Standard Operating Procedures for the Conduct of Clinical ... · Office of Research Administration...

Office of Research Administration

Standard Operating Procedures for the Conduct of Clinical Research

SOP Manual for Compliance with International Conference on Harmonization (ICH) Good Clinical Practice Guidelines and

FDA Regulations at the Investigative Site

Community Health Network Office of Research Administration SOPs for the Conduct of Clinical Research

*Templates are optional tools that can be used or revised per departmental procedures.

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TABLE OF CONTENTS LIST OF ABBREVIATIONS ........................................................................................... 4

LIST OF TEMPLATES ................................................................................................ 5

I. 100 GA GENERAL ADMINISTRATION.................................................... 8 101 Assuming and Fulfilling Responsibility for

Good Clinical Practice.................................................................. 9

102 SOP Development and Process ……………............................... 15

103 Ensuring Qualification of Site Personnel and Research Staff...... 18

104 Contracts………........................................................................... 23

105 Records Management, Accountability and Retention.................. 25

II. 200 RA REGULATORY AFFAIRS........................................................... 30

201 Essential Documents................................................................... 31

202 Initial and Ongoing Submissions................................................. 34

203 Reporting Requirements.............................................................. 37

III. 300 PM PROJECT MANAGEMENT......................................................... 40

301 Protocol Development.................................................................. 41

302 Assessing Study Feasibility.......................................................... 44

303 Study StartUp............................................................................... 49

304 Investigational Product Management........................................... 54

305 Source Documentation................................................................. 58

306 Monitoring Visits........................................................................... 61

307 Study Completion......................................................................... 66

308 Protocol Compliance.................................................................... 69

IV. 400 SM SUBJECT MANAGEMENT.......................................................... 72

401 Subject Recruitment and Screening............................................. 73

402 Informed Consent......................................................................... 78

403 Eligibility and Enrollment.............................................................. 83



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404 Subject Visits and Assessments.................................................. 86

405 AE Management.......................................................................... 91

V. 500 DM DATA MANAGEMENT................................................................ 95

501 Clinical Data Management........................................................... 96

VI. 600 QA QUALITY ASSURANCE............................................................. 100

601 Quality Assurance Audits............................................................ 101

602 Inspections by Regulatory Authorities......................................... 104

VII. TEMPLATES.......................................................................................... 108

VIII. GLOSSARY............................................................................................. 200



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LIST OF ABBREVIATIONS

AE Adverse Event (same as Adverse Drug Experience, Adverse Experience, Adverse Drug Reaction, Adverse Reaction)

CHNw Community Health Network, Inc.

CRC Clinical Research Coordinator

CRF Case Report Form

CRO Contract Research Organization

DMC Data Monitoring Committee

FDA Food and Drug Administration

GCP Good Clinical Practice

HIPAA Health Insurance Portability and Accountability Act of 1996

IB Investigator's Brochure

IBC Institutional Biosafety Committee

ICF Informed Consent Form

ICH International Conference on Harmonization

IND Investigational New Drug

IRB Institutional Review Board

NIH National Institutes of Health

OHRP Office for Human Research Protections

ORA Office of Research Administration

PI Principal Investigator

QA Quality Assurance

SAE Serious Adverse Event

SOP Standard Operating Procedure



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LIST OF TEMPLATES

SOP #

SECTION/TITLE TEMPLATE # TEMPLATE TITLE

GA 100 GENERAL ADMINISTRATION

GA 101 Assuming and Fulfilling Responsibility for Good Clinical Practice

GA 101-A Delegation of Authority <<Protocol>> Template

GA 101-B Form FDA 1572

GA 101-C Study Training Form Template

GA 102 Document Development and Change Control

GA 102-A Document Training Compliance Record Template

GA 102-B SOP Template

GA 102-C SOP Review

GA 103 Ensuring Qualified Site Personnel and Research Staff GA 103-A Orientation Template

GA 104 Contracts GA 104-A Contract Routing Form

GA 105 Records Management, Accountability, and Retention

GA 105-A Request for Medical Records

GA 105-B Offsite Storage Log Template

RA 200 REGULATORY AFFAIRS

RA 201 Essential Documents RA 201-A Regulatory and Study File Content Template

RA 201-B Table of ICH Essential Documents

RA 202 Initial and Ongoing Submissions RA 202-A Submission and Reporting Requirements

RA 203 Reporting Requirements RA 203-A

Reportable AE Decision Algorithm

PM 300 PROJECT MANAGEMENT

PM 301 Protocol Development

PM 301-A

Protocol Template

PM 301-B Chart Review Protocol Template

PM 302 Assessing Study Feasibility PM 302-A Study Review and Assessment Template

PM 302-B Study Effort and Cost Considerations Template



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SOP #


PM 302-C Salary Worksheet Template

PM 302-D Per Subject Cost Worksheet Template

PM 302-E Study Budget Worksheet Template

PM 302-F Pre-Study Qualification Visit Agenda Template

PM 302-G Pre-Study Qualification Visit Preparation Template

PM 303 Study Start-Up

PM 303-A Site Initiation Visit Preparation Template

PM 303-B Site Initiation Visit Agenda Template

PM 303-C Site Initiation Visit Management Template

PM 303-D Site Responsibility Log Template

PM 304 Investigational Product Management

PM 304-A Investigational Product Receipt Form Template

PM 304-B Subject Inventory Control Form Template

PM 304-C Investigational Product Accountability Form Template

PM 304-D Temperature Log Template

PM 305

Source Documentation

PM 305-A Source Documentation Template

PM 306 Monitoring Visits PM 306-A Monitoring Visit Preparation Template

PM 307 Study Completion PM 307-A End-of-Study Documentation Template

PM 308 Protocol Compliance PM 308-A Protocol Deviation Log Template

SM 400 SUBJECT MANAGEMENT

SM 401 Recruitment

SM 401-A Guideline for Recruitment and Advertising Practices

SM 401-B Model Screening Script Template

SM 401-C Recruitment Action Plan Template

SM 402 Informed Consent SM 402-A Informed Consent Process

SM 403 Eligibility and Enrollment SM 403-A Subject Eligibility Template

SM 403-B Screening and Enrollment Log Template



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SOP #


SM 404 Subject Visits and Assessments

SM 404-A Study Encounter Worksheet and Record – Screening Template

SM 404-B Study Encounter Worksheet and Record - Visit # Template

SM 404-C Study Encounter Record - Physical Exam - Visit # Template

SM 404-D Medical History – Screening Template

SM 404-E Adverse Event Log Template

SM 404-F Concomitant Medication Log Template

SM 405 AE Management SM 405-A Criteria for Recognizing and Managing AEs

DM 500 DATA MANAGEMENT

DM 501 Clinical Data Management NA

QA 600 QUALITY ASSURANCE

QA 601 Quality Assurance Audits QA 601-A Clinical Study Site Audit Template

QA 602 Inspections by Regulatory Authorities

QA 602-A Prepare for an FDA Inspection Template

QA 602-B Procedures during an FDA Inspection Template



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I. GA 100 GENERAL ADMINISTRATION

101 Assuming and Fulfilling Responsibility for Good Clinical

Practice

102 SOP Development and Process

103 Ensuring Qualified Site Personnel and Research Staff

104 Contracts

105 Records Management, Accountability, and Retention



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SOP: GA 101 Assuming and Fulfilling Responsibility for GCP

Version No.: 1.0 Effective Date: May 1, 2017 Supersedes Document: N/A

1. Procedure

Principal Investigator assumes the responsibility for the conduct of clinical research and shall, therefore, personally oversee the conduct of each clinical study; ensuring that the research is conducted according to GCP, complies with applicable regulations, guidelines and institutional policy for conducting human subject research and use of investigational products. These responsibilities include:

Conducting research according to - the signed investigator statement,

- the study plan/protocol, - applicable regulations

Ensuring that no changes to the study plan/protocol are made unless

- a request to make a change in the research is submitted to the sponsor and IRB and that the approval for the change is approved by the sponsor and IRB, or,

- if a change is necessary to protect the safety, rights, or welfare of subjects, to notify the IRB and the sponsor within the time specified by the protocol, applicable regulations, institutional policy, and/or conditions of IRB approval

Ensuring that the research is overseen by an IRB that complies with applicable regulatory

requirement(s) and that the information and materials required for such oversight shall be provided as follows:

- The initial and continuing review and approval of the proposed clinical study: the protocol and related material are submitted to the IRB as required by applicable

regulation, the protocol, and the IRB; study procedures are not initiated until receipt of documentation of IRB approval; contingencies for IRB approval and continuing approval are met.

- Promptly reporting to the IRB all changes in the research activity and all unanticipated

problems involving risk to human subjects or others.

- Not making any changes in the research, except where necessary to eliminate apparent immediate hazards to human subjects, without IRB approval.

Ensuring the process for obtaining and documenting the informed consent process is conducted

according to 45 CFR 46.

Ensuring the completion and submission of reports as required by the protocol, regulations, the IRB and sponsor or funding agency.

https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html



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Specifically reporting: - AEs that occur in the course of the investigation(s) or as specified after the

investigation is complete; - changes in the research activity; - all unanticipated problems involving risks to human subjects or others are reported as

required by regulation and IRB requirements.

Reading and understanding the information about the investigational product, including that which is in the IB, any supplemental or additional information supplied by the sponsor and published information.

Ensure that all associates, colleagues and employees assisting in the conduct of the study are

informed about their obligations relating to the study plan/protocol, applicable regulations and GCP.

Ensure that subject records and documentation are compiled, maintained and held in accordance

with the study plan/protocol, applicable regulations and GCP, and ensure that study documentation and records are available for inspection in accordance with regulatory requirements and institutional policy.

The responsibility to conduct the above activities may be delegated at the discretion of the PI to qualified individuals. Those individuals and entities also take on responsibility for meeting regulatory requirements on behalf of the PI, but the PI has the ultimate responsibility and shall, therefore, supervise those delegated activities effectively.

Task delegation will be to individuals qualified by education, experience and training. Training and documentation of training will be completed prior to completion of any study tasks by

an assigned individual.

2. Scope

This SOP defines the responsibilities of the investigator(s) conducting human-subjects research at CHNw. It identifies administrative accountability as well as general responsibilities of the research team and of individual team members for fulfilling regulatory and clinical requirements.

3. Responsibility

Responsibilities for implementing this SOP are indicated as follows:

Individuals who contribute, in a substantial way, to the scientific development or execution of the project

Specific studies: See Template GA 101-A: Delegation of Authority



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4. Applicable Regulations and Guidelines

FDA 21 CFR 50 Protection of human subjects 21 CFR 54 Financial disclosure by clinical investigators 21 CFR 312 Investigational new drug application

21 CFR 312.60 General responsibilities of investigators

21 CFR 312.61 Control of the investigational drug

21 CFR 312.62 Investigator recordkeeping and record retention

21 CFR 312.64 Investigator reports

21 CFR 312.66 Assurance of IRB review

21 CFR 312.68 Inspection of investigator's records and reports

21 CFR 312.69 Handling of controlled substances


21 CFR 812.110 Specific responsibilities of investigators

21 CFR 812.140 Records

21 CFR 812.150(a) Reports

Guidance for IRBs, Clinical Investigators, and Sponsors—IRB Continuing Review after Clinical Investigation Approval, February 2012

Information Sheet—Frequently Asked Questions—Statement of Investigator, May 2010

Guidance for Clinical Investigators, Industry and FDA Staff—Financial Disclosure by Clinical Investigators, February 2013

Guidance for Industry, Investigator Responsibilities—Protecting the Rights, Safety and Welfare of Study Subjects, October 2009

HHS 45 CFR 46 Protection of human subjects

ICH E6 Harmonized Tripartite Guideline for GCP

2 - The principles of ICH GCP

4 - Investigators

5. SOP Templates

GA 101-A: Delegation of Authority Template

GA 101-B: Form FDA 1572

GA 101-C: Study Training Form Template

http://www.ecfr.gov/cgi-bin/text-idx?SID=841d69f34da8bdb3b0b1f7fa59e8157a&mc=true&node=pt21.1.50&rgn=div5



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http://www.ecfr.gov/cgi-bin/text-idx?SID=841d69f34da8bdb3b0b1f7fa59e8157a&mc=true&node=pt21.5.312&rgn=div5%20-%20se21.5.312_160#se21.5.312_161






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https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf





https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM187772.pdf.



http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html



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6. Process Overview

A. Administration and Management of CHNw

B. Operational Procedures to Assume and Fulfill Responsibilities for GCP

7. Specific Procedures

A. Administration and Management of CHNw:

The Principal Investigator acknowledges that responsibility of delegation and supervision of all study-related tasks is ultimately his/her responsibility. However, responsibility may be delegated to support the day-to-day activities surrounding the tasks listed below.

Who Task

ORA,

Research Manager

Establish SOPs for study site administration and research activities

ORA,

Legal,

Research Manager

Maintain the integrity of the research site by:

• Developing, approving and modifying critical (controlled) documents in a controlled manner

- SOPs - regulatory documents - contracts and agreements - informed consent documents

• Developing and modifying forms (uncontrolled documents) as appropriate

• Delegating and documenting delegation of administrative and operational

responsibilities to qualified individuals

• Ensuring that research staff members are qualified by training, education and experience to fulfill their anticipated functions

Agreeing to conduct research that is scientifically, ethically and financially acceptable

• Ensuring regular, timely, effective and documented communication



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Who Task

Research Manager,

Staff,

Pharmacy

Maintaining a system that controls access, ensures security and meets regulatory requirements for the following activities:

• filing and maintaining required documents • storage and archiving • disposal • recording and managing study data and observations • protecting subjects’ privacy and confidentiality • maintaining control of the investigational product

ORA, IRB,

Research Manager

Assuring compliance and quality data through audits of clinical study conduct and data, internal procedures and documentation

ORA,

Research Manager

Ensuring all individuals are appropriately trained on SOPs

B. Operational Procedures to Assume and Fulfill Responsibilities for GCP

The PI acknowledges that responsibility of delegation and supervision of all study-related tasks is ultimately his/her responsibility. However, responsibility may be delegated to support the day-to-day activities surrounding the tasks listed below.

Who Task

Investigator,

ORA,

Research Manager

Ensure that each study is conducted according to the requirements of GCP by:

• Assessing each study in terms of ― scientific merit of design ― potential benefits of investigational product ― site's capabilities to perform study ― suitability of site’s patient population to the protocol ― access to patients outside of the site to support enrollment ― resources available to perform study

• For each study, delegating responsibility to staff members qualified to perform the delegated activity

• Supervising research staff to whom general and study specific responsibilities have been delegated

• Complying with the requirements of the protocol

• Meeting with sponsors’ representatives as appropriate to discuss planned and ongoing studies



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Who Task

• Submitting all required information, materials, reports, regulatory documents as required by the sponsor/ funding organization, and regulatory authority(ies)

• Recognizing, mitigating and reporting financial conflicts of interest as required by the sponsor and regulations

• Ensuring that the study is conducted under the oversight of a qualified IRB - study procedures are not initiated until receipt of documentation of IRB

approval; - contingencies for IRB approval and continuing approval are met

• Obtaining and documenting the informed consent of each human subject in accordance with the requirements of the regulatory authority, IRB and study protocol

• Assuring that training has been completed for assigned study staff prior to initiation of any study-related activities by that individual

• Ensuring the validity and quality of data generated

• Controlling the use and handling of the investigational product by:

- maintaining investigational product in a locked area with limited access under protocol-specified, controlled temperature and humidity conditions

- using the investigational product under the investigator's personal supervision or under the supervision of a sub investigator responsible to the investigator

- maintaining adequate records of the disposition product, including dates, quantity, and use by subjects

- returning the unused supplies to the sponsor, or otherwise provide for disposition of the unused supplies of the investigational product

Retaining records, source documents and regulatory files as required by the protocol, sponsor, institution and regulatory authority

Ensure access to subject data and the subject’s privacy and confidentiality are maintained



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SOP: GA 102 SOP Development and Processes


1. Procedure

This SOP describes the preparation and maintenance of SOPs that this research team follows to ensure compliance with GCP (and the policies of CHNw) for all clinical trials conducted under the jurisdiction of CHNw. This SOP also describes procedures for ensuring that staff know how to use the documents and implement the SOPs, and that staff are trained on any SOP updates or revisions.

2. Scope

This SOP applies to all activities relating to the development of SOPs used in the conduct of clinical research at CHNw.

3. Responsibility




FDA 21 CFR 312.62 Investigator recordkeeping and record retention



21 CFR 812.140 Records

21 CFR 812.150(a) Reports


2 - The principles of ICH GCP

4 - Investigators

5. SOP Templates

GA 102-A: Document Training Compliance Record Template

GA 102-B: SOP Template

GA 102-C SOP Review









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6. Process Overview

A. Developing and Modifying SOPs

B. SOP Implementation


A. Developing and Modifying SOPs

Who Task—SOPs to be reviewed every two (2) years to ensure no regulatory updates need to be applied

ORA,

Research Manager

Review SOPs every two (2) years for necessary regulatory updates

Determine the need for a new or updated SOP

Determine who will draft the first version of the new document or updates and who must review and approve the draft of the new document

Initiate the drafting process using templates where available

ORA,

Research Manager

Approve final draft

Give all newly approved documents a version number (-00) and effective date

Update related indices (e.g., SOP List) to reflect new document

Maintain an archive file with current and all prior versions of documents

B. Document Implementation

Who Task

ORA,

Research Manager

Notify all affected parties about changes to documents and provide new versions

If new documents or sections to SOPs are extensive or include new procedures, set up training for all affected personnel or their supervisors on the use of the new or revised document



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C. SOP Training

Who

Task

ORA,

Research Manager

SOP training must be completed every two (2) years by all applicable staff involved in clinical research to ensure continued understanding and adherence to procedures

Notify staff of training requirements

Provide a Training Compliance Record (See Template GA 102-A)



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SOP: GA 103 Ensuring Qualification of Site Personnel and Research Staff


1. Procedure

Only individuals qualified by training and experience shall be involved in the conduct of clinical research. Therefore, CHNw shall hire qualified research and administrative staff, provide adequate orientation and provide initial and ongoing training (as needed) and, thereafter, job performance shall be evaluated on a regular basis.

2. Scope

This SOP applies to anyone who is involved in the conduct and oversight of clinical research, including the administrative staff of CHNw.

3. Responsibility



Specific studies: See Template GA 101-A: Delegation of Authority <<Protocol>>


FDA 21 CFR 312.60 General responsibilities of investigators



Guidance for IRBs, Clinical Investigators, and Sponsors—IRB Continuing Review after Clinical Investigation Approval, February 2012

Information Sheet—Frequently Asked Questions—Statement of Investigator, May 2010

Guidance for Clinical Investigators, Industry and FDA Staff—Financial Disclosure by Clinical Investigators, February 2013

Guidance for Industry, Investigator Responsibilities—Protecting the Rights, Safety and Welfare of Study Subjects, October 2009

HHS 45 CFR 46 Protection of human subjects














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28 - Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective task(s)

41 - Investigator's qualifications and agreements

42 - Adequate resources

5. SOP Templates

GA 103-A: Orientation Template

6. Process Overview

A. Hiring Qualified Staff

B. Orientation and Training Plan

C. Continuing Training and Education

D. Performance Evaluation

E. Curriculum Vitae (CV) and License Updates


A. Hiring Qualified Staff

Who Task

ORA,

Research Manager

Draft job descriptions with Human Resources that set forth the qualifications, responsibilities and specific duties for all members of administrative and research staff

Maintain the job descriptions to ensure consistent qualification procedures for all staff

Using the job description, work with Human Resources to begin the recruitment process

Review applications, resumes and CVs via the CHNw applicant tracking software system to initially identify individuals who meet the requirements set forth in the job descriptions

Partner with Human Resources and stakeholders to set up interviews using a predetermined schedule




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Who Task

Qualify individuals through personal interviews

As appropriate, test individuals to ensure qualifications

Initiate interview process

Meet to review the results of interviews and determine the most likely candidate(s)

Partner with Human Resources to establish salary offer (lowest - highest range)

Obtain recommendation(s) if necessary

Human Resources will contact candidate

If candidate is interested in the job, HR recruiter will negotiate salary and partner with Leader to set start date

B. Orientation and Training Plan

Who Task

Director of Clinical Research,

Research Manager

Prior to new staff's start date,

• establish the orientation and training plan

• schedule and determine the goal of the plan

• identify how it will be determined that the goal has been met (this can be through testing, an interview or other means that ensure that the goal has been reached)

Make sure all appropriate staff understand the schedule and will be available when scheduled

Review and discuss the orientation and training plan with the staff member

If adjustments are to be made, revise the plan and notify the appropriate individuals regarding changes that may affect them

Initiate orientation and training document completion of each segment as needed

Upon completion of formal program, review with new staff member

If there are any aspects of the job that are still unclear make sure these areas are addressed as needed

Document completion of the formal orientation and training program and file



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C. Continuing Training and Education

Who Task

ORA,

Research Manager

Determine training requirements for staff and reassess on a regular basis (based on evaluations, regulatory changes, operational requirements, feedback from sponsors, staff, auditors and regulatory inspections)

Budget sufficient money for staff training and continuing education

Schedule training sessions in advance

Take appropriate measures to notify staff and inform supervisors of training requirements

As training is completed, document each staff member's completion and add to personnel file

On a continuing basis, notify staff of the opportunities and resources available for continuing education (subscriptions to periodicals that include CE credits, off-site meetings, on-site programs that provide CE credits, etc.)

Notify staff of such opportunities and encourage participation

D. Performance Evaluation

Who Task

ORA,

Research Manager

On a regular basis and using appropriate means, following CHNw Human Resources processes evaluate the job performance of each staff member

Job performance may be evaluated using the results of QA audits, manager evaluations or interactive performance-setting methods

Follow CHNw Human Resources processes to determine improvement criteria/action plan for deficient evaluations

Follow CHNw Human Resources processes to document and file evaluation in employee file



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E. CV and License Updates

Who Task

Research Manager,

Regulatory Coordinator

Every two (2) years CVs must be updated, signed and dated by all staff

At the time of CV review and updates, all licenses also must be checked to confirm date of renewal

Date of expiration must be documented on CV maintenance log and update provided and filed when due

Updated CVs should be filed in a central location and available for use as a reference for all active studies

Outdated CVs should be retained and stored as part of essential documents as historical documentation and reference for staff qualifications in previous years



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SOP: GA 104 Contracts


1. Procedure

Contracts and other agreements comply with legal, regulatory, ethical and CHNw’s standards. All contracts and agreements shall be drafted, reviewed and finalized according to the procedures of this SOP.

2. Scope

This SOP addresses the process to review, approve and sign contracts to conduct industry-sponsored clinical research.

3. Responsibility





FDA 21 CFR 50 Protection of human subjects


812110(b) Compliance


451 - Compliance with protocol

49 - Informed consent of trial subjects

5. SOP Templates

GA 104-A: Contract Routing Form


http://www.ecfr.gov/cgi-bin/text-idx?SID=841d69f34da8bdb3b0b1f7fa59e8157a&mc=true&node=pt21.5.312&rgn=div5%20-%20se21.5.312_160

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6. Process Overview

A. Requirements for Accepting Research Projects

B. Negotiation and Finalizing Sponsor/Investigator Contracts


A. Requirements for Accepting Research Projects

Who Task

ORA,

Legal,

Research Manager,


Upon being contacted by an industry sponsor or CRO interested in contracting with CHNw to conduct a research protocol request:

• confidentiality agreement

• copy of the proposed protocol

• CRF

• planned methodology for sponsor site monitoring (expected on site visits or risk-based monitoring expectations)

• contract and proposed budget

• any other information required to evaluate the feasibility of conducting the research

•

Upon receipt of the study material, initiate evaluation of the protocol and budget with required stakeholders

If project is accepted, send the contract and budget to ORA and Legal for evaluation

Contact the CHNw legal department and using their process, perform an initial review of the contract for completeness and inclusion of required elements

If there is a master contract on file for the sponsor/CRO, make sure the submitted and master contracts are the same

Ensure that no further (immediate) protocol amendments are planned prior to the final agreement

Notify Investigator if the contract is unacceptable

B. Negotiation and Finalizing Sponsor/Investigator Contracts

Who Task

ORA,

Legal,

Research Manager

If, after evaluation of the study, it is determined that there is no interest in conducting the research, discard study information by shredding or in a manner consistent with the terms of the confidentiality agreement

If there is interest in conducting the research, but the proposed budget is inadequate, determine if it is worthwhile to negotiate with the sponsor/CRO

Upon finalizing the contract, file a copy of the financial/legal documentation in the regulatory file



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SOP: GA 105 Records Management, Accountability and Retention


1. Procedure

Files specific to each subject that include confidential health information (Source Documentation) shall be maintained in a secure location and access limited to authorized staff.

Source Documents shall be assembled and maintained in the same manner for all subjects. Unless being used, Source Documents shall be stored separately from study records identified by a subject ID code.

A subject's medical record, Source Documents (hard copy and electronic) and the information contained therein may be used in the course of a clinical trial only as consented to and/or authorized by the subject, and a copy of the signed informed consent form shall be placed in the medical record or research shadow chart.

Only authorized staff may obtain and use medical records and Source Documents. All records shall be under the control of authorized staff at all times.

Upon completion of a research study, Study Files, CRFs or a copy of e-CRFs, and Regulatory Files shall be maintained on site or in a secure, off-site facility. All stored and/or archived documents and files shall be accessible and retrievable.

2. Scope

This SOP describes how medical records and documentation are to be accessed, tracked and accounted for when used for research related activities, which may include review, data abstraction, photocopying and data verification, as well as subject visits.

3. Responsibility







21 CFR 312.68 Inspection of investigator’s records and reports

21 CFR 812.140(a) Investigator records







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55 - Trial management, data handling and record keeping

515 - Record access

5. SOP Templates

GA 105-A: Request for Electronic Medical Records

GA 105-B: Off-site Storage Log Template

6. Process Overview

A. Accessing and Accounting for Research Files and Medical Records

B. Documentation of Study Communications

C. Copying, Scanning, E-mailing or Faxing Medical Records and Source Documents

D. Storing and Archiving Study Documents


A. Accessing and Accounting for Research Files and Medical Records

Who Task

CRC I, II, III For each study, create a series of file folders or start a binder for documents collected during the study

• Label a series of folders with the name of the protocol

• Identify a section in the records area to store CRFs, Regulatory Files, Study Files and Source Documents

• Label file cabinets and shelves as needed

As study-related documents are received, place each in an appropriate/designated file/location

Maintain and update the file folders or binder as necessary, adding appropriate documents as they are generated or received

Ensure that subject records and regulatory files are kept confidential and are stored in a secure, limited-access location




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Who Task

Prior to visits scheduled by monitors and auditors, review content of regulatory files and subject records for completeness

Ensure that files are organized and complete following the appointment

When the study is over, review the contents of the regulatory files and subject records for completeness

Medical Records:

If medical records for subjects are maintained separately in a study file within the research area, copies of all such documents must be filed, along with a copy of the consent form in an appropriate/designated file/location

For electronic medical records use, ensure that appropriate paperwork is completed to provide sponsor, CRO or auditors limited access to patient study records

Outside party access must be limited to patients who have signed an informed consent document for the study

Access to electronic records should be limited to read only

Contact CHNw IT

B. Documentation of Study Communications

Who Task

Research Manager;

CRC I, II, III;

Director;

Liaison;

Regulatory Coordinator;

Pharmacy;

Investigator

Document phone conversations that address the study and/or regulatory, legal or financial matters

Keep originals or photocopies of all relevant documentation, including facsimile confirmations and e-mail correspondence, and file in the study binder with appropriate documents

Copy sponsor/CRO on IRB communications such as SAEs, IND safety reports, IRB acknowledgment of reports received, amendment approvals, revised ICF and continuing approval for study

All incoming correspondence with study specific information (i.e. study newsletters, monitor follow-up letters) should be reviewed by the Investigator prior to filing in the study binder. The Investigator should initial and date hard copy, original correspondence when reviewed. For electronic correspondence, a read receipt will be printed and filed.

Financial correspondence should be maintained in a separate location independent of the study binder



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C. Copying, Scanning, E-Mailing, or Faxing Medical Records and Source Documents

Who Task

Research Manager;

CRC I, II, III;

Director;


Investigator

When copying/scanning medical records/source documents, use the copier/scanner located at designated departments

Never use a copier located in a public or highly trafficked area

Prepare records for copying in a private, uncluttered area as follows:

• Remove each record/document to be copied and replace it with a placeholder Close the file and either replace in the filing cabinet or in another secure area

• Copy/scan the documents, keeping them face down when not copying

• Return the original documents to the file

• In a private, uncluttered work area, using a permanent, wide stroke, black

marker, obliterate all identifiers (be sure to include numbers, such as patient identifiers, social security numbers, etc.)

