7.4 Research Involving Incapacitated or Decisionally Impaired Subjects

Note: This policy does not apply to the category of research conducted under 21 CFR 50.24. See Exceptions from Informed Consent for Studies Conducted in Emergency Settings

POLICY:

Individuals with diminished autonomy deserve added protection in order to maintain their rights and welfare. For all research involving patients who lack capacity or decisionally-impaired subjects, the capacity of the potential research subject shall be assessed prior to their enrollment and then periodically throughout the course of the research; it will never be presumed that a patient's condition renders him/her incompetent. A legally authorized representative may consent to an individual's participation in research under the appropriate circumstances. Under limited circumstances, as determined by the IRB and based on risk, potential benefit, and the urgency of initiating treatment, approval for consent to be given by a surrogate such as next-of-kin may be granted for a protocol. Approval for the use of surrogate consent will be considered by the IRB for individual protocols in accordance with current federal and state regulations and guidance.

GUIDANCE:

Applicable Terms and Definitions (See OPRR IRB Guidebook, 1993 for references) Cognitively Impaired: Having either a psychiatric disorder (e.g., psychosis, neurosis, personality or behavior disorders), an organic impairment (e.g., dementia) or a developmental disorder (e.g., mental retardation) that affects cognitive or emotional functions to the extent that capacity for judgment and reasoning is significantly diminished. Others, including persons under the influence of or dependent on drugs or alcohol, those suffering from degenerative diseases affecting the brain, terminally ill patients, and persons with severely disabling physical handicaps, may also be compromised in their ability to make decisions in their best interests. Competence: Technically, a legal term, used to denote capacity to act on one's own behalf; the ability to understand information presented, to appreciate the consequences of acting (or not acting) on that information, and to make a choice. (See also: Incompetence, Incapacity.) Competence may fluctuate as a function of the natural course of a mental illness, response to treatment, effects of medication, general physical health, and other factors. Therefore, mental status should be re-evaluated periodically. As a designation of legal status, competence or incompetence pertains to an adjudication in court proceedings that a person's abilities are so diminished that his or her decisions or actions (e.g., writing a will) should have no legal effect. Such adjudications are often determined by inability to manage business or monetary affairs and do not necessarily reflect a person's ability to function in other situations. Decisionally Impaired: State of diminished mental capacity that interferes with the ability to make sound, informed judgments regarding medical treatment, or, in the context of research, regarding participation in research studies. Health Care Proxy: Someone a person appoints to make health care decisions on his/her behalf in the event that he/she becomes unable to make those decisions for him/herself. See New York Health Care Proxy Law. Incapacity: Refers to a person's mental status and means inability to understand information presented, to appreciate the consequences of acting (or not acting) on that information, and to make a choice. Often used as a synonym for incompetence. Incompetence: Technically, a legal term meaning inability to manage one's own affairs. Often used as a synonym for incapacity. Institution: A residential facility that provides food, shelter, and professional services (including treatment, skilled nursing, intermediate or long-term care, and custodial or residential care). Examples include general, mental, or chronic disease hospitals; inpatient community mental health centers; halfway houses and nursing homes; alcohol and drug addiction treatment centers; homes for the aged or dependent, residential schools for the mentally or physically handicapped; and homes for dependent and neglected children. Legally Authorized Representative: An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research (45 CFR 46.102). In the case of children, this would be a parent or legal guardian. For adults, a legally authorized representative would have durable power of attorney for health care for the subject or some other court order authorizing him/her to be the legal representative. Next of kin: The person who is (or persons who are) most closely related to a given person.

There are a number of situations where research subjects may be or may become unable to consent for their own participation in a research protocol. These guidelines include but are not necessarily limited to the following categories of studies:

• Neurological/Psychiatric studies, where it is anticipated (but not presumed) that patients may be or become decisionally impaired
• Clinical protocols involving medical conditions which often (but not always) render a person physically unconscious or decisionally impaired (i.e., stroke, unstable or serious cardiac conditions, shock, mental status changes due to fever/infections or other reversible conditions, emergency, trauma and ICU research, drug abuse, etc.)
• All other research that may include subjects who might experience fluctuating decisional capacity (due to dementia, emotional distress, etc.)

Individuals in a wide variety of situations may have impaired decision-making capacity. For example, impairment may occur at times of great stress. Impaired capacity is not limited to individuals with neurologic, psychiatric, or substance abuse problems; conversely, individuals with neurologic, psychiatric, or substance abuse problems should not be presumed to be decisionally impaired. Some research questions may be answered only by research that involves persons with impaired decision making capacity; precluding this research would contribute to needless suffering.

Unlike research involving children, prisoners, pregnant women, and fetuses, no additional Department of Health and Human Services (DHHS) regulations specifically govern research involving persons who are cognitively impaired. While limited decision-making capacity should not prevent participation in research, it is important to keep in mind that additional scrutiny is warranted for research involving this population.

The NIH offers guidance (see Research Involving Individuals With Questionable Capacity to Consent: Points to Consider) to assist IRBs and clinical investigators in their effort to protect participants in research who are, or may be, or may become decisionally impaired, salient points of which are included below:

Conflicting Roles
Potential and actual research participants, especially those with permanent or transient cognitive impairments, may find it difficult to understand the difference between research and treatment, and to understand researchers' multiple roles, making "therapeutic misconceptions" particularly problematic, and possibly creating confusion among participants and their families.

It is essential that the consent process (including consent documents) clearly indicate differences both between individualized treatment and research and between clinician and clinical investigator.

Assessing Capacity to Consent
Individual's capacities, impairments, and needs must be taken into account in order to develop practical and ethical approaches to enable them to participate in research. A clear understanding of the implications of various cognitive impairments, along with a careful consideration of proposed clinical research methodology, is required. Assessment is complex; simply answering a certain number of factual questions about a protocol may not be an adequate assessment. A key factor in participants' decision-making is their appreciation of how the risks, benefits, and alternatives to participation in the study apply to them personally.

Limited decision-making capacity covers a broad spectrum. A healthy person in shock may be temporarily decisionally impaired. Another may have been severely mentally retarded since birth, while yet a third who has schizophrenia may have fluctuating capacity. Researchers should be sensitive to the differing levels of capacity and use assessment methods tailored to the specific situation. Further, researchers should carefully consider the timing of assessment to avoid periods of heightened vulnerability when individuals may not be able to provide valid informed consent.

Both IRBs and clinical investigators must keep in mind that decision-making capacity may fluctuate, requiring ongoing assessment during the course of the research. The consent process should be ongoing. The IRB, at its discretion, may require an outside witness to observe the consent process.

Determining Who May Consent for Incapacitated or Decisionally Impaired Subjects
Federal regulation allows for consent by a legally authorized representative when a research subject is incompetent. For research purposes, a legally authorized representative is the parent or legal guardian of a minor, someone who is explicitly defined in a Health Care Proxy as being able to consent on behalf of the individual to participate in research, or someone who is court-appointed as such.

Note: Under the NY State Health Care Proxy Statute, the act of executing a new proxy automatically voids any prior proxies. Therefore, it is recommended that investigators advise subjects who are signing a "health care proxy for research" to name the same person that they have chosen as a health care proxy for clinical care.

Although Federal and State laws are not specific, there are certain circumstances where it may be appropriate to allow a next-of-kin, who may not be a legally authorized representative, to provide consent on behalf of an individual. The determination as to whether or not it is appropriate to accept consent by a next-of-kin is considered for individual protocols by the IRB, and is based on the risk/benefit ratio and the implications of delaying study participation for the amount of time it would take to appoint a legal guardian. The following categories for research involving children, defined in the federal regulations in 45 CFR 46.404, 405, 406, 407, are used as a guideline by the IRB in making this determination.

