Polaris

HANDBOOK OFSOPs FOR GOODCLINICAL PRACTICESECOND EDITIONCeline M. CliveInterpharm/CRCBoca Raton London New York Washington, D.C.© 2004 by CRC Press LLC

IntroductionThis handbook is divided into three sections containing Standard Operating Procedures(SOPs) applicable to the activities of the three major groups involved in the clinicaldevelopment process:• The Sponsor/Contract 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 theSOP sections. Some of the forms may apply to more than one group affected by theSOPs. For example, the “Subject Information and Consent Form Checklist” may be usedby Study Coordinators, when they are developing the document, and IRB members, whenthey are reviewing it.The advantage of this handbook is that by using the material found on the CRC Web site:www.crcpress.com/e_products/downloads/download.asp, each SOP and all of the formscan be customized to the needs of the specific institution. To do this, the user should openthe document and make a global change replacing the word “Company” with thecompany’s actual name. Be aware that the length of the company’s name may affect lineand page spacing and that some minor formatting may be needed after this global changeis implemented. If the institution’s logo is added to the header of the first page, theformatting may also need to be checked. Finally, the effective date should be added to theheader of the second page. From there, it will automatically be captured on all subsequentpages.These templates should serve as a starting point for the development of SOPs. The usershould ensure that the specific processes at his/her 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.© 2004 by CRC Press LLC

About PolarisClinical Research Consultants, Inc.Polaris Clinical Research Consultants, Inc. is a training and auditing company specializing inclinical research topics and processes. Our mission is to enhance the productivity andefficiency of clinical research teams by providing training, auditing, and Standard OperatingProcedure (SOP) development to our clients.Polaris offers consulting services to pharmaceutical companies, Contract ResearchOrganizations (CRO), investigative sites, and Institutional Review Boards (IRBs). Thecompany offers several off-the-shelf training programs for Monitors, Investigators, StudyCoordinators, and IRB Members. Because we are interested in establishing collaborativerelationships with our clients, more often our training programs are customized to the specificneeds of our clients. We recognize the demand for experienced professionals exceeds thesupply 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 throughexercises, case studies, role-playing, and worksheets. This active involvement by theparticipant ensures that the lessons become more intrinsic and the learning becomes moreeffective.• Experienced personnel. Polaris ’ training programs are developed and delivered byexperts in various areas of the pharmaceutical industry. This provides students with highquality training that is realistic and practical.• Program flexibility. Polaris ’ training is delivered so that the point-of-view and needs ofboth the CRO and Sponsor company are discussed. Programs to investigative sites includediscussions on what site personnel are required to do by regulation and which tasks aredriven by Sponsor-specific requirements.Celine M. ClivePolaris Clinical Research Consultants, Inc.130 Iowa Lane; Suite 103Cary, NC 27511Telephone: 919-463-0003Fax: 919-463-0004E-mail: CMClive@AOL.com© 2004 by CRC Press LLC

Programs Available through Polaris• 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 Initiation• 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 Material/Drug 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© 2004 by CRC Press LLC

Table of ContentsMON-001.0MON-002.0MON-003.0MON-004.0MON-005.0MON-006.0MON-007.0MON-008.0MON-009.0MON-010.0MON-011.0MON-012.0MON-013.0Sponsor/Monitor/CRO SOPsPreparation, Issue, and Revision of Standard OperatingProcedures (SOPs)Training Clinical Research StaffSelecting Investigators and Study SitesDeveloping Informed Consent FormsConducting Site Evaluation VisitsConducting Study Initiation VisitsConducting Periodic Site VisitsReviewing Case Report Forms at the Study SiteReviewing Regulatory DocumentsAdverse Experiences (AEs), Serious Adverse Experiences(SAEs), and IND Safety ReportsManaging Study-Specific Clinical SuppliesConducting Study Termination VisitsTelephone Contact ReportsSITE-001.0SITE-002.0SITE-003.0SITE-004.0SITE-005.0SITE-006.0SITE-007.0SITE-008.0SITE-009.0SITE-010.0SITE-011.0Investigational Site SOPsPreparation, Issue, and Revision of Standard OperatingProcedures (SOPs)Training Study Site Clinical Research StaffAssessing Protocol FeasibilityInvestigator Agreements with Sponsors or Contract ResearchOrganizationsOrganizational Chart for the Study SiteInteractions with the Institutional Review BoardRecruiting Study PatientsStudy Initiation and ImplementationReviewing and Obtaining Informed ConsentAdverse Experiences (AEs), Serious Adverse Experiences (SAEs)and IND Safety ReportsDrug Storage and Accountability© 2004 by CRC Press LLC

SITE-012.0SITE-013.0SITE-014.0Managing Biological SamplesInteractions with the Sponsor or Contract Research Organization(CRO)Study Files and Record RetentionIRB-001.0IRB-002.0IRB-003.0IRB-004.0IRB-005.0IRB-006.0IRB-007.0IRB-008.0IRB-009.0File Name (.doc)Ad ReviewAmendmentBio SampleCRF ReviewDCF FormDispenseDispense by PtDrug DispositionDrug OrderDrug ReceiptDrug ReturnEnrollmentExpeditedICF ReviewInit Doc TrackInstitutional Review Board SOPsInstitutional Review Board ResponsibilitiesIRB Membership and TrainingInstitutional Review Board MeetingsIRB Record KeepingIRB Review of ResearchIRB Review of Informed ConsentIRB Review of AdvertisementsIRB Review of Unscheduled Mandatory ReportsCriteria for Exempt and Expedited ReviewForms – Alphabetical by File NameForm NameAdvertisement Review ChecklistProtocol Amendment FormBiological Samples InventoryCRF Review FormData Clarification FormDrug Dispensing LogStudy Subject Investigational Product Dispensing RecordClinical Trial Materials Disposition FormInvestigational Drug Shipping OrderInvestigational Product Receipt FormDrug Return FormScreening and Enrollment LogExpedited Review FormSubject Information and Consent Form ChecklistStudy Initiation Document Tracking Worksheet© 2004 by CRC Press LLC

Initial SubIRB MemberMinutes TemplateMonitor LogPatient MasterPhone RptProgress RptResponsibilitiesReview CklistReview ResultsSAESafety RptSig SheetSt Term AckSt Term NoticeTraining PlanTraining RecordTraining RequestTraining VerificationTrip Rpt EvaluationTrip Rpt InitTrip Rpt InterimTrip Rpt TerminationInitial Submission FormIRB Membership RosterIRB Meeting Minutes TemplateMonitoring LogMaster Subject LogTelephone Contact ReportIRB Progress Report FormStudy Responsibilities FormReviewer’s ChecklistIRB Review Results FormSerious Adverse ExperiencesSafety Information FormStudy Site Personnel Signature SheetIRB Study Termination AcknowledgementIRB Notification of Study Termination FormTraining Plan FormTraining Record FormStaff Training Request FormStaff Training Verification FormSite Evaluation Visit Trip ReportStudy Initiation Visit Trip ReportPeriodic Site Visit Trip ReportStudy Termination Visit Trip Report© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-001.0Title: Preparation, Issue, and Revision of SOPsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To describe the procedures by which Standard Operating Procedures (SOPs) forCompany are prepared, issued, and revised.• To provide a tool for training new personnel in the procedures by which specificactivities will be performed at Company.II.ScopeThis SOP will apply to all SOPs for Company.MON-001.0.doc© 2004 by CRC Press LLC

SOP# MON-001.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. The Department Head for each Department will determine which activities requireSOPs and will assign the responsibility for writing the initial version.B. All SOPs should include:1. 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 QualityAssurance (QA) representative.5. Revision history.6. Scope of the SOP (i.e., a statement that describes the personnel, projects, andsituations to which the SOP applies).7. Description of the procedure (i.e., a detailed description of all procedures to beconducted under the SOP, including when they are to be accomplished, where,and by whom). Each step in the procedure should be numbered. All new orunusual terms should be defined. If an abbreviation is associated with a term, itshould be placed in parentheses following the word. If specific forms orequipment are to be used, they should be specified. Copies of the applicableforms 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, and/or tables that will beused in executing the SOP). The Attachments section should begin with a list ofall the attachments that are included in the SOP. Attachments should be identifiedby letter.C. Review and Approval of SOPs1. The Author will circulate the draft SOP to the Author’s department members forreview and comment.2. The Department Head will perform the final review and edit of the SOP and willsubmit the final versions to QA for review.3. After completing its final review, QA will reconcile all questions and/orsuggested revisions with the Author prior to issue.4. The final version of each SOP must be approved by the Department Head and adesignated member of the QA Department before issuance. QA will obtainoriginal signatures on the SOP cover sheet before releasing the final versions ofan SOP.MON-001.0.doc© 2004 by CRC Press LLC

SOP# MON-001.0CompanyEffective Date: DD/MMM/YYD. Distribution of SOPs1. Each department will maintain an active SOP manual containing authorizedcopies of all current approved SOPs.2. QA will retrieve or discard all distributed versions of the SOPs (i.e., not thearchive copy) as new versions are implemented.E. Maintaining original, signed SOPs1. QA will maintain a complete collection of current Company SOPs and will retainall obsolete, discontinued, or otherwise superseded SOPs in an SOP archive.F. Revision of SOPs1. SOPs requiring permanent modifications will be revised by the Author orindividual designated by the Department Head. Revised SOPs will be circulatedfor review and approval as described in Section III.C.2. QA will update the cover page of the revised SOP to show subsequent revisionsof the SOP.G. Periodic Review of SOPs1. All SOPs will be reviewed on an annual basis to determine whether modificationsare needed or if the SOP remains in use. Annual review of SOPs will be initiatedby 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 storedby QA in the SOP archives.3. Changes to the SOP will be made according to procedures described inSection III.C.4. Documentation of annual SOP review will be maintained in the SOP archives.IV.ReferencesICH Guidelines for Good Clinical Practice (E6) 5.1 – Quality Assurance/Quality ControlV. AttachmentsNoneMON-001.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-002.0Title: Training Clinical Research StaffEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeScope• To ensure all clinical monitoring staff members are trained concerning FDAregulations, 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 andcontinuing education.This SOP applies to all employees and independent contractors for Company.MON-002.0.doc© 2004 by CRC Press LLC

SOP# MON-002.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Employee Training1. Initial Employee Training begins on the new employee’s starting date andcontinues throughout a training period determined by the department managerand/or selected department representative. Continuous Employee Training occursthroughout 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 theemployee’s signature on the Confidentiality Agreement and will place the signedAgreement in the employee’s file.2. The Human Resources Department or Department Head will give the EmployeeHandbook to the new employee on his/her start date. This handbook covers thecorporate history, policies, and general philosophies of the company.3. The Department Head will appoint a supervisor/mentor to be responsible for thenew employee’s training.4. The Supervisor will ensure proper training for the new employee by providingcopies of Company and Departmental SOPs and other educational materials to thenew employee. Based on the employee’s prior experience, the Supervisor andemployee will develop a training plan for the employee and a timeframe forcompletion. The training plan will be outlined on the Training Plan Form(Attachment A).5. The new employee will read the Employee Handbook and other educationalmaterials that pertain to his/her specific department and will acquire hands-ontraining for certain functions of the job.6. Appropriate staff will sign off on the employee’s Training Plan Form as thetraining is completed. When the Training Plan Form is complete, the employeewill return the form to his/her supervisor, who will file the document with theemployee’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 theemployee’s signature on the Confidentiality Agreement and will place the signedAgreement in the employee’s file.MON-002.0.doc© 2004 by CRC Press LLC

SOP# MON-002.0CompanyEffective Date: DD/MMM/YY2. The Department Head will appoint a supervisor/mentor to be responsible for thenew temporary employee’s training.3. The Supervisor will ensure proper training for the new temporary employee byproviding copies of appropriate Company and Departmental SOPs and othereducational materials to the new temporary employee. Based on the employee’sprior experience, the Supervisor and temporary employee will develop a trainingplan and a timeframe for completion. The training plan will be outlined on theTraining Plan Form (Attachment A).4. The new temporary employee will read the SOPs and other educational materialsthat pertain to his/her specific department and will acquire hands-on training forcertain functions of the job.5. Appropriate staff will sign off on the employee’s Training Plan Form as thetraining is completed. When the Training Plan Form is complete, the temporaryemployee will return the form to his/her supervisor, who will file the documentwith the employee’s training record.D. Continuous Training – All permanent and temporary employees are responsible forkeeping current with the industry and technology. To accomplish this, an employeeor the employee’s supervisor may identify the necessary training. All training mustbe 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) basedon 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 HRDepartment for archiving.3. If training was approved, the employee will complete any other forms (such asregistrations or the Travel Request Form) and submit them to the appropriatedepartment (e.g., Travel).4. The supervisor and employee will review the employee’s training record on atleast an annual basis.E. Employee Training Verification – When an employee receives training, he/she shouldcomplete the Staff Training Verification Form (Attachment C) and submit it to theappropriate department to be filed with the employee’s training records.MON-002.0.doc© 2004 by CRC Press LLC

SOP# MON-002.0F. Retention of Training FilesCompanyEffective Date: DD/MMM/YY1. Training records for each employee will be cumulative and will be retained foreach employee’s tenure with the Company.2. Training records are subject to inspection by authorized regulatory agencyinvestigators.G. Contents of Training Files – Each employee’s training record should contain aminimum of the following:1. Curriculum vitae (CV) or resume – updated annually and reflecting employmentat Company. Because this is a cumulative document, only the current version ofthe CV should be retained in the file.2. Current job description.3. Completed Training Record Form (Attachment D) with appropriatedocumentation attached (i.e., completed and updated training form(s) andcertificates of completion or diplomas received for training programs or othersupplemental education).IV.References21 CFR 312.53 – Selecting Investigators and MonitorsICH Guidelines for Good Clinical Practice (E6) section 5.18 – MonitoringAttachmentsAttachment A – Training Plan FormAttachment B – Staff Training Request FormAttachment C – Staff Training Verification FormAttachment D – Training Record FormMON-002.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-003.0Title: Selecting Investigators and Study SitesEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe procedures for selecting Investigators, including the preliminary evaluationof the qualifications of Investigators and other study personnel and an assessment of theability of a prospective clinic site to perform the proposed study.II.ScopeThis SOP will apply to the selection of all Investigators for Company.MON-003.0.doc© 2004 by CRC Press LLC

SOP# MON-003.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. The Project Leader will develop criteria by which the acceptability of a prospectiveInvestigator will be determined. These criteria will include:a. Investigator's clinical expertise and reputationb. Study staff competencec. Access to patientsd. Facilities and equipmente. Investigator’s level of cooperationf. Investigator’s level of accessibilityg. Time and cost factorsh. Site locationB. The Project Leader or designee will develop a list of potential Investigators for theclinical trial from the following sources:1. 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 discipline5. Members of FDA Advisory Panels6. Membership lists and Web listings for professional societies;7. Authors of scientific publications pertinent to therapeutic area/disease state;and8. Experts in the field of study.C. The Project Leader or Senior Clinical Research Associate will contact the potentialInvestigator, either by telephone or by faxing a questionnaire, to determine his/herinterest in the study.D. Members of Company Legal Department will develop a Confidentiality Agreementfor the potential Investigators.E. The Project Leader, Senior Clinical Research Associate, or designee will send theConfidentiality 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:1. Study synopsis and/or 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 andcompleted questionnaire), the Project Leader or Senior CRA will make follow-upphone calls to the potential Investigators to discuss the protocol in more detail and tolearn more about the site’s capabilities and patient population.MON-003.0.doc© 2004 by CRC Press LLC

SOP# MON-003.0CompanyEffective Date: DD/MMM/YYH. Site Evaluation Visits will be scheduled to the institutions where potentialinvestigators appear to meet the pre-determined selection criteria. Some additionalinvestigators may be approved or eliminated on the basis of Site Evaluation Visitfindings.IV.References21 CFR 312.50 – General Responsibilities of Sponsors21 CFR 312.53 – Selecting Investigators and MonitorsICH Guidelines for Good Clinical Practice (E6) section 5.6 – Investigator SelectionICH Guidelines for Good Clinical Practice (E6) section 5.9 – FinancingICH Guidelines for Good Clinical Practice (E6) section 5.10 – Notification/Submission toRegulatory AuthoritiesV. AttachmentsNoneMON-003.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-004.0Title: Developing Informed Consent FormsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To describe the information required to be included in all informed consentdocuments developed by Company.• To provide ancillary information to facilitate preparation of acceptable informedconsent forms.II.ScopeThis SOP will apply to all informed consent documents developed by Company.MON-004.0.doc© 2004 by CRC Press LLC

SOP# MON-004.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Informed Consent Form (ICF) Template AuthorThe template for an Informed Consent Form may be developed by an In-HouseClinical Research Associate or Clinical Research Associate, as long as someone at ahigher level approves the final document.B. Required Elements and Additional ConsiderationsThe Informed Consent Form will be developed so that all basic elements of consentand the applicable additional elements are contained in the document according to theregulations. Because the ICH guidelines make no distinction between basic andadditional elements (i.e., these guidelines state that all basic and additional elementsare required for all consent forms), Informed Consent Forms being developed fortrials that will have study sites outside the United States will be developed accordingto the more strict ICH guidelines.In addition to the basic elements of consent, the author will also consider thefollowing points when developing the document:1. The information must be given to the subject or the subject’s representative inunderstandable language (i.e., usually an eighth-grade reading and comprehensionlevel). Ultimately, the preferences concerning style, format, and specific wordingrequired by the IRB will be followed.2. The informed consent must not include any language suggesting that the subjectrelinquishes any legal rights or that he/she releases the Investigator, sponsor, orinstitution or their agents from liability for negligence.3. The content of the informed consent document must present the benefits and risksof the research in such a manner that the subject (or representative) can make aninformed choice concerning his/her participation in the study.C. FormatThe ICF template author will consider the following items:1. The first page will be on the institution’s letterhead or include the followinginformation:a. Name and address of the institutionb. Name and address of the Principal Investigatorc. Name and number of the protocol2. 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 thesignature line for the entire document).5. Each page will be numbered (e.g., Page 2 of 3).MON-004.0.doc© 2004 by CRC Press LLC

SOP# MON-004.0D. Template Consent FormsCompanyEffective Date: DD/MMM/YYUsually, an informed consent template will be developed because each IRB will havespecific wording requirements that will need to be incorporated into the documentused at that facility (e.g., how compensation will be handled in the event of a studyrelatedinjury). The In-House Clinical Research Associate (CRA) will send thetemplate to the Investigator and/or Study Coordinator with the protocol. Sitepersonnel will enter the site-specific wording and will return the document toCompany. The In-House CRA or Monitor will ensure that all elements of consentand other requirements (e.g., layman’s language) are met before the StudyCoordinator will submit the draft document to the IRB for approval. In considerationof the lead times required for submission of documents to the IRB, Company In-House CRA or Monitor will perform the review of the site-specific informed consentpromptly.E. Non-English Informed ConsentWhen a study population includes non-English speaking people, the Monitor willassist the Investigator to ensure that the translated version of the consent form isprepared and that the translation is accurate. The translation from English to anotherlanguage will be accomplished by someone who will certify in writing the accuracyof the translation. For non-English consent forms, the Monitor will ensure thatCompany and site study files contain:1. The name and address of the translator,2. A copy of the translator’s certificate, and3. A memo to the file signed by the translator that states that the foreign languageconsent document is an accurate translation of the English consent form.Note: Informed Consent Form authors should also check individual state laws thatmight concern the translation of legal or other documents. Specific IRBs may alsohave their requirements concerning what is acceptable practice and documentationfor the translation of consent forms.IV.References21 CFR 50.20 – General Requirements for Informed Consent21 CFR 50.23 – Exception From General Requirements21 CFR 50.25 – Elements of Consent21 CFR 50.27 – Documentation of Informed Consent45 CFR 46.116 – General Requirements for Informed Consent45 CFR 46.117 – Documentation of Informed ConsentICH Guidelines for Good Clinical Practice (E6) section 1.28 – Informed ConsentMON-004.0.doc© 2004 by CRC Press LLC

SOP# MON-004.0CompanyEffective Date: DD/MMM/YYICH Guidelines for Good Clinical Practice (E6) section 1.37 – Legally AuthorizedRepresentativeICH Guidelines for Good Clinical Practice (E6) section 4.8 – Informed Consent of TrialSubjectsFDA Information Sheets – Continuing Review After Study Approval, January 2001FDA Information Sheets – Guide to Informed Consent, 1998 UpdateFDA Information Sheets – Recruiting Study Subjects, December 1999FDA Information Sheets – Screening Tests Prior to Study Enrollment, December 1999Belmont ReportDeclaration of HelsinkiV. AttachmentsNoneMON-004.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-005.0Title: Conducting Site Evaluation VisitsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeThe 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.II.ScopeThis SOP will apply to all Site Evaluation Visits being conducted by Company personnel.MON-005.0.doc© 2004 by CRC Press LLC

SOP# MON-005.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. GeneralSite Evaluation Visits may also be known as site selection visits or pre-study sitevisits (PSSV). These visits may be conducted only by individuals at the level ofMonitor/Clinical Research Associate (CRA) or above. A Site Evaluation Visit isrequired unless someone from Company has conducted a visit to the site within thelast 12 months for a study in the same therapeutic area or which utilizes the samePrincipal Investigator. In this case, a memo will be written and kept in the CentralStudy File documenting the date and purpose of the previous site visit.B. Prior to the Site Evaluation VisitPrior to conducting a Site Evaluation Visit, the Monitor or Project Manager will:1. Confirm that a signed confidentiality agreement has been received from thePrincipal Investigator.2. Review the curriculum vitae of the Principal Investigator and StudyCoordinator(s) to assess qualifications, credentials, and experience in intendedtherapeutic area.3. Verify that medical licenses for the Principal Investigator and all medicalSubinvestigators are current.4. Check the names of all Investigators and Subinvestigators against the FDA list ofInvestigators Ineligible to Receive Investigational Products (i.e., the “blacklist”).5. Prepare the Study Initiation Document Tracking Worksheet to document sendingand retrieval of regulatory documents (Attachment A).6. Schedule a visit with the Investigator(s) and study personnel.7. Send confirmation letter outlining purpose of visit and items for discussion.8. Discuss applicable drug storage requirements with appropriate Companypersonnel.9. Discuss any special laboratory assays or procedures with appropriate Companypersonnel.C. Conducting the Site Evaluation VisitDuring the Site Evaluation Visit, the Monitor will:1. Evaluate the acceptability of the investigational site by touring the facilities todetermine:a. If the drug dispensing and storage area is secure, has limited access, and meetsthe storage conditions listed in the protocol;b. If the patient care areas and clinical laboratory being used for the study areacceptable;c. If protocol-required equipment is present and maintenance and calibrationrecords are present; andd. If the storage area for CRFs, study manuals, regulatory documents, and otherstudy-related supplies and materials are secure and adequate.MON-005.0.doc© 2004 by CRC Press LLC

SOP# MON-005.0CompanyEffective Date: DD/MMM/YY2. Meet with the Investigator and Study Coordinator to evaluate the site’s potentialfor 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 staffingprocedures;d. FDA (or other applicable regulatory authority) and sponsor requirements forregulatory documents;e. Whether or not the site is currently participating in or plans to participate inany competing protocols; andf. 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 IRBc. The date of the next IRB meeting and deadline for submission of documents;d. How often the IRB meets; ande. 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 VisitFollowing the Site Evaluation Visit, the Monitor will:1. Discuss findings with appropriate Company personnel to determine acceptabilityof site for proposed study.2. Document the Site Evaluation Visit by:a. Completing a Site Evaluation Visit trip report (Attachment B); andb. Writing a follow-up letter to the potential Investigator. If the decision hasbeen 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 thestudy file.IV.References21 CFR 312.53 – Selecting Investigators and Monitors21 CFR 312.55 – Informing Investigators21 CFR 312.56 – Review of Ongoing Investigations21 CFR 312.57 – Record Keeping and Retention21 CFR 312.58 – Inspection of Sponsor Records and ReportsMON-005.0.doc© 2004 by CRC Press LLC

SOP# MON-005.0CompanyEffective Date: DD/MMM/YY21 CFR 56.107 – IRB MembershipICH Guidelines for Good Clinical Practice (E6) section 3.1 – ResponsibilitiesICH Guidelines for Good Clinical Practice (E6) section 4.2 – Adequate ResourcesICH Guidelines for Good Clinical Practice (E6) section 4.5 – Compliance with ProtocolICH Guidelines for Good Clinical Practice (E6) section 5.18 – MonitoringV. AttachmentsAttachment A – Study Initiation Document Tracking WorksheetAttachment B – Site Evaluation Visit Trip ReportMON-005.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-006.0Title: Conducting Study Initiation VisitsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeThe purpose of this SOP is to describe the activities that will be accomplished at a StudyInitiation Visit. The purpose of a Study Initiation Visit is:• To review with the Investigator and staff the final protocol, the Investigator’sBrochure and regulatory requirements, and• To instruct study personnel in study procedures including, but not limited to patientrecruitment, informed consent, drug dispensing and accountability, and Case ReportForm completion.MON-006.0.doc© 2004 by CRC Press LLC

SOP# MON-006.0CompanyEffective Date: DD/MMM/YYII.III.ScopeThis SOP will apply to all Study Initiation Visits conducted by Company.ProceduresA. GeneralStudy Initiation Visits may be conducted only by individuals at the level ofMonitor/Clinical Research Associate (CRA) or above. If the Monitor for the studysite has been selected, it is recommended that he/she attend the Study Initiation Visit.The Monitor should ask to have all study personnel present at the Study Initiationmeeting. At the conclusion of the visit, the Monitor must be satisfied that all staffmembers participating in the study are sufficiently informed to competently fulfilltheir responsibilities. All unresolved issues should be discussed with the ProjectManager and then readdressed with the Investigator.A Study Initiation Visit will be conducted after a site has been selected to participatein a trial but before subject screening and enrollment begins. This visit allows allparticipants (including the pharmacist, radiologist, and other personnel who did notattend the investigator’s meeting) to receive detailed instruction concerning their rolein the study.B. Prior to the Study Initiation VisitPrior to the Study Initiation Visit, the Monitor will:1. Determine which regulatory documents are outstanding and should be retrieved atthe visit.2. Schedule the visit with Investigator(s) and study personnel.3. Send a confirmation letter outlining the purpose of the visit and items fordiscussion and listing outstanding regulatory documents to be retrieved.4. Gather study materials to carry/ship to the site, such as a sample Case ReportForm, 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 VisitDuring the Study Initiation Visit, the Monitor will:1. Meet with the Investigator to discuss federal requirements specified in FDA Form1572, including:a. Obtaining and documenting informed consent;b. IRB approval and progress reports, including amendments and SAEs;c. Protocol adherence;d. Drug accountability;MON-006.0.doc© 2004 by CRC Press LLC

SOP# MON-006.0CompanyEffective Date: DD/MMM/YYe. 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 placethem 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 andmajor 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 plansfor subject recruitment.c. IRB issues – including requirements for documentation of informed consent;requirement for periodic IRB review of the study; the need to obtain IRBapproval of protocol amendments prior to implementation; and therequirement to submit all serious adverse events to the IRB.d. Adverse/Serious Adverse Events (AEs/SAEs) – including definitions andreporting requirements; procedures for reporting AEs/SAEs to the sponsor;and Investigator requirements for reporting SAEs to the IRB.e. Delegation of study responsibilities – To document who will be responsiblefor specific study functions, the Study Responsibilities Form should becompleted and signed by the Investigator. (Attachment A)f. Contract and payment schedule issues – The Monitor may deliver the initialstudy payment, if appropriate.g. Record retention for study documents – Two (2) years after an NDA has beenapproved for the stated indication, or two (2) years after notification of FDAand 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 concerningdrug supplies and accountability – including inventory, dispensing procedures,storage and accountability procedures; handling and storage procedures forreturned drug; and the procedure for return of drug to the sponsor or destruction atstudy termination.5. Meet with the Study Coordinator and Lab Director or technician to reviewlaboratory issues including specimen collection and preparation; how results willbe handled; special assays and procedures; and the storage, preparation, andshipment of samples.6. Meet with the Study Coordinator to review:a. Case Report Form completion, includingi. General instructions for forms completion;MON-006.0.doc© 2004 by CRC Press LLC

