What is the purpose of this manual?
Study Submission Deadline and Contact Information
What is the Human Research Protection Program?
What is Human Research?
Exempt Human Research
What training do investigators and study staff need to conduct Human Research?
How to submit new non-exempt Human Research to the IRB
How to complete “FORM: Initial Application for Human Research”
How to write a Protocol Summary and/or Detailed Protocol
What financial interests have to be reported to the IRB?
How to create a consent/assent document
How does the IRB decide whether to approve Human Research?
Review Using the Expedited Procedure
Review by the Convened IRB
What will happen after IRB review?
Approval
Requires Modification(s)
Deferral/Disapproval
What are the Investigator’s obligations after IRB approval?
How to document consent
How to submit a modification
How to submit continuing review
How to close out a study
How long should records be kept?

What is the purpose of this manual?

This Investigator Manual is designed to guide investigators and study staff through policies and procedures related to the conduct of Human Research that are specific to Dimock Center (Dimock).

Information regarding the general conduct of Human Research is included in the required training. See “What training do investigators and study staff need to conduct Human Research?”

What is the Human Research Protection Program?

The organization’s Human Research Protection Program (HRPP) is a comprehensive system to ensure the protection of the rights and welfare of participants in Human Research.  It is comprised of the Dimock leadership, Institutional Review Board (IRB), investigators and their study staff, and relevant departments and units.  The document “HUMAN RESEARCH PROTECTION PROGRAM PLAN” describes the roles and responsibilities of each of the above-name parties as well as the Center’s overall plan to protect participants in Human Research.

What is Human Research?

Dimock follows the regulatory definitions of “Human Subject Research,” which are described in the document “HUMAN RESEARCH PROTECTION PROGRAM PLAN.” An algorithm for determining whether an activity is Human Research can be found in “CHECKLIST: Human Research Determination.”

Investigators are responsible for not conducting Human Research without prior IRB review and approval.  If investigators have questions about whether an activity is Human Research, contact the IRB office.

If an investigator would like a written determination, complete “FORM: Not Human Subjects Research Request” and submit it to the IRB office. 

The Office of IRB Operations (OIO) encourages investigators to maintain electronic Word documents of all information submitted to the IRB in case revisions are required.  In addition, an investigator must retain a hard copy or electronic version of the signed and dated submission as well as the IRB’s notification letters as part of the regulatory documentation.

Exempt Human Research

Certain categories of Human Research may be exempt from regulation but require IRB review. Investigators must obtain an IRB Exemption Determination prior to conducting exempt Human Research.  An algorithm for determining whether an activity is exempt from IRB approval can be found in “CHECKLIST: Exemption Determination.” 

Complete “FORM: Exemption Request” and submit it to the IRB office.  Of note, Principal Investigators must be a Dimock affiliate. 

The OIO encourages investigators to maintain electronic Word documents of all information submitted to the IRB in case revisions are required.  In addition, an investigator must retain a hard copy or electronic version of the signed and dated submission as well as the IRB’s notification letters as part of the regulatory documentation.

What training do investigators and study staff need to conduct Human Research?

All new investigators and study staff must review Dimock’s “HUMAN RESEARCH PROTECTION PROGRAM PLAN” as part of their initial orientation. OIO will provide specific training for current investigators and study staff as needed and/or upon request. 

Investigators, research staff, and others who are involved in the design, conduct, or reporting of the Human Research, and have (a) direct interaction with participants and/or (b) access to identifiable information must complete Harvard’s human research  training curriculum available through the Collaborative Institutional Training Initiative (CITI) Program, or acceptable equivalent, e.g., NIH, Family Health International (FHI). CITI is valid for a three year period, after which time a refresher course or additional training is required.  IRB approval may not be granted for proposed research in which investigators have not completed human research protections training.

How to submit new non-exempt Human Research to the IRB

Complete “FORM: Initial Application for Human Research,” and submit it to the IRB along with  any relevant attachments. 

OIO encourages investigators to maintain electronic Word documents of all information submitted to the IRB in case revisions are required.  In addition, an investigator must retain a hard copy or electronic version of the signed and dated submission as well as the IRB’s notification letters as part of the regulatory documentation.

