Research

Brown University Policies and Procedures for the Protection of Human Participants in Research

Introduction

Brown University is dedicated to the protection of the rights and welfare of human participants engaged in its research endeavors. To that end, the University has entered into an agreement [called a Multiple Project Assurance (MPA)] with the federal government, approved by the Office for Human Research Protections (OHRP) outlining the ethical principles to which the University is committed. It reads:

 

"This institution is guided by the ethical principles regarding all research involving humans as subjects, as set forth in the report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (entitled: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (the "Belmont Report")), regardless of whether the research is subject to Federal regulation or with whom conducted or source of support (i.e., sponsorship).

All institutional and non-institutional performance sites for this institution, domestic or foreign, will be obligated by this institution to conform to ethical principles which are at least equivalent to those of this institution, as cited in the previous paragraph or as may be determined by the DHHS Secretary."

In addition, the MPA stipulates that Brown will protect human research participants through a review process detailed in the Code of Federal Regulations 45 CFR 46. Through the MPA, the Institutional Review Board (IRB) is the sole authority at Brown for the approval of research with human participants. IRB review applies to research conducted by faculty, students, or staff, either on the Brown premises or utilizing the facilities or resources of Brown, as well as research conducted elsewhere by Brown personnel in connection with their institutional responsibilities. The review requirements apply to all research conducted under the auspices of Brown, regardless of funding source or University support.

 

Responsibilities of the IRB

In order to maintain a review process that is responsive to the concerns of all involved, the federal regulations require that the IRB membership reflect experience, expertise and diversity in academic, research and professional background, racial and cultural heritage, and a sensitivity to community attitudes. When the IRB reviews research involving a vulnerable category of participants, such as cognitively impaired individuals or prisoners, it is required to include one or more individuals qualified to represent that group, either through personal experience or experience working with that population.

 

The IRB is responsible for:

  • ensuring that all approved research complies with the letter and spirit of the human research participant protections regulations as well as the three principles defined in the Belmont Report, respect for persons, beneficence, and justice; and
  • examining recruitment procedures, proposed remuneration (in cash or in kind), the informed consent process, and evaluating the risks and potential benefits to participants outlined in each protocol. The review will help ensure that participants are recruited in an equitable, non-coercive manner, that participants are fully informed about the risks and benefits entailed in participation, and that participants are not exposed to disproportionate risks.

 

The review of a protocol to involve human participants in research is a process between the investigator and the IRB. This process begins with the submission of the protocol to the IRB and the IRB's determination of the appropriate category of review. The IRB has the authority to approve, to require modification in, or to disapprove proposed research involving human participants. In addition, the IRB also has the authority to suspend or revoke its approval of ongoing research (45 CFR 46.113). Failure to comply with IRB requirements is considered serious misconduct and may be subject to sanctions including possible termination of approved research.

 

IRB Considerations When Conducting an Initial Review

The IRB will consider the following issues when reviewing requests to involve human participants in research.

 

  1. Study Design: The IRB will examine the study design insofar as it has an impact on the rights and welfare of the human participants. At its discretion, it may request an expert consultant review in order to determine whether a study design places participants at unnecessary risk.

    The federal regulations allow the IRB to approve a study design that involves deception or withholding of information if the strategies are justified and the protocol provides for a post-study debriefing of the participants. The IRB may grant a waiver of the debriefing requirement if the debriefing may prove harmful to the participants.

  2. Risks and Benefits: The IRB will assess whether the risks to the research participants are reasonable in relation to the anticipated benefits, if any, to the research participants, and the importance of the knowledge reasonably expected to result from the research. The IRB will consider only those risks and benefits that may result from the research. The federal regulations do not allow the IRB to evaluate the possible long-range effect of applying the knowledge gained through the research (45 CFR 46.111).

    The IRB is required to review any possible benefits a research participant may derive from participation in research, and/or the benefits of new knowledge that may justify asking a person to undertake the risks of the study. Payment for participation in research is not considered a benefit.
  3. Equitable selection of research participants: The selection of research participants should be equitable and free of coercion. The IRB will consider the purpose of the research and the setting of the research. The IRB will closely examine research involving vulnerable subject populations, such as children, the elderly, pregnant women, prisoners, participants with cognitive disorders, or economically or educationally disadvantaged participants. Investigators should indicate in their submission how they will avoid the appearance of coercion in the recruitment of research participants. They should also detail any extra precautions taken to safeguard the rights and welfare of subject populations.
  4. Identification of Research Participants and Confidentiality: The IRB is required to review the method for prospective identification of research participants. They will examine the means of identifying and contacting potential research participants and the methods for ensuring the research participants' privacy and confidentiality. Investigators are required to submit plans for ensuring the confidentiality of research participants.
  5. The Informed Consent Process: The IRB will carefully review the informed consent process: when, where, and how consent is obtained and any provisions for the ongoing consent of research participants.
  6. Qualifications: The IRB will examine the qualifications of all investigators (faculty, students or staff). Procedures requiring special skills on the part of the investigators, licensure, accreditation, and/or experience in qualifying the investigator for the performance of the proposed procedures are reviewed by the IRB. In addition, the IRB will consider the facilities and equipment used to conduct the research and maintain the rights and welfare of the research participants.
  7. Additional Review: The IRB will determine, based on the evaluation of risks involved in the study and study population, whether a project requires more than annual review and may require an appropriate monitoring procedure that could include monitoring of the consent process, observation of the research procedures, and review of research related records. In some instances, the IRB may refer review of the research to an additional committee, such as a Data Safety Monitoring Board (DSMB) for projects that are clinical trials or research with cognitively impaired research participants, or an Independent Safety Monitoring Board (ISMB) assigned by the IRB to monitor individual projects.


