May 18, 2005
To provide a better understanding of the issue, I will discuss with you the evolution of HIV/AIDS and the management of the disease, pediatric AIDS and foster care, and the federal protections in place to ensure the safety of human subjects, including children and children who are wards, in research.
Evolution in the Management of HIV/AIDS
Despite these sobering statistics, dramatic advances have been made in the management of HIV infection since HIV was first discovered over two decades ago. In 1990, as many as 2000 babies were born infected with HIV; now that number has been reduced to a bit more than 200 a year in the U.S. From 1985 to 1999, AIDS cases in U.S. children decreased 81%. From 1998 to 2002, the estimated number of children dying from AIDS decreased 68%.
Much has been accomplished since the early days of the HIV/AIDS epidemic, including significant advances in treatment and prevention. HIV has evolved from a disease that kills to a disease that is chronic and manageable. Research has been pivotal to understanding HIV/AIDS and managing the disease. In the United States and other western countries, potent combinations of anti-HIV drugs have dramatically reduced the numbers of new AIDS cases and deaths due to HIV/AIDS. Today, there are over 20 antiretroviral medications that are approved by the Food and Drug Administration (FDA). As another example of the success of research, a pivotal National Institutes of Health (NIH)-supported study conducted in Uganda demonstrated that a single dose of the drug nevirapine given to an HIV-infected woman at the onset of labor, combined with a single dose for the infant just after birth, was 50 percent more effective in preventing transmission to the baby than was a short course of the drug AZT. Research is now underway to determine if the use of nevirapine or other drugs can prevent transmission through breastfeeding, a major mode of mother-to-infant transmission. Other HIV prevention strategies include development of effective chemical and physical barrier methods, research on the use of these methods among different populations, and a study of how antiretroviral therapy might prevent transmission by reducing how much virus a patient sheds in their genital track or in breast milk. However, the early clinical trials of these therapies were conducted only in adults. Pediatric formulations of these treatments were not approved for young children with HIV/AIDS because sufficient studies had not been conducted in children.
Importance of Clinical Research
As I will describe in more detail below, federal regulations provide specific protections for children and additional protections for wards of the state participating in some forms of clinical trials. Ultimately, however, it is the state, and in some cases county foster care agencies that decide how informed consent is provided for these children. Institutional Review Boards (IRBs) working with researchers, establish, within federal guidelines, what procedures should be followed to acquire consent in specific study protocols.
HHS continues to believe strongly that clinical trials to test new treatments in children are essential and that the framework established by the existing regulation offers adequate protection for individuals participating in trials. We also recognize, however, the importance of continued vigilance to ensure the regulations are adhered to by investigators and the IRBs that oversee their activities.
Pediatric AIDS and Foster Care – An Historical Perspective
As pediatric AIDS became more prevalent, little was known about the effectiveness or proper dosages in children of drug therapies that were yielding good results in adults. But these treatments seemed to hold the promise of longer and higher quality life for many children who otherwise seemed doomed. State child welfare agencies were strongly urged to reduce barriers to foster children’s participation in such trials. The fact that fewer than 2% of foster children diagnosed as HIV positive in 1989 were participating in clinical trials was viewed as evidence that "the foster care system has failed to competently and effectively cope with the influx of HIV-infected children" (McNutt, 1994).
A study published in 1990 found that only seven states had implemented formal policies regarding the participation of foster children in clinical trials, and five states had “mechanisms” through which it was possible to enroll such children in trials. Although the state had legal custody of the children, the permission of biological parents was required in four of the twelve states that had either “policies” or “mechanisms” (Martin and Sacks, 1990). The same research study found that 16 percent of 432 children enrolled in pediatric AIDS trials at the time were in foster care (a total of 69 children), and that nearly three times that many foster children were known to be eligible for those trials but could not be enrolled because a parent or guardian’s permission could not be obtained.
In the Omnibus Budget Reconciliation Act of 1987, (P.L. 100-203, section 9138), Congress required the Secretary of HHS to provide information about children with AIDS who had been placed in foster care. The report prepared in response to this congressional mandate found that, in 1989, the states were aware of 804 current and 979 cumulative cases of HIV positive children in foster care nationally, most of them concentrated in just a few states. By that year only 6 states had seen at least 50 cumulative cases of HIV among children in foster care, and 20 states had never cared for a foster child with HIV. At the time, most state laws allowed only for “standard medical treatment” for children in foster care. But because there were no standard treatments for HIV-infected children, this limitation represented a critical barrier to medical care for children with HIV. The report recommended that “State and local child welfare agencies should create systems to manage the participation of children in foster care in special medical treatment and experimental trials” (HHS/ASPE, 1989, p. 60).
