Medical Research in Prisons: Regulations and Ethical Implications
Due to ethical issues that we will soon explore, pharmaceutical-based clinical trials are strictly regulated in the US. However, with the highest incarceration level in the world, the over two million Americans in prison are often viewed as potential targets by researchers eager to conduct clinical experiments on a wide range of medical afflictions on a population always accessible and highly controlled.

Introduction

Due to ethical issues that we will soon explore, pharmaceutical-based clinical trials are strictly regulated in the US. However, with the highest incarceration level in the world, the over two million Americans in prison are often viewed as potential targets by researchers eager to conduct clinical experiments on a wide range of medical afflictions on a population always accessible and highly controlled [3]. The most frequent conditions in inmates are HIV/AIDS, cancer, hepatitis C and tuberculosis [1], [3]. In particular, the HIV rate in prisons is about six times greater than in the free population, and about 17 percent of Americans with HIV or AIDS have served time in prison. Also, populations in correctional facilities have the highest rates of hepatitis C, with an estimate of between 20 to 60 percent of inmates, depending on the state, carrying the virus [3]. Given this statistics, inmates represent a convenient test group for anti-viral vaccines and drugs. This paper provides a brief historical background of medical research in prisons, a review of the codes and legislation that govern it -with emphasis on the current law-, and a summary of the ethical debate around it. The paper closes with some final remarks that include our personal position on the subject.

Brief Historical Background

After World War II, medical experiments in America driven by federal funding were being conducted using inmates in prisons, academic-pharmaceutical alliances and the need to test products in humans to meet US FDA regulations. By 1972, the pharmaceutical industry was doing more than 90 percent of its phase I toxicity testing on inmates. Up until the '70s, scantly regulated experiments in prisons often resulted in abuses.

Dow Chemical and Johnson & Johnson, the University of Pennsylvania and a dermatologist were sued by hundreds of Holmesburg Prison inmates that were object of experimental research by the application of skin creams, cosmetics, dioxin and LSD between the '50s and the '70s [3]. The lawsuit claims that the inmates, who were paid $2 per day, were never informed of the risks of the trial. The surviving subjects suffer from breathing problems, skin rash, infections, and infertility.

Dozens of Washington State Prison inmates had their testicles exposed to radiation between 1963 and 1973 [4]. The subjects were assured that the tests were safe and were enticed with cash and suggestions that participating in the experiments could help them win parole.

Due to frequent abuses, from the late '70s through the early '90s new university regulations and state and federal laws regarding the protection of human subjects in medical, pharmaceutical and cosmetic experiments brought research in prisons to a halt.

Ethics Codes and Legislation

Relevant documents for ethics in medical research in correctional facilities include the Nuremberg Code, the Helsinki Declaration, the Belmont Report, and 45 CFR 46.

The Nuremberg Code was drafted in 1947 as the standard by which to judge physicians and scientists during their trial at Nuremberg at the end of World War II. It laid down 10 standards to which physicians must conform when carrying out experiments on human subjects and became an ethical standard for research for decades. The first of these standards states that "the voluntary consent of the human subject is absolutely essential ... [and] should be so situated as to be able to exercise free power of choice without ... the intervention of any element of force, fraud, deceit, duress ... or coercion". This standard has been widely interpreted as excluding prisoners from research, since incarceration is a necessarily coercive condition. [2]

The Helsinki Declaration of 1964 was the first significant effort by the medical community to regulate itself. It was developed by the World Medical Association, and is a set of ethical principles for the medical community regarding human experimentation. Since its adoption it has been amended multiple times. In early versions it made an important distinction between therapeutic and non-therapeutic research. However, this distinction was eliminated in later versions. Like the Nuremberg Code, the Declaration made informed consent a central requirement for ethical research. However, the Declaration allowed for surrogate consent when the research participant is incompetent, physically or mentally incapable of giving consent, or a minor. The Declaration states that research with these groups should be conducted only when the research is necessary to promote the health of the population represented and when this research cannot be performed on legally competent persons. [9]

In response to the growing public awareness of clinical research, the National Research Act was signed into law on July 12, 1974. It created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which we shall refer to as "the Commission". One of the Commission's goals was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects, and to develop guidelines to be followed to assure that such research is conducted in accordance with those principles. The Belmont Report [7] resulted from monthly deliberations of the Commission held over a four-year period. It was published in The Code of Federal Regulations (CFR), on April 18, 1979 as a statement of the Department of Health, Education, and Welfare's policy of ethical principles and guidelines for the protection of human subjects of research. Later this department evolved into the Department of Health and Human Services (DHHS), which remains responsible for the protection of human subjects involved in biomedical research through the Office of Human Research Protection (OHRP). The three basic principles that were detailed in the Belmont report were:

