October 1, 2001

Text of AHRP Amicus Brief filed with the Maryland Court of Appeals in support of the Court’s ruling against Kennedy Krieger Institute for exposing children to lead poison in an experiment. The Court of Appeals Decision Validates AHRP’s Stand Against Using Children in Harmful Research Experiments.
___________________________________________________

IN THE COURT OF APPEALS OF MARYLAND
No. 128
September Term, 2000

ERICKA GRIMES, Appellant
v.
KENNEDY KRIEGER INSTITUTE, INC., Appellee.
____________________________________________

No. 129

September Term, 2000

MYRON HIGGINS, a Minor, etc., et.al., Appellants
v.
KENNEDY KRIEGER INSTITUTE, INC., Appellee.

____________________________________________

MOTION OF AMICUS CURIAE FOR LEAVE TO FILE BRIEF
IN OPPOSITION TO APPELLEE’S MOTION FOR RECONSIDERATION
____________________________________________

Alliance for Human Research Protection (AHRP)
142 West End Ave, Suite 28P
New York, NY 10023

October 1, 2001

Howard Fishman, AHRP Steering Committee Member
Vera Hassner Sharav, AHRP President

Introduction

This honorable Court’s enlightened and responsible decision in the matter of Ericka Grimes v. Kennedy Krieger Institute, Inc. and Myron Higgins, A Minor, Etc., et. al. v. Kennedy Krieger Institute, Inc. is, above all, a clarion call for restoration of common sense, ethical sensitivity and professional integrity to the medical research enterprise.  We applaud the Court’s discerning decision and respectfully submit this brief in the hope that safeguards to protect the health and well-being of medical research subjects – whether adults or children – will be clarified, fortified, and implemented.  

This Court’s decision will have a profound impact on the medical research enterprise by restoring humane and ethical standards to the conduct of medical research, demonstrating respect for the subjects of research, and providing safeguards for the most vulnerable. We fervently hope that this court’s clearly articulated, sound and incisive decision will ensure that ethical standards will be implemented rather than circumvented. We also hope that this morally reassuring decision will serve to re-instill public trust in this critically important arena. Research is necessary and valued; it must be conducted in accordance with those ethical principles that distinguish this nation.

The Court is to be applauded for challenging the deficiencies in the medical research approval and oversight process. Whereas the research establishment and its stakeholders would have us believe that the rights of individual human subjects are well protected by Institutional Review Boards (IRB), this Court has rightfully recognized that IRBs are "primarily, in-house organs" which are neither designed to be objective nor are they "sufficiently concerned with the ethicality of the experiments they review as they are with the success of the experiments." The Court astutely observed that "failure in the informed consent process leads to serious inequities in research, specifically for the poor and less educated who bear most of the research burden [and that] the problem is perpetuated in pediatrics, where parents who volunteer their children were found to be significantly less educated and under represented in the professional and managerial occupations compared to their non-volunteering counterparts."

Most importantly, this Court has courageously challenged the assignment of unlimited authority to those who profit from the research enterprise by noting 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."

We pray for the Court’s indulgence in reference to any legal deficiencies in form or content that may be noted in this brief. We are not attorneys or legal scholars, but we wish to provide the court with additional evidence that may prove helpful in judicial deliberations. Please also note that while we make reference to various documents throughout this document, rather than burdening the Court with excessive paperwork, we have proffered citations. Upon request, we would be pleased to provide copies of the cited documents.

Children are increasingly being targeted for experiments, including those at the heart of the instant case, that are not in their best interests and which are as likely to harm them as to provide any benefit. We recognize that to include children in clinical trials presents a dilemma of truly Solomonic proportions. While certain types of medical research promise meaningful benefits, children are among those at highest risk of harm and exploitation if adequate safeguards are absent. Children cannot exercise their right to "voluntary, informed, comprehending and competent consent" to medical experimentation required under the Nuremberg Code, [1] nor can they protect themselves from risks in unwanted, painful biomedical experiments that are contrary to their best medical interests.

