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E. PRISONERS

INTRODUCTION

The involvement of prison inmates in research was once common because the stability of prison life (e.g., controlled diet, ready availability of subjects for follow-up) made prisons attractive research environments. More recently, however, ethicists and others concerned with the treatment of human participants in research recognized that the very fact of incarceration may make it difficult or impossible for prisoners to give voluntary, informed consent. In response to this growing concern, the National Commission for the Protection of Human Subjects was asked to consider the problem; the Commission issued its report and recommendations in 1976. In 1978, DHHS issued specific regulations governing research with prisoners [45 CFR 46 Subpart D]. The implementation of FDA regulations on research involving prisoners has been stayed until further notice [21 CFR 50 Subpart C]. Some federal agencies significantly limit the involvement of prisoners in biomedical research (e.g., Federal Bureau of Prisons).

DEFINITIONS

Minimal Risk: Risk of physical or psychological harm that is no greater in probability and severity than that ordinarily encountered in the daily lives, or in the routine medical, dental or psychological examinations of healthy persons [45 CFR 303(d)]. IRBs should note that this definition differs somewhat from that given for noninstitutionalized, competent adults [Federal Policy §___.102(i); 45 CFR 46.102(i)].

Prisoner: An individual involuntarily confined in a penal institution, including persons: (1) sentenced under a criminal or civil statute; (2) detained pending arraignment, trial, or sentencing; and (3) detained in other facilities (e.g., for drug detoxification or treatment of alcoholism) under statutes or commitment procedures providing such alternatives to criminal prosecution or incarceration in a penal institution [45 CFR 46.303(c)].

IRB CONSIDERATIONS

General Considerations. The first question IRBs must ask when a protocol proposes to use prison inmates as a study population is whether that population was chosen simply out of convenience to the investigator. Because the population is relatively stable and the life is routine, prisons have in the past seemed ideal environments in many ways for the conduct of certain types of research. Some procedures that would inconvenience free subjects are not a burden to prisoners. Since prison pay scales are notably lower than those in the free world, the cost of using prisoners as subjects may be less than using those who are not prisoners. And, unlike the general civilian population, they are all in one place. However, the nature of incarceration may conflict with the ethical principal of autonomy, captured in the Nuremberg Code provision requiring that the subject "be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion."

The primary issue surrounding the participation of prisoners in research has always been whether prisoners have a real choice regarding their participation in research, or whether their situation prohibits the exercise of free choice. A secondary issue is whether confidentiality of participation and of data can be adequately maintained in the prison.

The circumstances common in prisons create environments in which the offer to participate in research is necessarily coercive or creates a undue influence in favor of participation. To the extent that living conditions in prison are bad and the provision of health care is minimal or even nonexistent, the lack of control allowed prisoners and the desire to obtain the advantages offered to those who agree to participate may preclude their ability to weigh fairly the risks and benefits involved in participation. For example, the investigator may propose to move the research participants to special units where they are given medical care and where the living conditions are better than those provided to the general prison population. Another coercive situation would be where prisoners must earn money to purchase the means by which to maintain their health and personal hygiene, and one way to earn that money is by participating in research. Other rewards for participation, such as offering parole or a reduction in sentence, would constitute an undue inducement. Even the opportunity to leave the prison cell and interact with people from outside the prison may act as an undue inducement to participate in research.

Nancy Dubler (1982) has described the prison setting as "inherently coercive." She describes prisons as brutal and dangerous, "woefully overcrowded, understaffed, underprogrammed and ill-supported by any coherent philosophy of reform, or even punishment" [p. 10]. She provides the following quote from a report in a prison inmate magazine:

Louisiana pays its prisoners from two to five cents an hour for their labors, an amount grossly inadequate to meet their needs. To augment that income, many inmates sell their "plasma" twice weekly to the privately-owned plasma company located in the Main Prison, getting $9.50 each time. The process involves the plasma firm drawing a pint of blood from the inmate, extracting the plasma, then returning the "red blood" back to the inmate. Whenever the bag containing the donor's blood accidentally bursts, preventing the return of the blood into the inmate, the firm's policy is to suspend the inmate from the plasma program for six weeks to allow sufficient time for his blood cells to build back up. Such a suspension entails a total loss of $114 income for the inmate, money he would have earned during that six-week period.

But, as it turns out, the bursting of the blood bags of some donors weren't (sic) always caused by accidents. According to information from inmates and security personnel, a number of inmate-employees of the plasma firm were threatening to deliberately bust the bags of homosexuals and inmates in protective custody units if the inmate-victim did not agree to "belong" to them. It was reported that such threats were also utilized to extort sex from them.