• Research not involving greater than minimal risk
  Consent should be sought from a legally authorized representative, if reasonably available. If not, a family member, who is aware of the patient's values and believes the subject would have consented to participation may consent to their participation. The relationship between the subject and next-of-kin should be documented in the patient's research/medical record. (The following order should be used when seeking next-of-kin: spouse, adult children, parents, adult siblings, grandparents, close friend.)
• Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects
  A legally authorized representative may consent on behalf of an individual for participation in this category of research. A request for approval of surrogate consent (i.e., consent by a family member who is not a legally authorized representative) may be considered by the IRB if the research could not otherwise be carried out, and if exclusion of those individuals without a legally authorized representative denies them access to a potentially beneficial treatment where no other comparable treatment is available, and there is genuine uncertainty about the effectiveness of standard care (i.e., there is clinical equipoise). This may include placebo-controlled trials (when the research is above and beyond standard of care). In order to protect the rights and welfare of the research participant, the use of a surrogate to consent on behalf of another individual in research involving greater than minimal risk will be determined for individual protocols by the IRB after careful consideration of the research protocol and in accordance with current Federal and State regulations.
  
  

  The process for determining the appropriate surrogate should be carefully justified by the investigator for review by the IRB at the time of initial submission and, if granted, documented in the patient's medical/research record.

• Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition
  Only a legally authorized representative may consent on behalf of an individual for participation in this category of research.

• Research not otherwise approvable which presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of humans. Requests under this category of research are extremely rare. Surrogate consent is never acceptable for participation in research falling under this category of research.

  In addition to considering the risk/benefit ratio, the IRB will consider the following issues when making a determination regarding surrogate consent for a particular protocol in any/all categories of research:

  • Will patient care be compromised by restricting participation to those with legally authorized representatives? (i.e., could a potentially beneficial treatment be denied to patients?)
  • Will restricting the use of surrogates significantly affect study accrual for a beneficial study? (i.e. could the study practicably be carried out without the use of surrogates?)
  • Is there time to go to court and appoint a guardian?

Comprehension
The determination of a subject's ability to understand the implications of the decision to participate in research is best made by the clinician/investigator. In most cases, it will be the clinician/investigator who is in the ideal position to evaluate the subject's ability to understand the implications of the research and whether the subject is making a rational decision to participate. Likewise, in most studies it is the clinician/investigator who can best make a judgment of the subject's ability to understand and follow the protocol.

In developing the consenting process, the investigator is obligated to incorporate any special accommodations necessary to assure that the subject population or their surrogates comprehend the nature and purpose of the study. Useful techniques may include simplified consent documents, supplemental summary sheets, Q&A sessions for the subject and surrogate and/or family, and waiting periods after the initial discussion before the prospective subject actually enrolls.

There is no universally accepted test or standard for making a determination of comprehension. This process should operate in research studies in much the same manner as the informed consent process in clinical treatment that does not involve research. Investigators may use the Comprehension Evaluation Form to assist them with subject assessment.

For further guidance investigators are encouraged to access the following:

Guidelines for Assessing the Decision-Making Capacities of Potential Research Subjects with Cognitive Impairment from The American Journal of Psychiatry, 155:11, November 1998; and

Assent of the Decisionally Impaired
The IRB may determine that the assent of the individual should be sought. For certain populations where the incapacity of the subject may be temporary, the IRB may determine that the consent from the individual is necessary to continue their participation in the study once capacity has been restored.

The IRB may require that a health care proxy be identified for future decision-making on behalf of a particular group of subjects whose capacity is expected to diminish over time. For instance, subjects who are asked to participate in a research study on Alzheimer's disease who are capable of consenting for themselves, but whose capacity is most likely to deteriorate during the course of the research, may be asked to assign a health care proxy for future decision making as a condition of being enrolled or continuing in the study.

All provisions for additional protections (e.g. assent, surrogate consent, capacity assessments, etc.) required by the IRB for the conduct of a particular protocol involving patients who lack capacity or decisionally impaired subjects will be outlined in the individual approval letters for each protocol.

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7.5 Additional Special Classes of Subjects

POLICY:

In addition to the vulnerable populations discussed separately (children, fetuses/pregnant women/human in vitro fertilization, prisoners, incompetent/decisionally impaired), the IRB shall provide additional protection to other potentially vulnerable populations. This special class of subjects may include, but is not limited to, terminally ill patients, elderly/aged persons, minorities, student/employees/normal volunteers, economically or educationally disadvantaged persons, and international research participants.

GUIDANCE:

Much of the following information concerning special classes of subjects is taken from the OHRP IRB Guidebook (Chapter VI).

Terminally Ill Patients
Terminally ill patients are those who are deteriorating from a life-threatening disease or condition for which no effective standard treatment exists. It is generally considered unacceptable to ask such persons to participate in research for which alternative, not similarly burdened, populations of subjects exist. Nevertheless, it may often be necessary to involve terminally ill patients in research concerning their disease and its treatment. Further, terminally ill persons should not be excluded from research in which they may want to participate simply because of their status. One can imagine that altruism and a desire to bring good from adversity may well motivate persons suffering from life-threatening illnesses to become involved in biomedical or behavioral research. Still, terminally ill individuals are a vulnerable population of research subjects, and therefore, require additional protection against coercion and undue influence [45 CFR 46.111(b)].

The FDA has a program of Expanded Access that permits individuals who have serious or life-threatening diseases for which there are no alternative therapies to have access to investigational drugs and devices that may be beneficial to them (e.g. Treatment INDs, Parallel Track).

In many contexts, research on terminal illness and its treatment requires the involvement of terminally ill patients when alternative populations for study do not exist or when involving alternative populations would be ethically unjustifiable.

Two important reasons for concern regarding research involving terminally ill persons are:

1. They tend to be more vulnerable to coercion or undue influence than healthy adult research subjects; and
2. Research involving the terminally ill is likely to present more than minimal risk.

The risk of coercion and undue influence may be caused by a variety of factors. In addition to the fact that severe illness often affects a person's competence (see Research Involving Incapacitated or Decisionally Impaired Subjects), terminally ill patients may be vulnerable to coercion or undue influence because of a real or perceived belief that participation is necessary to receive continuing care from health professionals or because the receipt of any treatment is perceived as preferable to receiving no treatment. Although terminally ill patients should be protected from an understandable tendency to enroll in research under false hopes, IRBs should not take too protective an attitude toward competent patients simply because they are terminally ill. Some terminally ill patients may find participation in research a satisfying way of imparting some good to others out of their own misfortune.

It is important to distinguish between risks that may be justified by anticipated benefits for the research subjects and risks associated with procedures performed purely for research purposes. A particularly difficult issue relating to research involving terminally ill patients arises in connection with the conduct of Phase I drug trials in which the drugs involved are known to be particularly toxic (e.g., a new form of cancer chemotherapy). In some of these studies, any benefit to the subject is, at best, highly unlikely. Despite the "therapeutic intent" (the research physician's intent to provide some benefit to improving the subject's condition) of the investigators to benefit the subject, subjects may in fact experience a decline in health status, no improvements in terms of quality of life, or lengthened life for only a short time. It is extremely important that prospective subjects be clearly informed of the nature and likelihood of the risks and benefits associated with this kind of research. The challenge to the investigator and the IRB is to provide patients with an accurate description of the potential benefits without engendering false hope.

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Elderly/Aged Persons
As the American population ages, research on the aging process and conditions and diseases that disproportionately affect the elderly has become increasingly important. The participation of older subjects in research poses several issues for IRBs; primary among them is the question of whether and when the elderly need special protections. IRBs must maintain the balance between the need for protection and the need to provide respect for persons.

While the federal regulations call for additional protections for vulnerable populations, there are no specific regulations governing research with elderly subjects. It is generally agreed, however, that the elderly are, as a group, heterogeneous and not usually in need of special protections, except in two circumstances: cognitive impairment and institutionalization. Under those conditions, the same considerations are applicable as with any other, non-elderly subject in the same circumstances (see Research Involving Incapacitated or Decisionally Impaired Subjects).

There is no age at which prospective subjects should become ineligible to participate in research. Most older people are neither cognitively impaired nor live in institutional settings. Nevertheless, investigators may avoid elderly subjects because of recruiting/retention difficulty, hearing/vision impairment (making the consent process more difficult), memory impairment, etc.) However, inclusion of older persons in research is important, and they should have the opportunity to share in the benefits of burdens of research.