How to complete “FORM: Initial Application for Human Research”

 

A. Protocol Information

1. Protocol Number. Leave this field blank. Upon receipt, the Office of IRB Operations will assign this submission a five-digit protocol number followed by a three-digit suffix, e.g., 12345-101. Throughout the life of the study, the five-digit protocol number will not change; however, the three-digit suffix will increase with each subsequent submission, e.g., 12345-102 (continuing review application); 12345-103 (modification). 
2. Protocol Title. Enter the complete protocol title. If applicable, include in parentheses the cooperative group, sponsor protocol code or protocol number.
3. Principal Investigator / Degree(s). Provide the name and contact information of the investigator with overall responsibility for the conduct of the Human Research. The Principal Investigator must be a Dimock affiliate. The IRB may make an exception to this policy on a case-by-case basis with appropriate justification. To request an exception, submit a cover memo outlining why this arrangement is appropriate and the qualifications of the proposed PI. 
4. Additional Contact Person. If applicable, provide the name and contact information of the person who should receive a copy of all communications related to the protocol. There can only be one additional contact.

B. Procedures/Study Procedures Requiring Additional Review. Indicate within the Initial Application whether the Human Research involves any of the following:

1. Waiver or alteration of the consent process. Check if the Human Research does not include plans to obtain consent from participants, withhold information while obtaining consent, and/or involves deception.
2. Waiver of written documentation of consent. Check if the Human Research includes plans to obtain consent from participants, but will not require that participants sign a written consent document.
3. Individuals who are under legal age. Check if the Human Research involves children, adolescents, minors, or other individuals who have not reached the age of majority (as dictated by local law) to consent to the Human Research procedures.
4. Cognitively impaired adults. Check if the Human Research involves adults who may not have the ability, or may have limited ability, to consent to the Human Research procedures.
5. Pregnant women. Check if the Human Research may involve pregnant women at any time from the period of implantation until delivery, regardless of whether the Human Research is focused on or targets pregnant women.
6. Non-viable neonates. Check if the Human Research may involve non-viable neonates (newborns after delivery that, although living, are not able to survive to the point of independently maintaining heartbeat and respiration, given the benefit of available medical therapy), regardless of whether the Human Research is focused on or targets non-viable neonates.
7. Neonates of uncertain viability. Check if the Human Research may involve neonates of uncertain viability (newborns after delivery that, although living, may not be able to survive to the point of independently maintaining heartbeat and respiration, given the benefit of available medical therapy), regardless of whether the Human Research is focused on or targets neonates of uncertain viability.
8. Employees of the PI. Check if the Human Research may include employees of the PI, regardless of whether the Human Research is focused on or targets employees of the PI.
9. The use of any biohazards. Check if the Human Research requires the use of biohazard agents.
10. Drugs/Biologics. Check if the Human Research includes drugs for a use other than the approved medical use. Complete and submit
    “FORM: Drugs, Biologics and Devices.” Within this form, list all agents (drugs, biologics, dietary supplements, food additives) being used in the Human Research (approved and unapproved). For each, indicate whether it has an IND number. For each drug with an IND number, ensure that the application includes one of the following: (a) sponsor protocol with the IND number; (b) communication from the sponsor with the IND number; or (c) communication from the FDA with the IND number. Submit a copy of the Investigator Brochure and Package Insert.
11. Protected Health Information (PHI). Check if the Human Research involves the use of PHI. Protected Health Information includes all individually identifiable health information held or transmitted by or to a covered entity in any form or media, whether electronic, paper, or oral. 
12. Clinical trial. Check if the Human Research involves a clinical trial and the sponsor requires compliance with the International Council on Harmonization – Good Clinical Practice Guidelines (ICH-GCP). Submit a current copy of the Principal Investigator’s curriculum vitae. 

C. Funding Source(s). List all extramural funding sources here. Provide a complete copy of the grant application and/or subcontract, when applicable, and remove or black-out any salary information.

D. External Site(s). Provide the name, contact information and, when applicable, the Federalwide Assurance number for each external site(s) under the responsibility of the Principal Investigator. Indicate whether the site has an IRB and, when applicable, whether the said IRB will review the Human Research or rely on Dimock. Provide a copy of the written approval, e.g., IRB approval notice, from each site. When applicable, submit “FORM: IRB Authorization Agreement Request.”