According to an informed source, some of the inmate-victims complained to the Warden's office, providing names of those allegedly involved in the homosexual extortion scheme. And, in a move that caught the entire Main Prison by surprise, the Warden's Office ordered the immediate transfer of nine inmate plasma workers out of the Main Prison to outcamps, all those believed to be involved. "I've been in this business for a long time, and I thought I knew all the prison games," the source told The Angolite, shaking his head, "but this is a new one on me...'starving them out,' they called it."

In addition to problems of coercion and undue inducement, the involvement of prisoners in research raises questions of burden and benefit. Prisoners should neither bear an unfair share of the burden of participating in research, nor should they be excluded from its benefits, to the extent that voluntary participation is possible. Prisoners' rights to self-determination (autonomy) should not be circumscribed more than required by applicable regulations (see below). IRBs should refrain from assuming, without cause, that prospective prisoner-subjects will lack the ability to make autonomous decisions about participation in research. To the extent that prisoner-subjects are found able to voluntarily consent to participation, and to the extent allowable under applicable regulations, prisoners should be allowed the opportunity to participate in potentially beneficial research.

Another question is whether prisoner-subjects can ethically be paid for participation, and if so, how much. In nonprison settings, paying subjects to participate in research is considered ethically acceptable, so long as it is commensurate with the discomfort and/or inconvenience involved. Paying prisoners the same amount that would be paid to nonprisoners may, however, be seen as unduly influential in a setting where inmates can earn only a small fraction of that amount for any other "work" activity. On the other hand, paying prisoners a fraction of what would be paid to nonprisoners can be seen as exploitative. One suggestion that has been offered is to require that investigators pay prisoners at the same rate as they would pay nonprisoners, but that individuals would receive an amount comparable to that paid for other prison tasks. The difference would be paid into a general prison fund, to be used, for instance, to subsidize the wages paid to all prisoners, or to be used for educational or recreational purposes (to be determined by the prison population, not the administrators). Alternatively, the difference could be paid into an escrow account, to be distributed to the prisoner upon release or to be paid to the prisoner's family [Levine (1986), pp. 282-83; Veatch (1987), p. 60].

Finally, confidentiality is extremely difficult to maintain in an environment such as prisons in which there is no privacy. In prisons, people do not move about freely; the movements of prisoners are carefully tracked. When inmates are moved around (e.g., to go to a research appointment), everyone will know about it. Prison records, including medical records, are accessible to persons who in other settings would not have access to such personal information. Consider the inmate participating in HIV-related research. How will the sensitive nature of the research be kept secret? Before an IRB approves any research in prisons, the investigator must be able to ensure that the necessary confidentiality can and will be maintained so that the participants are not subjected to any risk from participation.

To protect prisoners from the exploitative conditions presented by these situations, DHHS issued regulations governing research with prisoners, limiting it to studies with an independent and valid reason for involving this particular population (e.g., studies of the effects of incarceration). These limitations were imposed in response to, but are more restrictive than, the recommendations of the National Commission. Writing about research on HIV infection and AIDS in prisons, Dubler and Sidel (1989) summarize the goals of protection of prisoners involved in research. They state that, "Inmates as a group need to be protected from research designs that can acquire the data through other routes and may present risks to inmates as a class. They need to be provided with access to clinical trials of new and innovative therapies that present the possibility of direct benefit to the subjects. They must be presented with the opportunity for informed choice when appropriate, despite recognition that the systematic deprivations and inherent coerciveness of the institutions...compromise the consent process" [p. 204].

Regulations. If a protocol involves the use of prisoners as subjects, both the general DHHS regulations governing research with human subjects and the special ones dealing specifically with prisoners apply. [See discussion in the Introduction to Chapter 6 on the question of applicability of DHHS regulations.] If, because of its nature, the IRB has reason to know that it will be reviewing protocols involving prisoners as subjects, IRB members should familiarize themselves with these regulations and discuss them before any actual prisoner protocols are presented.

DHHS regulations have special requirements regarding the membership of an IRB that reviews research involving prisoners [45 CFR 46.304]. At least one member of the IRB must be a prisoner or a prisoner representative with the appropriate background and experience to serve in that capacity. A majority of IRB members (exclusive of prison members), must have no other association, apart from IRB membership, with the prison(s) involved.

