SPECIAL ARTICLE |
Ethical Concerns About Federal Approval of Risky Pediatric Studies
* Department of Medical Humanities, Brody School of Medicine at East Carolina University, Greenville, North Carolina
Department of Medical Education, University of Illinois College of Medicine at Chicago, Chicago, Illinois
 |
ABSTRACT |
|---|
 TOP ABSTRACT THE CATEGORY OF 407...407 REVIEWSETHICAL AND PROCEDURAL CONCERNSCONCLUSIONS AND RECOMMENDATIONSREFERENCES |
|---|
The US Federal Code limits research with healthy children to no more than a minimal risk of harm; it restricts research with children who have some disorder or condition to no more than a minor increase over minimal risk, unless potential harms are offset by potential benefits to them, as in therapeutic studies. Higher risk studies require "407 approval," named after the relevant section of the code describing requirements. Rarely used until recently, 407 approval requirements include Institutional Review Board approval and authorization by the Secretary of the Department of Health and Human Services after consultation with a panel of experts; a period for public comment; and assurances that there are adequate permission, consent, and assent. This 407-approval mechanism contains both procedural and interpretative ambiguities, which raise ethical concerns about 1) the expertise represented on advisory panels, 2) the scope of the information offered to the public for comment and its potential conflicts with investigators’ intellectual property or commercial interests, 3) whether any upper level of risk exists, and 4) how it conforms with other policies such as the best interest of the child standard in the law or in medical decision making.
Key Words: children • ethics • experimentation • health policy • human subjects • IRBs • law • pediatrics • research
Abbreviations: IRB, Institutional Review Board • DHHS, Department of Health and Human Services • CFR, Code of Federal Regulations • OHRP, Office for Human Research Protections • NIH, National Institutes of Health • HIV, human immunodeficiency virus
The central moral and social problem at the heart of all research regulations regarding children concerns is what policy should be adopted to promote research to advance knowledge for children as a group while protecting individual research subjects. By the end of the 1980s, many countries had taken similar approaches to solve this problem. They may permit studies without direct benefit to healthy children, but only if the risks of harm are minimal; they may also allow studies that do not have direct benefit but have minor increase over minimal risk of harm, if the children have a disorder or condition. They forbid higher risk studies, however, unless direct benefits to the children exist and are at least as great as available alternatives, as in cancer therapy. Pediatric research regulations generally also require parental permission, the child’s assent if possible, confidentiality, minimizing potential harms, maximizing potential benefits, and previous review and approval by review boards such as Institutional Review Boards (IRBs), Independent Ethics Committees, or Research Ethics Committees.1
The United States stands alone in having a mechanism to allow exceptions, but this requires approval by the Secretary of the Department of Health and Human Services (DHHS) after consultation with a panel of experts and a period for public comment (see Table 1 for all requirements).2 This is called "407 approval," after its citation in the US Code of Federal Regulations (45 CFR 
46.407). Applications to conduct such research have been received by the Secretary only a small number of times, with many of those applications currently pending and in various states of evaluation and review. The largest number of applications for 407 reviews has come within the past 3 years, arguably as a result of more federal oversight about compliance with regulations and greater incentives to conduct pediatric studies.
|
The 407 approval procedures raise several important ethical questions: 1) Which experts should be placed on the "407 panel"? 2) How much information should be revealed about the study in the opportunity for public comment, especially if it threatens investigators’ intellectual property or commercial interests? 3) Is there an upper threshold of risk of harm to individual subjects in studies that do not hold out direct benefits for them even in light of the group benefit of doing the study? 4) How do these mechanisms square with other policies such as the best interests of the child standard as used in the law and medical decision making?
