1. FDA Drug Advisory Committee Pediatric Ethics Subcommittee Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty SUMMARY OF PUBLIC COMMENTS Gaithersburg, Maryland November 15, 2005

2. Melissa Harry Pt, rxd 9 mos w leuoprolide Pt, rxd 9 mos w leuoprolide “serious side effects” “serious side effects” “Enough research has been published to warrant discretion in the use of GnRH on vulnerable populations such as children.” “Enough research has been published to warrant discretion in the use of GnRH on vulnerable populations such as children.” References References

3. Lynne Millican RN Comment on “proposed research to use a challenge dose of leuprolide acetate (Lupron)…” Comment on “proposed research to use a challenge dose of leuprolide acetate (Lupron)…” Subjects should be informed it is listed as “hazardous drug” according to NIH, OSHA, MSDS” Subjects should be informed it is listed as “hazardous drug” according to NIH, OSHA, MSDS” –2 pairs of gloves and a chemotherapy gown –serious side effects: “memory loss, seizures, brain lesions, cardiac and gastrointestinal abnormalities, bone and joint abnormalities, immune dysfunction and death - to name a few.” “Lupron victims” network; thousands of victims; silenced “Lupron victims” network; thousands of victims; silenced Fabrication and falsification of in 4 studies (Federal Register) Fabrication and falsification of in 4 studies (Federal Register) Congressional testimony Congressional testimony “numerous Lupron adverse event product liability lawsuits that TAP has settled, all via secrecy agreements” “numerous Lupron adverse event product liability lawsuits that TAP has settled, all via secrecy agreements” 1999, 6,000 adverse events reported to FDA 1999, 6,000 adverse events reported to FDA

4. Lynne Millican RN “PI falsely claims that side effects are due to chronic leuprolide use in adults. I have seen internet messages … children underwent leuprolide challenge test and suffered ill effects afterwards.” “PI falsely claims that side effects are due to chronic leuprolide use in adults. I have seen internet messages … children underwent leuprolide challenge test and suffered ill effects afterwards.” “PI falsely claims … only Lupron depot has been responsible for adverse reactions.” “PI falsely claims … only Lupron depot has been responsible for adverse reactions.” Meaningful consent should involve Meaningful consent should involve –Hazardous drug –Whether NIH/OSHA standards will be used (double gloves, gowns) –Handout of all reported adverse effects –Informing there are Lupron victims –Agree to pay all costs associated with leuprolide adverse effects

5. Susan Hayward –Consumer of Lupron –High incidence of precocious puberty and endometriosis: answer lies in the food supply. More prevention research is needed –National Lupron Victims Network “taken down mysteriously” after 1 million hits –“I believe Taketa and Abbott Labs formed TAP as a hedge for future lawsuits, thereby protecting the parent companies” –Criticisms of TAP –Concern about patients with anti-thyroid antibodies receiving leuprolide –“Mood swings, suicidal ideation and attempt” following Lupron depot. –9 exhibits: references, package inserts, parents’ guide to precocious puberty

6. Andrea Dunaif MD President, The Endocrine Society President, The Endocrine Society “Supports the participation of normal children as control subjects in clinical research under clearly defined circumstances.” (not defined) “Supports the participation of normal children as control subjects in clinical research under clearly defined circumstances.” (not defined) “The regulations stipulating 407 review may substantially constrain the enrollment of normal children as control subjects in clinical research.” “The regulations stipulating 407 review may substantially constrain the enrollment of normal children as control subjects in clinical research.” “Increasingly narrow interpretation of acceptable risk is of particular concern…. The Society does not support the concept that any pharmaceutical, even if approved for children and routinely used in diagnostic testing, should be a consider a minor increase over minimal risk, and hence, by its use in healthy children, mandates a review by a 407 panel.” “Increasingly narrow interpretation of acceptable risk is of particular concern…. The Society does not support the concept that any pharmaceutical, even if approved for children and routinely used in diagnostic testing, should be a consider a minor increase over minimal risk, and hence, by its use in healthy children, mandates a review by a 407 panel.” Calls for “the rational use of the 407 process” and greater guidance to IRBs for determining “minor increase over minimal,” Calls for “the rational use of the 407 process” and greater guidance to IRBs for determining “minor increase over minimal,”

