To: Mary Faith Marshall, Ph.D, Chairperson,
National Human Research Protections Advisory Committee
Department of Health and Human Services

Re: Specific Comment on FDA's Decision to Adopt HHS 45 CFR 46 Subpart D, EXCLUDING §46.408 (c)

Dissenting opinion of Vera Hassner Sharav, Founder and President, AHRP: Alliance for Human Research Protection, member, Children's Workgroup of the National Human Research Protections Advisory Committee, Department of Health and Human Services (HHS)

This dissenting opinion reflects the position of AHRP and was prepared in collaboration with Howard Fishman, M.S. W., M.Ed, and John H. Noble, Jr., PhD, AHRP board members.
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On April 24, 2001, the Food and Drug Administration adopted "Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products." The safeguards adopted by FDA as an interim rule are the HHS regulations contained in 45 CFR 46 Subpart D. FDA excluded Section 46.408 (c), which gives institutional review boards authority to waive parental permission for research, because FDA correctly determined that Federal law doesn't allow.

45 CFR Subpart D, 46.408 ( c) states:

"If the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part.. provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, State, or local law. The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, statutes, and condition."

FDA's exclusion prompted HHS to initiate through the Office of Human Research Protection and its advisory panel (National Human Research Protection Advisory Committee, NHRPAC) and its Children's Workgroup to formulate a letter of recommendation to FDA. The OHRP / NHRPAC/Children's Workgroup recommendation "strongly urges" FDA to adopt Section 46.408 (c), arguing that the regulation "protects" "neglected or abused children," that it will apply to "mature adolescents" who are capable of giving "informed consent," and that its exclusion would result in the loss of "vital" information and benefit. Unacknowledged is the fact that the adoption of Section 46.408 (c) will increase the recruitment pool of child research subjects, thereby serving the interests of the biomedical research establishment under the guise of "protecting children.".

The following is a dissenting opinion by a member of the Children's Workgroup:

First, the language used in the Children's Workgroup letter recommending that FDA adopt 45 CFR Subpart D, 46.408 (c) misapplies the well defined legal concept of "informed consent" throughout the document. For example, "the informed consent of the adolescent is solicited and accepted as sufficient to proceed with research." "Research protocols went forward based on the informed consent of the adolescent." HHS regulations preclude children from giving valid "informed consent." Under HHS 45 CFR Subpart D, 46.402 (a) specifically defines "children" as "persons who have not attained the legal age for consent to treatments or procedures involved in the research" Under 45 CFR Subpart D, 46.402 (b) children are limited to giving "assent."

Second, the proposed language "strongly" endorsed by the Workgroup for FDA adoption departs so significantly from basic tenets of law and ethics that questions must be raised regarding the possible motives and ideology of those who propose to broaden its application to FDA regulated clinical trials, and the integrity of the process that led to its adoption by HHS. These concerns will inevitably be reflected in the following discussion and are, therefore, acknowledged as a preface to this dissenting statement.

The proposed statement of recommendation by the Workgroup contains manifold deficiencies. The following are among the most blatant:

1. No criteria are proposed for identifying potential child research subjects for whom "parental or guardian permission is not a reasonable requirement..." The example provided, i.e., "neglected or abused children," is vague and potentially misleading. In addition, it ignores fundamental constitutional and ethical considerations.

It appears that children are being loosely defined as "neglected or abused" regardless of whether the courts have adjudicated them as such, or not; regardless of whether they are in state custody, and regardless of the status of their parents' rights.

The issue of surrogacy, i.e., the appointment of a third party to represent the child's interests, is not relevant until and unless parental rights have been terminated. Thus, surrogacy should not be an option for researchers seeking human subjects. Clearly, there is no justification for waiving parental permission under any other circumstances. It is clear that such rights are not waived even when the child has been deemed dependent and has been placed in state care. [1]

2. Another concern is the matter of who might be entrusted to categorize children as neglected or abused? Given that more than 80% of the approximately three million reports of child abuse registered annually are ultimately determined to be false, one could hardly be sanguine about any such process. Furthermore, there is abundant evidence that self-reports are subject to massive distortion either because the child anticipates the rewards of victim status or because of manipulation by caseworkers and other child protection professionals.

