THE ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

www.ahrp.org

Proposed Changes to Subpart D Regulations Increase Risks to Children in Non-Therapeutic Research

Statement of the AHRP Opposing the SACHRP Children's Committee Recommendations

April 18, 2005

The Alliance for Human Research Protection (AHRP) welcomes the opportunity to respond to the question "What is the Best Way to Protect Children?"

Our recommendation - which is backed up by evidence that children have suffered harm in medical research - is to significantly limit the discretion of IRBs to approve greater than minimal risk research without direct benefit for the child-subjects under 46.406.

We recommend staying the course in requiring that any such proposed experiment undergo a transparent open evaluation with ample opportunity for public oversight and comment - as required under the provisions of 46.407.

AHRP opposes any changes to Subpart D regulations that would increase risks of harm to children who may be subjected to non-therapeutic experiments. The IRB track record in this regard is particularly discouraging.

We start by reminding the SACHRP panel of two judicial decisions involving non-therapeutic experiments. In 1995, a New York State Supreme Court[1] ruled that: "Parents may be free to make martyrs of themselves, but it does not follow that they may make martyrs of their children." In 2001, the Maryland Court of Appeals[2] rendered a comprehensive decision in the now infamous lead-poison experiment in which toddlers were exposed to lead which put them at risk of mental retardation "for the greater good of society."

I. The Maryland Court of Appeals Strongly Censured the Johns Hopkins University IRB:

• For failing to meet its mandate, that of "insuring the safety of the subjects and compliance with federal regulations, by approving an experiment that "was clearly nontherapeutic in nature. �The very inappropriateness of the research itself cannot be overlooked."
  
  "The experiment was simply a 'for the greater good' project. The specific children's health was put at risk, in order to develop low-cost abatement measures that would help all children, the landlords, and the general public as well."
  
  "Otherwise healthy children, [FN5] in our view, should not be enticed into living in, or remaining in, potentially lead-tainted housing and intentionally subjected to a research program, which contemplates the probability, or even the possibility, of lead poisoning or even the accumulation of lower levels of lead in blood, in order for the extent of the contamination of the children's blood to be used by scientific researchers to assess the success of lead paint or lead dust abatement measures."
  
  
• For misperceiving "the difference between therapeutic and nontherapeutic research and the IRB's role in the process."
  
  
• For "willing to aid researchers in getting around federal regulations designed to protect children used as subjects in nontherapeutic research."
  
  
• For having "abdicated [its] responsibility, instead suggesting to the researchers a way to miscast the characteristics of the study in order to avoid the responsibility inherent in nontherapeutic research involving children."

Accordingly, the Maryland Court of Appeals ruled that: "the research methods, the protocols, [we]re inappropriate." Therefore, "the consent of the parents, or of any consent surrogates, in our view, cannot make the research appropriate or the actions of the researchers and the Institutional Review Board proper."

Under the proposed Subpart D changes of the SACHRP Children's Committee would a non-therapeutic lead-abatement experiment such as this be approvable under any risk category?

II. Continuing Evidence of Serious IRB Compliance Problems:

The Maryland Court noted that some commentators have suggested that the failures and inappropriate actions by the Johns Hopkins IRB may be "endemic to the research community as a whole."

Indeed, the following are a small sample of IRB approved experiments[3] that would not pass the "permissible research" test:

• The EPA IRB approved an experiment that would have exposed toddlers to pesticides - a clear violation of The Nuremberg Code;
  
  
• Infants and children in foster care[4] were used as human guinea pigs in phase I and phase II AIDS drug experiments - in direct violation of section 46.409;
  
  
• At Yale University healthy adolescents are being exposed to the toxic effects of the antipsychotic drug, Zyprexa (olanzapine)[5] [6] despite the documented alarming risk of drug-induced diabetes, and to a lesser degree, cardiac arrest;
  
  
• Children, including pre-school children are being used in experiments that expose them to the harmful effects of powerful psychotropic drugs - including psychostimulants,[7] antidepressants and antipsychotics.[8] The drugs have never been proven effective in children, and their safety is being challenged as previously concealed evidence has been made public.[9] Indeed, the risk-benefit ratio was deemed negative by two FDA advisory panels. Since determining that the evidence showed that children were incurring a twofold increased risk of violence and suicide if exposed in even short clinical trials to SSRI antidepressants compared to those on placebo.