Two Signal Examples
"Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with ADHD," is an experiment conducted at the National Institute of Mental Health (NIMH) on six-year-old children who were loosely diagnosed with "conduct oppositional disorder." The children were subjected to painful lumbar punctures, without medical justification, but simply to test a questionable hypothesis. [2]

Preschool ADHD Treatment Study (PATS) is a controversial, federally sponsored drug experiment [3, 4, 5] conducted at multiple sites (including, coincidentally, Johns Hopkins University). Even Dr. Lawrence Greenhill, the principal investigator, acknowledges that ADHD is "not a well-defined psychiatric disorder in this age group." [6] Yet, children as young as three years old are being recruited to test a psychotropic drug whose safety and long-term consequences for young children is unknown. Parents are offered financial incentives [7] – $645 (beyond travel expenses) – if their child completes the protocol. [The case is discussed elsewhere in this brief.]

Federal policy adopted in 1983 [8] has protected children from non-essential, invasive, painful medical experiments that are not in their personal best 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] Until now, FDA acknowledges on its website, phase I studies which test for the first time the safety of new drugs in humans, were mostly conducted on healthy, normal, adult volunteers, or on patients with 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 ]

That posture has changed. On April 19, 2000, the FDA adopted a policy broadening the regulatory definition of "potential benefit" to include virtually all healthy children "who are not patients in pediatric pharmaceutical research." According to these new FDA guidelines, "any child has the potential to benefit from a treatment for otitis media" (i.e., ear infection); therefore, every child is available for recruitment into drug trials.

[ http://www.fda.gov/cder/pediatric/ethics-statement.htm ] This policy, the FDA acknowledges, "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." http://www.fda.gov/cder/pediatric/pedethics-1199.htm

It is noteworthy – and certainly not coincidental – that the shift in policy followed upon passage of 1997 federal law extending patent rights to pharmaceutical companies [9] that test their drugs on children in controlled clinical trials. Neither appellees, nor their member research institutions, nor Federal oversight agencies (FDA, National Institute of Health (NIH), Office of Research Protections (OHRP, formerly OPRR)) informed Congress that existing regulatory protections for children were wholly inadequate. Nor was Congress informed about systemic ethical violations [10] and evidence of preventable, research related adverse (sometimes fatal) consequences. Since 1997, a continuing stream of scandals has been uncovered by the media, revealing how vulnerable individuals are harmed and exploited in the absence of effective federal oversight and enforcement mechanisms.

Ethical standards for including children in clinical research are explicated in international codes and declarations. Even more detailed consideration was given to this issue by the Advisory Commission on Human Radiation Experiments (ACHRE). In its Final Report [11] (1994), the Commission expressed concern about the 30- year record of abuse of children in unethical, harmful, federally sponsored experiments including some conducted with parental consent. ACHRE emphasized the need for specific protections for those who are not in a position to give autonomous, legally valid consent to research (children and the disabled). Their recommendations questioned the legitimacy of parental permission for non-therapeutic research involving risks of harm:

"Where the research does not offer any prospect of benefit to the child, however, the legitimacy of the parent as authorizer is less clearRespect for the authority of parents to make decisions for their children and otherwise control their children’s lives is not without bounds. The law recognizes several exceptions, designed primarily to protect the child from what society at large considers to be unacceptable or unjustifiable harm or risk of harmIn the context of research, the question arises of whether a parent has the authority to permit a child to be put at risk of harm in an experiment from which the child could not possibly benefit medically. In this case, the child is to be used as a means to the ends of others." [11]

The Commission indicated clearly that such a use of children could not be rendered morally acceptable. We applaud the Maryland Court of Appeals for affirming in clear and straightforward language the fundamental distinction between "therapeutic" and "non-therapeutic" research, a distinction that has been sustained by the World Medical Association. [12] The distinction is recognized and understood by professionals and laymen alike. Appellees and their bio-ethicists, who are themselves beneficiaries of the medical research enterprise, [13] have been actively campaigning to eliminate that distinction by disingenuously claiming it is illogical. [14] Their real goal is to blur all indices of attendant risks that might limit the inclusion of children and incapable adults in non-therapeutic experiments.

The Court rightly recognized that "therapeutic" research is intended to benefit the individual research subject, and "non-therapeutic" research is not. The Court’s thoughtful evaluation of the instant case led it to conclude correctly that: "Nothing about the research was designed for treatment of the subject children." This statement essentially and succinctly defines non-therapeutic research. The Court affirmed the obligation to protect children from being placed "unnecessarily in potentially hazardous non-therapeutic research surroundings" by either scientific researchers or even by their parents and the court correctly noted that "parental consent, no matter how informed, is insufficient."

