FORMULA EPICYN ; ——— Mex! CO Cada 100 gramos contienen: Sodio Magnesio Fluorosilicato 5.0000 % > Polidimetitsiloxano 4.8000 % Fosfato de Sodio 0.2000 % Acido Hipocloroso 20,0032 % Hipociorito de Sodio 20.0008 % ‘Agua de super-oxidacién c.b.p 100.000 % ‘QFB Maria Cédula 5144662 Responsable SanitarioZZ OCULUS Innovative Sciences STUDY TITLE A Double-blind, Randomized Study to Determine the Substantial Equivalence of Microcyn Scar Management HydroGel, K 103163 vs. Kelocote Scar Gel for the Management of Hypertrophic or Keloid Scars PROTOCOL NO. ‘TP-XX-XXX SPONSOR Oculus Innovative Sciences, Ine. 1129N. McDowell Blvd, Petaluma, CA 94954 Tel: 707-559-2445 Fax: 415-462-5163 ORIGINAL PROTOCOL DRAFT 18 April 2012 ‘CONFIDENTIALITY STATEMENT ‘The information contained in this document, particularly unpublished data, is provided to you in Investigator, potential Investigator, or consultant for review by you, your staff, and an Review Board or Independent Ethics Committee. The information is only to be 1sed by you in connection with authorized clinical studies of the investigational product(s) described in the Protocol. You will not disclose any of the information to others without written authorization, except to ‘the extent necessary to obtain informed consent from those persons to whom the investigational product(s) may be administered.‘TP-XX.001 —_ DRAFT 19 ari 2011, SIGNATURE PAGE ‘On behalf of Oculus Innovative Sciences, Inc., I confirm that is the final version of the protocol which has been approved according to company operating procedures, ‘Clinical Operations Signature ‘Oculus Innovative Seiences, Ine. (Printed Namey Date Printed Name Dawe Regulatory = ‘Oculus Innovative Seiences, Ine. Prinied Namey Date Oculus innovative Sciences, Ine CONFIDENTIAL Page 2 of 46TP-XX-001 RAPT ATE ILL INVESTIGATOR’S AGREEMENT I have carefully read the protocol entitled: “A Double-blind, Randomized Study to Determine the Substantial Equivalence of Microcyn Scar Management HydroGel, K 103163 vs. Kelocote Scar Gel for the Management of Hypertrophic or Keloid Scars” and, | agree that the protocol contains the necessary information required to conduct the study. 1 also agree to conduct this study as outlined in and according to the obligations of Clinical Investigators and all other pertinent requirements in the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guideline, 1 agree to obtain approval of the protocol and informed consent prior to the start of the study by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that is registered with the US Department of Health and Human Services (HHS). | agree to obtain formal written informed consent in accordance with applicable federal and local regulations and international guidelines from all subjects prior to their entry into the study Uhave received and reviewed the Microcyn and Kelocote Device Description including the potential risks and side effects of the products and instructions for use. I agree to report to Oculus Innovative Sciences, Ine. adverse events that occur during the course of the study in accordance with the ICH GCP guideline and the protocol. agree to ensure that all associates, colleagues, and employees assisting me with the conduct of the study are informed of their responsibilities in meeting the above commitments and the commitments set forth in the Investigator’s Agreement. 1 agree to maintain adequate and accurate records and to make those records available for inspection in accordance with the ICH GCP guideline, and federal and local requirements ‘The Investigator, agreeing to be fully bound, hereby executes this agreement on the date as set forth below Tavestigator Signature Printed Name Date Aairess Phone Number, Oculus Innovative Sciences, Ine CONFIDENTIAL Page 3 0f 46‘TP-XX.001, $v arn zo PROTOCOL SYNOPSIS Name of Sponsor/Company: Oculus Innovative Seienoes, Ine. Name of Finished Product: Microcyn Scar Management HydtoGel, K103163 Title of Study: A Double-blind, Randomized Study to Determine the Substantial Equivalence of Microcyn Sear Management HydroGel vs. Silicon Gel for the Management of Hypertrophic or Keloid Sears Investigator(s) | Multiple investigators in the United States (US) Study Center(s): Upto 4 centers inthe US [Number of Subjects Planned: Up to 40 subjects will be enrolled Publication (Reference): NA Study Period! 112 days Phase of Development: 3 Objective: Evaluate the efficaey and tolerability of Microcyn Scar Management HydroGel_as compared to predicate device [Kelocote Scar Gel in adult subjects with hypertrophic or keloid sears Clinical Hypothesis: Microcyn Scar Management Hy droGel is substantially equivalent to Kelocote Scar Gel forthe management of old and new hypertrophic and keloid sears as measured by the modified Vancouver Sear Seale (VSS). Design and Methodology: This is a double-blind, multicenter study to evaluate the efficacy and tolerability of Microcyn Sear Management HydroGel as compared to Kelocoe in up fo 40 adult subjecs with hypertophic or keloid scars. Qualified sears include linear or widespread hypertrophic sears and major and minor Keoids. The age of target sears will ange between 3 months ata minimurn fo 3 years a a maxim, On the Baseline (Day 0) visit the target sear will be measured (Length, width and elevation) and classified ito one of the four qualified types: widespread hypertrophic, linear hypertrophic, minor keloid, or major keloid as described by Mustoe TA et al, 2002, Linear hypertrophic scar: Red, raised scar confined to the border oF the original surgery or trauma 2. Widespread hyperrophie sear: A widespread reuse scr tht eis within the borders ofthe evga jury asl cased by 4 bu, 3. Minor Keo: felis scar that extends ver ora tse = 4 Major Keo: lrg, used scar which may be sinful or ruts. Extend over Soi | sie ew eye vei singe Vato See VS), Que oes wil havea minimum total VSS score o 3. Pan and teh aptoms il be evaated byt sige Female sujet wil be gven a wine prenane test. The bie ile rndomized to either Mispp elo 1:1. The investigator wl apey te Est one oft ati othe ret ear The subject lee oo oo, 15 nse ues of est aril wih he instructions aol th investigational roduc tenes Sy proximately 8 hours apr. for 8 weeks The sujct wl be provided wih Sues plication nstvsns and [Stet Restcions as oullned in Sections 3.23 4.2.4respevey. The sujet wl tun oh lin or Oculus Innovative Sciences, Ine. CONFIDENTIAL Page 4 0f46TP-XX-001 DRAFT 19 APRIL 201, [Name of Sponsor/Company: Oculus Innovative Selenees, Ine. [Name of Finished Product: Microcyn Scar Management HydroGel, K103163, Tollow up visits on study Day 14 (Week 3), Day 28 (Week), Day 56 Week & ead af treatment) and Days $4 and 112 (Week 12 end Week 16 follow up). Investigator and subject will complete the VSS and symptom evaluations at each study vist. Subject Satisfaction anda global assessment ofeicacy willbe assessed bythe investigator at Day 56 (end of treatment) and Day 112 (or early termination). The investigator and the subject will ae the sear tcatment results as follows: Very Good, Good, Moderate or Unsatisfactory. Digital photographs willbe taken at each site at Baseline and each follow up vist (Day 14, 28, 36, 84 and 112) or eary termination. Study Visits: Baseline (Day 0, investigational product application, and follow-up visits at Day 14 (Week 2), Day 28 (Week 4), Day 56 Week 8), Day 84 (Week 12) and Day 112 (Week 16) Safety Evaluation + Adverse Events (AEs) starting at Baseline (Day 0, pre-and postapplication) and each study vist ‘+ Concomitant Therapy/Medication Baseline (Day 0, pre-application) and at each study visit ‘+ Urine pregnancy test (UPT) for women of childbearing potential (WOCBP) at Baseline (Day 0) and Final Evaluation (Day 112 or Early Termination) Efficacy Evaluations: Investigator Evaluation: ‘The VSS evaluation will be performed at Baseline (Day 0, pre-application) and at Days 14, 28, $6, 84 and 112. Digital photographs will be taken at Baseline, Days 14, 28,56, 84 and 112 (or early termination). Global assessment of efficacy will be performed at Day 56 (end of treatment) and Day 112 (or early termination), At these visits, the Investigator wil rate the efficacy ofthe device as either I, Very Good, 2 |Good, 3. Moderate or 4, Unsatisfactory. Patient Evaluation: The patient’ evaluation of pain and itch will be performed at Baseline (Day 0, pre- pplication) and at Days 14, 28, 6, 84 and 112 (or early termination). Global patient satisfaction willbe assessed at Day 56 (end of treatment) and Day 112 (or early termination) where the Patient will rate their satisfaction ofthe treatment ofthe sar as either [Link] Good, 2. Good, 3. Moderate or 4. Unsatisfactory. The Vancouver Scar Scale (modified) ‘Scar characteristic ‘Score Vascularity Normal 0 Pink 1 Red i Purple 3 Pliability Normal 0 Supple 1 Yielding 2 Firm 3 Height Flat ° <2mm ‘ Aycine 2-5 mm 2 NNW >5mm 3 (Oculus Innovative Seienees, Inc. CONFIDENTIAL Page 5 of 46‘TP-XX.001 DRAFT 19 APRIL 2011 Name of Sponsor/Company: Oculus Innovative Sciences Name of Finished Product: Microcyn Se: Management HyéroGel, K103163, Explanation of Wem measurement Vaseularity Presence of vessels in scar tissue assessed by the amount of redness liability Suppleness of the scar tested by wrinkling the scar between the thumb and index finger © Height Average distance between the subcutical-dermal border and the epidermal surface ofthe sear Patient’s Assessment Symptom _ Assessment ‘Score Pain None 0 Intermittent (occurs sometimes, but not bothersome) Moderate (occurs almost daily) 2 Severe (requires medication or intervention) 3 Itch None ° Intermittent (occurs sometimes, but not bothersome) Moderate (occurs almost daily) 2 Severe (requires medication or intervention) 3 Diagnosis and Main Eligibility Criteri Subjects must meet the following eligibility criteria to participate inthe study inclusion Criteria: Written informed consent including authorization to release health information Female or male, 18 to 65 years of age and in good general health Willing and able to follow study instructions and likely to complete all study requirements Have a linear or widespread hypertophic or minor or major keloid scar with a minimum VSS total score of 3 ina body area that ean be accessed for evaluation and thrice daly topial treatment; 5. WOCBP must have a negative UPT at the Baseline (Day 0) visit AN 6 WOCBP must agree to use an effective method of birth control during the course Shite day Exclusion Criteria 1. History of allergy or sensitivity to any components ofthe investigational product History of diabetes 3. History of collagen vascular disorders that impact healing and wound repair such as scleroderme, systemic lupus erythematosus (SLE), Ehler-Danlos syndrome, ete. 4. Anticipated need for surgery or hospitalization during the study 5._Pregnant, nursing or planning a pregnancy during the study; or is a WOCBP but is not willing to use (Oculus Innovative Sefenees, Inc. CONFIDENTIAL Page 6 0f 46‘TP-XX-001 DRAFT 19 APRIL 201 Name of Sponsor/Compa (Oculus Innovative Sciences, In. Name of Finished Product: Microcyn Scar Management HydroGel, KL03163 ‘a efiecive method of 16. Current enrollment in an investigational drug or device sty or participation in such a study within the| last 30 days prior to Baseline (Day 0) 7. Any condition o situation wich, in the Investigators opinion, puts the subject at significant isk, could confound the study results, o may interfere significantly with the subjest'spaicipaion inthe study ‘8. Target sear on the face, of which spans over a joint or requires the use of pressure bandage. 