1. FDA Drug Advisory Committee Pediatric Ethics Subcommittee Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty CHARGE TO COMMITTEE Norman Fost MD MPH, Chair, PES Gaithersburg, Maryland, November 15, 2005

2. Purpose of the study Purpose: “To establish the diagnostic effectiveness of a (leuprolide) test and the norms for it. This will improve the differential diagnosis of the most common disorders of puberty so that we may provide more accurate and earlier treatment for these disorders.” Purpose: “To establish the diagnostic effectiveness of a (leuprolide) test and the norms for it. This will improve the differential diagnosis of the most common disorders of puberty so that we may provide more accurate and earlier treatment for these disorders.”

3. Use of normal healthy controls §46.404 Research not involving greater than minimal risk §46.404 Research not involving greater than minimal risk –IRB determined the risk was greater than minimal §46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. §46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. –IRB: No direct benefit §46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition. §46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition. –Normal children do not have a “condition” §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.

4. Use of normal healthy controls §46.404 Research not involving greater than minimal risk §46.404 Research not involving greater than minimal risk –IRB determined the risk was greater than minimal §46.405 405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. §46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition. – –Normal children do not have a “condition” – –Therefore, can not be approved under Section 406 §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.

5. Options for the committee Can the use of normals be approved under Section 404? Can the use of normals be approved under Section 404? –§46.404 Research not involving greater than minimal risk. –DHHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in §46.408. §46.408

6. Minimal risk Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

7. Issues in determining minimal risk “Routine physical or psychological tests” interpreted variably by IRBs “Routine physical or psychological tests” interpreted variably by IRBs –Routine health supervision visit –Routine visit to a specialist Survey of IRB chairs Survey of IRB chairs

9. Section 407 (a) 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 (a) 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 (b) the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either: (b) the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either: (1) that the research in fact satisfies the conditions of §46.404, §46.405, or §46.406, as applicable, or (2) the following: (1) that the research in fact satisfies the conditions of §46.404, §46.405, or §46.406, as applicable, or (2) the following:§46.404§46.405 §46.406§46.404§46.405 §46.406 (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (i) the research 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 will be conducted in accordance with sound ethical principles; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §46.408. (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §46.408.§46.408

10. Recommend approval under 407.. 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.. 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 –Abnormal pubertal development is a serious problem –Is the availablity of a reliable diagnostic test a serious problem?

11. Vote: Issue #1 Does the proposal to study the response of normal children involve minimal risk? Does the proposal to study the response of normal children involve minimal risk? –Medical risks  Leuprolide  Procedures  Blood volume –Psychological risks of hospitalization and procedures

12. Vote: Issue #2 Is the need for improved diagnostic tests for diagnosis of problems of puberty a serious problem affecting the health of children? Is the need for improved diagnostic tests for diagnosis of problems of puberty a serious problem affecting the health of children?

13. Vote: Issue #3 Is the research designed in a way that “presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.” Is the research designed in a way that “presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.”