• Respect for persons: The report states that individuals should be treated as autonomous agents, and that those with diminished autonomy are entitled to protection. The report itself directly addresses the issue of prisoner participation in research: "Respect for persons demands that subjects enter into the research voluntarily and with adequate information." In some situations, however, application of the principle is not obvious. The involvement of prisoners as subjects of research provides an instructive example. On the one hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for research. On the other hand, under prison conditions they may be subtly coerced or unduly influenced to engage in research activities, for which they would not otherwise volunteer. Respect for persons would then dictate that prisoners be protected. Whether to allow prisoners to "volunteer" or to "protect" them presents a dilemma.
• Beneficence: The term "beneficence" is often understood to cover acts of kindness or charity that go beyond strict obligation. In the Belmont report, beneficence is understood as an obligation that implies "maximize possible benefits while minimize possible harms".
• Justice: The question of who ought to receive the benefits of research and bear its burdens is one of justice, in the sense of "fairness in distribution" or "what is deserved&rdquo.;

45 CFR 46 [8] was originally published in 1978 and later reviewed in 2001. It is the current US law that provides guidance regarding the inclusion of prisoners in research. It applies to all research involving human subjects that is conducted, supported by or otherwise subject to regulation by any federal department or agency. It provides direction on how agencies and institutions can file letters of assurance that they will comply with these regulations, the composition and duties of institutional review boards (IRBs) that oversee federally funded research, and requirements and documentation for informed consent. Informed consent is designed to protect individuals participating in clinical research trials. An individual interested in participating in a medical research trial will receive a document that contains information about the benefits and risk of the trial, the research procedures and the reasons for the research. The participant should be able to review the document with doctors and ask questions about things they do not understand. Official consent to participate in the trial is given when this document is signed, with the researcher and the participant retaining a copy. However, the process of informed consent should not end there. The researchers are obligated to keep the participant updated and answer any questions the participant has. Informed consent does not obligate the participant to finish the trial. A participant has the right to leave the trial at any time during the study. Subpart C lists additional protections pertaining to biomedical and behavioral research involving prisoners as subjects. 45 CFR 46 Subpart C covers the prisoner in the next ways by including a prisoner or a prisoner representative on the IRB reviewing the research, and by assigning additional duties to the reviewing IRB to be sure that the research is permissible, free of undue influence, safe, accessible and fair to all inmates, presented in understandable language, and does not have any effect on parole. Permissible research involving prisoners is limited to the following four cases:

(A) Study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects.

(B) Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects.

(C) Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that the study may proceed only after the Secretary [of the Department of Health and Human Services] has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of his intent to approve such research.

(D) Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject.

In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice in the Federal Register, of the intent to approve such research.

According to 45 CFR 46, permissible research includes not only social, behavioral, and psychological research, but also therapeutic trials using pharmaceutical agents for medical conditions that particularly affect inmates (though the use of placebos in this situation requires additional safeguards.) The example given in the law specifically mentions hepatitis, but the health condition that came to the forefront as a condition particularly affecting prisoners was HIV infection and AIDS. Under pressure from patients and patient advocacy groups, HIV clinical research moved from the strictly academic setting to a variety of other patient sites including non-university affiliated hospitals, private physician offices, and community consortiums. In the 1990s, when effective HIV treatment therapies were under investigation in multiple clinical trials, HIV clinical trials at some academic sites re-entered the prison setting. In this case, inclusion of prisoners was often justified as a means to provide access to cutting-edge therapies to persons living with HIV who were incarcerated. At several major medical centers, HIV research was extended into correctional facilities. For example, clinical trials being conducted at The University of Texas Medical Branch in Galveston and the University of Miami in Florida were offered to inmates in the Texas Department of Criminal Justice and the Florida Department of Corrections, respectively. Additionally, behavioral research regarding AIDS in the incarcerated population was being conducted by Yale and Brown Universities in their respective state jurisdictions. Not all of these studies fell under the purview of 45 CFR 46, as these regulations apply to federally funded studies and some of these investigations were funded by pharmaceutical industry support. Allowing prisoners to participate seemed appropriate since life-saving treatment, not available outside of clinical trials, became available to incarcerated patients with AIDS.

