Handbook of SOPs for Good Clinical Practice, Second Edition

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HANDBOOK OF SOPS FOR GOOD CLINICAL PRACTICE SECOND EDITION

This page intentionally left blank

HANDBOOK OF SOPS FOR GOOD CLINICAL PRACTICE SECOND EDITION

Celine M. Clive

* 0

Taylor & Francis Taylor b Francis Gmup

Boca Raton London New York Singapore

A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F lnforma plc.

Library of Congress Cataloging-in-PublicationData Clive, Celine. Handbook of SOPs for good clinical practice.- 2nd ed. / Celine Clive. p. ; cm. Rev. ed. of A handbook of SOPs for good clinical practice / Donald E. Maynard, B. Joyce Baird. c1996. Includes bibliographical references and index. ISBN 0-8493-2181-6 (alk. paper) 1. Clinical trials-Standards-Handbooks, manuals, etc. 2. Clinical trials-FormsHandbooks, manuals, etc. [DNLM: 1. Research-standards-Handbooks. 2. Clinical Trials-standards-Handbooks. 3 Human Experimentation-standards-Handbooks. 4. Legislation, Drug-Handbooks. W 49 C642h 20041 I. Title: Handbook of standard operating procedures for good clinical practice. TT. Maynard, Donald E. Handbook of SOPs for good clinical practice. 111. Title. R853 .C55C585 2004 61 0'.72'4-dc22

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. The consent of CRC Press does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press for such copying. Direct all inquiries to CRC Press, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe.

Visit the CRC Press Web site at www.crcpress.com O 2004 by CRC Press No claim to original U.S. Government works International Standard Book Number 0-8493-21 81-6 Library of Congress Card Number 2003064123 Printed in the United States of America 2 3 4 5 6 7 8 9 0 Printed on acid-free paper

Dedication The author gratefully dedicates this book to Patrick and Josephine Meehan for their continuous support and encouragement, and for providing an example to follow in life. Celine M. Clive


Introduction This handbook is divided into three sections containing Standard Operating Procedures (SOPs) applicable to the activities of the three major groups involved in the clinical development process: The SponsorIContract Research Organization (CRO) The study site The Institutional Review Board (IRB)

A fourth section, called Forms, contains all of the attachments that are referred to in the SOP sections. Some of the forms may apply to more than one group affected by the SOPs. For example, the "Subject Information and Consent Form Checklist" may be used by Study Coordinators, when they are developing the document, and IRB members, when they are reviewing it. The advantage of this handbook is that by using the disk that accompanies it, each SOP and all of the forms can be customized to the needs of the specific institution. To do this, the user should open the document and make a global change replacing the word "Company" with the company's actual name. Be aware that the length of the company's name may affect line and page spacing and that some minor formatting may be needed after this global change is implemented. If the institution's logo is added to the header of the first page, the formatting may also need to be checked. Finally, the effective date should be added to the header of the second page. From there, it will automatically be captured on all subsequent pages. These templates should serve as a starting point for the development of SOPs. The user should ensure that the specific processes at hislher institution are reflected in the final, approved SOP. The language in these SOPs may appear to be limited to drug development; however, with a few alterations, they may be adapted to medical devices and biologics as well.


About PoPolbnk Clinical Research Consultants, Inc. Polaris Clinical Research Consultants, Inc. is a training and auditing company specializing in clinical research topics and processes. Our mission is to enhance the productivity and efficiency of clinical research teams by providing training, auditing, and Standard Operating Procedure (SOP) development to our clients. Polaris offers consulting services to pharmaceutical companies, Contract Research Organizations (CRO), investigative sites, and Institutional Review Boards (IRBs). The company offers several off-the-shelf training programs for Monitors, Investigators, Study Coordinators, and IRB Members. Because we are interested in establishing collaborative relationships with our clients, more often our training programs are customized to the specific needs of our clients. We recognize the demand for experienced professionals exceeds the supply and we believe that through training we can help bridge that gap. Some of the advantages of using Polaris include: Active participation of the learners. Polaris' training programs are delivered through exercises, case studies, role-playing, and worksheets. This active involvement by the participant ensures that the lessons become more intrinsic and the learning becomes more effective. Experienced personnel. Polaris' training programs are developed and delivered by experts in various areas of the pharmaceutical industry. This provides students with high quality training that is realistic and practical. Program flexibility. Polaris3 training is delivered so that the point-of-view and needs of both the CRO and Sponsor company are discussed. Programs to investigative sites include discussions on what site personnel are required to do by regulation and which tasks are driven by Sponsor-specific requirements.

Celine M. Clive Pohris Clinical Research Consultants, Inc. 130 Iowa Lane; Suite 103 Cary, NC 275 11 Telephone: 9 19-463-0003 Fax: 919-463-0004 E-mail:

Programs Available through Pohris Overview of Drug Development Overview of Clinical Research History of the Regulations FDA Structure and Processes Regulations that Affect Clinical Research (FDA and ICH) The Responsibilities of Sponsors, Monitors, and Site Personnel The Responsibilities of Contract Research Organizations The Role of the Institutional Review Board Preparing Documents for Study lnitiation Selecting Investigators and Study Sites Developing Protocols and Case Report Forms Conducting the Study Initiation Visit Developing and Obtaining Informed Consent Conducting the Interim Visit Adverse Experiences and Serious Adverse Experiences Editing Case Report Forms Interacting with the Study Coordinator Reviewing Regulatory Documents Case Report Form Tracking and Management Managing Clinical Trial MaterialIDrug Accountability Writing Trip Reports and Follow-up Letters Role of Data Management in the Clinical Research Process Safety When Traveling Writing Protocols Designing Case Report Forms FDA Audits Detecting Fraud in Clinical Research

Table of Contents Sponsor/Monitor/CRO SOPs

Page

MON-00 1.O

Preparation, Issue, and Revision of Standard Operating Procedures (SOPs)

1

MON-002.0

Training Clinical Research Staff

5

MON-003.0

Selecting Investigators and Study Sites

9

MON-004.0

Developing Informed Consent Forms

13

MON-005.0

Conducting Site Evaluation Visits

17

MON-006.0

Conducting Study Initiation Visits

21

MON-007.0

Conducting Periodic Site Visits

27

MON-008.0

Reviewing Case Report Forms at the Study Site

33

MON-009.0

Reviewing Regulatory Documents

39

MON-0 10.0

Adverse Experiences (AEs), Serious Adverse Experiences (SAEs), and IND Safety Reports

51

MON-0 11.O

Managing Study-Specific Clinical Supplies

57

MON-0 12.0

Conducting Study Termination Visits

61

MON-0 13.0

Telephone Contact Reports

67

Investigational Site SOPs SITE-001.O

Preparation, Issue, and Revision of Standard Operating Procedures (SOPs)

69

SITE-002.0

Training Study Site Clinical Research Staff

73

SITE-003.0

Assessing Protocol Feasibility

77

SITE-004.0

Investigator Agreements with Sponsors or Contract Research Organizations

79

SITE-005.0

Organizational Chart for the Study Site

81

SITE-006.0

Interactions with the Institutional Review Board

83

SITE-007.0

Recruiting Study Patients

87

SITE-008.0

Study Initiation and Implementation

91

SITE-009.0

Reviewing and Obtaining Informed Consent

95

SITE-0 10.0

Adverse Experiences (AEs), Serious Adverse Experiences (SAEs) and IND Safety Reports

101

SITE-011.0

Drug Storage and Accountability

105

SITE-012.0

Managing Biological Samples

109

SITE-013.0

Interactions with the Sponsor or Contract Research Organization (CRO) Study Files and Record Retention

111

SITE-014.0

117

Institutional Review Board SOPS

IRB-00 1.o

Institutional Review Board Responsibilities

121

IRB-002.0

IRB Membership and Training

125

IRB-003.0

Institutional Review Board Meetings

131

IRB-004.0

IRB Record Keeping

137

IRB-005.0

IRB Review of Research

141

IRB-006.0

IRB Review of Informed Consent

147

IRB-007.0

IRB Review of Advertisements

153

IRB-008.0

IRB Review of Unscheduled Mandatory Reports

157

IRB-009.0

Criteria for Exempt and Expedited Review

161

Forms - Alphabetical by File Name

&

File Name (.dot)

Form Name

Ad Review

Advertisement Review Checklist

167

Amendment

Protocol Amendment Form

169

Bio Sample

Biological Samples Inventory

171

CRF Review

CRF Review Form

173

DCF Form

Data Clarification Form

175

Dispense

Drug Dispensing Log

177

Dispense by Pt

Study Subject Investigational Product Dispensing Record

179

Drug Disposition

Clinical Trial Materials Disposition Form

181

Drug Order

Investigational Drug Shipping Order

183

Drug Receipt

Investigational Product Receipt Form

185

Drug Return

Drug Return Form

187

Enrollment

Screening and Enrollment Log

189

Expedited

Expedited Review Form

191

ICF Review

Subject Information and Consent Form Checklist

193

Init Doc Track

Study Initiation Document Tracking Worksheet

197

Initial Sub

Initial Submission Form

199

IRE3 Member

IRl3 Membership Roster

207

Minutes Template

IRE3 Meeting Minutes Template

209

Monitor Log

Monitoring Log

213

Patient Master

Master Subject Log

215

Phone Rpt

Telephone Contact Report

217

Progress Rpt

IRE3 Progress Report Form

219

Responsibilities

Study Responsibilities Form

22 1

Review Cklist

Reviewer’s Checklist

223

Review Results

IRl3 Review Results Form

225

SAE

Serious Adverse Experiences

227

Safety Rpt

Safety Information Form

233

Sig Sheet

Study Site Personnel Signature Sheet

23 5

St Term Ack

IRB Study Termination Acknowledgement

237

St Term Notice

IRE3 Notification of Study Termination Form

239

Training Plan

Training Plan Form

24 1

Training Record

Training Record Form

243

Training Request

Staff Training Request Form

247

Training Verification

Staff Training Verification Form

249

Trip Rpt Evaluation

Site Evaluation Visit Trip Report

25 1

Trip Rpt Init

Study Initiation Visit Trip Report

255

Trip Rpt Interim

Periodic Site Visit Trip Report

259

Trip Rpt Termination

Study Termination Visit Trip Report

263

Index of Forms - In Alphabetical Order By Form Name

269


Company Standard Operating Procedure: MON-00 1.0

Effective Date: DDIMMMNY

Title: Preparation, Issue, and Revision of SOPs

Supersedes: N/A

AUTHOR Name: Title: Department: Signature and Date:

APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE

Name: Title: Department: Signature and Date: REVISIONS No.

I.

Section

Pages

InitialsJDate

Purpose To describe the procedures by which Standard Operating Procedures (SOPs) for Company are prepared, issued, and revised. To provide a tool for training new personnel in the procedures by which specific activities will be performed at Company.

11.

Scope This SOP will apply to all SOPs for Company.

MON-0Ol.O.doc

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Company Effective Date: DDIMMM/YY

111.

Procedures

A. The Department Head for each Department will determine which activities require SOPs and will assign the responsibility for writing the initial version.

B. All SOPs should include: l. Brief, informative title.

2. The SOP number on every page.

3. Effective date of the SOP on every page. 4. Dated approval signatures for the SOP'S Author, Department Head, and Quality Assurance (QA) representative. 5. Revision history.

6. Scope of the SOP (i.e., a statement that describes the personnel, projects, and situations to which the SOP applies). 7. Description of the procedure (i.e., a detailed description of all procedures to be conducted under the SOP, including when they are to be accomplished, where, and by whom). Each step in the procedure should be numbered. All new or unusual terms should be defined. If an abbreviation is associated with a term, it should be placed in parentheses following the word. If specific forms or equipment are to be used, they should be specified. Copies of the applicable forms should be attached to the SOP in the Attachments section.

8. References (i.e., citations of any applicable regulations, guidelines, publications, or other SOPs). Copies of the references do not need to be attached to the SOP. 9. Attachments (i.e., copies of any forms, checklists, charts, andlor tables that will be used in executing the SOP). The Attachments section should begin with a list of all the attachments that are included in the SOP. Attachments should be identified by letter. C. Review and Approval of SOPs l. The Author will circulate the draft SOP to the Author's department members for review and comment.

2. The Department Head will perform the final review and edit of the SOP and will submit the final versions to QA for review.

3. After completing its final review, QA will reconcile all questions andlor suggested revisions with the Author prior to issue. 4. The final version of each SOP must be approved by the Department Head and a designated member of the QA Department before issuance. QA will obtain original signatures on the SOP cover sheet before releasing the final versions of an SOP.

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D. Distribution of SOPs

1. Each department will maintain an active SOP manual containing authorized copies of all current approved SOPs. 2. QA will retrieve or discard all distributed versions of the SOPs (i.e., not the archive copy) as new versions are implemented. E. Maintaining original, signed SOPs

1. QA will maintain a complete collection of current Company SOPs and will retain all obsolete, discontinued, or otherwise superseded SOPs in an SOP archive. F. Revision of SOPs

1. SOPs requiring permanent modifications will be revised by the Author or individual designated by the Department Head. Revised SOPs will be circulated for review and approval as described in Section II1.C. 2. QA will update the cover page of the revised SOP to show subsequent revisions of the SOP.

G. Periodic Review of SOPs 1. All SOPs will be reviewed on an annual basis to determine whether modifications are needed or if the SOP remains in use. Annual review of SOPs will be initiated by QA. QA will issue a reminder that SOPs are due for review. 2. If a procedure is no longer in use, the SOP will be considered inactive and stored by QA in the SOP archives.

3. Changes to the SOP will be made according to procedures described in Section II1.C. 4. Documentation of annual SOP review will be maintained in the SOP archives.

IV.

References ICH Guidelines for Good Clinical Practice (E6) 5.1 - Quality Assurance/Quality Control

V.

Attachments None

MON-0Ol.O.doc

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Company Standard Operating Procedure: MON-002.0

Effective Date: DDIMMMIYY

Title: Training Clinical Research Staff

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initials/Date

Purpose To ensure all clinical monitoring staff members are trained concerning FDA regulations, ICH guidelines, and company policies and procedures. To describe the process for continuous employee training. To describe the procedures for maintaining documentation of initial training and continuing education.

Scope This SOP applies to all employees and independent contractors for Company.

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111.

Procedures A. Employee Training

1. Initial Employee Training begins on the new employee's starting date and continues throughout a training period determined by the department manager andlor selected department representative. Continuous Employee Training occurs throughout an employee's employment with Company. B. Permanent Employees - For all new permanent employees (full-time and part-time), the following tasks should be completed:

1. The Human Resources Department or Department Head will obtain the employee's signature on the Confidentiality Agreement and will place the signed Agreement in the employee's file. 2. The Human Resources Department or Department Head will give the Employee Handbook to the new employee on hisher start date. This handbook covers the corporate history, policies, and general philosophies of the company. 3. The Department Head will appoint a supervisorlmentor to be responsible for the new employee's training.

4. The Supervisor will ensure proper training for the new employee by providing copies of Company and Departmental SOPSand other educational materials to the new employee. Based on the employee's prior experience, the Supervisor and employee will develop a training plan for the employee and a timeframe for completion. The training plan will be outlined on the Training Plan Form (Attachment A). 5. The new employee will read the Employee Handbook and other educational materials that pertain to hisher specific department and will acquire hands-on training for certain functions of the job. 6. Appropriate staff will sign off on the employee's Training Plan Form as the training is completed. When the Training Plan Form is complete, the employee will return the form to hislher supervisor, who will file the document with the employee's training record.

C. Temporary Employees - For all new temporary employees (full-time and part-time), the following tasks should be completed:

1. The Human Resources Department or Department Head will obtain the employee's signature on the Confidentiality Agreement and will place the signed Agreement in the employee's file.

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2. The Department Head will appoint a supervisor/mentor to be responsible for the new temporary employee's training.

3. The Supervisor will ensure proper training for the new temporary employee by providing copies of appropriate Company and Departmental SOPs and other educational materials to the new temporary employee. Based on the employee's prior experience, the Supervisor and temporary employee will develop a training plan and a timeframe for completion. The training plan will be outlined on the Training Plan Form (Attachment A). 4. The new temporary employee will read the SOPs and other educational materials that pertain to hislher specific department and will acquire hands-on training for certain functions of the job. 5. Appropriate staff will sign off on the employee's Training Plan Form as the training is completed. When the Training Plan Form is complete, the temporary employee will return the form to hislher supervisor, who will file the document with the employee's training record. D. Continuous Training - All permanent and temporary employees are responsible for keeping current with the industry and technology. To accomplish this, an employee or the employee's supervisor may identify the necessary training. All training must be relevant to the employee's job.

1. To request training, the employee will complete the Staff Training Request Form (Attachment B) and will submit it to the appropriate manager(s). 2. The manager will review the form; check the appropriate box (Yes or No) based on whether the training request is approved or denied; sign and date the form; and (if appropriate) give the signed Staff Training Request Form to the HR Department for archiving. 3. If training was approved, the employee will complete any other forms (such as registrations or the Travel Request Form) and submit them to the appropriate department (e.g., Travel).

4. The supervisor and employee will review the employee's training record on at least an annual basis. E. Employee Training Verification - When an employee receives training, helshe should complete the Staff Training Verification Form (Attachment C) and submit it to the appropriate department to be filed with the employee's training records.

MON-002.0.doc

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Company SOP# MON-002.0

Effective Date: DDIMMM/YY

F. Retention of Training Files

1. Training records for each employee will be cumulative and will be retained for each employee's tenure with the Company. 2. Training records are subject to inspection by authorized regulatory agency investigators. G. Contents of Training Files minimum of the following:

-

Each employee's training record should contain a

l. Curriculum vitae (CV) or resume - updated annually and reflecting employment at Company. Because this is a cumulative document, only the current version of the CV should be retained in the file.

2. Current job description. 3. Completed Training Record Form (Attachment D) with appropriate documentation attached (i.e., completed and updated training form(s) and certificates of completion or diplomas received for training programs or other supplemental education).

IV.

References 21 CFR 3 12.53 - Selecting Investigators and Monitors ICH Guidelines for Good Clinical Practice (E6) section 5.18 - Monitoring

Attachments Attachment A - Training Plan Form Attachment B - Staff Training Request Form Attachment C - Staff Training Verification Form Attachment D - Training Record Form

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Title: Selecting Investigators and Study Sites

Supersedes: N/A

AUTHOR

Name: Title: Department: Signature and Date:

APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe procedures for selecting Investigators, including the preliminary evaluation of the qualifications of Investigators and other study personnel and an assessment of the ability of a prospective clinic site to perform the proposed study. 11.

Scope

This SOP will apply to the selection of all Investigators for Company.

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111.

Procedures

A. The Project Leader will develop criteria by which the acceptability of a prospective Investigator will be determined. These criteria will include: a. Investigator's clinical expertise and reputation b. Study staff competence c. Access to patients d. Facilities and equipment e. Investigator's level of cooperation f. Investigator's level of accessibility g. Time and cost factors h. Site location B. The Project Leader or designee will develop a list of potential Investigators for the clinical trial from the following sources: l. Investigators who have successfully completed previous trials with Company; 2. Referrals from professional colleagues; 3. Referrals from former Investigators; 4. Editors of medical journals in the relevant discipline 5. Members of FDA Advisory Panels 6. Membership lists and Web listings for professional societies; 7. Authors of scientific publications pertinent to therapeutic arealdisease state; and 8. Experts in the field of study. C. The Project Leader or Senior Clinical Research Associate will contact the potential Investigator, either by telephone or by faxing a questionnaire, to determine hisher interest in the study. D. Members of Company Legal Department will develop a Confidentiality Agreement for the potential Investigators. E. The Project Leader, Senior Clinical Research Associate, or designee will send the Confidentiality Agreement to Investigators who express an interest in the study. F. After receiving the signed Confidentiality Agreement from the potential Investigator, the Senior CRA or designee will send the following materials to the Investigator: l. Study synopsis andlor draft protocol (if available); 2. Investigator's Brochure; 3. Preliminary study-specific questionnaire (if not previously sent); 4. Request for current curriculum vitae (CV). G. Based on the previously developed criteria and the information received (CV and completed questionnaire), the Project Leader or Senior CRA will make follow-up phone calls to the potential Investigators to discuss the protocol in more detail and to learn more about the site's capabilities and patient population.

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Company


H. Site Evaluation Visits will be scheduled to the institutions where potential investigators appear to meet the pre-determined selection criteria. Some additional investigators may be approved or eliminated on the basis of Site Evaluation Visit findings.

IV.

References

21 CFR 3 12.50 - General Responsibilities of Sponsors 21 CFR 3 12.53 - Selecting Investigators and Monitors ICH Guidelines for Good Clinical Practice (E6) section 5.6 - Investigator Selection ICH Guidelines for Good Clinical Practice (E6) section 5.9 - Financing ICH Guidelines for Good Clinical Practice (E6) section 5.10 - Notification/Submission to Regulatory Authorities

V.

Attachments

None

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Title: Developing Informed Consent Forms

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the information required to be included in all informed consent documents developed by Company. To provide ancillary information to facilitate preparation of acceptable informed consent forms.

11.

Scope

This SOP will apply to all informed consent documents developed by Company.

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111.

Procedures

A. Informed Consent Form (ICF) Template Author The template for an Informed Consent Form may be developed by an In-House Clinical Research Associate or Clinical Research Associate, as long as someone at a higher level approves the final document. B. Required Elements and Additional Considerations The Informed Consent Form will be developed so that all basic elements of consent and the applicable additional elements are contained in the document according to the regulations. Because the ICH guidelines make no distinction between basic and additional elements (i.e., these guidelines state that all basic and additional elements are required for all consent forms), Informed Consent Forms being developed for trials that will have study sites outside the United States will be developed according to the more strict ICH guidelines.

In addition to the basic elements of consent, the author will also consider the following points when developing the document: 1. The information must be given to the subject or the subject's representative in understandable language (i.e., usually an eighth-grade reading and comprehension level). Ultimately, the preferences concerning style, format, and specific wording required by the IRB will be followed. 2. The informed consent must not include any language suggesting that the subject relinquishes any legal rights or that helshe releases the Investigator, sponsor, or institution or their agents from liability for negligence. 3. The content of the informed consent document must present the benefits and risks of the research in such a manner that the subject (or representative) can make an informed choice concerning hislher participation in the study. C. Format The ICF template author will consider the following items: 1. The first page will be on the institution's letterhead or include the following information: a. Name and address of the institution b. Name and address of the Principal Investigator c. Name and number of the protocol 2. There will be an appropriate heading for each paragraph. 3. The date of issue or revision will be included on every page. 4. There will be a space on each page for the subject's initials (in addition to the signature line for the entire document). 5. Each page will be numbered (e.g., Page 2 of 3).

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D. Template Consent Forms Usually, an informed consent template will be developed because each IRB will have specific wording requirements that will need to be incorporated into the document used at that facility (e.g., how compensation will be handled in the event of a studyrelated injury). The In-House Clinical Research Associate (CRA) will send the template to the Investigator andlor Study Coordinator with the protocol. Site personnel will enter the site-specific wording and will return the document to Company. The In-House CRA or Monitor will ensure that all elements of consent and other requirements (e.g., layman's language) are met before the Study Coordinator will submit the draft document to the IRB for approval. In consideration of the lead times required for submission of documents to the IRB, Company InHouse CRA or Monitor will perform the review of the site-specific informed consent promptly. E. Non-English Informed Consent When a study population includes non-English speaking people, the Monitor will assist the Investigator to ensure that the translated version of the consent form is prepared and that the translation is accurate. The translation from English to another language will be accomplished by someone who will certify in writing the accuracy of the translation. For non-English consent forms, the Monitor will ensure that Company and site study files contain: l . The name and address of the translator, 2. A copy of the translator's certificate, and 3. A memo to the file signed by the translator that states that the foreign language consent document is an accurate translation of the English consent form. Note: Informed Consent Form authors should also check individual state laws that might concern the translation of legal or other documents. SpeciJic IRBs may also have their requirements concerning what is acceptable practice and documentation for the translation of consentforms.

IV.

References

21 CFR 50.20 - General Requirements for Informed Consent 21 CFR 50.23 - Exception From General Requirements 21 CFR 50.25 - Elements of Consent 21 CFR 50.27 - Documentation of Informed Consent 45 CFR 46.116 - General Requirements for Informed Consent 45 CFR 46.117 - Documentation of Informed Consent ICH Guidelines for Good Clinical Practice (E6) section 1.28 - Informed Consent

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ICH Guidelines for Good Clinical Practice (E6) section 1.37 - Legally Authorized Representative ICH Guidelines for Good Clinical Practice (E6) section 4.8 - Informed Consent of Trial Subjects FDA Information Sheets - Continuing Review After Study Approval, January 200 1 FDA Information Sheets - Guide to Informed Consent, 1998 Update FDA Information Sheets - Recruiting Study Subjects, December 1999 FDA Information Sheets - Screening Tests Prior to Study Enrollment, December 1999 Belmont Report Declaration of Helsinki

V.

Attachments

None

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Title: Conducting Site Evaluation Visits

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

The purpose of this SOP is to describe the activities performed during a Site Evaluation Visit. The purpose of a Site Evaluation Visit is to evaluate: The ability of a study site to successfully conduct the proposed clinical trial; The credentials of study personnel; and The adequacy of clinic facilities. 11.

Scope

This SOP will apply to all Site Evaluation Visits being conducted by Company personnel.

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111.

Procedures

A. General Site Evaluation Visits may also be known as site selection visits or pre-study site visits (PSSV). These visits may be conducted only by individuals at the level of MonitorIClinical Research Associate (CRA) or above. A Site Evaluation Visit is required unless someone from Company has conducted a visit to the site within the last 12 months for a study in the same therapeutic area or which utilizes the same Principal Investigator. In this case, a memo will be written and kept in the Central Study File documenting the date and purpose of the previous site visit. B. Prior to the Site Evaluation Visit Prior to conducting a Site Evaluation Visit, the Monitor or Project Manager will: Confirm that a signed confidentiality agreement has been received from the Principal Investigator. Review the curriculum vitae of the Principal Investigator and Study Coordinator(s) to assess qualifications, credentials, and experience in intended therapeutic area. Verify that medical licenses for the Principal Investigator and all medical Subinvestigators are current. Check the names of all Investigators and Subinvestigators against the FDA list of Investigators Ineligible to Receive Investigational Products (i.e., the "blacklist"). Prepare the Study Initiation Document Tracking Worksheet to document sending and retrieval of regulatory documents (Attachment A). Schedule a visit with the Investigator(s) and study personnel. Send confirmation letter outlining purpose of visit and items for discussion. Discuss applicable drug storage requirements with appropriate Company personnel. Discuss any special laboratory assays or procedures with appropriate Company personnel. C. Conducting the Site Evaluation Visit During the Site Evaluation Visit, the Monitor will: 1. Evaluate the acceptability of the investigational site by touring the facilities to determine: a. If the drug dispensing and storage area is secure, has limited access, and meets the storage conditions listed in the protocol; b. If the patient care areas and clinical laboratory being used for the study are acceptable; c. If protocol-required equipment is present and maintenance and calibration records are present; and d. If the storage area for CRFs, study manuals, regulatory documents, and other study-related supplies and materials are secure and adequate.

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Company Effective Date: DDIMMMNY

Meet with the Investigator and Study Coordinator to evaluate the site's potential for enrolling study subjects by discussing: a. Timelines for study activities and enrollment expectations; b. Plans for advertising (if applicable); c. General clinic operations, including hours of operation and weekend staffing procedures; d. FDA (or other applicable regulatory authority) and sponsor requirements for regulatory documents; e. Whether or not the site is currently participating in or plans to participate in any competing protocols; and f. The amount of time the study staff has available to conduct the study, including the Principal Investigator's accessibility. 3. Obtain the following information about the IRB: a. Whether the site will use a local or central IRB; b. The name and location of the IRB c. The date of the next IRB meeting and deadline for submission of documents; d. How often the IRB meets; and e. If any other review committees are required to approve the protocol.

4. Retrieve available regulatory and study documents. D. Follow-up to the Site Evaluation Visit Following the Site Evaluation Visit, the Monitor will: 1. Discuss findings with appropriate Company personnel to determine acceptability of site for proposed study. 2. Document the Site Evaluation Visit by: a. Completing a Site Evaluation Visit trip report (Attachment B); and b. Writing a follow-up letter to the potential Investigator. If the decision has been made concerning whether this site will be included in the study or not, the decision should be included in the letter. 3. Place a copy of the Site Evaluation Visit trip report and the follow-up letter in the study file.

