MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CLINICAL RESEARCH STANDARD OPERATING PROCEDURES TABLE OF CONTENTS

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1 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CLINICAL RESEARCH STANDARD OPERATING PROCEDURES TABLE OF CONTENTS CATEGORY SOP # Clinical Research: Administrative Standard Operating Procedures (SOPs) 1.1 Outreach 1.2 Human Research Protection Program Monitoring 1.3 Clinical Research: Study Management Research Team Responsibilities 2.1 Management of Regulatory Files 2.2 Pre-Study Protocol Evaluation 2.3 Pre-Study Feasibility Evaluation 2.4 Developing a Budget 2.5 Pre-Study Site Evaluation Visit 2.6 Study Initiation Visit 2.7 Study Start-Up 2.8 Subject Recruitment and Screening 2.9 Obtaining Informed Consent 2.10 Study Conduct 2.11 Study Close Out 2.12 Clinical Research: HSRC Initial Application 3.1 Adverse Events/Unanticipated Problems Involving Risks 3.2 to Subjects or Others/Protocol Deviations Intra-Study Communication 3.3 Study Closure 3.4 Clinical Research: Project Activities Case Report Form Completion 4.1 Research Data Security and Storage 4.2 Audit Preparation and Participation 4.3 Investigational Drug Accountability 4.4 Investigational Device Accountability 4.5 Electronic Records and Signatures 4.6 Dry Ice Availability 4.7 Clinical Research: Education MMRF Employee Initial and Continuing Training and Education Non-Employee Initial and Continuing Training and 5.2 Education Guidance Guidance #1: Additional Requirements for Research Involving the Department of Defense (DoD) Guidance #2: Additional Requirements for Research Involving the Department of Justice (DOJ) Guidance #3: Additional Requirements for Identifying and Reporting Conflicts of Interest Appendix A: Glossary of Definitions Appendix B: Researcher Responsibilities Appendix C: The Belmont Report Appendix D: Contacts 5.1

2 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Administrative SUBJECT Standard Operating Procedures (SOPs) SOP # 1.1 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Describe the process for written procedures to ensure compliance with federal, state, local, and institutional regulations and guidelines that govern clinical research trials. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES REFERENCES TO RELATED SOPs All SOPs are related to this SOP ATTACHMENTS SOP Approval Form 1) SOP format a) MMRF name b) Category: Identifies a broad classing designation for pertinent SOPs c) Subject: Identifies the pertinent SOP d) SOP#: A uniquely assigned identification number. The first number identifies the category. The second number is the SOP identifier and is assigned numerically. e) Effective date: The date the SOP becomes official. f) Revision date: The date of the latest revision 2) SOP outline a) Objective: States the description of the SOP and to whom it applies. b) Applicable Regulations and Guidelines: Identifies pertinent regulations or guidelines that may be accessed for further information. c) References to Related SOPs: Direct reference(s) to related SOPs d) Attachments: Identifies attachments associated with the SOP. e) Procedures: Instruction for completing tasks contained in the SOP. 3) The SOP Approval Committee is responsible for approving SOPs with members reflecting their particular expertise. a) Members will have an administrative, clinical, and /or regulatory function within the MMRF. b) The SOP Approval Committee will consist at a minimum of the MMRF VP of Operations, the MMRF Director of Clinical Trials Training, the Director of Grants & Contracts, one noninvestigator MMRF staff member, and the HSRC Vice Chair. c) The SOP Approval Committee will be convened as necessary. SOPs must be approved by unanimous vote. SOPs may be approved traditionally or electronically with the Director of the Clinical Trials Training Office documenting each member s decision. i.) ii.) The SOP Approval Committee will review all new SOPs as well as applicable attachments. Applicability to current practice, compliance with regulations, and accuracy of the content will be considered. 1

3 d) Completed SOP Approval Forms will be archived in the Clinical Trials Training Office. 4) SOP addendums and/or revisions will outline new or modified procedures based on federal, local, or institutional changes affecting the conduct of clinical research. a) The Clinical Trials Training Office will review SOPs: i.) Upon request ii.) When internal policies or procedures are devised or changed iii.) When external polices or procedures are devised or changed b) Notify the Clinical Trials Training Office to request a new SOP or a revision to an existent SOP. i.) Provide the rationale for a change. ii.) Provide pertinent references for a change. c) SOP addendums and/or revisions may be administratively approved by the Director of the Clinical Trials Training Office for minor changes that do not reflect an institutional, federal, state, or local change in clinical research practice. d) The Clinical Trials Training Office will: i.) Maintain a current copy of the SOPs ii.) Maintain a historical archive of obsolete SOPs iii.) Work with the appropriate personnel to maintain current SOPs on the MMRF web site 5) SOPs will be accessible on the MMRF web site. a) New SOPs, addendums, or revisions will be disseminated via the MMRF Researched ListServ. b) All research personnel are responsible to review and enact SOPs. 6) SOPs are accessible for inspection in the Clinical Trials Training Office for authorized representatives of sponsors, federal agencies, or other pertinent administrative entities. 7) Copies of SOPs should not be given to external sponsors. A table of contents may be distributed. 2