Continuing Review

Once a project has been reviewed and approved by the IRB, a periodic review of the research must be conducted. Initial protocol approval may be granted for up to twelve months. The IRB will make the determination of annual review or more frequent review based on the degree of risk associated with the study and an evaluation of the study population and study procedures. At least 2 months prior to the expiration of IRB approval, the Investigator should receive a reminder memo from the Office of Research Administration. This memo will remind the investigator that protocol approval will lapse soon. If the project is ongoing, the investigator must submit a continuing progress report for review and approval prior to the anniversary of the prior approval. (A copy of the appropriate form to complete will be attached to the reminder memo.) Studies that do not have continued approval certified within 12 months must be suspended from engaging in any ongoing research activity.

 

The progress report serves to inform the IRB of the progress of the project. IRB review and approval of the progress report extends the approval of the project for another period of time, up to 12 months (to be determined by the IRB). As part of the progress report the investigator is required to incorporate the original protocol and modifications to the study during the previous twelve months (or less as determined by the IRB).

 

Should IRB approval lapse and the study is still ongoing, the study would no longer be eligible for the continuing review process and a new protocol must be submitted. Recruitment of participants and all other study procedures must cease until IRB approval is once again in place.

 

The IRB will provide a determination, in writing, to the Investigator regarding the review of the continuing progress report - outlining any requested additions/changes (if necessary) or indicating that approval has been granted and stating the period of approval.

 

Protocol Modifications

When any revision to an approved research protocol, written consent form and/or advertisement for participant recruitment is desired, the investigator must submit in writing to the IRB a modification request. The modification request must include a description of the original study in enough detail to allow the IRB to evaluate the requested change(s) and should explain the changes and the rationale for those changes. A revised copy of the pertinent documents (e.g., consent form and/or advertisement) must also be submitted with the changes italicized or underlined. A cover letter signed by Principal Investigator and additional information should be attached.

 

Modifications to approved protocols may not be initiated until IRB approval has been obtained, except where necessary to eliminate apparent immediate hazards to the participant.

 

The review of full board modifications will be completed at a scheduled meeting. Therefore, the regular submission deadlines must be met. At the discretion of the IRB, amendments that reflect simple/minor administrative changes, fit within the expedited categories, or those which do not increase the risk to the participant may be reviewed by an expedited process.

 

Notification of approval of a modification is handled with the same procedure as approval of original protocols.

 

A letter sent to the investigator and recorded in the IRB files may acknowledge non-substantive (administrative) changes to approved protocols. A modification to a protocol title is an example of a non-substantive changes.

 

Additional Responsibilities of the IRB for Vulnerable Populations

 

Women

Historically, in order to avert harm to a developing fetus in an unsuspected pregnancy, physicians and the lay community have expressed concerns regarding the participation of women of childbearing potential in research. As a result, federal agencies developed special guidelines ostensibly for the protection of the developing fetus that excluded women of childbearing potential from participation in some research. In 1977, for example, the FDA published a guideline that excluded most women of childbearing potential from early phases of drug trials. An exception was made for studies involving women with serious and life-threatening diseases.

 

Over the past decade, questions raised by grass roots, professional, consumer, and governmental groups regarding the adequacy and fairness in the distribution of the benefits and risks of research resulted in changes to the regulations for the involvement of women in research. At the same time improved pregnancy tests and methods of contraception became widely available. In 1988, the FDA issued guidelines that called for safety and efficacy profiles for women, elderly, and diverse racial groups as part of new drug applications (NDAs). Then in 1993, following broad public discussion about participation of women in clinical trials, the FDA issued a new guideline that eliminated restrictions on women of child-bearing potential participating in all phases of drug trials. The guideline detailed procedures for minimizing the risks of pregnancy in women participants, such as contraceptive counseling, pregnancy tests, timing of short-term studies in relation to the menstrual cycle, and the process of informed consent. Though the FDA emphasized the importance of risk/benefit determinations for participants entering various phases of clinical trials, they underscored that initial determinations regarding whether risks to a fetus were adequately addressed were best left to patients, physicians, local IRB's, and study sponsors. The new guideline also called for gender analysis with special attention to factors affecting the role of the menstrual cycle and exogenous hormone therapy in relation to the drug, as well as the influence of the drug on oral contraceptives.

 

The DHHS has also carefully examined the issue of participation of women in research. It is imperative to determine if an intervention or therapy being studied affects men and women differently. As stated in its new guideline, NIH Outreach Notebook of the Inclusion of Women and Minorities in Biomedical and Behavioral Research (1994), the NIH has concluded that the inclusion of women in research is sufficiently important that the only justifiable reason to exclude non-pregnant women of child-bearing potential from research is compelling evidence that the proposed project would be inappropriate with respect to the health of the participant or the purpose of the research.

 

The policy statement referenced above pertains primarily to the inclusion of women as research participants in clinical trials, i.e., medical research testing new treatments. However, the inclusion of women in behavioral research is also important and should be accomplished unless there is a compelling rationale that establishes that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research.

 

Significant portions of the text below are presented verbatim as published in the Code of Federal Regulations and the Federal Register.