IV.

References

21 CFR 3 12.53 - Selecting Investigators and Monitors 2 1 CFR 3 12.55 - Informing Investigators 21 CFR 312.56 - Review of Ongoing Investigations 21 CFR 3 12.57 - Record Keeping and Retention 21 CFR 3 12.58 - Inspection of Sponsor Records and Reports

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21 CFR 56.107 - IRB Membership ICH Guidelines for Good Clinical Practice (E6) section 3.1 - Responsibilities ICH Guidelines for Good Clinical Practice (E6) section 4.2 - Adequate Resources ICH Guidelines for Good Clinical Practice (E6) section 4.5 - Compliance with Protocol ICH Guidelines for Good Clinical Practice (E6) section 5.18 - Monitoring

V.

Attachments Attachment A - Study Initiation Document Tracking Worksheet Attachment B - Site Evaluation Visit Trip Report

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Title: Conducting Study Initiation Visits

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

The purpose of this SOP is to describe the activities that will be accomplished at a Study Initiation Visit. The purpose of a Study Initiation Visit is: To review with the Investigator and staff the final protocol, the Investigator's Brochure and regulatory requirements, and To instruct study personnel in study procedures including, but not limited to patient recruitment, informed consent, drug dispensing and accountability, and Case Report Form completion.

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11.

Scope

This SOP will apply to all Study Initiation Visits conducted by Company. 111.

Procedures

A. General Study Initiation Visits may be conducted only by individuals at the level of MonitorIClinical Research Associate (CRA) or above. If the Monitor for the study site has been selected, it is recommended that helshe attend the Study Initiation Visit. The Monitor should ask to have all study personnel present at the Study Initiation meeting. At the conclusion of the visit, the Monitor must be satisfied that all staff members participating in the study are sufficiently informed to competently fulfil1 their responsibilities. All unresolved issues should be discussed with the Project Manager and then readdressed with the Investigator. A Study Initiation Visit will be conducted after a site has been selected to participate in a trial but before subject screening and enrollment begins. This visit allows all participants (including the pharmacist, radiologist, and other personnel who did not attend the investigator's meeting) to receive detailed instruction concerning their role in the study.

B. Prior to the Study Initiation Visit Prior to the Study Initiation Visit, the Monitor will: l. Determine which regulatory documents are outstanding and should be retrieved at the visit. 2. Schedule the visit with Investigator(s) and study personnel. 3. Send a confirmation letter outlining the purpose of the visit and items for discussion and listing outstanding regulatory documents to be retrieved. 4. Gather study materials to carrylship to the site, such as a sample Case Report Form, regulatory documents binder, Study Procedures manual, etc. 5. Arrange for drug shipment to site. 6. Review budget and payment schedule. C. Conducting the Study Initiation Visit During the Study Initiation Visit, the Monitor will: l. Meet with the Investigator to discuss federal requirements specified in FDA Form 1572, including: a. Obtaining and documenting informed consent; b. IRB approval and progress reports, including amendments and SAEs; c. Protocol adherence; d. Drug accountability; MON-OO6.O.doc

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e. Maintenance of adequate and accurate case histories; f. Record retention. 2. Leave a copy of the regulations at the site and encourage site personnel to place them in the study files.

3. Meet with the Investigator and Study Coordinator to review the following: a. Investigator's Brochure - including a history of development of drug and major pre-clinical and clinical findings. b. Protocol - including study objectives and design, Inclusion/Exclusion criteria, Study procedures, the time and events schedule of visits/tests/exams and plans for subject recruitment. c. IRE3 issues - including requirements for documentation of informed consent; requirement for periodic IRB review of the study; the need to obtain IRB approval of protocol amendments prior to implementation; and the requirement to submit all serious adverse events to the IRE3. d. AdverseISerious Adverse Events (AEsISAEs) - including definitions and reporting requirements; procedures for reporting AEsISAEs to the sponsor; and Investigator requirements for reporting SAEs to the IRB. e. Delegation of study responsibilities - To document who will be responsible for specific study functions, the Study Responsibilities Form should be completed and signed by the Investigator. (Attachment A) f. Contract and payment schedule issues - The Monitor may deliver the initial study payment, if appropriate. g. Record retention for study documents - Two (2) years after an NDA has been approved for the stated indication, or two (2) years after notification of FDA and the investigator by the sponsor that the project has been completed, canceled, or discontinued, even if no NDA has been filed.

4. Meet with the Study Coordinator and Pharmacist to review issues concerning drug supplies and accountability - including inventory, dispensing procedures, storage and accountability procedures; handling and storage procedures for returned drug; and the procedure for return of drug to the sponsor or destruction at study termination. 5. Meet with the Study Coordinator and Lab Director or technician to review laboratory issues including specimen collection and preparation; how results will be handled; special assays and procedures; and the storage, preparation, and shipment of samples. 6. Meet with the Study Coordinator to review:

a. Case Report Form completion, including i. General instructions for forms completion;

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.. Completion of individual forms; ... m. Signature requirements; and 11.

iv. Procedures for correction/revision of recorded data. b. Additional study supplies, including i. Maintenance of the Regulatory Documents Binder; ii. Laboratory test kits; iii. The Monitoring Log; and iv. Study-specific forms, materials, and supplies, including . The Master Subject Log (Attachment B) . Screening and Enrollment Log (Attachment C) c. Monitoring visits, including i. Expectations for visits; .. 11. Frequency of visits; ... m. Source document reviews; and iv. Possible QA or FDA audits during study or after study close-out.

7. Retrieve outstanding study and regulatory documents. 8. Sign the Monitoring Log (Attachment D) and add the Site Evaluation Visit date to the log, if appropriate.

D. Follow-up to the Study Initiation Visit Following the Study Initiation Visit, the Monitor will document the visit by: 1. Completing a Study Initiation Visit trip report (Attachment E). If a slide presentation was used to present the study, a paper copy of the presentation material (e.g., handouts) must be attached to the trip report. 2. Writing a follow-up letter to the Investigator. The letter should outline what was accomplished in the meeting and should note any items that need additional attention. 3. Placing copies of the trip report and follow-up letters in the study file. For the purposes of a clinical study, certain information or data may be required that are not routinely documented in the medical records. The CRF may represent the sole documentation of such information. If this is the case, at study initiation, documentation must be included in the study files that specifically notes which elements of the CRF will not be documented in the investigator's records or may be documented in greater detail on the CRF than in the investigator's records.

IV.

References ICH Guidelines for Good Clinical Practice (E6) section 4.2 - Adequate Resources ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects

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ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRBIIEC ICH Guidelines for Good Clinical Practice (E6) section 4.5 - Compliance with Protocol ICH Guidelines for Good Clinical Practice (E6) section 4.6 - Investigational Products ICH Guidelines for Good Clinical Practice (E6) section 5.12 - Information on Investigational Products ICH Guidelines for Good Clinical Practice (E6) section 5.18 - Monitoring

V.

Attachments Attachment A - Study Responsibilities Form Attachment B - Master Subject Log Attachment C - Screening and Enrollment Log Attachment D - Monitoring Log Attachment E - Study Initiation Visit Report

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Title: Conducting Periodic Site Visits

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

The purpose of this SOP is to describe the activities that will be accomplished at a Periodic Site Visit. The purpose of a Periodic Site Visit is to ensure: the study is being conducted according to the study protocol and to the principles of Good Clinical Practice, and all activities are in compliance with applicable FDA regulations and ICH guidelines, and the facilities and staff at the investigational site continue to be acceptable for the conduct of the study.

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11.

Scope

This SOP will apply to all Periodic Site Visits conducted by Company. 111.

Procedures

A. General Periodic Site Visits (also known as Interim Visits) may be conducted only by individuals at the level of MonitorIClinical Research Associate (CRA) or above. The timing of Periodic Site Visits will vary by study and will be based on the: l. Number and rate of patients accrued in the study 2. Complexity of the study design 3. Experience with the investigator 4. Nature and number of problems encountered 5. Disease being treated. Phase I studies will be monitored at reasonable intervals as determined by the Project Leader andlor Medical Advisor. Each investigational site in Phase 11and 111studies must be monitored: 1. Prior to the start of the study (i.e., Study Initiation Visit); 2. Early in the study after a representative number of subjects have been enrolled and the Case Report Forms have been completed; 3. At least every eight weeks during the course of the study; and 4. After the last patient has been enrolled (i.e., Study Termination Visit). The frequency of monitoring visits may be decreased under special circumstances. However, all study sites must be visited at least once yearly. An explanation for any such decrease in monitoring frequency will be documented in the study file.

B. Prior to the Periodic Site Visit Prior to the Periodic Site Visit, the Monitor will review the current status of the trial and activities at the site and will: 1. Schedule a visit with the Investigator(s) and study personnel; 2. Send confirmation letter outlining purpose of the visit and items for discussion; 3. Review trip report from previous visit to follow-up on items that are outstanding or action items that need attention; 4. Compare enrollment vs. anticipated enrollment; 5. Review reported Serious Adverse Experiences (SAEs); 6. Review drop-outs; 7. Review outstanding data management issues; 8. Review outstanding laboratory issues; and 9. Gather any documents or materials necessary for the visit.

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C. Conducting the Periodic Site Visit l. Compliance with the Regulations and Protocol. To ensure adherence to the protocol, applicable FDA regulations, ICH guidelines, and Company requirements, the Monitor will: a. Perform a detailed review of all study procedures and records generated from the conduct of the study; b. Confirm that each subject meets eligibility criteria; c. Ensure protocol violations are documented in the source document and Case Report Form (CRF); d. Verify that adverse experiences have been appropriately reported and documented; e. Ensure correct randomization procedures and maintenance of blind (if applicable); and f. Document protocol violations, including violations of eligibility criteria, in the Periodic Site Visit Report and follow-up letter to the Investigator.

2. Data Verification. To ensure maintenance of adequate and accurate source documents and to ensure adequacy, accuracy, and completeness of the data recorded on the Case Report Form, the Monitor will: a. Review all source documents (e.g., office records, hospital/clinic charts, progress notes, laboratory data) covering the period during the subject's involvement in the study. b. Ensure that the subject's medical record documents subject enrollment, consent to participate in the study, and assessmentsltest results for each study-related visit. c. Resolve any apparent entry violation and ensure an explanatory comment is captured in the source document and CRF. d. Ensure that the date and the reason(s) for discontinuation are documented in the source documents and CRF for subjects who have been discontinued from the study. e. Bring discrepancies between the CRF and the source document to the attention of the Study Coordinator. When possible, corrections will be made before the Monitor leaves the site. When this is not possible, the Monitor will leave some form of written documentation that points out the discrepancies at the site. f. Confirm that the CRF contains the Investigator's signature and the date the page was signed. g. Document any unresolved discrepancies in the Periodic Site Visit trip report; and h. Make arrangements for the shipment of the completed CRFs to Data Management. The Company Monitor will not make entries in or alterations to a CRF or source document.

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3. Facilities and Staff. To ensure the continued acceptability of the facilities and staff, the Monitor will note if there have been any changes in space or equipment or accreditation of the clinical laboratory facilities and study site personnel. If necessary, the Monitor will update pertinent documents (e.g., FDA Form 1572) or may add other documents to the file (e.g., a new Study Coordinator's CV). 4. Drug Storage and Accountability. To ensure maintenance of accurate records of drug receipt and disposition and to ensure secure storage and adequate supplies of investigational drug, the Monitor will: a. Perform a routine check of all records dealing with the shipment, receipt, and dispensing of all test articles. b. Cross-check shipment records with records of receipt (i.e., contents of the shipment, corresponding identification numbers, and dates). c. Perform a routine check of the drug inventory to ensure that an adequate supply of test article is maintained, storage conditions are being met, and drug expiration dates are noted. d. Check the accuracy of dispensing and return records for test articles between the Investigator and the individual study subject (i.e., subject identification numbers, lot numbers, quantity dispensed and returned, dates dispensed and returned, label numbers, and balance on hand). Informed Consent. To verifl proper completion of the Informed Consent Form by each subject prior to study entry, the Monitor will: a. Ensure that a signed copy of the informed consent document is present for each subject enrolled in the study and each screen failure; b. Compare the date of initiation of therapy or prestudy testing with the date the subject signed the Informed Consent Form to ensure the subject consented to participate in the study before actual enrollment; and c. Document in the Periodic Visit trip report the patient numbers of the Informed Consent Forms that were reviewed at each visit and any irregularities found. Include a description of the irregularities in the followup letter to the Investigator. At a Periodic Site Visit, if a Monitor discovers that an outdated version of the consent form was used for a subject whose participation in the trial has not been completed, helshe will instruct the Study Coordinator to contact the subject and have the subject sign the correct version. When signing and dating the correct version, the subject should use the actual date (i.e., do not back-date the consent form or use the same date as on the first, incorrect version). The Monitor will instruct the Study Coordinator to maintain both signed versions of the consent in the files. An explanatory memo to the file is recommended so that future auditors will understand why two signed informed consent documents for the same subject are present in the file. If the Study Coordinator is unable to contact the subject, the explanatory memo should also document the dates and methods by which the attempts to reach the subject were made.

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At no time will the Monitor bring the signed informed consent forms in-house to either Company. 6. Adverse Experiences and Serious Adverse Experiences. To ensure collection and reporting of adverse experiences, the Monitor will: a. Review the documentation of all adverse experiences; b. Obtain additional SAE information from site as needed; c. Review laboratory AE experiences; d. Discuss adverse experiences that occur at other study sites with the investigator; and e. Document notable adverse experiences or trends in adverse experiences in the Periodic Site Visit Trip Report.

7. Regulatory and Other Study-Related Documents. To ensure maintenance of all study documents, the Monitor will check the investigator's study file to ensure that proper records are being maintained, including: a. Appropriate reports to the IRB concerning SAEs and amendments; b. Screening and Enrollment Log (Attachment A)

8. Biological Samples. To ensure adequate collection, labeling, storage, and packaging of protocol-required biological samples the Monitor will: a. Check the methods for biological sample collection, labeling, storage, packaging, and shipping. b. Ensure proper handling of special laboratory specimens and assays. c. Discuss changes in lab reference ranges. d. Discuss and resolve any laboratory problems. e. Assure continued licensing andlor certification. f. Discuss any problems with reporting of results. 9. Meet with the Investigator and Study Coordinator. At each Periodic Site Visit, the Monitor should make every effort to meet with the Investigator andlor appropriate study staff to discuss the findings of this visit. The Monitor should: a. Summarize the accomplishments b. Summarize any problems or issues c. Reach agreement on corrective actions that may be necessary d. Discuss any problems staff members are having with the study (e.g., subject accrual or compliance) e. Suggest tentative dates for next visit 10. Document the Visit. The Monitor will document the visit by signing the Monitoring Log (Attachment B).

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Company Effective Date: DDMMMNY

D. Follow-up to the Periodic Site Visit Following the Periodic Site Visit, the Monitor will document the visit by: 1. Completing a Periodic Site Visit trip report (Attachment C). 2. Writing a follow-up letter to the Investigator. The letter should outline what was accomplished during the visit and should note any items that need additional attention. 3. Placing copies of the trip report and follow-up letters in the study file. The Monitor will check to ensure that Data Management has received the Case Report Forms andlor Data Clarification Forms.

IV.

References

21 CFR 312.30 - Protocol Amendments 21 CFR 312.50 - General Responsibilities of Sponsors 21 CFR 3 12.56 - Review of Ongoing Investigations ICH Guidelines for Good Clinical Practice (E6) section 4.2 - Adequate Resources ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRB/IEC ICH Guidelines for Good Clinical Practice (E6) section 4.5 - Compliance with Protocol ICH Guidelines for Good Clinical Practice (E6) section 4.6 - Investigational Products ICH Guidelines for Good Clinical Practice (E6) section 4.7 - Randomization Procedures and Unblinding ICH Guidelines for Good Clinical Practice (E6) section 4.8 - Informed Consent of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 5.14 - Supplying and Handling Investigational Product(s) ICH Guidelines for Good Clinical Practice (E6) section 5.17 - Adverse Drug Reaction Reporting V.

Attachments

Attachment A - Screening and Enrollment Log Attachment B - Monitoring Log Attachment C - Periodic Site Visit Trip Report

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Title: Reviewing Case Report Forms at the Study Site

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To standardize procedures for review of Case Report Forms (CRFs) retrieved from clinical study sites and to establish a comprehensive plan for routing the CRFs from retrieval through submission to Data Management. 11.

Scope

This SOP will apply to all CRFs being processed by Company personnel.

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111.

Procedures

A. On-Site Review of CRFs To ensure that the data captured in the CRFs are accurate and complete, the Monitor will verify that all data captured in the CRF are supported by source documentation and will check the CRF to determine the following: 1. Are all pages present and in the correct order? 2. Do all blanks for data have complete entries? 3. Is the subject identifier on each page? 4. Are the data legible?

5. Are the dates present and is the sequence of dates logical? 6. Are the data logical and consistent? 7. Are errors properly corrected? a. Cross out with single line b. Initial and date the error c. Record the new data correctly d. "White-out" not used e. Overscribes not used 8. Are times recorded using a 24-hour clock system? 9. Does the subject fit entry criteria for the study?

10. Are required tests being recorded? 11. If a procedure has not been performed, has the Investigator explained this on the CRF? 12. Is the schedule of patient visits correct? 13. Are procedures and tests accomplished on schedule? 14. Are the CRFs complete and consistent with the source documents? 15. Are the appropriate units of measure being used for weight, height, lab values, etc.? 16. Are all calculations and scoring correct? 17. Is the dose of drug given to the subject correct? 18. Are the blinding procedures intact? 19. Has the investigator commented on clinically abnormal laboratory values? 20. Has the CRF been signed and dated by the Investigator? 2 1. Is there the possibility that some data may be missed due to comments on the CRF such as "See page 40" or "See reverse"? 22. Is there acceptable documentation in the CRF for a. Missing medications? MON-008.0.doc

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b. Protocol deviations, violations? c. Missing visits? d. Premature discontinuations? 23. Has the Adverse Experiences page been checked for a. Appropriate terminology/description used? b. Onset and cessation dates? c. Duration of the event? d. Severity of the event? e. Relationship of the event to the study drug?

24. Has the concomitant medications page been checked for a. Medications not allowed by protocol? b. Dosage including regimen, route? 25. Have related areas of the CRF been cross-checked? a. Dates from visit-to-visit b. Concomitant medications with adverse experiences

B. On-Site Data Clarifications During the site visit, the Monitor will bring discrepancies between the CRF and the source document to the attention of the Study Coordinator or other appropriate site personnel. When possible, corrections will be made before the Monitor leaves the site. When this is not possible, the Monitor will leave a completed CRF Review Form, which points out the items that need resolution, with the Study Coordinator (Attachment A). The Company Monitor will not make entries in or alterations to a CRF or source document. At the next site visit, the Monitor will confirm that all issues on the CRF Review Form have been addressed. The Monitor will ensure that no changes to the CRF occur after the Investigator has signed the CRF. C. Retrieval of the CRFs After the Monitor has verified that all of the data in the CRF are supported by source documents and that all issues on the CRF Review Form for a specific subject have been resolved, helshe will retrieve the original pages of the CRF. The Monitor will ensure that legible copies of all pages remain at the study site, before the original is collected. If the site's copy is not legible, the Monitor will make a copy of the original for the site's files before removing it from the site.

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Before the first Periodic Site Visit is conducted for the study, the Project Leader and Data Manager will make the decision concerning whether or not CRF pages that contain no data (e.g., pages for visits not accomplished due to early discontinuation) will be retrieved. This will vary on a project-by-project basis. If necessary, the Monitor will notify Data Management that a shipment of CRFs should be expected. The Monitor will specifl in the trip report, which CRF pages have been reviewed and which have been transmitted to Data Management. The original CRFs will be transported by one of the following methods: l . Hand-carried by the Monitor. If travel is by air, the CRFs will be part of the carry on baggage (i.e., not checked baggage). 2. Using an express package delivery service that can electronically track packages, (e.g., Federal Express, United Parcel Service). D. Data Queries After the CRFs have been removed from the study site, changes to the data on the retrieved pages that cannot be corrected without investigator verification will be accomplished using the Data Clarification Form (Attachment B). The person who discovers the discrepancy in the data will prepare a Data Clarification Form. If this person is in Data Management, helshe will forward the Data Clarification Form to the Monitor, who will forward it to the InvestigatorIStudy Coordinator for resolution. The Monitor will instruct the Study Coordinator to make a copy of the signed and completed Data Clarification Form before returning the original to the Monitor. The Study Coordinator will be encouraged to keep copies of the Data Clarification Forms with the CRFs. When the signed and completed Data Clarification Form is returned from the study site, the Monitor will forward it to Data Management. Personnel in the Data Management Department will follow their department's SOPS for tracking outstanding and resolved queries, updating the database, updating the working copy of the CRF, and filing the original Data Clarification Form.

IV.

References 21 CFR 3 12.32 - IND Safety Reports 2 1 CFR 3 12.44 - Termination ICH Guidelines for Good Clinical Practice (E6) section 4.5 - Compliance with Protocol ICH Guidelines for Good Clinical Practice (E6) section 4.9 - Records and Reports

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ICH Guidelines for Good Clinical Practice (E6) section 5.1 - Quality Assurance/Quality Control

V.

Attachments

Attachment A - CRF Review Form Attachment B - Data Clarification Form

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Title: Reviewing Regulatory Documents

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To name and describe the acceptable content of regulatory documents. To ensure that in the event of an inspection by a regulatory authority, the site's study materials can be readily identified and retrievable. 11.

Scope

This SOP will apply to all clinical studies for which Company is responsible for reviewing regulatory documents at the study site.

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111.

Procedures

A. Record Retention At the Study Initiation Visit, the Study Monitor should remind the Investigator that all study documents must be maintained for a period of two years following the date a marketing application is approved for the drug that is being investigated; or if the application is not approved for such indication, until two years after the investigation is discontinued and the sponsor notifies the FDA that the investigation is discontinued.

B. General Instructions Each section of the study file notebook should contain documentation or include a memo indicating that section is not applicable for that particular study, or a statement explaining where the information can be found. Information within each section must be filed in chronological order so that the most recent document is at the front of the section. Each protocol requires its own separate notebook. If several protocols are being conducted simultaneously, this may mean some documents should be copied so that they can be placed in both notebooks. No post-it notes or thermal fax documents should be present in the study file notebook. No draft versions of documents should be in the notebook after a document has been finalized. Explanatory memos to the file are encouraged to ensure clarity. C. Physical Organization of the Site's Study Files At the beginning of the study, the Monitor will provide the Investigator or Study Coordinator with a study file binder or comparable system for organizing regulatory documents. To help with identification, each study file notebook should display Company name, IND number, protocol number, Investigator name, and site number. Certain documents are required before study drug or other supplies are shipped to the study site. As the study progresses, documentation of the study conduct will be added to the files by study site personnel. At regular intervals while the study is ongoing, the Monitor will review the contents of the study binder to ensure it is current and complete. A thorough review of the study file notebook will be conducted at the Study Termination Visit.

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The physical organization of the file may vary from study-to-study; however, at a minimum, the site's file must include the following: l . Registration Documents a. Signed FDA Form 1572 b. Curriculum vitae for Investigator, Subinvestigator, and Study Coordinator c. Signed Financial Disclosure Forms for Investigator, Subinvestigator, and Study Coordinator 2. Background Materials a. Investigator Brochure or package insert 3. Protocol and Amendments 4. Institutional Review Board Materials a. IRB membership roster b. IRB approval of the protocol and consent c. IRB approval of advertisements and other recruiting materials, if applicable d. Correspondence between the Investigator and the IRB e. Submission of Progress Reports to the IRE3 f. Submission of SAEs and IND Safety Reports to the IRB g. Notification to the IRB concerning study termination 5. Informed Consent a. Blank copies of all versions of the consent and assent forms used in the study b. Signed consent forms 6. Clinical Trial Materials a. Drug shipment and receipt documentation (to the site) b. Drug accountability records c. Drug return or destruction documentation 7. Laboratory Certifications and Normal Ranges 8. Operations Manuals a. Study Procedures Manual (if available) b. Pharmacy Manual (if available) 9. Forms and Logs a. Screening and Enrollment Log (if applicable) b. Study Responsibilities Form c. Monitoring Log 10. Regulations 11. Standard Agreements a. Confidentiality Agreement (may also be stored in the institution's contract department) 12. Correspondence 13. Case Report Forms a. Blank CRF b. Completed CRFs 14. Patient Records The documents in the Investigator's study files should be similar to those in Company study files. However, there are some items in the investigator's files that may be

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more extensive than those in Company files (e.g., signed informed consent documents). D. Document Review Either in-house or at the study site, the Monitor will review the required regulatory documents for acceptable content. l . Signed FDA Form 1572 - Statement of Investigator a. The Monitor will ensure that the current version of the FDA Form 1572 accurately reflects the current status of the study at the site and the appropriate version of the form is present in the study file. b. No items may be left blank. c. The Monitor will review the completed FDA Form 1572 for the following: i.

..

11.

Section l (Name and Address of Investigator) Only one name should be listed. The full mailing address should be listed; it may or may not be the same as the address(es) listed in section 3. Section 2 (Investigator Qualifications) The box marked CV should be checked. If the study drug is a controlled substance subject to the Comprehensive Drug Abuse Prevention and Control Act of 1970, the Investigator must be registered with the Drug Enforcement Agency (DEA) and this registration number should be recorded on FDA Form 1572.

iii. Section 3 (Name and Address of the Study Site(s)) The complete mailing address for all sites where the study will be conducted should be listed. This address may or may not be the same as that listed in section l (i.e., the Principal Investigator's office address). If the address is the same as that in section l , it should be repeated here (i.e., The phrase "Same as section l" may not be used). Each address listed must be reflected in the CV of at least the Investigator or one of the Subinvestigators named in section 6. iv. Section 4 (Clinical Laboratory) The full name and address of all of the clinical laboratories being used in the study should be listed. This should include labs that perform assessments on biopsy samples as well as clinical pathology samples. v.

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Section 5 (Institutional Review Board (m)) The full name and address of each IRB responsible for reviewing the study should be listed. Page 42


If the study has been approved by more than one IRB,the names and addresses of each of them should be included. If more than one study site is used, an IRB must be listed for each site. In some cases, one IRB will be responsible for more than one site. In these cases, the IRB approval letter must state this responsibility. vi. Section 6 (Subinvestigators) The name and academic degree of each person assisting the Principal Investigator should be listed. A consistent format should be used (e.g., first name, middle initial, last name, academic degree). Non-physicians may be included. Whether or not the Study Coordinator should be included on FDA Form 1572 as a Subinvestigator will be decided by the Project Leader. This may vary on a study-by-study basis. vii. Section 7 ( Protocol) The protocol number followed by the complete protocol title as it appears on the title page of the protocol should be listed. No abbreviations or shortened title is allowed. viii. Section 8 (Protocol Information) The appropriate box should be checked. ix. Section 9 (Commitments) No action needed. X. Section 10 (Principal Investigator Signature) The Principal Investigator listed in section 1 must sign the form. xi. Section l l (Date) The date when the Principal Investigator signed the form must be entered. 2. Curriculum vitae (CV) a. A complete current CV for the Principal Investigator and all Subinvestigators should reflect the study staff members' qualifications for conducting the research study. b. The Principal Investigator's CV must contain the address listed in section 1 of FDA Form 1572. It must also contain at least one address listed in section 3 of FDA Form 1572. c. The Monitor should ensure that the CV is current (i.e., has been updated in the last two years; shows the investigator's employment at the study site; and notes board certification and all other accreditations, such as DEA).