In the past, persons in nursing homes or other institutions have been selected as subjects because of their easy accessibility. It is now recognized, however, that conditions in institutional settings increase the chances for coercion and undue influence because of the lack of freedom inherent in such situations. Research in these settings should therefore be avoided, unless the involvement of the institutional population is necessary to the conduct of the research (e.g. the disease or condition is endemic to the institutional setting itself).

Minorities
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, minority and non-minority alike. For generalizability purposes, investigators must include the widest possible range of population groups. Sometimes, however, minorities are subject to a differential risk. Some research, for example, relates to conditions that specifically affect various minority groups (e.g., sickle cell anemia or Tay Sachs disease), so that involvement of the relevant minority groups is imperative. 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 certain racial or ethnic groups. 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 way, the opportunity to benefit. A glaring example of abuse of minority populations' bearing the burden of research can be found in the Tuskegee 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.

The manner in which subjects are selected bears directly on the problem of inclusion of minorities. The choice of a geographic area for recruitment may affect the representation of racial and ethnic groups in study populations. Also, to the extent that minorities are reliant on public rather than private health care systems, recruitment of subjects from private physicians will tend to exclude minorities and recruitment from public health clinics will tend to over-include them. In fact, recruiting subjects from any health care system assumes that appropriate subjects have access to and exercise their ability to access a health care system, which may contribute to the homogeneity of the study population. Some writers have suggested that investigators change recruitment strategies so that they recruit subjects through community-based institutions such as churches and neighborhood organizations, rather than solely through health care institutions. In many studies, several institutions collaborate, thereby enrolling subjects from different geographic locations. Such collaborations may also provide a mechanism for ensuring appropriate representation of women and minorities in the study population.

One justification that is offered for research with homogeneous populations is that it is a simpler, less costly way to conduct clinical trials. The more diverse the study population, the larger the subject pool must be (to achieve statistical significance when controlling for differences in race, gender, and ethnicity) and the more variables must be accounted for in analyzing the data. Nonetheless, when homogeneous populations are used, study results are then limited in their applicability to the precise population involved in the study, and may, in fact, hide inaccuracies.

Normal Volunteers
Special concerns surround the involvement of normal (i.e., healthy) persons who volunteer to participate in research. Primarily, the principles involved are beneficence and respect for persons. In the Belmont Report, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research stated the two general rules that describe beneficent actions as: (1) do not harm, and (2) maximize possible benefits and minimize possible harms. Volunteers for whom no therapeutic benefit can result from participation in research, should therefore, be exposed to risks that are minimized to the greatest extent possible. While the minimization of risks is an important requisite for any research involving human participants, the altruistic motivation of the normal volunteer's agreement to participate (i.e., of contributing to scientific knowledge for the benefit of society) heightens the concern for the risks to which such participants should ethically be exposed.

The principle of respect for persons requires that research participants are, where capable of doing so, allowed to act autonomously and to express their right of self-determination. These principles are effectuated through the process of informed consent, which involves providing subjects with all relevant information about the study, including the risks and benefits involved, in clear and simple language, and ensuring that the information is understood and appreciated. Furthermore, the agreement to participate must be voluntary; the consent negotiations must be free from elements of coercion or undue inducement to participate. In research involving normal volunteers, particularly where the research involves more than minimal risk, IRBs must ensure that any monetary payments to subjects are not so great as to constitute an undue inducement. This issue may be particularly difficult for IRBs to deal with. Since subjects who volunteer to participate in such studies are usually compensated for their time and discomfort, IRBs should seriously scrutinize the payment schedules to ensure that any compensation offered is commensurate with the time, discomfort, and risk involved. Even so, where a research procedure involves serious discomfort and/or the real, though slight, possibility of serious harm (e.g., studies that involve the insertion and positioning of catheters in veins or the heart), one can easily imagine that the motivation of persons who volunteer to participate may be monetary. IRBs should pay particular attention to the proposed study population and whether it may comprise persons who are likely to be vulnerable to coercion or undue influence, such as persons who are educationally or economically disadvantaged. The federal regulations require that IRBs employ special safeguards under such circumstances [45 CFR 46.111(b)].

One area where normal volunteers are employed in research is in Phase 1 drug trials. The justification for the involvement of normal, healthy subjects is the need for volunteers whose experience with the trial materials is more easily analyzed because of the existence of fewer confounding factors. While Phase 1 trials are the first use of experimental drugs and devices in humans, preliminary studies involving animals provide investigators with data indicating a high likelihood of safe use in humans. Studies have indicated that the risk of injury from participating in Phase 1 studies is small, about the same as the risk of being injured while working as an office secretary [Levine (1982)]. The likelihood of risk, including the availability of animal data, should be scrutinized by IRBs.

Normal volunteers, like students and employees, should be recruited through general announcements or advertisements, rather than through individual solicitations. Personal solicitations increase the likelihood that participation will be the result of undue influence, either because of the relationship between the recruiter and the prospective subject, or methods of communication employed by the recruiter that may act to persuade prospective subjects to participate, thus compromising the voluntariness of the agreement to participate.

Investigators and IRBs should carefully consider what will happen if and when a normal volunteer should become sick or be injured during the research. As with any research involving human subjects, such issues should be clearly spelled out in the informed consent document, and should be reviewed carefully with the prospective subject. For example, subjects should be told: whether any medical treatments will be made available should injury occur and, if so, what they consist of; whom to contact should a research-related injury occur; and that they may discontinue participation at any time without penalty or loss of benefits to which they would otherwise be entitled [45 CFR 46.116(a)(6-8)]. In addition, where appropriate, subjects should be told whether they will be dropped from the study in the event of injury or illness, and whether they will be required to pay for treatment of research-related injuries or illness [45 CFR 46.116(b)(2-3)]. Where illness in healthy volunteers does occur, particularly during a drug study, investigation by an independent physician may be warranted. [See Fazackerley, Randall, and Pleuvry (1987)]

The issues raised by the involvement of healthy subjects in genetic research is discussed in Guidebook Chapter 5, Section H, "HumanGenetic Research."

Students
Universities, and the association of investigators with them, provide investigators with a ready pool of research subjects: students. Many IRBs have faced the question of whether ,and in what way, students may participate in research. Two questions that have been posed are whether students - medical students, in particular - should be allowed to participate in biomedical research (and whether special protections should be adopted to restrict their participation), and whether participation in research can appropriately be included as a course component for course credit. The latter practice is commonly employed in psychology departments.

The problem with student participation in research conducted at the university is the possibility that their agreement to participate will not be freely given. Students may volunteer to participate out of a belief that doing so will place them in good favor with faculty (e.g., that participating will result in receiving better grades, recommendations, employment, or the like), or that failure to participate will negatively affect their relationship with the investigator or faculty generally (i.e., by seeming "uncooperative," not part of the scientific community). Prohibiting all student participation in research, however, may be an over protective reaction. An alternative way to protect against coercion is to require that faculty-investigators advertise for subjects generally (e.g., through notices posted in the school or department) rather than recruit individual students directly. As with any research involving a potentially vulnerable subject population, IRBs should pay special attention to the potential for coercion or undue influence and consider ways in which the possibility of exploitation can be reduced or eliminated.

Whether medical students in particular require special protections has been hotly debated. Some universities have either prohibited their participation or severely restricted it to, for instance, research involving minimal risk and minimal interruption of time. Strong arguments have been made against such protections, including claims that as future physicians (and possibly researchers) they may be obliged to participate. Angoff has argued that protecting medical students to a greater degree than protecting other normal volunteers smacks of elitism. Angoff (1985) states, "One may wonder why it is acceptable to ask the masses to accept risk in the name of science but not the very people whose futures are linked to the successful perpetuation of biomedical research"[p. 10]. Nolan (1979), Levine (1984), Angoff (1985), and others have argued that medical students are in a particularly good position to participate in some biomedical research because of their ability to comprehend the procedures involved in studies and evaluate the risks involved, which may not be possible to achieve with other normal volunteers.  Angoff and others have also argued that it is acceptable to pay medical students as one would any research participant.