9, Target sear which is newer than 3 months or older than 3 year, Test Article, Dose, and Mode of Administration: Microcyin Sear Treatment Hy droGel or Kelocote, applied three times daily, topical administration ‘sontrod Statistical Analyses Efficacy Analyses: Etcacy analyses will consist of descriptive statistics forthe following assessments: ‘4 Comparison between the two dose groups inthe Vancouver Sear Scale total seore from Baseline (Day Oto Day 112 (Week 16 of Early Termination), . Comparison between the two dose groups inthe individual sign and symptom scores from Baseline (Day'0) to Day 112 (or carly termination) Comparison between the two dose groups inthe Investigators Global Assessment of Treatment at Day 56 and Day 112 (or easy termination) 44. Comparison berwecn the two dose groups inthe Patient’ (end of treatment) and Day 112 (Week 16 or Early Ter faction of Treatment Results at Day's $6 ion) Safety Analyses: -The safety population wil include all subjects exposed to the investigational product who have provided any post- treatment safety information, Ja Sie Sasifeatoas Up t0 40 subjects will be enrolled, Oculus Innovative Scienees, Ine. CONFIDENTIAL Page 7 of 46‘TP-XX-001 DRAFT 19 apr 2001 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS Abbreviation Definition AE ‘Adverse Event crR Code of Federal Regulations cre (Case Report Form CTEP-CTCAE Cancer Therapy Evaluation Program ~ Common Terminology Criteria for Adverse Events FDA Food and Drug Administration ocr Good Clinical Practices Has Health and Human Services Ic International Conference on Harmonisation EC Independent Ethics Committee IGA Investigator Global Assessment ea Investigator Pruitus Assessment IRB Institutional Review Board MedDRA Medical Dictionary for Regulatory Activites SAE Serious Adverse Event sas Statistical Analysis Software sia Subject Itch Assessment soP Standard Operating Procedure upr Urine Pregnancy Test us United States vss ‘Vancouver Sear Seale wocer ‘Woman of Cildbearing Potential (cul Innovative Ssiences, Inc, CONFIDENTIAL Page 8 of 46TP-XX-001 DRAFT 19 APRIL 2011 TABLE OF CONTENTS SIGNATURE PAGE. INVESTIGATOR'S AGREEMEN’ PROTOCOL SYNOPSIS LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS TABLE OF CONTENTS LIST OF TABLES. 1. INTRODUCTIOT LL. Background. 1.2. Study Rationale. 1.3. Dose Rationale. 14. Study Objective. 1.5. Clinical Hypothesis. 2. STUDY DESIGN. 2.4. Overall Design Dosage/Dose Regimen... Visit Schedule 2.2. Test Article. 2.3. Study Population 2.4. Eligibility Criteria........ revenese ee . 2.4.1. Informed Consent and Authorization to Release Health Information 2.4.2. Inclusion Criteria 24. 3. STUDY PROCEDURES AND METHODS 3.1. Subject Entry Procedures... 3.2, Schedule of Visits and Procedures. 3.2.1. Baseline Visit (Day 0). 3.2.2. follow-up visits (Day 14, day 28, Day $6, Day 84). 3.2.3 Final Evaluation (Day 112/Early Termination)... 3.2.3. subject application instructions... Exclusion Criteria... ‘Oculus Innovative Sciences, Ine CONFIDENTIAL Page 9 of 6,TP-XX-001 DRAFT 19 APRIL 2011 3.24. Discontinuation/ Withdrawal Procedures. 3.3. Variation from Scheduled Visit Days. 34. Safety Assessments 3.4.1. Pregnancy Test 3.4.2. Adverse Events 3.5. Efficacy Assessment 3.8.1. Vancouver Scar Scale (modified)... patient assessments, 3.8.3. PHotography 3.6. Screen Failures. 3.7. Protocol Deviations, 4. PROHIBITED medications and treatment 3. EVALUATION OF ADVERSE EVENTS. Definition Adverse Event Severity Grades.. Investigational product Causality . 5.2. Reporting Adverse Events ... 5.3. Immediately Reportable Events. 54. Pregnancy... 5.5. Follow-Up of Adverse Events 5.8.1. Follow-Up of Non-Serious Adverse Events ...n-0 5.5.2. Follow-Up of Post Study Serious Adverse Events... 6. STATISTICAL ANALYSIS. 6.1, General Consideration: Populations. ‘Overall Study Evaluations and Measurement Safety Efficacy. Sample Size.. 7. INVESTIGATIONAL product MANAGEMENT. 7.1. Receipt of Investigational PRODUCT. 7.2. Storage and dispensing of Investigational PRODUCT. 7.3. Investigational PRODUCT Accountability Ny 7.4, Returns and Destruction... 8. RECORDS MANAGEMENT. 8.1. Data Collection eae 8.2. File Management at the Study Site 38 (Oculus Innovative Sciences, Ine. CONFIDENTIAL Page 10 of 468.3. Records Retention at the Study Sit 9. MONITORING, COMPLIANCE, AND QUALITY. 9.1. Quality Assurance Audits and Quality Control 10. ETHICS AND RESPONSIBILITY... 11, CONFIDENTIALITY 12, AMENDMENT POLIC’ 13. USE OF INFORMATION AND PUBLICATION. 14, REFERENCES. APPENDIX A: STUDY RESPONSIBILITY LIST, Oculus Innovative Sciences, Ine CONFIDENTIAL Page 11 of 46TP-XX-001 $$$ __DAT LIST OF TABLES. Table 1: Schedule of Visits and Procedures. ‘Table 2: Allowed Variation from Scheduled Visit Days, ‘Table 3: Vancouver Scar Scale.. Table 4: Patient's Assessment., Oculus Innovative Seienees, Ine. CONFIDENTIAL Page 12 0f 46TP-XX-001 avo ar 2011 1. INTRODUCTION LI. BACKGROUND Hydrotropic scars commonly form after burns, surgical in yns or other trauma that extends into the reticular dermis. Once formed, there may be partial or complete resolution, oF they may remain permanent. (Abn, etal, 1991). Keloid scarring is caused by the growth of dense fibrous tissue developing from an abnormal healing response to a cutaneous injury, extending beyond the original borders of the wound. (Brissett and Sherris, 2001). Scarring can cause functional, cosmetic and psychological morbidity (Bock, et al, 2006). The clinical symptoms Of scars include tenderness, discoloration, Pruritus and disfigurement. Several treatments are used for scars including surgery, laser therapy, steroid injections and topical products including onion extract gel and silicon gel. Perkins, Davey, and Wallis (1982) demonstrated that split skin grafts treated with silicon gel refrain from shrinking while the arca around bburns healed by epithelialization without hypertrophy Oculus Innovative Sciences, Ine. (Oculus) has developed a topical device, Microcyn Scar Management HydroGel for the management of old and new hypertrophic and keloid scarring on sears resulting from bums, general surgical procedures and trauma wounds. The anticipated clinical benefit is the improvement in the appearance and associated symptoms (pain, and itching) of scars. This study will compare Microcyn Scar Management HydroGel with the predicate device, Kelocote Scar Gel. 12, STUDY RATIONALE Microcyn Sar Management HydroGel formulation is similar to Microcyn Skin and Wound HydroGel which was cleared for commercial distribution for pain and itch. The new formulation contains film forming agents and additional ingredients to address scar management. The predicate device, Kelocote Scar Gel, has been cleared for commercial distribution for scar treatment via K973572, October 21, 1997. ‘The purpose of this study is to demonstrate substantial equivalence of Microcyn Scar Management HydroGel with the predicate device, Kelocote Scar Gel. 2 Clinical studies of Microcyn Scar Management HydroGel will be conducted nde fee application K103163 for dermatological uses. 1.3, DOSE RATIONALE ‘The dosing regimen Microcyn Scar Treatment HydroGel or Kelocote Scar Gel three G) doses applied daily to the target scar, approximately 8 hours apart. Oculus Innovative Sciences, Inc, CONFIDENTIAL Page 13 of 46‘TP-XX-001 DRAFT 9 ri 2011 14. STUDY OBJECTIVE To evaluate the efficacy and tolerability of Microcyn Scar Management HydroGel as compared to predicate device Kelocote Scar Gel in adult subjects sears that are between 3 months and 3 years old. ith hypertrophic or keloid 1.5. CLINICAL HYPOTHESIS Microcyn Scar Management HydroGel is substantially equivalent to Kelocote Scar Gel for the management of hypertrophic or keloid scars as measured by the following: © Vancouver Scar Scale: Total score in the VSS at Day 56 (end of treatment) and Day 112 (or early termination) as compared to Baseline (Day 0) .Patient’s assessment of pain and itch at Day 56 as compared to Day 0. * Subject’s overall satisfaction of the scar treatment at Day 56 (end of treatment) and Day 112 (or early termination). * Investigator’s Global Assessment of Treatment Efficacy at Day 56 (end of treatment) and Day 112 (or early termination), (Oculus Innovative Seienees, Ine CONFIDENTIAL Page 14 of 46TP-XX-001 DRAFT 9 APRIL 2011 2. STUDY DESIGN 2.1, OVERALL DESIGN 21.1. STRUCTURE This is a randomized, double-blind, multi-center cli 2.2, DURATION ‘The study duration is up to 112 days on study. 213. CONTROLS An active control, Kelocote Scar Gel will be used as the predicate device. 