Only certain kinds of research conducted or supported by DHHS may involve prisoners as subjects: (1) studies (involving no more than minimal risk or inconvenience) of the possible causes, effects, and processes of incarceration and criminal behavior; (2) studies (involving no more than minimal risk or inconvenience) of prisons as institutional structures or of prisoners as incarcerated persons; (3) research on particular conditions affecting prisoners as a class (providing the Secretary, HHS, has consulted with appropriate experts and published [his or her] intent to support such research in the Federal Register); and (4) research involving a therapy likely to benefit the prisoner subject (and if the therapeutic research also involves nontherapeutic research with a control group, the Secretary, HHS, must also consult with appropriate experts and publish [his or her] intent to support the research in the Federal Register).

Much of the permissible research is behavioral. Biomedical research concerning, for example, the effects of limited exercise or prison diets on the overall physical condition of inmates may also be permitted, providing the research procedures present no more than minimal risk. IRBs should be alert to the possible risk of retaliation by other inmates or prison guards posed by a prisoner's participation in a study of such topics as HIV infection or AIDS, rape, drug use, or violent behavior within the institution.

The IRB has additional responsibilities when reviewing research involving prisoners [45 CFR 46.305]. It must determine whether any advantages the prisoners may obtain through participation in the research are of sufficient magnitude to impair the inmates' ability to choose to participate, given the institutional context of limited choice (advantage as compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings in the prison) [45 CFR 46.305(a)(2)]. The IRB must also decide if the risks involved in the research are commensurate with risks that would be accepted by nonprisoner volunteers [45 CFR 305(a)(3)]. It must ensure that the procedures for selecting subjects are fair and immune from arbitrary intervention by prison authorities or prisoners [45 CFR 305(a)(4)]. There must be adequate assurances that parole boards will not take a prisoner's participation in research into account when making parole decisions, and each prisoner must be clearly informed in advance that participation will have not effect on his or her parole [45 CFR 46.305(a)(6)]. The research institution must thereafter certify to the Secretary, HHS, that these special responsibilities have been fulfilled [45 CFR 46.305(c)].

An understanding of the definition of minimal risk provided in 45 CFR 46 Subpart C is critical. The risks to which prisoners may be exposed by participating in the research is not compared with the risks "normally encountered...by prisoners," but rather with risks "normally encountered in the daily lives, or in the routine medical, dental or psychological examination of healthy persons," i.e., nonprisoners. Dubler and Sidel (1989) have argued that in assessing risk, IRBs:

1. Ought not to use the risks that face prisoners in the prison setting as the standard for acceptable risk;
2. Ought not to judge even apparently ordinary risks at face value [e.g., confidentiality in prison is impossible to maintain];
3. Ought to allow only risks that are commensurate with those accepted by nonprisoners [pp. 199-200].

IRB members should be aware of any state law governing research with prisoners. More than half the states have legislation or regulations restricting research with prisoners; prisoners incarcerated in non-federal penal institutions in states with no specific law regarding prison research will lack the protection provided by such restrictions; IRBs reviewing protocols that propose to involve subjects in such institutions should therefore, recognize the special protective role they play. IRBs in such situations would be well advised to study the recommendations of the National Commission for the Protection of Human Subjects on research with prisoners. These recommendations describe a series of considerations that balance the risks of research with the conditions of incarceration.

Regulations promulgated by the FDA [21 CFR 50 Subpart C] have been stayed until further notice. IRBs should check the status of the FDA regulations when reviewing research to which FDA regulations would apply.

The Federal Bureau of Prisons places special restrictions on research that takes place within the Bureau of Prisons. Those regulations are published at 28 CFR Part 512. The restrictions apply to any research involving inmates in the custody of the Attorney General, and assigned to the Bureau of Prisons, regardless of the institution in which the inmate is incarcerated (e.g., even if the inmate is resident in a state institution). Primarily, research within the Federal Bureau of Prisons is limited to research involving no more than minimal risk, and, where applicable, must be consistent with the Bureau of Prisons' policy on medical experimentation and pharmaceutical testing [28 CFR 512.12]. Research proposals are reviewed by the Director, Bureau of Prisons, following review by the local institution and regional administrative units [28 CFR 512.14]. The policy on medical experimentation and pharmaceutical testing generally prohibits biomedical research and drug testing on its inmates, although individual prisoners in need of medical treatment and who qualify for experimental therapy may participate in DHHS-approved clinical trials "when recommended by the responsible physician and approved by the [Federal Bureau of Prisons'] Medical Director" [Federal Bureau of Prisons, Health Services Manual, Program Statement 6000.3, para. 6823]. For more information concerning biomedical research involving prisoners under the jurisdiction of the Federal Bureau of Prisons, contact:

Ms. Harriet Lebowitz
Office of Research and Evaluation
Federal Bureau of Prisons
Room 3007, 400 First Building
Washington, D.C. 20534
Tel: (202) 307-3871, ext. 120
Fax: (202) 307-5888

POINTS TO CONSIDER

1. Does the IRB have the necessary prisoner-related members?

2. Does the proposed research fall within one of the permissible categories of research with prisoners?

3. Is the use of prisoners as subjects justified?

4. Is there any evidence of duress, coercion, or undue influence in the particular prison(s) from which subjects will be recruited? (Does the prison facility meet all of the conditions set forth in applicable regulations?)

