Dissenting Opinion (NHRPAC Children Workgroup)
re: Proposed Reinterpretation of Fed. Regs Protecting Children
(45 CFR 46, sections 404 and 406)

May 14, 2002

To: Alan Fleischman, MD, Chair, Children’s Workgroup of NARPAC
       Mary Faith Marshall, Ph.D., Chair, NARPAC

From: Vera Hassner Sharav

Re: Dissenting Opinion re: Report to NHRPAC, proposing changed reinterpretation of federal regulations: 45 CFR 46 sections 404 and 406, May 1, 2002

Current federal regulations set no limits on the level of risk that a competent adult may voluntarily choose to undertake for the sake of science. The regulations require prior approval by a review board (IRB) to ensure the research meets scientific and ethical justification. The regulations rely on trust that the research stakeholders – the scientists, sponsors, and institutional review boards – will comply with the regulations, ensuring that the risks and benefits (if any) are fully disclosed to the subject, and that the subject can exercise the right to give or withhold informed consent. Thus, competent adults who can exercise their right to give or withhold informed consent may volunteer for nontherapeutic experiments that offer no direct benefit.

Children, however, are not legally competent to volunteer for research. Their inability to exercise informed consent or to protect themselves from unwanted experiments relegates children to the category of involuntary human subjects.

Children’s dependency on others to decide what serves their best interest places them at particular disadvantage. Regulations (45 CFR 46 Subpart D, sections 404-409) were adopted to protect children from harm and to ensure that they will not be exploited in non-therapeutic experiments involving greater than minimal risks or discomfort. Thus, federal regulations protect children by requiring a higher standard of justification for approval for pediatric research by setting limits on the level of risks.

45 CFR 46.102 defines "minimal risk" for adults and children alike:

"Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests."

The workgroup report, however, departs from the federal standard for assessing "minimal risk" in pediatric research by arguing that risks in research could be equated with risks in non-research situations, proclaiming, "IRBs need not limit the tests or procedures in the research to those actually used in routine physical or psychological evaluations." (underline added)

I strongly disagree with the proposition that the unnatural risks associated with participation in medical procedures can be equated to the risks incurred in volitional recreational sports activities. The optional nature of recreational risks underlies the necessity for and very existence of ethical codes for research. Furthermore, recreational activities offer the child the benefit of fun and pleasure – invasive medical procedures do not.

Federal regulations have imposed restrictions on the use of children – even when research offers a prospect of direct benefit to the child. The restrictions were imposed to ensure that children – who are not volunteers – are protected from undue risks of harm:

Research under 45 CFR 46.405, Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects is permissible only if:

"the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches."

Children are not volunteers. Therefore, statements such as, "all research must be voluntary" are a non-sequitors when research involves children. Implicit in Federal regulations is the recognition of children’s special vulnerability and the fact that those making decisions on their behalf may have conflicts of interest. Indeed, the historic and recent record of abuses demonstrates that even parents who are assumed to have their child’s best interest as heart – may have conflicts of interest that could undermine the child’s best interest. [1] The regulations are therefore guided by the time honored medical ethics principle, "above all, do no ham." When the research offers no possibility of a direct benefit (i.e., nontherapeutic), and it involves greater than minimal risk, the regulations restrict such research, requiring the investigator to demonstrate to the IRB that the proposed research is of "vital importance for the understanding or amelioration of the subjects’ disorder or condition."

45 CFR 46 Section 406: "Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition."

Under section 46.406 research may be conducted only if:

(a)   "the risk represents a minor increase over minimal risk; "the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;

(b)   the intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition."

Thus, there must be sufficient evidence to expect that the research "is likely" to provide essential knowledge which is of "vital importance" for "the subjects’ disorder or condition." The workgroup report misrepresents section 406 by suggesting that research involving more than minimal risk without a prospect of direct benefit is approvable based on the unproven claim of "long-term benefit of children."

The Children’s Workgroup report distorts the ethical principles that underlie federal safeguards for children in order to facilitate nontherapeutic experiments on otherwise healthy children. Normal stages of child development are being conceived as preludes to pathology: "prematurity, infancy, adolescence, poverty, living in a compromised physical environment, and institutionalization" are declared to be "disorders or conditions in children that ·warrant permissible research" that presents greater than minimal risk without a prospect of direct benefit to the child.

I strongly disagree with this radical departure from commonly held views about normal developmental stages of childhood.