|
THE CATEGORY OF 407 RESEARCH |
|---|
|
TOPABSTRACTTHE CATEGORY OF 407...407 REVIEWSETHICAL AND PROCEDURAL CONCERNSCONCLUSIONS AND RECOMMENDATIONSREFERENCES |
|---|
Four categories of pediatric research in the Department of Health and Human Regulations were derived from the 1978 work of the US National Commission for the Protection of Human Research of Biomedical and Behavioral Research3 (see Table 1). Commissioner Albert Jonsen has recalled the debate among the commissioners.4 With memories of the polio epidemic of the 1950s and 1960s still vivid, the commissioners favored a policy that protected children but did not want to frame guidelines that were so restrictive that they would have ruled out the sort of studies needed to test and develop polio vaccines for children. The commissioners wanted a mechanism for such extraordinary circumstances whereby IRBs might seek federal approval for more risky studies that are not otherwise approvable. Combating a great threat, such as the polio epidemic, commissioners reasoned, might sometimes justify higher risks to a few children. A method was recommended to permit research that involves more than a minor increase over minimal risk without the prospect of direct benefit, and this is reflected in 45 CFR
46.407. IRBs may review and approve 3 of the 4 categories of research, 404 to 406 (see Table 1). Many but not all federal agencies have adopted these rules, and they have increasingly become a national standard for all pediatric research. |
407 REVIEWS |
|---|
|
TOPABSTRACTTHE CATEGORY OF 407...407 REVIEWSETHICAL AND PROCEDURAL CONCERNSCONCLUSIONS AND RECOMMENDATIONSREFERENCES |
|---|
Although these regulations governing research with children have been in place for 2 decades, the scope of 407 approval is not well established. This is not surprising because only a very few reviews have been completed, although some are currently pending. Some information about these panels is available through requests for public comments in the Federal Register, the DHHS’s Office for Human Research Protections (OHRP; the successor of National Institutes of Health’s [NIH’s] Office for the Protection of Research Subjects) web site, and Freedom of Information Act Requests. The studies involving 407 reviews that are a matter of public record thus far are mentioned here to give some idea of the nature of the research and issues involved:
- In 1991, the New England Medical Center Hospital and an undisclosed party proposed a study entitled "Myoblast Transfer in Duchenne Muscular Dystrophy" that triggered 407 review.5 Very little information is publicly available about this study, other than that it was disapproved.
- In 1993, Children’s Hospital of Pittsburgh and researchers requested 407 review for a study of cognitive function and hypoglycemia in children with insulin-dependent diabetes. The study proposed to induce mild hypoglycemia in children through an insulin clamp to study certain cognitive functions. The study did not intend any benefits to the children under study. The study was allowed to go forward.6
- In 2000, OHRP notified a researcher who was studying causes of obesity that his study, although approved by an IRB at the National Institute of Child Health and Human Development, should have sought approval through the 407 process. OHRP found that aspects of this research, including the hyperglycemic and euglycemic-hyperinsulinemic clamp procedures, involved greater than minimal risk with healthy children. It halted aspects of the study.7 This study received publicity, in part because the IRB that initially approved this study as having only a minimal risk reasoned that "spending several hours in the Clinical Center in a clamp experiment would be safer than playing actively on sidewalks and streets" (ref. 7, p. 3).
- In 2002, a researcher at the University of Washington proposed a study, "Precursors to Diabetes in Japanese-American Youth."8 This study has been put forward for public comment twice and is described in detail in the next section. In August 2002, OHRP gave notice that it was prepared to recommend its approval but in December 2002 reopened the issue. The Secretary of DHHS has not made a final judgment.
- In 2002, public comment was sought on a study from Harbor-UCLA Medical Center that involved testing of diluted Dryvax smallpox vaccine in children.9 Most of the expert reviewers thought that the study should be approved, but some regarded it as unnecessary or worried about dangers of transmission of the virus used in the smallpox vaccine to others. The Secretary of DHHS did not approve the study.
- In 2003, DHHS received a request from UCLA for approval of a longitudinal study to test the hypothesis that children with prolonged human immunodeficiency virus (HIV) infections will have premature aging of their immune systems.10 The regenerative capacity of the immune systems of adolescents and young adults who ranged in age from 13 to 24 and acquired HIV perinatally is to be compared with those who get HIV from "adult behaviors" and with seronegative adolescents. Reviewers thought that it could be approved but, interestingly, some regarded it as a candidate for approval under 404, some under 405, others under 406, and still others under 407. The Secretary of DHHS has not made a final judgment.
- In 2003, a study was put out for public comment from University of North Carolina-Chapel Hill concerning newborn infants who receive a diagnosis of cystic fibrosis.11 The risks inherent in this longitudinal study include flexible fiber optics bronchoscopy and procedural sedation. Reviewers generally agreed that 407 approval was appropriate with some modifications. The Secretary of DHHS has not made a final judgment.
- In 2003, public comment was requested for a study from Albert Einstein on sleep mechanisms. It is designed for children 13 to 17 years of age.12 Risks include those from nuclear magnetic resonance and sleep deprivation for >24 hours. Expert panels disagree about whether this study should be approved, and some thought the monetary compensation might be coercive. The Secretary of DHHS has not made a final judgment.