• Add subject study number and/ or study initials as required by the study sponsor

D. Storing and Archiving Study Documents

Who Task

Research Manager The contract should specify the number of years study documentation needs to be retained

Research Manager;


CRC I, II, III

When the study is over, review the contents of regulatory files and subject records for completeness by comparing with the template, per department process

Obtain written confirmation from the appropriate regulatory authority or sponsor confirming that the study has ended If federally funded, obtain confirmation that final analysis of data has been completed

Following procedures in SOP 105, store on site until it has been determined that files can be archived

Prepare the files for storage:

• Inventory the contents of regulatory, study and source documentation files

• Follow up on and track any missing documentation



29

Who Task

Label storage boxes clearly and completely including the offsite storage label, sponsor name, protocol number/Short name, and description of contents (i.e. subject files xx-xx, regulatory documents, etc.)

• Request off site storage labels at http://www.grmdocumentmanagement.com/document-storage-solutions

• Document inventory of storage boxes

• Store in a secure location until ready to archive

Archive regulatory files and subject records Arrange to archive all patient files and source documents until sponsor notification/permission has been received to destroy

http://www.grmdocumentmanagement.com/document-storage-solutions



30

II RA 200 REGULATORY AFFAIRS

201 Essential Documents

202 Initial and Ongoing Submissions

203 Reporting Requirements



31

SOP: RA 201 Essential Documents


1. Procedure

CHNw shall maintain a complete set of files pertaining both to specific participants (Study Files and Source Documents) and to regulatory documentation, including study approvals, IRB correspondence and all general significant correspondence for each study conducted.

Documentation shall be maintained per SOP 105 and 201 as required by federal and local regulations, in alignment with ICH E6, Essential Documents, CHNw’s policies, and as stipulated in the protocol, if applicable.

Essential documents include all documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data produced.

Documents for each project shall be organized as follows:

Regulatory File—this file is composed of the documents that pertain to the overall governance of the study and includes evidence of required reviews and approvals. They would include the protocol(s), any amendment(s), master consent form(s), IRB approval documentation, etc. Documents in the study files include Telephone Contact Log, logs pertaining to the investigational product receipt and accountability, eligibility logs, Delegation of Authority, evidence of staff training, qualifications and education (including CVs, Licenses and training logs), significant study-related correspondence, monitoring logs, monitoring visit follow-up letters, etc.

Study File—a record of all data pertinent to the conduct of the investigation evidence that the study has been conducted according to the requirements of the protocol and pertinent regulations are included in this file. Study file also includes the CRFs, Source Documents and completed/signed patient Informed Consent Forms.

• Source Documents are records of observations and other data pertinent to the investigation on each subject enrolled in a study. Source Documents are the original records of the findings, results and notations from visits, procedures, interviews and tests for each subject enrolled in the study. Source Documents are the basis for the data that support the findings of the research and may be paper or electronic based, or a combination of both paper and electronic medical records (EMR).

2. Scope

This SOP, in conjunction with SOP 105, addresses the fulfillment of requirements for study documentation.



32

3. Responsibility





FDA 21 CFR 11 Electronic medical records

21 CFR 50 Protection of human subjects




21 CFR 812.140(a) Investigator records


210, 211 - The Principles of ICH GCP

49 - Records and reports

80 - Essential documents for the conduct of a clinical trial

5. SOP Templates

RA 201-A: Regulatory and Study File Content Template

RA 201-B: Table of ICH Essential Documents

6. Process Overview

A. Maintaining Research Documents and Files

B. Retention of Study Documents

http://www.ecfr.gov/cgi-bin/text-idx?SID=3c4e2c424fae7b01a228348a33f48687&mc=true&tpl=/ecfrbrowse/Title21/21cfr11_main_02.tpl









33


A. Maintaining Research Documents and Files

Who Task

Research Manager;

CRC I, II, III;


For each study, create a series of file folders or start a binder for documents collected during the study

Create the files to organize and account for the regulatory documents, study documents and any paper-based source documentation

Referring to SOP RA 201, maintain and update the file folders or binder as necessary, adding appropriate documents as they are generated or received

Documents should be filed in chronological or reverse order

For significant e-mail correspondence, only the latest and final chain including any final actions or decisions should be printed and retained

Retain copies of all original and revised documents (e.g., protocol, IB, ICF)

All newsletters, Monitor Visit Follow-Up Letters and any correspondence addressed to the PI should be initialed and dated by the PI or documentation of review/receipt as evidence of review prior to filing the documents

When the study is over, review the contents of regulatory files and subject records for completeness

Ensure that files are organized and complete by following SOP GA 105 procedures to access and maintain regulatory and study files

B. Retention of Study Documents

Who Task

Research Manager;

CRC I, II, III;


Following procedures for storage and archiving, ensure that documents are retained as required (see Note below) by federal regulations (may vary according to funding source, product and regulatory authority), local regulations (states may have certain requirements) and CHNw policies

Note: Requirements for document retention varies. While documents associated with FDA-regulated studies must be retained for at least two (2) years after the marketing application is approved for the drug/device (if an application is not approved, until two years after the complete drug/device investigation is completed), documentation may need to be retained for an extended period of time, i.e., up to 15 or 20 years.



34

SOP: RA 202 Initial and Ongoing Submissions


1. Procedure

Prior to enrolling the first subject, all regulatory, IRB and CHNw’s requirements shall be met. This SOP describes the steps for fulfilling the regulatory and clinical submissions and management of study startup and during the course of the study.

2. Scope

This SOP applies to submissions made prior to and during the course of research conducted at CHNw.

3. Responsibility





FDA 21 CFR 56 Institutional review boards

21 CFR 312 Investigational new drug application

21 CFR 812.110(a) (d) Specific responsibilities of investigators


5. SOP Templates

RA 202-A: Submission and Reporting Requirements Reference

Note: Contact IRB for submission requirements, application, amendments, continuing review, and all other IRB related document templates (Link to IRB online submission process: https://iris.ecommunity.com/)

http://www.ecfr.gov/cgi-bin/text-idx?SID=7821f269d2993339c1c60471616425d1&mc=true&node=pt21.1.56&rgn=div5


http://www.ecfr.gov/cgi-bin/text-idx?SID=7821f269d2993339c1c60471616425d1&mc=true&node=pt21.8.812&rgn=div5#se21.8.812_1110


https://iris.ecommunity.com/



35

6. Process Overview

A. Initial IRB Submission

B. Ongoing IRB Submissions

C. Other Submissions

D. Regulatory Document Submission to the Sponsor


A. Initial IRB Submission

Who Task

Research Manager;

CRC I, II, III;


Prior to initiation of study procedures, complete the IRB-specified application and submit to the IRB along with the protocol, informed consent, recruitment material, Investigator’s Brochure, Investigator Information and other information as required by the IRB

Note: Each IRB will have specific requirements for documents to be submitted All relevant IRB requirements must be reviewed and followed

Upon receipt of written documentation of IRB approval, submit a copy of the approval letter to the sponsor

Confirm with the sponsor if a study initiation visit will occur, date of visit and visit-specific expectations

If no study initiation visit is planned, then confirm if the sponsor has approved study to begin enrollment

Ensure all supplies are in order and all staff are aware of study-related responsibilities, and initiate study procedures

If additional study training is required for any assigned staff members, ensure training is completed and documented prior to allowing that individual to work on the study



36

B. Ongoing IRB Submissions

Who Task

Research Manager;

CRC I, II, III;


For all studies not receiving a written exemption from the IRB, renewal submissions will be required at least once a year, or more frequently depending on the specific IRB and type of study as documented by the written initial approval letter

Make additional submissions to the IRB as required per IRB policies

Submit periodic reports as stipulated by the IRB in the approval letter

Submit Amendments to the protocol as required by regulation, sponsor, funding source and policy

Maintain copies of all items and applications submitted, correspondence related to submissions and decisions and all final approvals or acknowledgements

Throughout the study, deviations or violations may need to be submitted to the IRB as they occur

This will be dependent on the IRB’s individual specifications and SOPs

IRB-specific policies should be reviewed and followed for each study

C. Regulatory Document Submission to the Sponsor

Who Task

Research Manager;

CRC I, II, III;


When notification of selection for a study has been provided by the sponsor, the sponsor will request copies of essential documents

A list of all required documents should be requested from the sponsor but, at a minimum, the following should be provided as a study start-up packet:

• Principal Investigator CV and license

• Sub Investigator(s) CV and license

• Statement of Investigator (1572 or similar depending on study)

• Conflict of Interest/Financial Disclosure (as applicable)

• IRB approval

• Membership list or assurance number

• Protocol signature page should also be submitted once available

Updated documents, such as renewed licenses or updated CVs, should be provided to the sponsor as they come available throughout the study



37

SOP: RA 203 Reporting Requirements


1. Procedure

Reports that are required by federal regulation, upon request from the reviewing IRB or FDA, or as mandated by local law, shall be provided according to regulation or according to agreement between CHNw and requesting entity.

Progress reports shall be completed and sent to the sponsor of the study as required by the sponsor. Progress reports shall be sent to the IRB periodically as required by the IRB.

Reports of AEs shall be reported as required by the sponsor. Reports of AEs shall be sent to the

IRB as required by the IRB.

Shortly after completion of CHNw’s participation in an investigation, and confirmation by the sponsor, a study closure report will be submitted to the IRB. Once reviewed/approved, the IRB notification of study closure will be forwarded to the study sponsor.

When conducting research involving products regulated by FDA, each investigator shall report

financial conflict of interest prior to study initiation and any relevant change in the status of an investigator's financial interest that may occur during the course of the investigation and for one year following the completion of the study as required by the sponsor of the research and in compliance with 21 CFR 54. All conflict of interest, whether financial or other, shall be disclosed and reported as required by the funding agency and CHNw’s policy.

In addition to submitting copies of reports to all required parties, CHNw also shall maintain a file copy of each required report in the regulatory file.

2. Scope

The requirements for reporting are detailed in the procedures set forth in this section.

3. Responsibility







38


FDA 21 CFR 56 Investigational review boards





410 - Progress reports

411 - Safety reporting

413 - Final report(s) by investigator

5. SOP Templates – None

6. Process Overview

A. Reporting AEs

B. Other Reporting Requirements


A. Reporting AEs & SAEs

Who Task

Research Manager;

CRC I, II, III;


Investigator

AEs shall be reported according to the federal regulations, requirements of the funding agency, the sponsor, institutional policy and the IRB

During the Initiation Visit, ensure that the monitor informs all members of the staff of the requirements for initial reporting and follow-up of SAEs

Immediately, within 24 hours of discovering the event or per the protocol, send report of SAE to sponsor and IRB Refer to IRB policy for SAE reporting and definition

Follow up SAE reports should be submitted as specified by the sponsor and every attempt should be made to obtain supporting information related to the SAE



http://www.ecfr.gov/cgi-bin/text-idx?SID=7ab2d47d077132d97e2c5621139f74e0&mc=true&node=pt21.8.812&rgn=div5%20-%20se21.8.812_1140%20-%20se21.8.812_1140#se21.8.812_1150




39

Who Task

Patients or Patients’ families/representatives should sign records release forms as applicable to obtain hospital records or death certificates (if needed)

B. Other Reporting Requirements

Who Task

Research Manager:

CRC I, II, III;


Investigator

Send periodic progress reports as required by sponsor

IRBs and sponsors should be notified of deviations from the protocol as specified per their reporting requirements

For all deviations, the site should maintain internal documentation related to the details of the deviation, reason for the deviation and any corrective and preventative measures taken to ensure the deviation does not reoccur

Final study reports should be completed and submitted as specified by IRBs and sponsors

IRBs will generally provide a specific study closeout report template which should be completed as specified and submitted to the IRB and a copy submitted to the sponsor at the study’s conclusion and after sponsor closeout of the site

Protocol violations, whether intentional or unintentional, shall be reported to the IRB and sponsor

During the Initiation Visit, review the sponsor's requirements for reporting protocol deviations

Review the IRB's requirements for reporting protocol deviations



40

III PM 300 PROJECT MANAGEMENT

301 Protocol Development

302 Assessing Study Feasibility

303 Study Start-Up

304 Investigational Product Management

305 Source Documentation

306 Monitoring Visits

307 Study Completion

308 Protocol Compliance



41

SOP: PM 301 Protocol Development


1. Procedure

Every research project/study begins with the development of a protocol. The protocol is a document that describes how a project/study will be conducted (the objective(s), design, methodology, statistical considerations and organization of a research project/study,) and ensures the safety of the trial subjects and integrity of the data collected.

A research protocol is a document that describes the background, rationale, objectives, design, methodology, statistical considerations, and organization of a clinical research project according to the ICH Good Clinical Practice guidelines.

The NIH provides many resources for protocol development to assist investigators in writing and developing research protocols that are in compliance with regulatory/GCP requirements. Some NIH institutes have a mandatory requirement for using their protocol templates.

2. Scope

This SOP applies to protocol development made prior to and during the course of research conducted at CHNw.

3. Responsibility








41 - Investigator's Qualifications and Agreements

42 - Adequate Resources

https://hub.ucsf.edu/sites/hub.ucsf.edu/files/Protocol_Template_JAN_07_2015.doc

http://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/pages/protdev.aspx


http://www.ecfr.gov/cgi-bin/text-idx?SID=7821f269d2993339c1c60471616425d1&mc=true&node=pt21.8.812&rgn=div5%20-%20se21.8.812_1110#se21.8.812_1110




42

5. SOP Templates

PM 301-A: Protocol Template

PM 301-B: Chart Review Protocol Template

6. Process Overview

A. Protocol Development


A. Protocol Development

Who Task

Research Manager,

CRC III,

Investigator

****Before writing protocol, contact ORA and IRB for guidance

Suggested step to consider:

• Perform literature search • Read pertinent literature to determine standardized/validated methods for evaluation and measurements • Determine the focus of your study and how it can add to scientific community • Form the study hypothesis • Determine study design • Discuss study with statistician; Use pilot data to perform power analysis • Develop proposed budget

Develop protocol that includes applicable items as follows:

• Title • Background Information • Objectives/Purpose • Study design • Selection for inclusion/exclusion of subjects • Study procedures • Recruitment • Consent process • Assessment of benefit/risk • Reporting of AEs • Conditions for discontinuation of study • Statistics • Data handling and recordkeeping



43

Who Task

• Data monitoring • Provisions to protect privacy • Publication policy • Project timetable/flowchart • Financial compensation • References • Supplemental documents/appendices

Once draft protocol is completed, contact ORA or department research manager for next steps



44

SOP: PM 302 Assessing Study Feasibility


1. Procedure

Feasibility assessment should be conducted for all potential studies presented to a research site. Feasibility assessment consists of a careful evaluation of whether a study is a good “fit” for the study site. This assessment should be conducted as soon as study details are presented to a site by a sponsor. Careful evaluation and consideration will include a compilation of information including, but not limited to, a site’s facilities, equipment, experience, interest, staff and subject recruitment and retention capabilities.

The site must carefully evaluate the scientific, ethical and financial merits of conducting the study in order to ensure that the study meets both the necessary requirements of the site and the sponsor. The sponsor may request the study site complete a feasibility evaluation form providing site specifics for the study in question. This SOP describes the steps for assessing the feasibility of conducting a successful study.

2. Scope

This SOP applies to the processes involved in assessing and evaluating protocols for studies conducted at this investigative site.

3. Responsibility







21 CFR Part 11 Electronic records, electronic signatures



42 - Adequate Resources



http://www.ecfr.gov/cgi-bin/text-idx?SID=3e3fab7c1dfc768c8661bc0c1cd44f71&mc=true&node=pt21.1.11&rgn=div5




45

5. SOP Templates

PM 302-A: Study Review and Assessment Template

PM 302-B: Study Effort and Cost Considerations Template

PM 302-C: Salary Worksheet Template

PM 302-D: Per Subject Cost Worksheet Template

PM 302-E: Study Budget Worksheet Template

PM 302-F: Pre-Study Qualification Visit Agenda Template

PM 302-G: Pre-Study Qualification Visit Preparation Template

6. Process Overview

A. Protocol Review and Assessment

B. Study Budget Development

C. Pre-Study Site Qualification Visit


A. Protocol Review and Assessment

Who Task

Investigator,

Research Manager,

and any other Departmental Committees/Cabinets

Prior to agreeing to review a protocol, execute the confidentiality agreement

Decide if there is enough information available to make an informed decision regarding feasibility of the study (is there a final protocol? is the CRF design available?)

In addition to the PI, documented departmental review and approval is required (e.g., protocol review committee)

Review the protocol and complete an assessment (See Template PM 302-A)

Items for consideration include:

• Interest in the study

• Therapeutic Area and application to site population

• Competing studies



46

Who Task

• Availability of staff resources

• Standard of care

• Ability to enroll a specified number of study subjects

• Study timelines

If possible, contact the sponsor for more information on the estimated site budget and let the sponsor know of any specific budget requirements that are anticipated (percent overhead, set start-up fees, hourly rate for PI and Coordinator(s), etc.) to ensure that the sponsor will be able to accommodate specific budget requirements

If it is required that your site use a local IRB to conduct the study, submission, review and approval timelines should be evaluated in comparison with the study timelines and expected start-up and enrollment window

(If a local IRB must be used and the approval process will take an extended period of time, it is important to confirm that there still will be adequate time for enrollment following approval)

Notify the sponsor regarding the decision to be further considered for, or of agreement to conduct, the study

If it is determined that the protocol is not a good fit for the site, or the potential budget cannot meet site requirements, the sponsor should be provided with the rationale for the decision

The protocol and other supporting materials must be disposed of as specified by the sponsor

If the site is interested in conducting the study, proceed to schedule the Pre-Study Site Qualification Visit or the Initiation Visit

B. Study Budget Development

Who Task

Research Manager,

Investigator

If it has been determined that the study is feasible for execution by the site, budget development and negotiations should begin

Using the protocol, CRF and Worksheets, develop a draft study budget

Create a spreadsheet and itemize every study-related procedure at each visit

• Consider the costs of activities that may not be itemized in the proposed budget

• If needed, draft a budget for contingencies (ranked by most likely to least likely)



47

Who Task

Negotiate the budget if necessary Be prepared to discuss the rationale for increases (Always have an analysis of costs associated with staff duties)

Consider and include provisions to amend study budget based on protocol amendments

Include reimbursement for pre-screening activities and screen fails

Consider unscheduled subject visit time requirements

Determine if sponsor will provide specialized equipment

Confirm if paper-based or electronic CFRs will be used, evaluate electronic data capture (EDC) system and consider time for data entry

Review monitoring expectations with sponsor/CRO

Confirm expected time on site for visits, number of monitoring visits and any impact for Risk-Based Monitoring implementation (i.e., expectation for source documents to be scanned in and faxed, remote access to subject information other than e-CRF records, remote monitoring visit teleconferences, need for internal quality control or assurance procedures, etc.)

C. Pre-Study Site Qualification Visit

Who Task

Research Manager;

Investigator;


CRC II, III

Identify key clinical research personnel likely to be involved in conducting the study under consideration, consider the role of pharmacist when investigational product is being utilized.

Ensure that the sponsor's Confidentiality Agreement (if applicable) has been signed by the PI and returned to the sponsor (Some sponsors/CROs have a central Confidentiality Agreement available; inquire and request)

Schedule the Pre-Study Site Qualification Visit with the sponsor/CRO and key staff

Obtain a copy of the confirmation letter and request or develop an agenda

Prepare for the visit:

• Request a list of documents that will be needed; gather them and have them ready for the visit



48

Who Task

• Prepare recruitment and retention plan and be prepared to explain how the site will meet enrollment goals

• Determine if the sponsor has any areas of special interest that require advance scheduling, such as:

- visiting the treatment site (clinic or hospital), pharmacy, central

laboratory or medical records department;

- seeing any specialized equipment needed to implement the study;

- meeting briefly with ancillary personnel involved in any specialized data collection;

- visiting any ancillary facilities

Meet with sponsor/CRO representatives to review protocol, IB and communication plan for sponsor/CRO and clinical site

Refer to Pre-Study Site Qualification Visit Template as needed

Before signing a contract to conduct the study, make sure all concerns have been addressed and the schedule of payments is satisfactory

Request an expected date for site selection letter

Confirm if a site initiation visit will occur or if an Investigator Meeting will serve as the site initiation visit and training

Confirm timelines for study start-up, Investigator Meeting and/or Site Initiation Visit



49

SOP: PM 303 Study Start-Up


1. Procedure

Prior to enrolling the first subject, all regulatory and institutional requirements must be met and preparations for protocol procedures must be complete.

The Initiation Visit may be conducted before an IRB approval letter is received for the site; however, the IRB approval letter and final approved consent document must be received prior to first subject being enrolled.

The objectives of the Initiation Visit (if applicable) are to:

• Verify that the site’s study preparation procedures are completed

• Verify that all regulatory documents are in place

• Verify that investigational product (if received) is available so that training can begin

• Verify that study supplies (if received) are available so that training can begin

• Review the protocol, CRFs and other worksheets

• Review all regulatory requirements

• Provide recruitment and retention plan

• Provide the plan for study monitoring

• Provide the site with all sponsor contact names and telephone numbers

• Confirm the sponsor’s expectations on the conduct of the study

• Train staff and ensure documentation has been completed

2. Scope

This SOP describes the steps for fulfilling the regulatory and clinical requirements of initiating a sponsored research study.

3. Responsibility






50


FDA 21 CFR 312.55 Informing investigators


21 CFR 8124.0 General responsibilities of sponsors


Form FDA 3454 Certification: Financial interests and arrangements of clinical

investigators

Form FDA 3455 Disclosure: Financial interests and arrangements of clinical

investigators



42 - Adequate resources

44 - Communication with IRB/IEC

5. SOP Templates

PM 303-A: Site Initiation Visit Preparation Template

PM 303-B: Site Initiation Visit Agenda Template

PM 303-C: Site Initiation Visit Management Template

PM 303-D: Site Responsibility Log Template

6. Process Overview

A. Investigator Meetings

B. Preparation for Study Start-Up

C. Study Initiation


A. Investigator Meetings

Who Task

Investigator;

Research Manager;

Identify clinical research personnel who will be involved in conducting the study (usually the lead study coordinator and the Principal Investigator)





https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048304.pdf





51

Who Task


CRC I, II, III

Ensure that travel arrangements and expense claim forms are in order for those who will be attending the Investigator Meeting

Meet with site staff to discuss protocol and collect comments and questions from staff not attending Investigator Meeting

Take advantage of the resources available at the meeting:

• During the meeting, clarify questions and concerns, especially those that relate to the protocol design and prior experience with the investigational product

• Discuss with other sites ideas and barriers

Upon return to site, meet with, or communicate with, other members of the research team to share information from the meeting

Gather and submit reimbursable receipts and expense claim form to sponsor/CRO

B. Preparation for Study Start-Up

Who Task

Investigator;

Research Manager;


CRC I, II, III

Once the contract has been reviewed and accepted, prepare the following:

• Informed consent document(s) (make sure the sponsor/CRO reviews the consent form prior to IRB submission)

• IRB submission (ensure all versions of the informed consent form are placed in the regulatory binder and BE CERTAIN you use the most current IRB-approved version)

• Submissions to other committees as required

• Most current version of source documents if applicable

Confirm whether the sponsor/CRO expects all approval documentation to be in place prior to the Study Initiation Visit

Make sure the following documents are available:

• Community Health Network Research Financial Disclosure Form • Executed financial contract with final budget (as applicable) a confidentiality

agreement(s) • Completed Form FDA 3454 or 3455 (if applicable)

Make arrangements for sponsor personnel to train site staff and document on training form

http://wwwfdagov/downloads/aboutfda/reportsmanualsforms/forms/ucm048310pdf



52

Who Task

Using the Initiation Visit Preparation Template, complete preparation for study start-up

Schedule the Site Initiation Visit, allowing a full day for all activities (If all approvals must be in place prior to the initiation meeting, do not schedule until all approvals have been documented and are in the regulatory files)

Assemble and review required documents and study materials and file in site regulatory binder

Confirm the meeting date and times with research staff who will be involved in conducting the study

Provide each staff member, who will have a key role in the study, with the materials needed for the meeting (protocol, CRFs, EDC, study supplies, sample study medication, etc.)

Continue to track all regulatory documents as they are received and file in the regulatory binder

Review regulatory files for completeness

• If the study already has been submitted to the IRB and other committees, review approval documentation that has been received

• Follow up on any submissions with pending approvals

• Document the status of pending approvals and expected approval timeframe

• Ensure PI reviews, initials and dates IRB correspondence and approvals

Prior to the Initiation Visit review the Initiation Visit Agenda with key staff

List questions and items that need to be clarified

C. Study Initiation

Who Task

Investigator;

Research Manager;


Review the Agenda, Initiation Visit Preparation Template, regulatory file and prepared study worksheets and associated materials

Ensure that all materials and supplies needed for the meeting (annotated CRFs, all study related logs, etc.) are available



53

CRC I, II, III;

Pharmacy

Ensure current version of the IRB-approved informed consent is available

Conduct the Site Initiation Visit

Complete the Initiation Visit Management Template, per department process, during the visit with the monitor

Ensure that the sponsor/CRO sends written documentation summarizing important agreements made during the Initiation Visit as needed/applicable

Be prepared to provide sponsor with an update on any study-related issues

Conduct and document in-service training for:

• staff involved in recruitment and pre-screening • referring and support staff (e.g., physicians, nurses, lab technicians, dispensing

pharmacist) if needed • staff involved in scheduling and conducting screening visits • staff involved in EDC entry • staff involved in IVRS/IWRS systems

Inventory and document investigational product received and ensure adequate storage requirements (If applicable, ensure unblinded staff are completing)

Inventory and document all study supplies, such as:

• CRFs • central lab supplies • supplies for subject use (i.e., diaries, self-assessment supplies, etc.) • sponsor-supplied equipment

Review study procedures with assigned research staff

Notify sponsor of launch date for recruitment and screening activities

Review recruitment and retention plan with site staff as needed



54

SOP: PM 304 Investigational Product Management


1. Procedure

All investigational product inventories shall be monitored and accounted for throughout the course of the study. The investigational product must be accounted for at all times and handled according to sponsor requirements; applicable local, state and federal regulations; sponsor or funding agency requirements and institutional policies.

Investigational products shall be stored in a secure environment. Access is limited to delegated study personnel, according to the storage requirements detailed in the protocol, other instructions supplied by its provider and CHNw’s policies. Only individuals delegated this responsibility by the PI and authorized according to the requirements of CHNw’s policies and local and state law are permitted to dispense investigational products to study subjects.

Procedures for receipt, storage, dispensing, reconciliation and return or authorized destruction of any investigational products shall comply with sponsor and CHNw’s requirements. At the completion of the study, investigational products shall be disposed of in accordance with CHNw’s requirements and in compliance with the written authorization of the sponsor or supplier and applicable local, state and federal regulations.

2. Scope

This SOP describes the processes at CHNw for the receipt, storage, dispensing, reconciliation, and return or authorized destruction of the investigational product.

3. Responsibility


• Individuals who contribute, in a substantial way, to the scientific development or execution of the project

• Specific studies: See Template GA 101-A: Delegation of Authority <<Protocol>>














55

21 CFR 812.110(c) Supervising device use

21 CFR 812.110(e) Disposing of device

21 CFR 812.140(a)(2) Records of receipt, use or disposition of a device

Guidelines for the Monitoring of Clinical Investigations, January 1988

Internal Compliance Program Guidance Manual 7348811: Clinical Investigators, September 1993


46 - Investigational Product(s)

5. SOP Templates

PM 304-A: Investigational Product Receipt Form Template

PM 304-B: Subject Inventory Control Form Template

PM 304-C: Investigational Product Accountability Form Template

PM 304-D: Temperature Log Template

6. Process Overview

A. Investigational Product Receipt, Storage and Disposure

B. Investigational Product Accountability


A. Investigational Product Receipt, Storage and Disposure

Who Task

Investigator;

Pharmacy;

Research Manager;

CRC I,II, III

Upon receipt of the study product, inventory and reconcile the shipment, ensuring the information on the packing slips matches exactly with what has been sent to the site, including:

• amount • lot numbers/batches • quantity per carrier/container (if easily verified) • temperature monitoring devices (if applicable) • IVRS/IWRS allocations (if applicable)




http://www.ahc.umn.edu/img/assets/19826/Clinical%20monitoring.pdf

https://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm




56

Who Task

Promptly bring any discrepancies to the attention of the sponsor and complete required forms (i.e. temperature deviations/excursions, lost or damaged containers)

If the sponsor includes a form in the shipment to acknowledge receipt, obtain the appropriate signature and forward the form to the sponsor/CRO

Retain a copy for the regulatory files

Ensure any supplies required for the blinding are available

Ensure back-up plan is in place in the event of power outage or failure of storage equipment

B. Investigational Product Accountability

Who Task

Investigator;

Pharmacy Staff;

Research Manager;

CRC I,II, III

Each time study product is dispensed, complete the Investigational Product Receipt Form (see Template PM 304-A) and/or applicable IP Logs Documentation will include:

• IVRS/IWRS dispensing confirmation (if applicable) • amount (and lot number, if appropriate) dispensed • name of site staff dispensing product • subject’s number • subject’s initials • date of dispensing • date and amount of investigational product returned

At baseline/randomization and all IP dispensing visits, instruct and document subjects regarding administration, storage and return of the study article for all investigational product that will be self-administered

Review, retrain and document dosing procedures as needed for all noncompliance

At each visit,

• perform IP accountability and document usage of the study article

• note any discrepancies between amounts used by subjects and amounts expected to be returned and document the reasons

• If any containers/units are missing, document the reasons

After accounting and documenting the subject's returned product, return all used containers/units to secure storage or to the pharmacy



57

Who Task

Ensure the supply of the investigational product and related materials are adequate and within an appropriate expiration date

Alert the monitor when additional supplies will be required and/or request re-supply via IVRS/IWRS

C. Investigational Product Transport

Who Task

Investigator;

Research Manager;

CRC I, II, III;

Pharmacy

Per departmental guidelines, contact ORA’s Research Pharmacist for the process and forms

JS Logistics is the CHNw’s courier



58

SOP: PM 305 Source Documentation


1. Procedure

Protocol-defined activities are conducted in strict adherence to the protocol throughout the study. Data and information generated from these activities are accurately noted or collected in source documents. This information then is accurately transcribed or entered into data collection media (CRF, which is either a paper-based document or an electronic database).