4 STANDARD OPERATING PROCEDURES APPROVAL FORM New SOP(s) SOP# SOP(s) Revision SOP# Rationale for Action: Approved by SOP approval committee? Yes No Administrative SOP committee member: Mary Bergaas YES NO SOP committee member: Karen Heim-Duthoy YES NO SOP committee member: Carla Erickson YES NO SOP committee member: Kim Miller YES NO SOP committee member: Barbara Wicklund YES NO Action taken? New SOP(s)/Guidance added Current SOP(s)/Guidance revised SOP(s)/Guidance retired 3

5 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Administrative SUBJECT Outreach SOP # 1.2 EFFECTIVE DATE November 2, 2009 REVISION DATE December 9, 2013 OBJECTIVE Describe the process by which information is provided to prospective research volunteers, actual research volunteers, and the community. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES REFERENCES TO RELATED SOPs ATTACHMENTS None 1) The Clinical Trials Training Office (CTTO) will maintain the MMRF FAQs WEB site, Related Links site, and the CTTO information pages. a) The CTTO s contact information will be publically available for current, prospective, or past research participants to discuss problems, concerns, or questions; obtain information; or offer input with an individual who was unaffiliated with the specific research protocol. b) As appropriate, callers will be referred to the Office for Human Subjects Research, Principal Investigator, or appropriate research personnel. 2) The CTTO will revise the Becoming a Research Volunteer as needed and provide HCMC the newest copy to HCMC Public Relations to distribute to outpatient clinics and other patient areas. a) The CTTO will keep copies of the brochure for quick distribution to study sites and callers as needed. b) The CTTO will track the number of brochures sent to callers. 3) CTTO staff will conduct training or presentations as requested regarding the research process or the rights of a research participant. 4) The CTTO will track the number and type of inquiries. Uncharacteristic or worrisome findings will be shared immediately with the Institutional Official and the Vice Chair of the Office for Human Subjects Research. 5) Outreach activities will be evaluated yearly and presented to the Institutional Official and the OHSR Chair and Vice Chair. a) Metrics collected will include, but not be limited to: i) Number of individuals looking for research participation opportunities and type of opportunities requested (i.e. phase I, hypertension) ii) Number of individuals looking for information concerning clinical research iii) Individuals looking for volunteer opportunities within MMRF iv) Outside agencies looking to place research within MMRF v) Complaints received from research participants vi) Resolution to all inquiries 1

6 b) Additional information will be added or changes made when appropriate. 6) The MMRF Communications Department will update the MMRF WEB site with varying articles, posts, and film clips to allow prospective participants and the community to observe various aspects about the research process. a) MMRF researcher publications, based on MMRF sponsored research projects, are posted annually on the MMRF WEB site. b) Historic citations are available from calendar year

7 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Administrative SUBJECT Human Research Protection Program Monitoring SOP # 1.3 EFFECTIVE DATE December 9, 2013 REVISION DATE N/A OBJECTIVE Describe the process by which information is collected and monitored to assess the quality, efficiency, and effectiveness of the Human Research Protection Program. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES REFERENCES TO RELATED SOPs ATTACHMENTS None 1) The Clinical Trials Training Office (CTTO) will annually assess three areas of the quality, efficiency, and effectiveness of the Human Research Protection Program. a) IRB metrics b) Random audits concerning the research process c) Investigator feedback 2) IRB metrics to be collected annually will include but not be limited to: a) Number of researchers. b) Mean number of days from submission to review at meeting and final determination for new protocols reviewed in the last year by the convened IRB. c) Mean number of days from submission to review and final determination for new protocols reviewed in the last year by the expedited procedure. d) Mean number of days from protocol submission to exempt determination in the last year. e) Number of protocols disapproved by the IRB in the last year. f) Number of reported protocol deviations in the last year. g) Number of cases of alleged non-compliance investigated in the last year. h) Number of determinations of serious non-compliance in the last year. i) Number of determinations of continuing non-compliance in the last year. j) Number of unanticipated problems in the last year. k) Number of unanticipated problems involving risks to participants or others in the last year. 3) Random audit metrics concerning the research process collected biannually will include, but not be limited to: a) The informed consent process. b) Documentation of research activities. c) Confidentiality procedures. d) Documentation of research activities. e) Confidentiality procedures. f) Protocol adherence and/or violations. g) Completion of research team required training. 1