E. Attachments. 

1. Study Personnel Information Form. List only Dimock affiliates involved in the design, conduct and/or reporting of the Human Research who have (a) contact with human participants or (b) access to identifiable data. Include external (non-Dimock) collaborators only in the absence of local IRB review. Each of the individuals listed must complete human research training. See “What training do investigators and study staff need to conduct Human Research?”
2. Indicate whether each listed individual has a financial conflict of interest relating to the Human Research. For more information, see “What financial interests have to be reported to the IRB?” If an individual has a financial interest, complete “FORM: Financial Interest Disclosure Form.”
3. Financial Interest Disclosure Form. Submit this form for each member of the study personnel who self-identifies a financial conflict of interest related to the research within the Study Personnel Information Form described above. For more information, see “What financial interests have to be reported to the IRB?”
4. Protocol Summary. See “How to write a Protocol Summary and/or Detailed Protocol.”
5. Detailed Protocol. See “How to write a Protocol Summary and/or Detailed Protocol.” 
6. Sponsor Protocol. Submit this document if applicable. Redact or black-out any salary information.
7. Grant Application/Subcontract. If applicable, submit a complete copy of the grant application and/or subcontract, regardless of funding source. Remove or black-out any salary information.
8. Research Tools, e.g., data collection instruments, educational materials. Documents must include a version date and/or version number. 
9. Advertisements. Guidance on what is appropriate to include and what is not appropriate to include within an advertisement can be found in “CHECKLIST: Review of Advertisements and Payments.” Advertising material must include version date and/or version number.
10. Recruitment Materials/Scripts. Each recruitment document/script must include version date and/or version number. 
11. Consent Forms/Scripts. See “TEMPLATE: Consent Document” and “TEMPLATE: Assent Document.” Consent documents must include version date and/or version number.
12. DHHS-approved sample consent document. Consent documents must include version date and/or version number.
13. Study Instruments, e.g., questionnaires/surveys/focus group discussion guides/interview guides. Study documents must include version date and/or version number.
14. External Sites’ Approval Notice. Submit an approval notice for each site listed in Initial Application for Human Research, section D. If local approval is not available at the time of submission, a copy must be submitted to the IRB prior to implementing any study procedures at external site(s).
15. “FORM: IRB Authorization Agreement.” When multiple institutions are engaged in the Human Research, submit this form to designate Dimock as the Reviewing Institution (responsible for IRB review) or Relying Institution. 
16. “FORM: Drugs, Biologics and Devices.” See Section B.13 and 14 above. 
17. Current Package Insert. Submit for each marketed drug involved in the Human Research.17 Current Product Information, e.g., Device Manual. Submit for each investigational device involved in the Human Research.
18. Curriculum Vitae. Submit a copy of the Principal Investigator’s current (signed/dated) CV when required by sponsor to follow the “International Council on Harmonisation – Good Clinical Practice E6.”
    

How to write a Protocol Summary and/or Detailed Protocol

The Protocol Summary is a synopsis of the entire study plan.  Its purpose is to provide IRB members and reviewers with sufficient information about the protocol in order to conduct a substantive review. A Detailed Protocol is a comprehensive outline of the study plan, which includes greater detail. Customarily, this document is required in the absence of a sponsor protocol and/or grant application; however, the IRB may request a copy when sufficient information is not captured in these documents. 

Prepare a document using “TEMPLATE: Protocol Summary” and, when required, “TEMPLATE: Detailed Protocol.”  A number of checklists are available on the website to guide investigators in drafting the Protocol Summary and Detailed Protocol. These checklists are referenced throughout this section when appropriate. 

OIO encourages investigators to maintain electronic Word documents of all information submitted to the IRB in case revisions are required.  In addition, an investigator must retain a hard copy or electronic version of the signed and dated submission as well as the IRB’s notification letters as part of the regulatory documentation.

1.      General Information.  Provide the version number/date, principal investigator, complete protocol title, sponsor/funding source, and target enrollment at Dimock and all sites.

2.      Study Objectives.  Describe the purpose, specific aims, or objectives of the Human Research. State the hypotheses to be tested.

3.      Background.  Provide the scientific or scholarly background and rationale for the Human Research based on the existing literature. Describe the relevant prior experience, gaps in current knowledge, and any relevant preliminary data. Explain the significance of the Human Research and how will it add to or enhance existing knowledge. Describe the importance of the knowledge expected to result. 

4.      Setting of the Human Research. Describe the study site(s), setting and location in which the Human Research will occur. Outline the Principal Investigator’s experience working in this setting and the study population(s) as well as his/her familiarly with the local culture.  If applicable, describe:

a.       Site-specific regulations or customs affecting the research, including local age of majority; mandatory reporting requirements.

b.      Local scientific and ethical review structure, e.g., national review system; institutional/organizational-level review.

c.       Composition and involvement of any community advisory board.

5.      Resources available to conduct the Human Research.  Demonstrate (based on retrospective data) a potential for recruiting the required number of suitable participants within the set recruitment period and the time frame necessary to implement and complete the protocol. Describe the qualifications of the study personnel, their experience in conducting research, their knowledge of the local study site(s), culture, and society.  Describe the facilities and the available equipment required to conduct the protocol. Describe the availability of medical and/or psychological resources that participants might need as a consequence of their participation in the Human Research. Describe the process to ensure that all persons assisting with the protocol are adequately informed about the protocol and study-related duties.