2.14, DOSAGE/DOSE REGIMEN Up to 40 subjects who have provided informed consent and have met the study el rit lity ia will be randomized to receive one 1.5 ounce tube of either study device at the Baseline (Day 0) visit. Subjects will apply the investigational product three times daily, approximately 8 hours apart for 56 days. Subject Instructions described in Section 3.2.3 and Subject Restrictions outlined in Section 3.2.4. will be provided to the subject at the baseline visit. ‘The initial treatment will be applied to the affected areas by the Investigator at the Baseline (Day 0) visit, The subject will then be instructed on the proper topical application of the study device, All remaining treatments will be applied by the subject. Subjects will bring the tube of study treatment to each follow-up visit (Days 14, 28 and 56). 2.45. VISIT SCHEDULE Up to 6 study visits are planned for this study. Study visits will take place at Baseline (Day 0, first investigational product application), Day 14 (Week 2), Day 28 (Week 4), Day 56 (Week 8), Day 84 (Week 12) and a final evaluation on Day 112, Week 16 (or Early Termination), (Oculus Innovative Sciences, Ine CONFIDENTIAL Page 15 of 46TP-XX-001 DRAFT 19 APRIL 2011 2.2. TEST ARTICLE ‘The test article, Microcyn Scar Management HydroGel, is a translucent, colorless emollient containing gel comprised of hypochlorous acid and sodium hypochlorite generated through ‘an electrochemical process. It is non-oily and pH neutral. The predicate device, Kelocote Scar Gel, isa similar appearing gel. 2.3. STUDY POPULATION Up to 40 subjects, female or male, 18 to 65 years of age, in good general health, with a hypertrophic or keloid sear present for at least 3 months but no more than 36 months 24. ELIGIBILITY CRITERIA 24.1. INFORMED CONSENT AND AUTHORIZATION TO RELEASE HEALTH INFORMATION Written informed consent will be obtained from all subjects before any study-related procedures (including any pre-treatment screening procedures) are performed. The Investigator may discuss the study and the possibility for entry with a potential subject without first obtaining consent. However, a subject wishing to participate must give written informed consent prior to any study-related procedures being conducted, including those performed solely for the purpose of determining eligibility for study participation, including ‘withdrawal from current medication (if required prior to study entry), The Investigator has both the ethical and legal responsibility to ensure that each subject being considered for inclusion in this study has been given a full explanation of the procedures and expectations for study participation. The site-specific informed consent must be forwarded to Oculus for approval prior to submission to an Institutional Review Board (IRB)/Independent Ethies Committee (IEC) that is registered with the US Department of Health and Human Services (HHS). Each subject will sign the consent form that has been approved by the same IRBJIEC that was responsible for protocol approval. Each informed consent document must adhere to the ethical principles stated in the Declaration of Helsinki and will include the elements required by FDA regulations in [Link] Part $0, as well as the elements required by the Intemational Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guideline, and applicable federal and local regulatory requirements. The consent form must also include a statement that Oculus, their designees, and auditing regulatory agencies will hay ifStt acs) t0 the subject's records and medical history. ty Oculus Innovative Sciences, Ine. CONFIDENTIAL Page 16 0f 46‘TP-XX.001 $$ DRAFT 9 APRIL 2011 ‘Once the appropriate essential information has been provided to the subject and fully explained by the Investigator (or a qualified designee) and it is felt that the subject understands the implications and risks of participating in the study, the IRB/IEC-approved consent document shall be signed and dated by both the subject and the person obtaining consent (Investigator or designee), and by any other parties required by the IRB/IEC or other regulatory authorities. The subject will be given a copy of the signed informed consent document with the original kept on file by the Investigator. All of the above activities must bbe completed before any study related procedures are conducted (including any pre-treatment study procedures). 2.4.2, INCLUSION CRITERIA All subjects must meet the following inclusion criteria to participate in the study: 1. Written informed consent including authorization to release health information 2. Female or male, 18 to 65 years of age, and in good general health 3. Willing and able to follow study instructions and likely to complete all study requirements 4, Have a hypertrophic (linear or widespread) or keloid (major or minor) scar in a body area that can be accessed for evaluation and thrice daily topical treatment by the subject. 5, Women of childbearing potential (WOCBP) must have @ negative urine pregnancy test (UPT) at the Baseline (Day 0) visit 6. WOCBP must agree to use an effective method of birth control during the course of the study 2.4.3. EXCLUSION CRITERIA Subjects will not be enrolled if they meet any of the following exclusion crite 1, History of allergy or sensitivity to any components of the investigational product 2. History of diabetes 3. History of collagen vascular disorders that impact healing and wound repair such as scleroderma, systemic lupus erythematosus (SLE), Ehler-Danlos syndrome, etc. 4. Anticipated need for surgery or hospitalization during the study 5, Pregnant, nursing, or planning a pregnancy during the study, or is a WOCBP but willing to use an effective method of birth control not 6 Current enrllment in an investigational drug or device stay oF participation in such a study within the last 30 days prior to Baseline (Day 0) WW (Oculus Innovative Seienees, Inc. CONFIDENTIAL Page 17 of 46TP-XX-001 $$ RAF 9 aR 2011 7. Any condition or situation which, in the Investigator’s opinion, puts the subject at ignificant risk, could confound the study results, or may interfere significantly with the subject’s participation in the study 8, Target scar on the face, or which spans over a joint or requires the use of a pressure bandage. 9. Target scar which is newer than 3 months or older than 3 years, Oculus Innovative Seiences, Ine, CONFIDENTIAL Page 18 of 46$a ar 200 3. STUDY PROCEDURES AND METHODS 3.1. SUBJECT ENTRY PROCEDURES Prospective subjects as defined by the eligibility criteria in Sections 2.4.2 and 2.4.3 (Inclusion/Exclusion Criteria) will be considered for entry into this study. Subject informed cconsent must be obtained prior to condueting Baseline procedures. After the required procedures are completed and study eligibility is confirmed, investigational product will be administered at Baseline (Day 0). 3.2. SCHEDULE OF VISITS AND PROCEDURES ‘A schedule of visits and procedures is provided in Table 1. Table 1: Schedule of Visits and Procedures Baseline Treatment/Follow-up Post-Treatment Day 14 | Day28 ] DayS6 | Day 4 | Day 112 Dayo | (Week2) | (Week 4) | (Weekes) | (Week 12) | (Week 16) Procedures Early Tem Informed Consent and Privacy Authorization m Inclusion/Exelusion * Medical History x Document Sear type, size, age, location = ‘VSS and patient assessment of Pain and x x ™ x * lich z Investigators Global Assesiment x x Patients Satisfaction of Sear Treatment x x Photography z = T * x x Urine Pregnaney Test (WOCBP only) x x Tnvestigational Produst Application x x * x ‘Concomitant Therapy/Medicat x x * x x ‘Adverse Events ~ x x * x x 3.2.1. BASELINE VISIT (DAY 0) The following procedures must be performed and recorded at the Baseline (Day 0) visit: 1, Review study procedures and information regarding the study with the subject and obt written informed consent 2. Review eligibility criteria; inclusior/exelusion Oculus Innovative Scfences, Ine. CONFIDENTIAL Page 19 oF 46TP-XX-001, EEO 3. Obtain medical/surgical history including demographic informati 4. Obtain UPT (WOCBP only) and evaluate results. If UPT is positive, the subject will not be allowed to participate in the study 5. Record concomitant therapy/medications documenting the dose and dosing regimen of all prescription and non-prescription therapies and medications including herbs, vitamins, or other nutritional supplements currently being used (refer to Section 4) Document scar description: length, width, age, type, cause Photograph the scar (selected sites) ‘Complete the VSS and patient’s assessment of scar pain and itch. Collect Adverse Events (AEs) prior to test article application 10. Apply a thin film of assigned test article to the target scar 11, Assess for AEs (postapplication) 12. Provide 1 tube of test article to the subject 13. Review Subject Instructions, Subject Diary Completion and Subject Restrictions with the subject 3.2.2, FOLLOW-UP VISITS (DAY 14, DAY 28, DAY 56, DAY 84) The following procedures and information will be performed and recorded at the Day 14 (Week 2), Day 28 (Week 4), Day 56 (Week 8) and Day 84 (Week 12) visits 1, Record concomitant therapy/medications documenting the dose and dosing regimen of all prescription and non-prescription therapies and medications including. herbs, vitamins, or other nutritional supplements administered currently being used (refer to Section 4) 2. Complete VSS and patient’s assessment of scar pain and itch. 3. Review subject diary for compliance with test article application. Dispense 1 new tube on Day 14 and 2 new tubes on Day 28, Collect all used and unused tubes by Day 56. 4. Complete Investigator’s Global Assessment of Treatment Efficacy and Patient's Satisfaction (Day 56 only). 