It is claimed in the report that healthy children – who would not legitimately be subjected to nontherapeutic research under 45 CFR 46.section 406 – may have a genetic predisposition which puts them "at risk" of assumed, unverified conditions (that may or may not develop). It is claimed (in the report) that such vaguely defined speculative "risks" "warrant permissible research that presents levels of risk that are a minor increase over minimal without prospect of direct benefit." Those assumptions are invalid because they are not based on scientific evidence, merely speculation. The Workgroup’s recommendations are governed by long-held assumptions about the value of early detection and intervention. Those assumptions are being widely challenged by independent scientists who have not only raised serious doubts about evidence of benefit, but have raised concern about the harm that followed from overdiagnosis[2] and unnecessary medical interventions.

The Neuroblastoma[3] case is an example:

A screening process was believed to save lives of babies with Neuroblastoma, a lethal childhood cancer of the nervous system. However, recent conclusions about its uselessness, demonstrate the pitfalls of conducting screening tests prior to proving their accuracy and life-saving value. Beginning in 1986, screening tests for neuroblastoma were conducted in Japan (then Quebec, and Germany). At firs, the results looked spectacular. By the 1990s, she reported, 80% of Japan’s infants were tested. The detection rate shot up as much as tenfold. And, it appeared, the rate of cure rose dramatically as well. The finding of those tests led to an array of invasive, potentially dangerous treatments to cure, what later turned out to be, a harmless variant of neuroblastoma, which disappears if left alone. The overall death rate from neuroblastoma remained unchanged, but otherwise healthy babies were harmed and suffered from needless interventions.

Those arguing that all children are potentially "at risk" of a future condition attempt to justify the inclusion of all children – be they healthy or critically ill – in experiments that expose them to pain and risks of harm even when there was no potential for an immediate direct benefit. By applying a broad standard to the definition of "potential benefit" in this way, children are being deprived of existing, more protective federal regulations under 45 CFR 46, Subpart D. Small children are subjected to discomfort and foreseeable risks of harm on the basis of a presumed potential risk for which there is no empirical evidence.[4] I strongly disagree with the workgroup interpretation of Section 406 which guidelines in that they would open access to children who do not have a bone fide condition as research subjects in experiments that would cause them pain and put them at risk of harm without a potential foreseeable benefit.

Surely, the concern expressed by renowned scientists (and others) about the possibility that early screening has led to overdiagnosis followed by unnecessary aggressive medical interventions that, in some cases, caused more harm than good, should inform advisory committees that are entrusted with recommending guidelines for research review boards. How can one justify putting children at greater than minimal risk of harm in the absence of valid evidence that there is a higher probability of benefit than harm.

What the report doesn’t address:

The workgroup guidelines fail to address the factors that threaten the well-being of children: such as being recruited to assume risks of harm and pain with no personal benefit.[5] Children are being recruited for speculative experiments whose value is questionable.[6] Indeed, a most telling observation in the 1994 report by the Advisory Commission on Human Radiation Experiments (ACHRE) is the following statement:[1]

"Many experiments that prove to be of little value in the advance of medical knowledge are, at the time they are implemented, well designed and appropriate attempts to address important research questions."

Passage of the FDA Modernization Act (FDAMA) has provided enormous financial incentives to the pharmaceutical industry for testing their patented drugs in children – i.e., a six-month patent exclusivity extension. The law, unfortunately, failed to balance financial incentives with new (or improved) safeguards to protect an increased number of young children being exposed to the hazards of research. As a result, children who are legally precluded from exercising the right to refuse are being aggressively recruited to bear the burden of testing drugs that may (or may not) be in their best interest. Under the FDA’s "Pediatric Rule" which has recently been challenged in court, suspended by the FDA and reinstated by the Secretary of HHS,[7] has introduced the specter of using children to test drugs whose safety is uncertain. The number of child research subjects has grown from about 16,000 in 1997 to about 45,000 in 2001.[8]

In 2001 Alice Dembner of the Boston Globe examined research conducted since 1994 that involved children. She reported (in a series of articles) that children had suffered and died in clinical trials in which ethical standards had been violated.[9] Financial incentives for parents, physicians, and researchers are undermining children’s welfare. Children are being recruited with Toys ‘R Us gift certificates. Parents in need of money are offered as much as $1,000 to "volunteer" their children for drug experiments that involve risks of harm.[10] The physicians who are engaged in such coercion receive as much as $5,000 referral fees (kickbacks) for the recruitment of children.[11] In the last seven years alone, according to Dembner, at least eight children died in medical experiments and hundreds suffered harmful side effects, and "there is strong reason to believe that deaths and injuries in research involving children are more widespread" than available statistics would indicate.[12]