5. Are there any applicable state laws with which the IRB must comply?

APPLICABLE LAWS AND REGULATIONS

Federal policy for the protection of human subjects

21 CFR 50 Subpart C[FDA: Regulations governing research with prisoners]
45 CFR 46 Subpart C[DHHS: Additional protections pertaining to biomedical and
behavioral research involving prisoners as subjects]
28 CFR 512[Department of Justice, Federal Bureau of Prisons: Research]

Federal Bureau of Prisons, Health Services Manual, Program Statement 6000.3

Regulations of the various components of the Defense Department

State statutes and regulations concerning research with prisoners

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F. TRAUMATIZED AND COMATOSE PATIENTS

INTRODUCTION

Research involving patients who require emergency treatment may involve the administration of an experimental emergency treatment or the close monitoring of a generally recognized emergency treatment. In either case, special problems of informed consent are raised.

OVERVIEW

Research involving subjects undergoing emergency care differs from clinical research in other settings because the patient's capacity to provide informed consent is often severely compromised, and decisions about participation in research may have to be made too quickly to obtain permission from the patient's legally authorized representative. The patient's altered mental status may vary from one of confusion and disorientation to coma. Altered mental status may result from an accident or emergency condition, a physiological response such as shock or infection, a psychological response (anxiety, grief, or physical pain), or the effects of drugs.

Research involving emergency patients is further complicated because there are a variety of state laws concerning informed consent for emergency treatment that might be applied to research on therapy for emergency patients. DHHS regulations (and the Federal Policy) permit the waiver of informed consent requirements only in the case of research that presents no more than minimal risk [45 CFR 46.116]. FDA regulations, on the other hand, permit exception from the informed consent requirement for patients confronted by a life-threatening situation where there is no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the subject's life [21 CFR 50.23]. Some legal scholars have suggested that experimental emergency treatment might be given to a patient who cannot give informed consent if, in the opinion of the physician, it is the most promising treatment available. DHHS regulations say only that "nothing in these regulations is intended to limit the authority of a physician to provide emergency medical care, to the extent the physician is permitted to do so under applicable Federal, State, or local law" [45 CFR 46.116(f)].

See also Guidebook Chapter 3, Section B, "Informed Consent," which discusses the circumstances under which the DHHS requirements for consent may be altered or waived, and Chapter 2, Section B, "Food and Drug Administration Regulations and Policies," which addresses the distinction between DHHS and FDA regulations on waiver of IRB review, waiver of informed consent, and emergency use of a test article.

IRB CONSIDERATIONS

The risks and benefits of studies in emergency care may each vary from extremely high to negligible. At one extreme, where significant incapacity or death is almost certain, a new therapeutic measure may offer a reasonable chance for recovery, sustaining life, or preventing serious and permanent deficits. In other situations, the potential benefits and risks may be equally great; one may not "outweigh" the other. Drugs given in an effort to save the lives of trauma victims might do so at the risk of preserving those lives in a persistent vegetative state. Many studies involving emergency care may be almost without risk yet yield information useful in the treatment of the patient (e.g., monitoring certain physiological events by noninvasive means).

The IRB should ensure that the risks are minimized, the confidence in the anticipated benefits is justifiable, and the risks are reasonable in relation to the anticipated benefits. According to DHHS regulations (and the Federal Policy), IRBs may waive the informed consent requirements when the risks are no more than minimal, the research could not reasonably be carried out without waiving the requirement of informed consent, and such a waiver would not adversely affect the subject's rights or welfare [45 CFR 46.116(d); Federal Policy §___.116(d)]. Subjects or their legally authorized representative should be provided with pertinent information when, and if, it becomes possible and appropriate. DHHS regulations and the Federal Policy preclude research presenting more than minimal risk without the subject's legally valid consent unless it is possible to obtain the permission of the patient's legally authorized representative. The mental state of family members in the emergency situation may, however, preclude good decision making. Further, it is often not possible to locate family members in time to make the decisions necessary in emergency care. IRBs and investigators should also note the distinction between "next-of-kin" and "legally authorized representative." Although "consent" by next-of-kin is traditionally accepted by physicians treating incompetent or comatose patients, family members do not have clear legal authority to give such consent except in a few states having statutes or case law on the subject.