8 4) Investigator feedback which is collected annually via survey by the HCMC Office of the Medical Director will be examined to ascertain: a) Helpfulness and knowledge of the OHSR staff. b) Helpfulness and knowledge of the Primary Reviewers. c) Helpfulness and knowledge of the Chair. d) Helpfulness and knowledge of the Vice Chair. e) Relevant information about the submission process and how to write an informed consent document is readily available. f) The primary review process is handled effectively by the HSRC. g) The continuing review process is handled effectively by the CRC. h) The OHSR provides timely service. i) The OHSR minimizes logistical hurdles where possible. j) The OHSR does an effective job of protecting human subjects. 5) The CTTO will annually compile results. Results will be compared to published metrics from AAHRPP. In addition changes noted over the past year will be highlighted. 6) Findings will be shared with the Institutional Official, the Chair, and the Vice Chair of the OHSR. 7) Noted outliers or changes will be highlighted and plans to correct or improve metrics will be discussed and instituted. 8) Results of improvement plans will be discussed with the next annual assessment or earlier if deemed necessary. 2

9 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Research Team Responsibilities SOP # 2.1 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Describe the general responsibilities of the research team in conducting clinical research trails. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46 Protection of Human Subjects 21 CFR 50 Protection of Human Subjects 21 CFR Selecting Investigators and Monitors 21 CFR General Responsibilities of Investigators 21 CFR Control of the Investigational Drug 21 CFR Investigator Record Keeping and Record Retention 21 CFR Investigator Reports 21 CFR Assurance of IRB Review 21 CFR Inspection of Investigator Records and Reports 21 CFR Handling of Controlled Substances 21 CFR Selecting Investigators and Monitors 21 CFR IRB Approval 21 CFR General Responsibilities of Investigators 21 CFR Records 21 CFR Reports FDA Guidance for Institutional Review Boards and Clinical Investigators MMRF Non-Payroll Business Expense Guidelines MMRF Sponsored Project Administration: Guidance and Procedures MMRF Clinical Research Job Descriptions MMRF Conflict of Interest Policy REFERENCES TO RELATED SOPs All SOPs are applicable to this SOP Sponsored Research: Research Administration SOP 1.1 ATTACHMENTS None 1) The Office for Humans Subjects Research (OHSR) and Human Subject Research Committee (HSRC) has jurisdiction over all human subject research as defined by DHHS and FDA definitions. a) One or more of the following criteria must be met along with #b: i) Performed on the combined campus of HCMC and MMRF ii) Performed by any employee of HCMC or MMRF iii) Sponsored by HCMC or MMRF iv) Involving patient data or patient access obtained through HCMC 1

10 b) The institution is engaged in the research. If there is a question regarding engagement of the institution, involvement of the MMRF Office of Grants and Contracts or other appropriate individuals based on the research proposal should be solicited. 2) The OHSR will provide a determination about whether an activity is research involving human subjects. OHSR staff will review all protocols submitted to the OHSR to determine jurisdiction. a) Jurisdiction of the OHSR over the protocol is based on the following: i) It meets the definition of human subjects research as defined under the federal regulations. (1) For DHHS regulated activity, research involving human subjects is determined by first deciding whether the activity is research as defined by DHHS regulations, and if so, confirming that it involves human subjects as defined by DHHS regulations (45 CFR 46). (2) For FDA regulated activity, research involving human subjects is determined by first deciding whether the activity is a clinical investigation as defined by FDA regulations, and if so, confirming that it involves human subjects as defined by FDA regulations (21 CFR 50). (3) For clinical oncology protocols conducted through the community institutions belonging to CCOP and CGOP, the Community Oncology Programs IRB will provide a central IRB for review as outlined in the Community Oncology Programs IRB Agreement. b) There may be activities that might not need to be overseen by the OHSR. These may include quality improvement, program evaluation, surveillance activities, and case reports. c) Researchers must contact the OHSR with questions about, and guidance for, OHSR jurisdiction on all research or potential non-research activities. Researchers can contact the IRB Coordinator at d) The Chair (or designee) will evaluate on a case-by-case basis and will make a determination regarding jurisdiction. i) Quality improvement, program evaluation, and/or surveillance activities are not considered research if the intention of the activity is to improve or inform within the institution. If the results will be generalized outside of the institution, the activity will be evaluated on a caseby-case basis. (1) Quality improvement activities are projects that are completed to improve quality of programs, improve services, or improve the provision of medical care, customer service, etc. and are usually done for internal purposes only. (2) Program evaluation activities are projects with a systematic collection of information about the activities, characteristics and outcomes of programs to make judgments about the program, improve program effectiveness, and/or inform decisions about future program development. (3) Surveillance activities are projects that collect, analyze, and interpret health-related data essential to planning, implementing and evaluating health care practice. ii) Case reports that are prepared and disseminated for educational purposes are not considered systematic investigations and therefore, not research. (1) A case report is a retrospective analysis of a clinical case. iii) If the proposed research involves only de-identified data and/or human biological specimens, it may be considered research that does not involve human subjects. (1) Research activities involving de-identified data and/or human biological specimens are projects that involve data and/or human biological specimens where all direct personal identifiers are permanently removed from the data or specimens, no code or key exists to link the materials to the original source(s), and the remaining information cannot reasonably be used by anyone to identify the source(s). iv) If the proposed research involves non-living individuals, it would not fall under OHSR jurisdiction. 2