The Workgroup proposal fails to provide any specific recommendations that would even approximate "an appropriate mechanism for protecting the children," an unmet requirement under HHS 45 CFR Subpart D, 46.408 (c). Indeed, the statement acknowledges the absence of any IRB "mechanism of review of these protocols" or the existence of "a system of IRB accountability." Nevertheless, the Workgroup statement "strongly" urges FDA to adopt this illegitimate policy, allowing waiver of parental permission without valid legal cause. By waiving parental rights, this Government intervention severs parental responsibility for children and puts the burden of protection from undue risks of harm on the fragile shoulders of children - even before any safeguards have been contemplated. Yet, sweeping statements based on assumptions that contradict the evidence, are made arguing that "consent of the adolescent, without parental involvement, is sufficient to permit research to proceed as long as procedural safeguards are in place to protect the interests of the subjects."

The assumptions that "procedural safeguards are in place," or that IRBs can be relied upon to make decisions that protect the best interests of human subjects - adults and children - has been debunked as the practices at one after another prestigious institution are exposed to public scrutiny. The fact is, there is no established "appropriate mechanism," no procedural safeguards, and no system of IRB accountability.

To recruit ever greater numbers of children for experiments involving risks of harm - some may prove to be long-term harm - without any demonstrable "appropriate mechanisms" in effect, is reckless endangerment, not "added protection." [2]

3. Research cannot be valid or reliable until and unless baseline data has been established. One of the many controversial questions that must be answered prior to undertaking research on "neglected and abused children" is whether or not they manifest characteristic differences - both physiologically and psychologically - from control groups (i.e., children who have not been neglected or abused).

Certain elements within the child abuse industry maintain that such children almost invariably suffer from severe - and sometimes irremediable - injuries. No reliable baseline data is available regarding the specific nature, source, or even presence of such characteristic differences [3,4]. Thus, any research based on this population of subjects would be compromised.

4. Informed consent for adults can be waived for adult subjects only if "the research involves no more than minimal risk to the subjects." [45 CFR 46.116. (d) (1)]

I note with profound concern that the language of HHS Subpart D, section 46.408 (c) blithely dismisses this restriction, by assuring that:

"The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, statutes, and condition."

The clear implication of this deviation from the standards for adult research protections is that dependent children and adolescents merit even less protection and concern than do adults.

Indeed, the evidence of abusive, high-risk experiments that have been conducted on children demonstrates their vulnerability and need of protection from exploitation. The following unethical experiments are discussed and documented in my paper: [2a]

100 children and babies with gastroesophageal reflux were subjected to a fatal Propulsid drug trial after the drug was linked to deaths; 68 children with hypertrophic cardiomyopaty were subjected to a NIH pacemaker experiment under coercion, some died - others' condition worsened; Preschool children are being recruited into an NIMH sponsored psychotropic drug trial that offers parents $645 above expenses if the children - some not even toilet trained - complete the 45 week experiment to test the effects of methylphenidate; Soon after Eli Lilly's powerful antipsychotic drug, olanzapine (Zyprexa) was approved for adult schizophrenia patients, 6 to 11 year old children were recruited for a clinical trial - despite the drug's documented serious adverse effects. All children experienced adverse effects, such as sedation, weight gain up to 16 pounds, extreme restlessness (akathesia) - none of the children were helped. The study was terminated before 6 weeks. 100 inner city minority children, aged 6 to 11, were exposed to a toxic drug that was subsequently withdrawn from the market, Fenfluramine. Thirty-four of the children were not diagnosed with any medical condition, the experiment was conducted to prove these children's predisposition to violence on the researchers' undocumented assumption that siblings of incarcerated brothers are "at risk" of a non-defined, non-medical condition - violence in the future; 45 children (6 to 12 years old) were subjected to methylphenidate / dextroamphetamine / pemoline and the pain and risks of spinal taps for non-therapeutic research purposes. Whereas evidence - now and historically - demonstrates the need to protect children by restricting their availability for potentially harmful experimental research, HHS, its agencies and advisory panels are attempting to undercut existing safeguards, such as they are, in the name of "protecting children."