Requiring participation in research for course credit (or extra credit) is also controversial, though common in the social and behavioral sciences. The justification offered for requiring student participation is educational benefit [Gamble (1982); Cohen (1982)]. Clearly, however, participation of students is seen by faculty-investigators as necessary to the conduct of their research. Grant budgets often do not allow investigators to pay subjects; giving course credit or extra credit is a means of obtaining sufficient participation rates. Again, the issue for IRBs is whether such arrangements for selecting subjects are fair and non-coercive.

Participation in studies might be mandatory or for extra credit. Students in beginning psychology courses, for instance, might be required to serve as subjects for a given number of hours of research or in a given number of research projects. Or they might be given the option of participating for additional grade credit. Several mechanisms have been suggested for diminishing or eliminating the coercive aspect of student participation for course credit that IRBs might find useful. Gamble (1982) describes a departmental guideline for research involving students where extra credit is offered for participation. Students are to be given other options for fulfilling the research component that were comparable in terms of time, effort, and educational benefit: "for example, short papers, special projects, book reports, and brief quizzes on additional readings" [p. 7]. He raises concerns about the comparability of such alternatives with participating in research (e.g., that if they participate in studies, all they have to do is show up and spend the time, but if they choose to write a paper, it gets graded, and if they do extra readings, they have to be tested on them), and concludes that paying student subjects as researchers would any other subject is the only way to protect students' freedom of choice to participate. Cohen(1982) describes a similar policy that seems to meet these concerns. To fulfill the research component, students can either participate in five hours of research, write a brief research paper, or attend faculty research colloquia. The paper is not graded, and students who attend the colloquia have only to show up. If students do choose to participate in studies, the policy seeks to increase the likelihood that participation is freely chosen by requiring: that students be given several studies to choose from and may not be required to volunteer for any particular study; that the studies must not involve more than minimal risk; that students can withdraw from the study at any time without losing the extra credit [p. 11].

Another concern raised by the involvement of students as subjects is confidentiality. As with research involving human subjects generally, IRBs should be aware that research involving the collection of data on sensitive subjects such as mental health, sexual activity, or the use of illicit drugs or alcohol presents risks to subjects of which they should be made aware and from which they should be protected, to the greatest extent possible. The close environment of the university amplifies this problem.

Where students are likely to be participating in research, IRBs should consider including a student member or consulting with students where appropriate.

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Employees
The issues with respect to employees as research subjects are essentially identical to those involving students as research subjects: coercion or undue influence, and confidentiality. As medical students have seemed ideal subjects by biomedical researchers, employees of drug companies have been seen by investigators as ideal subjects in some ways, because of their ability to comprehend the protocol and to understand the importance of the research and compliance with the protocol. Meyers (1979) provides a good summary of the structure of employee volunteer research programs. As student participation raises questions of the ability to exercise free choice because of the possibility that grades or other important factors will be affected by decisions to participate, employee research programs raise the possibility that the decision will affect performance evaluations or job advancement. It may also be difficult to maintain the confidentiality of personal medical information or research data when the subjects are also employees, particularly when the employer is also a medical institution [Meyers(1979)].

International Research Participants
The regulations recognize that "the procedures normally followed in the foreign countries [in which the research will take place] may differ from those set forth in this policy" [45 CFR 46.101(h)]. Research may be approved, therefore, if  "the procedures prescribed by the [foreign] institution afford protections that are at least equivalent to those provided in this policy." The foreign country's procedures may then be substituted for the procedures required by the federal regulations. Approval of the substitution is to be given by the relevant federal department or agency head after review of the foreign procedures; notice of actions taken on such reviews are to be published in the Federal Register (or elsewhere, as provided for in department or agency procedures). [Note that the FDA has not adopted this provision for research that it regulates. All FDA-funded research, however, must comply with both DHHS and FDA regulations.]

The procedure for approving DHHS-supported research with a foreign component begins with the domestic institution with which the U.S. investigator(s) are affiliated. If the U.S. institution has an approved MPA on file with DHHS, the proposed research must be reviewed and approved by the institution's IRB before submission for funding, as with any research involving human subjects. If DHHS funds the research, each foreign institution should, upon request, submit an appropriate Assurance to OPRR. Since, at the present time, no international code prescribes exactly the same procedures for protecting human subjects as do the U.S. regulations, OPRR reviews the actual procedures detailed by the foreign institution as the primary basis for negotiating acceptable Assurances. International codes will, however, be taken into consideration in the negotiations. If the institution's practices are not equivalent to the U.S. regulations, OPRR can require that particular procedures be followed before recommending approval of the substitution.

If the U.S. institution holds an MPA, but the research is funded by a non-DHHS source, DHHS is less involved in review of the protocols for human subjects protections. Rather, as required by 45CFR 46.103, the MPA-holding institution retains responsibility for protecting the rights and welfare of all human subjects involved in research under the institution's auspices.

One difficult issue is determining what constitutes "protections that are at least equivalent" to the federal regulations. In the case of DHHS, this determination is made by OPRR. The broad policy outlines of international standards, such as the Declaration of Helsinki or the Nuremberg Code, are a starting place, but are not alone sufficient. Written descriptions of the specific procedural implementation of such policies that have been adopted by the foreign institution are required.

Departments and agencies other than DHHS follow different procedures for reviewing and approving research with foreign components. IRBs should consult the particular department or agency involved.

PROCEDURES:

The IRB shall pay careful attention to research involving such special classes of subjects, and shall consider requiring special procedures for protecting the rights and well-being of these subjects on a case-by-case basis. The IRB shall evaluate the risks and benefits of the research, and ensure that the consent form properly conveys the nature, magnitude and probability of the risks and benefits clearly and accurately. The IRB will pay careful attention to the consent process to ensure that subjects are properly informed and not misled. All of the requirements for informed consent must be met. (See Policy 5: Informed Consent). Where necessary, in order to screen subjects for sufficient comprehension and recall of information presented during the consent process, a questionnaire may be required by the IRB, that involves a test of the subject's comprehension and recall of the information presented in the first part. (e.g. for elderly subjects whose comprehension is questionable).

The IRB shall evaluate the study population to ensure proper representation. Research designs that include diverse study populations will be encouraged. Investigators who wish to include a homogeneous study population must provide a justification for doing so. Recruitment methodology will be carefully reviewed to ensure that the appropriate mix of populations will be reached with information about the study. The IRB shall safeguard the rights and welfare of study populations by placing additional safeguards for studies that may present possible coercion or undue influence on such populations. The consent process will be evaluated to ensure proper communication between researcher and subject, and consent forms will be available in other languages as appropriate to the study population(s). The IRB may require additional safeguards as it deems appropriate.

HIV Populations
The IRB shall follow New York State Law regarding HIV testing. See http://www.health.state.ny.us/nysdoh/phforum/nycrr10.htm.

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Policy 8:   Emergency Use Exemption from Prospective IRB Approval for Use of Unapproved Drugs, Biologics or Devices  (Revised 7/21/09)

 

POLICY:

A one time “emergency use” of a test article without prospective IRB review is allowed if all of the conditions of 21 CFR 56.102(d) are met, providing that such use is reported to the IRB within 5 working days.  The IRB will review and acknowledge the use of this test article.  Any subsequent use of the investigational product must have prospective IRB review and approval at a convened meeting. Consistent with HHS regulations, when emergency medical care is initiated without prior IRB review and approval, the patient may not be considered as a research subject.

GUIDANCE:

“Emergency use exemption” refers to the use of an investigational drug or biological product with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval [21 CFR 56.102(d)].  The FDA exempts from prior IRB review and approval a one-time “emergency use” of a test article [21 CFR 56.104(c)], providing that such use is reported to the IRB within 5 working days, and requires that any subsequent use of the investigational product at the institution have prospective IRB review and approval.  Please note:  Compassionate use is not synonymous with emergency use. Compassionate use protocols may need prospective IRB approval, if they do not meet the criteria for emergency use exemption.

Definitions

Life-threatening, for the purposes of section 56.102(d), includes the scope of both life-threatening and severely debilitating, as defined below:

Life-threatening: diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the endpoint of clinical trial analysis is survival.  The criteria for life-threatening do not require the condition to be immediately life-threatening or to immediately result in death.  Rather, the subjects must be in a life-threatening situation requiring intervention before review at a convened meeting of the IRB is feasible.