- In 2003, a study from Rhode Island Hospital was put up for public comment concerning the effects of "small to moderate amounts of alcohol on sleep, waking performance, and circadian phase."13 Adolescents (15-16 years of age) and young adults (21-22 years of age) would participate to examine how the effects differ among people who have parents with a history of alcoholism and those who do not. Experts’ comments were not available, although they are likely to focus on the risks of giving alcohol to underage minors, especially those with alcohol-dependent parents. The Secretary of DHHS has not made a final judgment.
- Finally, although it did not receive review through the 407 process, a 1992 study can also be mentioned here because it was a federally sponsored review panel. This NIH study14 involved the administration of synthetic growth hormone to children with idiopathic short stature, many of whom were healthy and short because their parents were short. Technically an ad hoc panel, it was charged to determine whether the study was in compliance with federal guidelines and mirrored 407 panels in charge to evaluate high-risk or controversial research. It was designed as placebo-controlled, double-blinded, randomized trials with half of the children receiving growth hormone and the others a placebo 3 times a week for 4 to 7 years. The children were brought to the NIH each year for physical and psychological testing, including nude photographs and radiographs. The study is now completed.
|
ETHICAL AND PROCEDURAL CONCERNS |
|---|
|
TOPABSTRACTTHE CATEGORY OF 407...407 REVIEWSETHICAL AND PROCEDURAL CONCERNSCONCLUSIONS AND RECOMMENDATIONSREFERENCES |
|---|
The unique 407-review mechanism allows "research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children." This review process raises social and ethical problems, and we describe some of those here.
Review Panel Bias
To the degree that people’s responses are predictable, the results of a 407 panel’s deliberations can be shaped by the selection of its members. Civil rights attorneys are likely to have different views from investigators involved in the area of the research, advocates for those who have the disease under study, or representatives of the business community who are interested in marketing drugs under development in the study.
In the NIH growth hormone study, the majority of panelists were not only from the research community, but also one third were academic endocrinologists based at large research institutions. One might expect them to have more sympathy than others for research in their field, their colleague-investigators, and an industry that may fund projects in their home institutions; yet panelists were not asked to disclose conflicts of interest or conflicts of duties. It is now common practice to be asked about real or apparent conflicts of interest and how they will be managed when one publishes, reviews papers, or serves as a panelist, and this should be required for 407 panelists as well.
Some of the ethical issues that emerged from the now-completed, decade-old idiopathic short stature study reflect the ethical issues at stake with 407 studies generally. The majority of the committee thought that the study could be approved under 45 CFR 46.406, arguing that these procedures constituted a minor increase over minimal risk, although the study required hundreds of placebo injections for members of the control group.14 One of us (L.M.K.) was the only member who concluded that the risk of harm could not be justified, arguing that the double-blind, randomized, controlled method was not only morally problematic but also scientifically questionable; most children in the control group were not sick but short and were in a burdensome study that holds out no benefit to them; the children who got growth hormone generally had a growth spurt, which would tip off their endocrinologists and others. Although the study was approved by the majority of panelists and allowed to continue, they disagreed about the social utility of these studies, whether there were sufficient numbers of subjects to answer the research questions, the potential harms, the importance of the studies, whether normal but short was a condition that justified greater risk, and how to balance risks and potential benefits.
Expert in What?
An expert is someone with special knowledge, skill, or mastery of a particular subject. That is, an expert is always an expert with respect to a particular subject. The sort of expertise that seems especially important for 407 panelists is skill in deciding when it is justifiable to conduct a study within the 404, 405, or 406 framework or, if not, when an exception may be made. Such an expert would need to be able to decide whether a particular study is so important that it may justify placing children at more than a minor increase over minimal risk without direct benefit to them, and this is not an entirely scientific question. In reviewing the names of expert panelists from the recent group of 407 panelists, the same reviewers serve as experts time and time again. Although these reviewers are eminent in their areas and their involvement helps in terms of consistency, it is worth asking whether it might not make sense to rely on a broader range of reviewers to avoid real or perceived problems of insufficient diversity of opinion. To avoid these problems, review panels should have wide professional and public representation and rotation of membership, no matter whether the system now in place remains or DHHS institutes a standing review panel.