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3. Financial Disclosure Forms A Financial Disclosure Form, provided by the sponsor, should be signed by the Investigator and each Subinvestigator. If required by the sponsor, a signed Financial Disclosure Form will also be obtained from the Study Coordinator. 4. Investigator Brochure or Package Insert All revised versions of the brochure that are used during the clinical study should be included in the study file notebook. The earlier version of the brochure should not be discarded. Protocol and Amendments a. The Monitor will ensure that the protocol is signed and dated by the Investigator indicating hislher agreement to conduct the study according to the protocol. Drafts of protocols and protocol amendments do not need to be retained in the study file. b. As they are generated, signed and dated (original) protocol amendments should be attached to back of the protocol. If the sponsor generates a revised protocol that incorporates the amendment changes, this version of the protocol should be included in the study file notebook. However, previous approved versions should not be discarded. c. Drafts of the protocol and protocol amendments should not be included in the file unless they are accompanied by a memo to the file from the Study Monitor with an explanation. 6. IRB Membership Roster a. Prior to the shipment of study drug and supplies, the Monitor must obtain an IRB roster of voting members to ensure that the IRB is a valid board. b. If the IRE3 refuses to release a membership roster, the Monitor will obtain the Department of Health and Human Services (DHHS) assurance number (if there is one) or a written statement from the IRE3 chairman which states that the IRB complies with the requirements of 2 1 CFR Part 56. c. During the course of the study, the Monitor should ensure that this list remains current; however, copies of outdated lists should not be discarded.

7. IRB Approval of the Protocol and Consent a. Each IRB listed in section 5 of FDA Form 1572 must provide an approval letter. b. The Study Monitor should review the content of the approval to ensure the following: i. It contains the protocol number, protocol title, or reasonable information to determine specifically which protocol (and version) was approved. ii. It is provided on the IRB or institution letterhead and contains some identifying information to associate it with the IRB listed in section 5 of FDA Form 1572. iii. The date of the approval is after the date of the final protocol. iv. The approval is addressed to the Principal Investigator.

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v.

There is some indication that the full board approved the study and informed consent document (i.e., no expedited approval is allowed). It is acceptable if the letter does not mention the consent approval only if the IRB has stamped the consent document with its approval and date. vi. If the IRE3 approved the protocol and consent documents for multiple sites, then the letter must state that all sites listed on the FDA Form 1572 were approved. vii. If the Principal Investigator, Subinvestigator, or Study Coordinator is a voting member of the IRE3, the approval must state that this person refrained from voting on approval of the protocol. Alternatively, in separate correspondence, the IRB Chairman may state that the Principal Investigator, Subinvestigator, or Study Coordinator refrained from voting. viii. It is possible that an amendment could be submitted with the initial protocol for full board review. If this is the case, the approval letter must state that the amendment was also approved. 8. IRB Approval of Advertisements and Other Recruiting Materials, If Applicable For sites that advertise to recruit study subjects, the IRE3 must review and approve all advertisements. A copy of each advertisement and the IRE3 approval of the ads must be included in the study file notebook.

9. IRE3 Approval of Amendments, If Applicable The Monitor should consult the Project Manager to determine whether protocol amendments require IRB approval. In either case, the IRE3 approval of the amendment or the investigator's notification to the IRE3 about the amendment must be included in the study file notebook. 10. Submission of Progress Reports to the IRE3 a. The FDA requires at least annual review and re-approval of the study. Some IRE3s require re-approval more frequently than the federal regulations. If this is the case, the initial approval letter will state when the IRE3 wants to review the study again. b. Although some IRE3s will also notify the investigator when the renewal date approaches, the Monitor should not assume this will occur and should remind the investigator of this requirement at least two months in advance of the required re-approval date. A copy of all re-approvals should be placed in the study file notebook. 11. Submission of SAEs and IND Safety Reports to the IRB At each site visit, the Monitor will ensure that all deaths and serious or unexpected adverse experiences (regardless of causality or relation to the drug) were reported immediately by telephone to Company (and, depending on the IRB's requirements to the Investigator's IRB).

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12. Notification to the IRE3 Concerning Study Termination This may be a letter from the Investigator to the IRB, an IRB-specific form, or the IRE3 Study Termination Notification Form (Attachment A).

13. Correspondence Between the Investigator and the IRE3 Copies of all additional correspondence between the investigator and the IRB concerning the protocol should be included in the study file notebook (e.g., IRE3 requests for revisions to the informed consent document). 14. Blank Copies of All Versions of the Consent and Assent Forms Used in the Study When the IEU3 approves a consent or assent form, the Monitor should ensure that a blank copy of the form is included in the study file notebook. 15. Signed Informed Consent Forms a. At each site visit, the Monitor should ensure that the most recent IRE3approved informed consent document is being used. b. At study termination, the Monitor should ensure that the study file notebook contains a memo to the file that states where the signed documents can be found. c. For every subject enrolled in the study (and for screen failures), the Monitor should ensure that the consent form was signed by the subject before the initiation of any study procedures (i.e., by comparing dates) and should review the source documents to determine if a copy of the consent form was given to the subject. Deviations from this policy should be documented in the file. d. For non-English Informed Consent Forms, the study file notebook should either contain the name and address of the translator and a copy of the translator's certificate, or have the translator provide a memo to the file that states that the foreign language consent document is an accurate translation of the English consent form. In cases of oral translation, documentation should be attached to the Informed Consent Form indicating that the translation was orally performed and giving the name and address of the translator. A statement should also be written on the (English) consent to indicate that it was read to the subject (rather than the subject reading it himselflherself).

16. Clinical Trial Materials (includes placebo, active comparators, etc.) a. Although drug accountability might not be reviewed by the Monitor at each site visit, the study site's drug accountability records should always be current. b. Documentation should be clear so that the amount of clinical trial material shipped to the site, the amount (and specific numbers) provided to each subject, the amount used or returned, and the amount returned to the sponsor can easily be determined. c. In general, the Monitor must ensure that the appropriate forms are completed correctly and are placed in the study file notebook.

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17. Operations Manuals To provide evidence that Company Monitors have fulfilled their obligation to train the study staff, copies of all training reference materials should be included in the study file notebook. This includes the Study Procedures or Operations Manual (if there is one), andlor guidelines for completion of CRFs, handling adverse events, handling subject deaths, handling premature subject or study discontinuation, and handling, storing, andlor shipping biological samples (if appropriate). 18. Laboratory Certifications and Normal Ranges a. A clinical laboratory should be certified or licensed by at least one of three authorizing bodies: a state regulatory agency, the Communicable Disease Center, andlor the College of American Pathologists. (Certifications for study sites outside the United States will differ.) b. Due to the raised seal, photocopies of laboratory certificates often make the date of certification illegible. When this happens, the Monitor should write the date of the certification on the copy. c. If certification expires during the study, an updated certification or letter of inspection should be obtained. d. As the study progresses, the Monitor should ensure that the certifications cover the entire time interval of the study and are renewed or updated as necessary. e. If the lab is certified on a test-by-test basis, the Monitor should ensure that the laboratory is certified for all of the tests required by the study protocol. f. If more than one laboratory will be used, normal ranges for each test from each participating laboratory must be obtained. g. As the study progresses, the Monitor should ensure that the normal ranges are valid for the entire time interval of the study and are renewed or updated as necessary. h. If biological samples are sent to a lab that was not listed on the FDA Form 1572, the Form must be updated and normal ranges for the second lab must be obtained. i. A copy of the Laboratory Director's CV may be included in the file, but is not required.

19. Screening and Enrollment Log (if applicable) During the Periodic Site Visits, the Monitor will ensure that the information included in the Screening and Enrollment Log remains current (Attachment B). 20. Study Responsibilities Form a. At the Study Initiation Visit, the Monitor must ensure that the Study Responsibilities Form is completed to show who may perform specific studyrelated tasks (Attachment C). b. The Study Responsibilities Form must be signed and dated by the Investigator to reflect that he has authorized the delegation of the tasks to the people indicted.

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c. The Study Responsibilities Form must be updated as new personnel are added to and removed from the study and as responsibilities shift. 2 1. Signature Sheet At the Study Initiation Visit, the Monitor must personally meet all staff members involved in the study and record their names, work addresses, and telephone numbers on the study signature sheet. This sheet should be updated as new personnel are added to the study (Attachment D). 22. Regulations Because the Investigator promises to adhere to federal regulations when helshe signs the FDA Form 1572, the Monitor should provide a copy of the FDA regulations and ICH guidelines, if applicable regulations. These copies of the regulations should be included in the study file notebook. 23. Standard Agreements These may also be stored in the institution's contract department. 24. Study Reports a. Preliminary results written by the Investigator in the form of abstracts, posters, etc. and copies of all publications that resulted from the research study will be included in this section of the study file notebook. b. Final Study Reports that are generated by the sponsor are not required to be in this file. c. After the study is completed, and if the sponsor provides the Investigator with the random code for the subjects helshe enrolled in the study, the random code should be included in this section of the study file notebook. d. This file should also include any documentation regarding unblinding or other study errors. 25. Correspondence a. All significant correspondence within the study site concerning the protocol should be included in the correspondence section of the study file notebook (e.g., if the Principal Investigator writes a memo to the staff which informs them about who to contact while helshe is away at a professional meeting). b. If the study site personnel write telephone reports or keep a telephone log concerning the study, these should be placed in this section of the notebook. c. The Monitor should ensure that copies of all correspondence helshe has written to the Investigator, including follow-up letters, are included in the study file notebook. d. If several protocols are being monitored at a given investigational site, separate follow-up letters must be written for each protocol and copies must be placed in the corresponding study file notebook for each protocol. e. All correspondence to and from the Investigator and Company should be filed chronologically. Attachments should be cross-referenced to their own specific file (i.e., they should not be included in this file).

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26. Case Report Forms a. The Investigator's files should include a set of blank CRFs and all amendments to CRFs. These may be stored in a separate location, but a memo to the file should exist in this section which describes where the blank CRF can be found. b. Copies of the completed CRFs are normally kept in a separate storage area. At study termination, this section of the notebook should contain a memo which states where the completed CRFs can be found. c. Data Clarification Forms should be attached to completed CRFs. 27. Patient Records a. If there are any data required in the CRF that will not be recorded in the Investigator's source documents, a memo to the study file must note specifically which data in the CRF represent the sole documentation of such information. A copy of this memo should be included in the study file notebook. b. At study termination, this section of the notebook should include a memo that specifies where these records can be found.

E. Financial Information Correspondence between Company personnel or the sponsor and the Investigator concerning financial matters do not need to be included in an FDA inspection. Therefore, documents that contain financial information are included in a separate section of the study files, which may be removed during the audit. The budget agreement letter or any contract concerning the schedule of grant payments should be included in this section of the study file notebook.

IV.

References 21 CFR 3 12.30 - Protocol Amendments 21 CFR 312.32 - IND Safety Reports 2 1 CFR 3 12.55 - Informing Investigators 2 1 CFR 3 12.57 - Record Keeping and Retention 21 CFR 3 12.64 - Investigator Reports 21 CFR 54.4 - Certification and Disclosure Requirements 21 CFR 54.6 - Record Keeping and Record Retention 21 CFR 56.107 - IRB Membership 2 1 CFR 56.1 15 - IRB Records

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ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRBIIEC ICH Guidelines for Good Clinical Practice (E6) section 5.9 - Financing ICH Guidelines for Good Clinical Practice (E6) section 5.1 1 - Confirmation of Review by IRB/IEC ICH Guidelines for Good Clinical Practice (E6) section 5.12 - Information on Investigational Products ICH Guidelines for Good Clinical Practice (E6) section 5.14 - Supplying and Handling Investigational Product(s) ICH Guidelines for Good Clinical Practice (E6) section 5.15 - Record Access ICH Guidelines for Good Clinical Practice (E6) section 5.21 - Premature Termination or Suspension of a Trial FDA Information Sheets - Record Keeping in Clinical Investigations, October 1995

V.

Attachments

Attachment A - IEU3 Study Termination Notification Form Attachment B - Screening and Enrollment Log Attachment C - Study Responsibilities Form Attachment D - Signature Sheet

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Company Standard Operating Procedure: MON-0 10.0 Title: Adverse Experiences (AEs), Serious Adverse Experiences (SAEs), and WD Safety Reports

Effective Date: DDIMMMNY Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose To describe the processes involved in the receipt, evaluation, and reporting of non-serious and serious adverse experiences (SAE) occurring in clinical trial subjects.

11.

Scope This SOP will apply to all clinical trials involving non-marketed products.

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111.

Procedures

A. Definitions All Company personnel will use the defmitions of "adverse experience" and "serious adverse experience" found in the protocol and FDA regulations. For clinically significant lab abnormalities, Company personnel will follow the protocol to determine if such abnormalities meet the definition of an SAE. B. Non-Serious Adverse Experiences (AEs) l. Through telephone contacts and visits to the study site, the Monitor will ensure that the Investigator andor Study Coordinator inquires about adverse experiences at each study visit and document the inquiry in the subject's medical chart.

During visits to the site, the Monitor will ensure that if an adverse experience is found, the Study Coordinator documents the following in the subject's chart and Case Report Form: a. Date and time (if applicable) the event started and ended; b. Description of the event; c. Severity of the event; d. Outcome of the event; e. Action taken; and f. Relationship to study drug. 3. The Monitor will confirm that the Investigator determined the relationship of the event to the study drug and that the determination is recorded in the subject's chart.

4. The Monitor will remind the Investigator to follow-up on all drug-related AEs until they are resolved or until it is determined to be a permanent condition. C. Serious Adverse Experiences (SAEs) l. Reporting Timeframes - At the Investigator's Meeting or Study Initiation Visit, the Monitor will confirm the study staff S understanding that the following people should be notified (in the timeframes listed below) as soon as the SAE is known: a. Principal Investigator and Study Coordinator - immediately b. Company - in the timeframe stated in the protocol, but no later than 48 hours. If the SAE is life-threatening or a death, Company will be notified within 24 hours. c. Institutional Review Board ( m ) - in the timeframe required by the m , but no later than 48 hours.

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2. Initial Report - During the Investigator's meeting andlor Study Initiation Visit, the Monitor will provide the Investigator and Study Coordinator with the Serious Adverse Experience Reporting Form (Attachment A). Unless instructed otherwise by the sponsor or protocol, the Monitor will instruct the site personnel to use this form to capture the data concerning SAEs. When helshe receives the initial report of a SAE, the Monitor will confirm that the Investigator andlor Study Coordinator collected as much of the following information as possible for reporting to Company and IRB: Subject number and initials; Date of birth; Subject demographics; Date of the report; Description of event, including relationship to study drug; Determination of seriousness; Possible cause of SAE other than trial medication; Relevant medical conditions; Concomitant medications; Principal Investigator's name; and Name and telephone number of the person reporting the event. If there are issues that need additional follow-up, the Monitor will contact the Investigator or Study Coordinator by telephone or e-mail. If this contact is accomplished by phone, the Monitor will document it in a Telephone Contact Report (Attachment B). 3. Follow-up reports - The Monitor will encourage the Study Coordinator to collect whatever additional information is necessary (e.g., discharge summary, autopsy reports) and to send these to Company and IRB, if required.

4. Alerting Company Medical Staff - The Monitor will alert the Project Leader, project medical officer, and SAE Department (if applicable) concerning the occurrence of the SAE and will provide them with the completed SAE form and all available supporting documentation. These staff members will determine if the SAE qualifies for an IND Safety Report. Narrative Summaries - One of Company's medical staff will write a narrative summary for each SAE in a study, using the format of FDA Forms 3500 and 3500A. The author of the narrative summary will ensure that the following information is included: a. A brief description of the study b. Age and sex of the subject c. Subject's date of entry into the study d. Subject's medical history e. Description of the SAE f. Treatment and outcome

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g. Action taken regarding the investigational drug (if any) h. Investigator's opinion of the relationship of the event to the study drug If an event has led to the discontinuation of the subject from the study, the investigator must provide a detailed explanation of hislher reasons for the discontinuation and should comment on abnormal laboratory findings and possible etiology. 6. Site documentation. During the site visit, the Monitor will ensure that the SAE is properly documented in the subject's chart and CRF, and that the appropriate forms are retained in the Regulatory Documents Binder. D. Safety Reports l . If Company's medical staff determines that the SAE requires an IND Safety Report, the Monitor will work with the Investigator and Study Coordinator to ensure that Company can provide the report to the FDA within the timeframe stated in the regulations. 2. 7-Day Telephone Reports - Any event considered serious, unexpected, possibly or probably related to the investigational drug, and fatal or life-threatening will be reported by the sponsor to the FDA no later than seven (7) calendar days after receipt of the information. This report will be followed, no later than fifteen (15) working days after receipt of the initial report, by a detailed written report. 15-Day Written Reports - Any event associated with the drug that is both serious and unexpected but not fatal or life-threatening will be reported in writing to the FDA within fifteen (15) calendar days of receipt of the initial report. The Monitors will ensure that any event requiring the submission of an IND Safety Report will be reported to all clinical investigators participating in any trials of the drug. During site visits, the Monitors will follow-up with the Investigators to ensure they have transmitted the information to their IRBs and that the appropriate documentation is retained on-site in the Regulatory Documents Binder.

IV.

References 21 CFR 312.32 - IND Safety Reports 2 1 CFR 3 12.44 - Termination 21 CFR 3 12.50 - General Responsibilities of Sponsors 21 CFR 312.56 - Review of Ongoing Investigations 21 CFR 3 12.64 - Investigator Reports ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRBIIEC

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ICH Guidelines for Good Clinical Practice (E6) section 4.1 1 - Safety Reporting ICH Guidelines for Good Clinical Practice (E6) section 5.16 - Safety Information ICH Guidelines for Good Clinical Practice (E6) section 5.17 - Adverse Drug Reaction Reporting

Attachments Attachment A - SAE Reporting Form Attachment B - Telephone Contact Report

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Company Standard Operating Procedure: MON-0 l l .O


Title: Managing Study-Specific Clinical Supplies

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose To describe the mechanisms by which study-specific supplies of clinical trial material are acquired, inventoried, packed and shipped to sites, returned from sites, and, when applicable, destroyed.

11.

Scope This SOP will apply to all clinical trials where Company is responsible for monitoring the investigational product accountability.

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111.

Procedures

This SOP will refer to "clinical trial material (CTM)." This term will include all drugs, devices, placebos, and active comparators used in the trial. A. Prior to Shipment At the Site Evaluation or Study Initiation Visit, the Monitor will record the name of the pharmacist who will be responsible for the study and the address the CTM will be shipped to. The Monitor will ensure that all Company-required study initiation documents are present before clinical trial materials are shipped to the study site. When the documentation is complete, the Monitor will request that the clinical trial material be shipped to the site and should learn what date the shipment is expected to arrive. The Monitor should call the Pharmacist at the site and alert himher concerning the expected arrival. The Monitor will explain to the Pharmacist that the CTM will be accompanied by the Investigational Drug Shipment Order (Attachment A) or other similar form used by Company or the sponsor and that the Pharmacist should: 1. Confirm the shipment contents against the document; 2. Sign the document; 3. Fax a copy of the signed document to the Monitor; and 4. Place the original, signed document in the study or pharmacy files. B. Soon after Shipment At the first visit to the site after the CTM has been shipped, the Monitor should confirm that the CTM has arrived intact, that the expected amounts were included in the shipment, and that the CTM is being stored correctly. C. During Site Visits On a regular basis, during Periodic Site Visits, the Monitor will: 1. Review the Investigator/Pharmacist's CTM inventory record; 2. Perform a physical count of the CTM; 3. Check CTM storage conditions; 4. Verify each subject's compliance with the dosing requirements; 5. Confirm that the CTM labels are being handled as specified in the protocol; 6. Request additional CTM shipments, if needed; 7. Document monitoring of CTM records in the site visit report; and 8. Identify the specific amounts needed for: a. Each dose form of active drug, b. Placebos, and c. Comparative actives.

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The Monitor will check the log used by either the Investigator or pharmacist to record the number of bottles or tablets dispensed and number of bottles or tablets returned. Accountability and documentation will be checked for: 1. CTM shipped to the pharmacy; 2. CTM dispensed to each subject; 3. CTM returned from each subject; and 4. CTM returned to Company. The Monitor will ensure that the subject's records also account for CTM containers not returned to the Investigator by the subject. When reviewing storage conditions, the Monitor will check: l. Storage temperatures; 2. Humidity; 3. Light exposure; and 4. Security. The Monitor will remind the Pharmacist and Study Coordinator that: 1. CTM that is returned by the subject should be stored according to the instructions given in the protocol; 2. Partially filled containers may not be combined; and 3. Empty containers may not be discarded. D. Final Disposition of CTM During the Study Termination Visit (or at a Periodic Site Visit, if necessary), the Monitor will perform a thorough accounting of the physical inventory and compare this to the site's documentation. The Monitor will follow the protocol instructions concerning final disposition of CTM (i.e., returning the CTM to the sponsor or other facility or on-site destruction).

1. Return of CTM If the protocol requires return of the CTM to the sponsor or other location, the Monitor will: a. Ensure that the original label is on each container of unused CTM and can be clearly read; b. Carefully count the number of partial, full, and empty containers; c. Return all unused CTM in its original container; d. Prepare the CTM Disposition Form (Attachment B); and e. Include a copy of the CTM Disposition Form with the shipment. The Monitor will complete the CTM Disposition Form at study termination or any time unused CTM is returned or destroyed on-site.

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2. On-Site Destruction If the protocol allows on-site destruction, the Monitor will obtain a copy of the pharmacy or hospital's SOP for destruction of study products. The Monitor will ensure that a copy of the SOP is in the study file and that all documents required by the SOP are also present (e.g., signed certification of destruction). The Monitor will not give approval for destruction before helshe has completed the final accountability check and has completed the CTM Disposition Form.

IV.

References 21 CFR 3 12.40 - General Requirements for Use of an Investigational Drug in a Clinical Investigation 2 1 CFR 3 12.44 - Termination 21 CFR 3 12.59 - Disposition of Unused Supply of Investigational Drug ICH Guidelines for Good Clinical Practice (E6) section 4.6 - Investigational Products ICH Guidelines for Good Clinical Practice (E6) section 5.12 - Information on Investigational Products ICH Guidelines for Good Clinical Practice (E6) section 5.14 - Supplying and Handling Investigational Product(s)

V.

Attachments Attachment A - Investigational Drug Shipment Order Attachment B - CTM Disposition Form

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Title: Conducting Study Termination Visits

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


Section

Pages

Initialsmate

Purpose The purpose of this SOP is to describe the activities performed during the final monitoring visit to an investigational site at the conclusion of a clinical trial. The purpose of the Study Termination Visit is to: Verify the proper disposition of the study drug; Ensure that study records and data are accurate and complete; Retrieve or file copies of completed study records and regulatory documents; and Ensure that regulatory requirements for records retention are understood by the study staff.

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11.


Scope

This SOP will apply to all Study Termination Visits conducted by Company.

111.

Procedures

A. General Study Termination Visits (also known as Study Close-Out Visits) may be conducted only by individuals at the level of MonitorIClinical Research Associate ( C M ) or above. The Study Termination visit is usually conducted shortly after the last subject finishes the study, but it may also be performed at the final periodic site visit (i.e., the visit at which all remaining CRFs are retrieved). Some activities that are listed in this Study Termination Visit SOP may be accomplished toward the end of the study during Periodic Site Visits. B. Prior to the Study Termination Visit

Prior to the Study Termination Visit, the Monitor will perform a comprehensive review of the activities at the site and will: l. Schedule a visit with Investigator(s) and study personnel; 2. Send a confirmation letter outlining the purpose of the visit and items for discussion; 3. Discuss requirements for the return or destruction of the study drug with appropriate Company personnel; 4. Review the trip report from the previous visit to follow-up on items that are outstanding or action items that need attention; 5. Review SAEs; 6. Review drop-outs; 7. Review outstanding data management issues; 8. Review outstanding laboratory issues; and 9. Gather any documents or materials necessary for the visit; 10. Request that all remaining documents be completed and made available for retrieval, including: a. Case Report Forms; b. Data Clarification Forms; c. Laboratory reports; d. Drug dispensing and return records; and e. Final Serious Adverse Event information. C. Conducting the Study Termination Visit l. Compliance with the Regulations and Protocol - To ensure adherence to the protocol, applicable FDA regulations, and Company requirements regarding the obligations of the Investigator, the Monitor will:

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a. Perform a detailed review of all documents and subject records generated from the conduct of the study; b. Resolve any issues remaining from the Periodic Site Visits; c. Ensure the progress of any subject requiring additional follow-up has achieved a satisfactory resolution; and d. Resolve any unresolved entry violation or have the Investigator include an explanatory comment on the "Investigator's Comment" page of the CRF.

2. Return all original, completed CRFs - To ensure that all data are retrieved, the Monitor will: a. Ensure a completed CRF remains on site for each subject enrolled in the study; b. Resolve all remaining data clarification issues and confirm that they have been signed by the appropriate person; c. Return any remaining CRFs andlor data clarifications to data Management; d. Inform the Study Coordinator that data queries generated by the Statistics Department may still be forthcoming; and e. Ensure study site personnel understand record retention requirements for the data. 3. Study files - To ensure completeness of the study records and documentation, the Monitor will inspect the Investigator's files. The Monitor will ensure: a. A signed copy of the informed consent form is present for each subject enrolled in the study. Any irregularities concerning the informed consent forms which have not been previously documented will be discussed in the Study Termination Visit Trip Report. b. The documents in the Regulatory Documents Binder are present and complete, including, but not limited to: i. The signed protocol and amendments, if applicable ii. Investigator's Brochure iii. Drug receipt and return documentation iv. Drug accountability records v. Signed Form FDA 1572 and revisions, if applicable vi. Curriculum vitae for the Investigator, Subinvestigators, and Study Coordinator vii. IRE3 approval letters for protocol, consent, advertisements viii. Correspondence to and from the IRB including IND Safety reports and progress reports ix. Correspondence between the Investigator and Company X. Copies of all SAE reporting forms

The Monitor will also: a. Remind the Investigator of hislher obligation to retain the study records in accordance with FDA record retention requirements; b. Explain that in the event the Investigator retires, relocates, or for any reason withdraws from the responsibility for maintaining records for the period of

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time required, custody of the records must be transferred to another person who will accept the responsibility for the records. Notice of such transfer should be given in writing to Company; and c. Remind the Investigator that the FDA should have access to all study records for inspection and copying.

4. Drug records - To ensure accurate records of drug receipt and disposition, the Monitor will: a. Re-check all records dealing with the shipment, receipt, and dispensing of all test articles. b. Check all records of dispensing and return of test articles between the Principal Investigator and the individual study subjects for accuracy, including: i. Subject identification numbers ii. Lot numbers ... m. Quantity dispensed and returned iv. Dates dispensed and returned v. Label numbers vi. Balance on hand c. Ensure that any discrepancies between the expected and actual inventory should be resolved or otherwise acknowledged in a letter of explanation from the Investigator. A copy of this letter should be placed in the site's study file. d. Ensure the appropriate forms are completed and signed. e. Ensure all unused investigational drugs are accounted for and returned or destroyed. If not accomplished by the pharmacist or Study Coordinator, the Monitor should package all unused or partially used study medication and arrange for return shipment by the appropriate form. If this occurs, the Monitor should notify the sponsor of the pending return of the study medication and should request confirmation from the sponsor when the drug arrives. f. Document the successful or unsuccessful reconciliation of study medication in the Study Termination Trip Report. 5. Final Study Status Report - The Monitor will ensure that the Investigator completes a final study status report and sends a copy to hislher IRB and Company. A copy of the Investigator's fmal study status report to the IRB should be obtained for inclusion in the Investigator 'S study file and a second copy should be sent to Company.

6. Final meeting with Investigator and Study Coordinator - The Monitor should make every effort to meet with the Investigator and appropriate study staff to discuss the findings of this visit. The Monitor should: a. Summarize the accomplishments for the entire study; b. Summarize any remaining problems or issues; c. Reach agreement on corrective actions that may be necessary; d. Remind the Investigator of hislher obligations concerning records retention;

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e. Review fmal payment policy with the Investigator as stated in the Investigator's Agreement; f. Review Company publication policy; and g. Remind the Investigator that helshe should notify Company as soon as possible if the site is alerted that an inspection by the FDA is impending. D. Follow-up to the Study Termination Visit Following the Study Termination Visit, the Monitor will document the visit by: 1. Completing a Study Termination Visit Trip Report (Attachment A). 2. Writing a follow-up letter to the Investigator. The letter should outline what was accomplished during the visit and should note any items that need additional attention. 3. Placing copies of the trip report and follow-up letters in the study file. The Monitor will also: 1. Ensure that Data Management has received the Case Report Forms andlor Data Clarification Forms. 2. Make arrangements for final payment to the Investigator. 3. Place final copies of logs and forms in the study file.

