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Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty PRESENTATION TO FDA PEDIATRIC ADVISORY COMMITTEE

Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty PRESENTATION TO FDA PEDIATRIC ADVISORY COMMITTEE Norman Fost MD MPH, Chair, Pediatric Ethics Subcommittee Gaithersburg, Maryland, November 16, 2005. Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty

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Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty PRESENTATION TO FDA PEDIATRIC ADVISORY COMMITTEE

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  1. Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty PRESENTATION TO FDA PEDIATRIC ADVISORY COMMITTEE Norman Fost MD MPH, Chair, Pediatric Ethics Subcommittee Gaithersburg, Maryland, November 16, 2005

  2. Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty Principal Investigator: Dr Robert Rosenfield IRB: University of Chicago, Biological Sciences Division, School of Medicine

  3. 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.”

  4. The problem • Evaluation of children with disorders of pubertal development (precocious puberty, delayed onset of puberty) • Gold standard test (sleep study) expensive, not covered by insurance • Changing availability of gonadotropin releasing hormones • Normal values unavailable for current product (leuprolide, aka Lupron)

  5. Elements of the study • Healthy children controls, 7-18 yo • 2 day, 1 night admission to GCRC • Subcutaneous leuprolide 10 mcg/kg (gonadotropin releasing hormone) • FDA approved for treatment of pubertal disorders in children • Not approved as diagnostic agent • $150 to normals; no payment to patients

  6. Procedures • 36 hr admission • Leuprolide subcut injection • Physical Exam • Indwelling venous catheter (5-8 oz blood) • Bone age xrays • DNA banking • Discharge on oral iron

  7. Public Comments • 4 patients • Serious adverse effects (long term and short term use) • Hazardous chemical • Charges of misconduct against TAP • Secret settlement of lawsuits • Disappearance of popular website of Lupron victims • Inadequate consent about serious AE’s • Parent of child with cancer, in trial of GnRH • Drug safe/effective; trial low risk; need for better tests of precocious puberty

  8. Public Comments • Professional societies • The Endocrine Society • Lawson Wilkins Pediatric Endocrine Society • American Society for Reproductive Medicine • Importance of normal controls in pediatric research • Concerns about 407 process; variation in definition of minimal risk • No comment on this protocol

  9. Use of normal healthy controls • §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. • 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. • 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.

  10. University of Chicago IRB • Nov 2004 – Jan 2005 • Approved patients (§ 405: Minor increment over minimal risk with prospect of direct benefit) • Normal controls (§ 407: Need approval from Secretary of DHHS)

  11. Options for the committee • 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.

  12. 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.

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

  14. Issue #1 • Does the proposal to study the response of normal children involve more than minimal risk? • Medical risks • Leuprolide * • Procedures * • Blood volume (3 cc/kg) • Psychological risks of hospitalization and procedures * • Not approvable under §405 (minimal risk)

  15. Issue #2 • Is the need for improved diagnostic tests for diagnosis of problems of puberty a serious problem affecting the health of children? • Problems of puberty (yes) • Need for improved tests: Yes • Requires normal controls (7) • Can be obtained from patients who are found to be normal (2)

  16. 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.” • GCRC: Prior studies had low accrual (29/240) • PI: • Accrual of patients satisfactory to date • Normal controls (?)

  17. Issue 4 • Is it acceptable to give payment to the normal children and not to the patients? • Is the amount of payment: • Compensation for costs • Honorarium • Inducement • If an inducement, is an “undue inducement? • Consensus: Honorarium/inducement, not undue

  18. Modifications • No disclosure of results to normals • Opportunity for children to have samples destroyed • Consent form changes • Strengthen non-beneficial nature • Remove suggestions of benefit • Add notice of adverse effects of long term use

  19. Section 407 • (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; • (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. • Suggestion for assent monitoring

  20. Votes • Do you recommend • that the Secretary approve the study as written • Under 404 (minimal risk) • NO (unanimous) • Under 407 • NO • Approve with modifications • Yes (7-2) • Not approve

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