Submitted to the Office of Human Research Protection
by Vera Hassner Sharav and Marie M. Cassidy, Ph.D, D.Sc.

AHRP recognizes that to include children in clinical trials for any medication presents a dilemma of truly Solomonic proportions. It is a choice between continuing the practice of prescribing untested drugs for children, as is currently the operational system, or conducting meaningful trials to determine both safety and effectiveness.

Federal policy, until now, has been to protect children from non-essential, invasive, painful medical experiments that are not in their own best medical interests, by restricting their inclusion in experiments that involve: "greater than minimal risk and no prospect of direct benefit to individual subjects." [45 CFR 46.406] We question the ethics of the recent Food and Drug Administration (FDA) drug testing requirement that essentially opens the gates to the exploitation of children in medical experiments that cause them pain and discomfort and put them at risks of harm --without medical justification or the prospect of direct medical benefit. For example, phase I studies which, for the first time test the safety of new drugs in humans, were mostly conducted on healthy, normal, adult volunteers, or in patients suffering from life threatening conditions. In the past, phase I studies in children "had been primarily limited to life threatening diseases and children who had the disease for which the new drug was being proposed."

http://www.fda.gov/cder/pediatric/pedethics-1199.htm

In 1997, when Congress extended patent rights to pharmaceutical companies that test their drugs on children, in controlled clinical trials, they were not informed by the responsible Federal agencies--

FDA, National Institute of Health (NIH), Office of Research Protections (OHRP, formerly OPRR)--that existing regulatory protections were wholly inadequate. Nor was Congress informed about systemic ethical violations, and evidence of preventable, research related adverse (sometimes fatal) consequences. Since 1997, a continuing stream of scandals has been uncovered by the media, revealing the harmful human consequences resulting from the absence of effective Federal enforcement mechanisms.

Unethical research practices have emerged because inextricable conflicts of interest have led researchers to subordinate the health and welfare of human subjects--including helpless children-- for financial interests. Government investigations--between 1998 to date-- resulted in the shut-down of all research at six institutions, the suspension of all Federally funded research at another three institutions, and partial suspension of research at an unspecified number of institutions. Those revelations have seriously shaken public trust, and if nothing substantive is done to protect people in clinical research, public support for medical research is bound to suffer.

In her waning months as Secretary of Health and Human Services, Donna Shalala acknowledged in The New England Journal of Medicine: "I did not expect, or want, to complete my tenure as secretary of health and human services by raising questions about the safety of patients in clinical research. However, recent developments leave me little choice." And she added: "AHRP have a responsibility to make sure the money we invest -- money that comes from U.S. taxpayers -- is not used in ways that harm people participating in clinical trials or that unnecessarily risk harming them."

When he assumed the Directorship of the newly reconstituted Office of Human Research Protections (OHRP, formely, OPRR), Dr. Greg Koski stated the following to The New York Times: "the system may have gotten entirely out of control" and might have to be reorganized. "we must take steps to re-establish the public's trust in the goodness of our endeavors." He acknowledged that the problems pointed out by critics of the current ethics system, "are very real, very serious and a threat to our entire endeavor."

Dr. Mary Faith Marshall, Chair, National Human Research Protection Advisory Commission wrote:

"In spite of the response to the 1990 RCR [Responsible Conduct of Research] regulations, the research climate has worsened dramatically. Since January 1, 1999, [OPRR] has found that approximately 60 institutions, including some of our most prestigious universities, are not compliant with federal research regulations." Since July, 2000 OHRP has suspended a portion of Federally funded clinical trials at seven additional research centers.