5. Assess for AEs 6. Review Subject Instructions, Subject Diary Completion and Subject Restrictions with the subject 7. Photograph scar Oculus Innovative Sciences, Inc. CONFIDENTIAL Page-20 oF 46—. __——_ DRAFT 1 ar 2011 3.2.3 FINAL EVALUATION (DAY 112/EARLY TERMINATION) - Record concomitant therapy/medications documenting the dose and dosing regimen of all prescription and non-prescription therapies and medications including herbs, vitamins, or other nutritional supplements administered currently being used (refer to Section 4) Complete VSS and patient’s assessment of pain and itch Complete Investigator’s Global Assessment of Treatment Efficacy and Patient's Satisfaction Assessment, Fo Photograph scar Collect any used and unused test article tubes not collected at prior visit, Obtain UPT (WOCBP only) and evaluate results, 2 32.3, SUBJECT APPLICATION INSTRUCTIONS 1. Apply a thin film of the test article to the scar 2, Wash your hands following application of the gel 3. Repeat this procedure three (3) times a day, approximately 8 hours apart 4. Do not apply any other topical products to the treatment area, s When bathing or swimming is necessary, apply the gel following bathing. The test article should not be washed off for at least four (4) hours following application 6. Bring the test article tubes to every study visit 7. Do not allow anyone else to use the test article Keep the gel away from your eyes, lips and mouth 9. Keep the test article out of reach of children 10. Continue to use the test article even if your scar has improved 11. If you experience unacceptable burning, stinging or irritation at the application site which you believe to be due to the test article, discontinue use and contact the study doctor 12, Store the test article in a secure location at room temperature. rc f (Oculus Innovative Sciences, Ine (CONFIDENTIAL Page21 of 46‘TP-XX.001 BRA ar 2001 3.2.4. DISCONTINUATION/WITHDRAWAL PROCEDURES A subject may voluntarily withdraw from study participation at any time. If the subject withdraws consent and disco wes from the study, the Investigator will attempt to determine the reason for discontinuation and record the reason in the subject's study records ‘and on the case report form (CRF). Ifa subject withdraws consent because of an AE, that AE should be indicated as the reason for withdrawal. In the event of early discontinuation, (i.e., prior to Day 112) and whenever possible, the subject should be asked to return to the study center to complete the Day 112 evaluations. Subjects who withdraw from the study will not be replaced. Ifat any 1¢ during the study, the Investigator determines that it is not in the best interest of the subject to continue, the subject will be discontinued from part can discontinue a subject at any ion. The Investigator ime if medically necessary. The Investigator may discontinue a subject's participation if the subject has failed to follow study procedures or to keep follow-up appointments, Appropriate documentation in the subject’s study record and CRF regarding the reason for discontinuation must be completed. Prior to discontinuing a subject from study participation, the Investigator will discuss his/her intentions with the Medical Monitor or designee. All subjects who fail to return to the study center for follow-up on the Day 112 (Week 16) visit will be contacted by phone to determine the reason(s) why the subject failed to return for the necessary visit or elected to discontinue from the study. If a subject is unreachable by telephone after a minimum of two documented attempts (one attempt on two different days), a registered letter will be sent requesting that contact be made with the Investigator. Oculus has the right to terminate of to stop the study at any time. Should this be necessary, both Oculus and the Investigator will ensure that proper study discontinuation procedures are completed. 33. VARIATION FROM SCHEDULED VISIT DAYS To allow for scheduling flexibi , limited variation will be permitted from the specified calendar day of each visit as outline in Table 2. Table 2: Allowed Variation from Scheduled Visit Days Time Allowed Variation MENTO CO Baseline (Day 0) — { (Oculus Innovative Sciences, Ine CONFIDENTIAL ‘Page 22 oF 46TP-XX-001 —DRAFT 19 APRIL 2011 Time Day 14 (Week 2) Day28 (Week 4) Day 56 (Week 8) Day 84 (Week 12) Day 112 (Week 16) 3.4. SAFETY ASSESSMENTS 34.1. PREGNANCY TESTING All WOCBP will have a UPT at Baseline (Day 0) and if the result is positive, the subject will not be allowed to participate in the study. WOCBP will also have a UPT at their Final Evaluation visit, Day 112 (Week 16) or early discontinuation. If a UPT is positive at Week 16, the pregnancy must be confirmed by a serum pregnancy test. Refer to Section $.4 for further information. 34.2, ADVERSE EVENTS AEs will be graded based on the CTEP-CTCAE version 4.02 for severity, where applicable. AEs for which the CTEP-CTCAE grading scale is not applicable will be graded as mild, ‘moderate, severe, or life-threatening as defined in Section 5.1.1 of this protocol. AEs will be evaluated at the Baseline Visit (Day 0) subsequent to the subject signing the informed consent, pre- and post-treatment and at Day 14, 28, 56, 84 and 112 (or early discontinuation). Section 5 outlines the procedures for recording and reporting AEs. 3.5. EFFICACY ASSESSMENTS 3.5.1, VANCOUVER SCAR SCALE (MODIFIED) ‘The Vancouver Scar Scale (VSS) first described by Sullivan in 1990, is perhaps the most recognized scar assessment method. It assesses 4 variables: vascularity, height/thickness, pliability, and pigmentation, All items are scored on a scale of zero to three. This study will not assess pigmentation since it is not as applicable to keloids and hypertrophic sears. The VSS remains widely applicable to evaluate therapy and as a measure of outcomes (Nedelec, et al, 2000). The VSS will be performed at Baseline (Day 0) pre- treatment and follow-up visits, Day 14, Day 28, Day 56, Day 84 and Day 112 (or early termination), (Oculus Innovative Sciences, Ine CONFIDENTIAL Page 23 of 46‘TP-XX.001 19 APRIL 2011 Table 3: Vancouver Scar Scale (modified) The Vancouver Scar Scale ‘Scar characteristic Score Vascularity ‘Normal 0 Pink 1 Red 2 Purple 3 Pliability Normal 0 Supple 1 Yielding 2 Firm 3 Height Flat ° <2 mm 1 2-5 mm 2 >Smm 3 Explanation of item measurement: Vascularity Presence of vessels in scar tissue assessed by the amount of redness Pliability Suppleness of the scar tested by wrinkling the scar between the thumb and index finger ‘+ Height Average distance between the subcutical-dermal border and the epidermal surface of the scar 352, PATIENT ASSESSMENTS ‘The subject will be asked to assess the scar’s symptoms of itching and pain at Baseline (Day 0) pre-treatment and follow-up visits, Day 14, Day 28, Day 56, Day 84 and Day 112 (or early termination). In addition, subjects will assess their overall satisfaction with the sear treatment as Very Good, Good, Moderate or Unsatisfactory at Day 56 (end of treatment) and Day 112 (or early termination). Table 4: Patient Assessment Patient's Assessment Symptom Assessment Score ' Pain None 0 Intermittent (occurs sometimes, but not bothersome) Moderate (occurs almost daily) 2 Severe (requires medication or intervention) 3 Oculus Innovative Sciences, Ine CONFIDENTIAL Page 24 of 46TP-XX-001 RAFT i arr 20 Itch None 0 Intermittent (occurs sometimes, but not bothersome) Moderate (occurs almost daily) 2 Severe (requires medication or intervention) 3 35.3, PHOTOGRAPHY ‘The Investigator will take digital photographs at the baseline (pre-treatment) and each subsequent study visit to document the scar. No analysis of photographs is planned. 3.6. SCREEN FAILURES A screen failure subject will be a person from whom informed consent is obtained and is documented in writing (i.e., subject signs an informed consent form) but who does not meet the study eligibility requirements. 3.7, PROTOCOL DEVIATIONS This study will be conducted as described in this protocol, except for an emergency situation in which the protection, safety, and well-being of the subject requires immediate intervention, based on the judgment of the Investigator (or a responsible, appropriately trained professional designated by the Investigator). In the event of a significant deviation from the protocol due to an emergency, accident, or mistake, the Investigator or designee must contact Oculus at the carliest possible time by telephone. This will allow an early joint decision regarding the subject’s continuation in the study, ‘This decision will be documented by the Inve the Medical Monitor. Oculus Innow Sciences, Ine. CONFIDENTIAL Page 25 of 46TPXX-001 DRAFT 19 APRIL 2011 PROHIBITED MEDICATIONS AND TREATMENTS Concomitant medications include any prescription or over-the-counter preparations. Use of concomitant medications will be recorded on the Concomitant Medications CRF beginning at Baseline (Day 0) until the Final Evaluation, Day 112 (Week 16 or early termination) visit. No topical products other than the treatment gel are to be used near the treatment area. Oculus Innovative Sciences, Inc (CONFIDENTIAL Page 26 of 46TP-XX-001 ea a a SL SS et ate ae ame sete MARA EVALUATION OF ADVERSE EVENTS SLI. DEFINITIONS For this protocol, an adverse event (AE) is any untoward medical occurrence (e.g., sign, symptom, disease, syndrome, intercurrent illness, abnormal laboratory finding, injury, or accident) that emerges or worsens following administration of the informed consent and until the end of study participation. The untoward medical occurrence may not necessarily have a causal relationship to the administration of the investigational product. An AE can therefore bbe any unfavorable and/or unintended sign (including an abnormal laboratory result) symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A pre-existing condition is one that is present prior to the start of the study and is to be reported as part of the subject’s medical history. It should be reported as an AE only if the frequency, severity, or the character of the condition worsens during the study. An unexpected AE is one not identified in nature, severity, or frequency in the current protocol. A serious adverse event (SAE) includes any event that results in any of the following outcomes: * Death © Life-threatening (‘e., the subject was, in the opinion of the Investigator, at immediate risk of death from the event as it occurred. It does not apply to an AE that hypothetically might have caused death if it were more severe.) © Persistent or significant disability/ineapacity (i.e., the AE results in a substantial disruption of the subject's ability to carry out normal life functions) ‘© Requires in-patient hospitalization or prolongs hospitalization (ie., the AE required at least a 24-hour in-patient hospitalization or prolonged a hospitalization beyond the expected length of stay; hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine check-ups are not SAEs by this criterion) ‘© Congenital anomaly/birth defect (ive. an