cancer.uams.educancer.uams.edu/.../uploads/sites/97/2017/09/conductin… · web viewstudy title:...

WINTHROP P. ROCKEFELLER CANCER INSTITUTEConducting Translational and Clinical Research at the Winthrop P. Rockefeller Cancer Institute

WINTHROP P. ROCKEFELLER CANCER INSTITUTE

Conducting Translational and Clinical Research at the Winthrop P. Rockefeller Cancer Institute

of 128Dorothy Graves, PhD and Laura Hutchins, MDVersion 2.0 11/10/2017


Table of Contents1. Introduction2. Process of Conducting Research at the Winthrop P. Rockefeller Cancer Institute

2.1 Overview2.2 Institutional Oversight of Clinical Trials

2.2.1 Prior to Protocol Activation2.2.1.1 Cancer Institute Disease Oriented Committees (DOCs)2.2.1.2 Cancer Institute Cancer Clinical Trials Office (CCTRA)2.2.1.3 Cancer Institute Research Nurses

2.2.1.3.1 Clinical Trial Preparation2.2.1.3.2 Clinical Trial Referrals2.2.1.3.3 General Facilitation of Clinical Research Activities

2.2.1.4 Cancer Institute Protocol Review and Monitoring Committee (PRMC)2.2.1.5 UAMS Office of Research and Regulatory Affairs (ORRA)

2.2.1.5.1 IND and IDE Submissions2.2.1.5.2 Good Practices for Drug and Product Development (Quality Assurance)2.2.1.5.3 Contracts/Legal Review

2.2.1.6 UAMS Conflict of Interest (COI) Policies and Procedures 2.2.1.7 UAMS Institutional Review Board (IRB)

2.2.1.7.1 Principals Governing the Committee2.2.1.7.2 Authority of the Committee2.2.1.7.3 IRB Leadership and Committee Membership2.2.1.7.4 IRB Database – CLARA2.2.1.7.5 IRB and COIs

2.2.1.8 UAMS Biorepository2.2.1.8.1 Organization2.2.1.8.2 Services Provided2.2.1.8.3 Information Management2.2.1.8.4 Collections2.2.1.8.5 Fee Structure

2.2.2 Post Activation Study Management2.2.2.1 Cancer Institute DOCs2.2.2.2 Cancer Institute CCTRA2.2.2.3 Cancer Institute Research Nurses

2.2.2.3.1 Recruitment of Subjects to Clinical Trials2.2.2.3.2 Ensuring Adherence to Protocols2.2.2.3.3 Off Study Notifications

2.2.2.4 AR-Comprehensive Research Informatics Suite (AR-CRIS)2.2.2.4.1 Clinical Trials Management2.2.2.4.2 Electronic Data Capture



2.2.2.4.3 Adverse Event (AE) Reporting2.2.2.4.4 Biological Specimen Tracking2.2.2.4.5 Microarray Analysis2.2.2.4.6 Arkansas Clinical Data Repository(AR-CDRAR-CDR)2.2.2.4.7 Informatics for Integrating Biology and the Bedside (Trinetx)2.2.2.4.8 Honest Broker System2.2.2.4.9 Health Plan Claims Database

2.2.2.5 Cancer Institute PRMC2.2.2.6 UAMS ORRA2.2.2.7 UAMS IRB

2.2.2.7.1 Continuing Reviews2.2.2.7.2 Protocol Changes2.2.2.7.3 Audits

2.2.2.8 UAMS Research Pharmacy2.2.2.9 Study Training

3. Data Integrity and Subject Safety3.1 Data and Safety Monitoring

3.1.1 Risk Assessment3.1.2 Data and Safety Monitoring Plans (DSMPs)

3.1.2.1 Data and Safety Monitoring Board (DSMB)3.1.2.1.1 Utilization of a DSMB3.1.2.1.2 DSMB Membership3.1.2.1.3 DSMB COI3.1.2.1.4 Protocol Information Regarding DSMBs3.1.2.1.5 DSMB Operational Plan

3.1.3 Protocol Specific Monitoring3.1.3.1 Protocol Specific Monitoring Overview3.1.3.2 Protocol Specific Monitoring by UAMS ORRA3.1.3.3 Protocol Specific Monitoring by Risk Category

3.1.3.3.1 Investigator-Initiated High and Medium Risk Trials3.1.3.3.1.1 Pre-Study Investigator and Site Qualification Assessments3.1.3.3.1.2 Study Initiation Monitoring Assessment3.1.3.3.1.3 Interim Monitoring Assessments3.1.3.3.1.4 Close-Out Monitoring Assessments

3.1.3.3.2 Investigator-Initiated Low Risk Trials 3.1.3.3.2.1 Pre-Study Investigator and Site Qualification Assessments3.1.3.3.2.2 Monitoring Assessments

3.1.4 Medical Monitors3.1.5 Adverse Event (AE) Reporting

3.1.5.1 Identification of AEs3.1.5.2 Relationship of AEs to the Investigational Drug or Device3.1.5.3 Unanticipated Adverse Device Effects (include only for device studies)



3.1.5.4 Serious Adverse Events (SAEs)3.1.5.5 Deaths3.1.5.6 Pre-existing Conditions

3.1.6 Audits3.1.6.1 Routine Audits3.1.6.2 Targeted Audits3.1.6.3 Auditing Process3.1.6.4 Audits by Investigator3.1.6.5 Protocol Specific Auditing by CCTRA (CCTRA Quality Assurance)

3.2 Education, Training and Credentialing Requirements3.2.1 Cancer Institute CCTRA Training3.2.2 Cancer Institute Research Nurse Training3.2.3 Protocol Specific Training

4. AppendixI. Cancer Institute Organizational StructureII. Cancer Institute Research FlowchartIII. AR-Comprehensive Research Informatics Suite (AR-CRIS) WorkflowIV. PI Checklist for Cancer Institute ProtocolsV. Committee Workflow Details

a. Cancer Institute Disease Oriented Committees (DOCs)b. UAMS Institutional Review Board (IRB)c. Cancer Institute Protocol Review and Monitoring Committee (PRMC)d. UAMS Institutional Conflict of Interest Committee (ICOIC)

VI. Standard Operating Procedures (SOPs)a. Cancer Clinical Trials Office (CCTRA): Submitting to www.ClinicalTrials.gov

VII. Campus Resource Guide for Clinical TrialsVIII. CCTRA Protocol Template


http://www.ClinicalTrials.gov/


1. IntroductionThis document describes the process of carrying out translational and clinical research related to humans at the Winthrop P. Rockefeller Cancer Institute (Cancer Institute) on the campus of the University of Arkansas for Medical Sciences (UAMS). Translational and clinical research subject to oversight by Cancer Institute includes research conducted on the University of Arkansas for Medical Sciences (UAMS) campus that is cancer-related in nature. For the purposes of this document, research will be defined as follows: Cancer-Related – Research related to the etiology, prevention, treatment, survival or complications

of cancer Translational Research - A term used to describe the process by which the results of research done

in the laboratory are used to develop new ways to diagnose and treat disease [definition from the National Cancer Institute (NCI)]

Clinical Research/Clinical Trial - A prospective study involving human subjects designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions; these may include drugs, treatments, devices or behavioral or nutritional strategies. Participants in these trials may be patients with cancer or people without a diagnosis of cancer. [definition from the NCI]. Further clarification of this definition can be found at: http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page2#op_def .

2. Process of Conducting Research at the Winthrop P. Rockefeller Cancer Institute

2.1 OverviewThe Cancer Institute has a centralized clinical trials infrastructure that supports institution-wide cancer clinical research activities. Cancer Institute research is supported electronically by the AR-Comprehensive Research Informatics Suite (AR-CRIS). Cancer Institute studies are monitored in many ways during development, review and performance throughout the lifecycle of the research protocol. All Cancer Institute clinical trials undergo a centralized scientific and feasibility review as well as a data and safety monitoring process. Several Cancer Institute-specific and UAMS campus-wide committees/departments participate in this process providing comprehensive oversight of Cancer Institute translational and clinical research. These committees/departments include: UAMS Office of Research Compliance (ORC), UAMS Office of Research and Regulatory Affairs (ORRA), UAMS Conflict of Interest Committee (COIC), UAMS Institutional Review Board (IRB), UAMS Research Pharmacy, Cancer Institute Cancer Clinical Trials and Regulatory Affairs (CCTRA), Cancer Institute Disease Oriented Committees (DOCs), Cancer Institute Protocol Review and Monitoring Committee (PRMC) and Cancer Institute Data and Safety Monitoring Board (DSMB).

The CCTRA works with the UAMS Translational Research Institute (TRI) & its Clinical Research Center (CRC) when services are needed that are not typically offered by CCTRA. The goal is to leverage services for efficiency, cost savings and to avoid unnecessary duplication. An example of collaboration is in combined efforts when a DSMB is required.


Hutchins, Laura F, 11/08/17,

Please check link


Check that this is the correct term with Amy Jo Jenkins

http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page2#op_def


Please refer to Appendices I-VI for descriptions of the Cancer Institute organizational structure and research process workflows.

2.2 Institutional Oversight of Clinical Trials

2.2.1 Prior to Protocol Activation

2.2.1.1 Cancer Institute Disease Oriented Committees (DOCs) The Cancer Institute DOCs provide scientific development and institutional feasibility review of all potential clinical trial protocols that could be performed at the Cancer Institute. The DOCs program was developed in 2010 to create multidisciplinary disease site-specific committees composed of UAMS faculty and Cancer Institute research support staff. The DOCs nurture and support multi-level collaboration on basic, translational and clinical cancer research at the Cancer Institute. They provide an environment and forum that inspires research collaborations, wherein research study design is influenced by discussion among members including pathologists, statisticians, nurses, epidemiologists, basic scientists, medical, surgical and radiation oncologists and Cancer Institute clinical research infrastructure support staff. Under the direction of a DOC Coordinator, DOC members work together to develop optimal scientific approaches for clinical protocols and assess potential studies for the availability of institutional resources

Scientific review by the DOCs is characterized by the following: novelty and importance of the therapeutic questions, feasibility of the research plan, appropriateness of the methodology to answer the research question, capability of the research team to conduct the trial in a timely fashion and determination of whether the protocol is competing with other protocols already underway. Resource assessment includes, but is not limited to, eligible patient populations, specimens available for correlative study from the UAMS Biorepository and research funding. Approval by the appropriate DOC is required for all cancer-related protocols prior to the engagement of CCTRA to support the clinical research process.

Feasibility from a financial and logistics standpoint to ensure successful recruiting and study completion is a prime responsibility of the DOC working along with the CCTRA. A feasibility template is located in the appendix.

DOCs also rank priority of potential clinical trials so there is an ordered pipeline to determine which trials are next in line to be opened. With the assistance of staff from the Cancer Clinical Trials Office (CCTRA) and Office of Research and Regulatory Affairs (ORRA), DOC coordinators report their ranking of proposed trials to the Cancer Institute Associate Director for Clinical Research who then determines the final order in which trials will be opened at the Cancer Institute.



Additionally all DOC coordinators meet monthly for a DOC Coordinators Council meeting. In these DOC Coordinator meetings, clinical trial research infrastructure and resources are introduced, and ongoing components are evaluated. Additionally, the DOC Coordinator meetings serve as a forum wherein obstacles to the performance of clinical trials at the Cancer Institute are brought up for discussion and resolved in action following the meeting. DOC Coordinator meetings are led by the the Chair, Chair-elect and the Cancer Institute Associate Director for Clinical Research.

2.2.1.2 Cancer Institute Cancer Clinical Trials Office (CCTRA) The CCTRA is a Cancer Institute shared resource that provides central management and oversight for coordinating, facilitating and reporting on cancer clinical trials, regardless of the study origin (investigator-initiated, industry, cooperative group or other). This office provides a central location for Cancer Institute protocols, a centralized database of protocol-specific data, and an updated list of currently active protocols for use by investigators and status reports of protocols. The CCTRA allows oversight and quality control of the Cancer Institute’s entire clinical trials effort, but its scope of work does not include tasks involved in the actual direct conduct of the individual trials, such as source documentation, study medication, administration, etc.

All investigators are expected to utilize the services of the CCTRA.

Specifically, the CCTRA provides the following:

Protocol development for consistency in submissions to the PRMC and IRB. This includes preparation of the informed consent but does not include writing the protocol for the investigator

Coordination of protocol and informed consent amendments with the investigator for submission to the IRB

If the research project will be submitted to the FDA as a UAMS-sponsored IND/IDE application, CCTRA will send a copy of the IRB-approved protocol and informed consent to the ORRA for FDA submission.

Creation of common data elements (CDEs) Creation of electronic case report forms (eCRFs) Creation of clinical regulatory documents as needed for individual sponsors Submission and correspondence for approval of clinical trial regulatory documents

to required UAMS and Cancer Institute boards and committees, including the Institutional Review Board (IRB), Protocol Review and Monitoring Committee (PRMC), Radiation Safety Committee and Biosafety Committee

Maintaining protocol required training and delegation of authority logs Preparation and execution of study initiation visits



Development of clinical trial budgets to ensure adequate financial support for all study activities. The development of the budget includes a Medicare coverage analysis when necessary to assist investigators and the hospital in identifying those procedures that can be billed to Medicare and/or other third party payers and those that must be billed to a research account. In accordance with UAMS policy, the CCTRA develops the clinical research budgets using the Clinical Research Administrator (CLARA) budget tool. Key features include: electronic submission and approval of budgets, coverage reviews when appropriate, accurate assignment of research and clinical charges to appropriate accounts, integration with the IRB Clinical Research Administrator (CLARA) system and AR-Comprehensive Research Informatics Suite (AR-CRIS) components, electronic submission of other required reviews, contract review and approval and electronic routing and sign-off.

Initial registration of trials with www.clinicaltrials.gov. Review protocol entry into the Patient Study Calendar (PSC) and maintain the

correct date concordance.

2.2.1.3 Cancer Institute Research Nurses The Cancer Institute has registered nurses (RNs) assigned to support cancer clinical trials. Each nurse has assigned cancer disease sites, and each nurse supports clinical trials within his/her defined areas. These nurses help establish the studies once approved, recruit patients to the study, ensure adherence to the protocol throughout the life of the study and oversee subject removals from a study.

2.2.1.3.1 Clinical Trial Preparation Help with feasibility assessment Participate in budget development Attend site initiation visits (SIVs) for assigned studies Attend investigator’s meetings for assigned studies Attend National Clinical Trial Network (NCTN) meetings Assist in the development of treatment plans and orders in the electronic

medical record (EMR)

2.2.1.3.2 Clinical Trial Referrals Identify clinical trials for patients at other institutions Establish and maintain communication with other institutions for referral of

patients to participate in Cancer Institute clinical trials Provide medical records for referrals as requested Coordinate clinical trial activities at the Cancer Institute for patients enrolled

in clinical trials at other institutions

2.2.1.3.3 General Facilitation of Clinical Research Activities


http://www.clinicaltrials.gov/


Serve as an information resource for Cancer Institute clinical trials Attend PRMC meetings Serve as Nurse Liaison for National Clinical Trial Network (NCTN)NCTN

Committees Serve on NCTN Nursing Committees Serve as Coordinator of Nursing Workshop for NCTN Nursing Committees

2.2.1.4 Cancer Institute Protocol Review and Monitoring Committee (PRMC) The purpose of the PRMC is to ensure adequate internal oversight of the scientific aspects of all cancer clinical trials at UAMS. All trials evaluated by the PRMC for merit have access to Cancer Institute-supported centralized resources, such as Bioinformatics, Biostatistics and CCTRA.

Specifically the PRMC performs the following activities: Evaluate all therapeutic and prevention cancer center trials, whether derived and

supported from institutional sources or from industry. The PRMC does not duplicate traditional peer review, including that which is conducted through various NIH or other federal funding mechanisms.

The following types of clinical research are not subject to PRMC review:o Studies dealing with healthy human subjects and the population sciences,

e.g. observational and epidemiologic studieso Chart reviewso Cooperative group studies

Assess new trials for scientific rationale, study design, expected accrual rates, adequacy of biostatical input and feasibility for completion within a reasonable time period

Monitor ongoing studies to evaluate scientific progress, including reasonable accrual rates to ensure that the scientific aims of the study can be completed

With input from the Cancer Institute DOCs, prioritize the activation of cancer clinical protocols with respect to scientific merit and patient availability

The protocol review process is initiated by submission of required protocol information to the PRMC by CCTRA. The PRMC will not review a protocol until it has received prior approval from the appropriate DOC. Protocols may be submitted to the PRMC and IRB simultaneously, but studies cannot be activated until both the IRB and PRMC approve the study. Investigator-initiated studies requiring an IND or IDE additionally cannot be activated until the FDA has approved the IND/IDE application.

Investigator-initiated and industry protocols are assigned two scientific reviewers in the PRMC – a primary and secondary reviewer. These protocols are also reviewed by pharmacy services and the biostatistics office. A full copy of the protocol is distributed to each reviewer, and he/she completes a written review summarizing the protocol and



analyzing its design, including the background, objectives, methodology, treatment plan, biostatistical design issues, data collection and analysis and data and safety monitoring plan (DSMP).

The PRMC meets monthly. At the time of the PRMC meeting, the scientific, pharmacy and biostatistical reviewers discuss all the protocol’s scientific elements in detail. Following discussion by the full committee, a voice vote is taken, which in most cases reflects a consensus reached during the discussion. The committee chooses one of five recommendations: Approval: The study is approved by the PRMC. The study can proceed once it

receives IRB approval (and FDA approval of the IND/IDE application if required.) Approval with comments: The committee’s comments are suggestions to the PI, and

no further review by the PRMC is needed. The study can proceed once it receives IRB approval.

Approval with contingencies: The PI is informed of the committee’s suggested study modifications or clarifications, and the PI is required to respond adequately to these modifications and/or clarifications. The full PRMC reviews the PI’s response to the PRMC to determine if the study can proceed or further modifications are needed.

Tabled: The PI is informed that the study requires significant revision before it can be considered by the PRMC. The full PRMC will review the resubmission of these protocols.

Disapproved: The study is returned to the PI with a letter of explanation. The protocol must be re-written and submitted as a new study.

All PRMC decisions regarding the action of the committee are conveyed in writing to the study’s PI in a letter from the PRMC chair. For protocols that are approved with contingencies, tabled or disapproved, the PI is required to respond within 12 months. If no response from the PI is received within 12 months, the protocol is considered to have been withdrawn. The status of each protocol for which a response is pending is maintained and reported to the committee.

Expedited review is a process through which certain kinds of studies are reviewed by the PRMC chair, or reviewers designated by the chair, rather than the full PRMC. Expedited review is permitted when the project is found by the reviewer(s) to involve no more than minimal risk. Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. All retrospective studies undergo expedited review.

The PRMC assesses ongoing trials to assure that accrual is on target and closes studies not meeting accrual targets.



2.2.1.5 UAMS Office of Research and Regulatory Affairs (ORRA) As a protocol is being finalized, the UAMS ORRA assists with Investigational New Drug or Device submissions to the Food and Drug Administration (FDA). While the CCTRA provides initials registration of a trial in www.clinicaltrials.gov, ORRA then reviews the registration, finalizes and submits it.

2.2.1.5.1 IND and IDE SubmissionsThe ORRA Regulatory Affairs unit is responsible for all UAMS investigator-initiated drug and medical device studies where an Investigational New Drug (IND) application or an Investigational Device Exemption (IDE) is required. UAMS acts as the sponsor for all INDs and IDEs filed on behalf of UAMS investigators. This unit files all such applications with the U.S. Food and Drug Administration (FDA) and maintains the official UAMS IND/IDE regulatory files. This unit also ensures that all IND and IDE studies remain in compliance as required under Title 21 of the Code of Federal Regulations (21 CFR). Specific support services are detailed below:

Investigational New Drug Studies (IND): Regulatory Strategy – The Regulatory Affairs staff assists in helping

investigators with all of their regulatory needs throughout their series of investigations.

FDA Interaction – The Regulatory Affairs staff assist in seeking FDA input at various intervals, and all communication or correspondence with this government agency is conducted by the Regulatory Affairs staff or coordinated through their services. Examples include submissions, teleconferences and meetings.

Regulatory Review – The Regulatory Affairs staff will perform a review of the clinical protocol to determine if an IND or IND exemption may be needed.

IND – An IND will be needed if the protocol: 1) uses a new chemical/biological entity, 2) uses a marketed drug in support of a different indication, 3) significantly increases the risks associated with the use of the drug product (e.g. changes the route of administration, dosage level, patient population, etc.) 4) alters the manufacturing of a marketed drug product entity, or 5) does not purchase a marketed product but manufactures or contracts for the manufacture of the drug product.

IND Exemption – An IND exemption may be requested by the Regulatory Affairs staff if the drug is lawfully marketed in the United States and meets the following requirements: the investigation is not intended to be reported to the FDA as a well-controlled study in support of a new indication nor intended to change the labeling OR the investigation does not involve a route of administration, dosage level, use in a patient population or other risk factors that significantly increase the risks to subjects or decrease the




acceptability of the risks. In the case of marketed cancer drugs, an IND is not required if the study is determined to fit the exemption criteria in FDA’s Guidance “IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer”

Filing and Maintenance – The Regulatory Affairs staff assist investigators in the preparation, filing and maintenance of all applicable regulatory documents required to be submitted to the FDA. The Regulatory Affairs staff maintains the regulatory relationship between UAMS and the FDA throughout the trial life of the IND.

Investigational Device Exemption (IDE) Studies: Regulatory Strategy - The Regulatory Affairs staff assist in planning for the

regulatory needs throughout a product’s development lifecycle or throughout a series of investigations.

FDA Interaction - The Regulatory Affairs staff assist in seeking FDA input at various intervals, and all communication or correspondence with this government agency is conducted by the Regulatory Affairs Staff or coordinated through their services. Examples include submissions, teleconferences and meetings.

Risk Determinations and Project Evaluation - Device studies are evaluated on an individual basis by the Regulatory Affairs Unit, and if required, the Device Determination Committee of the ORRA, to determine if an Investigational Device Exemption (IDE) is required. If an evaluation cannot be completed, the Regulatory Affairs Unit will contact FDA for guidance.

Non-Significant Risk Device Investigations (NSR) - NSR devices are devices that do not meet the definition of a Significant Risk device as defined by FDA. An abbreviated IDE is required for these types of investigations. The Regulatory Affairs Unit will be responsible for maintaining the sponsor records and informing investigators of their regulatory responsibilities.

Significant Risk Device Investigations (SR) - These investigations require a full IDE submission to the federal agency. This submission will be completed by the Regulatory Affairs unit in conjunction with other units of ORRA and the investigator. Following FDA clearance, the IDE records will be maintained by the Regulatory Affairs unit. The unit will also be responsible for informing investigators of their responsibilities.

Premarket Notification (510K) or Premarket Application (PMA) - The Regulatory Affairs unit will serve as the coordinator of any submission in support of a 510K or PMA to the FDA. These are the two methods of obtaining clearance (510K) or approval (PMA) for a medical device to be marketed.

2.2.1.5.2 Good Practices for Drug and Product Development (Quality Assurance)



The Quality Assurance Unit (QAU) supports UAMS investigators by focusing on key quality issues associated with research protocols. The mission of the QAU is to maintain a quality program that ensures compliance with all federal, state and local regulations governing the manufacture of drugs, biologics, devices, human cells, tissues or tissue-based products to promote the health and safety of employees and research subjects at UAMS. Relying on QAU experience, the investigator may avoid delays in obtaining FDA and/or IRB approvals. The QAU will assist in identifying and preparing documentation necessary for use of any drug, biological or device made by UAMS researchers for use in preclinical or clinical trials. QAU is also responsible for approving all IND drug products, manufactured by UAMS, for use in the clinical trial based on predetermined specifications filed with FDA in the IND submission. QAU also provides vendor qualification services to approve contract manufacturers for use in a clinical trial. In addition, QAU is able to evaluate the need for standard operating procedures, equipment qualifications, spreadsheet validation, processing records and controls and environmental monitoring. QAU also provides consultation for researchers doing device research in the development of a device history file that is required by FDA in 21 CFR 820.30 (j). The ORRA QAU has been designated to fill the quality unit role for preclinical studies at UAMS conducted under the Good Laboratory Practice (GLP) regulations found in 21 CFR 58.

The QAU focuses on 6 key systems of good practice regulations for research and non-research entities: 1) Quality assurance 2) Facilities and equipment 3) Materials 4) Manufacturing and processing 5) Packaging and labeling and 6) Laboratory controls. These systems include GLP and Good Manufacturing Practices (GMP). The services provided by QAU are shown below: Consultation regarding applicable regulations Performance of manufacturing analysis Determination of facility requirements Drug manufacturing project management Review of drug substance Planning and establishment of manufacturing process controls Establishment of packaging and labeling controls Determination of analytical and documentation requirements Qualification/validation services Standard operating procedure development Record review and quality auditing services Environmental monitoring consultation

2.2.1.5.3 Contracts/Legal ReviewThe Office of General Counsel provides legal review and contract negotiation services for UAMS research contracts for both industry-sponsored research and


Laura Hutchins, 10/24/17,

Do we have this now?


investigator-initiated research projects. With financial support from the Cancer Institute, this unit provides priority services for Cancer Institute research. The ORRA legal team reviews contracts, including payment terms of the research project, and informed consent forms. Agreements such as Material Transfer Agreements (MTAs), HIPAA Data Use Agreements (DUAs) and other contracts related to research are vetted through this unit. Contracts are reviewed on a first in-first out basis.

Research related contracts for legal review include the following: Confidentiality Agreements and Non-Disclosure Agreements (NDAs) Investigator-initiated Clinical Trial Agreements (CTAs) receiving financial

support, drug, device or other materials from an entity outside of UAMS Industry sponsored CTAs Cooperative Group CTAs Compassionate / Emergency CTAs MTAs Research agreements Research testing agreements Research licensing agreements Vendor agreements for services and materials to be used in research Grant subaward agreements engaging UAMS as a subsite for a clinical trial or

research HIPAA DUAs HIPAA Business Associate Agreements (BAAs) Memorandum of Understanding (MOU) Agreements Letters of Intent (LOIs) to engage in research Independent consulting agreements between an outside entity and an

employee will be negotiated by the employee’s own legal counsel. However, independent consulting agreements should be sent to the ORRA Legal unit to determine conflict of interest or intellectual property issues.

