Contributors

The focus of the Special Section in this issue is the ethics of how knowledge is acquired through experiments on human subjects. Assuming that our use of language may have an effect on our thoughts and behavior, how we commonly understand the term “subject” in research with humans can undercut what is most important from an ethical perspective. The notion of “subject” can be crucially ambiguous in that it can refer to the units making up the “n” of a research study—those nameless, faceless, numbers supplying the information that supports, or fails to support, the researchers' hypothesis. On the other hand, “subject” can have a much deeper meaning. In addition to being participants in a study, the humans involved are, have been, or will be the subjects of lives—that is, they are real persons, with all the personal characteristics and social connections that entails. It is because of this status that they deserve to be regarded and protected. The degree to which we lose sight of this distinction increases the danger of crossing the ethical limits of human subjects research.

Due to modern biochemistry and, in particular, recent developments in genomics, proteomics, and bioinformatics, human samples (organs, tissues, cells, genes, etc.) have become the most important raw materials for advancement in the health sciences. Such material has been at the center of fundamental biomedical research for a long time. What is new is its increased usefulness in research with direct clinical relevance, such as the development of drugs. Because of the larger commercial involvement in such research, this has also led to greater economic interests in human biological material and in the information that can be extracted from it.

Research involving the dead has not been regulated, and little, if any, institutional oversight has been provided. As a result, the numbers and types of research projects involving the dead are at best poorly characterized and at worst, unknown. The University of Pittsburgh instituted a mechanism for oversight of such research in June 2002. In this article, we report the experience of that oversight body, the Committee for Oversight of Research Involving the Dead (CORID), during its first 18 months.

Informed consent is the bedrock principle on which most of modern research ethics rest. That principle, like most others, has some exceptions, such as for emergency situations and for some studies involving very low risk. But what about situations that do not fall into either of these categories? Are there such research studies that are so important to society that we nonetheless are willing to involuntarily enroll subjects, without their informed consent?

The first principle of the Nuremberg Code (1946) requires the informed consent of the subject. Proxy consent was not addressed until the Declaration of Helsinki (1964). U.S. policies regarding consent for the participation of children in research would not be finalized for almost two more decades (1983) in subpart D of the federal regulations that govern the participation of subjects in research. In October 2000, the Children's Health Act was passed. Title X required the Secretary of the Department of Health and Human Services (DHHS) to conduct a review of the regulations under subpart D and “to consider any modifications necessary to ensure the adequate and appropriate protection of children participating in research, and report the findings of the Secretary to Congress.” In this article, I provide a brief overview of the current informed consent requirements in pediatric research, which include requirements for parental permission and the child's assent. I then examine the moral bases for these requirements; whether the current policies are consistent with these moral foundations; and if not, how the policies ought to be modified.I would like to thank Walter Glannon, Ph.D., for reading an earlier version of this paper. The section of this paper entitled “Parental Permission” is based on an editorial: Ross LF. How many parents should be needed to consent to a child's participation in medical research? American Academy of Pediatrics, Section on Bioethics Newsletter May 2002:1, 4. Dr. Ross's research on children in research is funded by an NIH Grant (NLM 1 G13 LM07472-01).

Multiple groups, including the National Bioethics Advisory Commission, the American Society of Clinical Oncology (ASCO), the National Coalition of Comprehensive Cancer Centers (Personal communication with Robert B. Catalano, PharmD, Vice President for Regulatory Affairs, Coalition of National Cancer Cooperative Groups), Workgroup 6 of the Summit Series on Cancer, PRIM&R, the Bell Report, and prominent ethicists have called for replacing the current system of local institutional review with central review for multisite national trials. We argue that this need is particularly acute in pediatric oncology, as shown by the experience of the Children's Oncology Group (COG).

U.S. regulations do not afford consistent protections to human research subjects. One complaint is that they focus on federally sponsored research, with private research covered only if it falls under the jurisdiction of the Food and Drug Administration (FDA). This paper examines a deeper problem: Even when the regulations do apply, they still do not afford consistent standards of protection. The U.S. Common Rule and related FDA regulations lack a workable regulatory control mechanism.