adverse outcome in a child or fetus of a subject exposed to the molecule or investigational produet before conception or during pregnancy) ‘© Does not meet any of the above serious criteria but may jeopardize the subject or may. require medical or surgical intervention to prevent one of the outcomes lise above (‘e., is an important medical event) (Oculus Innovative Sciences, Ine. CONFIDENTIAL Page 27 of 46‘TP-XX.001 A, $1.2. ADVERSE EVENT SEVERITY GRADES ‘The Investigator is responsible for evaluating all AES and determining the severity of the event, Severity will be categorized by toxicity grade according to the CTEP-CTCAE version 4.02, when applicable. AEs not found in the list of AEs described in the CTEP-CTCAE listing will be graded according to the following definitions: © Mild — Grade 1: Event may be noticeable to subject; does not influence daily activities; usually does not require intervention * Moderate — Grade 2: Event may be of sufficient severity to make subject uncomfortable; performance of daily activities may be influenced; intervention may be needed ‘© Severe — Grade 3: Event may cause severe discomfort; usually interferes with daily activities; subject may not be able to continue in the study; treatment or other intervention usually needed © Life-Threatening — Grade 4: Event that, in the view of the Investigator, places the subject at immediate risk of death from the reaction as it occurred (ic., it does not include a reaction that, had it occurred in a more severe form, might have caused death) ‘The Investigator will follow all subjects who experience AEs until there is a return to the subject's baseline condition or until a clinically satisfactory resolution is achieved. The appropriate follow-up visits must be scheduled and the specific tests repeated or performed as necessary. 5.3. INVESTIGATIONAL PRODUCT CAUSALITY Relationship of an AE to investigational product will be assessed as follows: * Definite: There is a clinically plausible time sequence between the onset of the AE and the application of investigational product; when the event responds to withdrawal of investigational product and recurs with re-administration of investigational product © Probable: There is a clinically plausible time sequence between the onset of the AE and the application of investigational product; the AE is unlikely to be caused by the concurrent/underlying illness, other drugs or procedures ‘© Possible: There may or may not be a clinically plausible time sequence between the onset of the AE and the application of investigational product and a cause cannot be ruled out * Unlikely: There is probably not a clinical plausible time sequence between the onset of the AE and production administration; the AE is likely to be caused by a concurrent/underlying illness, other drugs, or procedures (if applicable) and the AE (Oculus Innovative Sciences, Ine CONFIDENTIAL Page 28 of 46TP-XX.001 DRAFT 19 April. 20) does not follow a clinically consistent resolution pattern on withdrawal of the product, + Unrelated: There is not a temporal or causal relationship to investigational product administration 5.2, REPORTING ADVERSE EVENTS The Investigator will assess subjects at each scheduled study visit for the occurrence of AEs, In order to avoid bias in el ig AEs, subjects should be asked the following non-leading question: “How have you felt since your last visit?” All AEs (serious and non-serious) reported by the subject must be recorded on the source documents and CRFs. In addition, Oculus must be notified within 24 hours of the Investigator’s knowledge of the event by telephone or fax of any immediately reportable events according to the procedure outlined below. Special attention should be paid to recording hospitalizations and concomitant therapies and medications, 5.3. IMMEDIATELY REPORTABLE EVENTS SAEs are considered immediately reportable events. If a subject experiences a SAE or pregnancy the Investigator must: 1. Report the SAE or pregnancy by telephone to the Oculus Medical Monitor (refer to Appendix C — Study Responsibility List) immediately (within 24 hours) after the Investigator becomes aware of the event. 2. Complete an SAE or Pregnancy Notification Form and fax or overnight courier to Oculus within 24 hours of knowledge of the event. Note: The SAE form is NOT the AE CRF. 3. Obtain and maintain all pertinent medical records, information and medical judgments of medical personne! who assisted in subject's treatment and follow-up. and document on CRF as appropriate 4. Provide a more detailed report to both Oculus and the IRB/IEC no later than seven days after the Investigator discovers the event as further information becomes available, and when necessary update the information with follow-up information including outcomes. This report should include a statement as to whether the event was or was not related to the use of investigational product. 5. The Investigator will notify the IRB/IEC of the SAE or pregnancy according to specific IRB/IEC requirements. Oculus will submit a written report to the regulatory authorities as soon as possible but no later than 15 calendar days after the initial receipt of the information tegarding any AE at least possibly associated with the use of the investigational product that is not defined at fatal (culus Innova fe Sciences, Inc. (CONFIDENTIAL Page 29 of 46‘TP-XX-001 ee ee or life threatening (based upon the FDA definition). Fatal or life threatening SAEs will be reported within 7 calendar days after initial receipt of the information. The Investigator will collect information on SAEs until subject’s health has returned to baseline status, until all parameters have returned to normal, or remaining health issues have otherwise been explained. 54. PREGNANCY WOCBP must use an effective method of birth control during the course of the study, such as the oral contraceptive pill, injection, implant, patch, vaginal ring, intrauterine coil, intrauterine device, barrier method used with an additional form of contraception (¢.g., sponge, spermicide or condom). Females with a history of tubal ligation or a vasectomized partner will undergo pregnaney testing. A female is considered to be of childbearing potential UNLESS she is post-menopausal (no menses for 12 consecutive months) or without a uterus and/or both ovaries. Before enrolling WOCBP in this clinical trial, Investigators must review guidelines about study participation for WOCBP. The topics should generally include: ‘© Informed consent document ‘* Pregnancy prevention information ‘© Risks to unborn et i(ren) © Any drug interactions with hormonal contraceptives * Contraceptives in current use ‘* Guidelines for the follow-up of a reported pregnancy Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy ipation in this clinical study and the potential risk factors for an unintentional ‘The subject must sign an informed consent document stating that the above- mentioned risk factors and the consequences were discussed with her. During the study, all WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual cycle). The Investigator must immediately notify Oculus of any female subject who becomes prégnant any time during study participation, record the information on the Pregnancy Notification Form and fax the form to the Oculus Medical Monitor. Oculus will ask the site to follow-up with the (Oculus Innovative Seienees, Ine CONFIDENTIAL Page 30 of 46TP-XX-001 RAT io ar 20 subject periodically during the pregnancy for ongoing health and safety information through term, as applicable. Subjects will remain on the study but will not receive re-treatment, Protocol-required procedures for the final Day 14 (Week 2) evaluations must be performed for the subject unless contraindicated by pregnancy. 5.8. FOLLOW-UP OF ADVERSE EVENTS $5.1, FOLLOW-UP OF NON-SERIOUS ADVERSE EVENTS Non-s ious AEs that are identified during the last scheduled study visit (Day 112 or early discontinuation) must be recorded on the AE CRF as ongoing, 55.2, FOLLOW-UP OF POST STUDY SERIOUS ADVERSE EVENTS SAEs that are identified on the last scheduled contact (Day 112 or early discontinuation) ‘must be recorded on the AE CRF page and reported to Oculus according to the reporting procedures outlined in Section 5,2. This may include unresolved previously reported SAEs, or new SAEs. The Investigator should follow these SAEs until the events are resolved, or the subject is lost to follow-up. The Investigator should continue to report any significant follow-up information to Oculus and the IRB/IEC up to the point the event has been resolved. Resolution means the subject has returned to the baseline state of health, or the Investigator does not expect any further improvement or worsening of the subject's condition. Any new SAEs reported by the subject to the Investigator that occur after the last scheduled contact and are determined by the Investigator to be reasonably associated with the application of investigational product should be reported to Oculus and the IRB/IEC. Oculus Innovative Sciences, Ine. CONFIDENTIAL Page 31 of 466 TP-XX001 —$ RAF roar zo STATISTICAL ANALYSIS 6.1, GENERAL CONSIDERATIONS All statistical programming will be performed using SAS version 9.1 or higher. Statistical significance will be based on two-sided tests at the 5% level of significance. 6.2. POPULATIONS All subjects will be included in the summaries of demographic and other baseline characteristics. The Safety population will include all subjects exposed to any investigational product and have provided any post-treatment safety information. ‘The Efficacy population will include all subjects who complete both a Baseline (Day 0) and Final Evaluation (Day 112) visit. 63. OVERALL STUDY EVALUATIONS AND MEASUREMENTS. Descriptive statistics will be used to summarize demographic characteristics (age, gender, race, baseline POSAS, ete.). Past or ongoing medical history, study treatment visit ‘compliance, and prior and concomitant medication usage will be summarized for all subjects and presented in a listing by subject. 