Data entered or transcribed into the CRF and entered into EDC shall be verified with source documents, which may include test reports, memoranda, subjects’ diaries, pharmacy dispensing records, output from automated instruments, Visit Worksheets, Data Records and chart notes, whether paper-based or electronic.

Therefore, staff shall record, maintain and control adequate and accurate records containing all information pertinent to the study for each study subject.

Each document that is the source for data entered in a CRF or EDC system, such as Visit Worksheets, lab reports and informed consent forms, must include at minimum the subject's initials, subject number, and date.

2. Scope

This SOP addresses the steps to ensure adequate source documentation to verify the data generated through clinical studies conducted at CHNw.

3. Responsibility

Investigators are responsible for ensuring site staff and delegated personnel are recording, recognizing and classifying data collected throughout the duration of the study on the source document in accordance with the sponsor, protocol, applicable regulations, laws and ICH guidelines



• Specific studies: See Template GA 101-A: Delegation of Authority


FDA 21 CFR 312.62(b) Case histories

21 CFR 812.140(a) (3) Records of each subject’s case history and exposure to the device

http://www.ecfr.gov/cgi-bin/text-idx?SID=709f63f24cce016d7e911b97f0f199cd&mc=true&node=pt21.5.312&rgn=div5#se21.5.312_162




59


491, 492 - Records and reports

5. SOP Templates

PM 305-A: Source Documentation Template

6. Process Overview

A. Maintenance of Source Documents

B. Ensuring Complete and Accurate Source Documentation


A. Maintenance of Source Documents

Who Task

Research Manager;


CRC I, II, III

Ensure most recent version of source documents are utilized when conducting a study visit

File results of laboratory reports, diagnostic test results, ECGs, etc. as they become available and after they are reviewed

If Visit Worksheets are used to collect data that are recorded in the CRF, the worksheets must be dated and signed by the recorder and retained as part of the source document

All source documentation must be accessed and maintained according to SOP 105




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B. Ensuring Complete and Accurate Source Documentation

Who Task

Investigator;

Research Manager;


CRC I, II, III;

Pharmacy

During each subject visit or encounter, ensure there is source documentation for all of the protocol-specific exams, tests, evaluations and assessments scheduled for the visit

Note any out-of-range values per protocol as either clinically significant or not clinically significant according to PI or delegated staff assessment

Ensure equipment has been calibrated within established calibration parameter timelines and applicable certificates have not expired

Review inventory of investigational product and study supplies that are needed to perform study-related procedures or record data during the visit or will be given to the subjects (such as diaries and self-assessment instruments) for accuracy

Record all data immediately and note that the study-related procedure has been completed or not completed per protocol or the reason it was not completed per protocol

Ensure documentation is completed appropriately by the person performing the study-related procedure

If corrections need to be made to source documents, using black pen cross out the incorrect entry with a single line, the correction written next to the original entry and the correction dated and initialed by delegated staff performing the study-related procedure

DO NOT: • obliterate the original entry • backdate corrections • change data values • ABSOLUTELY NO WHITE OUT

If a note of explanation is needed to clarify source documentation, record the information in ink, making sure the note does not obliterate any data entries

The notation should be signed and dated the date the explanation is documented and filed in the source document as a memo to file

Collect all results as soon as possible

Review the results and record as soon as possible and document review

Follow up on all outstanding test results until all data for the visit are accounted for

Record all AEs in source documents as described in SOP 304

Transcribe data per SOP 501

File source documents from the visit per SOP 501



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SOP: PM 306 Monitoring Visits


1. Procedure

It is expected that studies being conducted at CHNw shall be monitored by sponsors and others responsible for oversight of clinical research Investigators, research staff and others involved in the conduct of clinical research and will allocate adequate time for such monitoring activities. The Investigator also will ensure the monitor or other compliance or QA reviewer is given access to study-related documents (including electronic medical records or certified copies) and study-related facilities (e.g. pharmacy, diagnostic laboratory, investigational product storage facilities, etc.) and has adequate space to conduct the monitoring visit.

It should be discussed prior to study start if a sponsor/CRO is intending a risk-based monitoring approach and how data will be reviewed (on-site or remotely), what data will be reviewed and additional site expectations for documents that need to be provided to the monitors and/or staff time commitments.

2. Scope

This SOP addresses preparations for scheduling and conducting monitoring visits, and addressing follow-up activities and action items associated with the visit once the visit has been completed.

3. Responsibility





FDA 21 CFR 312.50 General responsibilities of sponsors

21 CFR 312.56 Review of ongoing investigations

21 CFR 312.59 Disposition of unused supply of investigational drug





21 CFR 812.45 Monitoring investigations











62

Compliance Program Guidance Manual 7348811: Clinical Investigators; September 1993

Compliance Program Guidance Manual 7348810: Sponsors, Contract Research Organizations and Monitors; September 1994

Guidance on Risk-Based Monitoring, August 2013




5. SOP Templates

PM 306-A: Monitoring Visit Preparation Template

6. Process Overview

A. Preparation for a Monitoring Visit

B. Monitoring Visit and Follow up


A. Preparation for a Monitoring Visit

Who Task

Research Manager;


CRC I, II, III;

Pharmacy

Work with the study monitor to schedule a mutually convenient date and time to conduct the monitoring visit either on site or for follow-up on a remote monitoring visit

Attempt to schedule the monitoring visit during days when subject visits are minimal to ensure adequate time to work with monitor

When scheduling monitoring visit, select a date when PI and key staff members involved with the study will be available

Confirm the date and time in writing with the monitor and with staff members who will need to be available

Follow up with monitor to ensure receipt of the interim monitor visit letter and file appropriately in the regulatory binder



https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf




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Who Task

Prior to initiating preparation for the monitoring visit, ask the monitor if there are specific study activities on which he or she will focus during the visit (The confirmation letter generally describes the specific intentions and follow-up activities for the visit)

Note any questions or concerns about protocol procedures or study-related activities that site staff would like to address

Review data:

• Contents of the regulatory files, CRFs and source documents

• Make sure: -CVs, licenses and training documentation are current

-IRB correspondence is current and that the PI has reviewed -CRFs are up to date -Missing data have been tracked and entered or accounted for -Data entered in CRFs corresponds with the source documentation -EDC entry has been completed for all subject visits

• Data queries issued to date have been resolved or are in the process of

resolution

• Review investigational product logs and inventory, resolve discrepancies Ensure monitor will have access to electronic medical records or prepare certified copies if requested by the monitor

Review previous monitoring reports for any outstanding action items that must be addressed prior to or during the next scheduled visit

• Tip: do not wait until right before the visit to address action items; these should be addressed immediately following each monitoring visit

Review inventory of investigational products, forms or other relevant study supplies and note any low inventory

If enrollment is behind schedule, determine why and discuss possible solutions with other staff Revise recruitment plan if necessary to present to monitor if applicable

Prepare a list of questions and issues generated by staff and review of study documents and status If there is time, send to the monitor prior to the meeting

Request any medical records or other documents not readily available

Reserve adequate work space for the monitor and, if needed, a conference room



64

Who Task

Ensure office equipment is working and accessible for monitor to use, i.e., copy machine, fax, internet, etc.

Confirm the scheduled date and time with any other personnel or departments involved in visit (i.e., the research pharmacist or unblinded staff)

Just prior to the visit, collect and organize the CRFs, source documents, regulatory files, logs, etc.

Prior to the visit review the follow-up letter from the previous visit for follow-up or action items for accuracy and discuss action with the monitor and request amended letter if applicable

B. Monitoring Visit and Follow-up

Who Task

Research Manager;


CRC I, II, III

Ensure that the monitor and a site staff member sign the monitoring visit log (supplied by sponsor)

Review the schedule for the visit and any specific areas the monitor or staff is interested in addressing during the visit

Review the documentation collected for monitoring

Be available to assist, answer questions and make introductions

Ensure the site Delegation of Responsibility Log is current

Ensure all training logs are current

Ensure the IP Accountability logs are current (unblinded staff if applicable)

Ensure lab samples/specimen logs are current

Throughout the visit, meet with the study monitor to discuss any issues related to:

• adherence to the protocol • protocol deviations • corrective action plan(s) • review of the regulatory files and correspondence with IRB



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Who Task

• verification of data in the CRFs with the source documentation, EDC entry, queries issued and resolution

• study drug storage, temperature logs, dispensing and accountability requirements for IP storage

• SAEs and Protocol Deviations

At the end of the visit, discuss action items and review any outstanding items with the monitor and other members of the research staff

As soon as possible, address any data discrepancies noted at the monitoring visit

Correct errors to the CRFs noted and EDC queries issued at the monitoring visit by using the procedures described in SOP 501

Ensure the data clarification forms are kept with the other study records in the regulatory files for this study per protocol requirements

Request follow-up letter as soon as possible to use for reference in preparing for the next monitoring visit



66

SOP PM 307 Study Completion


1. Procedure

Under FDA regulations, study completion occurs when all study subjects have completed the study at the investigative site. Federally funded research and investigator-initiated studies are considered complete after all data has been analyzed. A study may also end because the PI decides to stop participating or the sponsor terminates the study.

Clinical studies that have ended shall be closed out in an orderly and systematic manner that ensures all investigational product is accounted for and disposed of as required, specimens are stored, shipped or destroyed as required and associated source documents, study files and regulatory documentation are organized and stored in a manner that allows access by regulatory authorities and sponsor representatives for data verification and regulatory inspections.

If the trial is prematurely terminated or suspended for any reason, the Investigator or designee shall promptly inform the subjects, provide follow-up for the subjects and, where required, inform the regulatory authority(ies). In addition:

• If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.

• If the sponsor terminates or suspends a trial, the investigator shall promptly inform the IRB and provide the IRB a written explanation of the termination or suspension.

- If the IRB terminates or suspends its approval, the investigator shall notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

• IRB acknowledgement of study closure, termination or suspension shall be filed in the site regulatory file.

2. Scope

This SOP addresses the steps that shall be taken to close clinical studies that are complete, terminated or suspended.

3. Responsibility






67


FDA 21 CFR 312.50 General responsibilities of sponsors


21 CFR 312.59 Disposition of unused supply of investigational drug







412 - Premature termination or suspension of a trial

413 - Final report(s) by investigator

IRB Applicable Closeout Forms and Acknowledgements

5. SOP Templates

PM 307-A: End-of-Study Documentation Template

6. Process Overview

A. Completion of Study


A. Completion of Study

Who Task

Investigator;

Research Manager;


Upon verifying that a study is being closed, notify all staff involved in study activities to ensure their availability for resolving outstanding issues

If needed, meet in order to review status of the study and completion activities

http://www.ecfr.gov/cgi-bin/text-idx?SID=709f63f24cce016d7e911b97f0f199cd&mc=true&node=pt21.5.312&rgn=div5%20-%20se21.5.312_150#se21.5.312_150



http://www.ecfr.gov/cgi-bin/text-idx?SID=709f63f24cce016d7e911b97f0f199cd&mc=true&node=pt21.5.312&rgn=div5%20-%20se21.5.312_150%20-%20se21.5.312_150#se21.5.312_160








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Who Task

CRC I, II, III If still recruiting subjects, cease recruitment activities

Cancel screening visits set up for potential subjects who have not yet been screened

Contact study monitor to mutually arrange the date for the closeout visit, request a confirmation letter and a detailed list of required tasks that will occur during the closeout visit

Contact active subjects to schedule an early termination/completion visit

Follow protocol procedures for the early termination/completion visit

Issue pro-rated outstanding payment to all subjects if applicable

Review source documents for completeness and follow up on receipt of results from all study-related labs, diagnostic procedures and assessments

Complete all CRFs, EDC entry and queries issues to the extent possible

Follow up on any open AEs, SAEs and document in the subjects’ study research chart

Document the end of study participation in the subject’s research chart and remove any medication restrictions or study warnings, if applicable

Inventory and return all study supplies to the sponsor, if applicable

If the sponsor directs the site to dispose of or destroy remaining study supplies, request a confirmation letter with instructions/guidance

Inventory investigational product, complete all applicable logs

Ensure any discrepancies are carefully documented

Send all completed CRFs to the sponsor, if applicable

Maintain a copy of the CRFs for the subject when applicable

Notify the IRB that the study has ended by completing and submitting the appropriate IRB documentation

Follow up with IRB for its study closure acknowledgement and file appropriately in the site regulatory binder Forward a copy to the sponsor/CRO upon receipt

Organize all completed CRFs and complete regulatory documentation and source documentation

Follow procedures in SOP GA 105 and RA 201 to review, maintain and store study documents



69

SOP: PM 308 Compliance with Protocol


1. Procedure

The investigator shall not implement any changes to the protocol or deviate from the protocol without sponsor approval and prior review and documented approval from the IRB. Deviations from the protocol shall be documented with an explanation for the deviation and reported to the sponsor and the IRB immediately or as soon as possible.

A change to the protocol may be implemented without sponsor and IRB approval if necessary to protect the life or physical well-being of a subject in an emergency. In such a situation, as soon as possible, but in no event later than five working days after the emergency occurred, a description of the implemented change and the reasons for the change shall be submitted to the sponsor and the IRB.

2. Scope

This SOP addresses the steps to ensure changes to the protocol are not implemented without sponsor or IRB review and approval.

3. Responsibility

Investigators are responsible for ensuring site staff and delegated personnel are recording, recognizing and classifying data collected throughout the duration of the study in accordance with the sponsor, protocol, applicable regulations, laws and ICH guidelines.






21 CFR 812.110(b) Compliance

21 CFR 812.150 Deviations from the investigational plan

Guidance for Industry; Investigator Responsibilities—Protecting the Rights, Safety, and

Welfare of Study Subjects (2009)

http://www.ecfr.gov/cgi-bin/text-idx?SID=6542ceeb21978dc0f9d5b182e329d0b1&mc=true&node=pt21.8.812&rgn=div5#se21.8.812_1100



https://www.fda.gov/downloads/Drugs/.../Guidances/UCM187772.pdf

https://www.fda.gov/downloads/Drugs/.../Guidances/UCM187772.pdf



70


45 - Compliance with protocol

431 - Medical care for trial subjects

5. SOP Templates

PM 308-A: Protocol Deviation Log Template

6. Process Overview

A. Requesting a protocol waiver

B. Reporting a protocol deviation


A. Requesting a Protocol Waiver

Who Task

Research Manager;


CRC I, II, III

In order to accommodate a subject or subjects, it may be necessary to request a protocol waiver (e.g., waiver of an inclusion/exclusion criteria). This request requires prior approval from the sponsor and IRB. Protocol waivers should not be used when there is need to eliminate an immediate hazard to subjects.

Prepare requests for waiver in writing within a timely manner and submit to the sponsor and IRB before implementing changes

If it is felt that the change will occur frequently or apply to all subjects, discuss the details with sponsor/CRO and, if appropriate, request the sponsor amend the protocol

Contact the monitor by phone and advise that the request for waiver has been sent

Be prepared to answer questions and provide additional information

Do not initiate any changes until the waiver has been approved by both the sponsor and the IRB




71

B. Reporting a protocol deviation

Who Task

Research Manager;


CRC I, II, III

Follow the IRB and the sponsor’s procedures for reporting deviations

Ensure sponsor and IRB requirements are known and site staff has been adequately trained on the requirements

Upon becoming aware of an inadvertent deviation, inform the PI and report the deviation as required to the sponsor and IRB

If the deviation was minor, it may be reportable at the scheduled periodic or annual report Confirm with the monitor and IRB regarding requirements for reporting



72

IV SM 400 SUBJECT MANAGEMENT

401 Subject Recruitment, Screening and

Retention

402 Informed Consent

403 Eligibility and Enrollment

404 Subject Visits and Assessments

405 AE Management



73

SOP SM 401 Subject Recruitment, Screening and Retention


1. Procedure

Study recruitment evaluation should begin well in advance of accepting a new study. When presented with a potential study, a careful and detailed feasibility evaluation should be completed to ensure that adequate, qualifying subjects exist in the site database or, if it is required that subjects be recruited from outside the practice, a validated plan must be developed to ensure enrollment target can be met. Successfully recruiting and retaining subjects involves the development and implementation of a well-coordinated plan that may require the efforts of the entire research team.

Once in place, subject recruitment and retention efforts must be constantly assessed, with new strategies implemented as necessary. After potential subjects have been identified through recruitment efforts, the process of subject selection begins. Ongoing assessment must be incorporated to ensure subjects are retained in studies when possible.

2. Scope

This SOP describes the steps for fulfilling the regulatory and clinical requirements involved in study subject recruitment, screening and retention.

3. Responsibility





FDA 21 CFR 50.20 General requirements for informed consent

21 CFR 50.25 Elements of informed consent

21 CFR 56.109 IRB review of research

21 CFR 56.111(a)(3), 56.111(b) Vulnerable population

21 CFR 812.20(b)(11) Investigational device exemptions



Recruiting Study Subjects—Information Sheet, Guidance for IRBs and Clinical Investigators, Oct 18, 2010








http://www.fda.gov/RegulatoryInformation/Guidances/ucm126428.htm

http://www.fda.gov/RegulatoryInformation/Guidances/ucm126428.htm



74



5. SOP Templates

SM 401-A: Guideline for Recruitment and Advertising Practices

SM 401-B: Model Screening Script Template

SM 401-C: Recruitment Action Plan Template

6. Process Overview

A. Developing and Implementing a Recruitment and Retention Plan

B. Assessing the Effectiveness of the Recruitment and Retention Plan

C. Initiating Pre-Screening Procedures


A. Developing and Implementing an Overall Recruitment Plan

Who Task

Research Manager;

CRC I, II, III Based on the specific inclusion/exclusion criteria for a study, identify the target population for potential study subjects Based on the contracted enrollment goal, length of study, recruitment, screening and enrollment period, you will:

• Establish a recruitment action plan that meets the sponsor’s timeline • Validate enrollment potential based on actual numbers of qualifying patients in

site database • Identify sources of potential participants outside practice • Generate a list of patients who can be pre-screened based on preliminary

protocol criteria • Create pre-screening form and submit to the IRB for approval • Begin screening as soon as possible and using only IRB-approved materials • Evaluate potential transportation barriers • Evaluate potential holiday and vacation barriers • Evaluate potential schedule barriers




75

Who Task

Research Manager;


CRC I, II, III

Determine recruitment methods (e.g., space/radio ads, letters, community talks, print media, e.g., newspaper articles, patient support groups, internet, flyers, posters, community education opportunities)

Develop recruitment materials, submit to the IRB for approval and use only IRB-approved recruitment materials for the duration of the entire study

Use sponsor-provided materials that have been approved by the IRB

Investigator,

Research Manager

Project costs associated with each recruitment strategy (be careful to include a budget provision for additional financial support for recruitment costs)

Project staffing schedules to ensure adequate staffing throughout the entire duration of the study

Hire additional staff if necessary, provide and document all training

Research Manager;


CRC I, II, III

(Optional) Prepare an information packet for prospective subjects who will be scheduled for screening visits

Information may include:

• Introduction to clinical research (what it is, how patient’s rights and safety are managed, etc.)

• A letter explaining what to expect during the visit • Directions to <<Site>> • The names of the staff who will be involved in the screening visit • If possible, a visit "agenda" • If appropriate, a copy of the consent form • Contact information • Submit a sample packet to the IRB before using and wait to distribute until IRB

approval is received

Research Manager;

CRC I, II, III

(Optional) Develop instructions for scheduling the screening visit for research and administrative staff who will be involved in pre-screening and setting up screening visits

Research Manager;

CRC I, II, III

Evaluate and discuss with site staff potential barriers and methods to address recruitment and retention challenges



76

B. Assessing the Effectiveness of the Recruitment and Retention Plan

Who Task

Research Manager;


CRC I, II, III

Monitor progress and assess results of the recruitment strategy

Develop appropriate alternative strategies, if necessary, along with a budget for the activities

Consult with the sponsor if needed regarding resources available for recruitment

Institute alternative strategies if enrollment projections lag

Compare competing sites’ numbers to gauge effectiveness

Evaluate final results

Update recruitment action plan with results and additional strategies

If needed: Draft patient database study information letter

Be certain to use only IRB-approved version

If needed: Draft physician letter to outside physicians

Be certain to use only IRB-approved version

C. Initiating Pre-Screening Procedures

Who Task

Research Manager;


CRC I, II, III

Based upon the study inclusion/exclusion criteria, develop a pre-screening process

An IRB approved partial HIPAA Waiver must in place prior to contacting patients for the study (e.g., in person, by phone, email, etc.). Contact the IRB for guidance on this requirement.

Use an IRB approved prescreening script for any of the following: • For in-person contacts with potential subjects • For incoming phone calls from potential subjects • For calling potential subjects generated from an internal database of prospective

subjects or current patients • For contacts generated by a central recruitment or call center

*Contact your IRB for guidance or requirements for pre-screening procedures and only begin screening procedures after receipt of IRB approval



77

Who Task

Review pre-screening procedures with anyone who is expected to answer the phone to make sure he/she understand how to provide and record information

Document training on applicable training logs

Develop a pre-screening log to document results as applicable per log criteria

Record information, on each individual pre-screened who: • Qualified for screening • Did not qualify and the reason(s) based on exclusionary criteria number • Qualified for screening but chose not to continue and the reason(s) based on the applicable criteria

• If the study sponsor requests a copy of pre-screening log, submit without identifiers

Ensure HIPAA compliant procedures are in place for all screening activities

Note that when assembling lists of subjects to pre- screen, the expected number of screen fails and refusals must be taken into consideration in order to still have enough patients to enroll an adequate number of subjects into the study



78

SOP SM 402 Informed Consent/Assent


1. Procedure

The ethical conduct of clinical investigations is based on the voluntary consent of the subject, who has been appropriately informed about a study’s risks and benefits, and is designed to protect the rights, safety and wellbeing of human subjects. It is the responsibility of the investigator to ensure compliance with all ethical standards, guidelines and federal and state regulations have been met through the language of the informed consent document, and that informed consent itself has been properly obtained from the subject or the subject’s legal representative. Documentation of the informed consent process is required to establish that the subject was accurately and adequately informed and that no study-related procedures were initiated prior to obtaining informed consent.

2. Scope

This SOP describes the steps for fulfilling the regulatory and ethical requirements for developing the informed consent document and for appropriately obtaining the subject’s informed consent.

3. Responsibility





FDA 21 CFR 50.20 General Requirements for informed consents

21 CFR 50.25(a)(b) Elements of informed consent

21 CFR 50.56 Additional safeguards for children in clinical investigations of FDA-regulated products


21 CFR 56.111 Criteria for IRB approval of research

21 CFR 312.54 Emergency research under §5024 of this chapter




21 CFR 812.110(a) Awaiting approval

21 CFR 812.140(a)(3)(i) Documents evidencing informed consent














79

Internal Compliance Program Guidance Manual, 2008; 7348811: Clinical Investigators

Information Sheets for IRBs and Investigators, October 2012

Frequently Asked Questions—Informed Consent Process

Informed Consent Document Content

A Guide to Informed Consent—Information Sheet, August 2011

HHS 45 CFR 46116 General requirements for informed consent



Applicable state requirements for age of assent and specific requirements

5. SOP Templates

SM 402-A: Informed Consent Process & Template

6. Process Overview

A. Writing the Consent Document

B. Process for Informing Potential Subjects

C. Additional Processes for Exceptional Research


A. Writing the Consent/Assent Document

Who Task

Research Manager;


CRC II, III

Generally a sponsor or CRO will provide an informed consent/assent template with protocol-specific information

If the IRB, sponsor/CRO or cooperative group has a template, sample consent or requires specific information, refer to the information provided (Per IRB, use IRIS software and documents to develop consent/assent)

Link: https://iris.ecommunity.com/

If staff is developing the consent /assent documents, based on the protocol and investigator’s brochure, prepare a draft consent /assent form


https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm113709.htm


https://www.fda.gov/RegulatoryInformation/Guidances/ucm126420.htm#Informed%20Consent%20Process

https://www.fda.gov/RegulatoryInformation/Guidances/ucm126420.htm#Informed%20Consent%20Document%20Content

https://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm#content

https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/#46.116


https://iris.ecommunity.com/



80

Who Task

If the sponsor or cooperative group provides a consent/assent form, adapt the language to meet CHNw’s requirements

Consult with the sponsor/CRO or cooperative group, if needed, to reconcile local requirements with central requirements

Verify that all required and additional elements of the informed consent form are incorporated by using the Informed Consent template, per department process, and inserting the appropriate language as required by the IRB

Coordinate with the IRB to ensure the document also meets all state and local requirements

If changes are implemented, submit to sponsor for approval prior to submitting to the IRB

If approved by sponsor, submit the draft informed consent form to the IRB for review and approval along with the other IRB-required documents

In consultation with the sponsor/CRO or cooperative group, make modifications requested by the IRB

Research Manager;


CRC II, III

After the informed consent form document has been approved by the IRB, file the original IRB approval letter and informed consent form document appropriately and send copies of both documents to the sponsor/CRO or as required by the funding source, governing regulations

Research Manager; Regulatory Coordinator;

CRC II, III

If a protocol amendment changes the criteria for the informed consent/assent, ensure that applicable revisions are made (in conjunction with the sponsor), submit to the IRB for approval and ensure the revised IRB-approved version replaces the previous version

Research Manager;


CRC II, III

If required, ensure that currently enrolled subjects be re-consented with the new version of the consent/assent

Consult with the IRB regarding if all subjects must be re-consented with the new version and the timing (if subjects should be consented at next scheduled visit or brought in sooner for safety reasons)



81

B. Process for Informing Potential Subjects

Who Task

Research Manager;


CRC I, II, III

Before initiating any protocol-specific procedures, complete the process for informed consent/assent

Ensure that the most recent version of the IRB-approved consent /assent form is used to document that the prospective subject has given consent/assent

If the subject is unable to give written informed consent, provide the above information to the subject’s close relative (as per local law) or legal guardian

If the subject does not speak English, ensure that the above procedure is implemented in the subject’s language using a qualified interpreter

• Note: If an interpreter is used for the consent process, then an interpreter should be made available at each subject visit to ensure all information is appropriately conveyed and all questions are answered

The informed consent process includes a review of the informed consent by the subject

The person conducting the informed consent process should ensure that the patient adequately understands the information contained in the form by asking questions of the subject

After the informed consent is reviewed with the subject, it should be confirmed that all questions have been answered (by medically appropriate staff or the PI) and the process should be documented

If the subject does not speak English, ensure that both the subject and an impartial witness sign and date the informed consent document that has been translated into the language of the subject and approved by the IRB

Ensure any state-specific consent documents are reviewed, signed and dated

Ensure that the subject reads and understands HIPAA Authorization and signs after the informed consent processes have been completed (if the HIPAA language has not been included as part of the approved consent document)

Ensure that currently enrolled subjects be re-consented with the new version of the consent/assent (as required by the IRB)

Consent/Assent should be reviewed to ensure:

• All signatures are dated with the correct date by the individual(s) signing

• All information is complete (i.e., if a box should be checked confirming if subject allows collection of specimen for retention and later testing, that this box is appropriately checked)



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Who Task

Ensure the subject is provided with a copy of the informed consent document and the process is documented

C. Additional Processes for Exceptional Research

Refer to the Human Subjects Office for processes on exceptional research

(E.g., when research involves children or minors, when research takes place in an emergency setting, when informed consent cannot be obtained in an emergency, conducting the consent process using a short form)



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SOP SM 403 Eligibility and Enrollment


1. Procedure

Prospective subjects shall be carefully screened and only individuals who meet the eligibility criteria specified in the protocol shall be enrolled in a study.

The investigator shall follow the screening procedures specified in the protocol to enroll and, if applicable, randomize research subjects.

2. Scope

This SOP details the procedures for screening prospective subjects and enrolling subjects in a clinical trial.