IV.

References 2 1 CFR 3 12.44 - Termination 2 1 CFR 3 12.57 - Recordkeeping and Retention 21 CFR 3 12.58 - Inspection of Sponsor Records and Reports 21 CFR 3 12.59 - Disposition of Unused Supply of Investigational Drug ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRBIIEC ICH Guidelines for Good Clinical Practice (E6) section 4.5 - Compliance with Protocol ICH Guidelines for Good Clinical Practice (E6) section 4.12 - Premature Termination of Suspension of a Trial ICH Guidelines for Good Clinical Practice (E6) section 5.5 - Trial Management, Data Handling, Record Keeping, and Independent Data Monitoring Committee ICH Guidelines for Good Clinical Practice (E6) section 5.14 - Supplying and Handling Investigational Product(s) ICH Guidelines for Good Clinical Practice (E6) section 5.18 - Monitoring

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ICH Guidelines for Good Clinical Practice (E6) section 5.22 - Clinical TrialIStudy Reports

V.

Attachments Attachment A - Study Termination Trip Report

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Title: Telephone Contact Reports

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initials/Date

Purpose The purpose of this SOP is to describe how telephone contacts with the study site personnel will be documented.

11.

Scope This SOP will apply to all telephone contacts of substance with study site personnel.

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111.

Procedure In addition to visits to the study site, the Monitor will keep informed about a site's progress concerning study activities with regular telephone contacts. The Monitor will document the content of these discussions for topics of substance. This includes, but is not limited to the following: l. Questions regarding eligibility (inclusion/exclusion criteria); 2. Significant problems, issues, or deviations from the protocol; 3. Resolution to any significant outstanding issue; 4. Any conversation pertaining to the site possibly or actually breaking the blind; 5. New information regarding changes in site personnel or facilities; 6. Discussions resulting in protocol-specific education, including process changes; 7. Any information regarding an Serious Adverse Experience (SAE); and 8. Specific requests for regulatory documents. The initial request for documents does not have to be documented in a Telephone Contact Report; however, if multiple requests for the same document(s) are made, a Telephone Contact Report should be written to document the repeated attempts. To document these discussions, the Monitor may write an e-mail to the recipient of the call or may complete a Telephone Contact Report (Attachment A). If an e-mail is written, it should be printed out and placed in the study file. The signed Telephone Contact Report should also be placed in the study file.

IV.

References ICH Guidelines for Good Clinical Practice (E6) section 5.18 - Monitoring

V.

Attachments Attachment A - Telephone Contact Report

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Company Standard Operating Procedure: SITE-001.0


Title: Preparation, Issue, and Revision of SOPs

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the procedures by which Standard Operating Procedures (SOPs) for Company are prepared, issued, and revised. To provide a tool for training new personnel in the procedures by which specific activities will be performed at Company. 11.

Scope

This SOP will apply to all SOPs for Company.

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111.

Procedures

A. The Department Head for each Department will determine which activities require SOPs and will assign the responsibility for writing the initial version.

B. All SOPs will include: l. Brief, informative title.

2. The SOP number on every page.

3. Effective date of the SOP on every page. 4. Dated approval signatures for the SOP'S Author, Department Head, and Quality Assurance (QA) representative. 5. Revision history.

6. Scope of the SOP (i.e., a statement which describes the personnel, projects, and situations to which the SOP applies). 7. Description of the procedure (i.e., a detailed description of all tasks to be conducted under the SOP, including when they are to be accomplished, where, and by whom). Each step in the procedure should be numbered. All new or unusual terms should be defined. If an abbreviation is associated with a term, it should be placed in parentheses following the word. If specific forms or equipment are to be used, they should be specified. Copies of the applicable forms should be attached to the SOP in the Attachments section.

8. References (i.e., citations of any applicable regulations, guidelines, publications, or other SOPs). Copies of the references do not need to be attached to the SOP. 9. Attachments (i.e., copies of any forms, checklists, charts, andlor tables that will be used in executing the SOP). The Attachments section should begin with a list of the attachments that are included in the SOP. Attachments should be identified by letter. C. Review and Approval of SOPs l. The Author will circulate the draft SOP to the Author's department members for review and comment.

2. The Department Head will perform the final review and edit of the SOP and will submit the final versions to QA for review.

3. After completing its final review, QA will reconcile all questions andlor suggested revisions with the Author prior to issue. 4. The final version of each SOP must be approved by the Department Head and a designated member of the QA Department before issuance. QA will obtain original signatures on the SOP cover sheet before releasing the final versions of an SOP.

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D. Distribution of SOPs

1. Each department will maintain an active SOP manual containing authorized copies of all current approved SOPs. 2. QA will retrieve or discard all distributed versions of the SOPs (i.e., not the archive copy) as new versions are implemented. E. Maintaining Original, Signed SOPs

1. QA will maintain a complete collection of current Company SOPs and will retain all obsolete, discontinued, or otherwise superseded SOPs in an SOP archive. F. Revision of SOPs

1. SOPs requiring permanent modifications will be revised by the Author or individual designated by the Department Head. Revised SOPs will be circulated for review and approval as described in Section II1.C. 2. QA will update the cover page of the revised SOP to show subsequent revisions of the SOP.

G. Periodic Review of SOPs 1. All SOPs will be reviewed on an annual basis to determine whether modifications are needed or if the SOP remains in use. Annual review of SOPs will be initiated by QA. QA will issue a reminder that SOPs are due for review. 2. If a procedure is no longer in use, the SOP will be considered inactive and stored by QA in the SOP archives.

3. Changes to the SOP will be made according to procedures described in Section II1.C. 4. Documentation of annual SOP review will be maintained in the SOP archives.

IV.

References None

V.

Attachments None

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Title: Training Study Site Clinical Research Staff

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose

To ensure all staff members involved in clinical research are properly trained concerning FDA regulations, ICH guidelines, and company policies and procedures. To describe the process for continuous employee training. To describe the procedures for maintaining documentation of initial training and continuing education. 11.

Scope

This SOP applies to all employees and independent contractors for Company.

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111.

Procedures

A. Employee training l. Initial Employee Training begins on the new employee's starting date and continues during a training period determined by the department manager andor selected department representative. Continuous Employee Training occurs throughout an employee's employment with Company.

B. Permanent Employees - For all new permanent employees (full-time and part-time), the following tasks should be completed: l. The Human Resources Department or Department Head will obtain the employee's signature on the Confidentiality Agreement and will place the signed Agreement in the employee's file.

2. The Human Resources Department or Department Head will give the Employee Handbook to the new employee on hisiher start date. This handbook covers the corporate history, policies and general philosophies of the company. 3. The Department Head will appoint a supervisor/mentor to be responsible for the new employee's training.

4. The Supervisor will ensure proper training for the new employee by providing copies of Company and Departmental SOPS and other educational materials to new employee. Based on the employee's prior experience, the Supervisor and employee will develop a training plan for the employee and a timeframe for completion. The training plan will be outlined on the Training Plan Form (Attachment A). 5. The new employee will read company-specific materials (such as the Employee Handbook, if available) and other educational materials that pertain to hisiher specific department and will acquire hands-on training for certain functions of the job.

6. Appropriate staff will sign off on the employee's Training Plan Form as the training is completed. When the Training Plan Form is complete, the employee will return the form to hisiher supervisor, who will file the document with the employee's training record. C. Temporary Employees - For all new temporary employees (full-time and part-time), the following tasks should be completed: l. The Human Resources Department or Department Head will obtain the employee's signature on the Confidentiality Agreement and will place the signed Agreement in the employee's file.

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2. The Department Head will appoint a supervisorlmentor to be responsible for the new temporary employee's training.

3. The Supervisor will ensure proper training for the new temporary employee by providing copies of appropriate Company and Departmental SOPs and other educational materials to the new temporary employee. Based on the employee's prior experience, the Supervisor and temporary employee will develop a training plan and a timeframe for completion. The training plan will be outlined on the Training Plan Form (Attachment A). 4. The new temporary employee will read the SOPs and other educational materials that pertain to hisher specific department and will acquire hands-on training for certain functions of the job. 5. Appropriate staff will sign off on the employee's Training Plan Form as the training is completed. When the Training Plan Form is complete, the temporary employee will return the form to hisher supervisor, who will file the document with the employee's training record. D. Continuous Training - All permanent and temporary employees are responsible for keeping current with the industry and technology. To accomplish this, an employee or the employee's supervisor may identify the necessary training. All training must be relevant to the employee's job. l. To request training, the employee will complete the Staff Training Request Form (Attachment B) and will submit it to the appropriate manager(s).

2. The manager will review the form; check the appropriate box (Yes or No) based on whether the training request is approved or denied; sign and date the form; and (if appropriate) give the signed Staff Training Request form to the HR Department for archiving.

3. If training was approved, the employee will complete any other forms (such as registrations or the Travel Request Form) and submit them to the appropriate department (e.g., Travel). 4. The supervisor and employee will review the employee's training record on at least an annual basis. E. Employee Training Verification - When an employee receives training, helshe should complete the Staff Training Verification Form (Attachment C) and submit it to the appropriate department to be filed with the employee's training records.

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F. Retention of Training Files. l. Training records for each employee will be cumulative and will be retained for each employee's tenure with Company.

2. Training records are subject to inspection by authorized regulatory agency investigators. G. Contents of Training Files minimum of the following:

-

Each employee's training record should contain a

1. Curriculum vitae (CV) or resume - updated annually and reflecting employment at Company. Because this is a cumulative document, only the current version of the CV should be retained in the file. 2. Current job description.

3. Completed Training Record Form (Attachment D) with appropriate documentation attached (i.e., completed and updated training form(s) and certificates of completion or diplomas received for training programs or other supplemental education). IV.

References ICH Guidelines for Good Clinical Practice (E6) section 4.1 - Investigator's Qualifications and Agreements

Attachments Attachment A - Training Plan Form Attachment B - Staff Training Request Form Attachment C - Staff Training Verification Form Attachment D - Training Record Form

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Title: Assessing Protocol Feasibility

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose To describe the procedures for assessing the feasibility of conducting a specific protocol at Company.

11.

Scope This SOP will apply to all clinical studies being considered for conduct at Company.

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Company SOP# SITE-003.0

111.


Procedures A. When a SponsorICRO contacts the study site about a potential study, the Principal Investigator will assess whether or not it would be feasible to conduct the protocol with the existing staff and facilities.

B. The Investigators, Study Coordinators, and other appropriate site personnel will review the protocol to ensure the following: 1. The study objectives are clear. 2. The study design is feasible. 3. The study will not expose subjects to undue risk. 4. The study is ethically acceptable. 5. The study is financially and logistically feasible. 6. There are a sufficient number of potential subjects available for the study. 7. There are sufficient staff to conduct the study. 8. The site has the appropriate equipment to conduct the study. C. When it is determined that the protocol meets the criteria above, the Investigator or Study Coordinator will notify the SponsorICRO of the site's willingness to participate in the study.

IV.

References 21 CFR 3 12.30 - Protocol Amendments

V.

Attachments None

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Title: Investigator Agreements with Sponsors or Contract Research Organizations

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose To describe the manner in which regulatory documents and other study-related documents are to be maintained at an investigational site.

11.

Scope This SOP will apply to all industry-sponsored trials conducted at Company.

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$11.

Procedures

A. Regardless of whether a contract originates with the Sponsor or Contract Research Organization (CRO) or with Company, the Investigator, Research Director, and Legal Department will review the contract to ensure it contains: l . Sponsor's name and address 2. CRO's name and address, if applicable 3. Protocol title and number 4. Indemnification language 5. Confidentiality agreement (if not in a separate document) 6. Estimated start and finish dates 7. Estimated number of subjects expected to enrol1 from this site 8. Budget information and payment schedule, including terms for delays and termination of the study 9. The definition of a "completed" subject (i.e., fully paid) 10. Description of reimbursement for study subjects who experience an adverse event or who are injured while participating in the study l l . A list of the responsibilities assigned to the study site 12. A statement of whose Standard Operating Procedures will be followed (i.e., the Sponsor, CRO, or site's) 13. Publication rights 14. Data ownership rights B. All Investigator Agreements must be approved by the Legal Department, a representative of Company, and the Investigator.

C. If Company is preparing the Agreement, two originals will be prepared and sent to the SponsorICRO for signature. A copy will be retained in the interim; this copy will be discarded when the signed original is returned. The SponsorICRO will sign both originals, will keep one, and will return the other to Company. D. A signed Investigator's Agreement must be in place before any subjects are enrolled in the study.

IV.

References

None

v.

Attachments

None

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Title: Organizational Chart for the Study Site

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the items to be included in an organizational chart describing the responsibilities and duties of the clinical investigator and staff. 11.

Scope

This SOP will apply to all studies conducted by Company.

SITE-OO5.O.doc

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111.

Procedures A. The Principal Investigator, Research Director or representative of the Human Resources Department will: 1. Identify the staff members who will be involved in the study. 2. Develop and maintain position descriptions for each staff member who will be involved in clinical trials. 3. Maintain a file of current curricula vitae for each staff member who will be involved in the study.

4. Maintain the training records for all staff involved in clinical trails, including the Principal Investigator and Subinvestigators. 5. Prepare a detailed list of the duties and responsibilities of each staff member as they relate to specific studies or have the Investigator complete (and sign) the Study Responsibilities Form. (Attachment A) If the sponsor or contract research organization (CRO) has a similar form, this may be substituted. If new individuals are assigned to the project or if the responsibilities have been shifted to another person (e.g., due to attrition or promotion), the Investigator or Research Director should promptly update the Study Responsibilities Form.

B. Make all these documents available to the clinical monitor and to any properly credentialed representative of FDA or other regulatory entity. IV.

References 21 CFR 312.30 - Protocol Amendments 21 CFR 3 12.40 - General Requirements for Use of an Investigational Drug in a Clinical Investigation 2 1 CFR 3 12.44 - Termination 2 1 CFR 3 12.55 - Informing Investigators 21 CFR 3 12.60 - General Responsibilities of Investigators 2 1 CFR 3 12.61 - Control of the Investigational Drug 21 CFR 3 12.66 - Assurance of IRB Review ICH Guidelines for Good Clinical Practice (E6) section 4.1 - Investigator's Qualifications and Agreements ICH Guidelines for Good Clinical Practice (E6) section 4.9 - Records and Reports

V.

Attachments Attachment A - Study Responsibilities Form

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Title: Interactions with the Institutional Review Board

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the process of interactions with the Institutional Review Board (IRB). To describe what documentation should be retained to reflect interaction with the IRB. 11.

Scope

This SOP will apply to all studies being conducted at Company, regardless of whether a local or commercial IRB is being used.

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111.

Procedures A. Study Initiation

1. At study start-up, the Study Coordinator will obtain the appropriate forms from the IRB, including the IRB membership roster or DHHS assurance number. 2. The Study Coordinator will complete the IRE3 study initiation forms and, where necessary, will obtain the Principal Investigator's signature. 3. The Study Coordinator or Principal Investigator will forward the signed forms and documents to the IRB. These include, but are not limited to:

a. The most recent version of the Investigator's Brochure b. The final version of the protocol c. The fmal draft of the informed consent document d. A copy of advertisements, patient diaries, recruitment scripts, or other patient information sheets e. Other IRB-specific paperwork

4. The Study Coordinator will place the IRB membership roster or DHHS assurance number and a copy of all documents submitted to the IRE3 in the Regulatory Documents Binder. 5. If necessary, the Study Coordinator and Principal Investigator will follow-up on issues identified by the IRB.

6. The Study Coordinator will place a copy of the following documents in the Regulatory Documents Binder: IRB approval of the protocol, informed consent, advertisements, patient diaries, recruitment scripts, or other patient information sheets. The Study Coordinator will ensure that these documents contain identifying information (dates or version numbers) to reflect specifically which version of the document was approved. B. Study Progress

1. Annual Review - At the interval noted in the IRB approval of the study, the Principal Investigator will provide the IRB with a progress report. This will be accomplished at least annually. 2. Protocol Amendments - If the SponsorICRO requests a protocol amendment, the Study Coordinator or Principal Investigator will send the amendment and revised informed consent, if necessary, to the IRB. Unless the amendment affects subject

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safety, no change in study procedures will be implemented until IRE3 approval of the amendment and revised consent is received. 3. Change in Investigator or Subinvestigator - If there is an addition or deletion of the Principal Investigator or Subinvestigator, the Study Coordinator will notifl the IRB within one month of the change. C. Serious Adverse Experiences 1. Using the forms provided by the SponsorICRO or IRB, the Principal Investigator will notifl the IRE3 of all Serious Adverse Experiences (SAEs) that occur at this site. 2. The Investigator will forward copies of all IND Safety Reports that occur at any site on the study to the IRE3 within 72 hours of becoming aware of the report. 3. The Study Coordinator will make copies of all correspondence concerning SAEs and IND Safety Reports that are submitted to the IRE3 and will place them in the Regulatory Documents Binder. Copies of the IRB acknowledgement of these events will also be placed in the Binder. D. Study Termination l . At study termination, the Principal Investigator will notify the IRB of the study's completion using the IRB Notification of Study Termination Form (Attachment A) or similar form provided by the IRB or SponsorIContract Research Organization (CRO). 2. The Study Coordinator will place a copy of the documents notifying the IRB of study termination and any acknowledgements received in the Regulatory Documents Binder. If requested, the Study Coordinator will also provide a copy of these documents to the SponsorICRO.

IV.

References 21 CFR 3 12.32 - IND Safety Reports 21 CFR 312.66 - Assurance of IRE3 Review ICH Guidelines for Good Clinical Practice (E6) section 3.1 - Responsibilities ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRBIIEC ICH Guidelines for Good Clinical Practice (E6) section 4.10 - Progress Reports

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ICH Guidelines for Good Clinical Practice (E6) section 4.1 1 - Safety Reporting ICH Guidelines for Good Clinical Practice (E6) section 4.12 - Premature Termination of Suspension of a Trial ICH Guidelines for Good Clinical Practice (E6) section 4.13 - Final Reports by Investigator / Institution ICH Guidelines for Good Clinical Practice (E6) section 5.21 - Premature Termination or Suspension of a Trial

V.

Attachments Attachment A - IRB Notification of Study Termination Form

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Title: Recruiting Study Patients

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe procedures by which an Investigator and hislher staff may identify qualified subjects for a clinical trial. 11.

Scope

This SOP will apply to all clinical studies being conducted at Company.

SITE-007.0.doc

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111.

Procedures A. The Investigator, Research Director, and Study Coordinator will work with the SponsorICRO to develop a subject recruitment plan and ensure the budget reflects these activities.

B. Using the eligibility criteria for the study, the Research Director or Study Coordinator will review records from the Investigator's patient population to determine the suitability and availability of candidates for the protocol. In addition, the Investigator and staff will solicit study subjects through personal contacts in the community. C. The Investigator will review all advertisements and the mode of its communication, to determine that the procedure for recruiting subjects affords adequate protection. Advertisements include, but are not limited to, posters, flyers, form letters, public service announcements on local radio or TV stations (including community bulletin boards), newspaper ads, internet ads, and various electronic media. D. The Investigator andlor Study Coordinator will ensure that the advertisements are limited to: l. The name and address of the clinical investigator

2. The purpose of the research

3. A summary of the eligibility criteria that will be used to admit subjects into the study 4. A description of the benefits to the subject for participation in the study 5. The location of the research

6. The name and phone number of person to contact for further information They will also ensure that the advertisement makes no claims:

1. That the drug or device is safe or effective for the purposes under investigation 2. That the drug or device is in any way equivalent or superior to any other drug or device

E. When a potential subject is contacted concerning a specific study, the following information will be entered on the Screening and Enrollment Log (Attachment A): 1. Subject initials 2. Date of birth 3. Date screened

4. If enrolled, subject number 5. If not enrolled, the reason

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Page SS


F. When a subject is enrolled in a study, the following information will be entered on the Master Subject Log (Attachment B): 1. Subject number 2. Subject name and address 3. Contact information (i.e., home and work phone numbers and e-mail address) 4. Date of birth 5. Social security number 6. Date enrolled

7. Dates completed and discontinued (may be entered later) This is an internal document for Company. SponsorICRO.

IV.

It will not be shared with the

References 21 CFR 50.20 - General Requirements for Informed Consent 21 CFR 50.25 - Elements of Informed Consent 21 CFR 56.107 - IRE3 Membership 21 CFR 56.109 - IRB Review of Research 2 1 CFR 56.11 l - Criteria for IRE3 Approval of Research 2 1 CFR 56.115 - IRB Records 21 CFR 3 12.60 - General Responsibilities of Investigators 21 CFR 3 12.62 - Investigator Record Keeping and Record Retention ICH Guidelines for Good Clinical Practice (E6) section 3.1 - Responsibilities ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRE3/IEC FDA Information Sheets, Screening Tests Prior to Study Enrollment, December 1999 FDA Information Sheet, Recruiting Study Subjects, December 1999 FDA Information Sheet, Payment to Research Subjects, December 1999

V.

Attachments Attachment A - Master Subject Log Attachment B - Screening and Enrollment Log

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Title: Study Initiation and Implementation

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the processes that ensure the proper conduct of clinical trials at Company. 11.

Scope

This SOP will apply to all clinical trials at Company.

SITE-0OS.O.doc

Page 9 1


111.

Procedures A. Study Initiation

1. After the SponsorICRO has agreed to place a study at Company, the Study Coordinator will begin to collect regulatory documents and SponsorICROrequired forms. Unless the SponsorICRO prefers another method, the Study Coordinator or designee will use the Study Initiation Documents Checklist to track these documents (Attachment A). 2. The Study Coordinator will work with: a. The Contracts Department to ensure a contract is executed b. The Investigator and Budgets Department to ensure a financially feasible budget is developed and approved c. The IRB to obtain the IRB membership list and forms needed for submissions d. The Investigator and Subinvestigators to obtain copies of their curriculum vitae, medical licenses, and signed financial disclosure forms e. The Clinical Laboratory to obtain a copy of the lab certification and reference ranges f. The pharmacist to ensure the test article was received intact and that the appropriate forms for dispensing and accountability are available g. The SponsorICRO to ensure that the Case Report Forms, Regulatory Documents Binder, and the Study Procedures Manual (if applicable) have been received.

3. The Investigator, Research Director, Study Coordinator, or delegate will provide a protocol-specific training session to all members of the staff who will be involved in the project. The Research Director, Study Coordinator, or delegate will ensure that attendance sheets and other training documentation are provided to the Human Resources Department, so that individuals' training records can be updated. The protocol-specific training session will include, but is not limited to, the following: a. Time and events schedule for the protocol b. Subject recruitment c. Obtaining informed consent d. Procedure for dispensing the test article e. Test article storage and records f. Protocol-specific forms and procedures

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g. Source documentation h. Adverse experience reporting i. Additional information from the Investigator's Meeting 4. The Investigator, Research Director, and Study Coordinator will: a. Develop a recruitment plan for subjects b. Identify a back-up to the primary Study Coordinator 5. The Investigator will complete and sign the Study Responsibilities Form before the Study Initiation Visit is completed. B. Study Conduct l. While the study is ongoing, the Investigator and Study Coordinator will ensure the following:

All study activities are accomplished according to the protocol and FDA regulations. Data collected in the Case Report Form (CRF) are supported by source documents. Protocol deviations are noted in the source documents and appropriate CRF. Subjects sign the correct version of the consent form before any study-related procedures are accomplished. Adverse experiences are reflected in the source documents and captured in the CRF. Serious Adverse Experiences (SAEs) are reported to the Sponsor/CRO and IRB. IND Safety Reports are provided to the IRl3. The test article is being dispensed correctly and drug accountability records are being maintained. 2. While the study is ongoing, the Study Coordinator will ensure the following: a. The SponsorICRO is informed of all significant study events and staff members are documenting critical interactions with the SponsorICRO. b. Biological samples are being obtained, handled, stored, and shipped appropriately. c. Study supplies remain adequate. d. Study records remain confidential. e. All equipment is calibrated regularly and maintenance records are being kept.

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IV.

References

21 CFR 54.6 - Record Keeping and Record Retention ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 4.4 - Communication with IRB/IEC ICH Guidelines for Good Clinical Practice (E6) section 4.5 - Compliance with Protocol ICH Guidelines for Good Clinical Practice (E6) section 4.7 - Randomization Procedures and Unblinding ICH Guidelines for Good Clinical Practice (E6) section 4.9 - Records and Reports

FDA Information Sheets, Sponsor-Investigator-IRB Interrelationship, 1110 1/99 V.

Attachments Attachment A - Study Initiation Documents Checklist

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Title: Reviewing and Obtaining Informed Consent

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the information required to be included in informed consent documents associated with clinical trials. To ensure that a subject's consent is sought in such a way that the subject or hislher representative has ample opportunity to consider whether to participate in the study and under conditions that minimize the possibility of coercion or undue influence.

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11.

Scope This SOP will apply to all informed consents and assents being used for the evaluation of drugs, devices, or biologics at Company.

111.

Procedures In this procedure, tasks designated to the Study Coordinator may also be accomplished by a Research Manager or Regulatory Documents Administrator. A. Reviewing the Draft Informed Consent

1. Before the study begins, the Study Coordinator will contact the Institutional Review Board (m)to learn if that institution has specific formatting or wording requirements for informed consent in addition to those listed in the regulations. 2. Before the consent form is submitted to the IRB, the Study Coordinator will review the document to ensure that it is in compliance with the IRE3's requirements and with FDA regulations and ICH guidelines. The Study Coordinator may use the Subject Information and Consent Form Checksheet (Attachment A) to accomplish this, but the completed form does not need to be placed in the Regulatory Documents Binder. B. Obtaining Informed Consent from Adults

1. The Investigator and Study Coordinator are responsible for ensuring that the informed consent and assent, if applicable, have been approved by the IRE3 before they are used in a study and that the correct version of the documents are used when the study is ongoing. 2. Only those designated by the Principal Investigator on the Study Responsibilities Form can obtain consent from a subject (Attachment B). 3. The Investigator, Subinvestigator, Study Coordinator, or other delegate will explain the study to the potential subject before any study procedures, including screening evaluations, are accomplished. The person who explains the study will allow enough time for the potential subject to read the consent form and will answer any questions that are raised. If the person who provides this explanation is not a physician, helshe will ensure that a physician is available to answer the potential subject's questions, if necessary.

4. The person obtaining the consent will ensure the following: a. All of the subject's questions were answered. b. The subject understands the study requirements. c. The subject signed the consent voluntarily and without any changes.

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d. The consent form is signed and dated by the subject and the person who obtained the consent, and a witness or legal guardian, if applicable. e. Each page is initialed by the subject. f. The subject is given a copy of the signed document. 5. The Study Coordinator will ensure that the original, signed copy of the consent is stored in the study file. C. Obtaining Informed Consent from Children 1. Only those designated by the Principal Investigator on the Study Responsibilities Form can obtain assent from a subject. 2. Whether one or both parents must sign the consent form for a child's participation in a study will be determined by the IRB. (This may also vary depending on state laws.)

3. Whether or not an assent form is required for the study will be determined by the IRB. If it is required and the minor is reasonably able to understand the study purpose and requirements, then in addition to having a consent form signed by the parent, the minor must sign the assent form. 4. The Investigator, Subinvestigator, Study Coordinator, or other delegate will explain the study in language appropriate to the child's age before any study procedures, including screening evaluations, will be accomplished. This explanation will include a discussion of the discomforts or inconveniences the child may experience if helshe agrees to participate. 5. The person who explains the study will ensure that a parent or advocate for the child is present during the explanation and observes the assent procedure.

6. The person who explains the study will allow enough time for the minor to read the consent form and will answer any questions that are raised. If the person who provides this explanation is not a physician, helshe will ensure that a physician is available to answer the potential subject's questions, if necessary. 7. The person obtaining the assent will ensure the following: a. All of the parent's and minor's questions were answered. b. The parent and minor understand the study requirements. c. The parent signed the consent voluntarily and without any changes. d. The minor signed the assent voluntarily and without any changes. e. The consent form was signed and dated by the parent and the person who obtained the consent.

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f. The assent form was signed and dated by the minor and the person who obtained the consent. g. Each page of the consent is initialed by the parent and each page of the assent is initialed by the minor. h. The parent and minor are given a copies of the signed consent and assent. 8. The Study Coordinator will ensure that the original, signed copies of the consent and assent are stored in the study file.