64. SAFETY Adverse event analyses will be conducted. All treatment-emergent AEs occurring during the study will be recorded and classified on the basis of MedDRA terminology for the safety population. ‘Treatment-emergent AEs are those AEs with an onset on or after the date of study treatment, All treatment-emergent AEs will be summarized for the entire study period, presenting the number of subjects reporting treatment-emergent AEs by system organ class, preferred term, severity, relationship, and seriousness, Each subject will be counted only fonce within a system organ class or a preferred term using the event with the greatest relationship and greatest severity for the respective summarization. Serious adverse events (SAEs) will be listed by subject. SAEs will be summarized for the ‘entire study by severity and relationship to study treatment, Each subject will be counted only once within a system organ class or a preferred term using the event with the greatest relationship and greatest severity. All information pertaining to AEs noted during the study will be listed by subject, detailing Verbatim term given by the Investigator, prefered term, system organ class onset dae resolution date, maximum severity, seriousness, action taken regarding investigational product, corrective treatment, outcome, and relatedness. (Oculus Innovative Sciences, Ine CONFIDENTIAL Page 32 of 46‘TP-XX-001 RAFT 19 APRIL 2011, 6.8. EFFICACY Efficacy analyses will consist of descriptive statistics for the following assessment: a. Change from baseline (Week 16), VSS total score from Baseline (Day 0) to Day 112 b. Change from baseline in individual sign and symptom (pain, itch, vascularity, pliability and height) score from Baseline (Day 0) to Day 112 (Week 16), c. Investigator's Global Assessment and Patient's Satisfaction assessments at Day 56 and Day 112 (early termination). 6.6. SAMPLE SIZE Up to 40 subjects will be enrolled. ‘Gculus Innovative Sciences, Ine. CONFIDENTIAL Page 33 of 46TP-XX.001 rare ar 2001 INVESTIGATIONAL PRODUCT MANAGEMENT 7.1. RECEIPT OF INVESTIGATIONAL PRODUCT ‘Oculus will provide all investigational device product. 7.2, STORAGE AND DISPENSING OF INVESTIGATIONAL PRODUCT Investigational product will be stored under controlled room temperature conditions until «dispensing by the study site personnel to each subject. Subjects will be instructed to keep the investigational product tubes at room temperature and to retum with all assigned investigational product tothe investigative site at each scheduled visit, Subjects may need to be called or emailed a periodic reminder to retum to investigative site with their investigational product tubes as required by protocol. Upon receipt from Oculus, a study staff member will place all investigational product in a secure, locked location, Access to investigational product should be strictly limited to the study staff, Neither the Investigator nor any member of the study staff will distribute any of the investigational product to any person not participating in this study. ‘The investigational product will be dispensed at the discretion and by the direction of the Investigator in accordance with the conditions specified in this protocol. It is the Investigator’s responsibility to ensure that accurate records of investigational product issuance and return are maintained. 7.3. INVESTIGATIONAL PRODUCT ACCOUNTABILITY A study staff member will maintain an inventory of investigational product. This will include: * Dates and initials of person designated as responsible for the inventory of the investigational product © Amount received including date, and lot number © Amount currently in storage * Amounts dispensed to each subject, identified by subject initials and a unique subject number © Amount transferred to another location within the study site or destroyed — this should not occur without prior notification to Oculus © Non-study disposition (e.g., wasted, broken) '* Amount returned to Oculus or designee, if applicable Oculus Innovative Sciences, Ine. (CONFIDENTIAL Page 34 of 46‘TP-XX-001 DRAFT 19 APRIL 2011 ‘© Amount destroyed, if applicable Oculus, of its designee, will provide forms to facilitate investigational product inventory control. All investigational product accountability forms and treatment logs must be retained in the Investigator’s permanent study file. These records must be available for inspection by Oculus, its designees or by regulatory agencies at any time. 7.4. RETURNS AND DESTRUCTION Upon completion or termination of the study, it is the Investigator’s responsibility to ensure that all partially used investigational product is properly disposed of at the site, All used and unused investigational product must be accounted for by the Oculus Study Monitor prior to disposal. Oculus must approve the destruction of any investigational produet and receive a copy of the destruction record(s). (Oculus Innovative Seienees, Ine (CONFIDENTIAL Page 35 of 46TP-XX-001 RAPT APL, 8. RECORDS MANAGEMENT 8.1. DATA COLLECTION A set of CRFs will be provided for each study subject and the data will be recorded on these forms using a black or blue ballpoint pen. All corrections will be made by striking through the error with a single line and writing the correct data above, beside, or below the erroneous data so as not to obscure the original entry, Each correction must be initialed and dated by the person making the correction, If corrections are made after review and signature by the Investigator, he/she must be notified of the changes and document acknowledgment accordingly. In addition to signature confirmation that a subject meets the study eligibility criteria, upon each subject's completion of the study, the Investigator will sign a statement indicating that all pages of the subject’s case report in the study binder have been reviewed, Signature stamps and “per signatures” are not acceptable. It is Oculus’s policy that the study data be verifiable with the source data that necessitates access to all original recordings, laboratory reports, and other records for each subject. The Investigator must therefore agree to allow access to subjects” records, and source data must be made available for all study data. Subjects (or their legal representatives) must also allow access to their medical records. Subjects will be informed of the importance of increased record access and permission granted by signature on the informed consent document, Before the CRFs are formally submitted to Oculus, the Study Monitor, Medical Monitor or ‘Oculus may request copies of the CRFs for preliminary medical review. The Study Monitor will collect the original completed CRFs and forward to the data management group to be logged, stamped, copied and reviewed prior to entry into a computer database. Checks will be performed to ensure the quality, consistency, and completeness of the data. Instances of missing or un-interpretable data will be resolved with the Investigator or Study Coordinator. Data queries, documented on data query forms, will be sent to the research facility along with copies of the CRF pages that require clarification or correction when appropriate, Site personnel will be responsible for providing resolutions to the data queries and for correcting the CRFS, as appropriate. All unused CRFs and binders must be retumed to Oculus upon completion of the study. Oculus Innovative CONFIDENTIAL Page 36 of 46‘TP-XX-001 RAFT 9 ar 2001, tor must keep written or electronic source documents for every subject participating in the clinical study. The subject file that identifies the study in which the subject is participating must include the subject's available demographic and medical information including: © Name © Contact information + Date of birth + Sex © Medical history * Concomitant diseases + Concomitant therapies/medication © Study visit dates ‘© Performed examinations, evaluations, and clinical findings ‘Investigational product administration ‘+ AEs, SAEs, or pregnancy (as applicable) Additionally, any other documents with source data, especially original printouts of data that ‘were generated by technical equipment must be included in the subject's source document (eg, laboratory value listings). All these documents must have at least the subject’s initials, study number, and the date of the evaluation ‘The data recorded during the course of the study will be documented in the CRF and/or the study-specifie forms. Before or at study termination, all data must be forwarded to Oculus The data will then be recorded, evaluated, and stored in anonymous form in accordance with data-protection regulations. Subjects will authorize the use of their protected health information during the informed consent process in accordance with the applicable privacy requirements, Subjects who deny permission to use and disclose protected health information will not be eligible to participate in the study. The Investigator will ensure that the CRFs forwarded to Oculus, and any other documents, contain no mention of subject names. Any amendments and corrections necessary will be undertaken in both the source ddcuments and CRFs (as appropriate) and countersigned by the Investigator, or documented designee, stating the date of the amendmenveorrection, Errors must remain legible afd: may not be ‘Oculus Innovative Seiences, Ine CONFIDENTIAL Page 37 of 46‘TP-XX.001, 19 APRIL 2011 deleted with correction aids. The Investigator must state his/her reason for the correction of any data. In the case of missing data/remarks, the entry spaces provided in the CRF should be cancelled out so as to avoid unnecessary follow-up inquiries. Regulatory authorities, the IRB/IEC and/or the Oculus Quality Assurance group (or designee) ‘may request access to all source documents, CRFs, and other study documentation for on-site audit or inspection. The Investigator must guarantee direct access to these documents. The original set of CRFs will be kept by Oculus or an authorized designee in a secured area. Clinical data will be recorded in a computer format for subsequent statistical analyses, Data files will be stored on electronic media with a final master data file kept by Oculus after descriptive and statistical analyses and reports have been generated and are complete. 8.2. FILE MANAGEMENT AT THE STUDY SITE It is the responsibility of the Investigator to ensure that the study center file is maintained in accordance with Section 8 — Essential Documents for the Conduct of a Clinical Trial of the ICH Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance, 8.3. RECORDS RETENTION AT THE STUDY SITE It is an Oculus requirement that all Investigators participating in clinical studies maintain detailed clinical data for one of the following periods: © Country-specific requirements, or * A period of at least 2 years following the last approval of a marketing application approved by a Regulatory Authority in an ICH region or until there are no pending or contemplated marketing applications in an ICH region, or, ‘* A period of two years after Oculus notifies the Investigator that the data will not be submitted for review by any Regulatory Authority ‘The Investigator must not dispose of any records o essential documents relevant to this study without either (1) written permission from Oculus, or (2) prov Wg an opportunity for Oculus to collect such records. The Investigator shall take responsibility for maintaining adequate and accurate electronic or hard copy source documents of all observations and data generated during this study. Such documentation is subject to inspection by Oculus and relevant regulatory agencies. If the Investigator withdraws from the study (¢.g.. relocation, retirement), all study-related records should be transferred to a mutually agreed upon, designee. Notice of such transfer will be provided to Oculus in writing. (Oculus Innovative Sciences, Ine CONFIDENTIAL Page 38 of 469. MONITORING, COMPLIANCE, AND QUALITY All aspeets of the study will be monitored by Oculus or authorized representatives of Oculus according to Good Clinical Practices (GCP) and Standard Operating Procedures (SOPs) for compliance with applicable government regulations, (ie., Informed Consent Regulations [US 2ICFR, Part 50} and Institutional Review Board regulations [US 21CFR, Part 56.103]). Access 10 all records, both during the trial and after trial completion, should be made available to Oculus at any time for review and audit to ensure the integrity of the data. The Investigator must notify Oculus immediately if the responsible IRB/IEC has been disqualified or if proceedings leading to disqualification have begun ‘The Investigator must conduct the protocol in accordance with applicable GCP regulations and guidelines; applicable informed consent regulations (US 2ICFR, Part $0); and in compliance with the Declaration of Helsinki. Every attempt must be made to follow the protocol and to obtain and record all data requested for each subject at the specified times. If data is not recorded per protocol, the reasons must be clearly documented on the CRFirecords Before study initiation, at a site initiation visit or at a meeting with the Investigator(s), a Oculus representative will review the protocol and study CRFs with the Investigator(s) and their staff. During the study, the Study Monitor will visit the site regularly to check the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the protocol and to GCP, the progress of enrollment, and to ensure that consent is being sought and obtained in compliance with applicable regulations, and that the investigational product is being stored, dispensed and accounted for according to specifications. ‘The Investigator and key trial personnel must be available to assist the monitor during these visits. The Investigator must give the monitor access to relevant hospital or clinical records, to confirm their consistency with the CRF entries. No information in these records about the identity of the subjects will leave the study center. Monitoring standards require full verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of primary efficacy and safety variables. Additional checks of the consistency of the source data with the CRFs will be performed according to the study-specifie monitoring plan. The Investigator must promptly complete the CRFS after the subject’s visit. The monitor is responsible for reviewing them and clarifying and resolving any data queris, The completed and corrected CRFs for completed visits will be either collected by the’ monitor or sent (Oculus Innovative Sciences, Ine, CONFIDENTIAL Page 39 of 46‘TP-XX-001 ae: directly for data processing, as arranged by the monitor. A copy of the CRFs will be retained by the Investigator who must ensure that it is stored in a secure place with other study documents, such as the protocol, and any protocol amendments The Investigator must provide Oculus and the responsible IRB/IEC with a study summary shortly after study completion, or as designated by Oculus, 9.1. QUALITY ASSURANCE AUDITS AND QUALITY CONTROL In addition to the routine monitoring procedures, audits of clinical research activities in accordance with SOPs may be performed to evaluate compliance with the principles of GCP. A regulatory authority may also wish to conduct an inspection (during the study or even after its completion), If' regulatory authori Oculus immediately that this request has been made. requests an inspection, the Investigator must inform. Study conduct may be assessed during the course of the study by a Quality Assurance representative(s) to ensure that the study is conducted in compliance with the protocol and GCP. They will be permitted to inspect the study documents (study protocol, CRFs, investigational product, original study-relevant medical records). All subject data will be treated confidentially. Oculus Innovative 22s, In, CONFIDENTIAL Page 40 0f 46‘TP-XX-001, DRAFT 19 APRIL 201 10. ETHICS AND RESPONSIBILITY This study must be conducted in compliance with the protocol, the ICH Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance and the applicable regulatory requirements. Investigators must submit all essential regulatory documentation, as required by local and national regulations (including approval of the protocol and informed consent form by an HHS-registered IRB/IEC) to Oculus before investigational product will be shipped to the study site (Oculus Innovative Sciences, Ine. CONFIDENTIAL Page 41 of 4611, CONFIDENTIALITY Al information generated in this study must be considered highly confidential and must not be disclosed to any persons not directly concemed with the study without written prior permission from Oculus. Authorized regulatory officials and Oculus personnel (or their representatives) will be allowed full access to inspect and copy the records. All study investigational products, subject bodily fluids, and/or other materials collected shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by Oculus. Subjects will only be identified by initials and unique subject numbers on CRFS. (culus Innovative Seiences, Ine CONFIDENTIAL Page 42 of 46TP-XX-001 —_—). DRAFT irri 200 12. AMENDMENT POLICY Only Oculus may modify the protocol. Protocol amendments will only be made after consultation and agreement between Oculus and the Investigator(s). Amendments may be approved by all applicable national and local committees including, but not limited to, the ‘government regulatory authorities and/or regional IRB/IEC before implementation. ‘The only exception is when an Investigator considers that a subject may be harmed and immediate action is necessary. Under these circumstances, approval of the chairman of the IRB/IEC, or ‘an authorized designee must be sought immediately. The Investigator should inform Oculus, and the full IRB/IEC, no later than five working days after the emergency occurs. Protocol- specified safety reporting requirements must be adhered to independent of any other variables, All amendments that have an impact on subject risk, the study objectives or that require revision of the informed consent document must be approved by the IRB/IEC before implementation, Administrative changes to the protocol and/or changes that do not impact subject safety, risk, or comfort may be implemented prior to IRB/IEC approval if local institutional policy permits. A copy of the written approval of the IRB/IEC, which becomes part of the essential study documents file, must be given to the Study Monitor. Examples of ‘amendments requiring such approval are: ‘© A significant change in the study design ‘+ Am increase in the number of invasive procedures to which subjects are exposed ‘+ Anaddition or deletion ofa test procedure The Principal Investigator at each study site must sign the Investigator’s Agreement page of the amended protocol. cals Innova 1 Sciences, Ine CONFIDENTIAL Page 43 of 46TP-XX.001 DRAFT 19 APRIL 2011 13. USE OF INFORMATION AND PUBLICATION It is understood by the Investigator that the information generated in this study will be used by Oculus in connection with the development of the product and therefore may be disclosed to government agencies in various countries. To allow for the use of information derived from the study, it is understood that the Investigator is obliged to provide Oculus with all study data, and access to all study records. Any results of medical investigations with Oculus products and/or publication/lecture/ manuscripts based thereon, shall be exchanged and discussed by the Investigator and Oculus representative(s) 30 days before submission for publication or presentation, Due regard shall be given to Cculus’s legitimate interests for example, manuscript authorship, obtaining ‘optimal patent protection, coordinating and maintaining the proprietary nature of submissions to health authorities, coordinating with other ongoing studies in the same field, and protecting confidential data and information. Oculus shall be furnished with a copy of any proposed publication, Comments shall be rendered without undue delay. In cases of publications or presentations of material arising from multi-center clinical investigations, Oculus is to serve as coordinator and referee. Individual Investigators who are part of a multi-center investigation may not publish or present data that are considered common to a multi-center investigation without the consent of the other participating Investigators and the prior review of Oculus. In case of disagreement amongst the Investigators