Public Comment
The 407 regulations call for an "opportunity for public review and comment." To make public comment meaningful, all information that a reasonable person would consider salient should be provided to assess the study’s potential harms and benefits. 2002 seems to have been a watershed year for DHHS or OHRP in deciding which information to give out, as concern for researchers’ intellectual property and commercial interest gave way to the value of allowing enough information for genuine public comment.
In August of 2002, the DHHS requested public comment regarding the proposed research study entitled "Diabetes in Japanese American Youth." Although the published notice did not say so at the time, a copy of the review panel’s executive summary—including a majority and minority report—was available for public review on its Web site. The membership of the review panel was not made available, however, and an inquiry to learn the membership was met with a suggestion to file a Freedom of Information Act Request. According to the provisions in 45 CFR 46.407, the study must offer a "reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children" in the judgment of the reviewers. With 1 exception, according to the review panel’s report, the panelists found the research proposal justified and recommended that it be allowed. One of the review panelists, however, found "serious design flaws" in the study and recommended that it not go forward. Certain scientific considerations were brought forward to support this contention, including an inadequate observation period and insufficient sample size. In this unnamed expert’s opinion, the study would yield little, if any, knowledge about how to understand, prevent, or alleviate type 2 diabetes in children.
We mention the details of the minority report not to give it credence necessarily but to show that these claims went unanswered in the material made public. Consequently, the public had too little information about the study to participate meaningfully in its evaluation. The same lack of information hampered the ability to form well-reasoned evaluations of other aspects of the research, including the use of sedation, the nature of the children’s assent to the studies, and some unspecified genetic studies that were attached to the main study.
Criticized for its lack of openness in the news media,15 by December 2002, DHHS reopened the period of comment for this study, made additional information available, and allowed a longer period for public comment. The notice reported that several commentators (including L.M.K. and T.F.M.) objected to the short time frame for comment and to the limited information made available. In the second notice, the period for public commentary was extended to 1 month (rather than the previous 2 weeks) and the following information was made available: the research protocol as reviewed by the local review board; the child’s assent form; the parent’s consent form; and selected aspects of the grant application including the abstract, specific aims, background and significance, human subjects involvement, and cited literature.
Critics’ objections seem to have prevailed.16 In a stunning reversal, by 2003, OHRP began to post more information about requests for 407 reviews, protocols, permission/consent/assent forms, expert panelists’ reports, and the Secretary’s decisions. It remains to be seen whether the disclosure of this degree of information will be satisfactory to answer all questions that are important to a thorough evaluation of the nature, scope, and merits of studies under 407 review and what impact this may have on investigators’ concerns about their intellectual property or commercial interests.
Local Versus Federal Oversight
What is the advantage of seeking federal rather than local approval in the form of 407 reviews? Other sensitive matters are dealt with by local review boards by requiring the presence of certain kinds of experts to ensure due attention to subjects’ welfare. The regulations might have required that IRBs solicit, for example, evaluations from at least 2 nationally recognized experts in the field of the study and require that these come from outside the review board’s institution. The regulations might also have required a record of the deliberations and conclusions of each review board member to document fully the rationale for accepting or rejecting the particular study. Moreover, the local review board is well suited to develop a plan to monitor studies with higher risks. Through such an approach, one could argue, the local review board could act as the expert panel advising the Secretary of DHHS with less cost and fuss.
What benefits do the existing approach have that surpass alternatives in value? Some may argue that a national review committee might well be worth the cost, time, and trouble that it involves because it will be able to call on a broader range of talent and expertise than IRBs. However, this seems questionable as an absolute characterization because many IRBs have considerable talent and expertise in their membership or available to them for consultation, especially at premier institutions. Many IRBs are highly sophisticated and have a great deal of expertise when it comes to biomedical research across a range of human subjects. Nonetheless, there are few data about the competence of IRBs in general or regarding pediatric studies. Some admit that they rarely review studies with children or do not have pediatricians as members.
IRBs are entitled to approve research that might involve even the risk of death to minors, as long as a persuasive case exists that the intervention holds out benefit at least as great as the alternatives available, as in getting an innovative therapy for a life-threatening disease (see conditions for 405 approval in Table 1). By contrast, federal action is required to approve research that involves risks only greater than a minor increase over minimal risk without an anticipated benefit. Thus, life and death decisions are sometimes entrusted to IRBs when a case can be made that there is an anticipated benefit at least as great as the alternatives, whereas other research must pass federal review when there is more than a minor increase over minimal risk.
