Tel. 212-595-8974 (AHRP)
142 West End Ave. Suite 28P
New York, NY 10023
March 10, 2004
Dr. Michael Carome
Chief of Compliance
Office of Human Research Protections
Director, Office of Compliance
Food & Drug Administration
Dept. of Health and Human Services
cc: Dr. Bernard Schwetz, Director, OHRP
Dr. David Lepay, FDA
Dr. Mark McLellan, Director, FDA
RE: Phase I Drug trials used foster children in violation of 45 CFR 46.409 and 21 CFR 50.56
Dear Dr. Carome and Dr. Howrowiz:
The Alliance for Human Research Protection (AHRP) has reason to believe that federal regulations for the protection of children as research subjects have been seriously violated in federally funded HIV research.
We have learned that a series of Phase I and Phase II drug experiments were conducted on infants and children who were under the guardianship of the New York City Agency for Children's Services (ACS), and living at Incarnation Children's Center, a foster care facility under contract with ACS. The test subjects were children diagnosed with HIV infection - in some cases infants who were merely "presumed" to be HIV-infected. Phase I and Phase II experiments involve the greatest level of risk and discomfort for children insofar as they test the safety and toxicity of the drugs as well as maximum dose tolerance.
The New York State Department of Health guidelines for children and adolescents, and those of the New York City Agency for Children's Services, facilitate and encourage the enrollment of vulnerable children in foster care - who are wards of the state - in experimental research that exposes them to significant risks of drug toxicity and adverse drug side-effects. Such experiments are unlikely to have any benefit for the test subjects.
The AHRP believes that the guidelines of both the State Department of Health and the New York City Agency for Children's Services--"Enrollment Procedures for ACS-Approved Clinical Trials" - violate federal regulations that restrict the use of children who are wards of the state as experimental subjects. We further believe that the concerted effort by New York State / City agencies to use foster care children in Phase I and Phase II safety trials violates federal regulations for the protection of human subjects (45 CFR 46). Research involving human subjects "must comply with all sections" of these federal regulations. States may issue regulations "which provide additional protections for human subjects," but may not decrease the protections specified in federal guidelines. See: 45 CFR 46.101(6)(e)(f)
Specifically, the Code of Federal Regulations (45 CFR 46.409 and 21 CFR 50.56) prohibits the use of children who are wards of the state from being subjected to experiments involving greater than minimal risk. 45 CFR 46.409 (Wards) states:
(a) Children who are wards of the State or any other agency, institution, or entity can be included in research approved under 46.406 or 46.407 only if such research is:
related to their status as wards; or
conducted in schools, camps, hospitals, institutions, or similar setting in which the majority of children involved as subjects are not wards.
(b) If the research is approved under paragraph (a) of this section, the IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis.
The advocate shall be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child's participation in the research and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.
The HIV experiments in question are unrelated to the status of the children as wards. The focus of the ACS guidelines is on facilitating rapid enrollment of as many foster children as possible - rather than ensuring that the trials are in the children's best interest and their vulnerability is not being exploited, as herewith stated:
"ACS will review clinical trials protocols for HIV-infected children as soon as such protocols become available, before a specific hospital decides to participate in the study. The National Institutes of Health (NIH) and pediatric AIDS specialists throughout New York State will make ACS aware of protocols as soon as they are in final form, before hospitals are ready to enroll children. This procedure will expedite ACS' decision-making even before physicians are ready to start treating children in the protocols."
"Once the hospital and ACS have executed an agreement for the trial, ACS consents to enrollment of all children who fall within the parameters of the approved protocol; provided that the child's parents consents (if parental rights have been terminated such parental consent is not necessary)."
The ACS guidelines apply to foster care children only, thus, the research fails to meet federal regulatory requirements under paragraph (a) of section 409. Furthermore, federal regulations mandate that children who are wards of the state must be protected by a personal advocate for each child for the duration of the research. Such an advocate must agree to act in the best interest of the child, and may not be "associated in any wayŠwith the research, the investigator(s), or the guardian organization."
The New York City ACS guidelines waive a foster child's right to individual consent, as herewith stated: "Separate consent need not be obtained for each child."
This waiver, we believe, denies these children their basic human dignity and ascribes to them the status of guinea pigs.
The ACS guidelines are in violation of federally mandated protections for children, as herewith stated:
"After obtaining the parental consent of the agency, or certification of a diligent search, the physician may immediately enroll the child into the Phase I or Phase II clinical trial and then simply inform the Pediatric AIDS Unit of such enrollment provided that dosage and toxicity of the trial has already been tested in previous studies."
