Comments Re: DHHS Notice of Proposed Recommendation Regarding Support of Research Protocol: "Precursors to Diabetes in Japanese American Youth" Grant Number I R01 DK59234-01

The proposed experiment would involve 450 children healthy children, aged 8-10 years old, 300 of Japanese ancestry and 150 Caucasians. The experiment is not approvable under federal regulations, 45 CFR 46 Subpart D because it involves greater than minimal risk and no potential direct benefit to the children.

Ethical research involving human beings is predicated on the principles enshrined in the Nuremberg Code and every subsequent code of medical research ethics. Foremost among these principles is the inalienable right of every human being to freely exercise his /her right to informed consent to participate in medical research - or to refuse. Children, however, are precluded from exercising legally valid informed consent because of immaturity. This puts children in the category of non-consensual human subjects who must depend on others to decide what serves their best interest. The historical record amply documents that children have suffered unduly in experiments not intended for their benefit, that caused them pain and discomfort while putting their welfare at risks of harm[1]

In 1983, federal regulations were adopted for the purpose of protecting children from experiments that might put them in harm's way, and to ensure that children will not be exploited in experiments that are not in their best interest. (45 CFR 46 Subpart D, sections 404-409) For example, 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."

Thus, federal regulations require a higher standard of justification for approval of pediatric research by setting limits on the level of risks that children may be exposed to, and by restricting the inclusion of children in non-therapeutic research (i.e. of no therapeutic benefit to the individual child-subject).

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 procedurepresents 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, federal regulations require that sufficient evidence must exist to lead researchers to expect that the research "is likely" to provide "generalizable knowledge" which is of "vital importance" for "the subjects' disorder or condition."

Section 407: "Research not otherwise approvable" may be approved only after a two tier process of public review - by a panel of experts and lay citizens - under the direct auspices of the Secretary of Health and Human Services, approves it.

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

"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." [emphasis added]

Although the language of section 407 does not provide clear guidance about the standards of justification, it is a reasonable assumption that section 407 was not intended as an "escape hatch" from regulatory restrictions protecting children. Therefore, research "not otherwise approvable" - i.e., because the risks may be greater than "minor increase over minimal risk," and / or the children are healthy and will, therefore, derive no potential benefit - must meet scientific justification standards that go beyond those required under sections 404, 405 and 406. Thus, for a research project to be eligible under section 407, the IRB must have sufficient evidence to believe that the proposed research presents an exceptional opportunity to obtain vitally important knowledge that is likely to lead to important information that will "prevent or alleviate a serious problem affection the health and welfare of children." [2]

The validity of our position, namely, that the standards for approval under section 407 require the investigators to meet a higher standard of justification, is demonstrated by the fact that section 407 has been invoked only twice (perhaps, 3 times ?) since 1983, when federal protections for children were adopted.(45 CFR 46 sections 404-408)

In 1992, a human growth hormone (hGH) experiment on short children came under fire when the Physician's Committee for Responsible Medicine (PCRM) petitioned NIH to suspend the experiment.[3] NIH responded by convening a panel of experts - essentially as outlined in section 407 of 45 CFR 46 - to review the hGH trials.[4] The panel's analysis, disagreements, and conclusions proved highly problematic, particularly as the panel acknowledged a "paucity of good data about the probability of risks and by the absence of common measures of their significance."[5]

PCRM cited the following risks which the panel did not address: cancer from increased liver production of insulin growth factor, which is thought to increase breast cancer; aggravated kidney problems in some children; metabolic changes resulting in weight loss. Additionally, the panel failed to give serious consideration to the psychological risks of recruiting healthy children who do not have an actual physiologic, psychological, or behavioral condition who are being treated as though they are "abnormal."[3] Nor did they consider the diminished self-perception and shame felt by those children who "failed" to grow as expected with the injections. Another issue not addressed by the panel was the continued suspicion of a possible link between hGH treatment and Creutzfeldt-Jacob Disease.[6]

Dr. Loretta Kopelman, a co-chair of that panel of experts, has acknowledged that the panelists "strongly disagreed" about basic elements of the issues. They disagreed about whether three placebo injections a week constituted "minimal risk, a minor increase over minimal risk, or greater" the psychosocial risks of the study, or the impact of bringing children from early childhood to late teens to NIH for a battery of physical and psychological testing, including nude photographs.[7]