11 (1) Research activities involving non-living individuals are projects that collect information on deceased subjects. e) Researchers will be contacted by the OHSR for a final determination of status. f) If the activity does not fall under the jurisdiction of the OHSR, the researcher shall be referred to Information Security & Privacy, if applicable by the OHSR. 3) Human Subjects Research must be conducted in accordance with: a) The ethical principles outlined in the Belmont Report to protect the rights and welfare of research participants (see Appendix C). b) All federal, state, local, and other applicable regulations. c) Institutional policies and procedures of the MMRF and HCMC. d) The OHSR approved protocol. e) The safety and welfare of study subjects must be protected by all personnel by being knowledgeable about pertinent regulations, protocol(s), and investigational articles. Suspected or actual research misconduct may be reported to the HSRC, Institutional Official, Director of the Clinical Trials Training Office, or the Office of Grants and Contracts. f) All research team members must comply with federal, sponsor, and MMRF regulations governing disclosure of conflicts of interest. 4) The Principal Investigator (PI) must maintain knowledge of, and overall responsibility for, the conduct of the research. He or she is responsible to: a) Personally conduct or supervise the research. i) Evaluate proposed study protocols for completeness, budget adequacy, and feasibility for successfully carrying out the protocol. ii) Participate in the hiring and training of research team members. iii) Ensure that the study team is informed and updated on study related matters with scheduled meetings, memos, s, or other communication methods pertinent to the research environment. b) Ensure that resources are adequate to carry out the research safely. These include, but are not limited to, sufficient time, qualified research team members, equipment, and space. c) Delegate study responsibilities to the appropriate research personnel while maintaining overall responsibility. i) The PI must assure that all research staff is qualified, including, but not limited to, the appropriate training, education, expertise, credentials, and privileges to perform assigned responsibilities. d) Develop and/or review study budgets and maintain fiscal authority for the project. Provide a budget to the assigned MMRF Grant Administrator for review and assistance as needed. i) Submit all contracts, material transfer agreements, and confidentiality agreements to the Office of Grants and Contracts for review. ii) Document an approval train for charges made to the project. iii) Certify effort in accordance with MMRF policy. e) Conduct the research according to Good Clinical Practices and other federal, state, local, and other applicable regulations. i) Complete and sign the FDA 1572 or Investigator s Agreement (if pertinent). ii) Maintain current Minnesota licensure to practice medicine in accordance with license. (1) Responsible for all study related medical decisions. (2) Dispense study drug, biologic, or device. Maintain records to account for all articles. (3) Be familiar with the investigational product, assume responsibility for the investigational product at the trial site, and confirm that the investigational product is used only for eligible individuals. iii) Obtain informed consent. 3

12 iv) Ensure that research is conducted according to the OHSR approved protocol. v) Ensure that specific sponsor requirements are fulfilled. vi) Participate in monitoring visits and audits (internals, sponsor, regulatory). vii) Assure protocol compliance. f) Comply with all OHSR and HSRC initial protocol submission and continuing review reporting. i) Submit protocol changes, adverse events, and protocol deviations according to policy. ii) Respond to annual surveillance requests. g) Maintain appropriate data and records. i) Ensure the validity and confidentiality of the data reported to the sponsor, HSRC, and regulatory authorities. ii) Maintain records and study files for the regulated period after study discontinuation or completion. h) Complete appropriate federal, sponsor, and institutional financial disclosure forms. 5) Research team members a) Manage delegated areas of the research under the direction of the PI. May include, but not be limited to, screening, recruitment, obtaining informed consent, enrollment, follow-up, case report form completion, investigational product dispensing and log maintenance, reporting of adverse events, participating in monitoring visits, audits. b) Maintain accurate documentation including, but not limited to, regulatory documents, informed consent forms, HSRC approvals and communications, CRFs, source documentation, investigational drug/device dispensing logs, study-related communication. c) Ensure organizational management of all aspects of the investigational trial within delegation of authority. d) Communicate all protocol-related issues/problems to appropriate staff. e) Maintain correspondence with sponsors, HSRC, and subjects as required by sponsor, federal, state, and local regulations. f) Fulfill job responsibilities specific to job title and description. g) Complete appropriate federal, sponsor, and institutional financial disclosure forms. h) Maintain current Minnesota licensure as appropriate to education. 4

13 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Management of Regulatory Files SOP # 2.2 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Describe the responsibilities entailed in maintaining the regulatory files for clinical research trials. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46 Protection of Human Subjects 21 CFR 50 Protection of Human Subjects 21 CFR 54 Financial Disclosure by Clinical Investigators 21 CFR 56 Institutional Review Boards 21 CFR General Responsibilities of Investigators 21 CFR Control of the Investigational Drug 21 CFR Investigator Record Keeping and Record Retention 21 CFR Investigator Reports 21 CFR Assurance of IRB Review 21 CFR Inspection of Investigator Records and Reports 21 CFR IRB Approval 21 CFR General Responsibilities of Investigators 21 CFR Records 21 CFR Reports MMRF Sponsored Project Administration: Guidance and Procedures REFERENCES TO RELATED SOPs SOP 2.1 SOP 3.1 ATTACHMENTS Regulatory Files Content 1) Devise a regulatory binder for each study. a) Use sponsor binder if applicable. b) Add new or updated documents as appropriate. c) Identify required regulatory and sponsor mandated documents. d) Determine which documents must be original and which may be copied. e) Retain copies of all original and revised documents. f) Retain copies of all submissions and correspondence associated with the study. 2) Keep regulatory binder in a confidential and secure location. 1

