Office of the Dean of Research
Protocol Director Standards
In this chapter:
STANFORD policies, procedures, and education programs help Protocol Directors (PDs) and all STANFORD investigators carry out research studies in an ethical manner. In addition to following applicable federal, state, and local regulations, investigators 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, and have the protection of participants’ rights and welfare as their primary concern.
Section revised: 3/13/13
PDs and research staff are expected to follow Stanford University policies addressing the disclosure of conflicts of interest as described in Chapter 3.7 and the policies referenced therein.
Disclosures of potential conflicts of interest are reviewed and resolved by the COIRP/COIC. The IRB has the final authority to decide whether the potential conflict of interest and its management, if any, allows the research to be approved.
Section revised: 3/13/13
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. 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. The Protocol Application provides questions addressing the various considerations for sound study design. When designing studies, the PD should consult the guidance Evaluating Sound Study Design and include all pertinent information in the Protocol Application. The Protocol Application also includes a description of the provisions for monitoring the data and reporting to the IRB and other entities (see Chapter 14.3 below).
In developing, or in evaluating the adequacy of, a research design involving investigational drugs or biological products, the PD should refer to the FDA Guidance Documents representing the Agency's current thinking on good clinical practice (GCP) and the conduct of clinical trials, and including selected guidelines 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 Choice of Control Group and Related Issues, published May 2001. Although directly applicable to FDA-regulated trials involving investigational drugs or biological products, many of the principles can be applied to clinical trials in general.
See Other Federal Agencies - Additional Requirements [GUI-42] for other requirements depending on the source of support/funding (e.g., Department of Justice (especially for research conducted within the Bureau of Prisons)).
Section revised: 3/13/13
Risks may affect physical, psychological, social, legal or economic well-being, including loss of privacy or breach of confidentiality. The PD must minimize risks at all times by using procedures that are consistent with sound research design and that do not expose participants to unnecessary risks, and whenever appropriate, by using procedures already being performed on the participants for diagnostic or treatment purposes.
When submitting a Protocol Application to the IRB, the PD must:
· Describe the potential risks.
· Include, where possible, a scientific estimate of their frequency, severity, and reversibility. If statistical incidence of complication and the mortality rate of proposed procedures are known, this data should be included.
· Explain how risks will be minimized.
· Justify the level of risk.
· Describe adequate provisions for monitoring the data during the conduct of the research to minimize risk to participants (see Chapter 9.2).
For proposed changes to the research, including any change to mitigate potential harm to participants, the PD must submit a protocol Modification to the IRB describing any resulting changes in the level of risk to participants, and explaining the risk level and potential benefits.
At Continuing Review, the PD must indicate whether there has been an increase, no change, or a decrease in the level of risk of the study. If the risk assessment has changed the PD must update the information in the Risks section of the protocol.
All studies considered more than low risk must include a data and safety monitoring plan which describes how the PD will oversee the participants’ safety and welfare and how unanticipated problems involving risks to participants or others, and adverse events will be characterized and reported.
· Evaluating Sound Study Design [GUI-17]
· Data and Safety Monitoring [GUI-P20]
· Chapter 9 (measuring and minimizing risks to participants)
· Chapter 14.2 above (sound study design)
· Chapter 15.2 (Protocol Director responsibilities in assessing and reporting events).
Section revised: 3/13/13
PDs are referred to the STANFORD recruitment policies and procedures set forth in Chapter 10.2.
The PD must provide all necessary information on the protocol application to allow meaningful review by the IRB of the recruitment process. See Chapter 10.1.
VA Research: See VHA Handbook 1200.05 for Telephone Contacts with Subjects.
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. (45 CFR 46.111(a)(3); 21 CFR 56.111(a)(3))
Employees and Stanford University students
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 must provide a rationale for involvement of employees or students of Stanford University. When students are involved, the PD must explain:
· How they will be protected from coercion and undue influence, and
· What alternatives to participation exist.
Additionally, PDs are directed to the Research Policy Handbook RPH 5.5 Use of Employees or Laboratory Personnel as Research Subjects for policy on the use of employees or laboratory personnel as research participants.
Including Children as Participants
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 participants may not be of such an amount as to result in coercion or undue influence on the participant’s decision to participate.
Additional requirements might apply, depending on the source of support/funding (e.g., Department of Defense, Department of the Navy, Department of Justice): see Other Federal Agencies - Additional Requirements [GUI-42].
