Source: https://www.federalregister.gov/articles/2001/04/24/01-10008/additional-safeguards-for-children-in-clinical-investigations-of-fda-regulated-products
Timestamp: 2016-07-24 01:00:12
Document Index: 261805050

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Federal Register | Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products
Publication Date: Tuesday, April 24, 2001
Comments Close: 07/23/2001
-20600 (12 pages)
Document Number: 01-10008
Shorter URL: https://federalregister.gov/a/01-10008 Action
Additional Safeguards for Children in Clinical Investigations 2 actions from April 24th, 2001 to September 2009
Table 1.—Estimated Number of IRB Reviews Per Year for Clinical Investigations in Children
The Modernization Act (Public Law 105-115) established economic incentives for manufacturers to conduct pediatric studies on drugs for which exclusivity or patent protection is available under the Drug Price Competition and Patent Term Restoration Act (98) or the Orphan Drug Act (97). These provisions attach 6 months of marketing exclusivity to any existing exclusivity or patent protection on a drug for which FDA has requested pediatric studies and the manufacturer has conducted such studies in accordance with the requirements of the Modernization Act.
As of October 1, 2000, FDA had received 194 proposed pediatric study requests under the exclusivity provisions of the Modernization Act and had issued 157 Written Requests for pediatric studies. A Written Request is a specific document from FDA in which the agency requests submission of certain studies to determine if the use of a drug could have meaningful health benefits in the pediatric population. Sponsors have indicated they are conducting or planning to conduct over 80 percent of the studies for which Written Requests have been issued.
In addition to the Modernization Act and the 1998 pediatric rule, FDA has initiated other actions to encourage the development of adequate pediatric use information for drug and biological products. Among other actions, FDA has published several pediatric guidance documents. (See FDA’s pediatric website at http://www.fda.gov/cder/pediatric.)
The National Research Act (93), signed into law on July 12, 1974, created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (the Commission). One of the Commission’s charges was to make recommendations pertaining to research involving children, including the purposes of such research, the steps necessary to protect children as subjects, and requirements for the informed consent of children or their parents or guardians. The Commission was required to recommend to the Secretary (of HHS or the Department)
policies defining circumstances under which research with and for children might be appropriate. The recommendations of the Commission pertaining to research involving children were published in the Federal Register of January 13, 1978 (43 FR 2084). After review of the Commission’s report, recommendations, and public comments, the Secretary published in the Federal Register of July 21, 1978 (43 FR 31786), a notice of proposed rulemaking on research involving children conducted or supported by HHS. HHS reviewed the public comments received on the proposal and also considered the Basic HHS Policy for the Protection of Human Research Subjects (45 CFR part 46). On March 8, 1983, HHS published its final rule incorporating requirements for the protection of children involved as subjects in HHS-conducted or HHS-supported research (48 FR 9814). This rule is codified at 45 CFR part 46, subpart D. These regulations supplemented basic regulations governing the protection of human subjects involved in research conducted or supported by HHS (30 FR 18914, May 30, 1974).
Current FDA regulations in part 56 (21 CFR part 56) governing institutional review boards (IRBs) include children as a class of vulnerable subjects, but do not specifically address the enrollment of children in clinical investigations. Portions of part 56 address pediatric issues. In § 56.111(a)(3), IRBs are required to determine that the selection of subjects in research is equitable and, to do so, should be “particularly cognizant of the special problems of research involving vulnerable populations, such as children * * *.” Section 56.111(b) states, “When some or all of the subjects, such as children * * *, are likely to be vulnerable to coercion or undue influence [,] additional safeguards have been included in the study to protect the rights and welfare of these subjects.” Section 56.107(a) addresses IRB membership and provides that if an IRB “regularly reviews research that involves a vulnerable category of subjects, such as children, * * * consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects.”
FDA’s information sheets entitled “Guidance for Institutional Review Boards and Clinical Investigators” address issues regarding informed consent and the assent of children. This guidance states that although FDA regulations regarding informed consent do not specifically address the enrollment of children, the basic requirements of § 50.20 (21 CFR 50.20) regarding informed consent apply. The information sheets also state that HHS regulations for conduct of studies in children may be used as guidance for all pediatric studies. These information sheets are available at www.fda.gov/oc/oha/IRB/toc.html.
