"minimal risk" "minor increment of minimal risk" and "disorder or condition"

January 28, 2001

A cornerstone of the Declaration of Helsinki (adopted by the World Medical Association in 1964, and reaffirmed on Oct. 2000) is the distinction between research that is intended to be "therapeutic" (potentially beneficial) to the subject and "nontherapeutic" research, which is not intended to be beneficial to the subject. The U.S. Code of Regulations affirms that distinction for research involving children (45 CFR 46 Sections 405, 406), and the U.S. Code affirms that distinction for the military (10 USC 980).

The Advisory Commission on Human Radiation Experiments (ACHRE) evaluated the ethics of human radiation experiments (1994) by first identifying whether an experiment was therapeutic or nontherapeutic. The Commission affirmed that a different standard of acceptable risk pertains to experiments intended for therapeutic purposes from those that do not. Thus, the distinction between therapeutic and nontherapeutic research is a fundamental concept in any discussion about the ethics of human research. The concept is sustained, recognized, and well understood by professionals and laymen alike.

Specific reference to the distinction between therapeutic and nontherapeutic research - and a prohibition against putting children at risk of harm in nontherapeutic research - has been unequivocally affirmed by several U.S. courts of law, most recently by Maryland's highest court, the Court of Appeals. In a 6 to 1 decision, the Court ruled that: "in Maryland a parent, appropriate relative, or other applicable surrogate cannot consent to the participation of a child or other person under legal disability in nontherapeutic research or other studies in which there is any risk of injury or damage to the health of the subject." [Grimes v. Kennedy Krieger Institute / Johns Hopkins University, 2001]

In a NYS case, the Court ruled similarly: "Parents may be free to become martyrs themselves. But it does not follow they are free, in identical circumstances, to make martyrs of their children." (TD v NYSOMH, 1995)

NHRPAC's Children's Workgroup Draft interpretation of "Disorder or Condition" (1/22/02) introduces an alternative definition. The context of 45 CFR Section 46.406 makes clear that the phrase, "disorder or condition," refers to an empirical attribute of the individual subject: "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." The regulation further restricts such experiments by imposing limits on risk: "the risk represents a minor increase over minimal risk." The Draft, however, confounds the term "disorder or condition" by transferring the concept from its context as a diagnostic identifier for individual children to the broader context of research: "the presence or absence of any given condition can only be established within the context of a specific research question."

The Draft's broad interpretation eliminates current regulatory restrictions on the use of children as subjects - such as, the requirement that pediatric research must have a potential therapeutic benefit for the child-subject or the child's "disorder or condition." If the proposed interpretation were adopted, healthy children would become the means to an end. The Children's Workgroup Draft claims for research purposes, normal children may be regarded as having a "disorder or condition" or being "at risk" of the condition under study: For example, new born infants would be recruited to study "the normal physiologic immaturity of neonatal enzymatic metabolism, or the social condition of living in a home affected by environmental lead." We argue that this effort to promote the interests of research is accomplished by debases children by putting individual children at risk of unjustifiable medical interventions that are contrary to their best interests.

The risks of invasive research interventions cannot be justified by transference to "at risk" groups. This would unfairly elevate the risk for harm for individual members of the "at risk" group. A policy that blurs the distinction between therapeutic and nontherapeutic medical research, and between a patient with an identifiable ("disorder or condition") and an undefined, suspected member of an "at risk" group puts individual children at risk of harm from research. In this regard, common sense, and the "do no harm" medical ethics principle tells us that being "left alone" until therapeutic intervention is contemplated because of active signs and symptoms that would justify it, is inherently less risky than not being left alone. Furthermore, children are especially vulnerable in medical facilities - both to medical errors and a greater than normal risk of acquiring a nosocomial infection. [Webber, T. - Associated Press. 2001. Boston study finds medication errors common among hospitalized children. April 24: online at: http://www.boston.com/news/daily/24/medical_errors.htm

By eliminating these distinctions, the nature of some experiments remains hidden from prospective human subjects (or their parents), who may be led to believe (erroneously) that the research project will be of benefit to them (i.e., "therapeutic misconception"). By identifying the research as nontherapeutic, the volunteer is given at least a clue indicating that the research is not intended to be beneficial to him / her. Disclosure of such relevant information allows the volunteer to make an informed judgment about risk / benefit probabilities. Children, however, do not have either the capacity or legal right to exercise informed consent. For that reason, current federal regulations set limits on the recruitment of children for research, by protecting them from experiments involving greater than minimal risk, without the prospect of "direct benefit" - i.e., therapeutic benefit. (45 CFR 46 Sections 406, 407)

