Stanford University Office of the Dean of Research
Human Research Protection Program (HRPP)
DOMAIN III: INVESTIGATORS
STANFORD* uses policies, procedures, and education programs to help its investigators, particularly the Protocol Directors (PDs), carry out research studies ethically. In addition to following applicable federal, state, and local regulations, PDs follow ethical principles and standards appropriate for their discipline. In designing and conducting clinical trials, PDs follow Good Clinical Practice (GCP) guidelines defined by the Food and Drug Administration. In designing and conducting all research studies, PDs have as the primary concern protecting the rights and welfare of participants. (AAHRPP Standard III-1)
PDs and research staff consider conflicts of interest that might affect the relationship with the participant or the outcome of the research, and, together with STANFORD, identify and manage them. (AAHRPP Element III.1.A)
PDs are expected to be fully familiar with the STANFORD policy on investigator conflicts of interest as set forth in Chapter 3.7. STANFORD requires that PDs, as well as any other person who is responsible for the design, conduct, data analysis or reporting of research, make disclosures of certain financial interests in the manner and at the times required by Chapter 3.7 and as listed in the Protocol Application Form (Document F.1.a.).
PDs are required to follow procedures to report at the time of protocol submission and during the IRB review process when a financial interest, as defined in Chapter 3.7 and the Protocol Application Form, is involved in a study. The IRB defers its decision to approve, requests further modifications, or disapproves the project until the appropriate School Dean’s office has provided an Action Report (if any) and Management Plan (if any) to the IRB.
When a financial interest has been reported by the PD and reviewed by the School Dean’s office before protocol submission, the IRB will review the resulting Action Report and Management Plan (if any), as part of its review of the research.
When a financial interest is reported after the IRB has reviewed and approved the protocol, the PD must stop any enrollment into the study until the conflicting interest has been reviewed by the appropriate School Dean’s office and any Action Report and Management Plan provided to the IRB.
In rare situations in which a conflict of interest has been determined to exist and cannot be sufficiently eliminated, the IRB will review the Management Plan for the conflict of interest. The IRB may accept the plan, reject the plan, or require additional protections. Disclosure to participants may not alone be used to manage a financial interest that may affect participant protections.
PDs employ sound study design in accordance with the standards of the discipline and implement reporting mechanisms that provide information relevant to monitoring the rights and welfare of participants enrolled in the research. (AAHRPP Element III.1.B)
The significance of the research depends upon the validity of the results. It is unethical to put subjects at risk or to inconvenience them through participation in a study that may produce little or no reliable information. Research that is so poorly designed that meaningful results cannot be obtained is not approvable. Regardless of the source of funding, it is the PD’s responsibility to judge the research design to be sound enough to meet its objectives before submitting the protocol for IRB review.
In developing, or in evaluating the adequacy of, a research design involving investigational drugs or biological products, the PD should adhere to the GCP Guidelines prepared by the FDA under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”), as published in the Federal Register on May 9, 1997. The PD should also be familiar with the various types of control groups, their relative advantages and disadvantages, and the ethical issues associated with each control type, as outlined in the FDA Guidance entitled “Choice of Control Group and Related Issues,” as published May 2001 and available on the FDA website. While directly applicable to FDA-regulated trials involving investigational drugs or biological products, many of the following principles can also be applied to clinical trials in general.
Procedures
· The PD is instructed to follow Guidance for Sound Study Design in Clinical Trials (Document F.4.z.) when designing clinical trials and include all pertinent information in the protocol application form.
· The PD is required to complete a Principal Investigator’s Clinical Research Checklist (Document F.5.j.). The Checklist must be signed by the PD and submitted to the School of Medicine (SOM) Research Management Group (RMG) (Document C.4.g.ii.). If the PD is unable to answer the questions in the affirmative, RMG may not prepare a budget for the study.
· Sound study design must also be achieved in research other than clinical trials. The PD is instructed to follow Guidance for Sound Study Design in non-Clinical Research (Document F.4.aa.) and include all pertinent information in the protocol application form (Documents F.1.a. and F.1.b.).