Critics have noted that the panel of experts did not provide a reasoned rationale for conducting the hGH trial. Thus, the panel's recommendation to continue the experiment despite the uncertainties exacerbated the controversy. That public controversy may have served as a deterrent for those who would invoke section 207 today, to conduct risky experiments on children for hypothetical benefits that cannot be measured. But the intrusion of financial incentives for those who conduct experiments on children - including a 6 month patent extension[8] - has led the medical research community to accelerate the pace of pediatric trials and to seek child subjects for potentially risky experiments.[9]

Indeed, according to Dr. Greg Koski, Director of the Office of Human Research Protection (OHRP), during the year 2001, the Secretary of HHS received 26 requests for section 207 review.[10] "Precursors to Diabetes" appears to be the first of these 26 proposed pediatric research projects under section 207 review to be publicly announced.

Specific aspects of the proposed "Precursors to Diabetes" experiment:

The (undated) "Report on Expert Panel Review Under Subpart D of 45 CFR 46" by an expert panel that was convened Aug 13-14, 2001, indicates that the investigators claim that Asian adults have "a predisposition to accumulate central, abdominal fat and have an increased risk for type 2 diabetes" and that the risk is greatest "around puberty." The study is purported to seek to "increase understanding about the metabolic changes that precede the development of type 2 diabetes in children and the influence of Asian ethnicity on the diabetes risk."

Armed with nothing more than vague speculation about the possible influence of "pubertal hormonal effects on glucose metabolism and insulin resistance" on increased risk for type 2 diabetes, the investigators would plan to conduct a battery of medical procedures on 8 to 10 year old children. Some of the procedures involve unknown levels of risk - such as x-ray techniques (Dual Energy X-Ray Absorptiometry) and MRIs; some are invasive and painful - including blood draws and intravenous glucose tolerance tests involving the insertion of an intravenous catheter and infusion of glucose. And although children have no say about their genetic privacy - nor will they profit from genetic studies - their DNA will be collected "for future genetic studies." The researchers claim their study will help determine the influence of "both ancestry and pubertal hormone effects" on developing type 2 diabetes.

• What solid evidence is there to confirm that Asian adults have an ethnic "predisposition" to diabetes?
• Should not a survey be conducted first to find out about the true incidence of diabetes in this population instead of just assuming that it would be higher and, therefore, worthy of an invasive study?
• If an increased incidence of diabetes in Asian adults exists, is there any evidence that such predisposition can be detected in childhood, using the tests described?
• Do the investigators plan any intervention in children who test positive ?

Certain diets have been shown to push adult onset diabetes into remission (as well as contribute a host of other health benefits for children and adults). Therefore, nutritional counseling - which requires no invasive, uncomfortable screening tests - is a preferable alternative for lowering the risks for diabetes if there is no superior treatment or intervention other than dieting.

Maryland Court of Appeals standard: "Best interest of the child"

We note with misgivings that both the expert panel and OHRP administrators who recommend approval of the pre-diabetes experiment, set aside the "best interest of the child" standard - ignoring entirely the landmark decision (Grimes v Kennedy Krieger Institute, 2001) by the Maryland Court of Appeals.[11] That decision undercuts the assumptions under which the biomedical research community has approved and conducted nontherapeutic experiments on children and other persons under a legal disability who suffered as a result. The Court criticized the research community:

"The researchers and their Institutional Review Board apparently saw nothing wrong with the [re]search protocols that anticipated the possible accumulation of lead in the blood of otherwise healthy children as a result of the experiment, or they believed that the consents of the parents made the research appropriate."[12]

Maryland's highest Court rejected the self-serving utilitarian arguments made by a consortium of research stakeholders who claimed such experiments are "critically important" for the interest of children's health in general.

That Maryland Court decision is entirely compatible with the federal regulations which recognize the need to restrict the use of children in research that puts them at risk. But the Court framed the ethical issues from the perspective of law - not leaving any doubt about the distinction between research that is therapeutic - intended to benefit the subject - and research that is nontherapeutic - not intended to benefit the individual child. The Court left no room for linguistic calisthenics or semantic deconstruction, ruling that children have a right to be protected from experiments involving risks without a benefit for them. And the Court held that parents, researchers and institutions could be held accountable if they violate the legal standard of protecting "the best interest of the individual child."

Since nontherapeutic research presents the inherent possibility of harm, such research is not in the best interest of a child. The Maryland Court concurred with a 1995 decision by the New York State Supreme Court[13] which held that parents who might want to volunteer themselves for research lacked legal authority to volunteer their children for nontherapeutic research. To underscore the non-transferability of the right to informed consent to research, the New York Court held that parents have no right "to make martyrs of their children before they have reached the age of full and legal discretion when they can make that choice for themselves."