SOP# MON-006.0CompanyEffective Date: DD/MMM/YYii. Completion of individual forms;iii. Signature requirements; andiv. Procedures for correction/revision of recorded data.b. Additional study supplies, includingi. Maintenance of the Regulatory Documents Binder;ii. Laboratory test kits;iii. The Monitoring Log; andiv. Study-specific forms, materials, and supplies, including. The Master Subject Log (Attachment B). Screening and Enrollment Log (Attachment C)c. Monitoring visits, includingi. Expectations for visits;ii. Frequency of visits;iii. Source document reviews; andiv. 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 tothe log, if appropriate.D. Follow-Up to the Study Initiation VisitFollowing the Study Initiation Visit, the Monitor will document the visit by:1. Completing a Study Initiation Visit trip report (Attachment E). If a slidepresentation was used to present the study, a paper copy of the presentationmaterial (e.g., handouts) must be attached to the trip report.2. Writing a follow-up letter to the Investigator. The letter should outline what wasaccomplished in the meeting and should note any items that need additionalattention.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 thatare not routinely documented in the medical records. The CRF may represent thesole documentation of such information. If this is the case, at study initiation,documentation must be included in the study files that specifically notes whichelements of the CRF will not be documented in the investigator’s records or may bedocumented in greater detail on the CRF than in the investigator’s records.IV.ReferencesICH Guidelines for Good Clinical Practice (E6) section 4.2 – Adequate ResourcesICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsMON-006.0.doc© 2004 by CRC Press LLC

SOP# MON-006.0CompanyEffective Date: DD/MMM/YYICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECICH Guidelines for Good Clinical Practice (E6) section 4.5 – Compliance with ProtocolICH Guidelines for Good Clinical Practice (E6) section 4.6 – Investigational ProductsICH Guidelines for Good Clinical Practice (E6) section 5.12 – Information onInvestigational ProductsICH Guidelines for Good Clinical Practice (E6) section 5.18 – MonitoringV. AttachmentsAttachment A – Study Responsibilities FormAttachment B – Master Subject LogAttachment C – Screening and Enrollment LogAttachment D – Monitoring LogAttachment E – Study Initiation Visit ReportMON-006.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-007.0Title: Conducting Periodic Site VisitsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeThe purpose of this SOP is to describe the activities that will be accomplished at aPeriodic 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 ofGood 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 theconduct of the study.MON-007.0.doc© 2004 by CRC Press LLC

SOP# MON-007.0CompanyEffective Date: DD/MMM/YYII.III.ScopeThis SOP will apply to all Periodic Site Visits conducted by Company.ProceduresA. GeneralPeriodic Site Visits (also known as Interim Visits) may be conducted only byindividuals at the level of Monitor/Clinical Research Associate (CRA) or above. Thetiming of Periodic Site Visits will vary by study and will be based on the:1. Number and rate of patients accrued in the study2. Complexity of the study design3. Experience with the investigator4. Nature and number of problems encountered5. Disease being treated.Phase I studies will be monitored at reasonable intervals as determined by the ProjectLeader and/or Medical Advisor. Each investigational site in Phase II and III studiesmust 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 andthe Case Report Forms have been completed;3. At least every eight weeks during the course of the study; and4. 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 anysuch decrease in monitoring frequency will be documented in the study file.B. Prior to the Periodic Site VisitPrior to the Periodic Site Visit, the Monitor will review the current status of the trialand 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 outstandingor 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; and9. Gather any documents or materials necessary for the visit.MON-007.0.doc© 2004 by CRC Press LLC

SOP# MON-007.0CompanyEffective Date: DD/MMM/YYC. Conducting the Periodic Site Visit1. Compliance with the Regulations and Protocol. To ensure adherence to theprotocol, applicable FDA regulations, ICH guidelines, and Companyrequirements, the Monitor will:a. Perform a detailed review of all study procedures and records generated fromthe conduct of the study;b. Confirm that each subject meets eligibility criteria;c. Ensure protocol violations are documented in the source document and CaseReport Form (CRF);d. Verify that adverse experiences have been appropriately reported anddocumented;e. Ensure correct randomization procedures and maintenance of blind (ifapplicable); andf. Document protocol violations, including violations of eligibility criteria, inthe Periodic Site Visit Report and follow-up letter to the Investigator.2. Data Verification. To ensure maintenance of adequate and accurate sourcedocuments and to ensure adequacy, accuracy, and completeness of the datarecorded 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’sinvolvement in the study.b. Ensure that the subject’s medical record documents subject enrollment,consent to participate in the study, and assessments/test results for eachstudy-related visit.c. Resolve any apparent entry violation and ensure an explanatory comment iscaptured in the source document and CRF.d. Ensure that the date and the reason(s) for discontinuation are documented inthe source documents and CRF for subjects who have been discontinuedfrom the study.e. Bring discrepancies between the CRF and the source document to theattention of the Study Coordinator. When possible, corrections will be madebefore the Monitor leaves the site. When this is not possible, the Monitorwill leave some form of written documentation that points out thediscrepancies at the site.f. Confirm that the CRF contains the Investigator’s signature and the date thepage was signed.g. Document any unresolved discrepancies in the Periodic Site Visit trip report;andh. Make arrangements for the shipment of the completed CRFs to DataManagement.The Company Monitor will not make entries in or alterations to a CRF or sourcedocument.MON-007.0.doc© 2004 by CRC Press LLC

SOP# MON-007.0CompanyEffective Date: DD/MMM/YY3. Facilities and Staff. To ensure the continued acceptability of the facilities andstaff, the Monitor will note if there have been any changes in space or equipmentor accreditation of the clinical laboratory facilities and study site personnel. Ifnecessary, 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 ofdrug receipt and disposition and to ensure secure storage and adequate suppliesof investigational drug, the Monitor will:a. Perform a routine check of all records dealing with the shipment, receipt, anddispensing of all test articles.b. Cross-check shipment records with records of receipt (i.e., contents of theshipment, corresponding identification numbers, and dates).c. Perform a routine check of the drug inventory to ensure that an adequatesupply of test article is maintained, storage conditions are being met, anddrug expiration dates are noted.d. Check the accuracy of dispensing and return records for test articles betweenthe Investigator and the individual study subject (i.e., subject identificationnumbers, lot numbers, quantity dispensed and returned, dates dispensed andreturned, label numbers, and balance on hand).5. Informed Consent. To verify proper completion of the Informed Consent Formby each subject prior to study entry, the Monitor will:a. Ensure that a signed copy of the informed consent document is present foreach subject enrolled in the study and each screen failure;b. Compare the date of initiation of therapy or prestudy testing with the date thesubject signed the Informed Consent Form to ensure the subject consented toparticipate in the study before actual enrollment; andc. Document in the Periodic Visit trip report the patient numbers of theInformed Consent Forms that were reviewed at each visit and anyirregularities found. Include a description of the irregularities in the followupletter to the Investigator.At a Periodic Site Visit, if a Monitor discovers that an outdated version of theconsent form was used for a subject whose participation in the trial has not beencompleted, he/she will instruct the Study Coordinator to contact the subject andhave the subject sign the correct version. When signing and dating the correctversion, the subject should use the actual date (i.e., do not back-date the consentform or use the same date as on the first, incorrect version). The Monitor willinstruct the Study Coordinator to maintain both signed versions of the consent inthe files. An explanatory memo to the file is recommended so that future auditorswill understand why two signed informed consent documents for the same subjectare 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 theattempts to reach the subject were made.MON-007.0.doc© 2004 by CRC Press LLC

SOP# MON-007.0CompanyEffective Date: DD/MMM/YYAt no time will the Monitor bring the signed informed consent forms in-house toeither Company.6. Adverse Experiences and Serious Adverse Experiences. To ensure collectionand 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 theinvestigator; ande. Document notable adverse experiences or trends in adverse experiences inthe Periodic Site Visit Trip Report.7. Regulatory and Other Study-Related Documents. To ensure maintenance of allstudy documents, the Monitor will check the investigator’s study file to ensurethat 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, andpackaging 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 and/or 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 and/orappropriate study staff to discuss the findings of this visit. The Monitor should:a. Summarize the accomplishmentsb. Summarize any problems or issuesc. Reach agreement on corrective actions that may be necessaryd. Discuss any problems staff members are having with the study (e.g., subjectaccrual or compliance)e. Suggest tentative dates for next visit10. Document the Visit. The Monitor will document the visit by signing theMonitoring Log (Attachment B).MON-007.0.doc© 2004 by CRC Press LLC

SOP# MON-007.0CompanyEffective Date: DD/MMM/YYD. Follow-Up to the Periodic Site VisitFollowing 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 wasaccomplished during the visit and should note any items that need additionalattention.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 CaseReport Forms and/or Data Clarification Forms.IV.References21 CFR 312.30 – Protocol Amendments21 CFR 312.50 – General Responsibilities of Sponsors21 CFR 312.56 – Review of Ongoing InvestigationsICH Guidelines for Good Clinical Practice (E6) section 4.2 – Adequate ResourcesICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECICH Guidelines for Good Clinical Practice (E6) section 4.5 – Compliance with ProtocolICH Guidelines for Good Clinical Practice (E6) section 4.6 – Investigational ProductsICH Guidelines for Good Clinical Practice (E6) section 4.7 – Randomization Proceduresand UnblindingICH Guidelines for Good Clinical Practice (E6) section 4.8 – Informed Consent of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 5.14 – Supplying and HandlingInvestigational Product(s)ICH Guidelines for Good Clinical Practice (E6) section 5.17 – Adverse Drug ReactionReportingV. AttachmentsAttachment A – Screening and Enrollment LogAttachment B – Monitoring LogAttachment C – Periodic Site Visit Trip ReportMON-007.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-008.0Title: Reviewing Case Report Forms at the Study SiteEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo standardize procedures for review of Case Report Forms (CRFs) retrieved fromclinical study sites and to establish a comprehensive plan for routing the CRFs fromretrieval through submission to Data Management.II.ScopeThis SOP will apply to all CRFs being processed by Company personnel.MON-008.0.doc© 2004 by CRC Press LLC

SOP# MON-008.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. On-Site Review of CRFsTo ensure that the data captured in the CRFs are accurate and complete, the Monitorwill verify that all data captured in the CRF are supported by source documentationand 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 lineb. Initial and date the errorc. Record the new data correctlyd. “White-out” not usede. Overscribes not used8. 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 theCRF?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?21. Is there the possibility that some data may be missed due to comments on theCRF such as “See page 40” or “See reverse”?22. Is there acceptable documentation in the CRF fora. Missing medications?MON-008.0.doc© 2004 by CRC Press LLC

SOP# MON-008.0CompanyEffective Date: DD/MMM/YYb. Protocol deviations, violations?c. Missing visits?d. Premature discontinuations?23. Has the Adverse Experiences page been checked fora. 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 fora. 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-visitb. Concomitant medications with adverse experiencesB. On-Site Data ClarificationsDuring the site visit, the Monitor will bring discrepancies between the CRF and thesource document to the attention of the Study Coordinator or other appropriate sitepersonnel. When possible, corrections will be made before the Monitor leaves thesite. When this is not possible, the Monitor will leave a completed CRF ReviewForm, 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 aCRF or source document.At the next site visit, the Monitor will confirm that all issues on the CRF ReviewForm have been addressed.The Monitor will ensure that no changes to the CRF occur after the Investigator hassigned the CRF.C. Retrieval of the CRFsAfter the Monitor has verified that all of the data in the CRF are supported by sourcedocuments and that all issues on the CRF Review Form for a specific subject havebeen resolved, he/she 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 willmake a copy of the original for the site’s files before removing it from the site.MON-008.0.doc© 2004 by CRC Press LLC

SOP# MON-008.0CompanyEffective Date: DD/MMM/YYBefore the first Periodic Site Visit is conducted for the study, the Project Leader andData Manager will make the decision concerning whether or not CRF pages thatcontain 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 CRFsshould be expected.The Monitor will specify in the trip report, which CRF pages have been reviewedand which have been transmitted to Data Management.The original CRFs will be transported by one of the following methods:1. Hand-carried by the Monitor. If travel is by air, the CRFs will be part of the carryon 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 QueriesAfter the CRFs have been removed from the study site, changes to the data on theretrieved pages that cannot be corrected without investigator verification will beaccomplished using the Data Clarification Form (Attachment B).The person who discovers the discrepancy in the data will prepare a DataClarification Form. If this person is in Data Management, he/she will forward theData Clarification Form to the Monitor, who will forward it to the Investigator/StudyCoordinator for resolution. The Monitor will instruct the Study Coordinator to makea copy of the signed and completed Data Clarification Form before returning theoriginal to the Monitor. The Study Coordinator will be encouraged to keep copies ofthe Data Clarification Forms with the CRFs.When the signed and completed Data Clarification Form is returned from the studysite, the Monitor will forward it to Data Management. Personnel in the DataManagement Department will follow their department’s SOPs for trackingoutstanding and resolved queries, updating the database, updating the working copyof the CRF, and filing the original Data Clarification Form.IV.References21 CFR 312.32 – IND Safety Reports21 CFR 312.44 – TerminationICH Guidelines for Good Clinical Practice (E6) section 4.5 – Compliance with ProtocolICH Guidelines for Good Clinical Practice (E6) section 4.9 – Records and ReportsMON-008.0.doc© 2004 by CRC Press LLC

SOP# MON-008.0CompanyEffective Date: DD/MMM/YYICH Guidelines for Good Clinical Practice (E6) section 5.1 – Quality Assurance/QualityControlV. AttachmentsAttachment A – CRF Review FormAttachment B – Data Clarification FormMON-008.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-009.0Title: Reviewing Regulatory DocumentsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. 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 studymaterials can be readily identified and retrievable.II.ScopeThis SOP will apply to all clinical studies for which Company is responsible forreviewing regulatory documents at the study site.MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Record RetentionAt the Study Initiation Visit, the Study Monitor should remind the Investigator that allstudy documents must be maintained for a period of two years following the date amarketing application is approved for the drug that is being investigated; or if theapplication is not approved for such indication, until two years after the investigationis discontinued and the sponsor notifies the FDA that the investigation isdiscontinued.B. General InstructionsEach section of the study file notebook should contain documentation or include amemo indicating that section is not applicable for that particular study, or a statementexplaining where the information can be found.Information within each section must be filed in chronological order so that the mostrecent document is at the front of the section.Each protocol requires its own separate notebook. If several protocols are beingconducted simultaneously, this may mean some documents should be copied so thatthey can be placed in both notebooks.No post-it notes or thermal fax documents should be present in the study filenotebook.No draft versions of documents should be in the notebook after a document has beenfinalized.Explanatory memos to the file are encouraged to ensure clarity.C. Physical Organization of the Site’s Study FilesAt the beginning of the study, the Monitor will provide the Investigator or StudyCoordinator with a study file binder or comparable system for organizing regulatorydocuments. To help with identification, each study file notebook should displayCompany name, IND number, protocol number, Investigator name, and site number.Certain documents are required before study drug or other supplies are shipped to thestudy site. As the study progresses, documentation of the study conduct will be addedto 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 andcomplete. A thorough review of the study file notebook will be conducted at theStudy Termination Visit.MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YYThe physical organization of the file may vary from study-to-study; however, at aminimum, the site’s file must include the following:1. Registration Documentsa. Signed FDA Form 1572b. Curriculum vitae for Investigator, Subinvestigator, and Study Coordinatorc. Signed Financial Disclosure Forms for Investigator, Subinvestigator, andStudy Coordinator2. Background Materialsa. Investigator Brochure or package insert3. Protocol and Amendments4. Institutional Review Board Materialsa. IRB membership rosterb. IRB approval of the protocol and consentc. IRB approval of advertisements and other recruiting materials, if applicabled. Correspondence between the Investigator and the IRBe. Submission of Progress Reports to the IRBf. Submission of SAEs and IND Safety Reports to the IRBg. Notification to the IRB concerning study termination5. Informed Consenta. Blank copies of all versions of the consent and assent forms used in the studyb. Signed consent forms6. Clinical Trial Materialsa. Drug shipment and receipt documentation (to the site)b. Drug accountability recordsc. Drug return or destruction documentation7. Laboratory Certifications and Normal Ranges8. Operations Manualsa. Study Procedures Manual (if available)b. Pharmacy Manual (if available)9. Forms and Logsa. Screening and Enrollment Log (if applicable)b. Study Responsibilities Formc. Monitoring Log10. Regulations11. Standard Agreementsa. Confidentiality Agreement (may also be stored in the institution’s contractdepartment)12. Correspondence13. Case Report Formsa. Blank CRFb. Completed CRFs14. Patient RecordsThe documents in the Investigator’s study files should be similar to those in Companystudy files. However, there are some items in the investigator’s files that may beMON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YYmore extensive than those in Company files (e.g., signed informed consentdocuments).D. Document ReviewEither in-house or at the study site, the Monitor will review the required regulatorydocuments for acceptable content.1. Signed FDA Form 1572 – Statement of Investigatora. The Monitor will ensure that the current version of the FDA Form 1572accurately reflects the current status of the study at the site and the appropriateversion 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. Section 1 (Name and Address of Investigator)• Only one name should be listed.• The full mailing address should be listed; it may or may not be thesame as the address(es) listed in section 3.ii. Section 2 (Investigator Qualifications)• The box marked CV should be checked.• If the study drug is a controlled substance subject to theComprehensive Drug Abuse Prevention and Control Act of 1970, theInvestigator must be registered with the Drug Enforcement Agency(DEA) and this registration number should be recorded on FDA Form1572.iii. Section 3 (Name and Address of the Study Site(s))• The complete mailing address for all sites where the study will beconducted should be listed. This address may or may not be the sameas that listed in section 1 (i.e., the Principal Investigator’s officeaddress).• If the address is the same as that in section 1, it should be repeatedhere (i.e., The phrase “Same as section 1” may not be used).• Each address listed must be reflected in the CV of at least theInvestigator 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 usedin the study should be listed. This should include labs that performassessments on biopsy samples as well as clinical pathology samples.v. Section 5 (Institutional Review Board (IRB))• The full name and address of each IRB responsible for reviewing thestudy should be listed.MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YY• If the study has been approved by more than one IRB, the names andaddresses 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. Inthese cases, the IRB approval letter must state this responsibility.vi. Section 6 (Subinvestigators)• The name and academic degree of each person assisting the PrincipalInvestigator should be listed.• A consistent format should be used (e.g., first name, middle initial, lastname, academic degree).• Non-physicians may be included.• Whether or not the Study Coordinator should be included on FDAForm 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 itappears on the title page of the protocol should be listed. Noabbreviations 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 11 (Date)• The date when the Principal Investigator signed the form must beentered.2. Curriculum vitae (CV)a. A complete current CV for the Principal Investigator and all Subinvestigatorsshould reflect the study staff members’ qualifications for conducting theresearch study.b. The Principal Investigator’s CV must contain the address listed in section 1 ofFDA Form 1572. It must also contain at least one address listed in section 3of FDA Form 1572.c. The Monitor should ensure that the CV is current (i.e., has been updated in thelast two years; shows the investigator’s employment at the study site; andnotes board certification and all other accreditations, such as DEA).MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YY3. Financial Disclosure FormsA Financial Disclosure Form, provided by the sponsor, should be signed by theInvestigator and each Subinvestigator. If required by the sponsor, a signedFinancial Disclosure Form will also be obtained from the Study Coordinator.4. Investigator Brochure or Package InsertAll revised versions of the brochure that are used during the clinical study shouldbe included in the study file notebook. The earlier version of the brochure shouldnot be discarded.5. Protocol and Amendmentsa. The Monitor will ensure that the protocol is signed and dated by theInvestigator indicating his/her agreement to conduct the study according to theprotocol. Drafts of protocols and protocol amendments do not need to beretained in the study file.b. As they are generated, signed and dated (original) protocol amendmentsshould be attached to back of the protocol. If the sponsor generates a revisedprotocol that incorporates the amendment changes, this version of the protocolshould be included in the study file notebook. However, previous approvedversions should not be discarded.c. Drafts of the protocol and protocol amendments should not be included in thefile unless they are accompanied by a memo to the file from the StudyMonitor with an explanation.6. IRB Membership Rostera. Prior to the shipment of study drug and supplies, the Monitor must obtain anIRB roster of voting members to ensure that the IRB is a valid board.b. If the IRB refuses to release a membership roster, the Monitor will obtain theDepartment of Health and Human Services (DHHS) assurance number (ifthere is one) or a written statement from the IRB chairman which states thatthe IRB complies with the requirements of 21 CFR Part 56.c. During the course of the study, the Monitor should ensure that this list remainscurrent; however, copies of outdated lists should not be discarded.7. IRB Approval of the Protocol and Consenta. Each IRB listed in section 5 of FDA Form 1572 must provide an approvalletter.b. The Study Monitor should review the content of the approval to ensure thefollowing:i. It contains the protocol number, protocol title, or reasonable informationto determine specifically which protocol (and version) was approved.ii. It is provided on the IRB or institution letterhead and contains someidentifying information to associate it with the IRB listed in section 5 ofFDA 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.MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YYv. There is some indication that the full board approved the study andinformed consent document (i.e., no expedited approval is allowed). It isacceptable if the letter does not mention the consent approval only if theIRB has stamped the consent document with its approval and date.vi. If the IRB approved the protocol and consent documents for multiplesites, then the letter must state that all sites listed on the FDA Form 1572were approved.vii. If the Principal Investigator, Subinvestigator, or Study Coordinator is avoting member of the IRB, the approval must state that this personrefrained from voting on approval of the protocol. Alternatively, inseparate correspondence, the IRB Chairman may state that the PrincipalInvestigator, Subinvestigator, or Study Coordinator refrained from voting.viii. It is possible that an amendment could be submitted with the initialprotocol for full board review. If this is the case, the approval letter muststate that the amendment was also approved.8. IRB Approval of Advertisements and Other Recruiting Materials, If ApplicableFor sites that advertise to recruit study subjects, the IRB must review and approveall advertisements. A copy of each advertisement and the IRB approval of the adsmust be included in the study file notebook.9. IRB Approval of Amendments, If ApplicableThe Monitor should consult the Project Manager to determine whether protocolamendments require IRB approval. In either case, the IRB approval of theamendment or the investigator’s notification to the IRB about the amendmentmust be included in the study file notebook.10. Submission of Progress Reports to the IRBa. The FDA requires at least annual review and re-approval of the study. SomeIRBs require re-approval more frequently than the federal regulations. If thisis the case, the initial approval letter will state when the IRB wants to reviewthe study again.b. Although some IRBs will also notify the investigator when the renewal dateapproaches, the Monitor should not assume this will occur and should remindthe investigator of this requirement at least two months in advance of therequired re-approval date. A copy of all re-approvals should be placed in thestudy file notebook.11. Submission of SAEs and IND Safety Reports to the IRBAt each site visit, the Monitor will ensure that all deaths and serious orunexpected adverse experiences (regardless of causality or relation to the drug)were reported immediately by telephone to Company (and, depending on theIRB’s requirements to the Investigator’s IRB).MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YY12. Notification to the IRB Concerning Study TerminationThis may be a letter from the Investigator to the IRB, an IRB-specific form, or theIRB Study Termination Notification Form (Attachment A).13. Correspondence Between the Investigator and the IRBCopies of all additional correspondence between the investigator and the IRBconcerning the protocol should be included in the study file notebook (e.g., IRBrequests for revisions to the informed consent document).14. Blank Copies of All Versions of the Consent and Assent Forms Used in the StudyWhen the IRB approves a consent or assent form, the Monitor should ensure thata blank copy of the form is included in the study file notebook.15. Signed Informed Consent Formsa. At each site visit, the Monitor should ensure that the most recent IRBapprovedinformed consent document is being used.b. At study termination, the Monitor should ensure that the study file notebookcontains a memo to the file that states where the signed documents can befound.c. For every subject enrolled in the study (and for screen failures), the Monitorshould ensure that the consent form was signed by the subject before theinitiation of any study procedures (i.e., by comparing dates) and should reviewthe source documents to determine if a copy of the consent form was given tothe subject. Deviations from this policy should be documented in the file.d. For non-English Informed Consent Forms, the study file notebook shouldeither contain the name and address of the translator and a copy of thetranslator’s certificate, or have the translator provide a memo to the file thatstates that the foreign language consent document is an accurate translation ofthe English consent form.In cases of oral translation, documentation should be attached to the InformedConsent Form indicating that the translation was orally performed and givingthe name and address of the translator. A statement should also be written onthe (English) consent to indicate that it was read to the subject (rather than thesubject reading it himself/herself).16. Clinical Trial Materials (includes placebo, active comparators, etc.)a. Although drug accountability might not be reviewed by the Monitor at eachsite visit, the study site’s drug accountability records should always becurrent.b. Documentation should be clear so that the amount of clinical trial materialshipped to the site, the amount (and specific numbers) provided to eachsubject, the amount used or returned, and the amount returned to the sponsorcan easily be determined.c. In general, the Monitor must ensure that the appropriate forms are completedcorrectly and are placed in the study file notebook.MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YY17. Operations ManualsTo provide evidence that Company Monitors have fulfilled their obligation totrain the study staff, copies of all training reference materials should be includedin the study file notebook. This includes the Study Procedures or OperationsManual (if there is one), and/or guidelines for completion of CRFs, handlingadverse events, handling subject deaths, handling premature subject or studydiscontinuation, and handling, storing, and/or shipping biological samples (ifappropriate).18. Laboratory Certifications and Normal Rangesa. A clinical laboratory should be certified or licensed by at least one of threeauthorizing bodies: a state regulatory agency, the Communicable DiseaseCenter, and/or the College of American Pathologists. (Certifications for studysites outside the United States will differ.)b. Due to the raised seal, photocopies of laboratory certificates often make thedate of certification illegible. When this happens, the Monitor should writethe date of the certification on the copy.c. If certification expires during the study, an updated certification or letter ofinspection should be obtained.d. As the study progresses, the Monitor should ensure that the certificationscover the entire time interval of the study and are renewed or updated asnecessary.e. If the lab is certified on a test-by-test basis, the Monitor should ensure that thelaboratory 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 fromeach participating laboratory must be obtained.g. As the study progresses, the Monitor should ensure that the normal ranges arevalid for the entire time interval of the study and are renewed or updated asnecessary.h. If biological samples are sent to a lab that was not listed on the FDA Form1572, the Form must be updated and normal ranges for the second lab must beobtained.i. A copy of the Laboratory Director’s CV may be included in the file, but is notrequired.19. Screening and Enrollment Log (if applicable)During the Periodic Site Visits, the Monitor will ensure that the informationincluded in the Screening and Enrollment Log remains current (Attachment B).20. Study Responsibilities Forma. At the Study Initiation Visit, the Monitor must ensure that the StudyResponsibilities Form is completed to show who may perform specific studyrelatedtasks (Attachment C).b. The Study Responsibilities Form must be signed and dated by the Investigatorto reflect that he has authorized the delegation of the tasks to the peopleindicted.MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YYc. The Study Responsibilities Form must be updated as new personnel are addedto and removed from the study and as responsibilities shift.21. Signature SheetAt the Study Initiation Visit, the Monitor must personally meet all staff membersinvolved in the study and record their names, work addresses, and telephonenumbers on the study signature sheet. This sheet should be updated as newpersonnel are added to the study (Attachment D).22. RegulationsBecause the Investigator promises to adhere to federal regulations when he/shesigns the FDA Form 1572, the Monitor should provide a copy of the FDAregulations and ICH guidelines, if applicable regulations. These copies of theregulations should be included in the study file notebook.23. Standard AgreementsThese may also be stored in the institution’s contract department.24. Study Reportsa. Preliminary results written by the Investigator in the form of abstracts,posters, etc. and copies of all publications that resulted from the researchstudy 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 inthis file.c. After the study is completed, and if the sponsor provides the Investigator withthe random code for the subjects he/she enrolled in the study, the random codeshould be included in this section of the study file notebook.d. This file should also include any documentation regarding unblinding or otherstudy errors.25. Correspondencea. All significant correspondence within the study site concerning the protocolshould be included in the correspondence section of the study file notebook(e.g., if the Principal Investigator writes a memo to the staff which informsthem about who to contact while he/she is away at a professional meeting).b. If the study site personnel write telephone reports or keep a telephone logconcerning the study, these should be placed in this section of the notebook.c. The Monitor should ensure that copies of all correspondence he/she haswritten to the Investigator, including follow-up letters, are included in thestudy 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 mustbe placed in the corresponding study file notebook for each protocol.e. All correspondence to and from the Investigator and Company should be filedchronologically. Attachments should be cross-referenced to their own specificfile (i.e., they should not be included in this file).MON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YY26. Case Report Formsa. The Investigator’s files should include a set of blank CRFs and allamendments to CRFs. These may be stored in a separate location, but amemo to the file should exist in this section which describes where the blankCRF 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 memowhich states where the completed CRFs can be found.c. Data Clarification Forms should be attached to completed CRFs.27. Patient Recordsa. If there are any data required in the CRF that will not be recorded in theInvestigator’s source documents, a memo to the study file must notespecifically which data in the CRF represent the sole documentation of suchinformation. A copy of this memo should be included in the study filenotebook.b. At study termination, this section of the notebook should include a memo thatspecifies where these records can be found.E. Financial InformationCorrespondence between Company personnel or the sponsor and the Investigatorconcerning financial matters do not need to be included in an FDA inspection.Therefore, documents that contain financial information are included in a separatesection of the study files, which may be removed during the audit. The budgetagreement letter or any contract concerning the schedule of grant payments should beincluded in this section of the study file notebook.IV.References21 CFR 312.30 – Protocol Amendments21 CFR 312.32 – IND Safety Reports21 CFR 312.55 – Informing Investigators21 CFR 312.57 – Record Keeping and Retention21 CFR 312.64 – Investigator Reports21 CFR 54.4 – Certification and Disclosure Requirements21 CFR 54.6 – Record Keeping and Record Retention21 CFR 56.107 – IRB Membership21 CFR 56.115 – IRB RecordsMON-009.0.doc© 2004 by CRC Press LLC