FDA also has published a guidance entitled “E11 Clinical Investigation of Medicinal Products in the Pediatric Population” (ICH E11). This guidance was prepared by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) as part of the ICH effort to harmonize technical requirements for the registration of pharmaceutical products among the European Union, Japan, and the United States. ICH E11 addresses issues in pediatric drug development including ethical considerations in pediatric studies. It states that pediatric populations represent a vulnerable subgroup and special measures are needed to protect the rights of pediatric study participants. Section 2.6 of ICH E11 addresses relevant issues including: The roles and responsibilities of IRBs and independent ethics committees, recruitment of study participants, consent and assent, and minimizing risk and distress in pediatric studies.
II. Highlights of the Interim Rule Back to Top
FDA’s regulations governing informed consent and IRBs apply to clinical investigations that are subject to FDA’s jurisdiction. The scope of the regulations is described in §§ 50.1 (21 CFR 50.1) and 56.101 and includes all clinical investigations that are subject to requirements for prior submission under sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i) and 360j(g)) or that support an application for a research or marketing permit for a product regulated by the agency as defined in §§ 50.3(b) (21 CFR 50.3(b)) and 56.102(b). This includes color additive petitions, petitions submitted to establish that a substance that may become a component of food is generally recognized as safe for use, food additive petitions and petitions for establishing a tolerance for unavoidable contaminants in food, drug applications, biologics licenses, and medical device applications. In contrast, HHS subpart D regulations cover research involving children as subjects, conducted or supported by the Department. With minor exceptions, FDA does not conduct or support research involving human subjects. Instead, FDA regulates research conducted by outside sponsors and investigators, where the research is subject to IRB review and approval. Because of these differences, FDA is making some modifications to HHS subpart D. For example, throughout the interim rule, FDA has modified the description of the scope of the rule from applying to research conducted or supported by the Department as described in HHS subpart D, to applying to clinical investigations subject to FDA’s regulatory authority. Some research involving FDA-regulated products is also conducted or supported by HHS and falls within the scope of both HHS and FDA regulations.
Finally, FDA has made changes to the scope and definitions sections of part 50 (21 CFR part 50) and part 56 to reflect that studies of certain foods, dietary supplements, and infant formulas are covered by these regulations. The regulations in part 101 (21 CFR part 101) governing petitions for nutrient content claims state that clinical studies submitted in support of such a petition must be conducted in accordance with the requirements of parts 50 and 56 (§ 101.69(f)). The regulations governing petitions for health claims contain the same requirement (§ 101.70(d)). Therefore, the agency is clarifying that parts 50 and 56 govern clinical investigations, including those involving children, when such investigations may be submitted in a petition under § 101.69 or § 101.70. Consistent with the congressional directive that the protections of the HHS subpart D regulations be extended to all research involving children regulated by FDA, studies in children in support of infant formulas and in support of premarket notification of dietary supplements that contain new dietary ingredients are also subject to parts 50 and 56.
FDA is adopting several terms from 45 CFR 46.402 of HHS subpart D for inclusion in the FDA definitions at § 50.3. These include the terms “assent” (§ 50.3(n)), “children” (§ 50.3(o)), “parent” (§ 50.3(p)), “permission” (§ 50.3(r)), and “guardian” (§ 50.3(s)). The definitions of these terms in § 50.3 generally follow the definitions in HHS subpart D, with changes as identified and discussed below. In addition, FDA is defining the term “ward” (§ 50.3(q)) in a manner that is consistent with its use in HHS subpart D.
The definition of “assent” at § 50.3(n) is adopted from HHS subpart D with a minor change to clarify that the assent applies to participation in clinical investigations involving FDA-regulated products. FDA’s regulation, like the HHS regulation, defines assent as a child’s affirmative agreement to participate in research. FDA’s definition also states that mere failure to object to participation in clinical investigations should not, absent affirmative agreement, be considered assent.
The definition of “children” at § 50.3(o) includes persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations as determined under the applicable law of the jurisdiction in which the research will be conducted. This provision means that the law of the site of the research will determine the legal age of consent of the participant.
FDA did not previously have a definition for parent at § 50.3 and is adopting the definition from HHS subpart D. “Parent” is defined as a child’s biological or adoptive parent.
The term “ward” is used in HHS subpart D but is not defined. In § 50.3(q), FDA has developed a definition for ward that is consistent with the use of the term in HHS subpart D. Under § 50.3(q), a ward is a child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law.
The definition of “permission” at § 50.3(r) is adopted from 45 CFR 46.402(c) of HHS subpart D with a minor change to clarify that permission applies to participation in clinical investigations involving FDA-regulated products. FDA’s definition at § 50.3(r) generally adopts the HHS definition and states that permission is the agreement of parent(s) or guardian to their child’s or ward’s participation in a clinical investigation.