FDA regulations permit exception from the informed consent requirements when both the investigator and a physician not otherwise involved in the research certify in writing that: (1) the subject is confronted by a life-threatening situation necessitating the use of the test article; (2) informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from the subject; (3) there is not sufficient time to obtain consent from the subject's legally authorized representative; and (4) there is no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject available [21 CFR 50.23]. Documentation of such circumstances must be submitted to an IRB within five working days.

In contrast, under the DHHS regulations, if prior informed consent is not possible, and the IRB has not waived the informed consent requirements (e.g., if the research involves greater than minimal risk), the patient should be excluded from the study and provided with standard care. In cases in which the requirement for emergency care is foreseeable and subjects can be identified in advance (e.g., a study to be performed after elective major surgery), informed consent might be obtained well before the surgery.

IRBs and investigators should note that where a patient requires emergency care, DHHS regulations requiring prior IRB review remain in effect. While the regulations do not "limit the authority of a physician to provide emergency medical care" [45 CFR 46.116(f)], they also do not permit research activities to begin as part of emergency medical care unless the research has received prior IRB review and approval [45 CFR 46.103(b); "Emergency Medical Care," OPRR Reports (May 15, 1991)]. While such patients may receive emergency medical care, the patient may not be considered to be a research subject. "Such emergency care may not be claimed as research, nor may the outcome of such care be included in any report of a research activity" [OPRR Reports (May 15, 1991)].

In contrast, FDA regulations do allow for the emergency use of a test article, without prior IRB review and approval, so long as the emergency use is reported to the IRB within five working days of its occurrence. Any subsequent use of the test article is subject to IRB review [21 CFR 50.23; 21 CFR 56.104(c)]. The FDA's regulations on emergency use of test articles is discussed in greater detail in Guidebook Chapter 2, Section B, "Food and Drug Administration Regulations and Policies."

POINTS TO CONSIDER

1. Does the research pose more than minimal risk to subjects?

2. Do the anticipated benefits to the subjects justify proceeding with the research even though it is not possible to obtain their prior informed consent? (Proceeding with research without prior informed consent is acceptable only for minimal risk research under DHHS regulations and in life-threatening situations under FDA regulations.)

3. Is consent from the patient's next-of-kin required? Is it sufficient? (Check if there are any applicable state laws on this subject.)

4. If a preliminary consent procedure is employed, what amount of time should reasonably be allowed to elapse before requiring that a valid consent be obtained or the subject be removed from the study?

5. Is there a need for additional monitoring, either of the consent process or the conduct of the research itself?

APPLICABLE LAWS AND REGULATIONS

21 CFR 50.23[FDA: Informed consent]

Applicable state law concerning consent to experimental emergency medical treatment for persons incapable of consenting. Note that consent to medical treatment may differ from consent to research.

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G. TERMINALLY ILL PATIENTS

INTRODUCTION

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)]. If an IRB regularly reviews research involving the terminally ill, it should include among its members one or more individuals knowledgeable about and experienced in working with these subjects [45 CFR 46.107].

With the appearance of HIV, concerns have emerged about circumstances under which persons with serious and life-threatening conditions may have access to research drugs through expanded access programs. The FDA's Parallel Track program and Treatment IND regulations seek to address these concerns. [For a discussion of these two expanded availability mechanisms, see Guidebook Chapter 2, Section B, "Food and Drug Administration Regulations and Policies."] IRBs have a role both in considering circumstances in which terminally ill persons are appropriately excluded from research because they are a vulnerable group, and in providing persons who have no therapeutic alternatives the opportunity to receive the possible benefits of experimental interventions. [See also Guidebook Chapter 5, Section F, "AIDS/HIV-Related Research;" 21 CFR 312.34; and Federal Register 57:13250-13259 (April 15, 1992).]

DEFINITIONS

Expanded Availability: Policy and procedure 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. Examples of expanded availability mechanisms include Treatment INDs, Parallel Track, and open study protocols.

Therapeutic Intent: The research physician's intent to provide some benefit to improving a subject's condition (e.g., prolongation of life, shrinkage of tumor, or improved quality of life, even though cure or dramatic improvement cannot necessarily be effected.) This term is sometimes associated with Phase 1 drug studies in which potentially toxic drugs are given to an individual with the hope of inducing some improvement in the patient's condition as well as assessing the safety and pharmacology of a drug.

OVERVIEW

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, 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 1 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" 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. [See Ackerman (1990).]