SOP# MON-009.0CompanyEffective Date: DD/MMM/YYICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECICH Guidelines for Good Clinical Practice (E6) section 5.9 – FinancingICH Guidelines for Good Clinical Practice (E6) section 5.11 – Confirmation of Reviewby IRB/IECICH Guidelines for Good Clinical Practice (E6) section 5.12 – Information onInvestigational ProductsICH Guidelines for Good Clinical Practice (E6) section 5.14 – Supplying and HandlingInvestigational Product(s)ICH Guidelines for Good Clinical Practice (E6) section 5.15 – Record AccessICH Guidelines for Good Clinical Practice (E6) section 5.21 – Premature Termination orSuspension of a TrialFDA Information Sheets – Record Keeping in Clinical Investigations, October 1995V. AttachmentsAttachment A – IRB Study Termination Notification FormAttachment B – Screening and Enrollment LogAttachment C – Study Responsibilities FormAttachment D – Signature SheetMON-009.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-010.0Title: Adverse Experiences (AEs), Serious AdverseExperiences (SAEs), and IND Safety ReportsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the processes involved in the receipt, evaluation, and reporting of non-seriousand serious adverse experiences (SAE) occurring in clinical trial subjects.II.ScopeThis SOP will apply to all clinical trials involving non-marketed products.MON-010.0.doc© 2004 by CRC Press LLC

SOP# MON-010.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. DefinitionsAll Company personnel will use the definitions of “adverse experience” and “seriousadverse experience” found in the protocol and FDA regulations.For clinically significant lab abnormalities, Company personnel will follow theprotocol to determine if such abnormalities meet the definition of an SAE.B. Non-Serious Adverse Experiences (AEs)1. Through telephone contacts and visits to the study site, the Monitor will ensurethat the Investigator and/or Study Coordinator inquires about adverse experiencesat each study visit and document the inquiry in the subject’s medical chart.2. During visits to the site, the Monitor will ensure that if an adverse experience isfound, the Study Coordinator documents the following in the subject’s chart andCase 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; andf. Relationship to study drug.3. The Monitor will confirm that the Investigator determined the relationship of theevent to the study drug and that the determination is recorded in the subject’schart.4. The Monitor will remind the Investigator to follow-up on all drug-related AEsuntil they are resolved or until it is determined to be a permanent condition.C. Serious Adverse Experiences (SAEs)1. Reporting Timeframes – At the Investigator’s Meeting or Study Initiation Visit,the Monitor will confirm the study staff’s understanding that the following peopleshould be notified (in the timeframes listed below) as soon as the SAE is known:a. Principal Investigator and Study Coordinator – immediatelyb. 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 24hours.c. Institutional Review Board (IRB) – in the timeframe required by the IRB, butno later than 48 hours.MON-010.0.doc© 2004 by CRC Press LLC

SOP# MON-010.0CompanyEffective Date: DD/MMM/YY2. Initial Report – During the Investigator’s meeting and/or Study Initiation Visit,the Monitor will provide the Investigator and Study Coordinator with the SeriousAdverse Experience Reporting Form (Attachment A). Unless instructedotherwise by the sponsor or protocol, the Monitor will instruct the site personnelto use this form to capture the data concerning SAEs.When he/she receives the initial report of a SAE, the Monitor will confirm thatthe Investigator and/or Study Coordinator collected as much of the followinginformation as possible for reporting to Company 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; andk. Name and telephone number of the person reporting the event.If there are issues that need additional follow-up, the Monitor will contact theInvestigator or Study Coordinator by telephone or e-mail. If this contact isaccomplished by phone, the Monitor will document it in a Telephone ContactReport (Attachment B).3. Follow-Up reports – The Monitor will encourage the Study Coordinator to collectwhatever additional information is necessary (e.g., discharge summary, autopsyreports) 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 theoccurrence of the SAE and will provide them with the completed SAE form andall available supporting documentation. These staff members will determine ifthe SAE qualifies for an IND Safety Report.5. Narrative Summaries – One of Company’s medical staff will write a narrativesummary for each SAE in a study, using the format of FDA Forms 3500 and3500A. The author of the narrative summary will ensure that the followinginformation is included:a. A brief description of the studyb. Age and sex of the subjectc. Subject’s date of entry into the studyd. Subject’s medical historye. Description of the SAEf. Treatment and outcomeMON-010.0.doc© 2004 by CRC Press LLC

SOP# MON-010.0CompanyEffective Date: DD/MMM/YYg. Action taken regarding the investigational drug (if any)h. Investigator’s opinion of the relationship of the event to the study drugIf an event has led to the discontinuation of the subject from the study, theinvestigator must provide a detailed explanation of his/her reasons for thediscontinuation and should comment on abnormal laboratory findings andpossible etiology.6. Site documentation. During the site visit, the Monitor will ensure that the SAE isproperly documented in the subject’s chart and CRF, and that the appropriateforms are retained in the Regulatory Documents Binder.D. Safety Reports1. If Company’s medical staff determines that the SAE requires an IND SafetyReport, the Monitor will work with the Investigator and Study Coordinator toensure that Company can provide the report to the FDA within the timeframestated in the regulations.2. 7-Day Telephone Reports – Any event considered serious, unexpected, possiblyor probably related to the investigational drug, and fatal or life-threatening will bereported by the sponsor to the FDA no later than seven (7) calendar days afterreceipt 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.3. 15-Day Written Reports – Any event associated with the drug that is both seriousand unexpected but not fatal or life-threatening will be reported in writing to theFDA within fifteen (15) calendar days of receipt of the initial report. TheMonitors will ensure that any event requiring the submission of an IND SafetyReport will be reported to all clinical investigators participating in any trials of thedrug. During site visits, the Monitors will follow-up with the Investigators toensure they have transmitted the information to their IRBs and that theappropriate documentation is retained on-site in the Regulatory DocumentsBinder.IV.References21 CFR 312.32 – IND Safety Reports21 CFR 312.44 – Termination21 CFR 312.50 – General Responsibilities of Sponsors21 CFR 312.56 – Review of Ongoing Investigations21 CFR 312.64 – Investigator ReportsICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication with IRB/IECMON-010.0.doc© 2004 by CRC Press LLC

SOP# MON-010.0CompanyEffective Date: DD/MMM/YYICH Guidelines for Good Clinical Practice (E6) section 4.11 – Safety ReportingICH Guidelines for Good Clinical Practice (E6) section 5.16 – Safety InformationICH Guidelines for Good Clinical Practice (E6) section 5.17 – Adverse Drug ReactionReportingAttachmentsAttachment A – SAE Reporting FormAttachment B – Telephone Contact ReportMON-010.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-011.0Title: Managing Study-Specific Clinical SuppliesEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the mechanisms by which study-specific supplies of clinical trial material areacquired, inventoried, packed and shipped to sites, returned from sites, and, whenapplicable, destroyed.II.ScopeThis SOP will apply to all clinical trials where Company is responsible for monitoring theinvestigational product accountability.MON-011.0.doc© 2004 by CRC Press LLC

SOP# MON-011.0CompanyEffective Date: DD/MMM/YYIII.ProceduresThis 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 ShipmentAt the Site Evaluation or Study Initiation Visit, the Monitor will record the name ofthe pharmacist who will be responsible for the study and the address the CTM will beshipped to.The Monitor will ensure that all Company-required study initiation documents arepresent before clinical trial materials are shipped to the study site. When thedocumentation is complete, the Monitor will request that the clinical trial material beshipped 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 him/her concerning theexpected arrival. The Monitor will explain to the Pharmacist that the CTM will beaccompanied by the Investigational Drug Shipment Order (Attachment A) or othersimilar 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; and4. Place the original, signed document in the study or pharmacy files.B. Soon after ShipmentAt the first visit to the site after the CTM has been shipped, the Monitor shouldconfirm that the CTM has arrived intact, that the expected amounts were included inthe shipment, and that the CTM is being stored correctly.C. During Site VisitsOn 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; and8. Identify the specific amounts needed for:a. Each dose form of active drug,b. Placebos, andc. Comparative actives.MON-011.0.doc© 2004 by CRC Press LLC

SOP# MON-011.0CompanyEffective Date: DD/MMM/YYThe Monitor will check the log used by either the Investigator or pharmacist to recordthe 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; and4. CTM returned to Company.The Monitor will ensure that the subject’s records also account for CTM containersnot returned to the Investigator by the subject.When reviewing storage conditions, the Monitor will check:1. Storage temperatures;2. Humidity;3. Light exposure; and4. 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 instructionsgiven in the protocol;2. Partially filled containers may not be combined; and3. Empty containers may not be discarded.D. Final Disposition of CTMDuring the Study Termination Visit (or at a Periodic Site Visit, if necessary), theMonitor will perform a thorough accounting of the physical inventory and comparethis to the site’s documentation.The Monitor will follow the protocol instructions concerning final disposition ofCTM (i.e., returning the CTM to the sponsor or other facility or on-site destruction).1. Return of CTMIf the protocol requires return of the CTM to the sponsor or other location, theMonitor will:a. Ensure that the original label is on each container of unused CTM and can beclearly 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); ande. Include a copy of the CTM Disposition Form with the shipment.The Monitor will complete the CTM Disposition Form at study termination or anytime unused CTM is returned or destroyed on-site.MON-011.0.doc© 2004 by CRC Press LLC

SOP# MON-011.02. On-Site DestructionCompanyEffective Date: DD/MMM/YYIf the protocol allows on-site destruction, the Monitor will obtain a copy of thepharmacy or hospital’s SOP for destruction of study products. The Monitor willensure that a copy of the SOP is in the study file and that all documents requiredby the SOP are also present (e.g., signed certification of destruction). TheMonitor will not give approval for destruction before he/she has completed thefinal accountability check and has completed the CTM Disposition Form.IV.References21 CFR 312.40 – General Requirements for Use of an Investigational Drug in a ClinicalInvestigation21 CFR 312.44 – Termination21 CFR 312.59 – Disposition of Unused Supply of Investigational DrugICH Guidelines for Good Clinical Practice (E6) section 4.6 – Investigational ProductsICH Guidelines for Good Clinical Practice (E6) section 5.12 – Information onInvestigational ProductsICH Guidelines for Good Clinical Practice (E6) section 5.14 – Supplying and HandlingInvestigational Product(s)V. AttachmentsAttachment A – Investigational Drug Shipment OrderAttachment B – CTM Disposition FormMON-011.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-012.0Title: Conducting Study Termination VisitsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeThe purpose of this SOP is to describe the activities performed during the finalmonitoring visit to an investigational site at the conclusion of a clinical trial. The purposeof 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 studystaff.MON-012.0.doc© 2004 by CRC Press LLC

SOP# MON-012.0CompanyEffective Date: DD/MMM/YYII.ScopeThis SOP will apply to all Study Termination Visits conducted by Company.III.ProceduresA. GeneralStudy Termination Visits (also known as Study Close-Out Visits) may be conductedonly by individuals at the level of Monitor/Clinical Research Associate (CRA) orabove. The Study Termination visit is usually conducted shortly after the last subjectfinishes the study, but it may also be performed at the final periodic site visit (i.e., thevisit at which all remaining CRFs are retrieved). Some activities that are listed in thisStudy Termination Visit SOP may be accomplished toward the end of the studyduring Periodic Site Visits.B. Prior to the Study Termination VisitPrior to the Study Termination Visit, the Monitor will perform a comprehensivereview of the activities at the site and will:1. Schedule a visit with Investigator(s) and study personnel;2. Send a confirmation letter outlining the purpose of the visit and items fordiscussion;3. Discuss requirements for the return or destruction of the study drug withappropriate Company personnel;4. Review the trip report from the previous visit to follow-up on items that areoutstanding or action items that need attention;5. Review SAEs;6. Review drop-outs;7. Review outstanding data management issues;8. Review outstanding laboratory issues; and9. Gather any documents or materials necessary for the visit;10. Request that all remaining documents be completed and made available forretrieval, including:a. Case Report Forms;b. Data Clarification Forms;c. Laboratory reports;d. Drug dispensing and return records; ande. Final Serious Adverse Event information.C. Conducting the Study Termination Visit1. Compliance with the Regulations and Protocol – To ensure adherence to theprotocol, applicable FDA regulations, and Company requirements regarding theobligations of the Investigator, the Monitor will:MON-012.0.doc© 2004 by CRC Press LLC

SOP# MON-012.0CompanyEffective Date: DD/MMM/YYa. Perform a detailed review of all documents and subject records generatedfrom 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 achieveda satisfactory resolution; andd. Resolve any unresolved entry violation or have the Investigator include anexplanatory comment on the "Investigator's Comment" page of the CRF.2. Return all original, completed CRFs – To ensure that all data are retrieved, theMonitor will:a. Ensure a completed CRF remains on site for each subject enrolled in thestudy;b. Resolve all remaining data clarification issues and confirm that they havebeen signed by the appropriate person;c. Return any remaining CRFs and/or data clarifications to data Management;d. Inform the Study Coordinator that data queries generated by the StatisticsDepartment may still be forthcoming; ande. Ensure study site personnel understand record retention requirements for thedata.3. Study files – To ensure completeness of the study records and documentation, theMonitor will inspect the Investigator's files. The Monitor will ensure:a. A signed copy of the informed consent form is present for each subjectenrolled in the study. Any irregularities concerning the informed consentforms which have not been previously documented will be discussed in theStudy Termination Visit Trip Report.b. The documents in the Regulatory Documents Binder are present andcomplete, including, but not limited to:i. The signed protocol and amendments, if applicableii. Investigator’s Brochureiii. Drug receipt and return documentationiv. Drug accountability recordsv. Signed Form FDA 1572 and revisions, if applicablevi. Curriculum vitae for the Investigator, Subinvestigators, and StudyCoordinatorvii. IRB approval letters for protocol, consent, advertisementsviii. Correspondence to and from the IRB including IND Safety reports andprogress reportsix. Correspondence between the Investigator and Companyx. Copies of all SAE reporting formsThe Monitor will also:a. Remind the Investigator of his/her obligation to retain the study records inaccordance with FDA record retention requirements;b. Explain that in the event the Investigator retires, relocates, or for any reasonwithdraws from the responsibility for maintaining records for the period ofMON-012.0.doc© 2004 by CRC Press LLC

SOP# MON-012.0CompanyEffective Date: DD/MMM/YYtime required, custody of the records must be transferred to another personwho will accept the responsibility for the records. Notice of such transfershould be given in writing to Company; andc. Remind the Investigator that the FDA should have access to all study recordsfor inspection and copying.4. Drug records – To ensure accurate records of drug receipt and disposition, theMonitor will:a. Re-check all records dealing with the shipment, receipt, and dispensing of alltest articles.b. Check all records of dispensing and return of test articles between thePrincipal Investigator and the individual study subjects for accuracy,including:i. Subject identification numbersii. Lot numbersiii. Quantity dispensed and returnediv. Dates dispensed and returnedv. Label numbersvi. Balance on handc. Ensure that any discrepancies between the expected and actual inventoryshould be resolved or otherwise acknowledged in a letter of explanation fromthe 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 ordestroyed. If not accomplished by the pharmacist or Study Coordinator, theMonitor should package all unused or partially used study medication andarrange for return shipment by the appropriate form. If this occurs, theMonitor should notify the sponsor of the pending return of the studymedication and should request confirmation from the sponsor when the drugarrives.f. Document the successful or unsuccessful reconciliation of study medication inthe Study Termination Trip Report.5. Final Study Status Report – The Monitor will ensure that the Investigatorcompletes a final study status report and sends a copy to his/her IRB andCompany. A copy of the Investigator's final study status report to the IRB shouldbe obtained for inclusion in the Investigator 's study file and a second copy shouldbe sent to Company.6. Final meeting with Investigator and Study Coordinator – The Monitor shouldmake every effort to meet with the Investigator and appropriate study staff todiscuss 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 his/her obligations concerning records retention;MON-012.0.doc© 2004 by CRC Press LLC

SOP# MON-012.0CompanyEffective Date: DD/MMM/YYe. Review final payment policy with the Investigator as stated in theInvestigator’s Agreement;f. Review Company publication policy; andg. Remind the Investigator that he/she should notify Company as soon aspossible if the site is alerted that an inspection by the FDA is impending.D. Follow-Up to the Study Termination VisitFollowing 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 wasaccomplished during the visit and should note any items that need additionalattention.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 and/or DataClarification Forms.2. Make arrangements for final payment to the Investigator.3. Place final copies of logs and forms in the study file.IV.References21 CFR 312.44 – Termination21 CFR 312.57 – Recordkeeping and Retention21 CFR 312.58 – Inspection of Sponsor Records and Reports21 CFR 312.59 – Disposition of Unused Supply of Investigational DrugICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECICH Guidelines for Good Clinical Practice (E6) section 4.5 – Compliance withProtocolICH Guidelines for Good Clinical Practice (E6) section 4.12 – Premature Terminationof Suspension of a TrialICH Guidelines for Good Clinical Practice (E6) section 5.5 – Trial Management, DataHandling, Record Keeping, and Independent Data Monitoring CommitteeICH Guidelines for Good Clinical Practice (E6) section 5.14 – Supplying andHandling Investigational Product(s)ICH Guidelines for Good Clinical Practice (E6) section 5.18 – MonitoringMON-012.0.doc© 2004 by CRC Press LLC

SOP# MON-012.0CompanyEffective Date: DD/MMM/YYV. AttachmentsICH Guidelines for Good Clinical Practice (E6) section 5.22 – Clinical Trial/StudyReportsAttachment A - Study Termination Trip ReportMON-012.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: MON-013.0Title: Telephone Contact ReportsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeThe purpose of this SOP is to describe how telephone contacts with the study sitepersonnel will be documented.II.ScopeThis SOP will apply to all telephone contacts of substance with study site personnel.MON-013.0.doc© 2004 by CRC Press LLC

SOP# MON-013.0CompanyEffective Date: DD/MMM/YYIII.ProcedureIn addition to visits to the study site, the Monitor will keep informed about a site’sprogress concerning study activities with regular telephone contacts. The Monitor willdocument the content of these discussions for topics of substance. This includes, but isnot limited to the following:1. 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); and8. Specific requests for regulatory documents. The initial request for documents doesnot have to be documented in a Telephone Contact Report; however, if multiplerequests for the same document(s) are made, a Telephone Contact Report should bewritten to document the repeated attempts.To document these discussions, the Monitor may write an e-mail to the recipient of thecall or may complete a Telephone Contact Report (Attachment A). If an e-mail iswritten, it should be printed out and placed in the study file. The signed TelephoneContact Report should also be placed in the study file.IV.ReferencesICH Guidelines for Good Clinical Practice (E6) section 5.18 – MonitoringV. AttachmentsAttachment A – Telephone Contact ReportMON-013.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-001.0Title: Preparation, Issue, and Revision of SOPsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To describe the procedures by which Standard Operating Procedures (SOPs) forCompany are prepared, issued, and revised.• To provide a tool for training new personnel in the procedures by which specificactivities will be performed at Company.II.ScopeThis SOP will apply to all SOPs for Company.SITE-001.doc© 2004 by CRC Press LLC

SOP# SITE-001.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. The Department Head for each Department will determine which activities requireSOPs and will assign the responsibility for writing the initial version.B. All SOPs will include:1. 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 QualityAssurance (QA) representative.5. Revision history.6. Scope of the SOP (i.e., a statement which describes the personnel, projects, andsituations to which the SOP applies).7. Description of the procedure (i.e., a detailed description of all tasks to beconducted under the SOP, including when they are to be accomplished, where,and by whom). Each step in the procedure should be numbered. All new orunusual terms should be defined. If an abbreviation is associated with a term, itshould be placed in parentheses following the word. If specific forms orequipment are to be used, they should be specified. Copies of the applicableforms 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, and/or tables that will beused in executing the SOP). The Attachments section should begin with a list ofthe attachments that are included in the SOP. Attachments should be identified byletter.C. Review and Approval of SOPs1. The Author will circulate the draft SOP to the Author’s department members forreview and comment.2. The Department Head will perform the final review and edit of the SOP and willsubmit the final versions to QA for review.3. After completing its final review, QA will reconcile all questions and/orsuggested revisions with the Author prior to issue.4. The final version of each SOP must be approved by the Department Head and adesignated member of the QA Department before issuance. QA will obtainoriginal signatures on the SOP cover sheet before releasing the final versions ofan SOP.SITE-001.doc© 2004 by CRC Press LLC

SOP# SITE-001.0CompanyEffective Date: DD/MMM/YYD. Distribution of SOPs1. Each department will maintain an active SOP manual containing authorizedcopies of all current approved SOPs.2. QA will retrieve or discard all distributed versions of the SOPs (i.e., not thearchive copy) as new versions are implemented.E. Maintaining Original, Signed SOPs1. QA will maintain a complete collection of current Company SOPs and will retainall obsolete, discontinued, or otherwise superseded SOPs in an SOP archive.F. Revision of SOPs1. SOPs requiring permanent modifications will be revised by the Author orindividual designated by the Department Head. Revised SOPs will be circulatedfor review and approval as described in Section III.C.2. QA will update the cover page of the revised SOP to show subsequent revisionsof the SOP.G. Periodic Review of SOPs1. All SOPs will be reviewed on an annual basis to determine whether modificationsare needed or if the SOP remains in use. Annual review of SOPs will be initiatedby 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 storedby QA in the SOP archives.3. Changes to the SOP will be made according to procedures described inSection III.C.4. Documentation of annual SOP review will be maintained in the SOP archives.IV.ReferencesNoneV. AttachmentsNoneSITE-001.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-002.0Title: Training Study Site Clinical Research StaffEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To ensure all staff members involved in clinical research are properly trainedconcerning 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 andcontinuing education.II.ScopeThis SOP applies to all employees and independent contractors for Company.SITE-002.0.doc© 2004 by CRC Press LLC

SOP# SITE-002.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Employee training1. Initial Employee Training begins on the new employee’s starting date andcontinues during a training period determined by the department manager and/orselected department representative. Continuous Employee Training occursthroughout 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 theemployee’s signature on the Confidentiality Agreement and will place the signedAgreement in the employee’s file.2. The Human Resources Department or Department Head will give the EmployeeHandbook to the new employee on his/her start date. This handbook covers thecorporate history, policies and general philosophies of the company.3. The Department Head will appoint a supervisor/mentor to be responsible for thenew employee's training.4. The Supervisor will ensure proper training for the new employee by providingcopies of Company and Departmental SOPs and other educational materials tonew employee. Based on the employee’s prior experience, the Supervisor andemployee will develop a training plan for the employee and a timeframe forcompletion. 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 EmployeeHandbook, if available) and other educational materials that pertain to his/herspecific department and will acquire hands-on training for certain functions of thejob.6. Appropriate staff will sign off on the employee’s Training Plan Form as thetraining is completed. When the Training Plan Form is complete, the employeewill return the form to his/her supervisor, who will file the document with theemployee’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 theemployee’s signature on the Confidentiality Agreement and will place the signedAgreement in the employee’s file.SITE-002.0.doc© 2004 by CRC Press LLC

SOP# SITE-002.0CompanyEffective Date: DD/MMM/YY2. The Department Head will appoint a supervisor/mentor to be responsible for thenew temporary employee's training.3. The Supervisor will ensure proper training for the new temporary employee byproviding copies of appropriate Company and Departmental SOPs and othereducational materials to the new temporary employee. Based on the employee’sprior experience, the Supervisor and temporary employee will develop a trainingplan and a timeframe for completion. The training plan will be outlined on theTraining Plan Form (Attachment A).4. The new temporary employee will read the SOPs and other educational materialsthat pertain to his/her specific department and will acquire hands-on training forcertain functions of the job.5. Appropriate staff will sign off on the employee’s Training Plan Form as thetraining is completed. When the Training Plan Form is complete, the temporaryemployee will return the form to his/her supervisor, who will file the documentwith the employee’s training record.D. Continuous Training - All permanent and temporary employees are responsible forkeeping current with the industry and technology. To accomplish this, an employeeor the employee's supervisor may identify the necessary training. All training mustbe 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) basedon 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 HRDepartment for archiving.3. If training was approved, the employee will complete any other forms (such asregistrations or the Travel Request Form) and submit them to the appropriatedepartment (e.g., Travel).4. The supervisor and employee will review the employee’s training record on atleast an annual basis.E. Employee Training Verification - When an employee receives training, he/she shouldcomplete the Staff Training Verification Form (Attachment C) and submit it to theappropriate department to be filed with the employee’s training records.SITE-002.0.doc© 2004 by CRC Press LLC