Thus, we are dismayed that the questions posed by OHRP reveal utter ignorance about the full blown crisis that has developed as a direct consequence of the Federal system's failure to protect both adult and child subjects of research. The questions raised by OHRP presuppose an existent, functional system of protections for adults which, one is led to assume, needs only slight modifications for children. But that presumption is unsupportable by the weight of evidence demonstrating widespread ethical violations and preventable harm. To cite but a few investigative press reports: Propulsid, a deadly drug approved for heartburn, killed infants recruited into an FDA-approved trial--despite the drug having been linked to deaths in adults and children prior to the recruitment of babies. The Washington Post exposed unethical conduct in gene therapy experiments, resulting in the death of 18 year old, Jesse Gelsinger; another series in The Post, "Body Hunters," exposed unethical practices by American companies offshore; CBS 60 Minutes, "Dangers of Clinical Drug Trials," April 1, 2001 revealed that the system depends on whistle blowers, as did the copiously documented series, "Uninformed Consent," in The Seattle Times. Clearly, medical research is out of control--the evidence demonstrates that self-regulation by the research community may protect research institutions, but fails to protect patients from abuse, exploitation, and for some, permanent harm.

Before we address the 12 questions raised by OHRP, we, the Alliance for Human Research Protection (AHRP) would like to comment about the DHHS Draft proposal, "Policy and Procedures for DHHS Research Involving Children--45 CFR 46.407", revised March 12, 2001. Are these proposed changes, a notice of intent to regulate, subject to the Federal Administrations Procedures Act? The substantive reinterpretation of existing regulatory language follows the FDA's ill-advised policy change which has broadened the exposure of thousands of healthy children to risks in commercial drug trials. As the FDA's Center for Drug Evaluation & Research (CDER) website acknowledges, this recent FDA policy "has led to an increasing number of proposals for studies of safety and pharmacokenetics, including those in children who do not have the condition for which the drug is intended." This new policy promotes the enrollment of healthy children "who are not patients in pediatric pharmaceutical research."

Indeed, a growing body of evidence already demonstrates the need to curb the recruitment of children into risky drug experiments that exploit their helplessness. The Boston Globe reports that the drug industry is spending $1 billion a year on pediatric testing--there are 45,000 children participating in medical experiments this year--up from 16,000 in 1996. Researchers are getting bountiful financial incentives, $5,000 is not unusual, to recruit children. Business is so promising, reports the Globe, that the largest CROs --such as Quintiles and Parexel--have set up pediatric divisions in Philadelphia and Columbus, Ohio. Even industry consultants acknowledge that "there are some time bombs out there that are just focusing on the money and we don't have the infrastructure to monitor research from end to end." Robert Ward of the American Academy of Pediatrics, who pushed for the Federal changes, now is concerned about the lack of professional restraint. He is quoted stating: "we've heard of drug studies being conducted in motels, in which they rent a block of roomsthey're not provided with equipment to deal with complications or allergic reactions. That's inappropriate."

Without adequate current safeguards in place, untested techniques are being tried on children. The Boston Globe reports about the chairman of ophthalmology at the University of South Florida, "Medical records suggest that [Dr.] Rowsey performed a self-contained experiment on one toddler, doing traditional surgery on one eye and the new technique on the other, which resulted in unusual bleeding into the eye. Rowsey said he didn't do the new technique on the second eye because his new knife was being sharpened." This ophthalmologist split ownership of his surgical knife 50-50 with the institutional review board at the university, which waived informed consent requirements, oversight, or adverse event reporting. The Globe reports that there were "more than the usual complications, including transplants that slipped and wounds that broke open" when children were involved.

We question the DHHS policy that ignores entirely a growing body of evidence, including its own, of ethical violations even at prestigious research institutions, which have led OPRR to suspend research projects at 21 institutions--57% within the last three years (between January, 1990 to June, 2000) In light of the frenzy to recruit thousands of children, Federal protections need to be expanded, to ensure children are protected-- at least to the degree that animals are-- from undue pain and discomfort. Regulatory restrictions need to be enforced and strengthened to protect children from medical predators. Instead, DHHS is embarking on a policy to circumvent current regulatory restrictions by redefining the meaning of terms that current regulations use to restrict /prohibit the inclusion of children--who have no diagnosable condition, and therefore would derive no benefit--in experiments involving greater than minimal risks. These restrictions were adopted precisely to protect children from experimental exploitation. The DHHS Draft policy will further weaken current protections for children--weak as they now are.

