Protecting Human Subjects in Research: Are Current Safeguards Adequate?
AHRP Testimony submitted to Congressional Committee
April 23, 2002
- Vera Hassner Sharav, President, and John H. Noble, Jr., Ph.D., steering committee member, The Alliance for Human Research Protection (AHRP), before the Subcommittee on Public Health, Committee on Health, Education, Labor, & Pensions, United States Senate at Hearing, "Protecting Human Subjects in Research: Are Current Safeguards Adequate?" on April 23, 2002.
- Witness Short Title. The Alliance for Human Research Protection (AHRP) is a national network of lay people and professionals dedicated to advancing responsible and ethical medical research practices, to ensure that the human rights, dignity and welfare of human subjects are protected, and to minimize the risks associated with such endeavors.
- We thank the Senate Subcommittee on Public Health for this opportunity to present testimony on current weaknesses and flaws in the regulatory and oversight system for protecting the life safety and human rights of the child subjects of biomedical research. The testimony explains how recent government actions threaten to make a bad system worse.
IV. Minimal Risk for Children.
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, to ensure 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. The regulations rely on trust that the research stakeholders – the scientists, sponsors, and institutional review boards – will comply with the regulations. That trust, however, has been betrayed and even the nation’s prestigious research centers were found in violation of ethical standards, including informed consent.
Children present us with the greatest ethical problem because they are not legally competent to exercise informed consent or to protect themselves from unwanted experiments that put them in harm’s way. This status 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. In 1983 special 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 nontherapeutic experiments involving greater than minimal risks or discomfort. Thus, federal regulations protect children by requiring a higher standard of justification for approval of pediatric research by setting limits on the level of risk.
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.
Regulatory protections were adopted to ensure that children, who are not volunteers, are protected from undue harm under the provisions of 45 CFR 46.405 – Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.
Research under Section 405 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."
When the research offers no possibility of a direct benefit, i.e., is nontherapeutic, the regulations restrict such research to "minimal risk." If there is evidence that the research is of "vital importance for the understanding of the subjects’ disorder or condition" then the regulations permit children to be subjected to "a minor increase over minimal risk."
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 could be conducted only if:
- . . . 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;
- . . . 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. [Emphases added]
However, the 1997 FDA Modernization Act (FDAMA) offered the pharmaceutical industry enormous financial incentives – i.e., a six-month patent exclusivity extension – if they
tested their patented drugs on children. FDAMA was passed without any risk assessment by the FDA or NIH, and without Congress being informed about the potential unintended consequences that could result unless additional protections were enacted for children. 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. 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.
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. 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. The physicians who are engaged in such coercion receive as much as $5,000 referral fees (kickbacks) for the recruitment of children.
The number of child research subjects has grown from about 16,000 in 1997 to about 45,000 in 2001, and "there is strong reason to believe that deaths and injuries in research involving children are more widespread" than available statistics would indicate.
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. 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."
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."
V. Implementation of 45 CFR 46, Section 407
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 and approved only after consultation with a panel of appropriate experts and "following opportunity for public review and comment." This procedure in many respects parallels the process of initiating or changing regulations that is prescribed by the Administrative Rulemaking Act because of the gravitas of the issue.
The Department of Health and Human Services (DHHS), through its Office of Human Research Protections (OHRP), assisted by the National Human Research Protection Advisory Committee (NHRPAC), and its Food and Drug Administration (FDA) Pediatric Advisory Committee have embarked on initiatives to broaden the recruitment of children – even healthy children – for clinical trials that may undermine their health and welfare.
Indeed, in one 2000 DHHS draft policy and procedure document healthy children who are to be recruited for clinical trials are referred to as "risk-bearing normal control subjects."
These OHRP and FDA advisory committees are declaring normal stages of child development as if they were 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."
The regulatory protections
children have had since 1983 are being dismantled one section at a time. Federal policy is overturning regulatory prohibitions without issuing an advanced notice for proposed rulemaking changes (ANPRM) as required under the Administrative Rulemaking Act. Instead, a backdoor strategy is being pursued that redefines regulatory terms and protective restrictions in order to legitimize currently prohibited risky and painful experiments on young children.
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. The new policy 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. Children are being recruited to test drugs whose safety is uncertain. 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.
Dr. Benedetto Vitiello, NIMH’s Director of Child and Adolescent Treatment and Preventive Interventions Research Branch, provided confirmatory evidence in this regard 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." At the same time he acknowledges this is happening despite the existence of "diagnostic uncertainty surrounding most manifestations of psychopathology in early childhood." Dr. Vitiello also reveals "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."