 

Pregnant Women as Human Research Participants

Drug research using pregnant women as research participants is governed by the federal regulations (CFR 46, Subpart B).

 

In accordance with [45 CFR 46.207 (a)], "No pregnant woman may be involved as a subject in a human clinical research project unless: (1) the purpose of the activity is to meet the health needs of the mother and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus is minimal."

 

Research involving pregnant women is permitted only if the mother and father are legally competent and both have given their consent after having been fully informed regarding the possible impact on the fetus, except that the father's consent need not be secured if (1) the purpose of the activity is to meet the health needs of the mother; (2) his identity or whereabouts cannot reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted from rape [45 CFR 46.207(b)].

 

Women of Childbearing Potential as Human Research Participants

Non-pregnant women should not be excluded from any phase of research unless the science of the project or the health of the subject will be compromised. Regarding clinical drug research, Phase I, II and III trials should have the proportion of women in the study which at least reflects the proportion of women in the population which will receive the drug when it is marketed, and should enroll numbers adequate to detect clinically significant sex differences in drug metabolism and response.

 

Risk to Fertility

It is expected that both male and female research participants will be informed about potential risks to their fertility including the development of any abnormalities or abnormalities in function of reproductive organs as a consequence of the proposed study intervention.

 

"Where abnormalities of reproductive organs or their function (spermatogenesis or ovulation) have been observed in experimental animals as a consequence of the proposed study intervention, the decision to include patients of reproductive age in a clinical study should be based on a careful risk/benefit evaluation, taking into account the nature of the abnormalities, the dosage needed to induce them, the consistency of findings in different species, the severity of the illness being treated, the potential importance of the drug, the availability of alternative treatment and the duration of therapy.

 

"Where [subjects] of reproductive potential are included in studies of drugs showing reproductive toxicity in animals, the clinical studies should include appropriate monitoring and/or laboratory studies to allow detection of these effects. Long-term follow-up will usually be needed to evaluate the effects of such drugs in humans." (Federal Register, Vol. 58, No. 139, p 39411, H, Thursday, July 22, 1993)

 

Risk to Fetus and/or Infant

  1. General Guidelines: "Appropriate precautions should be taken in research studies to guard against inadvertent exposure of fetuses to potentially toxic agents and to inform subjects and patients of potential risk and the need for precautions. In all cases, the informed consent document and investigator's [drug information] brochure should include all available information regarding the potential risk of fetal toxicity. If animal reproductive toxicity studies are complete, the results should be presented, with some explanation of their significance in humans. If these studies have not been completed, other pertinent information should be provided, such as general assessment of fetal toxicity in drugs with related structures or pharmacological effects. If no relevant information is available, the informed consent should explicitly note the potential for fetal risk.

    "In general, it is expected that reproductive toxicity studies will be completed before there is large-scale exposure of women of child-bearing potential, i.e., usually by the end of Phase II and before any expanded access program is implemented." (Federal Register, Vol. 58, No. 139, p 39411, G, Thursday, July 22, 1993.)
  2. Minimizing the Possibility of Fetal Exposure: "Pregnancy testing may be used to detect unsuspected pregnancy prior to initiation of study treatment. Timing of the start of the study to coincide with or immediately follow the onset of menses is also an adequate indication that the subject is not pregnant. The investigator should ascertain that the subjects will responsibly employ a reliable method of contraception or abstinence for the duration of the drug or treatment exposure, which may exceed the length of the study. If requested, the investigator should be able to refer the subject to a knowledgeable counselor or physician for contraceptive advice."
  3. Inclusion of Women in Early Clinical Trials (Phase I and Early Phase II): "In some cases, there may be a basis for requiring [inclusion] of women in early studies. When the disease under study is serious and affects women, and especially when a promising drug for the disease is being developed and made available rapidly under FDA's accelerated approval or real access procedures, a case can be made for requiring that women [be allowed to] participate in clinical studies at an early stage. When such a drug becomes available under expanded access mechanism (for example, treatment IND or parallel track) or is marketed rapidly under Subpart E procedures because an effect of survival or irreversible morbidity has been shown in the earliest controlled trials), it is medically important that a representative sample of the entire population likely to receive the drug has been studied, including representatives of both genders. Under these circumstances, clinical protocols should not place unwarranted restrictions of participation of women." (Federal Register, Vol. 58, No. 139, p 39409, G, Thursday, July 22, 1993)
  4. Risk to Infant of Nursing Mother: The potential for harm from exposure to a drug with unknown risks exists for nursing infants as well as fetuses. Therefore, this policy applies to breastfeeding female subjects who are potential research participants in a drug trial in the same manner in which it applies to gestating women.

 

Sample Informed Consent Statement to be Included for a Potentially Toxic Drug Study

The following language is recommended when women of childbearing potential (non-pregnant) will be enrolled into a potentially toxic drug study:

 

"If you are a woman who is able to become pregnant, it is expected that you will use a medically accepted method of birth control [outline the recommended forms of birth control] to prevent exposing a fetus to a potentially dangerous agent with unknown risk. If you are pregnant or currently breast feeding, you may not participate in this drug study. If you are pregnant, if you become pregnant, or if you are breast-feeding during this study, you or your child may be exposed to an unknown risk. There are also known risks to you or your unborn baby, including (state specific risks).