The courts have unequivocally ruled that such nontherapeutic research on children was repugnant and violated the moral standards of the community: "Children, it should be noted, are not in our society the equivalent of rats, hamsters, monkeys and the like. 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 which proves to be, hazardous to the health of the child." [Grimes, 2001]

It is most disquieting that NHRPAC - and its sub-committees - whose mandate is to enhance the protections for human subjects, is actively engaged in linguistic tinkering to lift regulatory restrictions that were adopted to protect human subjects in order to accommodate the interests of research:

Maximum freedom to conduct research with minimum regulatory interference and no penalties for preventable ham or violations of ethical and / or scientific standards. Few mandatory requirements for rigorous independent review and risk analysis to ensure that predictable risks and burdens are weighed in comparison with foreseeable benefits to the subject. (as required under the Declaration of Helsinki, principle 16, October, 2000) Researchers have given themselves and each other, an escape clause, arguing: "We cannot be blamed for harmful consequences, research always involves risks" - even though harm could have been prevented. Or it has been argued, "It was the norm and practice at the time." The research community protects itself from being held accountable with the shield of "confidentiality."

In 1994, ACHRE examined 21 nontherapeutic pediatric radiation experiments conducted between 1944-1974, involving about 800 children. For example, in 1953, Johns Hopkins University researchers injected iodine 131 into 34 children, aged two months to fifteen years with hypothyroidism. The ACHRE Report states that an unknown number of healthy controls were also injected with Iodine 131. Hypothyroidism is a relatively common illness - 1 per 4,000 births - and can cause profound retardation if untreated. The purpose of the experiment was "to better understand the cause of this disease." Iodine 131 was used as a measure of thyroid function in children. Of the 21 pediatric radiation experiments examined by ACHRE, those involving Iodine 131 posed the highest risk for children, as it is the most carcinogenic compound used. [The maximum potential risk was 2.3 percent]

A most telling observation in the ACHRE report, is the following:

"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." Thus, if judged by the standards set by the biomedical research community - without consideration for community moral standards - the 21 nontherapeutic radiation experiments that put children at risk of cancer passed the researchers' standards.

If the distinction between therapeutic and nontherapeutic research were eliminated, children are likely to suffer and nontherapeutic experiments such as chemical "challenge" studies that use humans instead of animals to test speculative hypotheses would increase. Examples include the fatal hexamethonium inhalation experiment at Johns Hopkins University, the perchlorate ingestion experiment at Loma Linda, the ketamine injection experiments at Yale University and Maryland Psychiatric Research Center, and the pediatric fenfluramine experiments at New York State Psychiatric Institute and City University. In 1953, the risk of cancer was not as well documented, as was the risk of brain damage for children from lead paint in 1998.

In its effort to lift protections that restrict access to children for nontherapeutic research, NHRPAC has encouraged the Children's Workgroup to redefine "minimal risk" "minor increment over minimal risk" and "disorder or condition." If adopted, the proposed new guidelines would lend legitimacy to experiments that had been severely criticized, including the lead paint abatement study that so outraged the Maryland Court of Appeals. The Court affirmed "the 'best interests of the child" as the overriding concern. Those engaged in redefining regulatory concepts such as "disorder or condition," are exploiting poor children's deprivation, calling it a "condition" that qualifies them for nontherapeutic experimental research.

The Draft guidelines seem to infer that such underprivileged children will necessarily benefit from a study of lead abatement. For example, the Draft states that the regulatory requirement of direct benefit to the child - which is intended to prohibit the use of healthy children in research involving greater than minimal risk (45 CFR 46.405) - is met if the child is "living in a home which is affected by lead." They claim that living in impoverished circumstances is "the condition that establishes the prospect of direct benefit for any given child." We note, that it is nowhere stated that all the children will be provided (moved) to fully abated homes. Those who formulated the Draft guidelines clearly defy the Maryland Court of Appeals decision.

The other examples given include: a "Diabetes Prevention Trial," in which healthy siblings - including infants - of children with insulin dependent diabetes, are claimed to be at "high-risk" (50%) for developing diabetes. " The research question was whether the administration of either oral or subcutaneous insulin in low doses would delay or prevent the development of diabetes." The claims made in this example, are as misleading and false. "In families where there is already a first degree relative with this form of diabetes, the chances of a future of so far unaffected child developing this condition is about 5%; slightly higher if the father is affected and slightly lower if it is the mother." [George S. Eisenbarth, Prediction of Type I Diabetes: The Natural History of the Prediabetic Period. Chapter 11. http://www.childrenwithdiabetes.com/d_0n_520.htm