2.2.1.6 UAMS Conflict of Interest (COI) Policies and Procedures The UAMS COI Office was established in 2011 to continue UAMS' commitment to adhering to the highest standards of ethics, integrity and responsibility. The office is responsible for coordinating and monitoring the UAMS COI programs to assure compliance with federal and state laws and regulations, as well as UAMS policies. The Director of the COI Office reports to the Vice Chancellor for Institutional Compliance, who in turn reports to the Chancellor and the University Of Arkansas Board Of Trustees. All UAMS employees must submit COI disclosures annually, and these disclosures must be updated by investigators with each grant submission.



Research at UAMS is devoted to the advancement and dissemination of knowledge, education of students and improvement of the public health and welfare. Research devoted to these ends may also generate financial benefits to UAMS and individual investigators, such as through patents and licensing. The purpose of this policy is to provide appropriate institutional safeguards to assure that the potential for financial gain is not allowed to inappropriately influence the design, conduct, review or oversight of research performed at UAMS.

UAMS policy assures that institutional decision-making is free from improper influence resulting from conflicting financial or economic interests. This policy addresses situations where the decision-making of a UAMS official with respect to research activities may be or appear to be affected by a conflicting financial or economic interest of the official or UAMS. Because the existence or appearance of such institutional COIs can lead to perceived or actual bias, an environment of transparency is essential to allow UAMS leaders to deal appropriately with actual and potential COIs to assure integrity in research and education while allowing for newly discovered technologies to be used for public benefit. UAMS officials are responsible for disclosing potential institutional COIs so such conflicts may be appropriately managed in accordance with the mission of UAMS. Individual COIs of UAMS staff members who do not meet the definition of a UAMS official shall be governed by the UAMS COI policies for academic and non-academic staff members.

Administration of institutional COI matters is handled by the Conflict of Interest Office (COI Office).

The Institutional Conflict of Interest Committee (ICOIC) reviews and manages institutional COIs related to research. The ICOIC is a standing UAMS committee appointed by the Vice Chancellor for Institutional Compliance (VCIC). The ICOIC consists of seven voting members and a number of non-voting ex-officio members as determined by the VCIC. Members serve renewable three year terms. Two voting members are also members of the UAMS Academic Conflict of Interest Committee. Members may also be appointed from outside UAMS. A quorum consists of four voting members. Decisions of the ICOIC are by majority vote of the members present. The ICOIC is advisory to the Chancellor, who holds final authority regarding questions of institutional COIs. The ICOIC meets annually and on an ad hoc basis at the direction of the Chair to review existing and newly identified institutional COIs.

The COI Office reviews each disclosure and if any issues are identified, they are reviewed by the ICOIC and a management plan is developed and approved. The COI Office notifies the IRB when a staff member has been determined to have a COI. The staff member is placed under a management plan, and the IRB is provided with a copy of the plan. The



COI Office is also notified of all new IRB protocol submissions. If any investigators listed on a protocol have a potential COI, the COI Office notifies the IRB.

COIs are identified and managed through the online Total Research and Compliance Knowledge System (TRACKS).

2.2.1.7 UAMS Institutional Review Board (IRB) The UAMS IRB comprises four separate committees of healthcare providers from a variety of disciplines and lay representatives from the at-large community. The IRB has the authority to approve, disapprove or require modifications of research activities that fall within its jurisdiction. In addition, the IRB may work in conjunction with other university or institutional committees; however, it reviews research projects independently based upon the principle that human participants will be adequately protected.

The UAMS IRB serves the following institutions: UAMS, Arkansas Children’s Hospital (ACH), Arkansas Children’s Hospital Research Institute (ACRI), Arkansas Department of Health (ADH) and University of Arkansas Clinton School of Public Service.

UAMS received full reaccreditation from the Association for Accreditation of Human Research Protection Programs (AAHRPP) in 2012. This accreditation follows the demonstration of high scientific and ethical standards as well as policies and procedures that safeguard human research participants. The reaccreditation is valid through September 2016.

2.2.1.7.1 Principals Governing the CommitteeThe mission of the IRB is to review research involving human subjects and to ensure that the risks and benefits of the research are appropriate and to ensure that there is full compliance with federal regulations for the protection of human subjects in research. All human subject research overseen by the UAMS IRB is guided by the ethical principles set forth in the report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (the “Belmont Report”). The three basic principles relevant to the protection of human subjects in biomedical and behavioral research as set forth in the Belmont Report are: 1) Respect for Persons: recognition of the personal dignity and autonomy of individuals and special protection of those persons with diminished autonomy; 2) Beneficence: obligation to protect persons from harm by maximizing anticipated benefits and minimizing possible risks of harm; and 3) Justice: fairness in the distribution of research benefits and burdens. The IRB operates under a Federalwide Assurance (FWA) in which it agrees to uphold the ethical principles of the Belmont Report and to apply 45 CFR 46 and its subparts to all human subject research, regardless of funding source. In addition, the IRB



operates according to state and institutional regulations, and all IRB documents and proceedings are considered confidential and protected as such.

2.2.1.7.2 Authority of the CommitteeThe UAMS IRB has the authority to: 1) Approve, disapprove or require modifications of all human research activities 2) Require progress reports from the investigators and oversee the conduct of the studies 3) Suspend or terminate approval of an ongoing study 4) Reopen terminated/closed protocols 5) Observe or have a third party observe the consent and research processes.In order to approve human research, the IRB shall determine that all of requirements outlined in UAMS IRB Policy 7.1 are satisfied. In its review of human research, the IRB has jurisdiction over all aspects of research including, but not limited to:

methods of identifying potential subjects methods proposed for contacting potential subjects materials to recruit subjects and proposed compensation pilot studies proposals to use or provide stored blood, tissues or confidential data surveys and questionnaires the informed consent process and forms, surveys, questionnaires and any

other research-related materials that will be seen by the subject investigator COIs the protocol and summary of the research evaluation of risks and benefits to subjects unanticipated problems involving risk to subjects proposed changes to the research continuing reviews use of investigational drugs and devices in emergencies humanitarian use of drugs and devices eligibility for exemption or expedited review

No human research project may begin on the UAMS campus until IRB approval has been received. Human research approved by the IRB may be subject to further review by other institutional committees or officials. The institution where the research will be conducted retains the right to disapprove any research covered by these policies. However, an institution may not approve any research that the UAMS IRB has disapproved or declined.

2.2.1.7.3 IRB Leadership and Committee MembershipThe IRB Executive Committee is as an active resource to identify new IRB policies and procedures necessary to ensure the efficient operation of the IRB, to review


http://www.uams.edu/irb/03-23-2011%20IRB%20Policy%20Updates/Document%2014%20IRB%20Policy%207.1.pdf


and amend current policies and procedures as needed and to ensure compliance with the standards of human subject protections as set forth in the Belmont Report and federal, state and institutional rules and regulations. The Executive Committee consists of the Vice Chancellor for Research, the Chair(s) of the IRB, the Director of the IRB and the Research Compliance Officer or designee. As needed, IRB reviewers, research staff or representatives from other offices or institutions, such as the ORRA, ACHRI or the General Counsel’s office are included.

The UAMS IRB complies with the membership requirements of United States Department of Health and Human Services (DHHS) regulations defined in 45 CFR 46.107 and FDA regulations defined in 21 CFR 56.107 as follows: Each IRB has at least 5 members. IRB members possess varying backgrounds to promote complete and

adequate review of research activities commonly conducted at institutions where the UAMS IRB serves as the designated IRB.

IRB members are sufficiently diverse relative to race, gender, cultural background and sensitivity to community attitudes so as to promote respect for the IRB’s advice and counsel in safeguarding the rights and welfare of human subjects.

IRB members include persons able to ascertain the acceptability of proposed research in terms of institutional commitments, regulations, applicable law and standards of professional conduct and practice.

IRBs consist of qualified persons of both genders. No IRB consists entirely of members of one profession. Each IRB includes at least one member whose primary expertise is in a

scientific area. Each IRB includes at least one member whose primary concerns are in non-

scientific areas. Each IRB includes at least one member who is not otherwise affiliated with

the institutions governed by the IRB and who is not part of the immediate family of a person who is affiliated with any of these institutions.

Additionally, IRB reviewers have the right and obligation to report any undue pressure on them to make decisions at IRB meetings that would favor an investigator or the institution over the welfare and safety of the research subject. These circumstances may be reported directly to the IRB chair, IRB director, Vice Chancellor for Research, Legal Counsel, Deans or Department chairs. These circumstances may also be reported anonymously through the Compliance Hotline at 888-511-3969. The Vice Chancellor for Research will follow up on reports by leading an official investigation, and actions appropriate to the findings of the investigation will be taken.



In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law and standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects. These additional non-voting members serve at the request of the IRB and provide an essential representation and expertise to review of these protocols.

All IRB reviewers must complete initial orientation and the web-based Human Subject Protection training courses appropriate to IRB reviewers at http://www.citiprogram.org. Initial training covers the following areas: 1) IRB overview, regulatory criteria and HIPAA 2) How to review a protocol 3) How to use the reviewer checklists 4) Code of conduct for IRB membership 5) Introduction to CLARA 6) What to expect in an IRB meeting 7) IRB contacts and process for agenda assignments 8) Resources including IRB policies, The Nuremberg Code, Declaration of Helsinki, Belmont Report and select CFR sections.

Reviewers must also participate in at least one continuing education event every year. These opportunities include pertinent topics or policies and procedural changes discussed during scheduled IRB committee meetings, short educational messages called “IRB TIPS” sent to all IRB committee members and human research protections courses offered regularly by the ORC or ACH.

2.2.1.7.4 IRB Database - CLARAAll IRB submissions and correspondence are accomplished through the Clinical Research Administrator (CLARA). CCTRA staff submit all Cancer Institute protocols to the IRB on behalf of the PI through CLARA. The IRB support staff and committee members have access to CLARA, which contains information on all protocols, including the protocol number, protocol title, PI, sub-investigators, IRB approval date and protocol expiration date. The IRB database is a key element in coordinating human subject research. The IRB manager relies on this database to generate letters and reports and to ensure that the PI is conducting an approved study, and using an updated, appropriate and approved consent form.

2.2.1.7.5 IRB and COIs


http://www.citiprogram.org/


When managing conflicts of investigators involved in human subjects research, the COIC typically requests that the conflict be disclosed in informed consent documents and sometimes requests protocols be amended as part of the management plan. While the ICOIC is responsible for managing financial COIs, the IRB is responsible for the protection of human subjects. Therefore, the IRB will make the final determination of what should be included in an informed consent and how a protocol should be structured to protect human subjects. Since these responsibilities sometimes overlap, the IRB Director (who is also an ex-officio ICOIC member) and the Director of COI work together to assure appropriate communication and collaboration between the IRB and ICOIC.

2.2.1.8 UAMS Biorepository The UAMS Tissue Biorepository and Procurement Services and was created by the Cancer Institute and is a component of the UAMS Experimental Pathology shared resource. It supports cancer research initiated by the Cancer Institute, and specimens associated with Cancer Institute research receive priority. The UAMS Biorespository delivers a diverse, high quality human biospecimen repository with appropriate patient protections, best practice collection methodologies, clinical data capture mechanisms and integrated information technology. It is provided as a shared resource to UAMS research programs for the purpose of enhancing diagnostic, preventative and therapeutic cancer research efforts.

2.2.1.8.1 OrganizationThe Experimental Pathology Shared Resource is governed by a scientific advisory committee called the Steering Committee. The Biorepository Scientific Director serves on this committee and reports to the Cancer Institute Associate Director for Shared Resources. An external advisory committee is currently being formed.

The Steering Committee (SC) provides strategic guidance, scientific feedback and advice on resource development to the biospecimen resource management and stakeholders. The SC is composed of the following individuals: 1) Experimental Pathology Shared Resource Director 2) three at-large representatives each from the College of Public Health, College of Nursing and College of Medicine or College of Pharmacy 3) Cancer Institute Associate Director for Shared Resources 4) Cancer Institute Associate Director for Clinical Research 5) a representative from the Department of Pathology 6) a representative from the Division of Biomedical Informatics and 7) an external advisor.

2.2.1.8.2 Services ProvidedServices provided include: 1) Collection, processing, shipping and storage of samples and related data and 2) Provision of specimens and related data to



This may not be correct any longer

Laura Hutchins, 10/24/17,

Check with Dr. Post


investigators for research. The UAMS Biorepository supports the collection and use of specimens for individual protocols as well as general specimen collection. Use of UAMS Biorepository specimens for the purposes of research require an IRB-approved protocol authorizing specimen acquisition.

The Biorepository has a consent form available for use by all PIs interested in patient specimen collection. If the PI would like to use the Biorepository consent, his/her protocol can simply state that the tissue will be obtained from the UAMS Biorepository. A supplemental protocol to allocate specimens to a specific protocol and to specify specific processing procedures should be used and is in the appendix of this document.

In their review of all Cancer Institute protocols, the DOCs consider all proposals that involve a request for retrieval of tissues from the Biorepository and serve as the approving body for all research activities involving the Biorepository.

2.2.1.8.3 Information ManagementThe UAMS Biorepository uses caTissue for biospecimen inventory management, tracking and annotation. caTissue is a component of AR-CRIS, and caTissue details are provided below.

2.2.1.8.4 CollectionsThe biorepository is composed of solid tissue samples, serum samples, blood samples, urine samples and bone marrow aspirates. Most of these samples were collected by Cancer Institute investigators.

2.2.1.8.5 Fee Structure The Biorepository Laboratory has historically been solely funded by the Cancer Institute, with salary support from the Department of Pathology. A fee structure is being developed according to OMB-circular A-21 guidelines.

2.2.2 Post Activation Study Management

2.2.2.1 Cancer Institute DOCs Once a study has opened, DOC responsibilities include reviewing clinical trial enrollment and making regular determinations if enrollment is sufficient to justify the cost of keeping a trial open. Each DOC is tasked with keeping an average enrollment of 5 patients per trial per year. A monthly report is sent to the PRMC.

2.2.2.2 Cancer Institute CCTRA CCTRA provides the following support services after a clinical trial has been approved by the IRB and PRMC:



?????


?????

http://www.whitehouse.gov/omb/circulars_a021_2004


Maintain and store regulatory documents Enter and maintain clinical trials into the ClinicalTrials.gov database as needed Serve as a point of contact for internal offices and external agencies Coordinate and facilitate monitoring visits and study close-out process/visits Prepare and submit all regulatory documents including but not limited to protocol

amendments, consent form changes, deviations/violations and adverse events to the IRB and any other required units

Register subjects for clinical trials Enter study data into AR-CRIS Submit subject data to clinical trial sponsors and appropriate committees as needed Collaborate with internal offices and external agencies to fulfill research

requirements Coordinate the process and shipment of subject specimens Maintain study subject charts and verify source documentation for clinical research

purposes.

2.2.2.3 Cancer Institute Research Nurses

2.2.2.3.1 Recruitment of Subjects to Clinical Trials Present protocol information, Informed Consent forms and HIPAA

documents to potential study subjects Obtain patient consent and witness signature and provide a copy of the

document to the patient; document informed consent in the electronic medical record (EMR)

Maintain a current list of all patients in the evaluation process Obtain pathology, laboratory, radiology, treatment history, etc. as required

to verify clinical trial eligibility requirements Follow-up on screening test results Collaborate with investigators to complete eligibility screening Collaborate with the CCTRA Clinical Research Associate (CRA) to complete

study registration Document subject registration, ID number and randomization assignment in

the AR-CRIS and broadcasting to the EMR Register the subject to the clinical trial in AR-CRIS a UAMS institution-wide

clinical portal Screen new patients for protocol eligibility and notify investigators prior to

their appointment Review protocol eligibility with referring physician’s offices prior to referral Provide information to assist CRAs with completion of screening logs Maintain and answer the Clinical Trials Information phone

2.2.2.3.2 Ensuring Adherence to Protocols



Coordinate patient care for subjects entered on clinical trials Identify clinical trial subjects from the daily clinic schedule and coordinate

with the clinic nurse Synchronize the dates of visits with AR-CRIS. Coordinate protocol activities daily with the patient scheduler, CRAs. Verify that all clinical trial written orders have been scheduled Take/return phone calls and reply to emails from patients/family and

document Administer Quality of Life (QOL) assessments if required by the protocol Notify CRAs of adverse events for timely reporting to the IRB and protocol

sponsor Evaluate and document assessment of study subjects into the EMR at the

time of visit; assessments include symptom assessment, vital signs, concomitant medications, allergies, pain assessment.

Participate in physician visit if necessary Assist physician if necessary to order study treatment Assist physician as needed to complete return to clinic orders and verify that

all required orders are entered Photograph tumors if required by protocol Re-consent study subjects as required by study and document the re-consent

process in the EMR Serve as a resource for local physicians, nurses and laboratories that provide

care for patients who are enrolled in clinical trials Assist CRAs to resolve sponsor queries

2.2.2.3.3 Off Study Notifications Notify CCTRA CRA of subject’s off study status and reason for removal Document off study status in the EMR

2.2.2.4 AR-Comprehensive Research Informatics Suite (AR-CRIS) Since 2006 UAMS has been developing AR-CRIS, formerly known as the Clinical Trials Management Suite (CTMS). AR-CRIS is a comprehensive set of open source software tools for electronic management of clinical trials and associated data. Many of these tools were developed as part of the National Cancer Institute’s (NCI) Cancer Bioinformatics Grid (caBIG®) system. All components of the UAMS AR-CRIS are web-based, enabling sharing and integration of clinical research information for single and multi-site trials. All applications are integrated into a portal that allows a single point of access with a registered UAMS username and password. All AR-CRIS applications reside on a cluster server with failover capability behind the UAMS firewall, and thus workflow is shown in Appendix III.

2.2.2.4.1 Clinical Trial Management



UAMS TrialSearch is an application that provides internal publication of open and enrolling studies at UAMS. It provides basic study details and study status and allows CCTRA staff to edit study details such as enrollment eligibility and study objectives. The internal version also shows protocol and consent documents to be used in UAMS clinics for recruiting patients during an office visit.

The subject registration application, RPRS, enables efficient and streamlined registration of participants into clinical trials. It captures the consent signed date, eligibility criteria, screen failures, stratification, randomization and amendments. Clinical workflows are enabled by both subject- and study-centric views into the registration process. RPRS also enables multi-site clinical trials where registration information is entered locally at affiliate sites and completed by the coordinating site. Registration data can be pulled from UAMS to minimize manual data entry and enhance data quality. RPRS serves as a registration tool for therapeutic and observational studies.

Patient Study Calendar (PSC) is a standards-compliant application for creating and managing subject activities and study calendars. It provides the ability to create and edit study calendar templates, generate and view prospective calendars of subject activities, track activities as they occur and manage subject calendars as they change during a study. PSC accommodates all types of clinical studies and facilitates management of the screening process, registration, active monitoring and long-term follow-up.

EventTracker (ET) is an application for tracking key regulatory dates such as IRB submissions and approvals. Additionally it shows basic study details and past and upcoming continuing review reports. A study monitoring notification has been implemented to trigger notification based on protocol requirements of monitoring. Pre-study tracking is available to capture study details prior to IRB submission, and this allows the Cancer Institute to track the time it takes to open a study from the point of initial contact with the study sponsor.

The Delegation of Authority Log is an electronic delegation of authority available through ET. It allows each study to delegate research responsibilities to each individual on the study team. Their roles and responsibilities are assigned, the staff is given the ability to sign off on those responsibilities, and then the PI will approve and sign off on all delegations. All study stuff are trained according to the responsibilities of the study, and this training is tracked and documented on the Delegation of Authority Log. This process and documentation is available throughout the life of the study.

SugarCM is a customer relationship management tool that allows tracking of screening day events, creates reminders and creates purchase orders. SugarCM is used primarily for cancer control studies.



A number of reports have been created to easily retrieve data such as enrollment by physician and staff workload.

2.2.2.4.2 Electronic Data Capture OpenClinica is a 21 CFR Part 11-compliant application for electronic data

capture. The application supports data submission, validation, annotation, filtering and extraction as well as study oversight, auditing and reporting. It has sophisticated data security controls, allowing role-based access to allow researchers to access their studies and nothing else. OpenClinica is an integrated component of AR-CRIS.

LimeSurvey is a robust and user-friendly application for creating online surveys. It enables users to quickly create surveys, deliver questionnaires to respondents, collect responses and analyze or export results in various formats. In addition to a large range of question types and presentation methods, LimeSurvey allows for participant management through tokens and branching logic through conditional questions.

Redcap Pre Screening

2.2.2.4.3 Adverse Event (AE) Reporting AR_Adverse Event Reporting System (AR-AERS) was developed internally to

be used in the clinic to capture adverse events (AEs) based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4. It is an easy-to-use tool that integrates the data with the clinical EMR and OpenClinica. The CTCAE criteria and grades were created in LimeSurvey, and AR- AERS reads and manages LimeSurvey entries.

2.2.2.4.4 Biological Specimen TrackingcaTissue is a biorepository tool for biospecimen inventory management, tracking and annotation. It permits users to enter and retrieve data on the collection, storage, quality assurance and distribution of biospecimens. It supports multiple repositories and can log specimens by barcode. The application is currently used by the UAMS Biorepository, which coordinates and oversees the donation, processing, storage and dissemination of tissue specimens and related data.

2.2.2.4.5 Microarray AnalysiscaArray is an array data management system that allows researchers to collect, manage, annotate and exchange data from microarray experiments. It also facilitates integration of array data with diverse data types including clinical, imaging, tissue and other functional genomic data. caArray supports Illumina next generation sequencing, and caArray data is shareable across the caBIG® Grid. caArray furthers translational cancer research through acquisition, dissemination and aggregation of semantically interoperable array data to



Will need info


support subsequent analysis by tools and services on and off the Grid. As array technology advances and matures, caArray will extend its logical library of assay management.

2.2.2.4.6 Arkansas Clinical Data RepositoryData Warehouse (AR-CDR)In December 2011, UAMS launched an AR-CDR, called the UAMS Data Trust, to facilitate access to and integration of clinical, basic-science and other data for research and quality reporting. Currently, the UAMS Data Trust is updated monthly and contains electronic health care data from four clinical source systems. As time progresses, other sources of data will be identified and incorporated, and updates will occur more frequently.

2.2.2.4.7 TriNetx version of Informatics for Integrating Biology and the Bedside (i2b2)i2b2 is an open-source platform for retrieving de-identified data from the UAMS Data Trust. i2b2 is one of the NIH Roadmap initiatives and was designed primarily for cohort identification prior to starting a study, allowing users to perform queries to determine the existence of a set of patients meeting certain inclusion or exclusion criteria . This is accessed through a request to TRI.Honest Broker SystemIn August 2010, UAMS established an honest broker system to complement the UAMS Data Trust. In 2012, the Honest Broker Certification for Research program and policy were developed. All honest brokers must be certified according to UAMS policy. The Cancer Institute has its own designated certified honest broker.

An honest broker is defined as: A neutral intermediary (person or system) between the researcher and the individual whose tissue and data are being



Add the link


studied and the healthcare provider who obtained the tissue and data for patient care purposes. The honest broker collects and collates pertinent information regarding the tissue, data, biological specimens and/or images, replaces identifiers with a code and releases only coded information to the researcher (adapted from http://www.hhs.gov/ohrp/sachrp/20110124attachmentatosecletter.html ).

2.2.2.4.8 Health Plan Claims DatabaseThe LifeLink™ Health Plan Claims Database is comprised of commercial health plan information obtained from managed care plans throughout the United States. It includes information collected by the medical plans from medical service providers to facilitate the adjudication and payment of health insurance benefits on behalf of the plan’s enrolled members. It has fully adjudicated medical and pharmaceutical claims for over 61 million unique patients from more than 98 health plans across the nation. The database includes inpatient and outpatient diagnoses (in ICD-9-CM format) and procedures (in CPT-4 and HCPCS formats) as well as retail and mail-order prescription records. Available data on prescription records include the National Drug Code (NDC) as well as the quantity of the medication dispensed.

2.2.2.5 Cancer Institute PRMC Each Cancer Institute DOC reviews accrual to their disease site clinical trials throughout the year. On a monthly basis, the DOC coordinators provide the PRMC with accrual data and their committees’ recommendations for how to proceed with the studies. Options include keeping the study open, closing it or keeping it open for a defined period of time to determine if accrual can be increased. The PRMC is then responsible for taking action per the DOCs’ recommendations.

2.2.2.6 UAMS ORRA Once a clinical trial has been opened, UAMS ORRA Regulatory Affairs staff maintains all official IND/IDE regulatory files to ensure that all IND and IDE studies remain in compliance as required under 21 CFR. Additionally, the Regulatory Affairs staff coordinates all communication between UAMS study personnel and the FDA. The ORC oversees all FDA audits on the UAMS campus, but the ORRA RAU provides assistance in the case of investigator-initiated trials or otherwise UAMS-sponsored trials undergoing an FDA audit. In these cases, RAU staff will assist in making sure the PI and UAMS are prepared for that audit. If the clinical trial is under an IND/IDE, QAU would continue its supportive services in the manufacture and control of the product.

2.2.2.7 UAMS IRB

2.2.2.7.1 Continuing Reviews



Does this still apply How do we access?

http://www.hhs.gov/ohrp/sachrp/20110124attachmentatosecletter.html


Periodic review of all human research activities is necessary to determine 1) whether the risk/benefit ratio has changed, 2) whether there are unanticipated problems involving risks to subjects and 3) whether any new information regarding the risks and benefits should be provided to subjects. The UAMS IRB must conduct substantive and meaningful continuing review of research at intervals appropriate to the degree of risk. The IRB must decide the frequency of continuing review for each study protocol necessary to ensure the continued protection of the rights and welfare of research subjects. The IRB must review each study at least once per year and can require more frequent reviews. All non-exempt research protocols must be periodically reviewed, not less than one time per year, in accordance with UAMS policy.

Failure to submit a timely continuing review will result in expiration of the protocol. If the IRB has not reviewed and approved a research study by the continuing review expiration date, all research activities must stop. No new subjects may be recruited or enrolled.