SOP# SITE-002.0F. Retention of Training Files.CompanyEffective Date: DD/MMM/YY1. Training records for each employee will be cumulative and will be retained foreach employee’s tenure with Company.2. Training records are subject to inspection by authorized regulatory agencyinvestigators.G. Contents of Training Files – Each employee’s training record should contain aminimum of the following:1. Curriculum vitae (CV) or resume - updated annually and reflecting employmentat Company. Because this is a cumulative document, only the current version ofthe CV should be retained in the file.2. Current job description.3. Completed Training Record Form (Attachment D) with appropriatedocumentation attached (i.e., completed and updated training form(s) andcertificates of completion or diplomas received for training programs or othersupplemental education).IV.ReferencesICH Guidelines for Good Clinical Practice (E6) section 4.1 – Investigator’sQualifications and AgreementsAttachmentsAttachment A – Training Plan FormAttachment B – Staff Training Request FormAttachment C – Staff Training Verification FormAttachment D – Training Record FormSITE-002.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-003.0Title: Assessing Protocol FeasibilityEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the procedures for assessing the feasibility of conducting a specific protocolat Company.II.ScopeThis SOP will apply to all clinical studies being considered for conduct at Company.SITE-003.0.doc© 2004 by CRC Press LLC

SOP# SITE-003.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. When a Sponsor/CRO contacts the study site about a potential study, the PrincipalInvestigator will assess whether or not it would be feasible to conduct the protocolwith the existing staff and facilities.B. The Investigators, Study Coordinators, and other appropriate site personnel willreview 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 orStudy Coordinator will notify the Sponsor/CRO of the site’s willingness to participatein the study.IV.References21 CFR 312.30 – Protocol AmendmentsV. AttachmentsNoneSITE-003.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-004.0Title: Investigator Agreements with Sponsors orContract Research OrganizationsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the manner in which regulatory documents and other study-relateddocuments are to be maintained at an investigational site.II.ScopeThis SOP will apply to all industry-sponsored trials conducted at Company.SITE-004.0.doc© 2004 by CRC Press LLC

SOP# SITE-004.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Regardless of whether a contract originates with the Sponsor or Contract ResearchOrganization (CRO) or with Company, the Investigator, Research Director, and LegalDepartment will review the contract to ensure it contains:1. Sponsor’s name and address2. CRO’s name and address, if applicable3. Protocol title and number4. Indemnification language5. Confidentiality agreement (if not in a separate document)6. Estimated start and finish dates7. Estimated number of subjects expected to enroll from this site8. Budget information and payment schedule, including terms for delays andtermination of the study9. The definition of a “completed” subject (i.e., fully paid)10. Description of reimbursement for study subjects who experience an adverse eventor who are injured while participating in the study11. A list of the responsibilities assigned to the study site12. A statement of whose Standard Operating Procedures will be followed (i.e., theSponsor, CRO, or site’s)13. Publication rights14. Data ownership rightsB. All Investigator Agreements must be approved by the Legal Department, arepresentative of Company, and the Investigator.C. If Company is preparing the Agreement, two originals will be prepared and sent tothe Sponsor/CRO for signature. A copy will be retained in the interim; this copy willbe discarded when the signed original is returned. The Sponsor/CRO will sign bothoriginals, will keep one, and will return the other to Company.D. A signed Investigator’s Agreement must be in place before any subjects are enrolledin the study.IV.ReferencesNoneV. AttachmentsNoneSITE-004.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-005.0Title: Organizational Chart for the Study SiteEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the items to be included in an organizational chart describing theresponsibilities and duties of the clinical investigator and staff.II.ScopeThis SOP will apply to all studies conducted by Company.SITE-005.0.doc© 2004 by CRC Press LLC

SOP# SITE-005.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. The Principal Investigator, Research Director or representative of the HumanResources 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 beinvolved in clinical trials.3. Maintain a file of current curricula vitae for each staff member who will beinvolved in the study.4. Maintain the training records for all staff involved in clinical trails, including thePrincipal Investigator and Subinvestigators.5. Prepare a detailed list of the duties and responsibilities of each staff member asthey relate to specific studies or have the Investigator complete (and sign) theStudy Responsibilities Form. (Attachment A) If the sponsor or contract researchorganization (CRO) has a similar form, this may be substituted.If new individuals are assigned to the project or if the responsibilities have beenshifted to another person (e.g., due to attrition or promotion), the Investigator orResearch Director should promptly update the Study Responsibilities Form.B. Make all these documents available to the clinical monitor and to any properlycredentialed representative of FDA or other regulatory entity.IV.References21 CFR 312.30 – Protocol Amendments21 CFR 312.40 – General Requirements for Use of an Investigational Drug in a ClinicalInvestigation21 CFR 312.44 – Termination21 CFR 312.55 – Informing Investigators21 CFR 312.60 – General Responsibilities of Investigators21 CFR 312.61 – Control of the Investigational Drug21 CFR 312.66 – Assurance of IRB ReviewICH Guidelines for Good Clinical Practice (E6) section 4.1 – Investigator’sQualifications and AgreementsICH Guidelines for Good Clinical Practice (E6) section 4.9 – Records and ReportsV. AttachmentsAttachment A – Study Responsibilities FormSITE-005.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-006.0Title: Interactions with the Institutional Review BoardEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To describe the process of interactions with the Institutional Review Board (IRB).• To describe what documentation should be retained to reflect interaction with theIRB.II.ScopeThis SOP will apply to all studies being conducted at Company, regardless of whether alocal or commercial IRB is being used.SITE-006.0.doc© 2004 by CRC Press LLC

SOP# SITE-006.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Study Initiation1. At study start-up, the Study Coordinator will obtain the appropriate forms fromthe IRB, including the IRB membership roster or DHHS assurance number.2. The Study Coordinator will complete the IRB study initiation forms and, wherenecessary, will obtain the Principal Investigator’s signature.3. The Study Coordinator or Principal Investigator will forward the signed formsand documents to the IRB. These include, but are not limited to:a. The most recent version of the Investigator’s Brochureb. The final version of the protocolc. The final draft of the informed consent documentd. A copy of advertisements, patient diaries, recruitment scripts, or other patientinformation sheetse. Other IRB-specific paperwork4. The Study Coordinator will place the IRB membership roster or DHHS assurancenumber and a copy of all documents submitted to the IRB in the RegulatoryDocuments Binder.5. If necessary, the Study Coordinator and Principal Investigator will follow-up onissues identified by the IRB.6. The Study Coordinator will place a copy of the following documents in theRegulatory Documents Binder: IRB approval of the protocol, informed consent,advertisements, patient diaries, recruitment scripts, or other patient informationsheets. The Study Coordinator will ensure that these documents containidentifying information (dates or version numbers) to reflect specifically whichversion of the document was approved.B. Study Progress1. Annual Review – At the interval noted in the IRB approval of the study, thePrincipal Investigator will provide the IRB with a progress report. This will beaccomplished at least annually.2. Protocol Amendments – If the Sponsor/CRO requests a protocol amendment, theStudy Coordinator or Principal Investigator will send the amendment and revisedinformed consent, if necessary, to the IRB. Unless the amendment affects subjectSITE-006.0.doc© 2004 by CRC Press LLC

SOP# SITE-006.0CompanyEffective Date: DD/MMM/YYsafety, no change in study procedures will be implemented until IRB approval ofthe amendment and revised consent is received.3. Change in Investigator or Subinvestigator – If there is an addition or deletion ofthe Principal Investigator or Subinvestigator, the Study Coordinator will notifythe IRB within one month of the change.C. Serious Adverse Experiences1. Using the forms provided by the Sponsor/CRO or IRB, the Principal Investigatorwill notify the IRB of all Serious Adverse Experiences (SAEs) that occur at thissite.2. The Investigator will forward copies of all IND Safety Reports that occur at anysite on the study to the IRB within 72 hours of becoming aware of the report.3. The Study Coordinator will make copies of all correspondence concerning SAEsand IND Safety Reports that are submitted to the IRB and will place them in theRegulatory Documents Binder. Copies of the IRB acknowledgement of theseevents will also be placed in the Binder.D. Study Termination1. At study termination, the Principal Investigator will notify the IRB of the study’scompletion using the IRB Notification of Study Termination Form(Attachment A) or similar form provided by the IRB or Sponsor/ContractResearch Organization (CRO).2. The Study Coordinator will place a copy of the documents notifying the IRB ofstudy termination and any acknowledgements received in the RegulatoryDocuments Binder. If requested, the Study Coordinator will also provide a copyof these documents to the Sponsor/CRO.IV.References21 CFR 312.32 – IND Safety Reports21 CFR 312.66 – Assurance of IRB ReviewICH Guidelines for Good Clinical Practice (E6) section 3.1 – ResponsibilitiesICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECICH Guidelines for Good Clinical Practice (E6) section 4.10 – Progress ReportsSITE-006.0.doc© 2004 by CRC Press LLC

SOP# SITE-006.0CompanyEffective Date: DD/MMM/YYICH Guidelines for Good Clinical Practice (E6) section 4.11 – Safety ReportingICH Guidelines for Good Clinical Practice (E6) section 4.12 – Premature Termination ofSuspension of a TrialICH Guidelines for Good Clinical Practice (E6) section 4.13 – Final Reports byInvestigator / InstitutionICH Guidelines for Good Clinical Practice (E6) section 5.21 – Premature Termination orSuspension of a TrialV. AttachmentsAttachment A – IRB Notification of Study Termination FormSITE-006.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-007.0Title: Recruiting Study PatientsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe procedures by which an Investigator and his/her staff may identify qualifiedsubjects for a clinical trial.II.ScopeThis SOP will apply to all clinical studies being conducted at Company.SITE-007.0.doc© 2004 by CRC Press LLC

SOP# SITE-007.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. The Investigator, Research Director, and Study Coordinator will work with theSponsor/CRO to develop a subject recruitment plan and ensure the budget reflectsthese activities.B. Using the eligibility criteria for the study, the Research Director or Study Coordinatorwill review records from the Investigator’s patient population to determine thesuitability and availability of candidates for the protocol. In addition, the Investigatorand 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, publicservice announcements on local radio or TV stations (including community bulletinboards), newspaper ads, internet ads, and various electronic media.D. The Investigator and/or Study Coordinator will ensure that the advertisements arelimited to:1. The name and address of the clinical investigator2. The purpose of the research3. A summary of the eligibility criteria that will be used to admit subjects into thestudy4. A description of the benefits to the subject for participation in the study5. The location of the research6. The name and phone number of person to contact for further informationThey will also ensure that the advertisement makes no claims:1. That the drug or device is safe or effective for the purposes under investigation2. That the drug or device is in any way equivalent or superior to any other drug ordeviceE. When a potential subject is contacted concerning a specific study, the followinginformation will be entered on the Screening and Enrollment Log (Attachment A):1. Subject initials2. Date of birth3. Date screened4. If enrolled, subject number5. If not enrolled, the reasonSITE-007.0.doc© 2004 by CRC Press LLC

SOP# SITE-007.0CompanyEffective Date: DD/MMM/YYF. When a subject is enrolled in a study, the following information will be entered on theMaster Subject Log (Attachment B):1. Subject number2. Subject name and address3. Contact information (i.e., home and work phone numbers and e-mail address)4. Date of birth5. Social security number6. Date enrolled7. Dates completed and discontinued (may be entered later)This is an internal document for Company. It will not be shared with theSponsor/CRO.IV.References21 CFR 50.20 – General Requirements for Informed Consent21 CFR 50.25 – Elements of Informed Consent21 CFR 56.107 – IRB Membership21 CFR 56.109 – IRB Review of Research21 CFR 56.111 – Criteria for IRB Approval of Research21 CFR 56.115 – IRB Records21 CFR 312.60 – General Responsibilities of Investigators21 CFR 312.62 – Investigator Record Keeping and Record RetentionICH Guidelines for Good Clinical Practice (E6) section 3.1 – ResponsibilitiesICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECFDA Information Sheets, Screening Tests Prior to Study Enrollment, December 1999FDA Information Sheet, Recruiting Study Subjects, December 1999FDA Information Sheet, Payment to Research Subjects, December 1999V. AttachmentsAttachment A – Master Subject LogAttachment B – Screening and Enrollment LogSITE-007.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-008.0Title: Study Initiation and ImplementationEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the processes that ensure the proper conduct of clinical trials at Company.II.ScopeThis SOP will apply to all clinical trials at Company.SITE-008.0.doc© 2004 by CRC Press LLC

SOP# SITE-008.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Study Initiation1. After the Sponsor/CRO has agreed to place a study at Company, the StudyCoordinator will begin to collect regulatory documents and Sponsor/CROrequiredforms. Unless the Sponsor/CRO prefers another method, the StudyCoordinator or designee will use the Study Initiation Documents Checklist totrack these documents (Attachment A).2. The Study Coordinator will work with:a. The Contracts Department to ensure a contract is executedb. The Investigator and Budgets Department to ensure a financially feasiblebudget is developed and approvedc. The IRB to obtain the IRB membership list and forms needed for submissionsd. The Investigator and Subinvestigators to obtain copies of their curriculumvitae, medical licenses, and signed financial disclosure formse. The Clinical Laboratory to obtain a copy of the lab certification and referencerangesf. The pharmacist to ensure the test article was received intact and that theappropriate forms for dispensing and accountability are availableg. The Sponsor/CRO to ensure that the Case Report Forms, RegulatoryDocuments Binder, and the Study Procedures Manual (if applicable) havebeen received.3. The Investigator, Research Director, Study Coordinator, or delegate will provide aprotocol-specific training session to all members of the staff who will be involvedin the project. The Research Director, Study Coordinator, or delegate will ensurethat attendance sheets and other training documentation are provided to theHuman Resources Department, so that individuals’ training records can beupdated.The protocol-specific training session will include, but is not limited to, thefollowing:a. Time and events schedule for the protocolb. Subject recruitmentc. Obtaining informed consentd. Procedure for dispensing the test articlee. Test article storage and recordsf. Protocol-specific forms and proceduresSITE-008.0.doc© 2004 by CRC Press LLC

SOP# SITE-008.0CompanyEffective Date: DD/MMM/YYg. Source documentationh. Adverse experience reportingi. Additional information from the Investigator’s Meeting4. The Investigator, Research Director, and Study Coordinator will:a. Develop a recruitment plan for subjectsb. Identify a back-up to the primary Study Coordinator5. The Investigator will complete and sign the Study Responsibilities Form beforethe Study Initiation Visit is completed.B. Study Conduct1. While the study is ongoing, the Investigator and Study Coordinator will ensurethe following:a. All study activities are accomplished according to the protocol and FDAregulations.b. Data collected in the Case Report Form (CRF) are supported by sourcedocuments.c. Protocol deviations are noted in the source documents and appropriate CRF.d. Subjects sign the correct version of the consent form before any study-relatedprocedures are accomplished.e. Adverse experiences are reflected in the source documents and captured in theCRF.f. Serious Adverse Experiences (SAEs) are reported to the Sponsor/CRO andIRB.g. IND Safety Reports are provided to the IRB.h. The test article is being dispensed correctly and drug accountability recordsare being maintained.2. While the study is ongoing, the Study Coordinator will ensure the following:a. The Sponsor/CRO is informed of all significant study events and staffmembers are documenting critical interactions with the Sponsor/CRO.b. Biological samples are being obtained, handled, stored, and shippedappropriately.c. Study supplies remain adequate.d. Study records remain confidential.e. All equipment is calibrated regularly and maintenance records are being kept.SITE-008.0.doc© 2004 by CRC Press LLC

SOP# SITE-008.0CompanyEffective Date: DD/MMM/YYIV.References21 CFR 54.6 – Record Keeping and Record RetentionICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECICH Guidelines for Good Clinical Practice (E6) section 4.5 – Compliance with ProtocolICH Guidelines for Good Clinical Practice (E6) section 4.7 – Randomization Proceduresand UnblindingICH Guidelines for Good Clinical Practice (E6) section 4.9 – Records and ReportsFDA Information Sheets, Sponsor–Investigator–IRB Interrelationship, 11/01/99V. AttachmentsAttachment A – Study Initiation Documents ChecklistSITE-008.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-009.0Title: Reviewing and Obtaining Informed ConsentEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To describe the information required to be included in informed consent documentsassociated with clinical trials.• To ensure that a subject’s consent is sought in such a way that the subject or his/herrepresentative has ample opportunity to consider whether to participate in the studyand under conditions that minimize the possibility of coercion or undue influence.SITE-009.0.doc© 2004 by CRC Press LLC

SOP# SITE-009.0CompanyEffective Date: DD/MMM/YYII.ScopeThis SOP will apply to all informed consents and assents being used for the evaluation ofdrugs, devices, or biologics at Company.III.ProceduresIn this procedure, tasks designated to the Study Coordinator may also be accomplished bya Research Manager or Regulatory Documents Administrator.A. Reviewing the Draft Informed Consent1. Before the study begins, the Study Coordinator will contact the InstitutionalReview Board (IRB) to learn if that institution has specific formatting or wordingrequirements for informed consent in addition to those listed in the regulations.2. Before the consent form is submitted to the IRB, the Study Coordinator willreview the document to ensure that it is in compliance with the IRB’srequirements and with FDA regulations and ICH guidelines. The StudyCoordinator may use the Subject Information and Consent Form Checksheet(Attachment A) to accomplish this, but the completed form does not need to beplaced in the Regulatory Documents Binder.B. Obtaining Informed Consent from Adults1. The Investigator and Study Coordinator are responsible for ensuring that theinformed consent and assent, if applicable, have been approved by the IRB beforethey are used in a study and that the correct version of the documents are usedwhen the study is ongoing.2. Only those designated by the Principal Investigator on the Study ResponsibilitiesForm can obtain consent from a subject (Attachment B).3. The Investigator, Subinvestigator, Study Coordinator, or other delegate willexplain the study to the potential subject before any study procedures, includingscreening evaluations, are accomplished. The person who explains the study willallow enough time for the potential subject to read the consent form and willanswer any questions that are raised. If the person who provides this explanationis not a physician, he/she will ensure that a physician is available to answer thepotential 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.SITE-009.0.doc© 2004 by CRC Press LLC

SOP# SITE-009.0CompanyEffective Date: DD/MMM/YYd. The consent form is signed and dated by the subject and the person whoobtained 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 isstored in the study file.C. Obtaining Informed Consent from Children1. Only those designated by the Principal Investigator on the Study ResponsibilitiesForm can obtain assent from a subject.2. Whether one or both parents must sign the consent form for a child’s participationin a study will be determined by the IRB. (This may also vary depending on statelaws.)3. Whether or not an assent form is required for the study will be determined by theIRB. If it is required and the minor is reasonably able to understand the studypurpose and requirements, then in addition to having a consent form signed by theparent, the minor must sign the assent form.4. The Investigator, Subinvestigator, Study Coordinator, or other delegate willexplain the study in language appropriate to the child’s age before any studyprocedures, including screening evaluations, will be accomplished. Thisexplanation will include a discussion of the discomforts or inconveniences thechild may experience if he/she agrees to participate.5. The person who explains the study will ensure that a parent or advocate for thechild 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 readthe consent form and will answer any questions that are raised. If the person whoprovides this explanation is not a physician, he/she will ensure that a physician isavailable 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 whoobtained the consent.SITE-009.0.doc© 2004 by CRC Press LLC

SOP# SITE-009.0CompanyEffective Date: DD/MMM/YYf. The assent form was signed and dated by the minor and the person whoobtained the consent.g. Each page of the consent is initialed by the parent and each page of the assentis 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 consentand assent are stored in the study file.D. Revised Consent Forms1. When the Investigator and/or Study Coordinator receive updates to theInvestigator’s Brochure, IND Safety Reports, or protocol amendments, he/sheshould also review the informed consent to determine if it should be revised toreflect the new information.2. No changes to the study procedures that are a result of the protocol amendmentwill 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 StudyCoordinator will ensure that the revised consent is approved by the IRB.4. The Investigator, Study Coordinator, or Investigator’s delegate will explain thechanges to the subject and will provide the subject with the revised consent formfor review and signature.5. If the subject decides to continue in the study and signs the consent form, theStudy Coordinator or Investigator’s delegate will provide the subject with a copyof the revised consent and will place the original in the study file.E. Non-English Speaking Subjects1. If the patient population contains numerous non-English speaking people whomay qualify for the study, the Study Coordinator will ensure that the informedconsent is translated into the second language and that the translated consent formis also approved by the IRB.2. The Study Coordinator will file the certificate of translation in the RegulatoryDocuments Binder with the translated consent.3. If possible, someone at the study site who speaks the same language as thepotential subject will explain the study to the subject. This person will also beavailable at subsequent study visits to ensure that the subject’s questions can beanswered as the study progresses.SITE-009.0.doc© 2004 by CRC Press LLC

SOP# SITE-009.0CompanyEffective Date: DD/MMM/YY4. When a non-English speaking person signs the consent, a witness not associatedwith the study will observe the consent process and will sign the consent form.The Study Coordinator or person obtaining the consent will document the processin the subject’s medical record.F. Illiterate Subjects1. 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 thestudy will observe the consent process and will also sign the consent form.2. The Study Coordinator or person obtaining the consent will document the processin the subject’s medical record.G. If Incorrect Version UsedIf the Study Coordinator discovers that an outdated version of the consent form wasused for a subject whose participation in the trial has not been completed, he/she 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 correctversion (i.e., do not back-date the consent form or use the same date as on thefirst, 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 whytwo signed informed consent documents for the same subject are present in thefile. If the Study Coordinator is unable to contact the subject, the explanatorymemo should also document the dates and methods by which the attempts toreach the subject were made.IV.References21 CFR 50.20 – General Requirements for Informed Consent21 CFR 50.25 – Elements of Consent21 CFR 50.27 – Documentation of Informed Consent21 CFR 312.60 – General Responsibilities of Investigators45 CFR 46.116 – General Requirements for Informed Consent45 CFR 46.117 – Documentation of Informed ConsentICH Guidelines for Good Clinical Practice (E6) section 1.28 – Informed ConsentICH Guidelines for Good Clinical Practice (E6) section 1.37 – Legally AuthorizedRepresentativeSITE-009.0.doc© 2004 by CRC Press LLC

SOP# SITE-009.0CompanyEffective Date: DD/MMM/YYICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 4.8 – Informed Consent of TrialSubjectsFDA Information Sheets – Continuing Review After Study Approval, January 2001FDA Information Sheets – Guide to Informed Consent, 1998 UpdateBelmont ReportDeclaration of HelsinkiV. AttachmentsAttachment A – Subject Information and Consent Form ChecksheetAttachment B – Study Responsibilities FormSITE-009.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-010.0Title: Adverse Experiences (AEs), Serious AdverseExperiences (SAEs), and IND Safety ReportsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the processes involved in the receipt, evaluation, and reporting of non-seriousand Serious Adverse Experiences (SAEs) occurring in clinical trial subjects.II.ScopeThis SOP will apply to all clinical trials involving non-marketed products.SITE-010.0.doc© 2004 by CRC Press LLC

SOP# SITE-010.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. DefinitionsAll study staff will use the definitions of “adverse experience” and “serious adverseexperience” found in the protocol and FDA regulations.For clinically significant lab abnormalities, the study staff will follow the Sponsor’sinstructions or the protocol to determine if such abnormalities meet the definition ofan SAE.B. Non-Serious Adverse Experiences (AEs)1. The Investigator or Study Coordinator will inquire about adverse experiences ateach study visit and will document the inquiry in the subject’s medical chart. Ifan adverse experience is found, the Study Coordinator will document thefollowing in the subject’s chart and Case Report Form:a. Date and time (if applicable) the event started and endedb. Description of the eventc. Severity of the eventd. Outcome of the evente. Action takenf. Relationship to study drug2. The Investigator will determine the relationship of the event to the study drug andwill record this in the subject’s chart.3. The Investigator will follow-up on all drug-related AEs until they are resolved oruntil 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 aSAE, he/she will ensure that the following people are notified in the timeframeslisted below:a. Principal Investigator and Study Coordinator – immediately.b. Sponsor/Contract Research Organization (CRO) – in the timeframe stated inthe protocol, but no later than 48 hours. If the SAE is life-threatening or adeath, the Sponsor/CRO will be notified within 24 hours.c. Institutional Review Board (IRB) – In the timeframe required by the IRB, butno later than 48 hours.SITE-010.0.doc© 2004 by CRC Press LLC

SOP# SITE-010.0CompanyEffective Date: DD/MMM/YY2. Initial Report – The Study Coordinator should collect as much of the followinginformation as possible for reporting to the Sponsor/CRO and IRB:a. Subject number and initialsb. Date of birthc. Subject demographicsd. Date of the reporte. Description of event, including relationship to study drugf. Determination of seriousnessg. Possible cause of SAE other than trial medicationh. Relevant medical conditionsi. Concomitant medicationsj. Principal Investigator’s namek. Name and telephone number of the person reporting the eventThe Study Coordinator will use the SAE Reporting Forms provided by theSponsor/CRO and will follow the SAE reporting instructions in the protocol.3. Follow-Up Reports – The Study Coordinator will collect whatever additionalinformation is necessary (e.g., discharge summary, autopsy reports) and will sendthese to the Sponsor/CRO and IRB, if required.4. Documentation – The Study Coordinator will ensure that the SAE is properlydocumented in the subject’s chart and CRF, and that the appropriate forms areretained in the Regulatory Documents Binder.D. IND Safety Reports1. If the Sponsor determines that the SAE requires an IND Safety Report, theInvestigator and Study Coordinator will work with the Sponsor/CRO to ensurethat the Sponsor can provide the report to the FDA within the timeframe stated inthe regulations. If requested by the Sponsor/CRO, the Investigator will draft anarrative summary of the event.2. If the Investigator is informed that an IND Safety Report has been submitted tothe FDA for a SAE that occurred at another site, the Investigator or StudyCoordinator will make a copy of the report and forward it to the IRB. Theoriginal document will be retained in the Regulatory Documents Binder.E. Unblinding1. In the event of an SAE, the Investigator will follow the procedure for unblindingthe randomization code described in the protocol. Unless otherwise instructed inSITE-010.0.doc© 2004 by CRC Press LLC

SOP# SITE-010.0CompanyEffective Date: DD/MMM/YYthe protocol, the blind will remain intact until the Sponsor gives approval to breakit.IV.References21 CFR 312.32 – IND Safety Reports21 CFR 312.44 – Termination21 CFR 312.64 – Investigator ReportsICH Guidelines for Good Clinical Practice (E6) section 4.3 – Medical Care of TrialSubjectsICH Guidelines for Good Clinical Practice (E6) section 4.11 – Safety ReportingV. AttachmentsNoneSITE-010.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-011.0Title: Drug Storage and AccountabilityEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe requirements for the receipt, storage, dispensing, and return or destruction ofinvestigational material.II.ScopeThis Standard Operating Procedure (SOP) will apply to all studies being conducted atCompany.SITE-011.0.doc© 2004 by CRC Press LLC