6.      Study Design.

a.       Recruitment Methods.  Describe when, where, how, and by who potential participants will be recruited. Describe the source of participants and/or the methods employed to identify potential participants, and the materials used to recruit participants.

The IRB must review and approve the content of all recruitment and advertisement materials, including oral communications, before implementation in the field.  For advertisements, submit the final copy of printed advertisements. When advertisements are taped for broadcast, provide the final audio/video tape. To avoid re-taping due to inappropriate wording, submit the proposed (draft) wording of the advertisement to the IRB.

Otherwise, provide the final English copy of these materials and include a version number and/or date within each document.  For guidance on what to include in an advertisement, refer to “CHECKLIST: Advertisements and Payments.”

b.      Inclusion and Exclusion Criteria.  Describe the criteria that define who will be included and excluded in the protocol, and the expected number of participants needed to complete the Human Research.  If applicable, describe the screening procedures employed. 

c.       Study Endpoints.  Describe the primary and secondary study endpoints. When applicable, describe any primary or secondary safety endpoints. 

d.      Procedures involved in the Human Research.  Describe and explain the study design. Provide a timeline of all procedures being performed, including procedures being performed to monitor participants for safety or minimize risks. Describe procedures taken to lessen the probability or magnitude of risks. Identify which procedures are being done as part of the Human Research and which are being conducted anyway as part of routine standard of care or for other reasons. Describe the source records that will be used to collect data about participants. Describe what data will be collected including long-term follow-up. Provide the overall duration of the research.

e.       Data management.  Describe the data and specimens to be sent out or received. Describe what information will be included in that data or associated with the specimens. Describe who is responsible for receipt or transmission of the data and how specimens and data will be transported.  Describe the plan to manage the data. Describe any procedures that will be used for quality control of collected data. Describe the data analysis plan, including any statistical procedures. Provide a power analysis.

f.        Provisions to monitor the data for the safety of participants (Required when Human Research involves more than minimal risk to participants).  Describe the plans to periodically evaluate the data collected regarding both harms and benefits to determine whether participants remain safe. Describe who will review, what data are reviewed (including safety data, untoward events, and efficacy data), and the frequency or review.  

g.       Withdrawal of participants.  Describe anticipated circumstances under which participants will be withdrawn from the research without their consent. Describe any procedures for orderly termination. Describe procedures that will be followed when subjects withdraw from the research, including partial withdrawal from procedures with continued data collection.

7.      Risks to participants.  List the foreseeable risks, discomforts, hazards or inconveniences to participants. For each indicate the probability, magnitude, and duration. Consider physical, psychological, social, legal and economic risks.  Outline how each identified risk, discomfort, hazard, and inconvenience will be minimized.

If applicable, indicate which procedures may have risks to the participants that are currently unforeseeable. If participants may include pregnant women, indicate which procedures may have risks to an embryo or fetus.

8.      Potential benefits.  Describe the benefits that individual participants may experience; otherwise, indicate that there is no direct benefit to participants.  Describe any potential benefit to the country, population and/or society. For each expected benefit, indicate the probability, magnitude, and duration of each.  Of note, compensation is not a benefit and should not be addressed in this section.  

9.      Provisions to protect the privacy interests of participants.  Describe the steps that will be taken to protect participants’ privacy interests. “Privacy interest” refers to a person’s desire to control access of others to themselves. It involves consideration of whether the participants will be comfortable with the research procedures.

10.  Provisions to maintain the confidentiality of data.  Describe the steps that will be taken to limit dissemination of identifiable data. Describe where data will be stored, who will have access to the data, measures taken to secure the data, how long data will be stored, and, when applicable, how data will be archived and/or destroyed. 

11.  Medical care and compensation for injury.  If the research involves more than minimal risk to subjects, describe the provisions for medical care and what, if any, compensation will be available in the event of a research-related injury.

12.  Costs and payments to participants.  Describe any costs that participants may incur or payment that participants may receive through their participation in the protocol.