Severely debilitating: diseases or conditions that cause major irreversible morbidity.  Examples of severely debilitating conditions include blindness, loss of arm, leg, hand or foot, loss of hearing, paralysis or stroke.

Exception From Informed Consent Requirement

Even for an emergency use, the investigator is required to obtain the informed consent of the subject or the subject’s legally authorized representative unless both the investigator and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following [21 CFR 50.23(a)]:

• The subject is confronted by a life-threatening situation necessitating the use of a test article.
• Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject.
• Time is not sufficient to obtain consent from the subject’s legally authorized representative.
• No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject’s life.

If, in the investigator’s opinion, immediate use of the test article is required to preserve the subject’s life, and if time is not sufficient to obtain an independent physician’s determination that the four conditions above apply, the clinical investigator should make the determination and, within 5 working days after the use of the test article, have the determination reviewed and evaluated in writing by a physician who is not participating in the clinical investigation.  The investigator must notify the IRB within 5 working days after the use of the test article [21 CFR 50.23(c)].  The FDA must also be notified.

PROCEDURE:

A physician who wishes to use an investigational product in an emergency situation must do the following:

BEFORE USE:

1. Notify the IRB, by telephone or email, as soon as possible about the emergency use of the investigational drug or device. This notification is used to initiate tracking, to assure the investigator files a report with the IRB.
2. The investigator should contact the manufacturer of the drug/device to determine if it can be provided under an existing IND/IDE.  
   1. For drugs and biologics, if it is not available through an existing IND, the investigator should contact the FDA to obtain an Emergency IND.  FDA contact information can be found at:  http://www.fda.gov/RegulatoryInformation/Guidances/ucm126491.htm.
   2. For devices, the developer will need to notify CDRH (301-594-1190) immediately after the device is shipped for use. 

Determine whether informed consent is needed from the patient (see Guidance above on Exception from Informed Consent). If informed consent is needed and there is time, work with the IRB to create a consent form for the patient to sign before the test article is used.

AFTER USE:

1. Within 5 working days, a written notification must be sent to the IRB describing the emergency use in that particular individual.  The written notification must include:
   1. A letter to the Chairman of the IRB detailing the patient’s medical history, current situation, and a justification for the use of the non-approved treatment modality (drug, device, etc.)  The letter must be in sufficient detail to allow the department chairman and the IRB chair or designee to evaluate the treating physician’s request. 
   2. IRB Form 1 must be completed, including the patient’s initials (not their full name) following the title of the protocol.
   3. A copy of the signed consent form, if consent was obtained.  If the manufacturer does not have a consent for use, a clinical consent can be used.  The patient must understand the investigational nature of the product being used.
   4. A copy of any correspondence with the manufacturer
   5. A copy of any correspondence with the FDA (including a copy of the Emergency IND, if obtained).
   6. If consent was not obtained because the situation met the requirements outlined above for Exception from Informed Consent Requirement, the investigator must certify in writing how this determination was made.  This determination must be reviewed and evaluated in writing, preferably before the emergency use,  by a physician who is not otherwise participating in the clinical investigation.
   7. For devices - If an IDE exists, notify the sponsor of the emergency use. If an IDE does not exist, notify FDA of the emergency use (301-594-1190) and provide FDA with a written summary of the conditions constituting the emergency, subject protection measures and results.

Once this information is received, the IRB will send a written acknowledgment to the physician, acknowledging the use of this product. 

The protocol must be submitted to the IRB for full IRB review if it is anticipated that future patients may require the same treatment in the future. (See also FDA Information Sheets: Emergency Use of an Investigational Drug or Biologic and FDA Device Advice).

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Policy 9: Medical Devices

POLICY:

Investigators pursuing the use of an investigational device, the investigational use of an approved device, or the humanitarian use of a device (HUD), as defined in this policy, must obtain IRB approval for its use prior to implementation.

GUIDANCE:

A medical device is defined, in part, as any health care product that does not achieve its primary intended purposes by chemical action or by being metabolized. Medical devices include, among other things, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis (IVD) of disease and other medical conditions such as pregnancy.

Clinical investigations of medical devices must comply with the Food and Drug Administration (FDA) informed consent and Institutional Review Board (IRB) regulations [21 CFR parts 50 and 56, respectively]. Federal requirements governing investigations involving medical devices were enacted as part of the Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990. These amendments to the Federal Food, Drug, and Cosmetic Act (the Act) define the regulatory framework for medical device development, testing, approval, and marketing.

Except for certain low risk devices, each manufacturer who wishes to introduce a new medical device to the market must submit a pre-market notification to FDA.

510(k) devices
FDA reviews pre-market notifications to determine if the new device is "substantially equivalent" to a device that was marketed prior to passage of the Amendments (i.e., a "pre-amendments device"). If the new device is deemed substantially equivalent to a pre-amendments device, it may be marketed immediately and is regulated in the same regulatory class as the pre-amendments device to which it is equivalent. (The premarket notification requirement for new devices and devices that are significant modifications of already marketed devices is set forth in section 510(k) of the Act). Devices determined by FDA to be "substantially equivalent" are often referred to as "510(k) devices". If the new device is deemed not to be substantially equivalent to a pre-amendments device, it must undergo clinical testing and premarket approval before it can be marketed unless it is reclassified into a lower regulatory class.

Investigational Device Exemption (IDE)
An investigational device is a medical device which is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device. Clinical investigations undertaken to develop safety and effectiveness data for medical devices must be conducted according to the requirements of the IDE regulations [21 CFR part 812]. An IDE study may not necessarily commence 30 days after an IDE submission to FDA. Certain clinical investigations of devices (e.g., certain studies of lawfully marketed devices) may be exempt from the IDE regulations [21 CFR 812.2(c)]. Unless exempt from the IDE regulations, an investigational device must be categorized as either "significant risk" (SR) or "non-significant risk" (NSR). The determination that a device presents a non-significant or significant risk is initially made by the sponsor. The proposed study is then submitted either to FDA (for SR studies) or to an IRB (for NSR studies).

The IRB's SR/NSR determination has significant consequences for the study sponsor, FDA, and prospective research subjects. SR device studies must be conducted in accordance with the full IDE requirements [21 CFR part 812], and may not commence until 30days following the sponsor's submission of an IDE application to FDA. Submission of the IDE application enables FDA to review information about the technical characteristics of the device, the results of any prior studies (laboratory, animal and human) involving the device, and the proposed study protocol and consent documents. Based upon the review of this information, FDA may impose restrictions on the study to ensure that risks to subjects are minimized and do not outweigh the anticipated benefits to the subjects and the importance of the knowledge to be gained. The study may not commence until FDA has approved the IDE application and the IRB has approved the study.

In contrast, NSR device studies do not require submission of an IDE application to FDA. Instead, the sponsor is required to conduct the study in accordance with the "abbreviated requirements" of the IDE regulations [21 CFR 812.2(b)]. Unless otherwise notified by FDA, an NSR study is considered to have an approved IDE if the sponsor fulfills the abbreviated requirements. The abbreviated requirements address, among other things, the requirements for IRB approval and informed consent, record keeping, labeling, promotion, and study monitoring. NSR studies may commence immediately following IRB approval.

PROCEDURE:

The IRB shall make a determination as to whether the device can be classified as SR or NSR. The IRB shall then consider whether or not the study should be approved. In considering whether a study should be approved, the IRB shall use the same criteria it would use in considering approval of any research involving an FDA regulated product [21 CFR 56.111]. Some NSR studies may also qualify as "minimal risk" studies, and thus may be reviewed through an expedited review procedure [21 CFR 56.110]. FDA considers all SR studies to present more than minimal risk, and thus, full IRB review is necessary. In making its determination on approval, the IRB should consider the risks and benefits of the medical device compared to the risks and benefits of alternative devices or procedures.

Frequently Asked Questions About IRB Review Of Medical Devices
(FDA Information Sheets, 1998 Update)

1. What is meant by Class I, II and III devices?

The class distinction is made primarily on the level of risk to users/patients and, therefore, the level of FDA oversight needed to ensure that the device is safe and effective as labeled. Generally, but not always, this corresponds to logical risk evaluations.
 