2.2.2.7.2 Protocol ChangesThe UAMS IRB must review and approve all proposed modifications to approved research prior to implementation. The term “approved research” encompasses all study documents, processes and procedures. All modifications will be reviewed to determine that the research satisfies all of the regulatory approval criteria outlined in UAMS IRB Policy 7.1. When modifications affect one or more of the approval criteria, also called major modifications, the modification must be reviewed by the convened IRB. Minor modifications may be reviewed by the expedited review process.

The IRB must be notified within 30 days of a change in the PI. UAMS requires that when a PI leaves UAMS, the study is stopped or the protocol must be modified to reflect a new local affiliated investigator named as the PI. Sub-investigator changes are considered minor protocol revisions, but must also be approved by the IRB before the changes can be implemented.

2.2.2.7.3 AuditsThe IRB is charged with the task of overseeing all internal and external monitoring and/or auditing efforts in order to ensure the protection of human research participants and compliance with federal regulations and institutional policies. Audits conducted by the UAMS Office of Research Compliance (ORC) are shared with the IRB and the IRB considers the audit report and PI’s response before recommending action. If the trial is an IND and is manufacturing at UAMS, QAU will conduct periodic audits of the manufacturing operation in order to ensure compliance with GCMPs.


http://www.uams.edu/irb/03-23-2011%20IRB%20Policy%20Updates/Document%2014%20IRB%20Policy%207.1.pdf


2.2.2.8 UAMS Research Pharmacy The UAMS Research Pharmacy offers researchers excellent support during drug trials and through communication in the IRB review process. The Research Pharmacy oversees all investigational drug studies at UAMS hospitals and clinics, and all study medications should be handled by the Research Pharmacy.

2.2.2.9 Study Training – Section to be completed at a later date

3. Data Integrity and Subject Safety

3.1 Data and Safety Monitoring

3.1.1 Risk AssessmentBased on the complexity of the study design, study endpoints, clinical complexity and study population, geography, experience of the PI, experience of the sponsor with the PI, data capture requirements, safety of the investigational product and stage of the study, the sponsor determines the risk of the trial.

A trial’s risk category can be elevated but cannot be downgraded from the following categories:

High Risk studies include:• Trials for which the PI holds the IND or IDE• Investigator-initiated phase I and phase I/II trials• Investigator-initiated multi-center trials• Investigator-initiated interventional trials using investigational agents or devices• Trials for which UAMS or the Cancer Institute is manufacturing the study agent

Moderate Risk studies include:• Intervention trials sponsored by industry, national cooperative groups or NCI/NIH and

include appropriate/approved DSMPs• Investigator-initiated phase II, II/III or III single institution studies that utilize only FDA

approved agents/devices

Low Risk studies include:• Non-intervention trials, including epidemiology, observation, outcomes, QOL,

correlative, laboratory and ancillary trials• Intervention trials that are nutritional, behavioral or psychosocial in nature• Intervention trials that are diagnostic in nature

3.1.2 Data and Safety Monitoring Plans (DSMPs)



As stated in UAMS IRB Policy, “research that is submitted as, or determined to be, greater than minimal risk must provide a plan for monitoring the data to ensure the safety of the subjects. The plan should be tailored to fit the expected risk level, complexity, phase and size of the particular study.” PIs with studies that require a DSMP, must include a DSMP in their initial IRB submission. The DSMP must define the specific data to be monitored, identify the monitor, define the frequency of monitoring and define the procedures for communication from the monitor to the IRB. The PI is responsible for developing a monitoring plan appropriate to the risk of the trial.

3.1.2.1 Data and Safety Monitoring Board (DSMB) As defined by UAMS IRB Policy, “A DSMB is an independent committee set up to monitor data throughout the study to determine if continuation of the study is appropriate scientifically and ethically.”

3.1.2.1.1 Utilization of a DSMBThere are several reasons DSMB monitoring may be appropriate for a study. The FDA Guidance for Clinical Trial Sponsors defines the following criteria for DSMB monitoring: • The study endpoint is such that a highly favorable or unfavorable result, or

even a finding of futility at an interim analysis might ethically require termination of the study before its planned completion;

• There are a priori reasons for a particular safety concern, as, for an example, if the procedure for administering the treatment is particularly invasive;

• There is prior information suggesting the possibility of serious toxicity with the study treatment;

• The study is being performed in a potentially fragile population such as children, pregnant women or the very elderly, or other vulnerable populations, such as those who are terminally ill or of diminished capacity (45 CFR 46);

• The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint;

• The study is large, of long duration and multicenter

Each NIH Institute and Center (IC) has its own system for the appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of the data for all NIH-supported or conducted clinical trials. The establishment of a DSMB is required for multi-site clinical trials involving interventions that entail potential risk to the participants.

Individual funding agencies may impose additional DSMB requirements that would be followed by the UAMS DSMB.


http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf


3.1.2.1.2 DSMB MembershipUAMS employs a DSMB structure and process developed by the UAMS TRI. The DSMB for Cancer Institute studies would have additional oncology expertise added to the membership as appropriate.

Members of the TRI DSMB are appointed by the Vice Chancellor for Research. Membership duration is flexible at the discretion of the Vice Chancellor and the member. Members are chosen based on clinical research knowledge and expertise in varied areas of study. Members will be recused (including self-recusal) from particular protocols if a COI is present. All members will abide by federal, state and institutional regulations and policies. Members are expected to maintain confidentiality. A PI or the DSMB may request additional ad hoc members for specific protocols. Consultants will be asked to contribute expertise as needed. The DSMB Board will be comprised of at least three members and a chair. At least three voting members must be present for quorum. The chair will not vote unless there is a need for a tie-breaker.

3.1.2.1.3 DSMB COIPrior to serving on the DSMB, potential members will be asked to describe any COIs. General COI statements are on file in the UAMS ORSP. If there are COIs concerning individual protocols, the DSMB member will recuse him/herself from that study’s discussion or voting. Should a status change occur at any time that might result in a COI, the member of the DSMB will disclose to the Chair any real or perceived COI. The DSMB Chair will determine the appropriateness of the member serving on the Board and seek concurrence from the Vice Chancellor for Research.

3.1.2.1.4 Protocol Information Regarding DSMBsPIs are primarily responsible for tracking when their protocols are due to report to or meet with the DSMB. However, the Research Subject Advocate (RSA) office will seek to notify the investigator via email of planned DSMB meetings no less than one month prior to the DSMB meeting date. Data and Safety Monitoring reports will be completed by the PI and submitted to the RSA office no later than 10 working days before the DSMB meeting. DSMB members will be provided with the protocol, the DSMP and a Data Safety Monitoring Report.

3.1.2.1.5 DSMB Operational PlanMeetings will be based on individual protocol requirements. The frequency of the DSMB reviews will be determined by protocol requirements, but they will occur no less frequently than once a year. The chair may establish more frequent



What is this?


Need to check on this


meetings in the event enrollment is expected to finish quickly or as dictated by risk or safety concerns.

Meetings may be open or closed, the latter of which only includes DSMB members or their guests invited to contribute necessary expertise. Issues that may be discussed in the meetings include accrual, adverse events, serious adverse events, external and/or internal monitoring reports, integrity of data, compliance with the protocol, additional information that may impact the risk/benefit ratio for participants and appropriate intervals and types of DSMB monitoring.

Meetings are considered confidential and a letter from the DSMB to the PI will convey the need to report to the IRB, funding agencies or other applicable bodies. If a study is a double-blind study and it is determined that the data needs to be analyzed, the biostatistician member of the DSMB and the study’s PI will discuss the specifics related to unblinding the study for analysis. Recommendations from the DSMB require majority approval by the DSMB members.

3.1.3 Protocol Specific Monitoring3.1.3.1 Protocol Specific Monitoring Overview

Protocol specific monitoring is carried out by the Sponsor of the clinical trial. UAMS serves as the Sponsor for all investigator-initiated trials on the UAMS campus. The Monitoring unit of ORRA is responsible for monitoring all UAMS-sponsored investigator-initiated IND-IDE clinical research trials. UAMS trials that are investigator-initiated but not part of an IND-IDE application must have a data monitoring plan in the protocol to be carried out by the PI and study staff.

Industry-sponsored trials receive protocol specific monitoring through the sponsoring company. Cooperative group trials are not subject to protocol specific monitoring.

3.1.3.2 Protocol Specific Monitoring by UAMS ORRA The ORRA Monitoring unit carries out protocol specific monitoring according to the protocol’s DSMP. The protocol specific monitor is an ORRA staff member and should never be an individual that reports to anyone in the Cancer Institute.

The ORRA Monitoring unit works with PIs to ensure their studies are monitored as required by federal regulations. A trained ORRA monitor will implement monitoring activities ongoing to ensure that all sites are complying with regulatory and protocol requirements, data quality and subject safety. Monitoring occurs before the clinical phase of the protocol begins and continues during protocol performance through study completion.



Once a clinical trial has opened, ORRA schedules monitoring visits according to the monitoring plan defined in the protocol to review data collection, regulatory binders and drug/device accountability. These monitoring visits help the PI identify problem areas with the study, and they enable the correction of problems before they get out of control. ORRA’s goal is not to be punitive, but supportive. ORRA monitoring staff spends 1-2 days reviewing the records and, at the end of each visit, they meet with the PI and/or their staff for a few minutes to relay what was found during the visit. A formal letter with details of the findings is issued soon after the visit.

At the end of a clinical trial, ORRA monitors conduct a closeout monitoring visit to verify that all data has been collected. They perform a final drug/device accountability review of all regulatory documents to ensure the file is complete in the event of an audit. Should the study be audited by an internal auditor, ORRA can assist in making sure the PI and UAMS is prepared for that audit.

3.1.3.3 Protocol Specific Monitoring by Risk Category

3.1.3.3.1 Investigator-Initiated High and Medium Risk Trials

3.1.3.3.1.1 Prestudy Investigator and Site Qualification AssessmentsThe research experience of all prospective investigators and the feasibility of the prospective sites and their ability to comply with the CFR and GCPs are essential. The monitor is responsible for reviewing and documenting the experience of prospective investigators and the feasibility of prospective sites. The Sponsor is responsible for reviewing and assessing the site’s feasibility to conduct and contribute to the goals of the trial.

3.1.3.3.1.2 Study Initiation Monitoring AssessmentA study Initiation Monitoring Visit (SIV) will be provided by the Sponsor to the clinical investigators and the investigative team for all participating sites. A monitor may be assigned to conduct the SIV. The SIV will provide the appropriate training and documents to conduct the study in accordance with the approved protocol and with the applicable regulatory requirements and to confirm the continued acceptability of the investigator to conduct the study.

3.1.3.3.1.3 Interim Monitoring AssessmentsThe Sponsor or designated monitors will conduct monitoring visits to ensure that participating sites’ clinical investigators and study team members are compliant with the protocol, regulations and institutional policies, that data are of high quality and integrity and that the facilities and staffing are



adequate for continued participation in the study. The participating sites may be required to submit source documents to the coordinating center for monitoring. Participating sites are subject to on-site monitoring.

Monitoring practices may include, but are not limited to, source verification and review and analysis of the following: eligibility requirements of all participants, informed consent procedures, adverse events and all associated documentation, study drug administration/treatment, regulatory records and site trial master files, protocol deviations, pharmacy records, response assessments and data management.

All data submitted to the CCTRA will be monitored for timeliness of submission, completeness and adherence to protocol requirements. The designated monitor and the CCTRA CRA assigned to the study will perform the ongoing protocol data compliance monitoring with the support of the participating site’s coordinators, the site PI and the study PI.

Monitoring visits will be performed on a schedule according to the risk category of the trial. A risk-based approach will be used by the monitor to determine the number of participant charts and which data elements will be monitored.

Following each monitoring visit, the monitor will communicate the monitoring findings and any additional requests in a follow-up letter sent to the participating site’s site PI.

3.1.3.3.1.4 Close-out Monitoring AssessmentsThe close out monitoring visit is usually conducted when all participants have completed the study, including treatment and follow-up assessments. At the close-out monitoring visit, the sponsor is responsible for ensuring that the investigator(s) conducted the study according to the protocol and in compliance with GCP and federal and state laws and regulations. The monitor will also ensure that the investigator(s) is aware of his/her continued obligations. The close-out assessment visit is to finalize all the necessary procedures to conclude the clinical investigation at a specific investigator site.

3.1.3.3.2 Investigator-Initiated Low Risk Trials

3.1.3.3.2.1 Pre-Study Investigator and Site Qualification Assessments



The research experience of all prospective investigators and the feasibility of the prospective site and their ability to comply with the CFR and GCP is essential.

3.1.3.3.2.2 Monitoring AssessmentsThe Sponsor and/or PI is responsible to ensure that the participating site’s clinical investigators and study team members are compliant with the protocol, regulations and institutional policies, that data are of high quality and integrity and that the facilities and staffing are adequate for continued participation in the study. These low risk trials may not have a monitoring plan for regular assessment of the study; however, any monitoring decisions will be specified in the protocol meetings and documented in the minutes.

The participating sites may be required to submit source documents to the coordinating center for monitoring. The participating site will be subject to on-site monitoring.

Monitoring visits will be performed on a schedule according to the risk category of the trial. This may be accomplished by a documented study team meeting wherein the study conduct and adverse events are reviewed.

Monitoring practices may include, but are not limited to, source verification and review and analysis of the following: eligibility requirements of all participants, informed consent procedures, adverse events and all associated documentation, study drug administration/treatment, regulatory records and site trial master files, protocol deviations, pharmacy records, response assessments and data management.

All data submitted to the CCTRA will be monitored for timeliness of submission, completeness and adherence to protocol requirements. The designated monitor and the CCTRA CRA assigned to the study will perform the ongoing protocol data compliance monitoring with the support of the participating site’s coordinators, the site PI and the study PI.

The Sponsor and/or PI is required to provide oversight to ensure adequate protection of the rights, welfare and safety of study participants and the quality and integrity of the resulting data. In response to meeting this oversight role, designated trained monitors are required to report any observed, suspected or apparent research nonconformities to the IRB which will evaluate the event and determine whether it needs internal escalation. Further inquiries or investigations into the event may be needed, and the



outcome of these findings may result in increased monitoring, a for-cause audit or early closure of the trial.

3.1.4 Medical MonitorsAn independent Medical Monitor may be appointed by the study PI to oversee a clinical research project if there is more than minimal risk to the participants. The Medical Monitor will be independent of the study and have no real or apparent COI. Medical Monitors should never be a direct report to the PI of a study. In general, the Medical Monitor will have responsibilities similar to that of the DSMB and will operate in a similar manner.

3.1.5 Adverse Event (AE) ReportingAll AEs occurring during the course of the clinical study, whether drug- or device-related or otherwise, will be recorded on the AE case report form (CRF). For all AEs, the investigator will provide an assessment of the AE, its treatment and resolution and its relationship to the investigational drug or device. Special reporting procedures are required for certain AEs. The investigator will assess subjects for the occurrence of AEs at each study visit. All AEs (serious and non-serious) reported by the subject will be recorded on the source documents and CRFs.

3.1.5.1 Identification of AEs An AE is defined as any new medical problem or exacerbation of an existing problem experienced by a subject while enrolled in a study, whether or not it is considered drug/device-related by the investigator.

3.1.5.2 Relationship of AEs to the Investigational Drug or Device The investigator will assess the relationship of the AE to the investigational drug or device. The relationship will be assessed using the following categories:• Definitely Related: A direct cause and effect relationship between the investigational

drug or device/treatment and the AE exists.• Possibly Related: A direct cause and effect relationship between the investigational

drug or device/treatment and the AE has not been clearly demonstrated, but is likely or very likely.

• Unlikely Related: A direct cause and effect relationship between the investigational drug or device/treatment and the AE is improbable, but not impossible.

• Unrelated: The AE is definitely not associated with the investigational drug or device/treatment.

3.1.5.3 Unanticipated Adverse Device Effects (include only for device studies) An unanticipated adverse device effect is defined as “any serious adverse effect on health or safety, or 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 investigational plan, or application (including



supplementary application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.” If an unanticipated adverse effect occurs, the investigator will promptly notify the Sponsor of such an event within 24 hours of first learning of the event using the FDA MAR-CDRatch 3500A form. The form can be found online at: http://www.fda.gov/Safety/MAR-CDRatch/HowToReport/DownloadForms/

The investigator will promptly notify the UAMS IRB of such an event as soon as possible, but no later than 10 working days after first learning of the event.

3.1.5.4 Serious Adverse Events (SAEs) Each AE will be assessed for its seriousness using the criteria outlined below. The term SAE is not synonymous with a “severe” adverse event, which may be used to describe the intensity of an event experienced by the subject. An AE will be classified as serious if it meets any of the following criteria:• Results in, or contributes to, a death• Is life-threatening (i.e., the subject was, in the opinion of the investigator, at risk of

death at the time of the event, but it does not include an event that, had it occurred in a more severe form, might have caused death)

• Results in permanent disability or incapacity (i.e., permanent impairment of a body function or permanent damage to a body structure)

• Requires in-subject hospitalization or prolongs hospitalization• Necessitates medical or surgical intervention to preclude a permanent disability or

incapacity • Results in a congenital anomaly or birth defectNon-serious AEs are all events that do not meet the criteria for an SAE.

SAEs that meet the reporting requirements must be reported to the Sponsor as directed in the protocol. The investigator will also promptly notify the IRB of such an event. Each AE will be assessed for its severity, or the intensity of an event experienced by the subject, according to a grading scale that will be defined by the study. A sample grading scale is shown below:• Mild: Discomfort noticed, but no disruption to daily activity• Moderate: Discomfort sufficient to reduce or affect normal daily activity• Severe: Inability to work or perform normal daily activity

3.1.5.5 Deaths The investigator will notify the sponsor upon learning of a subject’s death as directed in the protocol. The investigator will also promptly notify the IRB of such an event as soon as possible. The investigator will attempt to determine, as conclusively as possible, whether the death is related to the drug or device. The cause of death and the investigator’s discussion regarding whether or not the death was drug- or device-related will be described in a written report.


http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/


3.1.5.6 Pre-existing Conditions Pre-existing conditions will not be reported as AEs unless there has been a substantial increase in the severity or frequency of the problem which cannot be attributed to natural history.

3.1.6 AuditsThe UAMS ORC is responsible for clinical trial compliance reviews (audits) on the UAMS campus. Any human subject research activity that is overseen by the UAMS IRB is subject to review. Individual studies are most commonly selected. Most often, ORC reviews studies that are reviewed by the full convened IRB, but studies that qualify for exempt or expedited status also may be chosen. Broader areas involved in research, such as a laboratory or department can also undergo review, including the UAMS IRB. ORC routinely looks at how the IRB reviewed a study. ORC also performs more general audits of the IRB. In addition to PI requests for audits, ORC performs routine and targeted audits.

3.1.6.1 Routine Audits Routine audits are the most common audit performed by ORC. ORC compiles a list of all open studies and then selects some for review using a random number table. ORC tries to focus on studies that have been open for no more than 12 months to enable helpful feedback early in the study’s course. ORC typically won’t review a PI’s study if that same PI has had another study routinely audited within the previous 12 months and the first review showed no significant problems. However, if multiple studies are funded by the same funding source, more than one of them may be audited within a single 12-month timeframe if they have different PIs.

3.1.6.2 Targeted Audits In these audits, particular studies are targeted, for eg., because they involve higher risk to subjects. Factors that may increase a study’s risk include, but are not limited to: higher-risk research procedures, such as gene therapy or phase 1 drug studies; the involvement of vulnerable populations or a study the IRB has determined requires continuing review more often than annually. If a complaint is made against a study or PI by a subject, employee or whistleblower, ORC will likely conduct a targeted audit on that study.

3.1.6.3 Auditing Process PIs are notified of an upcoming audit 2-6 weeks in advance. In the audit, ORC reviews the study material on file with the IRB prior to visiting the study site and will request documents to be reviewed on site at the audit in advance. ORC typically reviews all consent forms, the study’s regulatory binder and study records for at least 10 percent of subjects. ORC may also request other records as desired such as laboratory sample logs. ORC reviews focus on human subject protection compliance, and not on financial issues,



and ORC typically does not review financial records. Any financial questions that arise during an ORC audit are referred to another appropriate office for further inquiry.

At the end of the audit, ORC meets with the PI and any other available study staff to discuss initial observations. ORC will also meet with the PI and provide a written report two weeks later. The report will list the study strengths, recommendations, findings and suggested remediation. A copy will be sent to the IRB after review with the PI, and the PI will have two weeks to respond in writing. After reviewing the report and response, the IRB will send a letter to the PI listing specific remediation requirements.

3.1.6.4 Audits by Investigator The UAMS Director of Audit and Quality Control will review all audits conducted by the UAMS ORC. As warranted, the Director of Audit and Quality Control will report the results of the audits to the Cancer Institute Director and/or Associate Director for Clinical Research.

3.1.6.5 Protocol Specific Auditing by CCTRA (CCTRA Quality Assurance) CCTRA internally audits its studies for quality assurance. Details of this process will be documented at a later date.

3.2 Education, Training and Credentialing RequirementsThe UAMS ORC provides all Human Subject Protection Training, HIPAA Training and Responsible Conduct of Research training for the UAMS campus. Human Subject Protection Training for biomedical or behavioral research is offered through

http://www.citiprogram.org and training must be renewed every two years. All individuals conducting, reviewing or supporting human subject research at the Cancer Institute in any way are required to maintain current CITI Human Subject Training Certification.

HIPAA Privacy and Security Training is provided to all UAMS employees upon hire as part of the required orientation process. HIPAA research training is imbedded in the CITI training.

NIH and National Science Foundation (NSF) grant recipients must complete Responsible Conduct of Research (RCR) training at least once every four years. This training consists of 8 hours combined online and live training. The online component is offered through CITI. The live component is the Advanced Research Ethics course offered by the Compliance Education Program in ORC. It is taught by UAMS research faculty or coursework judged to be comparable.

The Certified Research Specialist (CRS) program provides essential training in key areas for individuals involved in research at UAMS. CRSs complete 26 hours of coursework and pass a comprehensive CRS Proficiency Exam. CRS certification is maintained by annual completion of 6 hours of elective coursework and maintenance of CITI training.

3.2.1 Cancer Institute CCTRA Training



?????

http://www.citiprogram.org/


All CCTRA staff must have the CRS certification within one year of hire. Senior CCTRA staff must obtain and maintain national Society of Clinical Research Associates (SOCRA) or Association of Clinical Research Professionals (ACRP) certification.

3.2.2 Cancer Institute Research Nurse TrainingCancer Institute Research Nurses must be certified in Oncology Nursing and Research and must maintain these certifications throughout employment.

3.2.3 Protocol Specific TrainingProtocol specific education includes the study initiation meeting and educational material for the study that is available on a need-to-know basis through UAMS Trialsearch.



Appendix I. Cancer Institute Organizational Structure



Appendix II. Cancer Institute Research Flowchart

Study Timelin

e

DOCS CCTRA Nurses PRMC ORRA IRB AR-CRIS

ORC

Pre-Study Concept feasibilityIdentification and involvement of collaboratorsAssistance with protocol development

Document preparation:- Protocol- Informed ConsentCommittee Submissions:- Institutional

Biological Safety

- Radiation Safety

- PRMC - IRB

Create CDEs and eCRFs

Coordinate SIVsBudget Development

Develop EMR templatesPrepare recruitment packetsPrepare study flow sheets

Scientific reviewStatistical reviewResource assessment

Contracts

Budget approval

IND/IDE applications and SIVs

Patient safety review:-

Protocol

- Informed Consent

COI review

Trialsearch

caTissue

AR-CDR and TriNetx

Honest Broker

Lifelink

-

Study Conduct

Monitor accrualand provide recommendations to PRMC quarterly

Register subjectsRegister and enter data into www.clinicaltrials.govEnter study data into AR-CRIS Prepare and submit regulatory documentsCoordinate monitoring visits

Recruit subjectsScreen subjectsOrder and perform study-related testsPrepare clinic documents for study visitsNotify CCTRA CRAs of AEs, SAEs and subjects off-study

Enforce accrual

Monitoring

IND/IDE support

FDA Reports

Patient safety reviews:-AEs-Protocol Deviations-

Continuing Reviews

- Protocol changes

- Respond to audits

RPRSPSCETDelegation of Authority LogOpenClinicaLimeSurveyAR-AERscaTissueAR-CDRSugarCMLifelinkHonest Broker

Audits

Post-Study

Enforce publications

Maintain study records


Appendix III. Comprehensive Research and Informatics Suite (AR-CRIS) Workflow


Appendix IV. PI Checklist for Cancer Institute Protocols

PI Checklist: Preparing and Implementing a Clinical Protocol in the Cancer Institute

Step Activity Resources for Cancer Trials1. Initiate and develop research idea, identify

collaborators and co-investigators.Seek input from one or more of the following:

Cancer Institute Disease Oriented Committees (DOCs) – DOCs review is required for all cancer related protocols. http://cancer.uams.edu/docs

Cancer Institute Research Program Leaders – contact Tom Kieber-Emmons, PhD [email protected], 501-526-5930

Translational Research Institute (TRI) – contact TRI Navigator at 501-614-2287 or [email protected]

Statistical services are available – contact Jeannette Lee, PhD at [email protected]

Clinical Trial Logistics and Navigation are available – contact Laura Hutchins, MD, Cancer institute Associate Director for Clinical Research at [email protected] or 501-686-8511

Office of Research and Regulatory Affairs (ORRA) Quality Assurance Unit is available for evaluation of drug manufacturing needs – contact Larry Parker at [email protected] or 501-686-6284

2. Seek funding for idea through intramural pilot funds or extramural grants.

Funding opportunities can be identified through the following:

Attending DOC meetings Cancer Institute Research Program Leaders TRI Novel Methodologies and Pilot Studies

program Opportunities posted on the UAMS

Announcements e-mails

3. Write and submit grant per funding guidelines.

The UAMS Office of Grants and Scientific Publications (OGSP) can assist with grant preparation if the funding source is – contact DeAnn Hubberd at [email protected] or visit www.cancer.uams.edu/OGSP

OGSP also provides training in grant writing throughout the year. Please contact them for information on the next training opportunities.