The Alliance for Human Research Protection (AHRP) believes that financial inducements of this size offered to vulnerable and easily exploitable poor parents are inherently coercive. It believes recent efforts to evade ANPRM and the Administrative Rulemaking Act are calculated to sanction the exploitation of children and thereby increase the profits of big business. A six-month extension for Prozac, for example, can mean an additional $831 million for Eli Lilly. What chance does a poor kid have against marketplace dynamics of such magnitude?
VI. Are these trials ethical?
Gage Stevens is a tragic example of the consequences of using babies to test drugs. In 1999 Propulsid’s sales reached $950 million, while its death rate – according to the FDA – had reached 80, including both adults and children. Yet, nine month old Gage Stevens was recruited into an FDA-approved clinical trial and given Propulsid and Tagament for four months. He died of cardiac arrhythmia – as had six-month-old Chase Brown the year before. By the time it was taken off the market, nineteen children who had been given Propulsid had died. The Pittsburgh Children’s Hospital consent forms signed by the parents of children in the Propulsid experiments stated the FDA had approved Propulsid for use in children. It was a false claim and one used to facilitate the testing of Propulsid on children. After his death, Gage Stevens’ parents said, "Little did we know that Gage was basically a guinea pig, and they never told us that [Propulsid] causes dangerous side effects, or there had been deaths." The final blow was delivered when the baby’s parents learned from the autopsy report that his esophagus "failed to show signs of significant inflammation or other hallmarks of gastroesophageal reflux." In other words, the baby didn’t have the condition for which he was used in the clinical trial.
The antipsychotic drug, Zyprexa, was approved for schizophrenia in adults. Its side effect profile is so severe that the FDA approved the drug for short-term use only in bi-polar patients. Yet five children aged six to eleven were recruited for clinical trials of the drug. According to their published report, investigators at the University of California-Los Angeles, tested Zyprexa on children who were not even diagnosed as having schizophrenia; they were diagnosed as having a variety of other questionable psychiatric disorders, including ADHD, a condition whose diagnostic validity has never been established. According to the published report, all the children in the UCLA trial who were given Zyprexa experienced adverse effects, including sedation, weight gains of up to 16 pounds, and akathisia. Further, none of the ch
ildren were helped by the drug, and the trial was terminated less than six weeks after it had begun.
Since nothing in the published report provides a medical justification for prescribing a powerful antipsychotic drug that exposed these young children to serious risks, the trial seems to have been conducted for other reasons. It seems likely that the decision to test Zyprexa in children was influenced by the powerful incentive of a possible six-month patent extension under FDAMA. In 1998 Zyprexa sales in the U.S. were $1 billion; in 2000, $2 billion; and in 2001 Zyprexa topped Prozac sales at $3 billion. Clearly, a six-month patent extension is enormously profitable and provides a powerful incentive to test every conceivable drug on children.
No doubt, the researchers and IRBs at the Kennedy Krieger Institute, who saw nothing wrong with approving an experiment that would expose healthy babies and toddlers to lead poison, regarded those children as "risk bearing subjects." The purpose of the experiment was to determine the effectiveness of varying degrees of lead paint abatement. During the experiment, the level of lead in the children’s blood was allowed to rise to hazardous levels. Researchers drew blood samples from the children, recorded the rise in lead poisoning, and did nothing to intervene. Fortunately, Maryland’s highest court (the Maryland Court of Appeals) issued a resounding ruling on behalf of children everywhere when it condemned this experiment and all nontherapeutic experiments that expose children to any but minimal risks. The Court cited international codes of ethics – the Nuremberg code and the Declaration of Helsinki – and federal regulations that affirmed the primacy of individual rights:
Whatever the interests of a parent, and whatever the interests of the general public in fostering research that might, according to a researcher’s hypothesis, be for the good of all children, this court’s concern for the particular childover-arches all other interests. It 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. [p. 80]
At the April 29, 2002 NHRPAC meeting, a report will be presented by its children’s workgroup, to which the AHRP President, Ms. Vera Hassner Sharav, will submit a dissenting opinion. The workgroup panel of experts – like most advisory panels – represent the interests of research institutions insofar as they are all affiliated with research centers or agencies that receive funding from the pharmaceutical industry and government. The panel claims 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 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." The assumption of genetic predisposition is invalid insofar as it is not based on scientific evidence – merely speculation. As the neuroblastoma case demonstrates, there is a possibility that more harm than good will be done and, therefore, the risks are not justified. In that case a screening test producing largely false-positive findings resulted in unnecessary surgery on thousands of Japanese babies.