14 REGULATORY FILES CONTENT 1. Curriculum Vitae principal investigator and sub-investigators 2. Delegation of Duties/Authority 3. Financial Disclosure Forms 4. Form FDA 1572 or Investigator Agreement 5. HSRC Approved Advertising/Recruitment Materials 6. HSRC Approved Informed Consent Form 7. HSRC Correspondence all correspondence between HSRC and investigative staff a. b. Fax c. Phone Contact 8. HSRC Protocol Initial Approval 9. HSRC Protocol Continuing Approval 10. HSRC Member List and/or FWA # 11. Investigational Product Accountability a. Product shipping inventory b. Dispensing log c. Product return or destruction documentation 12. Investigator s Brochure, Product Insert, Device Instruction for Use 13. Laboratory Certifications 14. Laboratory Normal Values for all laboratories utilized in the protocol 15. Licenses as appropriate i.e., MD state license, RN state license 16. Monitoring Logs 17. Protocol 18. Protocol Amendments 19. Protocol Correspondence all communication between investigative staff and sponsor a. b. Fax c. Phone Contact 20. Required Regulatory Approvals (i.e., Radiation Committee) 21. Screening Logs 22. Serious Adverse Event Reports and IND Safety Reports 23. Sponsor Correspondence all correspondence between Sponsor and investigative staff 24. Subject Enrollment Logs 25. Signature Pages 26. Telephone Log There may be required updates or renewals for long-term studies, such as CVs, protocol amendments, laboratory certification(s), or laboratory values. Ensure that a copy of outdated information is kept. *There may be different or additional files required by the Sponsor if it provides the Regulatory Binder. 2

15 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Pre-Study Protocol Evaluation SOP # 2.3 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Describe the steps entailed in evaluating the necessary protocol components for clinical research trials. This SOP may be used as a tool for investigators to evaluate investigator initiated protocols to ensure completeness and accuracy. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46 Protection of Human Subjects 21 CFR 56 Institutional Review Boards 21 CFR Phases of an Investigation 21 CFR General Responsibilities of Investigators 21 CFR General Responsibilities of Investigators REFERENCES TO RELATED SOPs SOP 2.1 ATTACHMENTS Sample Protocol Evaluation Checklist 1) The sample protocol evaluation checklist may be used to evaluate the protocol, Investigator s Brochure, and Clinical Trial Agreement to ensure that the appropriate information is available (if applicable) to the study. Evaluating the protocol will enhance the probability of timely and successful completion of the clinical research trial. 2) Notify the sponsor if the protocol does not meet minimum standards and cannot be executed as written. Collaborate with the sponsor to institute necessary changes. 3) The sample protocol evaluation checklist may be used as a template for Investigator Initiated studies. Consult the funding source for to obtain additional instructions, requirements, and templates for protocol development and evaluation. 1

16 SAMPLE PROTOCOL EVALUATION CHECKLIST STANDARD ELEMENT YES NO N/A General Information Is (are) there: A draft or final version designation A title, protocol identifying number, and date The name and address of the sponsor and monitor available The name, title, address, and phone number of the sponsor s medical expert The names and addresses of sponsor assigned ancillary central departments Background information Objectives and purpose Design Is (are) there: A name and description of the investigational product The phase of the study indicated An Investigational New Drug (IND) number or Investigational Device Exemption (IDE) number A summary of findings from non-clinical studies present A summary of relevant prior clinical trials A summary of known and potential risks/benefits A summary of relevant prior clinical trials A summary of known and potential risks/benefits Description and justification for the route of administration, dosage, dosage regimen, treatment periods (drug), description and justification for implantation and treatment periods (device) A statement that the trial will be conducted in compliance with the protocol, Good Clinical Practices, and applicable regulatory requirements A description of the population to be studied Relevant literature references Is (are) there: A detailed description of the objectives A detailed description of the purpose Is (are) there: Primary and secondary endpoints to be measured A description of the trial design A schematic design of the trial A description of the dosage form or device, packaging, and investigational product labeling Accountability procedures for the investigational product Expected duration of subject participation, including follow-up Stopping rules for subjects, portions of the trial, entire trial Maintenance of randomization codes Procedures for breaking randomization codes 2

