assurance process at NIH. enlarge the FDA inspection processes. nor increase IRB on-sight research practices. We are concerned that these recommendations will only serve to detract from the IRBs' effectiveness and efficiency, rather than enhance their performance and mission. The issue of improving the IRB system deserves thoughtful attention. As your subcommittee begins to examine possible methods of improving the IRB system, BIO hopes that you will continue to seek the advice of our organization and others that are currently involved in using IRBs. The National Bioethics Advisory Commission was charged with evaluating current federal protections for human subjects in research to ensure their rights and welfare; it is currently poised to examine the issue of IRBs. We encourage members of Congress to work with them and other experts as well as the biotech industry on this issue. Thank you for this opportunity to begin our conversation on this important issue. BIO's Bioethics Committee was formed several years ago to examine ethical issues involved in research, particularly biomedical research on people who volunteer to test experimental therapies. We are currently reviewing the issues raised in the OIG document. As we formulate a position on this issue, we will be happy to share our findings with you. We look forward to working with you and your staff on these critical issues in the near future. BOSTON UNIVERSITY MEDICAL CENTER BOSTON UNIVERSITY SCHOOL OF MEDICINE / SCHOOL OF PUBLIC HEALTH BOSTON UNIVERSITY GOLDMAN SCHOOL OF DENTAL MEDICINE BOSTON MEDICAL CENTER On April 24, 1998 I sent a letter to Clifford C. Sharke who heads the Assurance Office in the Office of Protection from Research Risks regarding their investigation of studies in which fenfluramine was administered to children in research that could not directly benefit the child-subjects. I am enclosing that letter to you and request that it be included in the record of the hearings that you have scheduled for June 11, 1998. While my letter directly addresses the fenfluramine studies under investigation, I think it is important to note that these studies raise generic questions concerning the appropriate use of children as research subjects and the effectiveness of the regulations found at 45 CFR 46.401 et seq. in adequately protecting children as research subjects. Those regulations were promulgated in 1983 and it is time to evaluate them. I am also enclosing a copy of a book co-edited by me and Dr. Michael A. Grodin entitled Children as Research Subjects: Science, Ethics and Law. I hope you will find this to be a useful reference during the course of your work on this topic. Clifford C. Scharke, D.M.D., M.P.H Division of Human Subjects Protections Dear Dr. Scharke, April 24, 1998 I am writing to support the request of attorneys Ruth Lowenkron and Cliff Zucker for your office to investigate certain research activities conducted on children that was made in a letter to you dated December 23, 1997. I also support the concerns that were expressed in a letter that was sent to you on February 16, 1998 by professors Elizabeth Iglesias and Francisco Valdes and numerous other concerned academics and child advocates. These letters concern three published research studies that purport to investigate the relationship between serotonin and aggression in prepubertal children. The studies in question that I wish to comment on are, Pine et al, Neuroendocrine Response to Fenfluramine Challenge in Boys, 54 Arch Gen Psych 839 (1997) and Halperin et al, Serotonin, Aggression, and Parental Psychopathology in Children with Attention Deficit Disorder, 36 J Am Acad Child Adolescent Psychiatry 1391 (1997). Recent newspaper reports indicate that the concern of the press, at least, is focused on the administration of fenfluramine to children. While this presents a serious problem I believe that your review of these studies should look at several other issues as well. Subject Selection The letter by Professors Iglesias and Valdes and others focuses primarily on the vastly disproportionate use of minority children as subjects in these studies. Since these studies clearly offer no benefit to the children while having the capacity to stigmatize this population of children, this raises a most serious question under 45 CFR 46.111(a)(3) which requires the "equitable" selection of subjects. This section further requires IRBs to be particularly scrupulous in this regard when the research involves "vulnerable" populations or “economically or educationally disadvantaged persons." Again, it is obvious from the published research papers that all the subjects fell into this vulnerable Clifford C. Scharke, DMD, MPH Recent newspaper reports indicate that a spokesperson for one of the institutions has argued that the vastly disproportionate African American and Hispanic make-up of the research subjects reflected the make-up of the population in its "catchment area." Even if this is true, it is entirely nonresponsive to the concern. The institution, in performing research, is not restricted to its catchment area for recruiting subjects. It could have recruited subjects that better represented the population if it chose to make the effort. By restricting its recruitment to its geographic location the researchers made it easier and somewhat less expensive for them to conduct the research. But convenience to the researchers