SOP# SITE-011.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Receipt of Study Drug1. Upon receipt of study drug, the pharmacist or other authorized individual (i.e.,authorization is indicated on the Study Responsibilities Form) will unpack thedrug and will check the drug inventory against the shipping form. Checking theinventory will include checking the subject numbers, the drug numbers, the lotnumbers, and the number of items in each container. If the sponsor or ContractResearch Organization (CRO) agrees, sealed containers do not need to be openedfor pill counts at this time.a. If there is no shipping or inventory form included with the drug, thepharmacist or Study Coordinator should complete the Investigational ProductReceipt Form (Attachment C).b. If the inventory matches the drug present, the pharmacist will sign theshipping receipt or Investigational Product Receipt Form, return a copy to thesponsor, and file the original in the study file.c. If any of the items in the shipment are damaged or if a discrepancy in theinventory is found, the pharmacist will notify the sponsor or CROimmediately. He/she will indicate the damage or discrepancy on the shippingor Investigational Product Receipt Form and will file it in the study file.B. Drug Storage1. The Study Coordinator or pharmacist will store the drug in a secure, limitedaccess area under temperature and humidity described in the protocol,Investigator’s Brochure, or package insert.C. Drug Dispensing1. The investigator, pharmacist, or other authorized individual (i.e., as indicated onthe Study Responsibilities Form) will dispense study drug to subjects who meetthe eligibility criteria in accordance with the protocol. If required by the sponsoror CRO, even sealed bottles will be opened for pill counts before the bottle isdispensed.2. The Pharmacist, Study Coordinator, or other authorized individual will ensure thateach subject has a unique subject identification number and will complete andmaintain the Drug Dispensing Log (Attachment A).3. Depending on the design of the Case Report Form (CRF), the tear-off portion ofthe drug’s label, containing the blinded information (if applicable), may beattached to the Drug Dispensing Log, to the CRF, or to another form provided bythe sponsor or CRO.4. The pharmacist or Study Coordinator will maintain a record of drug dispensed toand retrieved from each subject. To accomplish this, the pharmacist or StudySITE-011.0.doc© 2004 by CRC Press LLC

SOP# SITE-011.0CompanyEffective Date: DD/MMM/YYCoordinator will use the CRF, Study Subject Investigational Product DispensingRecord (Attachment D), or a similar form provided by the sponsor or CRO.5. The Study Coordinator will explain to each subject the drug accountability needsfor the study (e.g., the need for the subject to return unused, partially used, andempty packages).D. Study Drug Return1. The study subject will return all drug and study-related supplies to authorizedstudy personnel.2. The Study Coordinator or pharmacist will count the returned drug and comparethis with the amount of drug expected to have been used since the previous studyvisit. He/she will update the appropriate sections of the Drug Dispensing Log,including an explanation of discrepancies, if applicable. The appropriate data willalso be entered into the CRF, if appropriate. The Study Coordinator orpharmacist will keep the Drug Dispensing Log and the drug accountability CRFpages updated, regardless of when the monitor performs final accountability.3. The Study Coordinator or pharmacist will store the returned drug in a secure areauntil it is verified by the monitor.4. Whether the drug is returned to the sponsor or destroyed on-site will bedetermined by the instructions in the protocol.E. Return of Study Drug to Sponsor1. Depending on the protocol, the study drug will be returned to the sponsor at theend of the trial or at intervals specified by the sponsor. The Study Coordinatorwill follow the protocol or other instructions from the sponsor or CRO to decidewhether empty containers must be returned.2. The Study Coordinator will work with the Monitor to determine which carrier ispreferred for the shipment, and if the Monitor needs to complete an independentdrug 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 Return/Destruction Form (Attachment B) or similar formprovided by the sponsor or CRO.e. Include a copy of the signed and completed Drug Return Form with the drugshipment and place the original in the study file.SITE-011.0.doc© 2004 by CRC Press LLC

SOP# SITE-011.0CompanyEffective Date: DD/MMM/YYF. On-Site Destruction of Study DrugIf the sponsor or CRO requires on-site destruction of the study drug, the StudyCoordinator should:1. Obtain a copy of the site’s SOP for study drug destruction/disposition, provide acopy to the monitor, and file a copy in the study file.2. Obtain written confirmation from the monitor identifying the specific study drugthat can be destroyed.3. Obtain appropriate paperwork concerning destruction of the drug that is requiredin the site’s SOPs (e.g., signed incineration records) and place a copy in the studyfile.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 thesponsor or CRO. Provide a signed copy of the form to the monitor and retain theoriginal in the study files.G. Study Drug Record RetentionAt study completion, the Study Coordinator will file all drug records with otherregulatory documents in accordance with the record retention policy for the study. Ifdrug records are maintained by an institution’s pharmacy, they must be transferred tothe Study Coordinator for final record retention (or copied, if the pharmacy’s policy isto keep the records).IV.References21 CFR 312.44 – Termination21 CFR 312.59 – Disposition of Unused Supply of Investigational Drug21 CFR 312.60 – General Responsibilities of Investigators21 CFR 312.61 – Control of the Investigational Drug21 CFR 312.69 – Handling of Controlled SubstancesICH Guidelines for Good Clinical Practice (E6) section 4.6 – Investigational ProductsV. AttachmentsAttachment A – Investigational Product Receipt FormAttachment B – Drug Dispensing LogAttachment C – Drug Return/Destruction FormAttachment D – Study Subject Investigational Product Dispensing RecordSITE-011.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-012.0Title: Managing Biological SamplesEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe procedures for preparation, storage, and shipment of biological samples.II.ScopeThis SOP will apply to biological samples processed by Company, unless alternatedirections are provided by the sponsor or Contract Research Organization (CRO).SITE-012.0.doc© 2004 by CRC Press LLC

SOP# SITE-012.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Preparation of SamplesUsing a ball point pen, on each sample label, site personnel will record the patientinitials, and the date and time when the sample was obtained.B. Storage of SamplesBetween shipments, site personnel will store both urine and plasma samples at atemperature of at least 20ºC – or at a temperature designated by the sponsor.C. Shipment of SamplesSite personnel will:1. 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 (1 cubic foot) can be filled 2/3 with samples and 1/3 with dry ice.If any additional packing material is used, it will not be placed between thesamples 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.References21 CFR 312.57 – Record Keeping and RetentionV. AttachmentsAttachment A – Biological Samples InventorySITE-012.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-013.0Title: Interactions with the Sponsor orContract Research Organization (CRO)Effective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To describe the interactions with the Sponsor or Contract Research Organization(CRO) and Company.• To ensure proper documentation of communications with the Sponsor/CROconcerning study activities.II.ScopeThis SOP will apply to all clinical trials conducted at Company.SITE-013.0.doc© 2004 by CRC Press LLC

SOP# SITE-013.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Pre-Study Site Evaluation Visits1. To prepare for a pre-study visit, all staff involved in the study will read theprotocol and will prepare questions to clarify protocol procedures, subjecteligibility criteria, and other study-related issues. The Study Coordinator will alsoprepare requested documents and forms.2. During the pre-study visit, the Investigator, Study Coordinator, or designee willlead a tour of the facility. The tour will include examination rooms, drug storagearea and accountability records, clinical laboratory, monitors’ work area, storagearea for Case Report Forms (CRFs) and other regulatory documents. If specificequipment is needed for the study, this will also be shown along with themaintenance and calibration records for the equipment.3. The Investigator, Research Director, or Study Coordinator will discuss why thesite is equipped to perform the study. This discussion will include a descriptionof the potential subjects available for the study and methods being considered forrecruitment.4. If requested, the Research Director or Study Coordinator will allow theSponsor/CRO representative to review the training records of staff members whomay be working on the study.B. Study Initiation Visit1. Prior to the Initiation Visit, the Study Coordinator or designee will prepare thestudy initiation documents including:a. Signed FDA Form 1572b. Curriculum vitae for the Investigator and Subinvestigatorsc. Curriculum vitae for the Study Coordinators, if requestedd. Signed Financial Disclosure formse. Medical licenses for the Investigator and Subinvestigators, if appropriatef. Completed budget worksheet2. Prior to the Initiation Visit, the Investigator will review the Investigator’sBrochure to ensure his/her 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 questionsconcerning eligibility criteria, the time and events schedule, specific tests andSITE-013.0.doc© 2004 by CRC Press LLC

SOP# SITE-013.0CompanyEffective Date: DD/MMM/YYequipment, dispensing procedures and accountability records, serious adverseexperience (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 Sponsor/CROrepresentative.b. Confirm that lab supplies have arrived and have been inventoried.c. Meet with the Sponsor/CRO representative to learn how the Case ReportForms (CRFs) should be completed.d. Ensure the Sponsor/CRO representative signs the Monitoring Log(Attachment A).5. During the initiation visit, the Study Coordinator and Pharmacist will discuss howthe test article will be stored (e.g., security, temperature, humidity), dispensed tosubjects, and returned to the Sponsor.a. The Pharmacist will confirm that the test article has arrived and has beeninventoried.b. The Investigator and Study Coordinator will confirm the study requirementsfor AE and SAE reporting.c. The Investigator will complete and sign the Study Responsibilities Form.d. All study staff will meet with the Sponsor/CRO representative to review theprotocol and regulatory obligations of site personnel.e. Each staff member will sign and initial the Study Site Personnel SignatureSheet.C. Periodic (Interim) Site Visit1. 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 DocumentsBinder.e. Ensure specific CRFs and source documents that will be reviewed areavailable on the visit date.f. Set up appointments for the Monitor to meet with the pharmacist andInvestigator.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© 2004 by CRC Press LLC

SOP# SITE-013.0CompanyEffective Date: DD/MMM/YYb. 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 answerquestions 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 theMonitor’s findings.d. Ensure that the Monitor signs the Monitoring Log.D. Close-Out Visits1. 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 DocumentsBinder.e. Ensure all source documents are organized for easy retrieval during futureaudits.f. Ensure all drug accountability records are complete and that unused testarticles have been returned to the Sponsor or destroyed.g. Set up appointments for the Monitor to meet with the Investigator and studystaff 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 answerquestions 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 todiscuss study issues and concerns.d. Ensure that the Monitor signs the Monitoring Log.SITE-013.0.doc© 2004 by CRC Press LLC

SOP# SITE-013.0E. Sponsor ContactsCompanyEffective Date: DD/MMM/YY1. Telephone Contacts – All study personnel will document critical conversationswith the Sponsor/CRO, especially those pertaining to eligibility criteria, protocoldeviations, and serious adverse experiences. Unless the Sponsor/CRO hasrequested that another method be used, the Telephone Contact Report form willdocument these discussions (Attachment B). The Study Coordinator or delegatewill file the Telephone Contact Reports in the Regulatory Documents Binder.2. Letters and Faxes – All study personnel will make copies of all correspondencewritten to the Sponsor/CRO. The Study Coordinator or delegate will file thiscorrespondence in the Regulatory Documents Binder.3. E-mails – All study personnel will print out copies of critical e-mails with theSponsor/CRO. The Study Coordinator or delegate will file this correspondence inthe Regulatory Documents Binder.4. At a minimum, the Sponsor/CRO 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.ReferencesNoneV. AttachmentsAttachment A – Monitoring LogAttachment B – Telephone Contact ReportSITE-013.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: SITE-014.0Title: Study Files and Record RetentionEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. Purpose• To describe the manner in which regulatory documents and other study-relateddocuments are to be maintained at an investigational site.• To create a system of record retention that can facilitate document retrieval byMonitors, Quality Assurance Auditors, or FDA inspectors.II.ScopeThis SOP will apply to all industry-sponsored trials conducted at Company.SITE-014.0.doc© 2004 by CRC Press LLC

SOP# SITE-014.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Regulatory Documents1. Before the study initiation visit, the Study Coordinator will create, or be given bythe Sponsor/Contract Research Organization (CRO), a ring binder in which allrequired regulatory documents, forms and correspondence will be kept. If theSponsor/CRO requires additional forms, or documents, these will be maintainedin addition to the documents listed in Attachment A.2. The Study Coordinator will ensure that the appropriate documents are placed inthe Regulatory Documents Binder on a regular basis. The Study Coordinator willmake the Binder available for review by the Monitor at each site visit.B. Case Report Forms1. The Study Coordinator or delegate will transcribe the appropriate data from thesource 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 Sponsor/CRO may not see CRFs from another study).CRFs for one study will be stored together.C. Informed Consents1. Where the signed informed consents are stored will vary based on instructionsfrom the Sponsor/CRO. If the Sponsor/CRO has given no direction concerningstorage of informed consents, they will be stored together in the RegulatoryDocuments Binder.2. Signed informed consents for screen failures will be stored in the RegulatoryDocuments Binder.D. Source documents1. Original source documents will be kept in the subject’s medical chart. A separatefolder for each subject may be created if worksheets are used for the study.Where these are stored will be based on instructions from the Sponsor/CRO.E. Contracts1. Contracts such as the Confidentiality Agreement, Investigator Agreement, andPublication Policy Agreement will be stored in the management offices ofCompany (i.e., not with the study records).SITE-014.0.doc© 2004 by CRC Press LLC

SOP# SITE-014.0F. Records RetentionCompanyEffective Date: DD/MMM/YY1. 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 ordevice being studied, orb. If an application is not approved, for two (2) years after development of thedrug or device has been terminated and the FDA has been notified.After the two years has expired, no records will be destroyed without obtainingthe Sponsor/CRO’s written permission in advance.2. If on-site storage of the study records is impractical, they will be placed in asecure off-site facility where they may be readily accessed in the event of anaudit. Alternatively, with approval of Company, the records may be stored at theSponsor/CRO headquarters.3. If the Principal Investigator leaves Company, he/she will provide theSponsor/CRO with written notice of the location of the study records and thename and phone number of an alternate contact in the event of an audit.IV.References21 CFR 312.55 – Informing Investigators21 CFR 312.57 – Record Keeping and Record Retention21 CFR 312.58 – Inspection of Sponsor Records and Reports21 CFR 312.62 – Investigator Record Keeping and Record Retention21 CFR 312.64 – Investigator Reports21 CFR 54.4 – Certification and Disclosure Requirements21 CFR 54.6 – Record Keeping and Record Retention21 CFR 312.68 – Inspection of Investigator’s Records and Reports21 CFR 56.107 – IRB Membership21 CFR 56.115 – IRB RecordsICH Guidelines for Good Clinical Practice (E6) section 4.4 – Communication withIRB/IECICH Guidelines for Good Clinical Practice (E6) section 4.9 – Records and ReportsICH Guidelines for Good Clinical Practice (E6) section 5.22 – Clinical Trial/StudyReportsSITE-014.0.doc© 2004 by CRC Press LLC

SOP# SITE-014.0V. AttachmentsNoneCompanyEffective Date: DD/MMM/YYSITE-014.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-001.0Title: Institutional Review Board ResponsibilitiesEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe standards for the protection of the rights and welfare of human subjectsthrough initial and continuing review of research studies.II.ScopeThis SOP will apply to all IRB meetings for Company.IRB-001.0.doc© 2004 by CRC Press LLC

SOP# IRB-001.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Authority and ResponsibilityThe Company IRB has the authority and responsibility to:1. Review research activities and to approve, disapprove, or ask for modifications ofthe research.2. Require progress reports from Investigators so that the board can conductcontinuing 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 toimplementation, except where necessary to eliminate immediate hazard tosubjects.5. Suspend, restrict, or terminate the approval of previously approved research thatis not being conducted according to the IRB requirements or Federal Regulations.6. Perform audits of study sites to evaluate the consent process and compliance withthe protocol and regulations.Every IRB member will be expected to understand and promote the ethical principlesoutlined in The Belmont Report and to have a thorough knowledge of the FederalRegulations (45 CFR 46 and 21 CFR 50 and 56), International Commission onHarmonization guidelines (ICH), and Company policies and procedures governingresearch involving human subjects.B. Investigator Non-ComplianceIf an Investigator has failed to comply with the protocol or IRB requirements,including continuing review, the Investigator will be notified in writing about theboard’s concerns. If there is inadequate or no response from the Investigator, at thenext meeting, the board will decide if:1. Approval of the study should be suspended or withdrawn (i.e., no additionalsubjects will be enrolled in the study);2. The IRB should perform a site audit; or3. Other corrective action is needed.This discussion, decision, and timeline for correction will be included in the meetingminutes.If non-compliance is not corrected in the timeframe required, the board will close thestudy and will report the Investigator to Company management and to the appropriateregulatory authority, as required by regulation.IRB-001.0.doc© 2004 by CRC Press LLC

SOP# IRB-001.0CompanyEffective Date: DD/MMM/YYIf non-compliance is resolved, the IRB Chairperson will document the situation andwill place the documentation in the study file.IV.References21 CFR 56.108 – IRB Function and OperationsIRB and Clinical Investigator Information SheetsICH E6 3.1 – ResponsibilitiesV. AttachmentsNoneIRB-001.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-002.0Title: IRB Membership and TrainingEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the processes and procedures for forming and managing a duly-constitutedInstitutional Review Board within Company.II.ScopeThis SOP will apply to all research activity involving human subjects, whether federallyfunded or not, and without regard to the source of any supporting funds.IRB-002.0.doc© 2004 by CRC Press LLC

SOP# IRB-002.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Purpose of the BoardThe IRB assists researchers in the protection of the rights and welfare of humansubjects by conducting initial and continuing review of all research activitiesinvolving human subjects at Company. The IRB shall meet or exceed therequirements of federal policy set forth in 45 CFR 46, 21 CFR 50, and 21 CFR 56 andICH Guidelines 3.0.B. Appointment of Board MembersPrimary and alternate IRB members may be recruited from Company staff and fromthe local community by either recommendation by current IRB members,administrative staff, institutional management, or by public recruitment efforts. Eachprospective member must submit a curriculum vitae to the IRB Chairman andadministrative staff for review. Appropriate candidates must undergo a qualificationinterview with the IRB Chairman, board members, and/or administrative staff.During the interview, the candidate will be informed of his/her responsibilities, theresponsibilities of the Board as a whole, and the time requirements for the position.Candidates will be required to attend at least one IRB meeting as an observer prior tobecoming a board member. The candidate will sign a confidentiality agreement priorto attending the meeting as an observer.In appointing members to the IRB, the IRB Chairman, board members, andadministrative staff will consider the diversity of the members’ backgrounds,including race, gender, cultural backgrounds, and sensitivity to community attitudesand the candidate’s professional competence necessary to review the research.Consideration will also be given to the inclusion of one or more individuals who areknowledgeable 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 tomembership on the Board will be determined and documentation of the decision willbe recorded in the meeting minutes.C. Composition of the BoardThe IRB will be composed of no fewer than five (5) members sufficiently qualifiedto carry out the Board’s purpose.The Board may not consist entirely of members of a single profession and willinclude at least one member qualified in a scientific discipline (e.g., physicians andPh.D. level physical and biological scientists, nurses, pharmacists, or otherbiomedical health professionals) and one member with an unambiguouslynonscientific background (e.g., clergy and ethicists).IRB-002.0.doc© 2004 by CRC Press LLC

SOP# IRB-002.0CompanyEffective Date: DD/MMM/YYThe non-scientific member should not be vulnerable to intimidation by theprofessionals on the Board and his/her services should be fully utilized by the IRB.The IRB will include at least one member who is not otherwise affiliated withCompany and who is not part of the immediate family of a person who is affiliatedwith Company.Every non-discriminatory effort will be made to ensure the IRB is not composedentirely of men or women, so long as no selection is made to the IRB on the basis ofgender alone.When research involving a vulnerable population is being reviewed, at least onemember of the Board should have the appropriate background and experience inworking with these subjects.One individual can satisfy more than one of the membership requirements for theboard.The IRB may invite individuals with competence in special areas to assist in thereview of issues that require expertise beyond or in addition to that of the IRB. Theseindividuals may contribute to the discussion, but may not vote on the research.D. IRB ChairpersonThe IRB Chairperson will:1. Conduct meetings in an efficient and fair manner, and according to standardparliamentary procedures.2. Follow the agenda created for each meeting.3. Set a tone of openness to encourage dialogue in the meeting.4. Respect the diverse backgrounds, perspectives, and sources of expertise of all IRBmembers, especially for the contributions of the non-scientists, and the ability tofoster such respect among the IRB members.5. Uphold IRB judgments that may not always be popular with Investigators.6. Invest adequate time, interest, and commitment to provide guidance and expertiseto IRB members and Investigators.7. Assure that the Board receives appropriate and sufficient administrative support,meeting space, and other necessary resources to function efficiently, and willreport deficiencies in this support to Company management for correction.IRB-002.0.doc© 2004 by CRC Press LLC

SOP# IRB-002.0E. IRB SecretaryCompanyEffective Date: DD/MMM/YYThe IRB Secretary will be appointed by the IRB Chairman. He/she will prepare anddistribute the meeting agenda and will record the IRB meeting minutes. The IRBSecretary will maintain the following records:1. IRB membership roster2. Curriculum vitae for each board member3. Training records for each IRB member4. Documentation of training sessions attended by board members, including signedattendance sheets and a copy of the handouts and slides5. Documentation of resignation/termination6. IRB meeting minutes7. Correspondence with the Investigators8. Materials provided to board members for review9. Documentation of expedited review and approvalF. Alternate Board MembersAd hoc substitutes are not permissible as members of the IRB. Alternate boardmembers will be appointed and will function in the same manner as primary boardmembers. The IRB roster will identify the primary member(s) for whom eachalternate member may substitute. To ensure an appropriate quorum is maintained, thealternate’s qualifications will be comparable to the primary member being replaced.The IRB minutes will document when an alternate member replaces a primarymember. When alternates substitute for a primary member, the alternate member willreceive and review the same material that the primary members receive.G. Primary ReviewerThe Primary Reviewer will conduct an in-depth review of the research proposal andwill present the protocol, informed consent, and other study-related materials to thefull Board at the convened meeting.H. Membership RosterA current membership roster will be maintained by the IRB administrative staff. Thislist should include the following:1. Name2. Degrees3. Representative capacityIRB-002.0.doc© 2004 by CRC Press LLC

SOP# IRB-002.0CompanyEffective Date: DD/MMM/YY4. 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 todescribe 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 eachInvestigator conducting research under the IRB’s review and to federal or stateagencies which require copies of membership rosters as part of general/specificassurance reviews.I. Conflict of InterestA board member will be considered to have a conflict of interest when:1. He/she is the Investigator, Subinvestigator, or Study Coordinator for a study.2. He/she has a significant financial interest in the research activity underconsideration or the results of the study.3. He/she has a conflict of loyalty (e.g., promoting the work of subordinates orsupervisors).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 continuingreview of a project for which he/she has a conflict of interest; however, to provideinformation requested by the IRB, the individual may contribute to the discussion.Meeting minutes should reflect that the board member who had a conflict of interestabstained from the vote.J. Term of MembershipThe Chairman will be appointed for a term of one (1) year and may not serve morethan two (2) consecutive terms. The minutes of all meetings of the Board will besigned 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 sothat no more than three (3) members will be appointed in any one year. No membermay serve more than two (2) consecutive terms. In the event of the resignation ordeath of a member, the Chairman will appoint a member to serve the unexpiredportion of the resigning/deceased member’s term.IRB members who decide to resign must provide the IRB Chairperson with writtennotification of their proposed resignation date at least 30 calendar days prior to thenext 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 forbehavior unbefitting and possibly detrimental to the Board. In this case, the IRBIRB-002.0.doc© 2004 by CRC Press LLC

SOP# IRB-002.0CompanyEffective Date: DD/MMM/YYChairperson will provide the member with a letter of termination. Documentation ofthe termination will be recorded in the meeting minutes of the next duly constitutedIRB meeting and the IRB Membership Roster will be revised.K. Training IRB MembersBefore attending a meeting as a voting member, each new IRB member will berequired to attend a meeting as an observer. Documentation of the candidate’sattendance will be recorded in the meeting minutes.The IRB administrative staff will provide each new board member with the followingmaterials:1. 45 CFR 462. 21 CFR 503. 21 CFR 564. ICH Guidelines for Good Clinical Practices (E6)5. Declaration of Helsinki6. Belmont Report7. Company IRB’s Standard Operating ProceduresSigned documentation of the receipt of the training materials should be obtained foreach new member and filed with the new member’s curriculum vitae as part of thetraining record.The IRB Chair and administrative staff will arrange for special training or in-servicesessions for all IRB members and alternates at least once each year. Documentationof training materials will be maintained by the IRB Secretary.IV.References45 CFR 46.107 – IRB Membership21 CFR 56.107 – Institutional Review BoardsICH Guidelines for Good Clinical Practice E6 section 3.2 – Composition, Functions, andOperationsICH Guidelines for Good Clinical Practice E6 section 3.3 – ProceduresFDA Information Sheets for Institutional Review Boards and Clinical InvestigatorsV. AttachmentsAttachment A – IRB Membership Roster TemplateIRB-002.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-003.0Title: Institutional Review Board MeetingsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the processes and procedures for the conduct of IRB meetings.II.ScopeThis SOP will apply to all IRB meetings for Company.IRB-003.0.doc© 2004 by CRC Press LLC

SOP# IRB-003.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Regular MeetingsThe IRB will hold regular meetings at a time and place to be determined by the IRBSecretary. Written notice of the regular meeting will be given to each member nolater than seven (7) days before the meeting.B. Special MeetingsThe Chairperson may call a special meeting of the IRB when he/she determines it tobe necessary. Written notice of special meetings, including the time, place, andpurpose, will be given to each member no later than one day before the specialmeeting.C. QuorumA quorum will be necessary for the conduct of a meeting. The presence of one morethan 50% of the membership will constitute a quorum when considering attendance,except that the majority should include at least one member whose primary concern isthe non-scientific area. Advisory members and members with a conflict of interestmay 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 thequorum is restored. Any action taken without a quorum present will be consideredinvalid.D. Preparation for IRB MeetingsFor the initial review of research, Investigators will submit a study packet to the IRBSecretary no fewer than fourteen (14) days before the next scheduled meeting. Eachstudy packet will include the following:1. A completed Initial Submission Form (Attachment A)2. The most recent version of the protocol3. The current Investigator’s Brochure or Package Insert4. Draft Informed Consent Form5. Advertisements (if applicable) and/or study recruitment materialsIf this is the first time an investigator has submitted a study to the IRB, he/she shouldalso include a copy of his/her curriculum vitae and medical license.Case Report Forms may be omitted from the study packet unless specificallyrequested by the Board.IRB-003.0.doc© 2004 by CRC Press LLC

SOP# IRB-003.0CompanyEffective Date: DD/MMM/YYThe IRB Secretary will transmit the appropriate materials to each of the boardmembers at least three days before the scheduled meeting to allow thorough review ofeach proposal. The Chairperson will select at least one primary reviewer for eachproposal. 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 thecompletion of a study will be submitted to the Board in the same manner.E. Conduct of the MeetingsThe Chairperson is responsible for leading the meeting, conducting business so thateach proposal is fairly and completely reviewed, seeing that the Board reaches adecision on the disposition of each proposal, and communicating these decisions tothe individuals who submitted the proposals.At the board meeting, each proposal will be presented by a Primary Reviewer insufficient detail to assure adequate consideration. The presentation must include, butis 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 authorizedrepresentative.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 aconsensus can be reached. Clinical Investigators or ancillary staff may attend boardmeetings 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 ofthe meeting. Meeting minutes will reflect whether or not this requirement has beenmet. The Board may also request a review/opinion from one or more qualifiedoutside 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 byvideo-conference or conference telephone call; however, the member must havereceived a copy of the documents to be reviewed at the meeting. Such members mayvote and will be counted as part of the quorum. Opinions of absent members that aretransmitted by mail, telephone, fax, or e-mail may be considered by the attending IRBmembers but may not be counted as votes or the quorum for convened meetings.IRB-003.0.doc© 2004 by CRC Press LLC