Correctional clinicians and representatives from OHRP attended a "Clinical Trials in Corrections" meeting. The proceeds of the conference were published in 2001 in AIDS Reader [10]. What happened next had a profound effect on pharmaceutical medical research using prisoners as subjects. The IRBs at the University of Texas Medical Branch, the University of Miami, Brown University, and Yale University were reviewed by the OHRP and received "letters of determination" that the composition of the IRBs and their procedures to ensure the protection of prisoners were inadequate. In all cases, studies are required to present no more than a "minimal" risk to the prisoner. Yet in many of the clinical trials reported to the OHRP, those regulations were clearly violated.

University of Texas Medical Branch (UTMB). Revelations about medical research on prisoners began to come to light when the OHRP suspended federally funded research projects UMTB in Galveston because the university had not followed federal regulations aimed at protecting research-study volunteers. The OHRP would not provide any details about the studies and clinical trials, most of which involved treatments for HIV and AIDS. But documents obtained through a Freedom of Information Act request offer insight into the types of studies conducted on prisoners at UTMB. The September 14, 2000 letter from the OHRP to UTMB listed numerous research projects that did not fall into any of the categories of permissible research on prisoners, finding "scant evidence" that the university's IRB followed federal regulations when it reviewed and approved the studies like those on induction of labor among pregnant inmates, study of different methods of obtaining biopsies from inmates, phase I clinical trial involving an experimental HIV vaccine, phase I clinical trial using a new experimental therapy of the intra-hepatic delivery of a powerful chemotherapy drug, phase I study that used prisoners to test a radically experimental approach to treating lung cancer. The consent form for the latter study cites a long list of serious potential side effects and included the additionally disturbing warning that the university would not compensate a research subject in case of injury. Participants in the study signed a form that read: "I understand that I cannot receive financial remuneration for any injuries resulting from my participation in this project." though Federal regulations specifically prohibit any language in informed consent documents whereby a subject is made to release, or appear to release, the investigator or the institution from liability for negligence.

University of Miami. In 2000, the OHRP also directed the University of Miami to suspend enrollment of volunteers in a medical study of juvenile inmates, noting the existence of three other university studies involving prisoners that had not been reported to the appropriate federal office.

University of Florida, Yale and Brown Universities. In addition, the OHRP instructed the University of Florida, Yale University and Brown University to drastically improve their reporting and oversight procedures for several studies involving prisoners. Addressing a request for information about ongoing studies involving prisoners, Brown noted that a study in the Philippines examining STDs and the high-risk behaviors of female prisoners had ended.

Enrollment in clinic trials was suspended at the University of Texas Medical Branch at Galveston and the University of Miami. However, each of the universities cited above eventually received permission to resume research with prisoners.

What is in the future of 45 CFR 46? Secretary Tommy Thompson of the DHHS has speculated that it is time that Subpart C is re-evaluated again. To this end, the DHHS has asked the Institute of Medicine of the National Academy of Sciences to investigate the impact of Subpart C, and to determine if there should be any change in the current law. The Committee of Ethical Considerations for Revisions to the DHHS' Regulations for Protection of Prisoners Involved in Research was impaneled to examine whether the conclusions reached in the 70's remain appropriate today. The committee's final report is expected in March, 2006.

There is no federal data on the number of prisoners participating in medical research studies, so there is no clear data of how many prisoners are enrolled in clinical trials funded by the government. Moreover, OHRP does not keep track of the inmate deaths as a result of failure of the clinical trial. For privately funded trials, the situation is even less clear, since pharmaceutical companies would not publish results on failed trials so that competitors would not get advantage from that information.

The Ethical Debate

The multiple attempts to regulate medical experiments in correctional facilities highlight the fact that this is a controversial subject. Further, the impact on society as a whole is profound, as it involves inmates and their families, doctors at the prisons, ethicists, lawyers, prisoner advocates, prison administrators, pharmaceutical companies, and the medical community in general. Over the last decade an ethical debate was formulated, with most of participants belonging to one of these two camps [6]:

• No medical study can ethically include inmates, on the basis of their living in a coercive environment.
• Incarceration should not deny an individual of his or her right and ability to make an informed decision regarding participation as a research subject.