Furthermore, the arguments made about "life prolonging" research studies suggest a "therapeutic misconception" about the distinction between treatment and research.

(5) The logic behind the language in the HHS 45 CFR 46.408 can be best described as "in loco parentis run amok." This conclusion is based on a review of the government's track record in assuring the welfare of, for example, "neglected and abused" children. There are currently approximately 600,000 children in state care. A significant majority of those children have not been physically or sexually abused by their parents. They are, however, subject to extraordinary risks thanks to the dubious beneficence of state intervention into their lives. It has been estimated that children in state custody, when compared with children who reside with their parents, are at six times the risk of severe physical injury, fifteen times the risk of sexual abuse, and twenty-six times the risk of death.

An examination of the record of human casualties of medical research, demonstrates the combined failure of local IRBs and Government oversight agencies to protect adults and children from undue risks of harm in clinical trials. The nation's premier research centers have been found in gross violation of ethical standards that undermined patient safety. [5]

I cannot, therefore, subscribe to a recommendation that would add additional risks for children.

Conclusion

The specifics addressed in this statement are imbedded in a far more complex and controversial topic: the role of the government as it supports or undermines the integrity of the family. The cavalier treatment afforded parental rights in the HHS language suggests profound indifference to this focal social problem. Many other perspectives have been ignored. Thus, I have taken the liberty of attaching a list of readings that might help to identify and elucidate many of the issues that have been given short shrift by the proponents of this regulatory proposal. Howard Fishman, MED, MSW, an expert in the field who is a member of our organization compiled the list.

An argument made in the Workgroup statement is that FDA's decision not to adopt section 46.408 (c) "will potentially result in an incongruous system where the HHS regulation and the FDA regulation are in conflict." Our organization agrees and recommends, therefore, in the interest of increased protections for vulnerable children of all ages, that HHS eliminate that ill-advised clause permitting waiver of parental consent.

Regrettably, the Workgroup proposal does not qualify as a regulatory improvement for the protection or best interests of children, but rather an accommodation to researchers who have difficulty recruiting children of responsible parents. This proposal is an invitation to exploitation of children as research subjects.

Footnotes:

[1] It is important to note that such legal and ethical niceties are frequently ignored by spokespersons for the child abuse industry. The risks attendant to being in State care will be discussed elsewhere in this statement, but are raised here to underscore the fact that a great deal of research is currently ongoing with this population that is both illegal and unethical.

[2][2a] Children are being recruited aggressively to be test subjects in psychotropic drug trials that were approved for conditions the children do not have. In the process they are suffering severe adverse effects in trials intended to expand the pediatric market, not to benefit them.

Sharav VH, "Evidence Demonstrating The Need for A National Human Subject Protection Act," 2001, under review for publication.

[3] The controversy that ensued from the publication by the American Psychological Association of a meta-analysis suggesting that neglect and abuse does not necessarily cause profound and irremediable harm. The political brouhaha that erupted as a result of this article (not least of which was a Congressional resolution) has been extensively documented. It should be noted here, however, that no credible analysis has been produced to discredit the statistical conclusions reached by the authors Citation:

Rind et al. "A Meta-analytic Examination of Assumed Properties of Child Sexual Abuse Using College Samples, " Psychological Bulletin 124, 22 - 23 (1998).

Further, the declination by the National Academy of Sciences of an invitation to review the article's findings suggests that reputable scientists are not willing to challenge scientific findings on political grounds.

[4] One of the confounding variables almost invariably ignored by researchers in the child abuse industry is the psychological impact - and, ultimately, the physiological impact - on the child of removal from the family of origin.

[5] From UCLA, to the University of Maryland, Illinois, Oklahoma, South Florida, Texas, Cincinnati, Duke, NIH, Yale, the Hutch, Johns Hopkinswhere next?