FDA’s regulation at § 50.3(r) adds a sentence clarifying that permission must be obtained in compliance with part 50, subpart B and must include the elements of informed consent described in FDA’s regulations at § 50.25. This approach is consistent with HHS’s interpretation of the term “permission.” Under the requirements for permission by parents or guardians and assent by children, 45 CFR 46.408(d) of HHS subpart D states that permission by parents or guardians shall be documented in accordance with and to the extent required by 45 CFR 46.117 of HHS subpart A (45 CFR part 46, subpart A). Section 46.117 of HHS supbart A outlines the requirements for documenting informed consent. Addressing comments made on requiring parental consent to participation in research in the preamble to its final rule (48 FR 9814), the Department stated that inserting this reference to 45 CFR 46.117 of HHS subpart A clarified that the requirements for informed consent shall apply to permission.
The agency is retaining the term permission because this term is used in HHS subpart D and is familiar to IRBs. The term permission also distinguishes children from other participants in clinical investigations. Children are defined as persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations under the applicable law of the jurisdiction in which the clinical investigation will be conducted. Because children are unable, due to age, to give consent themselves, permission is provided by a parent or guardian on their behalf. The term informed consent under § 50.20 applies to other participants in clinical investigations. FDA solicits comments on its definition of permission.
FDA is adopting the term guardian because this term is currently used in HHS subpart D in the context of research involving children, and is familiar to IRBs. In contrast, FDA’s regulations at § 50.3 and HHS’s regulations at 45 CFR 46.102(c) use the term “legally authorized representative” for an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedures involved in the research. FDA’s definition of the term guardian is intended to clarify that a guardian must be an individual authorized to consent to a child’s participation in research. FDA seeks comments on its definition of the term guardian and any implications under State or local law.
FDA has adopted the provisions in 45 CFR 46.403 of HHS subpart D with minor changes. The provisions are included in FDA regulations at § 50.50. Section 50.50 directs that in addition to other responsibilities assigned under parts 50 and 56, IRBs must now review research covered by subpart D of part 50 and approve only research that satisfies the criteria described in § 50.51, § 50.52, or § 50.53 and the conditions of all other applicable sections of part 50, subpart D.
FDA has also made conforming changes to part 56 of its regulations governing IRBs. Under part 56, subpart C, describing IRB functions and operations, FDA is adding new paragraph (c) to § 56.111. New § 56.111(c) requires that to approve research in which some or all of the subjects are children, an IRB must determine that all such research is in compliance with part 50, subpart D.
Similarly, FDA has added new paragraph (h) to § 56.109 on IRB review of research to require that when some or all of the subjects of ongoing research are children, an IRB must conduct a review of the research to determine compliance with part 50, subpart D. This review of research that is ongoing on the effective date of this rule must be conducted either at the time of continuing review or, at the discretion of an IRB, at an earlier date. Under § 56.109(f), IRBs conduct continuing review of research at intervals appropriate to the degree of risk of the research, but not less than once per year. FDA expects that the degree of risk posed to children will be considered by the IRB in determining when to conduct a continuing review of an ongoing trial for compliance with part 50, subpart D.
FDA regulations set out criteria to be satisfied if an IRB is to approve research (§ 56.111). These criteria are the same for initial review and continuing review and include a determination by the IRB that:
Under new § 56.109(h), at the time of continuing review, or at an earlier date if the IRB so determines, the IRB must review research involving children, with reference to the risk categories and criteria as defined in part 50, subpart D, to determine if an ongoing clinical investigation fits into one of the risk categories at § 50.51, § 50.52, or § 50.53. If an IRB determines that the research does not fit any of these three categories, but that the research may fit under § 50.54, the IRB should contact FDA for further guidance. FDA emphasizes that it expects the volume of studies that are candidates for classification under § 50.54 to be extremely small. FDA believes it is appropriate to permit review of ongoing investigations for compliance with part 50, subpart D at the time of continuing review or at an earlier date identified by the IRB because this is the least disruptive way to ensure compliance. If an IRB determines that research in progress does not fit any of the four risk categories defined in part 50, subpart D, the IRB has authority to suspend or terminate approval of the research under § 56.113. Under § 56.113, the IRB must report any such action to FDA. FDA notes that many ongoing pediatric studies have been approved by IRBs based upon the standards described in HHS subpart D, so the agency anticipates that very few, if any, ongoing studies will be suspended or terminated.