13.  Consent process. 

a.       Describe the setting of the consent process; identify who will be responsible for obtaining consent, and how consent will be obtained, e.g., oral consent.  Describe the time that will be devoted to the initial consent discussion.  Describe any waiting periods between (a) informing the prospective participant and obtaining consent and (b) obtaining consent and carrying out the study procedures. Describe any steps that will be taken to minimize the possibility of coercion or undue influence.

b.      Indicate what language(s), if any, other than English are understood by prospective participants or their representatives. If participants who do not speak English will be enrolled, describe the process to ensure that the oral and written information provided to those participants will be in that language. Provide an English copy of the consent document(s).Include version number and/or version date within each document. 

c.       If the Human Research involves a waiver or alteration of the consent process (consent will not be obtained, required information will not be disclosed, or the research involves deception) review “CHECKLIST: Waiver or Alteration of the Consent Process” and address each of the criteria for approval in this section.

d.      If the Human Research involves persons who have not attained the legal age for consent to treatments or procedures involved in the research (“children”):

a.       Describe whether parental permission will be obtained from:

                                                                                       i.      Both parents unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.

                                                                                     ii.      One parent even if the other parent is alive, known, competent, reasonably available, and shares legal responsibility for the care and custody of the child.

b.      Describe whether permission will be obtained from individuals other than parents, and if so, who will be allowed to provide permission. Describe the process used to determine these individuals’ authority to consent to each child’s general medical care.

                                                                                       i.      Describe whether assent will be obtained from all, some, or none of the children, and if some children, which children will be required to provide assent.  Customarily, OIO advises that investigators obtain assent from individuals who are 7 years of age or older; however, this may not be appropriate for the specific target population. 

                                                                                     ii.      When assent of children is obtained, describe whether and how it will be documented.

                                                                                    iii.      Describe the procedures in place to obtain consent when, if any, children reach the local age of majority during the course of the protocol. 

c.       If the Human Research involves adults who may be unable to consent describe the process to determine whether an individual is capable of consent and address the following, if applicable:

                                                                                       i.      If permission of a legally authorized representative will be obtained:

1.      List the individuals from whom permission will be obtained in order of priority, e.g., durable power of attorney for health care, court appointed guardian for health care decisions, spouse, and adult child.

2.      Determine which individuals are authorized under applicable law to consent on behalf of a prospective participant to their participation in the research procedure(s).

3.      To make this determination, contact the IRB, which will review the definition of “legally authorized representative” in 45 CFR 46.102(c) or 21 CFR 50(l).

                                                                                     ii.      Describe the process for assent of the participants. Indicate whether:

1.      Assent will be required of all, some, or none of the participants. If some, indicated, which participants will be required to assent and which will not.

2.      If assent will not be obtained from some or all participants, include an explanation of why not.

3.      Describe whether assent of the participants will be documented and the process to document assent.

14.  Process to document consent in writing.  Describe whether and how consent of the participant will be documented in writing.

If the consent process will not be documented in writing, i.e., consent will be obtained, but the participant or representative will not sign a consent document, refer to “CHECKLIST: Waiver of Written Documentation of Consent” and address each of the criteria for approval within this section.

15.  Vulnerable populations.  If the Human Research involves individuals who are vulnerable to coercion or undue influence, describe additional safeguards in place to protect their rights and welfare.

If the Human Research involves adults unable to consent refer to “CHECKLIST: Research Involving Adults Unable to Consent” and address each of the criteria for approval.

If the Human Research involves persons who have not attained the legal age for consent to treatments or procedures involved in the research (“children”):

      Refer to “CHECKLIST: Research Involving Children” and address each of the criteria for approval.

·        Describe the criteria that will be used to determine whether a prospective participant has not attained the legal age for consent to treatments or procedures involved in the Human Research under the applicable law of the jurisdiction in which the Human Research will be conducted, e.g., individuals under the age of 18 years.

·        Determine which persons have not attained the legal age for consent to treatments or procedures involved in this Human Research, under the applicable law of the jurisdiction in which this Human Research will be conducted.

·        To make this determination, contact the IRB who will review the definition of “children” in 45 CFR 46.402(a) or 21 CFR 50(0).

If the Human Research involves pregnant women, refer to “CHECKLIST: Research Involving Pregnant Women” and address each of the criteria for approval.   

16.  Multi-site Human Research.  Describe the management of information, e.g., results, new information, unanticipated problems involving risk to participants or others, or protocol modifications, among sites to protect participants.

17.  Sharing of results with participants.  Describe the plans, if any, to share the results of the research with participants, e.g., Results Letter.

18.  Sending/Receiving Data/Specimens to/from Research Collaborators Outside of Dimock.  Describe what data/specimens will be sent to or received from outside collaborators, to/from whom data/specimens are sent/received, and whether data/specimens will contain identifiers.

What financial interests have to be reported to the IRB?