4. Prepare a draft clinical protocol. Cancer Clinical Trials Office (CCTRA) – contact Sandy Annis, CCTRA Director, at [email protected] or 501-526-6990 #8083

Prepared by the Principal Investigator (PI) if the PI chooses to not utilize CCTRA services

5. Once funded, develop a final version of the clinical protocol and protocol documents.

Collaborative effort between the PI and CCTRA DOCs are available to provide additional



Protocol template


Check? Service Now

mailto:[email protected]

http://www.cancer.uams.edu/OGSP







http://cancer.uams.edu/docs

assistance and feedback during protocol development

DOCs should also be notified of any funded grants resulting from collaborations occurring through the DOCs.

6. Submit final protocol for regulatory, scientific and budget approval.

Final protocols are submitted to CCTRA. CCTRA will review the final protocol and may request changes be made to the protocol before they submit it to the appropriate regulatory bodies. CCTRA is staffed with protocol experts and any protocol changes requested by CCTRA should be viewed as changes that will shorten the regulatory review process. CCTRA will make all submissions to the regulatory bodies required by the protocol. Investigators are advised to communicate with CCTRA about what submissions will be occurring.

CCTRA will prepare and submit documents to the following. These submissions are required for all protocols:

CLARA – budget, coverage analysis, legal contracts

Institutional Review Board (IRB) – human subject protection

Protocol Review and Management Committee (PRMC) - scientific review.

Other regulatory committees as required and appropriate for the protocol: Radiation Safety Committee Conflict of Interest Committee Institutional Biosafety Committee

Registration of therapeutic trials on www.clinicaltrials.gov.

Budget negotiations for industry-sponsored protocols

7. Conduct research and capture data. Research may begin only after the protocol is approved by all appropriately required regulatory bodies.

Cancer Institute Research Nurses will consent and enroll subjects.

Sub-investigators, Cancer Institute Research Nurses or the TRI Clinical Research Services Core (CORRA) will provide intervention (treatment) and obtain data or samples.

CCTRA will enter the protocol on www.clinicaltrials.gov

8. Analyze data and interpret results. PI, Co-Is and the UAMS Department of Biostatistics 9. Disseminate results, publish and make

appropriate citations and acknowledgements.

PI and Co-Is are advised to communicate with the DOCs about their results to further future collaborations.

DOCs should also be notified of any publications resulting from collaborations occurring through the DOCs.

CCTRA will upload therapeutic trial results to




www.clinicaltrials.gov

10. Close out the funding mechanism. CCTRA

11. Develop and commercialize the product (where appropriate).

UAMS BioVentures - contact or 501-686-8927

12. Develop next idea. Go back to Step 1.



Need to update

Appendix V. Committee Workflow Details

a. Cancer Institute Disease Oriented Committees (DOCs)

The DOCs are designed to promote collaboration and provide scientific and feasibility review for pre-clinical and clinical cancer-related research projects. Investigators are encouraged to share their research ideas with the appropriate DOC when initially developing their concept or idea; many investigators may find it additionally helpful to receive DOC input during the writing of the protocol prior to regulatory submissions. Investigators should contact the appropriate DOC coordinator about scheduling DOC review of their research concept/idea/protocol on an agenda. Approval by the appropriate DOC is required for all cancer-related protocols prior to the engagement of CCTRA to support the clinical research process.

A complete list of the DOC coordinators and their contact information can be found at http://cancer.uams.edu/docs. DOC meetings are open at all times and investigators with an interest in a particular type of tumor are encouraged to attend the corresponding DOC meetings whenever possible to contribute to the development of research in that area campus-wide and further collaborations.

Investigators wishing to perform a chart review study must gain approval from the appropriate DOC early in the concept design phase. If the DOC approves the concept and study design, the investigator will begin working with CCTRA to define the data elements and work in the AR-CRIS system, as with any other type of research project. If the DOC does not approve the concept and study design, the investigator may proceed with the chart review study without support from the Cancer Institute, including CCTRA.

The DOCs approval/rejection workflow process differs with the type of protocol under review:1. Cooperative Group or Industry sponsored studies are brought to the attention of the

appropriate DOC coordinator by the Clinical Research Project Director. If the DOC group or DOC coordinator rejects the study, the DOC coordinator will inform the Clinical Research Project Director verbally, by phone or email, and the Clinical Research Project Director will inform the sponsor. If the DOC group or DOC coordinator approves the study, the DOC coordinator will inform the Clinical Research Project Director verbally, by phone or email, and the Clinical Research Project Director will inform the sponsor and the Cancer Institute Protocol Review and Monitoring Committee (PRMC).

2. Investigator-initiated studies, regardless of sponsorship, are brought to the attention of the appropriate DOC coordinator by the study PI. The PI should contact the appropriate DOC coordinator and ask for time on an upcoming meeting agenda for presentation and discussion of the research idea or protocol. If the DOC group rejects the study, the PI will have received feedback from the DOC on how to improve the study and should consider those recommendations and return to the DOC at a later date for further discussion and hopeful approval. If the DOC group approves the study, the DOC coordinator will complete the Cancer Clinical Trials Office DOC approval form and


http://cancer.uams.edu/docs

submit it to the CCTRA Investigator-Initiated Studies Coordinator. The CCTRA Investigator-Initiated Studies Coordinator will then inform the PRMC of DOC approval status and begin working with the PI to move the study forward.

3. If a PI of an investigator-initiated study does not wish to utilize CCTRA services, he/she still must obtain DOC approval to move the study forward toward activation. After DOC approval, the PI is responsible for all regulatory and budget submissions as well as registration on www.clinicaltrials.gov if appropriate.

b. UAMS Institutional Review Board (IRB)

The CCTRA will be responsible for submitting to the IRB on behalf of the investigator. If the PI has chosen to not utilize CCTRA services, IRB submission is the responsibility of the PI. All IRB submissions are done through the UAMS Clinical Research Administrator (CLARA) tool. The following documents are needed for initial submission to the IRB for approval of research:

Protocol with IRB required elements Written informed consent with IRB required elements Description of consent process Surveys, questionnaires or any other research-related materials that will be seen by the

subject Information sheets that might be given to the subject Investigator’s Brochure (IB), package insert or device manual if applicable Letter from the U.S. Food and Drug Administration (FDA) or the UAMS Office of

Research and Regulatory Affairs (ORRA) regarding the test article, if applicable Recruitment plan to recruit subjects to the study Advertisements, flyers or other materials that will be used in the recruitment plan Approval from any other required committees (e.g. PRMC) Safety and/or efficacy assessment plan Data Safety Monitoring Plan (DSMP) Curriculum Vitae (CV) for each investigator listed on the study

The CCTRA is available to assist in the preparation of these documents, but a full IRB submission cannot be done until these documents are available and complete. The PI will be required to review and sign off on all submissions electronically through the CLARA tool.

c. Cancer Institute Protocol Review and Monitoring Committee (PRMC)

The CCTRA will be responsible for submitting to the PRMC on behalf of the investigator. If the PI has chosen to not utilize CCTRA services, PRMC submission is the responsibility of the PI. The following documents are required for submission to the PRMC:

Protocol Written Informed Consent (this may still be in draft form)



The CCTRA will complete the following forms for submission. If the PI has chosen to not utilize CCTRA services, submission of the following forms is the responsibility of the PI.:

PRMC PI Checklist PRMC Sub-Investigator Checklist PRMC Protocol Summary

d. UAMS Institutional Conflict of Interest Committee (ICOIC)

COIs are identified and managed through the online Total Research and Compliance Knowledge System (TRACKS). All UAMS employees are required to complete a COI disclosure form at least annually. Academic staff members complete their COI disclosure forms in the TRACKS system. Non-academic staff members complete their disclosure form in the UAMS Conflict of Interest system. Both systems can be accessed through the following link: https://secure.uams.edu/uamsforms/ .


https://secure.uams.edu/uamsforms/

Appendix VI. Standard Operating Procedures (SOPs)

a. Cancer Clinical Trials Office: Submitting to www.ClinicalTrials.gov


Appendix VII. Campus Resource Guide for Clinical Trials

Cancer Clinical Trials and Regulatory Affairs (CCTRA)CCTRA Office and Services: http://cancer.uams.edu/research/clinical-research/cancer-clinical-trials-office/CCTRA Contact Information: Call 501-686-8274 or Email Sandy Annis at [email protected] request CCTRA services, visit Service Now at … (updated intake process TBD in Dec, 2017).

Conflict of Interest (COI)UAMS COI Office: http://coi.uams.edu/ UAMS COI Policies: http://coi.uams.edu/policies/ How to submit your annually required COI Disclosure through TRACKS: http://coi.uams.edu/submit-a-coi-disclosure/

Disease Oriented Committees (DOCs)Cancer Institute DOCs Information: http://cancer.uams.edu/research/clinical-research/disease-oriented-committees-docs/List of Cancer Institute DOCs, leadership and meeting times and locations: http://cancer.uams.edu/research/clinical-research/disease-oriented-committees-docs/doc-table/

Institutional Review Board (IRB)UAMS IRB Information: http://irb.uams.edu/UAMS IRB Policies: http://irb.uams.edu/irb-policies/UAMS IRB Contact Information: Call 501-686-5667 or Email [email protected] Information and Link to Login: http://irb.uams.edu/clara/Tools and Training to Conduct Human Subject Research: http://irb.uams.edu/new-studies-staff/

Office of Research and Regulatory Affairs (ORRA)UAMS ORRA Information: http://researchservices.uams.edu/UAMS Research Policies: http://researchservices.uams.edu/related-policies/UAMS ORRA Contact Information: Call 501-526-6876

Tissue Biorepository and Procurement Service (TBAPS)TBAPs Contact Information: Call 501-686-7470 or email Remelle Eggerson at [email protected] Forms, workflows and more information about TBAPS can be found at http://cancer.uams.edu/research/shared-resources/translational-pathology/TBAPS

TriNetxTriNetX is a federated cohort estimation tool in which UAMS is a member. It can be accessed through the Translational Research Institute (TRI) Service Request Portal: http://tri.uams.edu/services-2/advice-consulation/


http://tri.uams.edu/services-2/advice-consulation/

http://cancer.uams.edu/research/shared-resources/translational-pathology/TBAPS


http://researchservices.uams.edu/related-policies/

http://researchservices.uams.edu/

http://irb.uams.edu/new-studies-staff/

http://irb.uams.edu/clara/


http://irb.uams.edu/irb-policies/

http://irb.uams.edu/

http://cancer.uams.edu/research/clinical-research/disease-oriented-committees-docs/doc-table/

http://cancer.uams.edu/research/clinical-research/disease-oriented-committees-docs/doc-table/

http://cancer.uams.edu/research/clinical-research/disease-oriented-committees-docs/

http://cancer.uams.edu/research/clinical-research/disease-oriented-committees-docs/

http://coi.uams.edu/submit-a-coi-disclosure/

http://coi.uams.edu/policies/

http://coi.uams.edu/


http://cancer.uams.edu/research/clinical-research/cancer-clinical-trials-office/

http://cancer.uams.edu/research/clinical-research/cancer-clinical-trials-office/

Appendix VIII. CCTRA Protocol Template

CCTRA utilizes the NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template v1.0, dated April 7, 2017. The template that begins on the next page may be used by copying and pasting into a new Word document and removing the footers associated with the Conducting Research document.


NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template

PREFACE

Remove this Preface before finalizing and distributing the clinical trial protocol.

This clinical trial protocol template is a suggested format for Phase 2 and 3 clinical trials funded by the National Institutes of Health (NIH) that are being conducted under a Food and Drug Administration (FDA) Investigational New Drug (IND) or Investigational Device Exemption (IDE) Application. Investigators for such trials are encouraged to use this template when developing protocols for NIH-funded clinical trial(s). This template may also be useful to others developing phase 2 and 3 IND/IDE clinical trials.

The goal of this template is to assist investigators to write a comprehensive clinical trial protocol that meets the standard outlined in the International Conference on Harmonisation (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (ICH-E6). Its use will also help investigators think through the scientific basis of their assumptions, minimize uncertainty in the interpretation of outcomes, and prevent loss of data. A common protocol structure and organization will facilitate protocol review by oversight entities.

It is important to note that the clinical trial protocol template is just one piece of information required for an IND or IDE submission. For complete details on IND or IDE submissions see 21 CFR Part 312: Investigational New Drug Application or 21 CFR Part 812: Investigational Device Exemptions, respectively.

How To Use This Template

It is important to incorporate all sections of the template into your protocol and to do so in the same order. If a particular section is not applicable to your trial, include it, but indicate that it is not applicable.

This template contains two types of text: instruction/explanatory and example.

Instruction/explanatory text are indicated by italics and should deleted. Footnotes to instructional text should also be deleted. This text provides information on the content that should be included. It also notes if a section should be left blank. For example, many headings include the instruction, “No text is to be entered in this section; rather it should be included under the relevant subheadings below.”

Example text is included to further aid in protocol writing and should either be modified to suit the drug, biologic or device (study intervention), design, and conduct of the planned clinical trial or deleted. Example text is indicated in [regular font]. Within example text, a need for insertion of specific information is notated by <angle brackets>.

Instruction/explanatory text should be deleted. Example text can be incorporated as written or tailored to a particular protocol. If it is not appropriate to the protocol, however, it too should be deleted. The section headers include formatting to generate a table of contents.

Version control is important to track protocol development, revisions, and amendments. It is also necessary to ensure that the correct version of a protocol is used by all staff conducting the study. With each revision, the version number and date located in the footer of each page should be updated. When making changes to an approved and “final” protocol, the protocol amendment history should be maintained (see Section 10.4).



RESOURCESRemove Resources before finalizing and distributing the clinical trial protocol.

Center for Medicare & Medicaid Services (CMS) Clinical Laboratory Improvement Amendments

Code of Federal Regulations (CFR) 21 CFR Part 11: Electronic Records, Electronic Signatures 21 CFR Part 50: Protection of Human Subjects 21 CFR Part 54: Financial Disclosure by Clinical Investigators 21 CFR Part 56: Institutional Review Boards 21 CFR Part 58: Good Laboratory Practice for Nonclinical Laboratory Studies 21 CFR Part 210: Current Good Manufacturing Practice In Manufacturing, Processing, Packing,

Or Holding Of Drugs; General 21 CFR Part 211: Current Good Manufacturing Practice For Finished Pharmaceuticals 21 CFR Part 312: Investigational New Drug Application 21 CFR Part 812: Investigational Device Exemptions 42 CFR Part 11: Clinical Trial Registration and Results Information Submission 45 CFR Part 46: Protection of Human Subjects Research

Food and Drug Administration (FDA) Compliance Actions and Activities FDA Regulations Relating to Good Clinical Practice and Clinical Trials Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs –

Improving Human Subject Protection Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data

Monitoring Committees Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance Guidance for Industry: Electronic Source Data in Clinical Investigations Guidance for Industry: Multiple Endpoints in Clinical Trials Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to

Monitoring Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Human

Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Standardized

Study Data Guidance for Industry: Safety Assessment for IND Safety Reporting

Department of Health and Human Services (HHS) The HIPAA Privacy Rule HIPAA Privacy Rule: Information for Researchers

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

Guidance for Industry, E6 (R2) Good Clinical Practice: Consolidated Guidance Guidance for Industry, M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical

Trials and Marketing Authorization for Pharmaceuticals



Guideline for Industry, E3 Structure and Content of Clinical Reports Guidance for Industry, E9 Statistical Principles for Clinical Trials Final Concept Paper E9(R1): Addendum to Statistical Principles for Clinical Trials on Choosing

Appropriate Estimands and Defining Sensitivity Analyses in Clinical Trials

International Organization for Standardization (ISO) Clinical Investigation of Medical Devices for Human Subjects -- Good Clinical Practice (ISO

14155:2011)

National Institutes of Health (NIH) Certificates of Confidentiality (CoC) Kiosk Clinical Trials Registration and Results Information Submission Financial Conflict of Interest Inclusion of Children- Policy Implementation Inclusion Of Women And Minorities As Participants In Research Involving Human Subjects-

Policy Implementation Page NIH Data Sharing Policies and Related Guidance on NIH-Funded Research Resources NIH Data Sharing Policy and Implementation Guidance NIH Genomic Data Sharing Policy NIH Grants Policy Statement, Section 8.2 Availability of Research Results: Publications,

Intellectual Property Rights, and Sharing Research Resources NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information NIH Public Access Policy Details Policy on Good Clinical Practice Training for NIH Awardees Involved in NIH-funded Clinical Trials Required Education in the Protection of Human Research Participants

Office for Human Research Protections (OHRP) Human Subject Regulations Decision Charts Informed Consent Checklist Informed Consent Tips IRBs and Assurances Regulations & Policy Index Unanticipated Problems Involving Risks and Adverse Events Guidance Vulnerable Populations

Other Citing Medicine, 2nd edition: The NLM Style Guide for Authors, Editors, and Publishers CONSORT statement International Committee of Medical Journal Editors (ICMJE): Recommendations Practical Aspects of Signal Detection in Pharmacovigilance: Report of CIOMS Working Group VIII


<Title>The title should be easy to remember, recognizable by administrative support staff, and sufficiently

different from other protocol titles to avoid confusion. Brevity with specificity and neutrality is the goal. If there is a “short title” (e.g., an abbreviation used to refer to the study title, include here and that can

be used throughout this document in place of the full title).

Protocol Number: < Number>

National Clinical Trial (NCT) Identified Number: <Number, if available>

Principal Investigator: < Principal investigator>

<IND/IDE> Sponsor: <Sponsor name, if applicable>Sponsor means an individual or pharmaceutical or medical device company, governmental agency, academic institution, private organization, or other organization who takes responsibility for and

initiates a clinical investigation.

Funded by: < NIH Institute or Center (IC)>

Version Number: v.<x.x>

<Day Month Year>All versions should have a version number and a date. Use the international date format (day month

year) and write out the month (e.g., 23 June 2015).

Summary of Changes from Previous Version:

Affected Section(s)

Summary of Revisions Made Rationale


Table of Contents

STATEMENT OF COMPLIANCE................................................................................................................21 PROTOCOL SUMMARY.....................................................................................................................2

1.1 Synopsis...........................................................................................................................................21.2 Schema.............................................................................................................................................2

1.3 Schedule of Activities (SoA)....................................................................................................2

2 INTRODUCTION....................................................................................................................................22.1 Study Rationale.............................................................................................................................22.2 Background.....................................................................................................................................2

2.3 Risk/Benefit Assessment..........................................................................................................22.3.1 Known Potential Risks............................................................................................22.3.2 Known Potential Benefits......................................................................................2

2.3.3 Assessment of Potential Risks and Benefits................................................23 OBJECTIVES AND ENDPOINTS...................................................................................................24 STUDY DESIGN.....................................................................................................................................2

4.1 Overall Design...............................................................................................................................24.2 Scientific Rationale for Study Design..................................................................................24.3 Justification for Dose..................................................................................................................24.4 End of Study Definition..............................................................................................................2

5 STUDY POPULATION.........................................................................................................................25.1 Inclusion Criteria...........................................................................................................................25.2 Exclusion Criteria.........................................................................................................................25.3 Lifestyle Considerations............................................................................................................25.4 Screen Failures.............................................................................................................................2

5.5 Strategies for Recruitment and Retention.........................................................................26 STUDY INTERVENTION....................................................................................................................2

6.1 Study Intervention(s) Administration...................................................................................26.1.1 Study Intervention Description............................................................................2

6.1.2 Dosing and Administration....................................................................................26.2 Preparation/Handling/Storage/Accountability..................................................................2

6.2.1 Acquisition and accountability.............................................................................2

6.2.2 Formulation, Appearance, Packaging, and Labeling...............................26.2.3 Product Storage and Stability..............................................................................2

6.2.4 Preparation..................................................................................................................26.3 Measures to Minimize Bias: Randomization and Blinding........................................2

6.4 Study Intervention Compliance..............................................................................................2

6.5 Concomitant Therapy.................................................................................................................26.5.1 Rescue Medicine......................................................................................................2

7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL........................................................................................................2

7.1 Discontinuation of Study Intervention.................................................................................2



7.2 Participant Discontinuation/Withdrawal from the Study..............................................2

7.3 Lost to Follow-Up.........................................................................................................................28 STUDY ASSESSMENTS AND PROCEDURES......................................................................2

8.1 Efficacy Assessments................................................................................................................28.2 Safety and Other Assessments.............................................................................................2

8.3 Adverse Events and Serious Adverse Events................................................................28.3.1 Definition of Adverse Events (AE).....................................................................2

8.3.2 Definition of Serious Adverse Events (SAE)................................................2

8.3.3 Classification of an Adverse Event...................................................................28.3.4 Time Period and Frequency for Event Assessment and Follow-Up..2

8.3.5 Adverse Event Reporting......................................................................................28.3.6 Serious Adverse Event Reporting.....................................................................2

8.3.7 Reporting Events to Participants.......................................................................2

8.3.8 Events of Special Interest.....................................................................................28.3.9 Reporting of Pregnancy.........................................................................................2

8.4 Unanticipated Problems............................................................................................................28.4.1 Definition of Unanticipated Problems (UP)...................................................28.4.2 Unanticipated Problem Reporting.....................................................................28.4.3 Reporting Unanticipated Problems to Participants....................................2

9 STATISTICAL CONSIDERATIONS...............................................................................................29.1 Statistical Hypotheses................................................................................................................29.2 Sample Size Determination.....................................................................................................29.3 Populations for Analyses..........................................................................................................29.4 Statistical Analyses.....................................................................................................................2

9.4.1 General Approach....................................................................................................29.4.2 Analysis of the Primary Efficacy Endpoint(s)...............................................29.4.3 Analysis of the Secondary Endpoint(s)...........................................................29.4.4 Safety Analyses.........................................................................................................29.4.5 Baseline Descriptive Statistics............................................................................2

9.4.6 Planned Interim Analyses.....................................................................................29.4.7 Sub-Group Analyses...............................................................................................2

9.4.8 Tabulation of Individual participant Data........................................................2

9.4.9 Exploratory Analyses..............................................................................................210 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS.....2

10.1 Regulatory, Ethical, and Study Oversight Considerations........................................2

10.1.1 Informed Consent Process...................................................................................2

10.1.2 Study Discontinuation and Closure..................................................................210.1.3 Confidentiality and Privacy...................................................................................2

10.1.4 Future Use of Stored Specimens and Data..................................................210.1.5 Key Roles and Study Governance....................................................................2

10.1.6 Safety Oversight........................................................................................................2



10.1.7 Clinical Monitoring....................................................................................................2

10.1.8 Quality Assurance and Quality Control...........................................................210.1.9 Data Handling and Record Keeping................................................................2

10.1.10 Protocol Deviations..................................................................................................2

10.1.11 Publication and Data Sharing Policy................................................................210.1.12 Conflict of Interest Policy.......................................................................................2

10.2 Additional Considerations.........................................................................................................210.3 Abbreviations.................................................................................................................................2

10.4 Protocol Amendment History..................................................................................................2

11 REFERENCES........................................................................................................................................2



STATEMENT OF COMPLIANCEProvide a statement that the trial will be conducted in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP) and applicable state, local and federal regulatory requirements. Each engaged institution must have a current Federal-Wide Assurance (FWA) issued by the Office for Human Research Protections (OHRP) and must provide this protocol and the associated informed consent documents and recruitment materials for review and approval by an appropriate Institutional Review Board (IRB) or Ethics Committee (EC) registered with OHRP. Any amendments to the protocol or consent materials must also be approved before implementation. Select one of the two statements below:

(1) [The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) and the following:

• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)

National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP Training.

The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the protocol and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the changes are implemented to the study. In addition, all changes to the consent form will be IRB-approved; a determination will be made regarding whether a new consent needs to be obtained from participants who provided consent, using a previously approved consent form.]

OR

(2) [The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the <specify NIH Institute or Center (IC) > Terms and Conditions of Award. The Principal Investigator will assure that no deviation from, or changes to the protocol will take place without prior agreement from the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, funding agency and documented approval from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have completed Human Subjects Protection and ICH GCP Training.

The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the IRB for review and approval. Approval of both the protocol and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the changes are implemented to the study. All changes to the consent form will be IRB approved; a determination will be made regarding whether a new consent needs to be obtained from participants who provided consent, using a previously approved consent form.]



1 PROTOCOL SUMMARY

No text is to be entered in this section; rather it should be included under the relevant subheadings below.

SYNOPSIS

Title: <Full title>Study Description: Provide a short description of the protocol, including a brief statement of

the study hypothesis. This should be only a few sentences in length. A detailed schematic describing all visits and a schedule of assessments should be included in the Schema and Schedule of Activities, Sections 1.2 and 1.3, respectively.

Objectives: Include the primary and secondary objectives. These objectives should be the same as the objectives contained in the body of the protocol. These align with Primary Purpose in clinicaltrials.gov1.<Primary Objective: Secondary Objectives: >

Endpoints: Include the primary endpoint and secondary endpoints. These endpoints should be the same as the endpoints contained in the body of the protocol. These align with Outcome Measures in clinicaltrials.gov. <Primary Endpoint:Secondary Endpoints: >

Study Population: Specify the sample size, gender, age, demographic group, general health status, and geographic location.

Phase: <2 or 3 or N/A> Phase applies to drugs and biologics2.Description of Sites/Facilities Enrolling Participants:

Provide a brief description of planned facilities/participating sites enrolling participants. Indicate general number (quantity) of sites only and if the study is intended to include sites outside of the United States.

Description of Study Intervention:

Describe the study intervention. If the study intervention is a drug or biologic, include dose and route of administration. For devices, provide a description of each important component, ingredient, property and the principle of operation of the device.

Study Duration: Estimated time (in months) from when the study opens to enrollment until completion of data analyses.

Participant Duration: Time (e.g., in months) it will take for each individual participant to complete all participant visits.

SCHEMA

This section should include a diagram that provides a quick “snapshot” of the study and ideally be limited to 1 page. Below are examples of schematics that show the level of detail needed to convey an overview of the study design.