7. Joe Sanfilippo MD, Robert W Rebar MD American Society for Reproductive Medicine American Society for Reproductive Medicine “Not familiar with the specific protocol” “Not familiar with the specific protocol” “Feel strongly that it can be important to obtain data from healthy children in order to improve our evaluation and treatment of young patients with hormonal problems. Without data from a normal population, it may be difficult if not impossible to ascertain the safety and efficacy of some medications and treatments.” “Feel strongly that it can be important to obtain data from healthy children in order to improve our evaluation and treatment of young patients with hormonal problems. Without data from a normal population, it may be difficult if not impossible to ascertain the safety and efficacy of some medications and treatments.”

8. Alan D Rogol MD PhD Lawson Wilkins Pediatric Endocrine Society Lawson Wilkins Pediatric Endocrine Society IRB classified the study as minor increase over minimal due to the length of hospitalization, and the use of leuprolide, which represent more medical attention than a healthy child would ‘ordinarily encounter in daily life or during the performance of routine physical or psychological tests.’” IRB classified the study as minor increase over minimal due to the length of hospitalization, and the use of leuprolide, which represent more medical attention than a healthy child would ‘ordinarily encounter in daily life or during the performance of routine physical or psychological tests.’” “LWPES does not review clinical research protocols and thus does not and cannot issue statements regarding the risk-benefit ratio of a specific project. However…. Leuprolide used in routine testing of children … highly useful test for which normative data are sparse and a necessary prerequisite for the precise diagnosis of pubertal disorders in children.” “LWPES does not review clinical research protocols and thus does not and cannot issue statements regarding the risk-benefit ratio of a specific project. However…. Leuprolide used in routine testing of children … highly useful test for which normative data are sparse and a necessary prerequisite for the precise diagnosis of pubertal disorders in children.” “The 407 process may suffer from uninformed or biased lay comments. “The 407 process may suffer from uninformed or biased lay comments.

9. Alan Rogol MD PhD “There is tremendous variation in the interpretation of minimal risk by different IRBs” (Threfore) LWPES strongly supports two panel members who are pediatric endocrinologists to represent the scientific and clinical viewpoints of their colleagues and the Society.” “There is tremendous variation in the interpretation of minimal risk by different IRBs” (Threfore) LWPES strongly supports two panel members who are pediatric endocrinologists to represent the scientific and clinical viewpoints of their colleagues and the Society.” “The Society does not support the concept that any pharmaceutical, even if approved for children and routinely used in diagnostic testing, should be a consider a minor increase over minimal risk, and hence, by its use in healthy children, mandates a review by a 407 panel.” “The Society does not support the concept that any pharmaceutical, even if approved for children and routinely used in diagnostic testing, should be a consider a minor increase over minimal risk, and hence, by its use in healthy children, mandates a review by a 407 panel.” “Supports the participation of normal children as control subjects in clinical research under clearly defined circumstances.” (not defined). “Supports the participation of normal children as control subjects in clinical research under clearly defined circumstances.” (not defined).

10. Judith O’Fallon PhD Member, Pediatric Advisory Committee Member, Pediatric Advisory Committee Questions “whether this study is large enough to provide scientific information of practical value to the medical community in dealing with these disorders.” Questions “whether this study is large enough to provide scientific information of practical value to the medical community in dealing with these disorders.” CRC Advisory Committee “… strong consideration should be given to inclusion of other centers and to expanding the sample size to augment the statistical power.” CRC Advisory Committee “… strong consideration should be given to inclusion of other centers and to expanding the sample size to augment the statistical power.” There are comments to suggest that it may not be feasible to accrue even the smaller number of patients. If this study is.. terminated short of its accrual goals, the effort of participating children … will likely be for naught. This is a substantial ethical issues to me.” There are comments to suggest that it may not be feasible to accrue even the smaller number of patients. If this study is.. terminated short of its accrual goals, the effort of participating children … will likely be for naught. This is a substantial ethical issues to me.” CRC Protocol Review: “The two previous protocols … date back to 1994 and 1998 yet only 29 of the 240 subjects required have been evaluated to date. Is this a feasible study?” CRC Protocol Review: “The two previous protocols … date back to 1994 and 1998 yet only 29 of the 240 subjects required have been evaluated to date. Is this a feasible study?”