Appellee’s motion for reconsideration includes the following in footnote 3:
      "It is not clear why parental consent under these or other circumstances is ineffective and not permitted.  Consider the parent who is asked to consent to a study of a vaccine provided for children at risk for a serious communicable disease.  Some of those children necessarily will be given a placebo, a "treatment" that places them at risk, or exposes them to elevated harm, by enhancing – or, at the least, failing to diminish – the risk that they will contract the disease. . . ."

Formulations such as these reinforce our concern that ethical safeguards for children are viewed simply as inconveniences that must be circumvented.   Furthermore, informed consent is the cornerstone of ethical medical research.  Parents are typically fully aware of the dangers associated with driving an automobile, engaging in athletics, and the like.  However, as the findings of the federal Office of Human Research Protections demonstrate [http://ohrp.osophs.dhhs.gov/detrm_letrs/lindex.htm], the hazards associated with research protocols are far too often not clearly and openly disclosed. When adverse outcomes occur in routine life activities, they are accidents; when adverse outcomes occur in research, they are either preventable, or, as often is the case, built into the protocol and, thus, are inflicted (non-accidental) injuries.

We are encouraged by the Court’s unequivocal affirmation of the overriding concern for "the best interests of the child":

"We have long stressed that the "best interests of the child" is the overriding concern of this Court in matters relating to children.  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 child and particular case over-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 non-therapeutic situation where his or her health may be impaired, in order to test methods that may ultimately benefit all children." [p.82]

The same moral sense guided Justice Edward Greenfield [15] when he struck down New York State’s mental health research regulations, stating:
"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 before they have reached the age of full and legal discretion when they can make that choice for themselves." [T.D. v NYSOMH, 1995]

This Court recognized that conflicts of interest are deeply embedded in the biomedical research enterprise, and it recognized the serious inequities arising from an inherently unfair playing field "specifically for the poor and less educated who bear most of the research burden." Appellees argue against the Court’s resolute ethical standard prohibiting the exposure of children to any unnecessary risks in non-therapeutic experiments. Appellees would wish to be the sole arbiters authorized to determine how levels of risk are to be interpreted. The Court, no doubt, is mindful of the fact that "minimal risk" has been invoked indiscriminately to facilitate even high risk research on children.

We offer the following examples:

Case 1: Institutional Review Board defines "minimal risk:"

As of October 2000, 100 obese children and 93 normal weight children, aged 6 to 10 years old, had been enrolled in an obesity experiment conducted at National Institute of Child Health and Development (NICHD). [16] [Attached, OHRP letter of findings.]

The experiment required a battery of painful tests and a two-day overnight hospital stay for intensive additional testing, including the insertion of several intravenous blood lines (one attached for 18 hours), MRI, a 2- hour hyperglycemic clamp (involves a second IV line), a 3 hour euglycemic clamp (involves two IV lines) and hyperinsulinemic clamp. The children were required to experience extremely high and extremely low blood sugar levels for hours at a time.

The experiment caused the children undue pain, put them at risk of allergic reactions, and most problematically, at risk of blood clots or phlebitis. The experiment offered these children absolutely no benefit.

IRB minutes [16] reveal that on March 27, 1996 the IRB approved the experiment as involving "greater than minimal risk." However, the minutes of a subsequent meeting on April 24, 1996 reveal that the principal investigator, Dr. Jack Yanovski, persuaded the IRB to approve the experiment under the "minimal risk" category: "The committee agreed unanimously that the level of risk to which children enrolled in this protocol are exposed falls within Section 46.404 of 45 CFR 46, Subpart D, namely not greater than minimal risk." Committee members rationalized the decision by declaring that the risks involved were no greater than "what a child might encounter while playing in traffic." Whose children, it might be asked, did the Committee assume to be playing in traffic?

In its November 3, 2000 letter of determination, [16] the Office of Human Research Protections (OHRP) acknowledged that "determinations regarding the risk level of research are based upon the subjective judgment of the IRB." It is of note that NICHD’s IRB also classifies phase I vaccine trials as "minimal risk" when such trials pose unknown, possibly high toxicity, risks. In contrast to the Agency’s ruling in the fenfluramine experiment (above) based on its accepting the "at risk of a condition" argument, OHRP ruled that the normal weight children "do not have a disorder or condition," and their inclusion in the experiment violated federal regulations. The experiment was suspended.