 

"To confirm to the extent medically possible that you are not pregnant, you are required to agree [to have a pregnancy test done before beginning this research study] [to begin the study after the onset of your next menstrual period] [choose one]. You must agree to avoid sexual intercourse or use a birth control method judged to be effective by the investigator and which will not interfere with the proposed investigation. Pregnancy could still result despite the responsible use of a reliable method of birth control while participating in this research study. You agree to notify the investigator as soon as possible of any failure of your birth control method, or if you become pregnant, either of which may result in your being withdrawn from the study." Prior to enrollment, investigators are required to discuss with subjects what will happen if pregnancy occurs.

 

Minorities

In addition to requiring the equitable selection of women as research participants, federal regulations require the equitable selection of minorities as research subjects [45 CFR 46.111.(a)(3)]. The inclusion of minorities in research is important both to ensure that they receive an equal share of the benefits of research and to ensure that they do not bear a disproportionate burden.

 

Most diseases affect all population groups. In order to contribute to the pool of generalizable knowledge, investigators are required to include the widest possible range of population groups in their research. However, sometimes minorities are subject to a different risk. For example, some research pertains to conditions such as sickle cell anemia or Tay Sachs disease that specifically affect only a few minority groups. Other research focuses on characteristics of diseases or effectiveness of therapies in particular populations (e.g., HIV transmission, treatment for hypertension), and may also concern conditions or disorders that disproportionately affect a certain racial or ethnic group. Exclusion or inappropriate representation of these groups, by design or inadvertence, would be unjust. Further, to the extent that participation in research offers direct benefits to the subjects (in HIV research, for example, the receipt of a promising new drug), under-representation of minorities denies them, in a systematic fashion, the opportunity for direct benefit. A glaring example of this type of research abuse of minority populations' bearing the burden of research can be found in the Tuskegee Syphilis study, in which a group of African-American men suffering from syphilis were left untreated, despite the availability of penicillin, in order to study the natural course of the disease.

 

Due to these concerns, the federal regulations require that research design include diverse populations. Investigators submitting protocols for IRB review that do not call for heterogeneous study populations are required to justify, in writing, in their submissions, why a homogeneous study population has been chosen.

 

After a heterogeneous population has been chosen, investigators should pay careful attention to the following two issues:

 

  1. Special vulnerabilities: The DHHS recognizes that certain subject populations may require additional protections because they are economically or educationally disadvantaged. The IRB will attempt to safeguard every participant's rights and welfare by making sure that any possible coercion or undue influence is eliminated (e.g., compensation that is not commensurate with risk, discomfort, or inconvenience involved, or recruiting in institutional settings where voluntary participation might be compromised). Investigators should address these issues specifically when submitting protocol information to the IRB for review.
  2. Consent Form Presentation: Effort should always be made to ensure that the consent process and the relationship between the investigator and prospective research participant are safeguarded. The federal regulations require the translation of consent documents into the language that is most easily understood by research subjects; the possibility of illiteracy should be accounted for, as should the need for communicating in non-English languages. The FDA indicated in October 1995, that non-English speaking subjects must have informed consent form information presented in a written language that they understand. (21 CFR 50.20 -27 and FDA Information Sheets, October 1, 1995, p 49) A potential participant's inability to read or to read English is not an appropriate basis for exclusion from most research.

    The IRB approved informed consent documents should be available in English and other languages as appropriate to the subject population(s). For investigators proposing to use non-English language consent documents, quality assurance procedures should be developed such as translation of the consent document from English to the second language and then back to English, to ensure that the information is correctly conveyed. The IRB is required to review all non-English consent forms and recruitment tools. The role of cultural norms of subjects should also be addressed. This information should be provided in a clearly identifiable form to the IRB for review.

 

Children

The legal mandate of the IRB is to protect the rights and welfare of human research participants. This task becomes more difficult when considering children and minors as study participants. The federal regulations provide for "Additional Protections for Children Involved as Subjects of Research" (45 CFR 46 Subpart D).

 

Parental Permission and Research of Minimal Risk

Parental permission is required in most circumstances for the participation of children in research. Investigators are required to gain parental permission from at least one of the child's parents or guardians if the research involves only minimal risk.

 

Parental Permission and Research of More than Minimal Risk

  • If the research poses more than minimal risk and no direct benefit to the child, the investigator is required to gain permission from both parents or the child's guardian in order for the child to participate in the research.
  • If the research poses more than minimal risk but may directly benefit the child, only one of the child's parents or guardian need give permission.
  • The investigator is not required to gain permission form both parents, if one of the parents is not reasonably available, deceased, unknown, legally incompetent, or from a parent who does not have legal responsibility for the care and custody of the child. This caveat does not exempt the investigator from obtaining the permission from at least one parent who has legal responsibility for the child.

 

The IRB is required to make additional considerations for the inclusion of children in research who are wards of the state or any other agency or institution. For research that involves more than minimal risk with no prospect of direct benefit to the individual participant or for research that requires approval of the DHHS Secretary, the study must either be 1) related to the research participant's status as a ward, or 2) be conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as participants are not wards (45 CFR 46.406-409). The IRB is required to appoint an advocate for each child who is a ward. The advocate is required to have the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child's participation in the research and who is not associated in any way with the research, the investigator, or the guardian organization. The requirement for an advocate is in addition to gaining permission from any other person acting on behalf of the child as guardian or in loco parentis.