In research involving greater than minimal risk to participants, the PD provides the IRB with an evaluation of less risky alternatives, if any, and with plans for detecting harm promptly and mitigating potential injuries. (AAHRPP Element III.1.C)
The PD must minimize risks at all time by using procedures that are consistent with sound research design and do not expose participants to unnecessary risks. Non-medical studies also involve risk such as emotional discomfort, invasion of privacy, or loss of confidentiality. The PD must explain in the protocol application how these risks will be minimized.
When submitting a new protocol application (Documents F.1.a. and F.1.b.) to the IRB, the PD is required to describe the potential risks, and include, where possible, a scientific estimate of the frequency, severity, and reversibility. If statistical incidence of complication and the mortality rate of proposed procedures are known, this data should be included.
Proper justification of the level of risk must be provided in the protocol application. The PD is instructed to refer to the Guidance for Sound Study Design in Clinical Trials and Guidance for Sound Study Design in non-Clinical Research found respectively in Documents F.4.z. and F.4.aa.
The protocol must include adequate provisions for monitoring the data during the conduct of the research to ensure the safety of subjects as required in Chapter 9.4: Data and Safety Monitoring Plan. For clinical research in which risks are greater than minimal, a data and safety monitoring plan must be submitted to the IRB as part of the protocol, including a method for future reporting of safety findings to the IRB. Additionally, the PD must make reports of certain events and information to the IRB as required in Chapters 3.10 and 15.2 and Document F.4.gg. Guidance for the Prompt Reporting of Unanticipated Problems.
The PD or research staff recruits participants in a fair and equitable manner, weighing the potential benefits of the research to the participants against their vulnerability and the risks to them as discussed in Chapter 10. (AAHRPP Element III.1.D)
PDs are referred for guidance to the STANFORD recruitment policies and procedures set forth in Chapters 9.2 and 10.2.
· The PD must provide all necessary information on the protocol application to allow meaningful review by the IRB of the recruitment process, as outlined in Chapter 10.1
· The PD is instructed to follow the guidances on recruitment, telephone screening (which includes phone script samples), and advertisements.
(See Recruitment website page).
In selecting a population from which to draw participants for a particular research protocol, the PD must consider whether the choice of population results in an equitable distribution of the burdens and benefits of research. The PD must provide appropriate justification in the protocol application when recruiting participants among vulnerable populations such as prisoners, pregnant women, economically and educationally disadvantaged, decisionally impaired, and homeless people.
PDs must provide a rationale for involvement of employees or students of Stanford. While employees and students are not vulnerable subpopulations per se, they may perceive that they are under some pressure from their superiors to agree to participate. PDs who contemplate enrolling employees or laboratory personnel are referred by IRB Staff to Section 7.5 of the Research Policy Handbook during protocol review and must state concurrence with the policy (Document A.3.p.).
Children should be included in research, along with adults, unless there is a compelling rationale for their exclusion. Research that limits enrollment to children is generally not appropriate unless:
i. The condition or disease is limited to children, or
ii. The research seeks to obtain information on a test article or procedure that previously had been studied only in adults.
Payments to research subjects may not be of such an amount as to result in coercion or undue influence on the subject’s decision to participate. Payments may not be provided to subjects on a schedule that results in coercion or undue influence on the subject’s decision to continue participation. For example, payment may not be withheld as a condition of the subject completing the research. If the subject withdraws early, payment must be prorated to reflect the time and inconvenience of the subjects participation up to that point.
PDs must document in the protocol application that there are adequate resources and facilities to carry out the research. (AAHRPP Element III.1.E)
All PDs must determine and document in the protocol application (Document F.1.a.) or during the review process that adequate space, personnel, services and equipment required for conducting the proposed research properly and safely is and will remain available throughout the research. These resources include: access to a population that will allow recruitment of the required number of individuals; sufficient time to conduct and complete the research; adequate nurses and qualified staff; adequate facilities; a process that ensures that all persons assisting with the research are adequately informed about the protocol and their research-related duties and functions; medical or psychological resources are available.
