Solicitation of Public Review and Comment on Research Protocol: Effects of a Single Dose of Dextroamphetamine in Attention Deficit Hyperactivity Disorder; A Functional Magnetic Resonance Study

AGENCY:

Office of Public Health and Science and Food and Drug Administration, HHS.

ACTION:

Notice.

SUMMARY:

The Office for Human Research Protections (OHRP), Office of Public Health and Science, Department of Health and Human Services (HHS) and the Food and Drug Administration (FDA), HHS are soliciting public review and comment on a proposed research protocol entitled “Effects of a Single Dose of Dextroamphetamine in Attention Deficit Hyperactivity Disorder (ADHD); A Functional Magnetic Resonance Study.” The proposed research would be conducted at the National Institutes of Health (NIH) and supported by NIH's National Institute of Mental Health (NIMH). Public review and comment are solicited regarding the proposed research protocol under the requirements of HHS and FDA regulations.

DATES:

To be considered, written or electronic comments on the proposed research must be received on or before 4:30 p.m. on August 20, 2004.

ADDRESSES:

Electronic copies of the documents for public review can be viewed at the Pediatric Advisory Committee (PAC) Docket site at http://www.fda.gov/ohrms/dockets/ac/acmenu.htm . (Click on the year 2004 and scroll down to PAC meetings.) Submit written comments to the Division of Dockets Management (HFA-305), Docket No. 2004N-0337, Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments . All comments should be identified with the docket number found in brackets in the heading of this document. Received comments may be viewed on the FDA Web site at: http://www.fda.gov/ohrms/dockets/dockets/04n0337/04n0337.htm , or may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

FOR FURTHER INFORMATION CONTACT:

Julia Gorey, Office for Human Research Protections, The Tower Building, 1101 Wootton Pkwy., suite 200, Rockville, MD 20852, 301-496-7005, FAX: 301-402-2071, e-mail: Jgorey@osophs.dhhs.gov; or Jan N. Johannessen, Office of the Commissioner (HF-33), Food and Drug Administration, 5600 Fishers Lane (for express delivery, rm. 17-51), Rockville, MD 20857, 301-827-3340, or by e-mail: jjohannessen@fda.gov.

SUPPLEMENTARY INFORMATION:

All studies conducted or supported by HHS which are not otherwise exempt and which propose to involve children as subjects require Institutional Review Board (IRB) review in accordance with the provisions of HHS regulations for the protection of human subjects at 45 CFR part 46, subpart D. Under FDA's interim final rule effective April 30, 2001 (21 CFR part 50, subpart D), FDA adopted similar regulations to provide safeguards for children enrolled in clinical investigations of FDA-regulated products. Because the proposed research, “Effects of a Single Dose of Dextroamphetamine in Attention Deficit Hyperactivity Disorder; A Functional Magnetic Resonance Study,” would be conducted and supported by NIH, a component of HHS, and would be regulated by FDA, both HHS and FDA regulations apply to this proposed research.

Under HHS regulations at 45 CFR 46.407, and FDA regulations at 21 CFR 50.54, if an IRB reviewing a protocol to be conducted or supported by HHS for a clinical investigation regulated by FDA does not believe that the proposed research involving children as subjects meets the requirements of HHS regulations at 45 CFR 46.404, 46.405, or 46.406, and FDA regulations at 21 CFR 50.51, 50.52, or 50.53, respectively, the research may proceed only if the following conditions are met: (1) The IRB 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; and (2) the Secretary (HHS) and the Commissioner (FDA), respectively, after consultation with experts in pertinent disciplines (e.g., science, medicine, education, ethics, law) and following opportunity for public review and comment, determine either: (a) That the research in fact satisfies the conditions of 45 CFR 46.404, 46.405, or 46.406 under HHS regulations, and 21 CFR 50.51, 50.52, or 50.53 under FDA regulations, or (b) that the following conditions are met: (i) The research or clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research or clinical investigation will be conducted in accordance with sound ethical principles; and (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in 45 CFR 46.408 and 21 CFR 50.55.

HHS has received a request on behalf of the IRB of NIMH, to review under 45 CFR 46.407 the protocol entitled “Effects of a Single Dose of Dextroamphetamine in Attention Deficit Hyperactivity Disorder; A Functional Magnetic Resonance Study.” The principal investigator proposes to administer a single 10-milligram dose of dextroamphetamine in conjunction with functional magnetic resonance imaging (fMRI) in healthy children and children with attention deficit hyperactivity disorder (ADHD), all between 9 and 18 years of age. Subjects of the study would include 10 children for piloting tasks; 14 healthy control children; 14 children with ADHD; 24 monozygotic twins (12 pairs), discordant for ADHD; and 24 dizygotic twins (12 pairs), discordant for ADHD.

The overall goal of the proposed study is to better understand the pathophysiology of ADHD. The three specific aims of the study are to: (1) Study brain activation patterns during response inhibition tasks in children with ADHD and in healthy controls; (2) simultaneously examine the central and behavioral effects of a single-dose of amphetamine versus placebo in the two groups; and (3) examine (using monozygotic and dizygotic twins) brain activation patterns in relation to clinical state and the degree of genetic relatedness.

The NIMH IRB determined that although the protocol was not approvable under 45 CFR 46.404, 46.405, or 46.406 because the administration of dextroamphetamine posed more than minimal risks to healthy children, the protocol was suitable for review under 45 CFR 46.407. Accordingly, the NIMH IRB forwarded the protocol to OHRP under 45 CFR 46.407. Because this clinical investigation is regulated by FDA, FDA's regulations at 21 CFR part 50, subpart D, specifically 21 CFR 50.54, apply as well.

In accordance with 45 CFR 46.407(b) and 21 CFR 50.54(b), OHRP and FDA are soliciting public review and comment on this proposed clinical investigation. In particular, comments are solicited on the following questions: (1) What are the potential benefits, if any, to the subjects and to children in general; (2) what are the types and degrees of risk that this research presents to the subjects; (3) are the risks to the subjects reasonable in relation to the anticipated benefits, and is the research likely to result in generalizable knowledge about the subjects disorder or condition; and (4) does the research present a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.

To facilitate the public review and comment process, FDA has established a public docket and placed in that docket the following information relating to the proposed clinical investigation, including: Correspondence from NIH referring the proposed research protocol to HHS for consideration under 45 CFR 46.407; correspondence from FDA to NIH regarding the proposed protocol; the NIMH research protocol; the IRB deliberations on the proposed research; the parental permission documents; and the assent documents. Electronic copies of these documents can be viewed at the Pediatric Advisory Committee (PAC) Docket site at http://www.fda.gov/ohrms/dockets/ac/acmenu.htm . (Click on the year 2004 and scroll down to PAC meetings.) These materials are also available on OHRP's website at: http://hhs.gov/ohrp/children/ .

All written comments concerning this proposed research should be submitted to FDA's Division of Dockets Management under 21 CFR 10.20, no later than 4:30 p.m. on August 20, 2004. The background materials and received comments may be viewed on the FDA Web site at: http://www.fda.gov/ohrms/dockets/dockets/04n0337/04n0337.htm or may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m. Monday through Friday. The background materials may also be viewed on OHRP's website at: http://hhs.gov/ohrp/children/ .