Class I:	General controls	crutches, band aids
Class II:	Special controls	wheelchairs, tampons
Class III:	PreMarket Approval	heart valves (known to present hazards requiring clinical demonstration of safety and effectiveness) - OR -not enough known about safety or effectiveness to assign to Class Ior II

2. What is the difference between marketing approval under a 510(k) and under a PMA?

A 510(k) application demonstrates that a new device is substantially equivalent to another device that is legally on the market without a PMA. If FDA agrees that the new device is substantially equivalent, it can be marketed. Clinical data are not required in most 510(k) applications; however if clinical data are necessary to demonstrate substantial equivalence, the clinical studies need to be conducted in compliance with the requirements of the IDE regulations, IRB review and informed consent (21 CFR parts 812, 56 and 50, respectively).

3. Why should an IRB decide whether a device is non-significant risk (NSR)?

The sponsors (usually the manufacturer of the device) make the initial decision whether a device imparts significant risk (SR) to study subjects or others. If so, the sponsor obtains an Investigational Device Exemption (IDE) from FDA. If the sponsor believes the device does not impart significant risk, IRB approval of a study as an NSR device can be sought. The NSR category was created to avoid delay and expense where the anticipated risk to human subjects did not justify the involvement of FDA. If the IRB agrees that the study is NSR, no submission to or review by FDA is necessary before starting studies in humans. If the IRB considers the study to be SR, the sponsor must obtain an IDE from FDA before proceeding with clinical studies.

4. What does FDA know about an NSR study?

"There is no requirement to report to FDA when an NSR study starts." The requirements for IRB review, informed consent, adverse event reporting and labeling still apply. In addition, the sponsor should understand that proceeding with an NSR study is at their risk (meaning that the FDA can later disagree) and they may voluntarily seek advice or inform FDA about the decision to proceed without filing an IDE with FDA.

5. How does an IRB decide whether a device is SR or NSR?

The IRB uses its best abilities, the information in the regulations and the guidelines, and the risk evaluation provided by the applicant. It can, as always, seek outside assistance. The IRB should have written policies and procedures regarding device review. The information sheet "Significant Risk and Non-Significant Risk Medical Device Studies" provides additional guidance.

6. Does an IRB that reviews medical device studies need written procedures for determining whether the device is SR or NSR?

When the IRB determines that an investigation presented for approval as involving an NSR device actually involves an SR device, 21 CFR 812.66 requires the IRB to so notify the investigator and, where appropriate, the sponsor. 21 CFR 56.108(a)(1) requires the IRB to follow written procedures for conducting its initial review of research and for reporting its findings and actions to the investigator. The procedures followed in determining whether a study is SR or NSR should be included among those written procedures.

7. Does FDA require IRB review of the off-label use of a marketed device?

YES, if the off-label use is part of a research project involving human subjects. NO, if the off-label use is intended to be solely the practice of medicine, i.e., for a physician treating a patient and no research is being done.

8. What is the meaning of exemption in 21 CFR812.2(c)(2)?

The exemption applies only to investigations in which 510(k)'d products are being used in accordance with the labeling cleared by FDA. Investigation of an off-label use of a 510(k) product takes it outside this exemption. A device subject to 510(k) remains "investigational" until the 510(k) is cleared by FDA and the investigational use is subject to the requirements of the IDE regulation, informed consent and IRB review (21 CFR 812, 50 and 56,respectively).

9. Must an IRB review a clinical investigation being done after submission of a 510(k)?

YES, if it's research the 21 CFR 50 and 56 regulations apply, and an IRB should review it. A 510(k) allows commercial distribution; it doesn't address research use. A 510(k) application can take time to process during which it remains an investigational product. It cannot be distributed except for investigational use until FDA clears the 510(k) application.

Also see FDA Information Sheets: "Medical Devices," "Significant Risk and Non-significant Risk Medical Device Studies" and "Emergency Use of Unapproved Medical Devices."

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Significant Risk and Non-significant Risk Medical Device Studies
The Investigational Device Exemption (IDE) regulations [21 CFR part 812] describe two types of device studies, "significant risk" (SR) and "non-significant risk" (NSR). An SR device study is defined [21 CFR 812.3(m)] as a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is intended as an implant; or (2) is used in supporting or sustaining human life; or (3) is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents impairment of human health; or (4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. An NSR device investigation is one that does not meet the definition for a significant risk study. NSR device studies, however, should not be confused with the concept of "minimal risk," a term utilized in the Institutional Review Board (IRB) regulations [21 CFR part 56] to identify certain studies that may be approved through an "expedited review" procedure. For SR and NSR device studies, IRB approval prior to conducting clinical trials and continuing review by the IRB are required. In addition, informed consent must be obtained for either type of study [21 CFR part 50].

Distinguishing Between SR and NSR Device Studies
The effect of the SR/NSR decision is very important to research sponsors and investigators. SR device studies are governed by the IDE regulations [21 CFR part 812]. NSR device studies have fewer regulatory controls than SR studies and are governed by the abbreviated requirements [21 CFR 812.2(b)]. The major differences are in the approval process and in the record keeping and reporting requirements. The SR/NSR decision is also important to FDA because the IRB serves, in a sense, as the Agency's surrogate with respect to review and approval of NSR studies. FDA is usually not apprised of the existence of approved NSR studies because sponsors and IRBs are not required to report NSR device study approvals to FDA. If an investigator or a sponsor proposes the initiation of a claimed NSR investigation to an IRB, and if the IRB agrees that the device study is NSR and approves the study, the investigation may begin at that institution immediately, without submission of an IDE application to FDA.

If an IRB believes that a device study is SR, the investigation may not begin until both the IRB and FDA approves the investigation. To help in the determination of the risk status of the device, IRBs should review information such as reports of prior investigations conducted with the device, the proposed investigational plan, a description of subject selection criteria, and monitoring procedures. The sponsor should provide the IRB with a risk assessment and the rationale used in making its risk determination [21 CFR812.150(b)(10)].

SR/NSR Studies and the IRB

The NSR/SR Decision
The assessment of whether or not a device study presents a NSR is initially made by the sponsor (in the case of an investigator initiated study, the sponsor is the investigator, who must then present and justify the NSR/SR decision). If the sponsor considers that a study is NSR, the sponsor provides the reviewing IRB an explanation of its determination and any other information that may assist the IRB in evaluating the risk of the study. The sponsor should provide the IRB witha description of the device, reports of prior investigations with the device, the proposed investigational plan, a description of patient selection criteria and monitoring procedures, as well as any other information that the IRB deems necessary to make its decision. The sponsor should inform the IRB whether other IRBs have reviewed the proposed study and what determination was made. The sponsor must inform the IRB of the Agency's assessment of the device's risk if such an assessment has been made. The IRB may also consult with FDA for its opinion.

The IRB may agree or disagree with the sponsor's initial NSR assessment. If the IRB agrees with the sponsor's initial NSR assessment and approves the study, the study may begin without submission of an IDE application to FDA. If the IRB disagrees, the sponsor should notify FDA that a SR determination has been made. The study can be conducted as a SR investigation following FDA approval of an IDE application.

The risk determination should be based on the proposed use of a device in an investigation, and not on the device alone. In deciding if a study poses a SR, an IRB must consider the nature of the harm that may result from use of the device. Studies where the potential harm to subjects could be life-threatening, could result in permanent impairment of a body function or permanent damage to body structure, or could necessitate medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to body structure should be considered SR. Also, if the subject must undergo a procedure as part of the investigational study, e.g., a surgical procedure, the IRB must consider the potential harm that could be caused by the procedure in addition to the potential harm caused by the device. Two examples follow:

• The study of a pacemaker that is a modification of a commercially available pacemaker poses a SR because the use of any pacemaker presents a potential for serious harm to the subjects. This is true even though the modified pacemaker may pose less risk, or only slightly greater risk, in comparison to the commercially-available model. The amount of potential reduced or increased risk associated with the investigational pacemaker should only be considered (in relation to possible decreased or increased benefits) when assessing whether the study can be approved.
• The study of an extended wear contact lens is considered SR because wearing the lens continuously overnight while sleeping presents a potential for injuries not normally seen with daily wear lenses, which are considered NSR. FDA has the ultimate decision in determining if a device study is SR or NSR. If the Agency does not agree with an IRB's decision that a device study presents an NSR, an IDE application must be submitted to FDA. On the other hand, if a sponsor files an IDE with FDA because it is presumed to be an SR study, but FDA classifies the device study as NSR, the Agency will return the IDE application to the sponsor and the study would be presented to IRBs as an NSR investigation.