in no way responds to the requirement that subject selection be "equitable." Risks The regulations require that an IRB find that the “risks to the subjects are reasonable in relation to anticipated benefits..." It is tempting to only review the risks of the administration of fenfluramine to children, particularly since the drug has apparently not been approved for use in children and was not administered with the intent to benefit the children but rather to induce a biological response. It is also important to review the risks to the children in terms of the psychiatric diagnoses or labels that were made purely for the purposes of the study. In the Pines study for example, it appears that children entered the study with no psychiatric diagnoses but left with diagnoses of oppositional defiant disorder, conduct disorder and attention-deficit hyperactivity disorder. Because labeling can have a negative impact on the way children are perceived and treated, and because these diagnoses were not made for the purposes of supplying treatment, this must be viewed as one of the significant risks these children incurred. Benefits It is without a doubt that these children-subjects were not intended to receive any benefit from participating in this research. As a result the question remains whether there was some other foreseeable benefit sufficient to justify the study under 45 CFR 46.111(2). In order to approve a research proposal, the IRB must determine the "importance of the knowledge that may reasonably be expected to result" from the research. The Pine study discusses the limits of the knowledge that could be gained from its results on page 844 of the published article. The authors note that they did not compare the children in this study with children who did not have a family history of delinquency, that there were no placebo challenges performed on a control arm, and that two dynamic constructs (rearing environment and serotonergic activity) were measured at single points in time. One could add to this that only children from minority groups were studied and so the relevance of the results to the general population cannot be known. Given these serious limitations in research design, all of which would be known at the time of IRB review, it is difficult to see how the IRB could determine that the “importance of the knowledge" could justify the approval of this research. Clifford C. Scharke, DMD, MPH In this instance, since this research is governed by 45 CFR 46.406 (discussed further below), the research study must produce "generalizable knowledge... of vital importance." No project with the admitted methodological limitations this project had could meet this standard. Assent The children in the Pine study were from 6 to 12 years old and the publication says that "36 of the 56 eligible boys agreed to participate." (page 840) Similarly, Halperin notes that "consent was obtained from the parent and assent was obtained from the child. (page 1393). The question that needs to be examined is how this was accomplished with children (as young as 6) who supposedly suffer from disorders that make them "oppositional," antisocial or unable to concentrate and listen closely. Indeed, one of the criterion for oppositional Defiant Disorder is, "often actively defies or refuses adult requests." (DSM-III-R diagnostic criteria for 313.81 Oppositional Defiant Disorder A.(3)). The related issue is how any efforts of the children to withdraw from the studies were handled. Since many of the children were diagnosed with conditions that supposedly affect their ability to comply with adult commands, to concentrate or even to sit still (“often fidgets,” “has difficulty remaining seated when required to do so,” “is easily distracted" - DSM-III-R criteria for 314.01 attention-deficit Hyperactivity Disorder) one would expect that at least some of the children would have tried to exercise their right to "discontinue their participation at any time.” (45 CFR 46.116(a)(8)) Indeed, one would expect that many children when confronted with a needle that would remain in their arms for five hours would make an effort to refuse to participate, and that others would make an effort to terminate participation during the five hours that the fenfluramine challenge took. As part of your investigation you should determine how this provision was interpreted and applied by the investigators. Payment Given the nature of these studies, one wonders why a parent would agree to their child's participation. One newspaper reported that the parents were paid $125 for their child's participation in one of the studies. Given the impoverished nature of the subject population, it is important for OPRR to determine if there was any undue influence in this regard. Further, it is important to determine how and when the money would be paid. Were the parents paid the full amount for enrolling their child or only when the child completed all the studies? If the latter, this could affect the child's ability to withdraw from the study as discussed above. Washout period The Halperin study, in which the subjects were all diagnosed with ADHD, included a "1-month washout period for subjects who were taking medication." (page 1393) The Pine study says that the children had to be "free of medications for at least 1 month," but does not say that the children were taken off medication for the purposes of the study. |