The Maryland Court put it this way:

"It is not in the best interest of a specific child, in a nontherapeutic research project, to be placed in a research environment, which might possibly be, or proves to be, hazardous to the health of the child. We have long stressed that the best interest of the child is the overriding concern of this Court in matters relating to childrenŠIt is, simply, and we hope, succinctly put, not in the best interest of any healthy child to be intentionally put in a nontherapeutic situation where his or her health may be impaired, in order to test methods that may ultimately benefit all children."[14]

In both cases, the Court stepped in because it was obvious to the Court that children - and other vulnerable persons who are legally disabled - were being exploited and those charged with overseeing the conduct of research and the approval process failed to protect them from experiments that are against their best interest. The Court held that such disadvantaged individuals may not be used in non-therapeutic experiments if there is "any risk or injury or damage to the healthy of the subject."[15]

The Maryland Court admonished the research community:

"[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."[16]

Indeed, the 1994 Report by the Advisory Commission on Human Radiation Experiments (ACHRE) report noted that if judged by the standards used at the time the radiation experiments were conducted, the 21 discredited radiation experiments identified by ACHRE in which children were put at increased risk of cancer, passed the researchers' standards. It is doubtful they would have been approved had a sizable number of members of the public served on the committees that approved them.

From the information provided by OHRP it is evident that the "Precursors to Diabetes" experiment does not even come close to meeting the ethical standards required for approval under federal regulations. Without access to the actual protocol, we can only infer from the expert panel's report, and from letter of determination suspending a similar pre-diabetes screening experiment at the National Institute for Child and Human Development,[17] that the risks for the 450 children are not justified by any claimed projected future benefit.

First, there is no evidence that that the children sought for recruitment are at real risk of diabetes. Second, there is no evidence to demonstrate that the research meets the "best interest of the child" standard - nor is there convincing evidence that it is "likely to yield generalizable knowledge" which is of "vital importance" that will help to "prevent, or alleviate a serious problem affecting the health and welfare of children." Indeed, the panel's report indicates that one of the expert panel members dissented from the panel's recommendation, and did not recommend approval.

The dissenting expert indicated that the "Precursor to Diabetes" experiment had "serious design flaws" and "will yield little, if any, knowledge about the problem it intends to address." This expert's opinion is that "the study would yield little, if any, reliable information that would help to better understand, prevent, or alleviate the serious problem of type 2 diabetes in children." Furthermore, this expert concluded: "only one subject [out of 450] would ultimately become diabetic."

From the information available to us, it is apparent to The Alliance for Human Research Protection that "Precursors to Diabetes in Japanese American Youth" fails to comply with the fundamental ethical standards of justification for conducting human experiments:

• "results for the good of society that are unprocurable by other methods or means of study." (Nuremberg Code, emphasis added);
• designed to yield generalizable knowledge that meets the standard of "vital importance." (45 CFR 46.406)
• "best interest of the child" (Maryland Court of Appeals)

We are concerned that the federal agency whose mission is to enforce federal regulations and protect human subjects - including children - is using its authority to encourage an experiment that will expose healthy children to undue risks of harm. The experiment appears to be a "fishing expedition" whose value is in doubt even by experts.

We believe that children should not be exposed to pain, discomfort and potential risks of harm in experiments, particularly when there is a high degree of scientific uncertainty about the knowledge to be gained from such experiments - unless the research is intended to provide treatment for a serious condition that the children actually have. This experiment appears to mirror the ethical and scientific flaws that were apparent in the growth hormone experiment: "paucity of good data about the probability of risks and by the absence of common measures of their significance."[3] By recommending approval of this experiment, the expert panel and OHRP are defying the Maryland Court ruling.

It is of note that pediatricians and primary care physicians consulted by AHRP concur with the Court's protective stance toward children. They reject the claims made by certain research stakeholders that assume that all children are "at risk" of one or another "condition" or "disorder." A hypothetical risk does not provide the justification for exposing healthy children to greater than minimal risk, not to mention pain and discomfort, in experiments that seek to identify a miniscule percentage of children who may be "at risk" of the condition being studied.

The process by which "Precursors of Diabetes" has been reviewed ­most importantly, the abridged, almost non-existent period provided for public review was neither transparent, nor in compliance with the spirit of the existing federal regulations. How else can DHHS explain the fact that the expert panel convened Aug 13-14, 2001 and a year later, the public announcement provided a mere two-week window for review and comment in the month of August?

Any decision to conduct medical experiments "not otherwise approvable" on children challenges the moral principles of our society, and will have impact on the health and well-being of children. It requires, therefore an adequate period "for public review and comment" - which has not been provided.

We ask the following:

1)      Online access to the research protocol and consent documents.
2)      Public disclosure of the names and affiliations of panel members who should be required to make a declaration about possible conflicts of interest.

3)      Each panel member's review should be publicly available online.

4)      Proposed 407 rulings should be advertised for greatest public access: Reuters Health; PubMed News; American Medical News; Associated Press; Chronicle of Higher Education; WebMD; Health Freedom Watch; Public Health Reports; American Family Physician; Informed Parent are some appropriate publications.

5)      A three-month period for public review and comments should be provided.

6)      Online publication of all the comments received.

7)      Review by Office of Inspector General's legal staff with publication of their opinion regarding how this research approval complies with existing federal regulations.

Sincerely,

Vera Hassner Sharav
Meryl Nass, MD
Loren Mosher, MD

Steering Committee
The Alliance for Human Research Protection

[1] The 1994 report of the Advisory Commission for Human Radiation Experiments (ACHRE) makes abundantly clear that parents have given permission for research to be conducted on their children that caused them harm. Some children were exposed to radiation and the risk of cancer, while others (at Willowbrook) were deliberately infected with hepatitis. See, Advisory Commission on Human Radiation Experiments (ACHRE). 1994. Chapter 7: "The Context for Nontherapeutic Research with Children. In Final Report." Online at: http://tis.eh.doe.gov/ohre/roadmap/achre/chap7_2.html

[2] The ethical standards under the Nuremberg Code, require that all human research must be justified by the fact that the information sought is "not procurable by other means."

[3] Physicians Committee for Responsible Medicine. Concerns about Growth Hormone Experiments in Short Children http://www.pcrm.org/issues/Ethics_in_Human_Research/ethics_human_growthhormone.html

[4] Health and Technology Advisory Committee. Executive Summary. The Use of Human Growth Hormone for Children with Idiopathic Short Stature. February 2000. http://www.health.state.mn.us/htac/hgh.htm

[5] Op. cit., PCRM

[6] Concern has been raised about the possible link between growth hormone to Creutzfeldt-Jacob Disease: http://www.niddk.nih.gov/health/endo/pubs/creutz/creutz.htm

[7] Kopelman, LM, "Pediatric research regulations under legal scrutiny: Grimes narrows their interpretation," J of Law, Medicine & Ethics, 30 (2002): 28-49. http://www.aslme.org/pub_jlme/Kopelman.pdf

[8] Food and Drug Administration Modernization Act, see U.S. Public Law 105-115, 21 USC 301.

[9] Sharav, VH. (2002) "Dissenting Opinion (NHRPAC Children's Workgroup) re: proposed reinterpretation to federal regs protecting children (45 CFR 46 sections 404 and 406). See, ref 5, 7, 8, 9.

http://www.ahrp.org/children/NHRPACdissent051402.php

See also, Vitiello, B. (2001). "Psychopharmacology for young children: Clinical needs and research opportunities," Pediatrics, 108: 983-990.

[10] NHRPAC transcript, Jan 29, 2002:

http://ohrp.osophs.dhhs.gov/nhrpac/mtg01-02/0129NHR.txt

[11] Grimes v. Kennedy-Krieger Institute and Higgins v Kennedy-Krieger Institute. Maryland Court of Appeals. August 16, 2001: online at: http://www.courts.state.md.us/opinions/coa/2001/128a00.pdf

[12] Grimes v KKI, p. 5 (pages from online print version).

[13] T.D. v NYSOMH, 1995, 626 N.Y.S.2d 1015.

[14] Grimes v KKI, p. 80.

[15] In rejecting defendants' request to reconsider, Oct 11, 2001, the Court explained that by "any risk" it meant, "any articulable risk beyond the minimal kind that is inherent in any endeavor." See, Grimes v KKI, at: http://www.courts.state.md.us/opinions/coa/2001/128a00.pdf

[16] Grimes v KKI, p11.

[17] "Population differences in the insulin sensitivity, resting energy expenditure, and boy composition of overweight children and children of overweight parents." NICHD, 2000. 96-CH-0101 http://ohrp.osophs.dhhs.gov/detrm_letrs/nov00a.pdf