2013 Ward 39;s Science Urinalysis

[Grimarlon Varner]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 50 and 56

[Docket No. 00N-0074] RIN 0910-AC07

Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim rule; opportunity for public comment.

SUMMARY: The Food and Drug Administration (FDA) is issuing an interim rule to amend its regulations to provide additional safeguards for children enrolled in clinical investigations of FDA-regulated products. This interim rule is intended to bring FDA regulations into compliance with provisions of the Children's Health Act of 2000 (the Children's Health Act), which requires that within 6 months of its enactment all research involving children that is conducted, supported, or regulated by the Department of Health and Human Services (HHS) be in compliance with HHS regulations providing additional protections for children involved as subjects in research. To comply with this congressionally mandated timeframe and for other reasons described in this document, FDA is publishing this regulation as an interim rule. FDA is requiring additional safeguards to protect children because of expected increases in the enrollment of children in clinical investigations as a result of recent pediatric initiatives. These initiatives include FDA's 1998 pediatric rule (the 1998 pediatric rule) and the pediatric provisions of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act).

FDA's authority includes regulation of safety and effectiveness testing in humans of certain FDA-regulated products. FDA-regulated products include human drug and biological products, medical device products, and dietary supplements, nutritional, food additive, and foods. This rule covers safety and effectiveness testing of FDA- regulated products in children. FDA expects an increase in testing of drug and biological products in children as a result of recent initiatives in pediatric research.

The 1998 pediatric rule (63 FR 66632, December 2, 1998) requires manufacturers to assess the safety and effectiveness of certain drug and biological products in pediatric patients. In the preamble to the 1998 pediatric rule, FDA stated that many drug and biological products marketed in the United States that are or could be used in children are inadequately labeled for use in pediatric patients or specific pediatric subgroups. FDA concluded that the absence of pediatric labeling information for these drug and biological products posed significant risks for children. The 1998 pediatric rule establishes a presumption that certain drug and biological products will be studied in pediatric patients. The 1998 pediatric rule also authorizes FDA to require pediatric studies of those marketed drug and biological products that: (1) Are used in a substantial number of pediatric patients for the labeled indications, and where the absence of adequate labeling could pose significant risks to pediatric patients; or (2) would provide a meaningful therapeutic benefit over existing treatments for pediatric patients for one or more of the claimed indications, and the absence of adequate labeling could pose significant risks to pediatric patients. 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 (Public Law 98-417) or the Orphan Drug Act (Public Law 97-414). 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. FDA expects that the combination of the pediatric exclusivity incentive of the Modernization Act and the requirements of the 1998 pediatric rule will significantly increase the number of FDA-regulated products for which pediatric studies will be conducted. This increase in studies has led to concern over the adequacy of existing safeguards for pediatric study subjects. 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 ) FDA's view that additional pediatric safeguards are necessary is underscored by title XXVII, section 2701 of the Children's Health Act (Public Law 106-310), in which Congress directs the Secretary of HHS (the Secretary) to require all research involving children that is conducted, supported, or regulated by HHS to be in compliance with 45 CFR part 46, subpart D (HHS subpart D) within 6 months of the date of enactment. The Children's Health Act was signed by the President on October 17, 2000. Clinical investigations involving FDA-regulated products, therefore, must comply with the standards of HHS subpart D by April 17, 2001. To respond to this congressionally mandated timeframe and for other reasons described in this document, FDA is publishing this regulation as an interim rule. In addition to requiring that HHS subpart D be applied to clinical investigations involving FDA-regulated products, Congress is requiring a substantive review of HHS subpart D. Title X, section 1003 of the Children's Health Act requires the Secretary to review HHS subpart D, consider any necessary modifications to ensure the adequate and appropriate protection of children participating in research, and report the findings to Congress. If, as a result of this evaluation, HHS proposes to modify HHS subpart D, FDA will review and modify this interim rule as appropriate.

The National Research Act (Public Law 93-348), 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)\1\ 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).

In the Federal Register of April 24, 1979 (44 FR 24106), FDA proposed regulations and solicited comments on applying the principles set forth in the HHS regulations to all pediatric research subject to FDA jurisdiction. This proposal was not finalized and was withdrawn on December 30, 1991 (56 FR 67440).

HHS subpart D provides protections for children involved in HHS- conducted or HHS-supported research. If an FDA-regulated clinical investigation is not conducted or supported by HHS, HHS subpart D does not impose requirements on the investigation. Nevertheless, FDA has historically relied on the HHS regulations to provide appropriate guidance for pediatric studies. In addition, as described below, there are other safeguards in place for pediatric research. 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 Sec. 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 Sec. 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

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