IRB and Sponsor Responsibilities Following SR/NSR Determination

If the IRB decides the study is Significant Risk:

1. IRB Responsibilities:

• Notify sponsor and investigator of SR decision
• After IDE obtained by sponsor, proceed to review study applying requisite criteria [21 CFR 56.111]

 2. Sponsor Responsibilities:

• Submit IDE to FDA or, if electing not to proceed with study, notify FDA (CDRH Program Operations Staff 301-594-1190) of the SR determination;
• Study may not begin until FDA approves IDE and IRB approves the study.
• Sponsor and investigator(s) must comply with IDE regulations [21 CFR part 812], as well as informed consent and IRB regulations [21 CFR parts 50 and 56].
• There is no requirement for the sponsor to notify FDA of the SR determination.

If the IRB decides the study is Non-significant Risk:

1. IRB proceeds to review study applying requisite criteria [21 CFR 56.111]. If the study is approved by the IRB, the sponsor and investigator must comply with "abbreviated IDE requirements" [21 CFR 812.2(b)], and informed consent and IRB regulations [21 CFR parts 50 and 56].

The Decision to Approve or Disapprove
Once the SR/NSR decision has been reached, the IRB should consider whether the study should be approved or not. The criteria for deciding if SR and NSR studies should be approved are the same as for any other FDA regulated study [21 CFR 56.111]. The IRB should assure that risks to subjects are minimized and are reasonable in relation to anticipated benefits and knowledge to be gained, subject selection is equitable, informed consent materials and procedures are adequate, and provisions for monitoring the study and protecting the privacy of subjects are acceptable. To assure that the risks to the subject are reasonable in relation to the anticipated benefits, the risks and benefits of the investigation should be compared to the risks and benefits of alternative devices or procedures. This differs from the judgment about whether a study poses a SR or NSR which is based solely upon the seriousness of the harm that may result from the use of the device. Minutes of IRB meetings must document the rationale for SR/NSR and subsequent approval or disapproval decisions for the clinical investigation.

FDA considers studies of all significant risk devices to present more than minimal risk; thus, full IRB review for all studies involving significant risk devices is necessary. Generally, IRB review at a convened meeting is also required when reviewing NSR studies. Some NSR studies, however, may qualify as minimal risk [21 CFR 56.102(i)] and the IRB may choose to review those studies under its expedited review procedures [21 CFR 56.110].

Examples of NSR/SR Devices
The FDA provides a list of examples to assist sponsors and IRBs in making SR/NSR determinations. The list includes many commonly used medical devices. Inclusion of a device in the NSR category should not be viewed as a conclusive determination, because the proposed use of a device in a study is the ultimate determinant of the potential risk to subjects. It is unlikely that a device included in the SR category could be deemed NSR due to the inherent risks associated with most such devices.

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Policy 10: Genetic Research and Tissue Banking

POLICY:

All research involving genetic testing, analysis and tissue banking shall be given special consideration with regard to the unique risks presented by such research, and according to current regulation governing such research. Click on http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm for OHRP guidance on research use of stored data or tissue.

GUIDANCE:

Any research that involves human DNA samples,genetic testing or genetic information is considered genetic research. That includes, but is not limited to, research examining mutations in DNA, research examining differences between traits in individuals with or without a certain disease, and records research involving information derived from previous genetic tests.

In genetic research and research using stored tissue samples, there are potential health, societal, emotional and legal issues to consider. Many subjects may be naive to these issues and it is therefore necessary for the IRB to evaluate the protocols and consent forms for such studies with great care. As this new science develops and laws evolve, it is important to continuously rethink and refine the issues and the way in which they are presented to subjects.

Applicable Terms and Definitions Genetic Research: Research using human DNA samples, genetic testing or genetic information Genetic Information: Information about an individual or an individual's blood relatives obtained from a genetic test Genetic tests: The analysis of human DNA, RNA, chromosomes, proteins or metabolites, that detect genotypes, mutations, or chromosomal changes. Genetic Characteristic: A gene, chromosome or alteration thereof that may be tested to determine the existence of or risk for acquiring a disease, disorder, trait, propensity or syndrome, or to identify a blood relative. Repository (tissue bank): A storage site for collections of human biologic specimens available for study. A repository may reside in one geographic location or may be a virtual collection of biologic specimens from many locations. Sample: In the context of genetic research, a sample is any human biological material. This includes, but is not limited to: molecular material such as DNA, cells, tissues (blood, bone, muscle, etc.), organs (liver, bladder, heart, etc.), gametes, embryos, fetal tissue, waste (hair, nail clippings, urine, feces, etc.) and other materials of human origin. Specimen: In reference to a human biological repository, a specimen is the quantity of material stored in the repository, while a sample refers to an aliquot of the specimen supplied to investigators. Types of studies: Prospective:studies in which the collection of the new samples is part of the study design. Retrospective: Studies that utilize previously obtained samples collected for a purpose that is different from that of the current study Types of Samples: Research samples are grouped into four levels of identification dependent upon the amount of information that is available about the subject from whom the sample was obtained. These levels include: Unidentified samples(anonymous): Samples that are/were obtained and stored without any identification that may link the specimen to a specific subject. Unlinked samples(anonymized or de-identified): Samples that may have been acquired from identified humans subjects, but all identifiers or codes have been removed and destroyed. For unlinked samples, it would be extremely difficult for the investigator, the repository or a third party to identify the person who provided an individual sample. (See de-identified information) Coded samples: Samples labeled with a code rather than a name or other personal identifier. When such samples are obtained from a tissue repository, the repository usually retains information that links the code to a particular individual. Using this information, the investigator, the repository or a third party could determine which particular person or small group of identifiable individuals provided the biological specimen. Depending on the nature of the identifiers related to the specimen, the sample may or may not meet the definition of a limited dataset under HIPAA. The IRB will make that determination and will decide whether the use of the sample, as specified in the protocol, requires a data use agreement,tracking of disclosures, or business associate agreement. See Policy 3:HIPAA. Identified samples: Samples collected and supplied to investigators with personal identifiers sufficient to allow person who provided the material to be identified.

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10.1 Research Using Prospectively Collected Samples

(Revised 12/30/10)

 

In general, research involving the prospective collection of coded or identified samples requires subject consent and authorization. Additionally the investigator has the obligation to maintain confidentiality to the extent permitted by law. (This is necessary unless the samples are collected anonymously.)

In addition to the standard elements of consent (see Policy 5: Informed Consent) the consent/authorization forms for such research should clearly indicate, as appropriate:

• What information could result from the research,
• What the implications and limitations are,
• That unexpected findings may result,
• What follow-up information subjects will receive (if any, as many studies are preliminary and results may not be meaningful or validated), and

If subjects have consented to and authorized storage of samples for future studies, they need to be informed of how long storage will continue and the possibility of storage failure. Subjects should be given the option of being re-contacted to consider use of their samples in future studies. See Guidelines for Preparing Research Consent Forms: Required and Suggested Language, for a description of sample consent language pertaining to genetic research and specimen banking.

Note:  A single authorization may cover uses and disclosures of PHI for multiple activities of a specific research study, including the collection and storage of tissues for that study. In addition, where two different research studies are involved, such as where a research study collects information for the study itself, and collects and stores PHI in a central repository for future research, North Shore LIJ permits these authorizations to be combined into one.  See memo issued on December 16, 2010.