The Alliance for Human Research Protection (AHRP) believes that the pain and risks of harm in a growing number of experiments that offer no personal benefit are against the best interest of children. Children are being recruited for speculative experiments whose value is questionable. Indeed, a most telling observation in this regard is found in the 1994 report of the Advisory Commission on Human Radiation Experiments (ACHRE):
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.
If the standard of permissible research is left to the judgment of the biomedical research community without the participation of community members whose moral standards are likely to differ from theirs, children will be unjustifiably exposed to harmful experiments. The evidence, then and now, confirms 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]
Whereas 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. Advisory panels convened by DHHS are now attempting to legitimize those very experiments through disingenuous linguistic tinkering. The attempt to broaden the interpretation of "minimal risk" and "a minor increase over minimal risk" will result in children being subjected to a higher threshold of pain and risks of harm greater than what current federal regulations permit.
Physicians whom the Alliance for Human Research Protection (AHRP) has consulted have indicated that the
designated risk categories recommended by the NHRPAC workgroup for invasive and, in some cases, exceedingly painful procedures, are astounding in their disregard for the welfare of children. Among the procedures designated as "minimal risk" are venipuncture, the glucose tolerance test, the indwelling heparin lock catheter, chest x-ray, and bone-density and bone-wrist x-ray. An indwelling heparin catheter is not something that a healthy child would experience, and venipuncture does pose risk of infection as does the glucose tolerance test. Single x-ray radiation exposure presents a small but cumulative risk of cancer. Because the magnitude of the risk is unknown and the impossibility of predicting the lifetime exposure for a particular child, it cannot be asserted 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."
The following exceedingly painful procedures involve measurable risks and require informed consent when used in standard clinical practice. How then can one justify classifying the following procedures as merely "a minor increase over minimal risk" when children would be subjected to the pain and risks?
It is hard to imagine that researchers from prestigious universities would volunteer their children for these procedures for the sake of science.
If adopted, the workgroup recommendations would lift the restrictions that currently provide children with some protection from unwanted experimentation. The draft fails to provide any guidance that would ensure compliance with the protective standards provided in the regulations – as though these were not major problems.
Last, the Alliance for Human Research Protection (AHRP) is concerned about the secrecy that surrounds implementation of the very Section 407 provisions that require public transparency. Recall that 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, by a panel of experts, and the public before it could be approved. On February 7, 2002, we requested (1) copies of current research proposals for which requests have been received for review by a HHS Secretarial panel of experts under 45 CFR 46 Subpart D, Section 407; and (2) the list of experts convened by the Sec for the purpose of advising him regarding these proposals.
We received the reply on March 29, 2002, from Ms. Darlene Christian, Public Health Service FOIA Officer, that currently seven protocols are pending for expert review under the provisions of Section 407 – not 26 – as stated by Dr. Greg Koski at the NHRPAC meeting on January 28, 2002, and that all seven have been reviewed by experts, but none have yet resulted in final determinations. How many are there really – seven or 26? The reply went on to say:
Release of information, at this stage, would interfere with the agency’s deliberative and decision-making processes. Further, each researcher has commercial and privacy interest in release of any information that would identify the researcher or the research prior to a funding decision. Therefore, at this time, I must deny you full access to these records.
With respect to your request for a list of experts, there is no fixed panel of experts for review under Sec 407. Panels of experts are formed for reviews dependent on the needs of each protocol. Release of expert identities associated with the review of individual protocols would interfere with the agency’s deliberative and decision-making processes and have a chilling effect on the ability of the agency to obtain frank and candid opinions from its reviewers. Accordingly, I must deny you access to the identities of the individuals who performed such reviews.
We leave the Senate Subcommittee on Public Health with this question to ponder, "How can the public ever obtain sufficient knowledge on which to provide the Secretary of HHS input pursuant to Section 407 requirements if "commercial and privacy interests" are allowed to trump access to needed information?" In a field rife with conflicts of interests, is it the expectation of the U.S. Congress that citizens receive only such information as government officials deem acceptable for their consumption?