A front page article in The New York Times [10] reveals that pillars of American psychiatry--including Drs. Jeffrey Lieberman, John Kane, and William Carpenter--are acknowledging that evidence is lacking to support the claims that the new antipsychotic drugs are any better than the old drugs for treating psychosis. Furthermore, they acknowledge that evidence does exist showing the new drugs--that they and the drug industry have jointly been touting as "wonder drugs" for years--are not benign. The new drugs, they concede, have severe, debilitating side effects - including a high risk of diabetes.

Given the evidence of systemic failure by the IRB system to protect research subjects from unethical experiments - in particular as it affects children--the AHRP believes the SACHRP Children's Committee proceeds on the flawed, unsustainable assumption that the IRB system can be trusted or is capable of assuming greater discretionary authority as the proposed changes to Subpart D would entail.

How widespread are IRB performance failures? Failures can in part be gleaned from a recent study[11] of FDA warning letters that were sent to out-of-compliance IRBs. The study makes known the kinds of IRB non-compliance problems that exist, but fails to document whether the FDA put the aberrant IRBs under surveillance to determine if definitive corrective action was taken. While limited in that respect, the study, nonetheless, concludes: "Our findings, in a setting of overburdened IRBs who, in general, passively monitor studies, raise concerns about study oversight and optimal protection of research subjects."

Similarly, a perusal of OHRP letters of determination paint a dismal picture. http://www.hhs.gov/ohrp/detrm_letrs/lindex.htm

For example, the latest letter posted (April 5) shows that the IRB at the University of Washington failed to document informed consent procedures in protocols involving vulnerable populations - which included pregnant women, fetuses, neonates, children, and prisoners. Since the letter of particulars is mostly redacted, it is only possible to know a portion of the violations by the UW IRB. Among the disclosed violations is the approval of research protocols without ascertaining whether safety issues had been resolved. See: http://www.hhs.gov/ohrp/detrm_letrs/YR05/apr05a.pdf

III. Countervailing Protections for Children Are Needed Against Their Use in Non-Therapeutic Research[12]

Given the record of overreaching research in which children are used as means to an end, offering no potential benefit for child subjects, and given mounting evidence of systemic IRB failures to protect children from harmful experiments, the AHRP recommends adoption of additional protections, not less.

Specifically, we recommend adoption of the "Children's Protection Committee" mechanism that was put forth in the original 1973 proposed federal regulations.[13] The 1973 proposed regulations reflected greater sensitivity to the history of research abuses and the vulnerability of children. By contrast, clinical research in today's climate of corporate expediency is driven by financial interests that conflict with the best interests of the child.

A "Children's Protection Committee" is needed because IRBs do not serve the best interest of child subjects who are non-consensual research subjects. The sole responsibility of the "Children's Protection Committee" would be to advocate for the child's best interest, with responsibility for monitoring the selection of child subjects, assessing the reasonableness of the parental consent, and assuring the ongoing willingness of the child subject to continue participation in the research.

IV. AHRP Proposal for Creation of a Research Ombudsman System under Court Oversight

As demonstrated by the Johns Hopkins lead-poison experiment, and the others in which children were enrolled against their best interest, parents were not fully informed about the nature of the research or the risks and discomfort their child would bear. Additionally, some parents can be swayed by financial incentives - even trinkets - to give permission for their children to be subjected to experimentation - especially if they are poor and educationally disadvantaged.

The Maryland Court of Appeals affirmed the absolute duty of society to protect vulnerable persons - including children and those who are mentally disabled - from non-therapeutic experiments involving risks of harm. The Court left no doubt that it is morally unacceptable to put children in harm's way by rationalizing that it is "for the greater good of society."

The Court also recognized that: "it 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]

The AHRP recommends, once more, that a research ombudsman system[14] - Children's Protection Committee - should operate under court oversight rather than the obviously flawed IRB system. The cost of affording greater protection than is now available is justified in view of the dismal record of IRB failure. The AHRP believes that public opinion will support the investment in the protection of children who, on rare occasions, may be needed to answer a question that can only be answered by implementation of an exceptional case of non-therapeutic research.