A persuasive case for federal review, we argue, is that a national panel would probably be more consistent, impartial, and transparent than a local board. Reviews at the national level might promote consistency because the studies themselves become paradigms of what can or cannot be approved. For example, consider the smallpox study discussed above. Some expert reviewers regarded it to be a study with no benefit and some with benefit; some assessed the risk level to be minimal, others a minor increase over minimal, and some as more than this. Some approved it under 404, some under 405, some under 406, and others under 407. In part, this is because there have been ongoing disputes about how to understand the "minimal risk" and "minor increase over minimal risk" thresholds.15 Working through these disputes at the federal level should help forge a more consistent national policy.
Making the 407 procedures transparent, we conclude, helps set standards. The opportunity for public comment, moreover, helps to educate the public, IRBs, and investigators about the kind of studies that should be conducted and approved. In contrast, local review board deliberations and decisions are rarely a matter of public record. A national review could also avoid the conflicts of interest endemic at institutions. For example, if researchers are successful and influential, then their colleagues might tend to give their studies a less critical review than they would receive from a national panel, having some degree of distance from the researcher. Arguably, some conflict of interest may be avoided at the institutional level only to resurface at the national level. One part of a remedy for conflict of interest is disclosure and transparency, and these touchstones should be assessed carefully for their value at the national level.
Is There an Upper Level of Risk?
According to Al Jonsen, the specter of another catastrophe like the polio epidemic motivated them to recommend the 407 mechanism. Clearly some of the studies under review do not come close to this threshold of danger; the more commonly that exceptions are made, the more that IRBs and investigators will be tempted to seek this form of approval.
Although no upper level of potential harm is indicated in the federal rules for 407 approval, these research rules exist in a web of legal, political, social, and moral considerations about how to protect children’s rights and welfare. Two different appellate-level courts concluded that in research, as in other situations, decision makers must act in incompetent people’s best interest, all things considered and given the options.17,18 In a research context, they concluded that this means that no one may enroll such people in research with more than a minimal risk of harm, unless it is designed to benefit them as much as available options, as in therapy.19 It is unclear how these views square with the possibility of 407 approvals for children (or, for that matter, 406 approval).18 What seems clear, however, is that from this legal perspective, there are limits regarding the risk to which children can be put for the sake of gaining information, even if they are not articulated in the guidelines. At least 1 court made it clear that duties to protect children from research risks are greater than the duties to advance knowledge.17 In seeking approval for studies whose risks are so high that they cannot normally be authorized, concern for the children’s safety should also override the duty to protect the investigators’ commercial interests or intellectual property, and the public should get all salient information to make a reasonable evaluation in a 407 appeal.
|
CONCLUSIONS AND RECOMMENDATIONS |
|---|
|
TOPABSTRACTTHE CATEGORY OF 407...407 REVIEWSETHICAL AND PROCEDURAL CONCERNSCONCLUSIONS AND RECOMMENDATIONSREFERENCES |
|---|
The primary moral question in all research with children is how to secure progress for children as a group while protecting the individual research subject’s rights and welfare. What is unresolved at this time is the extent to which children should be enrolled in research that has potential harms and offers them no anticipated direct benefit at least as great as alternatives. 407 approval has no upper limit of harm, so it is unclear whether the mechanism of 407 review is the best way to give due consideration to the imperatives to do research and protect children. 407 review, therefore, deserves close scrutiny not only for what it allows in principle but also for how it works in practice.
In light of the foregoing considerations, we offer the following recommendations to help in the ranking of the 2 central moral values at the heart of disputes about pediatric studies: the importance of helping children as a group and of protecting the rights and welfare of individual subjects.
- Transparency: Review panels should be public and transparent, unless a compelling reason can be given otherwise. The names of the expert panelists should be made public, along with their individual and collective reviews and reports. Such disclosures help promote a public discussion about a) the level of research risk that should be permitted with minor subjects and b) how the values of scientific progress and protection of the rights and welfare of subjects should be ranked when they conflict. Since 2003, the OHRP seems to have adopted this policy. In the past year, the 407 policies and procedures have become far more transparent, perhaps in response to public criticism. Transparency is necessary for the social scrutiny needed for a consistent, impartial, and fair policy and should not be treated as optional.