17 SAMPLE PROTOCOL EVALUATION CHECKLIST STANDARD ELEMENT YES NO N/A Subject selection and Is (are) there: withdrawal Inclusion criteria Exclusion criteria Subject withdrawal criteria Subject withdrawal procedures Subject treatment Efficacy assessments Safety assessments Scientific merit Ethics Miscellaneous Is (are) there: Subject risks minimized Subject benefits maximized Treatments and treatment periods listed, including the name of all products used Plans to use procedures already being performed for diagnostic and/or treatment purposes Medications permitted/not permitted before and during the trial Medication washout procedures Procedures for monitoring subject compliance Is (are) there: Efficacy parameters Methods and timing sequences for assessing, recording, and analyzing efficacy parameters Is (are) there: Safety parameters Methods and timing sequences for assessing, recording, and analyzing safety parameters Procedures for acquiring and reporting adverse event reports by the site and the sponsor Procedures for recording and reporting adverse events and concurrent illnesses Description of follow-up after adverse events Is (are) there: Scientific merit of the study is valid Planned statistical methods, including interim analysis(es) Number of subjects to be enrolled Power of the trial and level of significance Patient population to be included in the analyses A description of the Data and Safety Monitoring Board Is (are) there: A description of the ethical considerations relating to the trial Is (are) there: Specifications that the investigator and institution will permit trial-related monitoring, audits, IRB review, and regulatory inspections by providing direct access to source documents Descriptions of quality control and quality assurance measures A statement of compliance with HIPAA 3

18 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Pre-Study Feasibility Evaluation SOP # 2.4 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Describe the questions that should be asked when evaluating the feasibility of carrying out a clinical research protocol. This SOP may be used as a tool for investigators to evaluate Investigator Initiated protocols to ensure completeness and accuracy. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES 45 CFR 46 Protection of Human Subjects 21 CFR Phases of an Investigation 21 CFR General Responsibilities of Investigators 21 CFR General Responsibilities of Investigators REFERENCES TO RELATED SOPs SOP 2.1 SOP 2.3 SOP 2.5 ATTACHMENTS Sample Protocol Feasibility Checklist 1) The Sample Protocol Feasibility Checklist may be used to evaluate the feasibility of the site s ability to complete a study. Evaluating the feasibility of a protocol will enhance the probability of timely and successful completion of the clinical research trial. a) Notify the sponsor if the protocol cannot be executed as written. b) Collaborate with the sponsor to institute necessary changes. c) Collaborate with the appropriate Grant Administrator for budget needs, recommendations, and concerns. 2) The sample protocol feasibility checklist may be used as a template for Investigator Initiated studies. Consult the funding source for Investigator Initiated studies to obtain additional instructions, requirements, and templates for protocol development and evaluation. 1

19 SAMPLE PROTOCOL FEASIBILITY CHECKLIST ELEMENT YES NO Is the study plan feasible as written? Can the protocol be carried out as written Does the study rationale make sense? Planned assessments are appropriate for valid conclusions Is the study plan logical in light of prior research Are subject risks minimized? Can the study be carried out with available resources? Is there adequate space Is there adequate manpower Is there adequate equipment Will the patient population seen on campus support the protocol? Are there competing protocols that will reduce the subject pool Are there mechanisms to recruit subjects from other sources if needed Does the study plan require unfamiliar procedures? Is proper training available from the sponsor or other sources Does the study plan require unavailable tests or procedures? Will the sponsor allow appropriate substitutions Does the study plan require equipment not currently available? Is the equipment available from the sponsor Does the equipment require additional time and effort for in-servicing Will the sponsor provide in-servicing Is sufficient time available? Is there adequate time to recruit the assigned number of subjects Is there adequate time to fulfill regulatory obligations Is the time commitment for the whole study within reasonable proportions Is funding adequate? 2

20 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Developing a Budget SOP # 2.5 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Provide a guideline for preparing or evaluating clinical research trial budgets. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES Minneapolis Medical Research Foundation Sponsored Project Administration: Guidance and Procedures HCMC Research Resource Approval Process: REFERENCES TO RELATED SOPs SOP 2.1 SOP 2.3 SOP 2.4 ATTACHMENTS None 1) Define all study-related costs and cost recovery. Grant Administrators are available for advice as needed. a) The total study budget is the total anticipated study cost across all fiscal years including appropriate indirect costs. 2) Access the study schedule of activities. a) Develop a budget worksheet using the schema and protocol. b) Separate the budget worksheet into two sections for protocol costs and personnel costs. 3) Protocol costs a) Protocol costs are costs directly linked with the protocol, subject care, or subject related stipends. b) Protocol costs may be a one-time cost or recurring throughout the life of the subjects enrollment c) Protocol fees may include, but are not be limited to, IRB fees, test fees (laboratory, ECG, radiology, etc.), pro-fees, rental fees, copying costs, investigational pharmacy costs, advertising costs, mailing fees, or subject remunerations. d) Identify services and tests used in the protocol that are NOT standard care. e) Ensure that a HCMC Research Utilization Checklist is completed when enrolling HCMC patients, even if no HCMC resources will be used. f) Pricing information and contacts of various resources (i.e., Laboratory, Radiology) are available. Ensure that you have the research pricing information in writing. Some pricing is available on HCMC InfoOncall. g) Review the schematic design and add up the fees for all tests and services for one subject. Add any other recurring protocol induced costs for one subject. 1