A Utilitarian Culture of Opportunism Permeates American Research Ethics
Utilitarian business ethics in which the ends justify the means have infiltrated the academic research establishment, [17] including Government oversight agencies, thereby eliminating all essential checks and balances needed to protect vulnerable individual citizens from exploitation. A cadre of self-designated "bioethicists" who control the administrative apparatus of the medical research enterprise appear to be unconcerned about encroaching on the sacred bond between parents and children. [18]

The current insular self-regulating system relies entirely on a fraternity of mutual interest groups; thus, even experiments endorsed by the FDA and NIH put the interest of science and commerce above the welfare of human subjects. [19, 20] These interlocking interest groups are: (1) pharmaceutical sponsors[21] who insist on secrecy; [22] investigators[23] academic institutions having a financial stake in the enterprise; [24]

(3) in-house institutional review boards operating in secrecy[25]advance the interests of the institution employing them;[26] (4) scientific, peer reviewed journals that publish biased research findings;¹⁸ and (5) the federal government oversight agencies that increasingly promote industry interests. [28, 29]

There is a complete absence of judicial oversight regarding medical research transactions that involve the fundamental liberty rights of citizens guaranteed under the Fourteenth Amendment of the United States Constitution. Spurred on by the "carrot" of extended patents and other financial benefits, commercial interests have created an environment within medical research that justifies the unequal distribution of research burdens by embracing a philosophy of cultural relativism[30] and "science uber alles."[31]

Those with vested interests in medical research control the system[32] have given the research establishment, powerful research centers in particular, free rein to cut corners, to evade meaningful informed consent, and to facilitate "high risk, high impact" experiments. [33, 34] The Court was rightly critical of the Johns Hopkins University IRB which was shown to have actively collaborated with the researchers by suggesting "a way to miscast the characteristics of the study," rather than protecting the best interest of the subject children. To illustrate how endemic complicity to circumvent the informed consent process is within the IRB research fraternity, we bring to the Court’s attention the following published statement by Franklin Miller,[35] a fellow at the Kennedy Institute of Ethics and a member of the IRB of NIMH:

"Challenge studies in psychiatric research with decisionally incapacitated patients are morally problematic but justifiableIf the law makes challenge studies by their very nature more than a minor increase over minimal risk investigators will have very strong incentive to circumvent legal restrictions by taking the stance that all patients involved in these studies are fully capable of giving informed consent." [pp.197-198]

In this climate, even experiments lacking scientific justification are approved. For example, the scientific merit of speculative biochemical violence prediction experiments[36] and other such chemically induced symptom provocation experiments[37] have been questioned by the Director of the National Institute of Mental Health (NIMH), Dr. Steven Hyman. He suggests that "such approaches have revealed nothing about cause or mechanism and have been relatively sterile with regard to generating good follow-up questions."[36] Yet, as will be demonstrated, children are being subjected to such experiments.

Federal agencies entrusted with protecting the public health, and ensuring that the rights and safety of human research subjects are not violated in pursuit of scientific knowledge, have failed utterly to meet their public responsibility. They have instead set in motion a series of initiatives for the purpose of loosening existing federal restrictions-including travel to international meetings to argue against the unwanted provisions of the Declaration of Helsinki.[38] (Attachment, Pretoria)

Efforts to broaden the recruitment of children for clinical trials is demonstrated by several recent strategies embarked upon by the Department of Health and Human Services.

A draft document[39] (attachment) essentially redefines the terminology of existing federal regulations to further broaden the criteria under which healthy children would be recruited into research that may cause them pain and put them at risk of serious harm. The DHHS Draft indicates that "for the purposes of sec. 46.406" the term "condition" is redefined to include non-medical "conditions." The DHHS Draft would allow "a demographic [sic ] descriptor" to qualify as a "condition." These semantic gymnastics appear intended to legitimize experiments prohibited by current regulations. It appears that in some cases, racial profiling is employed in the research recruitment process. The Alliance for Human Research Protection (AHRP) has been singularly critical of this policy shift, and submitted several dissenting comments, [40] criticizing these disingenuous semantic manipulations. [Attached AHRP Comments Re: Interim Rule]

By twisting regulatory terminology, federal government policy makers attempt to legitimize experiments that put healthy children at risk of harm without scientific justification or potential personal benefit, thereby stripping children of existing federal regulatory protections. [8, 41] Healthy children are being sought as drug test subjects by drug companies who are spending $1 billion a year on pediatric testing. [4, 42] Federal bureaucrats have invented a dubious, new term for these children, namely, "risk-bearing children."[39]