The HIV epidemic has heightened awareness of mechanisms for including in research persons who have serious and life-threatening illness. Increasingly, individuals and advocacy groups have emphasized the need for opportunities for terminally ill persons to exercise their right of autonomy: to weigh themselves the risks and benefits of participating in research on drugs, even where relatively little is known about the safety or effectiveness of the drugs. Many desperately ill individuals would like to take investigational drugs that may not be available except through limited, well-controlled clinical trials because they are in the very early stages of development.

Although the HIV epidemic has created a demand for expanded access to investigational drugs, the issue is not new. In the 1970s, a number of physicians, generally at academic centers, had access to investigational drugs through protocols outside the controlled clinical trial prior to drug approval. This mechanism allowed these physicians to provide investigational drugs to persons without satisfactory alternative therapies, even though they were not part of a controlled trial and the drug was not yet approved. The drugs in these protocols were usually also under active development in controlled trials. A similar mechanism was developed to provide investigational drugs to persons with cancer. The FDA and the National Cancer Institute (NCI) developed a special category of drugs called "Group C." Group C drugs may be provided by oncologists to appropriate cancer patients through protocols outside the controlled clinical trial prior to the drug approval. In 1987, the FDA initiated a regulation establishing the treatment investigational new drug application (Treatment IND), and in 1992, instituted a policy providing for a "parallel track" mechanism [21 CFR 312.34; Federal Register 57:13250-13259 (April 15, 1992)]. Under a Treatment IND protocol, eligible patients have access to investigational new drugs intended to treat serious or life-threatening diseases; Parallel Track protocols enable persons with AIDS or HIV-related diseases who cannot participate in clinical trials to have access to investigational drugs. [See Guidebook Chapter 2, Section B, "Food and Drug Administration Regulations and Policies," for a discussion of expanded access mechanisms.]

IRB CONSIDERATIONS

IRBs should give research involving terminally ill individuals careful attention; they should also consider requiring special procedures for protecting the rights and well-being of these subjects. IRBs should satisfy themselves that the nature, magnitude, and probability of the risks and benefits of the research have been identified as clearly and as accurately as possible. Special attention should be paid to the consent process, both in terms of the accuracy of the information to be provided and the manner in which consent is sought. As a general rule, accurate information concerning eligibility for participation (i.e., diagnosis and prognosis), treatment options, and risks and benefits should be conveyed clearly and in a manner that will not either engender false hope or eliminate all hope.

IRBs must also consider including other information the patient might find relevant to making an informed decision to participate. For example, subjects should be told whether or not participation in the study is a condition for treatment at the institution; any costs to the patient of the research should be stated explicitly. IRBs should consider whether any payment might constitute an undue enticement, particularly if the subject population is economically disadvantaged. Patients should be provided with relevant information well in advance of making a decision about participation, and consultation with others such as family members, close friends, clergy, or medical consultants should be encouraged.

IRBs may also find it advisable to require that the clinical investigator be someone other than the patient's physician, that emergency services be readily available, or that there be frequent monitoring of the progress of the research. Factors to consider in making such decision include: anticipated toxicity of the therapeutic interventions; extent to which subjects are likely to be debilitated by either their illness or their therapy; the remaining life expectancy of the subjects; and whether participation in the research would require a change in residence (e.g., from home or hospice to a hospital or research institution).

POINTS TO CONSIDER

1. Must the research involve terminally ill patients to achieve its objectives?

2. Is a clear explanation of the patient's eligibility for the study provided?

3. Are specific treatment alternatives, including the option of no treatment, described?

4. Are the potential benefits and risks (and their probability) realistically and simply stated?

5. Are the ways in which participation may affect the patient's lifestyle clearly described (e.g., "You will be hospitalized each month for 5-7 days.")?

6. Is the patient assured that he or she can withdraw from the study at any time? If withdrawal from the research will result in a patient's discharge from a research unit or end the patient's access to health care that has been provided in conjunction with the research, is that fully explained?

7. Should a witness or patient advocate be present during consent negotiations?

8. Is there reason to require that the patient's physician not be the clinical investigator?

9. If the research is done under a Treatment IND or other expanded access mechanism, is the lack of conclusive effectiveness data made clear? Are all costs to subjects of receiving a drug or device under an expanded availability mechanism clearly specified?

10. If a drug is administered at the community level, does the subject's physician have access to information about the drug's potential usefulness and potential risks?

APPLICABLE LAWS AND REGULATIONS

45 CFR 46[DHHS: Protection of human subjects]
21 CFR 50[FDA: Informed consent]
21 CFR 56[FDA: IRB review and approval]
21 CFR 312[FDA: New drugs for investigational use]

Federal Register 57:13250-13259 (April 15, 1992) [FDA: Parallel Track policy]

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H. ELDERLY/AGED PERSONS

INTRODUCTION

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.