 

Subpart D of 45 CFR Part 46 requires the IRB to classify research involving children into one of the four following categories relating to the risks and benefits of the proposed research:

 

  1. research involving no greater than minimal risk;
  2. research involving greater than minimal risk, but presenting the prospect of direct benefit to individual participants. Research in this category is approvable by the IRB, provided: (a) the risk is justified by the anticipated benefit to the subjects; (b) the relationship of risk to benefit is at least as favorable as any alternative approach; and (c) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians;
  3. research involving greater than minimal risk and no prospect of direct benefit to individual participants, but likely to yield important generalizable knowledge about the participant's disorder or condition. Research in this category is approvable, by the IRB, provided: (a) the risk represents a minor increase over minimal risk; (b) the intervention or procedure presents experiences to participants that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (c) the intervention or procedure is likely to yield generalizable knowledge about the participants' disorder or condition which is of vital importance for the understanding or amelioration of the participants' disorder or condition; and (d) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians; and
  4. research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. This section provides a mechanism for the approval of research not falling under one of the three previous categories. The research must be approved by the Secretary of the Department of Health and Human Services (DHHS) if it is to be funded by the DHHS, after consultation with a panel of experts, and the panel must find that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a significant problem affecting the health and welfare of children.

 

When assessing risk to children and evaluating a research project proposing to involve children the IRB will consider the following issues:

 

  • Is the participation of children as research participants justified in this particular instance?
  • If this research question can be addressed initially in adults, has this work been conducted?
  • Have results from any adult research indicated that the proposed research would benefit, or at least would not be harmful to children?
  • Has every effort been made to ensure that a parent is present when the research intervention is conducted? This will not only comfort the child but will enable the parent to exercise the right to end the child's participation in the research project at any time. Investigators should note that in some cases (e.g. research into sensitive personal matters, physical examinations of adolescents, research into abuse, etc.) it may not be appropriate to have a parent present. If a parent will not be present during the course of the project, has the investigator clearly stated why in the protocol?
  • Are the personnel involved in the research, and the facility in which the research will be conducted, knowledgeable about and sensitive to the physical and psychological needs of the children and their families?
  • Have the investigators taken into account the child-participant's previous experience with illness and medical interventions? Some children may be able to cope with stresses of research better than others as a result of previous experiences with medicine. Younger, "less experienced" children may be unprepared for participation in a research study.
  • How the investigator determined the number of children to be enrolled for the study. Investigators should justify the number of subjects they propose to study. Biomedical Investigators should always plan to involve the fewest number of children necessary to obtain statistically significant data from which valid conclusions can be drawn.
  • Whether the proposed techniques are the least invasive (physically and psychologically) in order to obtain the information for the study.
  • Have the investigators clearly defined how the assent of the child-participants will be obtained?
  • For research involving medical interventions the IRB will consider previous research with animals. The investigator should indicate whether the animal research is completed and the results to date.

 

All personnel working with children must be familiar with State laws requiring reports of suspected child abuse or neglect.

 

The IRB cannot approve research that exposes children as research participants to more than minimal risk and does not satisfy the conditions outlined above. The federal regulations, however, provide a process for seeking approval for such research from the DHHS Secretary. Please contact RPO for more information about this process.

 

Terminally Ill Patients

Patients with a terminal illness may be willing to "try anything" that might offer hope of either a cure or a slowing of the disease process. Others, aware that nothing further can be done to cure their disease, might fear abandonment by the medical establishment and agree to participate in research as a means of maintaining contact with physicians expert in treating their condition. On the other hand, many terminally ill individuals are willing to submit to considerable discomfort and risk for the possible benefit of future patients suffering from the same condition, and will volunteer for Phase 1 clinical trials or basic research about their particular condition in hopes of helping other, similarly situated patients in the future.

 

Investigators should be sensitive to these matters and explain with care and clarity the likelihood (or lack thereof) that research participants will experience any personal medical benefit from their participation in a particular study. This is especially important in Phase 1 drug studies, since the research is designed to evaluate a potential treatment for their illness and as a result, may obscure the fact that the dosage research participants will be given is not expected to produce a therapeutic result.

 

At the same time, it is important not to treat terminally ill patients as incompetent or incapable of autonomous decision-making, just because they are critically ill.

 

Students

Medical students traditionally have served as subjects for biomedical research and psychology students have often participated as subjects in behavioral research. The obvious concern is that their participation may not be truly voluntary, because of a desire to appear particularly cooperative or highly motivated, or because participation in research is a course requirement.

Various procedures have been suggested to reduce the possibility of unintended coercion, while still permitting students to participate as subjects in research. These include:

 

  • posting IRB approved advertisements throughout the university to recruit subjects from a broad base of students;
  • avoiding any personal solicitations of students by faculty, graduate assistants, or fellow students;
  • providing a number of research projects from which to choose, if participating as a subject in research can be used as a course requirement; and
  • providing alternative and equal methods for meeting course credit (or extra credit) requirements, such as attending a series of research presentations by faculty, writing a brief paper, conducting one's own research.

 

Employees

University employees, such as office staff, lab technicians, and post-doctoral fellows, are similar to students in that they are vulnerable to perceived, even if not intended, pressures so as to appear cooperative and supportive of their supervisor's work. Accordingly, many of the same procedures (described above) to reduce the likelihood of coercion in recruiting student volunteers apply equally to university employees. It is IRB policy not to approve recruitment procedures that include employees from the investigator's own lab or office. The IRB, however, will reconsider policy on a case-by-case basis.