SOP# IRB-003.0F. VotingCompanyEffective Date: DD/MMM/YYAny board member with a conflicting interest in a proposal will abstain fromdeliberations and voting on that proposal, except to provide information as requestedby the Board. Such abstentions will be recorded in the minutes.By majority vote of the members present, the Board may reach one of the followingdecisions regarding each proposal:1. Unconditional approval – approved as presented.2. Conditional approval – approved, subject to specific modifications, such aschanges to the consent form.3. Disapproved – the board has decided that they cannot ethically approve theresearch.4. Deferred – no decision can be made yet, pending evaluation of additionalrequested information.If the Board approves a proposal subject to modifications, it must specify, by majorityvote of the members present, whether the changes will require full Board approval ormay 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 notlimited 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 forreview and approval at the next meeting. Minutes of the meetings will be signed bythe Chairperson following review and approval by the individual members of theBoard.G. Notification to the InvestigatorThe Board will provide the Investigator with written notification of its decision toapprove, disapprove, defer, or modify the research proposal. (See Attachment C forthe IRB Review Results Form.) If a proposal is disapproved, the reasons for suchdisapproval will be documented. The Investigator will also be notified of the durationof the Board’s approval, which will never exceed one year. The decisions of theBoard will be included in the files maintained by the Secretary.H. Confidentiality of the Review ProcessDuring the initial or continuing review of the research, material provided to IRBmembers will be considered confidential and the board members will assure theconfidentiality of the information provided to them.IRB-003.0.doc© 2004 by CRC Press LLC

SOP# IRB-003.0CompanyEffective Date: DD/MMM/YYIV. References21 CFR 56.108 – IRB Function and Operations21 CFR 56.115 – IRB Records45 CFR 46.108 – IRB Function and Operations45 CFR 46.109 – IRB Review of Research45 CFR 46.115 – IRB RecordsICH Guidelines for Good Clinical Practice (E6) 3.2 – Composition, Functions, andOperationsICH Guidelines for Good Clinical Practice (E6) 3.3 – ProceduresV. AttachmentsAttachment A – Initial Submission FormAttachment B – Reviewer’s ChecklistAttachment C – IRB Review Results FormIRB-003.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-004.0Title: IRB Record KeepingEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the procedures for documenting the IRB’s activities.II.ScopeThis SOP will apply to all research activity involving human subjects, whether federallyfunded or not, and without regard to the source of any supporting funds.IRB-004.0.doc© 2004 by CRC Press LLC

SOP# IRB-004.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. ResponsibilityThe IRB files will be maintained by the IRB Secretary at .B. IdentificationIRB records will include the following:1. IRB members’ recordsa. Curriculum vitae for each board memberb. Training records for each IRB memberc. Documentation of training sessions attended by board members, includingsigned attendance sheets and a copy of the handouts and slidesd. Documentation of resignation/termination2. IRB membership roster3. IRB meeting minutes4. Materials provided to board members for review (including, but not limited to,investigator brochures, protocols, amendments, consent forms, IND SafetyReports, progress reports)5. Correspondence with the Investigators6. Documentation of expedited review and approval7. Statements of new findings provided to subjects8. Standard Operating ProceduresC. Retention and AccessibilityAll IRB records will be retained for at least three (3) years after the completion of theresearch.IRB records will be made available for inspection and copying by authorizedrepresentatives of DHHS, FDA, and other regulatory authorities after receiving therequest in writing.D. IRB Minutes1. The minutes of the IRB meetings will be in sufficient detail to show the followingfor each research protocol:a. Attendance at the meetingb. A summary of the discussion and the resolution of controversial issuesc. Actions taken by the boardIRB-004.0.doc© 2004 by CRC Press LLC

SOP# IRB-004.0CompanyEffective Date: DD/MMM/YYd. Vote on the actionse. The basis for requiring changes or disapproving the researchf. IRB’s determination of riskg. IRB review date (date of progress report)2. The format of the IRB Meeting minutes will follow that outlined in AttachmentA.3. Each Primary Reviewer will verify the accuracy of that portion of the minutes forthe agenda items he/she presented.IV.References21 CFR 56.108 – IRB Function and Operations21 CFR 56.115 – IRB Records46 CFR 45.115 – IRB RecordsICH Guidelines for Good Clinical Practice (E6) section 3.4 – RecordsICH Guidelines for Good Clinical Practice (E6) section 4.13 – Final Reports byInvestigators/ InstitutionsV. AttachmentsAttachment A – IRB Meeting Minutes TemplateIRB-004.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-005.0Title: IRB Review of ResearchEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the processes for the initial and continuing review of research projects.II.ScopeThis Standard Operating Procedure (SOP) will apply to all research activity conducted atCompany that involves human subjects.IRB-005.0.doc© 2004 by CRC Press LLC

SOP# IRB-005.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Submission for Initial ReviewFor the initial review of research, Investigators will submit a study packet to the IRBSecretary no fewer than fourteen (14) days before the next scheduled meeting. Eachstudy packet will include the following:1. A completed Initial Submission Form (Attachment A)2. The most recent version of the protocol3. The current Investigator’s Brochure or Package Insert4. A draft Informed Consent Form5. Advertisements (if applicable) and/or study recruitment materialsIf this is the first time an investigator has submitted a study to the IRB, he/she shouldalso include a copy of his/her curriculum vitae and medical license.Case Report Forms may be omitted from the study packet unless specificallyrequested by the Board.B. IRB Initial Review ProcedureThe IRB Secretary will transmit the appropriate materials to each of the boardmembers at least three days before the scheduled meeting to allow thorough review ofeach proposal. The Chairperson will select at least one primary reviewer for eachproposal. 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 specialmeeting of the IRB. The Investigator may be invited to attend a portion of themeeting, so that board members have the opportunity to question him/her about theresearch proposal. After the research has been presented, the IRB Chairperson willcall for a discussion of the protocol, consent form, advertisements, and other subjectmaterials.The Primary Reviewer will make a motion concerning the protocol, consent form,and advertisements (i.e., approval, conditional approval, deferred, denied) and willnote when the next progress report will be expected. The motion will be secondedand the IRB will vote to approve or disapprove the research proposal. No member ofthe 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 majorityvote of the members present, whether the changes will require full Board approval ormay 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 notlimited to the final disposition of each proposal, will be made by the IRB Secretary.IRB-005.0.doc© 2004 by CRC Press LLC

SOP# IRB-005.0CompanyEffective Date: DD/MMM/YYC. Criteria for IRB Approval of ResearchThe IRB may approve research only after it has determined that all of the followingrequirements are satisfied:1. Risks to subjects are minimized by using procedures that are consistent withsound research design, and that do not unnecessarily expose subjects to risk.Whenever appropriate, researchers should employ procedures that are beingperformed on subjects for diagnostic or treatment purposes.2. Risks to subjects are reasonable relative to:a. anticipated benefits, if any, to subjects, andb. the importance of the knowledge that may reasonably be expected to result.3. The selection of subjects is equitable. In making this assessment the IRB musttake into account the purposes of the research and the setting in which it will beconducted. The IRB must be particularly attentive to the special problems thatmay arise when research involves vulnerable populations, such as children,pregnant women, prisoners, mentally disabled persons, or economically oreducationally disadvantaged persons. If any of the subjects is likely to besusceptible to undue influence or coercion, the IRB may require additionalsafeguards in the study to protect such subjects.4. Informed consent will be sought from each prospective subject, or the subject'slegally authorized representative, generally by means of a written consentdocument. The IRB will carefully review these documents to assure that theycontain the required elements of informed consent and that they areunderstandable 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 maintainthe confidentiality of data.7. The investigator is appropriately qualified and has the facilities to ensure allaspects of the research will be conducted with regard for the safety and well-beingof the subjects.When some or all of the subjects are likely to be vulnerable to coercion, the IRBshould add additional safeguards in the review of the research to ensure the rights andwelfare of these subjects are protected.D. Notification to the InvestigatorThe Board will provide the Investigator with written notification of its decision toapprove, disapprove, defer, or modify the research proposal (Attachment C – IRBReview Results Form). If a proposal is disapproved, the reasons for such disapprovalwill be documented. The Investigator will also be notified of the duration of theBoard’s approval, which will never exceed one year. The decisions of the Board willbe included in the files maintained by the Secretary.IRB-005.0.doc© 2004 by CRC Press LLC

SOP# IRB-005.0CompanyEffective Date: DD/MMM/YYE. Continuing ReviewThe IRBs will conduct continuing reviews of research at intervals appropriate to thedegree of risk, but not less than once a year, in order to reassure themselves,investigators, research subjects, and the public that appropriate measures are beingtaken to protect the rights and welfare of human research subjects.The IRB Secretary is responsible for tracking when continuing review is due for eachstudy.The Principal Investigator is responsible for timely submission of a continuing reviewapplication to the IRB that initially reviewed the protocol. The Investigator shouldsubmit the necessary documentation to the IRB Secretary in enough advance time sothat completion of continuing review can be accomplished by the due date.For continuing review, the Investigator will submit the following documents to theIRB Secretary:1. A copy of the currently approved protocol and consent document2. 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 forcontinuation. The review will take place at a convened meeting of the Board andmust be approved by a majority of the members present in a format similar to theinitial review. Criteria for approving the continuation of research are the same aswith the initial review. If the IRB gives conditional approval to the continuingreview, these conditions must be met before approval for continuation will begranted.F. Notification to the InvestigatorThe Board will provide the Investigator with written notification of its decisionconcerning the continuation of the research proposal (Attachment C – IRB ReviewResults Form). If a proposal is disapproved, the reasons for such disapproval will bedocumented. The Investigator will also be notified of the duration of the Board’sapproval, which will never exceed one year. The decisions of the Board will beincluded in the files maintained by the Secretary.G. Investigator’s Failure to Submit a Progress ReportIf an Investigator fails to submit a Progress Report by the scheduled review date, theIRB will suspend subject accrual for that study pending re-approval by the IRB. InIRB-005.0.doc© 2004 by CRC Press LLC

SOP# IRB-005.0CompanyEffective Date: DD/MMM/YYthis case, the IRB Chairperson will send a letter to the Principal Investigator notifyinghim or her that:1. The IRB has suspended subject accrual and no new subjects can be enrolled;2. Whether or not the IRB will allow the research to continue for those subjects whoare already enrolled; and3. The Investigator must submit a Progress Report within 30 days. Failure to do sowill result in withdrawal of the approval and notification to the sponsor andregulatory agencies of the withdrawal.H. IRB Notification of Study TerminationWhen the last subject enrolled in the study has completed his/her last study-relatedassessment, the Investigator must notify the IRB about the study termination usingthe IRB Notification of Study Termination Form (Attachment E).The IRB Chairperson or Secretary will notify the rest of the IRB concerning studyterminations at the next convened meeting. Study terminations may be reviewed andpresented to the Board on an expedited basis. The IRB Chairperson will complete theIRB Study Termination Acknowledgement and send it to the Investigator todocument this notification (Attachment F).IV. References21 CFR 56.108 – IRB Functions and Operations21 CFR 56.109 – IRB Review of Research21 CFR 56.111 – Criteria for IRB Approval of Research45 CFR 46.109 – IRB Review of Research45 CFR 46.111 – Criteria for IRB Approval of ResearchICH Guidelines for Good Clinical Practice (E6) section 3.1 – ResponsibilitiesICH Guidelines for Good Clinical Practice (E6) section 4.9 – Records and ReportsICH Guidelines for Good Clinical Practice (E6) section 4.10 – Progress ReportsICH Guidelines for Good Clinical Practice (E6) section 4.12 – Premature Termination orSuspension of a TrialV. AttachmentsAttachment A – Initial Submission FormAttachment B – Reviewer’s ChecklistAttachment C – IRB Review Results FormAttachment D – IRB Progress Report FormAttachment E – IRB Notification of Study TerminationAttachment F – IRB Study Termination AcknowledgementIRB-005.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-006.0Title: IRB Review of Informed ConsentEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the processes for the IRB review of informed consent documents.II.ScopeThis SOP will apply to all informed consent documents that accompany research activityconducted at Company.IRB-006.0.doc© 2004 by CRC Press LLC

SOP# IRB-006.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Submission for ReviewAs part of the study packet for the initial review of research, Investigators will submita draft Informed Consent Form to the IRB Secretary.Valid informed consent requires:1. Disclosure of relevant information to prospective subjects about the research;2. Comprehension of the information; and3. Voluntary agreement, free of coercion and undue influence, to researchparticipation.Changes to the consent form that result from protocol amendments will be handled inthe same manner as the original document.B. IRB Review of the Informed Consent DocumentThe IRB Secretary will transmit the appropriate materials to each of the boardmembers at least three days before the scheduled meeting to allow thorough review ofeach proposal. The Primary Reviewer selected to review the research proposal willalso review the accompanying consent. The Primary Reviewer will complete aSubject Information and Consent Form Checklist (See Attachment A), but all boardmembers are required to review the materials for all studies.C. Elements for Written Informed Consent DocumentsIRB members will review each Informed Consent document to ensure that it meetsthe 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 thesubject’s participation;3. A description of the procedures to be followed and identification of anyprocedures that are experimental;4. A description of any foreseeable risks or discomforts to the subject, an estimate oftheir likelihood, and a description of what steps will be taken to prevent orminimize them;5. A description of any benefits to the subject or to others that may reasonably beexpected from the research. Monetary compensation is not a benefit. Ifcompensation is to be provided to research subjects or healthy volunteers, theamount should be stated in the consent document;IRB-006.0.doc© 2004 by CRC Press LLC

SOP# IRB-006.0CompanyEffective Date: DD/MMM/YY6. A disclosure of any appropriate alternative procedures or courses of treatment thatmight be advantageous to the subject;7. A statement describing to what extent records will be kept confidential, includinga description of who may have access to research records;8. For research involving more than minimal risk, an explanation and description ofany compensation and any medical treatments that are available if researchsubjects are injured, where further information may be obtained, and whom tocontact in the event of a research-related injury;9. An explanation of whom to contact for answers to pertinent questions about theresearch and the research subject’s rights (include the Clinical Center’s PatientRepresentative and telephone number); and10. A statement that participation is voluntary and that refusal to participate ordiscontinuing participation at any time will involve no penalty or loss of benefitsto which the subject is otherwise entitled.IRB Reviewers will ensure that, when appropriate, the following additional elementswill be included in the consent form:1. If the subject is or may become pregnant, a statement that the particular treatmentor procedure may involve risks, which are currently unforeseeable, to the subjector to the embryo or fetus;2. A description of circumstances in which the subject’s participation may beterminated by the investigator without the subject’s consent;3. Any costs to the subject that may result from participation in the research;4. What will happen if the subject decides to withdraw from the research and howwithdrawal will be handled;5. A statement that the Principal Investigator will notify subjects of any significantnew findings developed during the course of the study that may affect them andinfluence their willingness to continue participation;6. The approximate number of subjects involved in the study;7. When appropriate, a statement concerning an investigator’s potential financial orother conflict of interest in the conduct of the study.B. Waiver or Alteration of the Required Elements of Informed ConsentOnly in those circumstances prescribed by the Federal Regulations (21 CFR 50.23and 50.24) will the IRB waive the requirement to obtain informed consent, or approvea consent process that does not include or alters some or all of the elements ofconsent.The Primary Reviewer will present the research proposal at a regular or specialmeeting of the IRB. The Investigator may be invited to attend a portion of themeeting, so that Board members have the opportunity to question him/her about theIRB-006.0.doc© 2004 by CRC Press LLC

SOP# IRB-006.0CompanyEffective Date: DD/MMM/YYresearch proposal. After the research has been presented, the IRB Chairperson willcall for a discussion of the protocol, consent form, advertisements, and other subjectmaterials.The Primary Reviewer will make a motion concerning the protocol, consent form,and advertisements (i.e., approval, conditional approval, deferred, denied) and willnote when the next progress report will be expected. The motion will be secondedand the IRB will vote to approve or disapprove the research proposal. No member ofthe 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 majorityvote of the members present, whether the changes will require full Board approval ormay 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 notlimited to the final disposition of each proposal, will be made by the IRB Secretary.E. Notification to the InvestigatorThe Board will provide the Investigator with written notification of its decision toapprove, disapprove, defer, or modify the informed consent document (Attachment B– IRB Review Results Form). If modifications are required, the description of thosemodifications will also be documented. The Informed Consent Form will not beconsidered fully approved until the required modifications are incorporated into thedocument.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 RetentionThe 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 forthree (3) years from the date of the completion of the study.IRB-006.0.doc© 2004 by CRC Press LLC

SOP# IRB-006.0CompanyEffective Date: DD/MMM/YYIV.References21 CRF 50.23 – Exceptions from General Requirements21 CFR 50.24 – Exception from Informed Consent Requirements for Emergency Research21 CFR 50.25 – Elements of Consent45 CFR 46.116 – General Requirements for Informed Consent45 CFR 46.117 – Documentation of Informed ConsentICH Guidelines for Good Clinical Practice (E6) section 1.28 – Informed ConsentICH Guidelines for Good Clinical Practice (E6) section 1.37 – Legally AuthorizedRepresentativeICH Guidelines for Good Clinical Practice (E6) section 4.8 – Informed Consent of TrialSubjectsIRB Information Sheets – Continuing ReviewIRB Information Sheets – Guide to Informed ConsentV. AttachmentsAttachment A – Subject Information and Consent Form ChecklistAttachment B – IRB Review Results FormIRB-006.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-007.0Title: IRB Review of AdvertisementsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the procedures for reviewing advertisements used to recruit study subjects.II.ScopeThis SOP will apply to all advertisements submitted to the IRB for review.IRB-007.0.doc© 2004 by CRC Press LLC

SOP# IRB-007.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. SubmissionInvestigators will be responsible for submitting all original or revised advertisingmaterial to the IRB. Advertising will include, but is not limited to, the following:1. 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 advertisements3. Videotapes and printed scripts for television advertisements;4. Copies of internet listings as they would appear on a webpage5. Copies of phone scripts used to screen callers for research eligibilityAn administrative staff member will review the proposed advertising material forcompleteness and will determine if it qualifies for expedited review or needs to bereviewed by the full Board. The staff member will pass the documents to theappropriate board members for review.B. Review of Advertising MaterialUsing the Advertisement Review Checklist (Attachment A), the designated reviewerwill review the material for content and the context in which it will be used. Inreviewing the advertisement, the Reviewer will evaluate the following items:1. The name and address of the clinical investigator and/or research facility2. The condition under study3. The purpose of the research4. A summary of the eligibility criteria5. A brief list of benefits6. Time or other commitments required of the subjects7. Location of the research8. Person to contact for further informationAll 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 fromdeliberations and voting on the associated advertisements, except to provideinformation as requested by the Board. Such abstentions will be recorded in theminutes.IRB-007.0.doc© 2004 by CRC Press LLC

SOP# IRB-007.0CompanyEffective Date: DD/MMM/YYBy majority vote of the members present, the board may reach one of the followingdecisions regarding each advertisement:1. Unconditional approval – approved as presented.2. Conditional approval – approved, subject to specific modifications.3. Disapproved – the Board has decided they cannot ethically approve theadvertisement.4. Deferred – no decision can be made yet, pending evaluation of additionalrequested information.If the Board approves an advertisement subject to modifications, it must specify, bymajority vote of the members present, whether the changes will require full Boardapproval or may be approved by the Chairperson or Primary Reviewer on behalf ofthe Board.C. Notification to the InvestigatorThe Board will provide the Investigator with written notification of its decision toapprove, disapprove, defer, or modify the advertisement (Attachment B). If anadvertisement 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.References21 CFR 56.111(a)(3) – Selection of SubjectsICH Guidelines for Good Clinical Practice (E6) part 3.1 – Responsibilities45 CFR 46.11 – Criteria for IRB Approval of ResearchV. AttachmentsAttachment A – Advertisement Review ChecklistAttachment B – IRB Review Results FormIRB-007.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-008.0Title: IRB Review of Unscheduled Mandatory ReportsEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the procedures for reviewing unscheduled reports to the Institutional ReviewBoard (IRB).II.ScopeThis SOP will apply to all serious adverse events (including deaths), protocolamendments, and unanticipated problems submitted to the IRB for review.IRB-008.0.doc© 2004 by CRC Press LLC

SOP# IRB-008.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. SubmissionDuring any period in which the approved research is being conducted, theInvestigator will submit the following information to the IRB:1. Serious Adverse Events, including deaths;2. Unanticipated problems; and3. Protocol amendments and revised consents, if applicable.An administrative staff member will review the submission for completeness and willpass the documents to the appropriate board members for review.B. Review of Serious Adverse Events, Including DeathsThe IRB will require that Investigators report all deaths that occur while the subject isparticipating in a research study to the IRB Chairperson. This must be accomplishedorally within 24 hours after the death and in writing within five (5) days of the death.Unless the IRB Chairperson believes a special meeting should be convened to discussthe death, IRB members will review the written report at the next regular meeting.The IRB will require that Investigators report all adverse experiences that areconsidered serious and unexpected and related to the investigational product whichoccur 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 writingwithin five (5) days of the event.Unless the IRB Chairperson believes a special meeting should be convened to discussthe event, IRB members will review the written report at the next regular meeting.Investigators will submit all safety information to the IRB using the SafetyInformation Form (Attachment A) supplemented with sponsor-requireddocumentation.C. Review of Unanticipated ProblemsThe IRB will require that Investigators report all unanticipated problems that occurwhile the subject is participating in a research study to the IRB Chairperson (e.g.,medication errors, unexpected complications, protocol violations). This must be inwriting within five (5) days of the event.Unless the IRB Chairperson believes a special meeting should be convened to discussthe problem, IRB members will review the written report at the next regular meeting.IRB-008.0.doc© 2004 by CRC Press LLC

SOP# IRB-008.0CompanyEffective Date: DD/MMM/YYD. Review of Protocol AmendmentsThe Sponsor and IRB will require that Investigators submit the protocol amendmentsand the Protocol Amendment Form (Attachment B) to the IRB before the change isimplemented, except when necessary to eliminate hazards to study subjects. Theprotocol amendment should include a description of the change in the research. Ifrevisions to the consent form are necessary as a result of the amendment, the revisedconsent should also be submitted.Expedited review will be allowed for protocol amendments that only includeadministrative changes to the protocol.The IRB Secretary will provide copies to all IRB members. When applicable, otherbackground information such as adverse events reports or continuing review reportswill be provided to the Reviewers. The review of revised protocols and consentforms will follow the same process as for the initial review of the study. IRBmembers will review the protocol amendment and the revised informed consent at thenext regular meeting.The Board will provide the Investigator with written notification of its decision toapprove, disapprove, defer, or modify the protocol amendment and revised consent(Attachment C – IRB Review Results Form). If an amendment is disapproved, thereasons for such disapproval will be documented. The decisions of the Board will beincluded in the files maintained by the Secretary.E. Revisions to the Informed ConsentUpon review of additional information, the IRB may determine that InformedConsent document should be revised. If this is true, the board members will advisethe Investigator about the needed revisions. New subjects will be provided with therevised consent form. The Board will need to determine if previously enrolledsubjects will need to be re-consented.IV.References21 CFR 56.108 – IRB Function and Operations21 CFR 312.32 – IND Safety ReportsICH Guidelines for Good Clinical Practice (E6) section 3.3 – ProceduresICH Guidelines for Good Clinical Practice (E6) section 4.11 – Safety ReportingV. AttachmentsAttachment A – Safety Information FormAttachment B – Protocol Amendment FormAttachment C – IRB Review Results FormIRB-008.0.doc© 2004 by CRC Press LLC

CompanyStandard Operating Procedure: IRB-009.0Title: Criteria for Exempt and Expedited ReviewEffective Date: DD/MMM/YYSupersedes: N/AAUTHORName:Title:Department:Signature and Date:APPROVED BY DEPARTMENT HEAD QUALITY ASSURANCEName:Title:Department:Signature and Date:REVISIONSNo. Section Pages Initials/DateI. PurposeTo describe the criteria for exempt and expedited review of research conducted atCompany.II.ScopeThis Standard Operating Procedure (SOP) will apply to all research submitted toCompany Institutional Review Board (IRB).IRB-009.0.doc© 2004 by CRC Press LLC

SOP# IRB-009.0CompanyEffective Date: DD/MMM/YYIII.ProceduresA. Exempt Research (Summarized from 45 CFR 46.101(b))Unless otherwise required by DHHS, the FDA, or other regulatory agency, allresearch using human subjects and conducted at Company will be reviewed by theIRB, with the following exceptions:1. 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 potentiallydamaging and/or sensitive research on identifiable subjects. All researchinvolving survey or interview procedures is exempt, without exception, when therespondents are elected or appointed public officials or candidates for publicoffice.4. Research involving the observation (including observation by participants) ofpublic behavior, except certain potentially damaging and/or sensitive research onidentifiable subjects.5. Research involving the collection or study of existing data, documents, records,pathological specimens, or diagnostic specimens, if these sources are publiclyavailable or if the information is recorded by the investigator in such a mannerthat subjects cannot be identified directly or through identifiers linked to thesubject.6. Unless specifically required by statute or regulation, research and demonstrationprojects that are conducted by or subject to the approval of the Department ofHealth and Human Services and that are designed to study, evaluate, or otherwiseexamine actual or proposed programs, procedures, or benefits under the SocialSecurity Act or other public benefit or service programs.The IRB Chairperson will be responsible for determining if the research activityqualifies for exempt status. If it qualifies, the IRB Secretary will notify theInvestigator in writing. This notice will include the specific criteria which justifiesthe exemption.B. Expedited review of research (Summarized from 45 CFR 46.110)Expedited review is a procedure through which certain kinds of research may bereviewed and approved without convening a meeting of the full Board. The IRB willreview certain categories of research through an expedited procedure only if theresearch involves no more than minimal risk to the subjects. Categories of researchwhich may be considered for expedited review include the following:IRB-009.0.doc© 2004 by CRC Press LLC

SOP# IRB-009.0CompanyEffective Date: DD/MMM/YY1. Minor changes in previously approved research during the period covered by theoriginal approval:a. Where the research is permanently closed to the enrollment of new subjects;all subjects have completed all research-related interventions; and the researchremains active only for long-term follow-up of subjects; orb. Where no subjects have been enrolled and no additional risks have beenidentified; orc. Where the remaining research activities are limited to data analysis.2. Collection of blood samples by finger stick, heel stick, ear stick, or venipunctureas follows:a. From healthy, non-pregnant adults who weigh at least 110 pounds. For thesesubjects, the amounts drawn may not exceed 550 ml in an 8-week period andcollection may not occur more frequently than 2 times per week; orb. From other adults and children, considering the age, weight, and health of thesubjects, the collection procedure, the amount of blood to be collected, thefrequency with which it will be collected. For these subjects, the amountdrawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8-week periodand collection may not occur more frequently than 2 times per week.3. Collection of hair, nail clippings, teeth, etc. in a non-disfiguring manner4. Collection of excreta and external secretions5. Collection of uncannulated saliva collected either in an unstimulated fashion orstimulated by chewing gumbase or wax or by applying a dilute citric solution tothe tongue6. Placenta removed at delivery7. Amniotic fluid obtained at the time of rupture of the membrane prior to or duringlabor8. Recording of data from subjects age 18 or older by non-invasive procedures9. Collection of gingival plaques provided the collection procedure is not moreinvasive than routine prophylactic scaling of teeth and the process isaccomplished in accordance with accepted prophylactic techniques10. Collection of data from voice, video, digital, or image recordings made forresearch purposes11. Moderate exercise by healthy volunteers12. Research involving materials (data, documents, records, or specimens) that havebeen collected or will be collected solely for non-research purposes (such asmedical treatment or diagnosis)13. Collection of data through noninvasive procedures (not involving generalanesthesia or sedation) routinely employed in clinical practice, excludingprocedures involving x-rays or microwavesIRB-009.0.doc© 2004 by CRC Press LLC