3. Responsibility





FDA Information Sheets for IRBs and Investigators, October 2010; Screening Tests Prior to Study Enrollment



5. SOP Templates

SM 403-A: Subject Eligibility Template

SM 403-B: Screening and Enrollment Log Template


https://www.fda.gov/RegulatoryInformation/Guidances/ucm126430.htm

https://www.fda.gov/RegulatoryInformation/Guidances/ucm126430.htm




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6. Process Overview

A. Screening Potential Subjects

B. Determining Eligibility


A. Screening Potential Subjects

Who Task

Research Manager;


CRC I, II, III;

Investigator

Prior to initiating any protocol-directed procedures, complete the informed consent/assent process as described in SOP 402

Be sure to give the subject a copy of the signed consent/assent form

As directed by the protocol, conduct the Screening Visit

Inform subjects of screening procedures and applicable timelines for receipt of results that will determine eligibility

B. Determining Eligibility

Who Task

Research Manager;


CRC I, II, III;

Investigator

If eligibility will be determined at the visit, (once the visit has begun) ensure that the subject remain in the facility while eligibility is determined and confirmed and, if eligible, either schedule the baseline visit/randomization visit, or enroll the subject according to protocol specifications

If eligibility cannot be determined on the day of the visit, inform the prospective subject that he or she will be contacted

Make sure the subject provides contact information and remind the subject of the site’s contact information located on the informed consent

Upon determination of eligibility, contact the individual to schedule the baseline visit/randomization visit

If the subject is eligible, document eligibility by:

• Ensuring the PI or delegated person documents, signs and dates that the subject meets eligibility requirements and may be enrolled into the study



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Who Task

• Entering subject information in a paper or electronic enrollment and screening log

• Reviewing source documentation to make sure all original eligibility criteria are verifiable

• Sending documentation of eligibility to the sponsor

If the individual is ineligible to participate in the study, document ineligibility by:

• Ensuring an Investigator documents that the subject does not meet eligibility requirements and may not be enrolled into the study

• Entering subject information in a paper or electronic enrollment and screening log

• Accurately denoting the exclusion criteria and that the subject was a screen fail • Retaining any supporting data available to verify ineligibility • Notifying the sponsor as required • If applicable, collect study-related supplies, any unused test article and any used

test article containers, and record data in the investigational drug log • Discuss alternatives with the subject if appropriate • Retain the original signed consent/assent forms at the site



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SOP SM 404 Subject Visits and Assessments


1. Procedure

During a clinical study, all protocol-related assessments and procedures shall be performed in a manner to ensure the collection of pertinent and reliable data and the well-being of the subjects. Visits shall be scheduled, managed and the results of procedures and encounters documented in a timely and accurate manner. Subjects shall be carefully monitored for adverse effects, changes in health status and compliance with the protocol. If the investigator determines that the well-being of the subject or the integrity of the data may be compromised due to a subject's participation in a study, the investigator may terminate that subject's participation in the study.

2. Scope

This SOP describes the steps for fulfilling the regulatory and clinical requirements to ensure adherence to study procedures for the evaluation of a subject’s response to the investigational article.

3. Responsibility





FDA 21 CFR 50.20 General requirements for informed consent






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5. SOP Templates

SM 404-A: Study Encounter Worksheet and Record-Screening Template

SM 404-B: Study Encounter Worksheet and Record-Visit # Template

SM 404-C: Study Encounter Record—Physical Exam-Visit # Template

SM 404-D: Medical History-Screening Template

SM 404-E: Adverse Event Log Template

SM 404-F: Concomitant Medication Log Template

6. Process Overview

A. Enrollment and Randomization

B. Preparing for and Conducting Study Visits

C. Communication with primary or referring medical providers

D. Specimen Collection and Handling

E. Follow-up, Completion and Early Termination from the Study


A. Enrollment and Randomization

Who Task

Research Manager;

Regulatory Coordinator,

CRC I, II, III;

Investigator

Conduct the baseline visit as required by the protocol to establish the subject’s baseline signs and symptoms

Research Manager;

Pharmacy;

CRC II, III;

Investigator

If applicable, randomize the subject

Dispense the test article

Review the following with the subject:

• The use of any study aids, such as a diary • The use of any current medication if required per protocol



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Who Task

• Required study procedures and visits • Specific dosing procedures or requirements for the use of the test article • Confirm any special handling or temperature requirements for the test article

• Provide contact information to the subject

Confirm preferred methods of contact to reach the subject, i.e., texting, e-mail, phone In addition, confirm alternate methods of contact to reach the subject (family contact numbers)

Schedule the follow-up visit

B. Preparing for and Conducting Study Visits

Who Task

Research Manager;

CRC II, III;

Investigator

Prior to scheduled visit, review protocol requirements for the visit

Research Manager;

CRC I, II, III;

Investigator;

Pharmacy

Review the list of all allowed and disallowed medication for the study

Prepare and partially complete Visit Worksheets, if applicable

If applicable, prepare a worksheet for each subject to correspond with the requirements for the visit

Review and inventory supplies, including supplies for laboratory tests, procedures, diaries and other supplies for subject use

Check investigational product inventory and expiration dates

Prepare requisition forms, prescriptions, if applicable, and confirm appointments with other departments

Requisition medical records if needed or confirm access to required medical records

Check source documents from previous visit and make sure CRFs are complete to date (and confirm any ongoing AEs that need to be followed up or queried with the subject)

On the worksheet, note any outstanding issues



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Who Task

Confirm date and time of appointment for subjects

Notify subject advocates and interpreters if needed

Obtain material needed to pay subjects, if applicable

Assemble all the material, documents and supplies for each subject

Double-check availability of exam rooms and, if necessary, reserve rooms for visits and procedures

Confirm schedule with phlebotomist, lab personnel and any other staff who will be involved with the visit, as applicable

C. Specimen Collection and Handling

Who Task

Research Manager;

CRC I, II, III;

Investigator

Observing appropriate precautions based on OSHA guidelines, infection control manual and/or the institutional procedure manual for the handling of bodily fluids, collect the appropriate specimens identified in the study protocol

Label the study-specific test tubes or other containers with subject identifiers and date

If required by the protocol, include the time collected and any other information to prepare for storage or shipment

Use a sharpie or other pen that will not run or smear if it gets wet and cannot be rubbed off

Process the specimen according to the specifics defined in the protocol (for example, centrifuge speed, duration, temperature requirements)

Spin, separate and transfer the specimen to the appropriate transport tube(s), as required

Complete the laboratory requisition slip Include one copy with the specimens when shipped Retain one copy and file with the other study-related subject records

In the subject’s medical record and/or on the CRF, note the date and time of the collection, as well as any relevant information pertaining to the subject’s status at the time of the procedure



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Who Task

Prepare and package the specimens according to the shipping instructions specified in the protocol and/or central laboratory procedure manual

Retain a copy of the shipping receipt and file with the other study-related subject records

D. Follow-up, Completion and Early Termination from the Study

Who Task

Research Manager;

CRC I, II, III;

Investigator

Scheduled completion As each subject completes the study, as directed by the protocol, conduct completion visit

If there is a follow-up period, schedule the next visit or discuss methods of follow up and instruct the subject

If applicable, discuss options available to the subject regarding access to the investigational product, return to current therapy, etc.

Early termination If a subject's participation is being terminated, it is critical that the reason for termination is accurately recorded (i.e., if the subject is withdrawing consent due to an AE, then document that the reason for early termination is due to an AE)

Document the reason(s) for the subject's early termination in the source document, along with related material such as:

• any details related to an AE • results of assessments, tests, procedures • notes of observations • reports from medical providers

Obtain as much information as possible from study subjects who drop out of the study The primary pieces of information are:

• AE(s) • concomitant medication status • return of study drug/device or amount left • last day of dosing or test article use compliance • contact information for follow up

Collect and account for used and unused investigational product Provide payment as outlined in the informed consent form



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SOP SM 405 Adverse Events (AEs) Management


1. Procedure

All (AEs) that occur during a study shall be managed according to the requirements of the protocol, in accordance with regulations and CHNw’s policy and in a manner to ensure the protection of subjects and collection of quality data.

2. Scope

This SOP addresses the procedures to recognize, identify, manage, document and report AEs that occur in the course of a clinical study.

3. Responsibility

Investigators or designated study team members are responsible for appropriately recognizing, classifying, recording and reporting these AEs.





FDA 21 CFR 312.32 IND safety reports

21 CFR 312.33 Annual reports

21 CFR 312.44 Termination

21 CFR 50.25 Elements of informed consent

21 CFR 56.108 IRB functions and operations


21 CFR 56.115 IRB records

Information Sheets, October 1998: Continuing Review after Study Approval

HHS 45 CFR 46.103 Assuring compliance with this policy—research conducted or supported by any Federal Department or Agency










https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html#46.103



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45 CFR 46.110 IRB records

45 CFR 46.116 General requirements for informed consent


432 - Medical care of trial subjects

411 - Safety reporting

5. SOP Templates

PM 405-A: Criteria for Recognizing and Managing AEs

6. Process Overview

A. Identifying SAEs and AEs

B. Management and Documentation of SAEs and AEs


A. Identifying SAEs and AEs

Who Task

Investigator;

Research Manager;

CRC II, III

At each contact with the subject, seek information on AEs by open questioning and, as appropriate, by examination

Questions should be posed related to any changes since the last subject visit such as:

• “Have you experienced any changes in your health since your last study visit?”

• “Have you had any other doctor visits since your last study visit?”

• “Have you started any new medications or changed any of your medications since your last study visit?”

In addition, AE information may be reported between visits through:

• Spontaneous reports by subjects • Observations by clinical research staff • Reports by family or medical care providers







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Who Task

• Question the subject or family member to determine if or when the subject should be seen

Assess the AE to determine:

• Date and time of onset • Its severity • Its seriousness • Its relationship to the investigational product • Any medications or use of therapeutic treatments • Action taken as related to test article (did subject stop using the test article or

should the subject stop using test article) • Date and time of resolution, if applicable

All signs, symptoms and abnormal diagnostic procedures results should be recorded in the source document, though they may be grouped under one diagnosis as appropriately applied by a qualified medical practitioner

Information on all AEs should be recorded immediately in the source document, and also in the appropriate AE module of the CRF

Any SAE must be reported within 24 hours to the sponsor or CRO as soon as the site is made aware of the event

Study-specific SAE forms and instructions will be provided in the protocol and with the CRFs

Policies for submitting SAEs to the IRB also must be confirmed and the IRB notified of SAEs within its required reporting time frame (as applicable)

B. Management and Documentation of SAEs and AEs

Who Task

Investigator;

Research Manager;

CRC II, III

If a relationship to the investigational product is suspected, follow as specified in the protocol or per discussion with the sponsor's medical monitor

Document any change in use or administration in the source document and notify the sponsor and IRB

Record information on all AEs immediately in the source document, including:

• Description of the event • Severity of the event • Probable relationship to the investigational product



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Who Task

• Date (and time) of AE onset • Include, as the information becomes available,

― Date (and time) of AE resolution, if available ― Start and stop dates of test article administration or dose reduction ― Results of any laboratory tests and/or diagnostic procedures ― Follow-up plan ― Outcome

Report SAEs to the Sponsor and IRB as required

Record in the appropriate AE module of the CRF

Follow the subject to assess the AE until stabilized or resolved

SAEs that are still ongoing at the end of the study period must be followed up to determine the final outcome

SAEs that occur after the study period (within a time specified in the protocol) and considered to be possibly related to the investigational product or research procedures should be documented, reported immediately and treated



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V DM 500 DATA MANAGEMENT

501 Clinical Data Management



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SOP DM 501 Clinical Data Management


1. Procedure

Only designated study staff delegated by the PI on the delegation of authority log may enter data into the CRF/eCRF and/or other required report forms Designated individuals must have documented training on file for entry into the e-CRF systems (as applicable).

All CRFs/eCRFs must be complete and/or updated per protocol requirements and/or as defined per contract between CHNw and sponsor/CRO Timelines for entry into eCRFs must be confirmed with the sponsor/CRO and designated staff should include data entry time into their schedules.

All information documented on the CRF/eCRF must have corresponding source documents present in the research chart or in the electronic medical records (as applicable) to substantiate the information entered into the sponsor-provided CRF/eCRF. All hard-copy study documents must be maintained in a secure location and available for inspection by FDA and sponsor/CRO upon request If electronic medical records are used or e-CRFs, each designated staff member must be granted a unique, secure password to allow appropriate access to the system (read or write access) that cannot be shared.

2. Scope

This SOP describes procedures to enter data into the CRF/eCRF and source document verification.

3. Responsibility





FDA

21 CFR 812 Subpart E Responsibilities of investigators

21 CFR 812 Subpart G Records and reports

21 CFR 11 Electronic records and electronic signatures

21 CFR 312.50 General responsibilities of sponsors



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21 CFR 312.70 Disqualification of a clinical investigator

Guidance for Industry—Computerized Systems Used in Clinical Investigations, May 2007

Guidance for Industry—Electronic Source Data in Clinical Investigations, September 2013


5. SOP Templates - None

6. Process Overview

A. Data Collection and Transcription


A. Data Collection and Transcription

Who Task

Investigator;

Research Manager;

CRC I, II, III

Data should be entered/recorded within a week (five business days) after each subject visit or encounter unless contract/protocol requires a shorter timeframe

When entering data:

• Confirm that the appropriate version/module is being used

• Follow the instructions

• If using a paper-based form, use permanent (preferably black) ink when entering data

• Fill in all of the spaces provided If data is not available for an entry, do not leave blank; instead, indicate reason there is no data, for example:

― Use “UNK” for unknown ― Use “ND” for not done ― Use “NA” for not applicable

• Record measurable values in the unit of measure specified by the protocol,

CRF/eCRF or program





https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070266.pdf






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Who Task

• Avoid using abbreviations in written comments

• Ensure all data that is available has been obtained, confirmed and documented in the source record by the designated staff member

• If a correction is necessary on paper (either the CRF or source document):

- Cross out the entry with a single line (in a manner that allows the original entry to be seen)

- Record the correct information

- If needed, briefly state why the change was made (for example, write ‘error’ next to the correction)

- Initial and date the correction next to the original entry

Never • Obscure the original entries by erasing, blackening or using correction fluid

• Backdate or pre-date a correction or data entry An explanation for a date difference should be added to the document when necessary

• If necessary, provide a written explanation regarding any significant changes, occurrences or deviations

• Any deviations should be accompanied by documentation of corrective and preventative actions taken to ensure the issue is corrected and will not re-occur

Review all entries against the source document for accuracy and completeness

If there are outstanding documents (test results, read-outs, etc.), indicate the section missing by documenting the reason on the source document and/or progress note

Follow up until all documentation is received

Before sending data to the sponsor or data center, review entered data to make sure there are no empty fields and that entered data is consistent with the corresponding source documents

Submit data to the sponsor according to the study’s data submission schedule

File copies of source documents, test results, readouts, etc., for each CRF/eCRF in the subject's research chart

If needed, send a copy of the source document to the medical record and/or primary medical provider



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B. Accessing, Entering and Managing Data

Who Task

Investigator;

Research Manager;

CRC I, II, III

The sponsor/CRO providing the system or software is responsible for training site staff on its use Document all training and maintain certificates in the site regulatory binder

When preparing to perform computer data entry or management functions, log in using assigned ID/password combination or other electronic signature

Enter all required data into the appropriate fields of e-CRFs captured in the source documents following the prompts of the data-entry program

Corrections:

• Follow the electronic data management systems instructions when making corrections (It is the sponsor/CRO’s responsibility to ensure that audit trail reviews are compliant, performed and documented at defined intervals)

• Note: If data is altered, the reason for the change should be reflected in the source document and any changes to the source document must be appropriately initialed and dated or have a corresponding audit trail if completed in an electronic system

Ensure that all annotations to electronic records are attributable as to who and when (date, time) the annotations are made

Check and correct (or annotate) all data before transmitting the e-CRF or entering into electronic data capture systems to the sponsor/CRO

Ensure that an original or certified copy of all electronic source documents and audit trail records are retained on file as applicable

• Note: If a certified copy is used, there must be documentation that the copy is certified by an appropriately delegated staff member, that the information is a complete and that it is an exact duplicate of the original records

With respect to an FDA audit, treat electronic records as you would paper records

Ensure that data management records are accessible to the FDA and sponsor/CRO upon request



100

VI QA 600 QUALITY ASSURANCE

601 Quality Assurance Audits

602 Inspections by Regulatory Authorities



101

SOP QA 601 Quality Assurance (QA) Audits


1. Procedure

Periodic QA audits of ongoing and completed research shall be conducted to ensure protocol compliance, regulatory compliance, data integrity and adherence to CHNw’s policies. CHNw shall be prepared to act on any significant findings of concern with an immediate corrective action plan, as well as the implementation of ongoing preventative process improvement procedures.

2. Scope

This SOP applies to the procedures to prepare for an internal and/or third-party audit of all clinical studies conducted at this site. It describes the steps followed by the site from the time the site receives notification of the audit, is scheduled, and until all follow-up activities associated with the audit have been completed.

3. Responsibility












21 CFR 812 E Responsibilities of investigators

21 CFR part 11 Electronic records; electronic signatures—scope and application

Internal Compliance Program Guidance Manual, 17348: 811 Clinical Investigators, September 1993

Program 7348811, Chapter 48—Bioresearch Monitoring Clinical Investigators and Sponsor-Investigators, Date of Issuance: December 8, 2008









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5. SOP Templates

QA 601-A: Clinical Study Site Audit Template

6. Process Overview

A. Internal Audits

B. Audits by Sponsors/Third Parties


A. Internal Audits

Who Task

Investigator,

Research Manager,

Regulatory Manager

Authorize at least one primary and one back-up individual within the department who is trained in assessing compliance with applicable regulations and SOPs to act as internal auditors as needed

Establish a schedule for conducting periodic internal audits (e.g., annually)

Ensure appropriate time is allocated for audits and assign a separate area to conduct audit

Conduct the audit using the template, per department process.

Require all staff to fully cooperate and participate during an internal audit

Direct the implementation of corrective actions and process improvements arising from the audit findings For formal corrective actions, a Corrective and Preventative Actions (CAPA) form should be completed for significant findings

Maintain a record of internal audit dates, reports and corrective action plans

NOTE: Important: Ensure the PI is available to participate throughout the audit, review all findings with the

entire staff and document all corrective action plans as a result of the audit process



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B. Audits by Sponsors/Third Parties

Who Task

Investigator;

Research Manager;


If contacted by a sponsor to schedule an audit, inform the PI, Legal, ORA, IRB, Compliance and appropriate management and staff

Ensure all key personnel are available to participate in the audit

Request the auditor provide an audit agenda, to ascertain the scope of the audit and the expected date the audit report will be given to CHNw

Request the auditor provide the number of personnel, names and credentials of all individuals within its team who will be present, and make accommodations to provide working space

Hold a meeting of all key personnel prior to the audit to review the agenda and ensure all necessary study-related documentation is available

Remind all key personnel to fully cooperate and participate with the auditor as needed and to discuss immediately any irregularities discovered with the auditor

During the audit, be honest, answer directly the question being asked and never answer outside your area of expertise or responsibility

Accompany the auditor(s) at all times during the audit to answer questions, retrieve requested study-related documentation and facilitate the completion of the audit

Ensure the auditor(s) are not left unattended with CHNw documentation other than the specific study being audited

Request a verbal summary of all audit observations and a written briefing of all significant findings from the auditor, and review those findings at the completion of the audit

Request a date of expected receipt of the complete audit report from the auditor as soon as possible after the audit is completed

Develop and implement an agreed upon corrective action plan (as appropriate)

Document all corrective action plan training and maintain in CHNw’s files

For formal corrective actions, a Corrective and Preventative Actions (CAPA) form should be completed for significant findings

At the end of the audit, schedule a close-out meeting to discuss observations



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SOP QA 602 Inspections by Regulatory Authorities


1. Procedure

In the event of an inspection by a regulatory authority (FDA, OHRP, etc.), CHNw shall cooperate with the regulatory authority to the fullest extent required Clinical study inspections shall not be viewed as adversarial proceedings and requests for documents and other information will be accommodated, provided such disclosure does not jeopardize the rights, safety and welfare of study subjects and the rights and privacy of CHNw.

2. Scope

This SOP includes the procedures to prepare for a regulatory inspection and the procedures to follow during the inspection. It describes the steps followed by the site from the time the site receives notification of the inspection, to when it is scheduled, and until all follow-up activities associated with the inspection have been completed.

3. Responsibility





FDA 21 CFR 312.62 Investigator recordkeeping and record retention


21 CFR 812 (E) Responsibilities of investigators

21 CFR part 11 Electronic records; electronic signatures—scope and application

Information Sheet Guidance for IRBs, Clinical Investigators and Sponsors

FDA Inspections of Clinical Investigators, June 2010

Compliance Program Guidance Manual, 7348810 Sponsors, Contract Research Organizations and Monitors

OHRP's Compliance Oversight Procedures for Evaluating Institutions, October 14, 2009



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http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf


https://www.hhs.gov/ohrp/compliance-and-reporting/evaluating-institutions/index.html



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41 - Investigator’s qualifications and agreements

515 - Record access

5. SOP Templates

QA 602-A: Prepare for a Regulatory Inspection Template

QA 602-B: Procedures during an FDA Inspection Template

6. Process Overview

A. Preparing for an Inspection

B. Conducting the Inspection


A. Preparing for a Regulatory Inspection

Who Task

Investigator,

Research Manager,


If contacted to schedule an inspection, confirm study to be inspected and if all records are to be inspected as related to the study

Upon being notified that there will be a regulatory inspection, begin preparation

Inform PI, ORA, IRB, Counsel and Compliance

Inform sponsor/CRO of the date, time and anticipated duration of the inspection and request sponsor/CRO representative contact information for daily briefings

Meet with appropriate staff to review steps to prepare for the inspection and to set up a timetable for preparation

Follow the template, per department process, to Prepare for a Regulatory Inspection

Assign responsibilities and make sure each individual who will be involved in the inspection understands what is expected




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Who Task

Prior to the inspection, meet with staff who will be involved to review conduct during the inspection

Assign a designee/scribe to document all communications during daily briefings or meetings with inspectors

Review Site Study Regulatory File(s), IRB Correspondence, SOPs, Site Staff Licensures & CVs for completeness

B. Conducting the Inspection

Who Task

Investigator,

Research Manager,


Upon arrival of the Inspector(s), request to be shown Inspectors Badge/Credentials (if possible make a copy of the Badge/Credentials), the Form FDA 482 Notice of Inspection, and have them sign the visitors’ book prior to the beginning of the inspection

Review Template, per department process, of Procedures during a Regulatory Inspection

Review assigned responsibilities and make sure each individual who is involved in the inspection understands what is expected

A staff member should be assigned to act as the “runner” for the FDA auditor—responsibilities will include obtaining requested documents for the auditor, making copies (one for the auditor, one for the site records)

Note: Always ensure any subject-identifying information is redacted prior to providing copies to the inspector

During the inspection, be helpful, professional and firmly respectful when disagreeing with observations not in line with CHNw’s actual practices

During the inspection, be honest, answer directly the question asked and never answer outside your area of expertise or responsibility

During the inspection, provide a daily update to internal stakeholders (e.g., ORA, Legal, CHNw IRB)

At the conclusion of the inspection, schedule a close-out meeting to discuss any deficiencies and/or findings

Request a date of expected receipt of the Establishment Inspection Report (EIR) or Form FDA 483



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Who Task

Develop and implement an agreed upon corrective action plan (as appropriate) in consultation with ORA and CHNw IRB

Document all corrective action plan training and maintain in CHNw’s files

For formal corrective actions, a Corrective and Preventative Actions (CAPA) form should be completed for significant findings

If a Form FDA 483 was issued, the PI and appropriate CHNw manager(s) will collaborate with ORA, Legal, Compliance and CHNw IRB to develop and issue a response to the FDA and Sponsor/CRO within the stipulated amount of time indicated by the FDA



108

VII TEMPLATES



109

Template GA 101-A

Delegation of Authority Template Version No. 1.0 Effective Date: May 1, 2017

PRINCIPAL INVESTIGATOR DELEGATION OF AUTHORITY

Sponsor Name: Investigator Name:

Study Title/Number: Site Number: Page ___ of ___

List the names, signatures, initials and procedure responsibilities for those individuals participating in the conduct of this trial

Name and Title

Listed On

1572? Signature Initials Delegation of Responsibilities (See below)

Involved From

DD-MM-YY

Involved To

DD-MM-YY PI Initials

� YES

� NO

A B C D E F G H I J K L M N O

� YES

� NO


� YES

� NO


� YES

� NO


� YES

� NO


Delegation of Responsibilities Codes A. Obtain Informed Consent B. Inclusion/Exclusion Criteria C. Medical History/Direct Patient Contact D. Data Collection for Study Requirements E. Physical Exam

F. Vital Signs G. Study Drug/Device

Administration/Accountability H. Reviews AEs I. Enters CRF Data J. Photographs (as applicable)

K. Recruits Patients L. Oversees Research Staff/Conduct

of Study M. Responsible for IRB/Regulatory N. Other (list): O. Other (list):

Principal Investigator Signature (Close Out): ___________________________ Date: ________________



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Template GA 101-B

Form FDA 1572 Version No. 1.0 Effective Date: May 1, 2017

To retrieve Form FDA 1572 go to FDA Forms:






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Template GA 101-C

Study Training Form Template Version No. 1.0 Effective Date: May 1, 2017

Protocol Title:

Sponsor Name: Site No:

Protocol No: Site Name & Address:

Investigator’s Name:

Trainee Role in

the study Topic

(Code) Date of

Training

Trainer

Name Signature &

Date Name

Signature &

Date

Topic Code: 1 – ICH-GCP, Schedule Y & regulatory guidelines 5 - Investigator Responsibilities 9 - Laboratory Procedures & related

2 – Inclusion/Exclusion Criteria & Study procedures 6 –CRF filling and completion guidelines 10 - Informed Consent Process & related

3 – Subject Completion / Early Discontinuation Procedures 7– Investigational Product Accountability 11 – Investigator Site Binder Maintenance

4 – SAE/ AE Reporting Timelines/ Procedures 8– Randomization / Blinding Procedures (if any)

12- Others (Specify): _____________

Investigator’s Signature: _________________________________ Date: _____________



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Template GA 102-A

Document Training Compliance Record Template Version No. 1.0 Effective Date: May 1, 2017

Document Training Compliance for

Name of employee

Document Title or SOP Number Review Date Initials

Approval:

Signature Date



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Template GA 102-B

SOP Template Version No. 1.0 Effective Date: May 1, 2017

(New SOP’s need to be reviewed and approved prior to implementation – contact ORA for instructions)

SOP: XX XXX Title: XXX

Version No.: Effective Date: Supersedes Document:

1. Procedure

2. Scope

This SOP defines XXX

3. Responsibility


General administration: See Template XXX

Specific studies: See Template XXX


5. SOP Templates

XX XXX-A:

XX XXX-B:

XX XXX-C:

XX XXX-D:

6. Process Overview

A. XXX

B. XXX

7. Specific Procedures A. Title

Who Task



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B. Title

Who Task

C. Title

Who Task



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Template GA 102-C

Standard Operating Procedure (SOP) Review Version No. 1.0 Effective Date: May 1, 2017

Criteria for SOP Review

1. SOPs must be reviewed every two (2) years as applicable to ensure SOPs are current with

regulations and guidance documents

2. When an SOP is updated, all staff must review the updated SOP

3. Staff must sign the Document Training Compliance Record when SOPs are reviewed (initially or following updates)



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Template GA 103-A (1 of 3 pages)

Orientation Template Version No. 1.0 Effective Date: May 1, 2017

Orientation Template for

Name of employee

Person orienting Date

scheduled Done

Administrative

Overview of site organization Introductions

research site staff administrative staff essential contacts

Communications phone system

Computer systems email address and log-on protocol system security electronic signatures

Ordering supplies Securing equipment Reserving space Accounting

SOPs Introduction to accessing and using the SOPs Schedule for SOP review

Committees IRB IRB policies and procedures

IRB staff contacts

Other committees



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Name of employee


scheduled Done

Review ongoing protocols/studies Conflict of interest disclosure requirements Files and records handling Accessing and accountability of medical records Filing and archiving of study documents Study files/department files Source documentation Research subject visits Scheduling appointments (visits) Preparation for research subjects' visits Conducting study visits Specimen collection and handling Laboratory tests and procedures

phlebotomy procedures requisitions shipping

Equipment Paying subjects Investigational product management

dispensing investigational product returning unused product

Subject recruitment—policies and procedures Soliciting referrals



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Name of employee


scheduled Done

Reviewing charts and records Review and placement of recruitment advertisements Screening potential subjects

incoming (subject initiated) contact outgoing (site initiated) contact

Use and disposition of personal screening information Informed Consent process

informing subjects about a study, including: available resources (of interpreters, advocates, etc.) environment and waiting times (if applicable) documentation of Informed Consent retention and use

Privacy Practices

Signature Date



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Template GA 104-A

Contract Routing Form Version No. 1.0 Effective Date: May 1, 2017 Contact Community Health Network Legal Department for Current Contract Routing Form



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Template GA 105-A

Request for Password for Electronic Medical Records Version No. 1.0 Effective Date: May 1, 2017

Complete DP39 form within Community Health Network INCOMM to gain access to Electronic Medical Records

Link: https://incomm.ecommunity.com/DP39/

https://incomm.ecommunity.com/DP39/



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Template GA 105-B

Offsite Storage Log Template Version No. 1.0 Effective Date: May 1, 2017

Box Number

Protocol # / Short name

Sponsor Description of Contents Offsite Storage Label #

Date placed in storage

Study start date

Study stop date



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Template RA 201-A (page 1 of 4)

Regulatory and Study File Content Template Version No. 1.0 Effective Date: May 1, 2017

A complete Site Study File is maintained at each site and contains information relevant to it and to individual subjects. It should be organized in chronological order with the most recent entries in the front.