Prisoners

Prisoners are considered vulnerable because they are in a restrictive, institutional environment that affords little opportunity for making choices, earning money, communicating with outsiders, or obtaining medical care. The National Commission for the Protection of Human Subjects found that prisoners often volunteer for medical research as a means of access to a competent medical examination, because health care may be inadequate in some prisons.

 

Because their autonomy is limited, prisoners may participate only in certain categories of research, and special precautions are needed to assure that their consent to participate in the research is both knowing and voluntary (45 CFR 46.302).

 

Categories of Research in Which Prisoners May Participate

Prisoners may participate in the following permissible categories of research:

  • studies of the possible causes, effects, and process of incarceration and criminal behavior, if those studies present no more than minimal risk or inconvenience to the subjects;
  • studies of prisons as institutions, or of prisoners as incarcerated persons, if those studies present no more than minimal risk or inconvenience to the subjects;
  • research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that the study may proceed only after the Secretary has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of his intent to approve such research; or
  • research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the intent to approve such research.

 

Note: DHHS biomedical or behavioral research protocols involving the use of prisoners MUST fall into one of the above categories.

 

Additional Responsibilities/duties of the IRB

Prior to reviewing any protocol involving the use of prisoners as participants, the IRB must have at least one member who is a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity. Once the membership is established, the IRB is then required to first confirm that the proposed study fits within one of the permissible categories of research described above. Once the permissible category is established the IRB will determine whether:

 

  • any advantages that prisoners may realize as a result of participating in the research, when compared to the general living conditions within the prison, are not so great as to impair prisoners' ability to weigh the risks and benefits of participation and freely choose whether or not to participate;
  • the risks involved in the research are commensurate with risks that would be accepted by non-prisoner volunteers;
  • procedures for selecting subjects within the prison are fair, and free from arbitrary manipulation by prison authorities or prisoners;
  • control subjects will be selected randomly from among the group of eligible volunteers, unless the principal investigator justifies a different procedure;
  • the information presented during recruitment and consent procedures is in a language, and level of complexity, understandable to the subject population;
  • the IRB is assured that the parole board will not take research participation into account in making decisions about parole, and each prisoner is informed in advance that participation will have no effect on the possibility of parole; and
  • if medical follow-up is necessary to protect the health and welfare of the subjects, adequate provision is made for such care, taking into account the varying length of prisoners' sentences, and for informing participants of this fact.

 

The institution is required to certify to the Secretary, in such form and manner as the Secretary may require, that the duties of the IRB have been fulfilled.

 

For research conducted or supported by DHHS involving prisoners, two actions must occur: (1) the institution must certify to the Secretary (via OHRP) that it has reviewed and approved the research in accordance with the above and (2) the Secretary (OHRP) must determine that the proposed research falls within one of the categories of permissible research identified above.

 

For each protocol involving prisoners, the investigator will complete a form (see appended document "Checklist Form for Research Involving the Use of Prisoners as Study Participants) identifying the permissible category of research. The minutes of the convened IRB meeting will specifically address the discussion determining the appropriate category selected by the IRB members and the accomplishment of the additional responsibilities/duties as outlined above.

 

Responsibilities of the Investigator

In order for any investigator to begin their research involving humans as participants, the investigator will:

 

  • acknowledge and accept their responsibility for protecting the rights and welfare of human research participants and for complying with all applicable provisions of Brown University's MPA with the federal government. This is accomplished by signing the certification on IRB Form #1;
  • make an initial determination, to be confirmed or changed by the IRB, of the appropriate review category by completing the IRB Form #1;
  • be responsible for ensuring that all personnel have been adequately trained in the conduct of human participant research;
  • ensure that all appropriate key personnel involved in human participant research involving National Institutes of Health funding have successfully completed an educational program;
  • advise the IRB, Office of Research Administration, and the appropriate officials of other institutions of the intent to admit human research participants (e.g., into a hospital) who are involved in research protocols for which Brown's MPA or any related Inter-Institutional Amendment or Non-institutional Investigator Agreement applies. When such admissions are a planned part of DHHS supported research, those institutions must possess an applicable OHRP approved Assurance prior to involvement of such persons as human research participants in those research protocols at those institutions;
  • ensure that only procedures in the IRB approved protocol are conducted (including the consent process are performed and/or supervised by the listed investigator or other authorized personnel);
    notify the IRB in writing if the investigator or other key personnel have changed;
  • provide the IRB with the appropriate information on the research protocol including initial information, notification of subsequent modifications, terminations, and adverse reactions, etc.,
  • provide a copy of the IRB approved informed consent document to each research participant at the time of consent and after signing by the research participant, unless the IRB has specifically waived this requirement. All signed consent documents are to be retained in accordance with the Record Retention section below;
  • promptly submit proposed changes in previously approved human subject research activities to the IRB. The proposed changes will not be initiated without IRB review and approval, except where necessary to eliminate apparent immediate hazards to the participants;
  • report the progress of approved research to the Office of Research Administration, as often as and in the manner prescribed by the approving IRB on the basis of risks to subjects, but not less than once per year;
  • immediately report to the IRB the death of a research participant, regardless of cause;
  • promptly report to the IRB any injuries, adverse events, or other unanticipated problems involving risks to subjects or others;
  • promptly report to the IRB any significant findings that become known in the course of the research that might affect the willingness of a research participant to participate in the study or, once enrolled, to continue to take part;
  • ensure that IRB approval is in place for the use of data collection during the provision of emergency medical care. Otherwise, the investigator will not seek to obtain research credit for, or use data from, patient interventions that constituted the provision of emergency medical care;
  • ensure that no research (including modifications/amendments to already approved protocols) will be initiated (except Emergency Use) until IRB approval is received;
  • ensure the timely completion and submission of the continuing review report; it is the responsibility of the principal investigator to ensure that continuing review is completed and approved by the IRB prior to the protocol expiration date;
  • maintain confidentiality of all records;
  • report in writing to the IRB any severe adverse reaction or injury arising during the conduct of an IRB-approved protocol; and
  • notify the IRB when the study has been completed.