Efforts in the early 1990s to increase the enrollment of foster children in clinical trials affected state policies that in many cases continue to the present. Today, child welfare agencies continue to differ in their policies regarding whether or under what circumstances children in foster care may be enrolled in clinical trials. Information gathered from several state foster care agencies suggests that authority to provide permission for other than standard medical treatment typically lies either with the judge supervising the foster care case, with a senior official within the foster care agency, or with a guardian ad litem. Some states continue to preclude the enrollment of foster children in experimental trials altogether, or will provide permission on behalf of the child only if the biological parents also give permission for the child’s participation. Under the federal foster care program, health care decisions on behalf of individual foster children are left to states that are acting as parents with respect to children in their custody and that are responsible for assuring the health care needs of foster children are met. With respect to enrolling children in particular clinical trials, the procedures established for each study by the IRB and researcher, working within the federal human subjects regulations described below, would guide children’s participation.
Protection of Human Subjects Regulations
The HHS and FDA Protection of Human Subject Regulations are codified at 45 CFR part 46, and 21 CFR part 50 and 56, respectively. The regulations in subpart A of 45 CFR part 46 include basic protections for human subjects involved in both biomedical and behavioral research.
In 1991, 14 other Federal departments and agencies joined HHS in adopting a uniform set of regulations that are identical to subpart A of 45 CFR part 46. This uniform set of regulations is known as the Federal Policy for the Protection of Human Subjects, also referred to as the Common Rule. FDA’s Protection of Human Subjects regulations at 21 CFR parts 50 and 56 are similar to those in the Common Rule.
The HHS protection of human subject regulations are based in large part on the Belmont Report written in 1978 by the Congressionally created National Commission for the Protection of Human Subjects of Biomedical Behavioral Research. The Belmont Report identifies three fundamental ethical principles for all human subjects research – respect for persons, beneficence, and justice.
The HHS regulations at 45 CFR part 46 apply to all non-exempt research involving human subjects that is conducted or supported by HHS. These regulations include provisions for IRB review, informed consent, and assurances of compliance. For example, through an assurance of compliance that is approved by the Department’s Office for Human Research Protections (OHRP), an institution pledges to conduct its HHS- funded or supported research in accordance with the human subjects protections of 45 CFR part 46. An institution also may voluntarily extend its assurance to apply to all human subjects research it conducts regardless of funding source.
In addition to assurances of compliance required by the HHS regulations at 45 CFR part 46, the HHS and FDA regulations also contain a number of other requirements for institutions engaged in HHS-conducted, -supported, or FDA regulated research involving humans, including requirements relating to, for example, IRB membership and procedures, criteria for IRB approval of research, suspension or termination of IRB approval of research; and general requirements for informed consent.
Additional Protections for Children Involved in Research
When a proposed research study involves children and is supported or conducted by HHS funding, the research institution’s IRB must take into consideration the special regulatory requirements that provide additional protections for the children who would be involved in research. If the proposed research involves FDA-regulated products, then FDA’s parallel regulations would apply.
Both the HHS’ and FDA’s Subpart D regulations permit IRBs to approve three categories of research or clinical investigations involving children as research subjects:
45 CFR 46.404 and 21 CFR 50.51- Research or clinical investigations not involving greater than minimal risk to the children. To approve a research study or clinical investigation in this category, the IRB must make the following determination:
45 CFR 46.405 and 21 CFR 50.52 - Research or clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to the individual child subjects. To approve a research study or clinical investigation in this category, the IRB must make the following determinations:
45 CFR 46.406 and 21 CFR 50.53 - Research or clinical investigations involving greater than minimal risk and no prospect of direct benefit to the individual child subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition. In order to approve a research study or clinical investigation in this category, the IRB must make the following determinations:
A fourth category of research or clinical investigation requires a special level of HHS review beyond that provided by the IRB:
45 CFR 46.407 and 21 CFR 50.54– Research or clinical investigation that the IRB believes does not meet the above categories of the HHS or FDA regulations, but 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. The research or clinical investigation may proceed only if the following conditions are met:
In all cases noted above (i.e., 45 CFR 46.404, 46.405, 46.406, and 46.407), the IRB must ensure that adequate provisions have been made for soliciting permission of parents or legal guardians and the assent of the children, to the extent required by HHS and FDA regulations.
Additional Protections for Children Who are Wards
Before children who are wards of the State or any other agency, institution, or entity can be included in either of the two categories of research or clinical investigations described above, the research must meet the following conditions:
One individual may serve as advocate for more than one child, and must 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. The advocate should represent the individual child subject's interests throughout the child's participation in the research. The HHS and FDA regulations further require that the advocate not be 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.
HHS Compliance Oversight Activities
For-Cause Compliance Oversight Investigations
Institutions engaged in human subject research that is conducted or supported by HHS must provide written Assurances of Compliance to HHS describing the means that they will employ to comply with the HHS Regulations. OHRP approves these Assurances on behalf of the HHS Secretary. An Assurance approved by OHRP commits the institution(s) and its personnel to full compliance with the HHS regulations. In carrying out its oversight responsibility, OHRP evaluates all substantive written allegations or indications of noncompliance with the HHS regulations derived from any source.
OHRP holds accountable and depends upon institutional officials, committees, research investigators, and other agents of the institution to assure conformity with the institution's Assurance and, thus, with the regulations. Only through the partnership established by the Assurance can the shared responsibility to protect the rights and welfare of human subjects be discharged in accordance with Section 491 of the Public Health Service Act.
Sequence of Events for an OHRP For-Cause Compliance Oversight Investigation
(1) OHRP discovers or receives a substantive written allegation or indication of noncompliance with the HHS Regulations (45 CFR Part 46).
(2) OHRP determines that it has jurisdiction in the matter on the basis of HHS support and/or an applicable Assurance of Compliance.
(3) Upon confirmation that it has jurisdiction, OHRP initiates a compliance oversight investigation by writing to appropriate institutional officials to advise them of OHRP’s investigation and to request that the institution investigate the matter and report back to OHRP by a specified date. Activities expected of the institution are explained in writing initially and at appropriate times during the course of the evaluation. Except in rare circumstances when sound ethics dictates the need to act immediately, OHRP takes no action against any institution without first affording the institution an opportunity to offer information which might refute indications of noncompliance or to develop satisfactory corrective actions if the allegations or indications of noncompliance are substantiated.
(4) OHRP evaluates the institution's report and any other pertinent information to which it has access. OHRP may (a) request that the institution submit additional information in writing; (b) conduct telephone interviews with institutional officials, committee members, and/or research investigators; or (c) conduct an on-site evaluation of protections under the applicable Assurance of Compliance.
(5) OHRP issues in writing a determination for each evaluation to appropriate institutional officials. The determination letter to the institution summarizes (i) findings of noncompliance with the HHS Regulations, if any; and/or (ii) the corrective actions proposed and/or implemented by the institution that appropriately address the findings of noncompliance. In such circumstances, any complainant(s) are ordinarily informed in writing of OHRP's determination upon completion of its investigation.
(6) An OHRP determination letter is made accessible on the OHRP website (http://www.hhs.gov/ohrp) once the document has been requested under FOIA, or ten working days after the document is issued to the institution, whichever occurs first.
(7) An institution may request review by the Director of OHRP of determinations and findings resulting from a compliance oversight evaluation.
Possible Outcomes of an OHRP For-Cause Compliance Oversight Investigation
OHRP's compliance oversight evaluations may result in one or more of the following outcomes:
(1) OHRP may determine that protections under an institution's Assurance of Compliance are in compliance with the HHS Regulations.
(2) OHRP may determine that protections under an institution's Assurance of Compliance are in compliance with the HHS Regulations but that recommended improvements to those protections have been identified.
(3) OHRP may determine that protections under an institution's Assurance of Compliance are not in compliance with the HHS Regulations and require that an institution develop and implement corrective actions.
(4) OHRP may restrict its approval of an institution's Assurance of Compliance. Affected research projects continue to be supported by HHS only if the terms of the restriction are being satisfied. Examples of such restrictions include, but are not limited to:
(a) suspending the Assurance's applicability relative to some or all research projects until specified protections and corrective actions have been implemented;
(b) requiring prior OHRP review of some or all research projects to be conducted under the Assurance;
(c) requiring that some or all committee members and institutional officials, as well as investigators conducting research under the Assurance, receive appropriate human subject education; and
(d) requiring special reporting to OHRP.
(5) OHRP may withdraw its approval of an institution's Assurance of Compliance. The institution's research projects cannot be supported by any HHS component until an appropriate Assurance is approved by OHRP.
(6) OHRP may recommend to appropriate HHS officials that:
(a) an institution or an investigator be temporarily suspended or permanently removed from participation in specific projects, and/or
(b) peer review groups be notified of an institution's or an investigator's past noncompliance prior to review of new projects.
(7) OHRP may recommend to HHS that institutions or investigators be declared ineligible to participate in HHS-supported research, known as Debarment. Note that a suspension of eligibility for Federal funding may precede a Debarment. If OHRP makes this recommendation, the Debarment process will be initiated in accordance with the procedures specified at 45 CFR Part 76. Any Debarment is Government-wide, and not just applicable to HHS funding.
Not-for-cause Compliance Oversight Surveillance Evaluations
FDA’s Bioresearch Monitoring Program
FDA conducts IRB inspections to determine if IRBs are operating in compliance with current FDA regulations and if the IRBs are following their own written procedures. The FDA regulations pertinent to IRBs include 21 CFR Part 50 (Protection of Human Subjects), Part 56 (Institutional Review Boards), Part 312 (Investigational New Drug Application), and Part 812 (Investigational Device Exemptions).
FDA inspections of IRBs generally fall into one of two categories:
During an inspection at the site of a clinical investigator, FDA personnel typically verify:
FDA personnel also audit the study data by comparing the data filed with the Agency or the sponsor with all available records that support the data. These records may come from the doctor’s office, hospital, nursing home, laboratories, and other sources. FDA may also examine patient records that predate the study to find out whether: the medical condition under study was in fact diagnosed; the study eligibility criteria were met; and the patient received a possibly-interfering medication before the study began. FDA personnel may also review records covering a reasonable period after completion of the study to determine if there was proper follow-up as outlined in the protocol, and if the clinical investigator reported all signs and symptoms reasonably attributable to the product's use.
After headquarters review, one of the following types of letters is typically sent from the Center to the IRB or clinical investigator depending upon the type of inspection:
(1) A letter that generally states that FDA observed no significant deviations from the regulations. This letter does not require any response. Note that a letter may not always be sent when FDA observes no significant deviations.
(2) An informational or untitled letter that identifies deviations from regulations and good clinical practices. This letter may request a response from the recipient. If FDA requests a response, the letter will describe what is necessary and identify a contact person for questions.
(3) A Warning Letter that identifies serious deviations from regulations needing prompt correction and a formal written response to FDA. The letter will identify an Agency contact person for questions. For investigator inspections, FDA may inform both the reviewing IRB and the study sponsor of the deficiencies and advise the sponsor if the clinical investigator's procedural deficiencies suggest ineffective monitoring by the sponsor.
In addition to issuing these letters, FDA may take regulatory actions for serious deviations from the regulations. FDA may disqualify the IRB, institution, or clinical investigator. A disqualified clinical investigator is ineligible to receive investigational products. FDA may also place lesser administrative sanctions on the IRB.
Under the BIMO program, FDA conducts approximately 1000 inspections annually of all of the various parties that conduct or oversee clinical research studies (i.e., clinical investigators, sponsors, monitors, contract research organizations, and IRBs). Of these inspections, about two-thirds are clinical investigator inspections, approximately 250 -300 are inspections of IRBs (mostly drawn from FDA's inventory of about 1600 IRBs identified as responsible for reviewing FDA-regulated research), and the remainder are sponsor or monitor/contract research organization inspections. For clinical investigations of drugs alone, FDA conducted approximately 75 inspections of studies involving pediatric subjects from 2001 to 2004.
Review and Analysis of Institutional Reports
(1) any unanticipated problems involving risks to subjects or others;
(2) any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and
(3) any suspension or termination of IRB approval.
(See 45 CFR 46.103(b)(4)(iii) for HHS-conducted or -supported research and 21 CFR 56.108(b) for FDA-regulated research.)
When reviewing a report of an unanticipated problem, OHRP or FDA assesses most closely the adequacy of the actions taken by the institution to address the problem. Likewise, when reviewing reports of non-compliance or suspension or termination of IRB approval, OHRP or FDA assesses most closely the adequacy of the corrective actions taken by the institution. In particular, an assessment is made whether or not the corrective actions will help ensure that the incident will not happen again, either with the investigator or protocol in question, or with any other investigator or protocol. When appropriate, corrective actions are applied institution-wide.
Conclusion We continue to address challenges posed by the threat of HIV/AIDS and are committed to basic and clinical research to strengthen the nation’s ability to cope with this infectious disease. The protection of human subjects, including children, in clinical trials has been and will remain a top priority for HHS. HHS is firmly committed to the protection of the rights and welfare of every individual who participates in human research consistent with sound ethical standards and regulatory requirements.
Last Revised: May 19, 2005