Regulatory File Content Template

For Protocol

Section Contents Version Date/Comment

Protocol and Related Reports

Confidentiality Agreement

Protocol(s) – all versions, most recent first (attach copies of the IRB approval letters for each version)

Amendment 1 (attach copies of the IRB approval letters for each version)



Investigator Brochure or Report of Prior Investigations

Sponsor Safety Reports (attach documentation of IRB submission)

Decoding procedures for blinded studies

SAE Reports: initial reports and follow up, (attach documentation of IRB submission)

Request(s) for Waiver of Protocol (attach documentation of IRB submission) and documentation of sponsor's reply

Report(s) of Protocol Violation(s) (attach documentation of IRB submission) and any follow up

Annual Reports

Final clinical study report

FDA inspection report



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IRB* *Note: Create similar file for any other applicable regulatory authority, e.g., Radiation Safety Committee, Institutional Biosafety Committee

Copy of initial IRB application (with copies of submitted material)

Documentation of IRB approval of the study and accompanying material

Consent form with documentation of IRB approval

Amended consent form with documentation of IRB approval

Amended consent form with documentation of IRB approval

All recruitment materials with documentation of IRB approval

Additional recruitment materials with documentation of IRB approval

IRB approval of Amendment




Copies of periodic reports with documentation of IRB continuing approval

Copies of requests for protocol waiver with documentation of IRB approval

Copies of reports of protocol deviations with documentation of submission to the IRB (i.e., IRB acknowledgement form/letter)

Final Report

Documentation of site-IRB communications (copies of letters, email, faxes, phone log, etc.)

IRB member roster(s) and credentials (members at initial and each periodic review)

Regulatory File Content Template

For Protocol

Section Contents 1572/Investigator Agreement(s)

Site Documentation

Study personnel

CVs of Investigator, sub investigators, other key personnel Licenses/Training Certificates Financial disclosure information (as required by sponsor/1572) Personnel Delegation of Authority Log

Facilities

Clinical Laboratory Certifications (CAP, CLIA) (initial and periodic) Laboratory normal ranges Documentation of validation/calibration for equipment used to generate data



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Regulatory File Contents

Investigational product and study-related supplies

Equipment and supplies (receipt, calibration logs) Documentation of receipt of investigational product(s) and any control product Documentation of dispensing of investigational product(s) and any control product Product release forms Shipping records, packing slips Investigational product accountability forms Product disposition record (return, destruction)

Data monitoring and verification

Site visit/monitoring reports Monitoring logs Follow-up correspondence/communication documentation Data queries Sponsor audit documents Study closeout information

Financial

Preliminary and ongoing budget estimates Insurance (indemnification) statement Original signed clinical study contract Subject compensation documentation

Study File Content Template

For Protocol

Section Contents

Study Logs and Records

Subject Screening Log

Subject identification code list

Subject enrollment log

Record of retained tissue/fluid samples

Training log

Other:

Data Management

Copy of Case Report Form template (paper or electronic)

Data Handling Guidelines

Subject Records Original Case Report Forms

Source documents



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Source Documents* Electronic records

Signed Consent Forms

Inpatient and outpatient medical records

Progress notes

Consults

Nursing notes

Pathology reports

Radiology reports

Medicine/radiation administration records

Surgical reports

Laboratory reports

Admission forms

Flow sheets that are signed and dated

Protocol or study road maps

Participant diaries/calendars

Appointment books Deviation reports

* A source document is any document, form or record in which specific participants' data is first recorded ICH guidelines define source documents as original documents, data and records.

FDA [21 CFR 31262 (b)] requires that the investigator "prepare and maintain accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated with the investigational drug or employed as a control in the investigation."



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Template RA 201-B (1 of 3 pages)

Table of ICH Essential Documents Version No. 1.0 Effective Date: May 1, 2017

TABLE OF ICH ESSENTIAL DOCUMENTS

E6 Ref Before the trial starts

Spon

sor

Site

IRB

8.2.1 Investigator Brochure 8.2.2 Signed protocol, amendments, if any, and sample Case Report Form

8.2.3

Information given to trial subject -Informed Consent Form (including all applicable translations) -Other written information -Recruitment advertisements (if used)

8.2.4 Financial aspects of the trial 8.2.5 Insurance statement (where required) 8.2.6 Signed agreement between involved parties

8.2.7

Dated, documented approval/favorable opinion of IRB/EC of the following: -Protocol and amendments -CRF (if applicable) -Informed Consent Form(s) -Other written information to be provided to the subject(s) -Recruitment advertisement -Subject compensation (if any) -Any other documents given approval/favorable opinion

8.2.8 IRB/EC composition 8.2.9 Regulatory approval/notifications of protocol (if required)

8.2.10 CVs and/or other relevant documents evidencing qualifications of Investigator(s) and sub investigator(s)

8.2.11 Normal value(s)/range(s) for procedure(s) and test(s) included in the protocol

8.2.12

Medical/laboratory/technical procedures/tests -Certification -Accreditation -Established quality control and/or external quality assessment -Other validation

8.2.13 Sample labeling for investigational product container(s)

8.2.14 Instructions for handling of product(s) and other trial-related materials (if not included in protocol or IB)

8.2.15 Shipping records for product(s) and trial-related materials 8.2.16 Certificate(s) of analysis of product(s) shipped 8.2.17 Decoding procedures for blinded trials 8.2.18 Master randomization list

8.2.19 Pretrial monitoring report

8.2.20 Trial initiation monitoring report



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E6 Ref Documents required during the clinical trial

Spon

sor

Site

IRB

8.3.1 Investigator Brochure updates

8.3.2

Any revision to: - Protocol/amendment(s) and CRF - Informed Consent Form - Any other written information provided to subjects - Advertisement for subject recruitment (if used)

8.3.3

Dated, documented approval of IRB/EC of the following: Protocol amendment(s) Revision(s) to:

- Informed Consent Form - Any other written information to be provided to the subject - Advertisement for subject recruitment - Any other documents given approval/favorable opinion

Continuing review of trial

8.3.4 Regulatory approvals/notifications (if needed) for protocol amendment(s) and other documents

8.3.5 CVs for new investigator(s) and/or sub investigator(s)

8.3.6 Updates to normal value(s)/range(s) for medical/laboratory/ technical procedure(s)/test(s) included in the protocol

8.3.7

Updates of validation/certification for facilities where protocol mandated procedures and tests are performed Certification Accreditation Established quality control and/or external quality assessment Other validation (where required)

8.3.8 Documentation of product and related material shipment 8.3.9 Certificate(s) of analysis for new batches of product 8.3.10 Monitoring visit reports

8.3.11

Relevant communications other than site visits - Letters - Meeting notes - Notes of telephone calls

8.3.12 Signed Informed Consent Forms 8.3.13 Source documents

8.3.14 Signed, dated and completed Case Report Forms (CRF) copy

orig

8.3.15 Documentation of CRF corrections copy

orig

8.3.16 Notification by Investigator to sponsor of serious AEs and related reports

8.3.17 Notification by sponsor/investigator to regulatory authorities and IRB(s) of unexpected serious AEs



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E6 Ref Documents required during the clinical trial

Spon

sor

Site

IRB

8.3.18 Notification by sponsor to Investigators of safety information 8.3.19 Sponsor interim/annual reports to authorities Investigator interim/annual reports to IRB 8.3.20 Subject Screening Log 8.3.21 Subject identification code list 8.3.22 Subject Enrollment Log 8.3.23 Investigational products accountability at the site 8.3.24 Signature sheet 8.3.25 Record of retained body fluids/ tissue samples (if any) After Completion or Termination of the Trial 8.4.1 Investigational product(s) accountability at site 8.4.2 Documentation of investigational product destruction 8.4.3 Completed subject identification code list 8.4.4 Audit certificate 8.4.5 Final trial closeout monitoring report 8.4.6 Treatment allocation and decoding documentation 8.4.7 Final report by Investigator to IRB/EC, where applicable, to the regulatory authorities Final report by Investigator to the regulatory authorities 8.4.8 Clinical Study Report



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Template RA 202-A

Submission and Reporting Requirements Version No. 1.0 Effective Date: May 1, 2017

Submission/Report To Timeframe

IRB

Spo

nsor

New Study Prior to initiation of protocol procedures

Conflict of Interest Per IRB and funding source/sponsor

Annual Report Per protocol

Periodic Report As stipulated in IRB approval, but at least annually

SAE Report – phoned As determined by the sponsor

SAE Report – written As determined by the sponsor

IND Safety Report

AE Periodic report and CRF or Annual Report (per sponsor/IRB)

IRB termination of study ASAP but not later than 5 calendar days after determination

Sponsor termination of study due to risk to subjects Implement immediately, notify IRB immediately thereafter

Protocol amendment see "Amendment Submission Requirements"

New Investigator Prior to involvement in study activities

Protocol deviation

Request for protocol waiver Prior to initiating waiver



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Template RA 203-A

Reportable AE Decision Algorithm Version No. 1.0 Effective Date: May 1, 2017

(Contact IRB and use IRB online software for submission Link: https://irisecommunitycom/)

• A Serious Adverse Event- is any adverse event that results in:

o Death o Life threatening (places the subject at immediate risk of death from the event as is occurred) o Results in inpatient hospitalization or the prolongation of an existing hospitalization o Results in a persistent or significant disability/incapacity o Results in a congenital anomaly/birth defect o Or based upon appropriate medical judgment, may jeopardize the subject’s health and may

require medical or surgical intervention to prevent one of the other outcomes listed in this definition



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Template PM 301-A (1 of 5 pages)

Protocol Template Version No. 1.0 Effective Date: May 1, 2017 Before writing protocol, contact ORA and IRB for guidance

PROTOCOL TITLE:

Include the full protocol title

PRINCIPAL INVESTIGATOR:

Name Department Telephone Number Email Address

VERSION DATE:

Include the version date. This is the date this protocol version was finalized.

10. Purpose of the Study:

1. Describe the purpose, specific aims, or objectives State the hypotheses to be tested or the research questions that will guide the study

20. Background / Literature Review / Rationale for the study:

1. Briefly:

a. Describe the relevant current context of the study and gaps in current knowledge

b. Provide the scientific or scholarly background for, rationale for, and significance of the research based on the existing literature and how will it add to existing knowledge

c. Add relevant references at the end of the protocol (not at the end of this section)

30. Inclusion and exclusion criteria:

1. Briefly describe the total number of participants and the criteria (such as age, gender, language, etc.) that define who will be included or excluded in your study sample

2. Indicate specifically whether you will include or exclude any special populations: (You may not include members of these populations as participants in your research unless you indicate this in your inclusion criteria)

a. Adults unable to consent

b. Individuals who are not yet adults (minors): infants, children, teenagers

c. Pregnant women (where the activities of the research may affect the pregnancy or the fetus)

d. Prisoners or other detained individuals

40. Procedures Involved:

1. Describe the setting of the study, including all locations where research procedures will be performed

2. Describe the study design including the rationale

3. Provide a description of all research procedures and activities

4. Include when they are performed, and any procedures being used to monitor participants for safety or minimize risks



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5. Describe the study timelines including: the duration of an individual subject’s participation in the study and the overall anticipated duration of the project

6. Describe the actual source records or measures that will be used to collect data about participants (All surveys, interview scripts, and data collection forms will be attached elsewhere in the application. Do not add other documents to the protocol. Describe what data will be collected and how it will be collected at all measurement/data collection time-points.

7. If doing online research, include the URL where the data collection will occur

60. Incomplete Disclosure or Deception:

If the study will use incomplete disclosure or deception, please provide a rationale. Please also provide a description of the debriefing process that will be used to make participants aware of the deception and their right to withdraw any record of their participation. Include here if re-consent will occur.

70. Recruitment:

1. Describe when, where, and how potential participants will be recruited

2. Describe the types of strategies and materials that will be used to recruit participants

80. Consent Process

1. If obtaining consent using a written consent document, describe:

a. Where the consent process will take place

b. Any process to ensure ongoing consent if appropriate. This may include re-consent for longitudinal studies or if there are multiple stages to a project over time

c. The details of the consent process including:

i. The role of the individuals listed in the application as being involved in the consent process

ii. The amount of time that will be devoted to the consent discussion

iii. Steps that will be taken to minimize the possibility of coercion or undue influence

iv. Steps that will be taken to ensure the participants’ understanding

2. If there are non-English speaking participants who will be enrolled, describe the process to ensure that the oral and written information provided to those participants will be in the language with which they are most comfortable speaking or writing Indicate the language that will be used by those obtaining consent. If you will be using a translator during recruitment, consent, data collection, or data analysis specify how you will identify an appropriate translator and what the provisions will be for protecting the confidentiality of participants.

3. Participants who are not yet adults (infants, children, teenagers):

a. Describe whether parental permission will be obtained from:

i. Both parents unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child

ii. One parent even if the other parent is alive, known, competent, reasonably available, and shares legal responsibility for the care and custody of the child

iii. Individuals other than parents, and if so, who will be allowed to provide permission. Describe the process used to determine these individuals’ authority to consent to each child’s participation.

b. Describe the process for assent of the participants Indicate whether:



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i. Assent will be required of all, some, or none of the participants If some, indicated, which participants will be required to assent and which will not

ii. If assent will not be obtained from some or all participants, an explanation of why not

iii. Describe whether assent of the participants will be documented and the process to document assent. The IRB allows the person obtaining assent to document assent on the consent document and does not routinely require assent documents and does not routinely require participants to sign assent documents.

4. Cognitively Impaired Adults:

Describe the process to determine whether an individual is capable of consent 5. Adults Unable to Consent:

a. List the individuals from whom permission will be obtained in order of priority (E.g., durable power of attorney for health care, court appointed guardian for health care decisions, spouse, and adult child)

100. Risks to Participants:

1. List the reasonably foreseeable risks, discomforts, hazards, or inconveniences related the participants’ participation in the research

2. Describe the probability, magnitude, duration, and reversibility of the risks

3. Consider physical, psychological, social, legal, and economic risks as well as community or group harms

4. If applicable, describe risks to others who are not participants

5. Withdrawal of Participants:

a. Describe anticipated circumstances under which participants will be withdrawn from the research without their consent

b. Describe procedures that will be followed when participants withdraw from the research, including withdrawal from some but not procedures with continued data collection

c. Describe the use of data after withdrawal

110. Potential Benefits to Participants:

Note: participation in the research itself and compensation from participating in the research are not benefits

1. Describe the potential benefits that individual participants may experience from taking part in the research

2. Describe also the probability, magnitude, and duration of the potential benefits

3. Indicate if there is no direct benefit to participants Do not include benefits to society or others

120. Financial Compensation:

1. Describe any financial compensation that will be provided to participants Include how much money or what gifts will be provided and for what activities

2. Include whether compensation will be prorated if there are multiple research activities or if a participant withdraws from the study before finishing

3. Describe any costs that participants may be responsible for because of participation in the research

130. Provisions to Protect the Privacy Interests of Participants:

1. Describe the steps that will be taken to protect participants’ privacy interests throughout the research activities



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2. Indicate who on the research team and how the research team is permitted to access any sources of information about the participants

140. Confidentiality and Data Management:

1. Describe how data (and if applicable, biological specimens) will be handled study-wide including:

a. What information will be included as data (or associated with the specimens)? “Data” includes all information collected in the conduct of the research, such as but not limited to: consents, surveys, interview notes, audio or video recordings, photographs, notes of observations, field notes, etc.

b. Where and how will data (or specimens) be stored? How will data be transported from the point of collection to where they will be stored? Note: electronic storage of data in both domestic and international research must be secured using adequate protections

c. How long will the data or specimens be stored? (Note: IRB policy is 7 years after the completion of the study However, there are circumstances when other time frames may apply)

d. Who will have access to the stored data or specimens?

e. Who is responsible for receipt or transmission of the data or specimens?

2. Describe the steps that will be taken secure the data (e.g., training, authorization of access, password protection, encryption, physical controls, certificates of confidentiality, and separation of identifiers and data) during storage, use, and transmission

3. Describe any procedures that will be used for quality control of collected data If conducting online research, specify if you will be using any attention check measures. If yes, you need to indicate what you will be doing and what happens if a participant fails the attention checks

4. Describe the data analysis plan, including any statistical procedures is applicable

150. Data Monitoring Plan to Ensure the Safety of Participants:

1. Describe the plan to periodically evaluate the information collected regarding risks or harms to determine whether participants remain safe. For example, if you are collecting depression or suicidality data, what is your plan for monitoring severity? Note: the plan might include establishing a data monitoring committee and a plan for reporting their findings to the IRB and the sponsor It also could include referral to an appropriate resource Include the following:

a. What information / data are reviewed, including safety data, untoward events, and efficacy data

b. How the safety information will be collected (e.g., with case report forms, at study visits, by telephone calls with participants)

c. The frequency of data collection, including when safety data collection starts

d. Who will review the data

e. The frequency or periodicity of review of cumulative data

f. The statistical tests for analyzing the safety data to determine whether harm is occurring

g. Describe any conditions where the research team may intervene and what the plan is for intervening (For example, if a participant identifies harm to self or others)

h. Describe any conditions that might trigger an immediate suspension of the research

160. Data and if applicable, Specimen Banking:

1. If data or specimens will be banked for future use, describe where the data or specimens will be stored, how long they will be stored, how the data or specimens will be accessed, and who will have access to the specimens



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2. If storing data electronically, include a plan for managing the long term storage of the data if appropriate

3. If storing data in a data repository outside of CHNw, include the agreement with the entity where the data will be stored

4. List the data to be stored or, in the case of specimens what information will be associated with each specimen

5. Describe the procedures to release data or specimens, including: the process to request a release, approvals required for release, who can obtain data or specimens, and the data to be provided with specimens

170. Attachments

1. Schematic of Study Design

2. Study Schedule

3. Consent Document

4. Case Report Form



136

Template PM 301-B (1 of 4 pages)

Chart Review Protocol Template Version No. 1.0 Effective Date: May 1, 2017

CHART REVIEW PROTOCOL

Principal Investigator:

Address:

IRB Project Title:

Site(s) where study will be performed:

Protocol Version Date:

1.0 Introduction - Background and Rationale (include references)

2.0 Hypothesis/Key Questions (the hypothesis being evaluated; the key questions being asked in the research)

3.0 Objectives (Primary endpoints of study, listed and numbered individually)

4.0 Selection of Patients 4.1 Inclusion Criteria: 4.2 Exclusion Criteria: 4.3 Age Range:

Note: With regard to research involving pregnant women, prisoners, or minors, the IRB must review the study in accordance with Subparts B, C or D of the federal regulations. If it can be presumed that the subjects are not pregnant, incarcerated, or under the age of 18 during the conduct of the chart review, the Subparts do not apply. If, however, during the course of the chart review, the investigator becomes aware that the subjects meet one or more of these conditions, the PI must either exclude such subjects from the dataset, or the IRB must promptly re-review the proposal in accordance with the requirements of Subparts B, C or D.

5.0 Indicate if this is a retrospective and/or prospective chart review

5.1 _____ Retrospective Chart Review (Retrospective means the data is already in existence when the project is submitted to the IRB for initial review

5.2 _____ Prospective Chart Review (Prospective means the data is not in existence when the project is submitted to the IRB for initial review)

5.3 Provide the date range of the chart review (if this is a retrospective chart review, the end date must come before the IRB submission date): mm/dd/yyyy to mm/dd/yyyy

6.0 Study Methods 6.1 Source (location) of records to be reviewed: 6.2 Describe how the charts to be reviewed will be identified:



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6.3 Describe who will identify charts to be reviewed:

7.0 Confidentiality of data 7.1 Describe how data (both paper and electronic) will be stored to safe-guard confidentiality (e.g. in a

locked cabinet, password protected computer): 7.2 Specify who will have access to harvested patient data: 7.3 Clarify how long collected patient data will be stored and how it will be destroyed when no longer

needed:

8.0 Consent: (Describe the type of consent to be obtained and justification for the choice [written, waiver, or verbal].For additional information, please see the Guidance and Instructions at the end of the protocol

9.0 Risks and Benefits: (modify as needed) 9.1 Risks: A confidentiality breach is a risk associated with chart review research 9.2 Benefits: The subject’s whose charts are reviewed are not likely to receive any benefit from the

proposed research; however, society and investigators will benefit from the knowledge gained

10.0 Statistical Considerations 10.1 Proposed sample size (number of records to be reviewed) 10.2 Proposed time period to be evaluated: 10.3 Specify how data will be analyzed and by whom:

11.0 Appendices: The following appendices must be attached to the protocol 11.1 Appendix A: Data Collection Form (This form should list the data elements that will be collected

from the medical record It should not contain any direct or indirect identifiers except for a unique subject code)

11.2 Appendix B: Coded Identifier List (This form should serve as the link between the unique subject code and any identifiers you will need to conduct this chart review study [e.g., name , medical record number, date of birth, address, telephone number, social security number])

APPENDIX A: DATA COLLECTION FORM

1. Unique Subject Code 2. List all elements to be collected during the chart review

APPENDIX B: CODED IDENTIFIER LIST

1. Unique Subject Code 2. List all identifiers to be collected or used in this study (e.g., name , medical record number, date of

birth, address, telephone number, social security number)



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Chart Review Guidance and Instructions:

1. What is the difference between a retrospective and prospective chart review?

A Retrospective Chart Review evaluates patient data that is existing at the time the project is submitted to the IRB for initial review.

A Prospective Chart Review evaluates patient data that does not yet exist at the time the project is submitted to the IRB for initial review.

2. When completing the eIRB, should I request exempt, expedited or full board review?

Exempt: Exempt review should only be requested if the information to be collected already exists and is publicly available or data will be recorded in such a manner that subjects cannot be identified, either directly or indirectly (Exempt Category #4). As data must exist at the time the project is submitted to the IRB, this limits exempt review to retrospective chart reviews. In the majority of cases, chart reviews do not qualify for exempt status because most investigators need to retain identifiers at least through the data collection process. Even if an investigator plans to eventually discard all identifiers once data collection is complete, this is not sufficient for the project to qualify for exempt review.

Expedited: Expedited review can be granted for retrospective and prospective chart reviews under expedited category #5 which is defined as: Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis). Most chart reviews fall into this category.

Full Board: While rare, full board review may be required for both retrospective and prospective chart reviews. Some circumstances under which this occurs is if the investigator plans to collect sensitive data, or if the chart review results in a change in care for the patients whose data is being collected.

3. What type of consent should I apply for?

Waiver of Consent: Waiver of consent is the most frequently requested type of consent for both retrospective and prospective chart reviews. In order for the IRB to approve a waiver of consent, the IRB must be satisfied that the following criteria are met:

(1) The research involves no more than minimal risk to the subjects;

(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects;

(3) The research could not practicably be carried out without the waiver or alteration; and

(4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation

Waiver of Documentation of Consent: This type of consent is not usually requested for a chart review. Under a waiver of documentation of consent, an investigator must still obtain consent from the subject.



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Template PM 301-B (4 of 4 pages) However, the investigator does not need to obtain a signed consent form from subjects if the IRB agrees that the following criteria are met:

(1) That the only record linking the subject and the research would be the consent document and the

principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or

(2) That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

Written Consent: In certain instances the IRB may determine that written consent is required if the investigator is unable to justify why it’s impracticable to conduct the research without a waiver. This is more often the case for prospective chart review studies, but sometimes occurs in retrospective chart review studies. For example, an investigator wishes to review the charts of all of his patients he refers onward for a colonoscopy to collect outcome measures. The IRB may determine that the investigator should obtain written consent since he will have the chance to obtain consent from the patients during their clinic visit with him.



140


Study Review and Assessment Template Version No. 1.0 Effective Date: May 1, 2017

Study Review and Assessment Template

Protocol Title

Yes No 1. General assessment of study acceptability

Is there enough information regarding the study requirements to make an assessment?

If no, what additional material, information is required?

Does this site have experience with this study indication?

Will the study require subcontractors/outside vendors?

Does the study require any staff members? Are there any unique protocol procedures/requirements that will require additional training? Is the objective clear and will the study design generate sufficient data to meet the objective? Will the IRB have concerns with any aspects of this protocol? Is this study desirable to do from a scientific standpoint? Comments

2. Per subject evaluations

Can the study visit schedule be accommodated? Are there any conflicting or competing studies? Can all of the evaluations be performed readily within this facility? Will transportation to study procedure location(s) be a barrier? Will additional staffing be required?

Comments

3. Recruitment and retention

Is the number of subjects to be enrolled realistic? Is the time frame for subject enrollment acceptable? Is the anticipated completion rate for subjects reasonable? Do you anticipate a higher-than-expected rate of non-compliance? Is this a study patients will be interested in? Is there an anticipated issue with study visit windows and patient schedules?

Is there concern over conflict with standard of care practices (does the protocol deviate from what patients expect)?

Is there a possibility of over-enrolling?

Comments



141



Protocol Title

Yes No 4. Changes to study design/procedures

Are amendments to the study design likely? If yes, what additional resources, equipment or staff will be needed?

Comments

5. Data Management

Does this site have the resources and personnel to handle data collection, recording and data entry?

Will special training, resources or technology be required? Are the data entry requirements reasonable and attainable for this site?

Will the sponsor monitor on a Risk-Based Monitoring approach? If so, what is the expected relationship/communication with data management? Comment:

Is the time frame for data entry of e-CRFs reasonable? Note number of days available for data entry:

Is expected query turnaround time reasonable? Comment on expected turnaround time? Does the site have prior experience with the IRT/EDC/CTMS being used? Comments

6. Investigational Product

Is the investigational product dispensing/accountability complicated? Does the study require IVRS/IWRS? Does the investigational product require special handling or storage?

Does the site have storage space and/or equipment to accommodate the investigational product?

Will the Sponsor/CRO supply the special equipment and monitoring devices required for the investigational product?

Does the site require special staff to monitor, reconcile and/or dispense investigational product?

Comments

7. Risk/Benefit

Are any risks associated with study procedures or product(s) balanced by potential benefit? Will our subject population benefit directly from the study? Will the study conflict with the site’s standard of care?

Comments



142



Protocol Title

Yes No 8. Budget

Is the proposed budget offered adequate? Will the Sponsor/CRO negotiate budgetary issues? Is there potential for unanticipated expenses?

Will the Sponsor/CRO provide source document? If no, will they reimburse for the site to create?

Is the Sponsor/CRO willing to amend budget if amendments are made to the study design or protocol that require additional procedures or timelines for the site?

Will the Sponsor/CRO reimburse the site for pre-screening activities and screen-fails? Will the Sponsor/CRO reimburse the site for subcontractors/outside vendors if required? Will the Sponsor/CRO reimburse the site for outside medical record requests? Will the Sponsor/CRO reimburse for SAEs? Comments

Do you recommend that the study be conducted at this site? Comments

Signature of person completing form Date

Principal Investigator Signature Date



143


Study Effort and Cost Considerations Template Version No. 1.0 Effective Date: May 1, 2017

Protocol Title

Per Subject Costs1 In proposed budget

Medical history

AE assessment

Concomitant medications

Medical record review

Vital signs Physical exam

Full Physical

Limited Physical Lab tests

Phlebotomy

Urinalysis

Drug Tests

Other: Diagnostic tests

X-rays

Electrocardiogram

Ultrasound

Spirometry

Oxygen Saturation Procedures

Biopsy

Culture Assessments

Questionnaires (i.e., quality of life)

Mental status tools

Efficacy evaluations

Counseling (i.e., diet, genetic, etc.) Investigational product/Device accountability Pharmacy (Consult Research Pharmacist)

Return unused/damaged investigational product

Dispense investigational product

Reconcile investigational product



144


Protocol Title

Per subject costs1 In proposed budget

Visit preparation

Requisition medical record review

Requisition and set-up procedures, tests

Unscheduled visits

Early Termination visits Process laboratory samples Store/ship samples and tissue samples Case Report Form completion Other per/subject costs

Subject travel reimbursement

Stipends

Parking

Per-person supplies (i.e., thermometers, urine collection)

Use of interpreter, subject advocate, etc.