participating in a multi-center investigation, Oculus will be the final arbiter, Comments shall be given without undue delay. If they are not accepted, the senior author of the manuscript and representatives of Oculus shall promptly meet to discuss further and endeavor to agree mutually on the final wording and/or disposition of the publication. The above procedure also applies to information on prematurely discontinued and other non-completed studies. Results from investigations shall not be made available to any third party by the investigating ‘team outside the publication procedure as outlined previously. Oculus will not quote from publications by Investigators in its scientific information and/or promotional material without full acknowledgment of the source (i.e., author and reference). Oculus Innovative Scfences, In. CONFIDENTIAL Page 44 0f 46,TP-XXx-001 $$ _____ DAF ar nn. 14. REFERENCES Ahn ST, Monafo W, Mustoe T. Topical Silicone Gel for the Prevention and Treatment of Hypertrophic Sear. Arch Surg. April 1991; 126: 499-504. Bock O, Schmid-Ott G, Malewski P, et al.: Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res 2006; 297:433-8 Brissett AE, Sherris DA: Scar contractures, hypertrophic scars and keloids. Facial Plast Surg 2001, 17:263-72. ‘Common Terminology Criteria for Adverse Events (CTCAE), Version 4.02; US Department of Health and Human Services, National Institutes of Health, National Cancer Institute; September 2009 Declaration of Hel World Medical Associ ttp/[Link],nete/ethiesunivhelsinki,htm Nedelec B, Shankowsky A, Tredgett EE. Rating the resolving hypertrophic scar: comparison of the Vancouver Scar Scale and scar volume. J. Burn Care Rehabil. 2000; 21:205-12. ion, Available from: Sullivan T, Smith J, Kermode J, et al. Rating the burn scar. J Burn Care Rehabil, 1990;11:256-60. ICH Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance; April 1996. Perkins K, Davey RB, Wallis A. Silicone gel: a new treatment for burn scars and contractures. Burns, 1982; 9:201-204. Title 21 Code of Federal Regulations (CFR) Part 312. A\ hw w/seripts/edrh/cfdocs/efetr/ vailable from: Oculus Innovative Sciences, Inc. CONFIDENTIAL Page #5 of 4601 DRAFT 19 APRIL 2011 APPENDIX A: STUDY RESPONSIBILITY LIST om a Suuly Se 10 Oculus, Contaet Medical Monitor, or Clin tor, listed below. During umes that may be diferent than the Medical and Safety [TBD Consultant Medical Director Monitor Fax: Oculus Innovative Sciences, Ine Mobile HIN. MeDowell Blvd e-mail: Petaluma, CA. 94954 Tap Clinieal Operations Director Phone Oculus Innovative Sciences, Ine Faw 1129. MeDowell Bld, e-mail Petaluma, CA 94954 Tavestigator Tsp Dermatology Consuling Servioes Phone: thd 22444 North Main Steet, Fox: thd High Point, NC 27262 e-mail: tba (cul Innovative Seiences, Ine CONFIDENTIAL Page 46 0f 46,usp 36 Table 4 (Continued) Relative | Relative | Acceptance! Retention | Response | Criteria, Name Time Factor | _ NM (99) | ‘any vnspecied impurity at 245 2 = 10 on Total impartes = oa 170977 Bhydronrnety SAGE metivene Foxe Te-pegn- ene BV argh oe, ore Seppo s87B158 6b then Po peg toot “SATIS 16SOmethfencandos sere: 17-done, {ethan} mathyene sneer tne 2 cto 117d 78138 6B +10: 7gregn-ene 2a ian sa silent epaspene : i 7e.15816Bdimethyene 0x0 7e-pegn-ene2 cr tao sae Silene sree — £17ydroxy59 16Bmethyene3.ox0:7a-pregn-+-ene21-cafboyc 1th 158m ore of [Link] 678 meinene 3-00-17. ae serge 7eeteneo.-aregrtene "17 neny Behigmethy.13816imeyene ox 17epren-tane Tyco ac lane, 8 hve \2-Rydroy-7Bchirometiy 158 16Smethyene-0%-17Bpregnene- ‘Webonte ts pacer Sn sbmenve sai 7 -Hyarony-7Bnyronymeng 158, 168-methylee-17a-pregn 3.56) dene 2-carbonyc a6, atone SPECIFIC TESTS ‘= Ormicat RorATION, Specific Rotation (7815) ‘Sample solution: 10 mg/ml. in methanol ‘Acceptance criteria: “187” to -193" at 20° on the an- hydrous and solvent-free basis ‘+ MELTING RANGE OR TEMPERATURE, Class (741): "198°-203, [NOTE—Dry over slca gel for NIT 24 h before testing.] ‘+ WATER DETERMINATION, Method (921): NMT 0.29% ADDITIONAL REQUIREMENTS ‘+ PACKAGING AND STORAGE: Preserve in tight containers, ‘and store at controlled room temperature. ‘+ USP REFERENCE STANDARDS (11) USP Drospirenone RS USP Drospirenone Related Compound A RS 17-Hydroxy-68,7215B,16Bdimethylene-3-0x0-17f- regn-4-ene-21-carboxylic acid, lactone, uO) 366.49 Drospirenone and Ethinyl Estradiol Tablets DEFINITION Drospirenone and Ethiny! Estradiol Tablets contain. NLT 190.0% and NMT 110.086 of the labeled amount of dro- spirenone (CuttioO)) and NLT 90.0% and NMT 110.08 Of the labeled amount of ethinyl estradiol (CisH:.0%). IDENTIFICATION A Te enn tines of he drperore and shiny ‘estradiol sample solution correspon those of fhe Stondord solution, a obtained inthe Assy. + Procepure Solution A: Dissolve 132 g of dibasic ammonium phos- phate in 0.8 L of water, adjust with phosphoric acid to 8 pH of 6.8, and dilute to 1 L. lution A and water (1:24) : Acetonitrile and Solution B (1:1). Adjust ‘with phosphoric acid to a pH of 68, Official from A Official Monographs / Drospirenone 3351 Standard solution: (1/25) mg/mL of USP Drospirenone ‘RS and of USP Ethinyl Estradiol RSin Mobile phase, Wwihere L's the Tablet label claim, in mg/Table, of each ‘compound Sample solution: Transfer 10 Tablets to a 250smt yolu: ‘mete flask, dd 230 mL of Mabie prose, and sonicate So nein shaking for CT 10, rl he ablets are completely dispersed. Equiforate to room Temperature ite wth Hobie phe to wolume and entfuge the sample until a cletr supernatant Is'ob- Bind. Use the supernatant. chromatographic system Cae Crematorophy (62), System Suit) Detector 1: UV 270 nm for drospitenone Detector 2: Fluorescence, exctation wavelensth at 285 rim emision wavelength at 315 nm for ethinyl e+ tradi [NoTe~Detector I and Detector 2are Cone clare Sant < 12cm 34um packing At ‘olumn: 4-mm x 12.S-cm, 34um packing Column temperature: 254 3° Flow rate: 122 mL/min Injection size: 20 ul system suitability fample:_ Standard solution Sultaility requirements Talling factor: Between 0.8 and 1.8 for both drospire- Tone and ethinyl estradiol Relative standard deviation: NMT 2.0% for both ‘drospirenone and ethinyl estradiol Analysis Samples: Standard solution and Sample solution Calculate the percentage of the labeled amount of dro- Spirenone (CisHi:0s) in the portion of Tablets taken (uri) x (CG) x 100 1y = peak response of drospirenone from the ‘Sample solution, yeak response of drospirenone from the Cs = concentration of USP Drosptenone RS in the Sond dln gn minal concentrator of drosp Semple suition (mg/m ples: Standard solaion and Sample solution Caltlte the percentage ofthe labeled amount of thy esrdol (aff. in the portion of Tes ‘Sten none in the Result = (rut) x (CJC) x 100 fy = peak response of ethinyl estradiol from the ak response ethinyl estracil rom th 15 = peak Fesponse of ethinyl estradiol from the Standard solution C= concentration of USP Ethiny Estradiol RS in the Standard solution (mg/ml) Gy —_-= nominal concenvation of ethinyl estradiol in the Sample solution (mg/ml) ‘Acceptance criteria: $0.0%-110.0% of ethinyl estradiol; '90.0%6-110.0% of drospirenone PERFORMANCE TESTS S"Dusoumon (711) "Test 1: For drug products labeled to contain 3 mg of arspenone and 0,03 mg of ey eal Sng fosprenone and 0 ethinyl estradia Mediums Water: 900 m2 230 pm 30 min Standard solution: (1/900) mg/ml. of USP Drospre- none RS and US ethinyl fn Medan, ‘Where Lis the Tabet label claim of each compound. A Volume of methanol not exceeding 296 of the nal3352 Drospirenone / Official Monographs total volume of solution may be wed toad in dsl Ing there compounds, Sample solution: Post portion of the solution under ‘est tough suitable cellos iter of OAS pore 1, dsaraing the fet 10 mL Mobite phase: Acetonitile and water (40:60) (sce certo SN, Sater Sta (See Chromatc ), System Suitability.) Mode: LC ae Detector: UV 270 nm (for drospirenone), in series with a fluorescence detector (for ethinyl estradiol), with excitation at 210 nm and detection at 315 nm, ‘or with excitation at 281 nm and detection at 305, Column: 4,[Link] x 6-cm; 3-um packing LI Chew eee Flow rate: 1/ml/min Injection size: 100 ul. System suitably imple: Standard solution Suitability requirements ILT 2000 for both drospirenone Column efficien ‘and ethinyl estradiol Talling factor: Between 0.8 and 1.5 for both drospi- enone and ethinyl estradiol Relative standard deviation: NMT 3% for both dro- spirenone and ethinyl estradiol Samples: Standard solution and Sample solution INOTE—in Medium, drospirenone is partially converted, into 17-epidrospirenone, which has a relative reten- tion time of approximately 1.2 relative to drospire- ‘none. The amount of drospirenone dissolved is calcu: lated from the sum of drospirenone and 17-epidros- jrenone | Calculate the percentage of drospirenone and ethinyl estradiol dissolved: Result = (raft) x (Gill) x Vx 100 ‘uy =peak response from the Sample soliton Deak reponse from the Stondord solution Concent ote tnd’ sin = labeP aim (mg/Tablet) V2 volume of Medury, 960 mb ee NEP HB (othe bed amount of one and NLT 25% (G) ofthe abled smount we think ada alec, ™ rest 3: For drug products absied to contain. 3. ef Serb ona 3 ma product complies with tne test, the labeling Indicates Gist itmeets USP Dissolution Test 2 Machu ving 906m Apparatus 256 rpm mes 30 min Standard solution: (1/900) mat of USP Drospire- one RS and of USP Ethnyt Eatradot Rs In edu, tnre isthe Tabet label cai of eath compourd. sample solution: Centifuge a porton of the Soluton under testa 3500 rpm for 13" and use the stpemetant Mobile phase: Acetonitrile, methanol, and water ees romatographlc sytem Gee hroneisrpiy (SN, Stem stain) Mode: Detector: UV 260 nm (for drospirenone), in series with a fluorescence detector (for ethinyl estradiol), with excitation at 280 nm and detection at 310 nim UsP 36 Column: 4.6mm x 10. | FANOS Relacién de especialidades farmacéuticas susceptibles de incorporarse al Catalogo de Medicamentos Genéricos, se detains n las pruebas que deberdn aplicarseles y sefiala el medicamento de referencia designado ‘Abril de 2011 Gosrenno DRZLAOA sven ta Orzo TOLL stein i DOXAZOSINA, Mestatn Tablet be CARDURA ‘3549 SSA | Pfizer. 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