Under § 50.51, an IRB may approve a clinical investigation in which no greater than minimal risk is presented only if an IRB finds and documents that adequate provisions are made for soliciting the assent of the children involved and the permission of their parents or guardians as set forth in § 50.55. In adopting this provision, FDA has made minor changes to the language used in 45 CFR 46.404 of HHS subpart D. Rather than stating that HHS will “conduct or fund research” in which the IRB finds no greater than minimal risk to children, FDA has modified this language to state the conditions under which an IRB may approve a clinical investigation involving an FDA-regulated product in which there is no greater than minimal risk to children. FDA believes this change is required by the scope of FDA’s regulatory authority. Similar changes have been made as necessary throughout the codified section to reflect the scope of FDA’s regulatory authority.
FDA previously adopted the Department’s definition of minimal risk (45 CFR 46.102(g) of subpart A) without change in § 50.3. FDA anticipates that among the types of procedures that might be used in a clinical investigation that would present no more than minimal risk to children would be clean-catch urinalysis, obtaining stool samples, administering electroencephalograms, requiring minimal changes in diet or daily routine, or the use of standard psychological tests. Examples of the types of clinical investigations that would present no more than minimal risk would include a taste test of an excipient or tests of devices involving temperature readings orally or in the ear. FDA anticipates that there may be circumstances under which products with an established safety profile in adults may present no more than minimal risk in children.
Under § 50.52, an IRB may approve a clinical investigation in which an IRB finds more than minimal risk to children but that presents the prospect of direct benefit to individual subjects only if the IRB finds and documents that:
(3) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in § 50.55.
Section 50.52 adopts the provisions of 45 CFR 46.405 of HHS subpart D with minor changes to conform to FDA’s regulatory authority. FDA expects that many clinical investigations of FDA-regulated products in children will be allowed to proceed under § 50.52. These clinical investigations generally are performed in children with the disease or condition for which the product is intended.
The agency also recognizes that the requirement for the prospect of direct benefit to individual subjects may create ambiguity about whether placebo-controlled clinical investigations may be conducted in children. FDA believes that clinical investigations involving placebos in children may be conducted in accord with § 50.52. There is evidence of direct benefit to subjects from participating in placebo-controlled trials, including increased monitoring and care of subjects, even though a subject may not actually receive the test product. FDA invites comment on the issue of conducting placebo-controlled trials in children.
(4) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians as set forth in § 50.55.
FDA recognizes that § 50.53 raises issues similar to those raised by § 50.52 about standards for IRBs to use in assessing when a clinical investigation involves more than minimal risk. Some comments submitted previously on HHS’s proposed rule (43 FR 31786, July 21, 1978) indicated that no attempt should be made to define the concept of “minor increase” or to provide guidance to IRBs on evaluating whether a “minor increase over minimal risk” is involved. These comments stated that because of varying situations and circumstances, IRBs would need to make judgments on a case-by-case basis. FDA believes that IRBs are qualified to assess and document when a specific protocol falls under this category. However, FDA is soliciting comments on whether further definition should be provided to aid IRBs in making such determinations, including: (1) How to measure a minor increase in risk, (2) at what point a minimal risk develops into a major risk, and (3) whether IRBs have the expertise necessary to determine minor increases over minimal risk.
Section 50.53(c) contains the phrase “likely to yield generalizable knowledge about the subjects’ disorder or condition.” The criterion in § 50.53(c) raises the question whether clinical investigations of FDA-regulated products conducted to determine the safety and effectiveness of such products yield generalizable knowledge about a subject’s disorder or condition that is of vital importance for the understanding or amelioration of the subjects’ disorder or condition. FDA believes there are circumstances in which clinical investigations yield such information. Such circumstances may include cases where a child has been identified as at high risk for a disease and receives investigational interventions to prevent the disease or ameliorate manifestations of the disease in the future. In these situations, even in children who would not otherwise have manifested the disease, the clinical investigations may yield important information that might contribute to the understanding of a disease, disorder, or condition. FDA believes that IRBs are capable of making this assessment. Therefore, FDA is adopting this provision from HHS subpart D.
