and duration of: Narcotics, Antibiotics, Skin grafting.

Study Therapy: CytoPRO Cream for treatment of partial and full-thickness 2nd and 3rd degree burns.Duration of Study Follow-Up: Daily for week one, then weekly visits until complete re-epithelialization.

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Clinical Protocol

1. Introduction

1.1 Background

There are an estimated 1.1 million burns treated in the United States each year and five percent are full thickness, or third degree, burns. 15,000 people die each year from burns with children and the elderly disproportionately represented. Partial and full thickness or second and third degree burns are treated with exposition, mechanical debridement, topical ointments and skin grafting. Intravenous rehydration, antibiotics and narcotics are standard of care. Skin grafting with autologous or artificial skin is performed with sutures, staples or glue. Complications include pain, dehydration, infection, scarring, narcotic addiction, multi-system organ failure and death. Post skin-grafting contracture and disfigurement often require physical and occupational therapy.

CytoPRO evolved from a naturopathic technique of treating burns that has been demonstrated highly successful in reducing or eliminating the need for narcotics, antibiotics, IV hydration and skin grafting. Over 2,500 individual are known to have successfully used the method in the last 5 years. Most recently 27 cases have been managed by traditional medical providers in community and university hospital settings under informed consent.

This study will evaluate CytoPRO in the treatment of 2nd and 3rd degree burns.

CytoPRO is a cream which incorporates honey, lanolin, wheat germ oil, aloe vera, bees wax, glycerin, myrrh and an oleic extract of, comfrey, white oak bark, lobelia, wormwood, and marshmallow root.

Pre-clinical biocompatibility tests for CytoPRO have shown it to be biocompatible. Tests performed to date include, cytotoxicity, sensitization, irritation.

CytoPRO analogs been used for over 25 years by the Plain Community to successfully treat 1st, 2nd and 3rd degree burns. Over 2500 cases have been successfully treated.

CytoPRO, has to our knowledge, not been withdrawn from investigation or marketing in any country for any reason related to safety or effectiveness.

1.2 Rationale:

Pre clinical biocompatibility tests and clinical use has shown that CytoPRO is safe and effective for treating 2nd and 3rd degree burns. CytoPRO cream is bacteriostatic and permits the body to “part with” the devitalized tissue without mechanical debridement. Its

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formula prevents fluid loss from the burn bed and I.V. fluid is generally required only in the emergency department. The bacteriostatic effect appears to inhibits the “quorum response” relied upon by the pathogenic klebsiella, psuedomonas and clostridia bacteria, reducing the amount of antibiotics required. The free nerve ending nicotinic acetylcholine receptors are blocked, reducing painful stimulation caused by air and mechanical debridement, and thus reducing the need for narcotics. Most subjects become and remain pain free within 30 minutes of the initial CytoPRO dressing application. Most remarkably however, the patients regenerate new epithelium without skin grafting and with minimal scarring.

Over 2,500 individual are known to have successfully used the method in the last 5 years. Most recently 27 cases have been managed by traditional medical providers in community and university hospital settings under informed consent.

CytoPRO treatment consists of applying a thin layer of the cream to the burn wound which is then covered by dressings. The cream and dressings are changed every 12 hours until healing is accomplished.

The populations that will be included in the proposed clinical study include:

Age range: 2-65 years of ageGender: Male and FemaleCondition: Partial and full thickness 2nd and 3rd degree burns

2. Clinical Study Objectives :

2.1 Primary objective:

The primary objective is to evaluate the safety of CytoPRO in comparison to Silvadene in patients with partial and full-thickness second and third degree burns, through the clinical report, physical examination and the infection rates.

2.2 Secondary objectives:

The secondary objectives are to evaluate the efficacy of CytoPRO in comparison to Silvadene in patients with partial and full-thickness second and third degree burns, through the assessment of analgesic effect, wound healing time in days, wound healing rate and the wound healing quality.

3. Study Design :

The study is to be a randomized, parallel group, active controlled trial. Randomization will be achieved by rotating date and time of admission.

Routine burn treatment protocols will be followed for both CytoPRO and Silvadene treatment groups. The burn wounds will be gently cleaned and

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debrided and CytoPRO and Silvadene will be applied to the burns. The creams will be applied twice daily to a thickness of approximately 1/16th of an inch. The creams will then be dressed in standard fashion.Treatments will continue until wound healing is complete.

3.1 Study design schematic

4. Subject Selection :

The clinical study will be conducted at:

Mario Catarino Rivas Hospital, San Pedro Sula, Honduras

There will be 20 subjects who complete the study. Enrollment in the study is defined as providing informed consent for study participation per the IRB policies.

4.1 Subject inclusion criteria

Inclusion Criteria: The area of the burn injury is at least 200cm2 (1% TBSA in adults) if a

contiguous wound, or at least 100cm2 for each of 2 non-contiguous wounds The area of total burn injury is 1-20% TBSA

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Assessed for Eligibility

Randomized

Allocated to Intervention

Received Intervention

Discontinued Intervention

Followed Up

Analyzed Analyzed

Followed Up

Discontinued Intervention

Lost to Follow-up

Lost to Follow-up

Not AnalyzedNot Analyzed

Received Intervention

Allocated to Intervention

Did Not Receive Intervention

Did Not Receive Intervention

The study treatment area is a second degree or third degree burn injury The subject is between 2-65 years of age The subject is willing to complete all follow-up evaluations required by the study

protocol The subject is to abstain from any other treatment of the wound(s) for the

duration of the study unless medically necessary The subject agrees to abstain from enrollment in any other clinical trial for the

duration of the study The subject and/or guardian are able to read and understand instructions and

give informed, voluntary, written consent The subject is able and willing to follow the protocol requirements4.2 Subject exclusion criteria

Exclusion Criteria:

The subject's burn injuries were caused by chemicals, electricity, and/or radioactive substances

The total subject burn injury is less than 1% or more than 20% TBSA The subject has a microbiologically proven pre-existing local or systemic

bacterial infection The subject is known to have a pre-existing condition that may interfere with

wound healing ( e.g. malignancy, diabetes, or autoimmune disease) The subject is unable to follow the protocol The subject is taking medication known to have an effect on wound healing or

skin pigmentation ( e.g. systemic corticosteroids, retinoids, etc) The subject has other concurrent conditions that in the opinion of the investigator

may compromise patient safety or study objectives

5. Study Treatments :

CytoPRO Burn Cream TreatmentCytoPRO Burn Cream (CytoPRO LLC, Pelham AL USA) will be one of the treatments of this study. CytoPRO has not been evaluated by the FDA at this time. Approximately 1/16th inch layer of CytoPRO Burn Cream will be applied to cover the burn wound and then covered with a gauze and then compressive dressing. Every 12 hours the dressing will be removed and the CytoPRO will be reapplied. Treatment will continue until the wound is healed.

Silvadene Cream 1% TreatmentSilvadene Cream 1% will serve as the control treatment for this study. Silvadene is a soft, white water-miscible cream containing the antimicrobial agent silver sulfadiazine in micronized form. Each gram of Silvadene Cream 1% contains 10 mg of micronized silver sulfadiazine. The cream vehicle consists of white petrolatum, stearyl alcohol, isopropyl myristate, sorbitan monooleate, polyoxyl 40 stearate, propylene glycol, and water, with methylparaben 0.3% as a preservative. Silvadene was grandfathered into the FDA. Silvadene will be the second treatment arm in this study. Silvadene will be applied as directed by the manufacturer.

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Approximately 1/16th inch layer of Silvadene will be applied to cover the burn wound and then covered with a gauze dressing. Every 12 hours the dressing will be removed and the Silvadene will be reapplied. Treatment will continue until the wound is healed.

Silvadene is a topical cream that is used on severe burns, 2nd and 3rd degree.. Silvadene is a sulfa medicine used to prevent and treat bacterial or fungus infections. Silvadene should be applied using a sterile technique to the affected areas. These areas should be washed before applying. Avoid applying Silvaden to the face. It should not be use in newborns, infants younger than 2 years or in late pregnancy. A prescription is necessary in order to get Silvadene.

5.1 Allocation to treatment Eligible patients who consent to participate will be randomly assigned with equal probability to CytoPRO, or Silvadene groups. Randomization will be achieved and managed by the data coordinating staff.

5.2 Breaking the blind

The patient is blinded to the treatment. Should a given subject suffer a serious adverse event wherein knowledge of the identity of the drug received by the subject is necessary for effective emergency treatment, the blind will be broken.

5.3 Treatment adherence/Study compliance

Patients in both groups will maintain a home therapy log and record their dressing changes. A minimum of once daily will be scheduled for the first week. Once or twice weekly office visits will be scheduled thereafter at the treating physicians discretion. At these visits, the patients dressing logs will be reviewed and clinicians will evaluate healing, subjective pain, narcotic usage, need for antibiotics and need for skin grafting.

Subjects will be withdrawn from the study due to non-compliance with the treatment regimen and/or the study procedures or investigators instructions.

Subjects withdrawn from study participation due to noncompliance will be replaced with subjects that meet the inclusion/exclusion criteria.

5.4 Treatment supplies

5.4.1 Formulation and packaging

CytoPRO Cream will be supplied by CytoPRO, LLC. It will be packaged in plastic jars with screw lids and prepared dressing sheets

The Silvadene Cream 1% will be the comparator treatment (control) and will be packaged as furnished commercially.

Both treatments will be labeled with their commercial labels.

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5.4.2 Preparing and dispensing

Both CytoPRO and Silvadene will be provided in ready to use forms.

The CytoPRO comes in a tub, or as a pre-impregnated dressing that can be removed from its packaging and directly applied to the burn wound.

Silvadene will be applied directly onto the wound and then spread evenly to achieve an approximate uniform 1/16” thick layer.

5.4.3 Treatment administration

Intial CytoPRO and Silvatene treatment will be administered by the clinician. The clinician will apply the the burn creams to the burn areas, cover with dressings and then repeat every 12 hours until the wound is healed. Patients and/or guardians will be trained to change the dressings so they can be done on an outpatient basis.

5.5 Treatment storage and accountability

CytoPRO and Silvadene will be stored in their packaging until the time of use. They should be stored at room temperature.

The inventory of CytoPRO and Silvadene at each of the burn centers will be stored in a secure location with access available only to the study directors and study clinicians. For outpatient use, the appropriate amounts of CytoPRO and Silvadene will be given to the patient for the specified time period and documented in the patient records and the inventory log.

5.6 Concomitant Medications

Antibiotics, analgesics, narcotics and skin grafting may be used at the clinicians discretion. A record of all medications and procedures performed will be documented

5.6.2 Rescue Medication

The use of rescue medications constitute a measureable outcome and must be thoroughly documented

   AnalgesicsDoctors may prescribe analgesics for subjects who suffer from thermal burns, if required. Analgesics are used for pain control and to ensure that the patient is as comfortable as possible.

Nonsteroidal Anti-inflammatory Agents (NSAID)

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Ibuprofen is usually used during the initial therapy. Other NSAIDs may be prescribed. This is used for patients who are suffering from mild to moderate pain.

NarcoticsFor severe pain Morphine, Vicodin or Demerol may be prescribed.   

AntibioticsFor control of infection that develops in spite of the treatment

Dermabrasion Local anesthesia and a sedative may be used.

Skin graftingIn the event the wound has not healed at 6 weeks

Cross-over (changing treatment groups) After 3 weeks cross-over is permitted, at the treating physicians discretion. The reasons for cross-over will be documented.

6. Study Procedures :

6.1 Screening

The following procedures will be performed at subject screening to verify subject eligibility for study participation:

Patient and/or guardian are asked if they are interested in being part of the study.

Patient and/or guardian meets with the study coordinator and clinician to discuss medical history

Study coordinator and clinician verifies that all necessary inclusion criteria are meet and that no exclusion criteria apply for the patient

Patient and/or guardian read and sign informed consent.

6.2 Study treatment(s)

Active comparator study

Initial CytoPRO and Silvadene treatment will be administered by the clinician. The clinician will apply the the burn creams to the burn areas, cover with dressings and then repeat every 12 hours until the wound is healed. Patients and/or guardians will be trained to change the dressings so they can be done on an outpatient basis.

6.3 Follow-up

Dressings for each patient will be replaced every 12 hours until the wound heals. The initial changes will be performed by trained clinicians and then the patients or guardians will be trained to change the dressings on an outpatient basis.

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Patients will be examined every day for the first week and then once or twice a week until the wound heals.

6.4 Schedule of activities (Study Table)

Treatment Time ProceduresScreening Patient expresses interest in study

Patient meets with study coordinator/clinicianInclusion and exclusion criteria are verifiedPatient is accepted or rejected from studyPatient and/or guardian read and sign informed consent.

Treatments CytoPRO or Silvadene is applied to wound and dressedDressing is changed every 12 hours

Follow-up Patients are examined every day the first week and then 1-2 times a week until the wound heals

7. Efficacy and Safety Assessments :

7.1 Efficacy assessments

Efficacy assessment will include the following:

Time for 75% re-epithelialization Time for full re-epithelialization Wound healing rate Infection rate and need for antibiotics Pain assessment and need for analgesics Dermabrasion Skin grafting

Re-epithelializationStudy wounds will be evaluated, beginning at day 1 after treatment and at least every day thereafter for the first week, for reepithelialization. Thereafter burn sites will be evaluated 1-2 times per week. Each burn site will be photographed at evaluation times.

Wound Healing RateStudy wound will also be evaluated for percentage of closure of the wounds by two independent observers. Percentage of closure will be rated, by visual estimation, to the nearest 5%, up to 90% and by single percentage points above 90%.

Infection RateAfter placement of CytoPRO and Silvadene and prior to reepithelialization,each study wound will be assessed for signs of infection. A clinical assessment will be made daily for the presence of fever and/or reddening of the wound to

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indicate infection. If fever of greater than 38.5°C is present and there was evidence of local burn wound infection (inclusive of but not limited to spreading wound erythema, black/brown patches of discoloration, rapid eschar separation, conversion of wounds to full thickness, and/or punctate hemorrhagic subeschar lesions). Presence or lack of presence of infection will be documented for each patient and used to determine infection rates for each treatment.

Pain AssessmentThe Wong-Baker Faces Pain Rating Scale and Numerical Rating Scale will be used to assess pain of the patients each day.

7.2 Safety assessments

Safety assessments during the study will include monitoring of adverseevents.An adverse event is defined as any undesirable experience that occurredto a patient during the study, regardless of whether it was related to the study treatment. Adverse events will be assessed by the investigator as being causally related to the study treatment with:

Highly probable, Probable, Possible or Not assessable

Criteria to determine causal relationship to the study treatment.

8. Adverse Event Reporting :

8.1 Adverse event definitions

Adverse event. Any untoward medical occurrence in a clinical study; regardless of the causal relationship of the event with the investigational drug or study treatment(s).

Associated with the use of the investigational drug or study treatment(s). There is a reasonable possibility that the adverse event may have been caused by the investigational drug or study treatment(s).

Disability. A substantial disruption of a person’s ability to conduct normal life functions.

Life-threatening adverse event. Any adverse event that places the patient or subject, in the view of the investigator, at immediate risk of death from the event as it occurred (i.e., does not include an adverse event that, had it actually occurred in a more severe form, might have caused death).

Serious adverse event. Any adverse event occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.

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Hospitalization shall include any initial admission (even if less than 24 hours) to a healthcare facility as a result of a precipitating clinical adverse event; to include transfer within the hospital to an intensive care unit. Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical adverse event

Unexpected adverse event. Any adverse event, the frequency, specificity or severity of which is not consistent with the risk information described in the clinical protocol.

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8.2 Recording/Reporting requirements

8.2.1 Eliciting adverse event information

Clinical study subjects will be routinely questioned about adverse events at study visits.

8.2.2 Recording requirements

All observed or volunteered adverse drug events (serious or non-serious) and abnormal test findings, regardless of treatment group or suspected causal relationship to the investigational drug or study treatment(s) will be recorded in the subjects’ case histories. For all adverse events, sufficient information will be pursued and/or obtained so as to permit 1) an adequate determination of the outcome of the event (i.e., whether the event should be classified as a serious adverse event) and; 2) an assessment of the casual relationship between the adverse event and the investigational drug or study treatment(s).

Adverse events or abnormal test findings felt to be associated with the investigational drug or study treatment(s) will be followed until the event (or its sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the investigator-sponsor.

8.2.2.1 Abnormal test findings

An abnormal test finding will be classified as an adverse event if one or more of the following criteria are met:

The test finding is accompanied by clinical symptoms.

The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention; including significant additional concomitant drug treatment or other therapy

o Note: simply repeating a test finding, in the absence of any of the other listed criteria, does not constitute an adverse event.

The test finding leads to a change in study dosing or discontinuation of subject participation in the clinical study

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The test finding is considered an adverse event by the investigator-sponsor

8.2.2.2 Causality and severity assessment

The investigator-sponsor will promptly review documented adverse events and abnormal test findings to determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a reasonable possibility that the adverse event was caused by the investigational drug or study treatment(s); and 3) if the adverse event meets the criteria for a serious adverse event.

If the investigator-sponsor’s final determination of causality is “unknown and of questionable relationship to the investigational drug or study treatment(s)”, the adverse event will be classified as associated with the use of the investigational drug or study treatment(s) for reporting purposes.

If the investigator-sponsor’s final determination of causality is “unknown but not related to the investigational drug or study treatment(s)”, this determination and the rationale for the determination will be documented in the respective subject’s case history.

8.3 Reporting of adverse events

8.3.1 Reporting adverse events to the responsible IRB

In accordance with applicable policies of the Institutional Review Board (IRB), the investigator-sponsor will report, to the IRB, any observed or volunteered adverse event that is determined to be 1) associated with the investigational drug or study treatment(s); 2) serious; and 3) unexpected. Adverse event reports will be submitted to the IRB in accordance with the respective IRB procedures.

Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later than 10 calendar days following the investigator-sponsor’s receipt of the respective information. Adverse events which are 1) associated with the investigational drug or study treatment(s); 2) fatal or life-threatening; and 3) unexpected will be reported to the IRB within 24 hours of the investigator-sponsor’s receipt of the respective information.

Follow-up information to reported adverse event will be submitted to the IRB as soon as the relevant information is available. If the results of the

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sponsor-investigator’s follow-up investigation show that an adverse event that was initially determined to not require reporting to the IRB does, in fact, meet the requirements for reporting; the investigator-sponsor will report the adverse event to the IRB as soon as possible, but in no event later than 10 calendar days, after the determination was made.

9. Statistical Methods/Data Analysis :

9.1 Study endpoints

9.1.1 Primary endpoint(s)

The primary end points are defined as:A. Time to 75% healing, B. Post-dressing pain assessment at each dressing C. Infection rateD. Amount and type of antibiotic usedE. Amount and type of analgesic used F. Frequency of dermabrasionG. Number and size of skin grafts required

9.1.2 Secondary endpoints

The secondary endpoints include tracking and documenting any adverse events.

9.2 Sample size determination

Twenty (20) subjects will be enrolled into this clinical study, ten (10) in each treatment arm. This should provide sufficient numbers for initial statistical comparisons.

9.3 Efficacy analysis

The endpoints of: time to 75% healing, subjective pain, need for antibiotics, need for analgesics and need for skin grafting will be compared.

10. Quality Control and Quality Assurance :

Independent monitoring of the clinical study for protocol and GCP compliance will be conducted periodically (i.e., at a minimum of annually) by the IRB

11. Data Handling and Record-Keeping :

11.1 Data recording/Case Report Forms

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A Case Report Form (CRF) will be completed for each subject enrolled into the clinical study. The investigator-sponsor will review, approve and sign/date each completed CRF; the investigator-sponsor’s signature serving as attestation of the investigator-sponsor’s responsibility for ensuring that all clinical and laboratory data entered on the CRF are complete, accurate and authentic.

Source Data are the clinical findings and observations, laboratory and test data, and other information contained in Source Documents.

Source Documents are the original records (or certified copies of original records); including, but not limited to, hospital medical records, physician or office charts, physician or nursing notes, subject diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, x-rays, etc.

11.2 Record maintenance and retention

The investigator-sponsor will maintain records in accordance with Good Clinical Practice guidelines; to include:

FDA correspondence related to the IND and clinical protocol, including copies of submitted Safety Reports and Annual Reports

IRB correspondence (including approval notifications) related to the clinical protocol; including copies of adverse event reports and annual or interim reports

Current and past versions of the IRB-approved clinical protocol and corresponding IRB-approved consent form(s) and, if applicable, subject recruitment advertisements

Curriculum vitae (investigator-sponsor and clinical protocol sub-investigators) Listing of printed names/signatures of investigator-sponsor and listed sub-

investigators Normal value(s)/range(s) for medical/laboratory/technical procedures or tests

included in the clinical protocol Laboratory certification information Instructions for on-site preparation and handling of the investigational drug(s),

study treatment(s), and other study-related materials (i.e., if not addressed in the clinical protocol)

Signed informed consent forms Completed Case Report Forms; signed and dated by investigator-sponsor Source Documents or certified copies of Source Documents Monitoring visit reports Copies of investigator-sponsor correspondence to sub-investigators,

including notifications of safety information Subject screening and enrollment logs Subject identification code list Investigational drug accountability records, including documentation of drug

disposal. Final clinical study report

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The investigator-sponsor will retain the specified records and reports for up to 2 years.

12. Ethics :

12.1 Institutional Review Board (IRB) approval

The investigator-sponsor will obtain from the Institutional Review Board (IRB), prospective approval of the clinical protocol and corresponding informed consent form; modifications to the clinical protocol and corresponding informed consent forms, and advertisements (i.e., directed at potential research subjects) for study recruitment.

Phase 2 AB clinical studies : The investigator-sponsor will submit (i.e., in advance of implementing the change) a Protocol Amendment describing any change to the protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study, to the IRB. Examples of Phase 2 clinical protocol changes requiring the submission of a Protocol Amendment include:

o Any increase in drug dosage or duration of exposure of individual subjects to the investigational drug beyond that described in the current protocol, or any significant increase in the number of subjects under study.

o Any significant change in the design of the protocol (such as the addition or deletion of a control group).

o The addition of a new test or procedure that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor the safety of the investigational drug.

12.2 Ethical and scientific conduct of the clinical study

The clinical study will be conducted in accordance with the IRB-approved clinical protocol and ICH Guidelines on Good Clinical Practices.

12.3 Subject informed consent

The investigator-sponsor will make certain that an appropriate informed consent process is in place to ensure that potential research subjects, or their authorized representatives, are fully informed about the nature and objectives of the clinical study, the potential risks and benefits of study participation, and their rights as research subjects. The investigator-sponsor, or a sub-investigator(s) designated by the investigator-sponsor, will obtain the written, signed informed consent of each subject, or the subject’s authorized representative, prior to performing any study-specific procedures on the subject. The date and time that the subject, or the subject’s authorized representative, signs the informed consent form and a

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narrative of the issues discussed during the informed consent process will be documented in the subject’s case history. The investigator-sponsor will retain the original copy of the signed informed consent form, and a copy will be provided to the subject, or to the subject’s authorized representative.

The investigator-sponsor will make certain that appropriate processes and procedures are in place to ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and that the subjects are informed of any new information that may affect their decision to continue participation in the clinical study. In the event of substantial changes to the clinical study or the risk-to-benefit ratio of study participation, the investigator-sponsor will obtain the informed consent of enrolled subjects for continued participation in the clinical study

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