In other words, much of the ethical debate is fueled by the need to balance the human rights of a vulnerable population (i.e. prisoners) with respect for their individual autonomy to decide over their own actions. It is worthwhile to mention that both camps cite the well-being of the inmate population as the source for their positions. For reasons that need no elaboration, benefits to the pharmaceutical industry are not given as a primary reason for either of the two positions.

Proponents of a ban or strict limits on medical research on inmates argue that socioeconomic factors make very difficult for inmates to understand the implications of the research, a necessary requirement to be able to provide informed consent. Further, it is argued that real or perceived "perks" make the decision to participate a coerced one. For example, prisoners often assume that their participation in studies will result in material gains in either money or kind (e.g. cigarettes), favorable treatment (e.g. better prison housing), reduced sentences and early parole. It seems reasonable to assume that misguidance by prison personnel and administrators of the studies in the early years of unregulated research contributed to create this perception of expected rewards.

On the other hand, proponents of the right of inmates to freely choose to participate in medical research highlight the fact that there are tangible benefits that should not be denied to this population. For example, drug trials can provide inmates -a population, as we saw earlier, afflicted by serious illnesses at rates higher than the general population- with better medical care at no cost, including monitoring and access to qualified specialists, drugs and equipment). Also, proponents argue, things like honest eagerness to do something good for society as a measure of redemption, and a patriotic call to make contributions during military conflicts should not be denied to prisoners.

Final Remarks

Considering both arguments in the ethical debate valid, it seems sensible to try to find a compromise solution that would bridge the gap between the two sides of the debate. Our personal belief is that generic or random clinical trials that have no therapeutic benefit to the inmate should not be allowed on the grounds of the serious questions surrounding the inmate's ability to understand the consequences of failure of the clinical trial. This is be in line with a concern stated on paragraph 1 of the 'Nuremberg Code': "and [the inmate] should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision". Medical research conducted in prisons should be limited to those that could benefit prisoners as individuals or as a group. That would provide incarcerated individuals with access to state of the art therapies. This is particularly important for prisoners with chronic illnesses, given that medical care in correctional settings is generally substandard.

Finally, we believe that the ethical debate still needs to tackle two very important issues that are yet to be addressed. The first issue involves the mechanism for informing inmates of the potential risks and benefits of medical research. What is the best way to provide prisoners with the information they need to make a decision? Should this transfer or sharing of information be carried out by an independent body? The second issue is based on the fact that, as noted earlier, the United States has the highest incarceration rate in the world. A figure often overlooked is that, in addition to the over 2 million Americans in prison, there are about 3.5 ex-inmates. This population still exhibits many of the traits seen inside the correctional facilities, such as lower socioeconomic background and higher rates of infectious diseases. If not taken into account the population of former inmates could become target of unscrupulous medical research.

For over half a century the subject of research in prisons has been at the center of an ethical debate on medical research. Evolution in societal attitudes has triggered significant changes in regulations and legal codes in America. Far from over, it is expected that the subject will continue to spark debate among inmate advocates, lawyers and the medical community for generations to come.

References

[1] Robert Whitaker, Boston Globe, 11 Oct 1999, page A03.
[2] The Nuremberg Code, (from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182. Washington, D.C.: U.S. Government Printing Office, 1949.)
[3] Silja Talvi, "The Prison as Laboratory: Experimental medical research on inmates is on the rise", 'These Times', January 7-21, 2002.
[4] Rick Anderson, 'Great Balls of Fire', 4 Jan, 2000.
[5] Sydney Freedberg, "Questions raised over AIDS research on inmates", 'St. Petersburg Times', 19 Mar, 2000.
[6] David Paar, MD, D. Thomas, MD, "Research in Corrections", IDCR, September 2005 Vol. 8, Issue 9.
[7] The Belmont Report.
[8] 45 CFR 46.
[9] The Helsinki Declaration.
[10] DeGroot AS, et al. "HIV in clinical trials: right or retrogressions?", 'AIDS Reader', 2001; 11(1):34-40.

Other Links

• OHRP: DHHS Office for Human Research Protections.
• NIH Clinical Trials.
• NIH Office of Extramural Research Human Subjects.
• DHHS OHRP Guidance on the Involvement of Prisoners in Research.
• American Correctional Association (ACA).
• The World Medical Association (WMA).
• IDCR (former HEPP report): Infection Diseases in Corrections Report.

Publicado por Nuria De Francisco @ 4/14/2006 11:12:00 PM