The DHHS Draft policy redefines the terms "disorder or condition" [45 CFR 46.406] and "reasonable opportunity," in an effort to broaden the criteria under which healthy children may be subjected to research "not otherwise approvable" under existing Federal regulations.

Under 45 CFR 46.406 "Research involving greater than minimal risk and no prospect of direct benefit to individual subjects" is permissible only if it is "likely to yield generalizable knowledge about the subject's disorder or condition." The Draft policy, however, redefines "condition" by stating: " for the purposes of s 46.406The concept of 'condition' need not be limited to a medical condition, but might apply to a demographic or other descriptor if it can be shown to define a group of children for whom the research is likely to yield important generalizable knowledge." It is interesting that the DHHS Draft should obliquely acknowledge the fact that the concept "condition" has a medical meaning in other contexts, but "for the purposes of s 46.406" it is being reinterpreted to include non-medical "conditions" to test medical interventions.

Under the ethical standards of the Nuremberg Code and the Declaration of Helsinki, "Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation." Under 45 CFR 46.407, "Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children" [45 CFR 46.407] can be conducted only if: (a) the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children, and (b) 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"[45 CFR 46.407 ]

The proposed DHHS Draft equivocates and weakens those criteria by stating: "'Reasonable opportunity' may include the concepts of scientific validity, timeliness, and feasibility." Such a change would overturn the universal standard requiring scientifically rigorous justification for conducting human research.

By twisting regulatory terminology (i.e., protection) experiments that put children at risks without scientific justification or a potential benefit, that is to say, unethical experiments would be legitimized by Government policy makers. An example, is the notorious New York State Psychiatric Institute fenfluramine violence prediction experiment, conducted on healthy 6 to 11 year old minority children who had no medical condition. We filed a complaint with NBAC and OPRR in 1998. The Psychiatric Institute justified the experiment by invoking the concept "at risk of a condition," rationale, the hypothesized condition is not a medical one, but a supposed predisposition to violence in non-violent minority children. OHRP (then OPRR) failed to address serious concerns about the ethical and scientific legitimacy of the experiment, glossed over the trauma and risks involved for the children, and accepted the strained, one might say, racial-profiling rationalizations of the research institution. However, since a lawsuit has been filed, the legitimacy of that experiment will be tested in a court of law.

On what basis does DHHS, a Government oversight agency, reinterpret existing regulations so that safeguards for children are effectively diluted rather than strengthened? This ill-advised policy is encouraging thousands of healthy but helpless, younger and younger children to be recruited to serve as drug testing subjects --even when those drugs' safety has not been proven. At a minimum, the DHHS Draft policy should receive benefit of full public comment pursuant to the requirements of the Federal Administrative Procedures Act.

Whose children are being sought? Do those who profit from trials volunteer their own children for science? Who has the moral right to volunteer children into drug trials that are against their own best medical interests?

The DHHS Draft ignores and conflicts with the recommendations of the National Bioethics Advisory Commission (NBAC) which if endorsed and adopted would improve research safeguards for adults and children. First, AHRP concurs with NBAC's analysis [ch 3, p. 25] about the inherent flaw in current regulations that have encouraged IRBs to designate risks into categories such as "minimal risk"-- without first examining both the probability and degree of severity of risks. This lack of clarity has fostered misrepresentation of the nature of the risks involved to prospective subjects and IRBs--thereby undermining the latter's ability to both evaluate and minimize all aspects of the risks involved. The NBAC recommended framework for analyzing risks is on a two- dimensional continuum: (a) the probability (likelihood) of harm, from zero to certainty of harm, and (b) the magnitude (severity) of potential harm, from trivial to fatal. This approach is both scientifically appropriate, and will facilitate improvement of safeguards for human subjects. It will also lead to standardized full disclosure of risks to patients with the eventual creation of a database for use by future researchers.