An IRB may allow a clinical investigation that does not meet the requirements of § 50.51, § 50.52, or § 50.53 to proceed only if the IRB finds and documents that the clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and the Commissioner of Food and Drugs (the Commissioner) determines that the conditions of § 50.54(b) are met. After consultation with a panel of experts and following opportunity for public review and comment, the Commissioner must determine, under § 50.54(b)(1), that the clinical investigation satisfies the conditions of § 50.51, § 50.52, or § 50.53 or, under § 50.54(b), that three conditions are met. The conditions in § 50.54(b) are as follows:
FDA’s regulation in § 50.54 generally follows the provisions in 45 CFR 46.407 of HHS subpart D with some modification. In § 50.54(b), FDA has charged the Commissioner with determining whether such a clinical investigation can proceed. The Commissioner is to consult with a panel of experts. FDA anticipates that this panel may include an advisory committee supplemented, if needed, by appropriate experts. This provision also provides for public review and comment on the Commissioner’s pending decision. However, FDA may not be able to provide for public review and comment on the Commissioner’s pending decision if the sponsor is unwilling to publicly disclose necessary information. FDA’s trade secret and commercial confidentiality requirements (21 CFR 20.61) protect certain types of information from public disclosure. This type of privileged information is sometimes included in INDs and IDEs. Because FDA believes full public review and comment is critical in determining whether a clinical investigation should proceed under these circumstances, if a sponsor is unwilling to waive this privilege, FDA may not be able to satisfy the public review and comment requirement and any such clinical investigation could not proceed.
FDA has adopted in § 50.55 the provisions of 45 CFR 46.408 of HHS subpart D, describing when assent may be waived. Even in cases where an IRB determines waiver of assent is necessary, FDA regulations require the permission of parents or guardians to the extent informed consent is required in part 50. Documentation of permission must be consistent with the documentation required for informed consent at § 50.27.
FDA has not adopted the provisions of 45 CFR 46.408(c) that allow an IRB to waive the requirements for obtaining permission in certain circumstances. Section 46.408(c) of HHS subpart D allows an IRB to determine that a research protocol is designed for conditions or for a subject population for which the permission of parents or guardians is not a reasonable requirement to protect the subjects. This provision allows the IRB to substitute an appropriate mechanism to protect children who will participate as subjects in research.
FDA has adopted in § 50.56 the provisions of 45 CFR 46.409 of HHS subpart D describing when children who are wards of the State or any other agency, institution, or entity may be included in research.
Under § 50.3(q), a ward is defined as a child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law. Under § 50.56(a), wards can be included in clinical investigations only if such research is: (1) Related to their status as wards, or (2) conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards. Section 50.56(a) is written to ensure that if wards of the State participate in clinical investigations, they do so not because it is administratively convenient for a clinical investigator or sponsor to include them as participants, but because they are subject to potential benefit from the clinical investigation.
FDA believes that wards require special protections. FDA also believes that § 50.56(b) provides protection from any conflict of interest issues that may arise in the appointment of an advocate. FDA notes that any issues relating to compensation or funding for advocates or the liability of advocates are left to the IRBs and other involved institutions, agencies, or entities to resolve. FDA is soliciting comments on any difficulties such entities may have with the appointment of advocates.
FDA is issuing this interim rule to comply with the Children’s Health Act. Generally, the Administrative Procedure Act and FDA regulations require notice to the public and an opportunity for comment prior to the effective date of a rule (5 U.S.C. 553(b) through (d); 21 CFR 10.40(b)). This process may be dispensed with under 5 U.S.C. 553(b)(3)(B) and § 10.40(e)(1) (21 CFR 10.40(e)(1)) if the Commissioner finds, for good cause, that notice and public procedures would be impracticable, unnecessary, or contrary to the public interest. This interim rule meets these standards.
In addition, for the reasons described above, the Commissioner of Food and Drugs also finds good cause under 5 U.S.C. 553(d)(3) and § 10.40(c)(4)(ii) for making this interim rule effective in less than 30 days.
This interim rule requires IRBs reviewing FDA-regulated clinical investigations involving children to apply FDA’s new regulations establishing additional safeguards for children in clinical investigations, as adopted from HHS subpart D. Until now, FDA has relied primarily on its own regulations governing adult studies, in combination with HHS subpart D, as guidance for the review of clinical investigations in children. In this rule, FDA requires the IRB to review and document the risks to children participating in clinical investigations before the clinical trial may proceed. In some instances, this may be a departure from current practice and may place additional requirements on IRBs. FDA believes the burden of these added requirements to be small. Under current standards, IRBs are already required to make several determinations concerning subject risk and to document subject risks. The additional requirements of this rule state that IRBs must specifically identify which of the four risk categories applies to pediatric subjects in a clinical investigation. We expect that this determination would require some additional effort, but take at most one person-hour of additional time. To estimate costs, FDA multiplied the estimated number of clinical investigations in children subject to the rule’s requirements by the estimated additional time required of the affected IRBs for each trial reviewed. Then FDA multiplied the total estimated time by a standardized cost of $75 per man-hour.