IRB CONSIDERATIONS

Aside from the regulatory requirement that IRBs provide additional protections for specially vulnerable persons [Federal Policy §___.111], there are no specific regulations governing research with elderly subjects. It is generally agreed, however, that the elderly are, as a group, heterogenous 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, nonelderly subject in the same circumstances.

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 difficulties in recruiting them to participate. Older persons tend to avoid research that interrupts their daily routine, is uncomfortable or inconvenient, or is not designed to provide direct benefits to them [Levine (1986), p. 85; Sachs and Cassel (1990), p. 236; Cassel (1985), p. 46]. Also, conducting research with older patients may be more difficult and more costly. Elderly persons may have hearing or vision problems and may therefore require more time to have the study explained to them. They also drop out of studies at a higher rate than do younger subjects, so that investigators may need to recruit more subjects initially to account for this possibility.

Despite these difficulties, the inclusion of older persons in the research enterprise is important. IRBs should ensure that where they are excluded or treated specially, older subjects are in need of protection and are not the object of disdain, stereotyping, or paternalism. Together, researchers and the IRB should enable older persons to share in the benefits and burdens of research.

IRBs should treat cognitive impairment in elderly subjects as they would cognitive impairment in any prospective subject. [See Guidebook Chapter 6, Section D, "Cognitively Impaired."] The subject population should comprise cognitively impaired persons only under the following circumstances: when competent subjects are not appropriate for the study; if the study is related to a problem unique to persons with that disability; and if the study involves minimal risk [Annas and Glantz (1986), p. 1157].

The use of age as the criterion of ability to consent and therefore participate in research is not valid. Studies have shown that education, health status, and inadequate communication about the research rather than age contribute to lack of comprehension and recall [Sachs and Cassel (1990), pp. 235-36]. While it is recognized that memory may be a problem for some elderly subjects (thus putting into question their ability to provide continuing consent), the question for the IRB is whether, despite some impairment to competence, subjects can make reasonable choices. It has been suggested that in order to screen subjects for sufficient comprehension and recall, a two-part consent process be used, where the second part involves a test of the subject's comprehension and recall of the information presented in the first part. Repeated tests have been found to improve recall. Prospective subjects who do not remember the important facts about participation in the research after repeated testing should not be included in the study [Levine (1986), p. 85; Sachs and Cassel (1990), pp. 235-236].

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, persons who suffer from the disease or condition reside primarily in institutions, or the study focuses on the institutional setting itself). [See Guidebook Chapter 6, Section D, "Cognitively Impaired" for a discussion of the problems of research involving institutionalized subjects.] Annas and Glantz (1986) suggest that "a nursing home council, composed primarily of residents, should review and approve any protocol before the research can be conducted at their facility. Research that may seem trivial to us in terms of risk, discomfort, disorientation, or dehumanizing effects may not seem so trivial to this vulnerable and often frightened population" [p. 1157].

POINTS TO CONSIDER

1. Does the proposed consent process provide mechanisms for determining the adequacy of prospective subjects' comprehension and recall?

2. How will subjects' competence to consent be determined?

3. Will the research take place in an institutional setting? Has the possibility of coercion and undue influence been sufficiently minimized?

APPLICABLE LAWS AND REGULATIONS

45 CFR 46[DHHS: Protection of human subjects]

State and local laws regarding research involving institutionalized individuals

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I. MINORITIES

INTRODUCTION

The participation in research by members of racial and ethnic minority groups raises concerns about appropriate levels of inclusion and generalizability of study results; the issues are parallel to those raised with respect to the inclusion of women in studies. [See Guidebook Chapter 6, Section B, "Women."] In addition, the involvement of minorities raises concerns about the selection of subjects, the possibility of special vulnerability on the part of some prospective subjects, and about consent and the relative strengths or weaknesses of vulnerable groups in the consent process.

IRB CONSIDERATIONS

The federal regulations require the equitable selection of subjects [Federal Policy ___.111(a)(3)]. In addition, NIH requires that applicants for all research grants, cooperative agreements, and contracts involving human subjects include minorities (and women) in study populations "so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them." Investigators must provide a "clear compelling rationale for their exclusion or underrepresentation" [PHS Grant Application form 398, pp. 21-22]. The complete text of the policy and discussion of the issue of inclusion of women and minorities in study populations is provided in the Guidebook in Chapter 6, Section B, "Women."

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 nonminority 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), underrepresentation 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 overinclude 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 more simple, 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.