The New York State Department of Health (DOH) guidelines for Clinical Care of Adolescents and Children with HIV Infection note:
". . . in the uninfected infant, passively acquired maternal lgG antibodies disappear on average in 7 to 10 months, but may occasionally persist until 18 months. Therefore, a positive HIV antibody test in the young infant merely confirms maternal HIV infection but is not diagnostic for HIV infection specific to the infant." See: http://www.hivdent.org/pediatrics/_doh/1section1iii.htm
Yet, one, three, and six month old infants have been subjected to toxic experimental drugs in Phase I clinical trials. Furthermore, whereas NYS law requires written informed consent of a child's parent or legal guardian before a child can be tested for HIV, "all children entering the foster care system are required to be assessed for capacity to consent and to have an HIV risk assessment within 5 days of placement."
The DOH guidelines misrepresent clinical trials, stating "Such trials minimize patients' exposure to ineffective or potentially harmful experimental treatments" - when by their nature, clinical trials involve risk, expose subjects to possible ineffective and potentially harmful experimental treatments. The Department of Health guidelines acknowledges children's "lack of political power" noting that children have "few advocacy groups " but the guidelines imply that these deprivations are "barriers to enrollment in clinical trials."
Under the section "children who are wards of the state," the DOH guidelines specifically direct interested parties to the New York City Administration for Children's Services for information about how to enroll foster care children "whose parents are deceased, or cannot be located, or when parental rights have been terminated or surrendered."
Among the Phase I and Phase II experiments testing the safety and maximum dose tolerance in foster care children are the following:
According to study records (abstract) "IL-2 has not been tested in HIV-infected children. Experience with IL-2 in pediatric populations is extremely limited." The experiment was conducted on 3 to 12 year old children. The experiment was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development (NICHD).
Infants 4 months of age and children up to 17 years of age were the subjects. These experiments were sponsored by NIAID and INCHD.
Children were randomized to test one of three vaccines at both low and high doses, testing these experimental treatments even before tests in adults had been shown to be safe and effective: "This immunotherapy trialŠis currently being tested in [ ] adult counterparts." The trial was sponsored by NIAID, Genentech, and MicroGeneSystems.
Test subjects were children 4 to 12 years of age. Purpose was "to obtain tolerance, safety and pharmacokinetic data." The experiment was terminated
Children 2 to 18 years tested anti-HIV drugs and received different vaccine combinations (tetanus vaccine, diphtheria, and acellular pertussis vaccine). An amendment to this study, 5/3/-2001, "strongly recommended, but not required, that the first and second cycles of IL-2 are given in the hospital on an inpatient basis.' This suggests that there were serious adverse effects requiring hospitalization. The study was sponsored by NIAID and NICHD.
Children 12 month to 8 years of age who were "either asymptomatic or mildly symptomatic for HIV infection" were used as test subjects, This is a VZV vaccine. According to the study abstract, "VZV can cause many serious complications in HIV-infected children." Changes in the study protocol, on September 9, 1999, exclude children with VZV infections. This raise concern about what happened to children with VZV infections who had been exposed to the vaccine before the change went into effect? This study was sponsored by the NIAID and NICHD.
This Safety Study tests the safety of ritonavir alone and in combination with other anti-HIV drugs in infants 1 month to 2 years of age who are "either presumed HIV infected or have already been shown to be HIV-infected." The infants are "presumed" HIV infected because their mothers were infected. However,
Infants 2 to 6 months of age were the subjects of this Phase I vaccine trial "to assess whether this vaccine is more immunogenic than placebo following the third vaccination." Additionally these infants received PNU-IMUNE 23 vaccine at 24 months of age
The experiment was sponsored by Lederle-Praxis Biologicals
A Freedom of Information request for adverse event reports from these trials was rejected by the National Institute of Allergy and Infectious Diseases (NIAID) citing exemptions 4 and 6. It is difficult to justify the invocation of exemption 4, "Trade secrets & confidential commercial or financial information," and exemption 6, "Unwarranted invasion of privacy."
The Alliance for Human Research Protection calls for a moratorium on the enrollment of foster care children with or without HIV-infection for Phase I clinical trials. We ask for an investigation into the recruitment practices; compliance with 45 CFR 46.409; full disclosure of the adverse effects suffered by these children; disclosure of institutional and physician conflicts of interest; and the children's condition following their participation in clinical trials.
Vera Hassner Sharav, President
The Alliance for Human Research Protection