1 From ClinicalTrials.gov Protocol Data Element Definitions available at: https://prsinfo.clinicaltrials.gov/definitions.html. Accessed March 2017.2 From 21 CFR 312.21 “Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug 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. Phase 2 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 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.”


https://prsinfo.clinicaltrials.gov/definitions.html


Depending on the nature of your study, one example may be more appropriate than another. Regardless, the examples included here are intended to guide the development of a schematic that is appropriate to the planned study design and will need to be customized for the protocol. Revise with study-specific information and adapt the diagram to illustrate your study design (e.g., changing method of assignment to study group, adding study arms, visits, etc.). The time point(s) indicated in the schematic should correspond to the time point(s) in Section 1.3, Schedule of Activities, e.g., Visit 1, Day 0; Visit 2, Day 30 ± 7; etc.

Example #1 Flow diagram (e.g., randomized controlled trial)



Prior to Enrollment

Visit 1Time Point

Visit 2Time Point

Visit 3Time Point

Visit 4Time Point

Visit XTime Point


Total N: Obtain informed consent. Screen potential participants by inclusion and exclusion criteria; obtain history, document.

Perform baseline assessments.<list specimens to be collected, examinations or imaging or laboratory assays to

be performed, questionnaires to be completed OR refer to Section 1.3, Schedule of Activities>

Administer initial study intervention.

Follow-up assessments of study endpoints and safety<list specimens to be collected, examinations or imaging or laboratory assays to


Follow-up assessments of study endpoints and safety<list specimens to be collected, examinations or imaging or laboratory assays to


Final Assessments<list analyses to be performed OR refer to Section 1.3, Schedule of

Activities>

Arm 2N

Arm 1N

Repeat study intervention (if applicable).

Randomize


Example #2 provided as a guide, customize as needed: Process diagram (e.g., randomized controlled trial)


ScreeningWeek/Day (Insert time)Total n=xObtain informed consentScreen potential participants by inclusion and exclusion criteriaObtain history, document

RandomizationWeek/Day (Insert time)Intervention Group 1 (n=y)Placebo (n=z)

Baseline assessments/ Study InterventionWeek/Day (Insert time)<List specimens to be collected, examinations or imaging or laboratory assays to be performed, questionnaires to be completed OR refer to Section 1.3, Schedule of Activities>Administer initial dose of study intervention

Follow-up assessments of study endpoints and safety

Week/Day (Insert time)<List specimens to be collected, examinations or imaging or laboratory assays to be performed, questionnaires to be completed OR refer to Section 1.3, Schedule of Activities>

Follow-up assessments of study endpoints and safetyWeek/Day (Insert time)<List specimens to be collected, examinations or imaging or laboratory assays to be performed, questionnaires to be completed OR refer to Section 1.3, Schedule of Activities>

End of Study AssessmentsWeek/Day (Insert time)<List specimens to be collected, examinations or imaging or laboratory assays to be performed, questionnaires to be completed OR refer to Section 1.3, Schedule of Activities>

Follow-up Telephone CallWeek/Day (Insert time)<List questionnaires to be completed OR refer to Section 1.3, Schedule of Activities>


Example #3 provided as a guide, customize as needed: Timeline diagram (e.g., randomized controlled trial)


# in-clinic visits and

# telephone

Placebo N=

Study Intervention N=

Follow-up Phone CallWeek 28-29

End of Study Assessments (EOS)Week 27

Dose TaperWeek 26

MaintenanceWeeks 2 - 25

TitrationWeek 1

RandomizationDay 1

ScreeningDay -7 to Day -1


SCHEDULE OF ACTIVITIES (SOA)

The schedule below is provided as an example and should be modified as appropriate.

The schedule of activities must capture the procedures that will be accomplished at each study visit, and all contact, with study participants e.g., telephone contacts. This includes any tests that are used for eligibility, participant randomization or stratification, or decisions on study intervention discontinuation. Only include procedures that contribute to participant eligibility and study objectives and endpoints. Other procedures should be done sparingly and with consideration, as they may add unnecessary complexity and detract from recruitment.

Allowable windows should be stated for all visits. To determine the appropriate windows, consider feasibility and relevance of the visit time points to study endpoints (e.g., pharmacokinetic (PK) studies may allow little or no variation, with required time points measured in minutes or hours, whereas a 6-month follow-up visit might have a window of several weeks).

Procedures

Scre

enin

gDa

y -7

to -1

Enro

llmen

t/Ba

selin

eVi

sit 1

, Day

1

Stud

y Vi

sit 2

Da

y 7

+/-

1 da

ySt

udy

Visit

3Da

y 14

+/-

1 d

aySt

udy

Visit

4Da

y 21

+/-

1 da

y

Stud

y Vi

sit 5

Day

28 +

/-1

day

Stud

y Vi

sit 6

Day

35

+/-1

day

Stud

y Vi

sit 7

Day

42 +

/-1

day

Stud

y Vi

sit 8

Day

49 +

/-1

day

Stud

y Vi

sit 9

Day

56 +

/-1

day

Stud

y Vi

sit 1

0Da

y 63

+/-

1 da

y

Stud

y Vi

sit 1

1Da

y 70

+/-

1 d

ay

Stud

y Vi

sit 1

2Da

y 77

+/-

1day

Fina

l Stu

dy V

isit 1

3Da

y 84

+/-

1 da

y

Informed consent XDemographics XMedical history XRandomization XAdminister study intervention X X X XConcomitant medication review X X---------------------------------------------------------------------------------------------X

Physical exam (including height and weight) X X X X X X

Vital signs X X X X X XHeight XWeight X X X X X X X XPerformance status X X X X X X X XHematology X X X X X X X X X X X X X Xserum chemistry a X X X X X X X X X X X X X XPregnancy test b XEKG (as indicated) XAdverse event review and evaluation X X---------------------------------------------------------------------------------------------X X

Radiologic/Imaging assessment X X X X

Other assessments (e.g., immunology assays, pharmacokinetic)

X X X X X X X X X X X X X X

Complete Case Report Forms (CRFs) X X X X X X X X X X X X X X

a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, AST, ALT, sodium.

b: Serum pregnancy test (women of childbearing potential).

<Insert table>



INTRODUCTIONNo text is to be entered in this section; rather, it should be included under the relevant subheadings below.

The following subsections should include relevant background information and rationale for the clinical trial. This should be a brief overview (e.g., approximately 3-7 pages). Referring to the Investigator’s Brochure (IB) for more detail is also appropriate.

STUDY RATIONALE State the problem or question (e.g., describe the population, disease, current standard of care, if one exists, and limitations of knowledge or available therapy) and the reason for conducting the clinical trial

<Insert text>

BACKGROUND This section should include:

• A summary of findings from nonclinical in vitro or in vivo studies that have potential clinical significance

• A summary of relevant clinical research and any history of human use or exposure to the study intervention, including use in other countries, and clinical pharmacology studies

• Discussion of important literature and data that are relevant to the trial and that provide background for the trial (reference citations should be listed in Section 11, References)

• Applicable clinical, epidemiological, or public health background or context of the clinical trial

• Importance of the clinical trial and any relevant treatment issues or controversies

<Insert text>

RISK/BENEFIT ASSESSMENT No text is to be entered in this section; rather it should be included under the relevant subheadings below.

The following subsections should include a discussion of known risks and benefits, if any, to human participants.

KNOWN POTENTIAL RISKS Include a discussion of known potential risks from either clinical or nonclinical studies. If a package insert or device labeling from a licensed or approved product is available, it should be used as the primary source of risk information. If the product is investigational, the IB should be the primary source of the risk information. In addition, relevant published literature can also provide relevant risk information. If the risk profile cannot be described from the package insert, device labeling, or the IB, the risk information discussion will result from published literature and should be included and referenced appropriately.

Describe any physical, psychological, social, legal, economic, or any other risks to participants by participating in the study that the Principal Investigator (PI) foresees, addressing each of the following:



• Immediate risks

• Long-range risks

• If risk is related to proposed procedures included in the protocol, describe alternative procedures that have been considered and explain why alternative procedures are not included

<Insert text>

KNOWN POTENTIAL BENEFITS Include a discussion of known potential benefits from either clinical or nonclinical studies. If a package insert or device labeling from a licensed or approved product is available, it should be used as the primary source of potential benefit information. If the product is investigational, the IB should be the primary source of the potential benefit information. In addition, relevant published literature can also provide potential relevant benefit information. If the potential benefit cannot be described from the package insert, device labeling, or the IB, the potential benefit information discussion will result from published literature and should be included and referenced appropriately.

Describe any physical, psychological, social, legal, or any other potential benefits to individual participants or society in general, as a result of participating in the study, addressing each of the following:

• Immediate potential benefits

• Long-range potential benefits

Note that payment to participants, whether as an inducement to participate or as compensation for time and inconvenience, is not considered a “benefit.” Provision of incidental care is also not to be considered a benefit.

<Insert text>

ASSESSMENT OF POTENTIAL RISKS AND BENEFITS Include an assessment of known potential risks and benefits, addressing each of the following:

• Rationale for the necessity of exposing participants to risks and a summary of the ways that risks to participants were minimized in the study design

• Justification as to why the risks of participation in the study outweigh the value of the information to be gained

<Insert text>

OBJECTIVES AND ENDPOINTSFor purposes of registration and reporting to ClinicalTrials.gov, the terms Objectives and Endpoints as used in this template align with the terms Primary Purpose and Outcome Measures in ClinicalTrials.gov, respectively. Provide a description of the study objectives and endpoints, as well as a justification for selecting the particular endpoints, in the table format included below. This will provide clear articulation of how the selected primary and secondary endpoint(s) are linked to achieving the primary and secondary objectives and an explanation of why endpoint(s) were chosen. Data



points collected in the study should support an objective or have a regulatory purpose. Therefore, careful consideration should be given prospectively to the amount of data needed to support the study’s objectives.

An objective is the purpose for performing the study in terms of the scientific question to be answered. Express each objective as a statement of purpose (e.g., to assess, to determine, to compare, to evaluate) and include the general purpose (e.g., efficacy, effectiveness, safety) and/or specific purpose (e.g., dose-response, superiority to placebo, effect of an intervention on disease incidence, disease severity, or health behavior).

A study endpoint is a specific measurement or observation to assess the effect of the study variable (study intervention). Study endpoints should be prioritized and should correspond to the study objectives and hypotheses being tested. Give succinct, but precise definitions of the study endpoints used to address the study’s primary objective and secondary objectives (e.g., specific laboratory tests that define safety or efficacy, clinical assessments of disease status, assessments of psychological characteristics, patient reported outcomes, behaviors or health outcomes). Include the study visits or time points at which data will be recorded or samples will be obtained. Describe how endpoint(s) will be adjudicated, if applicable.

Primary and secondary endpoints should be adjusted for multiplicity. If a claim is sought for the secondary endpoints, the statistical plan for adjustment for multiplicity should be aligned with those objectives.

OBJECTIVES ENDPOINTS JUSTIFICATION FOR ENDPOINTS

PrimaryThe primary objective is the main question. This objective generally drives statistical planning for the trial (e.g., calculation of the sample size to provide the appropriate power for statistical testing).

The primary endpoint(s) should be clearly specified and its importance and role in the analysis and interpretation of study results should be defined. The primary endpoint(s) is the basis for concluding that the study met its objective (e.g., “the study wins”). Often Phase 2 and 3 trials include primary objectives, and therefore primary endpoints, to demonstrate effectiveness. Generally, there should be just one primary endpoint that will provide a clinically relevant, valid, and reliable measure of the primary objective. Additional primary endpoints may require an adjustment to the sample size calculations and p-value threshold. However, this is not always the case. For example, in many trials of medical devices there are primary endpoints for both safety and effectiveness.

In a trial designed to establish efficacy, a primary endpoint should measure a clinically meaningful therapeutic effect or should have demonstrated ability to predict clinical benefit.

Briefly explain why the endpoint(s) were chosen.

Secondary



OBJECTIVES ENDPOINTS JUSTIFICATION FOR ENDPOINTS

The secondary objective(s) are goals that will provide further information on the use of the intervention.

Secondary endpoints should be clearly specified and may include, for example, endpoints related to efficacy, safety, or both. Secondary endpoints are those that may provide supportive information about the study intervention’s effect on the primary endpoint or demonstrate additional effects on the disease or condition. It is recommended that the list of secondary endpoints be short, because the chance of demonstrating an effect on any secondary endpoint after appropriate correction for multiplicity becomes increasingly small as the number of endpoints increases.


Tertiary/Exploratory Tertiary/exploratory objective(s) serve as a basis for explaining or supporting findings of primary analyses and for suggesting further hypotheses for later research.

Exploratory endpoints should be specified. Exploratory endpoints may include clinically important events that are expected to occur too infrequently to show a treatment effect or endpoints that for other reasons are thought to be less likely to show an effect but are included to explore new hypotheses.

Endpoints that are not listed in an alpha conserving plan will be considered exploratory.


STUDY DESIGN No text is to be entered in this section; rather it should be included under the relevant subheadings below.

OVERALL DESIGNThe scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design should be consistent with the Protocol Synopsis (section 1.1) and Protocol Schema (section 1.2) and include:

• A statement of the hypothesis

• Phase of the trial of 128

Dorothy Graves, PhD and Laura Hutchins, MDVersion 2.0 11/10/2017


• A description of the type/design of trial to be conducted (e.g., randomized, placebo-controlled, double-blinded, parallel design, open-label, dose escalation, dose-ranging, adaptive, cluster randomized, group sequential, multi-regional, superiority or non-inferiority design)

• A description of methods to be used to minimize bias

• Dose escalation or dose-ranging details should be contained in Section 6.1.2, Dosing and Administration

• The number of study groups/arms and study intervention duration

• Indicate if single site or multi-site

• Name of study intervention(s)

• Note if interim analysis is planned and refer to details in Section 9.4.6, Planned Interim Analysis

• Note if the study includes any stratifications and if so, identify the stratification planned (e.g. sex, race/ethnicity, age, dose) and refer to details in Section 9.4.7, Sub-Group Analyses

• Name of sub-studies, if any, included in this protocol

<Insert text>

SCIENTIFIC RATIONALE FOR STUDY DESIGNDescribe the rationale for the type and selection of control (e.g. placebo, active drug, dose-response, historical) and study design (e.g., non-inferiority as opposed to superiority). Discuss known or potential problems associated with the control group chosen in light of the specific disease and intervention(s) being studied.

<Insert text>

JUSTIFICATION FOR DOSEProvide a justification for the route of administration, planned maximum dosage, and dosing regimen, including starting dose, of the study intervention(s) and control product(s).

<Insert text>

END OF STUDY DEFINITIONA clinical trial is considered completed when participants are no longer being examined or the last participant’s last study visit has occurred.

Example text provided as a guide, customize as needed:

[A participant is considered to have completed the study if he or she has completed all phases of the study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 1.3.

The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial globally.]



<Insert text>

STUDY POPULATIONNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

The following subsections should include a description of the study population and participant recruitment. The study population should be appropriate for clinical trial phase and the development stage of the study intervention. Given the continuing challenges in achieving clinically relevant demographic inclusion in clinical trials, it is important to focus on clinically relevant potential participants at the earliest stages of protocol development. Therefore, it is essential that the population’s characteristics be considered during the trial planning phase to ensure the trial can adequately meet its objectives and provide evidence for the total population that will potentially utilize the study intervention under evaluation (e.g., elderly and pediatric populations, women, and minorities).

Use the following guidelines when developing participant eligibility criteria to be listed in Sections 5.1 Inclusion Criteria and 5.2 Exclusion Criteria:

The eligibility criteria should provide a definition of participant characteristics required for study entry/enrollment. If participants require screening, distinguish between screening participants vs enrolling participants. Determine if

screening procedures will be performed under a separate screening consent form.The risks of the study intervention should be considered in the development of the inclusion/exclusion criteria so that

risks are minimized.The same criterion should not be listed as both an inclusion and exclusion criterion (e.g., do not state age >18 years

old as an inclusion criterion and age ≤18 years old as an exclusion criterion).Identify specific laboratory tests or clinical characteristics that will be used as criteria for enrollment or exclusion.If reproductive status (e.g., pregnancy, lactation, reproductive potential) is an eligibility criterion, provide specific

contraception requirements (e.g., licensed hormonal or barrier methods). If you have more than one study population, please define the common inclusion and exclusion criteria followed by

the specific inclusion and exclusion criteria for each subpopulation.

INCLUSION CRITERIAInclusion criteria are characteristics that define the population under study, e.g., those criteria that every potential participant must satisfy, to qualify for study entry. Provide a statement that individuals must meet all of the inclusion criteria in order to be eligible to participate in the study and then list each criterion. Women and members of minority groups must be included in accordance with the NIH Policy on Inclusion of Women and Minorities as Participants In Research Involving Human Subjects.

Some criteria to consider for inclusion are: provision of appropriate consent and assent, willingness and ability to participate in study procedures, age range, health status, specific clinical diagnosis or symptoms, background medical treatment, laboratory ranges, and use of appropriate contraception. Additional criteria should be included as appropriate for the study design and risk.


[In order to be eligible to participate in this study, an individual must meet all of the following criteria:1. Provision of signed and dated informed consent form



2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged <specify range>4. In good general health as evidenced by medical history or diagnosed with <specify condition/disease> or

exhibiting <specify clinical signs or symptoms or physical/oral examination findings>5. <Specify laboratory test> results between <specify range>6. Ability to take oral medication and be willing to adhere to the <study intervention> regimen7. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to

screening and agreement to use such a method during study participation and for an additional <specify duration> weeks after the end of <study intervention> administration

8. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner

9. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration]

<Insert text>

EXCLUSION CRITERIAExclusion criteria are characteristics that make an individual ineligible for study participation. Provide a statement that all individuals meeting any of the exclusion criteria at baseline will be excluded from study participation and then list each criterion. If specific populations are excluded (e.g., elderly or pediatric populations, women or minorities), provide a clear and compelling rationale and justification, to establish that inclusion is inappropriate with respect to the health of the participants or the purpose of the research. Limited English proficiency cannot be an exclusion criterion.

Some criteria to consider for exclusion are: pre-existing conditions or concurrent diagnoses, concomitant use of other medication(s) or devices, known allergies, other factors that would cause harm or increased risk to the participant or close contacts, or preclude the participant’s full adherence with or completion of the study. Additional criteria should be included as appropriate for the study design and risk.

Include a statement regarding equitable selection or justification for excluding a specific population.

Example text provided as a guide, customize as needed (including adding a statement about equitable selection):

[An individual who meets any of the following criteria will be excluded from participation in this study:

1. Current use of < specify disallowed concomitant medications>

2. Presence of <specific devices (e.g., cardiac pacemaker)>

3. Pregnancy or lactation

4. Known allergic reactions to components of the <study intervention>, <specify components/allergens>

5. Febrile illness within <specify time frame>

6. Treatment with another investigational drug or other intervention within <specify time frame>

7. Current smoker or tobacco use within <specify timeframe>



8. < Specify any condition(s) or diagnosis, both physical or psychological, or physical exam finding that precludes participation>]

<Insert text>

LIFESTYLE CONSIDERATIONSInclude content in this section if applicable, otherwise note as not-applicable.

Describe any restrictions during any parts of the study pertaining to lifestyle and/or diet (e.g., food and drink restrictions, timing of meals relative to dosing, intake of caffeine, alcohol, or tobacco, or limits on activity), and considerations for household contacts. Describe what action will be taken if prohibited medications, treatments or procedures are indicated for care (e.g., early withdrawal).


[During this study, participants are asked to:

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, [pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices] from [X days] before the start of <study intervention> until after the final dose.

Abstain from caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for [x hours] before the start of each dosing session until after collection of the final pharmacokinetic (PK) and/or pharmacodynamic sample.

Abstain from alcohol for 24 hours before the start of each dosing session until after collection of the final PK and/or pharmacodynamic sample.

Participants who use tobacco products will be instructed that use of nicotine-containing products (including nicotine patches) will not be permitted while they are in the clinical unit.

Abstain from strenuous exercise for [x hours] before each blood collection for clinical laboratory tests. Participants may participate in light recreational activities during studies (e.g., watching television, reading).

Minimize interactions with household contacts who may be immunocompromised.]

<Insert text>

SCREEN FAILURESParticipants who are consented to participate in the clinical trial, who do not meet one or more criteria required for participation in the trial during the screening procedures, are considered screen failures. Indicate how screen failures will be handled in the trial, including conditions and criteria upon which re-screening is acceptable, when applicable.


[Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently randomly assigned to the study intervention or entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting



Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any serious adverse event (SAE).

Individuals who do not meet the criteria for participation in this trial (screen failure) because of a <specify modifiable factor> may be rescreened. Rescreened participants should be assigned the same participant number as for the initial screening.]

<Insert text>

STRATEGIES FOR RECRUITMENT AND RETENTIONIdentify general strategies for participant recruitment and retention. This section may refer to a separate detailed recruitment and retention plan in the manual of procedures (MOP) and site specific plans could be included in a site-specific standard operating procedure (SOP). Consider inclusion of the information below either in this section or the MOP.

Target study sample size by gender, race and ethnicity, and age; identify anticipated number to be screened including women and minorities in order to reach the target enrollment (should be consistent with information contained in Section 9.2, Sample Size Determination)

Anticipated accrual rate

Anticipated number of sites and participants to be enrolled from the U.S. and outside the U.S.

Source of participants (e.g., inpatient hospital setting, outpatient clinics, student health service, or general public)

Recruitment venues

How potential participants will be identified and approached

Types of recruitment strategies planned (e.g. patient advocacy groups, national newspaper, local flyers; social media, specific names of where advertisements may be planned are not needed)

If the study requires long-term participation, describe procedures that will be used to enhance participant retention (e.g., multiple methods for contacting participants, visit reminders, incentives for visit attendance).

Specific strategies that will be used to recruit and retain historically under-represented populations in order to meet target sample size and conform with the NIH Policy on Inclusion of Women and Minorities as Participants In Research Involving Human Subjects. Include the number of women and minorities expected to be recruited, or provide justification on those rare occasions where women and/or minorities will not be recruited.

In addition, this section should address:

If appropriate, include justification for inclusion of vulnerable participants and recruitment strategy. Vulnerable participants include, but are not limited to pregnant women, those who lack consent capacity, including the mentally ill, prisoners, cognitively impaired participants, children, and employee volunteers. Include safeguards for protecting vulnerable populations. Please refer to OHRP guidelines when choosing the study population.



Note that these regulations apply if any participants are members of the designated population, even if it is not the target population (e.g., if a participant becomes a prisoner during the study).

If participants will be compensated or provided any incentives (e.g. vouchers, gift cards,) for study participation, describe amount, form and timing of such compensation in relation to study activities (include financial and non-financial incentives). Describe who will receive incentives (if not the participant). For example, if minors, state whether the minor or the parent/guardian will receive the incentive. If incapacitated adults, state if payment will be provided to the participant or to a legally authorized representative or guardian.

<Insert text>

STUDY INTERVENTIONNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

The following subsections should describe the study intervention that is being tested for safety and effectiveness in the clinical trial, and any control product being used in the trial. The study intervention may be a drug (including a biological product), imaging intervention, or device subject to regulation under the Federal Food, Drug, and Cosmetic Act that is intended for administration to humans or use in humans, and that has been or has not yet been approved by the Food and Drug Administration (FDA). This also includes a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, when used for an unapproved indication or when used to gain further information about an approved use.

If multiple study interventions are to be evaluated in the trial, Section 6.1 Study Intervention(s) Administration and Section 6.2 Preparation/Handling/Storage/Accountability and their accompanying subsections, should clearly differentiate between each product. Address placebo or control product within each part of Section 6.1 and Section 6.2. If the control product is handled differently than the study intervention, be sure to state how they are each handled, separately. If the control product is handled the same as the study intervention, state as such. In addition, all sections may not be relevant for the trial. If not relevant, note as not applicable in that section.

STUDY INTERVENTION(S) ADMINISTRATIONNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

STUDY INTERVENTION DESCRIPTIONDescribe the study intervention(s) and control product. Product information can usually be obtained from the:

IB for an investigational drug or biologic

Package insert for a licensed or approved drug or biologic or device labeling for a licensed device

Proposed labeling and/or material safety data sheet (MSDS) for an investigational device

Final labeling for a marketed device

In addition:

• If a device study is being conducted under an IDE, and is determined to be non-significant risk, such that only abbreviated IDE requirements apply, provide justification here.



• Indicate if the study intervention is commercially available and is being used in accordance with approved labeling. For a device, note if any modifications have been performed for the study.

• If conducting a study with a device, the following information should be included:

o Device size(s)

o Device model(s)

o Description of each component

o Device settings and programming (if applicable)

o Duration of implant or exposure (if applicable)

o Frequency of exposure (if applicable)

o If a device has not been approved or cleared for the indications the protocol is designed to investigate, then a summary/report of test validation studies should accompany this protocol

<Insert text>

DOSING AND ADMINISTRATIONDescribe the procedures for selecting each participant's dose of study intervention and control product. For drugs, that includes the timing of dosing (e.g., time of day, interval), the duration (e.g., the length of time study participants will be administered the study intervention), the planned route of administration (e.g., oral, nasal, intramuscular), and the relation of dosing to meals.

State the starting dose and schedule of the study intervention and control product, including the maximum and minimum duration for those participants who continue in the study. For example, in some oncology trials for participants with no available therapeutic alternatives, intervention continues even after disease progression. In this instance, consider alternative designs that enable participants to rollover to a continued treatment arm and include appropriate instructions to guide this implementation.

If applicable, describe the dose escalation scheme and dose regimen (using exact dose, rather than percentages). State any minimum period required before a participant’s dose might be raised to the next higher dose or dose range. If applicable, the protocol should state the conditions under which a dose change will be made, particularly in regard to failure to respond or to toxic or untoward changes in stipulated indicators (e.g., white blood cell count in cancer chemotherapy). Address dose modifications for specific abnormal laboratory values of concern or other adverse events (AEs) that are known to be associated with the planned study intervention. The protocol must state explicitly the dose-limiting effects that are anticipated. Provide criteria that will be used to determine dose escalations. If a participant is responding positively to the intervention, the protocol should specify whether study intervention administration would progress to still higher doses. If appropriate, provide a dose de-escalation schema with intervention modifications. Do not restate reasons for withdrawal of participants. Cross-reference relevant sections, as appropriate.

Any specific instructions to study participants about when or how to prepare and take the dose(s) should be described, including how delayed or missed doses should be handled. Include any specific instructions or safety precautions for



administration of the study intervention. Discuss the maximum hold time once thawed/mixed, if appropriate, before administration.