Research designs that include diverse study populations are, therefore, highly desirable. IRBs should require investigators to justify protocols that call for homogeneous study populations. They should also be aware of the implications of various recruiting strategies, and be prepared to suggest alternative recruitment methods so as to ensure an appropriately diverse or focused subject population. In doing so, the IRB should also be aware of the special needs of prospective subjects, such as the provision of child care or transportation.

In addition to ensuring adequate appropriate representation of minorities in study populations (and guarding against inappropriate overburdening of minorities), IRBs must ensure that any special vulnerabilities of subjects are accounted for and handled appropriately. To the extent that prospective minority study populations are also economically or educationally disadvantaged, IRBs should safeguard their rights and welfare by making sure that any possible coercion or undue influence is eliminated (e.g., compensation that is not commensurate with the risk, discomfort, or inconvenience involved, or recruiting in institutional settings where voluntary participation might be compromised).

IRBs should also safeguard the consent process (and, indeed, the entire research relationship) to ensure open and free communication between the researcher and the prospective subject. Consent documents must be written in language easily understandable to subjects; the possibility of illiteracy should be accounted for, as should the need for communicating in foreign languages. The informed consent documents should be available in English and other languages as appropriate to the subject population(s). Foreign language consent documents should be developed using quality control procedures such as translation from English to the other language and then back to English, to ensure that the information is correctly conveyed. The role of cultural norms of subjects should also be addressed [Federal Policy ___.111(b)]. The involvement of representatives from the target population(s) may also be pertinent to IRB review.

IRBs should keep in mind that the goal here is to ensure that minorities share fairly the benefits and burdens of the research enterprise. In offering protection, however, IRBs should avoid paternalism and stereotyping.

POINTS TO CONSIDER

1. Is the subject population appropriately drawn? Will minority subjects likely be appropriately and adequately represented? If not, is the homogeneity of the study population justified?

2. Are subject recruitment strategies appropriate for obtaining a diverse subject population?

3. Have the special needs of prospective subjects been addressed (e.g., child care, transportation)?

4. Has the possibility of undue influence or coercion been eliminated?

5. Does the proposed consent process ensure open and effective communication between the researcher and prospective subjects? Are the consent documents written in language that will be easily accessible to subjects? Are documents in foreign languages necessary? Is foreign language facility on the part of the research staff necessary (both for obtaining consent and conducting the research)?

APPLICABLE LAWS AND REGULATIONS

Federal Policy ___.111[Criteria for IRB approval of research]

NIH policy concerning inclusion of women and minorities in study populations. NIH Guide for Grants and Contracts 20 (No. 32, August 23, 1991): 1-3. The policy also appears in the application packet for Public Health Service Grants, form PHS 398, pp. 21-22, and in NIH Requests for Proposals (RFPs).

Application for Continuation of a Public Health Service Grant, form 2590, pp. 7-9 and Form Page 7.

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J. STUDENTS, EMPLOYEES, AND NORMAL VOLUNTEERS

INTRODUCTION

The involvement of students, employees, and normal volunteers in research may present special concerns with which IRBs should be familiar. The federal regulations do not provide explicit protections for subjects in these categories.

IRB CONSIDERATIONS

Normal Volunteers. Strange as it may seem at first, 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 [Federal Policy §___.111(b); 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 [Federal Policy §___.116(a)(6-8); 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 [Federal Policy §___.116(b)(2-3); 45 CFR 46(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, "Human Genetic 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 is fair and noncoercive.

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.

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)].

APPLICABLE LAWS AND REGULATIONS

45 CFR 46[DHHS: Protection of human subjects]
21 CFR 50[FDA: Informed consent]
21 CFR 56[FDA: IRB review and approval]

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K. INTERNATIONAL RESEARCH

INTRODUCTION

It is important that all research with human subjects adequately protect the rights and welfare of the subjects. All human subjects research in which American investigators are involved, and which would be subject to the federal regulations if it were conducted wholly within the United States, must comply with the federal regulations for the protection of human subjects in all material respects.

IRB CONSIDERATIONS

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" [Federal Policy §___.101(h); 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 45 CFR 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. [See list of persons to contact in Appendix 3.]

APPLICABLE LAWS AND REGULATIONS

Federal Policy §___.101(h)[To what does this policy apply (foreign research)]
45 CFR 46.101(h)[DHHS: To what does this policy apply? (foreign research)]

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SUGGESTIONS FOR FURTHER READING

A. Fetuses and Human In Vitro Fertilization

B. Women C. Children and Minors D. Cognitively Impaired Persons E. Prisoners F. Traumatized and Comatose Patients G. Terminally Ill Patients H. Elderly/Aged Persons I. Minorities J. Students, Employees, and Normal Volunteers K. International Research

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Chapter VI: Special Classes of Subjects