21 4) Personnel (staffing) costs a) Evaluate the time required by study personnel to complete study specific tasks for one subject. b) In addition, do not forget time needed for non-subject duties such as screening, completing case report forms, participating in study monitor visits, answering study queries, corresponding with the sponsor, IRB, laboratory etc., and maintaining regulatory files. c) Ensure that all personnel are accounted for including coordinator, PI, ancillary staff. 5) Direct costs a) Once you have the per-subject protocol and personnel costs added, multiply it by the number of subjects to be enrolled at the site. b) Add the one time protocol cost fees. c) The resulting number will be the total direct costs for the study. 6) Consider the need to budget time for increased screening. Common characteristics make it more difficult to recruit thus necessitating increased screening time. These common characteristics include: a) The complexity of the protocol b) The time commitment of the protocol c) Length of subject follow-up d) Complicated inclusion and/or exclusion criteria e) It is more difficult to recruit children, minorities, women, and the elderly f) Requiring DNA or genetic sampling as part of the protocol 7) Institutional indirect costs a) Add the appropriate indirect costs to the direct costs and you will have the total costs for the study. b) THERE ARE DIFFERENT FORMULATIONS TO USE DEPENDENT ON THE TYPE OF PROJECT (FEDERAL VS. NON-FEDERAL). 8) Federal indirect costs a) Indirect costs are taken at the time of expense by the project. b) The federally negotiated indirect cost rate is based on salaries/wages only, therefore the federal indirect cost rate is calculated only on salaries and wages budgeted for the project. c) Total salaries/wages*indirect cost rate = total indirect costs. d) Total salaries/wages + indirect costs = TOTAL COSTS. 9) Non-Federal indirect costs a) Indirect costs for non-federal projects are charged based on cash receipts or project income. b) This means that indirect costs are taken at the time of payment by the sponsor instead of at the time of expense by the project. c) This is an important distinction; if non-federal indirect costs are not calculated correctly, a project may not have enough revenue to cover direct cost. d) When calculating indirect costs on a cash receipts basis, determine the total direct costs necessary to complete the work. Divide the total direct costs by one minus the overhead rate. This will calculate the total dollars needed to pay direct and indirect costs. e) Direct Costs/1 - Overhead Rate = TOTAL COSTS. 10) Ensure that the assigned Grant Administrator is aware of budgetary requirements so that s/he may negotiate with sponsor as needed. 2

22 11) EPIC a) If research is performed at HCMC, set up an EPIC research HAR (hospital account record.) b) When scheduling a research encounter this HAR# must be used. c) The MMRF study becomes the guarantor when the HAR# is used. d) It is important that subjects or insurance NOT BE charged for research activities. e) Contact for HCMC HAR set-up is: i) Deanna Cable at ii) Sue Falldin at

23 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Pre-Study Site Evaluation Visit SOP # 2.6 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Provide the common steps for participating in pre-study evaluation visit for clinical research trials. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR General Responsibilities of Sponsors 21 CFR Transfer of Obligations to a Contract Research Organization 21 CFR General Responsibilities of Investigators 21 CFR Assurance of IRB review 21 CFR General Responsibilities of Investigators Minneapolis Medical Research Foundation Sponsored Project Administration: Guidance and Procedures %20Guidance%206th%20Ed-Final%20Aug13.pdf REFERENCES TO RELATED SOPs SOP 2.1 ATTACHMENTS None 1) Ensure that the sponsor s confidentiality agreement has been signed and returned (check with the appropriate Grant Administrator). 2) Review protocol materials to assess study protocol and feasibility of carrying out the protocol. 3) Identify personnel to be assigned to the study. 4) Ascertain whom the sponsor/cro will want to meet with. Collaborate with the sponsor/cro to schedule a mutually convenient date and time when all required parties can attend. 5) Prepare explanatory information for the sponsor/cro. This may include, but not be limited to: a) Dates of HSRC meetings b) Dates of other regulatory meetings, e.g., HCMC Radiation Safety Committee c) Overview of the local protocol review process d) Overview of MMRF, Grants Administration, Accounting 6) Collect supporting documentation. These may include but not be limited to: a) Organizational Charts of MMRF and HCMC as appropriate b) Copies of medical licenses of PI and sub-investigator(s) c) Current signed and dated curriculum vitae for PI and sub-investigator(s) d) Copies of nursing licenses if required 1

24 e) Staff curricula vitae if required f) Copy of institutional laboratory certification(s) 7) Collaborate with all desired attendees and develop a schedule for the sponsor/cro to meet personnel and tour the facility. Individuals and /or areas the sponsor/cro may want to visit include: a) PI b) Sub-investigator(s) c) Pertinent research personnel d) Grant Administrator e) Research pharmacist f) Office areas of the research team g) Research pharmacy h) Clinical laboratory i) Radiology j) In-patient hospital areas or out-patient clinic areas k) Storage area for investigational drug if out-patient study l) Storage area(s) for investigational devices 8) Be prepared to discuss: a) The protocol b) Central facilities that will be used c) Grants Administration d) HSRC process e) Special needs the sponsor/cro should be willing to supply (i.e., equipment, training) f) Anticipated study timeline g) Investigators meeting and/or study initiation meeting h) Sponsor/CRO chain of command and communication plan 9) Determine if there is other information required by the sponsor/cro. 10) Request that the sponsor/cro notify the site in writing if selected to participate in the trial. 2