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10.2  Retrospective Studies of Existing Samples

When retrospective research is done using anonymous or anonymized samples, consent from subjects is not necessary, since the subjects cannot be individually identified and there is no expected risk to the subject.  For research using samples that are identifiable, consent must be obtained.  In certain cases the investigator may seek a waiver as detailed in 45 CFR 46.116 (see Policy 5: Informed Consent).

See Guidelines for Preparing Research Consent Forms: Required and Suggested Language, for a description of sample consent language pertaining to genetic research and tissue banking.
 

 

10.3  Specimen and Data Repositories

(Revised 12/27/10)

Specimens and/or data stored for unspecified or planned future research is considered a specimen and/or data repository. In order to establish a specimen and/or data repository, IRB review and approval must be obtained. Subjects must give explicit consent and authorization for the collection and storage of samples unless a waiver of consent and/or authorization is granted by the IRB.

A repository may consist of the collection, maintenance and management, and distribution of specimens and/or data to internal and external investigators for research purposes. The term “repository” may also be referred to as a “tissue bank” “data bank” or “registry”. Specimens and data collected and maintained for routine clinical care or clinical purposes (e.g. pathology or blood banks), quality assurance, or as defined by a single research protocol does not qualify as a repository unless they are to be used for future research, research beyond the aims of the original protocol, or shared with other investigators for other research purposes.

Specimens and data gathered for non-research purposes or from an existing research protocol can be converted to a repository with IRB review and approval.

Minors

If minors are enrolled in a repository, they may need to be consented as adults when they turn 18. Generally if specimens and/or data were collected from a minor, but no new information will be gathered after they have turned 18, re-consent may not be necessary. On the other hand, if new specimens and information will be collected after they turn 18, you will need to obtain their consent as adults for continuation of participation. Plans for seeking consent or a waiver of consent from the IRB along with a justification should be outlined in your protocol.

See Specimen and Data Repository Guidance for more information.

 

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10.4  Disclosure of Results to Subjects

Disclosure of genetic research findings to a research subject, in general, should not occur. Disclosure may be approved in rare circumstances, but only when all of the following apply:

• The research findings are scientifically valid and confirmed (done in a CLIA approved lab);
• The findings have significant implications for the subject’s or the public’s health; and
• A course of action to ameliorate or treat the subject’s or the public’s health concerns is readily available.

If results are to be given, subjects should be offered counseling, as appropriate, since results from such research could lead to adverse psychological outcomes, social stigmatization and discrimination.  In certain cases subjects should be given the option to determine whether they want to be informed of the results of their testing. 

10.5 Protocol/Consent Requirements for Genetic Research or Tissue Banking

In addition to standard submission requirements (see Policy 2: How to Prepare a Protocol for IRB Review), protocols and consent forms involving genetic research or tissue banking should specifically address the following:

Purpose of the Study

• That the sample will be used for genetic research.

Duration

• How long sample will be stored

Control and Ownership of Specimens/Materials

• Who owns specimens/materials
• If research could lead to commercially valuable product
• Whether subjects will receive a portion of profits

Subject Access to Genetic Information

• What information subjects are entitled to receive
• If results ill not be provided to subjects and why
• If findings are to be disclosed, procedures for doing so (e.g., genetic counseling)
• The point in the research at which the findings will be disclosed (e.g., interim results)
• The policy regarding disclosure of incidental findings

Secondary Use

• Will subsequent investigators be given access to samples with direct or indirect identifiers?
• Will subjects be given option of consenting now to future second use?
• Will subjects be informed that they may be re-contacted? or
• Will subjects be given option to indicate if they are willing to be re-contacted?
• Will subjects have the option of limiting use of samples?

Risks

• Social Risks: Breach of confidentiality could impact insurability, employability, reproduction plans, family relationships (including paternity), etc.
• Psychological Risks: If information is disclosed, impact of learning results; impact if no effective therapy exists; psychological stress for family members
• Physical Risks: Physical risks associated with collecting samples for research purposes and/or for gene therapy procedures
• Unknown Risks: Subjects should be told that there may be risks that are presently unknown

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Policy 11: Research Investigators

POLICY:

The principal investigator (PI) must be on staff or hold an academic appointment within the North Shore-Long Island Jewish Health System (NSLIJHS). Studies originating from another institution that will include a NSLIJHS investigator or site engaged in research as defined by the DHHS Office for Human Research Protections must be reviewed by a health system authorized IRB and have a designated principal investigator from NSLIJHS.   A health system authorized IRB is one listed on the North Shore-LIJ Health System Federal Wide Assurance (FWA 00002505) as having the authority to review human subject research at NSLIJHS facilities.  An IRB authorization agreement (IAA) must be executed if utilizing an external or alternative IRB.  The Institutional Official for Human Subject Protections or designee is the only individual authorized to enter into an IAA.  

All documents associated with the study submitted to the North Shore-LIJ Health System IRB should consistently list the designated on-site PI first. Students doing research must have a mentor from the Health System to oversee the conduct of the research listed on the protocol application as a co-investigator. This includes all residents and students (medical, nursing, administrative, etc.). If the student is not on staff at NSLIJHS, the mentor must be listed as the PI. The IRB does not recognize the designation of co-principal investigators. There must be one PI who has overall responsibility for the study; all others are co-investigators or sub-investigators.

In addition to the designation of a PI, all research protocols submitted for IRB review must list all co-investigators who will be involved in the research on IRB Form1a; only those individuals so listed may recruit subjects and participate in the study. An investigator may not participate in research until he/she has complied with institutionally mandated researcher registration and researcher education. Based on current regulatory requirements, the IRB may mandate additional education prior to an individual's involvement in research. Protocols involving more than one area of expertise should include co-investigators from the appropriate disciplines to ensure proper execution and oversight of the protocol. If the protocol involves a special area of investigation, including radioisotopes, animals, biohazards, rDNA, investigational drugs, or the utilization of the General Clinical Research Center (GCRC), it is the responsibility of the PI to contact and receive approval from the appropriate committees or individuals with oversight responsibility in these areas (see Consultations and/or Approvals for Research Projects).

The PI of a clinical research study at NSLIJHS must accept the following responsibilities:

• Ensuring that individuals involved in the conduct of the study are qualified by education, training, and experience to perform his/her respective task.
• Protecting the rights and welfare of human research subjects. The health and well-being of the individual patient/subject must be the first priority. 
• Complying with all federal, state and Institutional regulations as set forth in the Institutional Policies and Procedures, the Federalwide Assurance (FWA), all other pertinent regulatory documents and their amendments.
• Complying with all requirements set forth in the clinical protocol and contract. This includes the performance of all protocol-required testing, maintenance of complete and accurate records as per the sponsor's requirements, and complete and timely communication with the sponsor and IRB. 
• Controlling drugs, biological products, and devices under investigation.
• Submitting each research activity to the Office of the IRB for determination as to whether it qualifies as exempt or needs expedited or full IRB review. 
• Ensuring proper execution of the informed consent process (see Policy 5: Informed Consent), including efforts to ascertain that the subject has comprehended the information in the consent form, as well as retaining all original, signed consent forms. The most recently approved version of the consent form must be used when obtaining consent from a subject. 
• Ensuring all proposed changes in previously approved research activities are submitted to the IRB and that no changes are initiated prior to IRB review and approval, except where necessary to eliminate immediate hazards to the subjects.
• Submitting progress reports, as requested, in a timely fashion (see Policy 6.1: Progress Reports). 
• Complying with all decisions and requirements of the IRB. 
• Promptly reporting any serious, unanticipated problems involving risks to subjects or others to the IRB (see Policy 6.8: Serious Adverse Events/Unanticipated Problems). 
• Providing the IRB with accurate and up-to-date information regarding the research. 
• Ensuring additional personnel are added, as necessary, in order to include the appropriate expertise for carrying out the protocol. 
• Attending or completing education and training sessions offered by the Institution. 

NOTE: Key personnel are defined as, and should be limited to, individuals who contribute in a substantive way to the scientific development or execution of the project. This includes all investigators who meet this definition, including research coordinators and nurses. Consultants should be listed only when their level of involvement meets the definition of key personnel. Individuals providing technical services as they would outside the context of an individual study (such as the performance of routine laboratory testing) would not automatically be considered key personnel.

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