Medical record request

Other Study Efforts2 In proposed budget

Recruitment

Meeting with referral sources

Creating pre-screening questionnaire

Initial screening

Screen-failure documentation

Creating recruitment material(s)

Submitting recruitment material to IRB/ Sponsor/CRO

Records review

Preparing/amending recruitment plan

Subjects dropping out or terminated for non-compliance

Documenting

Replacing dropouts



145


Protocol Title

In proposed budget

Amendments

Reviewing and assessing the amendment

Revising the consent form if necessary

Revising the pre-screening questionnaire if necessary

Submitting the amendment and associated materials to the IRB

Clarify information and communicating with the IRB and Sponsor/CRO

Following up with the IRB

Re-consenting subjects

Serious Adverse Events

Initial investigation of SAE report

Initial report to Sponsor/CRO, IRB, others

Medical record request from treating facility

Documenting treatment and subsequent data

Follow-up reports to Sponsor/CRO, IRB, others

Communicating with Sponsor/CRO, IRB, others

Data Management: Collection and Recording

Complexity of CRFs (or other medium for data collection)

Complexity and detail of AE/SAE documentation

Amount and detail of data to be gathered and recorded at each visit

Diary review/transcription

AE review

Concomitant medication(s) review

Medical history review

Data transmission into collection source (i.e., electronic diaries, etc.)

Data entry into Metadata system(s)

Investigational Product

Investigational product dispensing/accountability

Special handling and/or storage



146


Protocol Title

Costs associated with most studies3 In proposed budget

Start-Up activities

Investigators’ meeting

Developing/revising the consent form

IRB submission(s)

Submissions to other committees (Biosafety, RAC, etc.)

Site initiation visit

Design of internal process and forms (source documents)

Protocol training (research staff)

EDC/IVRS/IWRS training (research staff)

In-service (non-research staff)

Setting up accounts

Installing and initiating IT systems

Setting up services with other departments

Setting up services with subcontractors/ outside vendors Ongoing activities

Interim monitoring visits

Preparation

Visit

Follow-up

Subject management

Follow-up phone calls

Subject scheduling and rescheduling

Locating subjects lost to follow-up

Communicating and reporting to primary physician

Data management

Data entry

Resolution of data queries

Troubleshooting data management issues

Accounting and financial management

Subject payments



147


Protocol Title

Costs associated with most studies3 In proposed budget

Coordinating with other departments

Tracking missing records and reports

General shipping

Services and supplies

Shipping supplies

Postage

Scanning documents

Fax use

Long-distance phone calls

Copying

Stationery

Lab supplies

Dry ice

Footnotes:

1. All items listed in these categories should be associated with a specific subject visit and should be itemized in the protocol.

2. These activities are ongoing and the effort/cost may be significant. Each protocol must be assessed carefully to anticipate the effort that may go into these activities.

3. Although the effort may vary from study to study, these activities are generally associated with the conduct of any study.



148

Template PM 302-C

Salary Worksheet Template Version No. 1.0 Effective Date: May 1, 2017

Protocol Title

Activity Est Time # minutes

Frequency Number of subjects

Total time required

Recruitment

Pre-screening

Screening

Consent process

Per-visit activities

Vital signs

Diagnostic tests

Lab processing

Interview for medical history and concomitant medications

AE review/follow up

Prep, assist/perform procedures

IVRS/IWRS/IRS confirmation

Investigational product dispensing and accountability

Instructing, training subject and scheduling visit(s)

Counseling subject

Data transmission into collection system

Post-procedure(s) observation

Faxing or scanning documents for remote monitoring activities

CRF completion

EDC entry and query resolution

Monitor visits and CRF clarifications

SAE management, documenting, reporting

IRB submissions and correspondence

Sponsor/CRO communications

Other

TOTAL

Hourly rate

Estimated number of hours

Total base salary

% fringe benefits

Total cost employee/project



149

Template PM 302-D (1 of 2 pages)

Per Subject Cost Worksheet Template Version No. 1.0 Effective Date: May 1, 2017

Protocol

Item Screen Visit ___ Visit ___ Visit ___ Visit ___ Visit ___ Other/ Misc. Termination Visit Total

Procedure/Tests/Labs

X-rays

Electrocardiogram

Ultrasound

Spirometry

Safety panel labs

Urinalysis

Drug tests

Biopsy

Oxygen Saturation

Culture

Physical exam

Medical history

Medication review

Inclusion/Exclusion Criteria review

Vital signs

AE/SAE review

Salaries

PI

Sub investigator(s)

Study nurse

Coordinator

Research Pharmacist

Data manager

Lab technician

Secretary

Security

Data Manager

Other



150

Template PM 302-D (2 of 2 pages)

Per Subject Cost Worksheet Template Version No. 1.0 Effective Date: May 1, 2017

Fees

Pharmacy

Lab

Subcontractors/ outside vendors

Other

Recruitment

Subject payments

Travel reimbursement

Supplies

Data storing and archiving

Total cost per subject

Signature Date



151

Template PM 302-E

Study Budget Worksheet Template Version No. 1.0 Effective Date: May 1, 2017

Protocol Title

Direct Expenses Cost per Subject # of Subjects

see Subject Cost Worksheet

Enrolled Subjects x =

Screened x =

Screen failed X =

Unscheduled visits x =

Early termination visits X = Total per subject direct expense

2 Other expenses

New equipment

IRB fee

Other Total other direct expense TOTAL DIRECT COSTS

3 Indirect expenses

Direct Costs % Overhead

x = TOTAL COST TO CONDUCT THE STUDY



152

Template PM 302-F

Pre-Study Site Visit Agenda Template Version No. 1.0 Effective Date: May 1, 2017

Protocol

Date Location

Time Duration Topic Participants



153

Template PM 302-G (1 of 2 pages)

Pre-Study Site Visit Preparation Template Version No. 1.0 Effective Date: May 1, 2017

Protocol Title

Prior to the visit Confirmed

Get potential visit dates and times 1 2 3 4 5

Name of staff

Notify staff expected to attend

Determine the date

Confirm their attendance

1 2 3 4 5

Schedule the visit with the Sponsor/CRO

Request Pre-Study Visit Agenda from Sponsor/CRO

Put together the Pre-Study Visit Agenda

Send to the Sponsor/CRO representative and confirm the meeting date and time Provide directions to the investigative site

Send the agenda and a copy of the protocol and CRFs to each staff member who will be involved in the site visit Confirm, once again, that they will be available

Prepare information on:

Dates of regulatory meetings, such as the IRB, for the next three to six months

1.

2.

3.

4.

Names of key contacts, telephone numbers and e-mail addresses for individuals at the site involved in contract review and signoff

1.

2.

3.

4.

Names and qualifications of:

Investigator(s), Sub-investigators: training and experience to conduct the study

1. 2. 3.

Key staff (specify any certifications) 1. 2.



154

Template PM 302-G (2 of 2 pages)

Confirmed

Other personnel who will participate in the study

1. 2. 3. 4.

Laboratory capacity to meet the needs of the protocol

The number of potential study participants

Proposed recruitment plan, including primary and secondary resources

Supporting documentation (list as applicable) for:

Current organizational chart and proposed management of the study

List of generic clinical trials (overall and completed recently)

Copies of published papers by investigators relevant to study

Copies of current medical and nursing licenses, certifications

Procedures to monitor, calibrate and document the maintenance of equipment

Procedures for power outages and investigational product management

Laboratory certification

CLIA Waiver (if applicable)

Temperature logs

Notify staff the Sponsor/CRO will be visiting the facility (and advise staff of the approximate times) and the facility areas expected to be visited, for example:

Reception and waiting room area Exam rooms and treatment rooms (alternate areas if subjects are scheduled) Laboratory area Any special testing areas (alternate areas if subjects are scheduled) Pharmacy; satellite pharmacy, if appropriate Investigational product storage area CRF/subject file storage area



155


Site Initiation Visit Preparation Template Version No. 1.0 Effective Date: May 1, 2017

Protocol Title

If it is decided that the study will be conducted

Execute the trial agreement/contract

Finalize the budget

Upon receipt of the final protocol, prepare the:

Site-specific consent form

Recruitment plan and initial material

Submissions for the IRB and other committees

Source document study forms and binders

Get potential visit dates and times

1 2 3

4

Notify staff expected to attend Name

Principal Investigator*

Sub investigator(s)

Research Manager

Research Coordinator(s)*

Data Manager(s)*

Research Pharmacist (Monitor will want to visit pharmacy)

Research Assistant

Lab Technician

Regulatory Specialist

Quality Assurance

Determine the date

Confirm their attendance

Attendance (for a portion of the visit, at least) is mandatory

1 2 3 4

5

6

7

8

9

10 Schedule the visit with the Sponsor/CRO

Put together and/or request the Site Initiation Visit Agenda

Send to the Sponsor/CRO representative and confirm the meeting date and time; provide directions to the investigative site

Send the agenda and a copy of the protocol and CRFs to each staff member who will be involved in the site visit Confirm, once again, that they will be available



156


Assemble documents to be provided to Monitor:

Signed Protocol Signature Page(s)

Signed Investigational Brochure Page(s)

Signed Investigator Contract (if applicable)

CVs of all Investigators, Sub investigators and study staff

Licenses of all Investigators, Sub investigators and study staff

Documentation of presence or absence of COI

Financial disclosure(s) for all study staff

Written IRB Approval (if available)

IRB Membership Roster/List

Approved Informed Consent Form (If available)

Other Regulatory Approvals (if available)

Other Contracts (if available)

Laboratory Licensure (if needed)


Normal Values (if needed)

Temperature logs

Equipment calibration documents



157

Template PM 303-B

Site Initiation Visit Agenda Template Version No. 1.0 Effective Date: May 1, 2017

Initiation Visit Agenda

Protocol

Date Location

Time Duration Topic Participants



158

Template PM 303-C (1 of 3 pages)

Site Initiation Visit Management Template Version No. 1.0 Effective Date: May 1, 2017

Protocol Title

Participants-Sponsor/CRO

Monitor(s)

Name Name

Participants-Investigative Staff

Principal investigator

Sub-investigator(s) Name Name

Key staff/contacts Name Name

Name Name

Other Participants

Title/Function Name

Title/Function Name

Documents to be provided to Monitor Materials to be provided by Sponsor/CRO

Signed Protocol signature page(s)

Signed Investigator Brochure signature page(s)

Signed Investigator Contract

CVs of Investigator, Sub investigators & study staff

Documentation of presence or absence of COI

Financial disclosure for all study staff

Written IRB Approval (if available)

IRB Membership Roster/List

Approved Informed Consent Form (If available)

Other Regulatory Approvals

Other Contracts (if available)

Laboratory Licensure (if needed)

Normal Values (if needed)

Temperature logs, maintenance records and temperature monitoring system(s) logs

Equipment calibration documents

Meeting agenda

Site Study File Binder(s)

CRFs and/or source documents

Other Study Worksheets, questionnaires, etc.

Investigator/Subject Instructions

Training log(s) and certificate of completion

Subject Diary(ies)

Investigational Product and Logs

Other Supplies/Accessories

Product Inventory and Re-supply Forms

Telephone Contact Log

Site Visit Log

Staff Signature Log

Site Responsibility Log

Study Monitoring Plan

Completed Comments

A. Introduction Yes No NA

Relevant Sponsor/CRO SOPs Other Requirements



159


Protocol Title

Completed Comments

B. Study Team Roles Defined Yes No NA

Investigator Sub-investigator(s) Study nurse Study Coordinator IT Manager Research Pharmacist Lab Technician Sponsor Medical Monitor CRO Project Manager Monitor

C. Study Commitment Reviewed

Investigator’s Agreement Site Confidentiality Agreement Study Timelines Subject Enrollment Period Timelines Study Database Lock Timelines Data Entry Timelines Investigational Product Accountability Specimen Management Protocol Compliance

D. Documents/Processes Reviewed

Study Files Protocol Review to include Inclusion and Exclusion Investigator Brochure GCP and other regulatory requirements CFR Part 11 compliance guidelines CRFs and Source Documents completion guidelines

Subject Case History Records Subject Coding and Randomization IVRS/IWRS/IRS System(s) EDC System and Query Resolution Study related procedures Laboratory collection, handling and shipping procedures



160


Protocol Title

Completed Comments

Yes No NA

Informed Consent Process

Data Management requirements

Inventory Control Records and re-ordering requirements

Study Document Retention requirements E. Monitoring

Monitoring Visit Schedule

Monitoring Procedures/Expectations

Access to Source Documents

Access to CRF and worksheets

Investigator/Monitor meetings F. Investigational Product

Randomization, handling, storage, dispensing Required records and accountability Logs Inventory Disposition, destruction and/or return

G. Reporting Requirements

Data Reporting to Sponsor/CRO Protocol Reporting requirements Reporting SAEs and follow up IND Safety Report requirements Reporting Unexpected Problem/Events Reporting AEs IRB Reporting requirements FDA Reporting requirements

H. Site Initiation Complete

Have all materials and supplies been received? Have questions been addressed? Has the final protocol been reviewed? Have adequate CRFs been received? Has the site received IRB approval to initiate study?

Has Sponsor/CRO approved site to initiate study? Has study-related training been completed and documented?

Observations



161

Template PM 303-D

Site Delegation Log Template Version No. 1.0 Effective Date: May 1, 2017

Site Responsibility Log Investigator

Site Name and Number

Address

Protocol

Print Name, Enter Investigator on first line

Signature and Initials of Site Staff

From Date

To Date

Role Delegated Activities*

PI Initials Date

Principal Investigator

* Activity Codes Activity Code Activity Code Activity Code

Consent subjects A. Laboratory sample collection, processing and shipping

G. Receive, Reconcile and Return/Destroy Investigational Product

M.

Screen subjects B. Lab report review, assess and sign off

H. Administer/Dispense Investigational Product

N.

Perform subject physical examinations

C. CRF and eCRF review and sign off

I. Subject Inventory Control Form

O.

Perform Study Assessments

D. Collect AEs and SAEs J. Other: P.

Perform Study Procedures

E. Assess AEs’ causality K. Other: Q.

Medical treatment F. CRF and eCRF completion and correction

L. Other: R.



162

Template PM 304-A

Investigational Product Receipt Form Template Version No. 1.0 Effective Date: May 1, 2017

Investigational Product Receipt Form Investigator

Site Name

Site Number

Protocol

Investigational Product Received Product Lot # and Expiration Date Description or Comments

Received by Date of Receipt

Inventoried by Date of Inventory

Investigational Product Not Received, Received Damaged or Temperature Excursion Product Lot # Description or Comments

Was the Sponsor/CRO notified YES NO NA Explain: * Sign Staff Signature Log

Completed by

Signature Date



163

Template PM 304-B

Subject Inventory Control Form Template Version No. 1.0 Effective Date: May 1, 2017

Subject Initials: Subject Study Number:

Investigator

Site Name

Site Number Protocol

Date Item Description/ Number

Amount Used

Amount Unused/ Returned

Dispensed by* Comments

* Sign Staff Signature Log

Completed by

Signature Date



164

Template PM 304-C

Investigational Product Accountability Form Template Version No. 1.0 Effective Date: May 1, 2017

Investigator

Site Name

Site Number

Protocol

Inventory Record Subject Initials and Study Number

Lot Number and Expiration Date

Number Used

Number Unused

Comments

Investigational Product not returned or accounted for Subject Initials and Study Number

Date Dispensed

Lot Number and Expiration Date

Description or Comments

Date remaining Investigational Products were returned to Sponsor

* Sign Staff Signature Log

Completed by

Signature Date



165

Template PM 304-D

Temperature Log Template Version No. 1.0 Effective Date: May 1, 2017

Study medication must be stored at [55 to 80º F] Checked every business day

Date Temperature Min/Max

Temp Initials Comments



166

Template PM 305-A

Source Documentation Template Version No. 1.0 Effective Date: May 1, 2017

Source Documentation Template for Protocol

Subject Initials and ID

Source documentation for each subject enrolled in the above study must include:

Note that Subject’s Bill Of Rights (if applicable) was given to subject (or subject’s legally authorized representative) for review and signed on (date) and (time), received a copy prior to the Informed Consent process and before any study-related procedures were performed

Note that written Informed Consent was obtained on (date) and (time); Consent form reviewed, dated and signed by subject (or subject’s legally authorized representative) and received a copy before any study-related procedures were performed

PI Name and Protocol Number, Site Name and Number, Subject Initials, Subject Study Number, Date of Visit

Original or copies of the results of all screening tests, evaluations or procedures used to determine eligibility

Subject has met all of the Inclusion and none of the Exclusion and is eligible to enroll in the study; signed and dated by PI or delegated staff

Date of enrollment/randomization into the study, protocol number and subject number Record any concomitant medications and medications discontinued (as specified by the protocol) Record subject’s diagnosis and status prior to treatment, including documentation of medical history,

particularly that relevant for the disease or condition being treated

Record names of study drugs and dosing times, or other investigational product use Document the dates and the results of evaluations and procedures required by the study; note any

deviations from the protocol and provide an explanation

Review and record any Unanticipated Problems/Events, Adverse Events or SAEs that occurred during the treatment period and for a period specified by Sponsor/CRO following the last use of the investigational product; record any treatment administered and/or recommended

Record subject’s condition during and/or after treatment Document final disposition of the subject and subject status at time of study completion

Completed by

Signature Date



167


Monitoring Visit Preparation Template Version No. 1.0 Effective Date: May 1, 2017

Protocol #

Visit Date Monitor

CHNw Personnel Department Scheduled

Review Study Status

Total # Subjects Enrolled Total # Subjects In Screening

# Subjects Screen Failures Total # Subjects Completed

# Subjects Active # Subjects Prematurely Withdrawn

# Subjects Early Terminated # Subjects Lost To Follow Up

# Open Queries # Unanticipated Problems/Events

# Unresolved AEs # CRF Collected To Date

# Protocol Deviations This Visit Verification of Documents and Records

A Documents Revision # N/A

Current/approved protocol/amendment(s) Current/approved investigator brochure/other Current/approved informed consent form Current/approved source documents

B Records Yes No N/A

Site Responsibility Log Telephone logs current Site visit logs current

Informed Consent Log Written correspondence current Clinical study contract Current Curricula Vitae (CV) of site personnel, licenses, certifications IRB Approval Letter, Ongoing Approval Letter



168


Yes No N/A

Monitoring reports Lab certification and normal ranges Lab sample/specimen logs Subject enrollment, screening, Master Subject ID logs Temperature logs Investigational product shipping and accountability records Equipment Calibration records Site Training records are current Corrective action plan(s) Investigational Product Accountability

Are product storage facilities adequate, secure? Has location of product storage changed since last visit? Logs and forms complete and up to date? Was product inventory checked and counted? Accountability Form complete and up to date? Temperature deviations/excursions reported Subject Accountability Is subject enrollment log up to date? Do subjects meet eligibility requirements? Have subjects signed HIPAA or other state required documents? Have subjects signed Informed Consent form? Are CRF/eCRF completed properly and on a timely basis? Are CRF legible, accurate and complete? Are other worksheets legible, accurate and complete? Were source documents checked for CRF/eCRF review? Were the data collected verifiable? Were there any inconsistencies noted in reviews? Did subjects have required lab work, etc.? Is follow up current and properly documented? Are dropouts/withdrawn/Lost to Follow Up (LTFU) subjects documented? Have Adverse Events been adequately documented? Have SAE’s been adequately documented? Have there been any protocol violations since last visit?



169

Template PM 307-A

End-of-Study Documentation Template Version No. 1.0 Effective Date: May 1, 2017

Complete

Resolve all outstanding data queries

Resolve any outstanding EDC queries

Resolve any pending monitoring findings/queries

Ship all pending biological specimens to the <<designated lab>>

After all protocol-specified laboratory testing is completed, archive or destroy all remaining stored specimens as specified in the Protocol (specimens obtained from participants who did not provide Informed Consent for post-study specimen storage and possible future research testing must be destroyed)

In accordance with instructions provided by the Sponsor/CRO and as specified in the Protocol, return or dispose of/destroy all investigational drug/product supplies

Review and assemble for long-term storage all required essential study documents, including:

Administrative and regulatory documentation

Log linking participant names and ID numbers (which also serves as the completed participant identification code list required by ICH GCP guidelines)

All study documents bearing participant names

All study documents bearing participant identifiers

All investigational product receipt, dispensing, accountability, monitoring and final disposition documentation

Updated financial disclosure if any relevant changes occur during the course of the study or for one year following completion of the study, if applicable

Final report by investigator to IRB/IEC where required, and where applicable to the regulatory authority(ies)

Clinical study report

To the extent possible, organize and categorize all study documentation according to ICH GCP guidelines (ICH E6, Section 84)

Prepare a written inventory of all documentation and storage locations

Documents must be stored securely and with adequate protection of participant confidentiality for a period of [insert appropriate timeframe for IND or non-IND study]

Prepare for and take part in a study close-out visit; resolve all visit findings/queries; and file all visit documentation with other study documentation

Complete, sign and date this template. File original with other study documentation



170

Template PM 308-A

Protocol Deviation Log Template Version No. 1.0 Effective Date: May 1, 2017 PI:

Protocol #:

Ref No Subject ID

Date of Deviation

Date Identified

Deviation Description

Resultant in AE?

Did Subject Continue in Study?

Meets IRB Reporting Req. (Yes/No)

IRB Reporting date if applicable



171

Template SM 401-A (1 of 2 pages)

Guideline for Recruitment and Advertising Practices Version No. 1.0 Effective Date: May 1, 2017

Guideline for Recruitment and Advertising Practices Yes No Comment Do the materials imply or state that the study’s outcome will be favorable or that there are benefits for subjects beyond what is reasonable or expected? If yes, not okay to use

Is there any claim, explicitly or implicitly, that the product is safe, superior and/or effective for the purposes under investigation? If yes, not okay to use

Are any of the following terms used: “new”, “treatment”, “safe”, “effective”, “best”, “cure”, “therapy”, “free”? If, yes, not okay to use

Is there a promise of “free” medical treatment, “free” medication or “free” therapy? If yes, not okay to use

Do the materials emphasize the payment amount, imply that participation is an easy way to make money or otherwise promote payment as a benefit rather than compensation? If yes, not okay to use

Do the recruitment method and procedures appear to put individuals in a situation in which they may feel coerced, compelled, forced or intimidated to enter the study? If yes, not okay to use

Are the materials written in simple language (6th-8th grade reading level)? If yes, okay to use

Do the materials comply with state and local laws? If yes, okay to use

Do the materials meet IRB requirements for approval? Okay to use after receiving IRB approval

Do the materials indicate that the research study involves “investigational use” of an applicable drug? If yes, okay to use

This advertisement was submitted to and approved by the sponsor (NOTE: materials must be approved by the sponsor prior to submitting to the IRB)

This advertisement is acceptable and may be submitted to the appropriate IRB(s)

This ad is not acceptable because:

Reviewed by

Signature Date



172


Notes: • The ad should not state that subjects will receive “free medication” or “treatment at no cost.” Since

these products are investigational and have not been demonstrated to be effective, they cannot be considered to be “treatment.”

• If the study includes a placebo, do not state that all subjects will receive “study medication” or “study-related treatment.” The term “study article” or “placebo” should be used, if applicable.

• If subjects are being paid for their participation in a research study, the payment must be reasonable in relationship to study requirements (frequency and duration of visits, invasive procedures and tests, etc.), and should not be so excessive as to be coercive to potential subjects.

• Certain recruitment methods might be coercive, even if coercion is not intended; for example, recruitment during a support group that might cause an individual to feel a certain amount of peer pressure to volunteer for a study.

• Radio advertisements and videos (such as are used for television) also must be IRB approved prior to use. These should be submitted prior to production to avoid costly revisions.

• If the advertisement is translated, the translation must be submitted for IRB approval with a copy of the original English version for review and approval.

• Internet (web) postings must be submitted to the IRB for approval However, internet-based database

listings (such as ACTIS), which are strictly limited to the study title, the eligibility criteria and contact information, may not require IRB approval (For more information see FDA Guidance, Recruiting Study Subjects - Information Sheet, Oct 18, 2010, link at http://www.fda.gov/RegulatoryInformation/Guidances/ucm126428htm)

Ads may include the following information but it is not required:

1. The name and address of the clinical Investigator and/or research facility 2. The condition under study and/or the purpose of the research 3. In summary form, the criteria that will be used to determine eligibility for the study 4. A brief list of participation benefits, if any (e.g., a no-cost health examination) 5. The time or other commitment required of subjects 6. The location of the research and the person or office to contact for further information



173

Template SM 401-B

Model Screening Script Template Version No. 1.0 Effective Date: May 1, 2017 <<Organization/Department>>, Ms./Mr. <<Designee>> speaking

Caller: I'm calling about the study advertised in this morning's paper related to osteoarthritis pain

<<Designee>> Thank you so much for calling The study we are conducting is a research study for an IND to treat pain related to arthritis symptoms. The FDA has approved further research of this product, but has not yet approved it for marketed use. Are you interested in learning more about the study and exploring whether you may qualify for the specific study entry criteria?

Caller: That sounds interesting; can you tell me a little bit more before I make a decision to share my information?

<<Designee>> Of course! It is important for you to know that this is a randomized study, which means you will be assigned, like with a flip of a coin, to one of two treatment arms, and you may be assigned to receive the placebo This means you may receive either active pain medication or a comparator, called a placebo, which has no active ingredients and may not help your pain

Caller: If I am in pain can I take other medicine, such as Tylenol?

<<Designee>> Yes, we will provide Tylenol as what is referred to as “rescue” medication in case you need it. Let me tell you a little more about the study. We will be asking patients to complete a series of questionnaires and interviews about their quality of life and current pain management strategies. We will also collect a blood sample at each visit to verify your general health and to monitor for any changes. In addition, the doctor and research staff will spend time evaluating your medical history, medications, previous x-rays and questionnaires. Do you still think you may be interested in participating in this study?

<<Designee>> {If No}: Thank you very much for calling

<<Designee>> {If Yes}: Before enrolling you in this research study, you will need to come to the research office for more tests to see if you are eligible. Before we set up an appointment, I would like to ask you some questions about your current medications and past medical history, to determine if you meet some of the preliminary eligibility criteria to participate in the research study.

There is a possibility that some of these questions may make you uncomfortable or distressed; if so, please let me know. You don’t have to answer those questions if you don’t want to but, of course, if you don't, we have no way of determining if you are eligible to enroll in the study.

All information that I receive from you by phone, including your name and any other identifying information, will be strictly confidential, and this screening form will be kept confidential, but it may be reviewed by representatives from the pharmaceutical company, along with your medical records, if you qualify and choose to enroll in the study.

Remember, your participation is voluntary; you do not have to complete these questions and you can withdraw at any time,

Do I have your permission to ask you these questions?