- Expertise: Review panels should have expertise in relevant areas, including those familiar with other social and legal policies and with developmental stages of children and adolescents. Because making exceptions to social policy is not entirely a scientific matter, there is no reason to adopt a policy whereby many or most of the 407 panelists are from the specialty area of the research. Although it is important to include those with scientific and medical expertise, it will also be essential to include people who understand the moral and social issues that work to justify exceptions to established policies and those who understand the risks and benefits to children relative to their ages, maturity, and experiences. Review boards should have wide professional and public representation and should rotate membership.
- Conflicts of interest: Potential panelists must reveal real, potential, or apparent conflicts of interest or conflicts of duties and state how they will manage them. New policies have been developed on the local, state, and federal levels to manage conflicts of interest or duty, and they should be adapted and used for 407 panels. Because there has been so little work done by 407 panels, it is difficult to say that there have been patterns that should be cause for particular concern.
- Commercial Interests and Intellectual Property: When a choice must be made between withholding salient information about the study to protect the investigators’ commercial interests or intellectual property in authorizing higher risk studies and protecting children’s rights and welfare, protecting the children is the higher value. To make public comment meaningful, DHHS should routinely provide all information about the study that a reasonable person would need to assess the study’s potential harms and benefits, including the protocols, consent, permission, and assent forms, names of expert panelists, and their collective and individual responses.
- Risk limits: More study is needed of the relation of this policy with other established legal and social policies for children. Two appellate-level courts have been critical of exposing people who cannot give legal consent for themselves to more than a minimal risk of harm unless the study holds out the prospect of direct benefit at least as great as available alternatives. The Grimes court argued that the best interests of the child standard is the bedrock of legal policy in its jurisdiction and does not permit greater than a minimal risk to children in studies that do not hold out direct benefit.19 It is unclear whether this policy is compatible with 407 (or 406) approval.19 It will be important to resolve the growing tension between federal regulations and the courts over how to protect children from harm while advancing pediatric knowledge.
|
FOOTNOTES |
|---|
Received for publication Mar 17, 2003; Accepted Dec 22, 2003.
Reprint requests to (L.M.K.) Department of Medical Humanities, Brody School of Medicine at East Carolina University, Greenville, NC 27858-4354. E-mail: kopelmanlo{at}mail.ecu.edu
|
REFERENCES |
|---|
|
TOPABSTRACTTHE CATEGORY OF 407...407 REVIEWSETHICAL AND PROCEDURAL CONCERNSCONCLUSIONS AND RECOMMENDATIONSREFERENCES |
|---|
1. Kopelman LM. Minimal risk as an international ethical standard in research. J Med Phil.2004; 29 :351 –378
2. Code of Federal Regulations. 45 CFR 46:401-409. Additional protections for children involved as subjects in research. (Subpart D): US Department of Health and Human Services. Fed Reg.1983; 48 :9816 –9820
3. Department of Health, Education and Welfare, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Research Involving Children Report and Recommendation. Washington, DC: Department of Health, Education and Welfare; 1977 (Publication no. [OS] 77-0004)
4. Jonsen AR. The Birth of Bioethics. New York, NY: Oxford University Press; 1998
5. Department of Health and Human Services. Proposed protocol, "myoblast transfer in Duchenne muscular dystrophy." Fed Reg.1991; 56 :49189 , microfiche
6. Department of Health and Human Services, National Institutes of Health. Cognitive function and hypoglycemia in children with IDDM. Fed Reg.1993; 58 :40819 , microfiche
7. Department of Health and Human Services. November 3, 2000. Re: Human Research Subject Protection Inver Multiple Assurance (MPA) M-100 Research Project Population Differences in the Insulin Sensitivity, Resting Energy Expenditure, and Body Composition of Overweight Children and Children of Overweight Parents. (Protocol no. 96-CH 0101) Available at: ohrp.osophs.dhhs.gov/detrm_letrs/nov00a.pdf