Furthermore, AHRP concurs with NBAC's recommendation that research studies "with risks falling on the extreme upper end of the continuum--very risky or unknown risks--" should not be left to the discretion of one local IRB, but rather should be reviewed by "a national review panel, with public input into the review process." [Ch.3, p 25, L 19] AHRP also concur with NBAC's recommendation for greater public accountability: investigators contemplating high- risk research "should engage the target community of participants in discussion, because having only one or two members who represent the pool of prospective participants on the IRB may not provide sufficient input." [Ch 3, p. 25, L 20 -22] Indeed, to provide the public and Congress with the assurance necessary that research involving high or unknown risks is being undertaken appropriately, independent oversight at the national level is needed.

Our comments to OHRP 12 Questions:

The questions raised by OHRP presuppose an existent, functional system of protections for adults which, one is led to assume, needs only slight modifications for children. But that presumption is unsupportable by the weight of evidence demonstrating widespread ethical violations and preventable harm.

1. Are the regulations appropriate for differing age groups and maturity levels?

AHRP: As has been demonstrated, the current regulations are inadequate to protect children from exploitation.

2. Is the definition of "minimal risk" for a healthy child or a child with illness adequate?

AHRP: Current regulations define "minimal risk" in terms of what is "ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests." The definition is simply inadequate for children when even benign, but painful invasive medical procedures are planned. A distinction should be made between medical procedures and non-invasive observational or sociological research. The application of that standard permits recruitment of healthy children into research that may cause them pain and not be in their best interests.

3. Are definitions of "assent", "permission", and "adequate provisions" for obtaining children's "agreement" appropriate?

AHRP: The role of cognitive development in children/adolescents and how it relates to informed consent needs to be considered by policy makers before making unsubstantiated assumptions about "assent" and children's decision making process. It is important to distinguish between chronological age and developmental stage. Children 7 to 12 can describe the purpose of research studies, but cannot understand the possible risks and benefits of participating. The consent process will have to be different for children in the preoperational stage (ages 2-6), concrete operational stage (ages 7-12), and formal operations stage (ages 13 and beyond).

A cautionary note: Children have been shown to be extremely malleable to suggestions, thus the way the questions are framed will usually determine "assent" or not, rather than an informed willingness. Assent may merely indicate the child's uninformed perception and willingness to accept what grownups tell them will be "good" or "bad" for them. On the other hand, those contemplating the recruitment of adolescents with lower levels of cognitive capacity: Orr and Ingersoll (1995) found that adolescents who were at lower levels of cognitive complexity and who began puberty earlier than their peers were more likely to engage in risky behavior. Those adolescents who had higher levels of cognitive complexity and who began puberty later than their peers were less likely to engage in risky behavior. This might have an impact on their willingness to engage in research risks without an appreciation of consequences.

Any refusal by a child should override parental consent to research--unless the child's condition is life-threatening and no alternative standard of treatment exists, or an appointed independent pediatrician--not affiliated with the research team or institution--determines it is in the child's best interest.

4. Are definitions of "direct benefit to the individual subjects" and "generalizable knowledge about the subject's disorder" adequate?

AHRP: Direct medical benefit --including the assurance of after care guaranteed by a no-fault insurance policy and assured lifetime aftercare. Potential benefit includes the prospect of gaining significant information useful to give guidance to treating physician about improved care after research. Determination of more than minimal risks should be in accordance with the NBAC recommended scientific framework for evaluating the probability of risk--from zero to likely harm-- and magnitude of risk--from minor to fatal. This framework provides meaningful standards which should be disclosed in the consent process, are the framework provides the basis for tracking the outcomes and reassess the accuracy of the determination. [Ch 3, p. 25]

When the subjects are children who, by definition, cannot make self-determining decisions, i.e., informed consent, who has the moral right to put healthy children at risks of "reasonable" harm, and undefined levels of pain when they are not even the intended beneficiaries? This moral dilemma cannot be relegated to institutional review boards who are employed by the major stakeholders in the research enterprise. There is need for greater specificity in duly promulgated Federal regulations containing the criteria by which the moral dilemma is to be resolved.