SOP# IRB-009.0CompanyEffective Date: DD/MMM/YY14. Research on individual or group characteristics or behavior (including, but notlimited to, research on perception, cognition, motivation, identity, language,communication, cultural beliefs or practices, and social behavior), or researchemploying survey, interview, oral history, focus group, program evaluation,human factors evaluation, or quality assurance methodologies15. Research on drugs or devices for which an IND or an IDE (Investigational DeviceExemption) is not requiredThe expedited review procedure may not be used:1. When the research involves more than minimal risk to the subjects2. Where identification of the subjects and/or their responses would reasonably placethem at risk of criminal or civil liability or be damaging to the subjects' financialstanding, employability, insurability, reputation, or be stigmatizing, unlessreasonable and appropriate protections will be implemented so that risks related toinvasion of privacy and breach of confidentiality are no greater than minimal3. For classified research involving human subjects4. For studies intended to evaluate the safety and effectiveness of medical devices,including studies of cleared medical devices for new indicationsIf expedited review is being requested for the initial review of research, theInvestigator will submit the Initial Submission Form (Attachment A) and attach allappropriate documents. For expedited review of research that has already beenapproved by the IRB, the Investigator will submit a study packet to the IRB Secretarywhich 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 applicable3. The current Investigator’s Brochure or Package Insert4. A draft Informed Consent Form5. Advertisements (if applicable) or subject recruitment materialsIf this is the first time an Investigator has submitted a study to the IRB, he/she shouldalso include a copy of his/her curriculum vitae.The IRB Secretary will review the study packet for completeness and will forward itto the Reviewer. The Reviewer may be the Chairperson or any primary or alternateIRB member who does not have a conflict of interest with the research proposal. TheReviewer may exercise the authority of the IRB, except he/she cannot disapprove aresearch project. If the Reviewer believes the research should be disapproved, he/shewill bring it to the attention of the full Board.IRB-009.0.doc© 2004 by CRC Press LLC

SOP# IRB-009.0CompanyEffective Date: DD/MMM/YYThe 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 researchproposal submission.The IRB Secretary will track all research approved by expedited review and willinform the full board at the next convened meeting. A vote on expedited reviews isnot required but the IRB has the prerogative to discuss, rescind or amend expeditedactions.As with full Board approval, the IRB will provide the Investigator with writtennotification of its decision concerning the outcome of the expedited review of theresearch proposal (Attachment D – IRB Review Results Form). The Investigator willalso be notified of the duration of the Board’s approval, which will never exceed oneyear. The decisions of the Board will be included in the files maintained by the IRBSecretary.IV.References21 CFR 50 – Protection of Human Subjects21 CRF 56.104 – Exemptions from IRB Requirement21 CFR 56.107 – Waiver of IRB Requirement21 CFR 56.110 – Expedited review procedures for certain kinds of research involving nomore than minimal risk, and for minor changes in approved research45 CFR 46.110 – Expedited review procedures for certain kinds of research involving nomore than minimal risk and for minor changes in approved researchFDA Information Sheets for Institutional Review Boards and Clinical Investigators:Clinical Investigations which may be reviewed through expedited reviewprocedures set forth in FDA regulationsV. AttachmentsAttachment A – Initial Submission FormAttachment B – Expedited review FormAttachment C – Reviewer’s ChecklistAttachment D – IRB Review Results FormIRB-009.0.doc© 2004 by CRC Press LLC

CompanyAdvertisement Review ChecklistProtocol #:Investigator:Date of Review:Reviewer:Advertisement Title or Identification:1. Is the mode of communication appropriate?2. Does the advertising material, which will be used to recruit potential subjects,afford adequate protection?3. Does the advertising material explicitly state that this is a “research study” or“clinical research trial”?4. Is the material misleading or coercive?5. Does the advertisement contain any of the following unacceptable elements?• Claims, either explicitly or implicitly, that the drug or device is safe oreffective for the purposes under investigation• Claims that the drug or device is in any way equivalent or superior to anyother drug or device• Implied or express claim of safety or effectiveness of study medication• References to free medical treatment (“research-related” medicaltreatment is allowed)• Undue emphasis on subject compensation (such as “free” or the $ amountbolded or underlined)• Any claim that the research will (as opposed to “may”) improve thesubject’s medical condition• Any express or implied statement that the research is FDA approved• The words “medicine” or “medication” unless modified with terms suchas “research,” “investigational,” “experimental,” “study,” etc. It should beclear 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 druguse (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)Ad Review.doc© 2004 by CRC Press LLC

CompanyProtocol Amendment FormProtocol #: Investigator/Site #:Investigator:Sponsor:SiteAddress:Study Title:Attached is Amendment #__ (dated xx/xx/xx, version ___) for Protocol #___ (dated xx/xx/xx,version ___).A revised protocol, which incorporates the changes in Amendment #__:is included (dated xx/xx/xx, version ___).is not included.Changes to the informed consent document (dated xx/xx/xx, version ___):is necessary. A revised draft (dated xx/xx/xx, version ___) is attached.is not necessaryEnrollmentThis study isongoing (i.e., subjects continue to be enrolled) orenrollment is closed and subjects are being seen for follow-up assessments only.Number of subjects expected to enroll in this studyNumber of subjects screened Number of drop-outsNumber of subjects enrolledNumber of subjectscompletedWill the protocol amendment affect the risk benefit ratio of this study? Yes NoIf “yes,” explain:_______________________________________________Has the Principal Investigator, Subinvestigators, or Study Coordinatorchanged?If “yes,” explain:_______________________________________________YesNoPrincipal Investigator (print) Investigator’s Signature DateAmendment.doc© 2004 by CRC Press LLC

CompanyBiological Samples InventoryDrug name:Protocol #:Investigator:Address:Date of Shipment:Sponsor:Site contact person:Contact person’sphone number:SampleIdentifierSubjectNumberSubjectInitialsDateSampleObtainedTimeSampleObtainedSample Type(Use CodeBelow)CommentsUse the following abbreviations for “type of sample”:PK – Blood for pharmacokinetic analysis EL – Blood for electrolyte analysisPD – Blood for pharmacodynamic analysis UR – Urine for urinalysisHM – Blood for hematology analysis UC – Urine collection in jug for creatinine clearanceCO – Blood for coagulation analysis UD – Urine for analysis of drug levelsCC – Blood for clinical chemistry analysisBio Sample.doc© 2004 by CRC Press LLC

CompanyCRF Review FormProtocol #: Investigator/ Site #:Monitor:Visit Date:SubjectIDQuestion CRF page Resolved?CRF Review.doc© 2004 by CRC Press LLC

CompanyData Clarification FormCompound #/Name: Subject number:Protocol #: Subject Initials:Investigator: Monitor:CRFPage #Data ID Data Query ResolutionPage __ of ___Date documented: ____/____/____dd /mmm/ yyAfter completing all resolutions, sign below:Signature: ____________________________________ Date: __________DCF Form.doc© 2004 by CRC Press LLC

CompanyDrug Dispensing LogDrug name: Protocol #: Investigator/Site #:Investigator: Sponsor: IND #:SubjectNo.SubjectInitialsContainerNumberDateDispensedAmountDispensedDispensedByAmountReturnedDateReturnedRetrievedByExplanationforDiscrepancyAuditDatePhysicalCountInitialsofMonitorTOTALS:Dispense.doc© 2004 by CRC Press LLC

CompanyStudy Subject Investigational Product Dispensing RecordDrug name: Protocol #: Subject Initials:Investigator: Investigator/Site #: Subject #:VisitNo.DateDispensedContainerNumberAmountDispensedDispensedByWhomAmountUsedAmountReturnedDate ReturnedRetrievedBy WhomExplanation for Discrepancy,If ApplicableDispense by Pt.doc© 2004 by CRC Press LLC

CompanyClinical Trial Materials Disposition FormDate: Ship from: Ship to:Sponsor:Protocol #:IND #: Attention:Shipped via: Account #: Tracking #(name of carrier)SubjectNumberBottle Numbers Lot Numbers Product DescriptionQuantityDestroyedOn-siteQuantityReturnedCommentsStatus of StudyDrug Supply:(Check only one)I am not returning unused drug because all of the unused drug listed above was destroyed at the study site.I am not returning unused drug because all drug was used on the study.I am returning all unused drug. All other drug was used on the study; this shipment is final.I am returning all unused drug. More unused drug may/will follow.I am returning all unused drug in response to a recall notice or drug expiration.Shipment returned by: _____________________________________________________ Date: _______________________Drug Disposition.doc© 2004 by CRC Press LLC

CompanyInvestigational Drug Shipping OrderDate: Ship from: Ship to:Sponsor:Protocol #:IND #: Attention:Shipped via: Account #: Tracking #(name of carrier)QuantityOrderedUnit ofMeasureLot NumberExpiry/Retest dateProduct DescriptionQuantityShippedReason forshipment:Initial supplyResupplyOther (explain): _____________Special Information:Reference number: __________Subject number: ____________Strata number: ______________Shipment requested by:_________________________Date: ______________________Phone number: ______________Acknowledgement of receipt Shipment received by: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:Date: _________________________After completing the acknowledgement and signing this form, please fax it to XXX-XXX-XXXXDrug Order.doc© 2004 by CRC Press LLC

CompanyInvestigational Product Receipt FormDrug name: Investigator:Sponsor: Investigator/Site #:Protocol #: IND #:“Containers” (below) means: Bottles Vials/ampoules Blister cards/packs Boxes Tubes Other: ________SubjectIdentifierContainerNumbersLot Numbers Product Description Number ofContainersCheck ifDamagedShipment received by: _______________________________________________________ Date: _______________________Drug Receipt.doc© 2004 by CRC Press LLC

CompanyDrug Return FormDrug name: Ship from: Shipping Service: ______________Sponsor: Account #: ___________________Protocol #: Tracking #: ___________________Investigator: Ship to:Investigator/ Site #:IND #:Special servicePriority overnight2nd day deliverySaturday delivery“Containers” (below) means: Bottles Vials/ampoules Blister cards/packs Boxes Tubes Other: ________SubjectIdentifierContainer Numbers Lot Numbers Product DescriptionNumber ofContainersReturned orDestroyed?Shipment returned by: _____________________________________________________ Date: _______________________Drug Return.doc© 2004 by CRC Press LLC

CompanyScreening and Enrollment LogProtocol #: Investigator/Site #:Investigator:Sponsor:SiteAddress:Study Title:SubjectInitialsDate ofBirthDateScreenedIf Enrolled,Subject No.If Not Enrolled, Give ReasonEnrollment.doc© 2004 by CRC Press LLC

CompanyScreening and Enrollment Log (continued)SubjectInitialsDate ofBirthDateScreenedIf Enrolled,Subject No.If Not Enrolled, Give ReasonEnrollment.doc© 2004 by CRC Press LLC

CompanyExpedited Review FormStudy InformationProtocol Number:Protocol Title:Protocol Date and/or Version Number:Date of IRB’s Initial Approval of Research:IRB’s Identifying Number:Why does this request qualify for expedited review?Investigator and Study Staff InformationInvestigator name:Investigator phone:Investigator e-mail:Study Coordinator name:Study Coordinator phone:Study Coordinator e-mail:General InformationHow many subjects are expected to enroll in this study?How many subjects are expected to enroll at this site?Did recruitment begin? Yes No If “yes”, date:When is recruitment expected to end?Expedited.doc© 2004 by CRC Press LLC

CompanyInformed ConsentExpedited Review Form (continued)Will revisions to the consent form be needed? Yes NoIf “yes,” specify date or version number of most recently approvedconsent:_______________Serious Adverse EventsHave any Serious Adverse Events occurred on this study? Yes NoHave any IND Safety Reports been submitted for this study? Yes NoRecruitmentWhich of the following arebeing recruited for thisstudy? (Check all that apply.)Existing patientsReferral patientsPrivate Practice patientsOut-patientsIn-patientsPaid volunteersEmployees of SponsorEmployees of InvestigatorIlliteratesPregnant womenPrisonersPediatric patientsGeriatric patientsMentally retarded/disabledHomeless/ShelterPoor/uninsuredTerminally illNon-English speakingStudents to be recruited in their educational settingMilitary personnel to be recruited by military personnelOther?(explain) __________________________________Document Checklist (Please attach these documents.)Protocol (and amendments, if applicable)Consent form (dated _______; version ________)Current Investigator’s Brochure or package insertPatient diaries (if applicable)Copies of advertisements and all subject recruiting materials (if applicable)Expedited.doc© 2004 by CRC Press LLC

CompanySubject Information and Consent Form ChecklistProtocol #: Investigator/Site #:Protocol Date orVersion Number:Reviewer:Sponsor:Date:Element of Informed ConsentAdequateNotadequateNotapplicableSimple explanation of the consent processStatement that the study involves researchIdentification of any experimental proceduresPurpose of the research (always includes an evaluation of safety)Expected duration of the subject’s participationFrequency of visits to the study site and length of stay for eachvisitList of study proceduresA description of what will be expected of the subject, includingbefore entering the study (e.g., refrain from smoking and/oralcohol, discontinue some medications, etc.)Identification of experimental procedures and drugsProbability of random assignment to treatment arms, includingplaceboAcknowledgment of the use of placeboStatus of test article or drugList of foreseeable risks or discomforts; and when possible, thelikelihood, severity, and duration of those risks.List of benefits to the subject or to others that can be reasonablyexpected, including the possibility of no guarantee of benefits, ifapplicableICF Review.doc© 2004 by CRC Press LLC

CompanySubject Information and Consent Form Checklist (continued)Element of Informed ConsentAdequateNotadequateNotapplicablePayment schedule and amount is defined, including proratingList of alternative procedures or treatmentsAddresses confidentiality of recordsAllows Sponsor, CRO, IRB, and FDA full access to medicalrecordsExplains whether (and what) medical treatment or compensationis available if subject is injured; may include a statement of whowill be responsible for any additional expenses, especially if thereis the possibility that the subject’s insurance company or otherthird party may refuse to pick up the costs. (Regulations do notlimit injury to “physical injury.”)Contains name of contact person and phone number for questionsabout research-related injury or the research study. This needs tobe a 24-hour number.Contains name of contact person and phone number for questionsabout research rights. This is usually the IRB’s phone number.Statement that participation is voluntary and subject canwithdraw without penaltyAcknowledgment of risks that are currently unforeseeableStatement of risks during pregnancy, including risks to a fetus orembryo if the subject should become pregnantStatement that subject’s participation may be terminated withoutconsent of subjectReasons why subjects may be asked to leave the study withoutthe subject’ consentConsequences of a subject’s decision to withdraw from the study and adescription of the procedures when the subject’s participation isterminated (when applicable)ICF Review.doc© 2004 by CRC Press LLC

CompanySubject Information and Consent Form Checklist (continued)Element of Informed ConsentAdequateNotadequateNotapplicableConsequences of a subject’s decision to withdraw from the study and adescription of the procedures when the subject’s participation isterminated (when applicable)Description of additional costs to the subject resulting fromparticipation in the research (if applicable)Statement of obligation to share new findings during the study whichmay relate to the subject’s willingness to continue participation in thestudyDescription of procedures for withdrawal from the study andconsequences for withdrawalStatement of number of subjects and centers involvedOther IssuesAdequateNotadequateNotapplicableIs layman’s language used and the consent understandable to thesubject?Is the consent written in the second person? (e.g., First person: “Iunderstand that…” can be interpreted as suggestive and may be acoercive influence)Does the information given to the subject include any language thatwould imply that the subject releases the sponsor, investigator, or studysite from liability for negligence?Does the information given to the subject include any language thatappears to waive the subject’s legal rights?Is the consent written on the institution’s letterhead or does it containthe name, address, and telephone number of the institution typed on thefirst page?Does the informed consent identify the protocol (either by title orprotocol 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 whoexplained the study to the subject?ICF Review.doc© 2004 by CRC Press LLC

CompanyStudy Initiation Document Tracking WorksheetInvestigator:Site:Site number:Monitor:The following documents must be received by the Sponsor or CRObefore drug will be shipped to the study site.Letter of confidentialityInvestigator’s BrochureFDA Form 1572CV for Principal InvestigatorCVs for SubinvestigatorsCVs for Study CoordinatorFinancial Disclosure for PIFinancial Disclosure for SubinvestigatorFinancial Disclosure for Study CoordinatorProtocolSigned Protocol Signature PageTemplate Informed ConsentIRB approval of ProtocolIRB approval of Informed ConsentIRB approval of advertisementsList of IRB members or assurance #Investigator’s budgetLaboratory certificationLaboratory normal valuesBudget approvalContract approvalDate Sent toInvestigatorDate Rec’d fromInvestigatorCommentsInit Doc Track.doc© 2004 by CRC Press LLC

CompanyStudy Initiation Document Tracking Worksheet (continued)Other Study-Specific FormsDate Sent toInvestigatorDate Rec’d fromInvestigatorCommentsProtocol AmendmentSigned Amendment Signature PageRegulations (FDA, ICH)Case Report FormsStudy Procedures ManualRegulatory Documents BinderPharmacy ManualList Names of Investigator, Subinvestigators,and Study CoordinatorCV PresentMedical LicensePresentFinancialDisclosurePresentExp:Exp:Exp:Exp:Exp:Exp:Name of Lab Certifying Body Expiration date Lab NormalsInit Doc Track.doc© 2004 by CRC Press LLC

CompanyInitial Submission FormStudy InformationProtocol number:Protocol title:Protocol date and/or version number:Has this Principal Investigator and/or research study been disapproved by another IRB?If “yes,” explain:Investigator and Study Staff InformationInvestigator name:Investigator mailing address:Investigator phone:Investigator fax:Investigator e-mail:Study Coordinator name:Study Coordinator mailing address:Study Coordinator phone:Study Coordinator fax:Study Coordinator e-mail:Location where research will beconducted if different fromInvestigator’s address:List all Subinvestigators or attach acopy of Form FDA 1572:How long has the Principal Investigator been conducting clinical research? ___years____monthsHow many studies is the Principal Investigator currently supervising? _________Approximately how many active patients are in those studies? _________Initial Sub.doc© 2004 by CRC Press LLC

CompanyInitial Submission Form (continued)For the Investigator or any of the Subinvestigators in this study, have any of the following everbeen, 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 everwithdrawn, or failed to proceed with an application, for any of the following:Research privileges at this site….……………………………………... Yes NoMedical licensure in any state……………………………………..…...Other professional registration/license……………………………...…Membership on any hospital staff..…………………………………….Clinical privileges …………………………………………...………...Professional society membership or fellowship/board certification…...Any other type of professional sanction………………………………Provide documentation for all “yes” answers.YesYesYesYesYesYesNoNoNoNoNoNoStudy Site InformationType of research facility:Private practice (nonresearch)Psychiatric institutionCommercial laboratoryResearch facilityCorporate facilityHospitalClinicSchoolUniversity/CollegeOther (explain)_____________________Describe the on-site emergency equipment available:Emergency medicationsCrash cartOther (explain)_____________________Name of nearest hospital and distance from site:Does the Principal Investigator have admitting privileges at this facility? Yes NoHas the FDA, OHRP, or any other regulatory agency everaudited 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© 2004 by CRC Press LLC

CompanyInitial Submission Form (continued)General InformationHow 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: Yes NoResearch ProceduresList all tests and procedures which will be performed for research purposes only (i.e., that fall outsithe standard of care and may not be billable to third party payers).RecruitmentWho will perform the screening evaluation of the potential subjects to determine if they areeligible for the research study?Will advertisements, posters, television or radio announcements, websites,etc. be used to recruitment purposes? (If “yes,” copies must be provided forreview.)Which of the following will be recruited for this study? (Check all that apply.)Existing patientsReferral patientsPrivate Practice patientsOut-patientsIn-patientsPaid volunteersIlliteratesHomeless/ShelterPoor/uninsuredTerminally illEmployees of SponsorEmployees of InvestigatorYesNoPregnant womenPrisonersPediatric patientsGeriatric patientsMentally retarded/disabledStudents to be recruited in their educational settingMilitary personnel to be recruited by military personnelOther (explain) __________________________________Initial Sub.doc© 2004 by CRC Press LLC

CompanyInitial Submission Form (continued)Which of the following recruitment methods will be used?If pediatric subjects will be enrolled in this study, will assent be obtained?(Assent documents must be approved by the IRB prior to use)Solicitation letterAdvertisingPhysician referralsFinders fee paidOther (explain)Will non-English speaking subjects be recruited for this research project? Yes NoIf “yes,” number of non-English speaking subjects anticipated:Language(s) of non-English speaking subjects:Yes________________________NoInformed ConsentWho will discuss the Subject Information and Consent Form withthe subject for this research study?InvestigatorSubinvestigatorResearch CoordinatorOther (explain)______________________When will consent be obtained?Will a translated version of the consent form be needed for theresearch study? Yes NoIf “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? Yes NoIf “yes,” specify amount:Total: ______________Per visit: ____________If amount varies, list prorated amount for each visit:Will the subjects be paid for expenses only? Yes NoInitial Sub.doc© 2004 by CRC Press LLC

CompanyInitial Submission Form (continued)ConfidentialityWill the research use directidentifiers?NameAddressTelephone numberOther (explain) _______How will the confidentiality of this information be protected?Social security numberHospital chart numberInsurance claim numberWill the research use indirectidentifiers that could be linked todirect identifiers?Study code numbersInitialsOther(explain) _______How will the confidentiality of this information be protected?PseudonymsWho will have access to the subject’s documents and medical records?Will a translated version of the consent form be needed for theresearch study? Yes NoIf “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 SpecimensWill the research involve the collection of biological specimens?(If “no,” skip this section.)Will the data/specimens be collected anonymously (i.e., no way to link thesample with the subject’s identity)?Will the data/specimens be collected in an identifiable manner (i.e., coded)? Yes NoWill the samples be collectedretrospectively (i.e., specimens are already collected at the time of this application) orprospectively (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 orfrom future, discarded clinical samples?Is genetic testing of these specimens proposed? Yes NoYesYesNoNoInitial Sub.doc© 2004 by CRC Press LLC

CompanyInitial Submission Form (continued)Drugs If this study involves a drug, complete this section.This study is: Phase I Phase II Phase III Phase IV TreatmentIND # (if applicable):______________Is there a washout period associated with this study? Yes NoWill placebo be used during the washout period? Yes No Not applicableIf “yes,” will subjects be monitored during this period? Yes NoDescribe: ______________________________________________________________Devices If this study involves a device, complete this section.Class of device: Class I Class II Class III UnclassifiedThis device is: Investigational MarketedIDE # (if applicable):______________ or 510(k) clearanceThis is a significant risk non-significant risk study.FinancialDoes the Investigator, Subinvestigator, or Study Coordinator havea financial or commercial interest in the study being conducted?(If “yes,” this information must be disclosed on the consent form.)If “yes,” explain: _____________________________________________________________YesNoSponsor InformationIs 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© 2004 by CRC Press LLC

CompanyInitial Submission Form (continued)Document Checklist (Please attach these documents.)ProtocolCurriculum vitae for Principal InvestigatorCopy of medical license for Principal InvestigatorForm FDA 1762, if applicableDraft consent form (dated _______; version ________)Investigator’s Brochure or package insertPatient diaries (if applicable)Copies of advertisements and all subject recruiting materials (if applicable)Initial Sub.doc© 2004 by CRC Press LLC

CompanyIRB Membership RosterMultiple Assurance # (if applicable): ___________ Effective Date of Roster: _____________Membership Status Name DegreesRepresentativeCapacity(Scientific/Nonscientific)RelationshipwithCompanyExperienceChairmanSecretaryPrimary Voting MemberPrimary Voting MemberPrimary Voting MemberPrimary Voting MemberPrimary Voting MemberAlternate Voting MemberAlternate Voting MemberAlternate Voting MemberAlternate Voting MemberAlternate Voting MemberNon-voting ConsultantNon-voting ConsultantNon-voting ConsultantIRB Member.doc© 2004 by CRC Press LLC

CompanyIRB MEETING MINUTES TEMPLATEMeeting Minutes for ___________(date)__________Chair: • Name Guest (if applicable): • NamePresent: • Name • Name • Name• Name • Name • NameCALL TO ORDERThe meeting was convened at ____ at by _______, IRB Chair. A quorum waspresent.OLD/UNFINISHED BUSINESSReview and approval of minutes from meeting held ______________ were reviewed.Suggested changes were noted.APPROVED by a vote of __ for __ against __ abstainINITIAL REVIEWSPrincipal Investigator:Protocol Title:Protocol Summary:Discussion:General:Specific (include the following headings):• Scientific design.• Risks/benefits (Assign a level of risk here or at the time of the IRB decision andvote below. If children are to be enrolled, cite the regulatory reference).• Subject selection (Discuss populations to be studied and recruitment plan).• Additional safeguards for vulnerable subjects.• Minimization of risks to subjects.• Privacy and confidentiality.• Consent document (Document if all required elements are present).• Additional considerations (e.g., ionizing radiation; collaborative research; IND,other. State if these considerations do not apply).• Document the reason(s) for the minority opinion(s).Stipulations (number the stipulations):Minutes Template.doc© 2004 by CRC Press LLC

CompanyRecommendations (number the recommendations): 1IRB Decision and Vote:APPROVED by a vote of __ for __ against __ abstain 2Follow same format as above for additional new protocols.EXPEDITED REVIEWSPrincipal 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 anyexpedited actions. A vote is not required but the IRB has the prerogative to discuss, rescind, oramend expedited actions.)List additional expedited actions following above format.CONTINUING REVIEWSPrincipal Investigator:Protocol Title:Protocol Number:Expiration Date:Protocol Summary:• Discussion:• Stipulations (number the stipulations):• Recommendations (number the recommendations):• IRB Decision and Vote (Include IRB’s reaffirmation of the level of risk or establishment of anew risk level.)Follow the same format as above for additional continuing reviews.1 If the protocol is approved with stipulations and/or recommendations, the minutes must state whether the IRBrequires that the stipulations and/or recommendations are to be reviewed by the Chair, by a subcommittee of theIRB, or by the full IRB.2 Members who are affiliated with the protocol must abstain from the vote. The minutes should state whichmember(s) abstained. If a quorum is lost because members recuse themselves, no action may be taken on theprotocol.Minutes Template.doc© 2004 by CRC Press LLC

CompanyAMENDMENTSPrincipal 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 levelof 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 IRB’s acknowledgement of receipt of theadverse event report(s) and discussion, including immediate actions taken by the Investigator asa result of the event; recommendations by the IRB for further actions, if any, (e.g., suspension ofsubject 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 noaction is required on the IRB’s part, acknowledgement of the report(s) should be documented.Follow the same format as above for additional adverse events.Single Patient Exemption(s):Announcements:Other:INFORMATION ITEMSMinutes Template.doc© 2004 by CRC Press LLC

CompanyThe meeting adjourned at --:-- (a.m./p.m.).ADJOURNMENTApproved by:Name of IRB ChairDateMinutes Template.doc© 2004 by CRC Press LLC

CompanyMonitoring LogProtocol #: Investigator/Site #:Investigator:Sponsor:SiteAddress:Study Title:Visit DateSiteRepresentative’s SignatureSponsor/CRORepresentative’s SignatureReason for VisitMonitor Log.doc© 2004 by CRC Press LLC

CompanyMaster Subject LogProtocol #:Study Title:Investigator:Site Address:Sponsor:SubjectnumberSubject Name and AddressPhone and E-mailDate ofBirthSocial SecurityNumberDateHome: 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:Patient Master.doc© 2004 by CRC Press LLC