25 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Study Initiation Visit SOP # 2.7 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Provide the common steps for participating in a study initiation visit for clinical research personnel performing clinical research trials. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR General responsibilities of sponsors 21 CFR Transfer of obligations to a contract research organization 21 CFR General responsibilities of investigators 21 CFR Assurance of IRB review 21 CFR General Responsibilities of Investigators REFERENCES TO RELATED SOPs SOP 2.1 SOP 2.6 ATTACHMENTS None 1) Ensure that all documentation and materials associated with the study are provided to assigned personnel. 2) Ascertain whom the sponsor/cro will want to meet with. Collaborate with the sponsor/cro to schedule a mutually convenient date and time when all required parties can attend. 3) Prepare for and meet with the Clinical Research Associate (Monitor). S/he will want to: a) Conduct a final protocol review. b) Ascertain that the study team is familiar with the protocol. c) Ensure that staffing and the physical environment is the same as documented during the pre-study site evaluation. d) Ensure that study procedures are compatible with site routines or that special plans have been made to accommodate the protocol. e) Ensure that the study team is comfortable with the process to fill the case report forms. f) Confirm that the study team understands and is willing to follow all regulatory obligations. g) Verify that all needed supplies are present and ready. h) Familiarize the study team with the monitoring plan. 4) The study team should: a) Obtain answers to any final questions. b) Clarify communication procedures with the sponsor/cro. 1

26 5) If all preparatory activities are complete, the sponsor/cro will issue a written official notification that the PI is free to begin the study. The study and administration of the test article should not begin until this is received. 2

27 MINNEAPOLIS MEDICAL RESEARCH FOUNDATION CATEGORY Clinical Research: Study Management SUBJECT Study Start-Up SOP # 2.8 EFFECTIVE DATE August 6, 2008 REVISION DATE December 9, 2013 OBJECTIVE Provide the common steps for reviewing the preparations for study start-up when participating in clinical research trials. These procedures apply to all clinical research activities approved by the Office for Human Subjects Research conducted within the Hennepin County Medical Center campus. APPLICABLE REGULATIONS AND GUIDELINES 21 CFR General Responsibilities of Investigators 21 CFR Investigator Recordkeeping and Record Retention 21 CFR Inspection of Investigator s Records and Reports 21 CFR General Responsibilities of Investigators 21 CFR Records REFERENCES TO RELATED SOPs SOP 2.1 SOP 2.2 SOP 2.5 SOP 3.1 ATTACHMENTS Sample Delegation of Authority Form 1) The PI is responsible for, or may delegate study start up procedures. These include, but are not limited to: a) Ensure that all duties of the study have been delegated and that all individuals are knowledgeable about their responsibilities. Fill out a Delegation of Authority Form b) Verify that all personnel have completed required training c) Ensure that all pre-study activities required by other ancillary service providers have been completed d) Order any needed supplies not directly provided by the sponsor. Contact Supply Chain Management at e) Ensure that reserved space for conducting trial visits, storage of study related materials, and equipment is prepared f) Develop (or utilize sponsor-generated) worksheets, checklists, and flow sheets to assist study personnel to conduct the study g) Confirm that the contract has been fully executed (talk with the appropriate Grant Administrator) h) Review study procedures with assigned study staff. i) Assure that any applicable HCMC employees are apprised and knowledgeable about the study. Notify manager/supervisor of appropriate department(s). Items to discuss with manager/supervisor and involved staff include, but are not limited to: i) Name of the study ii) Rationale for the study iii) Responsibilities to be performed by HCMC staff iv) Prohibited medications or other interventions outlined by the protocol v) Potential adverse events to monitor participant for vi) Name and number of PI 1

28 vii) Name and number of research coordinator j) Place EPIC Research FYI into EMR if applicable 2) Ensure that all regulatory documents are complete, up-to-date, and in the regulatory binder. 3) Evaluate the trial to assess the need to register it according to guidelines of the International Committee of Medical Journal Editors (ICMJE). ICMJE member journals require, as a condition of consideration for publication, registration in a public trials registry. The ICMJE defines a clinical trial as: Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Health-related interventions include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-or-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events. Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator will not require registration. 4) Federal agencies including the FDA and NIH also have registration policies. See for further information. 5) Contact the Clinical Trails Training Office at if the trial qualifies to begin the registration process. a) PI or research staff is responsible for entering and updating information in the registry. b) Notify the CTTO if the investigator is the holder of an IND. c) Sponsor/CROs usually have already registered their study. Check to assess if they are registered. Notify sponsor/cro personnel if the study is not listed. 2