Similar unfounded claims were made in a "Schizophrenia Prevention" experiment at Yale University, in which healthy siblings of schizophrenia patients were being exposed to olanzapine, a potent drug with severe adverse side effects, on the basis of conjecture rather than empirical evidence. Those promoting these exploratory research forays do so without medical justification: "The condition that is addressed in this [diabetes prevention] research is the risk of developing the disease. As the serological testing [for diabetes] could be considered minimal risk, the infants undergoing serological testing did not need to have a condition." [Draft "Disorder or Condition]

It is abundantly clear from this line of reasoning, that if "disorder or condition" were not held to strict verifiable standards of empirical evidence, risk assessment would take a back seat and healthy children would be exploited as "risk bearing" test subjects: "The research was considered to have some risk but was justified as having the potential to benefit those children with that condition." [Draft]

By redefining "condition" children would be subjected to the whims of investigators who would be free to test the entire medical armamentarium, disregarding the best interests of the individual child: " There are a number of tests that can be performed to look at insulin response and resistance, specifically an oral glucose tolerance test, a frequently sampled intravenous glucose tolerance test, and an insulin clamp study." Another example cited is the Draft proposal is to test "the activity of neonatal drug metabolizing enzymes" in infants using an over the counter drug, dextromethorphan. Three pediatricians told us that they would never prescribe such drugs for infants, when all that's necessary is a vaporizer. How many infants must be sacrificed to test drugs (e.g., cisapride, Propulsid) for minor conditions, or merely hypothesized conditions? Draft of proposed guidelines, indicated: "immaturity was a "condition" warranting special attention."

Another example is a research protocol that would expose healthy siblings to SPECT scans (single photon emission computed tomography) and the psychostimulant drug, methylphenidate (Ritalin). Among other things, the drug has been linked to addiction: In 1996, Dr. Steven Hyman, former Director of NIMH, wrote that whether abused or prescribed, the mechanisms by which psychotropic drugs work are the same. He indicated that "chronic administration of psychotropic drugs cause neural adaptations that lead to substantial and long-lasting alterations in neural function." In the case of psychostimulant drugs (e.g., cocaine, amphetamine, methylphenidate) "the adaptive response of the nervous system is addiction."

[Hyman SE and Nestler EJ, "Initiation and adaptation: a paradigm for understanding psychotropic drug action," Am J Psychiatry 1996; 153:151-162. See also, Lambert, N. "Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants," J.of Learning Disabilities 1998, 31:533-44]

Methylphenidate has recently been found to be more potent than cocaine. Brookhaven Laboratories investigators led by Nora Volkow, M.D. found that "instead of being a less potent transport inhibitor than cocaine, methylphenidate was more potent."

Volkow ND, et al., "Is methylphenidate like cocaine? Arch Gen Psychiatry 1995, vol.52, pp.456-63; Vastag B, "Pay Attention: Ritalin Acts Much Like Cocaine," Journal of the American Medical Association, August 22/29, 2001, Vol. 286 No. 8, http://jama.ama-assn.org/issues/v286n8/ffull/jmn0822-1.html

Under the Draft guidelines, healthy children would be exposed to a drug that Dr. Steve Hyman found caused "substantial and long-lasting alterations in neural function" and addiction. The claim by some psychopharmacologists, "previous studies have demonstrated an increase in dopaminergic transporter (DAT) density in children diagnosed with ADHD" has not been replicated or proven. In fact, expert panels convened by NIH (1998), Agency for Healthcare Research and Quality (1999), and the American Pediatric Association (2000) all acknowledged that there are no objective diagnostic criteria for ADHD.

As William Carey, M.D. put it: "the unresolved basic issue [is] that the diagnostic criteria for ADHD are so vague and subjective that one cannot tell precisely who is being included in any study population."

[Carey, W "Is ADHD a Valid Disorder?" Invited paper presented at NIH Consensus Panel, Diagnosis and Treatment of ADHD. NIH Consensus Development Conference. 1998 Nov 16-18; 16(2): 1-37. NIH Panel. Final Statement online: http://odp.od.nih.gov/consensus/cons/110/110_statement.htm" ; Treatment of ADHD, Evidence Report / Technology Assessment: Number 11. AHCPR Publication No. 99-E017, December 1999. Agency for Health Care Policy and Research, Rockville. American Academy of Pediatrics, Committee on Quality Improvement Subcommittee on ADHD, "Clinical Practice Guideline: Diagnosis and evaluation of the child with ADHD," Pediatrics, 2000, 105: 1158-1170.]

All of the examples given in the Draft raise questions: What is the condition and what is the degree of risk with unfavorable health outcome? What is magnitude of the supposed risk of that condition, and what is the evidence to back it up? Is there a reliable screening test and does an effective intervention exist or that condition? If there is no effective intervention then what's the point of screening for the condition? What is the magnitude and probability of risk of the proposed intervention compared to the probability of risk of the condition?

Vera Hassner Sharav President, AHRP