In order to minimize the actual or potential conflicts of interest in human research, the Office of IRB Operations (OIO) requires all individuals involved in the design, conduct, or reporting of the research to report all “Financial Interests Related to the Research” to the IRB.  Of note, “all individuals involved in the design, conduct, or reporting of the research” is broader than principal investigators and co-investigators and may include study coordinators, research nurses, data coordinators, and other support staff possible not captured in the Study Personnel Information form.

To disclose, submit “FORM: Financial Interest Disclosure Form” at the time of initial review and each subsequent continuing review.  In addition, investigators must report any change(s) to this disclosure to the IRB within ten business days.

The definitions of important terms are as follows:

·         “Financial Interest Related to the Research” means any of the following interests in the sponsor, product or service being tested, or competitor of the sponsor held by the individual or the individual’s immediate family:

o       Ownership interest of any value including, but not limited to stocks and options.

o       Compensation of any amount including, but not limited to honoraria, consultant fees, royalties, or other income.

o       Proprietary interest of any value including, but not limited to, a patents, trademarks, copyrights, and licensing agreements.

o       Board or executive relationship, regardless of compensation.

·        “Immediate Family” means spouse, domestic partner, children, and dependents.

How to create a consent/assent document

The Office of IRB Operations requires that investigators use “TEMPLATE: CONSENT DOCUMENT” and/or “TEMPLATE: ASSENT DOCUMENT” to create consent/assent documents for Human Research.  If an alternative format is preferred or required, i.e., by the Sponsor, include a cover memo with the submission justifying its use. 

How does the IRB decide whether to approve Human Research?

The criteria for IRB approval or non-exempt Human Research can be found in “CHECKLIST: Criteria for Approval and Additional Considerations.”  Additional checklists maybe applicable depending on the nature of the proposed Human Research, e.g., inclusion of children will prompt the use of “CHECKLIST: Research Involving Children.” 

These checklists are used by IRB members and reviewers at the time of initial review, continuing review, and review of modifications to previously approved Human Research.  Investigators are also encouraged to use the checklists as a reference or guide when writing Human Research protocols in a way that addresses the criteria for approval.

Review Using the Expedited Procedure

Certain categories of non-exempt Human Research may qualify for review using the expedited procedure. Review “CHECKLIST: Eligibility for Review Using the Expedited Procedure” for reference on applicable categories of research.

Review by the Convened IRB

Non-exempt Human Research that does not qualify for expedited review must be reviewed by the convened IRB. The IRB meets once a month. 

What will happen after IRB review?

Within 24 hours of receipt of the submission, the Principal Investigator and the designated Additional Contact Person will receive an email indicating whether the submission is complete or incomplete.  If incomplete, submit the requested materials within 45 calendar days after which time the submission will be withdrawn.  If the submission is complete, the notification email will provide the assigned reviewer’s name and contact information.  Once the submission is complete, the IRB will begin its review. 

When the IRB has completed its review, it will provide the Principal Investigator with a notification letter (a copy will be provided to the designed Additional Contact Person).  This notification letter will state that either the IRB has approved the Human Research, requires modifications to secure approval, or has deferred/disapproved the Human Research.

Approval

If the IRB has approved the Human Research, the Human Research may commence once all other organizational and/or local approvals have been secured.  IRB approval is granted for a limited period of time, not exceeding one year, which is noted in the approval notification letter.

Requires Modification(s)

If the IRB requires modifications to secure approval, the notification letter will outline specific revisions to the Human Research protocol and/or study materials, e.g., consent form.  Human Research may not commence until the IRB grants final approval.

If the Principal Investigator accepts the required modifications, s/he should submit the revised materials to the IRB within 45 calendar days using “FORM: Modifications Required to Secure Approval of Human Research.”  If all requested modifications are made, the IRB will issue a final approval notification letter after which time the Human Research can begin. 

If the Principal Investigator does not accept the modifications, s/he should write a response detailing why such modifications are not appropriate and/or feasible and submit it to the IRB within 45 calendar days.  If the Principal Investigator does not respond to the IRB within 45 calendar days, the offer of approval with the requested modifications will be withdrawn. 

Deferral/Disapproval

If the IRB defers or disapproves the Human Research, the IRB will provide a statement of the reasons for this decision.  Deferral or Disapproval means that the Human Research, as proposed in the submission, cannot be approved and the IRB was unable to articulate specific modifications that, if made, would allow the Human Research to be approved.  

In most cases, if the IRB’s reasons for the deferral or disapproval are addressed in a modification, the Human Research can be approved.  In all cases, the Principal Investigator has the right to address his/her concerns to the IRB directly at an IRB meeting and/or in writing.

What are the Investigator’s obligations after IRB approval?

1) Personally conduct or supervise the Human Research:

a) Do not implement any Human Research activities until receipt of final approval letter (Dimock and external study sites).
b) Conduct the Human Research in accordance with the relevant current protocol as approved by the IRB.
c) Use only IRB approved versions of study materials, including informed consent documents and recruitment materials. IRB approval is evident by a Dimock validation stamp and/or reference to applicable version numbers/dates in IRB Notification letters.
d) When required by the IRB, ensure that consent or permission is obtained in accordance with the relevant current protocol as approved by the IRB.
e) Do not modify the Human Research without prior IRB review and approval unless necessary to eliminate apparent immediate hazards to participants.
f) Protect the rights, safety, and welfare of participants involved in the research. 

2) Submit to the IRB:

a) Proposed modifications as described in this manual.
b) A continuing review application using “FORM: Continuing Review Application.”
c) A continuing review application to close out Human Research using “FORM: Continuing Review Application.”
d) Additional requirements of federal agencies (e.g. FDA) as applicable. 

3) Report the following to the IRB within five business days using “FORM: Reportable New Information:”

a) Information that indicates a new or increased risk or a safety issue for the research. For example:

i) An interim analysis, safety monitoring report, publication in the literature, or revised investigator brochure that indicates an increase in the frequency or magnitude of a harm, uncovers a new risk, or provides more information about the benefits of the Human Research.

ii) An Investigator Brochure, package insert or device labeling revised to indicate an increase in the frequency or magnitude of previously known risk, or describe a new risk.

iii) Change in FDA labeling,withdrawal, restriction or modification from marketing of a drug, device, or biologic used in a Human Research protocol.

iv) Protocol violation that harmed participants or others or that indicates participants or others might be at increased risk of harm.

v) Complaint of a participant that indicates participants or others might be at increased risk of harm or at risk of a new harm.

b) Local/internal adverse event which in the opinion of the investigator are unexpected and at least possibly related to the study procedures.

i) A harm is “unexpected” when its specificity and severity are not accurately reflected in the consent document.
ii) A harm is “at least possibly related if the research procedures more likely than not caused the event/harm.

c) External adverse event which in the opinion of the sponsor or investigator requires changes to the protocol or informed consent form.
d) Finding of Non-Compliance with federal regulations or determinations made by the IRB or Allegation of Non-Compliance.
e) Audit, inspection, or inquiry by a federal agency.
f) Failure to follow the protocol due to the action or inaction of the investigator or study staff. 
g) Breach of confidentiality.
h) Change to the protocol taken without prior IRB review to eliminate an apparent immediate hazard to a participant.
i) Incarceration of a participant in a protocol not approved to enroll prisoners.
j) Complaint of a participant that cannot be resolved by the research team.
k) Unanticipated problems (other than those events captured at 3b above) involving risks to subjects or others (including adverse device effect)
l) Revised Investigator Brochure (NOT indicating an increase in the frequency or magnitude of risk) 

4) Do not accept or provide payments to professionals in exchange for referrals of potential participants (“finder’s fees.”) 

5) Do not accept payments designed to accelerate recruitment that were tied to the rate or timing of enrollment (“bonus payments.”) 

6) Maintain signed and dated consent documents for six years after completion of the research. Maintain signed and dated HIPAA authorizations and consent documents that include HIPAA authorizations for six years after completion of the research. 

7) For studies involving drugs being studied under an IND or devices being studied under an IDE or abbreviated IDE:

a) Inform any potential subjects of all drugs or devices being used for investigational purposes.
b) Review and understand the information in the investigator’s brochure/manual, including the potential risks and side effects of the drug or device.
c) Prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the Human Research on each individual administered the investigational drug or device, or employed as a control in the Human Research. Case histories include:

i) Case report forms
ii) Supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual’s hospital chart(s), and the nurses’ notes.

d) Retain all records for six years after study completion, i.e., closure of the Human Research protocol, or longer if required by the sponsor.
e) Control the investigational drugs and devices being used in the research:

i) Personally supervise the administration of the drug or device to enrolled participants subjects.
ii) Do not supply the drug or device to any person not authorized under this part to receive it.
iii) Maintain adequate records of the disposition of the drug or device, including dates, quantity, and use by participants.
iv) If the investigation is terminated, suspended, discontinued, or completed, return the unused supplies of the drug or device to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 21 CFR §312.59.
v) If the investigational drug is subject to the Controlled Substances Act, take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution. 