While much of the above section is specific to drugs, similar considerations apply to certain devices. For example, some devices have adjustable settings including those related to energy delivery to participants. Other devices must be sized correctly for individual participants. Similar to the discussion above for dosage of drugs, such considerations should be described for devices, as applicable.

<Insert text>

PREPARATION/HANDLING/STORAGE/ACCOUNTABILITYNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

ACQUISITION AND ACCOUNTABILITYState how the study intervention and control product will be provided to the investigator. Describe plans about how and by whom the study intervention will be distributed, including participation of a drug repository or pharmacy, and plans for disposal of expired or return of unused product. Detailed information may be provided in a MOP or a separate SOP.

<Insert text>

FORMULATION, APPEARANCE, PACKAGING, AND LABELINGDescribe the formulation, appearance, packaging, and labeling of the study intervention and control product, as supplied. Information in this section can usually be obtained from the IB or the package insert, or device labeling. This section should include the name of the manufacturer of the study intervention and control product.

<Insert text>

PRODUCT STORAGE AND STABILITYDescribe storage and stability requirements (e.g., protection from light, temperature, humidity) for the study intervention and control product. For studies in which multi-dose vials are utilized, provide additional information regarding stability and expiration time after initial use (e.g., the seal is broken).

<Insert text>

PREPARATIONDescribe the preparation of the study intervention and control product, including any preparation required by study staff and/or study participants. Include thawing, diluting, mixing, and reconstitution/preparation instructions in this section, as appropriate, or within a MOP or SOP. For devices, include any relevant assembly or use instructions.

<Insert text>

MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDINGThis section should contain a description of randomization and blinding procedures (if applicable to the study design). It should include a description or a table that describes how study participants will be assigned to study groups, without being so specific that blinding or randomization might be compromised (e.g., the ratio between intervention and placebo



groups may be stated). If adaptive randomization or other methods of covariate balancing/minimization are employed, include a cross link to the methods of analysis in Section 9, Statistical Considerations. In addition, details regarding the implementation of procedures to minimize bias should be included in this section. DO NOT include details that might compromise these strategies. Design techniques to avoid bias can be found in the ICH Guidance for Industry E9 Statistical Principles for Clinical Trials.

Plans for the maintenance of trial randomization codes and appropriate blinding for the study should be discussed. The timing and procedures for planned and unplanned breaking of randomization codes should be included. Include a statement regarding when unblinding may occur and who may unblind. Provide the criteria for breaking the study blind or participant code. Discuss the circumstances in which the blind would be broken for an individual or for all participants (e.g., for serious adverse evets (SAEs)). Indicate to whom the intentional and unintentional breaking of the blind should be reported.

Sometimes blinding is attempted but is known to be imperfect because of obvious effects related to study intervention or control product in some participants (e.g., dry mouth, bradycardia, fever, injection site reactions, and changes in laboratory data). Such problems or potential problems should be identified and, if there are plans to assess the magnitude of the problem or manage it, these should be described (e.g., having endpoint measurements carried out by study staff shielded from information that might reveal study group assignment).

If the study allows for some investigators to remain unblinded (e.g., to allow them to adjust medication), the means of shielding other investigators should be explained. Describe efforts to ensure that the study intervention and control/placebo are as indistinguishable as possible. Measures to prevent unblinding by laboratory measurements, if used, should be described.

Include a description of your plans to manage and report inadvertent unblinding. If blinding is considered unnecessary to reduce bias for some or all of the observations, this should be explained (e.g., use of a random-zero sphygmomanometer eliminates possible observer bias in reading blood pressure and Holter tapes are often read by automated systems that are presumably immune to observer bias). If blinding is considered desirable but not feasible, the reasons and implications should be discussed.

<Insert text>

STUDY INTERVENTION COMPLIANCEDefine how adherence to the protocol (e.g., administration of study intervention, use of device,) will be assessed, and verified (if applicable, e.g., plasma assays, electronic monitoring devices, daily diaries). Include a discussion of what documents are mandatory to complete (e.g., participant drug log) and what source documents/records will be used to calculate study intervention compliance.

<Insert text>

CONCOMITANT THERAPYInclude content in this section if applicable, otherwise note as not-applicable.

This section should be consistent with the medication restrictions in the inclusion/exclusion criteria previously listed. Describe the data that will be recorded related to permitted concomitant medications, supplements, complementary and



alternative therapies, treatments, and/or procedures. Include details about when the information will be collected (e.g., screening, all study visits). Describe how allowed concomitant therapy might affect the outcome (e.g., drug-drug interaction, direct effects on the study endpoints) and how the independent effects of concomitant and study interventions could be ascertained.


[For this protocol, a prescription medication is defined as a medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are concomitant prescription medications, over-the-counter medications and supplements.]

<Insert text>

RESCUE MEDICINEInclude content in this section if applicable, otherwise note as not-applicable.

List all medications, treatments, and/or procedures that may be provided during the study for “rescue therapy” and relevant instructions about administration of rescue medications.


[The study site <will/will not> supply <specify type> rescue medication that will be <provided by the sponsor/obtained locally>. The following rescue medications may be used <specify name(s)>.

Although the use of rescue medications is allowable <at any time during the study>, the use of rescue medications should be delayed, if possible, for at least <insert timeframe> following the administration of <study intervention>. The date and time of rescue medication administration as well as the name and dosage regimen of the rescue medication must be recorded.] <Insert text>

STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWALNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

Participants may withdraw voluntarily from the study or the PI may discontinue a participant from the study. This section should state which adverse events would result in discontinuation of study intervention or participant discontinuation/withdrawal. In addition, participants may discontinue the study intervention, but remain in the study for follow-up, especially for safety and efficacy study endpoints (if applicable). Consider requiring separate documentation for study intervention discontinuation and participant discontinuation/withdrawal from the study. In addition, a dedicated Case Report Form (CRF) page should capture the date and the specific underlying reason for discontinuation of study intervention or participant discontinuation/withdrawal.

DISCONTINUATION OF STUDY INTERVENTIONDescribe the criteria for discontinuing the study intervention (e.g., halting rules), including any monitoring test(s) and associated clinical decision point(s). Include reasons for temporary discontinuation of the study intervention (e.g., type and quantity of adverse events), clearly stating the length of time, if applicable, and describe the data to be collected at



the time of study intervention discontinuation and approaches for restarting administration of or rechallenging with study intervention.

Describe efforts that will be made to continue follow-up of participants who discontinue the study intervention, but remain in the study for follow-up, especially for safety and efficacy study endpoints (if applicable). Reasonable efforts must be made to undertake protocol-specified safety follow-up procedures to capture adverse events (AE), serious adverse events (SAE), and unanticipated problems (UPs).


[Discontinuation from <study intervention> does not mean discontinuation from the study, and remaining study procedures should be completed as indicated by the study protocol. If a clinically significant finding is identified (including, but not limited to changes from baseline) after enrollment, the investigator or qualified designee will determine if any change in participant management is needed. Any new clinically relevant finding will be reported as an adverse event (AE).

The data to be collected at the time of study intervention discontinuation will include the following:

<Describe the procedures and data to be collected, as well as any follow-up evaluations>]

<Insert text>

PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDYProvide a list of reasons participation may be discontinued. It may be appropriate to provide distinct discontinuation criteria for participants and cohorts. If so, both sets of criteria should be listed separately and the distinction between the two must be stated clearly. Also, note that participants may withdraw voluntarily from the study or discontinue the study intervention at any time. But, investigators should seek to minimize participant discontinuation/withdrawal from study except for safety reasons.

In studies of implantable devices, a discussion should be included of any pertinent information that will be provided to withdrawn or discontinued participants (e.g., whether and how the device can be removed, how to replace batteries, how to obtain replacement parts, who to contact). In addition, it is important to capture the reason for withdrawal or discontinuation, as this may impact inclusion of participant data in the analysis of results (see Section 9, Statistical Analyses).

This section should include a discussion of replacement of participants who withdraw or discontinue early, if replacement is allowed. This section should not include a discussion of how these participants will be handled in the analysis of study data. This should be captured in the Section 9, Statistical Analyses.


[Participants are free to withdraw from participation in the study at any time upon request.An investigator may discontinue or withdraw a participant from the study for the following reasons:

Pregnancy



Significant study intervention non-compliance

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs such that continued participation in the study would not be in the best interest of the participant

Disease progression which requires discontinuation of the study intervention

If the participant meets an exclusion criterion (either newly developed or not previously recognized) that precludes further study participation

Participant unable to receive <study intervention> for [x] days/weeks.]

The reason for participant discontinuation or withdrawal from the study will be recorded on the <specify> Case Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive the study intervention may be replaced. Subjects who sign the informed consent form, and are randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, <will> or <will not> be replaced.]

<Insert text>

LOST TO FOLLOW-UPThe protocol should describe the nature and duration of study follow-up. Validity of the study is a potential issue when participants are lost to follow-up, as information that is important to the endpoint evaluation is then lost. Participants are considered lost to follow-up when they stop reporting to scheduled study visits and cannot be reached to complete all protocol-required study procedures. Describe the plans to minimize loss to follow-up and missing data.


[A participant will be considered lost to follow-up if he or she fails to return for <specify number of visits> scheduled visits and is unable to be contacted by the study site staff.

The following actions must be taken if a participant fails to return to the clinic for a required study visit:

The site will attempt to contact the participant and reschedule the missed visit <specify time frame> and counsel the participant on the importance of maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter to the participant’s last known mailing address or local equivalent methods). These contact attempts should be documented in the participant’s medical record or study file.

Should the participant continue to be unreachable, he or she will be considered to have withdrawn from the study with a primary reason of lost to follow-up.]

<Insert text>

STUDY ASSESSMENTS AND PROCEDURES




EFFICACY ASSESSMENTS List and describe all study procedures and evaluations to be done as part of the study to support the determination of efficacy, as per the primary and secondary objectives outlined in this protocol. Discuss the sequence of events that should occur during the screening process and any decision points regarding participant eligibility. Include the time frame prior to enrollment within which screening procedures/ evaluations must be performed (e.g., within 28 days prior to enrollment). If a separate screening protocol is developed, describe how the screening protocol will be used to identify participants for this study. In addition, discuss any special conditions that must be achieved during the enrollment and/or initial administration of study intervention. Include the procedures for administering the study intervention and follow-up procedures after administration (e.g., assessment of vital signs), as well as any specifics about subsequent follow-up visits, and unscheduled visits. Also, note if a specifically qualified person (e.g., physician, psychologist) should be performing any of the assessments. Include any definitions used to characterize outcomes (e.g., criteria for determining occurrence of acute myocardial infarction, characterization of a stroke as thrombotic or hemorrhagic, distinction between transient ischemic attack and stroke), should be explained fully.

For participants that may discontinue or withdraw early, it is important to capture the rationale during the final visit. See Section 7, Study Intervention Discontinuation and Participant Discontinuation/Withdrawal, for details.

Note that the protocol should provide a high-level discussion of all procedures and detailed information can be further provided in a MOP or SOP. Provide justification for any sensitive procedures (e.g., provocative testing, deception). In addition, note where approaches to decrease variability, such as centralized laboratory assessments, are being employed. The specific timing of procedures/evaluations to be done at each study visit are captured in Section 1.3, Schedule of Activities (SoA) and the time points of these procedures do not need to be included here. In addition, indicate where appropriate, that procedures/evaluations will be performed by qualified personnel.

This section may include a list and description of the following procedures/evaluations, as applicable:

Physical examination (e.g., height and weight, organ systems, motor or vision assessment, or other functional abilities). If appropriate, discuss what constitutes a targeted physical examination.

Radiographic or other imaging assessments. State the specific imaging required and, as appropriate, provide description of what is needed to perform the specialized imaging. Details describing how to perform the imaging in a standard fashion and equipment specifications may be described in the study’s MOP or a separate SOP.

Biological specimen collection and laboratory evaluations. Include specific test components and estimated volume and type of specimens needed for each test. Specify laboratory methods to provide for appropriate longitudinal and cross-sectional comparison (e.g., use of consistent laboratory method throughout study, use of single, central laboratory for multi-site studies). If more than one laboratory will be used, specify which evaluations will be done by each laboratory. In addition, compliance with Clinical Laboratory Improvement Amendments (CLIA) of 1988 should be addressed. If such compliance is not required, a brief discussion should be included explaining why this is the case. In addition, discussion should include whether any laboratory tests (e.g., diagnostics) that will be used are being developed concurrently or are commercially available. Special instructions for the preparation, handling, storage, and shipment of specimens should be briefly explained in this section with detailed discussion in the study’s MOP.

Special assays or procedures required (e.g., immunology assays, pharmacokinetic studies, flow cytometry assays, microarray, DNA sequencing). For research laboratory assays, include specific assays, estimated volume



and type of specimen needed for each test. If more than one laboratory will be used, specify which assays will be done by each laboratory. Special instructions for the preparation, handling, storage, and shipment of specimens should be briefly explained in this section with detailed discussion in the study’s MOP.

Administration of questionnaires or other instruments for patient-reported outcomes, such as a daily diary. Procedures that will be completed during the study as part of regular standard of clinical care.

Include in this section a discussion of the results of any study specific procedures that will be provided to participant (e.g., radiographic or other imaging or laboratory evaluations). Address when endpoints will be assessed with respect to dosing of rescue medication, if applicable.

If an individual’s medical chart or results of diagnostic tests performed as part of an individual’s regular medical care are going to be used for screening or as a part of collection of trial data, Health Insurance Portability and Accountability Act (HIPAA) rules, other relevant federal or state laws, and local institutional requirements should be followed, as applicable. If this is the case, this section should note which information is to be obtained through review of existing data.

<Insert text>

SAFETY AND OTHER ASSESSMENTSList and describe all study procedures and evaluations to be done as part of the study to monitor safety and support the understanding of the study intervention’s safety or that are done for other purposes (e.g., screening, eligibility, enrollment).

Discuss the sequence of events that should occur during the screening process and any decision points regarding participant eligibility. Include the time frame prior to enrollment within which screening procedures/ evaluations must be performed (e.g., within 28 days prior to enrollment). If a separate screening protocol is developed, describe how the screening protocol will be used to identify participants for this study. In addition, discuss any special conditions that must be achieved during the enrollment and/or initial administration of study intervention.

Note that the protocol should provide a high-level discussion of all procedures and detailed information can be further provided in a MOP or SOP. In addition, note where approaches to decrease variability, such as centralized laboratory assessments, are being employed. The specific timing of procedures/evaluations to be done at each study visit are captured in Section 1.3, Schedule of Activities (SoA) and the time points of these procedures do not need to be included here. In addition, indicate where appropriate, that procedures/evaluations will be performed by qualified personnel.

This section may include a list and description of the following procedures/evaluations, as applicable:

Physical examination (e.g., height and weight, organ systems, motor or vision assessment, or other functional abilities). If appropriate, discuss what constitutes a targeted physical examination.

Vital signs (e.g., temperature, pulse, respirations, blood pressure). Carefully consider which vital signs (if any) should be measured to ensure that only essential data are collected. Include any specific instructions with respect to the collection and interpretation of vital signs.

Electrocardiograms (EKGs): specify if the EKG is for screening purposes only. Include any specific instructions for the collection and interpretation of the EKG (e.g., time points relative to dosing with study intervention or other evaluations). If EKGs will be analyzed at a central laboratory, instructions for the collection (e.g., equipment),



transmission and archiving of the EKG data should be summarized in this protocol, and further outlined in the MOP. If the EKG will be read locally, indicate how these will be handled and in what format (e.g., digital or paper), as well as instructions with respect to local review.

Radiographic or other imaging assessments. State the specific imaging required and, as appropriate, provide description of what is needed to perform the specialized imaging. Details describing how to perform the imaging in a standard fashion and equipment specifications may be described in the study’s MOP or a separate SOP.

Biological specimen collection and laboratory evaluations. Include specific test components and estimated volume and type of specimens needed for each test. Specify laboratory methods to provide for appropriate longitudinal and cross-sectional comparison (e.g., use of consistent laboratory method throughout study, use of single, central laboratory for multi-site studies). If more than one laboratory will be used, specify which evaluations will be done by each laboratory. In addition, compliance with Clinical Laboratory Improvement Amendments (CLIA) of 1988 should be addressed. If such compliance is not required, a brief discussion should be included explaining why this is the case. In addition, discussion should include whether any laboratory tests (e.g., diagnostics) that will be used are being developed concurrently or are commercially available. Special instructions for the preparation, handling, storage, and shipment of specimens may be briefly explained in this section; detailed discussion should be included in the study’s MOP.

Special assays or procedures required (e.g., immunology assays, pharmacokinetic studies, flow cytometry assays, microarray, DNA sequencing). For research laboratory assays, include specific assays, estimated volume and type of specimen needed for each test. If more than one laboratory will be used, specify which assays will be done by each laboratory. Special instructions for the preparation, handling, storage, and shipment of specimens should be briefly explained in this section with detailed discussion in the study’s MOP.

Counseling procedures, including any dietary or activity considerations that need to be adhered to during study participation.

Assessment of study intervention adherence or see Study Intervention Compliance, section 6.4

Administration of questionnaires or other instruments for patient-reported outcomes, such as a daily diary.

Assessment of adverse events. Describe provisions for follow-up of ongoing AEs/SAEs.

Include in this section a discussion of the results of any study specific procedures that will be provided to participant (e.g., radiographic or other imaging or laboratory evaluations).

As previously noted, if an individual’s medical chart or results of diagnostic tests performed as part of an individual’s regular medical care are going to be used for screening or as a part of collection of trial data, Health Insurance Portability and Accountability Act (HIPAA) rules, other relevant federal or state laws, and local institutional requirements should be followed, as applicable. If this is the case, this section should note which information is to be obtained through review of existing data.

<Insert text> ADVERSE EVENTS AND SERIOUS ADVERSE EVENTSNo text is to be entered in this section; rather it should be included under the relevant subheadings below.



The following subsections are intended to highlight the specific assessments related to safety and the aspects of the study which are proposed to ensure the safety of trial participants. Consider developing this section in consultation with the study Medical Monitor. Consider the risks of the study intervention and other study procedures and the characteristics of the study population (e.g., vulnerable populations such as children). This section should be tailored for specific study characteristics, including but not limited to the following:

The study involves an investigational new drug or investigational device

The study involves washout from current medication regimen

The study involves the use of placebo in a population with a diagnosed disease

The study requires selection of an appropriate toxicity grading scale

The study involves risks to individuals other than research participants (e.g., household or intimate contacts or communities, study clinicians, pharmacists or interventionists, etc.)

Reporting of certain events (e.g., suspected child abuse or substance abuse) is mandatory because of the study population or study design characteristics

The study is conducted at multiple sites, and will require centralized safety oversight

In developing this section, consider the risks of the study intervention. Review and reference the applicable sources of information, such as the IB, package insert, device labeling, literature and other sources that describe the study intervention.

DEFINITION OF ADVERSE EVENTS (AE)Provide the definition of an AE being used for the clinical trial. The FDA definition of an AE is used in this template since this template is for phase 2 or 3 IND and IDE studies. For some studies, definitions from the OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events; or ICH GCP definition may be more appropriate. However, it is important to note that FDA regulations require reporting based on the definition included in 21 CFR 312.32 (a) for studies performed under an IND, regardless of the definition of AE used in the protocol.


[Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).]

<Insert text>

DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) Provide the definition of an SAE being used for the clinical trial. The FDA definition of an SAE is used in this template since this template is for phase 2 or 3 IND and IDE studies. It is important to note that FDA regulations require reporting based on the definition included in 21 CFR 312.32 (a) for studies performed under an IND, regardless of the definition of SAE used in the protocol. Note that the example text provided is from the drug regulations (21 CFR 312.32 (a)). There is no definition for SAE in the device regulations. Therefore, investigators should develop an appropriate definition for their



study. This definition could include an unanticipated adverse device effect, but an SAE is broader than that definition. According to 21 CFR 812.3(s), an “unanticipated adverse device effect means any serious adverse effect on health or safety or 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 investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.”


[An adverse event (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 adverse event, 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 participant 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.]

<Insert text>

CLASSIFICATION OF AN ADVERSE EVENT


The following subsections will include a discussion of how AEs will be classified.

1.1.1.1 SEVERITY OF EVENTAll AEs will be assessed by the study clinician using a protocol defined grading system. Describe the method of grading an AE for severity. For example, many toxicity tables are available for use and are adaptable to various study designs. Selection of a toxicity table or severity scale should be made in consultation with the study Medical Monitor.


[For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will be used to describe severity.

• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.

• Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate events may cause some interference with functioning.

• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.]



<Insert text>

1.1.1.2 RELATIONSHIP TO STUDY INTERVENTIONAll AEs will have their relationship to study intervention or study participation assessed with a level of specificity appropriate to the study design. The clinician’s assessment of an AE's relationship to study intervention (drug, biologic, device) is part of the documentation process, but it is not a factor in determining what is or is not reported in the study. Describe the method of determining the relationship of an AE to a study intervention. If there is any doubt as to whether a clinical observation is an AE, the event should be reported. Some protocols may use a binary assessment (related/not related); others may have a scale of relatedness. Evaluation of relatedness must consider etiologies such as natural history of the underlying disease, concurrent illness, concomitant therapy, study-related procedures, accidents, and other external factors. In a clinical trial, the study intervention must always be suspect.


[All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of certainty about causality will be graded using the categories below. In a clinical trial, the study product must always be suspect.

• Related – The AE is known to occur with the study intervention, there is a reasonable possibility that the study intervention caused the AE, or there is a temporal relationship between the study intervention and event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study intervention and the AE.

• Not Related – There is not a reasonable possibility that the administration of the study intervention caused the event, there is no temporal relationship between the study intervention and event onset, or an alternate etiology has been established.

OR

• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs in a plausible time relationship to study intervention administration and cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention (dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary.

• Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time after administration of the study intervention, is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition.

• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within a reasonable time after administration of the trial medication). However, other factors may have contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although an AE may rate only as



“possibly related” soon after discovery, it can be flagged as requiring more information and later be upgraded to “probably related” or “definitely related”, as appropriate.

• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal relationship to study intervention administration makes a causal relationship improbable (e.g., the event did not occur within a reasonable time after administration of the study intervention) and in which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments).

• Not Related – The AE is completely independent of study intervention administration, and/or evidence exists that the event is definitely related to another etiology. There must be an alternative, definitive etiology documented by the clinician.]

<Insert text>

EXPECTEDNESS Expected adverse reactions are AEs that are known to occur for the study intervention being studied and should be collected in a standard, systematic format using a grading scale based on functional assessment or magnitude of reaction. Identify the source of the reference safety information used to determine the expectedness of the AE (e.g., IB, approved labeling). Expectedness is assessed based on the awareness of AEs previously observed, not on the basis of what might be anticipated from the properties of the study intervention.

An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the IB, package insert, or device labeling 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 protocol, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB or package insert 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 or package insert 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, package insert, or device labeling as occurring with a class of drugs (or other medical products) or as anticipated from the pharmacological properties or other characteristics of the study intervention, but are not specifically mentioned as occurring with the particular study intervention under investigation.


[<Insert role> will be responsible for determining whether an adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously described for the study intervention.]

<Insert text>

TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UPDescribe how AEs and SAEs will be identified and followed until resolved or considered stable. Specify procedures for recording and follow-up of AEs and SAEs that are consistent with the information contained within Section 8.2, Safety and Other Assessments including what assessment tools will be used to monitor AEs. Include duration of follow-up after appearance of events (e.g., 1 week, 2 months).



An unsolicited AE would occur without any prompting or in response to a general question such as “Have you noticed anything different since you started the study; began the study intervention, etc.” A solicited AE is one that is specifically solicited such as “Have you noticed any dry mouth since you started the study medication?”

• Describe which AEs will be collected as solicited events. Plan the reporting and data collection system to avoid double capture (captured both as an unsolicited and a solicited AE).

• Describe how unsolicited events will be captured.

• Include time period of collection (e.g., Days 0 -28) and note how long SAEs are collected – usually collected through entire study.


[The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study personnel during study visits and interviews of a study participant presenting for medical care, or upon review by a study monitor.

All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate case report form (CRF). Information to be collected includes event description, time of onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study must be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution.

Any medical condition that is present at the time that the participant is screened will be considered as baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, it will be recorded as an AE.

Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration of each episode.

<Insert role or name> will record all reportable events with start dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until resolution or stabilization.]

<Insert text>

1.1.2 ADVERSE EVENT REPORTING This section addresses responsibilities of investigators for reporting of AEs. However, it is important to recognize that sponsors have additional responsibilities under regulations that are not described in this template and should be incorporated into relevant SOPs.

Describe the AE reporting procedures, including timeframes. Further details should be included in a MOP or SOP including a description and a flow chart of when events are reported to various oversight (e.g., Data and Safety Monitoring Board (DSMB), safety monitoring committee, independent safety monitor) and regulatory groups, and what



study staff are responsible for completing and signing off on the AE reports, and who will receive notification of AEs. According to 21 CFR 312.64(b), “…The investigator must record nonserious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol”.

In addition, list any disease-related events (DREs) common in the study population (e.g., expected), which will not be reported per the standard process for reporting, as applicable. Describe how these events will be recorded and monitored.

<Insert text>

1.1.3 SERIOUS ADVERSE EVENT REPORTING This section addresses responsibilities of investigators for reporting of SAEs. However, it is important to recognize that sponsors have additional responsibilities under regulations that are not described in this template and should be incorporated into relevant SOPs.

Describe the SAE reporting procedures, including timeframes. Further details should be included in a MOP or SOP including a description and a flow chart of when events are reported to various oversight and regulatory groups, and what study staff are responsible for completing and signing off on the SAE reports, and who will receive notification of SAEs.

Generally, any AE considered serious by the PI or Sub-investigator or which meets the definition of an SAE included in Section 8.3.2, Definition of Serious Adverse Events must be submitted on an SAE form to the Data Coordinating Center (DCC) if one exists for the study. Studies overseen by a DSMB or other independent oversight body (e.g., safety monitoring committee, independent safety monitor), may be required to submit expedited notification of all SAEs or only SAEs thought to be related to study intervention.