This policy shift is made clear by the Director of the Federal Office of Human Research Protections, the federal agency with responsibility for monitoring IRB operations and to uproot and sanction unethical research when discovered. In an article published in the Journal of Law, Medicine & Ethics, Dr. Greg Koski[43] stated: "as we understandably increase the extent to which needed research is conducted on vulnerable populations, such as children, it may well be necessary to redefine our notions of consent and assent for purposes of recruiting subjects." Even if we ignore the violations of law implicit in this pronouncement, we cannot ignore the fact that it sends a signal of intent by the highest research enforcement official in the federal government. That signal reveals the agency’s intent to override the restrictions imposed by the Hippocratic Oath ("first, do no harm"), the Nuremberg Code,[1] the Declaration of Helsinki,[12] and the Belmont Report. [44]

The Human Consequences of a Policy of Self-Interest
Case 2: In 1998, AHRP identified two wholly non-therapeutic "challenge" experiments that exposed 6 to 11 year old children to fenfluramine, a serotonin depleting drug so that researchers could test a speculative violence prediction hypothesis. One experiment was conducted at NYS Psychiatric Institute [45] on 34 healthy minority children. The companion experiment, conducted at the Mount Sinai Medical Center,[46] included some children diagnosed with ADHD; others were normal controls. The experiments had each been approved by five Institutional Review Boards[47] who saw nothing wrong with exposing the children to discomfort, trauma, and risks associate with exposure to a neurotoxic drug.[48] The investigators hoped to find "proof" that these children were predisposed toward violence even though they were not behaving violently.[49] At best, these experiments were conducted to test a dubious, pseudo-scientific hypothesis.

The approval of these experiments demonstrates that the current self-regulating system is riddled with conflicts of interest, [24, 25, 26] and fails to protect children even from ethically and scientifically questionable experiments.

In the NYSPI experiment, only healthy African American and Hispanic boys were recruited, their names obtained from the New York City Parole Department. OPRR accepted the specious argument (made by the NYS Research Foundation for Mental Hygiene) that although the children had no diagnosable condition, they were "at risk" of a condition. That condition, "predisposition to violence," is not defined in medicine, and is therefore, not medically treatable. These "fine points" notwithstanding, children were subjected to an invasive medical experiment that put them at risk of harm. It is clear that had the experiment involved laboratory animals protected under the Animal Welfare Act (1966),[50] such disingenuous arguments aimed at circumventing a protective prohibition would not have been entertained.

The fact that OPRR determined that the NYSPI experiment on healthy children complied with Federal regulations, while the Mount Sinai experiment that included both healthy controls and children diagnosed with ADHD did not, demonstrates that federal regulations are applied inconsistently. Concern about fenfluramine’s neurotoxicirty led 22 neuroscientists, [51] in 1993, to petition the FDA against its approval. The drug was withdrawn after it caused fatal heart valve damage.[52] The inconsistency between the disclosure of risks in the informed consent documents[53] of the two fenfluramine pediatric experiments demonstrate the inherent flaws in current informed consent compliance. It also demonstrates that current federal safeguards are inadequate for protecting children from unnecessary, invasive, even hazardous research.

The NYSPI consent form signed by parents acknowledged "possible side effects of fenfluramine: nausea, stomach aches, headaches, anxiety, dry mouth, drowsiness, diarrhea, sleepiness and a mild feeling of euphoria. Low blood pressure, tremor, low blood sugar, increased urination, depression, dizziness, and rapid heartbeats may also occur with this medication, but are uncommon. These side effects have been reported when fenfluramine is continued over a number of days, not with a single dose" The Mount Sinai consent form presented a positive spin without disclosing known risks: "None of the these tests or observational procedures are dangerous or pose any risk to your childThe fenfluramine challenge test is also safe and poses no significant risk to your child. A single dose of fenfluramine is unlikely to cause any side effects. Higher doses, for extended periods of time (up to 9 months), have been used with children with occasional mild side effects such as sleep disturbances, weight loss and irritability being reported. No side effects have been reported in the literature after a single dose. We have found that a small proportion of children (less than 5%) experiences mild headaches or nausea, but all were fine by the next morning." Neither consent form mentioned the most serious risk: neurotoxicity to children’s developing brains.