 

The IRB will mail original correspondence only to the investigator. It is the responsibility of the investigator to insure that copies of IRB letters are distributed to appropriate individuals (e.g. grant and contract administrators, department administrators, granting agencies or pharmaceutical sponsors, participants, etc.).

 

Components of a Protocol

In order to submit a complete protocol the following items are required:

 

Completed and signed IRB Form #1

This form is considered to be the cover page of the protocol. Students conducting research MUST indicate their advisor's approval of the protocol by having the advisor sign and date this form. (Note: A student as an investigator on a full board protocol must attend, along with their advisor, the IRB meeting at which their protocol will be reviewed.)

 

Proposal/application
If a proposal/application is submitted for funding either internally or to an external sponsor, the protocol must include a complete copy.

 

Project aims and methodology (what, why, how, and who)

A description of the project, purpose, procedures, participant population (criteria for inclusion/exclusion including the attempts made to include women and members of minority groups), recruitment procedures, and how confidentiality of data will be maintained (where is data kept, who has access to it, and how is it kept secure). The following list provides areas of explanation within this section of the protocol:

 

  • background and prior pertinent experimental findings or animal data, if any. This is especially important in protocols for studies of investigational drugs or investigational devices;
  • purpose or hypothesis of the study, including potential knowledge to be gained;
  • description of protocol methodology;
  • anticipated duration of protocol;
  • location where research is to be conducted;
  • description of experimental controls and use of placebos;
  • type and number of research participants, including method of participant selection, randomization, and inclusion and exclusion criteria, if any;
  • description of the statistical analysis to which the data will be subjected. This allows the IRB to ensure that study will produce statistically valid conclusions to justify the research on human participants;
  • payment to participants: Study participants may be offered a reasonable, but not coercive, payment to participate in the protocol. All projects, that promise to provide payments to participants must include details regarding the payment amount and payment plan, within the protocol and consent form. The reasonableness of the amount offered will depend on the degree of discomfort the participants experience, the invasiveness of the procedure or investigation, the character of the research, the population likely to be attracted by the protocol, the method in which the protocol will be advertised, the amount of time a participant is expected to devote to the protocol, and related considerations. In addition, such protocols and consents should either (1) describe the plan for pro-rated payment to participants if they choose to withdraw voluntarily from the protocol or if, upon the suggestion of a physician or investigator, early withdrawal is necessary or (2) provide justification as to why prorated payment is not being offered to the participants;
  • procedures which will be used to maintain confidentiality of research and participant information;
  • bibliographic references to support the hypothesis and the justification for the use of human participants and in particular the inclusion of any vulnerable populations;
  • a description of recruiting methods (i.e. advertisements, physician referrals). If advertisements are to be used, indicate where they will be placed and who will handle responses to them. Note: In general, finders fees are not permitted by the IRB. A detailed explanation is necessary within the protocol;
  • if applicable, the protocol should clarify whether female participants will be asked to take a pregnancy test before and, as applicable, during the study; and
  • as applicable, provide a rationale for excluding women, minorities and/or children from participation. It is a policy of National Institutes of Health that all research involving human participants includes women, minorities and children. All protocols that explicitly exclude any of these populations must provide sufficient rationale for the exclusion of such. Sufficient rationale might include a discussion of the inappropriate study population with respect to the health of the participants or the purpose of the research. The expectation that additional costs may be incurred by including women, minorities and children cannot be a reason for excluding these populations. Note: Protocols involving children must conform to the requirements of 45 CFR 46 subpart D.

 

Risks and Benefits

This section describes the potential risks to participants and how the experimental design will minimize those risks and a description of the anticipated benefits, whether to the individual or to the body of science.

 

Informed Consent

Explain the methods to be used in obtaining and recording the informed consent of the research participants. The recommended informed consent format is appended. Written consent of the research participant is strongly recommended. If the investigator feels that a verbal consent procedure is more appropriate for the population and circumstances, an explanation for the deviation from the preferred procedure is required along with a written version of the consent monologue. Whether written or verbal, the basic elements of informed consent must be present as outlined.

 

The following elements must be included in the informed consent document:

 

  • a statement that the protocol is a Brown University research study, an explanation of the purposes of the research and the expected duration of the participant's participation, a description of the procedures to be followed, and identification of any procedures, drugs or devices which are experimental;
  • a description of any reasonably foreseeable risks or discomforts to the subject.
  • a description of any benefits to the participant or to others that may reasonably be expected from the research, (payment to participate is not considered a benefit but a reimbursement);
  • disclosures of appropriate alternative procedures or courses of treatment, if applicable, that might be advantageous to the participant;
  • a statement describing how confidentiality will be maintained;
  • for research involving more than minimal risk, a statement that in the event of physical injury, free emergency care only will be provided if necessary. If desired, non-emergency care will be provided, but the Institution, investigator, or sponsor assumes no responsibility to pay for such care or to provide financial compensation;
  • a statement as to whom to contact for answers to pertinent questions involving the research and research participant's rights, and whom to contact in the event of a research-related injury to the participant;
  • a statement similar to "participation is voluntary" or "you may choose not to participate," as well as a statement that refusal to participate, or discontinuing participation at any time, will involve no penalty or loss of benefits to which the participant is otherwise entitled.

 

In addition, the following elements, though not all inclusive, should considered for inclusion in the informed consent document, as appropriate for the research:

 

  • any costs to the participant that might result from participation in the research;
  • a provision for the date of the participant's consent;
  • the consequence of a participant's decision to withdraw from the research and procedures for orderly termination;
  • a statement that significant new findings developed during the course of the research that may relate to the participant's willingness to continue participation will be provided to the subject;
  • a provision for participants to be given a copy of the consent (or assent form in the case of minors) form, if the consent is written;
  • in the case of research involving FDA-regulated products, information that FDA and the study sponsor may inspect records identifying research participants;
  • in the case of sponsor supported studies, the sponsor's name must appear in at the end of the first paragraph of the consent form;
  • if blood is to be withdrawn, the standard blood withdrawal information including: amount of blood to be withdrawn (in teaspoons or tablespoons); number of times; period of time covered; and potential hazards, such as "a bruise at the site of vein puncture"; and
  • disclosure of videotaping, audiotaping and/or photography of subjects and an explanation of how they will be used (i.e., research, diagnostic, or educational) must be included in the consent form.

 

Other Relevant Materials

Depending on the research study, the following relevant items are required in the complete protocol package:

 

  • copies of investigational new drug/investigational device exemption information;
  • copies of the investigator's brochure or other materials provided by a company sponsor;
  • copies of all advertisements (including print, internet, radio, TV, or other means) or other methods of recruitment to be used. Advertisements must include contact information of the investigator, the purpose of the research, the eligibility criteria that will be used to admit subjects into the study, and the location of the research. The IRB must review the exact wording to be used except for the date and time the research is to be initiated;
  • assent form for minors;
  • letters of support from collaborating sites signed by an authorized individual;
  • complete copies of any survey(s), questionnaire(s), interview(s) or other written testing instruments to be used (including "standard" tests).

 

Protocol Submission Requirements/Procedures

When a full board protocol is complete and all necessary signatures have been obtained on the cover sheet, the original and eleven (11) copies are delivered to the RPO in sufficient time to meet the agenda deadline. For expedited or exempt protocols an original protocol must be sent to RPO at least two (2) weeks prior to the preferred start date of the study to allow for sufficient time review and revisions, if necessary. (See the appended document "What Makes a Complete Protocol")


Reporting of Unanticipated Adverse Events and Death

Anticipated adverse events are required to be described within a protocol. In situations where a serious and unexpected adverse event or death occurs, it is the responsibility of the investigator to report (include IND Safety Report, MedWatch, when appropriate) to the IRB, FDA (if the study involves a drug, biologic, or device) and as appropriate, the sponsor. The investigator is required to report any death of a research participant occurring during the course of a study, regardless of the cause, to the IRB Manager (call RPO at x3-3050) within 24 hours of the event. The investigator is required to submit a written report to the IRB within seven (7) days of an unanticipated adverse event or death. The report will include the following information:

 

  • title of protocol;
  • description of the unanticipated adverse event;
  • a determination of whether the event was related to the research study;
  • name of the drug if appropriate;
  • where and when the event occurred; and
  • to whom else has the event been reported.

 

Upon receipt of a notification of an unanticipated adverse event or death, the IRB will determine whether further investigation of the event is required. Depending on the circumstances the investigator may be required to suspend the study pending the outcome of an IRB review. Also, the IRB may require modification of the risks section of the consent form.

 

Termination

In order to formally complete a research study, the investigator must officially notify the IRB when a study is completed which includes data analysis. Notification of termination may be accomplished via a memo.

 

Record Retention

 

Investigator Records

Investigators are required to maintain a research file. The requirements for a research file include but are not limited to, all correspondence with the IRB and the sponsor (as applicable), and documentation of participant eligibility as well as a copy of the signed consent (and assent forms when appropriate) forms obtained from all research participants participating in and/or who have participated in the protocol regardless of whether or not the subjects completed the study. The research file should also contain any data derived from the study. This file will act as the investigator's documentation regarding the proper performance of the study. This information is subject to review by the IRB, Internal Audit, federal, state or local authorities, sponsors, and other authorized individuals as appropriate to ensure proper performance of the study. To determine data retention requirements, see applicable sponsor guidelines.

 

Note: All signed consents forms must be maintained in a secure location as described in the approved protocol and for an additional three (3) years beyond the completion of the project unless extended by the IRB and the Office of Research Administration.

IRB Records

The IRB keeps permanent records of all its proceedings, including minutes of each meeting, all correspondence, and all submitted protocols (including proposal where applicable), modifications, advertisements, consent forms, survey instruments, continuing reviews, statements of significant findings provided to subjects, and a list of IRB members. These records will be maintained for at least a period of three (3) years beyond the completion of the project. All IRB records are accessible for inspection and reproduction by appropriate authorized individuals and agencies.

 

{Brown University acknowledges and appreciates the contributions to this document by the University of California, Los Angeles, and the University of Chicago.}

 

APPENDIX