The last two decades have witnessed intense debate over the ethical legitimacy of placebo controlled trials (PCTs). Most of the arguments for and against the use of PCTs turn on one of the following issues: (1) the compatibility of the obligations of clinicians and researchers with PCTs, (2) the scientific merit of PCTs, and (3) the influence of patients' and subjects' perceptions, ability to consent, expectations, and rights on the permissibility of PCTs. I introduce each of these categories and assess the principal arguments in each group. I argue that, although some of the arguments against PCTs have limitations, they do inform the debate in significant ways by pointing to important constraints on PCTs. Those concerning patients' and subjects' perceptions, capacity to consent, expectations, and rights are particularly instructive. They do not, for the most part, sustain an absolute prohibition of PCTs, but they do suggest types of PCTs that are inappropriate and they indicate issues that must be addressed when PCTs are conducted. I argue that we should look to the reasonableness and permissibility of informed refusals of care (1) to evaluate the extent to which a trial is a legitimate PCT (e.g., cases in which clinicians would be highly suspect of accepting informed refusals may be more problematic than PCTs in situations in which clinicians would be comfortable accepting informed refusals); (2) to determine which potential subjects should be considered eligible to enroll in a PCT (e.g., those who would not be permitted to refuse treatment generally might not be eligible to enroll in a PCT); and (3) to inform the language that should be used in describing the study as part of the informed consent process (e.g., prospective subjects should be asked if they are willing to forgo treatment and not enroll in the trial).

Intersexual infants and infants with other genital abnormalities often receive genital surgery for sex assignment or for normalizing purposes. The wisdom and beneficence of these practices have been questioned by intersexual individuals, support groups, some doctors, and the media. Because the practices have been developed without long-term studies to evaluate them, pediatric urologists and parents of such children must face decisions with very little guidance from empirical support. In the face of ignorance about what is really the best medical response to intersexuality or genital abnormalities, some have argued for a moratorium on infant genital surgery until empirical studies are available. The urgent need for retrospective studies is now being recognized in medical journals. Because genital surgery may be appropriate and beneficent in some of these conditions, or in some degrees of these conditions, but not in others, retrospective studies must be devised to examine the degree of success of surgery for each of these conditions, or levels thereof.

In a recent edition of the Medical Journal of Australia, Greg Dore and David Cooper called on persons in developed nations like Australia to bridge the divide between resource-rich countries to nations in the developing world, where therapies to ease or halt the ravages of the virus are nonexistent or in short supply.

CQ Sources/Bibliography.

In November 2003, researchers at Cambridge University announced they had identified a gene associated with an elevated risk of breast and related ovarian cancers. The gene—christened EMSY in honor of a breast-cancer nurse who is the sister of the study's lead author—is particularly significant because it is linked to so-called sporadic cancers. Such cancers do not arise from hereditary mutations of the BRCA1 and BRCA2 genes, in which genes that ordinarily prevent breast and ovarian cancers are altered, often giving rise to multiple cases of cancer within a family as the mutation is passed along. The Cambridge researchers determined that the presence of extra copies of EMSY in an individual may instead switch off a healthy BRCA2 gene.

The Big Fix: How the Pharmaceutical Industry Rips Off American Consumers, by Katharine Greider. New York: Public Affairs; 2003. 189 pp.

The Big Fix is, as Greider describes, “the utter folly of allowing a profit-driven industry to name its price, while quietly making over our public-health agenda in its own image”—the theme of the book. Written in an easy-to-understand, conversational manner targeted to the American consumer, The Big Fix is a comprehensive description of the commonly held views of critics of the pharmaceutical industry, although most of the points made are not novel. In eight chapters, each given a catchy descriptive title, Greider does a good job of detailing the issues and citing well-known experts and critics of the industry, such as Marcia Angel and Thomas Bodenheimer, even though she does not always provide the exact sources of these citations for those academic types who may want to know more.

Busy physicians and scientists tend to be willfully naive about politics. Physics, chemistry, and biology are clean—that is, subject to relatively consistent and identifiable laws or at least trends and, certainly in the case of medicine, beneficial when properly applied. Politics, on the other hand, tend to be unpredictable, murky, and dirty—that is, too often all about self-serving power and, ultimately, money.

This section is meant to be a mutual effort. If you find an article you think should be abstracted in this section, do not be bashful—submit it for consideration to feature editor Kenneth V. Iserson care of CQ. If you do not like the editorial comments, this will give you an opportunity to respond in the letters section. Your input is desired and anticipated.