OPRR, the Federal oversight agency entrusted with protecting research subjects failed to examine the major ethical deficiencies:[54] dubious scientific rationale, lack of a medical condition to be treated; selection criteria that violated equitable distribution requirements, and coercive recruitment procedures. Research on human beings that lacks rigorous scientific basis is a fundamental violation of international and national standards. [1, 12, 43] Failure to address these issues has spawned experiments that similarly use the "at risk of a condition" argument for recruiting healthy children into medical experiments that offer them no benefit but put them at risk.

Case 3: Propulsid, a drug approved for heartburn was found to cause cardiovascular and gastrointestinal adverse side effects. The drug prolonged the QT interval, an indication of cardiac dysrhythmia. FDA’s director of cardiology, Dr. Raymond Lipicky,[55] warned in the American Journal of Cardiology that if a drug that prolonged the QT interval had a benefit that was "less than lifesaving . . . any risk of death would likely be considered unacceptable." Despite warnings by FDA’s cardiology and gastrointestinal division experts and despite FDA warnings to the drug manufacturer that Propulsid was "not approvable" for children, 100 babies with gastroesophageal reflux (a condition most babies outgrow by one year) were put in a Propulsid clinical trial. The risks associated with the drug were not disclosed to parents, neither were they told that deaths had occurred. [56, 57] Propulsid’s sales in 1999 had reached $950 million, while its death rate – according to the FDA – had by then reached 80 (adults and children).[58]

Case 4: Pacemaker surgical experiment: 68 children underwent surgery at NIH to test whether a pacemaker could treat or cure hypertrophic cardiomyopathy,[59] an inherited heart disease that can cause thickening of the heart and sudden death. Doctors disagree about the need or justification for this radical intervention. Some children died, while others got worse, not better. It was reported that the family of a child who died claims: "NIH doctors used undue pressure to get their children into an experiment that was unlikely to help them." [60] In addition, the parents of a child whose condition at age 12 worsened after the insertion of the pacemaker say they were "stampeded into a pacemaker for their son without even being told it was an experiment."[60] His mother charges that they were told he would die if they didn’t act quickly. According to the Wall Street Journal’s investigative 1996 report,[59] the harshest criticism of this experiment and the intimidating recruitment tactics come from prominent scientists who served at the NIH and then moved on to the private sector. The Journal quotes former NIH researcher Dr. Paolo Spirito, now a heart specialist in Genoa, Italy: "It’s unbelievable that pacemakers were allowed to be put in children with no severe disease and no symptoms." And Dr. Mark Josephson, professor of medicine at Harvard Medical School, is quoted: "There’s a lot of witchcraft here."

Case 5. Olanzapine (Zyprexa) was approved by the FDA in 1996 for psychosis in adult schizophrenia patients. The Boston Globe[61] reported that in pre-marketing clinical trials, the drug was linked to life-threatening adverse drug side effects in 22% of the adult patients tested. FDA data[62] reveal that there were 27 deaths, 15 of which were suicides and the drop-out rate during 6-week clinical trials was 65%. In an extended (one year) trial, the drop out rate was 83%. Since its approval, additional serious adverse effects have been reported [63] including: new onset diabetes reported within 3 to 6 months of initiation of olanzapine[64] liver abnormalities; induced mania[65], seizures, and neuroleptic malignant syndrome, which is potentially fatal.

Despite these severe side effects, 6 to 11 year old children were recruited into an experiment to test olanzapine in a clinical trial soon after it was approved for adults. The children were not diagnosed with schizophrenia, but with varying psychiatric diagnoses (including the controversial diagnosis of ADHD, whose validity is not even certain).[66] The experiment was conducted at the University of California Los Angeles.[67] According to the published report, all children experienced adverse effects and none were helped, necessitating the termination of the study before 6 weeks of its inception. The adverse effects reported included sedation, weight gain of up to 16 pounds, and akathisia.

The experiment cannot be justified on ethical or medical / scientific grounds. Children were exposed to the known severe adverse effects associated with the drug, and to potential long-term hazards. The best interest of the children in this experiment were not served. Nevertheless the IRBs approved it. AHRP filed a complaint with OHRP on April 9, 2001.