SubjectnumberSubject Name and AddressCompanyMaster Subject Log (continued)Phone and E-mailDate ofBirthSocial SecurityNumberDateHome: 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:Home: Enrolled:Work: Completed:E-mail: Discontinued:Patient Master.doc© 2004 by CRC Press LLC

CompanyTelephone Contact ReportDate:Protocol:Call from:Sponsor:Call to: Investigator:Contact: Person-to-person or Voice-mail message Site:Subject:Summary of DiscussionAction RequiredSignature: ___________________________________________Phone Rpt.doc© 2004 by CRC Press LLC

CompanyIRB Progress Report FormProtocol #: Investigator/Site #:Investigator:Sponsor:SiteAddress:Study Title:EnrollmentThis study isongoing (i.e., subjects continue to be enrolled) orenrollment is closed and subjects are being seen for follow-up assessments only.Number of subjects expected to enroll in this studyNumber of subjects screened Number of drop-outsNumber of subjects enrolledNumber of subjects completedDrop-outs No drop-outs have occurredSubject Initials Subject Number Reason for Drop-OutChanges in ResearchHave there been any protocol amendments since the time this study wasinitially approved? Yes NoIf “yes,” were these reported to this IRB? Yes NoAre there any new findings that may affect the risk benefit ratio of thisstudy? Yes NoIf “yes,” explain:_______________________________________________Progress Rpt.doc© 2004 by CRC Press LLC

CompanyIRB Progress Report Form (continued)Has the Principal Investigator, Subinvestigators, or Study Coordinatorchanged? Yes NoIf “yes,” explain:_______________________________________________Has the Principal Investigator, Subinvestigators, or Study Coordinatorreceived a revocation, sanction, or suspension of his/her state medicallicense since the study began? Yes NoIf “yes,” explain:_______________________________________________Has the FDA, OHRP, or other regulatory agency audited your site sincethis study was started? Yes NoIf “yes,” attach a copy of the 483 and your response.Summary of SAEsSubjectInitialsSubjectNumberNo SAEs have occurred.SAEOutcome of theSAESummary of GCP ViolationsSubjectInitialsSubjectNumberNo GCP violations have occurred.GCP ViolationPrincipal Investigator (print) Investigator’s Signature DateProgress Rpt.doc© 2004 by CRC Press LLC

CompanyStudy Responsibilities FormProtocolNumber:Study Title:InvestigatorName:Site Address:Sponsor:Staff Member’s Name(Please Print)DetermineIf SubjectMeetsEligibilityCriteriaIndicate which of the responsibilities below are assigned to each staff member.ObtainInformedConsentObtainMedicalHistoryPerformPhysicalExaminationsDispenseStudyDrugPerformDrugAccountabilityCollectAE/SAEData andFollow-UpEnterData inCRF orEDCSystemCorrectData inCRFsResponsibilities.doc© 2004 by CRC Press LLC

CompanyStaff Member’s Name(Please Print)CollectandPrepareLabSpecimensStudy Responsibilities Form (continued)MaintainStudy-RelatedRecordsIf any study-specific responsibilities have been assigned to specific staff members, write thetask in the gray area below and indicate which staff member is responsible.I authorize the individuals listed on this form to perform the study functions as indicated.Investigator’s signature and date:Responsibilities.doc© 2004 by CRC Press LLC

CompanyReviewer’s ChecklistProtocol Number: Investigator/Site #:Protocol Date orVersionNumber:Reviewer:Sponsor:Date:Regulatory Review Requirement1. 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 exposingsubjects 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?2. Risks to subjects are reasonable in relation to anticipated benefits to subjects, and to the importance ofknowledge that may reasonably be expected to result.Yes No (a) What does the IRB consider the level of risk to be?Yes No (b) What does the Investigator consider the level of risk/discomfort/inconvenience to 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?3. Subject selection is equitable.Yes No (a) Who is to be enrolled? Men? Women? Ethnic minorities? Children (rationale forinclusion/exclusion 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 bemore susceptible to risks presented in this research?Yes No (e) Would it be possible to conduct the study with less vulnerable subjects?Review Cklist.doc© 2004 by CRC Press LLC

CompanyReviewer’s Checklist (continued)Regulatory Review Requirement4. 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?5. 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?6. 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 processenhance 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 unexpectedresults 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 accessor use?Yes No (b) Are special privacy and confidentiality issues properly addressed, (e.g., use of geneticinformation)?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 andpractices; use of alcohol, drugs, or other additive products; the individual’s mentalhealth)?Reviewer’s CommentsIn relation to the degree of risk associated with the research activity, how often should periodicreview be conducted by the IRB to determine if the risk/benefit ratio has changed? __________Review Cklist.doc© 2004 by CRC Press LLC

CompanyIRB Review Results FormProposal 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) andthe 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 theconduct of the trial;• Promptly report all serious adverse events and/or unanticipated risks to the IRB; and• Obtain advance approval of changes in the research, except when necessary to eliminatehazards to study subjects.Sincerely,ChairmanReview Results.doc© 2004 by CRC Press LLC

CompanySerious Adverse Subject Initials: Protocol Number:Experiences Subject #: Drug Name:(Page 1)Date of Report: Investigator Name:Sex Weight Height Date of Birth Race___ Male ___ Female ___ ___ ___ lbs. ___ ___ in.___ White ___ Black___ Asian ___ Hispanic___ Other (specify): ____________________Diagnosis (if known)or Signs / symptomsList one per line.DateStartedDD/MM/YY*Intensity*Outcome*ActionRelationshipto TrialMedication*Date StoppedPoststudyDD/MM/YY*Withdrawal*Seriousness* See facing page for codes./ / / // / / // / / /Possible causes of SAE other than trial medication Disease under study Concurrent disorder. Specify: Treatment failure Concurrent medication. Specify:Withdrawal of trialmedicationActivity related to study participation(e.g., procedures). Specify:SAE.doc© 2004 by CRC Press LLC

Code INTENSITY as:1 = Mild2 = Moderate3 = Severex = Not applicableCode OUTCOME as:R = ResolvedS = Resolved with sequelaeN = Not resolvedCompanyCODES FOR SERIOUS ADVERSE EXPERIENCESCode ACTION TAKEN WITH TRIAL MEDICATION AS A RESULT OF THE NON-SERIOUS ADVERSE EXPERIENCE as:0 = None1 = Dosage adjusted2 = Temporarily interrupted3 = Permanently discontinuedx = Not applicableCode WITHDRAWAL as:Y = Yes, subject did withdraw from the study as a result of this serious adverse experience.N = No, subject did not withdraw from the study as a result of this serious adverse experience.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 trialmedication.N = No, there is a not reasonable possibility that the non-serious adverse experience may have been caused by the trialmedication.Code SERIOUSNESS as:A = FatalB = Life-threateningC = Disabling/incapacitatingD = Hospitalization required or prolongedE = OverdoseF = Grade 4 laboratory abnormalitySAE.doc© 2004 by CRC Press LLC

CompanySerious Adverse Subject Initials: Protocol Number:Experiences Subject #: Drug Name:(Page 2)Date of Report: Investigator Name:Relevant Medical ConditionsSpecify any relevant past or currentmedical disorders, allergies, surgeries,etc. that can help explain the SAE.Date startedDD/MMM/YY//Was conditionpresent at the timeof the SAE?Y = Yes N = NoIf “No,” date of last occurrenceDD/MMM/YY//////////////Other Relevant Risk FactorsSpecify any family history or any socialhistory (e.g., smoking, alcohol, diet, drugabuse, occupational hazard, etc.) relevantto the SAE.SAE.doc© 2004 by CRC Press LLC

CompanySerious Adverse Subject Initials: Protocol Number:Experiences Subject #: Drug Name:(Page 3)Date of Report: Investigator Name:Trial Medication DetailsDate of Dose DD/MMM/YY Time of Dose Treatment Total Dose// : Relevant Concurrent MedicationsInclude any concurrent medications that may contribute to the occurrence of the SAE.Drug trade name Dose Units*Frequency*RouteDate startedDD/MMM/YYPrestudyDate stoppedDD/MMM/YYPost-SAEConditions TreatedIndication/ / / // / / // / / // / / /Details of Relevant AssessmentsProvide details of other assessments (e.g., laboratory data with normal ranges) or supplemental examinations.SAE.doc© 2004 by CRC Press LLC

CompanySerious Adverse Subject Initials: Protocol Number:Experiences Subject #: Drug Name:(Page 4)Date of Report: Investigator Name:Narrative/CommentsProvide a textual description of the serious adverse experience (including the treatment of the event).Reporting InvestigatorTo the best of my knowledge, all information entered on this Serious Adverse Experience CRF for this subject is correct.Date DD/MMM/YY Name Address// Print name:Signature:SAE.doc© 2004 by CRC Press LLC

CompanySafety Information FormProtocol #: Investigator/Site #:Investigator:Sponsor:SiteAddress:Study Title: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:fatallife-threateningpermanently disablingrequired in-patient hospitalizationcongenital anomalyan important medical eventassociated with the use of the drugnot associated with the use of the drugquestionable or unknownChanges to the informed consent document (dated xx/xx/xx, version ___):is necessary. A revised draft (dated xx/xx/xx, version ___) is attached.is not necessary.EnrollmentNumber of subjects expected to enroll in this studyNumber of subjects screenedNumber of drop-outsNumber of subjects ongoingNumber of subjects completedexpectedunexpectedPrincipal Investigator (print) Investigator’s Signature DateSafety Rpt.doc© 2004 by CRC Press LLC

CompanyStudy Site Personnel Signature SheetProtocol #: Investigator/ Site #:Investigator:Sponsor:SiteAddress:Study Title:Name (Print):Initials:Signature:Study assignment or role: Principal Investigator Telephonenumber:Name (Print):Initials:Signature:Study assignment or role: Study Coordinator Telephonenumber:Name (Print):Initials:Signature:Study assignment or role: Subinvestigator Telephonenumber:Name (Print):Initials:Signature:Study assignment or role: Subinvestigator Telephonenumber:Sig Sheet.doc© 2004 by CRC Press LLC

CompanyStudy Signature Sheet (contd.)Name (Print):Initials:Signature:Study assignment or role:Telephonenumber:Name (Print):Initials:Signature:Study assignment or role:Telephonenumber:Name (Print):Initials:Signature:Study assignment or role:Telephonenumber:Name (Print):Initials:Signature:Study assignment or role:Telephonenumber:Name (Print):Initials:Signature:Study assignment or role:Telephonenumber:Sig Sheet.doc© 2004 by CRC Press LLC

CompanyIRB Study Termination AcknowledgementProposal No. _________Protocol No. _________Dear Dr. On , the received notification of the termination of the protocol entitled. No additional subjects may beenrolled 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. Inthe event that you retire, relocate, or for any reason withdraw from the responsibility formaintaining records for the period of time required, custody of the records must betransferred to another person who will accept the responsibility for the records. Notice ofsuch 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,ChairmanSt Term Ack.doc© 2004 by CRC Press LLC

CompanyIRB Notification of Study Termination FormProtocol #: Investigator/Site #:Investigator:Sponsor:SiteAddress:Study Title:This is to notify you that the study listed above is completed at this site. The last subject hascompleted his/her last study evaluation. No additional subjects will be enrolled. The followinginformation is pertinent concerning the study:EnrollmentNumber of subjects screenedNumber of subject enrolledNumber of drop-outsNumber of subject completedDrop-outsSubject Initials Subject Number Reason for Drop-OutSt Term Notice.doc© 2004 by CRC Press LLC

CompanySummary of SAEsSubjectInitialsSubjectNumberSAEOutcome of theSAESummary of GCP ViolationsSubjectInitialsSubjectNumberGCP ViolationIf you have any questions concerning the information in this report, please contact me at (phonenumber) ___________________.Principal Investigator (print) Investigator’s Signature DateSt Term Notice.doc© 2004 by CRC Press LLC

CompanyTraining Plan FormEmployee:Supervisor/Mentor:TrainingInstructorInstructor’sInitials*DatecompletedEmployee HandbookCompany SOPsDepartmental SOPsProject-Specific SOPsProtocol _________Investigator’s Brochure for _________* Instructor’s initials indicate student has completed that portion of the training plan.Training Plan.doc© 2004 by CRC Press LLC

CompanyTraining Record FormEmployeeCurriculum vitae (CV)(List each date CV has been revised. Only the current version of the CV is required for this file.)In-house training(List in-house programs attended by employee. Attach Training Verification Forms for each program listedbelow.)Date Program title Instructor Program lengthTraining Record.doc© 2004 by CRC Press LLC

CompanyEmployeeProject-specific training(List project-specific training attended by employee, including Investigator Meetings. Attach TrainingVerification Forms for each program listed below.)Project Date Program title Instructor ProgramlengthTraining Record.doc© 2004 by CRC Press LLC

CompanyEmployeeExternal programs (List outside training programs and professional conferences attended by employee.Attach Training Verification Forms for each program listed below.)Date Program title Instructor Program lengthTraining Record.doc© 2004 by CRC Press LLC

CompanyStaff Training Request FormEmployee requesting trainingTraining program being requestedTraining date(s)Location of trainingCost of training program(registration and fees)Additional costs anticipated(hotel, airfare, etc.)Training description(attach program outline, if available)Purpose of the trainingEmployee’s signature and date:Supervisor’s signature and date:Approved? Yes NoTraining Request.doc© 2004 by CRC Press LLC

CompanyStaff Training Verification FormEmployeeTraining programTraining date(s)Location of trainingTraining description(attach certificate of attendance andprogram agenda, if available)Employee’s signature and date:Training Verification.doc© 2004 by CRC Press LLC

CompanySite Evaluation Visit Trip ReportProtocol #: Investigator Name: Visit Date:Drug/Device: Institution Address: Visit Conducted By:Study Site PersonnelList the study personnel, role and responsibilitiesRole / Study Responsibilities Name Present at Meeting?Principal Investigator Yes NoSubinvestigator Yes NoSubinvestigator Yes NoStudy Coordinator Yes NoPharmacist Yes NoInstitutional Review BoardYesYesYesYesYesYesYesNoNoNoNoNoNoNoIRB name:Chairman:IRB address:Will the protocol need to be reviewed by any other committee in addition to the IRB?Does the Investigator, Subinvestigator, or Study Coordinator serve on the IRB?How often does IRB meet?What are the dates of the next three meetings?1.2.3.Trip Rpt Evaluation.doc© 2004 by CRC Press LLC

CompanyPharmacyPharmacist 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 DOCUMENT WAS RETRIEVED AT THISVISIT.Signed FDA Form 1572IRB approval of Protocol and ICFCV for Principal InvestigatorIRB approval of AdvertisementsCVs for Subinvestigators List of IRB members or assurance #CVs for Study CoordinatorFinancial Disclosure for InvestigatorFinancial Disclosure for SubinvestigatorFinancial Disclosure for Study CoordinatorSigned Protocol Signature PageDraft Informed ConsentInvestigator's budgetBudget approvalIndemnificationLaboratory certificationLaboratory normal valuesOther:Overall Assessment Yes No CommentInvestigator and staff are qualified to conduct the studyInvestigator and staff has adequate time to conduct the studyInvestigator has access to adequate number of patients for the studyRecruitment is expected tobe ____ subjects per ____Investigator agrees to conduct study as outlined in Protocol/1572Facilities and equipment are adequate for studyAppropriate maintenance and calibration records are availablePatient care areas are acceptableClinical laboratory is acceptableStorage area for CRFs and regulatory documents is acceptableTrip Rpt Evaluation.doc© 2004 by CRC Press LLC

CompanyOverall Assessment (continued) Yes No CommentSupport staff are available to study personnel if neededStudy staff agree to provide access to medical recordsDoes the site have any studies that may impact accrual?If yes, comment:Has the Investigator or any of the Subinvestigators ever beendisqualified from receiving investigational products?If yes, comment:Additional Comments/ObservationsSignature of person who conducted the visitDateTrip Rpt Evaluation.doc© 2004 by CRC Press LLC

CompanyStudy Initiation Visit Trip ReportProtocol #: Investigator Name: Visit Date:Drug/Device: Institution Address: Visit Conducted By:Meeting ParticipantsList the study personnel who were present during the visit and indicate their roles and responsibilities.Role / Study ResponsibilitiesPrincipal InvestigatorSubinvestigatorSubinvestigatorStudy CoordinatorPharmacistNameSTUDY INITIATION DOCUMENTSSigned FDA Form 1572CV for Principal InvestigatorCHECK IF DOCUMENT WAS RETRIEVED AT THISVISIT.IRB approval of Protocol and ICFIRB approval of advertisementsCVs for Subinvestigators List of IRB members or assurance #CVs for Study CoordinatorFinancial Disclosure for InvestigatorFinancial Disclosure forSubinvestigatorFinancial Disclosure for StudyCoordinatorSigned Protocol Signature PageDraft Informed ConsentInvestigator’s budgetBudget approvalIndemnificationLaboratory certificationLaboratory normal valuesOther:Trip Rpt Init.doc© 2004 by CRC Press LLC

CompanyMEETING CONTENTINDICATE WHICH STUDY SITE PERSONNEL WERE PRESENT DURING THE DISCUSSION OF THETOPICS BELOW1. Investigator’s regulatory obligations2. Investigator’s Brochure and study drugbackground3. Protocol objectives and endpoints4. Study time and events schedule5. Inclusion/exclusion criteria6. Recruitment strategies, includingadvertising7. Informed consent and assent procedures8. Screen failure documentation, ifapplicable9. Procedures for handling protocoldeviations10. IRB issues11. Adverse Events and Serious AdverseEvents12. Guidelines for handling subject deaths13. Guidelines for handing subjectdiscontinuation14. Guidelines for handing studydiscontinuation15. Contract and payment schedule16. Record retention17. Drug supplies and accountability18. Dosing schedule19. Concomitant medication restrictions20. Randomization and assigning subjectnumbers21. Protection of the study blind, ifapplicable22. Unblinding procedures23. Handling and delivery of samples to thelab24. Laboratory test kitsPI Subinv StudyCoordPharmacistLabDirectorOtherNotdiscussedTrip Rpt Init.doc© 2004 by CRC Press LLC

CompanyMeeting Content (continued)PI Subinv StudyCoordPharmacistLabDirectorOtherNotdiscussed25. Case Report Form completion26. Regulatory Documents and binder27. Study-specific forms28. Monitoring visits and accessibility tosource documents29. Publication policy30. Audit possibilities31. Record retention32. Other (explain):33. Other (explain):34. Other (explain):Additional Comments/ObservationsRefer to the number in the Meeting Content section.Signature of person who conducted the visitDateTrip Rpt Init.doc© 2004 by CRC Press LLC

CompanyPeriodic Site Visit Trip ReportProtocol #: Investigator Name: Visit Date:Drug/Device: Institution Address: Visit Conducted By:Site Visit PersonnelList the study personnel who met with the Monitor during the visitName Study Role Screened:Enrolled:Ongoing:Completed:Discontinued:Enrollment StatusSee Comments section for a description ofdiscontinued subjects.Monitoring ActivitiesComment required for all shaded answers.Yes No N/A Comment1. Were there any violations of the regulations since thelast monitoring visit?2. Were there any deviations from the eligibility criteria?3. Were there any protocol deviations or violations?4. Are there any problems recruiting subjects?5. Have all new subjects been randomized correctly?6. Is the blind being maintained correctly?7. Are corrections to the data being made by authorizedpersonnel?8. Were there any changes in site personnel?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 orInvestigator payment?12. Are there any issues concerning handling or deliveryof laboratory samples?13. Are there any issues concerning laboratory test kits?Trip Rpt Interim.doc© 2004 by CRC Press LLC

Company14. Are there any issues concerning the reporting oflaboratory results?15. Did the Monitor meet with the Investigator to discussthe findings at this visit?16. Does the Principal Investigator continue to beinvolved in the study?Yes No N/A CommentInformed ConsentYes No Comment17. Were the informed consents reviewed for all new subjectsenrolled in the study?18. Were the informed consents present for all new screenfailures?19. Are the correct versions of the consent forms being signed bystudy subjects?20. Have all new subjects and screen failures signed the consentform before any study-related assessments were made?21. Were any consent forms unsigned or unavailable for review?22. Informed consents were checked for the following subjects:Case Report Form ReviewYes No Comment23. Are CRFs being competed in a timely manner?24. Are there any issues concerning accessibility to sourcedocuments?25. Have all of the retrieved CRFs been signed by theInvestigator?26. Were the data in the CRFs verified against the sourcedocuments?27. Were the all requested data clarifications made at the time ofthe visit?28. Source documents for the following CRFs were reviewedSubject #SubjectInitialsStudy Visits or CRF pagescheckedCommentTrip Rpt Interim.doc© 2004 by CRC Press LLC

CompanySERIOUS ADVERSE EXPERIENCESSince the last monitoring visit the following SAEs have occurredNoneSAEStartDateStopDateRelationshipto drugExpected orUnexpectedOutcomeStudy DrugYes No Comment29. Was study drug inventory checked?30. Were there any problems with study drug inventory?31. Are study drug storage conditions appropriate?32. Are there any problems with the dosing schedule?33. Are there any problems with the blind?34. Are there any problems with drug expiration dates?35. Is an adequate supply of drug available?36. Are there any discrepancies between what wasdispensed to and returned from the subject?37. Are there any discrepancies between what wasdispensed to and returned from the pharmacy?38. Are there any discrepancies between what wasdispensed to and returned from the sponsor?39. Are there any issues with concomitant medications?40. Has any drug been returned or disposed of?REGULATORY DOCUMENTS AND STUDY-RELATED FORMSDo any of the following documents require follow-up or revision? Yes No Comment41. IRB membership list42. Laboratory certification43. Lab normal ranges44. FDA Form 157245. Curriculum vitae46. Financial disclosure47. Other:Trip Rpt Interim.doc© 2004 by CRC Press LLC

CompanyInstitutional Review BoardDo any of the following items need to be submitted to the IRB? Yes No Comment48. IND Safety Report49. SAE Report50. Protocol Violation51. Progress Report52. Protocol Amendment53. Revised consent form54. Advertisement or other recruitment material55. Updated Investigator’s brochure56. Other (e.g., Patient diary)Were all Action Items in the previous trip report accomplished? Yes NoIf “no,” repeat outstanding items in section below.ACTION ITEMSAction needed Person responsible Date dueAdditional Comments/ObservationsSignature of person who conducted the visitDateTrip Rpt Interim.doc© 2004 by CRC Press LLC

CompanyStudy Termination Visit Trip ReportProtocol #: Investigator Name: Visit Date:Drug/Device: Institution Address: Visit Conducted By:Site Visit PersonnelList the study personnel who met with the Monitor during the visitName Study Role Screened:Final Enrollment StatusEnrolled:Ongoing:Completed:Discontinued:Monitoring ActivitiesComment required for all shaded answers.1. Were there any violations of the regulations since the last sitevisit?2. Were there any deviations from the eligibility criteria sincethe last site visit?3. Was the Subject Enrollment Log completed and a copyretrieved for Company files?4. Are any blank CRFs or study supplies remaining at the site?Yes No CommentInformed ConsentYes No Comment5. Were the informed consents reviewed for all subjects enrolledin the study?6. Were the informed consents present for all screen failures?7. Have all subjects and screen failures signed the consent formbefore any study-related assessments were made?8. Were any consent forms unsigned or unavailable for review?9. Informed consents were checked for the following subjects:Trip Rpt Termination.doc© 2004 by CRC Press LLC

CompanyCase Report Form ReviewYes No Comment10. Has a completed CRF been retained in the file for eachsubject enrolled in the study?11. Have all of the retrieved CRFs been retrieved?12. Do any data clarifications need to be resolved?13. Source documents for the following CRFs were reviewed at this visit:Subject #SubjectInitialsStudy Visits or CRF pagescheckedCommentSerious Adverse ExperiencesYes No NA Comment14. Do any of the previously reported SAEs needadditional follow-up?Since the last monitoring visit, the following SAEs have occurredSAE Start date Stop date Relationshipto drugExpected orUnexpectedNoneOutcomeStudy DrugYes No NA Comment15. Was the final study drug inventory checked?16. Were there any problems with study drug inventory?17. Were study drug storage conditions appropriate?18. Were problems with the dosing scheduledocumented?19. Were problems with the blind documented?Trip Rpt Termination.doc© 2004 by CRC Press LLC

CompanyStudy Drug (continued)Yes No NA Comment20. Were problems with drug expiration datesdocumented?21. Are there any discrepancies between what wasdispensed to and returned from the subject?22. Are there any discrepancies between what wasdispensed to and returned from the pharmacy?23. Are there any discrepancies between what wasdispensed to and returned from the sponsor?24. Were any issues with concomitant medicationsdocumented?25. Has any drug been returned or disposed of?Regulatory Documents and Study-Related FormsDo any of the following documents require follow-up or revision? Yes No Comment26. Lab certification27. Lab normal ranges28. FDA Form 157229. Financial disclosure30. Other:Institutional Review BoardHave all of the following documents been submitted to the IRB overthe course of the study?Yes No Comment31. IND Safety Reports?32. SAE Reports?33. Protocol Violations?34. Progress Reports?35. Protocol Amendments?36. Revised consent forms?37. Advertisement or other recruitment materials?38. Updated Investigator’s brochures?39. Other (e.g., Patient diary)?Trip Rpt Termination.doc© 2004 by CRC Press LLC

Company40. Has the Investigator submitted the final study statusreport to the IRB?41. Has a copy of the final study status report beenobtained for the Company study files?42. Was the blind maintained correctly throughout thestudy?43. Have the protocol deviations or violations beendocumented correctly?Study Termination Activities44. If any issues with randomization occurred during thestudy, have they been documented in the site’s studyfile?45. If any issues with handling or delivery of laboratorysamples occurred during the study, have they beendocumented in the site’s study file?46. If any issues concerning the reporting of laboratoryresults occurred during the study, have they beendocumented in the site’s study file?47. Has the progress of any subject requiring additionalfollow-up has achieved a satisfactory resolution?48. Has the Investigator included an explanatorycomment on the "Investigator's Comment" page ofthe CRF for all unresolved entry violations?49. Have all remaining data clarification issues beenresolved?50. Have any remaining CRFs and/or data clarificationsbeen returned to Data Management?51. Has the Study Coordinator been informed that dataqueries generated by the Statistics Department maystill be forthcoming?52. Do study site personnel understand record retentionrequirements for the data?53. Have all discrepancies between the expected andactual inventory been resolved or otherwiseacknowledged in a letter of explanation from theInvestigator?54. Are all unused investigational drugs are accountedfor and returned or destroyed?55. Has the successful or unsuccessful reconciliation ofstudy medication been documented?56. Has the Monitoring Log been signed for this visitand a copy retrieved for the Company files?Yes No NA CommentTrip Rpt Termination.doc© 2004 by CRC Press LLC

CompanyMeeting with InvestigatorDid the Monitor meet with the Investigator to discussthe following:Yes No Comment57. Accomplishments of the study site58. Remaining problems or issues and corrective actionsneeded59. Investigator obligations concerning records retention60. Final payment policy61. Publication policy62. What to expect in the event of an FDA inspection63. Notify Company as soon as possible if the site isalerted that an inspection by the FDA is impendingWere all Action Items in the previous trip report accomplished? Yes NoIf “no,” repeat outstanding items in section below.Action ItemsAction needed Person responsible Date dueAdditional Comments/ObservationsSignature of person who conducted the visitDateTrip Rpt Termination.doc© 2004 by CRC Press LLC