According to 21 CFR 312.64(b), “An investigator must immediately report to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the event to the sponsor…”

According to 21 CFR 312.32(c)(1), “the sponsor must notify FDA and all participating investigators…in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting… In each IND safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information. The sponsor must report any suspected adverse reaction that is both serious and unexpected. The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as:

(A) A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);(B) One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture);



(C) An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group.”

Furthermore, according to 21 CFR 312.32(c)(2), “the sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the information.”

As noted previously, an unanticipated adverse device effect could be considered an SAE (Section 8.3.2, Definition of Serious Adverse Events). For IDE studies, according to 21 CFR 812.150(a)(1), “an investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.” In addition, according to 21 CFR 812.150(b)(1), “A sponsor who conducts an evaluation of an unanticipated adverse device effect under 812.46(b) shall report the results of such evaluation to FDA and to all reviewing IRB's and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests.”


Example 1, applicable for a drug or biologic protocol:

[The study clinician will immediately report to the sponsor any serious adverse event, whether or not considered study intervention related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the study intervention caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the event to the sponsor.

All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or the participant is stable. Other supporting documentation of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be provided as soon as possible.

The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the sponsor's initial receipt of the information. In addition, the sponsor must notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting.]

OR

Example 2, applicable for device protocol:

[The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit to the study sponsor and to the reviewing Institutional Review Board (IRB) as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect. The study sponsor is responsible for conducting an evaluation of an



unanticipated adverse device effect and shall report the results of such evaluation to the Food and Drug Administration (FDA) and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter, the sponsor shall submit such additional reports concerning the effect as FDA requests.]

<Insert text>

1.1.4 REPORTING EVENTS TO PARTICIPANTS Include content in this section if applicable, otherwise note as not-applicable.

Describe how participants will be informed about AEs and SAEs, and study-related results on an individual or aggregate level. In addition, describe plans for detecting and managing incidental findings associated with study procedures.

<Insert text>

1.1.5 EVENTS OF SPECIAL INTEREST Include content in this section if applicable, otherwise note as not-applicable.

Describe any other events that merit reporting to the sponsor, study leadership, IRB, and regulatory agencies. For example, in oncology trials, secondary malignancies are often captured.

Include any other reportable events not already included in the previous sections, such as cardiovascular and death events, medical device incidents (including malfunctions), laboratory test abnormalities, and study intervention overdose.

<Insert text>

1.1.6 REPORTING OF PREGNANCY Include content in this section if applicable, otherwise note as not-applicable. Pregnancy is not an adverse event, but some studies will require unique considerations if pregnancy was to occur during the study.

State the study’s pregnancy-related policy and procedure. Include appropriate mechanisms for reporting to the DCC or NIH, the IND or IDE sponsor, study leadership, IRB, and regulatory agencies. Provide appropriate modifications to study procedures (e.g., discontinuation of study intervention, while continuing safety follow-up, requesting permission to follow pregnant women to pregnancy outcome).

<Insert text>

1.2 UNANTICIPATED PROBLEMSNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

1.2.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP)



The reporting of UPs applies to non-exempt human subjects research conducted or supported by HHS. Provide the definition of an UP being used for this clinical trial. An incident, experience, or outcome that meets the definition of an UP generally will warrant consideration of changes to the protocol or consent in order to protect the safety, welfare, or rights of participants or others. Other UPs may warrant corrective actions at a specific study site. Examples of corrective actions or changes that might need to be considered in response to an UP include:

• Modification of inclusion or exclusion criteria to mitigate the newly identified risks

• Implementation of additional safety monitoring procedures

• Suspension of enrollment of new participants or halting of study procedures for enrolled participants

• Modification of informed consent documents to include a description of newly recognized risks

• Provision of additional information about newly recognized risks to previously enrolled participants.


[The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to participants or others to include, in general, any incident, experience, or outcome that meets all of the following criteria:

• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved research protocol and informed consent document; and (b) the characteristics of the participant population being studied;

• Related or possibly related to participation in the research (“possibly related” means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and

• Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

Additional example text, applicable for device protocols:

[This definition could include an unanticipated adverse device effect, any serious adverse effect on health or safety or 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 investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)).]

<Insert text>

1.2.2 UNANTICIPATED PROBLEM REPORTING This section addresses responsibilities of investigators for reporting of UPs. Describe the UP reporting procedures, including timeframes. Further details should be included in a MOP or SOP including a description and a flow chart of



when events are reported to various oversight (e.g., DSMB, safety monitoring committee, independent safety monitor) and regulatory groups, and what study staff are responsible for completing and signing off on the UP report forms.

Institutions engaged in human subjects research conducted or supported by Department of Health and Human Services (DHHS) must have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and any supporting department or agency head of any unanticipated problem involving risks to subjects or others (45 CFR 46.103(b)(5)). Furthermore, for research covered by an assurance approved for federal wide use by OHRP, DHHS regulations at 45 CFR 46.103(a) require that institutions promptly report any unanticipated problems to OHRP.


[The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board (IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will include the following information:

• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number;

• A detailed description of the event, incident, experience, or outcome;

• An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP;

• A description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the UP.

To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:

• UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study sponsor within <insert timeline in accordance with policy> of the investigator becoming aware of the event.

• Any other UP will be reported to the IRB and to the DCC/study sponsor within <insert timeline in accordance with policy> of the investigator becoming aware of the problem.

• All UPs should be reported to appropriate institutional officials (as required by an institution’s written reporting procedures), the supporting agency head (or designee), and the Office for Human Research Protections (OHRP) within <insert timeline in accordance with policy> of the IRB’s receipt of the report of the problem from the investigator.]

Additional example text, applicable for device protocol:

[An investigator shall submit to the sponsor and to the reviewing Institutional Review Board (IRB) a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect (21 CFR 812.150(a)(1)), A sponsor who conducts an evaluation of an unanticipated adverse device effect under 812.46(b) shall report the results of such evaluation to the Food and Drug Administration (FDA) and to all reviewing IRB's and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests (21 CFR 812.150(b)(1)).

<Insert text>



1.2.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS Include content in this section if applicable, otherwise note as not-applicable.

Describe how participants will be informed about UPs on an individual or aggregate level.

<Insert text>

2 STATISTICAL CONSIDERATIONS No text is to be entered in this section; rather it should be included under the relevant subheadings below.

The following subsections should describe the statistical tests and analysis plans for the protocol. They should indicate how the study will answer the most important questions with precision and a minimum of bias, while remaining feasible. Many elements below can be found in ICH Guidance for Industry E9 Statistical Principles for Clinical Trials and the CONSORT statement which describes standards for improving the quality of reporting randomized controlled trials.

State whether there will be a formal Statistical Analysis Plan (SAP). A formal SAP should be completed prior to database lock and unblinding of the study data. The SAP generally includes additional statistical analysis detail (e.g., more detail of analysis populations, summary of statistical strategies). If a separate SAP will be developed, subsections below can be summarized.

2.1 STATISTICAL HYPOTHESESState the formal and testable null and alternative hypotheses for primary and key secondary endpoints, specifying the type of comparison (e.g., superiority, equivalence or non-inferiority, dose response) and time period for which each endpoint will be analyzed.

Primary Efficacy Endpoint(s):

<Insert text>

Secondary Efficacy Endpoint(s):

<Insert text>

2.2 SAMPLE SIZE DETERMINATIONInclude number of participants to recruit, screen, and enroll to have adequate power to test the key hypotheses for the study. Provide all information needed to validate your calculations and judge the feasibility of enrolling and following the necessary number of participants. In particular, specify all of the following:

• Outcome measure used for calculations (almost always the primary variable)• Test statistic• Null and alternative hypotheses• Type I error rate (alpha)



• Power level (e.g., 80% power) Assumed event rate for dichotomous outcome (or mean and variance of continuous outcome) for each study

arm, justified and referenced by historical data as much as possible Statistical method used to calculate the sample size, with a reference for it and for any software utilized Anticipated impact of dropout rates, withdrawal, cross-over to other study arms, missing data, etc. on study

power (see also 9.4.2 Analysis of the Primary Efficacy Endpoint(s) and 9.4.3 Analysis of the Secondary Endpoint(s))

Method for adjusting calculations for planned interim analyses, if any (Section 9.4.6, Planned Interim Analyses).

Further, present calculations from a suitable range of assumptions to gauge the robustness of the proposed sample size.

Discuss whether the sample size provides sufficient power for addressing secondary endpoints or exploratory analyses (e.g., subgroup analyses or moderator analyses involving an interaction term, Section 9.4.9, Exploratory Analyses).

<Insert text>

2.3 POPULATIONS FOR ANALYSESClearly identify and describe the analysis datasets (e.g., which participants will be included in each). As a guide, this may include, but is not limited to, any or all of the following:

Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants) Modified Intention-to-Treat Analysis Dataset (e.g., participants who took at least one dose of study intervention

and/or have some particular amount of follow-up outcome data) Safety Analysis Dataset: defines the subset of participants for whom safety analyses will be conducted (e.g.,

participants who took at least one dose of study intervention) Per-Protocol Analysis Dataset: defines a subset of the participants in the full analysis (ITT) set who complied with

the protocol sufficiently to ensure that these data would be likely to represent the effects of study intervention according to the underlying scientific model (e.g., participants who took at least 80% of study intervention for 80% of the days within the maintenance period)

Other Datasets that may be used for sensitivity analyses

<Insert text>

2.4 STATISTICAL ANALYSESNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

The following subsections should include a description of the planned statistical methods.

2.4.1 GENERAL APPROACHAs a guide, the following should be addressed, as appropriate:

For descriptive statistics, describe how categorical and continuous data will be presented (e.g., percentages, means with standard deviations, median, range).



For inferential tests, indicate the p-value and confidence intervals for statistical significance (Type I error) and whether one or two-tailed.

Indicate whether covariates will be pre-specified in the sections below or later in a SAP. State whether checks of assumptions (e.g., normality) underlying statistical procedures will be performed and

whether any corrective procedures will be applied (e.g., transformation or nonparametric tests).

<Insert text>

2.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S)For each primary endpoint:

Define the measurement or observation and describe how it is calculated, if not readily apparent Describe the scale (nominal/binary/categorical, ordinal, interval); state if it is measured as a single

endpoint/summary measure or repeated measure Describe the statistical procedure(s) that will be used to analyze the primary endpoint (e.g., multiple regression,

repeated measures mixed models, logistic regression, Analysis of Covariance (ANCOVA)). Describe the covariates and factors in the model. Provide your rationale for covariates and how they will be selected to achieve a parsimonious model. If the decision to specify covariates is deferred for the SAP, indicate here.

Describe how results of statistical procedure(s) will be presented (e.g., adjusted means (Least-squares means (LSMEANS)) with standard errors, odds ratios with 95% confidence intervals, prevalence rates, number-needed-to-treat)

Describe details to check assumptions required for certain types of analyses (e.g., proportional hazards, transformations or, when appropriate, nonparametric tests)

Describe the Populations for which the analysis will be conducted, as discussed in Section 9.3, Populations for Analyses

Describe how missing data will be handled (e.g., type of imputation technique, if any, and provide justification), and approach to handling outliers, nonadherence and lost to follow-up

If there is more than one primary endpoint or more than one analysis of a particular endpoint, state the statistical adjustment used for Type I error criteria or give reasons why it was considered unnecessary.

Note if more than one endpoint: the statistical approach for endpoints with the same analytic issues can be described as a group.

<Insert text>

2.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S)For each secondary endpoint:

Note if analysis of secondary endpoint(s) are dependent on findings of primary endpoint Define the measurement or observation and describe how it is calculated, if not readily apparent Describe the scale (nominal/binary/categorical, ordinal, and interval); state if it is measured as a single

endpoint/summary measure or repeated measure. Describe the statistical procedure(s) that will be used to analyze the secondary endpoint (e.g., multiple

regression, repeated measures mixed models, logistic regression, ANCOVA). Describe the covariates and factors in the model. Provide rationale for covariates and how they will be selected to achieve a parsimonious model. If decision to specify covariates is deferred for the SAP, indicate here.



Describe how results of statistical procedure(s) will be presented (e.g., adjusted means (LSMEANS) with standard errors, odds ratios with 95% confidence intervals, prevalence rates, and number-needed-to-treat).

Describe details to check assumptions required for certain types of analyses (e.g., proportional hazards, transformations or, when appropriate, nonparametric tests).

Describe the Populations for which the analysis will be conducted as discussed in Section 9.3, Populations for Analyses.

Describe how missing data will be handled (e.g., type of imputation technique, if any, and provide justification), and approach to handling outliers, nonadherence and lost to follow-up.

If there is more than one primary endpoint or more than one analysis of a particular endpoint, state the statistical adjustment used for Type I error criteria or give reasons why it was considered unnecessary.

Note if more than one endpoint: the statistical approach for endpoints with the same analytic issues can be described as a group.

<Insert text>

2.4.4 SAFETY ANALYSESDescribe how safety endpoints will be analyzed (e.g., as summary statistics during treatment and/or as change scores from baselines such as shift tables). If your study is evaluating a formal safety endpoint, all of the factors to be included in Section 9.4.2, Analysis of the Primary Efficacy Endpoint(s) should be included here. Describe how AEs will be coded (e.g., Medical Dictionary for Regulatory Activities (MedDRA)), calculated (e.g., each AE will be counted once only for a given participant), presented (e.g., severity, frequency, and relationship of AEs to study intervention will be presented by System Organ Class (SOC) and preferred term groupings) and what information will be reported about each AE (e.g., start date, stop date, severity, relationship, expectedness, outcome, and duration). Adverse events leading to premature discontinuation from the study intervention and serious treatment-emergent AEs should be presented either in a table or a listing. The information included here should be consistent with the information contained within Section 8.2, Safety and Other Assessments.

<Insert text>

2.4.5 BASELINE DESCRIPTIVE STATISTICSInclude content in this section if applicable, otherwise note as not-applicable.

Intervention groups should be compared on baseline characteristics, including demographics and laboratory measurements, using descriptive statistics. Discuss planned baseline descriptive statistics, indicate whether inferential statistics will be used.

<Insert text>

2.4.6 PLANNED INTERIM ANALYSES Include content in this section if applicable, otherwise note as not-applicable.

This section should describe the types of statistical interim analyses and halting guidelines (if any) that are proposed, including their timing and who reviews the interim analyses. In addition, if the interim analyses could result in an



adjusted sample size, discuss the statistical algorithm to be used when evaluating results. Pre-specify, to the extent possible, the criteria that would prompt an interim review of safety and efficacy data and trial futility. Describe who performs the statistical analysis and who reviews the analysis. In addition, discuss whether they are unblinded and how the blinding will be preserved.

If statistical rules will be used to halt enrollment into all or a portion of the study (e.g., for safety or futility), describe the statistical techniques and their operating characteristics. If formal interim analyses will be performed, provide unambiguous and complete instructions so that an independent statistician could perform the analyses.

Describe safety findings that would prompt temporary suspension of enrollment and/or study intervention use until a safety review is convened (either routine or ad hoc). Provide details of the proposed rules for halting study enrollment or study intervention/administration of study product for safety, including whether they pertain to the entire study, specific study arms or participant subgroups, or other components of the study.

State how endpoints will be monitored, the frequency of monitoring, and the specific definitions of proposed halting guidelines. Examples of findings that might trigger a safety review are the number of SAEs overall, the number of occurrences of a particular type of SAE, severe AEs/reactions, or increased frequency of events.

Also, discuss the impact of the interim analysis (if being done) on the final efficacy analyses, particularly on Type I error.

This section should be consistent with Section 7, Study Intervention Discontinuation and Participant Discontinuation/Withdrawal.

<Insert text>

2.4.7 SUB-GROUP ANALYSESDescribe how the primary endpoint will be analyzed based on age, sex, race/ethnicity or other demographic characteristic(s) or provide justification for why such analyses are not warranted (e.g., study intervention only for use in men or children).

Describe how the secondary endpoint(s) will be analyzed based on age, sex, race/ethnicity or other demographic characteristic(s) or provide justification for why such analyses are not warranted (e.g., study intervention only for use in men or children).

<Insert text>

2.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATAState whether individual participant data will be listed by measure and time point.

<Insert text>

2.4.9 EXPLORATORY ANALYSESExploratory analyses cannot be used as confirmatory proof for registration trials. All planned exploratory analyses should be specified in the protocol.



<Insert text>

3 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONSNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

3.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONSNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

The following subsections should include a description of the regulatory and ethical considerations, and context for the conduct of the trial. Of note, the guiding ethical principles being followed by this study are included in the Statement of Compliance at the beginning of this protocol. For NIH Intramural Research Program studies only: A statement referencing compliance with NIH Human Research Protections Program policies and procedures is adequate for Subsection 10.1.1, Informed Consent Process.

3.1.1 INFORMED CONSENT PROCESSNo text is to be entered in this section; rather it should be included under the relevant subheadings below.

The following subsections should describe the procedures for obtaining and documenting informed consent of study participants. State if a separate screening consent will be used. If a separate screening consent will not be used, the study consent must be signed prior to conducting study screening procedures.

In obtaining and documenting informed consent, the investigator must comply with applicable regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should adhere to ICH GCP. Prior to the beginning of the trial, the investigator should have the IRB’s written approval for the protocol and the written informed consent form(s) and any other written information to be provided to the participants.

3.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTSThis section should demonstrate that the consent form contains all required regulatory elements. List all consent and/or assent documents and materials submitted with this protocol. Include consent and/or assent forms, printed or web-based materials, phone scripts and any other related material.

If needed, describe special documents or materials (e.g., Braille, another language, audio recording)


[Consent forms describing in detail the study intervention, study procedures, and risks are given to the participant and written documentation of informed consent is required prior to starting intervention/administering study intervention. The following consent materials are submitted with this protocol <insert list>.]

<Insert text>



3.1.1.2 CONSENT PROCEDURES AND DOCUMENTATIONDescribe how informed consent will be administered. Describe any proposed waivers or alterations to informed consent. Describe any special circumstances regarding obtaining consent. Describe plans for obtaining consent from speakers of language other than English. Describe procedures for obtaining surrogate consent for those unable to consent on their own behalf. This section should be consistent with Section 5.5, Strategies for Recruitment and Retention when describing consent plans and special considerations for children or other vulnerable participants. Address re-consent processes for children who become adults or emancipated during a study.


[Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and continues throughout the individual’s study participation. Consent forms will be Institutional Review Board (IRB)-approved and the participant will be asked to read and review the document. The investigator will explain the research study to the participant and answer any questions that may arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential risks of the study and of their rights as research participants. Participants will have the opportunity to carefully review the written consent form and ask questions prior to signing. The participants should have the opportunity to discuss the study with their family or surrogates or think about it prior to agreeing to participate. The participant will sign the informed consent document prior to any procedures being done specifically for the study. Participants must be informed that participation is voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the informed consent document will be given to the participants for their records. The informed consent process will be conducted and documented in the source document (including the date), and the form signed, before the participant undergoes any study-specific procedures. The rights and welfare of the participants will be protected by emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in this study.]

<Insert text>

STUDY DISCONTINUATION AND CLOSUREList possible reasons for termination or temporary suspension of the study (e.g., study closure based on PI decision, sponsor/funder decision, regulatory or other oversight bodies; review of serious, unexpected, and related AEs; noncompliance; futility). For any study that is prematurely terminated or temporarily suspended, the PI will promptly inform study participants, the IRB, and sponsor and provide the reason(s) for the termination or temporary suspension.

When a study is prematurely terminated, refer to Section 7, Study Intervention Discontinuation and Participant Discontinuation/Withdrawal, for handling of enrolled study participants.


[This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to <study participants, investigator, funding agency, the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor and regulatory authorities>. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule.



Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility

Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).]

<Insert text>

3.1.2 CONFIDENTIALITY AND PRIVACY This section will describe protections for maintaining confidentiality of participant data, including, but not limited to forms, records and samples and participant privacy.

Include procedures for maintaining participant confidentiality, privacy protections, any special data security requirements, and record retention per the sponsor’s requirements. Describe who would have access to records, including the investigator and other study staff, the clinical monitor, funding institutions, representatives of the NIH Institute or Center (IC), IND/IDE sponsor, representatives from the IRB, regulatory agencies, and representatives of the pharmaceutical company supplying product to be tested. In addition, consider inclusion of the following information:

Describe whether identifiers will be attached to data/samples, or whether data will be coded or unlinked.

If unlinked or coded, and additional information (e.g., age, ethnicity, sex, diagnosis) is available, discuss whether this might make specific individuals or families identifiable.

If research data/samples will be coded, describe how access to the “key” for the code will be limited. Include description of security measures (password-protected database, locked drawer, other). List names or positions of persons with access to the key.

Include a discussion of the circumstances in which data or samples will be shared with other researchers.

Include a discussion of plans to publish participant’s family pedigrees, with a description of measures to minimize the chance of identifying specific families.

Describe any situations in which personally identifiable information will be released to third parties.

State who has access to records, data, and samples. Consider if monitors or auditors outside of study investigators will need access.



Discuss any additional features to protect confidentiality (e.g., use of a certificate of confidentiality).

Approaches to ensure privacy of study participants

For some studies, a Certificate of Confidentiality (CoC) may be necessary. A CoC provides protection to researchers and research institutions from being forced to provide identifying information on study participants to any federal, state or local authority. Authorization comes from NIH through section 301 (d) of the Public Health Service Act (42 U.S.C. 241 (d)) which provides the Secretary of Health and Human Services the authority to protect the privacy of study participants. Refer to the NIH Certificate of Confidentiality Kiosk, for more details.

Example text provided as a guide, customization will be required to address all aspects that should be included in this section:

[Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor.

All research activities will be conducted in as private a setting as possible.

The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records.

The study participant’s contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements.

Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the <specify name of Data Coordinating Center>. This will not include the participant’s contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by <specify name of Data Coordinating Center> research staff will be secured and password protected. At the end of the study, all study databases will be de-identified and archived at the <specify name of Data Coordinating Center>.

Certificate of Confidentiality (if applicable)

To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.]



<Insert text>

3.1.3 FUTURE USE OF STORED SPECIMENS AND DATA If intended specimens or residual specimens are retained after the study is complete, include the provisions for consent and the options that are available for the participant to agree to the future use of his/her specimens, images, audio or video recordings. Specify the location(s), if other than the clinical site, where specimens or other data will be maintained, how long specimens or other data will be stored, if the site's IRB will review future studies, and protections of confidentiality for any future studies with the stored specimens or data (e.g., specimens will be coded, bar-coded, de-identified, identifying information will be redacted from audio recording transcripts). Include a statement that genetic testing will or will not be performed.

See also Section 10.1.3, Confidentiality and Privacy and Section 10.1.9, Data Handling and Record Keeping, for further information on future use of study records.


[Data collected for this study will be analyzed and stored at the <specify name of Data Coordinating Center >. After the study is completed, the de-identified, archived data will be transmitted to and stored at the <specify name of Data Repository>, for use by other researchers including those outside of the study. Permission to transmit data to the <specify name of Data Repository> will be included in the informed consent.

With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified biological samples will be stored at the <specify name of Biosample Repository> with the same goal as the sharing of data with the <specify name of Data Repository>. These samples could be used to research the causes of <specify condition(s)>, its complications and other conditions for which individuals with < specify condition(s)> are at increased risk, and to improve treatment. The <specify name of Repository> will also be provided with a code-link that will allow linking the biological specimens with the phenotypic data from each participant, maintaining the blinding of the identity of the participant.

During the conduct of the study, an individual participant can choose to withdraw consent to have biological specimens stored for future research. However, withdrawal of consent with regard to biosample storage may not be possible after the study is completed.

When the study is completed, access to study data and/or samples will be provided through the <specify name of Repository>.]

<Insert text>

3.1.4 KEY ROLES AND STUDY GOVERNANCE

Provide the name and contact information of the Principal Investigator and the Medical Monitor.

Principal Investigator Medical MonitorName, degree, title Name, degree, titleInstitution Name Institution Name Address Address



Phone Number Phone NumberEmail Email

In addition, briefly describe any study leadership committees (e.g.: Steering Committee, Executive Committee, Subcommittee) and their roles. Note that it is not necessary to list specific members. Also, describe country-specific administrative requirements or functions that materially affect the conduct of the study. The MOP should include a list of study team roles and responsibilities of those involved in the conduct, management, or oversight of the trial.

<Insert text>

3.1.5 SAFETY OVERSIGHTAppropriate safety oversight should be used for each trial. This could include a Safety Monitoring Committee (SMC)3, Data Safety Monitoring Board (DSMB)4, Safety Assessment Committee5, and/or an Independent Safety Monitor (ISM)6. Independent oversight is an important component to ensure human subjects’ protection and data integrity and should be considered for each study. In this section, the type of safety oversight should be clearly identified along with any known responsibilities for the oversight of safety and data integrity in the study. Describe the composition of the SMC or DSMB, frequency of interim data review, final data analysis and method of reviews. A separate DSMB Charter will provide further detail of DSMB membership, responsibilities and administration of the DSMB.


[Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of individuals with the appropriate expertise, including <list expertise>. Members of the DSMB should be independent from the study conduct and free of conflict of interest, or measures should be in place to minimize perceived conflict of interest. The DSMB will meet at least semiannually to assess safety and efficacy data on each arm of the study. The DMSB will operate under the rules of an approved charter that will be written and reviewed at the organizational meeting of the DSMB. At

3 A Safety Monitoring Committee (SMC) is a small group of experts with at least two members who are independent of the protocol who review data from a particular study. Generally, independent investigators and biostatisticians should be included. The primary responsibility of the SMC is to monitor participant safety. The SMC considers study-specific data as well as relevant background information about the disease, intervention, and target population under study.4 A Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises funding IC(s) and the study investigators. The members of the DSMB provide their expertise and recommendations. The primary responsibilities of the DSMB are to 1) periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and, when appropriate, efficacy, and 2) make recommendations concerning the continuation, modification, or termination of the trial. The DSMB considers study-specific data as well as relevant background knowledge about the disease, intervention, or target population under study.5 As noted on page 4 of the FDA Draft Guidance for Industry: Safety Assessment for IND Safety Reporting, “A group of individuals chosen by the sponsor to review safety information in a development program (i.e., across trials, INDs, and other sources) for IND safety reporting purposes...The safety assessment committee should oversee the evolving safety profile of the investigational drug by evaluating, at appropriate intervals, the cumulative serious adverse events from all of the trials in the development program, as well as other available important safety information (e.g., findings from epidemiological studies and from animal or in vitro testing) and performing unblended comparisons of event rates in investigational and control groups, as needed, so the sponsor may meet its obligations under § 312.32(b) and (c). The safety assessment committee’s primary role should be to review important safety information on a regular basis, with additional reviews as needed, and make a recommendation to the sponsor to help the sponsor determine whether an event or group of events meets the criteria for IND safety reporting. The safety assessment committee, possibly together with other parties (e.g., steering committees, data monitoring committees [DMCs]), can also participate in decisions about whether the conduct of the study should be revised (e.g., change ineligibility criteria, revision of informed consent).6 An Independent Safety Monitor (ISM) is a physician, nurse, or other individual with relevant expertise whose primary responsibility is to provide independent safety monitoring in a timely fashion. This is accomplished by review of adverse events, immediately after they occur or are reported, with follow-up through resolution. The ISM evaluates individual and cumulative participant data when making recommendations regarding the safe continuation of the study.



this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to <specify the study sponsor/National Institutes of Health staff/other>.]