Case 6: Investigators at NIMH[2] and four research centers[68] conducted a nine-week cross-over multiple drug experiment on 45 children (6 to 12 years old) who were diagnosed with hyperactive behavior, or "mild overanxious disorder." (The Court should note that this language has no scientific validity.  Though some researchers clearly consider it to be state of the art, it is actually nothing more than psychobabble). The purpose was to test the effect of stimulant drugs (methylphenidate, dextroamphetamine, and pemoline) on the cerebrospinal fluid levels of homovanillic acid (CSF HVA) and to find a correlation with the children’s behavior. The children were subjected to pain and exposed to risks of harm enduring invasive, painful spinal taps[2] for non-therapeutic experimental purposes. It was not clear why the children had to undergo lumbar punctures since HVA is excreted in urine and could be measured without this painful procedure. It is difficult to comprehend the mindset of those who would suggest that a 6 year- old child could or would volunteer to endure a spinal tap for the sake of relieving a "mild overanxious disorder." In fact, it might be suggested that this procedure would be likely to exacerbate such a condition.

Should parents be allowed to volunteer their child for non-therapeutic, painful experiments?

Should those who stand in the place of parents be allowed to volunteer their wards?

Children are being recruited, some would say bribed, with Toys ‘R’ Us gift certificates[69] to assume risks ("risk bearing children")[39] as human subjects in drug trials which are not in their best interests. Children, including toddlers and healthy children, are being traded like commodities, undermining family values and medical ethics. Parents of limited means are encouraged to abdicate their parental responsibility for cash payments and to "volunteer" their children for drug experiments whose risks they are either uninformed about or do not understand.

Alice Dembner, a reporter for The Boston Globe, [4, 60, 70] examined research involving children (since 1994). She found that children have suffered and died in clinical trials in which ethical standards had been violated. She found that in the last seven years, at least eight children have died in medical experiments, while hundreds suffered harmful side effects. She also observed that "there is strong reason to believe that deaths and injuries in research involving children are more widespread than what is reported to government offices that handle complaints." [4, 60] The number of children currently serving as research subjects has increased to 45,000 in 2001 compared to 16,000 in 1997. Attachments to the brief [39, 40] and other documents cited [43, 3, 81] reveal a disturbing trend by federal agencies whose mandate is to ensure that human subjects, children in particular, are protected from abuse. Officials of DHHS, FDA, OHRP have initiated steps to weaken rather than strengthen federal protections for children.

The circumstances that led to the preventable death of Jesse Gelsinger [71] in a gene transfer experiment at the University of Pennsylvania, reveal a pervasive widespread problem, namely; Federal regulatory protections are being violated, circumvented, reinterpreted, and deconstructed and human subjects are at increased risks of harm. Physicians are engaging in coercion and violating the Code of Ethics of the American Medical Association [72] by accepting $5,000 referral fees (kickbacks) to recruit children for clinical trials. And parents, who are too often uninformed about the actual risks involved, are being offered financial incentives to volunteer their children. A survey by an NIH researcher found that amounts "typically ranged from $200 to $400, but occasionally reached $1,000." [60, 69] In April 2001, FDA announced a reversal of its policy: [73] FDA would no longer accept data derived from healthy children for pediatric exclusivity as authorized under the FDA Modernization Act of 1997[9] (FDAMA).

Case 7: "Risk-Bearing" Preschool Tots

NIMH is sponsoring a controversial – and we believe – irresponsible experiment that exposes young children to the risks of psychostimulant drugs in the absence of any validated medical condition, [74] or demonstrated benefit outweighing the risks. Preschool ADHD Treatment Study (PATS) is a multi-center pediatric research initiative to test psychostimulant drugs in 4,000[75] children including 312 children as young as three years old[3] – some not yet toilet-trained. In 1998 an NIMH Consensus Conference concluded that there is no agreement in the field regarding either the ADHD diagnostic criteria and the safety of treating children with psychostimulant drugs.[66] Some physicians have suggested that ADHD is a "bogus" diagnosis that was created to pacify anxious parents and teachers. [76] Since these drugs’ safety is disputed, and there is evidence that they may potentially cause irreversible harm to these young children’s developing central nervous system and brain cells, [66, 77] we deem it an understatement to suggest that this project is highly questionable. Indeed, we would argue that this experiment extends clinical malpractice of over prescribing of psychotropic drugs to research to research. We also question the payment scheme associated with the experiment. To facilitate recruitment for this controversial experiment, the federal government has earmarked a $645 cash payment to parents (above $15 travel expenses for each visit) to volunteer their preschool children as "risk bearing children."