The Alliance for Human Research Protection (AHRP) is hopeful that this is not the intent of the U.S. Congress; indeed, we hope the U.S. Congress will affirm that no barriers will be permitted to come between citizens and information needed to protect against potential harm. In our view, no research protocol can be legitimately processed under Section 407 provisions without full disclosure of all relevant information, including that which some petitioners may perceive to ill serve their "commercial and privacy interests." Citizens resent being patronized and manipulated by those appointed to faithfully discharge the requirements of law and regulation.
The Alliance for Human Research Protection (AHRP) suggests that a recommendation in the original regulations proposed in 1973 for the protection of children should be adopted. These proposed regulations reflected greater sensitivity to the history of research abuses and the vulnerability of children. They would have required review by a "Protection Committee" in addition to review by an IRB. The Protection Committee was to serve as the child subjects’ advocates, monitoring their selection, assessing the reasonableness of their parents’ consent, and monitoring their continued willingness to participate in the research.
Clinical research in today’s climate of corporate expediency is driven by financial interests that conflict with the best interests of the child. Some parents are too-easily swayed by financial incentives and too-quick to give permission to conduct research on a child – especially if they are poor and educationally disadvantaged. The recent flip-flopping of the U.S. Department of Health and Human Services about implementation of the so-called FDA Pediatric Rule poses a large threat to children’s health, safety and dignity. We sincerely hope the Senate Subcommittee on Public Health will insist on proper safeguards for the protection of children’s life safety and human rights, asking the question, "Whose children will be used as test subjects?"
See Dembner, A. (2001, Feb. 18). Dangerous dosage. Boston Globe: Front page. Online at:
Dembner A. (2001, March 20). Teddy bears and veiled threats. Boston Globe: C-1. Online at:
Dembner, A. (2001, March 20). Should a healthy child ever be a test subject? Boston Globe: C-3. Online at:
Dembner, A. (2001, March 25). Who’s protecting the children? Drug research raises concerns about policy and penalties. Boston Globe: Front page. Online at:
Jetter A. (2000, Sept. 12). Efforts to test drugs on children hasten drive for research guidelines. NY Times. Online at:
fSee Dembner, "Teddy Bears" and "Dangerous Dosage" (Ref. 1)
Advisory Subcommittee (1999, Nov. 5). Ethics Presentation Online. Ethical issues in pediatric pharmaceutical research where there is no primary intention of direct benefit. Online at:
See also FDA Center for Drug Evaluation and Research, Pediatric Information. FDA Ethics Working Group Consensus Statement on the Pediatric Advisory Subcommittee’s November 15, 1999 Meeting; Final, April 19, 2000. Online at:
"Uncertainty about the diagnosis of mental disorder in preschoolers has precluded FDA from requesting studies of psychoactives in younger children," according to Vitiello, B. (2001). Psychopharmacology for young children: Clinical needs and research opportunities. Pediatrics, 108: 983-990.
Ibid. p. 985.
http://www.nytimes.com/2001/02/11/national/11DRUG.html; and Dembner, A. (2001, March 20), Ref. 1.
Among the warnings issued by Janssen Pharmaceutica to physicians was:
Pediatric Use: Safety and effectivenesss in pediatric patients have not been established. Although causality has not been established, serious adverse events, including death, have been reported in infants and children treated with cisapride. Several pediatric deaths were due to cardiovascular events (third degree heart block and ventricular tachycardia). Pediatric deaths have been associated with seizures and there has been at least one case of sudden unexplained death’ in a 3-month-old infant. (Janssen Pharmaceutica "Dear Doctor" letter, June 26, 1998.)
See also Willman D. (2000, Dec. 20). Propulsid: A heartburn drug, now linked to children’s deaths. Los Angeles Times: Front page. Online at:
The risks of treatment, particularly the use of stimulant medication, are of considerable interest. Substantial evidence exists of wide variations in the use of psychostimulants across communities and physicians, suggesting no consensus among practitioners regarding which ADHD patients should be treated with psychostimulants. However, there is no evidence regarding the appropriate ADHD diagnostic threshold above which the benefits of psychostimulant therapy outweigh the risks Finally, after years of clinical research and experience with ADHD, our knowledge about the cause or causes of ADHD remains largely speculative. Consequently, we have no documented strategies for the prevention of ADHD. See Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder. NIH Consensus Statement, November 16-18, 1998. Online at:
See Roig-Franzia, M. and Weiss, R. (2001, Aug. 20). Md. appeals court slams researchers. Washington Post: Front page. Online at:
Brownlee, S. (2002). Why mammograms are not the answer: Search and destroy. New Republic. Online at: