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Pediatric Research Contraints

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David S. Wendler is Head, Unit on Vulnerable Populations, in the Department of Bioethics at the NIH Clinical Center. His work focuses on the ethics of research with individuals who cannot give informed consent. In his book, The Ethics of Pediatric Research, he looks at what appears to be an irresolvable dilemma: either we can protect pediatric subjects from exploitation, or we can protect pediatric patients from dangerous medicines, but not both. Wendler offers an original justification for pediatric research based on an in-depth analysis of when it is in our interests to help others. In the excerpt below we learn the history of pediatric research constraints.

The early history of pediatric research includes far too many examples of abusive research. One account maintains that: “The history of pediatric experimentation is largely one of child abuse.” In addition, many of the abuses cited by Henry Beecher in his famous 1966 article listing research abuses at prominent institutions in the United States included children, and a number of these studies focused on children specifically. Pappworth also cites many abusive studies involving children. There is inevitable debate over whether one or another of the cited examples in fact involved abusive research. What options did the children have? How are those options relevant to the appropriateness of the study in question? What impact did the study in fact have on the participating children?

Bracketing these questions, which largely are of historic interest, it is clear that many instances of unethical and abusive studies have occurred in the history of pediatric research. One of the earliest recorded cases of abuse occurred in 1892 when Albert Niesser, a medical professor at Breslau, gave serum taken from syphilis patients to unwitting individuals. Several of the recipients contracted syphilis, leading to public outcry and a government ruling, promulgated in 1900 and codified in the 1931 German guidelines, resulting in perhaps the first systematic regulations governing clinical research. These guidelines explicitly prohibit nonbeneficial research with children, as well as pediatric research that “in any way endangers the child.” It is difficult to imagine a research study that does not pose some risks to participating children. Seemingly innocuous surveys of health behavior, for instance, pose some chance of upsetting children. Even widely accepted pediatric research that offers a compensating potential for clinical benefit poses some chance of harm. In practice, then, these guidelines may prohibit essentially all pediatric research.

The German ruling of 1900 is one instance among many in which research guidelines were developed in response to a specific scandal. Most famously, in response to the horrific experiments perpetrated by the Nazis, the Nuremberg Code stipulates that participants’ consent is “essential” to ethical research. This approach, even more so than the German guidelines of 1931, appears to prohibit essentially all research with children. There is an obvious and very important virtue to this approach. If children are prohibited from being enrolled in clinical research, it will be difficult for investigators to exploit them in that context.

By the 1960s, increasing sentiment indicated that the Nuremberg Code needed to be modified in several important respects, especially to address the fact that it did not include a requirement that clinical research studies should be reviewed and approved by an independent ethics board. This requirement was included in the Declaration of Helsinki, promulgated by the World Medical Association in 1964, and intended to address the shortcomings in the Nuremberg Code. The Declaration of Helsinki also is based on recognition of the short-comings of attempting to protect individuals who cannot consent by excluding them from clinical research. This approach protects individuals in the short term but dramatically undermines investigators’ ability to identify better medical treatments for these groups. The Declaration of Helsinki attempts to protect individuals who cannot consent without excluding them from the potential benefits of clinical research by allowing them to be enrolled in clinical research based on the permission of an appropriate surrogate. This clause allows the enrollment of children in clinical research based on the permission of a legal guardian, typically the child’s parents.

The abuses perpetrated as part of the famous Tuskegee syphilis study were made public in 1972, 40 years after the study was initiated. The resulting outcry led to the formation of the U.S. National Commission, which was charged with evaluating the ethics of clinical research with humans and developing recommendations regarding appropriate safeguards. As part of its deliberations, the National Commission spend a good deal of time considering whether it can be acceptable to expose children to research risks for the benefit of others. These deliberations resulted in an entire volume dedicated to the ethics of pediatric research, including what are still some of the most important writings on the topic. These deliberations also produced a series of recommendations for the conduct of pediatric research, which became the framework for the existing U.S. regulations for research with children, one more instance in which scandal led to new regulations for clinical research.

Current Regulations

National regulations governing human subjects research are relatively recent. The U.S. federal regulations for clinical research are not yet 30 years old…

Unlike the early German regulations and the Nuremberg Code, current research regulations around the world attempt to allow important pediatric research while still protecting pediatric research participants. They try to achieve this balance by mandating specific safeguards, especially safeguards concerning risk level. The National Commission argued, and the framers of the U.S. regulations agreed, that what I am calling nonbeneficial pediatric research can be acceptable provided the risks are sufficiently low and several other safeguards are satisfied, including independent review and approval, and permission of the child’s parent or legal guardian…

The U.S. regulations, unlike most other regulations around the world, allow nonbeneficial pediatric research of greater risk in two circumstances. Review boards can approve nonbeneficial pediatric research when the risks are greater than minimal provided they are no more than a “minor” increase over minimal and several additional safeguards have been satisfied. In addition, the Secretary of the Department of Health and Humans Services (DHHS) may approve research that poses risks too great for review board approval following review by a panel of experts. In principle, if not in practice, these regulations would allow approval of nonbeneficial pediatric research that posed risks substantially higher than those average, healthy children face in daily life…

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