D. Revised Consent Forms l. When the Investigator andlor Study Coordinator receive updates to the Investigator's Brochure, IND Safety Reports, or protocol amendments, helshe should also review the informed consent to determine if it should be revised to reflect the new information.

2. No changes to the study procedures that are a result of the protocol amendment will be implemented until the IRB approval of the amendment is received.

3. If the consent form is changed as a result of a protocol amendment, the Study Coordinator will ensure that the revised consent is approved by the IRB. 4. The Investigator, Study Coordinator, or Investigator's delegate will explain the changes to the subject and will provide the subject with the revised consent form for review and signature. 5. If the subject decides to continue in the study and signs the consent form, the Study Coordinator or Investigator's delegate will provide the subject with a copy of the revised consent and will place the original in the study file. E. Non-English Speaking Subjects

1. If the patient population contains numerous non-English speaking people who may qualifl for the study, the Study Coordinator will ensure that the informed consent is translated into the second language and that the translated consent form is also approved by the IRB. 2. The Study Coordinator will file the certificate of translation in the Regulatory Documents Binder with the translated consent. 3. If possible, someone at the study site who speaks the same language as the potential subject will explain the study to the subject. This person will also be available at subsequent study visits to ensure that the subject's questions can be answered as the study progresses.

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4. When a non-English speaking person signs the consent, a witness not associated with the study will observe the consent process and will sign the consent form. The Study Coordinator or person obtaining the consent will document the process in the subject's medical record. F. Illiterate Subjects l . If the potential subject speaks English, but is unable to read, the subject may sign (or make his mark) on the consent form, but a witness not associated with the study will observe the consent process and will also sign the consent form. 2. The Study Coordinator or person obtaining the consent will document the process in the subject's medical record. G. If Incorrect Version Used If the Study Coordinator discovers that an outdated version of the consent form was used for a subject whose participation in the trial has not been completed, helshe will: 1. Contact the subject and have the subject sign the correct version. 2. Instruct the subject to use the actual date when signing and dating the correct version (i.e., do not back-date the consent form or use the same date as on the first, incorrect version). 3. Maintain both signed versions of the consent in the files. 4. Write an explanatory memo to the file so that future auditors will understand why two signed informed consent documents for the same subject are present in the file. If the Study Coordinator is unable to contact the subject, the explanatory memo should also document the dates and methods by which the attempts to reach the subject were made.

IV.

References

21 CFR 50.20 - General Requirements for Informed Consent 21 CFR 50.25 - Elements of Consent 21 CFR 50.27 - Documentation of Informed Consent 21 CFR 3 12.60 - General Responsibilities of Investigators 45 CFR 46.1 16 - General Requirements for Informed Consent 45 CFR 46.117 - Documentation of Informed Consent ICH Guidelines for Good Clinical Practice (E6) section 1.28 - Informed Consent ICH Guidelines for Good Clinical Practice (E6) section 1.37 - Legally Authorized Representative

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ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 4.8 - Informed Consent of Trial Subjects FDA Information Sheets - Continuing Review After Study Approval, January 200 1 FDA Information Sheets - Guide to Informed Consent, 1998 Update Belmont Report Declaration of Helsinki

V.

Attachments Attachment A - Subject Information and Consent Form Checksheet Attachment B - Study Responsibilities Form

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Company Standard Operating Procedure: SITE-0 10.0 Title: Adverse Experiences (AEs), Serious Adverse Experiences (SAEs), and IND Safety Reports

Effective Date: DDIMMMNY Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose

To describe the processes involved in the receipt, evaluation, and reporting of non-serious and Serious Adverse Experiences (SAEs) occurring in clinical trial subjects. 11.

Scope

This SOP will apply to all clinical trials involving non-marketed products.

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111.

Procedures A. Definitions All study staff will use the definitions of "adverse experience" and "serious adverse experience" found in the protocol and FDA regulations. For clinically significant lab abnormalities, the study staff will follow the Sponsor's instructions or the protocol to determine if such abnormalities meet the definition of an SAE. B. Non-Serious Adverse Experiences (AEs) l. The Investigator or Study Coordinator will inquire about adverse experiences at each study visit and will document the inquiry in the subject's medical chart. If an adverse experience is found, the Study Coordinator will document the following in the subject's chart and Case Report Form:

a. Date and time (if applicable) the event started and ended b. Description of the event c. Severity of the event d. Outcome of the event e. Action taken f. Relationship to study drug

2. The Investigator will determine the relationship of the event to the study drug and will record this in the subject's chart.

3. The Investigator will follow-up on all drug-related AEs until they are resolved or until it is determined to be a permanent condition. C. Serious Adverse Experiences (SAEs)

1. Reporting Timeframes - As soon as a study staff member becomes aware of a SAE, helshe will ensure that the following people are notified in the timeframes listed below: a. Principal Investigator and Study Coordinator - immediately. b. SponsorIContract Research Organization (CRO) - in the timeframe stated in the protocol, but no later than 48 hours. If the SAE is life-threatening or a death, the SponsorICRO will be notified within 24 hours. c. Institutional Review Board (m)- In the timeframe required by the IRB, but no later than 48 hours.

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2. Initial Report - The Study Coordinator should collect as much of the following information as possible for reporting to the SponsorICRO and IRB: a. Subject number and initials b. Date of birth c. Subject demographics d. Date of the report e. Description of event, including relationship to study drug f. Determination of seriousness g. Possible cause of SAE other than trial medication h. Relevant medical conditions i. Concomitant medications j . Principal Investigator's name k. Name and telephone number of the person reporting the event The Study Coordinator will use the SAE Reporting Forms provided by the SponsorICRO and will follow the SAE reporting instructions in the protocol.

3. Follow-up Reports - The Study Coordinator will collect whatever additional information is necessary (e.g., discharge summary, autopsy reports) and will send these to the SponsorICRO and IRB, if required. 4. Documentation - The Study Coordinator will ensure that the SAE is properly documented in the subject's chart and CRF, and that the appropriate forms are retained in the Regulatory Documents Binder. D. IND Safety Reports l. If the Sponsor determines that the SAE requires an IND Safety Report, the Investigator and Study Coordinator will work with the SponsorICRO to ensure that the Sponsor can provide the report to the FDA within the timeframe stated in the regulations. If requested by the SponsorICRO, the Investigator will draft a narrative summary of the event.

2. If the Investigator is informed that an WD Safety Report has been submitted to the FDA for a SAE that occurred at another site, the Investigator or Study Coordinator will make a copy of the report and forward it to the IRB. The original document will be retained in the Regulatory Documents Binder. E. Unblinding

1. In the event of an SAE, the Investigator will follow the procedure for unblinding the randomization code described in the protocol. Unless otherwise instructed in SITE-010.0.doc

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the protocol, the blind will remain intact until the Sponsor gives approval to break it.

IV.

References

21 CFR 312.32 - IND Safety Reports 2 1 CFR 3 12.44 - Termination 21 CFR 312.64 - Investigator Reports ICH Guidelines for Good Clinical Practice (E6) section 4.3 - Medical Care of Trial Subjects ICH Guidelines for Good Clinical Practice (E6) section 4.1 1 - Safety Reporting

V.

Attachments None

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Company Standard Operating Procedure: SITE-0 l l .O


Title: Drug Storage and Accountability

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initials/Date

Purpose To describe requirements for the receipt, storage, dispensing, and return or destruction of investigational material.

11.

Scope This Standard Operating Procedure (SOP) will apply to all studies being conducted at Company.

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111.

Procedures A. Receipt of Study Drug

1. Upon receipt of study drug, the pharmacist or other authorized individual (i.e., authorization is indicated on the Study Responsibilities Form) will unpack the drug and will check the drug inventory against the shipping form. Checking the inventory will include checking the subject numbers, the drug numbers, the lot numbers, and the number of items in each container. If the sponsor or Contract Research Organization (CRO) agrees, sealed containers do not need to be opened for pill counts at this time. a. If there is no shipping or inventory form included with the drug, the pharmacist or Study Coordinator should complete the Investigational Product Receipt Form (Attachment C). b. If the inventory matches the drug present, the pharmacist will sign the shipping receipt or Investigational Product Receipt Form, return a copy to the sponsor, and file the original in the study file. c. If any of the items in the shipment are damaged or if a discrepancy in the inventory is found, the pharmacist will notify the sponsor or CRO immediately. Helshe will indicate the damage or discrepancy on the shipping or Investigational Product Receipt Form and will file it in the study file. B. Drug Storage

1. The Study Coordinator or pharmacist will store the drug in a secure, limited access area under temperature and humidity described in the protocol, Investigator's Brochure, or package insert. C. Drug Dispensing

1. The investigator, pharmacist, or other authorized individual (i.e., as indicated on the Study Responsibilities Form) will dispense study drug to subjects who meet the eligibility criteria in accordance with the protocol. If required by the sponsor or CRO, even sealed bottles will be opened for pill counts before the bottle is dispensed. 2. The Pharmacist, Study Coordinator, or other authorized individual will ensure that each subject has a unique subject identification number and will complete and maintain the Drug Dispensing Log (Attachment A). 3. Depending on the design of the Case Report Form (CRF), the tear-off portion of the drug's label, containing the blinded information (if applicable), may be attached to the Drug Dispensing Log, to the CRF, or to another form provided by the sponsor or CRO.

4. The pharmacist or Study Coordinator will maintain a record of drug dispensed to and retrieved from each subject. To accomplish this, the pharmacist or Study SITE-0l 1.O.doc

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Coordinator will use the CRF, Study Subject Investigational Product Dispensing Record (Attachment D), or a similar form provided by the sponsor or CRO.

5. The Study Coordinator will explain to each subject the drug accountability needs for the study (e.g., the need for the subject to return unused, partially used, and empty packages). D. Study Drug Return

1. The study subject will return all drug and study-related supplies to authorized study personnel. 2. The Study Coordinator or pharmacist will count the returned drug and compare this with the amount of drug expected to have been used since the previous study visit. Helshe will update the appropriate sections of the Drug Dispensing Log, including an explanation of discrepancies, if applicable. The appropriate data will also be entered into the CRF, if appropriate. The Study Coordinator or pharmacist will keep the Drug Dispensing Log and the drug accountability CRF pages updated, regardless of when the monitor performs final accountability.

3. The Study Coordinator or pharmacist will store the returned drug in a secure area until it is verified by the monitor. 4. Whether the drug is returned to the sponsor or destroyed on-site will be determined by the instructions in the protocol.

E. Return of Study Drug to Sponsor 1. Depending on the protocol, the study drug will be returned to the sponsor at the end of the trial or at intervals specified by the sponsor. The Study Coordinator will follow the protocol or other instructions from the sponsor or CRO to decide whether empty containers must be returned. 2. The Study Coordinator will work with the Monitor to determine which carrier is preferred for the shipment, and if the Monitor needs to complete an independent drug accountability review before it is shipped back to the sponsor.

3. Unless instructed otherwise by the monitor, the Study Coordinator will: a. Perform an inventory of the drug supplies. b. Compare this with the study medication records. c. Document discrepancies in the CRF or in a memo to file. d. Complete the Drug RetudDestruction Form (Attachment B) or similar form provided by the sponsor or CRO. e. Include a copy of the signed and completed Drug Return Form with the drug shipment and place the original in the study file.

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F. On-Site Destruction of Study Drug If the sponsor or CRO requires on-site destruction of the study drug, the Study Coordinator should: 1. Obtain a copy of the site's SOP for study drug destruction/disposition, provide a copy to the monitor, and file a copy in the study file. 2. Obtain written confirmation from the monitor identifying the specific study drug that can be destroyed. 3. Obtain appropriate paperwork concerning destruction of the drug that is required in the site's SOPS(e.g., signed incineration records) and place a copy in the study file. 4. Provide the monitor with written proof of study drug destruction from the site. 5. Complete the Drug Return/Destruction Form or similar form provided by the sponsor or CRO. Provide a signed copy of the form to the monitor and retain the original in the study files. G. Study Drug Record Retention At study completion, the Study Coordinator will file all drug records with other regulatory documents in accordance with the record retention policy for the study. If drug records are maintained by an institution's pharmacy, they must be transferred to the Study Coordinator for final record retention (or copied, if the pharmacy's policy is to keep the records).

IV.

References 2 1 CFR 3 12.44 - Termination 21 CFR 3 12.59 - Disposition of Unused Supply of Investigational Drug 21 CFR 3 12.60 - General Responsibilities of Investigators 2 1 CFR 3 12.61 - Control of the Investigational Drug 21 CFR 312.69 - Handling of Controlled Substances ICH Guidelines for Good Clinical Practice (E6) section 4.6 - Investigational Products

v.

Attachments Attachment A - Investigational Product Receipt Form Attachment B - Drug Dispensing Log Attachment C - Drug RetudDestruction Form Attachment D - Study Subject Investigational Product Dispensing Record

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Title: Managing Biological Samples

Supersedes: NIA


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose To describe procedures for preparation, storage, and shipment of biological samples.

11.

Scope This SOP will apply to biological samples processed by Company, unless alternate directions are provided by the sponsor or Contract Research Organization (CRO).

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111.


Procedures A. Preparation of Samples Using a ball point pen, on each sample label, site personnel will record the patient initials, and the date and time when the sample was obtained. B. Storage of Samples Between shipments, site personnel will store both urine and plasma samples at a temperature of at least 20°C - or at a temperature designated by the sponsor. C. Shipment of Samples Site personnel will: l . Clear the shipping date and time with the person receiving the samples. 2. Ship samples in styrofoam boxes containing no less than 10 lb. of dry ice. Large boxes ( l cubic foot) can be filled 213 with samples and 113 with dry ice. If any additional packing material is used, it will not be placed between the samples and the dry ice. 3. Include a Biological Sample Inventory listing of all samples in the shipment (Attachment A).

4. Keep a photocopy of the Biological Sample Inventory page in the study file. 5. Only send shipments on Sunday through Thursday.

IV.

References 21 CFR 3 12.57 - Record Keeping and Retention

V.

Attachments Attachment A - Biological Samples Inventory

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Title: Interactions with the Sponsor or Contract Research Organization (CRO)

Supersedes: NIA


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose To describe the interactions with the Sponsor or Contract Research Organization (CRO) and Company. To ensure proper documentation of communications with the SponsorICRO concerning study activities.

11.

Scope This SOP will apply to all clinical trials conducted at Company.

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111.

Procedures A. Pre-Study Site Evaluation Visits

1. To prepare for a pre-study visit, all staff involved in the study will read the protocol and will prepare questions to clarifl protocol procedures, subject eligibility criteria, and other study-related issues. The Study Coordinator will also prepare requested documents and forms. 2. During the pre-study visit, the Investigator, Study Coordinator, or designee will lead a tour of the facility. The tour will include examination rooms, drug storage area and accountability records, clinical laboratory, monitors' work area, storage area for Case Report Forms (CRFs) and other regulatory documents. If specific equipment is needed for the study, this will also be shown along with the maintenance and calibration records for the equipment. 3. The Investigator, Research Director, or Study Coordinator will discuss why the site is equipped to perform the study. This discussion will include a description of the potential subjects available for the study and methods being considered for recruitment.

4. If requested, the Research Director or Study Coordinator will allow the SponsorICRO representative to review the training records of staff members who may be working on the study. B. Study Initiation Visit l. Prior to the Initiation Visit, the Study Coordinator or designee will prepare the study initiation documents including:

a. Signed FDA Form 1572 b. Curriculum vitae for the Investigator and Subinvestigators c. Curriculum vitae for the Study Coordinators, if requested d. Signed Financial Disclosure forms e. Medical licenses for the Investigator and Subinvestigators, if appropriate f. Completed budget worksheet

2. Prior to the Initiation Visit, the Investigator will review the Investigator's Brochure to ensure hislher understanding of previous experience with the drug, adverse experiences seen with the drug, and the rationale for the current study. 3. Prior to the Initiation Visit, the Investigator, Subinvestigators, Study Coordinator, Pharmacist, and other study staff will review the protocol and prepare questions concerning eligibility criteria, the time and events schedule, specific tests and

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equipment, dispensing procedures and accountability records, serious adverse experience (SAE) reporting procedures, and other study issues.

4. During the initiation visit, the Study Coordinator will: a. Provide copies of outstanding regulatory documents to the SponsorICRO representative. b. Confirm that lab supplies have arrived and have been inventoried. c. Meet with the SponsorICRO representative to learn how the Case Report Forms (CRFs) should be completed. d. Ensure the SponsorICRO representative signs the Monitoring Log (Attachment A).

5. During the initiation visit, the Study Coordinator and Pharmacist will discuss how the test article will be stored (e.g., security, temperature, humidity), dispensed to subjects, and returned to the Sponsor. a. The Pharmacist will confirm that the test article has arrived and has been inventoried. b. The Investigator and Study Coordinator will confirm the study requirements for AE and SAE reporting. c. The Investigator will complete and sign the Study Responsibilities Form. d. All study staff will meet with the SponsorICRO representative to review the protocol and regulatory obligations of site personnel. e. Each staff member will sign and initial the Study Site Personnel Signature Sheet. C. Periodic (Interim) Site Visit l. Prior to the Periodic (Interim) Site Visit, the Study Coordinator will:

a. Prepare a list of questions related to the study. b. Ensure all original, signed informed consent documents are available. c. Ensure all CRFs are complete and signed, if appropriate. d. Ensure the appropriate documents are filed in the Regulatory Documents Binder. e. Ensure specific CRFs and source documents that will be reviewed are available on the visit date. f. Set up appointments for the Monitor to meet with the pharmacist and Investigator.

2. Prior to the Periodic (Interim) Site Visit, the Investigator will: a. Prepare a list of questions related to the study. SITE-013.0.doc

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b. Review data collected and sign CRFs for completed subjects. 3. During the Periodic (Interim) Site Visit, the Study Coordinator will:

a. Interact with the Monitor to validate the data in the CRFs and answer questions about the data or regulatory documents. b. Follow-up on outstanding data clarifications. c. Attend a meeting with the Monitor and Investigator to learn about the Monitor's findings. d. Ensure that the Monitor signs the Monitoring Log. D. Close-Out Visits

1. Prior to the Close-Out Visit, the Study Coordinator will: a. Prepare a list of questions related to the study. b. Ensure all original, signed informed consent documents are available. c. Ensure all CRFs and data clarification forms are complete and signed. d. Ensure the appropriate documents are filed in the Regulatory Documents Binder. e. Ensure all source documents are organized for easy retrieval during future audits. f. Ensure all drug accountability records are complete and that unused test articles have been returned to the Sponsor or destroyed. g. Set up appointments for the Monitor to meet with the Investigator and study staff to discuss study issues and concerns. h. Ensure that the Monitor signs the Monitoring Log.

2. Prior to the Close-Out Visit, the Investigator will: a. Prepare a list of questions related to the study. b. Review data collected and sign CRFs for completed subjects. 3. During the Close-out Visit, the Study Coordinator will:

a. Interact with the Monitor to validate the data in the CRFs and answer questions about the data or regulatory documents. b. Follow-up on outstanding data clarifications. c. Attend a meeting with the Monitor, Investigator, and other study staff to discuss study issues and concerns. d. Ensure that the Monitor signs the Monitoring Log.

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E. Sponsor Contacts 1. Telephone Contacts - All study personnel will document critical conversations with the SponsorICRO, especially those pertaining to eligibility criteria, protocol deviations, and serious adverse experiences. Unless the SponsorICRO has requested that another method be used, the Telephone Contact Report form will document these discussions (Attachment B). The Study Coordinator or delegate will file the Telephone Contact Reports in the Regulatory Documents Binder. 2. Letters and Faxes - All study personnel will make copies of all correspondence written to the SponsorICRO. The Study Coordinator or delegate will file this correspondence in the Regulatory Documents Binder.

3. E-mails - All study personnel will print out copies of critical e-mails with the SponsorICRO. The Study Coordinator or delegate will file this correspondence in the Regulatory Documents Binder. 4. At a minimum, the SponsorICRO should be notified: a. When the first subject is enrolled in the study. b. When there is a question concerning a potential subject's eligibility. c. When recruitment issues occur. d. When a protocol violation occurs. e. When an SAE occurs.

IV.

References

None

V.

Attachments

Attachment A - Monitoring Log Attachment B - Telephone Contact Report

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Title: Study Files and Record Retention

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the manner in which regulatory documents and other study-related documents are to be maintained at an investigational site. To create a system of record retention that can facilitate document retrieval by Monitors, Quality Assurance Auditors, or FDA inspectors. 11.

Scope

This SOP will apply to all industry-sponsored trials conducted at Company.

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111.

Procedures

A. Regulatory Documents 1. Before the study initiation visit, the Study Coordinator will create, or be given by the SponsorIContract Research Organization (CRO), a ring binder in which all required regulatory documents, forms and correspondence will be kept. If the SponsorICRO requires additional forms, or documents, these will be maintained in addition to the documents listed in Attachment A. 2. The Study Coordinator will ensure that the appropriate documents are placed in the Regulatory Documents Binder on a regular basis. The Study Coordinator will make the Binder available for review by the Monitor at each site visit. B. Case Report Forms 1. The Study Coordinator or delegate will transcribe the appropriate data from the source documents into each subject's Case Report Form (CRF). 2. The Study Coordinator will ensure that the CRFs are stored in a secure location (i.e., Monitors from one SponsorICRO may not see CRFs from another study). CRFs for one study will be stored together. C. Informed Consents l. Where the signed informed consents are stored will vary based on instructions from the SponsorICRO. If the SponsorICRO has given no direction concerning storage of informed consents, they will be stored together in the Regulatory Documents Binder.

2. Signed informed consents for screen failures will be stored in the Regulatory Documents Binder. D. Source documents l. Original source documents will be kept in the subject's medical chart. A separate folder for each subject may be created if worksheets are used for the study. Where these are stored will be based on instructions from the SponsorICRO.

E. Contracts l. Contracts such as the Confidentiality Agreement, Investigator Agreement, and Publication Policy Agreement will be stored in the management offices of Company (i.e., not with the study records).

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F. Records Retention 1. All records pertaining to a clinical trial must be retained for: a. Two (2) years after the approval of an NDA or PLA for the compound or device being studied, or b. If an application is not approved, for two (2) years after development of the drug or device has been terminated and the FDA has been notified. After the two years has expired, no records will be destroyed without obtaining the SponsorICRO's written permission in advance. 2. If on-site storage of the study records is impractical, they will be placed in a secure off-site facility where they may be readily accessed in the event of an audit. Alternatively, with approval of Company, the records may be stored at the SponsorICRO headquarters. 3. If the Principal Investigator leaves Company, helshe will provide the SponsorICRO with written notice of the location of the study records and the name and phone number of an alternate contact in the event of an audit.

IV.

References

2 1 CFR 3 12.55 - Informing Investigators 21 CFR 3 12.57 - Record Keeping and Record Retention 21 CFR 3 12.58 - Inspection of Sponsor Records and Reports 21 CFR 3 12.62 - Investigator Record Keeping and Record Retention 21 CFR 312.64 - Investigator Reports 21 CFR 54.4 - Certification and Disclosure Requirements 21 CFR 54.6 - Record Keeping and Record Retention 21 CFR 3 12.68 - Inspection of Investigator's Records and Reports 21 CFR 56.107 - IRB Membership 21 CFR 56.115 - IRB Records ICH Guidelines for Good Clinical Practice (E6) section 4.4 IRBIIEC

-

Communication with

ICH Guidelines for Good Clinical Practice (E6) section 4.9 - Records and Reports ICH Guidelines for Good Clinical Practice (E6) section 5.22 Reports

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-

Clinical TrialIStudy

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V.


Attachments None

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Company Standard Operating Procedure: IRB-00 1.0


Title: Institutional Review Board Responsibilities

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe standards for the protection of the rights and welfare of human subjects through initial and continuing review of research studies. 11.

Scope

This SOP will apply to all IRB meetings for Company.

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Company Effective Date: DD/MMMNY

111.

Procedures A. Authority and Responsibility The Company IRE3 has the authority and responsibility to: l. Review research activities and to approve, disapprove, or ask for modifications of the research.

2. Require progress reports from Investigators so that the board can conduct continuing review of the research at intervals of not less than one year.

3. Determine which studies need review more often than annually. 4. Require Investigators to report changes to the protocol to the IRB prior to implementation, except where necessary to eliminate immediate hazard to subjects.

5. Suspend, restrict, or terminate the approval of previously approved research that is not being conducted according to the IRE3 requirements or Federal Regulations. 6. Perform audits of study sites to evaluate the consent process and compliance with the protocol and regulations. Every IRB member will be expected to understand and promote the ethical principles outlined in The Belmont Report and to have a thorough knowledge of the Federal Regulations (45 CFR 46 and 21 CFR 50 and 56), International Commission on Harmonization guidelines (ICH), and Company policies and procedures governing research involving human subjects.

B. Investigator Non-Compliance If an Investigator has failed to comply with the protocol or IRB requirements, including continuing review, the Investigator will be notified in writing about the board's concerns. If there is inadequate or no response from the Investigator, at the next meeting, the board will decide if: 1. Approval of the study should be suspended or withdrawn (i.e., no additional subjects will be enrolled in the study); 2. The IRB should perform a site audit; or

3. Other corrective action is needed. This discussion, decision, and timeline for correction will be included in the meeting minutes. If non-compliance is not corrected in the timeframe required, the board will close the study and will report the Investigator to Company management and to the appropriate regulatory authority, as required by regulation.

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Company


If non-compliance is resolved, the IRB Chairperson will document the situation and will place the documentation in the study file.

IV.

References

21 CFR 56.108 - IRB Function and Operations IRE3 and Clinical Investigator Information Sheets

ICH E6 3.1 - Responsibilities

v.

Attachments

None

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Company Standard Operating Procedure: IRB-002.0


Title: IRB Membership and Training

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose To describe the processes and procedures for forming and managing a duly-constituted Institutional Review Board within Company.

11.

Scope This SOP will apply to all research activity involving human subjects, whether federally funded or not, and without regard to the source of any supporting funds.

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111.

Procedures

A. Purpose of the Board The IRE3 assists researchers in the protection of the rights and welfare of human subjects by conducting initial and continuing review of all research activities involving human subjects at Company. The IRE3 shall meet or exceed the requirements of federal policy set forth in 45 CFR 46,21 CFR 50, and 21 CFR 56 and ICH Guidelines 3.0. B. Appointment of Board Members Primary and alternate IRE3 members may be recruited from Company staff and from the local community by either recommendation by current IRB members, administrative staff, institutional management, or by public recruitment efforts. Each prospective member must submit a curriculum vitae to the IRE3 Chairman and administrative staff for review. Appropriate candidates must undergo a qualification interview with the IRE3 Chairman, board members, andlor administrative staff. During the interview, the candidate will be informed of hislher responsibilities, the responsibilities of the Board as a whole, and the time requirements for the position. Candidates will be required to attend at least one IEU3 meeting as an observer prior to becoming a board member. The candidate will sign a confidentiality agreement prior to attending the meeting as an observer.

In appointing members to the IEU3, the IRB Chairman, board members, and administrative staff will consider the diversity of the members' backgrounds, including race, gender, cultural backgrounds, and sensitivity to community attitudes and the candidate's professional competence necessary to review the research. Consideration will also be given to the inclusion of one or more individuals who are knowledgeable about vulnerable populations, such as children, prisoners, handicapped, or mentally disabled persons. At the next duly constituted IRB meeting, confirmation or denial of the candidate to membership on the Board will be determined and documentation of the decision will be recorded in the meeting minutes. C. Composition of the Board The IRE3 will be composed of no fewer than five (5) members sufficiently qualified to carry out the Board's purpose. The Board may not consist entirely of members of a single profession and will include at least one member qualified in a scientific discipline (e.g., physicians and Ph.D. level physical and biological scientists, nurses, pharmacists, or other biomedical health professionals) and one member with an unambiguously nonscientific background (e.g., clergy and ethicists).