For example, if participants require extensive monitoring during the first six hours after initial administration of an investigational article, the PD should ascertain that the nurse/patient ratio in the unit where the test article will be administered is sufficient to carry out that monitoring. If laboratory tests are required as part of the monitoring, the PD should ascertain that the results will be available in the time required to protect participants. If a purpose of a research procedure is to induce an untoward response in the participant (e.g., abnormal heart rhythm, allergic reaction) the PD should ascertain that emergency care is immediately available to safeguard the participant’s health if the response exceeds defined limits. In non-medical settings, the PD should ascertain that adequate support and care is available if a research procedure (e.g., interview, questionnaire) elicits reactions that may endanger the participant or others.
PDs of clinical trials must also complete a Principal Investigator’s Clinical Research Checklist before beginning research (Document F.5.j.). The Checklist must be signed by the PD and submitted to the Research Management Group (RMG) (Document C.4.g.ii.). If the PD is unable to answer the questions in the affirmative, RMG will not prepare a budget for the study.
If the resources required for the proper conduct of the research cease to be available at any point after the research has begun, the PD should stop the research and immediately notify the IRB.
The informed consent process involves one or more discussions with potential participants to explain the nature and purpose of the research and to answer any questions that arise. The written form documents the information conveyed to the individual during the informed consent process, as well as the individual’s willingness to participate in the research.
The PD is responsible for obtaining and documenting the informed consent of individuals who participate in research, unless the requirement to obtain and document informed consent is altered or waived by the IRB. The PD may delegate all or a portion of the informed consent process to others on the research team, such as co-investigators or research coordinators. However, it is ultimately the responsibility of the PD to ensure that those individuals carry out their tasks properly.
The PD should plan to discuss research with potential participants at a time when they are not under duress, and to allow sufficient time and opportunity to ask questions and to consider whether or not to participate in the research before agreeing to participate.
In discussing research with potential participants, the PD may not describe items or procedures under investigation as if they were known to be safe and effective as a treatment for the potential participant’s disease or condition, or presenting a known advantage. The PD may not understate the risks of the research, as there may be no countervailing benefits to participants.
Once consent is given it may be withdrawn at any point. Accordingly, the PD should regard the informed consent process as continuing throughout the duration of the research. The PD should continue to answer any concerns, complaints, or specific questions the participants may raise about the research and to be alert to correct any misunderstandings on the part of the participant as to what the research involves.
The purpose of medical or behavioral treatment is to provide interventions designed solely to enhance the well-being of the patient or client. By contrast, research is designed primarily to develop generalized knowledge rather than to benefit each participant in the research. Research involves activities to test a hypothesis and draw conclusions, and any therapeutic benefit to the participants is secondary to the objectives of the research. This distinction is especially important if the PD is also the potential participant’s attending physician, a situation that increases the risk of confusion between treatment and research.
Research involving randomization of participants to one or the other of two proven treatments raises further issues. In these circumstances, the PD should ensure that each participant understands that the assignment will not be based upon the attending physician's clinical judgment as to which treatment may prove more beneficial to that participant, and may involve additional testing that would not be performed in the treatment context.
In the event that the PD proposes to use a consent document that has already been developed by the sponsor or a cooperative multi-site research group, the PD is responsible for reviewing the existing document to determine if it fairly and adequately describes the research aims, procedures, risks, and benefits. The explanation of risks in the consent document should be based upon information presented in such documents as the protocol, the investigator’s brochure, any previous research reports, and, where applicable, the labeling for the drug or device.
If the research involves extensive screening procedures, the PD may wish to develop a separate consent document that explains the screening procedures in detail and provides a brief summary of the underlying research. In such circumstances, screening could begin after the individual signed the screening consent form but before the signing of the main consent document, which would be signed only if the individual satisfied the screening criteria and was actually enrolled in the study.
No research procedures, including screening procedures to determine if an individual is eligible to enroll in the research, may begin until after the participant has signed the consent form, unless the IRB has approved a waiver or alteration of consent. Retroactive consent – i.e., consent obtained or documented after the participant has undergone one or more research procedures – is not acceptable.
Procedures
· The PD is instructed to consult the consent form education material provided at http://humansubjects.stanford.edu/research/medical/med_consent.html for medical research and http://humansubjects.stanford.edu/research/nonmedical/nm_consent.html (Document D.1.g.) for nonmedical research. Those pages also provide links to the informed consent templates and the Informed Consent Checklist.