The ethical standards of the Nuremberg Code and the Declaration of Helsinki[12] require that:

"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." [12]

The proposed DHHS Draft[39] equivocates and thereby weakens international criteria for ethical research by stating: "’Reasonable opportunity’ may include the concepts of scientific validity, timeliness, and feasibility." Indeed, an investigation into the preventable death of a young healthy research subject at the Johns Hopkins University found that not even a basic literature search using MEDLINE had been conducted by either the investigators or the IRB[78] prior to subjecting human beings to an invasive, non-therapeutic, exploratory medical experiment with hexamethonium, a substance withdrawn from the market in the 1970s.[79]

Children and Families at Risk
On April 24, 2001, the Food and Drug Administration adopted an interim rule incorporating the HHS regulations contained in 45 CFR 46 Subpart D, "Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products."[41] The safeguards adopted by FDA excluded Section 46.408 (c) – which states:

"If the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part and paragraph (b) of this section, provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that this waiver is not inconsistent with Federal, State, or local laws. The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition."

Section 408 (c) gives institutional review boards discretionary authority to waive parental permission for unspecified research involving (for example) children who are loosely referred to as "neglected and abused." FDA correctly determined that it lacks authority under Federal law to empower IRBs to waive parental consent. FDA’s decision prompted an advisory committee of OHRP (the National Human Research Protection Advisory Committee, NHRPAC),[80] to apply pressure by urging the FDA to adopt section 46.408 (c ). NHRPAC’s position ignores entirely the role of the Court in adjudicating the status of a child as "neglected or abused." The Committee took the position that adolescents with sexually transmitted diseases are "mature" and should, therefore, be "permitted to consent for clinical research studies related to such disorders and diseases without parental permission."

"We STRONGLY believe that in specific circumstances the consent of the mature adolescent, without parental involvement, IS SUFFICIENT to permit research to proceed as long as procedural safeguards are in place to protect the interests of the subjects. We request that the FDA aggressively interpret its legal authority and adopt this section of the regulations as part of additional safeguards for children in clinical investigations of FDA-regulated products. Adoption of this section for application to research proposals involving mature adolescents does not eliminate informed consent."[81] (Emphasis in original)

NHRPAC misrepresented the issue by conflating research with treatment: they argued that HIV infected adolescents would be denied life prolonging treatment and "the benefits that might have accrued from participation in [sic] clinical trials if parental permission were required."[81] In fact, testing the safety and efficacy of new drugs involves added risks for patients, which is why informed consent requirements for research are more stringent than in clinical care. Furthermore, federal regulations do not differentiate between children of any age neither do federal regulations recognize "informed consent" from minors. This stance illustrates a proclivity to ride roughshod over the rights and responsibility of parents to protect their children from risks of harm, and on the inviolability of the parent-child relationship.

Conflicts of Interest
AHRP has consistently raised questions about the conflicts of interest that permeate the medical research industry, including federal agencies established to monitor human research, their advisory panels (such as NHRPAC), the research institutions, and the local institutional review boards (IRBs).  We address a number of deficiencies that contributed to the Kennedy Krieger debacle by calling for:
A.  Disclosure of conflicts of interest by all IRB members and all federal officials involved in regulating and/or monitoring medical research.
B.  Community representation equal to or even greater than "stakeholder" representation in the composition of IRBs.
C.  Clear delineation of the role of IRB as protectors of the public interest.  In this regard, we encourage the unfettered creativity of researchers in devising research proposals, but call upon IRBs to apply the relevant legal and ethical standards.  In essence, the IRB must serve as the "conscience" of the medical research enterprise-unless community interests are equally represented, that is unlikely to occur.

We understand the Court’s "no risk" ruling to mean "no reasonably perceivable risk," a construction that comprehends the now out-of-fashion "prudent person" standard.  We do so because the history of the "minimal risk" standard, as has been demonstrated, is fraught with purposeful distortions beyond reason. For example, the National Institute for Child Health and Development categorizes phase 1 vaccine trials as "minimal risk," thereby evading rigorous review and oversight.

Appellees’ Motion for Partial Reconsideration and Modification of Opinion
Appellees have asserted:  "On the day this mandate issues, hundreds of fully accredited medical research projects now conducted in Maryland will terminate."
We believe that this statement may, in fact, be accurate.  If so, such an eventuality will serve as prima facie evidence of the fact that hazards of the magnitude identified in the instant case and similar unacceptable risks to the health and we