Provide contact name, but do not ask for caller's name until permission is asked and granted

The word “research” should be included early on in the script and emphasized

A brief description of the study design and purpose of the study should be provided in lay language (6th-8th grade reading level)

Emphasize that the participants may be randomized to the placebo arm and the possible consequences

Briefly describe the procedures, potential risks and benefits

Callers should be asked if they may be interested in participating in the study

The purpose and nature of the current screening process should be described

Describe potential discomforts

State that the caller can refuse to answer any question

Script should state how confidentiality will be maintained If the caller’s name is recorded, that must be mentioned

State that participation is voluntary and the subject may withdraw consent from the study at any time

Callers should be asked explicitly for permission to be asked questions



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Template SM 401-C

Recruitment Action Plan Template Version No. 1.0 Effective Date: May 1, 2017 RECRUITMENT AND RETENTION PLAN

Date Implemented:

Protocol:

Investigator:

Recruitment plan:

____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Revised date:

___________________________________________________________________________________

Revised date:

___________________________________________________________________________________

Retention plan:

____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Revised date:

____________________________________________________________________________________

Revised date:

____________________________________________________________________________________



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Informed Consent Process Version No. 1.0 Effective Date: May 1, 2017

Informed Consent Process

Protocol

Prior to the first study visit (screening visit)

Prior to the visit, find out if the prospective subject can understand and comprehend spoken English well enough to understand and participate in a verbal discussion about the study and read and comprehend the consent If the prospective subject is hearing or visually impaired, determine and confirm prior to beginning if he or she would like to have a friend, relative or legally authorized representative involved in the discussion

Investigators should carefully consider the ethical/legal ramifications of enrolling subjects when a language barrier exists

A person who speaks and understands English but does not read and write can be enrolled in a study by "making their mark" on the consent document, when consistent with applicable state law, but every effort must be made to provide the consent in the subject’s native language and to have an appropriately qualified translator available

Preparation for discussions with the prospective subject The prospective subject should be comfortable, so initiate the consent process in a private office, a treatment room or other environment in which the prospective subject will feel comfortable and that ensures privacy

The subject and investigator should be able to interact as equals; for example, the subject should be fully dressed, (not in a hospital gown or paper examining gown) during the discussion, and the subject and investigator should be talking face to face (both sitting or standing)

Before beginning the discussion of the research, try to ascertain the individual's level of education, ability to listen and understand, and any preconceptions about the research

Keep in mind that the study design and purpose of the study should be provided in lay language (i.e. 6th-8th grade reading level, depending on local IRB and state requirements)

The purpose of the research In language appropriate to the individual's educational attainment, experience, level of comprehension and rationality, explain the objective of the study and that it involves research, why the study is being conducted and the reason he or she is being asked to participate

Explain the investigational products, the design of the study and, if applicable, the probability for random assignment to either the investigational product or control

Discuss the consequences of assignment to active or current standard of care or placebo, whichever is applicable to the study

Discuss the difference between research and treatment, and make sure the potential subject understands that the primary purpose of the research is not to treat his or her medical condition, but to provide enough data to meet the objective of the study

Note: If there is a dose-finding protocol and subjects have a terminal, life-threatening or serious condition for which there is no effective treatment, it is important for potential subject to understand they may not receive a dosage level expected to be high enough to be effective



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What happens during the study Explain the requirements of the protocol and the responsibilities of the subject including:

• The number and frequency of visits, tests, evaluations and procedures at each visit (or in aggregate, depending on the protocol design)

• What subjects are expected to do between visits (diaries, special diets or activities, administration of the investigational product/study medication

• Pay special attention to any procedures that are invasive, may be very uncomfortable, painful, unpleasant or experimental

• Expected duration of the subject's participation in the trial

Tell the prospective subject how many subjects are expected to be in the study*

It has been suggested that it would be more meaningful to tell prospective subjects how many subjects have been in clinical trials testing the investigational product prior to the point in time that a prospective subject is considering entering a study, rather than the number who are going to be enrolled in a particular study

What happens after the study Discuss what will happen when the subject's participation is complete, especially access to the product

The risks and benefits Discuss whether or not participation in the study is expected to benefit subjects or not

Even if there is the possibility that subjects might benefit by participating in the study, make it clear if there is no intended clinical benefit to the subject Make it clear if there are no expected or possible benefits to the subject

Explain the known risks or inconvenience to the subjects and the likelihood and severity of harm associated with the investigational product, control and procedures

Discuss the alternative treatment that may be available (explain that no treatment is also an option, especially when the investigational product offers little chance of benefit and carries a high probability of serious adverse effects)

Discuss appropriate alternative procedures or courses of treatment, if any might be advantageous to the subject

List the treatment available in the event of study-related injury and who subjects can contact for further information

Explain the plan to provide, or not provide, treatment or monetary compensation for study-related injury

Other options and dropping out Discuss the alternative treatment that may be available (explain that no treatment is also an option, especially when the investigational product offers little chance of benefit and carries a high probability of serious adverse effects)

Assure the individual that participation in the trial is voluntary and that he/she may refuse to participate

Explain that even after agreeing to be in the study, he or she can withdraw from the study at any time (without penalty or loss of benefits to which he or she is entitled)

Make sure the individual understands that signing the Consent Form does not obligate anyone to stay in a study—subjects have the right to drop out of the trial, and they are not required to provide an explanation



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Confidentiality Tell the prospective subject about everyone who will have access to his or her medical records, including:

• Representatives of the sponsor (monitors, auditors) • Employees of the regulatory authority (FDA inspectors) • Members or representatives of the IRB

Records identifying him/her will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available

If the results of the trial are published, the subject’s identity will remain confidential

Although every effort is made to protect the confidentiality of information and privacy of the individuals, there is no absolute guarantee of either

Other Discuss the anticipated prorated payment, if any, to the subject for participating in the trial

Discuss the anticipated expenses, if any, to the subject for participating in the trial

Assure that the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial

Provide the name(s) of the person(s) to contact for further information regarding the trial and the rights of trial subjects, and in the event of trial-related injury

Explain to the subject/patient the foreseeable circumstances and/or reasons under which his/her participation in the trial may be terminated



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Template SM 403-A

Subject Eligibility Template Version No. 1.0 Effective Date: May 1, 2017

Protocol

Subject DOB Gender: Male Female

Eligible: Yes No If No, reason

Screened by On Name Date

Inclusion criteria (To be eligible, all must be answered “Yes”) Yes No

1. 2. 3. 4. 5. Etc. Exclusion criteria (To be eligible, all must be answered “No”) Yes No

1. 2. 3. 4. 5. Etc.

Reviewed by

Signature Date

INSTRUCTIONS FOR SUBJECT ELIGIBILITY TEMPLATE

• If the Investigator or designee determines the subject meets the protocol eligibility criteria, he/she must mark “Yes” in the section marked “Eligible” at the top of the form, and complete the “Screened by” section

• If the Investigator or designee determines the subject does not meet the protocol eligibility criteria, he/she must mark “No” in the section marked “Eligible” at the top of the form, document the reason for ineligibility and complete the “Screened by” section

• If a designee completed the Subject Eligibility Template and made the eligibility determination, the template and final determination must be reviewed and approved by the Investigator



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Template SM 403-B

Screening and Enrollment Log Template Version No. 1.0 Effective Date: May 1, 2017

Screening and Enrollment Log

Protocol

Screening Enrolled

Date ID # Informed by Consent documented

Date ID # If not enrolled, explain (reference protocol

inclusion/exclusion number if applicable)

Staff initials



180

Template SM 404-A

Study Encounter Worksheet and Record—Screening Template Version No. 1.0 Effective Date: May 1, 2017

Screening Visit for

Date Subject Name

Included To come Notes/Comments

Informed Consent Date:

Time:

Height

Weight

Vital Signs Temp Pulse BP

Record any clinically significant abnormality as a preexisting condition

At the end of the study, any new clinically significant findings/abnormalities that meet the definition of an Adverse Event must also be recorded and documented as an Adverse Event

Physical Exam Completed

Medical History

Labs Medical history and physical exam findings should be consistent (i.e., if a scar is noted from an appendectomy on the physical exam, then appendectomy should be recorded in the medical history)

Results:

Next Visit:

Completed by Date

signature



181

Template SM 404-B

Study Encounter Worksheet and Record—Visit # Template Version No. 1.0 Effective Date: May 1, 2017

Visit <<#>> for

Date Subject Name

Encounter Activities

Documentation Notes/Comments

Height Included To come

Weight

Vital Signs Temp Pulse BP

Interim New medications/Changes in medications

Confirmation of ongoing medications

Medical History Symptom Log

Adverse Event monitoring (Query any changes from baseline health)

Physical Exam

Labs

CBC

Hct

BUN

Urinalysis

Procedures

Product Returned

Code Returned Used Lost



Dispensed

Product

Diary

Supplies

Next Visit:

Completed by Date

Signature



182

Template SM 404-C

Study Encounter Record, Physical Exam—Visit # Template Version No. 1.0 Effective Date: May 1, 2017

URINE PREGNANCY TEST

Females Only

Date of UPT: ____________

MM/DD/YYYY Type of Pregnancy test:_____________________________ Lot number:_______________________________

Negative

Positive (Complete Pregnancy Surveillance Form)

Not done (e.g. - lost to follow up) VITAL SIGNS

Temperature Heart Rate Blood Pressure

___ ___ ___ ___ ◦F

◦C ___ ___ ___ per minute ___ ___ ___ / ___ ___ ___ mmHg

PHYSICAL EXAMINATION

Weight

___ ___ ___ ___ lb. kg

Normal Abnormal Not Done If Abnormal or Not Done, comment:

General Appearance

Skin (other than studied disease)

Cardiovascular

Respiratory

Gastro-Intestinal

Hemato-Lymphatic

Neurological

Musculoskeletal

Other: ____________________

Note: Any worsening of the recorded condition or disability during the study must by recorded as an Adverse Event

If ‘Other” was assessed at Screen then it must be re-evaluated at this visit

Signature of staff member completing the PE_______________________________ Date: ___________



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Template SM 404-D

Medical History—Screening Template Version No. 1.0 Effective Date: May 1, 2017

Medical History—Screening for

Date Subject Name

Dates Event/Condition

Update primary physician re: study? Yes No

Primary physician name

Address/phone

Date

signature



184

Template SM 404-E

Adverse Event Log Template Version No. 1.0 Effective Date: May 1, 2017

Protocol ___________________ Subjects Initials _______________ Subject # __________

Adverse Event

Start Date

Stop Date

Frequency

1=Once

2=Intermittent

3=Continuous

Severity

1=Mild

2=Moderate

3=Severe

4=Life Threatening

5=Death

Treatment

1=None

2=Meds

3=Non Med

4= 2& 3

5 = Hospitalized

Effects on Dosing

0=NA

1=Drug Withheld

2=Discontinued

3=Dose Adjusted

Related to study

0=definite

1=probable

2=possible

3=unrelated

Unanticipated Event

0=No

1=Yes

Serious FDA Definition

0=No

1=Yes

Serious IRB Definition

0=No

1=Yes

Investigator initials and date



185

Template SM 404-F

Concomitant Medication Log Template Version No. 1.0 Effective Date: May 1, 2017

Protocol ___________________ Subjects Initials _______________ Subject # __________

Medication Start Date Stop Date Dose Indication



186


Criteria for Recognizing and Managing AEs Version No. 1.0 Effective Date: May 1, 2017

CRITERIA FOR RECOGNIZING AND MANAGING AES

1 Recognizing Adverse Events

An Adverse Event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course of the study

Intercurrent illnesses or injuries should be regarded as Adverse Events Abnormal results of diagnostic tests or procedures are considered Adverse Events if the abnormality:

-results in study withdrawal -is associated with a Serious Adverse Event -is associated with clinical signs or symptoms -leads to additional treatment or to further diagnostic tests -is considered by the Investigator to be of clinical significance

Abnormal Laboratory Values A clinical laboratory abnormality should be documented as an Adverse Event if any one of the following conditions is met: -The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality -The abnormality suggests a disease and/or organ toxicity -The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, etc.

Serious Adverse Event A Serious Adverse Event is any Adverse Event that is:

-Death -life-threatening (places the subject at immediate risk of death from the event as is occurred) -requires or prolongs hospital stay* -results in persistent or significant disability or incapacity -a congenital anomaly or birth defect -an important medical event

*The hospitalization, prolongation or surgery would not be reported as an AE if it is due to one of the following criteria:

1. Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting condition

2. Surgery should not be reported as an outcome of an Adverse Event if the purpose of the surgery was elective or diagnostic and the outcome was uneventful

3. Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study

4. Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a worsening or increase in frequency of hospital admissions as judged by the clinical Investigator

If the event leading to hospitalization, prolongation or surgery does not meet one of these four criteria, it should be reported as an AE or Serious AE per the definitions previously provided



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Post-study Adverse Event All unresolved Adverse Events should be followed by the Investigator until the events are resolved, the subject is lost to follow up, or the Adverse Event is otherwise explained per Sponsor or protocol. At the last scheduled visit, the Investigator should instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal physician, believes might reasonably be related to participation in this study.

Pre-existing Condition

A pre-existing condition is one that is present at the start of the study. A pre-existing condition should be recorded as an Adverse Event if the frequency, intensity or character of the condition worsens during the study period At screening, any clinically significant abnormality should be recorded as a pre-existing condition. At the end of the study, any new clinically significant findings/abnormalities that meet the definition of an Adverse Event must also be recorded and documented as an Adverse Event.

2 RECORDING OF ADVERSE EVENTS

All Adverse Events occurring during the study period must be recorded.

Information on all Adverse Events should be recorded immediately in the source document and also in the appropriate Adverse Event module of the Case Report Form. All clearly related signs, symptoms and abnormal diagnostic procedures results should be recorded in the source document, though they should be grouped under one diagnosis.

Any Serious Adverse Event that occurs after the study period and is considered to be possibly related to the study treatment or study participation should be recorded and reported immediately.

Adverse Event Reporting Period

The study period during which Adverse Events must be reported usually is the period from the initiation of any study procedures to the end of the study treatment follow up.

The AE reporting period after the end of administration or use of the investigational product should be specified in the protocol.

The Investigator should notify the study sponsor of any death or Adverse Event occurring at any time after a subject has discontinued or terminated study participation that may reasonably be related to this study. The sponsor should also be notified if the Investigator should become aware of the development of cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study.

IRB Notification by Investigator

Reports of all Serious Adverse Events (including follow-up information) must be submitted to the IRB within the IRB required timeline(s). Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s binder.

3 MANAGING ADVERSE EVENTS At each contact with the subject, the Investigator must seek information on Adverse Events by specific

questioning and, as appropriate, by examination. The clinical course of each event should be followed until resolution, stabilization, or until it has been determined that study treatment or participation is not the cause. Serious Adverse Events that are still ongoing at the end of the study period must be followed up to determine the final outcome.



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Important medical events are those that may not be immediately life threatening, but clearly are of major clinical significance. They may jeopardize the subject and may require intervention to prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in in-patient hospitalization or intensive treatment of bronchospasm in an emergency department would typically be considered serious.

Unblinding Procedures While the safety of the subject always comes first, it is still important to seriously consider if unblinding the study therapy is necessary to ensure a subject’s safety. This section should clearly describe the procedures for unblinding study therapy on a subject, including documentation of this in the subject’s source document. For Investigators, other than the sponsor-Investigator, state that the Investigator must inform the sponsor of all subjects whose treatment was unblended—and describe the timelines for such reporting. In most cases, the unblinding will be part of managing an SAE, and will be reported with the SAE; however, in cases in which unblinding was not associated with an SAE, such actions should be reported in a timely manner. While there is no regulation governing this timeline, it is suggested to use the same timeline requirements for Investigator reporting of SAEs, (i.e., notification of sponsor within 24 hours by phone or fax, followed by a written narrative of the event within 48 hours).

Stopping Rules In studies with a primary safety endpoint or studies with high risk to study subjects, rules should be developed that clarify the circumstances and procedures for interrupting or stopping the study. If a central Data and Safety Monitoring Board (DSMB) or Committee (DSMC) is set up for the study, stopping rules should be incorporated into its safety analysis plan as well.

Medical Monitoring It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This safety monitoring will include careful assessment and appropriate reporting of Adverse Events as noted above, as well as the construction and implementation of a site data and safety-monitoring plan (see Section 9, Auditing, Monitoring and Inspecting). Medical monitoring will include a regular assessment of the number and type of Serious Adverse Events.



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NONE ADVERSE EVENT #_____ INITIAL_______ FOLLOW-UP #_______

1 Adverse event diagnosis (ONE PER PAGE, use precise and concise medical terminology, describe sign or symptom only if diagnosis is unknown):

2 Date of Onset:

____/____/20_____

MM/DD/YYYY

3 Time (OPTIONAL):

_____:_____

HR MIN

4 Serious (see definitions)

NO YES*

5 AE of special interest (see definitions)

NO YES**

6 Subject discontinued study due to this event?

NO YES (complete Exit Form with discontinuation reason: Adverse Event)

10 Relationship of event to study drug (see definitions)

Related Not Related

7 Severity (see definitions):

Mild Moderate Severe

Not applicable (Follow-up only: for resolved AE)

11 Outcome of event

Ongoing (Explain in comments section below)

Resolved, no residual effects (Date below)

Resolved date ____/____/20____

MM/DD/YYYY

Resolved, residual effects present

(Date below and explain in comments section)

Resolved date ____/____/20____

MM/DD/YYYY

Subject lost to follow up (no further data available)

Subject died *

8 Action taken with study drug (Only one box is ticked)

None

Study drug regimen reduced or discontinued temporarily (Complete medication compliance page if applicable or explain in comments)

Discontinued study drug permanently

Return to normal study drug regimen (Follow-up only)

No change from previous AE report (Follow-up only)

9 Treatment for event (If necessary, tick several boxes)

None

Began and/or changed in concomitant therapy (Complete Concomitant Therapy Form)

Inpatient hospitalization/prolongation of hospitalization*

Non drug therapy (Complete procedure page if applicable or explain in comments)

Other, specify_______________________________

No change (Follow up only)

ADVERSE EVENT COMMENTS:

As an Investigator for this study, I certify that all data collected on this page is accurate

____________________________________________________________________ _____/_____/20_____

PRINCIPAL INVESTIGATOR’S/SUBINVESTIGATOR’S SIGNATURE DATE (MM/DD/YYYY)



190

Template QA 601-A (1 of 4 pages)

Clinical Study Audit Template Version No. 1.0 Effective Date: May 1, 2017

Clinical Study Audit Template

Protocol Audit Dates from to

Questions Responses

A. PI and Support Personnel Yes No NA

1. Is the Principal Investigator’s CV and statement on file? 2. Are all sub-investigator(s) and study staff’s CVs on file? 3. Are all Confidentiality Agreements on file? 4. Is the investigator’s contract on file? 5. Are all site’s personnel’s names, titles, credentials and current licensures on file? 6. Are all staff appropriately delegated tasks on the Investigator Delegation Log? B. Study Documents Yes No NA

1. Are copies of the original protocol and all amendments to the protocol on file? 2. Does the last protocol version used correspond with the sponsor’s version? 3. Are copies of all original and/or amended CRFs on file? 4. Are copies of all other original and/or amended data collection sheets on file? 5. Are other study-required documents in place (e.g., laboratory accreditation and/or

inspection surveys)?

6. Are all sponsor-required reports on file (e.g., progress, AEs, and serious AEs)? 7. Are relevant events, e.g., change in staff, new facility policy, etc., documented? 8. Are all study training logs/records on file? 9. Are all (applicable) equipment calibration certificates and monitoring logs on file?

Action Item/Issue with recommended Corrective and Preventative Action(s) (CAPA) Priority Level

Urgent ASAP

A. PI and Support Personnel B. Study Documents

Comment:



191


Questions Responses

C. Study Records Yes No NA

1. Are all Informed Consents in the PI’s study files? 2. Are all Informed Consents signed by the PI or appropriate delegated staff? 3. Are all completed CRFs and other data collection sheets in the PI’s study files? 4. Do corrections and changes to CRFs and other data collection sheets comply with the

sponsor’s data management requirements? (e.g., data clarification/correction forms)

5. Has PI signed all CRFs, other data sheets? 6. Are all protocol violations recorded? 7. Are all protocol deviations/unanticipated problems recorded? 8. Are all violations, deviations, unanticipated problems signed by PI? 9. Is the sponsor's Site Visit Log complete? 10. Are Telephone Contact Logs complete? 11. Are correspondence files complete? 12. Is the study close-out/suspension/ termination letter with records retention

requirements on file?

13. Is the study communication file complete? D. Source Document Review Yes No NA

1. Are medical and other data records (samples) complete and accurate? 2. Were protocol inclusion/exclusion criteria met? 3. Were patient signs/symptoms within protocol criteria? 4. Were patient histories confirmed? 5. Were sample requirements met? 6. Were all source documents for audited patients reviewed by the auditor? 7. Were discrepancies found? (If Yes, state number and describe in observations) E. Investigational Product Accountability Yes No NA

1. Are all investigational product release forms complete? 2. Are all investigational product receipt forms complete? 3. Have all investigational product temperature excursions been reported to the sponsor/CRO?

4. Are all subject inventory and product accountability forms complete? 5. Was unused investigational product disposed of according to sponsor's instructions? 6. If not disposed, is remaining investigational product being stored in a secure area? 7. Was all unused investigational product inventoried and shipped back to the sponsor? Action Item/Issue with recommended Corrective and Preventative Action(s) (CAPA) Priority Level

Urgent ASAP

C. Study Records D. Source Document Review E. Investigational Product Accountability



192


Questions RESPONSES

F. Human Subject Protection Yes No NA

1. Is/are IRB approval letter(s) on file? 2. Is/are current IRB membership roster/list on file? 3. Was Informed Consent required? 4. Are copies of original and/or amended, approved ICF(s) on file? 5. Were all required and relevant additional items in the approved ICF? 6. Did all enrolled subjects sign an ICF? 7. Did all enrolled subjects sign revised ICFs (as applicable)? 8. Did all enrolled subjects sign Subjects Bill of Rights (as applicable)? 9. Were any subjects enrolled who did not sign a consent form? 10. Were any subjects enrolled before they signed a consent form? 11. Did investigator report these protocol violations to the IRB and sponsor/CRO? 12. Are all IRB-required reports/acknowledgements on file? G. Subject Population and Specimens Yes No NA

1. Did all subjects meet all enrollment requirements? 2. Did site enroll required number of subjects? 3. Did the site over-enroll subjects? 4. Is the sponsor/CRO approval letter to over-enroll on file? 5. Were necessary equipment/accessories provided according to sponsor’s SOP? 6. Did site properly use all necessary equipment and accessories? 7. Were specimens collected, transported, tested and stored per the protocol? H. Significant Study Dates Enter Date(s)

1. Date of IRB approval letter

2. Date of Qualification Site Visit

3. Date of Initiation Visit and site training

4. Date subject enrollment began

5. Date subject enrollment ended

6. Date(s) of routine monitoring visit(s)

7. Date(s) of unscheduled monitoring visit(s)

8. Date of close-out visit

Action Item/Issue with recommended Corrective and Preventative Action(s) (CAPA) Priority Level

Urgent ASAP

F. Human Subject Protection G. Subject Population and Specimens H. Significant Study Dates Comment:



193


Questions Responses

I. Sponsor Regulatory Requirements Yes No NA

1. Are study files complete and accurate? 2. Are all reports complete and accurate? 3. Are IRB files complete and accurate (approval letter(s), correspondence, reports)? 4. Are all monitoring visits recorded on the Site Visit Log? 5. Are reasons for unscheduled monitoring visits documented? 6. Are all monitoring confirmation letters and follow-up letters on file? 7. Are all monitoring confirmation letters and follow-up letters reviewed and signed by the PI or delegated study staff?

8. Are unresolved action items/corrections made between visits? 9. Were all sponsor regulatory requirements met?

Action Item/Issue with recommended Corrective and Preventative Action(s)(CAPA) Priority Level

Urgent ASAP

I. Sponsor Regulatory Requirements

Comment:

Audit Summary 1. Strengths

2. Weaknesses

3. Recommendations

Completed by

Signature

Date

Reviewed by

Signature Date



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Prepare for Regulatory Inspection Template Version No. 1.0 Effective Date: May 1, 2017

Investigator

Protocol

1. ORGANIZATION N/A Comments

Notifications Sponsor Notify all parties involved with the clinical study

IRB

Sub investigators

Pharmacy

Laboratories

Medical records

Administration

Legal counsel

CRO

Subcontractors/outside vendors

Work space for FDA inspector

If possible, reserve work space that is convenient for staff but private

Study summary General overview of the study

List personnel and responsibilities (compare with study delegation of authority log)

List of subjects Screened Include name, address and/or phone number, date enrolled and completed, and medical record number (reference for site study staff)

Screen failed

Enrolled

Lost to Follow Up

Withdrawn

Early termination

Completed

2. FILES MANAGEMENT

Regulatory Protocol (all versions) Organize all regulatory files by general heading arranged in chronological order

Investigator's Brochure (all versions)

Protocol amendment(s)

Original and revised approved consent form(s)

Subject’s Bill of Rights (if applicable)

Screening forms/questionnaires (all versions)



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IRB N/A Comments

Approval letter(s) for Initial study submission, including:

Protocol and Consent form(s)

Recruitment advertisement(s)

Protocol amendment(s)

Revised Consent form(s)

Renewal of IRB approval(s)

Documentation of IRB submissions

Periodic reports

Conflict of interest statement(s)

Reports of Serious AEs

Safety reports

Protocol deviations/violations/waivers

Notice of study termination

Final report

Status reports

Annual or ongoing renewal(s)

Serious AEs

Unanticipated problem/event report(s)

Deaths

Study termination

Final summary

Study Closeout Confirmation

Communications Sponsor correspondence

CRO correspondence

Monitoring log(s)

Laboratory Laboratory certification

Study value ranges

Equipment calibrations


Investigational product records

Accountability Log(s)

Receipt of product

Dispensing

Return

Temperature Logs

Subject documents CRFs Have completed CRF for each subject enrolled with corresponding source documents Related source documents (all

versions)



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3. REVIEW N/A Comments

Subject documentation

CRFs

Data clarification/correction forms

Source documentation for each subject that verifies:

Screening Date subject(s) screened

Date Consent obtained and circumstances

Assessments carried out as required

Laboratory tests

Diagnostic evaluations

Physical exam and history (including meds)

Enrollment Inclusion/exclusion criteria were met

Blinding, randomization, etc.

Investigational product dispensing and accountability

During study, at intervals per protocol

Date, time, location of each visit/encounter

Concomitant medications

Assessments carried out as required

Laboratory tests

Diagnostic evaluations

Physical exam and history (including meds)

Dose/use modifications

Subject diaries

AEs: documented, treated, evaluated

Protocol exemptions

Investigational product reconciliation

Early termination



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Template QA 602-B (1 of 3 pages)

Procedures during a Regulatory Inspection Template Version No. 1.0 Effective Date: May 1, 2017

Inspection Manager(s) Date

Responsibility Activity Comment 1. <<Designee>>

(Receptionist) FDA inspector arrival Call <<Designee>> (inspection coordinator)

Ask investigator(s) to remain in the reception area until inspection coordinator has arrived

2. (Manager) Alert and assemble team Notify key stakeholders about FDA Inspector arrival (e.g., Investigator, research team, ORA, Legal, CHNw IRB, and Compliance)

3. <<Designee>> (inspection coordinator)

Greet inspector Ask to see the FDA investigator’s credentials* Review FDA Notice of Inspection (Form FDA 482)

Credentials are a badge with a photograph of the inspector (*The investigator will initiate this action as required by FDA inspection policy) Also, copy badge if permitted

Do not begin the inspection until the FDA investigator has provided an FDA Notice of Inspection (Form FDA 482) and the purpose of the inspection has been ascertained

4. Introduce staff members involved in the inspection and their roles

Introduce member(s) who will accompany investigator, take notes and make copies

5. With the investigator, develop a schedule (number of days, times) for the inspection (to the extent possible)

Discuss the preferred time to begin and end the inspection each day (e.g., start and close of business) with the FDA investigator

6. Review inspection policy Policy may include: If the investigator requests an affidavit or any other document be signed, initialed or otherwise ratified, CHNw will not comply until counsel has been consulted If the investigator seeks to inspect an area or document that is outside the “legally permissible” scope of the current inspection under the Act, a request must be made in writing and the matter referred to counsel If the investigator insists on using still or video camera equipment during the inspection, consult with counsel to decide whether this request should be honored If the investigator requests to view electronic data files on a computer and make copies of electronic data files on a disk to be provided to him/her as part of the inspection document collection process, consult with counsel to respond to that request as appropriate Original documents or records may not be removed from the premises, nor may an FDA investigator personally make any copies or make any marks on original documents and records



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Responsibility Activity Comment 7. Provide the FDA investigator

with adequate space to review documents and records

The space should be relatively private, convenient for staff and allow easy access to documents and to a copier

8. Assign a knowledgeable staff member to accompany the investigator for the duration of the inspection

Permit the FDA investigator to speak with other appropriate staff, as requested Caution staff not to volunteer any information, but to answer questions that are asked truthfully and directly Answer questions as they occur

9. Take notes to capture all relevant discussions and requests

Email daily summary to key stakeholders (Investigator, ORA, Legal, CHNw IRB, Compliance)

10. Make copies of documents as requested

Make two (2) copies of every document requested by the FDA investigator—one for him/her and one for CHNw records Mark confidential documents as such Review copies to redact any personal or confidential information before the copy is given to the investigator

11. If objectionable observations are noted, request an opportunity to immediately correct the finding and do so

An individual who has authority to answer questions and/or immediately correct procedures should be available at all times during the inspection However, this person does not need to accompany the inspector

12. Meet with all relevant staff to discuss and summarize the day’s events after the FDA investigator has departed

13. Convene all relevant study team members for the closeout meeting with the FDA investigator At this time, the investigator will provide a signed Form FDA 483 to <<Designee>> if any objectionable observations were made during the inspection

Review the Form FDA 483 carefully and confirm that corrected items were not listed or the 483 is annotated to show a correction was instituted while the inspection was underway Request such deletions or annotations if not already present Ask the FDA investigator to clarify any items and provide as much detail as needed for items that need clarification Express disagreements or explanations about any items or issues politely, but clearly and assertively Advise the FDA investigator that a written response to the Form 483 will be sent to the office he/she specifies



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Responsibility Activity Comment 14. Ensure that all promised

corrective actions are carried out expeditiously and within promised timeframes

Collaborate with Investigator, ORA, Legal, CHNw IRB and Compliance

15. Submit a full, written response to the Form 483, item by item, within 10 days of the inspection’s conclusion, indicating all corrective actions taken to date and summarizing actions yet to be taken, with a proposed time frame for completion

Collaborate with Investigator, ORA, Legal, CHNw IRB and Compliance

16. Thirty days after the inspection, send a written request through the Freedom of Information Act for a copy of the Establishment Inspection Report (EIR)

If investigative sites were also inspected, request copies of Form 483, EIR, inspection classification from any investigators who were inspected by the FDA as a result of participating in the study

17. If a letter classifying the inspection is not received within 45 days of the inspection, contact the FDA office and request the status of that letter



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VIII GLOSSARY



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GLOSSARY (COMMON TERMS)

Note:

Most definitions are adapted from the International Conference on Harmonization; Good Clinical Practice: Consolidated Guideline (E6) Glossary, as published in the Federal Register, Volume 62, No. 90, May 9, 1997, from Title 21 of the FDA Code of Federal Regulations and applicable Guidance Documents, or from 45 CFR 46, HHS. Terms and definition that are applicable to the HIPAA Privacy Rule are from 45 CFR 164 (HHS).