· A description and discussion of the elements of informed consent is found at Chapter 12.1.
· The PD must describe the consent process in the application form (Documents F.1.a. and F.1.b.) in enough details to allow for a meaningful review by the IRB.
· The PD is responsible for making all revisions to the proposed consent document requested by the IRB.
· The PD must use the informed consent document currently approved by the IRB. No participants may be involved in research prior to the IRB approval date that appears on the document, and no participants may be involved in research using a document whose approval period has expired. No changes may be made to the consent document until after the IRB has reviewed and approved the proposed change.
· The PD or delegate is responsible for giving the participant a copy of the signed informed consent document, and for keeping the original form.
· Unless the IRB waives the documentation requirement, the PD must include in the protocol application a proposed written informed consent document that addresses each of the elements of informed consent in the context of his or her research.
· The PD must submit to the IRB any written material to be given to prospective participants to explain the nature of the research.
· When the PD requests a waiver of the documentation requirement, he/she must submit a written summary of what will be covered in the oral discussion with potential participants.
· When submitting an application to the IRB for review of a research protocol, the PD may request a waiver or alteration of the requirement to obtain informed consent or a waiver of the requirement to obtain a written signed informed consent document. The requirements for the two types of waiver differ, and the PD is expected to be familiar with the requirements for each. These requirements are described at Chapter 12.6 and 12.7.
· The PD must notify the IRB promptly and in any case within 5 working days, if the PD involves an individual in research without first obtaining the individual’s informed consent and a signed informed consent document (unless the IRB has explicitly waived these requirements).
· The PD must notify the IRB promptly if the PD involves an individual in research using a consent form other than the current IRB-approved form.
· The PD must notify the IRB promptly if the PD believes informed consent documents have been lost, misplaced, or destroyed.
The PD and research staff respond to participants' complaints or requests for information. (AAHRPP Element III.1.G)
The PD and members of the research staff are required to respond promptly and adequately to all requests for information received from participants, prospective participants and their family members or designated representatives. In addition to providing information and answering questions that arise as part of the informed consent process, the PD must inform the participant that he/she is available to answer any questions that arise about the research in the future.
The PD is also expected to receive and follow the proper procedure for complaints. A complaint is a formal or informal, written or oral, expression of dissatisfaction by the participant or the participant’s representative that cannot be resolved promptly by the PD or member of the research staff to whom it is made. An expression of dissatisfaction that does not involve risk to the participant is not regarded as a complaint if the issue can be resolved promptly, on the spot, or within a 24-hour period, by the PD or research staff. For purposes of making a complaint, the consent form must list the full names and contact information for the PD, research study staff and other investigators who are involved in the research, in the form indicated on the template consent forms (Documents F.3.e.-o.) The consent form must also inform participants how to reach the IRB if they have any questions about their rights as research subjects. If the PD or research staff to whom the dissatisfaction is expressed is unable to resolve the problem promptly, the procedures set out below must be followed:
· Research staff who receives a complaint from a participant or participant’s representative must notify the PD.
· A PD who receives a complaint, whether directly from a participant or participant’s representative or indirectly through his or her research staff, must notify the relevant IRB Staff who will refer the matter to the Sr. IRB Manager and IRB Chair. The PD is then directed to submit a brief description of the complaint and the circumstances in which the complaint was made. The complaint is handled in accordance with the policies described in Chapters 3.9 and 3.10.
· If the PD determines that the complaint may relate to an event reportable under Chapter 3.10 as a possible unanticipated problem involving risks to participants or others, the PD should follow the procedures for reporting unanticipated problems involving risks to participants or others, including adverse events, as set out in Chapter 3.10. The PD should attach a description of the complaint to the Stanford Report Form (Document F.2.f.) on which the event is reported.
If the complaint is not directly related to the conduct or design of the research, the IRB staff may choose to refer the complaint to the appropriate STANFORD institutional official or committee, for example, as provided for in the applicable hospital policy on the handling of patient grievances. In circumstances in which the complaint is referred, the IRB staff should provide the participant with the name and contact information for the referral.