AHRP believes that some practices should not be permissible in children research: for example, exposing young children to powerful psychotropic drugs with demonstrable serious, disabling adverse side-effects. Until these drugs' long-term safety is established, children should be protected from potential permanent brain damage; chemical provocation experiments that exacerbate disabling conditions for the purpose of studying the effects on children's brains. Similar such experiments in adults were suspended by NIMH.

5. Should payment be provided to child or parent / guardian?

AHRP: There should be no financial incentives other than travel expenses. AHRP strongly opposes financial inducement to parents --i.e., bribes--to facilitate the recruitment of children. Indeed, parents who volunteer their children for cash may be liable to prosecution under state child abuse statutes. Child abuse--whether the offender is a parent or other÷is punishable under state laws that also mandate reported suspected child abuse to state child welfare agencies.

6. Are children / parent expectations for direct benefits from research based on full disclosure?

AHRP: Evidence does not demonstrate that full disclosure to parents about the likely risks of research and unlikely benefit to their children is made clear. AHRP strongly believe that before any experimental procedure is conducted on children, all possible safety hazards have first been tested in animals and adults--children should not be subjected to safety tests first. There should be full disclosure of the probability and magnitude of the potential risks, alternatives and previous adverse events, outcomes in children, adults, and animals.

7. Are there safeguards for children in emergency situations?

AHRP: Emergency research is permissible only if it is life threatening for the child and there is no available standard treatment.

8. Should parents and children be notified whenever regulations have not been complied with?

AHRP: Any violation should, of course be disclosed, and all documents should be forwarded to the child's parents and appointed pediatrician /ombudsman .

9. Does the evidence demonstrate compliance with the regulationsmonitoring of compliance, and enforcement actions?

AHRP: Compelling evidence [see full comments above] demonstrate the absence of any reliable monitoring or enforcement mechanisms to protect children from harm and exploitation. Regulatory restrictions need to be enforced and strengthened to protect children from medical predators. There is a demonstrable need for independent, mandatory monitoring of compliance and enforcement, such as Dr. Koski has suggested, not institution-dependent.

10. Are current practices for recruiting children appropriate?

AHRP: Recruitment practices are not only inappropriate, they are downright exploitative--one can truly say that recruitment practices today create a "moral hazard" for everyone involved--investigators, institutions, IRBs, sponsors and of course, the patients and human subjects being sought.

11. Does the evidence demonstrate the need to establish data and safety monitoring boardsto review adverse events?

AHRP: An essential safeguard for children is an independent pediatrician who would act as the child's ombudsman, there is also a pressing need for the creation of a database of adverse events, and for obtaining long-term monitoring data for children's outcomes.

12. Is IRB oversight of clinical trials involving children adequate for the protection of children?

AHRP: Independent checks and balances are needed to protect human subjects--especially if they are children. In addition to those specified above, these include:

• Separation of IRBs from the institutions that employs them, as Dr. Koski recommended when intervieAHRPd in the April 1, 2001 edition of nationally-televised "60 Minutes."

• Extension of existing Federal whistle-bloAHRPr legislation to cover allegations of unethical practice pursuant to 45 CFR 46.

• Provision of mandatory no-fault insurance coverage for human subjects comparable to Workers' Compensation for "death, disability, and injuries arising out of or in the course of participation in research."

• AHRP concur with the NBAC recommendation for greater public accountability: research studies "with risks falling on the extreme upper end of the continuum--very risky or unknown risks--" should not be left to the discretion of one local IRB, but rather should be reviewed by "a national review panel, with public input into the review process." And investigators contemplating high risk research "should engage the target community of participants in discussion, because having only one or two members who represent the pool of prospective participants on the IRB may not provide sufficient input." [Ch 3, p. 25]

*Comments were originally submitted under the corporate name, CIRCARE. Marie M. Cassidy is deceased, Vera Hassner Sharav has since formed a new organization:

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)