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The non-scientific member should not be vulnerable to intimidation by the professionals on the Board and hislher services should be fully utilized by the IRB. The IRE3 will include at least one member who is not otherwise affiliated with Company and who is not part of the immediate family of a person who is affiliated with Company. Every non-discriminatory effort will be made to ensure the IRB is not composed entirely of men or women, so long as no selection is made to the IRB on the basis of gender alone. When research involving a vulnerable population is being reviewed, at least one member of the Board should have the appropriate background and experience in working with these subjects. One individual can satisfy more than one of the membership requirements for the board. The IRE3 may invite individuals with competence in special areas to assist in the review of issues that require expertise beyond or in addition to that of the IRB. These individuals may contribute to the discussion, but may not vote on the research. D. IRE3 Chairperson The IRE3 Chairperson will: Conduct meetings in an efficient and fair manner, and according to standard parliamentary procedures. Follow the agenda created for each meeting. Set a tone of openness to encourage dialogue in the meeting. Respect the diverse backgrounds, perspectives, and sources of expertise of all IRB members, especially for the contributions of the non-scientists, and the ability to foster such respect among the IRB members. Uphold IRBjudgments that may not always be popular with Investigators. Invest adequate time, interest, and commitment to provide guidance and expertise to IRB members and Investigators. Assure that the Board receives appropriate and sufficient administrative support, meeting space, and other necessary resources to function efficiently, and will report deficiencies in this support to Company management for correction.

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E. IRB Secretary The IRE3 Secretary will be appointed by the IRB Chairman. Helshe will prepare and distribute the meeting agenda and will record the IRB meeting minutes. The IRB Secretary will maintain the following records:

1. IRB membership roster 2. Curriculum vitae for each board member 3. Training records for each IRB member

4. Documentation of training sessions attended by board members, including signed attendance sheets and a copy of the handouts and slides 5. Documentation of resignationltermination 6. IRB meeting minutes

7. Correspondence with the Investigators 8. Materials provided to board members for review

9. Documentation of expedited review and approval

F. Alternate Board Members Ad hoc substitutes are not permissible as members of the IRB. Alternate board members will be appointed and will function in the same manner as primary board members. The IRB roster will identify the primary member(s) for whom each alternate member may substitute. To ensure an appropriate quorum is maintained, the alternate's qualifications will be comparable to the primary member being replaced. The IRE3 minutes will document when an alternate member replaces a primary member. When alternates substitute for a primary member, the alternate member will receive and review the same material that the primary members receive.

G. Primary Reviewer The Primary Reviewer will conduct an in-depth review of the research proposal and will present the protocol, informed consent, and other study-related materials to the full Board at the convened meeting. H. Membership Roster

A current membership roster will be maintained by the IRB administrative staff. This list should include the following: l. Name

2. Degrees

3. Representative capacity

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4. Relationship between the member and Company (e.g., full-time employee, stockholder, unpaid consultant) 5. Indication of experiences (such as board certifications and licenses) sufficient to describe each member's anticipated contributions to the deliberations. The IRB membership Roster Form template is included in Attachment A. Any changes in the IRB membership will be documented and reported to each Investigator conducting research under the IRE3's review and to federal or state agencies which require copies of membership rosters as part of generallspecific assurance reviews. I. Conflict of Interest

A board member will be considered to have a conflict of interest when: l. Helshe is the Investigator, Subinvestigator, or Study Coordinator for a study. 2. Helshe has a significant financial interest in the research activity under consideration or the results of the study. 3. Helshe has a conflict of loyalty (e.g., promoting the work of subordinates or supervisors). 4. The Board's decision may have an impact on the board member's research. The IRB will not have any member participate in the vote for the initial or continuing review of a project for which helshe has a conflict of interest; however, to provide information requested by the IRB, the individual may contribute to the discussion. Meeting minutes should reflect that the board member who had a conflict of interest abstained from the vote.

J. Term of Membership The Chairman will be appointed for a term of one (1) year and may not serve more than two (2) consecutive terms. The minutes of all meetings of the Board will be signed by the Chairman after review and approval by the members. Members will be appointed for a term of two (2) years. Terms will be staggered so that no more than three (3) members will be appointed in any one year. No member may serve more than two (2) consecutive terms. In the event of the resignation or death of a member, the Chairman will appoint a member to serve the unexpired portion of the resigningldeceased member's term. IRB members who decide to resign must provide the IRB Chairperson with written notification of their proposed resignation date at least 30 calendar days prior to the next scheduled meeting. IRB members may be terminated for non-attendance (i.e., misses more than three regularly scheduled meetings in one year) or non-participation (i.e., fails to perform duties as assigned or leaves meetings prior to voting), or for behavior unbefitting and possibly detrimental to the Board. In this case, the IRE3

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Chairperson will provide the member with a letter of termination. Documentation of the termination will be recorded in the meeting minutes of the next duly constituted IRB meeting and the IRB Membership Roster will be revised. K. Training IRB Members Before attending a meeting as a voting member, each new IRB member will be required to attend a meeting as an observer. Documentation of the candidate's attendance will be recorded in the meeting minutes. The IRB administrative staff will provide each new board member with the following materials: 1. 45CFR46 2. 21 CFR50 3. 21 CFR 56 4. ICH Guidelines for Good Clinical Practices (E6) 5. Declaration of Helsinki 6. Belmont Report 7. Company IRB's Standard Operating Procedures Signed documentation of the receipt of the training materials should be obtained for each new member and filed with the new member's curriculum vitae as part of the training record. The IRB Chair and administrative staff will arrange for special training or in-service sessions for all IRB members and alternates at least once each year. Documentation of training materials will be maintained by the IRB Secretary.

IV.

References 45 CFR 46.107 - IRB Membership 21 CFR 56.107 - Institutional Review Boards ICH Guidelines for Good Clinical Practice E6 section 3.2 - Composition, Functions, and Operations ICH Guidelines for Good Clinical Practice E6 section 3.3 - Procedures FDA Information Sheets for Institutional Review Boards and Clinical Investigators

V.

Attachments Attachment A - IRB Membership Roster Template

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Title: Institutional Review Board Meetings

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose To describe the processes and procedures for the conduct of IRB meetings.

11.

Scope This SOP will apply to all IRB meetings for Company.

IRB-003.0.doc

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111.

Procedures

A. Regular Meetings The IRB will hold regular meetings at a time and place to be determined by the IRE3 Secretary. Written notice of the regular meeting will be given to each member no later than seven (7) days before the meeting. B. Special Meetings The Chairperson may call a special meeting of the IRE3 when helshe determines it to be necessary. Written notice of special meetings, including the time, place, and purpose, will be given to each member no later than one day before the special meeting. C. Quorum A quorum will be necessary for the conduct of a meeting. The presence of one more than 50% of the membership will constitute a quorum when considering attendance, except that the majority should include at least one member whose primary concern is the non-scientific area. Advisory members and members with a conflict of interest may not be counted as present for the purpose of determining a quorum. Should the quorum fail during the meeting (e.g., those with conflicts being excused, early departures, loss of the non-scientist), no further votes will be held until the quorum is restored. Any action taken without a quorum present will be considered invalid. D. Preparation for IRB Meetings For the initial review of research, Investigators will submit a study packet to the IRB Secretary no fewer than fourteen (14) days before the next scheduled meeting. Each study packet will include the following: l. A completed Initial Submission Form (Attachment A)

2. The most recent version of the protocol

3. The current Investigator's Brochure or Package Insert 4. Draft Informed Consent Form

5. Advertisements (if applicable) andlor study recruitment materials If this is the first time an investigator has submitted a study to the IRB, helshe should also include a copy of hislher curriculum vitae and medical license. Case Report Forms may be omitted from the study packet unless specifically requested by the Board.

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The IRE3 Secretary will transmit the appropriate materials to each of the board members at least three days before the scheduled meeting to allow thorough review of each proposal. The Chairperson will select at least one primary reviewer for each proposal. Primary reviewers will complete a Reviewer's Checklist (Attachment B), but all board members are required to review the materials for all studies. Investigator requests for amendments, re-approval, cancellation or certification of the completion of a study will be submitted to the Board in the same manner. E. Conduct of the Meetings The Chairperson is responsible for leading the meeting, conducting business so that each proposal is fairly and completely reviewed, seeing that the Board reaches a decision on the disposition of each proposal, and communicating these decisions to the individuals who submitted the proposals. At the board meeting, each proposal will be presented by a Primary Reviewer in sufficient detail to assure adequate consideration. The presentation must include, but is not limited to, the following points:

1. Risks to the subjects are minimized. 2. Risks to the subjects are reasonable in relationship to the anticipated benefits. 3. Subject selection is equitable.

4. Informed consent will be obtained from the subject or legally authorized representative. 5. The proposal ensures subject safety through the monitoring of the data. 6. The proposal ensures subject privacy and confidentiality of the data, if applicable.

The presentation will be followed by discussion among the board members until a consensus can be reached. Clinical Investigators or ancillary staff may attend board meetings to answer questions and to provide additional information on the proposal, but they should be absent from the room during the discussion and voting phases of the meeting. Meeting minutes will reflect whether or not this requirement has been met. The Board may also request a reviewlopinion from one or more qualified outside experts; however, these experts will not be allowed to vote on the proposal.

A member who is unable to be present at the convened meeting may participate by video-conference or conference telephone call; however, the member must have received a copy of the documents to be reviewed at the meeting. Such members may vote and will be counted as part of the quorum. Opinions of absent members that are transmitted by mail, telephone, fax, or e-mail may be considered by the attending IRE3 members but may not be counted as votes or the quorum for convened meetings.

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F. Voting Any board member with a conflicting interest in a proposal will abstain from deliberations and voting on that proposal, except to provide information as requested by the Board. Such abstentions will be recorded in the minutes. By majority vote of the members present, the Board may reach one of the following decisions regarding each proposal: l. Unconditional approval - approved as presented.

2. Conditional approval - approved, subject to specific modifications, such as changes to the consent form. 3. Disapproved - the board has decided that they cannot ethically approve the research.

4. Deferred - no decision can be made yet, pending evaluation of additional requested information. If the Board approves a proposal subject to modifications, it must specify, by majority vote of the members present, whether the changes will require full Board approval or may be approved by the Chairperson or primary reviewer on behalf of the Board. A summary of the Board's discussions and a record of its decisions, including but not limited to the final disposition of each proposal, will be made by the IRB Secretary. The meeting minutes will reflect the number of "Yes," "No," and "Abstain" votes. Copies of the meeting minutes will be submitted to the members of the Board for review and approval at the next meeting. Minutes of the meetings will be signed by the Chairperson following review and approval by the individual members of the Board. G. Notification to the Investigator

The Board will provide the Investigator with written notification of its decision to approve, disapprove, defer, or modify the research proposal. (See Attachment C for the IRB Review Results Form.) If a proposal is disapproved, the reasons for such disapproval will be documented. The Investigator will also be notified of the duration of the Board's approval, which will never exceed one year. The decisions of the Board will be included in the files maintained by the Secretary. H. Confidentiality of the Review Process During the initial or continuing review of the research, material provided to IEU3 members will be considered confidential and the board members will assure the confidentiality of the information provided to them.

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Company Effective Date: DD-

IV. References 2 1 CFR 56.108 - IRB Function and Operations 2 1 CFR 56.1 15 - IRE3 Records 45 CFR 46.108 - IRB Function and Operations 45 CFR 46.109 - IlU3 Review of Research 45 CFR 46.1 15 - IRB Records ICH Guidelines for Good Clinical Practice (E6) 3.2 - Composition, Functions, and Operations ICH Guidelines for Good Clinical Practice (E6) 3.3 - Procedures

V. Attachments Attachment A - Initial Submission Form Attachment B - Reviewer's Checklist Attachment C - IRE3 Review Results Form

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Title: IRB Record Keeping

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the procedures for documenting the IRB's activities. 11.

Scope

This SOP will apply to all research activity involving human subjects, whether federally funded or not, and without regard to the source of any supporting funds.

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Company SOP# IRB-004.0

111.

Effective Date: DD/MMMNY

Procedures

A. Responsibility The IRE3 files will be maintained by the IRE3 Secretary at . B. Identification IRE3 records will include the following:

IEU3 members' records a. Curriculum vitae for each board member b. Training records for each IRB member c. Documentation of training sessions attended by board members, including signed attendance sheets and a copy of the handouts and slides d. Documentation of resignationltermination IRE3 membership roster IRB meeting minutes Materials provided to board members for review (including, but not limited to, investigator brochures, protocols, amendments, consent forms, IND Safety Reports, progress reports) Correspondence with the Investigators Documentation of expedited review and approval Statements of new findings provided to subjects Standard Operating Procedures C. Retention and Accessibility All IEU3 records will be retained for at least three (3) years after the completion of the research. IRB records will be made available for inspection and copying by authorized representatives of DHHS, FDA, and other regulatory authorities after receiving the request in writing.

D. IRB Minutes 1. The minutes of the IRE3 meetings will be in sufficient detail to show the following for each research protocol: a. Attendance at the meeting b. A summary of the discussion and the resolution of controversial issues c. Actions taken by the board

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d. Vote on the actions e. The basis for requiring changes or disapproving the research f. IRE3's determination of risk g. IRB review date (date of progress report) 2. The format of the IRB Meeting minutes will follow that outlined in Attachment A. 3. Each Primary Reviewer will verify the accuracy of that portion of the minutes for the agenda items helshe presented.

IV.

References 21 CFR 56.108 - IRB Function and Operations 21 CFR 56.115 - IRE3 Records 46 CFR 45.1 15 - IRB Records ICH Guidelines for Good Clinical Practice (E6) section 3.4 - Records ICH Guidelines for Good Clinical Practice (E6) section 4.13 - Final Reports by Investigators/ Institutions

V.

Attachments Attachment A - IRB Meeting Minutes Template

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Title: IRB Review of Research

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose To describe the processes for the initial and continuing review of research projects.

11.

Scope This Standard Operating Procedure (SOP) will apply to all research activity conducted at Company that involves human subjects.

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111.

Procedures

A. Submission for Initial Review For the initial review of research, Investigators will submit a study packet to the IRE3 Secretary no fewer than fourteen (14) days before the next scheduled meeting. Each study packet will include the following: 1. A completed Initial Submission Form (Attachment A) 2. The most recent version of the protocol 3. The current Investigator's Brochure or Package Insert 4. A draft Informed Consent Form 5. Advertisements (if applicable) andlor study recruitment materials If this is the first time an investigator has submitted a study to the IRB, helshe should also include a copy of hislher curriculum vitae and medical license. Case Report Forms may be omitted from the study packet unless specifically requested by the Board. B. IRB Initial Review Procedure The IRB Secretary will transmit the appropriate materials to each of the board members at least three days before the scheduled meeting to allow thorough review of each proposal. The Chairperson will select at least one primary reviewer for each proposal. Primary reviewers will complete a Reviewer's Checklist (Attachment B), but all Board members are required to review the materials for all studies. The Primary Reviewer will present the research proposal at a regular or special meeting of the IRB. The Investigator may be invited to attend a portion of the meeting, so that board members have the opportunity to question himher about the research proposal. After the research has been presented, the IRE3 Chairperson will call for a discussion of the protocol, consent form, advertisements, and other subject materials. The Primary Reviewer will make a motion concerning the protocol, consent form, and advertisements (i.e., approval, conditional approval, deferred, denied) and will note when the next progress report will be expected. The motion will be seconded and the IRB will vote to approve or disapprove the research proposal. No member of the Board with a conflict of interest will be allowed to vote on the proposal. If the Board approves a proposal subject to modifications, it must specify, by majority vote of the members present, whether the changes will require full Board approval or may be approved by the Chairperson or Primary Reviewer on behalf of the Board. A summary of the Board's discussions and a record of its decisions, including but not limited to the final disposition of each proposal, will be made by the IRB Secretary.

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C. Criteria for IRB Approval of Research The IRB may approve research only after it has determined that all of the following requirements are satisfied: l. Risks to subjects are minimized by using procedures that are consistent with sound research design, and that do not unnecessarily expose subjects to risk. Whenever appropriate, researchers should employ procedures that are being performed on subjects for diagnostic or treatment purposes.

2. Risks to subjects are reasonable relative to: a. anticipated benefits, if any, to subjects, and b. the importance of the knowledge that may reasonably be expected to result. 3. The selection of subjects is equitable. In making this assessment the IRE3 must take into account the purposes of the research and the setting in which it will be conducted. The IRE3 must be particularly attentive to the special problems that may arise when research involves vulnerable populations, such as children, pregnant women, prisoners, mentally disabled persons, or economically or educationally disadvantaged persons. If any of the subjects is likely to be susceptible to undue influence or coercion, the IRB may require additional safeguards in the study to protect such subjects.

4. Informed consent will be sought from each prospective subject, or the subject's legally authorized representative, generally by means of a written consent document. The IRB will carefully review these documents to assure that they contain the required elements of informed consent and that they are understandable to a lay person. 5. The research plan makes adequate provisions for ensuring the safety of subjects.

6. There are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. 7. The investigator is appropriately qualified and has the facilities to ensure all aspects of the research will be conducted with regard for the safety and well-being of the subjects. When some or all of the subjects are likely to be vulnerable to coercion, the IRB should add additional safeguards in the review of the research to ensure the rights and welfare of these subjects are protected. D. Notification to the Investigator

The Board will provide the Investigator with written notification of its decision to approve, disapprove, defer, or modify the research proposal (Attachment C - IRB Review Results Form). If a proposal is disapproved, the reasons for such disapproval will be documented. The Investigator will also be notified of the duration of the Board's approval, which will never exceed one year. The decisions of the Board will be included in the files maintained by the Secretary.

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E. Continuing Review The IRBs will conduct continuing reviews of research at intervals appropriate to the degree of risk, but not less than once a year, in order to reassure themselves, investigators, research subjects, and the public that appropriate measures are being taken to protect the rights and welfare of human research subjects. The IRB Secretary is responsible for tracking when continuing review is due for each study. The Principal Investigator is responsible for timely submission of a continuing review application to the IRB that initially reviewed the protocol. The Investigator should submit the necessary documentation to the IRB Secretary in enough advance time so that completion of continuing review can be accomplished by the due date. For continuing review, the Investigator will submit the following documents to the IRB Secretary:

1. A copy of the currently approved protocol and consent document 2. A completed copy of the IRB Progress Report Form (Attachment D) The IRB Secretary will distribute the materials to all board members at least three (3) days in advance of the meeting. Protocols that required full IRB review will be reviewed by the full IRB for continuation. The review will take place at a convened meeting of the Board and must be approved by a majority of the members present in a format similar to the initial review. Criteria for approving the continuation of research are the same as with the initial review. If the IRB gives conditional approval to the continuing review, these conditions must be met before approval for continuation will be granted. F. Notification to the Investigator The Board will provide the Investigator with written notification of its decision concerning the continuation of the research proposal (Attachment C - IRB Review Results Form). If a proposal is disapproved, the reasons for such disapproval will be documented. The Investigator will also be notified of the duration of the Board's approval, which will never exceed one year. The decisions of the Board will be included in the files maintained by the Secretary. G. Investigator's Failure to Submit a Progress Report

If an Investigator fails to submit a Progress Report by the scheduled review date, the IRB will suspend subject accrual for that study pending re-approval by the IRB. In

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this case, the IRE3 Chairperson will send a letter to the Principal Investigator notifying him or her that: l . The IRE3 has suspended subject accrual and no new subjects can be enrolled; 2. Whether or not the IRE3 will allow the research to continue for those subjects who are already enrolled; and 3. The Investigator must submit a Progress Report within 30 days. Failure to do so will result in withdrawal of the approval and notification to the sponsor and regulatory agencies of the withdrawal. H. IRB Notification of Study Termination When the last subject enrolled in the study has completed hislher last study-related assessment, the Investigator must notifl the IRE3 about the study termination using the IRE3 Notification of Study Termination Form (Attachment E). The IRE3 Chairperson or Secretary will notifl the rest of the IRE3 concerning study terminations at the next convened meeting. Study terminations may be reviewed and presented to the Board on an expedited basis. The IRE3 Chairperson will complete the IRB Study Termination Acknowledgement and send it to the Investigator to document this notification (Attachment F).

IV. References 21 CFR 56.108 - IRE3 Functions and Operations 21 CFR 56.109 - IEU3 Review of Research 2 1 CFR 56.111 - Criteria for IRB Approval of Research 45 CFR 46.109 - IEU3 Review of Research 45 CFR 46.11 1 - Criteria for IRB Approval of Research ICH Guidelines for Good Clinical Practice (E6) section 3.1 - Responsibilities ICH Guidelines for Good Clinical Practice (E6) section 4.9 - Records and Reports ICH Guidelines for Good Clinical Practice (E6) section 4.10 - Progress Reports ICH Guidelines for Good Clinical Practice (E6) section 4.12 - Premature Termination or Suspension of a Trial

V. Attachments Attachment A - Initial Submission Form Attachment B - Reviewer's Checklist Attachment C - IRE3 Review Results Form Attachment D - IEU3 Progress Report Form Attachment E - IRE3 Notification of Study Termination Attachment F - IRB Study Termination Acknowledgement

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Title: IEU3 Review of Informed Consent

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the processes for the IRB review of informed consent documents. 11.

Scope

This SOP will apply to all informed consent documents that accompany research activity conducted at Company.

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111.

Procedures

A. Submission for Review As part of the study packet for the initial review of research, Investigators will submit a draft Informed Consent Form to the IRB Secretary. Valid informed consent requires: l. Disclosure of relevant information to prospective subjects about the research; 2. Comprehension of the information; and 3. Voluntary agreement, free of coercion and undue influence, to research participation. Changes to the consent form that result from protocol amendments will be handled in the same manner as the original document.

B. IRB Review of the Informed Consent Document The IRB Secretary will transmit the appropriate materials to each of the board members at least three days before the scheduled meeting to allow thorough review of each proposal. The Primary Reviewer selected to review the research proposal will also review the accompanying consent. The Primary Reviewer will complete a Subject Information and Consent Form Checklist (See Attachment A), but all board members are required to review the materials for all studies. C. Elements for Written Informed Consent Documents IRB members will review each Informed Consent document to ensure that it meets the following basic elements of consent:

1. A statement that the study involves research; 2. An explanation of the purpose of the research and the expected duration of the subject's participation;

3. A description of the procedures to be followed and identification of any procedures that are experimental; 4. A description of any foreseeable risks or discomforts to the subject, an estimate of their likelihood, and a description of what steps will be taken to prevent or minimize them; 5. A description of any benefits to the subject or to others that may reasonably be expected from the research. Monetary compensation is not a benefit. If compensation is to be provided to research subjects or healthy volunteers, the amount should be stated in the consent document;

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6. A disclosure of any appropriate alternative procedures or courses of treatment that might be advantageous to the subject; 7. A statement describing to what extent records will be kept confidential, including a description of who may have access to research records;

8. For research involving more than minimal risk, an explanation and description of any compensation and any medical treatments that are available if research subjects are injured, where further information may be obtained, and whom to contact in the event of a research-related injury; 9. An explanation of whom to contact for answers to pertinent questions about the research and the research subject's rights (include the Clinical Center's Patient Representative and telephone number); and 10. A statement that participation is voluntary and that refusal to participate or discontinuing participation at any time will involve no penalty or loss of benefits to which the subject is otherwise entitled. IRB Reviewers will ensure that, when appropriate, the following additional elements will be included in the consent form: If the subject is or may become pregnant, a statement that the particular treatment or procedure may involve risks, which are currently unforeseeable, to the subject or to the embryo or fetus; A description of circumstances in which the subject's participation may be terminated by the investigator without the subject's consent; Any costs to the subject that may result from participation in the research; What will happen if the subject decides to withdraw from the research and how withdrawal will be handled; A statement that the Principal Investigator will notify subjects of any significant new findings developed during the course of the study that may affect them and influence their willingness to continue participation; The approximate number of subjects involved in the study; When appropriate, a statement concerning an investigator's potential financial or other conflict of interest in the conduct of the study. Waiver or Alteration of the Required Elements of Informed Consent Only in those circumstances prescribed by the Federal Regulations (21 CFR 50.23 and 50.24) will the IRB waive the requirement to obtain informed consent, or approve a consent process that does not include or alters some or all of the elements of consent. The Primary Reviewer will present the research proposal at a regular or special meeting of the IRB. The Investigator may be invited to attend a portion of the meeting, so that Board members have the opportunity to question himher about the IRB-006.0.doc

Page 149


research proposal. After the research has been presented, the IRB Chairperson will call for a discussion of the protocol, consent form, advertisements, and other subject materials. The Primary Reviewer will make a motion concerning the protocol, consent form, and advertisements (i.e., approval, conditional approval, deferred, denied) and will note when the next progress report will be expected. The motion will be seconded and the IRB will vote to approve or disapprove the research proposal. No member of the Board with a conflict of interest will be allowed to vote on the proposal. If the Board approves a proposal subject to modifications, it must specify, by majority vote of the members present, whether the changes will require full Board approval or may be approved by the Chairperson or Primary Reviewer on behalf of the Board. A summary of the Board's discussions and a record of its decisions, including but not limited to the final disposition of each proposal, will be made by the IRB Secretary. E. Notification to the Investigator The Board will provide the Investigator with written notification of its decision to approve, disapprove, defer, or modify the informed consent document (Attachment B - IRB Review Results Form). If modifications are required, the description of those modifications will also be documented. The Informed Consent Form will not be considered fully approved until the required modifications are incorporated into the document. Approval dates will be indicated on all IRB-approved informed consent documents. Only copies of these dated documents will be used to obtain the consent of subjects. F. Record Retention The IRB Secretary will file a copy of the approved informed consent for each study. If there are revisions to the consent form that are the result of a protocol amendment, these revised, approved consents will also be filed. All records will be retained for three (3) years from the date of the completion of the study.

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IV.

References

21 CRF 50.23 - Exceptions from General Requirements 21 CFR 50.24 - Exception from Informed Consent Requirements for Emergency Research 21 CFR 50.25 - Elements of Consent 45 CFR 46.116 - General Requirements for Informed Consent 45 CFR 46.117 - Documentation of Informed Consent ICH Guidelines for Good Clinical Practice (E6) section 1.28 - Informed Consent ICH Guidelines for Good Clinical Practice (E6) section 1.37 Representative

-

Legally Authorized

ICH Guidelines for Good Clinical Practice (E6) section 4.8 - Informed Consent of Trial Subjects IRE3 Information Sheets - Continuing Review

IRB Information Sheets - Guide to Informed Consent V.

Attachments

Attachment A - Subject Information and Consent Form Checklist Attachment B - IEU3 Review Results Form

IRB-006.0.doc

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Title: IRB Review of Advertisements

Supersedes: N/A

AUTHOR


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose

To describe the procedures for reviewing advertisements used to recruit study subjects. 11.

Scope

This SOP will apply to all advertisements submitted to the IRB for review.

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111.

Procedures

A. Submission Investigators will be responsible for submitting all original or revised advertising material to the IRB. Advertising will include, but is not limited to, the following: l. Copies of the advertisement as it will appear in print (i.e., newspapers, magazines, billboards, posters, fliers)

2. Audio tapes and printed scripts for radio advertisements 3. Videotapes and printed scripts for television advertisements;

4. Copies of internet listings as they would appear on a webpage 5. Copies of phone scripts used to screen callers for research eligibility An administrative staff member will review the proposed advertising material for completeness and will determine if it qualifies for expedited review or needs to be reviewed by the full Board. The staff member will pass the documents to the appropriate board members for review.

B. Review of Advertising Material Using the Advertisement Review Checklist (Attachment A), the designated reviewer will review the material for content and the context in which it will be used. In reviewing the advertisement, the Reviewer will evaluate the following items: l. The name and address of the clinical investigator andlor research facility

2. The condition under study

3. The purpose of the research 4. A summary of the eligibility criteria 5. A brief list of benefits 6. Time or other commitments required of the subjects

7. Location of the research 8. Person to contact for further information

All of the items above are not required to be included in all advertisements. Any board member with a conflicting interest in a study will abstain from deliberations and voting on the associated advertisements, except to provide information as requested by the Board. Such abstentions will be recorded in the minutes.

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By majority vote of the members present, the board may reach one of the following decisions regarding each advertisement: l. Unconditional approval - approved as presented.

2. Conditional approval - approved, subject to specific modifications. 3. Disapproved - the Board has decided they cannot ethically approve the advertisement. 4. Deferred - no decision can be made yet, pending evaluation of additional requested information. If the Board approves an advertisement subject to modifications, it must specify, by majority vote of the members present, whether the changes will require full Board approval or may be approved by the Chairperson or Primary Reviewer on behalf of the Board. C. Notification to the Investigator The Board will provide the Investigator with written notification of its decision to approve, disapprove, defer, or modify the advertisement (Attachment B). If an advertisement is disapproved, the reasons for such disapproval will be documented. The decisions of the Board will be included in the files maintained by the Secretary.