New trials for pre-2001 drug and biological products
Annual review of ongoing trials
Post-1/1/2001 drug and biological products
Post-1/1/2001 devices
In addition to these annual costs, we assume that each IRB reviewing FDA-regulated pediatric clinical trials will have to conduct a one-time review and update of their standard operating procedure (SOP) documents to include the requirements of this rule. Experts at FDA estimate that up to 1,500 IRBs may review protocols for research performed under an IND or IDE. Because we believe that most IRBs currently follow procedures similar to those required by this rule, we estimate that changes to existing SOPs will require no more than 8 man-hours. Multiplying the 1,500 IRBs by 8 and applying a standardized cost of $75 per man-hour equals a one-time cost of $900,000. This one-time cost would occur in the year 2001, following implementation of the rule.
VIII. Opportunity for Public Comment Back to Top
§ 50.1 [Amended]
2. Amend § 50.1 Scope as follows:
3. Amend § 50.3 by adding paragraphs (b)(23), (b)(24), (b)(25), (n), (o), (p), (q), (r), and (s) to read as follows:
(24) Data and information submitted in a petition for a nutrient content claim, described in § 101.69 of this chapter, or for a health claim, described in § 101.70 of this chapter.
(25) Data and information from investigations involving children submitted in a new dietary ingredient notification, described in § 190.6 of this chapter.
(r) Permission means the agreement of parent(s) or guardian to the participation of their child or ward in a clinical investigation. Permission must be obtained in compliance with subpart B of this part and must include the elements of informed consent described in § 50.25.
Subpart D—Additional Safeguards for Children in Clinical Investigations Back to Top
50.50IRB duties.
50.51Clinical investigations not involving greater than minimal risk.
50.52Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.
50.53Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition.
50.54Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.
50.55Requirements for permission by parents or guardians and for assent by children.
50.56Wards.
§ 50.51 Clinical investigations not involving greater than minimal risk.
Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which no greater than minimal risk to children is presented may involve children as subjects only if the IRB finds and documents that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians as set forth in § 50.55.
§ 50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.
Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject’s well-being, may involve children as subjects only if the IRB finds and documents that:
(c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians as set forth in § 50.55.
§ 50.53 Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition.
Any clinical investigation within the scope described in§§ 50.1 and 56.101 of this chapter in which more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is not likely to contribute to the well-being of the subject, may involve children as subjects only if the IRB finds and documents that:
(d) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians as set forth in § 50.55.
§ 50.55 Requirements for permission by parents or guardians and for assent by children.
(1) Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient, if consistent with State law, for clinical investigations to be conducted under § 50.51 or § 50.52.
(2) Where clinical investigations are covered by § 50.53 or § 50.54 and permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child if consistent with State law.
(f) Permission by parents or guardians must be documented in accordance with and to the extent required by § 50.27.
§ 50.56 Wards.
(a) Children who are wards of the State or any other agency, institution, or entity can be included in clinical investigations approved under § 50.53 or § 50.54 only if such clinical investigations are:
§ 56.101 [Amended]
6. Amend § 56.101 Scope in the first sentence of paragraph (a) by adding after the word “including” the phrase “foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas,”.
7. Amend § 56.102 by adding paragraphs (b)(21), (b)(22), and (b)(23) to read as follows:
(22) Data and information submitted in a petition for a nutrient content claim, described in § 101.69 of this chapter, and for a health claim, described in § 101.70 of this chapter.
(23) Data and information from investigations involving children submitted in a new dietary ingredient notification, described in § 190.6 of this chapter.
8. Amend § 56.109 by adding paragraph (h) to read as follows:
§ 56.109 IRB review of research.
(h) When some or all of the subjects in a study are children, an IRB must determine that the research study is in compliance with part 50, subpart D of this chapter, at the time of its initial review of the research. When some or all of the subjects in a study that is ongoing onApril 30, 2001 are children, an IRB must conduct a review of the research to determine compliance with part 50, subpart D of this chapter, either at the time of continuing review or, at the discretion of the IRB, at an earlier date.
9. Amend § 56.111 by adding paragraph (c) to read as follows: