Human subjects research protocols with multiple sub-studies (PMSS) have the potential to be highly complex, especially when they involve different study populations or risk levels. Complex PMSS can present challenges for reviewers who are responsible for ensuring regulatory compliance and appropriate safeguards for participants, and for Principal Investigators (PIs) and research personnel, who are responsible for implementing protocol adherence.

Brown University’s (Brown) Human Research Protection Program (HRPP) developed this directive and the following criteria to describe when human subjects research PMSS are eligible for consideration as a single protocol submission through Brown’s HRPP for review by Brown’s Institutional Review Board (IRB). It further defines the requirements for submitting single protocol PMSS for review to Brown’s IRB. It also outlines the responsibilities of PIs and sub-study lead investigators.

It may be acceptable to submit a PMSS as a single protocol submission if it is clear that submission has:

1. Defined, established goals that the protocol and all sub-studies must satisfy;
2. Shared hypotheses or research questions that guide all sub-studies under the protocol;
3. Specific aims or objectives for each sub-study to address the goals of the protocol;
4. Similar eligibility criteria or participant populations for the protocol and sub-studies;
5. Similar research locations for the protocol and sub-studies.

It may not be acceptable to submit a PMSS as a single protocol submission if the submission has:

1. Broad goals for the protocol and sub-studies with a general purpose, or are otherwise ill-defined;
2. No common hypotheses or research questions to guide sub-studies;
3. No unique aims or objectives for sub-studies that would allow them to meet the goals of the protocol;
4. Been determined by the IRB/HRPP to be too complex to evaluate the risks to participants in relation to the anticipated benefits. For example, the submission includes:
   1. Different levels of anticipated risk to participants;
   2. Separate eligibility criteria or participant populations, including vulnerable populations; and/or
   3. Various research locations, including national and international sites.

Examples of PMSS that are eligible for single protocol submission:

• A Brown University professor serves as the PI and submits a PMSS. The PMSS follows their course syllabus, describing the specific purpose and goals of their course. Graduate students enrolled in the course are expected to serve as lead investigators and conduct their own research projects as sub-studies on the PMSS with their own research questions and objectives that align with the goals of the protocol and meet the requirements of the course. Additionally, all sub-studies will be conducted in Rhode Island and interact with similar study populations or their information.
   
• A Brown University institute director serves as the PI and submits a PMSS. The PMSS describes collaborating with school districts across the US to collect secondary data from the school districts with the specific goal of assessing the impact of different tutoring programs on the learning, behaviors, and perceptions of K-12 students, their teachers, and families. As part of this collaboration, all lead investigators conducting sub-studies must focus on the conditions and accommodations required for effective tutoring implementation, and whether tutoring programs improve educational outcomes for K-12 students.

A PMSS single protocol submission must include:

1. A defined, shared goals for the protocol and all sub-studies;
2. Shared hypotheses or research questions that set the parameters for all sub-study hypotheses and research questions that will be reviewed under the protocol;
3. Specific aims or objectives for each sub-study that align with the goals of the protocol;
4. Use of a consistent naming convention for all study materials to easily determine which documents belong to each lead investigator and sub-study; and
5. A management plan describing how the PI will oversee the protocol and sub-studies. At a minimum, this plan should describe tracking the:
   1. Names lead investigators;
   2. Sub-study titles;
   3. Sub-study start and end dates, if known at the time of submission; and
   4. Number of participants to be enrolled and/or identifiable private records accessed.

For PMSS single protocol submissions that involve obtaining informed consent, the IRB/HRPP submission must:

1. Describe the consent process for each sub-study;
2. Submit a separate IRB/HRPP consent document for each sub-study, if appropriate;
3. Include the title of the protocol and the title of the sub-study in the applicable sections of the consent template; and
4. Include the name of the PI and sub-study lead investigator.

The PI of the single protocol submission is not required to conduct any of the sub-studies; each sub-study may be conducted by a different lead investigator. Lead investigators on sub-studies may be Brown faculty, staff, or students.

Any student serving as the lead investigator must have a human subjects research advisor. The human subjects research advisor must meet all of the applicable qualifications described in the Human Subjects Principal Investigator Eligibility Policy and Principal Investigator (PI) Eligibility & Advisor Qualifications guidance. Therefore, the PI of the PMSS will serve as the student’s human subjects research advisor by default, unless the student expressly requests another appropriately-qualified human subjects research advisor. In this situation, the student’s requested human subjects research advisor must join the PMSS as research personnel, as they assume joint responsibility with the student for the ethical conduct of research and the protection of participants.

The PI is ultimately responsible for the:

• Conduct of, and adherence to, the PMSS;
• Ethical conduct of all sub-study lead investigators;
• Protection of the rights and welfare of participants enrolled in the protocol and all sub-studies;
• Protection of participant information and/or biospecimens;
• Compliance with applicable federal regulations, state laws, Brown policies; and
• Any stipulations imposed by the IRB/HRPP.

Delegation of the PI’s responsibilities can only be made to qualified and trained investigators and research personnel.

A sub-study lead investigator reports directly to the PI (or their delegate) and is responsible for the:

• Ethical conduct of their sub-study;
• Protection of the rights and welfare of participants enrolled in their sub-study;
• Protection of participant information and/or biospecimens in their sub-study;
• Compliance with applicable federal regulations, state laws, Brown policies applicable to their sub-study;
• Strict adherence to their sub-study and the parameters of the protocol; and
• Any stipulations imposed by the IRB/HRPP.

The IRB/HRPP will review single protocol PMSS and any subsequent revision requests using the same review criteria and standards as all other human subjects research protocols covered under the federal regulations in 45 CFR 46.

At any time, if the PI requests changes to an existing single protocol PMSS and/or requests the addition of a new sub-study that does not meet the criteria for eligibility as a single protocol submission, the IRB/HRPP reserves the right to require that the PI submit a new and separate protocol.

Brown University

• Forms and Templates:
  • Consent/Assent Forms & HIPAA Authorizations
• HRPP Glossary
• IRB Guidance & Policies:
  • Human Subjects Research Principal Investigator Eligibility Policy
  • Principal Investigator (PI) Eligibility & Advisor Qualifications

U.S. Department of Health and Human Services (DHHS) Federal Regulations

• Definition for purposes of this policy – 45 CFR 46.102
• Protection of Human Subjects – 45 CFR 46