1. The definition of Authorization is from the Office for Civil Rights, Privacy Rule Guidance, Questions and Answers, URL < www.hhs.gov/ocr/privacy/ > (answer ID 264).

Adverse Drug Reaction (or Experience) (ADR or ADE)

In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase "responses to a medicinal product" means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility, i.e. the relationship cannot be ruled out. Regarding marketed medicinal products, an ADR is a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

Adverse Event (AE) Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research. Adverse events encompass both physical and psychological harms.

Amendment (to the Protocol)

See Protocol Amendment.

Applicable Regulatory Requirement(s)

Any law(s) and regulation(s) addressing the conduct of clinical studies of investigational products.

Applicant The party who submits a marketing application to the FDA for approval of a drug, biologic or medical device. The applicant is responsible for submitting the appropriate financial certification or disclosure statements (Forms FDA 3454 or FDA 3455) to the FDA.

Application Integrity Policy (AIP)

Application Integrity Policy (AIP) is FDA's policy for the integrity of data or information submitted in an application. If it is suspected that an applicant has submitted false or misleading information, the data are thoroughly investigated. Submitting false or misleading information may result in FDA refusal to review submissions until certain requirements are met.

Approval (in Relation to Institutional Review Boards)

The affirmative decision of the institutional review board (IRB) that the clinical study has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP) and the applicable regulatory requirements.

Archive File A file in which the original and all subsequent revised versions of a standard operating procedure (SOP) or other document (including those marked as “Obsolete”) are maintained, so that the origination and revision history for an SOP or other document is available for review.

Assent In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, psychological status, and health condition of the children involved. Assents may apply to all or some of the children involved in the research. In general, the IRB will require assent from children ages seven (7) to seventeen (17); however, the IRB acknowledges there are situations in which it may be appropriate for younger children, depending on their aptitude/ability to provide assent. Alternatively, there may be situations in which older children with higher cognitive



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ability may be able to read, understand, and subsequently sign the adult consent document. In these instances, the investigator must prospectively justify this scenario in the IRB submission and make the necessary changes to the informed consent document (for example the inclusion of “you/your child” language and a child signature line).

Associated with the Use of the Drug

For FDA safety reporting purposes, there is a reasonable possibility that the AE may have been caused by the drug. Determination of causality could include the following definitions:

Definitely—The AE follows a reasonable temporal sequence from drug administration, abates upon discontinuation of the drug, is confirmed by reappearance of the reaction on repeat exposure (re-challenge).

Probably—The AE follows a reasonable temporal sequence from drug administration, abates upon discontinuation of the drug, cannot be reasonably explained by the known characteristics of the patient’s clinical state.

Possibly—The AE follows a reasonable temporal sequence from drug administration, could have been produced by the patient’s clinical state or by other modes of therapy administered to the patient.

Unrelated—The AE is definitely produced by the patient’s clinical state or by other modes of therapy administered to the patient.

Audit A systematic and independent examination of study-related activities and documents to determine whether the evaluated study-related activities were conducted and that the data were recorded, analyzed and accurately reported according to the protocol, sponsor’s SOPs, GCP and the applicable regulatory requirements.

Audit Certificate A written statement, signed by an institutional official or an auditor, which documents that an audit was performed.

Audit Report A written evaluation by the auditor of the results of the audit.

Audit Trail The documentation (“paper trail”) that allows reconstruction of the course of events. When referring to electronic systems, it means a secure, computer-generated, time-stamped electronic record that allows reconstruction of the course of events relating to the creation, modification and deletion of an electronic record.

Auditor A person qualified by training and experience to conduct an audit.

Authorization A detailed document that gives covered entities permission to use protected health information for specified purposes, which are generally other than treatment, payment or healthcare operations, or to disclose protected health information to a third party specified by the individual.1 (HIPAA)

Biologic Product Any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product or analogous product applicable to the prevention, treatment or cure of diseases or injuries to humans. Biologic products include, but are not limited to, bacterial and viral vaccines, human blood and plasma and their derivatives and certain products produced by biotechnology, such as interferons and erythropoietins. In contrast to most drugs, which are chemically synthesized and whose structure is known, biologics are derived from living sources, such as humans, animals, plants and microorganisms. With respect to clinical investigations to assess safety and effectiveness, investigational biologics are treated as investigational new drugs.

Biometrics A method of verifying an individual’s identity based on measurement of the individual’s physical feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.



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Blinding/Masking A procedure in which one or more parties to the study are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware and double-blinding usually refers to the subject(s), investigator(s), monitor and, in some cases, data analyst(s) being unaware of the treatment assignment(s).

Case Report Form (CRF) A printed, optical or electronic document designed to record protocol-required data for each study subject and sent to the sponsor for purposes of statistical analysis.

Certified Copy A copy of original information that has been verified, as indicated by dated signature, as an exact copy having all of the same attributes and information as the original.

Clinical Investigator For the purpose of financial disclosure, only a listed or identified investigator, co-investigator or sub investigator who is directly involved in the treatment or evaluation of research subjects. The term also includes the spouse and each dependent child of the clinical investigator.

Clinical Research As defined by the National Institutes of Health (NIH), research performed on human subjects or on material or information obtained from human subjects as part of human experimentation.

Clinical Investigation Clinical investigation: Involves use of a test article (i.e., drug, device, food substance, or biologic), one or more human subjects, meets requirements for prior submission to the FDA (involves drugs or medical devices other than the use of FDA approved drugs or medical devices in the course of medical practice), or results are intended to be part of an application for research or a marketing permit.

Clinical Study Report A written description of a study of any therapeutic, prophylactic or diagnostic agent conducted in human subjects in which the clinical and statistical description, presentations and analyses are fully integrated into a single report.

Clinical Trial See Clinical Study

Closeout Visit A final site visit by a monitor that must be conducted after a study has been completed, suspended or terminated for any reason.

Cohort A group of subjects who share a common exposure or research experience. Examples are the treatment and control cohorts.

Co-investigator Two or more investigators who have equivalent authority and responsibility in the conduct of a clinical study. They may be considered co-investigators or co-principal investigators. See also Investigator.

Common Rule The colloquial name for 45 CFR 46, Subpart A, the basic Department of Health and Human Services (HHS) policy for protection of human research subjects. This regulation consolidates requirements for IRB review and informed consent to participate in human subject research. It applies to any HHS-funded research conducted on human subjects. FDA regulations (21 CFR Parts 50 and 56) closely mirror the Common Rule. Both sets of regulations apply when research is FDA-regulated and federally funded (wholly or partially).

Comparator An investigational or marketed product (i.e., active control) or placebo, used as a reference in a clinical study.

Compensation Affected by the Outcome of Clinical Studies

Compensation that could be higher for a favorable outcome than for an unfavorable outcome, such as compensation that is explicitly greater for a favorable result or compensation to the investigator in the form of an equity interest in a sponsor of a covered study or in the form of compensation tied to sales of the product, such as a royalty interest.

Complaint Any concern communicated by a person questioning any act or failure to act relating to an individual's rights to access to his/her protected health information (PHI), to maintain the privacy of his/her health information, to request restrictions on uses or disclosures of his/her PHI, to request confidential communications regarding his/her PHI, to request amendment of his/her PHI or to receive an accounting of disclosures of his/her PHI. (HIPAA)

Compliance Adherence to all study-related requirements, GCP requirements and the applicable regulatory requirements.



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Computerized System Computer hardware, software and associated documents (e.g., user manual) that create, modify, maintain, archive, retrieve or transmit in digital form information related to the conduct of a clinical study.

Confidentiality The prevention of disclosure, other than to authorized individuals, of a sponsor’s proprietary information or of a subject’s identity or other medical information.

Contract A written, dated and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters.

Contract Research Organization (CRO)

An organization (commercial, academic or other) contracted by a sponsor to perform one or more of that sponsor’s clinical study-related duties and functions.

Controlled Document A document whose initial version and each subsequent modification must undergo review and approval, as defined by the sponsor, before the document can be implemented. Examples of controlled documents may include regulatory submissions, protocols, protocol amendments, CRF, the Investigator's Brochure (IB) and templates.

Controlled Substance A drug or other substance, or immediate precursor, included in schedule I, II, III, IV or V of part B of Title 21 of the United States Code, Food and Drugs, Chapter 13, Drug Abuse Prevention and Control, Subchapter I, Control and Enforcement, also cited as the “Controlled Substances Act.”

Covered Clinical Study For financial disclosure purposes, any study of a drug/ biologic/medical device in humans submitted in a marketing application or reclassification petition subject to FDA regulations that the applicant or the FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety. This would, in general, not include Phase I tolerance studies or pharmacokinetic studies, most clinical pharmacology studies (unless they are critical to an efficacy determination), large open safety studies conducted at multiple sites, treatment protocols and parallel track protocols.

Data Safety Monitoring Board (DSMB)

See Data Monitoring Committee.

Data Monitoring Committee (DMC)

An independent DMC that may be established by a sponsor to assess at intervals the progress of a clinical study, the safety data and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify or stop a study. The terms "data safety monitoring board" and "independent data monitoring board" are synonymous with DMC.

Deviation (from the Protocol)

Any change to a process, procedure, test or other requirement stated in an approved protocol. See also Protocol Violation.

Digital Signature An electronic signature based upon cryptographic methods of originator authentication, computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified.

Direct Access Permission to examine, analyze, verify and reproduce any records and reports that are important to evaluation of a clinical study. Any party (e.g., domestic and foreign regulatory authorities, sponsors, monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities and sponsors’ proprietary information.

Direct Entry Recording data where an electronic record is the original capture of the data. Examples are the keying by an individual of original observations into the system, or automatic recording by the system of the output of a balance that measures subject’s body weight. In these cases, the electronic document is the source document.

Disability For FDA safety reporting purposes, a substantial disruption of a person's ability to conduct normal life functions.

Disclosure The external release, transfer, provision of access to or divulging in any other manner, of PHI by a Covered Entity. (HIPAA)



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Documentation All records, in any forms (including, but not limited to, written, electronic, magnetic and optical records; and scans, x-rays and electrocardiograms) that describe or record the methods, conduct and/or results of a study, the factors affecting a study and the actions taken.

Effective Date The date on which an SOP or other document becomes available for use by personnel, after documented training.

Electronic Case Report Form (e-CRF)

An auditable electronic record that is used in place of or in conjunction with the paper CRF defined above.

Electronic Media The mode of electronic transmission. It includes the Internet (wide-open), Extranet (using Internet technology to link a business with information only accessible to collaborating parties), leased lines, dial-up lines, private networks and those transmissions that are physically moved from one location to another using magnetic tape, disk or compact disk media.

Electronic Patient Diary An electronic record into which a subject participating in a clinical study directly enters observations or directly responds to an evaluation template, per department process.

Electronic Record Any combination of text, graphics, data, audio, pictorial or other information representation in digital form that is created, modified, maintained, archived, retrieved or distributed by a computer system.

Electronic Signature A computer data compilation of any symbol or series of symbols executed, adopted or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.

Eligibility The determination that a potential subject satisfies or meets the enrollment criteria for inclusion into a clinical study. Subjects not meeting the criteria are ineligible to participate in the study.

Enrollment The point at which a potential subject, who has met the enrollment criteria and any other study screening processes, has completed the informed consent process and is ready to actively participate in a study.

Enrollment Criteria A set of specific criteria (demographic, physical, laboratory) that determine whether or not a potential subject can be enrolled into a clinical study. They may also be referred to as inclusion and exclusion criteria.

Essential Documents All the documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data produced.

FDA-Regulated Human Subject Research

Any research conducted on human subjects using investigational drugs, biologics and medical devices that is intended to support an application to the agency.

Form A tool used to facilitate the implementation of SOPs, e.g., to record data and information required by an SOP.

Good Clinical Practice (GCP)

A standard established by the International Conference on Harmonization (ICH) for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical studies that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of study subjects are protected.

Good Laboratory Practice (GLP)

Refers to the FDA regulation 21 CFR 58, Good Laboratory Practice for Non-clinical Laboratory Studies. Non-clinical laboratory study means in vivo or in vitro experiments in which investigational products are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether an investigational product has any potential utility or to determine physical or chemical characteristics of the investigational product.

Health Oversight Agency An agency or authority of the United States or State that is authorized by law to oversee the healthcare system (whether public or private) or government programs in which health information is necessary to determine eligibility or compliance, or to enforce civil rights laws for which health information is relevant.



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Human Subject A living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information.

Impartial Witness A person who is independent of the study, who cannot be unfairly influenced by people involved with the study, who attends the informed consent process if the subject or the subject’s legally authorized representative cannot read and who reads the informed consent form and any other written information supplied to the subject.

Implant Implant is a device that is placed into a surgically or naturally formed cavity of the human body and is intended to remain there for a period of 30 days or more. In order to protect public health, FDA may determine that devices placed in subjects for shorter periods are also implants.

IND Amendment Refers to the submission to the FDA of a change or an addition to an IND that is currently in effect.

Independent Data Monitoring Committee (IDMC)

See Data Monitoring Committee.

Individually Identifiable Health Information (general definition) – see CHNw HIPAA Policy

Information that is a subset of health information, including demographic information collected from an individual, and Is created or received by a healthcare provider, health plan, employer or health care clearinghouse; and Relates to the past, present or future physical or mental health or condition of an individual; the provision of healthcare to an individual; or the past, present or future payment for the provision of healthcare to an individual; and That identifies the individual; or With respect to which there is a reasonable basis to believe the information can be used to identify the individual. (HIPAA)

Informed Consent The process by which a subject voluntarily confirms his or her willingness to participate in a particular study, after having been informed of all aspects of the study that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form (ICF).

Informed Consent Form (ICF)

The form on which the process of conducting and achieving informed consent from potential study subjects is documented.

Interaction Interaction includes communication or interpersonal contact between investigator and subject.

Intervention Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.

Initiation Visit A meeting between the sponsor representative(s) and investigator(s) (and other key personnel), at which the objectives and the methodology of the clinical study are defined, regulatory requirements are reviewed and appropriate training of the site’s key personnel is conducted.

Inspection The act by a regulatory authority of conducting an official review of documents, facilities, records and any other resources that are deemed by the authority to be related to the clinical study and that may be located at the site of the study, at a sponsor’s and/or CRO’s facilities or at other establishments deemed appropriate by the regulatory authority.

Institutional Biosafety Committee (IBC)

A committee that reviews, approves and oversees clinical research studies in accordance with the responsibilities defined in the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines).

Institutional Review Board (IRB)

An independent body constituted of medical, scientific and nonscientific members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a research study by, among other things, reviewing, approving and providing continuing review of studies, of protocols and amendments



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and of the methods and material to be used in obtaining and documenting informed consent of the study subjects.

Interim Study Report A report of intermediate results and their evaluation based on analyses performed during the course of a study.

International Conference on Harmonization (ICH)

A tripartite group comprised of representatives from industry and regulatory agencies from the European Union, Japan and the United States that seeks to harmonize regulatory requirements for pharmaceutical products.

Investigation Investigation is a clinical investigation or research involving one or more subjects to determine the safety and/or effectiveness of a device.

Investigational device Investigational device is a device, including a transitional device that is the object of an investigation.

Investigational device exemption (IDE)

IDE refers to the regulations under 21 CFR 812. An approved IDE means that the IRB (and FDA for significant risk devices) has approved the sponsor’s study application and all the requirements under 21 CFR 812 are met.

Investigational Drug Product

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical study, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Investigational New Drug (IND)

Refers to the regulations in 21 CFR 312. An IND that is in effect means that 30 days have elapsed from the date that a complete IND application was submitted to FDA and an appropriate IRB has reviewed and approved the sponsor’s clinical study, all the requirements under 21 CFR 312 are met and an investigational product can be distributed to investigators.

Investigator A person who participates in the conduct of the clinical study at a study site. If a team of individuals at a site conducts a study, the investigator who is the responsible leader of the team may be called the principal investigator (PI).

Investigator's Brochure (IB)

A document that is provided by a clinical study sponsor to investigators participating in that study. It is a compilation of the clinical and non-clinical data on the investigational product(s) relevant to the study of the investigational product(s) in human subjects.

Key Personnel As defined by NIH, all individuals responsible for the design and conduct of a research study.

Label According to the FDA, a display of written, printed or graphic matter upon the immediate container of any article.

Labeling According to the FDA, all labels and other written, printed or graphic matter upon any article or any of its containers or wrappers, or accompanying such article.

Lead Monitor See Monitor.

Legally Authorized Representative

An individual, judicial or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject’s participation in the procedures(s) involved in the research. The term is synonymous with Legally Acceptable Representative.

Life-threatening Adverse Drug Experience

For FDA safety reporting purposes, any adverse drug experience that places the subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death.

Minor Protocol Changes Editorial changes and the correcting of typographical errors, which do not affect a study design. Changes to study design are not considered minor changes, e.g., changing enrollment criteria or capturing additional data not specified in the original protocol.

Monitor (noun) The person who periodically oversees the progress of a clinical study and ensures that it is conducted, recorded and reported in accordance with the protocol, SOPs, GCP and applicable regulatory requirement(s). The lead monitor is the monitor who



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assumes a supervisory role when more than one monitor participates in the monitoring of a clinical study.

Monitor or Monitoring (verb)

The act of overseeing the progress of a clinical study and of ensuring that it is conducted, recorded and reported in accordance with the protocol, SOPs, GCP and applicable regulatory requirement(s).

Monitoring Report A written report from the monitor to the sponsor after each monitoring visit and/or other study-related communication according to the sponsor’s SOPs.

Multicenter Study A clinical study conducted according to a single protocol but at more than one site and, therefore, carried out by more than one investigator.

New Drug Application (NDA)

An FDA submission for marketing approval of new drugs.

Non-clinical Laboratory Study

In vivo or in vitro experiments in which investigational products are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether an investigational product has any potential utility or to determine physical or chemical characteristics of the investigational product. (See also GLP)

Noncontrolled Document A working form or other tool (e.g., template, log) that, once developed, may be modified as necessary, provided a list of modifications is maintained.

Objective Evidence Verifiable qualitative or quantitative information, records or factual statements pertaining to an item or process and used by an auditor to support an observation made during an audit.

Observation A statement of fact made during an audit and substantiated with objective evidence.

Participant See Subject.

Phase I Study The initial introduction of an IND/biologic into humans, Phase I studies are primarily designed to evaluate safety and usually include healthy subjects (depending on a number of factors, including expected toxicity and side effects, may be conducted using subjects with the disease or condition under study). Data from Phase I studies are used to determine the metabolism and pharmacologic actions of the drug/biologic in humans, the side effects associated with increasing doses and, if possible, to gain early evidence on effectiveness.

Phase II Study Conducted subsequent to Phase I, Phase II studies are designed to evaluate the effectiveness of the drug/biologic for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug/biologic. Phase II studies are typically well-controlled, closely monitored and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.

Phase III Study Phase III studies are performed after preliminary evidence suggesting effectiveness of the drug/biologic has been obtained, and are intended to gather the additional information about effectiveness and safety needed to evaluate the overall benefit-risk relationship of the drug/biologic and to provide an adequate basis for physician labeling. Phase III studies are expanded controlled and uncontrolled studies that usually include from several hundred to several thousand subjects.

Phase IV Study Phase IV studies are conducted after marketing approval has been granted. Also known as post-marketing studies, they may be conducted as a condition of marketing approval or at a sponsor’s initiative. Since many more patients receive the drug/biologic once it is approved for use than received it during the formal clinical investigation phases, less common toxicities may be recognized. Populations not specifically targeted in the earlier phases of investigation may be included in Phase IV studies.

Premarket Approval (PMA)

A premarket approval means any premarket approval application for a Class III medical device, including all information submitted with or incorporated by reference therein. (21 CFR 814.3)

Premarket Notification [PMN or 510(k)]

510(k) refers to the type of submission to FDA described under 21 CFR 807 Subpart E in which the applicant must establish that their device is substantially equivalent to



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a legally marketed device. This type of submission is used for most Class II devices and some Class I devices.

Principal Investigator (PI) See Investigator.

Private Information Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.

Proprietary Interest (in the Product)

Property or other financial interest in the product including, but not limited to, a patent, trademark, copyright or licensing agreement.

Protected Health Information (PHI) - see CHNw HIPAA Policy.

Individually identifiable health information that is

• Transmitted by electronic media;

• Maintained in any medium described in the definition of electronic media;

• Transmitted or maintained in any other form or medium. (HIPAA)

Protocol A document that describes the objective(s), design, methodology, statistical considerations and organization of a study. The protocol usually also gives the background and rationale for the study, but these could be provided in other protocol referenced documents.

Protocol Amendment Any revision to a previously approved protocol for an investigation of an unapproved drug, biologic or medical device, or any change of investigator or sub-investigator that must be reported to regulatory authorities.

Protocol Violation Any deviation from an approved protocol, except if intended to eliminate a hazard to subjects or to protect the life or well-being of subjects in an emergency.

Protocol Waiver An authorization to deviate from an approved protocol. Note, even if a waiver is granted, this is still considered a protocol deviation.

Protocol-Related Procedures

Any examination, interview or test that is performed for the sole purpose of determining a subject’s eligibility to participate in a clinical study (screening) or, once enrolled, performed on the subject as part of the study protocol. Protocol-related procedures may not be conducted until the potential subject has given informed consent. However, if in the course of routine medical care certain examinations, procedures or tests are being or have been performed, these may be used to assess eligibility if allowed by the protocol, even if they were not obtained as a direct result of screening for a specific protocol.

Public Health Authority An agency or authority of the United States or a State that is responsible for public health matters as part of its official mandate, or a person or entity acting under a grant of authority from such public agency. (EUD equivalent—Competent Authority)

Quality Assurance (QA) All those planned and systematic actions that are established to ensure the study is performed and the data are generated, documented (recorded) and reported in compliance with GCP and the applicable regulatory requirement(s).

Quality Control (QC) The operational techniques and activities undertaken within the QA system to verify that the requirements for quality of the study-related activities have been fulfilled.

Randomization The process of assigning study subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.

Record Any item, collection or grouping of information that includes protected health information and is maintained, collected, used or disseminated by or for a Covered Entity. (HIPAA)

Regulatory Authorities Bodies having the power to regulate. In the ICH GCP Guidelines, regulatory authorities include those authorities that review submitted clinical data and those that conduct inspections, such as the FDA. In the European Union, these bodies are sometimes referred to as competent authorities.



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Regulatory Master File (RMF)

The term used in this template to designate a file, which is maintained by the sponsor, that contains the documentation verifying that a clinical trial has been conducted in accordance with regulatory requirements. This may also be referred to as a Trial Master File (TMF).

Research A systematic investigation designed to develop or contribute to generalizable knowledge [45CFR 46.102(d)]. Activities which meet this definition constitute research, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities. Some research development or testing and evaluation may also meet this definition.

Screening A planned examination and/or interview process of a potential subject to assess his/her eligibility for enrollment in a clinical study.

Screening Failure When a potential subject does not meet one or more criteria for inclusion in a clinical study.

Serious Adverse Drug Reaction (or Experience)

For FDA safety reporting purposes, any adverse drug experience occurring at any dose that results in any of the following outcomes:

• Death,

• A life-threatening adverse drug experience,

• Inpatient hospitalization or prolongation of existing hospitalization,

• A persistent or significant disability/incapacity, or

• A congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening or require hospitalization may be considered serious adverse drug experiences when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization or the development of drug dependency or drug abuse.

The term "serious adverse event" is used consistently in this template in place of serious adverse drug reaction or experience.

Serious Adverse Event (SAE)

For FDA safety reporting purposes, an AE or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Severity Definitions The severity of adverse changes in physical signs or symptoms may be classified as follows:

• Mild—Transient or mild discomfort; no limitation in activity; no medical intervention/therapy required.

• Moderate—Mild to moderate limitation in activity, some assistance may be needed; no or minimal medical intervention/therapy required.

• Severe—Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible.



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• Life threatening—Extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitalization or hospice care probable.

Significant Equity Interest (in a sponsor of a covered study) – FDA definition

Any ownership interest, stock options or other financial interest whose value cannot be readily determined through reference to public prices (generally, interests in a non-publicly traded corporation), or any equity interest in a publicly traded corporation that exceeds $50,000 during the time the investigator is carrying out the study and for one year following completion of the study.

Significant Payments (of Other Sorts)

Payments made by a sponsor of a covered study to the clinical investigator or the institution to support activities of the clinical investigator that have a monetary value of more than $25,000, exclusive of the costs of conducting the clinical study or other clinical studies (e.g., a grant to fund ongoing research, compensation in the form of equipment or retainers for ongoing consultation or honoraria) during the time the clinical investigator is carrying out the study and for one year following the completion of the study.

Significant risk device (SR device)

Significant risk device is an investigational device that: (1) is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; (2) is for use in supporting or sustaining human life and represents a potential for serious risk to the health, safety, or welfare of a subject; (3) is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or (4) otherwise presents a potential for serious risk to a subject.

Source Data All information in original records and certified copies of original records of clinical findings, observations or other activities in a clinical study/trial necessary for the reconstruction and evaluation of the study. Source data are contained in source documents (original records or certified copies).

Source Documents Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation templates, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files and records kept at the pharmacy, the laboratories and medico-technical departments involved in the clinical study).

Sponsor An individual, company, institution or organization that takes responsibility for the initiation, management and/or financing of a clinical study.

Sponsor-Investigator An individual who both initiates and conducts, alone or with others, a clinical study, and under whose immediate direction the investigational product is administered to, dispensed to or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.

Standard Operating Procedure (SOP)

A document that specifies all the operational steps, acceptance criteria, personnel responsibilities and materials required to accomplish a task.

Sub investigator Any individual member of the clinical study team designated and supervised by the principal investigator at a study site to perform critical study-related procedures and/or to make important study-related decisions (e.g., associates, residents, research fellows).

Subject An individual who participates in a clinical study, either as a recipient of the investigational drug or medical device, or as a control. The terms subject and participant are used synonymously.

Subject Identification Code

A unique identifier assigned by the investigator to each study subject to protect the subject’s identity and used in lieu of the subject’s name when the investigator reports AEs and/or other study-related data.

Suspected Adverse Reaction

Suspected adverse reaction means any AE for which there is a reasonable possibility that the drug caused the AE. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the



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drug and the AE. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any AE caused by a drug.

Template A document that contains all the required elements and format for another final, controlled document, e.g., the SOP Template.

Test Article For AE reporting, a product given to a study subject, including the investigational product, a comparator or a placebo.

Transitional device Transitional device is a device subject to section 520(l) of the FD&C Act and which FDA previously regulated as a new drug or an antibiotic drug before May 28, 1976.

Treatment (in the context of clinical research)

The period of use of any investigational product, including comparators and placebo, administered during the course of the study and during a period extending to four weeks after the last dose, or longer if necessitated by the half-life of the test drug. It does not include placebo run-in periods or non-drug periods prior to randomization, unless defined otherwise in the protocol or other study-specific document.

Treatment (in the context of the Privacy Rule)

The provision, coordination or management of healthcare and related services by one or more healthcare providers, including:

• Coordination or management of healthcare by a healthcare provider with a third party

• Consultation between healthcare providers relating to a patient; or

• Referral of a patient for healthcare from one healthcare provider to another. (HIPAA)

Treatment-Emergent AEs AEs that occur after the start of dosing in a clinical study or are present prior to the start of dosing but are reported at an increase in severity after the start of dosing. These AEs are considered treatment emergent. An example could be mild headache that was present prior to dosing. After dosing is initiated, the patient reports a severe headache. This change in severity allows this AE to be defined as treatment-emergent.

Treatment Use Any use of an investigational drug/biologic/medical device in a patient who is not otherwise enrolled as a subject in a clinical study of that investigational product, but who has a serious or life-threatening disease or condition that qualifies him/her for that treatment use.

Unexpected An adverse drug experience that has not been previously observed and included in the Investigator's Brochure (IB). If the adverse drug experience has been previously observed but not included in an updated IB, then it continues to be reported as unexpected.

Unanticipated Adverse Device Effect

Unanticipated adverse device effect is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

Unexpected Adverse Drug Experience (Reaction)

For FDA safety reporting purposes, an AE or suspected adverse reaction is considered “unexpected” if it is not listed in the Investigator Brochure (IB) or is not listed at the specificity or severity that has been observed; or, if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the IB listed only cerebral vascular accidents. "Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions that are mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.

Violation (of the Protocol) See Protocol Violation.

Vulnerable Subject An individual whose willingness to volunteer in a clinical study may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case



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of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental and nursing students; subordinate hospital and laboratory personnel; employees of the pharmaceutical company; members of the armed forces; and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors and those incapable of giving consent.

Waiver See Protocol Waiver.

Waiver of Authorization An alteration to or waiver, in whole or in part, of the individual authorization required by §164.508 for use or disclosure of protected health information in accordance with 45 CFR 164.512 (i) (HIPAA)

Well-being (of the Subjects)

The physical and mental integrity of the subjects participating in a clinical study.

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