IV.

References

21 CFR 56.11 1(a)(3) - Selection of Subjects ICH Guidelines for Good Clinical Practice (E6) part 3.1 - Responsibilities 45 CFR 46.11 - Criteria for IRB Approval of Research

V.

Attachments Attachment A - Advertisement Review Checklist Attachment B - IRB Review Results Form

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Title: IRE3 Review of Unscheduled Mandatory Reports

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

Initialsmate

Purpose To describe the procedures for reviewing unscheduled reports to the Institutional Review Board ( m ) .

11.

Scope This SOP will apply to all serious adverse events (including deaths), protocol amendments, and unanticipated problems submitted to the IRE3 for review.

IRB-0OS.O.doc

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111.

Procedures

A. Submission During any period in which the approved research is being conducted, the Investigator will submit the following information to the IEU3: l. Serious Adverse Events, including deaths;

2. Unanticipated problems; and

3. Protocol amendments and revised consents, if applicable. An administrative staff member will review the submission for completeness and will pass the documents to the appropriate board members for review.

B. Review of Serious Adverse Events, Including Deaths The IRE3 will require that Investigators report all deaths that occur while the subject is participating in a research study to the IRE3 Chairperson. This must be accomplished orally within 24 hours after the death and in writing within five (5) days of the death. Unless the IRE3 Chairperson believes a special meeting should be convened to discuss the death, IEU3 members will review the written report at the next regular meeting. The IRB will require that Investigators report all adverse experiences that are considered serious and unexpected and related to the investigational product which occur while the subject is participating in a research study to the IRB Chairperson. This must be accomplished orally within 24 hours after the event and in writing within five (5) days of the event. Unless the IRB Chairperson believes a special meeting should be convened to discuss the event, IEU3 members will review the written report at the next regular meeting. Investigators will submit all safety information to the IRE3 using the Safety Information Form (Attachment A) supplemented with sponsor-required documentation. C. Review of Unanticipated Problems The IRE3 will require that Investigators report all unanticipated problems that occur while the subject is participating in a research study to the IRB Chairperson (e.g., medication errors, unexpected complications, protocol violations). This must be in writing within five (5) days of the event. Unless the IRB Chairperson believes a special meeting should be convened to discuss the problem, IRE3 members will review the written report at the next regular meeting.

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D. Review of Protocol Amendments The Sponsor and IRE3 will require that Investigators submit the protocol amendments and the Protocol Amendment Form (Attachment B) to the IRB before the change is implemented, except when necessary to eliminate hazards to study subjects. The protocol amendment should include a description of the change in the research. If revisions to the consent form are necessary as a result of the amendment, the revised consent should also be submitted. Expedited review will be allowed for protocol amendments that only include administrative changes to the protocol. The IRE3 Secretary will provide copies to all IRE3 members. When applicable, other background information such as adverse events reports or continuing review reports will be provided to the Reviewers. The review of revised protocols and consent forms will follow the same process as for the initial review of the study. IRE3 members will review the protocol amendment and the revised informed consent at the next regular meeting. The Board will provide the Investigator with written notification of its decision to approve, disapprove, defer, or modify the protocol amendment and revised consent (Attachment C - IRE3 Review Results Form). If an amendment is disapproved, the reasons for such disapproval will be documented. The decisions of the Board will be included in the files maintained by the Secretary. E. Revisions to the Informed Consent Upon review of additional information, the IRB may determine that Informed Consent document should be revised. If this is true, the board members will advise the Investigator about the needed revisions. New subjects will be provided with the revised consent form. The Board will need to determine if previously enrolled subjects will need to be re-consented.

IV.

References 21 CFR 56.108 - IRB Function and Operations 21 CFR 312.32 - IND Safety Reports ICH Guidelines for Good Clinical Practice (E6) section 3.3 - Procedures ICH Guidelines for Good Clinical Practice (E6) section 4.1 1 - Safety Reporting

v.

Attachments Attachment A - Safety Information Form Attachment B - Protocol Amendment Form Attachment C - IRE3 Review Results Form

IRB-OO8.O.doc

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Title: Criteria for Exempt and Expedited Review

Supersedes: N/A


APPROVED BY

DEPARTMENT HEAD

QUALITY ASSURANCE


I.

Section

Pages

InitialsJDate

Purpose To describe the criteria for exempt and expedited review of research conducted at Company.

11.

Scope This Standard Operating Procedure (SOP) will apply to all research submitted to Company Institutional Review Board (IRB).

IRB-009.0.doc

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111.

Procedures A. Exempt Research (Summarized from 45 CFR 46.10 1(b)) Unless otherwise required by DHHS, the FDA, or other regulatory agency, all research using human subjects and conducted at Company will be reviewed by the IRB, with the following exceptions: l. Research conducted in established or commonly accepted educational settings, involving normal educational practices.

2. Research on unidentified subjects involving the use of educational tests (cognitive, diagnostic, aptitude, achievement).

3. Research involving survey or interview procedures, except certain potentially damaging andlor sensitive research on identifiable subjects. All research involving survey or interview procedures is exempt, without exception, when the respondents are elected or appointed public officials or candidates for public office. 4. Research involving the observation (including observation by participants) of public behavior, except certain potentially damaging andlor sensitive research on identifiable subjects. 5. Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified directly or through identifiers linked to the subject. 6. Unless specifically required by statute or regulation, research and demonstration projects that are conducted by or subject to the approval of the Department of Health and Human Services and that are designed to study, evaluate, or otherwise examine actual or proposed programs, procedures, or benefits under the Social Security Act or other public benefit or service programs. The IRB Chairperson will be responsible for determining if the research activity qualifies for exempt status. If it qualifies, the IRB Secretary will notify the Investigator in writing. This notice will include the specific criteria which justifies the exemption. B. Expedited review of research (Summarized from 45 CFR 46.110) Expedited review is a procedure through which certain kinds of research may be reviewed and approved without convening a meeting of the full Board. The IRB will review certain categories of research through an expedited procedure only if the research involves no more than minimal risk to the subjects. Categories of research which may be considered for expedited review include the following:

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Minor changes in previously approved research during the period covered by the original approval: a. Where the research is permanently closed to the enrollment of new subjects; all subjects have completed all research-related interventions; and the research remains active only for long-term follow-up of subjects; or b. Where no subjects have been enrolled and no additional risks have been identified; or c. Where the remaining research activities are limited to data analysis. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: a. From healthy, non-pregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 m1 in an 8-week period and collection may not occur more frequently than 2 times per week; or b. From other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 m1 or 3 m1 per kg in an 8-week period and collection may not occur more frequently than 2 times per week. Collection of hair, nail clippings, teeth, etc. in a non-disfiguring manner Collection of excreta and external secretions Collection of uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue Placenta removed at delivery Amniotic fluid obtained at the time of rupture of the membrane prior to or during labor Recording of data from subjects age 18 or older by non-invasive procedures Collection of gingival plaques provided the collection procedure is not more invasive than routine prophylactic scaling of teeth and the process is accomplished in accordance with accepted prophylactic techniques 10. Collection of data from voice, video, digital, or image recordings made for research purposes 11. Moderate exercise by healthy volunteers 12. Research involving materials (data, documents, records, or specimens) that have been collected or will be collected solely for non-research purposes (such as medical treatment or diagnosis) 13. Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves

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14. Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior), or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies

15. Research on drugs or devices for which an IND or an IDE (Investigational Device Exemption) is not required The expedited review procedure may not be used: l. When the research involves more than minimal risk to the subjects

2. Where identification of the subjects andlor their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal

3. For classified research involving human subjects 4. For studies intended to evaluate the safety and effectiveness of medical devices, including studies of cleared medical devices for new indications If expedited review is being requested for the initial review of research, the Investigator will submit the Initial Submission Form (Attachment A) and attach all appropriate documents. For expedited review of research that has already been approved by the IRB, the Investigator will submit a study packet to the IRB Secretary which will include the minimum of the following documents: 1. A completed Expedited Review Form (Attachment B)

2. The most recent version of the protocol and amendments, if applicable 3. The current Investigator's Brochure or Package Insert

4. A draft Informed Consent Form

5. Advertisements (if applicable) or subject recruitment materials If this is the first time an Investigator has submitted a study to the IRB, helshe should also include a copy of hislher curriculum vitae. The IRB Secretary will review the study packet for completeness and will forward it to the Reviewer. The Reviewer may be the Chairperson or any primary or alternate IRB member who does not have a conflict of interest with the research proposal. The Reviewer may exercise the authority of the IRB,except helshe cannot disapprove a research project. If the Reviewer believes the research should be disapproved, helshe will bring it to the attention of the full Board.

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The expedited review of the research will be guided by the Reviewer's Checklist (Attachment C). This completed checklist will be retained as part of the research proposal submission. The IRB Secretary will track all research approved by expedited review and will inform the full board at the next convened meeting. A vote on expedited reviews is not required but the IRB has the prerogative to discuss, rescind or amend expedited actions. As with full Board approval, the IRB will provide the Investigator with written notification of its decision concerning the outcome of the expedited review of the research proposal (Attachment D - IRB Review Results Form). The Investigator will also be notified of the duration of the Board's approval, which will never exceed one year. The decisions of the Board will be included in the files maintained by the IRB Secretary.

IV.

References 21 CFR 50 - Protection of Human Subjects 2 1 CRF 56.104 - Exemptions from IEU3 Requirement 2 1 CFR 56.107 - Waiver of IRB Requirement 21 CFR 56.110 - Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research 45 CFR 46.110 - Expedited review procedures for certain kinds of research involving no more than minimal risk and for minor changes in approved research FDA Information Sheets for Institutional Review Boards and Clinical Investigators: Clinical Investigations which may be reviewed through expedited review procedures set forth in FDA regulations

V.

Attachments Attachment A - Initial Submission Form Attachment B - Expedited review Form Attachment C - Reviewer's Checklist Attachment D - IEU3 Review Results Form

IRB-009.0.doc

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Company Advertisement Review Checklist Protocol #:

Date of Review:

Investigator:

Reviewer:

Advertisement Title or Identification:

Is the mode of communication appropriate? Does the advertising material, which will be used to recruit potential subjects, afford adequate protection? Does the advertising material explicitly state that this is a "research study" or "clinical research trial"? Is the material misleading or coercive? Does the advertisement contain any of the following unacceptable elements? Claims, either explicitly or implicitly, that the drug or device is safe or effective for the purposes under investigation Claims that the drug or device is in any way equivalent or superior to any other drug or device Implied or express claim of safety or effectiveness of study medication References to free medical treatment ("research-related" medical treatment is allowed) Undue emphasis on subject compensation (such as "free" or the $ amount bolded or underlined) Any claim that the research will (as opposed to "may") improve the subject's medical condition Any express or implied statement that the research is FDA approved The words "medicine" or "medication" unless modified with terms such as "research," "investigational," "experimental," "study," etc. It should be clear that the drug is not an approved drug. The actual drug name, unless the sponsor approves its use Information that is incorrect according to protocol If this is a Screening script, does it ask questions related to alcohol or drug use (i.e., asked before consent is signed)? Recommendations of Reviewer: Advertisement acceptable and does not require follow-up action (Approved) Advertisement acceptable but suggested corrections need to be incorporated (Conditional) Advertisement not acceptable and requires revision (Disapproved)

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Company Protocol Amendment Form Protocol #:

InvestigatorISite #:

Investigator:

Sponsor:

Site Address: Study Title:

Attached is Amendment #version A.

(dated xx/xx/xx, version )

for Protocol #_

(dated xx/xx/xx,

A revised protocol, which incorporates the changes in Amendment #-: is included (dated xx/xx/xx, version 3. is not included. Changes to the informed consent document (dated xx/xx/xx, version -1: is necessary. A revised draft (dated xx/xx/xx, version )is attached. is not necessary Enrollment

This study is

ongoing (i.e., subjects continue to be enrolled) or enrollment is closed and subjects are being seen for follow-up assessments only.

Number of subjects expected to enrol1 in this study Number of subjects screened

Number of drop-outs

Number of subjects enrolled

Number of subjects completed

Will the protocol amendment affect the risk benefit ratio of this study? If "yes," explain:

Has the Principal Investigator, Subinvestigators, or Study Coordinator changed? If "yes," explain:

Principal Investigator (print)

Amendmentdoc

Investigator's Signature

Date

Page 169


Company Biological Samples Inventory Drug name:

Date of Shipment:

Protocol #:

Sponsor:

Investigator:

Site contact person:

Address:

Contact person's phone number:

Sample Identifier

Subject Number

Subject Initials

Date Sample Obtained

Time Sample Obtained

Sample Type (Usecode Below)

Comments

Use the following abbreviations for "type of sample": PK - Blood for pharmacokinetic analysis EL - Blood for electrolyte analysis UR - Urine for urinalysis PD - Blood for pharmacodynamic analysis HM - Blood for hematology analysis UC - Urine collection in jug for creatinine clearance UD - Urine for analysis of drug levels CO - Blood for coagulation analysis CC - Blood for clinical chemistry analysis

Bio Sample.doc

Page 171


Company

CFW Review Form Protocol #:

Investigator1 Site #:

Monitor:

Visit Date:

Subject ID

CRF Review.doc

Question

CRF page

Resolved?

Page 173


Company

Compound #/Name:

Subject number:

Protocol #:

Subject Initials:

Investigator:

Monitor:

Data Clarification Form

CRF Page #

Page

Data ID

of

p

Date documented:

Data Query

l

1

dd Immml YY

DCF Form.doc

Resolution

After completing all resolutions, sign below: Signature:

Date:

Page 175


Company Drug Dispensing Log Drug name:

Protocol #:

Investigator/Site #:

Investigator:

Sponsor:

IND #:

Subject No.

Subject Initials

Container Number

Date Dispensed

Amount Dispensed

Dispensed BY

Amount Returned

Date Returned

Retrieved BY

Explanation for Discrepancy

Audit Date

Physical Count

Initials of Monitor

TOTALS:

Dispense.doc

Page 177


Company Study Subject Investigational Product Dispensing Record Drug name:

Protocol #:

Subject Initials:

Investigator:


Subject #:

Dispense by Pt.doc

Page 179


Company Clinical Trial Materials DisDosition Form Ship from:

Date:

Ship to:

Sponsor: Protocol #: Attention:

IND #: Shipped via:

Tracking #

Account #:

(name of carrier)

Subject Number

Bottle Numbers

Status of Study Drug supply: (Check Only One)

Product Description

Quantity Destroyed On-site

Quantity Returned

Comments

0I am not returning unused drug because all of the unused drug listed above was destroyed at the study site. 0I am not returning unused drug because all drug was used on the study. 0I am returning all unused drug. All other drug was used on the study; this shipment is final. 0I am returning all unused drug. More unused drug may/will follow. 0I am returning all unused drug in response to a recall notice or drug expiration.

Shipment returned by:

Drug Disposition.doc

Lot Numbers

Date:

Page 181


Company Investigational Drug Shipping Order Date:

Ship to:

Ship from:

Sponsor: Protocol #: Attention:

IND #: Shipped via:

Account #:

Tracking #

(name of carrier)

Quantity Ordered

shipment:

Unit of Measure

Resupply

Lot Number

0Other (explain):

Expiry1 Retest date

Special Information: Reference number: Subject number: Strata number:

Acknowledgement of receipt Are the description and quantity listed above found in this shipment? Did the product arrive in acceptable condition? If either of the questions above were answered "no," explain:

Product Description

Quantity Shipped

Shipment requested by: Phone number: Shipment received by:

After completing the acknowledgement and signing this form, please fax it to XXX-XXX-XXXX

Drug 0rder.doc

Page 183


Company Investigational Product Receipt Form Drug name:

Investigator:

Sponsor:

InvestigatorBite #:

Protocol #:

WD #:

I “Containers” (below) means: 0Bottles 0Vials/ampoules 0Blister carddpacks 0Boxes 0Tubes 0Other: Subject Identifier

~

Container Numbers

Shipment received by:

Drug Receipt.doc

Lot Numbers

Number of Containers

Product Description

Check if Damaged

Date:

Page 185


Company D r u Return ~ Form Drug name:

Ship from:

Shipping Service:

Sponsor:

Account #:

Protocol #:

Tracking #:

Investigator:

Special service Priority overnight

Ship to:

2nd day delivery


Saturday delivery

I "Containers" (below) means: Subject Identifier

Container Numbers

Shipment returned by:

Drug Retumdoc

Bottles

Vialslampoules Lot Numbers

Blister cardslpacks

Boxes

Tubes

Number of Containers

Product Description

I

Other: Returned or Destroyed?

Date:

Page 187


Company Screening and Enrollment Log Protocol #:


Investigator:

Sponsor:


Page 189

Company Screening and Enrollment Log (continued) Subject Initials

Enrollment.doc

Date of Birth

Date Screened

If Enrolled, Subject No.

If Not Enrolled, Give Reason

Page 190

Company Expedited Review Form Study Information I

I Protocol Number:

I Protocol Date andlor Version Number:

I

Protocol Title:

1 Date of m ' s Initial Approval of Research: IRB' S Identifying Number: Why does this request qualify for expedited review?

Investigator and Study Staff Information

1 Investigator name:

1 Investigator phone:

1 Investigator e-mail:

1 Study Coordinator name:

1 Study Coordinator phone:

1 Study Coordinator e-mail: General Information

1 How many subjects are expected to enroll in this study?

1 How many subjects are expected to enroll at this site? 1 Did recruitment begin?

Yes

No

If "yes", date:

1 When is recruitment expected to end?

Expedited.doc

Page 191

Company Expedited Review Form (continued) Informed Consent Will revisions to the consent form be needed?

0 Yes 0 No

If “yes,” specify date or version number of most recently approved consent: Serious Adverse Events Have any Serious Adverse Events occurred on this study? Have any IND Safety Reports been submitted for this study?

0 Yes 0 No 0 Yes 0 No

Recruitment Which of the following are being recruited for this study? (Check all that apply.)

0 Existing patients 0 Pregnant women 0 Referral patients 0 Prisoners 0 Private Practice patients 0 Pediatric patients 0 Out-patients 0 Geriatric patients 0 In-patients 0 Mentally retarded/disabled 0 Paid volunteers 0 Homeless/Shelter 0 Employees of Sponsor 0 Poor/uninsured 0 Employees of Investigator 0 Terminally ill 0 Ill’iterates 0 Non-English speaking 0 Students to be recruited in their educational setting 0 Military personnel to be recruited by military personnel 0 Other?(explain)

Document Checklist (Please attach these documents.)

I0

I0 0 0 I0

I

Protocol (and amendments, if applicable)

I

Consent form (dated ; version ) Current Investigator’s Brochure or package insert Patient diaries (if applicable)

I

Copies of advertisements and all subject recruiting materials (if applicable)

I

I0

Expedited.doc

Page 192

Company Subject Information and Consent Form Checklist Protocol #:


Protocol Date or Version Number:

Sponsor:

Reviewer:

Date:

Simple explanation of the consent process Statement that the study involves research

I

I

Not applicable

Not adequate

Adequate

Element of Informed Consent

I

I

Identification of any experimental procedures Purpose of the research (always includes an evaluation of safety) Expected duration of the subject's participation Frequency of visits to the study site and length of stay for each visit List of study procedures

I

A description of what will be expected of the subject, including before entering the study (e.g., refrain from smoking andlor alcohol, discontinue some medications, etc.) Identification of experimental procedures and drugs

I

Probability of random assignment to treatment arms, including placebo Acknowledgment of the use of placebo Status of test article or drug

I I

List of foreseeable risks or discomforts; and when possible, the likelihood, severity, and duration of those risks. List of benefits to the subject or to others that can be reasonably expected, including the possibility of no guarantee of benefits, if applicable

ICF Review.doc

Page 193

Company Subject Information and Consent Form Checklist (continued) Element of Informed Consent Payment schedule and amount is defined, including prorating List of alternative procedures or treatments Addresses confidentiality of records Allows Sponsor, CRO, IRB, and FDA full access to medical records Explains whether (and what) medical treatment or compensation is available if subject is injured; may include a statement of who will be responsible for any additional expenses, especially if there is the possibility that the subject's insurance company or other third party may refuse to pick up the costs. (Regulations do not limit injury to "physical injury.") Contains name of contact person and phone number for questions about research-related injury or the research study. This needs to be a 24-hour number. Contains name of contact person and phone number for questions about research rights. This is usually the IRB's phone number. Statement that participation is voluntary and subject can withdraw without penalty Acknowledgment of risks that are currently unforeseeable Statement of risks during pregnancy, including risks to a fetus or embryo if the subject should become pregnant Statement that subject's participation may be terminated without consent of subject Reasons why subjects may be asked to leave the study without the subject' consent Consequences of a subject's decision to withdraw from the study and a description of the procedures when the subject's participation is terminated (when applicable)

ICF Review.doc

Page 194

Company

Subject Information and Consent Form Check st (continued) Element of Informed Consent Consequences of a subject’s decision to withdraw from the study and a description of the procedures when the subject’s participation is terminated (when applicable) Description of additional costs to the subject resulting from participation in the research (if applicable) Statement of obligation to share new findings during the study which may relate to the subject’s willingness to continue participation in the study Description of procedures for withdrawal from the study and consequences for withdrawal Statement of number of subjects and centers involved

Other Issues Is layman’s language used and the consent understandable to the subject? Is the consent written in the second person? (e.g., First person: “I understand that.. .” can be interpreted as suggestive and may be a coercive influence) Does the information given to the subject include any language that would imply that the subject releases the sponsor, investigator, or study site from liability for negligence? Does the information given to the subject include any language that appears to waive the subject’s legal rights?

Is the consent written on the institution’s letterhead or does it contain the name, address, and telephone number of the institution typed on the first page? Does the informed consent identify the protocol (either by title or protocol number)? Should the consent form be translated into another language? Does the form have a place for the subject’s signature and date? Does the form have a place for the signature and date of the person who explained the study to the subject?

ICF Review.doc

Page 195


Company Study Initiation Document Tracking Worksheet Investigator: Site:

Site number:

Monitor: The following documents must be received by the Sponsor or CRO before drug will be shipped to the study site. Date Sent to Investigator

I Financial Disclosure for PI

Date Rec'd from Investigator

I

I

I Financial Disclosure for Study Coordinator I I Protocol I

I

I Financial Disclosure for Subinvestigator I

Comments

I

I IEU3 approval of Protocol I List of IEU3 members or assurance # I Investigator's budget I Budget approval Contract approval

h i t Doc Track.doc

Page 197

Company Study Initiation Document Tracking Worksheet (continued)

List Names of Investigator, Subinvestigators, and Study Coordinator

CV Present

Medical License Present

Financial Disclosure Present

Exp : Exp : Exp : Exp : Exp : Exp :

Name of Lab

h i t Doc Track.doc

Certifying Body

Expiration date

Lab Normals

Page 198

Company Initial Submission Form Study Information I

I Protocol number:

I Protocol date andlor version number:

I

Protocol title:

Has this Principal Investigator andlor research study been disapproved by another IRB? If "yes," explain: Investigator and Study Staff Information

Investigator name:

I

I

Investigator mailing address: Investigator phone: Investigator fax: Investigator e-mail: Study Coordinator name: Study Coordinator mailing address:

I

Study Coordinator phone: Study Coordinator fax: Study Coordinator e-mail: Location where research will be conducted if different from Investigator's address: List all Subinvestigators or attach a copy of Form FDA 1572: How long has the Principal Investigator been conducting clinical research? y e a r s

months

How many studies is the Principal Investigator currently supervising? Approximately how many active patients are in those studies?

Initial Sub.doc

Page 199

Company Initial Submission Form (continued) For the Investigator or any of the Subinvestigators in this study, have any of the following ever been, or are any currently in the process of being, voluntarily or involuntarily, denied, revoked, suspended, reduced, limited, placed on probation, not renewed, relinquished, or have you ever withdrawn, or failed to proceed with an application, for any of the following: .. Research privileges at this site.. ............................................... [7 Yes [7 No state.. ................................................

Yes

No

Other professional registrationllicense.......................................

Yes

No

Membership on any hospital staff.............................................

Yes

No

Medical licensure in

Clinical privileges ...............................................................

[7 Yes [7 No

Professional society membership or fellowship/board certification.. ....

Yes

No

Any other type of professional sanction.. ..................................

Yes

No

Provide documentation for all "yes" answers. Study Site Information

Type of research facility:

Private practice (nonresearch) Psychiatric institution Commercial laboratory Research facility Corporate facility

Describe the on-site emergency equipment available:

Hospital Clinic School UniversityICollege Other (explain) Emergency medications Crash cart Other (explain)

Name of nearest hospital and distance from site: Does the Principal Investigator have admitting privileges at this facility?

Yes

No

Has the FDA, OHRP, or any other regulatory agency ever audited this site, Principal Investigator, or Subinvestigators? If "yes," attach the audit findings including Form 483 and the response letter. How will the Investigator, pharmacist, and other study staff be trained for the study?

Initial Sub.doc

Page 200

Company Initial Submission Form (continued) General Information

How many subjects are expected to enroll in this study? How many subjects are expected to enroll at this site? When is recruitment expected to begin? When is recruitment expected to end? What is the expected duration of the subject's participation (number of hours, days, weeks)? Will the subjects pay for any study-related procedures or articles (i.e., visits, tests, drug, etc.)? If "yes," describe:

[7 Yes [7 No

-

the standard of care and may not be billable to third party payers).

Recruitment

Who will perform the screening evaluation of the potential subjects to determine if they are Aigible for the research study? Will advertisements, posters, television or radio announcements, websites, etc. be used to recruitment purposes? (If "yes," copies must be provided for review.)

[7 Yes [7 NO

Which of the following will be recruited for this study? (Check all that apply.) Illiterates Pregnant women Existing patients HomelessIShelter Prisoners Referral patients Poorluninsured Pediatric patients Private Practice patients Terminally ill [7 Geriatric patients Out-patients Mentally retardedldisabled Employees of Sponsor In-patients Employees of Investigator Paid volunteers Students to be recruited in their educational setting Military personnel to be recruited by military personnel Other (explain)

Initial Sub.doc

Page 201

Company Initial Submission Form (continued) Which of the following recruitment methods will be used?

0

Solicitation letter Advertising Physician referrals Finders fee paid Other (explain)

If pediatric subjects will be enrolled in this study, will assent be obtained? (Assent documents must be approved by the IRB prior to use) Will non-English speaking subjects be recruited for this research project?

Yes Yes

No No

If "yes," number of non-English speaking subjects anticipated: Language(s) of non-English speaking subjects: Informed Consent

Who will discuss the Subject Information and Consent Form with the subject for this research study?

Investigator Subinvestigator Research Coordinator Other (explain)

When will consent be obtained? Will a translated version of the consent form be needed for the research study?

Yes

No

If "yes," specify language(s) needed: (Translated consent forms must be approved by the IRB prior to use.) How will consent be obtained from non-English speaking subjects (if applicable)?

Payments to Subjects (Include this information in the consent form.)

Will the subjects be paid for participation? If "yes," specify amount:

Yes

No

Total: Per visit:

If amount varies, list prorated amount for each visit: Will the subjects be paid for expenses only?

Initial Sub.doc

Yes

No

Page 202

Company Initial Submission Form (continued) Confidentiality

Will the research use direct identifiers?

Name Address Telephone number Other (explain)

Social security number Hospital chart number Insurance claim number

How will the confidentiality of this information be protected? Will the research use indirect identifiers that could be linked to direct identifiers?

Study code numbers Initials Other(exp1ain)

Pseudonyms

How will the confidentiality of this information be protected? Who will have access to the subject's documents and medical records? Will a translated version of the consent form be needed for the research study?

Yes

No

If "yes," specify language(s) needed: (Translated consent forms must be approved by the IRB prior to use.) How will consent be obtained from non-English speaking subjects (if applicable)?

Biological Specimens

Will the research involve the collection of biological specimens? (If "no," skip this section.)

Yes

No

Will the datalspecimens be collected anonymously (i.e., no way to link the sample with the subject's identity)?

Yes

No

Will the datalspecimens be collected in an identifiable manner (i.e., coded)?

Yes

No

Will the samples be collected retrospectively (i.e., specimens are already collected at the time of this application) or prospectively (i.e., specimens have not been collected at the time of this application)? If the samples are going to be collected prospectively, will the specimens be obtained: from procedures performed specifically for this research or from future, discarded clinical samples? Is genetic testing of these specimens proposed?

Initial Sub.doc

Yes

No

Page 203

Company Initial Submission Form (continued) Drugs IS this study iti\~olvcsa drug. complctc this section.

1 This study is: Phase I 1 IND # (if applicable):

Phase I1

Phase III

1 Is there a washout period associated with this study?

Phase IV Yes

No

Yes Will placebo be used during the washout period? If "yes," will subjects be monitored during this period? Describe:

No Yes

Devices

Treatment

Not applicable No

11' this study involvcs a dcvicc, complelc this scction.

1 Class of device:

1 This device is:

Class I

Class II

Investigational

1 IDE # (if applicable):

1 This is a

significant risk

Class III

Unclassified

Marketed

5 10(k) clearance

or

non-significant risk study.

Financial

Does the Investigator, Subinvestigator, or Study Coordinator have a financial or commercial interest in the study being conducted? (If "yes," this information must be disclosed on the consent form.)

1

Yes

No

If "yes," explain: Sponsor Information

Is the research investigator initiated?

Yes

No (If "yes," skip this section.)

Sponsor company: Sponsor contact name: Sponsor contact mailing address: Sponsor contact phone: Sponsor contact fax: Sponsor contact e-mail:

Initial Sub.doc

Page 204

Company Initial Submission Form (continued) Document Checklist (Please attach these documents.)

Protocol

Curriculum vitae for Principal Investigator Copy of medical license for Principal Investigator Form FDA 1762, if applicable Draft consent form (dated

;version

)

Investigator's Brochure or package insert Patient diaries (if applicable) Copies of advertisements and all subject recruiting materials (if applicable)

Initial Sub.doc

Page 205


Company

IRB Membership Roster Multiple Assurance # (if applicable):

Membership Status

Effective Date of Roster:

Name

Representative Capacity (Scientific1 Nonscientific)

Degrees

Relationship with Company

Experience

Chairman Secretary Primary Voting Member Primary Voting Member Primary Voting Member Primary Voting Member Primary Voting Member Alternate Voting Member Alternate Voting Member Alternate Voting Member

I

I

I

I

I

I

Alternate Voting Member Alternate Voting Member Non-voting Consultant Non-voting Consultant Non-voting Consultant

IRB Member.doc

Page 207


Company IRB MEETING MINUTES TEMPLATE Meeting Minutes for

Chair: Present:

(date)

Guest (if applicable): Name Name

Name Name Name

Name Name Name

CALL TO ORDER

The meeting was convened at present.

,IRE3 Chair. A quorum was

at by

OLDIUNFINISHED BUSINESS

Review and approval of minutes from meeting held Suggested changes were noted. APPROVED by a vote of for against

were reviewed. abstain

INITIAL REVIEWS Principal Investigator: Protocol Title: Protocol Summary: Discussion: General: Specific (include the following headings): Scientific design. Riskslbenefits (Assign a level of risk here or at the time of the IRE3 decision and vote below. If children are to be enrolled, cite the regulatory reference). Subiect selection (Discuss populations to be studied and recruitment plan). Additional safeguards for vulnerable subiects. Minimization of risks to subiects. Privacy and confidentiality. Consent document (Document if all required elements are present). Additional considerations (e.g., ionizing radiation; collaborative research; W, other. State if these considerations do not apply). Document the reason(s) for the minority opinion(s). Stipulations (number the stipulations):

Minutes Ternplate.doc

Page 209

Company Recommendations (number the recommendations):' IRB Decision and Vote: APPROVED by a vote of

for

against

abstain2

Follow same format as above for additional new protocols. EXPEDITED REVIEWS Principal Investigator: Title and type of expedited action: Date approved by IRB Chair or designee: Description of expedited action: (The Reviewer should provide a brief explanation of any expedited actions. A vote is not required but the IRB has the prerogative to discuss, rescind, or amend expedited actions.) List additional expedited actions following above format.

CONTINUING REVIEWS Principal Investigator: Protocol Title: Protocol Number: Expiration Date: Protocol Summary: Discussion: Stipulations (number the stipulations): Recommendations (number the recommendations): IRB Decision and Vote (Include m ' s reaffirmation of the level of risk or establishment of a new risk level.) Follow the same format as above for additional continuing reviews.

1

If the protocol is approved with stipulations andor recommendations, the minutes must state whether the IRB requires that the stipulations andor recommendations are to be reviewed by the Chair, by a subcommittee of the IRB, or by the full IRB. 2

Members who are affiliated with the protocol must abstain from the vote. The minutes should state which member(s) abstained. If a quorum is lost because members recuse themselves, no action may be taken on the protocol.

Minutes Template.doc

Page 210

Company AMENDMENTS Principal Investigator: Protocol Title: Protocol Number: Expiration Date: Description of the amendment: Discussion: Stipulations (number the stipulations): Recommendations (number the recommendations): IRB Decision and Vote: (Include a statement indicating whether or not the protocol's level of risk is altered by the amendment.) Follow the same format as above for additional amendments. ADVERSE EVENT(S) Principal Investigator: Protocol Title: Protocol Number: Date of Adverse Event(s): Description of the Adverse Event(s): (Document IRE3's acknowledgement of receipt of the adverse event report(s) and discussion, including immediate actions taken by the Investigator as a result of the event; recommendations by the IRE3 for further actions, if any, (e.g., suspension of subject accrual, etc.), and recommendations for further reporting (FDA or NIH officials, OHSR, etc.). If the adverse events are reported from non-NIH sites for the IRB's information only, and no action is required on the IRE3's part, acknowledgement of the report(s) should be documented. Follow the same format as above for additional adverse events. INFORMATION ITEMS Single Patient Exemption(s): Announcements: Other:


Page 211

Company

ADJOURNMENT

The meeting adjourned at --:--(a.m.1p.m.). Approved by: Name of IRB Chair


Date

Page 212

Company Monitoring Log Protocol #:


Investigator:

Sponsor:


Visit Date

Monitor Log.doc

Site Representative's Signature

SponsorICRO Representative's Signature

Reason for Visit

Page 213


Company Master Subject Log Protocol #:

Investigator:

Study Title:

Site Address:

Sponsor:

Phone and E-mail

Patient Master.doc

Date of Birth

Social Security Number

Date

Home:

Enrolled:

Work:

Completed:

E-mail:

Discontinued:

Home:

Enrolled:

Work:

Completed:

E-mail:

Discontinued:

Home:

Enrolled:

Work:

Completed:

E-mail:

Discontinued:

Home:

Enrolled:

Work:

Completed:

E-mail:

Discontinued:

Home:

Enrolled:

Work:

Completed:

E-mail:

Discontinued:

Page 2 15

Company Master Subiect LOP(continued) -

Subject Name and Address

-

~~

Phone and E-mail

U

\

Date of Birth

Social Security Number

Date

Home:

Enrolled:

Work:

Completed: Discontinued:

E-mail: P -

Home:

Enrolled:

Work:


E-mail: P -

Home:

Enrolled:

Work:


E-mail: P -

Home:

Enrolled:

Work:


E-mail: P -

Patient Master.doc

Home:

Enrolled:

Work:

Completed:

E-mail:

Discontinued:

Home:

Enrolled:

Work:

Completed:

E-mail:

Discontinued:

Page 216

Company Telephone Contact Report Date:

Protocol:

Call from:

Sponsor:

Call to: Contact:

Investigator: Person-to-person or

Voice-mail message

Site:

Subject:

Summary of Discussion

Action Required

Signature:

Phone Rpt.doc

Page 217


Company

IRB Progress Report Form Protocol #:


Investigator:

Sponsor:


Enrollment

This study is

ongoing (i.e., subjects continue to be enrolled) or enrollment is closed and subjects are being seen for follow-up assessments only.


Number of drop-outs

Number of subjects enrolled


Dropouts Subject Initials

No drop-outs have occurred Subject Number

Reason for Drop-Out

Changes in Research Have there been any protocol amendments since the time this study was initially approved?

If "yes," were these reported to this IRB? Are there any new fmdings that may affect the risk benefit ratio of this study? If "yes," explain:

Progress Rpt.doc

Yes

No

Yes

No

Yes

No

Page 219

Company IRB Progress Report Form (continued) Has the Principal Investigator, Subinvestigators, or Study Coordinator changed? If "yes," explain:

Yes

No

Has the Principal Investigator, Subinvestigators, or Study Coordinator received a revocation, sanction, or suspension of hislher state medical license since the study began? If "yes," explain:

Yes

No

Has the FDA, OHRP, or other regulatory agency audited your site since this study was started? If "yes," attach a copy of the 483 and your response.

Yes

No

Summarv of SAEs

No SAEs have occurred.

Summary of GCP Violations Subject Initials

Subject Number


Progress Rpt.doc

No GCP violations have occurred. GCP Violation


Date

Page 220

Company Study Responsibilities Form Protocol Number:

Investigator Name:

Study Title:

Site Address:

Sponsor:

Responsibilities.doc

Page 22 1

Company Studv Res~onsibilitiesForm (continued)

I authorize the individuals listed on this form to perform the study functions as indicated. Investigator's signature and date:

Responsibi1ities.doc

Page 222

Company Reviewer's Checklist Protocol Number:


Protocol Date or Version Number:

Sponsor:

Reviewer:

Date:

Regulatory Review Requirement 1.

2.

3.

The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk. Yes

No

(a) Is the hypothesis clearly stated?

Yes

No

(b) Is the study design appropriate to prove the hypothesis?

Yes

No

(c) Will the research contribute to generalizable knowledge and is it worth exposing subjects to risk?

Yes

No

(d) Is the scientific rationale for the study (history and background) clear?

Yes

No

(e) Are the treatment arms clear (active, placebo, crossover)?

Yes

No

( f ) If a placebo arm is used, is this appropriate?

Yes

No

(g) Are visits and procedures clearly described?

Yes

No

(h) Are experimental procedures differentiated from standard treatment?

Risks to subjects are reasonable in relation to anticipated benefits to subjects, and to the importance of knowledge that may reasonably be expected to result. Yes

No

(a) What does the IRE3 consider the level of risk to be?

Yes

No

(b) What does the Investigator consider the level of risk/discomfort/inconvenienceto be?

Yes

No

(c) Is there prospect of direct benefit to subjects?

Yes

No

(d) Are risks minimized as much as possible?

Yes

No

(e) Are foreseeable risks clearly defined, including likelihood, severity, and duration (including reversibility)?

Yes

No

( f ) Are the benefits clearly stated?

Subject selection is equitable. Yes

No

(a) Who is to be enrolled? Men? Women? Ethnic minorities? Children (rationale for inclusiordexclusion addressed)? Seriously ill people? Healthy volunteers?

Yes

No

(b) Are these subjects appropriate for the protocol?

Yes

No

(c) Do the eligibility criteria minimize risks to subjects?

Yes

No

(d) Are there groups of people who should be excluded from this study because they might be more susceptible to risks presented in this research?

Yes

No

(e) Would it be possible to conduct the study with less vulnerable subjects?

Review Cltlist.doc

Page 223

Company Reviewer's Checklist (continued) Regulatory Review Requirement 4.

5.

Additional safeguards required for subjects likely to be vulnerable to coercion or undue influence. Yes

No

(a) Are appropriate protections in place for vulnerable subjects, (e.g., pregnant women, fetuses, socially or economically disadvantaged, decisionally impaired)?

Yes

No

(b) Does the nature of the disease or behavioral issue being studied permit free consent?

Yes

No

(c) Are recruitment procedures designed to assure that informed consent is freely given?

Informed consent is obtained from research subjects or their legally authorized representative(s). Yes

No

(a) Does the informed consent document include the eight required elements?

Yes

No

(b) Is the consent document understandable to subjects?

Yes

No

(c) Who will obtain informed consent (Investigator, nurse, other?) and in what setting?

Yes

No

(d) If appropriate, is there a children's assent?

Yes

No

(e) Is the IRB requested to waive or alter any informed consent requirement?

5. Subject safety is maximized. Yes

No

(a) Does the research design minimize risks to subjects?

Yes

No

(b) Would use of a data and safety monitoring board or other research oversight process enhance subject safety?

Yes

No

(c) Is the Investigator competent in the area being studied?

Yes

No

(d) Is there a mechanism for providing information to the IRB in the event that unexpected results are discovered?

Yes

No

(e) Should a data and safety monitoring board be asked to monitor the study under review?

7. Subject privacy and confidentiality are maximized. Yes

No

(a) Will personally identifiable research data be protected to the extent possible from access or use?

Yes

No

(b) Are special privacy and confidentiality issues properly addressed, (e.g., use of genetic information)?

Yes

No

(c) If specimens are being retained, are there adequate protections (i.e., identifiable or nonidentifiable)? Is the future use of these samples clearly described?

Yes

No

(d) Does the proposed research collect sensitive information (e.g., sexual attitudes and practices; use of alcohol, drugs, or other additive products; the individual's mental health)?

Reviewer's Comments

In relation to the degree of risk associated with the research activity, how often should periodic review be conducted by the IRB to determine if the risklbenefit ratio has changed?

Review Cltlist.doc

Page 224

Company IRB Review Results Form Proposal No. Protocol No.

Dear Dr. On , the approved the protocol entitled and the accompanying informed consent form (version #dated: xx/xx/xx)>. The Board also approved the patient diary (version #- dated: xx/xx/xx) and the advertisement . These approvals expire and a continuing review of the research must be accomplished by (xx/xx/xx). To be in compliance with the requirements of this Board, FDA regulations, and ICH guidelines, you must: Conduct the study in accordance to the protocol and regulations; Use only the IRB-approved informed consent and subject recruitment materials; Promptly report new information that may affect adversely the safety of subjects or the conduct of the trial; Promptly report all serious adverse events andlor unanticipated risks to the IRB; and Obtain advance approval of changes in the research, except when necessary to eliminate hazards to study subjects. Sincerely, Chairman

Review Results.doc

Page 225


Company

Serious Adverse Experiences

Subject Initials:

Protocol Number:

Subject #:

Drug Name:

(Page 1)

Date of Report:

Investigator Name:

Sex Male

Weight Female

Diagnosis (if known) or Signs 1 symptoms List onc pcr line.

1

*

Race Black White Asian Hispanic Other (specify):

in.

lbs.

Date Started DDIRI 3 IIYY

Date of Birth

Height

"Intensity

Date Sto7ped Poststudy

*Outcome

l

1

"Action

*Withdrawal

Relationship to Trial Medication*

*Seriousness

l

See facing page for codes.

Possible causes of SAE other than trial medication

0

SAE.doc

Disease under study

Concurrent disorder. Specify:

Treatment failure

Concurrent medication. Specify:

Withdrawal of trial medication

Activity related to study participation (e.g., procedures). Specify:

Page 227

Company CODES FOR SERIOUS ADVERSE EXPERIENCES Code INTENSITY as: l = Mild 2 = Moderate 3 = Severe X = Not applicable Code OUTCOME as: R = Resolved = Resolved with sequelae S N = Not resolved Code ACTION TAKEN WITH TRIAL MEDICATION AS A RESULT OF THE NON-SERIOUS ADVERSE EXPERIENCE as: 0 = None l = Dosage adjusted 2 = Temporarily interrupted 3 = Permanently discontinued X = Not applicable Code WITHDRAWAL as: = Yes, subject did withdraw from the study as a result of this serious adverse experience. Y = No, subject did not withdraw from the study as a result of this serious adverse experience. N Code RELATIONSHIP TO TRIAL MEDICATION as: Y = Yes, there is a reasonable possibility that the non-serious adverse experience may have been caused by the trial medication. = No, there is a not reasonable possibility that the non-serious adverse experience may have been caused by the trial N medication. Code SERIOUSNESS as: A = Fatal B = Life-threatening = Disablinglincapacitating C D = Hospitalization required or prolonged E = Overdose = Grade 4 laboratory abnormality F

SAE.doc

Page 228

Company Serious Adverse Experiences (Page 2)

Subject Initials:

Protocol Number:

Subject #: Date of Report:

Drug Name: Investigator Name:

Date started DD/MMM/YY

present at the time of the SAE?

If “NO,”date of last occurrence DD/MMM/YY

0 017 0/n 0

0 017 0 0/00 Other Relevant Risk Factors

Specify any family history or any social history (e.g., smoking, alcohol, diet, drug abuse, occupational hazard, etc.) relevant to the SAE.

SAE.doc

Page 229

Company Serious Adverse Experiences

Subject Initials:

Protocol Number:

Subject #:

Drug Name:

(Page 3

Date of Report:

Investigator Name:

Trial Medication Details Date of Dose DDINIMMIYY

Time of Dose

Treatment

Total Dose

Relevant Concurrent Medications Include anv concurrent medications that mav contribute to the occurrence of the SAE. 4

Drug trade name

Dose

Units

*hepency

*Route

Date started DDIMMMIYY

I

1

Prestudy

Date stopped DDlMMMlYY

I

PostSAE

Conditions Treated indication

1

Details of Relevant Assessments Provide details of other assessments (e.g.. laboratory data with normal ranges) or supplemental examinations.

SAE.doc

Page 230

Company Serious Adverse Experiences

Sub ect Initials : Subject #:

Drug Name:

(Page 4)

Date of Report:

Investigator Name:

Protocol Number:

Reporting Investigator To the best of my knowledge, II information entered on this Serious Adverse Experience CRF for this subject is correct. Name Address Print name:

Signature:

SAE.doc

Page 23 1


Company Safety Information Form Protocol #:


Investigator:

Sponsor:


Attached is: An updated version of the Investigator's Brochure (dated xx/xx/xx, version An updated package insert (dated xx/xx/xx, version -) IND Safety Report (# ,dated xx/xx/xx) IND Safety Report (# ,dated xx/xx/xx) IND Safety Report (# ,dated xx/xx/xx) IND Safety Report (# ,dated xx/xx/xx) An SAE Report for an event that occurred at this study site (# ,dated xx/xx/xx) This SAE was: fatal life-threatening permanently disabling required in-patient hospitalization congenital anomaly an important medical event

associated with the use of the drug not associated with the use of the drug questionable or unknown

expected unexpected

Changes to the informed consent document (dated xx/xx/xx, version -1: is necessary. A revised draft (dated xx/xx/xx, version )is attached. is not necessary. Enrollment


Number of drop-outs

Number of subjects ongoing



Safety Rpt.doc


Date

Page 233


Company Study Site Personnel Signature Sheet Protocol #:


Investigator:

Sponsor:


Initials:

Name (Print): Signature: Study assignment or role:

Principal Investigator

Telephone number:

Name (Print):

Initials:

Signature: Study assignment or role:

Study Coordinator

Telephone number:

Name (Print):

Initials:


Subinvestigator

Telephone number:

Name (Print):

Initials:


Sig Sheet.doc

Subinvestigator

Telephone number:

Page 235

Company Study Signature Sheet (contd.) Initials:

Name (Print): Signature: Study assignment or role:

Telephone number:

Name (Print):

Initials:


Telephone number:

Name (Print):

Initials:


Telephone number:

Name (Print):

Initials:


Telephone number:

Name (Print):

Initials:


Sig Sheet.doc

Telephone number:

Page 236

Company

IRB Study Termination Acknowledgement Proposal No. Protocol No.

Dear Dr. On , the received notification of the termination of the protocol entitled . No additional subjects may be enrolled in this study. To be in compliance with the requirements of this Board and FDA regulations, you must: Retain the study records for a period of two years after the NDA is submitted to the FDA. In the event that you retire, relocate, or for any reason withdraw from the responsibility for maintaining records for the period of time required, custody of the records must be transferred to another person who will accept the responsibility for the records. Notice of such transfer should be given in writing to the sponsor and to this Board. Allow FDA, OHPR, and other regulatory authorities access to the study records. Sincerely, Chairman

St Term Ack.doc

Page 237


Company

IRB Notification of Study Termination Form Protocol #:


Investigator:

Sponsor:


This is to notify you that the study listed above is completed at this site. The last subject has completed hislher last study evaluation. No additional subjects will be enrolled. The following information is pertinent concerning the study: Enrollment Number of subjects screened

Number of drop-outs

Number of subject enrolled

Number of subject completed

Subject Initials

St Term Notice.doc

Subject Number

Reason for Drop-Out

Page 239

Company Summary of SAEs

Summarv of GCP Violations Subject Initials

Subject Number

GCP Violation

If you have any questions concerning the information in this report, please contact me at (phone number)

Principal Investigator (print) St Term Notice.doc


Date Page 240

Company Training Plan Form Employee:

Training Employee Handbook

Instructor's Initials*

Instructor

I

I

Date completed

I

Company SOPs Departmental SOPs Project-Specific SOPs Protocol Investigator's Brochure for

:

Instructor's initials indicate student has completed that portion of the training plan.

Training Plan.doc

Page 241


Company Training Record Form Employee

Training Record.doc

Page 243

Company

Employee

Training Record.doc

Page 244

Company

Employee

Training Record.doc

Page 245


Company Staff Training Request Form

Employee requesting training Training program being requested Training date(s) Location of training Cost of training program (registration and fees) Additional costs anticipated (hotel, airfare, etc.)

Training description (attach program outline, if available)

Purpose of the training

Employee's signature and date: Supervisor's signature and date: Approved? Yes

Training Request.doc

Page 247


Company Staff Training Verification Form

Employee Training program Training date(s) Location of training

Training description (attach certificate of attendance and program agenda, if available)

Employee's signature and date:

Training Verification.doc

Page 249


Company Site Evaluation Visit Trip Report Protocol #:

Investigator Name:

Visit Date:

DrugIDevice:

Institution Address:

Visit Conducted By:

Principal Investigator

yes

Subinvestigator

yes

Subinvestigator

yes

Study Coordinator

yes

Pharmacist

yes

q yes

ONO ONO ONO ONO ONO ONO

IRE3 name: Chairman: IRE3 address:

Will the protocol need to be reviewed by any other committee in addition to the Does the Investigator, Subinvestigator, or Study Coordinator serve on the m ? How often does IRB meet? What are the dates of the next three meetings?

Trip Rpt Evaluation.doc

Page 251

Company Pharmacy Pharmacist name: Pharmacist address:

Will the drug be shipped to the same institution where the Investigator is present? Are the drug storage facilities secure? Are the drug storage conditions adequate (e.g., light, humidity, etc.)? STUDY INITIATION DOCUMENTS

CHECK IF DOCIJMENT WAS RETRIEVED AT THIS

VISIT. Signed FDA Form 1572

IRB approval of Protocol and ICF

CV for Principal Investigator

IRE3 approval of Advertisements

I List of IRB members or assurance I Investigator's budget

CVs for Subinvestigators CVs for Study Coordinator

I ~ u d g eapproval t l Indemnification

Financial Disclosure for Investigator Financial Disclosure for Subinvestigator

Draft Informed Consent

0 0

I Laboratory certification

Financial Disclosure for Study Coordinator Signed Protocol Signature Page

#

0 I Laboratory normal values q I Other:

Overall Assessment

Yes

No

Comment

Investigator and staff are qualified to conduct the study Investigator and staff has adequate time to conduct the study

00 1 Recruitment is expected to be subjects per

Investigator has access to adequate number of patients for the study

p

Investigator agrees to conduct study as outlined in Protocol/l572

00 1

Facilities and equipment are adequate for study Appropriate maintenance and calibration records are available Patient care areas are acceptable Clinical laboratory is acceptable Storage area for CRFs and regulatory documents is acceptable


00 1 00 1 00 1 00 1 Page 252

Company Overall Assessment (continued)

Yes

Comment

No

Support staff are available to study personnel if needed Study staff agree to provide access to medical records

00 If yes, comment:

Does the site have any studies that may impact accrual?

Has the Investigator or any of the Subinvestigators ever been disqualified from receiving investigational products?

If yes, comment:

Additional Comments/Observations

Signature of person who conducted the visit


Date

Page 253


Company Study Initiation Visit Trip Report Protocol #:

Investigator Name:

Visit Date:


Visit Conducted By:

Principal Investigator Subinvestirzator Subinvestigator Study Coordinator Pharmacist

Signed FDA Form 1572

I IRB approval of Protocol and ICF

CV for Principal Investigator

IRE3 approval of advertisements

CVs for Subinvestigators

List of IRE3 members or assurance #

CVs for Study Coordinator

Investigator's budget

Financial Disclosure for Investigator

Indemnification

Financial Disclosure for Study Coordinator

Laboratory certification

Signed Protocol Signature Page Draft Informed Consent

Trip Rpt Init.doc

0 0

I Budget approval

Financial Disclosure for Subinvestigator

0

I Laboratory normal values 0 l Other: Page 255

Company

1.

Investigator's regulatory obligations

2.

Investigator's Brochure and study drug background

3.

Protocol objectives and endpoints

4.

Study time and events schedule

5.

Inclusion/exclusion criteria

6.

Recruitment strategies, including advertising

7.

Informed consent and assent procedures

8.

Screen failure documentation, if applicable

9.

Procedures for handling protocol deviations

10. IRE3 issues 11. Adverse Events and Serious Adverse Events 12. Guidelines for handling subject deaths 13. Guidelines for handing subject discontinuation 14. Guidelines for handing study discontinuation 15. Contract and payment schedule 16. Record retention 17. Drug supplies and accountability 18. Dosing schedule 19. Concomitant medication restrictions 20. Randomization and assigning subject numbers 21. Protection of the study blind, if applicable 22. Unblinding procedures 23. Handling and delivery of samples to the lab 24. Laboratory test kits

Trip Rpt Init.doc

Page 256

Company

30. Audit possibilities 3 1. Record retention

32. Other (explain): 33. Other (explain): 34. Other (explain):


Trip Rpt Init.doc

Date

Page 257


Company Periodic Site Visit Trip Report Protocol #:

Investigator Name:

Visit Date:

DrugIDevice:


Visit Conducted By:

Enrolled: Ongoing: Completed: Discontinued: See Comments section for a description of discontinued subjects.

3.

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

Were there any protocol deviations or violations?

6.

Is the blind being maintained correctly?

7.

Are corrections to the data being made by authorized

9.

Were there any changes in facilities or equipment?

10. Is the Screening and Enrollment Log current? 11. Are there any issues concerning the budget or Investigator payment?

13. Are there any issues concerning laboratory test kits?

Trip Rpt 1nterim.doc

Page 259

Company

\.es

No

YIA

yes

NO

c'omn~ent

YCS

NO

~oturncnt

Comment

th the Investigator to discuss

Informed Consent

22. Informed consents were checked for the following subjects:

Case Report Form Review

28. Source documents for the following CRFs were reviewed Subject

Subject Initials


Study Visits or CRF pages checked

Comment

Page 260

Company SERIOUS ADVERSE EXPERIENCES

I Since the last monitoring visit the following SAEs have occurred SAE

Start Date

Stop Date

Relationship to drug

yes

Study Drug I

Expected or Unexpected

None Outcome

C'oolalent

KO I

I

I

45. Curriculum vitae


Page 261

I

Company

Were all Action Items in the previous trip report accomplished? If "no," repeat outstanding items in section below.



Yes

No

Date

Page 262

Company Study Termination Visit Trip Report Protocol #:

Investigator Name:

Visit Date:

DrugIDevice:


Visit Conducted By:

Enrolled: Ongoing: Completed: Discontinued:

c

2.

Were there any deviations from the eligibility criteria since the last site visit?

3.

Was the Subject Enrollment Log completed and a copy retrieved for Company files?

4.

Are any blank CRFs or study supplies remaining at the site?

Informed Consent

yes

NO

Comment

ed consents reviewed for &subjects l enrolled

9.

Informed consents were checked for the following subjects:

Trip Rpt Termination.doc

I

Page 263

Company

Case Report Form Review

YCS

Co~nment

KO

10. Has a completed CRF been retained in the file for each subject enrolled in the study?

1 13.

Source documents for the following CRFs were reviewed at this visit:

Subject #

Subject Initials

Study Visits or CRF pages checked

Comment

14. Do any of the previously reported SAEs need additional follow-up?

I Since the last monitoring visit, the following SAEs have occurred SAE

Study Drug

Trip Rpt Termination.doc

Start date

Stop date Relationship to drug

yes

NO

N:\

Expected or Unexpected

Outcome

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