The FDA acknowledged that before FDAMA the use of children as subjects in phase I safety drug studies "had been primarily limited to life threatening diseases and children who had the disease" in question.[13] The policy prior to FDAMA protected children from harmful experiments in accord with the 1983 federal regulations (45 CFR 46.404-409). Following passage of FDAMA, however, federal policy broadened the criteria for inclusion of children in research generally and for participation of children entered in high-risk experiments. In 1999 the FDA acknowledged that the post-FDAMA policy change "led to an increasing number of proposals for studies of safety and pharmacokinetics, including those in children who do not have the condition for which the drug is intended."[14]

One can only speculate about the negative impact this policy change had on the healthy children who had been subjected to drug trials before the FDA rescinded the policy. FDA Associate Director of Pediatrics, Dr. Dianne Murphy, was reported to have stated at a conference (April 3, 2001): "FDA will no longer accept information submitted to the agency for pediatric exclusivity if the data is derived from children who are not patients and for whom there is no foreseeable benefit."[15]

Yet, young children who have not been diagnosed with any psychiatric disorder are being exposed to potent psychiatric drugs with foreseeable risks of harm – among these is the risk of addiction. Even the Director of Child and Adolescent Treatment and Preventive Interventions Research Branch of the National Institute of Mental Health acknowledges (repeatedly) "diagnostic uncertainty surrounding most manifestations of psychopathology in early childhood" 4 Indeed, Dr. Benedetto Vitiello also acknowledged: "only limited data exist on the efficacy and safety of antidepressants and mood stabilizers in school-age prepubertal children. Clinical trials of these agents in preschoolers do not seem possible given the current uncertainties about diagnostic validity of mood disorders in children <6 years old."[16]

Nevertheless, small children are being subjected to the drugs on the basis of a presumed potential risk for which there is no empirical evidence. Dr. Benedetto Vitiello, NIMH’s, provided confirmatory evidence that FDAMA has been a catalyst for recruitment of children for drug trials when stating "pediatric psychopharmacology has recently seen an unprecedented expansion . . . NIMH-funded research for clinical trials in youths has more than doubled in the last few years."[17] Considering that a six-month patent extension for Prozac, for example, can mean an additional $831 million for Eli Lilly,[18] what chance does a poor kid have against marketplace dynamics of such magnitude?

Despite the public expression of serious misgivings by one of its officials, NIMH has embarked upon a highly controversial psychotropic drug experiment on preschool children – Preschool ADHD Treatment Study (PATS) – in which some of the children being recruited are as young as three years old.[19] Their parents are being seduced with financial incentives beyond travel expenses‑‑$645 – if the child completes the study.[20]

I believe that such financial inducements are unseemly and inherently coercive and that NHRPAC should consider recommending that limits be set on inducements offered to parents. Children should not be treated as commodities to increase the profits of big business.[21]

These disturbing ethical deviations violate the dignity of children as human beings. They demonstrate the precarious lot of children who must depend upon others. The workgroup report reflects the interest and perspective of major stakeholders in the biomedical research enterprise, since the members have a direct interest in expanding the human research subject base. This bias is reflected in the draft report: it assumes that more research on otherwise healthy children is a moral good that outweighs the potential risks of harm to those children. I strongly disagree with that assumption, and the debate currently raging among scientists about the great harm from unnecessary interventions and overdiagnosis should lead advisory panels and policy makers to rethink their unproven assumptions. If adopted, the workgroup recommendations will provide profitable research opportunities for the privileged, by exploiting children as means to that end.

As I considered the draft guidelines and the (yet to be submitted) accompanying tables listing medical (and behavioral) procedures to which the Children’s Workgroup has assigned suggested levels of risk, I decided to conduct a reality check to find out whether my growing concern that these guidelines would put children at increased risk of harm and unnecessary pain and discomfort was colored by bias on my part. I therefore sought the opinion of several physicians and ethicists (outside the parochial perspective of the workgroup). These consultations have validated my own concerns that the workgroup is guided by utilitarian ethics and that the intent of current regulations is being distorted. No thought is being given to the likely harmful consequences to be borne by children.

In the original 1973 proposed federal regulations a "Protection Committee" was proposed to serve as the children subjects’ advocates. The Committee was to monitor the selection of child subjects, assess the reasonableness of the parents’ consent, and monitor the child subject’s continued willingness to participate in the research. [22] The time has come to implement that proposal, and I strongly urge NHRPAC to embrace it.

The physicians whom I consulted were concerned by the level of risk assigned to invasive and painful procedures – particularly since children would be subjected to them without a therapeutic purpose. An underlying sub-text is implicit in the draft guidelines, as is the complete disregard for the judiciary. The courts have unequivocally ruled that absent a benefit for the child involved, nontherapeutic research that posed greater than minimal risk was repugnant and violated the moral standards of the community.[23] In sharp contrast, the report attempts to legitimize those very experiments through disingenuous linguistic tinkering. The attempt to broaden the interpretation of "minimal risk", "more than a minor increase over minimal risk", and disorder or condition" will raise the threshold of pain and risks of harm to which children would be subjected. The proposed recommendations would exceed the level of risk permitted under existing federal regulations.

For example, venipuncture, glucose tolerance test, indwelling heparin lock catheter, chest x-ray, bone density and bone wrist x-ray have been designated by the Children’s Workgroup as "minimal risk." I am informed that an indwelling heparin catheter is not something that a healthy child would experience, and venipuncture does pose risk of infection, as does glucose tolerance test. Single x-ray radiation exposure poses a small, but cumulative risk of cancer.[24] Because the magnitude of the risk is unknown, and it is impossible to predict the lifetime exposure for a particular child, it cannot be stated that these procedures expose a child to "minimal risk." Indeed, the MEDLINE PLUS Encyclopedia states: "There is a general agreement that routine chest X-rays should not be done on healthy people for screening purposes. There is little benefit of a chest X-ray in screening smokers who have no symptoms."[25]

The following exceedingly painful procedures involve measurable risks and require informed consent when used in standard clinical practice. How then, can one justify classifying these procedures as merely "a minor increase over minimal risk"?

Lumbar puncture,[26] skin punch biopsy,[27] bone marrow aspirate,[28] nasogastric tube insertion, an uretha catherization are not expected in the life of a healthy child. Tympanocentesis, which the workgroup regards as "generally minor increase over minimal risk" is an extremely painful surgical procedure involving the insertion of a needle through the ear drum to drain the ear of infectious matter. The American Academy of Pediatrics indicates "the patient must be completely immobile while the needle is inserted through the tympanic membrane. A papoose board or a sheet can be used to immobilize the body. An extra attendant is required to hold the patient’s head steady" [29]

It is hard to imagine that researchers, IRB members, or ethicists would volunteer their own children for these procedures for the sake of science.

If adopted, these guidelines would lift the restrictions that currently provide children with some protection from unwanted experimentation. The Workgroup report fails to provide any guidance that would ensure compliance with the protective standards provided in the regulations – as though these were not major problems.

It is clear that children currently do not have independent advocates to protect their best interests in the research oversight system. Beyond representation on IRBs children need their own advocates throughout the research process. In today’s climate of corporate expediency clinical research is driven by financial interests that conflict with the best interests of the child. Even parents may be swayed by financial incentives to give permission to conduct research on a child – especially if they are poor and educationally disadvantaged.

The disturbing trend in pediatric research and the workgroup’s report confirm the judgment by the Maryland Court of Appeals, which stated: "[I]t is clear to this court that the scientific and medical communities cannot be permitted to assume sole authority to determine ultimately what is right and appropriate in respect to research projects involving young children." [p. 80] It is clear to me that the moral standards of community members differs from that of research stakeholders. It is, therefore, essential for community members – not just a single token – to be full participants if children are to be protected from unjustifiable risk of harm.

An unstated goal of this advisory process is to encourage IRBs not to involve the Secretary of HHS as required under 45 CFR 46 Section 407:

"Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children."

Section 407 requires nontherapeutic research involving greater than minimal risk and no potential benefit for the child subjects to be reviewed by the Secretary of Health and Human Services, a panel of experts, and public review before it could be approved:

"the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment."

Indeed, on February 7, 2002, the Alliance for Human Research Protection (AHRP) requested a copy of 26 current proposals that have been received by the Secretary of HHS in accordance with Section 407 of federal regulations. Our request was forwarded to the OHRP, and it was denied with the following statement:[30] "Release of information would interfere with the agency’s deliberative and decision-making processes. Further, each researcher has a commercial and privacy interest in the release of any information·." The A similar reason was given for denying disclosure of the list of experts: "Release of expert identities associated with the review of individual protocols would interfere with the agency’s deliberative and decision-making process and have a chilling effect on the ability of the agency to obtain frank and candid opinions from its reviewers."

Federal regulations guarantee public review and comment of research submitted to the Secretary of HHS because it is not otherwise approvable under federal regulations. Public review is guaranteed for the protection of children from unwarranted medical experiments. AHRP’s request was appropriate under section 407. The response by the Freedom of Information officer on behalf of OHRP is an inappropriate effort to block public review of potentially harmful and unjustifiable experiments on children.