<Insert text>

3.1.6 CLINICAL MONITORINGSite monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, and with applicable regulatory requirement(s).

This section should give a general description of how monitoring of the conduct and progress of the clinical investigation will be conducted (i.e., who will conduct the monitoring, the type, frequency, and extent of monitoring, who will be provided reports of monitoring, if independent audits of the monitoring will be conducted). This section may refer to a separate detailed clinical monitoring plan.

A separate clinical monitoring plan (CMP) should describe in detail who will conduct the monitoring, at what frequency monitoring will be done, at what level of detail monitoring will be performed, and the distribution of monitoring reports. A CMP ordinarily should focus on preventing or mitigating important and likely risks, identified by a risk assessment, to critical data and processes. The types (e.g., on-site, centralized), frequency (e.g., early, for initial assessment and training versus throughout the study), and extent (e.g., comprehensive (100% data verification) versus targeted or random review of certain data (less than 100% data verification)) of monitoring activities will depend on a range of factors, considered during the risk assessment, including the complexity of the study design, types of study endpoints, clinical complexity of the study population, geography, relative experience of the PI and of the sponsor with the PI, electronic data capture, relative safety of the study intervention, stage of the study, and quantity of data.

If a separate CMP is not used, include all the details noted above in this section of the protocol.

Example text when a separate CMP is being used is provided as a guide, customize as needed:

[Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).

• Monitoring for this study will be performed by <insert text>. • <Insert brief description of type of monitoring (e.g., on-site, centralized), frequency (e.g., early, for initial

assessment and training versus throughout the study), and extent (e.g., comprehensive (100% data verification) versus targeted or random review of certain data (less than 100% data verification or targeted data verification of endpoint, safety and other key data variables)>.

• <Insert text> will be provided copies of monitoring reports within <x> days of visit.• Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP describes in

detail who will conduct the monitoring, at what frequency monitoring will be done, at what level of detail monitoring will be performed, and the distribution of monitoring reports.

• Independent audits <will/will not> be conducted by <insert text> to ensure monitoring practices are performed consistently across all participating sites and that monitors are following the CMP.]



OR

Example text when a separate CMP is not being used is provided as a guide, customize as needed:

[Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).

• <Insert detailed description of who will conduct the monitoring, the type of monitoring (e.g., on-site, centralized), frequency (e.g., early, for initial assessment and training versus throughout the study), and extent (e.g., comprehensive (100% data verification) versus targeted or random review of certain data (less than 100% data verification or targeted data verification of endpoint, safety and other key data variables)), and the distribution of monitoring reports>

• Independent audits <will/will not> be conducted by <insert text> to ensure monitoring practices are performed consistently across all participating sites.]

<Insert text>

3.1.7 QUALITY ASSURANCE AND QUALITY CONTROLThis section will briefly describe the plans for quality management, the system for assessing the quality of processes within a system. Quality management encompasses quality assurance (QA)7 and quality control (QC)8.

Each site, both clinical and laboratory, should have SOPs for quality management that describe:

How data and biological specimens (when applicable) will be evaluated for compliance with the protocol, ethical standards, regulatory compliance, and accuracy in relation to source documents.

The documents to be reviewed (e.g., CRFs, clinic notes, product accountability records, specimen tracking logs, questionnaires, audio or video recordings), who is responsible, and the frequency for reviews.

Who will be responsible for addressing QA issues (e.g., correcting procedures that are not in compliance with protocol) and QC issues (e.g., correcting errors in data entry).

Staff training methods and how such training will be tracked.

If applicable, calibration exercises conducted prior to and during the study to train examiners and maintain acceptable intra- and inter-examiner agreement.

Regular monitoring and an independent audit, if conducted, must be performed according to ICH GCP. See also Section 10.1.7, Clinical Monitoring.7 All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with ICH GCP and the applicable regulatory requirement(s) (ICH E6 Section 1.46).8 The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled (ICH E6 Section 1.47).




[Each clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site’s quality management.]

Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution.

Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).

The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.]

<Insert text>

3.1.8 DATA HANDLING AND RECORD KEEPING No text is to be entered in this section; rather it should be included under the relevant subheadings below.

Each participating site will maintain appropriate medical and research records for this trial, in compliance with ICH GCP and regulatory and institutional requirements for the protection of confidentiality of participants. As part of participating in a NIH-sponsored or NIH-affiliated study, each site will permit authorized representatives of the NIH, sponsor, and regulatory agencies to examine (and when permitted by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, and evaluation of the study safety, progress, and data validity. Describe in this section who will have access to records.

The following subsections should include a description of the data handling and record keeping for the conduct of the trial.

3.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES Provide details regarding the type(s) of data capture that will be used for the study and any relevant data standards or common data elements that are being utilized as a part of the trial. Specify whether it will be paper or electronic, distributed or central, batched or ongoing processing, and any related requirements. Indicate expectations for time for submission of CRFs. Further details should be provided in the MOP or the data management plan, including detailed descriptions of source documentation, CRFs, instructions for completing forms, data handling procedures, and procedures for data monitoring.



Source data are all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Electronic source data are data initially recorded in electronic form. Examples of source data include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, participants’ memory aids or evaluation checklists, pharmacy dispensing records, audio recordings of counseling sessions, 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, and participant files and records kept at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source documents. If this is the case, it should be stated in this section what data will be collected on CRFs and what data will be collected from other sources.

It is not acceptable for the CRF to be the only record of a participant’s inclusion in the study. Study participation should be captured in a participant’s medical record. This is to ensure that anyone who would access the patient medical record has adequate knowledge that the patient is participating in a clinical trial.

Describe responsibilities for data handling and record keeping as they specifically relate to the IND/IDE sponsor (if applicable), the award site, clinical site(s), laboratory(ies), and DCC. Information should include the role in data collection, review of data, trial materials, and reports, as well as retention of source documents, files, and records. Describe coding dictionaries to be used and reconciliation processes (if applicable).

If data are to be generated in one location and transferred to another group, describe the responsibilities of each party.

Provide a list of planned data standards, formats, terminologies and their versions, used for the collection, tabulation, analysis of study data. Refer to the FDA Guidance for Industry, Providing Regulatory Submissions in Electronic Format — Standardized Study Data, Study Data Technical Conformance Guide and FDA Guidance for Industry, Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.


[Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported.

All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.

Hardcopies of the study visit worksheets will be provided for use as source document worksheets for recording data for each participant enrolled in the study. Data recorded in the electronic case report form (eCRF) derived from source documents should be consistent with the data recorded on the source documents.

Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) and clinical laboratory data will be entered into <specify name of data capture system>, a 21 CFR Part 11-compliant data capture system provided by the <specify Data Coordinating Center>. The data system includes password protection and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source documents.]

<Insert text>



3.1.8.2 STUDY RECORDS RETENTION Specify the length of time for the investigator to maintain all records pertaining to this study. The investigator should use the most conservative rule for document retention – i.e., retention should follow the rule that has the longest period. For NIH, grantees must retain records for a period of three years from the date of Federal Financial Report (FFR) submission.

Indicate whether permission is required (and from whom) prior to destruction of records. If under an IND/IDE, records should not be destroyed without the IND/IDE sponsor’s agreement. Pharmaceutical companies who supply unapproved products should be consulted.

Study intervention records may be described here if not addressed elsewhere in the protocol.


[Study documents should be retained for a minimum of 2 years after the last approval of a marketing application in an International Conference on Harminosation (ICH) region and until there are no pending or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development of the study intervention. These documents should be retained for a longer period, however, if required by local regulations. No records will be destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these documents no longer need to be retained.]

<Insert text>

3.1.9 PROTOCOL DEVIATIONS Plans for detecting, reviewing, and reporting deviations from the protocol should be described. A statement should be included to indicate that deviations are not allowed, unless a statement is included in the investigator agreement. Provisions for approval of deviations can be described.


[A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the site and implemented promptly.

These practices are consistent with ICH GCP:

• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3

• 5.1 Quality Assurance and Quality Control, section 5.1.1

• 5.20 Noncompliance, sections 5.20.1, and 5.20.2.

It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations within <specify number> working days of identification of the protocol deviation, or within <specify number> working days of the scheduled protocol-required activity. All deviations must be addressed in study source documents, reported to <specify NIH Institute or Center (IC)> Program Official and <specify Data Coordinating Center or sponsor>. Protocol deviations



must be sent to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further details about the handling of protocol deviations will be included in the MOP.]

<Insert text>

3.1.10 PUBLICATION AND DATA SHARING POLICYThe publication and authorship policies should be described in this section. For example, for a study with multiple investigators, this section might state that an Executive Committee will be responsible for developing publication procedures and resolving authorship issues. Please refer to your specific contract, grant, and/or Clinical Trials Agreements. If details of the publication policy will be described in the study’s MOP, refer to it here. The study must comply with:

The NIH Public Access Policy, the NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information, The Food and Drug Administration Amendments Act of 2007 (FDAAA), Clinical Trials Registration and Results Information Submission rule,

The NIH Data Sharing Policy (if applicable), The NIH Genomic Data Sharing Policy, (if applicable), and The NIH Data Sharing Policy and Implementation Guidance, Any other relevant policies (e.g., NIH IC-specific data sharing or publication policy)


[This study will be conducted in accordance with the following publication and data sharing policies and regulations:

National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication.

This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers x years after the completion of the primary endpoint by contacting <specify person or awardee institution, or name of data repository>.

In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-funded research that generates large-scale human or non-human genomic data, as well as the use of these data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data.]

<Insert text>

3.1.11 CONFLICT OF INTEREST POLICYThis section should include a description of how the study will manage actual or perceived conflicts of interest.




[The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the <specify NIH Institute or Center (IC)> has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.]

<Insert text>

3.2 ADDITIONAL CONSIDERATIONSThis section should include a description of any additional considerations not currently covered in this protocol template, such as particular institutional or IRB-related requirements.

<Insert text>



3.3 ABBREVIATIONSThe list below includes abbreviations utilized in this template. However, this list should be customized for each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be added to this list).

AE Adverse EventANCOVA Analysis of CovarianceCFR Code of Federal RegulationsCLIA Clinical Laboratory Improvement AmendmentsCMP Clinical Monitoring PlanCOC Certificate of ConfidentialityCONSORT

Consolidated Standards of Reporting Trials

CRF Case Report FormDCC Data Coordinating CenterDHHS Department of Health and Human ServicesDSMB Data Safety Monitoring BoardDRE Disease-Related EventEC Ethics CommitteeeCRF Electronic Case Report FormsFDA Food and Drug AdministrationFDAAA Food and Drug Administration Amendments Act of 2007FFR Federal Financial ReportGCP Good Clinical PracticeGLP Good Laboratory PracticesGMP Good Manufacturing PracticesGWAS Genome-Wide Association StudiesHIPAA Health Insurance Portability and Accountability Act IB Investigator’s BrochureICH International Conference on Harmonisation ICMJE International Committee of Medical Journal EditorsIDE Investigational Device ExemptionIND Investigational New Drug ApplicationIRB Institutional Review BoardISM Independent Safety MonitorISO International Organization for StandardizationITT Intention-To-TreatLSMEANS Least-squares MeansMedDRA Medical Dictionary for Regulatory ActivitiesMOP Manual of ProceduresMSDS Material Safety Data SheetNCT National Clinical TrialNIH National Institutes of HealthNIH IC NIH Institute or CenterOHRP Office for Human Research ProtectionsPI Principal InvestigatorQA Quality AssuranceQC Quality ControlSAE Serious Adverse Event



SAP Statistical Analysis PlanSMC Safety Monitoring CommitteeSOA Schedule of ActivitiesSOC System Organ ClassSOP Standard Operating ProcedureUP Unanticipated ProblemUS United States



3.4 PROTOCOL AMENDMENT HISTORYThe table below is intended to capture changes of IRB-approved versions of the protocol, including a description of the change and rationale. A Summary of Changes table for the current amendment is located in the Protocol Title Page.

Version Date Description of Change Brief Rationale

4 REFERENCES



Include a list of relevant literature and citations for all publications referenced in the text of the protocol. Use a consistent, standard, modern format, which might be dependent upon the required format for the anticipated journal for publication (e.g., N Engl J Med, JAMA, etc.). The preferred format is International Committee of Medical Journal Editors (ICMJE). Include citations to product information such as manufacturer’s IB, package insert, and device labeling.

Examples:

Journal citationVeronesi U, Maisonneuve P, Decensi A. Tamoxifen: an enduring star. J Natl Cancer Inst. 2007 Feb 21;99(4):258-60.

Whole book citationBelitz HD, Grosch W, Schieberle P. Food chemistry. 3rd rev. ed. Burghagen MM, translator. Berlin: Springer; 2004. 1070 p.

Chapter in a book citationRiffenburgh RH. Statistics in medicine. 2nd ed. Amsterdam (Netherlands): Elsevier Academic Press; c2006. Chapter 24, Regression and correlation methods; p. 447-86.

Web Site citationComplementary/Integrative Medicine [Internet]. Houston: University of Texas, M.D. Anderson Cancer Center; c2007 [cited 2007 Feb 21]. Available from: http://www.manderson.org/departments/CIMER/.

Electronic Mail citationBackus, Joyce. Physician Internet search behavior: detailed study [Internet]. Message to: Karen Patrias. 2007 Mar 27 [cited 2007 Mar 28]. [2 paragraphs]

References to package insert, device labeling or investigational brochureCite date accessed, version number, and source of product information.


IX. Plain Language Consent Template

CCTRA utilizes the Plain Language Consent Template that was developed by the UAMS Center for Health Literacy to apply many simplified language best practices. The template is shown below. It may also be accessed at https://view.officeapps.live.com/op/view.aspx?src=http://irb.uams.edu/files/2016/09/September-2016-Plain-Language-Consent-Template.docx


https://view.officeapps.live.com/op/view.aspx?src=http://irb.uams.edu/files/2016/09/September-2016-Plain-Language-Consent-Template.docx

https://view.officeapps.live.com/op/view.aspx?src=http://irb.uams.edu/files/2016/09/September-2016-Plain-Language-Consent-Template.docx

Study Title:PI (researcher):Institution:Sponsor: If applicableSupport: If applicable

[Follow the instructions in green. Complete all sections applicable to your study. Write in plain language (6th grade reading level or below). Delete all instructions. Delete sections and language that do not apply. Please revise template language as needed for your individual study. If study is not at UAMS, revise as appropriate. See IRB policy 15.1, Elements of Informed Consent, for overview of all ICF required elements.]

University of Arkansas for Medical Sciences Informed Consent Form

Why am I being asked to be in this research study?

We want to learn more about (insert condition/topic) or how to help people who have (insert condition).

This study will help us learn more about (insert specifics).

We are asking people like you who have/are (insert condition or status if applicable, i.e. “Type I diabetes” or “healthy”) to help us. (Insert total number of participants) people (insert age range) years old will be part of this study. (IF MULTIPLE SITES ADD - Of those (total #), XX will join the study at UAMS.)

If this is a drug or medical device study, add information about the approval status of the drug/device.

Version #: insert version no. IRB# 123456Date: insert version date

Page 119 of 128Dorothy Graves, PhD and Laura Hutchins, MDVersion 2.0 11/10/2017

We are asking you to be in a research study.

You do not have to be in the study.

If you say yes, you can quit the study at any time.

Please take as much time as you need to make your choice.

You can still get your medical care from UAMS even if you are not in the study.

During the study, we will tell you if we learn any new information that might affect whether you wish to stay in the study. (Include only if applies)

http://irb.uams.edu/irb-policies/current-irb-policies/consent/

http://irb.uams.edu/irb-policies/current-irb-policies/consent/


What if I don’t understand something?

This form may have words you don’t understand. Research staff will read it with you, if you like.

You may ask as many questions as you like before you decide whether you want to be in this study.

You are free to ask questions at any time before, during, or after you are in the study.

What if I say yes, I want to be in this study? (In this section, describe all study procedures completely and in lay terms. Delete any suggested items that do not apply.)

We first will see if you qualify to be in the study. We will … (describe process for determining eligibility)

If you qualify, we will do these things:

ask about (describe items, e.g., your health, what you eat, and if you exercise, smoke, or drink alcohol, and what medicines you take)

give you a form with questions about (describe questions)

let you skip any question you do not want to answer

read the questions out loud and fill out the form with you, if you like.

Describe all procedures for visits, follow-up communications and specimen/information collection in chronological order. Include standard of care when that is part of the study protocol. Describe what procedures are experimental.

If this is an intervention study, describe the intervention. Include a description, in simple lay terms, of the randomization, if relevant. Explain the probability of being assigned to each group, whether the assignment is blinded/masked, and if so, a statement that the researcher can break the blind in an emergency. Define “random” – “like a flip of a coin toss.”

Include the amount of time expected for visits/encounters and study activities.

List the types of tests (including imaging, blood draws, physical exams, etc.).

Describe the types of health information to be obtained from medical records and the timeframe for collection.

Describe aspects of protocol that are optional, e.g., collection of certain specimens or health information.




How long will this study take?

The study will take about (insert expected start and end date of study, length of study, number of visits, and visit schedule). Include information about duration of information collection after active participation in study activities has ended; e.g., “We will continue to collect information from your medical records for the next 6 months after study visits end.”

Who will see the information about me that is collected?

The local study team will know your name and have access to your information.

We will do our best to make sure no one outside the study knows you are part of the study.

We will or will not take your name off of information and study samples that we collect from you during the study.

When we share the results of the study (insert details here, e.g., in medical journals). We will not include your name (insert other information that will not be disclosed).

There are people who make sure the study is run the right way. These people may see information from the study about you. They are

Insert study sponsor or funding source

OHRP (Office for Human Research Protections), a federal agency

UAMS Institutional Review Board

Other institutional oversight offices

Insert any other applicable group that may access the records or provide oversight, including the FDA (Food and Drug Administration)

State law requires that we report to the Arkansas Department of Health cases of certain diseases that a sick person could give to someone else. If you have such a disease, we will share your name and contact information with the health department. (Include only if applicable, i.e. testing for one or more reportable disease(s), AND list disease(s) in question)

State law requires we tell the authorities if we learn

about possible child or adult abuse

that you might hurt yourself or someone else




Where and how long will my information and samples be kept?

(Describe steps to minimize risks to confidentiality, who will have access to information/samples, where and how long it will be stored, when it will be destroyed.)

Include all that applies:

We will code your information and study samples and keep the code in a locked file.

Only (insert appropriate parties) will have access to the code for your information.

For UAMS patients, choose from these options; modify as needed (ACH requires a copy of the ICF in the MR):

We will/will not put information about you from the study in your medical record. (Say what information will be put in the participant’s medical record.)

If the study tests a drug or medical device, include this:

We will put a copy of this form in your medical record.

What if I say no, I do not want to be in this study?

Nothing bad will happen.

You can still get medical care at UAMS.

What happens if I say yes, but change my mind later?

You can stop being in the study at any time.

Nothing bad will happen.

You can still get medical care at UAMS.

If you decide to stop being in the study, call (insert head researcher name) at (insert phone #).

Can I be taken out of the study even if I want to continue?

Yes, the study doctor (or head researcher) can take you out of the study if:

You do not follow study instructions.

It is not in your best interest to continue.




The study is stopped for any reason.

List any other applicable reason, e.g. the test article becomes unavailable, etc.

If I stop being in the study, what will happen to any information or samples collected from me in the study?

Choose from these options; modify as needed:

We will/will not be able to take your information/samples out of the study after it has started.

OR

If you wish to have your information/samples taken out of the study, call (insert head researcher name) at (insert phone #). Delete for FDA-regulated research.

Will my information or samples from the study be used for anything else, including future research?


No. Your information and samples will be used only in this study.

OR

Yes. (Explain why the information/specimens are needed, the types of future research anticipated, where the information/specimens will be stored, steps to minimize risks to confidentiality, how long the they will be stored and how subjects may request to withdraw information/specimens).

Include if applicable. If not, delete this box and the corresponding sections on signature page.

Will it cost me anything to be in the study?

The study will not cost you anything. You

or your insurance company will be responsible for your regular medical care as usual. (If there are costs that may reasonably occur, change this statement to reflect those costs.)



There will be a place at the end of this form for you to say whether

You agree to be contacted for future research related to this study.

You agree that your information and samples collected in this study may be used in future research.


Will I be paid? Choose from these options; modify as needed:

Yes. We will give you (insert amount). This is to pay for your parking or travel. You will be paid in (cash, gift card, etc.) at the end of each visit/end of the study.

OR

Yes. We will give you (insert amount). This is to thank you for your time. We will give it to you (insert time and method of payment). If you change your mind and decide not to be in the study, you will only be paid for the parts you completed.

(Include this statement for all studies that pay.) If you receive more than $600 in one year (January-December) from (insert institution) we may send you a tax form if required by law.

OR

No. You will not be paid for being in this study.

Will being in this study help me in any way?

Being in the study may or may not help you, but may help people with (insert condition) in the future. What we learn may help in the following ways:

(using bulleted list, describe direct or potential benefits, excluding compensation).

What are the risks of being in this study?

The risks are: (Select those that apply; modify as needed)

The risks for this study are no more than what happens in everyday life.

Someone could find out that you were in the study and learn something about you that you did not want others to know. We will do our best to protect your privacy.

The questions could make you sad or upset.

Describe other possible harms/discomforts/risks to the participant (or embryo/fetus, if participant is or becomes pregnant) and relative chance of occurrence and severity.

For drug or device studies, there needs to be a statement something like “This study may involve risks that are not currently known.”

If the study involves ionizing radiation and it is an increase in radiation exposure over standard of care, this should be described.




Insert details regarding accommodation or referrals, e.g., for counseling, if applicable.

If applicable, include here an explanation of risks associated with genetic testing (including re-identification), GINA protections and the limits of those protections. If data are to be shared broadly with national databases, the consent form must include language informing the participants, along with a description of whether those data will include identifiers.

What if I get sick or hurt while I’m in this study? If the study is greater than minimal risk, include an explanation as to whether or not any compensation and/or treatment is available for injury. If applicable:

If you get hurt when you are here for the study, we will help you get the care you need. This may include first aid, emergency care and/or follow-up care.

If you are not here and get hurt or sick, and think it is because of the study, do these things:

call your doctor or if an emergency, call 911

give your doctor or ER staff

o the name of this study (insert name of study)

o the name of the head researcher for this study (insert researcher name)

o a copy of this form if you have it

call the head of the study (insert researcher name and 24 hour phone #)

Choose from these options:

This treatment may be billed to you or your insurance company in the normal manner. Normally, no other form of payment is available.

OR

Insert details of agreement negotiated with sponsor

What are the alternatives to being in this study?

You do not have to be in this study.


There are no alternatives to being in this study.

ORVersion #: insert version no. IRB# 123456Date: insert version date



If you do not want to be in this study, options are:

Describe alternative treatments or courses of action that may be advantageous to the subject.)

What if new information comes up about the study?

We want you to know about anything that may change your mind about being in the study.

The researcher will let you know by (modify as needed)

calling you

sending you a letter

telling you at a follow up visit

Where can I find more information about this clinical trial?

A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website any time. (For studies that require ClinicalTrials.gov registration by law, this exact clause must be included. If your study will be registered for publication purposes (i.e., ICMJE requirements) and not because of a statutory requirement, then this clause does not have to be included.)

What if I have questions?

Please call the head researcher of the study (insert researcher name and phone #), if you

have any questions about this study

have questions about your rights

feel you have been injured in any way by being in this study

You can also call the office that supervises research (UAMS Institutional Review Board) at 501-686-5667 if you

have questions about this study

have questions about your rightsVersion #: insert version no. IRB# 123456Date: insert version date


http://www.ClinicalTrials.gov/


can’t reach the study team

need to speak to someone not directly involved with this study

What should I do if I want to be in the study?

Sign this form. We will give you a copy of this form to keep.

By signing the document I am saying:

I understand that joining this study is voluntary.

I agree to be in the study.

Someone talked with me about the information in this document and answered all my questions.

I have been asked if I wish to talk directly to the study doctor. (if applicable)

I know that:

I can stop any and all parts of the study at any time and nothing bad will happen to me.

I can call the office that supervises research (UAMS Institutional Review Board) at 501-686-5667 if I have any questions about the study or about my rights.

My decision will not change my medical care at UAMS.

I do not give up any of my rights by signing this form.

I agree to be part of this study:

____________________________ ____________________________

Your name (please print) Your signature

___________________________

Date

If someone is signing this form for the subject, explain why:

_____________________________ ______________________________

Name of legally responsible person (please print) Signature of legally responsible person




Relationship to you: ________________________________________________________

__________________________________ _______________________________

Name of person obtaining consent (please print) Signature of person obtaining consent

____________________________

Date

Include if applicable. If not, delete:

I agree to being contacted for future (insert specific type here) research related to this study.

___ YES ___ NO

__________________________________ ________________________________


____________________________

Date

Include if applicable. If not, delete:

My samples and information collected in this study may be used in future (insert specific type here) research. (This section may be revised or split into parts as appropriate.)

___ YES ___ NO

__________________________________ ________________________________


____________________________

Date



cancer.uams.educancer.uams.edu/.../uploads/sites/97/2017/09/conductin… · web viewstudy title:...

Documents