8. Department of Health and Human Services. Precursors to Diabetes in Japanese-American Youth. Fed Reg. 2002;67:51283–51284.Available at: ohrp.osophs.dhhs.gov/pdjay/frpdjay.pdf. Reopened Fed Reg.2002; 67 :77495 –77496 (Materials are available for review on the OHRP web site at: ohrp.osophs.dhhs.gov/pdjay/pdjayindex.htm)
9. Department of Health and Human Services. Subpart D Panel Review of DMID Protocol 01–650 "A Multicenter, Randomized Dose Response Study of the Safety Clinical and Immune Responses of Dryvax Administered to Children 2 to 5 Years of Age." Fed Reg.2002; 67 :66403 –66404 (Initial request for comment was at: ohrp.osophs.dhhs.gov.panel/fr1031.pdf, and information about the protocol, consent forms, experts’ comments, and the judgment of the Secretary of DHHS and the Commissioner of the FDA are at: ohrp.osophs.dhhs.gov/dpanel/dpindex.htm)
10. Department of Health and Human Services. Proposed research, "HIV Replication and Thymopoiesis in Adolescents." Fed Reg.2003; 68 :42061 –42062. Available at: ohrp.osophs.dhhs.gov/references/fr07–16.pdf (Materials regarding this proposed research protocol is available for review on the OHRP web site at: ohrp.osophs.dhhs.gov/panels/407–04pnl/pindex.htm)
11. Department of Health and Human Services. Proposed research "Characterization of Mucus and Mucins in Bronchoalveolar Lavage Fluids from Infants with Cystic Fibrosis." Fed Reg.2003; 68 :35414 –35415. Available at: ohrp.osophs.dhhs.gov/references/fr06–13n.pdf (Materials regarding this proposed research protocol are available for review on the OHRP web site at: ohrp.osophs.dhhs.gov/panels/407–02pnl/pindex.htm)
12. US Department of Health and Human Services. Proposed research "Sleep Mechanisms in Children: Role of Metabolism. " Fed Reg.2003; 68 :35415 –35416. Available at: ohrp.osophs.dhhs.gov/references/fr06–13h.pdf (Materials are available for review on the OHRP web site at: ohrp.osophs.dhhs.gov/panels/407–03pnl/pindex.htm)
13. Department of Health and Human Services. Proposed research "Alcohol, Sleep and Circadian Rhythms in Young Humans, Study 2—Effects of Evening Ingestion of Alcohol on Sleep, Circadian Phase, and Performance as a Function of Parental History of Alcohol Abuse/Dependence. " Fed Reg.2003; 68 :17950. Available at: ohrp.osophs.dhhs.gov/references/fr04–14pdf (Materials are available for review on the OHRP web site at: ohrp.osophs.dhhs.gov/panels/407–01pnl/pindex.htm)
14. National Institutes of Health. Human Growth Hormone Protocol Review Committee. 1992. Report of the NIH Human Growth Hormone Protocol Review Committee. Bethesda, MD: National Institutes of Health; 1992
15. Kopelman LM. Children as research subjects: a dilemma. J Med Phil.2000; 25 :745 –764
16. Kaiser J. Human subjects. Ethicists fault review of children’s study. Science.2002; 297 :1461
17. Grimes v. Kennedy Krieger Institute, Inc. 782 A. 2d 807 (Md. 2001) and No. 128. (Md Oct 11, 2001) (order denying motion for reconsideration)
18. T.D. et al v New York State Office of Mental Health et al. December 22, 1997. 91 N. Y. 2d 860, 690 N. E. 2d 1259, 668 N. SY. S. 2d 153
19. Kopelman LM. Pediatric research regulations under legal scrutiny: Grimes narrows their interpretation. J Law Med Ethics.2002; 30 :38 –49[Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Rapoport Addressing Ethical Concerns Regarding Pediatric Palliative Care Research Arch Pediatr Adolesc Med, August 1, 2009; 163(8): 688 - 691. [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Berg, M. J. Mehlman, D. B. Rubin, and E. Kodish Making All the Children Above Average: Ethical and Regulatory Concerns for Pediatricians in Pediatric Enhancement Research Clinical Pediatrics, June 1, 2009; 48(5): 472 - 480. [Abstract] [PDF]
|
|
|
|
 |
|
 K. C. Glass and A. Binik Rethinking risk in pediatric research. J. Law Med. Ethics, September 1, 2008; 36(3): 567 - 576. [PDF]
|
|
|
|
 |
|
 D.J.H. Mathews, J. Sugarman, H. Bok, D. M. Blass, J. T. Coyle, P. Duggan, J. Finkel, H. T. Greely, A. Hillis, A. Hoke, et al. Cell-based interventions for neurologic conditions: Ethical challenges for early human trials Neurology, July 22, 2008; 71(4): 288 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ross, L. M. Kopelman, and T. F. Murphy The Need for Consistency in 407 Reviews Pediatrics, September 1, 2004; 114(3): 901 - 902. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