8) Furnish all reports, such as adverse events, progress report/final report, and financial disclosures, to the sponsor according to the protocol or sponsor agreement.

9) Upon request from appropriate federal government agencies, such as FDA and NIH, at reasonable times, permit such officers or employees to have access to, and copy and verify any records or reports. 

10) Assure that an IRB complies with the requirements set forth in 45 CFR 46 or 21 CFR 56 and will be responsible for the initial and continuing review and approval of the proposed clinical study. 

11) Ensure that all associates, colleagues, and employees assisting in the conduct of the Human Research are informed about their obligations in meeting the above commitments. 

12) When required by sponsor, comply with the International Council on Harmonization – Good Clinical Practice Guidelines (E6). 

How to document consent

Combine the Human Research consent with the HIPAA authorization if applicable, i.e., some study procedures are conducted at a HIPAA-covered entity. Use the signature block approved by the IRB when obtaining informed consent. Ensure that all items in the signature block are complete, including dates and applicable checkboxes (e.g. sample storage)

The following are the requirements for customary (long form) consent documents:

·        The participant or representative signs and dates the consent document.

·        The individual obtaining consent signs and dates the consent document.

·        Whenever required by the IRB, the participant’s or representative’s signature is to be witnessed by an individual who signs and dates the consent document.

·        For participants who cannot read and whenever required by the IRB or the sponsor, a witness to the oral presentation signs and dates the consent document.

·        A copy of the signed and dated consent document is to be provided to the participant.

The following are the requirements for short form consent documents:

·        The participant or representative signs and dates the consent document.

·        The individual obtaining consent signs and dates the consent document and the summary.

·        The witness to the oral presentation signs and dates the consent document and the summary.

·        A copy of the signed and dated consent document is to be provided to the participant.

How to submit a modification

The IRB must review and approve all modifications to the Human Research before implementation in the field.  To request modifications, submit “FORM: Modification of Approved Human Research” along with any relevant attachments including new or study materials. 

When the modification is limited to a change to Principal Investigator, complete “FORM: Change to Principal Investigator” along with any relevant attachments.

OIO encourages investigators to maintain electronic Word documents of all information submitted to the IRB in case revisions are required.  In addition, an investigator must retain a hard copy or electronic version of the signed and dated submission as well as the IRB’s notification letters as part of the regulatory documentation.

How to submit continuing review

Complete “FORM: Continuing Review Application,” and submit it to the IRB along with any relevant attachments, including study materials that will be used in the upcoming approval period. If the study is currently open for data analyses only, a Protocol Summary/Detailed Protocol is no longer required with the submission.

OIO encourages investigators to maintain electronic Word documents of all information submitted to the IRB in case revisions are required.  In addition, an investigator must retain a hard copy or electronic version of the signed and dated submission as well as the IRB’s notification letters as part of the regulatory documentation.

If the continuing review involves modifications to previously approved research, submit those modifications as a separate request for modification using “FORM: Modification of Approved Human Research.”

If the continuing review application is not received by the submission deadline, the Principal Investigator will be restricted from submitting new Human Research until the completed application has been received.

If IRB approval of the Human Research expires, all study procedures related to the protocol under review must cease, including recruitment, advertisement, screening, enrollment, consent, interventions, interactions, and collection of private identifiable information.  Continuing Human Research procedures is a violation of federal regulations. 

If current participants will be harmed by stopping Human Research procedures that are available outside the Human Research context, provide these on a clinical basis as needed to protect current participants. If current participants will be harmed by stopping Human Research procedures that are not available outside the Human Research context, immediately contact the IRB Chair and provide a written list of the currently enrolled participants and an explanation of why they would be harmed by stopping Human Research procedures.

How to close out a study

Study closure is appropriate when (a) the research is permanently closed to enrollment; (b) all participants have completed all research-related interventions/interactions; (c) collection of private identifiable information is completed, and (d) analyses of private identifiable information is completed.  Under close-out status, analyses of de-identified data can occur indefinitely. 

To request closure, complete “FORM: Continuing Review Application,” and submit it to the IRB along with any relevant attachments.  Maintain electronic copies of all information submitted to the IRB in case revisions are required.  In addition, the PI is required to keep a copy of the signed and dated submission as part of the regulatory documentation.

How long should records be kept?

Investigators must maintain Human Research records, including signed and dated consent documents and other records related to HIPAA compliance, for at least six years after closing out the Human Research.

If the Human Research is sponsored, contact the sponsor before disposing of Human Research records as there may be specific policies related to record retention.