Payments may not be provided to participants on a schedule that results in coercion or undue influence on the participant’s decision to continue participation. For example, payment may not be withheld as a condition of the participant completing the research. If the participant withdraws early, payment must be prorated to reflect the time and inconvenience of the participant’s participation up to that point.
See Payment – Ethical Considerations [GUI-39].
Section revised: 3/13/13
Protocol Directors (PDs) are required to indicate in the Protocol Application whether they will have access to adequate resources to carry out the research. Resources, including space, personnel, services and equipment required for conducting the proposed research properly and safely, must remain available as needed throughout the research. The PD must provide information about the qualifications and number of study staff, personnel training, available facilities, and the time available to conduct and complete the research, and must demonstrate sufficient access to a population allowing recruitment of the required number of participants.
PDs should continually monitor the resources allocated for their research and notify the IRB if any change in the availability of resources may adversely impact the rights and welfare of participants.
In addition to IRB approval of the protocol, human participant research (including recruitment and enrollment) which is sponsored cannot begin until a contract has been finalized, or a grant award activated. See Research Policy Handbook RPH 13.1 Definition of Sponsored Projects and Distinctions from Other Forms of Funding.
For research that does not otherwise undergo scientific review, the Division Chief, Department Chair, School Dean or their designee must provide review of the scientific and scholarly validity of the proposed research. A Review of Scientific and Scholarly Validity must be completed and submitted to the IRB, as a condition of protocol approval. This requirement does not apply to minimal risk retrospective chart reviews.
Student projects (with student PDs) and department or gift funded research involving human participants (including recruitment and enrollment) cannot begin until the appropriate Division Chief or Chair of the PD’s department in the School of Medicine, or the Dean or designee of other schools, has confirmed there are adequate resources to complete the study. If a study has an academic sponsor, that sponsor is responsible for research oversight and must complete and submit an Academic Sponsor – Review of Scientific and Scholarly Validity and Oversight to the IRB, as a condition of protocol approval.
Section revised: 3/13/13
Also see Chapter 12 on informed consent and assent.
Informed Consent is a Continuing Process
Informed consent is a continuing process whereby the investigator and research participant have an on-going dialogue about all aspects of a research study that might inform a participant’s decision to take part in the study, and their decision to continue their involvement as a participant. Although consent is given it may be withdrawn at any point. The informed consent process should be regarded as continuing throughout the duration of the research. The purpose of the consent process is to assure knowledgeable decision-making and voluntary participation.
This process generally includes:
· Bringing the research study to the notice of potential participants.
· Presentation and explanation by the investigator or delegate of the study and study activities to the participant or their legally authorized representative (LAR).
· Documentation of informed consent via a signed and dated written consent document.
· Ongoing discussions between the investigator and the participant regarding continued participation in the study.
The PD is expected to be familiar with:
· The informed consent policies in Chapter 12 , including the criteria for a legally effective informed consent process, and any additional federal, state (California), VA-specific (per VHA Handbook 1200.05), and institutional requirements.
· Additional requirements might apply depending on the source of support/funding (e.g., Department of Defense, Department of the Navy, Department of Justice): see Other Federal Agencies - Additional Requirements [GUI-42].
· The consent process information and consent form templates provided on the Human Subjects Research website Informed Consent - Medical and Informed Consent - Nonmedical pages. The Informed Consent Checklist, used by IRB reviewers, is also available, and might provide additional insight to investigators on particular items that should be included.
The basic and possible additional consent requirements, and those specific to certain types of research activity (such as genetic testing, data and tissue repositories, and xenotransplantation), are addressed in Chapter 12.1.
Consent requirements for research involving vulnerable and other special populations - including consent from a legally authorized representative (LAR) – are described in Chapter 12.2. This addresses adults with impaired decision-making capacity, prisoners, children, pregnant women, fetuses and neonates, and Stanford employees and students.
The Consent Document
The Human Subjects Website provides consent form templates, including VA specific templates, which address the required elements of informed consent, as well as providing language for other situations, (such as MRI, tissue banking), in which certain additional information may need to be disclosed to participants. For research involving children, an Assent Template is also provided.
To assist PDs in preparing consent documents comprehensible to lay persons (i.e., at approximately 8th grade level) a glossary of lay terms is also available on the website.
The IRB encourages and recommends the use of a full consent form, translated into the participant’s language whenever possible. In certain situations, the use of a ‘short form consent process’ may be permitted by the IRB, incorporating the use of a short form consent document translated into the participant’s language. Templates of short form consent documents translated in a variety of languages and incorporating the basic required elements of informed consent are provided on the Human Subjects Website.
In the event that the PD proposes to use a consent document based on one already 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.
See Chapter 12.1 for detailed information on consent documents, the long form, and the use of the short form consent process.
Providing Consent Process Information to the IRB
In the Protocol Application, the PD must:
· Describe the consent process in enough detail to allow for meaningful review by the IRB,
· Include the proposed written informed consent document(s) that address(es) each of the elements of informed consent in the context of the research (unless the IRB waives the documentation requirement – see below), and
· Include any written material to be given to prospective participants to explain the nature of the research.
The PD is responsible for making all revisions to the proposed consent document as requested by the IRB. Any other change to the consent document must be submitted to the IRB for prior review and approval.
Requesting Waivers or Alteration of Consent Requirements
Under specific circumstances, the PD may request that the IRB grant a:
· Waiver or alteration of the consent process – i.e., the requirements for obtaining informed consent, or
· Waiver of documentation – i.e., the requirement to obtain a signature on a written consent document.
The requirements for these two options differ. Refer to Chapter 12.5 for explanation.
Obtaining Informed Consent
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.
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.
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 and in accordance with regulatory and IRB requirements.
The PD must use the consent document currently approved by the IRB. The IRB approval date must appear on (at least) the signature page of the consent document.
No participants should be involved in research prior to the IRB approval date, and no participants should be involved in research using a consent document whose approval period has expired.
The PD or their delegate 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 or their delegate:
· 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 as if they present a known advantage,
· May not understate the risks of the research, as there may be no countervailing benefits to participants.
The PD or their delegate is responsible for giving the participant a copy of the signed informed consent document, and for maintaining the original form.
Obtaining Informed Consent in the Clinical Research Context - Special Considerations
The distinction between treatment and research is especially important if the PD is also the potential participant’s attending physician, a situation that increases the risk of confusion. Thus, it must be clearly stated to the participant that they will be involved in research and that if randomization is involved, that this is also described.
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.
Research involving randomization of participants, whether to proven or experimental procedures, 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 as clinical care.
Consent Situations Requiring Prompt Reporting to the IRB
Situations where informed consent is not properly obtained or not documented, and no corresponding waiver or alteration of the consent process has been granted by the IRB, may constitute noncompliance. Such circumstances may require reporting to the IRB. These include, but are not limited to:
· Involving an individual in research without first obtaining their informed consent and a signed informed consent document (unless the IRB has explicitly waived these requirements).
· Involving an individual in research using a consent form other than the current IRB-approved form.
· Situations where the PD believes informed consent documents have been lost, misplaced, or destroyed.
· Chapter 15.2 for information on reporting to the IRB
Researchers and Research Staff have a process to address participants’ concerns, complaints, or requests for information.
Section revised: 3/13/13
Requests for information
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 consent form must list the full name and contact information for the PD, and other research study staff as appropriate. The consent form must also inform participants how to reach the IRB if they have any questions about their rights as research subjects (see Stanford University consent form template for contact information language)
The PD is expected to investigate and respond promptly to complaints, and to follow the proper procedure for addressing and reporting complaints to the IRB. A complaint is a formal or informal, written or oral, expression of dissatisfaction by the participant or the participant’s representative. Complaints that are not resolved promptly by the PD or member of the research staff must be reported to the IRB as follows:
· Complete and submit a Report Form to the IRB
· Include with the Report Form a brief description of the complaint and the circumstances in which the complaint was made and any action taken to date in addressing the complaint. Complaints are handled in accordance with the policies described in Chapters 3.9 and 3.10.
If the complaint is not directly related to the conduct or design of the research, the IRB staff may refer the complaint to the appropriate STANFORD institutional official or committee (e.g., as provided for in the applicable University or hospital policy on the handling of 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.
On Continuing Review, investigators are required to list all complaints received about the research in the past year, whether or not they were previously reported to the IRB.
If the complaint involves STANFORD privacy practices, all documentation relating to the complaint must be retained for at least six years from the date of creation.
If such a complaint cannot be handled promptly, the appropriate STANFORD Privacy Officer should be notified.