To recognize what is at stake, ask yourself the question, "Would I, as a parent, not want the option of having a person who is more knowledgeable than I am to give me the information I need to decide whether or not to permit my child's participation in non-therapeutic research that might well involve procedures which pose risk or discomfort? Such research is almost invariably described by a self-interested research team as merely carrying 'minimal risk,' or a 'minor increase over minimal risk,' or its 'equivalent risk.'

Contact:

Vera Hassner Sharav
President
212-595-8974

John H. Noble, Jr. Ph.D
Treasurer
703-425-2120

[1] T.D. v The NYS Office of Mental Health (1995).

[2] Higgins v. Kennedy Krieger Institute, Court of Appeals of Maryland, Nos. 128, 129, Sept. Term, 2000, August 16, 2001.

[3] See: Sharav VHS. Children in clinical research: a conflict of moral values. American Journal of Bioethics 2003; 3(1): InFocus online at: http://s97929468.onlinehome.us/journal/pdf/3_1_IF_w12_Sharav.pdf

[4] See AHRP letter of complaint at: http://www.ahrp.org/ahrpspeaks/HIVkids0304.php

[5] See Goode E. (1999, Dec. 7). Doctors try a bold move against schizophrenia. New York Times, F-1.

[6] See Zimmerman R. (2000, July 26). Radical study on schizophrenia may be expanded: Researchers seek to discover whether antipsychotic drugs can prevent the disease. Wall Street Journal. Retrieved July 26, 2000 from http://www.contac.org/contaclibrary/research70.htm

[7] "New Frontiers in Pediatric Psychopharmacology" at the 47th annual meeting of the American Academy of Child and Adolescent Psychiatry, October 24 - 29, 2000. PATS trial sites were at Columbia University, Duke University, Johns Hopkins University, New York University, and the University of California campuses at Los Angeles and Irvine.

[8] As early as 1993, the Food and Drug Administration found that in clinical trials Jennsen Pharmaceuticals had failed to prove that its antipsychotic drug, Risperdal, was any better than Haldol, but that one in every 35 patients in Risperdal clinical trials had suffered a "serious adverse event."

See Temple R. (1993, Dec. 29). Risperdal approval letter (obtained under Freedom of Information Act).

[9] Vastag B. 2001. Pay Attention: Ritalin acts much like cocaine. Journal of the American Medical Association 2001; 286(8): http://jama.ama-assn.org/issues/v286n8/ffull/jmn0822-1.html. See also Volkow ND, Wang GJ, Fowler JS, et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. Journal of Neuroscience 2001; 21: RC121.

[10] Goode E. (2003, May 20). Leading drugs for psychosis come under new scrutiny. New York Times: http://query.nytimes.com/gst/health/article-printpage.html?res=990CE0DB103EF933A15756C0A9659C8B63

[11] Bramstedt KA, Kassimatis K. A study of warning letters issued to Institutional review boards. Clin Invest Med 2004; 27(6): 316-23. http://www.cma.ca/index.cfm/ci_id/42728/la_id/1.htm

[12] "Much of the argument in support of and in opposition to the motion for reconsideration centered on the question of what limitations should govern a parent's authority to provide informed consent for the participation of his or her minor child in a medical study. In the Opinion, we said at one point that a parent "cannot consent to the participation of a child ... in nontherapeutic research or studies in which there is any risk of injury or damage to the health of the subject." As we think is clear from Section VI of the Opinion, by "any risk," we meant any articulable risk beyond the minimal kind of risk that is inherent in any endeavor. The context of the statement was a non-therapeutic study that promises no medical benefit to the child whatever, so that any balance between risk and benefit is necessarily negative. As we indicated, the determination of whether the study in question offered some benefit, and therefore could be regarded as therapeutic in nature, or involved more than that minimal risk is open for further

factual development on remand." See: Maryland Court of Appeals, op. cit., Reconsideration Denied Oct. 11, 2001.

[13] See 28 Fed. Reg. 31,738 (1973). Also see: Glantz L. Research with children. American Journal of Law and Medicine 1998; 26: 229-230, Ref 194.

[14] AHRP Testimony (2002, April 23). Sub-Committee on Health, Education, Labor, & Pensions, United States Senate Hearing, "Protecting Human Subjects in Research: Are Current Safeguards Adequate?" at: http://www.ahrp.org/testimonypresentations/childrenApril02.php