> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH (CDER)
>
> **ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE**
>
> **MEETING**
>
> Tuesday, June 10, 2003
>
> 8:30 a.m.
>
> Holiday Inn Select
>
> 8120 Wisconsin Avenue
>
> Bethesda, Maryland 20814
>
> PARTICIPANTS
>
> Glenn Braunstein, M.D., Chairman
>
> Dornette Spell-LaSane, A.N.P, M.H.A., Executive Secretary
>
> MEMBERS
>
> Marie C. Gelato, M.D., Ph.D.
>
> Deborah Grady, M.D., M.P.H.
>
> William V. Tamborlane, M.D.
>
> Dean Follman, Ph.D.
>
> Paul Woolf, M.D.
>
> Nelson Watts. M.D.
>
> David S. Schade, M.D.
>
> CONSUMER REPRESENTATIVE
>
> Nancy Worcester, Ph.D.
>
> NON-VOTING INDUSTRY REPRESENTATIVE
>
> George Goldstein, M.D., F.A.A.P.
>
> SPECIAL GOVERNMENT EMPLOYEE CONSULTANT (VOTING)
>
> Jose Cara, M.D.
>
> GUEST SPEAKER (NON-VOTING)
>
> Harvey John Guyda, B.Sc. (Med), M.D., FRCPC
>
> FDA REPRESENTATIVES
>
> David Orloff, M.D.
>
> Dragos Roman, M.D.
>
> Robert Meyer, M.D.
>
> [C O N T E N T S]{.underline}
>
> [Page]{.underline}
>
> Call to Order and Introduction
>
> Glenn Braunstein, M.D., Chair 5
>
> Conflict of Interest Statement
>
> Dornette Spell-LeSane 6
>
> Welcome and Introductory Comments
>
> David Orloff, M.D. 9
>
> **sNDA 19-640/S-033, Humatrope® (somatropin \[rDNA origin\] for
> injection) Eli Lilly and Company**
>
> Proposed for the indication of non-growth hormone
>
> deficient short stature
>
> **Sponsor Presentation**
>
> Introduction
>
> Gregory Enas, Ph.D.
>
> Director, U.S. Regulatory Affairs 15
>
> Eli Lilly and Company
>
> Rationale for Treatment
>
> Raymond Hintz, M.D.
>
> Professor of Pediatrics
>
> Stanford University Medical Center 20
>
> Efficacy
>
> Gordon Cutler, M.D.
>
> Director, Growth and Recovery Research
>
> and Clinical Investigation
>
> Eli Lilly and Company 30
>
> Safety
>
> Charmian Quigley, M.B.B.S.
>
> Senior Clinical Research Physician
>
> Endocrinology
>
> Eli Lilly and Company 54
>
> Benefit-Risk Assessment and Risk
>
> Management Plan
>
> Charmian Quiqley, M.B.B.S. 69
>
> Concluding Statements
>
> Margaret MacGillivray, M.D.
>
> Professor of Pediatrics
>
> University of Buffalo
>
> Pediatric Endocrinologist
>
> School of Medicine & Biomedical
>
> Sciences
>
> Children\'s Hospital Buffalo 91
>
> [C]{.underline} [O]{.underline} [N]{.underline} [T]{.underline}
> [E]{.underline} [N]{.underline} [T]{.underline} [S]{.underline}
>
> Committee Discussion 98
>
> Presentation
>
> Harvey John Guyda, B. Sc. (Med), M.D.
>
> FRCPC
>
> Professor, Department of Pediatrics
>
> McGill University 149
>
> Committee Discussion 164
>
> Open Public Hearing 183
>
> Committee Discussion 211
>
> Charge to the Committee
>
> David Orloff, M.D. 246
>
> Committee Discussion/Questions 254
>
> Summary 322
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Introductions**
>
> DR. BRAUNSTEIN: Good morning. I\'d like to call the meeting to order.
> I\'m Glenn Braunstein. This is the Endocrinolgic and Metabolic Drugs
> Advisory Committee Meeting.
>
> We\'ll start by having introductions of the individuals around the
> table. We\'ll start with Dr. Meyer.
>
> DR. MEYER: I\'m Dr. Robert Meyer. I\'m the Director of the Office of
> Drug Evaluation II in CEDR.
>
> DR. ORLOFF: I\'m David Orloff, Director of the Division of Metabolic
> and Endocrine Drug Products in CEDR.
>
> DR. ROMAN: I\'m Dragos Roman, Medical Officer, Division of Metabolic
> and Endocrine Drug Products.
>
> DR. FOLLMAN: I\'m Dean Follman, Assistant Institute Director for
> Biostatistics at NIAID.
>
> MS. SPELL-LASANE: Dornette Spell-LeSane, Executive Secretary for the
> Committee.
>
> DR. BRAUNSTEIN: I\'m Glenn Braunstein, Chairman of Medicine,
> Cedars-Sinai Medical Center.
>
> DR. CARA: I\'m Jose Cara, Division Head of Pediatric Endocrinology and
> Diabetes at Children\'s Hospital of Michigan, Wayne State University
> in Detroit.
>
> DR. TAMBORLANE: I\'m Bill Tamborlane. I\'m Chief of Pediatric
> Endocrinology at Yale.
>
> DR. SCHADE: I\'m David Schade. I\'m Chief of Endocrinology at the
> University of New Mexico School of Medicine.
>
> DR. WOOLF: I\'m Paul Woolf, Chairman of Medicine, Crozer Chester
> Medical Center.
>
> DR. GELATO: Marie Gelato, Professor of Medicine, SUNY Stonybrook.
>
> DR. WATTS: Nelson Watts, an endocrinologist at the University of
> Cincinnati.
>
> DR. WORCESTER: Nancy Worcester, professor, University of Wisconsin
> Madison\--the consumer rep on this panel.
>
> DR. GOLDSTEIN: I\'m George Goldstein, Vice President, Regulatory
> Affairs, Mankind Corporation\--
>
> DR. BRAUNSTEIN: Thank you.
>
> DR. GOLDSTEIN: \--industry representative.
>
> DR. BRAUNSTEIN: Thank you.
>
> Ms. Spell-LeSane will then read the conflict of interest statement.
>
> **Conflict of Interest Statement**
>
> MS. SPELL-LeSANE: The following announcement addresses the issue of
> conflict of interest with regard to this meeting, and is made a part
> of the record to preclude even the appearance of such at this meeting.
>
> Based on the submitted agenda for the meeting and all financial
> interests reported by the committee participants, it has been
> determined that all interests in firms regulated by the Center for
> Drug Evaluation and Research which have been reported by the
> participants present no potential for an appearance of a conflict of
> interest with this meeting, with the following exception.
>
> Dr. Glenn Braunstein has been granted a waiver, under 21 U.S.C.
> 355(n)(4), an amendment of Section 505 of the Food and Drug
> Administration Modernization Act, for ownership of stock in a
> competitor valued between \$5,001 to \$25,000. Because this stock
> interest falls below the de minimis exemption allowed under 5 C.F.R.
> 2640.202(a)(2), a waiver under 18 U.S.C. 208 is not required.
>
> Dr. William Tamborlane has been granted a waiver under 18 U.S.C.
> 208(b)(3) for his membership on an unrelated advisory board for a
> competing firm. He receives less than \$10,000 a year.
>
> Dr. Paul Woolf has been granted waivers under 18 U.S.C. 208(b)(3) and
> under 21 U.S.C. 355(n)(4), an amendment of Section 505 of the Food and
> Drug Administration Modernization Act for ownership of stock in a
> competing firm, valued between \$25,001 and \$50,000.
>
> A copy of these waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A30 of the Parklawn Building.
>
> With respect to FDA\'s invited guest speaker, there are reported
> interests which we believe should be made public to allow the
> participants to objectively evaluate his comments.
>
> Dr. Harvey Guyda owns stock in Pfizer, and has attended scientific
> meetings sponsored by Serono, Pharmacia and Novo Nordisk in the past.
> He has also attended a scientific program sponsored by Genentech, at
> one time registered a few patients in their post-marketing
> surveillance program, and was a paid consultant on one occasion when
> he attended a meeting.
>
> In addition, we would like to disclose that Dr. George Goldstein is
> participating in this meeting as an acting industry representing,
> acting on behalf of regulated industry. In the event that the
> discussions involve any other products or firms not already on the
> agenda, for which an FDA participant has a financial interest, the
> participants are aware of the need to exclude themselves from such
> involvement, and their exclusion will be noted for the record.
>
> With respect to all other participants,
>
> we ask in the interest of fairness that they address any current or
> previous financial involvement with any firm whose product they may
> wish to comment upon.
>
> Thank you.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. David Orloff will give the Welcome and Introductory Comments.
>
> **Welcome and Introductory Comments**
>
> DR. ORLOFF: Thank you.
>
> I want to start by thanking in advance the members of the committee,
> consultants and guests, for their participation in this meeting.
>
> FDA advisory committees serve critical functions in FDA\'s regulatory
> decision-making process, and we very much appreciate the time and
> effort of all who have agreed to participate, with the full
> realization of the value of your time and the significance, therefore,
> of this sacrifice.
>
> Let me also note that there are two members of today\'s committee for
> whom this meeting marks the end of their term on our official roster.
> They are Drs. Marie Gelato and Dr. William Tamborlane. \|I would like
> to thank them formally for their valuable contributions over the past
> three years, and to say that I hope and expect that we will be calling
> on them as consultants and/or guests in future meetings.
>
> Finally, I wish to welcome back Dr. Glenn Braunstein to the committee
> and to the chair position he has generously and skillfully filled in
> the past.
>
> Now, to the subject of today\'s meeting. This meeting is taking place
> a little less than 16 years after an earlier FDA advisory committee
> was convened to discuss the methodological approaches to and endpoints
> of the safety and efficacy of growth hormone in pediatric patients
> with idiopathic short stature. The committee at that time readily
> agreed on the need for final heights in the context of a blinded,
> randomized placebo-controlled trial in order to determine if, and to
> what degree, non-syndromic children\--short but not meeting criteria
> for growth hormone deficiency would achieve final heights in excess of
> those predicted at baseline.
>
> Leading up to that 1987 advisory committee meeting, the 1983 National
> Institutes of Child Health and Human Development Conference on uses
> and possible abuses of human growth hormone, looking toward the
> imminent approval of recombinant human growth hormone and resultant
> unlimited availability of the drug, concluded that there was \"an
> urgent need for therapeutic trials to determine the effect of human
> growth hormone in short children who do not have growth hormone
> deficiency.\"
>
> Indeed, over the 20 years since that time, there seems to have been
> general agreement in the field on the need for data on clinical safety
> and efficacy in what\'s called \"non-growth hormone deficiency short
> stature\" in order to inform final judgment on the wisdom of use of
> growth hormone in these children. More recently, in a 1997 Guidelines
> document on the use of recombinant growth hormone in children from the
> American Academy of Pediatrics, the product of a panel of
> pediatricians, investigators, psychologists, psychiatrists and
> ethicists\--among others\--caution was advised, in light of the lack
> of data addressing this use of growth hormone.
>
> The central question of today\'s meeting is, now that we have the data
> that will be presented, are they adequate to support the safety and
> efficacy and to guide the safe and effective use of human growth
> hormone in children with non-growth hormone deficient short stature.
>
> We\'ve asked Lilly to present the results of their pivotal study, as
> well as the supportive data that address the safety and efficacy to
> growth hormone for this new indication. In our discussions with the
> company leading up to the meeting, we requested that at a minimum they
> focus their presentation on several areas that we believe require
> discussion. They are as follows.
>
> Obviously\--what is the effect on linear growth of growth hormone
> administration in children with severe idiopathic short stature. What
> is the safety profile of growth hormone in these patients?
> Specifically, is it different than the safety profile in other
> pediatric populations?
>
> Is there a need for growth-enhancing therapy in such children? Will
> the endorsement of the use of growth hormone in non-syndromic children
> not meeting criteria for GHD mean that growth hormone deficiency and
> idiopathic short stature will be lumped together into a category
> defined by diagnostic exclusion, such that growth hormone deficiency
> itself will no longer be formally diagnosed; or, worse yet, perhaps
> lead to overall less thorough evaluation of children with extreme
> short stature?
>
> And, finally, to the extent that approval for the treatment of
> non-growth hormone deficient short stature may be construed as
> treatment of normal or of short normal children, what are the risks of
> off-label use to enhance the height of children who are simply shorter
> than they or their parents might want them to be?
>
> Lilly has produced a briefing document that addresses these issues and
> questions, as well as others. They have presented the data from their
> pivotal placebo-controlled trial of growth hormone in non-GHD short
> stature, with final height as the primary efficacy parameter. They\'ve
> also presented the results of a supportive, open-label dose response
> study in somewhat younger children. And, finally, they have summarized
> the data from a published meta-analysis of trials of growth hormone in
> idiopathic short stature.
>
> Note also that the sponsor has proposed and outlined a risk-management
> program to obviate inappropriate or injudicious use of growth hormone
> in children with short stature.
>
> This advisory committee meeting will take a format that is a departure
> from what has been the usual in deliberations on pending drug
> applications by the Division of Metabolic and Endocrine Drug Products;
> that is, in the absence of disagreements over the facts of the
> case\--in other words, the results of the analyses of the data from
> the trials\--FDA will make no formal presentations. We\'ve asked Lilly
> to present their data and to address the concerns raised in earlier
> discussions, as I\'ve noted. The Division will do its utmost to
> respond to any questions from the Chair or from the Committee, as they
> may arise.
>
> Finally, the Division has also asked Dr. Harvey Guyda of the
> Department of Pediatrics at McGill in Montreal, and an important
> researcher and voice in the growth hormone academic community, to
> participate in the discussion, and to present his views on the matter
> before the Committee and the Agency.
>
> The Division, in discussion with the company, has formulated a series
> of questions in order to frame the discussion after the presentations.
> Some of the questions will require specific expertise that not all of
> the committee possess\--we realize that. And I\'ll review the
> questions in more detail when I make my formal charge to the
> committee.
>
> And I turn it back to Dr. Braunstein.
>
> DR. BRAUNSTEIN: Thank you, Dr. Orloff.
>
> We\'ll now move into the presentation by Lilly. And I think that
> probably, as far as the format\'s concerned, we\'ll ask the committee
> to hold all questions until after the full presentation has been made.
> We invite you to write down the questions, and then we\'ll have plenty
> of time to ask them.
>
> I believe Dr. Gregory Enas is going to make the initial presentation.
>
> **Sponsor Presentation**
>
> **Introduction**
>
> DR. ENAS: Thank you, Chairman Braunstein\--and good morning. Thank
> you, Dr. Meyer and Dr. Orloff, members and guests of the Advisory
> Committee and the FDA. Thank you for this opportunity to present this
> data that Dr. Orloff has briefly overviewed for you in the treatment
> of pediatric patients who have non-growth hormone deficient short
> stature.
>
> My name is Greg Enas, and I\'m the Director of U.S. Regulatory Affairs
> for Endocrine Research and Development with Eli Lilly and Company. We
> have the opportunity today to provide information about this
> supplemental indication for this marketed product in children now with
> non-growth hormone deficient short stature.
>
> Humatrope has previously been approved by the agency for children who
> are growth hormone deficient, as well as for girls with Turner\'s
> syndrome who have short stature without having growth hormone
> deficiency.
>
> As you can see, the approved dose has been increased to 0.30 mg per kg
> per week, while in Turner\'s syndrome a weekly dose of 0.375 mg per kg
> per week has been approved. Greater efficacy has been observed with
> these higher doses.
>
> Similarly, other recombinant human growth hormones have been approved
> to treat short stature in various patient populations, with doses
> ranging from 0.16 to 0.70 mg per kg per week.
>
> This morning, we will use the trade name Humatrope when we discuss the
> Lilly recombinant human growth hormone, and we will use and refer to
> either \"somatropin\" or \"growth hormone\" when we refer to all
> recombinant human growth hormone approved in the United States.
>
> Note that none of the previous new drug applications leading to
> approval for somatropin in the U.S. have included randomized
> double-blind placebo controlled final height data, and this morning we
> have the opportunity to discuss such data with you.
>
> Our clinical development program in children with non-growth hormone
> deficient short stature commenced following this plea from the
> National Institute of Child Health and Human Development International
> Conference on the Uses and Abuses of Growth Hormone. They stated that
> there was an urgent need for therapeutic trials to determine the
> effect of growth hormone in short children who were not growth hormone
> deficient. Four years later, guidance was received from the
> Endocrinologic and Metabolic Drugs Advisory Committee asking that a
> study in this patient population, for which there is no approved
> treatment, should be a randomized placebo-controlled study, whereby
> patients should be treated and followed until their ultimate final
> height was achieved. And subsequent to that recommendation, Eli Lilly
> and Company and NICHD co-sponsored what we believe to be the first and
> only placebo-controlled study to final height, in this or any other
> growth disorder.
>
> Though a number of patient populations with short stature are now
> indicated for treatment with growth hormone here in the U.S., we are
> aware that this potential new indication may raise a number of issues
> and questions. To ensure that these potential issues are addressed,
> the following questions will be answered in the presentations that
> follow.
>
> First, how will potential risks be managed and safety be monitored?
>
> Second, will this indication obviate the need for diagnostic
> evaluation in children with growth disorders?
>
> Third, will this indication open the floodgates for inappropriate use?
>
> Fourth, are there ethical issues regarding growth hormone treatment of
> non-growth hormone deficient short stature?
>
> And, fifth, is it appropriate to treat patients whose short stature is
> not clearly associated with a defined disease?
>
> Sixth, should psychological or quality of life benefits be required
> outcomes of treatment with growth hormone?
>
> And, finally, what is the clinical relevance of the efficacy?
>
> To address these questions and provide a complete perspective on this
> new indication, we have invited a number of external consultants to
> participate in this meeting. In particular, Drs. Raymond Hintz and
> Margaret MacGillivray will make presentations from the podium. Drs.
> Judith Ross, Melvin Grumbach, Gary Koch and Ron Rosenfeld are also
> here with us and are available to address any questions the committee
> might have.
>
> Our presentation will begin with Dr. Hintz, and he will provide the
> rationale for treatment in this patient population. Following Dr.
> Hintz, Drs. Cutler and Quigley will provide the evidence for the
> efficacy and safety of this treatment, as well as an overview of the
> risk-management program being proposed, and an overall assessment of
> the benefit-risk profile.
>
> Dr. Cutler is the Medical Director for the Humatrope product team at
> Eli Lilly, and Dr. Quigley is a Senior Clinical Research Physician in
> the Endocrine Division of Lilly U.S.A. Dr. Margaret MacGillivray,
> Professor of Pediatrics at the University of Buffalo will provide
> concluding statements. Following her remarks, Drs. Cutler and Quigley
> will be here at the podium to facilitate responses to any questions
> that you may have this morning.
>
> With that, I now introduce Dr. Raymond Hintz, Professor of Pediatrics
> at Stanford University, who will discuss the rationale for Humatrope
> treatment. Dr. Hintz has nearly 30 years of clinical and research
> experience in the etiology, diagnosis and management of childhood
> growth disorders, and has authored over 200 publications in this area.
>
> Dr. Hintz.
>
> **Rationale for Treatment**
>
> DR. HINTZ: Thank you. Greg. Good morning, ladies and gentlemen. As
> Greg has told you, I\'m here today to discuss the rationale for growth
> hormone treatment in patients with non-growth hormone deficient short
> stature.
>
> First of all, some definitions, for those of you that are not
> pediatricians. \"Growth failure\" is a decline in the growth rate of
> linear growth. \"Short stature\" has been defined by both American
> Academy of Pediatrics and American Association of Clinical
> Endocrinologists, as well as the Growth Hormone Research Society and,
> for that matter, Lawson Wilkins Pediatric Endocrine Society, as height
> more than two standard deviations below the mean for age and sex.
>
> There are many endocrine and non-endocrine causes of growth failure
> and short stature. And the Growth Hormone Research Society, in a
> recent statement, recommended investigation of children with short
> stature whose height falls below the minus-two standard deviation
> score.
>
> Again, to orient you to what is short stature, this is a chart
> familiar to every pediatrician, and probably to every parent, in which
> on the y-axis is plotted the height, and on the x-axis is plotted age
> in years\--in this case, from 2 to 20 years of age. And there are
> lines indicated\--the 0 percentile which is, of course, the mean, and
> plus or minus two standard deviation marks.
>
> The plus-two standard deviation mark is the equivalent of 97.7th
> percentile, and the minus-two standard deviation is the equivalent of
> the 2.3 percentile. And this is the generally accepted definition of
> the normal range.
>
> In terms of adult height, this means that a male of 5\'3\" or a female
> of 4\'11\" is at the minus-two standard deviation mark.
>
> So why should one treat short stature? Children and adults with short
> stature, irrespective of cause, may well have disadvantages compared
> to their peers. On this slide is summarized some of the studies in the
> literature about the disadvantages of short stature during childhood
> and during adulthood.
>
> Second, growth hormone treatment, in many cases, improves growth and
> effectively corrects short stature. Indicated here is a history,
> again, of the approved uses of growth hormone in this country,
> starting with the approval of rDNA growth hormone in 1985. Since that
> time, chronic renal insufficiency, Turner\'s syndrome, Prader-Willi
> syndrome and small-for-gestational age infants who fail to catch up
> have all been approved, and it is important to note that all the
> pediatric indications approved after 1985 are for non-growth hormone
> deficient short stature conditions.
>
> And we\'re here today to propose to you that non-growth hormone
> deficient short stature also be approved for growth hormone treatment.
>
> So, just to emphasize: these patients are heterogeneous in their
> etiology, but on the other hand, so are growth hormone deficiency,
> Turner syndrome, and small-for-gestational-age infants. So the fact
> that they are heterogeneous in etiology is not unique to this group.
>
> In addition to heterogeneous in etiology, they\'re heterogeneous in
> phenotype\--but, again, so are growth hormone deficiency, Turner
> syndrome, and small-for-gestational-age infants.
>
> On this slide, courtesy of Dr. Judy Ross, is a pair of fraternal
> twins. Julian, we\'ll call him, is essentially at the mean height for
> his age, and his brother James, who\'s almost a head shorter, is at
> the minus-2.8 standard deviation score. And this is typical of what we
> see in this syndrome\--short stature equivalent to growth hormone
> deficiency and the other causes of growth hormone failure\--normal
> growth hormone tests; etiology is undefined in most cases; diagnosis
> has to be by excluding all the other important endocrine and
> non-endocrine diseases that can cause short stature. And, at the
> moment, these children are not eligible for growth hormone treatment.
>
> So the features of this syndrome are that they have growth failure
> during childhood and their height is below the minus-two standard
> deviation score. There\'s actually no distinguishing phenotypic
> features in these patients, and amongst the heterogeneous etiologies
> that we can identify\--familial and genetic abnormalities in the
> growth hormone IGF axis and abnormal growth plate response to growth
> hormone. And they do have a unimodal distribution of their height
> deficit.
>
> Shown on this slide is a cartoon showing the normal short stature
> population shown here in white, in which the mean height at the time
> of reaching adult life is 5\'9\" for males in our society, and 5\'4\"
> in females. But, as is true of almost every biological variability,
> there\'s variation around the mean, so that this shows that.
>
> The patients that we\'ve defined as non-growth hormone deficient short
> stature have a peak height close to minus-three standard deviations.
> And, in terms of their adult heights, they are seven to eight inches
> shorter than their peers who are within the normal range.
>
> So, let\'s review who is and is not eligible for growth hormone
> therapy under the present approval structure.
>
> Eligible are patients that have a peak growth hormone below a certain
> threshold\--frequently 7 or 10 on a series of testing, and these
> patients are classified as \"growth hormone deficient\" and eligible
> for treatment for growth hormone deficiency.
>
> Four non-growth hormone disorders have been approved so far: Turner\'s
> syndrome, chronic renal insufficiency, Prader-Willi syndrome, and
> small-for-gestational-age children\--irrespective of their growth
> hormone secretion status or, for that matter, degree of short stature.
>
> Those that are ineligible at this time are those who have a peak
> growth hormone response above a certain threshold, who are now terms
> \"non-growth hormone deficient,\" despite the fact that they are
> equivalent short stature to those with growth hormone deficiency and
> other non-growth hormone deficient conditions.
>
> So why should children with non-growth hormone deficient short stature
> be eligible for growth hormone? Well, first of all, as I\'ve already
> told you, growth failure in these patients is equivalent to that in
> other growth disorders. Shown on this slide is a compilation of data
> from the literature. On the left axis is a their height standard
> deviation score. The pale blue outlines the patients that are in the
> normal range. Zero, again, is the 50th percentile.
>
> And you can see that whether you have growth hormone deficiency,
> chronic renal insufficiency, Turner\'s syndrome, SGA, or non-growth
> hormone deficient short stature, all of these patients are close to
> the minus-three standard deviation score at the time that they are
> started on treatment. So they are indistinguishable.
>
> Second, untreated patients do not achieve their adult height
> prediction, and this is shown in a variety of studies in the
> literature. And Dr. Cutler will later present data from the controlled
> study of patients with non-growth hormone deficient short stature,
> showing that the control patients failed to reach their predicted
> adult height.
>
> Growth hormone treatment in other conditions actually treats the short
> stature or growth failure, not the disease. Shown on this slide, on
> the left panel, is a patient with Turner\'s syndrome. On the right is
> a patient with non-growth hormone deficient short stature. And you can
> see that the patient\--this happened to be Halloween time, so that\'s
> her goody back\--the patient with Turner\'s syndrome has a height
> that\'s about two years behind\--two to three years behind the height
> of her age-mates, so that she is at the minus-three standard deviation
> mark. And on the right there\'s a similar situation in the boy who\'s
> 11 years old.
>
> So the degree of short stature is similar and, in fact, the response
> to treatment is similar and clinically meaningful, as we will show
> you.
>
> We do not feel that an unknown or heterogeneous etiology of a
> condition should justify exclusion from treatment. Shown on this slide
> is a listing of some of the diseases that we\--conditions of unknown
> or heterogeneous etiology that certainly deserve and receive
> treatment. And if you scan down the list, I suspect that a majority of
> the audience has, or is now on treatment for some of these conditions;
> most commonly, perhaps, hypercholesteremia and hypertension.
>
> And then, finally, non-growth hormone deficient short stature is
> responsive growth hormone treatment. This has been shown by a long
> history of research. Between 1964 and \'71, early studies demonstrated
> an increase in growth rate in patients with non-growth hormone
> deficient short stature. And, as I look around the room, there are
> several people in the room that have published studies on this.
>
> In 1983, as Greg has already told you, the NICHD International
> Conference recommended studies of growth hormone deficiency treatment
> in non-growth hormone deficient conditions. And then also, in 1987,
> the FDA advisory committee meeting recommended placebo-controlled
> studies to final height. And between 1985 and 2000, more that 40
> studies were published on growth hormone treatment in non-growth
> hormone deficient short stature patients.
>
> Shown on this slide is a study that I was a lead author on, sponsored
> by Genentech, published in the [New England Journal]{.underline} in
> 1999. You can see that we had a total of 80 patients that reached
> adult height, and they were treated with .3 mg per kg per week of a
> recombinant growth hormone. At the beginning of treatment they were at
> nearly minus-three standard deviations for height on the average, and
> in the first year there was a placebo control in which they did\--I\'m
> sorry, not a placebo, but a non-treatment control group that, over
> that year of observation, did not have any significant increase in
> their stature.
>
> On the other hand, the patients that were treated with growth hormone
> at that dosage, within two years the average was within the normal
> range and continued treatment brought them up so that at the end of
> the study they\'d gained almost two standard deviations in their
> height.
>
> So, what we\'re here today to do is discuss the studies that Lilly has
> done in the non-growth hormone deficient short stature patients
> between 1988 and 2001. But before I turn the podium over for that
> discussion, let me just review the key reasons why children with
> non-growth hormone deficient short stature should be eligible for
> growth hormone treatment.
>
> First of all, growth failure in these patients with non-growth hormone
> deficient short stature is equivalent to that in other growth
> disorders. Second, growth hormone treatment in other conditions treats
> the short stature or growth failure, not the disease, and it is, in
> fact, unfair to not offer such treatment to children that have just as
> much of a problem. And then, finally, unknown or heterogeneous
> etiology does not justify exclusion for treatment.
>
> And I\'d now like to have Dr. Gordon Cutler, from Eli Lilly, come and
> present the data on the efficacy.
>
> **Efficacy**
>
> DR. CUTLER: Thank you, Dr. Braunstein, members and guests of the
> Advisory Committee, Dr. Orloff.
>
> During the efficacy portion of the presentation I will address four
> questions. First, is growth hormone treatment effective in children
> with non-GHD short stature? Second, is there a dose response for the
> dose of .37, compared to .24 mg per kg per week? Third, are there
> supportive published data? And, fourth, is the efficacy similar to
> that in Turner\'s Syndrome and other approved indications?
>
> Implicit in these questions is the goal of safe and effective
> treatment for children with non-GHD short stature who are just as
> short and just as deserving of treatment as children with other causes
> of growth failure. We seek your recommendation that Humatrope be
> approved for the treatment of these children based on the data that
> will be discussed today.
>
> The data in our submission come from three sources: the pivotal study,
> GDCH; the dose-response study E001; and a meta-analysis published by
> Finkelstein and colleagues in 2002.
>
> Let\'s begin with study GDCH. As recommended by the Endocrinologic and
> Metabolic Drugs Advisory Committee 16 years ago, the study GDCH was a
> double-blind, randomized, placebo-controlled trial to final height,
> with a planned enrolment of approximately 80 subjects, approximately
> 40 in each arm. The Humatrope dose chosen for the study was .22 mg per
> kg per week, given three times per week. When this study was designed,
> the approved dose was .18 for growth hormone deficiency. Today, with
> GH doses up to .7 approved for pubertal patients with GH deficiency,
> .22 is considered a low dose.
>
> In addition, daily or six times per week administration has been shown
> to be more effective than three times per week. And today growth
> hormone is usually given daily or six times per week.
>
> Treatment in the study continued until height velocity fell below 1.5
> centimeters per year, and the final height was then obtained one year
> later. Final height standard deviation score\--or SDS\--was the
> primary endpoint of the study, because final height was the endpoint
> recommended by the Endocrinologic and Metabolic Drugs Advisory
> Committee for registration trials in non-GHD short stature 16 years
> ago.
>
> The analysis populations for efficacy included all randomized
> population, the efficacy evaluable population, which had an on-study
> height measurement at or beyond six months of treatment; the final
> height population, which had a final height measurement, including
> eight patients who discontinued early and came back for a final height
> measurement after height velocity had fallen below 1.5 centimeters per
> year. And the final height population minus those eight patients\--the
> protocol complete population\--remained continuously on study until
> their final height measurement.
>
> The primary analysis was an ANCOVA\--or analysis of covariance\--of
> the final height standard deviation score, with baseline predicted
> height standard deviation score as the co-variate. For all of the
> ANCOVAs that I will discuss today, baseline predicted height standard
> deviation score was chosen as the covariate because it is a strong
> predictor of final height.
>
> In addition to the primary analysis, the protocol specified a number
> of sensitivity analyses which are listed here. Since all of these
> analyses are in the briefing document, this presentation will focus
> only on the most important results.
>
> The baseline characteristics of patients, randomized to the two
> treatment arms, were similar, and there were no statistically
> significant differences between groups. The mean age was 12-1/2; the
> mean height standard deviation score was minus 2.8, which is similar
> to the height of untreated patients with GH deficiency, or Turner\'s
> syndrome.
>
> The next slide will provide the primary analysis. The light blue
> shaded region represents the lower half of the normal height SDS range
> as defined by the American Academy of Pediatrics. Humatrope results
> are in green, placebo in pink. After treatment for a mean of 4.4
> years, the mean final height standard deviation score of the Humatrope
> group was within the normal range, at minus 1.8, and was significantly
> greater than that of the placebo group, which remained below normal at
> minus 2.3. By ANCOVA, the mean treatment effect corresponded to 3.7
> centimeters. Thus, the primary analysis indicated that Humatrope is
> effective in increasing the final height of children with non-GHD
> short stature. This is what we set out to learn 16 years ago.
>
> We next asked: did the fact that some patients were not available for
> final height measurements bias the primary analysis? To answer this,
> we examined efficacy in the broader efficacy evaluable population
> because if the primary analysis had been biased by the drop-out of
> poorly responding patients the efficacy in this broader population
> would be lower.
>
> This slide shows, in the left panel, the protocol-specified ANCOVA of
> \"last observed height standard deviation score.\" The mean treatment
> effect corresponded to 3.8 centimeters, nearly identical to that of
> the primary analysis. The right panel indicates a repeated measures
> analysis of height standard deviation score at age 18 years, which is
> a statistical approach complementary to the analysis of last observed
> height SDS. The mean treatment effect corresponded to 5.0 centimeters
> per year. Both of these analyses were highly statistically
> significant.
>
> These modified intent-to-treat analyses, by their close similarity to
> the primary analysis, provides strong evidence against drop-out bias
> in the primary analysis. As a further test of such bias, we performed
> intent-to-treat analyses for all 71 randomized patients as assigned.
> By both parametric and non-parametric approaches, the
> Humatrope-treated patients had significantly last-observed height SDS,
> and the magnitude of the effect from the parametric analyses was
> similar to that of the primary analysis.
>
> Thus, the close similarity of the estimates of treatment effect among
> the primary, modified intent-to-treat and intent-to-treat analyses
> argues against drop-out bias in the primary analysis, and provides
> clear evidence that Humatrope is effective in increasing the final
> height of patients with non-GHD short stature.
>
> I have not yet, however, addressed this question: given that
> intent-to-treat analyses are ordinarily preferred for clinical trials,
> why was the primary analysis restricted to the final height
> population? The answer relates to uncertainty about how the growth
> hormone treatment effect would evolve over time.
>
> There was concern that growth hormone might accelerate not just height
> velocity, but also bone maturation. This would cause a transient
> increase in height relative to control that would not be sustained
> because of earlier cessation of growth in the treated patients. Thus,
> the maximum treatment effect might occur during treatment, and the
> inclusion of non-final height data from this period might lead to an
> overestimate of the treatment effect. So it was to avoid any
> possibility of overestimating the treatment effect that the primary
> analysis was restricted to patients with final height measurements.
>
> Well, now that the results are available, let\'s examine whether or
> not growth hormone accelerated bone maturation, and whether or not the
> pattern of the treatment effect was a transient increase and decline.
>
> This slide shows bone age on the y-axis by year of study in the
> final-height population, the non-final-height sub-group of the
> efficacy evaluable population, and the full efficacy evaluable
> population. In each of the groups there were no significant
> differences between bone age in the placebo treated and the
> Humatrope-treated patients. Thus, for the growth hormone regimen used
> in this study, growth hormone did not accelerate bone maturation.
> Given this result, one would predict that the temporal pattern of the
> effect would not be an increase and then decline, and this is, in
> fact, what was observed, as shown on the next slide.
>
> This slide shows the increase in height standard deviation score over
> baseline for the patients in each group. And, for this analysis, the
> time at which final height or the last observed height was measured
> was set equal to zero in order to synchronize the observation around
> final or last observed height. The temporal pattern of the treatment
> effect was one of a gradual divergence of the two groups; a gradual
> increase over the initial years of the study, followed by
> stabilization, but not a decline in treatment effect, during the three
> years before final height measurement.
>
> For example, in the final-height population, the mean treatment effect
> ranged from .42 to .51 standard deviation score over the three years
> prior to final height measurement. A similar treatment effect of 0.55,
> rounded to .6 on this slide, was also seen in the non-final-height sub
> group. Apparently, the mean treatment duration of three years in this
> group was sufficient to reach the maximum effect.
>
> The combination of these two groups, which comprises the efficacy
> evaluable population also showed a quite stable treatment effect but
> not a decline over the three years prior to last observed height.
>
> The evidence on this slide, against a transient increase in the
> decline of the treatment effect removes the principal objection to the
> inclusion of non-final-height data in the efficacy analysis. Based on
> these data, for this regimen, the concern that such data would lead to
> an overestimate of the treatment effect is not justified.
>
> One additional point about this slide: the fact that the treatment
> effect stabilizes and sort of remains stable during continued
> treatment does not mean that it would remain stable if treatment were
> discontinued early. Early discontinuation has been shown in a number
> of studies to result in a rapid deceleration of height velocity, and
> for this reason growth hormone for all of the pediatric indications is
> normally continued until near adult height.
>
> The next slide simply shows mean height standard deviation score by
> year on study for the two treatment groups. And as in the study that
> Dr. Hintz showed, by about two years into treatment, the mean height
> SDS was at the lower limit of normal, which means that approximately
> half of these children had caught up to their peers and now had height
> SDS\'s within the normal range for age and gender.
>
> Let\'s now summarize the key results from this study. The primary
> analysis indicated a treatment effect corresponding to 3.7
> centimeters; the modified intent-to-treat corresponding to 3.8 to 5
> centimeters; and the full intent-to-treat analyses confirmed was
> significantly greater height standard deviation score of the
> Humatrope-treated patients.
>
> Now, given the 3.7 centimeters efficacy from this study\--height
> increase\--we wondered did the low dose of .22, and the low-dose
> frequency of three days per week result in a smaller height increase
> than would have been observed with a larger growth hormone dose given
> more frequently.
>
> Results from the E001 dose-response study will address this question.
> Study E001 was a three-arm randomized, dose-response study comparing a
> lower dose\--.24\--with a higher dose\--.37. There was also an
> intermediate dose with a lower dose for one year and the higher dose
> thereafter. The primary analysis was a comparison between the lower
> and the higher dose of the increase in height velocity over the first
> two years. There was then an extension to final height to examine the
> dose effect on final and last-observed height.
>
> Study E001 was a European multi-center study conducted in 10
> countries, and final height was defined as the last height measurement
> after height velocity fell below 2 centimeters per year. Since results
> of all three treatment arms are in the briefing document, in this
> presentation I will focus just on the comparison of the lower and the
> higher dose arms.
>
> The analysis populations for this study were the all-randomized
> population; the two-year height velocity population who completed two
> years of treatment; and the final-height population that had a
> final-height measurement. And because I will be focusing just on two
> arms, the relevant numbers of patients in the higher and lower-dose
> arms are shown in the brackets, with the middle dose omitted.
>
> The primary analysis\--on the next slide\--was an increase in height
> velocity measured from zero to two years between the higher and
> lower-dose arm. Secondary analyses included an ANCOVA of
> height-last-observed height SDS, and a repeated measures analysis of
> height SDS at age 18 years, as in the previous study.
>
> We also examined final height minus baseline predicted height as a
> measure of the overall efficacy within each dose group. And for this
> analysis the final height of each patient is compared with the height
> that they were predicted to achieve without treatment.
>
> The baseline characteristics of patients randomized to the higher and
> lower-dose arms were similar, although the patients randomized to the
> higher dose were slightly taller at baseline. Mean age was 9 to 10, or
> about two years younger than in the previous study.
>
> The next slide shows the primary analysis. After two years of
> treatment, mean height velocity for the lower-dose arm had increased
> to 7.5 centimeters per year; for the higher-dose arm, to 8.5
> centimeters per year. The between-dose effect\--or the incremental
> increase of the higher compared to the lower-dose was .8 centimeters
> per year, which was highly statistically significant. Thus the primary
> analysis indicated that the .37 dose is more effective than the .24
> dose in the increase in two-year height velocity.
>
> What we next asked: what was the effect of the higher dose of
> last-observed height SDS, and height SDS at 18 years? This slide
> shows, in the left panel, the ANCOVA of last-observed height SDS. The
> between-dose effect corresponded to 3.3 centimeters. The right panel
> indicates the repeated measures analysis of height SDS at age 18
> years. The between-dose effect corresponded to 2.8 centimeters. Both
> of these effects were statistically significant.
>
> Now, these between-dose effects refer to the incremental effect\--the
> incremental height gain\--of the higher-dose group compared to the
> lower-dose group, and should not be confused with the overall efficacy
> of the higher-dose group, which I will discuss in a moment. Now, just
> as in the previous study we showed that growth hormone did not
> accelerate bone maturation, it was important in this study to examine
> whether or not the higher .37 dose accelerated bone maturation
> relative to the lower dose.
>
> This next slide shows bone age by year on study for the final-height
> population, the non-final-height sub-group of the patients who
> complete two years of treatment, and the full two-year height velocity
> population. In all three groups there were no significant differences
> in the rate of bone age progression between the two dose arms. And
> this is really reflected by the slope of the lines, because there is
> some slight imbalance in the baseline values. Thus, there were no
> dose-related differences in bone age progressions, and the dose of .37
> does not accelerate bone age relative to the lower dose.
>
> Well, this concludes my comments on dose effect, and I\'m now going to
> turn to the analysis of final height minus baseline predicted height
> as a measure of the overall efficacy within each dose arm. And, again,
> for this analysis we\'re comparing, within group, the final height of
> each patient with the height they were predicted to achieve without
> treatment.
>
> On this slide, after a mean treatment duration of six-and-a-half
> years, the final height of the lower-dose group exceeded their
> baseline prediction by 5.4 centimeters, and for the higher-dose group,
> by 7.2 centimeters. Both of these results were highly statistically
> significant. Thus, by this measure of efficacy, the overall efficacy
> of the higher-dose group is 7.2 centimeters.
>
> Now, the validity of this measure depends on the accuracy of the
> heights that the patients were predicted to achieve. So how accurate
> are these baseline height predictions? To examine this, we both
> reviewed the literature and the results of our own placebo-treated
> patients from the previous study. And in the literature we found that,
> on average, when patients with non-GHD short stature are followed to
> final height without treatment, on average they fall slightly below
> their baseline predicted height. Similarly, in our own placebo-treated
> patients\--on this next slide\--in the left panel\--bar\--shown in
> pink, the mean final height of the placebo patients fell slightly
> below by .7 centimeters below their baseline prediction.
>
> Now, this evidence that on average untreated patients fall slightly
> below their prediction led us to conclude that the amount by which a
> treated patient exceeds their prediction is a valid and, indeed, a
> conservative measure of overall efficacy. Thus, we concluded that the
> overall efficacy of the .47 dose is at least 7.2 centimeters.
>
> Let\'s summarize, then, the between-dose effects and these overall
> efficacy results for this study.
>
> The primary analysis indicated a greater increase in two-year height
> velocity by .8 centimeters per year, and a greater\--in the secondary
> analyses\--a greater overall height gain in the higher dose,
> corresponding to 2.8 to 3.3 centimeters. And the overall efficacy for
> the lower dose was 5.4 centimeters; for the higher dose, 7.2
> centimeters.
>
> The next two slides will summarize the final height SDS results for
> both of these studies. This summary provides an alternate way of
> looking, or viewing, the overall efficacy of the .37 dose relative to
> this within-group comparison I just gave you earlier, of the final
> height compared to what they were predicted.
>
> This alternate way of viewing the data is that it has two components:
> it\'s the incremental effect of the higher relative to the lower dose,
> which was 2.9 centimeters from the final-height SDS ANCOVA, which is
> shown here, plus whatever the overall efficacy of the lower dose is.
> Now, I gave you earlier a within-group approach to that, but this can
> also be estimated from the pivotal study, which used a slightly lower
> dose. That study gave an efficacy for the .22 dose at 3.7 centimeters,
> and combining these two components, one gets an overall efficacy of 6
> to 7 centimeters, or about one SDS. This estimate is similarly to the
> 7.2 centimeters estimate that I gave you for the within-group
> comparison against baseline predicted height, and it simply shows the
> internal consistency between that within-group analysis and these
> between-group analyses on this slide.
>
> Now, the individual final-height data that\'s represented by each of
> these bars will be shown on the next slide. For the placebo-treated
> patients, shown in pink, most of the patients\--most of their final
> heights fell below the normal range, and none of them exceeded the
> fifth percentile of the general population. By contrast, for patients
> treated in the higher-dose arm, 94 percent had final-height standard
> deviation scores that were within the normal range. And even the one
> patient who failed to reach the normal range had a height SDS gain of
> 0.9 from a very low starting point.
>
> Now, the next slide will show these same final-heights plotted in
> relation to their individual baseline predicted heights; the heights
> they were predicted to achieve without treatment. These baseline
> predicted heights are shown in inches on the x-axis; the final-heights
> they achieved on the y-axis. A line of identity is this diagonal. And
> so the amount by which a patient exceeds this line is the amount by
> which they exceed the height that they were predicted to achieve
> without treatment. So, for example, this patient ended up 6.4 inches
> above the height that he was predicted to achieve without treatment.
>
> Now, if we examine the placebo-treated patients, we can see that most
> of them fell either on, near or slightly below\--somewhat below\--what
> they were predicted to achieve without treatment. By contrast, most of
> the treated patients exceeded what they were predicted to achieve, and
> particularly in the high-dose group\--shown by these blue symbols\--62
> percent of these patients were more than two inches about their
> predicted height, and 31 percent were more than four inches above the
> height that they were predicted to achieve without treatment.
>
> Well, given the efficacy observed in these studies, we asked: are
> there supportive studies in the literature on effectiveness of growth
> hormone in children with non-GHD short stature? To answer this we
> examined the recent meta-analysis by Finkelstein and colleagues,
> published last year. Since these results are in the briefing document,
> for the sake of time in this presentation I will only summarize their
> conclusion.
>
> Based on four controlled studies to final-height, the authors
> concluded that the mean growth hormone effect on adult height in this
> group was 4 to 6 centimeters. A similar treatment effect was also seen
> in eight uncontrolled studies to final-height. Thus, published studies
> do support the efficacy of growth hormone in non-GHD short stature,
> and the magnitude of the effect in these other previous studies is
> similar to that observed in the Lilly studies.
>
> We next asked: is the efficacy in non-GHD short stature similar to
> that in Turner\'s syndrome, which is an approved and widely accepted
> indication? And we chose Turner\'s syndrome for this comparison
> because it\'s the only previously approved indication for which
> controlled final-height data was required for the approval, and thus
> we can make an apples-and-apples comparison of the results. And we
> chose for the comparison the study that was most similar in design to
> that of our pivotal study, GDCH.
>
> This next slide indicates that study GDCT was a randomized study with
> an untreated control group. This was performed in Canada, followed all
> the way to adult height. The growth hormone regimen was .3\--a dose of
> .3 given six times per week. And from the planned interim analysis,
> which was used to support the use of Humatrope for Turner\'s syndrome
> in 1997, the treatment effect from the primary analysis was 3.9
> centimeters, quite similar to the 3.7 centimeters from the pivotal
> study; and from a sensitivity analysis, 5.4 centimeters.
>
> In addition to this efficacy being similar to that in Turner\'s
> syndrome, the efficacy in non-GHD short stature is also similar to
> that in other indications, such as growth hormone deficiency. For
> example, in our registration trial\--although the approval was based
> on short-term data\--30 patients from our original registration trial
> for GH deficiency were followed all the way to adult height. The mean
> height SDS gain for those patients of 1.5 was very similar to the gain
> of 1.55 which was seen for the lower-dose arm of our E001
> dose-response study, and was actually slightly below what we had seen
> in the higher-dose arm, which was 1.85. Thus, the efficacy in children
> with non-GHD short stature is similar to that in Turner\'s syndrome,
> and in other indications.
>
> We then asked: how does the variability of the height SDS gain in
> Turner\'s syndrome compare to the variability of that in non-GHD short
> stature? This was of interest, because some had predicted that non-GHD
> short stature, lacking a defined etiology, might have a more variable
> response to growth hormone.
>
> The next slide shows these distributions of height SDS gain, with the
> percentage of patients with each range of gain on the y-axis, and the
> actual ranges of height SDS gain on the x-axis. So, for example, the
> patients represented by this bar gained 0 ti 1 SD, 1 to 2 SD, 2 to 3
> SD, 3 to 4, 4 to 5, and so on. Patients with Turner\'s syndrome are
> shown in the lower panel. Patients with non-GHD short stature from the
> pivotal study in the middle panel, and from the dose response study,
> in the upper panel.
>
> In each of these panels the distribution of height SDS gain is
> uni-modal and with similar variance. Thus, the variability in height
> SDS gain in children with non-GHD short stature is also similar to the
> variability that is seen in Turner\'s syndrome\--and, for that matter,
> although we didn\'t plot it, a very similar variability is seen in GH
> deficiency.
>
> In conclusion, consistent efficacy was demonstrated in the pivotal
> study, the dose-response study, and in the literature meta-analysis.
> The effect size was 3.7 centimeters for the low .22 dose; 7.2
> centimeters for the higher .37 dose. The effect is therefore dose
> responsive, with greater height velocity increase, and greater overall
> height gain, with the higher compared to the lower dose. And the
> overall efficacy is similar to that seen in Turner\'s syndrome and
> other approved indications, such as growth hormone deficiency.
>
> Well, given these mean height gains\--3.7 centimeters at the lower
> dose, 7.2 at the higher dose\--the question has been raised: what is
> the clinical relevance of these height gains?
>
> This is not an easy question, because ultimately clinical relevance is
> unique to each patient. For one patient it may be a life-long dream of
> becoming a pilot, or pursuing any of the careers which encompass
> millions of jobs in the United States for which there is a minimum
> height requirement. For another child, it may simply be the desire to
> catch up to one\'s peers, to reduce the likelihood of being repeatedly
> mistaken for a child three or four or five years younger; or being
> teased, bullied or excluded, simply because of one\'s side.
>
> So let me conclude by summarizing the evidence that the height
> increases observed in these studies are sufficiently large to be
> clinically relevant.
>
> First, most of the patients caught up with their peers and reached the
> normal height range during childhood. Second, there was a similar
> height benefit to that seen in Turner\'s syndrome and, indeed, in the
> other indications including growth hormone deficiency. Third, 62
> percent of final-height patients in the higher-dose group gained more
> than two inches; 31 percent gained more than four inches; one gained
> more than six inches above their baseline predicted height that was
> expected without treatment. And 94 percent of final heights in the
> higher-dose group were within the normal range, thus conferring on
> these patients the lifelong benefit of normal adult statute.
>
> This concludes the efficacy presentation, and Dr. Charmian Quigley
> will now present the safety data, the risk management program, and the
> risk-benefit discussion for growth hormone treatment of these
> patients.
>
> Dr. Quigley?
>
> **Safety**
>
> DR. QUIGLEY: Good morning, Chairman Braunstein, members of the
> committee, members of the FDA and guests.
>
> Having heard the efficacy presented by Dr. Cutler, to allow you to
> adequately assess the appropriateness of an approval of treatment for
> this patient population, it\'s now my responsibility to present to you
> the safety.
>
> And to do this, I\'ll take the same approach that Dr. Cutler took, and
> ask three questions. First, is somatropin safe in pediatric patients?
> Second, are there any new significant adverse events or safety
> concerns in this patient population? And, third, is there an increased
> frequency of the adverse events currently described in the product
> label in this population?
>
> I should remind the audience that somatropin is not a new product. It
> has a 16 year safety history, and it can be estimate pharmacovigilance
> and post-marketing research studies that over 200,000 patients have
> been exposed to this product worldwide, across all brands of the
> product, amount to something over half a million patient years of
> exposure\--a truly sizable data base.
>
> In this time, a well accepted safety profile has been developed in
> five currently approved pediatric indications at doses up to 0.7 mg
> per kg per week. A small number of uncommon but well characterized
> events have been found to be associated with growth hormone exposure,
> but these are considered relatively mild and typically transient.
>
> Because of their importance, there are two key areas of focus with
> respect to growth hormone treatment, and these are the potential
> impact of growth hormone on carbohydrate metabolism and potential
> relationship to development of neoplasia.
>
> Over this period of time, a comprehensive literature has been
> developed that addresses the safety in over 200 publications in the
> peer-reviewed literature. And, most recently, the Growth Hormone
> Research Society reviewed this literature and summarized, in a
> consensus statement, as follows.
>
> They indicated that recombinant growth hormone has undergone and
> unprecedented level of scrutiny that has lasted more than 15 years and
> continues today; concluding, \"The extensive data to date collected on
> large numbers of children and adults treated with growth hormone
> indicates that for the current approved indications growth hormone is
> safe.\"
>
> In discussions and correspondence prior to this meeting it was agreed
> that an appropriate approach to evaluating the safety in this new
> population would be to compare this population with the populations of
> patients for which Humatrope is currently approved: those with
> Turner\'s syndrome and growth hormone deficiency. So, on this slide I
> show the five studies\--registration studies\--that will be included
> in this safety comparison.
>
> In the growth hormone deficient population\--abbreviated as
> \"GHD\"\--we have 333 patients who received doses ranging from .18
> from .24 mg per kg per week in the registration study. In the
> Turner\'s syndrome population\--abbreviated as TS\--approximately 300
> patients across the two different registration studies received doses
> ranging from .7 to .36 mg per kg per week. The number here in
> parentheses represents the total patient population, including those
> in the untreated control group.
>
> In the non-growth hormone deficiency short stature\--abbreviated as
> \"NGHDS\"\--again, close to 300 patients across the two studies
> received doses ranging from .22 to .37 mg per kg per week.
>
> There are three key take-home points from this slide with respect to
> the similarities in this safety comparison. And that is the numbers of
> patients exposed; the doses of growth hormone that they received; and
> the patient years of exposure, which amount to over 1,200 in each
> patient group. There is one caveat, however, with respect to this
> comparison, and that is that study designs differed, patient
> populations differed, and so these comparisons must be judged with
> those points in mind.
>
> The analyses that will be presented here in this safety section are
> listed on this slide\--and I\'ll go through these one by one.
>
> Beginning with patient deaths, fortunately there were few patient
> deaths in any of the studies. There was one patient death during study
> in a patient in the growth hormone deficient studies, and two patients
> died after study. The details are provided in your briefing document,
> so I won\'t go into these. One patient in the Turner\'s syndrome study
> died during study, however this was a control patient not receiving
> Humatrope. And one patient in the non-GHD short stature study died
> after study, and I\'ll detail his findings shortly.
>
> Similarly, rates of discontinuation due to adverse events were also
> low, amounting to no greater than 3 percent across any of the studies
> in any of the patient populations. I should point out that in this
> slide and the next slide, the column headed \"n\" represents only
> those patients receiving Humatrope, not the control patients.
>
> Serious adverse events were generally slightly lower for patients in
> the non-
>
> growth hormone deficient short stature group than the other two
> patient populations, likely relating to the greater level of baseline
> abnormalities and disease in the other two populations.
>
> Turning specifically to the serious adverse event of neoplasia, there
> were six cases of neoplasia during the growth hormone deficiency
> studies; one patient who underwent a new diagnosis of a
> craniopharyngioma; one patient who had the diagnosis of papillary
> thyroid carcinoma\--this patient has previously received treatment for
> leukemia, and this is a predisposing factor; and four patients who had
> recurrence or progression of preexisting intra-cranial tumors.
>
> No patient in the Turner\'s syndrom studies suffered a neoplastic
> disease, and two patients in the non-growth hormone deficient short
> stature studies had neoplastic conditions\--which I\'ll detail in the
> next two slides.
>
> The first is a patient in study GDCH, our placebo-control trial, who
> was diagnosed at the age of 11 years with stage III-B Hodgkin\'s
> disease\--a quite advanced stage of Hodgkin\'s disease\--after only
> nine weeks on study. Now, in retrospective review of this patient\'s
> case, we discovered a number of factors that led to our conclusion
> that this patient very likely\--and almost certainly\--had this
> disease at study entry. The first was the fact that on a chest x-ray
> performed two months prior to study, the patient was reported to have
> a widened mediastinum. At the time the radiologist suggested that this
> might be due to a thymus remnant, but, in fact, it\'s well known that
> Hodgkin\'s disease commonly presents with mediastinal widening.
> Second, at study entry the patient had a high normal sedimentation
> rate of 32 mm per hour\--you can see the reference range in
> parentheses\--and had an elevated LDH\--lactic dehydrogenase. This is
> a non specific marker of systemic disease.
>
> By 12 weeks on study, the patient had a frankly elevated sed rate of
> 58, and continued to have an elevated LDH. And I reviewed this case
> with an external pediatric endocrinologist who concluded that the
> clinical features, and the fact that the patient had such advanced
> stage of disease at study entry, indicated that he did have
> sub-clinical disease at study entry\--I\'m sorry\--the advanced stage
> of disease at diagnosis.
>
> Now, moving to the second case, this is an unusual tumor called a
> \"desmoplastic small round cell tumor.\" This was diagnosed in a
> 12-year-old boy in the lower-dose group of study E001, after
> six-and-a-half years on study. The patient discontinued from study at
> diagnosis and, unfortunately, died approximately four years later. We
> were subsequently able to find the karyotype report from this tumor,
> which showed that there was an unusual translocation, with the
> translocation break-points occurring at chromosome 11-P-1-3, which is
> the locus of the Ewing sarcoma gene, and chromosome 22-Q-1-2, which is
> the locus of the Wilms tumor suppressor gene. It\'s very important to
> note that this karyotype is the hallmark of this tumor. And this
> translocation produces an oncogenic fusion gene whereby the five-prime
> portion of the Ewing sarcoma gene is placed upstream of the
> three-prime portion of the Wilms tumor suppressor gene. This is very
> important with respect to t the pathobiology of this tumor, because
> it\'s important to recognize the translocations are not associated
> with growth hormone therapy.
>
> Furthermore, there has been no additional case of this tumor in a
> growth hormone treated patient, either in Lilly\'s pharmacovigilance
> database, or in the literature. I also reviewed this case with an
> external expert in the biology of the desmoplastic small round
> tumor\--in fact, the individual who first reported the existence of
> these tumors\--and he also believed that this was unrelated to the
> patient\'s growth hormone exposure.
>
> Returning now to treatment emergent adverse events\--or TEAEs\--as
> expected in pediatric studies, the majority of patients did experience
> TEAEs, but most of these\--also as expected\--were common childhood
> illnesses like pharyngitis, flu\--typical things. There was some
> slight difference in the pattern of TEAEs that were reported across
> the different patient populations\--again very likely relating to the
> different baseline diseases.
>
> Importantly, there were no significant differences in the rates of
> TEAEs for the Humatrope versus the placebo group in study GDCH, or for
> the lower versus the higher-dose group in study E001; and no new
> adverse events were seen in the non-growth hormone deficient short
> stature population.
>
> Now, with specific reference to the events that are currently listed
> in the Humatrope label, this table shows in the left column the events
> that are currently listed as events to be searched for in the
> Humatrope label, and the comparison is between the growth hormone
> deficient, Turner\'s syndrome, and non-growth hormone deficient short
> stature population. And the key from this slide is that for the
> non-GHD short stature population, rates of these common TEAEs are
> either lower\--such as here, with otitis media\--or similar to, such
> as disturbances of carbohydrate metabolism, the other two
> indications\--indicating no increase in the rates of these well-known
> adverse events.
>
> To evaluate the potential differences between doses with respect to
> adverse events, we have study E001 where, in the lower-dose group we
> see that serious adverse events were reported in 14 percent of
> patients, and in a similar rate of 19 percent of patients in the
> higher-dose group, with the intermediate dose group\--which, in fact,
> received this higher dose of growth hormone for about three quarters
> of their time on study\--having a much lower rate. So this obviously
> suggests no dose-related pattern in serious adverse event development.
>
> Similarly, in treatment-emergent adverse events, we evaluated those
> events that occurred in more than a single patient during the course
> of the study. Nine events occurred most frequently in the lower-dose
> group; similar number of 11 events occurred most frequently in the
> higher-dose group; and 18 events occurred most frequently in the dose
> group that changed whilst on study. So there is no clear pattern of
> effect of different Humatrope doses on adverse event profiles.
>
> Turning form our own studies to the literature, as I mentioned in the
> beginning there\'s really a comprehensive literature on safety in this
> patient population\--or in all populations\--starting with the Kabi
> International Growth Study, the recent publication from Dr. Wilton in
> 1999 on the safety data from that study, addresses close to 26,000
> patients, and over 62,000 patient years of exposure. The events here
> are reported as adverse events per 1000 treatment years. And what can
> be seen, comparing these different forms of growth failure and growth
> disorder that received growth hormone treatment is that idiopathic
> short stature\--or what we would term \"non-growth hormone deficient
> short stature,\" in fact has the lowest overall rate of adverse events
> across all of these different conditions.
>
> Looking at some specific adverse events, a number of these are listed
> here in this first column that were evaluated in this report. Here I
> would like to point out that patients exposed to close to
> 35,000\--that\'s a pretty decent number to be evaluating\--and, again,
> what we saw here, as we did in our own studies, is that event rates
> are either similar to\--such as arthralgia, the other conditions
> listed here\--or lower than\--such as Type II diabetes\--than the
> other conditions receiving growth hormone treatment.
>
> Similar data can be evaluated from the National Cooperative Growth
> Study, the U.S. study in which there have been over 100,000 years of
> patient exposure. The data here are shown in a slightly different way,
> in that event rates are shown relative to the percentage of the total
> database that the individual indication represents. So, for idiopathic
> short stature, there are over 5.5 thousand patients in the database at
> the time of this 2000 report, and 17 percent of the database is
> represented by this diagnosis. And you can see that for each of the
> conditions listed, all serious adverse events\--sorry, \"all adverse
> events,\" \"serious adverse events,\" and then the individual
> events\--the event rate occurrence for idiopathic short stature is
> less than the 17 percent of the database that these patients
> represent.
>
> I\'m turning now from adverse events to laboratory analyses, and here
> we\'ll focus on parameters that evaluate carbohydrate metabolism in
> both study GDCH and study E001, and parameters that evaluate insulin
> like growth factor 1.
>
> First I\'ll orient you to the format of this slide, as subsequent
> slides show the same format. On the left axis is the reference\--the
> units of measures for the analyte of interest, given in typical U.S.
> units, and on the right y-axis, in Systeme Internationale units. The
> reference range is shown in the shaded blue area; placebo patients in
> pink on the left; Humatrope patients in green on the right.
>
> Within each group, baseline values are shown in the left group of
> symbols, and last on-study values shown in the right group of symbols,
> and individual patients are shown by the open symbols, and solid
> symbols represent the means.
>
> So, here it\'s obvious that there is no Humatrope effect on fasting
> glucose. We see essentially no change in the fasting glucose from
> baseline to endpoint, and no difference between placebo and Humatrope.
>
> Similarly, in study E001, we see no dose effect on fasting glucose.
> Here we see the baseline points for the lower-dose group and the
> higher-dose group being very similar.
>
> Turning to fasting insulins, the effect here is a slight increase in
> fasting insulin from baseline to endpoint. To evaluate this with more
> rigor, we then performed quantitative insulin sensitivity check index
> analysis, which integrates both glucose and insulin to give a measure
> of insulin sensitivity\--shown on this slide. And in this analysis,
> higher values represent higher insulin sensitivity. Lower values
> represent lower sensitivity.
>
> What this analysis demonstrates is that there is significant
> variability across the patients in each of the groups\--perhaps
> slightly more variability in the Humatrope group than the placebo
> group\--but that there is no clear pattern of effect in either group,
> with some patients increasing, some patients decreasing, and some
> patients just staying the same. And so there is no obvious effect of
> Humatrope with respect to insulin sensitivity in this study.
>
> Concluding the laboratory analyses with IGF-1, this graph represents
> IGF-1 as a standard deviation score. And we can see\--we would have
> expected to see some increase in serum IGF-1 from baseline whilst on
> treatment, and the IGF-1 values stay well within the normal range
> throughout the duration of the study, and the peak achieved was, in
> fact, around 0 standard deviation scores.
>
> So, to summarize the safety, this treatment in this patient
> population, we had a single post-study death due to an unusual
> abdominal tumor, which is believed to be unrelated to Humatrope
> exposure. We saw no difference from growth hormone deficiency or
> Turner\'s syndrome for the rates of serious adverse events,
> discontinuations due to adverse events, or treatment-emergent adverse
> events.
>
> There were no significant difference in adverse event rates between
> the Humatrope and the placebo groups in study GDCH, and between the
> lower and higher growth hormone dose groups in study E001.
>
> Laboratory analyses showed no Humatrope effect and no dose effect on
> fasting glucose or hemoglobin A1c\--I did not show you those data, but
> they are in your briefing document\--and no significant Humatrope
> effect on insulin sensitivity. And, finally, the IGF-1 values remained
> within the normal range.
>
> So, to conclude, these data demonstrate that somatropin is safe in
> pediatric patients. It has a well-characterized safety profile, with
> over 15 years of accumulated experience. There were no new significant
> adverse events or safety concerns in this patient population, and no
> increase in frequency of the adverse events currently described in the
> product label.
>
> So, in concluding, I have answered the three questions that I began
> this presentation with, to conclude that the safety profile of
> Humatrope in this patient population is similar to that in the
> currently approved indications.
>
> **Benefit-Risk Assessment and Risk Management Plan**
>
> DR. QUIGLEY: Well, I\'ve demonstrated that Humatrope has an excellent
> safety profile. But to address the potential use of this product in a
> new population, Lilly is also proposing a comprehensive
> risk-management program.
>
> And to evaluate this, I\'m going to return to the questions that Dr.
> Enas asked at the beginning of this presentation. And in this section,
> I will address the first three questions that Dr. Enas posed,
> beginning with \"How will the potential risks be managed and safety be
> monitored?\"
>
> Well, the cornerstones of a risk-management program are appropriate
> labeling and pharmacovigilance. But Lilly recognizes that there have
> been concerns raised about the potential for inappropriate use in this
> patient population. And so we\'ve gone beyond the standard
> risk-management to include a number of elements that create a
> comprehensive risk-management program that I\'ll detail in subsequent
> slides.
>
> First, the proposed label wording, and that is: \"Humatrope is
> indicated for the long-term treatment of non-growth hormone deficient
> short stature, defined by height standard deviation score less than or
> equal to minus-2.25, in pediatric patients whose epiphyses are not
> closed, and in whom diagnostic evaluation excludes causes of short
> stature that should be treated by other means.\"
>
> Now, this restrictive label is highlighted here in yellow\--the two
> key restrictive elements of the label. And this, in particular\--the
> height standard deviation score of minus-2.25 recommended for this
> proposed label may lead you to ask: why did we choose this
> restriction?
>
> The first reason was that we received recommendation from the FDA that
> for this patient population we should provide, within the label,
> guidelines to prevent over prescribing, which is a concern that has
> been raised. And thus we chose a guideline\--a threshold that we feel
> will accomplish this goal.
>
> This threshold reflects the pivotal trial inclusion criterion for
> height, as the majority of the patients in the pivotal trial were
> enrolled in the study under this height criterion. And, finally, this
> criterion will limit access by excluding all patients whose heights
> fall within the normal range\--that is, above minus-2 SD scores, and
> excludes almost half of patients whose heights, in fact, do represent
> short stature by falling below minus-2 SD scores. And, in doing this,
> Lilly believes that we strike a balance between providing treatment to
> those for whom treatment is appropriate, and restricting access to
> this therapy from those who should not receive it.
>
> With these restrictions in place, we maintain that no additional label
> restrictions should be required. Note that this is the only growth
> hormone label that contains any form of height restriction or
> threshold, and that this restriction excludes 46 percent of the
> patients who could be diagnosed as having non-growth hormone deficient
> short stature.
>
> Now, a number of other factors have been suggested as possible factors
> to be included\--or may be suggested as possible factors to include as
> label restrictions, such as height velocity, or bone age, or target
> height. However, these are really not appropriate for inclusion as
> restrictions; this is the practice of clinical pediatric
> endocrinology. These are the factors that pediatric endocrinologists
> integrate when they\'re evaluating patients to make appropriate
> treatment decisions. So these should not be included as label
> restrictions, but should be left for the practice of clinical
> pediatric endocrinology.
>
> Moving to the second element of our risk-management program, this
> focuses on sufficient education, which will ensure that physicians
> understand these label restrictions that I\'ve just detailed, and
> understand the process for making an accurate diagnosis of non-growth
> hormone deficient short stature; and also that they are well aware of
> the benefit to risk profile that I will detail shortly. The methods
> utilized will by physician-to-physician educational programs and
> continuing medical education.
>
> The third element of our risk-management program is limited marketing.
> WE have a small sales force of under 100 sales representatives, who
> will undergo comprehensive training regarding the patient
> characteristics that represent this patient population , the
> diagnostic process that must be undertaken to make this diagnosis, and
> the benefit-risk profile. These sales specialists will call only on
> pediatric endocrinologists for this indication, and there will be no
> direct consumer advertising.
>
> The fourth key element of our risk-management program is controlled
> distribution. And here I must point out that this has been in place
> ever since Humatrope was first launched in the mid-1980s, because of
> the concerns regarding potentially inappropriate prescribing. The
> first element of this is that a statement of medical necessity is
> required, both by Lilly and by insurers for all new patient diagnoses.
> And this collects information such as the diagnostic information,
> growth hormone test results, growth parameters, etcetera.
>
> Second, Lilly\--Humatrope is shipped only through Lilly-approved
> closed specialty pharmacies. It is not shipped to retail pharmacies.
> So a patient cannot simply turn up at the GP\'s office, get a
> prescription for Humatrope and go to the corner drug store and get it
> filled. This simply cannot happen.
>
> Third, Lilly monitors prescribing behavior. And if potential problems
> are detected on this monitoring, these are investigated and corrective
> action has occurred in cases where inappropriate prescribing has been
> detected, and can include denial of access to prescribing Humatrope.
> Further details of this process have been provided to the FDA.
>
> Finally, how will we monitor safety in this risk-management program?
> There are two key elements here: standard pharmacovigilance, which is
> the collection of adverse event data, and the observational
> post-marketing research program. Within our pharmacovigilance system,
> which is a worldwide pharmacovigilance system, we screen for adverse
> events that may be associated with growth hormone treatment; we
> regularly evaluate any events that we detect for potential safety
> concerns; and we communicate any findings with worldwide regulatory
> agencies.
>
> Now, our observational post-marketing research program is known as
> GeNeSIS\--the Genetics and Neuro-endocrinology of Short Stature\--and
> I\'ll describe this a little further shortly. Returning to the
> specifics of the safety monitoring, these listed here are the
> precautions that are currently present in the Humatrope label to be
> evaluated. So the label states that \"careful monitoring or follow-up
> is recommended for those with pre-existing scoliosis, skin lesions or
> tumors, hypothyroidism, insulin resistence and decreased glucose
> tolerance, intracranial hypertension, otitis media and other ear
> disorders, and slipped capital femoral epiphysis. And these conditions
> will continue to be monitored throughout post-marketing research, such
> that no further precautions are required for the Humatrope label.
>
> Turning now to this post-marketing research program, as I mentioned,
> its name is GeNeSIS. It is currently running in 30 countries
> worldwide, at over 400 study sites, currently of which 140 are in the
> United States, and we are continuing to enroll addition sites on a
> progressive basis. Any Humatrope-treated patient at any study site is
> eligible to enroll, irrespective of whether they are currently
> receiving treatment or just starting treatment. And, in addition,
> there are two sub-studies within this program that enroll untreated
> patients, to allow us to better characterize the relationships between
> Humatrope treatment and any efficacy and safety issues. And I\'ll
> provide a little more information on these subsequent.
>
> Now, this slide provides some of the details. I won\'t go into the
> details of what the information is that we collect in the program,
> other than to highlight the fact that we collect a lot of information
> on history, diagnostic and efficacy information. But because I\'m
> focusing on safety, I\'m going to highlight what we collect with
> respect to the safety data.
>
> In addition to the spontaneous adverse event data, this program is
> actually unique because we have, within the program, a module that
> solicits proactively a number of conditions that have been associated
> with growth hormone exposure. And so patients are asked about these on
> every study visit, and these are reported into the program at each
> visit.
>
> Another key difference between this program and previous programs is
> that we have within it a sub-study that targets neoplastic disease,
> knowing that this has been a concern in the community for a long time.
> The sub-study collects information on patients with a prior history of
> neoplasia who are either treated or not treated with growth hormone
> for long term. And then the other key difference in this program is
> that we also provide, as a safety tool, IGF-1 and IGFBP-3 as a service
> to all patients in the program.
>
> The data are reported regularly, annually, to the study investigators
> in annual investigator meeting, and safety data as a whole are
> reported annually to regulatory agencies, and we also provide ad hoc
> reports whenever these are requested. In addition, the Lawson Wilkins
> Pediatric Endocrine Society requests and receives, from all growth
> hormone manufacturers, annual safety reports with specific focus on
> neoplasia.
>
> So we will monitor for any safety concerns using our GeNeSIS program,
> spontaneous case reports that appear in our pharmacovigilance
> database, and any literature reports.
>
> The second question that was asked is: \"Will this new indication
> obviate the need for diagnostic evaluation in children with growth
> disorders?\" This question was also raised by Dr. Orloff. And the
> clear answer to this is that this will not happen, because this is the
> practice of pediatric endocrinology; this is what I as a pediatric
> endocrinologist and many of my colleagues do, is we evaluate the
> causes of growth failure. And this is what we\'re trained to do, and
> it\'s very important to do this because growth failure is a very key
> symptom that may indicate a serious underlying condition.
>
> Furthermore, the peer professional societies under which we work\--the
> Lawson Wilkins and the American Academy of Pediatrics\--regularly
> provide guidance regarding diagnosis of growth disorders, and are
> likely to update their guidelines. And the insurance companies will
> require this work-up and statement of medical necessity before they
> will reimburse for treatment. And Lilly itself will enforce this, both
> through our label wording and through our educational programs.
>
> The third question that was asked is: \"Will approval for this new
> indication open the floodgates for inappropriate treatment?\" There
> are a number of reasons why Lilly maintains that this will not occur.
> The first is the label that we propose. The height threshold\--I\'ll
> remind you\--of minus-2.25 standard deviation excludes all children
> whose heights are in the normal range, and also excludes 46 percent of
> children with sub-normal heights below the minus-2 standard deviation
> score mark.
>
> Second, the pediatric endocrine community does not want this to
> happen. Pediatric endocrinologists are relatively conservative and
> view themselves, in fact, as the gatekeepers of growth hormone
> therapy. The observational studies that Dr. Hintz showed indicate that
> they prescribe growth hormone quite conservatively across all
> indications, for heights that average around minus-2.8 to minus-3
> standard deviation scores. Again, we expect the peer organizations
> will update their guidelines on appropriate treatment of patients with
> growth disorders. The insurance companies, again, will play a role
> here, because they will impose controls of their own, for their own
> financial reasons, and will continue to require a statement medical
> necessity before reimbursing treatment.
>
> The final two features here are that Lilly has its controlled
> distribution process, and the fact that we will market only to
> pediatric endocrinologists for this indication. These two factors will
> also limit the likelihood of any inappropriate prescribing.
>
> But more than this, there are some intrinsic factors to growth hormone
> treatment that will help prevent this inappropriate treatment. Growth
> hormone treatment is not a small thing. Many decisions are required;
> many decisions must be gone through before a patient receives growth
> hormone treatment, and these decision steps will limit its use.
>
> The first is the decision of the family to consult their primary
> physician about a concern regarding growth. The second is for that
> physician to refer the patient to a pediatric endocrinologist. The
> third decision point is for that endocrinologist to decide that the
> child has a disorder that warrants a work-up, because these work-ups
> are, in and of themselves, not small things; they\'re quite invasive,
> they require a half-day hospitalization in most cases. But, having
> done that work-up, the next decision point is for the endocrinologist
> to recommend growth hormone treatment to the family. The next decision
> is for the family to accept that treatment\--and that\'s not just the
> family, but the patient. And, finally, the decision of the insurance
> company to reimburse for that therapy.
>
> So, with all these decisions in place, and the thought process, and
> the time that it takes to go through this, it is very unlikely that
> inappropriate treatment will occur.
>
> But this may lead, then, to the next question as to: \"With a new
> indication, how many patients with this condition will actually end up
> being treated?\"
>
> To address this we began by evaluating the prevalence of non-growth
> hormone deficient short stature as defined by our label wording\--our
> label cut-off of minus-2.25 standard deviation scores. And by
> \"prevalence\" I mean the number of children in the U.S. today who
> fulfill these criteria. And this would be approximately 400,000
> children between the ages of 7 and 15 years. And I should point out
> that this is only twice the number that is represented by an orphan
> drug indication.
>
> Now, this 400,000 children are not all going to receive this
> treatment. In fact, once the various decision points have been gone
> through, this will be significantly whittled down. So following the
> selective referral by primary care physicians, the conservative
> treatment recommendations by pediatric endocrinologists, and the
> limited insurer reimbursements, we have projected that approximately
> 10 percent of these patients will end up on treatment at five years
> after approval, totaling about 30,000 to 40,000 patients across all
> brands of growth hormone.
>
> So, to conclude, Lilly is committed to the appropriate use of
> Humatrope in this patient population, and a multi-level program will
> be in place to help manage any risks.
>
> Having addressed now the rationale for treatment, the efficacy, the
> safety and the risk-management program, I\'m now in a position to
> characterize for you the benefit-risk profile of treatment in this
> patient population. And to do this I will return again to the slide
> first shown by Dr. Enas, and address the last four questions that Dr.
> Enas raised.
>
> First, \"Are there ethical issues regarding growth hormone treatment
> of non-growth hormone deficient short stature?\"
>
> The first concern refers to a social justice issue related to access
> to growth hormone therapy; that is, which patients should have access
> to this therapy? But we would point out that this is not unique to
> this indication. This is true for all of the other growth hormone
> indications and, furthermore, it\'s not unique to growth hormone as a
> drug but, in fact, refers to\--could be referred to many drugs. And,
> indeed, an approved indication would provide more equitable access to
> patients across a broad range of socioeconomic groups.
>
> The second concern raised is regarding resource allocation, and
> whether increased use of growth hormone will significantly impair the
> health care system from being able to take care of other health care
> needs. Here we point out that the growth hormone\--that growth hormone
> itself accounts for a very small proportion of the overall health care
> budget, of less than .05 percent. So a slight increase in the use of
> growth hormone should not have any negative impact on the ability of
> the health care system to address other health needs.
>
> The third issue raised has been whether the treatment effect
> adequately balances the cost and potential discomfort of treatment in
> this condition. However I would point out that this\--basically, this
> is a cost-benefit analysis, and this cost-benefit balance has been
> well accepted for the four other non-growth hormone deficient growth
> disorders for which Humatrope is currently approved, and there is no
> difference in this balance in patients with non-growth hormone
> deficient short stature and patients with the other non-growth hormone
> deficient growth disorders.
>
> The fourth issue raised regarding ethics of this treatment is the
> difficulty in differentiating between normality and abnormality. This
> is something that pediatric endocrinology has struggled to deal with
> for the last 20 years, with respect to growth hormone stimulation test
> results, and which patients fall within the normal and the abnormal
> categories of growth hormone stimulation testing. So, again, this is
> not unique to this indication of non-growth hormone deficient short
> stature; and, furthermore, it\'s not unique to growth hormone either.
> For example, where does one draw the line between normal and abnormal
> blood pressure? This is constantly changing. And so this
> differentiation has been a situation in a variety of different
> conditions.
>
> But Lilly has proposed an objective criterion to help address this;
> and that is the label criterion that we\'ve discussed\--the minus-2.25
> standard deviation scores. Pediatric endocrinologists, in evaluating
> the patients appropriate for treatment, weigh in many factors to
> determine who is appropriate, because they realize that normality and
> abnormality are not black and white, in life or in medicine but, in
> fact, form a continuum.
>
> The final question\--or the final issue raised\--has been the
> potential for growth hormone to be used as augmentation therapy; that
> is, to be used to treat children whose heights are normal to make them
> taller, even though they\'re already in the normal range.
>
> This is something that, as a pediatric endocrinologist, I\'m well
> aware that my colleagues do not support. This potential has existed
> ever since growth hormone was first marketed, and this new indication
> will make no difference to that potential misuse of growth hormone.
> Pediatric endocrinologists do not support this type of treatment and,
> furthermore, the label restriction will eliminate patients whose
> heights are within the normal range. Our risk-management program that
> I\'ve already elucidated, also addresses this issue.
>
> Having raised and discussed some of these ethical issues, the final
> question in this area is: \"If there are potential ethical issues, who
> should address these?\"
>
> Lilly maintains that, assuming that the sponsor has established
> efficacy, safety and a positive risk-benefit, provides an effective
> risk-management program, and satisfies the FDA requirements sufficient
> for approval, that the most appropriate people\--or groups of
> people\--to evaluate any potential ethical issues are the pediatric
> endocrine community and the families of the patients themselves; and,
> further, that it is not ethical to exclude from growth hormone
> treatment children who are just as short as those currently approved
> for treatment, when the established risk-benefit is similar.
>
> The next question asked is: \"Is it appropriate to treat patients
> whose short stature is not clearly associated with a defined
> disease?\" And here I\'ll return to a point that Dr. Hintz made
> elegantly in his presentation, is that many conditions that deserve
> and receive treatment may not be accepted by everybody as diseases.
> And listed here are a number of such conditions. Listed in Dr.
> Hintz\'s slide were other such conditions. This is not a relevant
> question with respect to the appropriateness of treatment.
>
> Growth hormone treatment and, in fact, the label indications for
> growth disorders, indicate that we are treating the growth failure or
> the short stature associated with various conditions, but not the
> underlying condition or the disease. For example, growth hormone has
> no impact on any other aspect of patients with chronic renal
> insufficiency or Turner\'s syndrome beyond their growth. We are simply
> treating their growth failure and their short stature. And the growth
> failure, as we have reiterated\--the growth failure in this group of
> patients is very similar to that seen in patients with other growth
> disorders.
>
> The next question raised is: \"Should psychological or quality of life
> benefits be required outcomes of growth hormone treatment?\"
>
> While this is a relevant question, I would point out that this has not
> been conclusively demonstrated for either growth hormone deficiency or
> for any other growth disorder that is currently approved for
> treatment. And this has not been required for growth hormone approval
> for any other growth disorder. And, furthermore, when the
> Endocrinologic and Metabolic Drugs Advisory Committee gave their
> recommendations back in 1987, they did not specify benefits other than
> growth as required outcomes of treatment.
>
> Finally: \"What is the clinical relevance of the efficacy?\"
>
> Most patients reached normal height during childhood. Similar growth
> improvement was seen to that in other indications, and similar
> final-height benefit was seen to patients with Turner\'s syndrome.
> Eighty-two percent of final-height patients in the higher-dose group
> gained at least one standard deviation score in height, and this is
> equivalent to two-and-a-half inches at adult height. Sixty-two percent
> of the final-height patients in the higher-dose group gained more than
> two inches, and 31 percent gained more than four inches over their
> baseline predicted height; and 94 percent of patients in the
> higher-dose group were in the normal range of height at their final
> height.
>
> So what this effectively does\--this height gain\--is to start to
> shift patients from this distribution to this distribution, and
> thereby to trim back some of this gap in height that exists between
> the average-statured population and those with non-growth hormone
> deficient short stature. And with this change in height, and with this
> improvement in height, what are the potential outcomes?
>
> Well, I return again to a slide similar to that shown by Dr. Hintz,
> where we listed a number of the potential disadvantages of short
> stature. So what the treatment may have the opportunity to do is to
> prevent this boy from being constantly treated as a child three or
> four years younger than his best friend here, and to prevent him from
> being excluded from many peer activities. And in adulthood, this
> treatment might provide the opportunity to this woman to buy clothes
> off the rack at a regular store, as opposed to having to buy
> children\'s clothes, or have them altered; may allow her to obtain a
> job that she would otherwise have been ineligible for due to the
> height restrictions; and may provide her the opportunity to sit the
> requisite 10 inches away from the steering wheel that is required for
> air bag safety.
>
> So to conclude the benefit-risk assessment, these last presentations
> have demonstrated that Humatrope is clearly effective and safe for the
> treatment of non-growth hormone deficient short stature, and that a
> dosage of .37 mg per kg per week confers greater benefit, without
> evidence of increased risk. Therefore the benefit-risk profile of
> Humatrope in non-GHD short stature is favorable, and is similar to
> that in other approved indications.
>
> And this now allows me to conclude with the eight reasons why this
> committee is asked to recommend that Humatrope be approved for
> patients with non-growth hormone deficient short stature.
>
> First, these patients are as short, and as deserving of treatment as
> those with current indications.
>
> Second, recognizing the unmet medical need of these patients, the 1987
> Endocrinologic and Metabolic Drugs Advisory Committee recommended a
> placebo-controlled study to final height; a truly rigorous
> gold-standard study.
>
> Third, the pivotal study that was run by Eli Lilly and Company and the
> NIH used this rigorous recommended design to run a study over 13
> years, taking patients to final height. And a study such as this will
> never be repeated.
>
> Fourth, this pivotal study demonstrates unequivocal efficacy in this
> patient population. The supportive study demonstrates a greater
> benefit at a higher Humatrope dose. There is consistent efficacy
> across the published literature and Lilly studies. The efficacy is
> clinically relevant and is similar to that in other conditions. And,
> finally, the safety is similar to current indications.
>
> The benefit-risk balance therefore justifies approval, and there now
> remains no valid scientific, medical, regulatory or ethical reason to
> withhold treatment from these patients.
>
> And I\'ll now hand the podium over to Dr. Margaret MacGillivray for
> some concluding remarks.
>
> **Concluding Statements**
>
> DR. MacGILLIVRAY: Dr. Braunstein, members of the Advisory Committee,
> members of the FDA and guests.
>
> My experience with human growth hormone began in the early 1960s when
> pituitary-derived growth hormone first became available for clinical
> use. Over the past 40 years we have learned a great deal about the
> benefits and risks of growth hormone therapy. Growth hormone treatment
> is effective and safe for children with growth hormone deficiency. It
> corrects their height deficit in childhood and renders normal adult
> heights.
>
> When the FDA approved recombinant growth hormone in 1985 for the
> treatment of growth failure in children with growth hormone
> deficiency, they did so without requiring a placebo-controlled study
> or requiring long-term adult height outcome. However, they did mandate
> that a post-marketing surveillance study containing safety and
> efficacy data be contained in a database, and that database\--the
> National Cooperative Growth Study\--has tracked more than 40,00
> children on growth hormone treatment, and the cumulative exposure for
> growth hormone in this population is 113,000 patient years. Few other
> drugs in the history of therapeutics has had such close scrutiny.
>
> On December the 10th, 1996, I recommended to the FDA advisory
> committee that approval be given for recombinant growth hormone to be
> used to treat the short stature of Turner\'s syndrome. And this
> approval was given, even though these children do not have growth
> hormone deficiency. Final-height outcome data was provided in this
> population, and this was the first approved indication for which
> adult-height data was given as a proof of efficacy.
>
> At the present time, FDA has approved treatment of growth hormone for
> three additional non-growth hormone deficient conditions: chronic
> renal insufficiency, Prader-Willi syndrom, and children born
> small-for-gestational-age with persistence of poor growth. The
> approval was given in each of these conditions without considering the
> growth hormone secretion status of these patients, and without
> requiring long-term outcome data or placebo-controlled trials.
>
> Five-and-a-half years have passed since the FDA gave approval for
> growth hormone treatment in girls with non-growth hormone deficient
> Turner\'s syndrome, and today Lilly has presented on the efficacy and
> safety of growth hormone in severely short but otherwise healthy,
> non-growth hormone deficient children. The etiology of the growth
> deficit in this population has not been defined, but it is apparent
> that these children do respond favorably to growth hormone treatment.
>
> What are some of the arguments against treating these children with
> growth hormone? They do not have psychological decompensation, and
> therefore they do not need growth hormone treatment. However
> psychological decompensation has never been a prerequisite for
> treatment in growth hormone deficient children, or in any of the other
> approved indications of non-growth hormone deficient short stature
> groups. These are healthy children, and their normal peak growth
> hormone response to growth hormone stimulation tests mean that they do
> not need growth hormone treatment. However, we know that growth
> hormone stimulation tests are not the gold standard for evaluating
> growth hormone secretion, and they do not predict an individual
> child\'s response to growth hormone therapy.
>
> This line of reasoning is also invalid because these children do not
> spontaneously correct their height deficits and reach normal adult
> heights. And this was shown in the placebo arm of Lilly\'s pivotal
> trial, and also from abundant observational study data in the
> literature. In a large sub-study within NCGS, non-growth hormone
> deficient short children who were not treated, versus those who were
> treated, showed that the not treated group did not grow more rapidly,
> and they did not improve their height SD scores, whereas the children
> with growth hormone treatment did improve their height SD scores. And
> when this data was compared to the growth hormone deficient population
> who were not treated, versus treated, the similarities in these two
> groups was striking.
>
> The evidence presented today by Eli Lilly on the pivotal double-blind,
> randomized, placebo-controlled trial to adult height shows
> unequivocally that the treatment is efficacious and safe in non-growth
> hormone deficient children with significant growth failure. Further
> supportive information came from Lilly\'s dose-response study using
> larger doses of growth hormone, and showed that these children had
> greater height gains and better height outcomes.
>
> Additional evidence came from the meta-analysis of Finkelstein and
> colleagues, who shoed that using global studies of controlled and
> uncontrolled populations of children treated with growth hormone, that
> the treatment was efficacious.
>
> The efficacy information from the NIH pivotal study is particularly
> meaningful because the dose of growth hormone in the trial was
> sub-optimal, and it was given three times weekly, rather than daily.
> Furthermore, the late age\--12-1/2 years of age when these children
> started growth hormone therapy\--was not ideal, because many
> participants were peri-pubertal or pubertal, thereby shortening the
> effective treatment time.
>
> Non-growth hormone deficient short stature is not a new condition. It
> wasn\'t invented by pediatric endocrinologists or by growth hormone
> manufacturer. In my over 40 years of clinical practice in a regional
> referral children\'s hospital, I have seen hundreds of these children
> whose families come seeking help so that they may be freed from
> teasing and being mistaken for children younger than their actual age.
> They want the opportunity to have height in the normal range during
> childhood and during adulthood.
>
> The growth disorder in these non-growth hormone deficient
> growth-delayed children is effectively and safely treated by growth
> hormone treatment, as shown by Lilly. Ninety-four percent of the
> treated patients reached adult height in the normal range. The
> evidence p resented today indicates that these children should have
> the same access to growth hormone treatment that is currently
> available to other groups of non-growth hormone deficient short
> children.
>
> I will end by showing a video of a former patient of mine who came
> when she was 2.8 standard deviations below the mean for age, and her
> peak growth hormone was 16 nanogram per mil. On growth hormone
> treatment she reached a height of 5\'3\", and in the interview she
> discusses how she felt before receiving growth hormone treatment and
> what the treatment did to change her life.
>
> \[From video\]
>
> PATIENT: You know, you can blow it off when it\'s just your older
> brother making fun of you, but my friends and my peers were always
> saying, \"Oh my God, she\'s so short,\" and \"Oh, you\'re not old
> enough to be hear,\" and like normal people that I passed on the
> street, or, you know, when I was shopping in the mall didn\'t take me
> seriously.
>
> It\'s such a drastic change. It helped in my self-esteem. I could do
> sports, I could join sports team. I\'m now a lifeguard, which I
> probably would never have been doing before.
>
> DR. MacGILLIVRAY: The comments made by her does show the clinical
> relevance of the treatment, in terms of what it meant to her life.
>
> In conclusion, as I did in 1996 for Turner\'s syndrome, I again
> recommend to the advisory committee and the FDA that approval be given
> for Humatrope to be given an indication for non-growth hormone
> deficient short stature children who have significant growth failure.
>
> Thank you.
>
> DR. BRAUNSTEIN: Thank you for a series of very enlightening
> presentations.
>
> We\'ll now take a 15-minute break and then reconvene for questions.
>
> \[Off the record.\]
>
> DR. BRAUNSTEIN: Back on the record.
>
> We\'d like the committee members to take their seats, please.
>
> \[Pause.\]
>
> **Committee Discussion**
>
> DR. BRAUNSTEIN: Well, we\'ll start with asking committee members to
> pose questions to Lilly, based on the presentations and the documents
> that they\'ve received.
>
> Dr. Woolf?
>
> DR. WOOLF: I would like to address some of the psycho-social issues
> that have been raised. In the briefing documents some of the
> information was actually in the very extensive bibliography that was
> sent to us. But it\'s a little bit, I think, in conflict to what
> we\'ve heard. And there was a paper from Children\'s Hospital in
> Buffalo, looking at the psycho-social screening project in 258
> children.
>
> The conclusion was, \"These findings suggest that despite the presence
> of negative psycho-social experiences related to short stature, these
> children are functioning generally well. The effects that these
> stressors exert are likely only contributing to variability in
> psycho-social functioning that falls within the normal range.\"
>
> So I have a few questions relating to this issue.
>
> As an adult endocrinologist, I\'m not really sure\--what is a
> clinically significant increase in height? Is it one inch, two inches,
> five inches, eight inches? I don\'t know.
>
> What age should growth hormone treatment be started, if we\'re going
> to approve it? Should it be started at age three, five, eight, 10? Any
> time before puberty?
>
> And, finally, what is the evidence that if these children do have
> psycho-social problems that treatment with growth hormone and
> improvement in their height will reverse these problems?
>
> DR. BRAUNSTEIN: Dr. Cutler?
>
> DR. CUTLER: Yes. I think that\--let me begin with the first one, the
> question of a clinically meaningful difference in height. I\'m not
> sure there\'s a perfect number you can give. It may be different for
> each child. This may be something where our consultants can help on
> this, and it may matter where you are. For example, if you\'re 4\'9\",
> for example, being 4\'10-1/2\" will actually allow you to get certain
> jobs that you couldn\'t have gotten, or may allow you to drive a car
> safely, for example\--4\'11\". So an inch-and-a-half can be
> meaningful, depending on where you are in the height range.
>
> And certainly, I think that the mean treatment benefit of three
> inches, which was what was seen in the higher dose arm, is, I think, a
> quite meaningful benefit to most patients. And if a patient doesn\'t
> feel like that level of benefit would be meaningful, this is a patient
> who probably\--you know, and this is the kind of thing that pediatric
> endocrinologists do in real-life practice, is they have a risk-benefit
> discussion and will make a judgment. And that\'s one of the reason
> that some children elect not to be treated. They feel that the
> benefit-risk, or whatever, for them is not where they want to go.
>
> The second point, about age: this is really, I think, a matter of
> clinical judgment. We looked at age as a predictor. And right out to
> the maximum ages of children enrolled in both of these studies, we
> didn\'t see any decrement in benefit. There was a decrement in the
> height over predicted height, but that was also true for the placebo
> group, which tended to catch up somewhat. And so when they were older
> they caught up last. The Humatrope exceeded their prediction by last,
> but the net difference between them didn\'t really change up to at
> least an age of about 15, or a bone age of about 13. So we didn\'t
> see, up to the ranges in this protocol, any age, and that included
> children who were up to as far as Tanner stage 3 of puberty\--although
> there were very few children at that point.
>
> So\--and in terms of a minimum age, children are rarely, for a variety
> of reasons related to all these decisions, treated much earlier than
> five, which was the lower age in our E001 study, and the majority of
> patients, the mean age, really, of treatment I think in the
> observational studies is more like nine or ten.
>
> Psychological data\--there were psychological data collected in this
> study, but it was decided at the time that Lilly and the NIH decided
> to work together that the NIH would be responsible for collecting an
> analyzing those data. They were not on any of the Lilly case report
> forms; they\'re not in the Lilly database.
>
> Now, the NIH has collected them, and Dr. Judy Ross actually is here,
> from Philadelphia. She was the principal investigator of the
> Philadelphia site, and could give you a several-minute overview of the
> outcome of the psychological data from this study, if you would
> like\--or I could give you just a very high level summary. Really,
> it\'s your discretion\--depending on how important it is to you.
>
> DR. BRAUNSTEIN: Why don\'t we have Dr. Ross give that presentation.
>
> Dr. Ross?
>
> DR. ROSS: Well, I\'m very pleased to be here and have an opportunity
> to go over this data with you.
>
> I\'ll remind you, this is the results of self-image and behavior
> questionnaires collected as part of the GDCH study. This was the
> placebo-controlled, randomized trial that was done by both Eli Lilly
> and NICHD in conjunction.
>
> As part of this, two questionnaires were utilized. One was the
> self-perception profile. This was a child report completed by the
> child at the visit. It assesses domain-specific judgment of confidence
> and perception of worth.
>
> The second questionnaire was the child behavior checklist. This is a
> parental report, completed by, usually, the mother at the visit. It
> assesses behavior problems and social competencies in several
> sub-scales.
>
> These questionnaires were distributed to the child and the parent at
> baseline and yearly. And the statistics that I will report to you are
> t-tests done year-by-year across the treatment groups.
>
> Now, first off, there\'s some controversy in terms of the literature,
> but in our hands, in this study, the results of the self-perception
> profile and the child behavior checklist were normal at baseline. I\'d
> also like to add that these are instruments that are widely used both
> in the United States and Europe. The child behavior checklist has been
> available since the 1970s, and is one of the instruments that was
> reported by Dr. Sandburg in the [Buffalo Review]{.underline} that Dr.
> Woolf just referred to.
>
> So this shows you the baseline results from the child behavior
> checklist\--and I have three summary scores, each of which encompasses
> several of the sub-scores within this test. And they are reported as
> t-scores, which means that the average, or the mean, is reported as
> 50, and the standard deviation is reported to be\--is normalized to
> 10. So this is a standardized way of reporting this data.
>
> And, as you can see, the placebo group and the Humatrope group were
> normal at baseline and really quite comparable to each other.
>
> So these are our treatment results. For the self-perception profile,
> the child questionnaire, there was no difference between the Humatrope
> and placebo-treated groups during the four year treatment interval. In
> contrast, for the child behavior checklist\--the parental
> questionnaire\--the Humatrope group had improved scores on the problem
> behavior summary score, the externalizing summary score, and the
> internalizing summary score at the four-year treatment interval,
> compared to the placebo group. And I\'ll be telling you a little bit
> more about these.
>
> First, the child behavior\--the problem behavior total sub-scale. This
> is a summary score reflecting eight component scales. And they include
> social problems, anxiety, depression, somatic complaints, etcetera.
> And, again, as I told you, it\'s reported as a standardized t-score
> with a mean of 50, and one standard deviation being 10. And in this
> particular case, a higher score indicates more problem behaviors.
>
> So, this is the first result\--the problem behavior total. And here on
> the y-axis is the change in score from the baseline value obtained.
> And so a change of 10 is equal to one standard deviation score. And so
> this is really a substantial effect size.
>
> This is the year in study\--one, two, three and four. The Humatrope
> group is shown in green; the placebo group is shown in pink. And these
> are the numbers within each of those groups, according to year.
>
> And these are the p values for the t-test done year-by-year, across
> the groups. And so, as you look at this first one, you can see that at
> one and two years there was not much change or difference between the
> two groups. By years three and four, there\'s greater separation,
> where the placebo group has a rise in score, and a worsening of their
> problem behavior profile.
>
> I would add that these results are reflected by the components, which
> either also showed statistical significance, or no significant change.
> I would also like to add that at the zero point, the mean age was
> about 12-1/2, and by three years, where we\'re starting to see a
> separation between the placebo and the control groups, they\'re about
> 15-1/2 on average, and well into adolescence.
>
> The next summary score is the child behavior externalizing sub-scale.
> This is also a summary score of under-controlled type problem
> behaviors, and it encompasses the delinquent and aggressive
> sub-scales, and includes acting out or aggressive behaviors. And this
> shows you again the change in score versus the year in study for our
> two treatment groups. And for this externalizing summary scale, it
> looks very much like the total problem behavior scale, with
> differences beginning to emerge at three years and four years that are
> significant at p less than .05.
>
> And the last one I will show you is the internalizing sub-scale. And
> this is, again, a summary score in the child behavior checklist,
> encompassing the withdrawn, somatic, anxiety and depression
> sub-scales. And this is related to internalizing-type behaviors,
> excessive worrying and depression. And I show you, again, the
> internalizing behavior total; the change in score versus the year in
> study for our Humatrope versus placebo groups. And you can see, again,
> similar changes emerging at the third and fourth year into the study,
> when they are well into adolescence.
>
> Now, these results are inconclusive, and there are several reasons for
> it. First, the small sample size\--and you could see from the numbers
> that, by the fourth year, the numbers had really started to drop off,
> in terms of the available evaluable data.
>
> There was missing or incomplete data on the questionnaires, which
> eliminated them from being included in any kind of analysis. There may
> have been a drop-out bias, in terms of who completed these
> questionnaires, and the psychological data that we did have available.
>
> There was no correction for the multiple comparisons and the multiple
> sub-scales. And I didn\'t show you this, but there was no correlation
> with change in growth rates or height SDS when we looked at it from
> that vantage point.
>
> But I would summarize by saying that these results are unique, because
> they control for placebo effect, which can have tremendous impact on
> self-image, or psychological results. It eliminated any kind of study
> participation effects and placebo effects. I think on the basis of
> what I\'ve shown you, we can safely conclude that growth hormone does
> not deleterious effects on self-image or behavior.
>
> And, last, there was a trend towards positive growth hormone effects
> on problem behaviors, externalizing, and internalizing behaviors in
> the child behavior checklist.
>
> Thank you. And I\'d be happy to take any questions.
>
> DR. BRAUNSTEIN: Thank you Ross.
>
> Dr. Woolf, is that\--
>
> DR. WOOLF: It answered my question.
>
> DR. BRAUNSTEIN: Thank you. Appreciate it.
>
> Yes. Dr. Grady?
>
> DR. GRADY: I\'m basically just trying to get this straight, in terms
> of what we\'re asking ourselves here. And just\--I just want to ask
> you if it\'s correct to assume that we\'re really talking about
> treating short stature in kids along about the age of 10, to make them
> taller along about the age of 17 or 18. And we\'re talking about
> defining that in kids whose height is more than 2.25 standard
> deviations below the mean, which would encompass one in a hundred of
> every kids. Is that right?
>
> And our best estimate of what this effect is going to have is probably
> to increase their height, perhaps on the order of one-and-a-half to
> three inches. So they\'re going to go from what we\'d estimate here as
> something like 4\'10\" in girls, and 5\'3\" in boys, up to something
> like 4\'11\--up as far as 5\'1\" in the women, and in the boys, from
> 5\'3\" up to maybe 5\'4\" to 5\'6\"? Is that right?
>
> DR. CUTLER: Well, there is one additional\--it\'s close to being
> correct, but the final heights that we\'ve given you are the gain over
> placebo, essentially, in the pivotal study. And there was some gain of
> the placebo patients who were untreated, which corresponded to
> probably about an inch, if you really looked at it.
>
> So, there\'s some gain in this group because they have a bone-age
> delay, so that the actual final heights might be another inch or so.
> But that\'s very close.
>
> Essentially what you\'re saying is correct, but if you remember the
> height SDS increase, when I showed you it temporally, by
> year-on-study, there was an increase in height SDS for the placebo
> group as well. So if you don\'t add that in to the baseline starting
> height, you\'ll end up with a little shorter height than you would be
> getting.
>
> So someone, for example, who\'s 4\'9\", who would have ended up at
> 4\'10\", for example, without any treatment, now ends up at either
> 4\'11-1/2\" if they use the low dose, or 5\'1\" if they use a high
> dose\--higher dose.
>
> DR. GRADY: Ahh\--okay.
>
> DR. CUTLER: On average\--and that\'s just a\--that\'s obviously the
> mean result for the population.
>
> DR. GRADY: My other question\--I mean, I\'m trying to get an idea
> whether\--I think in some ways it might make a difference whether they
> gain one inch or three inches.
>
> What was compliance like in your pivotal study?
>
> DR. CUTLER: It was 84 percent for the placebo group, and 88 percent
> for the Humatrope group, based on compliance diaries, where they kept
> a record of every injection.
>
> DR. GRADY: And I\'m assuming they had a lot of support for compliance;
> that they had study visits, physician seeing them fairly
> frequently\--all of that sort of thing that happens in a trial?
>
> DR. CUTLER: It was a highly selective group, and we certainly tried to
> reinforce compliance at each six-month visit. But these patients were
> coming from all over the country to the NIH, and we basically really
> didn\'t see them in the six months between. We obviously hoped that
> they were complying, but there was rather little we could do, other
> than at each six months we would re-emphasize the importance of
> compliance to get a meaningful outcome.
>
> DR. GRADY: And am I also correct in thinking that compliance\--two
> things. I mean, I think that the shorter\--it seems to me, from
> looking at this stuff, that the shorter the height to begin with, the
> greater the effect. And, of course, the inverse of that is that the
> taller the child is to begin with, the less the effect, so that
> compliance and baseline height have a fairly important effect on the
> final result?
>
> DR. CUTLER: Umm\--I\'m not\--could you clarify how you came to the
> conclusion about baseline height? Because I\'m not sure that baseline
> height really has much effect on the incremental gain above where they
> started.
>
> DR. GRADY: Basically, looking at the height\--you know, the predicted
> height increases from multiple studies, it just seems like the shorter
> the kid is to begin with, the more the effect.
>
> So you didn\'t do that in your study? You didn\'t look at baseline
> height as a predictor of effect?
>
> DR. CUTLER: We have looked at it, and it was not statistically
> significant. It was\--the correlation coefficient was .25, and so
> the\--and the p value was .26. And so it really explained a pretty
> small amount of the variance\--maybe 5 percent\--6 percent, I guess.
>
> DR. GRADY: Okay.
>
> DR. BRAUNSTEIN: Dr. Cara?
>
> DR. CARA: A couple of questions.
>
> Can you explain what you just said about the final height actually
> being a little bit more than the placebo group?
>
> DR. CUTLER: Ahh\--yes. These patients often have some bone-age delay,
> and so if they come in with a baseline height SDS of minus-2.8, they
> might have a predicted height of minus-2.3 or 4, for example. And, in
> fact, you may remember that at baseline the placebo patients had a
> mean height SDS of minus-2.8. But without any treatment, they ended up
> at minus-2.3. And that really is a little bit of catch-up related to
> their bone-age delay and the fact that they really have a little bit
> more time to grow because of the bone-age delay.
>
> DR. CARA: But there was no real difference between the predicted
> height SDS and the final height SDS.
>
> DR. CUTLER: That\'s right. That\'s right. In other words, they were
> minus-2.8 at baseline, minus-2.3 when they finished, and their
> predicted might have been just a tad above that. They were just lest
> than a centimeter below their mean predicted.
>
> So they did have a predicted height that was higher than their
> baseline height SDS, factoring in that bone-age delay that\'s often
> seen in this group.
>
> DR. CARA: Another question is related to your intent to do a\--or your
> desire to do an intent-to-treat analysis in the pivotal study. If you
> look at your slides\--and I\'m looking specifically at slides\--let\'s
> see here\--
>
> \[Pause.\]
>
> \--the final-height population versus the efficacy evaluable
> population, in terms of their final-height SDS. The efficacy evaluable
> population ends up being about .3 SDS taller than the actual
> final-height population. I\'m looking at slides number 61 and 62.
>
> DR. CUTLER: Okay.
>
> DR. CARA: Now, usually in an intent-to-treat analysis, the
> intent-to-treat analysis versus the actual protocol completers is
> generally downplaying the effect of therapy. But here it\'s actually
> enhancing therapy.
>
> How can you explain that?
>
> DR. CUTLER: Yeah\--I\'m not sure that I have the same slide number
> that you have. Is this\--
>
> DR. CARA: Sorry, it\'s 41 and 42.
>
> DR. CUTLER: 41 and 42\--okay.
>
> DR. CARA: So this is the final-height population\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--and the final height is minus-1.8.
>
> DR. CUTLER: Right.
>
> DR. CARA: And then if you look at the next slide\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--the efficacy evaluable population\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--the height SDS at 18 years for the Humatrope treated is
> minus-1.5.
>
> DR. CUTLER: Right.
>
> DR. CARA: Now, these are presumably kids that have either completed
> the protocol, gotten some growth hormone and dropped out, or got one
> dose of growth hormone and dropped out. Is that correct
>
> DR. CUTLER: Right. This is\--well, this is the efficacy evaluable
> population first\--and I probably will defer in a moment to our
> statistician if need be\--but in this analysis, this is people who
> were treated at least six months. And so they had, in the Humatrope
> group, they had at least six months of treatment, and then wherever
> they\--you know, and then they dropped out at variable points between
> there and final height.
>
> Now, because this is efficacy evaluable, this includes the
> final-height patients. So the final-height patients are in this
> analysis, and the non-final-height. So you can sort of think of the
> efficacy evaluable as having two sub-groups. I had a lot of tripartite
> slides. One sub-group is the final-height, the other is those who
> didn\'t make it all the way to final height. This is a combined
> analysis of both, and the repeated measures approach basically models
> the ones who didn\'t get to final height based on ones who did, and
> projects where they would have ended up.
>
> So it is not\--not all of these are measured. This is a combination.
> If they were at final height, this is a measured\--you know, or if
> they went to 18, if they had a height past 18 this is a measured
> height, but if they didn\'t get there, it\'s what they were projected
> to by the repeated measures analysis.
>
> DR. CARA: I see. And actually what you\'re saying\--that it includes
> two populations. It actually\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--it actually includes three populations. It includes the
> patients that were treated for a minimum of six months and then
> dropped out\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--patients that were protocol completers\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--and then patients that were no protocol completers,
> but\--
>
> DR. CUTLER: \--came back for a final height. Right.
>
> DR. CARA: And the final-height slide that you show, it\'s slide 41, I
> believe\--and then again, in the slide that shows the individual data
> points\--although I don\'t know if you had it for this study\--can you
> give me an idea of where the actual protocol completers were, versus
> the non-completers?
>
> DR. CUTLER: Yes\--and just give me a second and see if I can\--either
> I or our team can give you an analysis that looks like this.
>
> Well, let me tell you that the protocol-complete\--simply to
> summarize\--the protocol-complete results look quite similar to the
> final-height population, because it\'s mostly protocol-complete
> patients. So it had an effect size. It was a little bit smaller. It
> was .46 SDS versus .51 for the final-height population, but very
> similar effect size between the final-height population that you\'re
> seeing on 41.
>
> The difference between this\--and if you didn\'t look closely at it,
> the protocol-complete population will look very similar to this,
> except the effect size is 0.46, which is about 10 percent less.
>
> DR. CARA: And then a related question, related to the supporting
> study\--the E001 study\--a similar trend, I think, is shown in the
> slide\--let\'s see, slide 53, I believe, showing the secondary
> analysis; the two year height-velocity population where, again, it
> seems that the two year height-velocity population actually, in the
> long run, do better than the final-height population.
>
> DR. CUTLER: Yes. Maybe\--you know, it might\--I will\--let me take a
> moment to do this, and if\--again, if you\'re not satisfied with my
> ability to explain this, I\'ll be happy to get our statistician to do
> it as well.
>
> These are sort of two complementary analyses. And I\'m happy to
> explain these, because I had to be taught what they are. And we\'ll
> see if it works.
>
> Here what\'s done is the last observed height SDS. If it\'s a final
> height, it\'s the actual final height. But if it\'s a dropout\--and it
> could be, in this case, a dropout at six months\--we take whatever the
> height SD was at the very last observation, and then you simply
> analyze it. So they\'re all observed.
>
> DR. CARA: Can I just interrupt you for just one minute?
>
> DR. CUTLER: Yes.
>
> DR. CARA: And in your protocol\--your\--what am I trying to say?\--in
> your placebo group, if anything, you showed that the patients actually
> did better than that\--in the long run. If you took their SDS and
> assumed that they continued at that SDS all along, their final height
> was actually a little bit better than that; about an inch better.
>
> DR. CUTLER: Well, it\'s about an inch better than where they\' started
> but, remember, they started at minus-2.8, and the placebo patients
> ended up at minus-2.3 in the final-height population, and minus-2.4
> for the last observed height.
>
> DR. CARA: So what you\'re doing here\--if I\'m understanding you
> correctly, is you\'re talking the SDS at the last observed height\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--and then following it through\--
>
> DR. CUTLER: Carrying it forward, in a sense. Right.
>
> DR. CARA: \--carrying it forward\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--assuming that they would stay in the same SDS. But, in
> fact, your placebo group ended up a little bit taller than that.
>
> DR. CUTLER: Right. It\'s\--this is often called a \"last observation
> carried forward\" approach. That\'s exactly right.
>
> DR. CARA: So why is it that those patients do better than the actual
> patients that completed to final height?
>
> DR. CUTLER: Now, which group? Better than the placebo?
>
> DR. CARA: No\--better than the Humatrope-treated patients that
> completed final height.
>
> DR. CUTLER: Umm\--well, I think if we\--maybe we should\--the
> final-height population for this group is shown\--
>
> DR. CARA: I think it\'s the slide before.
>
> DR. CUTLER: It\'s like one of the 60\'s or so. Well, the final height
> for the dose study, for this\--this group is minus-2 for
> last-observed. Do we have the final height? It\'s about slide 60 or
> something like that. It\'s the one where I summarized the final height
> SDS for the two studies.
>
> DR. CARA: Yes, it\'s slide 58, I believe.
>
> DR. CUTLER: 58, maybe\--if we go back\--yeah.
>
> So, no\--yeah, okay. So that was about minus-2, but the final height
> is minus-6. So the last-observed height was down here, and the actual
> final heights were about minus-1.6. So it was somewhat better
> than\--the ones who were followed all the way through on the .24 dose
> were better than the ones who were just last-observed.
>
> DR. CARA: But if you look at the higher dose, they ended up at
> minus-0.8.
>
> \[Pause.\]
>
> DR. CUTLER: Okay. Yeah, we need to\--
>
> DR. CARA: And the lower-dose ended up at 1.3 when measured at 18.
>
> DR. CUTLER: Yes. Can we go to the next slide?
>
> DR. CARA: So I\'m not quite sure why you\'re saying they ended up
> better?
>
> DR. CUTLER: Oh, you\'re thinking about the repeated-measures analysis
> now.
>
> DR. CARA: Right.
>
> DR. CUTLER: Can we go back to about\--to the earlier one?
>
> DR. CARA: Slide 63?
>
> DR. CUTLER: I\'m trying to understand\--are you concerned about the
> slight differences in the numbers on these different\--and what they
> really mean on the different analyses? Or\--
>
> DR. CARA: No. I\'m looking at the fact that the height SDS at 18
> years\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--was better for the\--
>
> DR. CUTLER: Repeated measures.
>
> DR. CARA: \--repeated measures than it was for the actual treated.
>
> DR. CUTLER: Right. And it is a model. It\'s a statistical model that
> is modeling some for whom we don\'t have final heights\--
>
> DR. CARA: And based on your placebo data, if anything, this model is
> actually under-predictive of final height.
>
> \[Pause.\]
>
> DR. TAMBORLANE: What I think Dr. Cara is referring to is that with
> prolonged treatment, over time, at the high dose, you may actually
> start losing a little final height. If you\--you know, when
> you\--because normally, if you\'re taking the last observation carried
> forward, you\'re not seeing the true drug effect with the low dose you
> see that. You don\'t see the full drug effect until the final height
> measurement.
>
> But, in this case, you\'re saying that you see a projected
> last-observation carried forward which would be .8. But when you
> actually look at the actually people who get to 18, it\'s 1.2.
>
> DR. CUTLER: Yes, well, let me\--that\'s the point.
>
> DR. TAMBORLANE: I mean, obviously they\'re different subjects, and
> that may be just\--
>
> DR. CUTLER: Yes.
>
> DR. TAMBORLANE: \--you know, a subject effect. But it\'s an
> interesting idea.
>
> DR. CUTLER: Let me summarize these numbers. It\'s hard to do. We
> haven\'t put them all on one slide. And I\'m not sure I can interpret
> them, but let me just reiterate, then.
>
> So, the last observation carried forward for the higher dose gives a
> last-observed height SDS mean of about minus-1.4. If you actually look
> at the actual mean final heights\--this is now 48 patients. Of the 17
> patients who got to final height, it\'s a little bit higher at
> minus-1.2
>
> If you now take the ANCOVA model, which requires having a baseline
> predicted height, four of those 17 were too young to have a baseline
> predicted, so they get dropped out. And with the 13, and an ANCOVA
> output\--the output of the ANCOVA, a final height SDS for this group
> is minus-1.0. And the repeated measures analysis, which
> estimates\--takes both measured and then, in a sense, project heights
> based on the trajectory\--and even if it\'s a trajectory going up and
> down, the repeated measures essentially will try to mimic that,
> whatever it was, for those who got to final height, it\'s minus-0.8.
>
> So, in a sense, what you\'re pointing out is that there were different
> estimates of where this group ended up, based on different numbers and
> different statistical analyses, ranging from about minus-.8 to
> minus-1.2. And beyond that, I think they\'re somewhat different
> approaches statistically, and they involve somewhat different
> patients. And that\'s probably about the best we can say about where
> these patients really are likely to have ended up.
>
> DR. BRAUNSTEIN: Dr. Watts?
>
> DR. WATTS: I\'m convinced that there are gains in height that are
> significant with this treatment, but I have some conceptual questions
> about the use of the standard deviation scores.
>
> One is that it\'s a potentially moving target. As people\--the general
> population get taller, the mean will change, and the variability
> around that mean may also change. So if the average in the population
> is taller but the variability is greater, the standard deviation score
> may stay the same. That\'s sort of a comment.
>
> The question is, in looking at the growth chart that Dr. Hintz showed
> earlier, there\'s a spread that changes from pre-adolescence, through
> adolescence to final. And I deal with this regularly in looking at
> bone density, where we think about z scores. And if you look at the
> variability around the mean at age seven, it\'s very tight, because
> most seven-year-olds are very close to the mean.
>
> If you look at age 12, it\'s pretty wide. And so a 12-year-old may
> actually be further away from the mean, and yet have a better standard
> deviation score simply because of the variability being greater in the
> population at that age.
>
> So is there some artifact in this SDS score that might particularly
> affect the last measure carried forward, where if you\'re calculating
> the SDS score at a time when the variability in the population is
> great, you\'re carrying forward a better score.
>
> DR. CUTLER: Well, your points are very astute, and particularly for a
> non-pediatrician. I mean, this is exactly right\--all of these points.
>
> But they are pretty subtle. And I think all I can say is it\'s one way
> to do the analyses. It seems to be the one that pediatric
> endocrinologists prefer as having the least problems of all the
> various ways they can go about it. But I think your points are
> correct.
>
> Maybe if you had given me the growth chart\--I\'m willing to show this
> again, just as a refresher. Because I think it is true that standard
> deviation, first of all, tends to increase somewhat with age. And over
> the age range of these studies, which is pretty much from\--I mean, we
> had some children as young as five, but the mean ages were about nine
> to ten; for the dose-response, about 12.
>
> From here on through to adulthood, there is a gradual increase, but it
> is not an enormous change in standard deviation score. It seems to
> be\--you know, it\'s pretty well behaved, I guess I would say. So it
> doesn\'t\--I don\'t believe, as best we can tell, at least to anything
> that\'s misleading about the data, it might help explain some of the
> very minor inconsistencies that you\'re picking up between the
> different analyses, going .1 or .2 SDS one way or the other.
>
> DR. BRAUNSTEIN: Dr. Follman was next.
>
> DR. FOLLMAN: Yes, you showed a slide earlier\--slide 46\--which shows
> the trends in SDS in the pivotal study. When I looked at this I was
> struck by what happened in the placebo, which shows an increase. And I
> sort of think, you know, if you\'re at the 3rd percentile today, you
> should generally track and stay around the 3rd percentile as you get
> older.
>
> That\'s not being shown here at all in the placebo group. You show an
> increase of about a half an SDS.
>
> Now when I saw this, before your presentation today, I was wondering
> if this might be due to sort of a dropout bias, where patients who are
> not improving so well don\'t show up later on. And that\'s a bit of a
> concern for me, but I\'ve had\--I looked at the data more thoroughly,
> and I\'ve had discussions with the FDA and I think, in terms of the
> dropout\--in terms of the treatment effect, I\'m willing to accept an
> estimate of, say, an inch-and-a-half in the study.
>
> However, you pointed out that perhaps a reason for this increase was
> not dropout but this is just what happens with SDS in short stature
> children. Is that your basic point?
>
> DR. CUTLER: Yes, I think this is not primarily a dropout bias. This
> is\--and it\'s one of the reasons why it\'s very important to have a
> placebo-controlled trial. These patients tend to have a little bit of
> a bone-age delay, and they do catch up somewhat in height standard
> deviation score. They don\'t say exactly had the same height standard
> deviation score.
>
> DR. FOLLMAN: Well, this made me think of another issue, which is in
> your labeling you aren\'t proposing a chronological age, it\'s just
> based on the SDS. And so if you have a young person, maybe seven years
> old, or five, which, you know, was included in the E001 study, they
> might have a low SDS, which perhaps it\'s not calibrated so well at
> this end of the spectrum, and with two or three years\' waiting might
> increase their SDS some. That\'s what we\'re seeing here.
>
> So, this raises an issue about not having a chronological age
> cut-point for this indication, when there\'s evidence here that the
> SDS is not stable, and that it increases over time for these children;
> these short children.
>
> DR. CUTLER: Well, I think this is one of the\--the key thing about
> your observation is, I think, an important one. I mean, pediatric
> endocrinologists do not want to treat children who are going to end up
> at a normal height without treatment. And it\'s one of the things that
> they spend, you know, three years of intensive training trying to
> learn how to do. It\'s not perfect. But there are factors, like
> predicted height and so forth\--how short they are\--and many of us
> will actually, if we\'re uncertain about what the progress is going to
> be, will follow a child for some period of time before making a
> definite decision about treatment.
>
> I think the purpose of the\--what you\'re suggesting is the idea that
> the cut-off ought to somehow be age-dependent. I think that would
> become very complicated. And this is effectively, I think, a way to
> select a patient population within which pediatric endocrinologists
> can appropriately make further decisions about who should be treated
> and who not to be treated.
>
> DR. FOLLMAN: Well, I wasn\'t really thinking of an age-specific SDS
> score necessarily, but just\--I was concerned about the same
> phenomenon you were talking about that they might, you know, show
> improvements if you wait a little while, and basically not need the
> therapy. And you\'re not really requiring that in your proposed label.
>
> DR. BRAUNSTEIN: Dr. Tamborlane?
>
> DR. TAMBORLANE: I have one for Dr. Quigley.
>
> So seemed to implicate that there wasn\'t evidence for insulin
> resistence with growth hormone treatment. Do you really believe that a
> dose of .375 mg of growth hormone per kg per week is not going to
> reduce insulin responsiveness?
>
> DR. QUIGLEY: We did not see any evidence for insulin resistence in the
> placebo-controlled study. We don\'t have the data in the .37 study,
> but what we do have is data from our registration studies in Turner\'s
> syndrome, which used quite similar doses. And so\--
>
> DR. TAMBORLANE: Similar to what? 3.7\--
>
> DR. QUIGLEY: Yes\--.27 and .36\--if I could have the Turner\'s
> syndrome insulin data\--and what we saw, at least in fasting
> insulins\--we don\'t have the QUICKI analyses, but in the fasting
> insulins we saw no differences across the different doses in this
> study.
>
> So this was our registration trial, and here we see the baseline
> values, which are not particularly what you\'re interested in. But
> here at 18 months\--this was a placebo-controlled study\--at 18 months
> we see no differences in the fasting insulins between the dosages
> groups, or between these groups and the placebo group. So at least up
> to that level\--up to about .37, in a population that\'s already more
> insulin resistant than we expect these patients to be, I don\'t think
> we would see a differential dose effect.
>
> If you go all the way up to something like .7, you might.
>
> DR. TAMBORLANE: But\--I mean, one of the problems with using the
> fasting insulin as your marker, I mean it may actually be
> relatively\--a good marker in severe insulin-resistant states like
> obesity and things like that. But\--I mean, there are data that
> suggest that growth hormone is primarily affecting peripheral glucose
> uptake, more in the fed state. So do you have any data as far as, you
> know, glucose-stimulated insulin responsiveness in any of these kids?
>
> DR. QUIGLEY: We do have some post-prandial insulin data\--again, from
> the old Turner\'s syndrome studies.
>
> DR. TAMBORLANE: But not in the\--
>
> DR. QUIGLEY: Not in this\--no, not in this patient population.
>
> DR. TAMBORLANE: Now, the other thing that\--I\'m almost certain that
> the .375 is going to affect insulin responsiveness, and probably
> insulin levels. That, of itself, may not be bad, because I think that
> actually may be part of the metabolic cascade that drives the
> improvement in growth.
>
> The things you worry about are subtle effect of hyperinsulinemia on
> other systems. As far as I can see, from the safety data, there was
> only, you know, one child who develop hypertension. But do you have
> more complete analysis, looking at changes in, say, blood pressure SDS
> scores in these kids over time? Because we know that changes. Do you
> have any data as far as lipid profiles, or other\--you know,
> potentially concerning changes as you go up on growth hormone doses?
>
> DR. QUIGLEY: We have\--that patient with\--quote\--\"hypertension\"
> actually had an elevated blood pressure at five weeks on study, which
> completed resolved thereafter spontaneously. So probably, in fact, did
> not have hypertension.
>
> I don\'t believe we have any\--we did not see any outstanding changes
> in blood pressure across the durations of the study. I don\'t think we
> expressed them as standard deviation scores, but in the age range that
> they were in, they may not change markedly across that time period.
>
> DR. TAMBORLANE: A normal child will have an increase in blood pressure
> over time.
>
> DR. QUIGLEY: Right.
>
> DR. TAMBORLANE: So if you didn\'t see a change in blood pressure\--
>
> DR. QUIGLEY: What I mean\--
>
> DR. TAMBORLANE: \--I\'m questioning\--who was measuring the blood
> pressure? Not that\--you know, to not see an effect.
>
> DR. QUIGLEY: I may not have been clear. I didn\'t say we didn\'t see a
> change. I meant we did not see a change between the groups across the
> duration.
>
> DR. BRAUNSTEIN: Dr. Schade?
>
> DR. SCHADE: I have a couple of metabolic questions.
>
> Nobody seemed to address the mechanism of the growth. Does Lilly think
> that that\'s due to the normalization of the small increase in IGF-1
> that occurs?
>
> The reason I\'m asking this question is that I gathered from the data
> you presented that not everybody responded. And my question\--if
> that\'s true\--my question is what are the guidelines for physicians
> as to when to stop therapy. This is a very expensive therapy, and it
> occurs over years. I mean, the data you just showed, over five years.
> And if there are non-responders, what are guidelines or mechanistic
> ways that we know to say, well, this child is not going to respond to
> this treatment. We don\'t know why\--obviously, we don\'t know why
> this child has short stature to begin with, because theoretically, the
> child has been worked up for known causes of short stature.
>
> My question is what can we tell the physician about when we know this
> therapy, after a year or two, is not going to suddenly add another one
> or two inches of growth?
>
> DR. CUTLER: Well, I certainly agree there\'s variability of response,
> but it\'s not clear that the higher dose that we looked at in the
> dose-response study that there were non-responders. All of those
> patients\--or 94 percent of the patients made it into the normal
> range, and the one who didn\'t had a very appreciable increase in the
> height SDS of 0.9 over the course of the study.
>
> The mean gain in standard deviation score was 1.85 for that group,
> which is well above\--way above anything that could be expected
> spontaneously.
>
> So, I\'m not confident that there are non-responders. I think that, in
> terms of the variability of response, we really don\'t have a
> validated way today to pick the very good responders, who are going to
> have more than a four-inch gain over the baseline predicted height,
> from the patients who are going to have a two-inch gain.
>
> And that, I think, is something that\'s of interest to us, that we\'re
> looking at, as are others. It\'s part of our GeNeSIS program to have a
> growth-prediction module, which we\'re inviting patients to take part
> in, where we\'re collecting a number of parameters and looking at
> improving short-term and long-term prediction.
>
> But, at this point, we really don\'t have a way to predict the
> variability of response in advance.
>
> DR. SCHADE: Okay. Well, let me ask you a little more specifically\--I
> hear you saying there\'s no correlation, then, between the change in
> IGF-1 or the levels of growth hormone that might be achieved. I
> realize you\'re using different dosages, but if you actually look at
> the growth hormone levels achieved, there is no correlation between
> the response and the change in IGF-1 or growth hormone levels
> achieved\--not the dose.
>
> DR. CUTLER: Mm-hmm. There\'s very poor correlation between the changes
> in IGF-1 and the changes in growth. I wouldn\'t say there\'s no
> correlation, but way below what could be useful for clinical
> prediction. And this has been found in all of the indications,
> actually, even in growth hormone deficiency where you would think, if
> anything, it would be strong. It just has not proved to be a reliable
> predictor.
>
> DR. SCHADE: Okay. Well, let me ask you one further question\--just to
> help the physician.
>
> If you treat the child for a year, and you get a certain degree of
> response, either the rate of increase\--whatever\--can the physician
> use that data, then, to predict what will happen over the next four
> years? Or the subsequent four years?
>
> DR. CUTLER: Just let me be sure I understood the question that I was
> also thinking that Charmian\--
>
> DR. SCHADE: Well, I\'m asking about\--
>
> DR. CUTLER: The short term response and long term?
>
> DR. SCHADE: I\'m asking about poor responders\--
>
> DR. CUTLER: right.
>
> DR. SCHADE: And what the physician can tell the mother or father about
> what will happen subsequently. Because somebody is paying \$20,000, or
> whatever the cost is, per year\--
>
> DR. CUTLER: Right.
>
> DR. SCHADE: \--and does the first year response automatically predict
> the subsequent four years\' response?
>
> DR. CUTLER: Right.
>
> DR. SCHADE: That type of information, I think, the physician needs\--
>
> DR. CUTLER: Right.
>
> DR. SCHADE: \--because a mother\'s going to come in and say, \"Well,
> my child hardly grew this year.\" What will I know about the
> subsequent four years?
>
> DR. CUTLER: Right. The simple answer is that there is some predictive
> value of the early\--or there may be, let me say. It hasn\'t been
> excluded. But from our data, very, very weak. We\'ve done this for six
> months\' height velocity, and the correlation coefficient was .07. So
> almost zero.
>
> And one of the reasons you can imagine that might be the case as we
> study a peri-pubertal group, where some of the children might be
> beginning to enter puberty, and having growth spurts that were
> puberty-related, it has not been very useful. However, it is not an
> uncommon practice, if you give growth hormone and there really is no
> increase in growth velocity\--which is pretty uncommon at a higher
> dose, but could occur at a lower dose\--either to increase the
> dose\--and some practitioners will take this approach\--or to
> discontinue therapy, if you\'re at the highest dose you\'re
> comfortable using.
>
> DR. BRAUNSTEIN: I have a few questions, also.
>
> We had requested the actual final height data from the pivotal study.
> And in calculating the difference there was actually\--it worked out
> to about 2.8 centimeters. Yet your slides, using the SDS and then
> converting it to centimeters was 3.7 centimeters.
>
> I know that that could be a statistical quirk, but the actual height
> difference only appears to be 2.8 centimeters in total, which is less
> than an inch-and-a-half.
>
> DR. CUTLER: This is the difference in final height minus baseline
> predicted height\--
>
> DR. BRAUNSTEIN: Yes.
>
> DR. CUTLER: \--for the two groups? Right.
>
> And you know, if you look at the extended tables\--and that analysis
> is correct. And actually it\'s also shown on one of the later slides.
>
> I think what we can say is there are a range of efficacy estimates in
> the package. And we\'ve given all of them to you. They range from a
> low of about 2.4 to a high of about 6.7, and I think there are 30
> different efficacy estimates in the briefing document. The median of
> them happens to fall right on the primary analysis of 3.7.
>
> And I think what you have to realize is they\'re each different
> methods. They each have their strengths and weaknesses. Height
> prediction has variability and error, and it could go one way or
> another.
>
> So I\'m not convinced that that analysis is lower because it would
> always turn out that way, as much as that\'s just what happens if you
> do a number of analyses, you\'ll find different results.
>
> DR. BRAUNSTEIN: But that\'s what the data showed.
>
> DR. CUTLER: Yes.
>
> DR. BRAUNSTEIN: I mean, you had the height prediction to begin with,
> and then you had the actual measurements afterwards.
>
> DR. WATTS: Are you looking at this\--
>
> DR. BRAUNSTEIN: Yes.
>
> DR. WATTS: That\'s in inches, not centimeters.
>
> DR. BRAUNSTEIN: Yes\--I converted it to centimeters, though. Because
> they\'re using centimeters.
>
> DR. WATTS: It\'s two inches, so it would be 4.6 centimeters.
>
> DR. BRAUNSTEIN: No, no, no. I\'m sorry. I didn\'t mean inches. I meant
> 2.8 centimeters. It works out to 2.8 centimeters when we do the
> conversion.
>
> DR. CUTLER: Maybe you could\--
>
> DR. BRAUNSTEIN: It was a little over 1.1 inches.
>
> DR. CUTLER: \--show me which figure, or table\--which analysis you\'re
> looking at, just so I\'ll\--
>
> DR. BRAUNSTEIN: This is the\--we had requested the actual data on the
> 11 control patients and the 22 Humatrope-treated patients\--
>
> DR. CUTLER: Right.
>
> DR. BRAUNSTEIN: \--looking at the predicted height and the final
> height, and the difference. And when you add that up, if you do it in
> inches, the Humatrope-treated patients gained a mean of .84 inches,
> and the placebo patients lost a mean of .274 inches. So when you add
> that together, you get a little over 1.1 inches difference between the
> placebo group and the Humatrope-treated group, which is less than 3.7
> centimeters difference.
>
> DR. CUTLER: Right. Right.
>
> DR. BRAUNSTEIN: And so what I\'m saying is\--
>
> DR. CUTLER: Can I explain the difference?
>
> Let me tell you how the 3.7 centimeters\--let me tell you how the two
> were calculated, and I think you\'ll understand. I hope you\'ll be
> able to explain why they\'re different.
>
> The 3.7 comes from an analysis of covariance. And basically in that
> data you plot, you know, all of the final heights versus baseline
> predicted, very much like one of the core slides, with that diagonal
> there. And then the model simply does a least-squares mean through the
> two populations and tells you that the mean difference, making the
> slopes for those lines being the same, is 3.7. So it is attempting to
> correct for baseline predicted height.
>
> You will not get the same answer if you take each individual patient
> and then subtract their individual baseline prediction and average it,
> as you do if you get a least-squares mean.
>
> Now, the statisticians for some reason feel that the ANCOVA model,
> where you basically have a regression line through the green points, a
> regression line through the pink points that\'s forced to have the
> same slope and you take the difference, that difference corresponds to
> 3.7 centimeters. That is not the same as taking this, plus this, plus
> this, plus this, plus this and averaging them. And\--they just come
> out different. I mean they\'re two statistical approaches to look at a
> similar thing, and they don\'t come out the same. But there is no
> intrinsic reason to believe that that averaged approach is more valid.
> In fact, I think the statisticians feel that the least-squares mean is
> likely to be a more appropriate analysis.
>
> And I probably said more statistics than I should already.
>
> DR. BRAUNSTEIN: Let me ask one more question.
>
> It seems to me that there\'s two problems that you want to correct
> with the short kids. One is you want to correct the childhood
> shortness, and have them come closer to their peers\--their taller
> peers, and the second is you want them to turn out to be normal sized
> adults. So those are the two issues.
>
> As far as\--and a lot of the arguments that you use concern what
> happens to short adults as far as their ability to manage their
> environment, and how they\'re perceived and things like that.
>
> Taking that into consideration, why not use a predicted height less
> than 2.25 standard deviations below the mean, rather than taking the
> actual height at the time the child presents, since we do know that
> many of these children have a delayed bone age, and therefor their
> predicted height will be greater than the minus-SDS that they\'re
> presenting with?
>
> DR. CUTLER: I think the key reason is that most of the pediatric
> endocrine community recognize that predicted height is a useful
> research tool, it\'s also a useful clinical tool as an aid to
> judgment, but it\'s, in the real world, fairly imprecise in its
> application. It often depends on the radiologist\'s reading of a bone
> age or, even if it\'s individual physicians reading the bone age,
> it\'s a fairly imprecise element.
>
> I think that all of the people that we\'ve talked to in the pediatric
> endocrine community feel it would be much better to stick with a real
> measured height, and a real measured height SDS than to introduce that
> variability.
>
> And I might\--I think I\'d like to get one of our\--maybe Dr.
> Rosenfeld, if you\'d like to comment on some of our consultants who
> are really doing this every day.
>
> DR. ROSENFELD: Well, I think the\--my name\'s Ron Rosenfeld from the
> Packard Foundation and Stanford University.
>
> I think Dr. Braunstein\'s question is one that, in fact, we debated
> quite considerably with the people from Lilly. I think you are right
> in saying that there are some children, because of delayed puberty,
> who may catch up. But you have to put into perspective the kinds of
> children we\'re talking about here.
>
> As Dr. Cutler showed you these children, on average, are coming in
> minus-2.8, minus-2.9 standard deviation. Very few of those children
> are likely to enter into the normal growth curve anytime during
> childhood or adolescence. Very few are likely to achieve a normal
> adult height. And the experience of the pediatric endocrine community
> has been that evaluation of skeletal age simply has not proven to be
> an effective way of predicting which children are likely to enter into
> the normal adult range.
>
> Given the inability to predict effectively, and given the fact that
> these children are so dramatically short when they present to a
> pediatric endocrinologists, it was our feeling that we could not
> discriminate between the group that would catch up and those that
> wouldn\'t, and that our recommendation would be that all at least have
> access to growth hormone therapy.
>
> The point was made earlier that there appeared to be, on some of the
> slides from Lilly, a small catch-up period that accumulated over time.
> In fact I believe you raised that point.
>
> In fact if you look at that slide, what we\'re talking about is an
> average of a .1 standard deviation per year in this spontaneous
> growth. That\'s a remarkably small spontaneous catch-up. These
> children come in, on average, at age seven, minus-2.9 standard
> deviations; they\'re going to come back at age eight at minus-2.8
> standard deviations; at age nine, minus-2.8 or minus-2.7 standard
> deviations. It\'s very difficult for us to withhold the availability
> of growth hormone to such patients, when at the same time we\'re
> treating other patients with the same degree of short stature.
>
> DR. BRAUNSTEIN: I think what we\'ll do is we\'ll give Lilly a break
> for a little while, take the next presentation and then some questions
> on the presentation and break for lunch. And then we\'ll have ample
> opportunity to continue the questions after lunch.
>
> So\--thank you.
>
> Yes?
>
> \[Voice off mike.\]
>
> DR. BRAUNSTEIN: One more minor statistical question. Dr. Grady.
>
> DR. GRADY: You know, I\'m trying to figure out the different\--there
> was different\--I think you reported, although it was hard to figure
> out which population you were talking about\--a different duration of
> follow-up. And it looked like it was as much as half a year longer in
> the treated group than in the placebo group.
>
> And I can\'t quite figure out how that affects your efficacy
> estimates. I mean, if it\'s ANCOVA that we\'re looking at, then that
> could be an issue. Could you discuss that?
>
> DR. CUTLER: You\'re talking about the pivotal study and the final
> height. And actually the final height was measured six months later in
> the placebo group than in the Humatrope group, although it was
> not\--that was not a statistically significant difference. The placebo
> group at 19.1, and the growth hormone-treated at 18.6.
>
> And I think the longer duration of growth in the placebo group might
> account for that very small difference in the FDA briefing document,
> where they did the whole analysis in actual final height centimeters
> and came up with 3.2, whereas if you do it in height SDS\--which
> really corrects for a single age\--the way that\'s traditionally done
> is you take the SDS at the end, and then in converting to centimeter
> estimates you convert it to height SDS at 18 years, in order to try to
> remove that age imbalance. That\'s sort of the way it\'s done when
> you\--traditionally when you convert these difference to the
> centimeter equivalent.
>
> So it essentially the way that we have done it removes the age
> imbalance, and I don\'t think it\'s a significant issue.
>
> DR. BRAUNSTEIN: Okay. Thank you.
>
> The FDA has invited Dr. Harvey Guyda to make a presentation. He\'s
> professor of the Department of Pediatrics at McGill University, and
> has extensive experience in this field and has written extensively
> about it.
>
> **Presentation**
>
> DR. GUYDA: Good morning. I guess it\'s almost good afternoon. Thank
> you to the committee for inviting me.
>
> To give you just a bit about my credentials, I\'ve been in the
> fraternity of pediatric endocrinology for 37 years. It seems longer
> than that some days. I also have to add another disclaimer to what
> Dornette has given you: I am from Canada but I do not come from
> Toronto.
>
> My task\--and I\'ve allotted myself only 20 minutes\--is to focus on
> three areas. And the first is some comments regarding efficacy for
> final height; some comments regarding cost-benefit analysis; and some
> comments related to ethics, particularly psycho-social enhancement.
> And I am not going to talk about social policy, equity, fairness and
> resource allocation. That\'s been partly covered in a few words this
> morning already, but also is covered in some of the reference
> materials that\'s been provided, and quite a bit in the literature.
>
> So, definition of \"short stature\"\--you\'ve heard quite a bit of
> what\'s normal, so I thought I\'d just review that, from my
> perspective, very quickly. And this actually comes from a consensus
> statement that was published in 1996, following a meting of my
> esteemed colleagues.
>
> The first\--and the one I want to remark on most\--is the \"normal
> size at birth\"\--and of course this was violated by both studies, the
> E001 and the trial from the NIH; significant short stature is, you\'ve
> heard generally, minus-2 standard deviations. And we\'ve heard the
> problems of SDS and how it varies over time.
>
> The issue of tempo of growth during childhood is one that has been
> either taken into full account or disregarded. I personally think
> it\'s an important aspect in assessing a child with growth failure,
> but this was not put into the consensus statement, and was not a
> parameter in the randomized controlled study at the NIH, but was a
> parameter in the European controlled trial.
>
> And, of course \"no evidence of systemic disease\"\--this was also
> violated in at least one of the patients in the controlled trial, had
> hypothyroidism on T-4 treatment.
>
> So what\'s \"normal?\" I thought I\'d just spend a few minutes for
> those who are not pediatric endocrinologists. You\'ve heard about
> disease scores, or STD scores\--they\'re on your left. The percentiles
> are on the far right. And I\'ve just listed some numbers so that you
> can put this in perspective of what kind of numbers we\'re talking
> about.
>
> You heard the definition that I gave you on a previous slide of
> minus-2 standard deviations. That\'s actually 2.3 percentile, and
> these are the actual figures in centimeters. You can see they\'re very
> close to these two numbers over here. So, about 59 inches, and just a
> little over 63 inches in your terminology.
>
> The criteria being proposed today are the 1.2 percentile. That\'s
> equivalent to 5\'3, and about 58-1/2 inches. And note that the
> minus-2.5, which is a 0.6 percentile is 58 and 62 inches respectively.
> Note, however, that even if you\'re able to move someone from this
> percentile over here, or this SDS score, they\'re still going to be a
> considerable way from the 50th percentile, which is listed at the very
> bottom of your slide for reference.
>
> This is some earlier data I published in 1999, before I reviewed some
> of the current data that\'s been presented this morning. This was the
> consequence of an international survey\--again, uncontrolled data, but
> it\'s remarkable how it came very close to the overall bottom line,
> which is a change in centimeters of 2.7 centimeters, and a change in
> SDS of 0.4\--not unlike what we\'ve just heard attributed to growth
> hormone this morning.
>
> This is also a study that is a little bit of an outlier that Ray Hintz
> has published, and the reason for the slight improved benefit, in
> terms of 5.5 centimeters, 4.9 centimeters remain unexplained, expect
> perhaps younger age and less advancement in bone age. Correct?
>
> \[Comment off mike.\]
>
> DR. GUYDA: Higher dose.
>
> Now, this has been common\--and there was a question from the panel,
> statements just recently from Dr. Rosenfeld, and I beg to differ.
> Short kids do catch up. And this is a total of almost 500 children.
> This is their initial height at assessment. This is their final adult
> height. These are measured, these are not predicted adult heights. And
> you can see that the average at baseline, when they were first
> observed was 2.2 SDS, and they gained as a group, collectively,
> 1.2\--this is greater than your Humatrope effect that\'s been reported
> this morning. And the same for females, identically. And this is a
> very large study. It\'s larger than both of the studies combined, in
> terms of final height.
>
> So if I make some comments on the GDCH study, this is my particular
> interpretation. Height velocity was only calculated before
> randomization for six months. It\'s well known that transient growth
> deceleration can be a severe phenomenon in a few kids\--not all kids,
> but some kids\--and then over a subsequent six months over observation
> they can show a catch up. In one study we reported there was doubling
> of the growth velocity. So measuring children and enrolling them in a
> study after only six months of observation I do not think is a wise
> choice.
>
> As I said earlier, it included small-for-gestational-age children.
> These, by definition are not idiopathic short stature. They have
> pre-natal onset of growth failure of undetermined origin.
>
> Also, there was an inclusion, to get enough patients in the study, up
> to a bone-age of 13 in boys, 11 in girls, and the complicating factor
> of trying to assess growth change in children undergoing puberty of
> course became paramount because a significant number were already in
> puberty when they began the growth hormone treatment. And I made
> reference to the hypothyroidism issue.
>
> You\'ve just heard, and it\'s been acknowledged, that the dose was on
> the low side. Particularly for those children who have normal growth
> hormone secretion the current data is that you need to give more
> growth hormone if you\'re expecting to see some benefit. And, again,
> the issue of only three times a week\--this was actually discussed in
> the minutes of the FDA meeting in 1987. It was pointed out even then
> that three times a week was not as good as daily or six times a week.
>
> What concerns me particularly is the high dropout rate. Only 16
> patients were left in the growth hormone arm, and 9 in the placebo,
> leading to only 42 percent of the original cohort for growth hormone,
> and 27 percent placebo. That suggests that there could be a positive
> bias of those who, in fact, remain in a treatment arm.
>
> The overall treatment effect, in my opinion, was quite modest. The
> gain we\'ve heard and were discussing whether it\'s really 3.7 or 2.8
> or 9\--it\'s in the range of a half SDS. Again, that will depend on
> how you convert that. But take a look at what this would actually do.
> If, in fact, the entrance criteria is minus-2.2 SDS, and you\'re
> successfully able to add a half an SDS to that child, it gets them up
> to the 3rd percentile, however, he\'d still be 12 centimeters below
> the mean. So then it becomes a moot question: what\'s normal? Are you
> normal when you\'re at the mean? Are you normal at the 5th or 10th
> percentile, or are you still normal when you\'re at the 3d percentile?
>
> Up until this morning we did not have access to the psychological
> data. And, as you\'ve heard, it would appear that the data is
> inconsequential.
>
> These are re-analysis from the statistical consultant to this
> committee. So there are two figures coming up. On the left-hand side
> is the no-final-height grouping, and those on the right are the
> final-height patients. Again, look at the numbers. The Humatrope, in
> the females, there were only four; there were 18 males. And there are
> the placebo in pink. And what we\'re arguing\--or discussing, I guess
> is a fairer word\--is this benefit up here for these four or five
> patients. There are the placebo, and there are the growth hormone
> treatment. And there\'s even a bigger scatter in this group over here.
>
> So, visually, the dots do not suggest a huge impact on many children
> and, in fact, they were no different than the placebo group.
>
> This is just segregating them by where they\'re coming from, in terms
> of predicted height of less than 5\'6\" or more than 5\'6\". And,
> again, the data are similar. There\'s some modest benefit shown with
> Humatrope, but it\'s not an overwhelming visual impact when you look
> at the data points.
>
> In terms of the E001 study, there was a dose effect, as indicated here
> on the slide, and which you heard reference to. Again, significant
> numbers, when you look at the raw data points, overlap with the
> placebo group of the GDCH study.
>
> Again, a very high dropout rate\--almost 13 percent during the first
> two-year evaluation period, and there were actually only 50,
> representing 21 percent of the original randomized subjects in the
> final-height cohort, and half of these were seen in one center
> only\--22 patients in one center. It was a Dutch center, and one might
> suggest there may be some genetic influence on that particular
> population for example.
>
> Interestingly, the highest dropout rate\--38 or 46 percent\--was in
> the high-dose group. And that was particular to me if, in fact, that
> group was showing the highest benefit, why that group would have the
> highest dropout rate.
>
> In trying to analyze the meta analysis, which is an interesting feat
> sometimes, I actually asked a consultant who works with me in my
> department\--she\'s a pediatric editor of the Cochrane Reviews\--she
> assessed the merit of this meta analysis at level two. For those of
> you not familiar with this scoring, a level one is a top-graded meta
> analysis, a level three is not worth really spending too much time on,
> and this is level two\--in between. And it was rated this way because
> of the fact that it was a mixture of controlled, uncontrolled data,
> non-randomized, and very small numbers in many of the studies. And so
> this could lead to a likely bias for positivity.
>
> As you heard earlier this morning, there were only four controlled
> studies to adult height; 84 on Humatrope, and 104 controlled. There
> were multiple dropouts during the group ending up in adult height.
> Again, observed was similar to what you\'ve heard earlier; a gain of
> half a standard deviation score, in the range of 3 to 4.6 centimeters
> over predicted, and over the control group, .84 and 5 to 6
> centimeters. It is likely if these were randomized controlled studies,
> the smaller effect would be seen.
>
> Again, the parameters were different from the randomized controlled
> study at the NIH. Less than 10 percentile was used\--and we haven\'t
> heard much discussion about whether that really is abnormal, and why
> those patients were getting growth hormone treatment. We\'ve heard
> that minus-2 standard deviations is the benchmark. And, again, SGAs
> were included.
>
> Some cost factors\--this is something published by Bailey in 1992. I
> guess you can multiply up the numbers, since things have escalated.
> And the estimate at that time, if you were to treat the lowest 1
> percent of the population in the United States, you would spend
> approximately 3 billion. Estimates in our materials provided to us
> were in the range of 10 to 20 billion, potentially. And, again, you
> have to look at the poor lowly NIH\--although it has had a recent
> burst.
>
> This is an interesting study, and I recommend this for those who
> haven\'t come across it yet. This came out of Brant in the U.K., and
> it\'s a very large analysis of cost-effectiveness of various
> treatments in different categories. So I\'ve listed, for a reference,
> what the normal range is; untreated adult height, the growth hormone
> dose, the growth hormone adult height estimated mean, and the cost,
> that I\'ve converted into U.S. dollars from the British pound\--cost
> per centimeter.
>
> And, again, the growth hormone deficient is the most efficient, if you
> will, and achieved relatively good adult heights for the lowest
> cost-per-centimeter, roughly 10K. Chronic renal failure, quite
> variable, depending on what age you\'re treating, so the size of the
> patient. And, again, achieving low normal heights but, \$10,000 to
> \$40,000 per centimeter. And this is per centimeter.
>
> Here\'s the group for idiopathic short stature. And, again, the doses
> are in this range. Predictions are potentially that mean adult height,
> and the doses are up, again, as high as 40-odd thousand dollars per
> centimeter. So, times three centimeters, that would be about
> \$120,000, roughly. And then Turner\'s, for reference, is at the
> bottom here, again with the highest dose that\'s been approved so far,
> costing roughly \$25,000 to \$30,000 per centimeter.
>
> So these are very expensive centimeters.
>
> The other issue is: is this really a medical problem or a social
> problem, or whose problem is it? Short stature is not a medical
> diagnosis, as you\'ve heard. It\'s really a descriptive term for a
> person whose height is considered to be significantly below some
> arbitrary normal range for that age, gender, racial group and family
> structure.
>
> It\'s also a statistical term, and that\'s what we\'ve focused on
> mostly this morning. It\'s generally referring to people who are
> shorter than the 97th percentile of their age and sex-matched peers.
> Thus, in any population, nearly three out of a hundred would meet this
> definition and be called short stature, even though they have no
> medical abnormality.
>
> And, as we all know, height perception is influenced by a wide variety
> of factors, including culture, gender, family background and
> psychological state.
>
> I\'d like to address the psychological state issue, briefly. These are
> just some of the references that have been published on this topic.
> Basically, dating back almost 10 years\--and this was made reference
> to earlier this morning\--if you look at short stature in a
> population-based group and not in a clinic-referred population, there
> is not a clinically significant psycho-social morbidity. Several
> studies from Gilmore and Skuse in the U.K.\--little evidence to
> suggest that even in a clinic-referred population, untreated short
> stature children are psychologically maladjusted.
>
> And then Downie\--there was actually a study involving growth hormone
> treatment and not-growth hormone treatment, and there was no
> psychological benefit of growth hormone treatment in that particular
> study.
>
> And then, finally, looking at adults who were short stature in
> childhood, and evaluating them as adults, they did not show any
> psycho-social distress or impairment, and therefore did not provide
> evidence for growth hormone treatment of short stature in childhood.
>
> I\'d like to just refer you to equipoise, and how this could be
> applied to this discussion. Equipoise demands that the following three
> psychological effects are considered before assigning benefit in short
> children treated with growth hormone. The first that, indeed, it\'s
> beneficial, improved self-esteem due to increased height velocity or
> increased final adult height; it\'s harmful, due to disappointment
> with final adult height or poor self-esteem due to increased
> medicalization, daily injections and other issues related to
> non-improvement; and then neutral, no psychological benefit. And
> that\'s, I think, what we heard from the randomized trial this
> morning.
>
> So, in summary, the number of subjects in randomized controlled
> studies of growth hormone therapy to final height is very limited, and
> this includes the small numbers in GDCH.
>
> The final\--again, just to repeat, as you\'ve heard many times\--and
> the real question we\'re debating\--is this clinically significant,
> considering that there was quite an overlap with the placebo group who
> showed spontaneous catch up? A majority of studies are uncontrolled,
> and final adult height attainment over predicted adult height\--which
> we\'ve heard the problems of predicted adult height\--has indeed
> averaged less than one standard deviation, and this is presented to
> you, identical what has been published in almost 500 children with
> spontaneous height gain in children who were called idiopathic short
> stature.
>
> An interesting study, again, from Ranke: in 236 normal short children,
> two-thirds spontaneously achieved normal adult height. One quarter did
> not, and only 10 percent did not reach the familial target height. So
> the outcome for this logged cohort was actually quite positive.
>
> Few studies have actually addressed the downside or negative outcome.
> You can infer this, maybe, from dropouts. In Australia, in a study in
> 1996, out of almost 1,400 children who were receiving growth hormone
> for idiopathic short stature, one-third did not complete the three
> years of treatment. And this is, as in the studies reported this
> morning, due to patient decisions in the large main. In the particular
> GDCH study reported this morning, only 28 of the placebo and 42
> percent of the growth hormone therapy group actually completed the
> study.
>
> And as I\'ve indicated, few studies have addressed the psychological
> benefit of growth treatment to final height for idiopathic short
> stature, and this continues to remain unproven.
>
> Thank you. This is the reference, for those who would like to have the
> full reference.
>
> DR. BRAUNSTEIN: Thank you.
>
> **Committee Discussion**
>
> DR. BRAUNSTEIN: We\'ll take some questions for Dr. Guyda\'s
> presentation.
>
> Dr. Gelato?
>
> DR. GELATO: Maybe I\'ll just bring this up now, and sort of get
> people\'s feel about it.
>
> In August of 2002, the Lawson Wilkins Society gave recommendations for
> giving children who have short stature a trial of growth hormone if
> they met certain criteria. And I just wondered what people thought
> about the Lawson Wilkins proposal, which listed several things: a
> height more than three standard deviations below the mean age, or two
> standard deviations below mid-parental height centile; a growth
> velocity less than 25th percentile for bone-age; a bone-age that was
> delayed by more than two standard deviations below the mean; and then
> a low serum IGF-1 and/or IGF-BP3, or other clinical features of growth
> hormone deficiency.
>
> And their feeling was that if children met most of these criteria, it
> would make sense to give them a trial of growth hormone. And I just
> wonder what people thought, because this seems to be different than
> what we\'ve been talking about. Obviously these are children who are
> more severely affected, but still was the recommendations of one of
> the pediatric societies. And I just, you know, throw it out for a
> point of discussion in terms of everything that we\'ve been talking
> about, and what people feel about it.
>
> DR. BRAUNSTEIN: Harvey, you want to comment?
>
> DR. GUYDA: Hah\--is that question for me?
>
> DR. GELATO: Well, I just\--I\'m just curious, because, you know,
> they\'ve given guidelines, and yet it seems like there\'s\--
>
> DR. GUYDA: I actually would like to comment on guidelines, because
> earlier we heard this morning that the pediatric endocrine fraternity,
> to which I belong, are efficient gatekeepers. If you look at the
> databases\-- and you saw presented by Dr. Quigley this
> morning\--there\'s almost 6,000 short children in NCGS, and almost
> 4,000 in KIGS who are getting growth hormone treatment\--off-label
> use; gatekeepers giving it to all those children. That represents
> about 25 percent of NCGS.
>
> So, gate-keeping and making recommendations don\'t seem to translate
> into what happens out in the field. And if you recall the last
> published statement of the Lawson Wilkins was that growth hormone
> should not be used for non-growth hormone deficient short children,
> and this has not prevented this\--it\'s over 10,000 children in the
> U.S. getting growth hormone for short stature.
>
> DR. BRAUNSTEIN: Dr. Cara?
>
> DR. GUYDA: I agree the more rigid you are and more strict you are, you
> might identify those children who are going to have potentially a
> better benefit. And I think the target for all of us in pediatric
> endocrinology is: how to dice up those kids? How do you find the ones
> who are going to be above the placebo, and the ones who are going to
> benefit? And we haven\'t gotten there.
>
> And I know Ron, and Ray and others have tried very hard to look at
> short-term and long-term predictive\--both biochemical and oxyological
> data. It just hasn\'t worked in large groups. Individually sometimes
> it works, but in large groups it hasn\'t been very useful.
>
> DR. BRAUNSTEIN: Dr. Cutler, you want any of your consultants to also
> comment on the question?
>
> Dr. Hintz?
>
> DR. HINTZ: Dr. Hintz, from Stanford. Just a quick comment on the
> implication that that was an official statement from the whole Lawson
> Wilkins Society. That was, you know, three people from the Drug and
> Therapeutics Committee writing and article with some proposed
> criteria.
>
> So\--and I personally felt at the time that those were extremely
> conservative criteria. In fact, if you fit all those, you\'ve got
> growth hormone deficiency.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Cara?
>
> DR. CARA: Harvey, could you comment on the sort of observed efficacy
> of growth hormone as a function of time? Specifically during the
> pubertal years, and perhaps related to a graph that the FDA presented
> on page 27 of their briefing document\--of their review\--looking at
> 12-month height velocity, versus years of study.
>
> I don\'t know if you saw that?
>
> DR. GUYDA: Actually, I\'m thinking more of what the statistical
> consultant did with that kind of data. It was clear that some children
> actually accelerated and gained in their SDS, but when you follow them
> to the end, they actually ended up not quite as high as they had been.
>
> So\--the numbers are small. And we\'ve heard that bone-age in puberty
> were not different, but the numbers are too small to really indicate
> whether, in fact, that particular subset of patients did have an
> earlier puberty, an earlier acceleration and ended their growth
> earlier, and then started to fall off.
>
> DR. BRAUNSTEIN: Yes\--Dr. Grady?
>
> DR. GRADY: I just wanted to ask for your opinion. You know, again,
> we\'re talking about here perhaps making eligible one in every hundred
> children for treatment with a hormone at\--early in life, for multiple
> years. And we haven\'t spent much of any time on the potential adverse
> effects.
>
> Clearly, the studies have been too small to give us much information
> on death or serious adverse events. But, I mean, are we\--is this
> assumed by most pediatric endocrinologists to be a safe therapy?
>
> DR. GUYDA: Ahh\--well, actually, I was going to ask the question, but
> I realized it was committee-only asking questions earlier.
>
> When Dr. Quigley was presenting the safety data, and was using the
> reference as indicated use currently, it was curious to me that the
> recent sudden publication of seven deaths in Prader-Willi were not
> mentioned. So there are surprises out there. Whether that\'s directly
> related to growth hormone or not is still a moot point. We\'ll have to
> wait over time and see.
>
> I can\'t use the CJD model, because that was pituitary extracted,
> obviously; the leukemia model caused a big flurry, but over time that
> seemed to settle down and did not seem to be statistically more
> increased.
>
> I think one of the concerns\--two areas of concern bother me. Dr.
> Tamborlane made reference to the possibility of the insulin glucose
> issue and prolonged hyperinsulinemia over time, and what that might do
> over time. And the other issue\--are the values of IGF-1
> really\--particularly if we\'re going to go up to .375 or higher\--are
> they going to be above normal, and what is that impact going to be on
> tissues who are both sensitive during pubertal growth spurts, but
> ultimately down the road, in terms of neoplasia.
>
> And I think that remains a big concern for me, even though there\'s no
> data to support the fact that that\'s going to happen, we can
> anticipate there may be something along that line, but we don\'t have
> the data on that.
>
> DR. BRAUNSTEIN: Other questions from the committee?
>
> DR. FOLLMAN: Yes, I have one.
>
> Slide 5 you showed the spontaneous adult height in children with short
> stature, and you showed some very large increases\--like on the order
> of greater than one standard deviation score.
>
> Could you go into a little more detail about that data?
>
> DR. GUYDA: This is\--
>
> \[Pause.\]
>
> \--sorry. Not my computer. Find the mouse here. Here we go. Aw, this
> is going to take forever.
>
> \[Pause.\]
>
> DR. BRAUNSTEIN: Yes, this is the slide.
>
> DR. GUYDA: This is just published literature again. It\'s measured
> height, not predicted; and Ranke particularly is someone who is very
> interested in the whole issue of short stature.
>
> The other issue that we didn\'t touch on too much, and I didn\'t
> stress in my publication, in both the randomized study, controlled
> study, at the NIH and in the European study, there\'s about a two-year
> delay in bone age\--as a pediatric endocrinologists in my clinic, when
> I was taught by Robert Blizzard, if you had more than one standard
> deviation delay in bone age, that then had to raise the concern of
> whether you had a chance for a delay in puberty and a different
> prognosis than someone who only has\--quote\--a \"normal\" bone age
> within, say, one standard deviation.
>
> So there is a delayed bone-age effect, and a good part of this data
> would be probably related to kids who have a delayed bone age and get
> to be\--I think you asked the earlier question\--if you\'re starting
> at minus-2 standard deviations, and then you have a delayed bone age,
> you\'re going to probably get to be taller than that eventually.
>
> And I think this is partly what this data reflects. It\'s very hard to
> distinguish kids who are absolutely just normal short stature, and
> those who have some delay in bone age, some potential for delay in
> puberty.
>
> Does that answer your question? I\'m not sure\--
>
> DR. FOLLMAN: Well, I had a question\--that partially answers it. I was
> curious about how these patient were selected. Were these just all
> observational studies of short stature children that they got at the
> clinic? Or\--
>
> DR. GUYDA: No, these are pediatric endocrine clinics. It\'s the single
> most common cause of referral to a pediatric endocrine clinic, so you
> can run up these numbers pretty quickly.
>
> DR. FOLLMAN: Thank you.
>
> DR. BRAUNSTEIN: Yes\--Dr. Woolf?
>
> DR. WOOLF: Getting back to the\--let\'s say the non-orthodox use of
> growth hormone in short stature, and your allusion to gatekeepers, how
> do those people\--how did these kids in the States, do you think, got
> treated if, in fact, all these checks and balances are in place to
> prevent that?
>
> DR. GUYDA: I really think that should come from the providers of
> growth hormone.
>
> DR. BRAUNSTEIN: And we can ask that question after lunch.
>
> A few others?
>
> DR. MacGILLIVRAY: It\'s important to remember that the children we\'re
> talking about are as short as the children with growth hormone
> deficiency, but test out with a peak growth hormone above 10 nanogram
> per mil. And the insurance companies approve growth hormone for growth
> hormone deficiency based on the stimulation tests. So the children who
> are currently receiving growth hormone from\--for idiopathic growth
> failure or short stature, or non-growth hormone deficient growth
> failure are children who have pathologic height and often pathologic
> growth rate, and when they\'re followed over time, their height is
> progressively falling further away from the 3rd centile.
>
> When you apply to the insurance companies, you will get rejected. And
> then the next thing is you make an application for some of the
> foundations run by certain pharmaceutical companies to assist you with
> a six-month treatment trial. If in that six-month treatment trial you
> show a significant improvement in growth rate\--by that I mean a
> growth rate annualized of 9 to 12 centimeters a year, you go back to
> the insurance companies and say to them: it is possible that that
> child\'s able to respond to stimulation tests, but they\'re
> pituitaries may be under-producing growth hormone because of
> insufficient GHRA, or that the potency of the growth hormone they
> produce is sub-optimal, but they are responding to growth hormone.
>
> So it\'s extremely important to look at responsive children, and then
> you make the decision to keep going every six months. So a majority of
> these children are receiving growth hormone because they are
> responders in the first six months.
>
> DR. BRAUNSTEIN: Dr. Grumbach, do you want to comment?
>
> DR. GRUMBACH: I think that Harvey has pointed out something important,
> but I\'d like to criticize some of the data on that slide.
>
> For example, the Crowne studies from Manchester\--and their study was
> looking at kids with very marked constitutional delay in adolescence.
> Now, they got to 1.8, but that was less than their\--what you would
> get from family height. In other words, their\--based on mid-parental
> height, they were still below what they should have achieved.
>
> That\'s also true of the LaFranke study, which was from
> Portland\--both of these are really very nice studies\--again delayed
> adolescence. They got to 1.2, but that was about a mean of over a
> centimeter less than their mid-parental height; what their predicted
> height was.
>
> So I think what Harvey has up there are a lot of kids that we all see,
> with severe constitutional delay; very marked delay in bone age, and
> we\'re all aware that many of these catch up.
>
> But the important point that\'s come out of these long-term
> studies\--that they don\'t catch up to their predicted height; to what
> their\--based on mid-parental height. They all end up, as a group,
> lower.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Rosenfeld?
>
> DR. ROSENFELD: I\'m a little bit concerned that Drs. Cutler and
> Quigley are somewhat constrained in their presentation by feeling a
> need to adhere strictly to the data from the Lilly studies. And I\"d
> like to just take a minute and put it in a broader context.
>
> First of all, I was quite struck by their data, in that it is, for
> better or worse, the one and only placebo-controlled trial to adult
> height and will never be duplicated. Even given the fact that, as Dr.
> Guyda pointed out, they used initially sub-optimal dosages,
> sub-optimal regimen, in terms of three times per week, and an older
> age group than one would ideally choose if one were doing this study
> now, they still showed a statistically significant effect, no matter
> what statistical parameters were employed.
>
> Secondly, in their dose-response study, they corroborated their
> ability to show a statistically significant effect, and a
> dose-response.
>
> I think, given that context, and given everything that we\'ve seen
> over the last 20 years, in terms of growth hormone administration, I
> think that perhaps those of us who are not so constrained to use the
> Lilly data would say that this is a highly conservative estimate of
> what the impact of growth hormone therapy can be in this group of
> severely affected non-growth hormone deficient short stature children.
>
> The data show that these children do not enter into the normal adult
> height spontaneously; that there is a dose-response; that, given
> optimization of regiment and higher dosages, just as has been seen
> with other applications of growth hormone, as in Turner\'s syndrome,
> this is a highly conservative estimate.
>
> So, while I understand that we are limited to some extent by the data
> that are presented, I don\'t think we should close our eyes to the
> fact that these children are severely growth retarded. They are as
> growth retarded as all of the other FDA approved indications. They do
> not catch up on their own. And that the data presented are likely to
> represent\--as the Lilly dose response data have shown\--a
> conservative estimate of the impact of growth hormone therapy in this
> group.
>
> DR. BRAUNSTEIN: Dr. Guyda, we\'ll give you the last word before we
> break for lunch.
>
> Dr. Grady first.
>
> DR. GRADY: Can you just tell me, in the cost-effectiveness analysis
> that you presented\--what was the assumed dose, and what the assumed
> duration of treatment.
>
> DR. GUYDA: Again, the dosing varied, depending on the
> indication\--whether it was renal failure, or growth hormone
> deficiency. The lowest doses tend to be for growth hormone deficiency,
> and the\--
>
> DR. GRADY: But for the idiopathic short stature group.
>
> DR. GUYDA: Idiopathic\--the range that I presented there was .2 to
> .4\--so in the range that we\'re discussing this morning, up to .375
> in the high-dose study that was reported this morning. So that was the
> dose range.
>
> DR. GRADY: And for how many years?
>
> DR. GUYDA: Again, most of those treatment effects will vary depending
> on diagnosis. Chronic renal failure tend to use it for a period to get
> them tall enough for transplant, so it\'s never a final height data
> particularly. But in the idiopathic short stature group, it\'s usually
> in the range of four to five years.
>
> DR. BRAUNSTEIN: Dr. Cutler, did you have a comment?
>
> DR. CUTLER: I just wanted to\--I thought I ought to point out just two
> things about this review that Harvey has shown us.
>
> And one of the things I thought was somewhat deceptive about Dr.
> Price\'s review is the title is \"Spontaneous Adult Height in Patients
> with Idiopathic Short Stature.\" Yet, if you actually read the titles
> of the papers, all but one of them use \"constitutional delay of
> growth in adolescence.\" Their\--they have selected out that group
> that we all know catches up because they have the family history of a
> catch-up, and so forth. It\'s the group that we all try not to treat.
>
> And one other thing I would say is that of these studies, only one of
> them has even a mean height that is below the cut-off that we\'re
> recommending. All the others have a mean height\--this one even has a
> mean height well into the normal range. So this is a different
> population from what we\'re talking about. We\'re talking about a much
> shorter group, and not a group that is specifically being perceived by
> the authors to have constitutional delay. This is just really echoing
> the point that Dr. Grumbach made.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Guyda?
>
> DR. GUYDA: I think what we\'ve heard is there are diagnostic dilemmas
> and there are patient management dilemmas, and there\'s no easy
> solution to this.
>
> The issue of what\'s constitutional delay something we discuss in our
> clinic and teach to our trainees all the time, in the context of short
> stature. I would ask Dr. Cutler, who spoke most recently: is a
> two-year delay in bone-age normal short stature? Or has that got some
> constitutional delay in it?
>
> Sorry about that.
>
> DR. CUTLER: Yes, I think if we had to settle a definition of
> constitutional delay we probably would be here all day.
>
> I think there is a criterion\--and we could actually show it later, if
> you all want\--that is published in Williams\' textbook. It was the
> only one we were able to find that could actually be rigorously
> applied, because it was specific enough. And it\'s quite lengthy. So
> it\'s much more than just\--it does have a bone-age delay, but it\'s
> not just a bone-age delay. And, certainly, a bone-age delay per se, in
> my judgment, is not enough\--if someone\'s, you know, minus-3 or 4 SD,
> with a two-year bone-age delay, that\'s not enough to say they have
> constitutional delay in my judgment.
>
> DR. BRAUNSTEIN: Dr. Tamborlane.
>
> DR. TAMBORLANE: But, Gordon, don\'t you think\--I mean, the indication
> says \"height less than 2.24 standard deviation score.\" So when
> people are actually applying this, then they\'re not going
> to\--there\'s nothing that says anything about without a more than
> three-year delay in bone-age. So this really opens up treatment for
> constitutional delay of growth and development.
>
> DR. CUTLER: Well, that certainly would not be our intention. And I
> think it also would not be the intention of the pediatric
> endocrinologists because, as you know, we\'re all trained not to treat
> constitutional delay. And the issue, I think, that you\'re raising\--
>
> DR. TAMBORLANE: I went to parochial school, and the nuns told me about
> intentions\--good intentions, and where you lead you.
>
> \[Laughter.\]
>
> DR. CUTLER: Well, I think there will be\--this is a good point, and
> I\'m sure there will be time for more discussion about this.
>
> The issue is whether you practice medicine in the label. This is
> already the only label for any growth hormone indication that has any
> restriction on even a height cutoff. So this is already the most
> restrictive. If it should be more restrictive is the kind of debate
> and discussion you were asked to have.
>
> DR. BRAUNSTEIN: Dr. Guyda? Final comments?
>
> DR. GUYDA: No. I\'m done. Thank you.
>
> DR. BRAUNSTEIN: Great. Thank you very much.
>
> We\'ll break for lunch and reconvene at 1:30. Thank you.
>
> \[Whereupon, a luncheon recess was taken to reconvene at 1:30 p.m.,
> this same day.\]
>
> AFTERNOON SESSION
>
> DR. BRAUNSTEIN: If we could have the committee take its seats, please.
>
> \[Pause.\]
>
> **Open Public Hearing**
>
> Okay. We\'ll now open the Open Public Hearing. And we\'ll have read
> into the record a letter that\'s been received.
>
> MS. SPELL-LeSANE: Thank you, Dr. Braunstein.
>
> This letter was addressed to the committee from the Short Child
> Family, regarding FDA Hearing on June 10, 2003.
>
> \"We are writing to support the application by Eli Lilly Company for
> approval to treat non-growth hormone deficient short stature with
> growth hormone.
>
> \"We understand that an FDA hearing is scheduled for June 10, 2003. We
> would like our letter to be noted and read for that hearing, since we
> cannot be present in person to testify.
>
> \"We want to tell you our story so that the FDA will understand how
> approval of this new indication will affect our family. My son Bradley
> is 15 years old, and when he started the growth hormone therapy he was
> only 4\'10\" tall. People still look at him as a young child; child
> rate at the movies and the theme parks.
>
> \"Bradley always looked at himself as a short kid. Now he has grown
> 2-1/2 inches since January, and now his self-esteem is great. He is
> always measuring himself to see if he has grown.
>
> \"As a parent, I am very glad there is something out there to help my
> son. Please do not take this away from him. It was not easy to get the
> insurance company to pay for the growth hormone. We went through a lot
> just to get started. It just does not seem fair to take it away.
>
> \"Again, Bradley has made a significant growth spurt since on growth
> hormone. We anxiously await the public announcement of your decision
> on this matter. Respectfully, the Short Child Family, Bobbie, Vicki,
> Bradley, Amanda and Amber.\"
>
> DR. BRAUNSTEIN: Okay.
>
> There\'s also an additional letter in the folder for the committee to
> read.
>
> Our first public speaker is Patricia Costa from the Human Growth
> Foundation.
>
> MS. PATRICIA COSTA: Hello everyone. I am Patricia Costa, the Executive
> Director of the Human Growth Foundation. I have paid for my own
> expenses to be here today.
>
> The Human Growth Foundation is located in Glen Head, New York. It is a
> non-profit organization that has been in existence for over 38 years.
>
> Our mission statement is: \"The Human Growth Foundation helps adults
> and children with disorders related to growth or growth hormone,
> through education, support, advocacy and research.\" We receive our
> funding from our membership dues, the Combined Federal Campaign,
> United Way, health care providers, pharmaceutical companies, including
> Eli Lilly, several private foundations, and many individual donors.
>
> On May 9th I read an e-mail from one of our members on our HGF-Peds
> list. That is one of our internet support groups. In her e-mail, this
> member stated that her child\'s pediatric endocrinologist had told her
> that a new drug application for RGH was being considered for use in
> children who are not growth hormone deficient. Prior to viewing this
> communication, I had heard about this through a doctor from Eli Lilly.
>
> I then asked our list administrator to look into this matter further.
> He found additional information and posted his findings, along with
> the FDA website, on our list. I then spoke with several of our board
> members, who felt that it was important for us to have a presence here
> today, to speak on behalf of the children who would be helped from
> this application.
>
> When I started to prepare this statement I knew that all the clinical
> data, studies and testimony of the experts in the field of growth
> would have been heard and recorded. I am here today to ask all of you
> not only to consider the medical data that\'s before you, but also to
> measure the psycho-social well-being of these children.
>
> Every year we receive hundreds of inquiries from parents who are
> concerned about their child\'s height. Inevitably, in every one of
> these conversations, these parents make reference to their child\'s
> low self-esteem. They speak of the teasing, the bullying and the
> isolation that their child deals with because of their abnormal short
> stature.
>
> During this initial conversation, we explain the normal protocol that
> is necessary for this child to be diagnosed. We send them our
> educational booklets. These are medical booklets on various disorders
> that have been written for a non-professional to be able to
> comprehend. We advise them of our HGF-Peds list, a place where they
> can communicate with other parents who share the same concerns.
>
> These first communications usually prompt two or three additional
> calls from these parents. They call not only to inform us of their
> child\'s diagnosis, but also to receive the assurance that they will
> be able to give their child the daily shot, and that quickly this will
> become a normal pattern in their everyday life.
>
> The next call is a joyous one\--the one where the parent informs us
> that not only has the child grown, but that he or she is happier. One
> mother told me about the conversation she and her son had after they
> left the doctor\'s office after his first three-month visit. Her son
> told her how happy he was, because some day he was going to be the
> same size as his friends. The mother then became emotional and said to
> me, \"Patty, I never heard those words \'my friends\' come out of my
> son\'s mouth.\"
>
> However, all of our calls do not have such a happy ending. For parents
> whose children are abnormally short and their problems could not be
> identified, these parents now have dual concerns: their child\'s short
> stature, and their child\'s self-esteem that is plummeting. We have
> heard stories of children who have become withdrawn, coming home from
> school and staying alone in their room; the child who, he himself now
> might have become the class bully; or another child who is being
> labeled the class clown. On rare occasions, we hear, as one father
> informed us, every morning his kitchen has become a battlefield, with
> his daughter crying and refusing to go to school because everyone
> laughs at her because she is so tiny.
>
> How can we continue to justify to these children that we know the
> solution, but because we can\'t pinpoint the problem, they do not have
> the right to it? We all know that at some time in every child\'s life
> they want to be somebody; they look up to somebody. It might be a
> movie star, a baseball player, or the President of the United States.
> And we all recognize this is normal. What also should be normal is for
> these children to be able to see eye to eye with everyone else.
>
> You have a recommendation before you, the denial of which will result
> in a lifetime for these children. These children are our future.
> Please allow them to grow to their full potential; to grow up to be
> adults who believe in a system that works and, more importantly, in
> themselves.
>
> Thank you.
>
> DR. BRAUNSTEIN: Thank you.
>
> Our next speaker is Nicole Costa.
>
> MS. NICOLE COSTA: Good afternoon. I\'m Nicole Costa. I live in Glen
> Head, New York. All of my expenses to be here today were paid for by
> my parents. They knew that I felt it was important, not only for you
> to hear my story, but for you to see with your own eyes the results of
> the application that is before you today.
>
> Before I share my story with you, I would like to thank you for giving
> me the opportunity to participate in this hearing, and to let you know
> how lucky I feel to be able to stand in front of you without the aid
> of a box. This result is due to the wisdom of my endocrinologist.
>
> According to my parents, I had always been on the very bottom of the
> growth chart. I never reached the 5th percentile\--the magical number
> that you say is normal\--that says you\'re normal. When I was three
> years old, my pediatrician told my parents to take me to a pediatric
> endocrinologist because of my short stature. At that initial
> appointment, my height and weight were taken; my head, torso and limbs
> were also measured.
>
> My growth chart from the pediatrician was observed, and my parents\'
> history of their height and development was recorded. We left the
> doctor\'s office with prescriptions for several blood tests, a test to
> karyotype for Turner\'s syndrome, and an appointment for me to have a
> growth stimulation test.
>
> Two months later we returned, having completed all the tests. The
> doctor told us that the tests were all normal. From the test results
> she could not tell us the reason for my slow growth pattern. The
> doctor told us to come back in six months so she could monitor my
> growth.
>
> We continued these six month visits for three-and-a-half years. By
> then, I was six-and-a-half years old. The doctor, after watching my
> growth for three-and-a-half years, estimated my adult height would be
> approximately 4\'8\". It was at that moment that my doctor recommended
> growth hormone therapy, to see if this would change my growth pattern.
>
> After being on growth hormones for three months we returned to the
> doctor\'s office. I had grown 3/4 of an inch. On a good year for me,
> that was the growth for an entire six months.
>
> I continued on growth hormone therapy for almost seven years. It was
> then that my bones fused together and I reached the height of 5\'2\".
> I can\'t honestly tell you what my life would have been if I was only
> 4\'8\", however I do know I would never have been able to go into a
> department store and buy something off the rack. I would not be able
> to reach the items on the upper shelves of supermarkets. And, most
> definitely, I would not be able to drive a normal size car.
>
> What I can share with you are some of the experiences that I went
> through because of my short stature. I was not able to reach the
> kindergarten water fountain when I was thirsty. No one on the
> playground chose me to be on their team because, in their words, \"You
> can\'t run fast enough because your legs are too short.\" How lonely I
> felt sitting on the park bench at the amusement park waiting for my
> peers to get off a ride; a ride that I wasn\'t allowed to go on
> because I was too small.
>
> When it came time for my first communion, my mother said that it was a
> special day and it required a special dress. We went to the dressmaker
> to have it handmade. Neither of us ever mentioned the real reason,
> which was there wasn\'t a manufacturer who made a communion dress
> small enough for me to wear.
>
> In second grade, the teacher required that everyone\'s feet had to
> touch the ground when we were seated at our desks. They had to bring
> in a chair from the kindergarten class for me to meet that
> requirement. You can imagine how embarrassed I felt.
>
> I always loved sports and wanted to play. However, because of my
> height I was restricted in my choices.
>
> I began my comments by saying how lucky I was that I was given the
> opportunity to reach my full growth potential. I hope that by the end
> of this day, after listening to my story and seeing the positive
> results of the drug application that is before you, this opportunity
> will be made available to all the children who now walk in the shoes I
> outgrew.
>
> This drug application will make a world of difference to these
> children. It will make their world a different place.
>
> Thank you.
>
> DR. BRAUNSTEIN: Thank you.
>
> The next speaker is Deno Andrews.
>
> MR. ANDREWS: Thank you.
>
> On my knees, today, I stand two inches taller than the first
> endocrinologist told my mother that I would ever reach as an adult.
> However, I was treated successfully with growth hormone, as you guys
> can see. And I reached a very normal adult final height.
>
> I was lucky. There was a clear diagnosis for me: growth hormone
> deficiency. My pituitary gland produced no growth hormone whatsoever.
>
> But many children are not as lucky as I was. Their diagnostic tests
> sometimes suggest that they are not growth hormone deficient.
>
> My name is Deno Andrews. Again, I was successfully treated with growth
> hormone. And I hope that my story will offer you another perspective
> to consider before making such an important decision today.
>
> When I turned five, my mother insisted to our pediatrician that
> something was wrong. Our pediatrician told my mother that I was a late
> bloomer; that I would catch up; that nothing was wrong\--despite the
> fact that my sister, who was two years younger than I was catching up
> to me in growth.
>
> By the time I was seven, I was not only the shortest child in the
> first grade, most kids in kindergarten stood taller than me, including
> my sister.
>
> As you can imagine, this was a very difficult time for me. On a daily
> basis I was called words like \"midget,\" \"shrimp,\" \"small-fry,\"
> \"shorty,\" and a number of other derogatory terms. Life on the
> playground wasn\'t easy either. I was always the last one chosen to
> play on any sports team. I was laughed at in gym because I was so much
> smaller than everybody, that I couldn\'t run as fast as everybody
> else. Basketball was a joke. I was always pointed and laughed at
> whenever I had the ball in gym class.
>
> I was so small that the gym teacher wouldn\'t allow me to climb across
> the stall bars like all the other children. Instead, I had to climb
> up, hang for a few seconds, and then climb down. So, again, I was
> singled out because of my height.
>
> Take all these factors, and it\'s no wonder that I became a bad
> student. I was detached and alone most of the time, and the last place
> in the world I wanted to be was at school, where every child belongs.
> Needless to say, I spent some time during school days watching the
> Cubs lose\--mostly\--in the late \'70s, for Wrigley Field was right
> down the street from Children\'s Memorial Hospital, where I began
> therapy\--being treated with human growth hormone from cadavers.
>
> In the late \'70s, human growth hormone was in short supply, and
> common thought was to deliver growth hormone in the muscle, not in the
> subcutaneous tissue as it is done today. So when I started therapy, it
> was using very large needles only three times a week. This sort of
> therapy was rare and unknown by most.
>
> My mother searched for information, mostly unsuccessfully. There was a
> small group at the time called the Human Growth Foundation\--you\'ve
> just heard from them\--and the Human Growth Foundation, at the time,
> was the only organization that offered any sort of information to the
> lay person, outside of the typical doctor talk that you\'d hear in an
> endocrinologist\'s office.
>
> My mother became involved with the Human Growth Foundation and quickly
> became the director of chapter development. She flew around the
> country and organized groups of people that all had children affected
> by growth disorders; whether growth hormone deficient, or idiopathic
> short stature. After some time, the direction of the organization was
> not exactly in line with what my mother had in mind for an advocacy
> group. So she decided, with a small group of other parents, to start
> the Magic Foundation for Children\'s Growth.
>
> This organization started in a bedroom\--my bedroom. I was kicked out
> and I had to go live in another bedroom. They started with a telephone
> and a typewriter. And 13 years later, they\'re now one of the largest
> organizations, and a leader in bringing advocacy and information to
> parents of affected children. They have members\--over 12,000
> worldwide\--from Nebraska to New Zealand.
>
> And while I\'m here on my own today, not as a representative of the
> Magic Foundation but, instead, as a patient and as an advocate, I do
> believe it\'s right that I disclose that the Magic Foundation, which
> does have a familial association, is funded through private donations,
> memberships, and grants from pharmaceutical companies, including Eli
> Lilly.
>
> What being a leader in endocrine advocacy means for my mother is not
> glory, or a feeling of dominance in the marketplace but, instead,
> tears. That\'s right\--tears. It is not uncommon for her to bring
> letters to me at family dinners or events. These letters usually talk
> about how difficult a time some child is having because they\'re
> short. And all these years I thought I had it bad, being picked on and
> called names. Some of the children I hear about are being physically
> abused or hazed on the playground and in the locker room, and are
> often detached from society.
>
> When I hear of studies that conclude that short kids don\'t suffer
> psychologically because of their height I know they are mistaken. You
> see, these short kids have to be tough; to build up a thick skin just
> to have the confidence to go to school everyday. So, when they\'re in
> a study and somebody is asking them whether or not their life is
> different because they\'re short, what these kids have to tell
> themselves and others is: \"No, of course, I\'m perfectly normal.\"
> And this comes out only after a great deal of trust and time is spent
> with each of these patients, may the truth possibly surface. And, in
> most cases, it doesn\'t.
>
> Dr. Guyda referenced a few of these studies in his presentation. What
> I suggest to anybody who\'s interested to see if short kids are
> affected by their height is that they come to the Magic Foundation
> national meeting\--it\'s next month, in Chicago. There you can meet
> hundreds of children\-- who are being treated, and not treated\--with
> growth hormone deficiency, idiopathic short stature and a number of
> other growth disorders.
>
> In this place you can find the truth. You can see kids talking to
> other kids about how bad their lives are, and what they share. Because
> they\'re in a group with their peers, they feel a little bit more open
> and address these issues much more than they would in a clinical
> office space in a research study.
>
> I lied. I\'ve been in more than one study in my life. In fact, I\'ve
> been in several studies. And whenever the question comes up how was my
> life, being short? Well, I don\'t know this person with whom I\'m
> speaking. Of course I\'m going to lie. Kids do not want to open
> themselves up to that sort of interrogation in a clinical setting.
> It\'s just not going to happen.
>
> Until that time that the truth is learned about short kids, I\'m here
> to tell you that the conclusions are incorrect. And I\'m okay with the
> act that my childhood was miserable until I started to reach my peers
> with regard to stature. I don\'t think most people who go through
> something like what I went through would be comfortable discussing the
> topic. Luckily, most of the kids that are diagnosed growth hormone
> deficient and experience a positive therapeutic course.
>
> However the story doesn\'t end there, does it? What about the kids who
> are not technically growth hormone deficient, and do not get treated,
> despite the obvious need for growth hormone\--to an endocrinologist,
> of course.
>
> So how is it that kids can technically not be growth hormone deficient
> but still respond favorably to growth hormone? Well, the fact is that
> endocrinology, with regard to growth disorders, in many ways has yet
> to be discovered. Simply deciding whether or not a child is growth
> hormone deficient, based on an arbitrary number\--mostly set by
> insurance companies, as is done today\--is just not good diagnostic
> medicine. In fact, in my opinion, it\'s quite irresponsible.
>
> We need to look at the big picture. And the big picture is this. It
> tells us that if a patient is more than 2.25 standard deviations below
> the mean in height, that something is wrong, more times than not. So,
> forget about whether or not a pituitary stimulation test reveals true
> growth hormone deficiency. If a child is short enough to be off the
> charts, there is no reason why growth hormone treatment shouldn\'t be
> tried, if a trained pediatric endocrinologist sees a need for it.
>
> What\'s great about growth hormone is that the results are pretty
> clear in the first year, if dosed properly. If a child responds
> well\--great. A life is forever improved. If there is no response, at
> least there will never be the \"what if?\" question asked by the
> endocrinologist or a family.
>
> What bothered me most as a child was that I was treated according to
> my height and not my age. At age seven, people spoke to me as though I
> were four or five years old. And until I was mature enough to realize
> what was happening, I thought they were a bunch of really stupid
> people in Chicago.
>
> \[Laughter.\]
>
> Being treated according to size has been a theme I\'ve watched
> throughout my life. And I\'ve found it to be more common than it
> should be. For nearly three years I worked for a pharmaceutical
> company selling growth hormone. I visited on the average of two
> endocrine offices a day. What I saw day-to-day was shocking to me.
> Doctors and nurses treating kids according to their size and not their
> age. Now, imagine what this must be like in real life for a child
> visiting an endocrine office and being treated in this way, where
> endocrinologists deal with growth disorders.
>
> The fact is that short kids are at a disadvantage. So the question is:
> is it right to treat someone who hasn\'t a clear diagnosis of growth
> hormone deficiency\--basically, is it right to treat idiopathic short
> stature with growth hormone?
>
> I say the answer is yes. It is as right as getting corrective lenses
> for eyesight that is abnormal. It is as right as an insurance company
> paying to repair a dent in a car. It is as right as getting a tutor or
> extra help at school for a child who isn\'t performing well.
>
> Most everything we know is measured against what we know as normal.
> From a statistical standpoint, negative 2.25 standard deviations below
> the mean falls just over the bottom 1 percent. What would you do if
> your child, for no reason, was learning at a rate below 2.25 standard
> deviation below the mean? Would you wait to see if they\'d catch up?
> Or would you do something about it? How about your 401(k)s\--your
> retirement plans? If your investments are performing at such a bad
> level, are you going to make the adjustment, or are you going to wait
> and see what happens?
>
> Would you send your child to a school that was in the bottom 1 or 2
> percent in the state\--or in the country, for that matter? Remember,
> this treatment is not around for kids to get tall. It is around so
> kids can get normal.
>
> So why am I speaking today? Why did I spend the money out of my pocket
> to be here today? This is something I\'ve been asking myself for
> weeks, since I discovered this proposed indication.
>
> The reason\--truthfully\--is that I\'m here to fight for all the other
> kids who deserve a fighting change to receive therapy that can and
> does improve life every day; to fight for therapy that is safe, that
> is abundant, well-regulated and monitored, and accepted as commonplace
> in the endocrine community.
>
> Your decision today can give endocrinologists the tools to help these
> really, really short kids reach a somewhat normal stature. People
> fought for me when I needed help, and I am here fighting for those
> kids who need help now.
>
> So, to borrow a line from my mother, Mary Andrews: \"Please remember,
> before you make your decision, that children have only a short time to
> grow, and a lifetime to live with the results.\"
>
> Thank you for your time.
>
> DR. BRAUNSTEIN: Thank you.
>
> The last public speaker is Dr. Sydney Wolfe, Director of Public
> Citizens Health Research Group.
>
> DR. WOLFE: Thank you for having the public session, which is an
> important part of meetings.
>
> I\'m just going to spend a few minutes talking about the benefits of
> this therapy, particular for people with idiopathic short stature;
> something about the risks; a little bit about the floodgate of
> unapproved uses that Lilly talked about in some statements it made to
> the press yesterday; and then just some concluding remarks by a couple
> people who have thought a lot about this issue, from a medical and
> psychological standpoint.
>
> First, as you heard in the presentations this morning, the average in
> the randomized placebo-controlled trial, the average increase was 1.44
> inches\--or possibly less. But that\'s the general range. There was,
> as you also saw, no evidence of any psychological improvement in those
> who got the drug, as opposed to placebo.
>
> I was very disturbed to hear the flippant Lilly response to the
> question this morning, which was: is it possible to predict who\'s
> going to have a benefit or not? And the response was: well, you can\'t
> tell whether they\'re going to grow two inches or four inches\--quote,
> quote. In fact, that\'s way above what the average is\--1.44 inches.
>
> Other phrases that were used this morning by Lilly, whether this is a
> \"pathologic\" height abnormality, and it\'s difficult to withhold
> treatment for people such as this. As Dr. Guyda said\--and I
> agree\--this is not a medical diagnosis but a description.
>
> I want to just spend a little bit of time on the risks, and just
> complain about the fact that I believe this is the first FDA advisory
> committee I\'ve ever been to in 32 years\--probably 50 or 100
> meetings\--where there\'s been no FDA presentation. If they had been
> here, they might have made a presentation about, certainly, one of the
> more worrisome risks, which is pseudo-tumor cerebrae, or a condition
> of increased intracranial pressure, with headache, nausea, vomiting,
> increased pressure reflected in papilledema and the optic nerve
> ending. And whereas the FDA has earlier, in 1995 and 1993, published
> some case reports, we reviewed the database and found an additional 25
> cases in children of intracranial hypertension or pseudo tumor
> cerebrae, for a total of 53 cases that the FDA is aware of. And many
> of these are four, five, six, seven-year-old children.
>
> Aside from the problem of having three or\--as Dr. Guyda
> suggested\--possibly five or six shots a week, once the child starts
> complaining of headache, nausea, vomiting and has possibly some visual
> changes, which occur commonly, they are subject to the same kind of
> work-up that you would have to do to rule out cancer. This is not
> cancer\--repeat\--but it\'s a condition clinically close enough to
> cancer that you\'d have to do an extensive work-up, including a lumbar
> puncture and an MRI and CAT scan and so forth.
>
> So, 53 cases\--this is as of the end of last year, and it\'s missing
> two or three years of data. So it\'s at least that high, and those are
> only the cases that are reported. It\'s estimated by the FDA itself
> that only about 1 out of 10 cases of adverse reactions are reported to
> the government.
>
> I\'d like to just go on to the issue\--again, Lilly raised this issue
> in comments made in the context of this hearing, that there might be a
> floodgate of use of this once the barrier is down. You heard this
> morning that there already is sort of a floodgate\--10,000 people were
> estimated\--10,000 children were estimated to be getting this for
> idiopathic short stature.
>
> This is, now, from a website from another group\--not the ones you
> heard of, but this one is called \"ShortSupport.org.\" It has links to
> Lilly for information about Humatrope, and it has links to Genentech.
> Now this is the first paragraph in it, and it flies in the face of\--I
> mean, the anecdotes you\'ve heard, particularly the last one from
> someone who actually has growth hormone deficiency, are real. You
> can\'t deny anecdotes, but the reason you do placebo-controlled trials
> is to see how the group getting a placebo compares with the other
> group.
>
> This is the opening paragraph on a website\--a widely-read website,
> apparently: \"Our society places a high value on a person\'s height,
> almost more than any other characteristic. Children who are shorter
> than their peers face significant challenges. They are often teased,
> often on the receiving end of name-calling prejudices. They may deal
> with their frustration by becoming depressed, angry or aggressive. If
> they do not experience a growth spurt they will face other challenges
> as adults. Parents need to be aware of these challenges so they can
> help their children become happy and productive.\" Again, the
> psychological evaluation in that study did not show that at all.
>
> This page describes some of the causes and treatments for short
> stature children: \"Administering human growth hormone is one
> treatment in certain cases, but we also explore other ways that
> parents can help children.\" Only several pages into this website do
> you find out that that\'s not approved for idiopathic short stature.
>
> Another example of the floodgate was a successful criminal prosecution
> of Genentech in 1999 by the Justice Department for illegal, off-label
> promotions; the first time there\'s ever been a criminal prosecution
> of a drug company for violating FDA rules. More recently there\'s been
> the TAP-1, concerning Lupron, but this is an early one. The company
> had to pay \$50 million, including \$30 million in criminal penalties,
> and \$20 million in civil penalties for illegally marketing
> Protropin\--their version of human growth hormone\--for treating
> children who were short for reasons other than a lack of adequate
> growth hormone, etcetera\--Turner\'s syndrome.
>
> So we already have a history of criminal off-label use. There is
> off-label use going on now. I have no evidence whatsoever that Lilly
> is doing anything like this, but the point is that the floodgate has
> already been opened to some extent. There would not be
> any\--quote\--\"denial\" of children who are already getting this if
> your committee decides not to approve it.
>
> But I would strongly urge against approval. And I\'d just like to
> close, as I said, with a couple comments from people who\'ve written
> about this. One is Dr. Vos, in the United Kingdom, who said,
> \"There\'s little evidence that the short but otherwise healthy child
> is inevitably disadvantaged or in any way missing the opportunity for
> individual fulfillment.\" She goes on to say, \"Even when a child is
> initially unconcerned, any attempt by the parent or doctor to modify
> his or her appearance may signal tacit disapproval. The short child,
> alternatively, who has unrealistic expectations as to the benefits of
> treatment may respond negatively to what is perceived as treatment
> failure.\" Again the majority of these people are not going to have
> very much of a growth spurt. Again, average 1.44 centimeters over
> four-and-a-half years. So the expectations are really very different
> than, I think, what the reality is likely to be.
>
> I\'m going to read one more thing. This is from a paper\--it\'s listed
> as a reference in the FDA handout\--from 1999, by Dr. Oberfield, a
> physician at Columbia College of Physicians and Surgeons. She says the
> following: \"one may ask whether the actual gain at final height in
> some children with idiopathic short stature who are treated with
> growth hormone is of real clinical or psycho-social importance. Can
> we, as we approach a new era of growth hormone augmentation therapy,
> continue to practice medicine without responding to pressure from
> society, parents, or our own biases\--\"\--and I would add pressure
> from the pharmaceutical industry.
>
> She goes on to say, \"I suggest we can practice and resist the
> pressure, and that we should heed the advice of the Greek philosopher
> Epictitus who stated that \'reason is not measured by size or height
> but by principles.\'\"
>
> Finally, Dr. Vos, who I quoted before, distinguishes between
> efficacy\--average height gain of 1.44 above placebo\--and benefit.
> And the case she makes is that in this circumstance, even if you can
> measure a statistically\--although questionably
> clinically\--significant increase in efficacy, the evidence of the
> benefit is just really not there.
>
> So, again, I urge you strongly not to approve of this for a number of
> reasons which have been stated more succinctly than I have.
>
> Thank you.
>
> DR. BRAUNSTEIN: This concludes the open hearing.
>
> **Committee Discussion**
>
> DR. BRAUNSTEIN: And before going and asking Dr. Orloff to give the
> committee the charge, I\'d like to reopen the discussion from the
> committee to Lilly to answer any questions that are still remaining.
>
> \[Pause.\]
>
> Yes\--Dr. Watts?
>
> DR. WATTS: We\'ve heard that the children in this trial, by height,
> were no different from children with growth hormone deficiency, and
> that they\'re growth response to treatment was no different than in
> children with growth hormone deficiency. Clearly they had different
> responses to provocative tests.
>
> Can you tell us about any other differences? Were there differences in
> body composition, for example\--or anything\--just anything other than
> short stature to suggest that their own growth hormone secretion or
> action was different from normal?
>
> DR. CUTLER: The main difference\--and this went by, probably, pretty
> fast in the baseline characteristics, because this group, as a whole,
> did have a rather low IGF-1 level. In standard deviation score, it was
> minus-1.6, I think, in one of the arms, and right at minus-1.2\--yeah,
> minus-1.5 in the placebo, and minus-2 in the Humatrope arm. And, on
> average, it was about, therefore, something like minus-1.7.
>
> And this is something that\'s been seen repeatedly in this group of
> children. It does suggest that they have at least about\--close to
> have of them actually have IGF-1 deficiency, even though the peak
> growth hormone tests are normal. And it\'s resulted in some people
> feeling that this should be called \"growth hormone action
> deficiency\" in some sense, because they seem not to be responding
> normally. Dr. Hintz likes that because that\'s the term he wants it to
> be called.
>
> But that\'s the main other difference.
>
> To my knowledge, no one has shown body composition differences, for
> example, in fat mass or lean body mass, or other differences of that
> sort, between the patients who test normally and those patients who
> have the average kind of response in growth hormone deficiency, say,
> between a peak level of 3 and 10.
>
> The extreme growth hormone deficient patients\--those who are either
> genetically or very, very deficient\--I think are often recognized by
> some phenotypic features that are well know, both morphologic and also
> tending to have about a half of a standard deviation higher body mass
> index and fat mass.
>
> DR. BRAUNSTEIN: Dr. Woolf?
>
> DR. WOOLF: Going through the flow chart of the pivotal trial, there
> were as many patients who discontinued growth hormone treatment on
> their own as completed the trial.
>
> What were the reasons that these people who\--these kids who were
> treated for at least six months discontinued the treatment?
>
> DR. CUTLER: The main reason for discontinuation was patient decision.
> And in contrast to normal practice, where you\'re going to a nearby
> office, almost all of these patients were referred from great
> distance. So they had to make\--and they were seen every six months.
> They had to make trips to the NIH every six months, and they received
> rather intensive investigation there. You saw some of the psychometric
> measures, for example, earlier. And just\--for some of them, it just
> was more than they wanted to maintain.
>
> I would say that at the time of dropout, that the mean duration of
> treatment in the non-final-height group was just over three years, on
> average. So they did stick with us for a fair period of time, and
> that\'s probably one of the reasons there\'s so little difference
> between the broader efficacy-evaluable and the final-height. They had
> a lot of treatment. But ultimately they were, you know,
> mid-adolescence, 15 or 16, they said, \"I\'ve just been traveling back
> and forth, missing enough school and so forth long enough,\" and chose
> to drop out.
>
> DR. WOOLF: Before they dropped out what kind of response to the
> treatment did they have?
>
> DR. CUTLER: Umm\--maybe the easiest thing would actually be to go back
> to the core slide, either the\--I think maybe the most useful one is
> actually the one that has the non-final-height sub-group. It\'s the
> one right before this one\--45.
>
> So these are\--these are all patients who dropped out, and therefore
> they\'re in the non-final-height sub-group. And these are placebo
> patients who dropped out. And the mean difference between them, in
> terms of growth hormone treatment effect, was .55. It\'s been rounded
> to .6 on this slide.
>
> The primary analysis result, which is basically here, was .51 SDS. So
> very similar, at least at their last observed height, to what was seen
> for the primary analysis.
>
> DR. BRAUNSTEIN: Dr. Cara?
>
> DR. CARA: Gordon, a couple questions, and then maybe a comment.
>
> Well\--we\'ve been talking about non-growth hormone deficient short
> stature as a sort of part of, or in the same sort of mind-set as
> Turner\'s syndrome, Prader Willi syndrome, chronic renal
> insufficiency. But I think that there are significant differences
> between those patient population and the children with non-growth
> hormone deficient short stature.
>
> One of the main issues that I\'ve been concerned about regarding
> growth hormone in this group of children is the fact that when it
> comes to children with Turner\'s syndrome, for example, growth hormone
> can be utilized well into late adolescence because of the fact that we
> are essentially controlling the timing of puberty.
>
> If you look at girls with Turner\'s syndrome who have spontaneous
> puberty, their final heights are actually much less than those in whom
> we actually induce puberty. And the reason for that, obviously, is
> because of the sex steroid mediated effect on bone epiphyseal fusion.
> In children with isolated short stature, non-growth hormone deficient
> short stature, we don\'t have the luxury of being able to time
> puberty.
>
> And it brings up the issue of whether or not growth hormone actually,
> beyond two or three years of therapy, when kids are actually in the
> midst of puberty, actually improves their chances of reaching a normal
> adult height.
>
> Have you looked at patients that were treated before puberty versus
> during puberty, to look at changes of standard deviation scores, in
> terms of their height progression? And be able to make some
> conclusions about how growth hormone works, either prepubertally or
> during puberty?
>
> DR. CUTLER: Yes\--I thought you were going to ask me whether growth
> hormone advances puberty. You\'re really asking me to predict response
> relative to puberty, and that\'s difficult. Because the design of the
> study was to basically treat to final height. That\'s sort of what we
> were asked to do.
>
> I guess the best way to get at that might be\--you\'re really asking
> me if you treated the patients longer\--if you had a chance to treat
> them prepubertally, did they have a better response?
>
> And over the range that we looked at in this study\--and about half
> were pre-pubertal; about half were early pubertal, almost all Tanner
> 2\--so the earliest stage of puberty at the start. Over the age range,
> which went from 9 to about 15, we actually\--the limit was 16 in boys,
> but the oldest enrolled patients were boys who were about 15. And over
> that age range there was a relationship\--you have to listen to this
> carefully\--but there was a significant relationship between age and
> the final height over baseline predicted. So that, at first blush it
> looked like the younger you were the greater the height SDS gain.
>
> The problem was that the same thing happened in the placebo group, and
> to virtually the same degree, so that the actually placebo/growth
> hormone difference really did not seem to differ over this entire age
> range. There was no significant apparent effect\--somewhat to our
> surprise. So that even boys treated at 15, who had a bone age of 13 at
> that point, got virtually the same benefit over the, say, placebo who
> were treated at the same age, as did a younger child, maybe, who was
> 10 or 11. And that\'s about the best I could say.
>
> Over the range that we studied, we didn\'t see much in the way of an
> age effect.
>
> DR. CARA: One of the ways that we looked at that question in girls
> with Turner\'s syndrome was to look at girls that had been started on
> sex steroids before\--at around 13 years of age, versus after 13 years
> of age\--say, about 15 years of age.
>
> DR. CUTLER: Mm-hmm.
>
> DR. CARA: And I was wondering if you had looked at the timing of
> puberty as it related to growth response.
>
> DR. CUTLER: I\'m going to have to ask my\--our statisticians. We have
> done a tremendous number of analyses, and I\'m not sure I remember
> them all. This is not one that is immediately in my memory bank.
> And\--
>
> DR. CARA: Again, the reason why I\'m asking this is because if you
> look at the data on height velocity data\--it\'s on page 27 of the FDA
> briefing document\--again shows that most of the gain is early on,
> within the first three years of therapy, and then sort of wanes and,
> if anything, falls below the placebo group.
>
> It relates, again, to the question that I asked you during the first
> half\--
>
> DR. CUTLER: Right.
>
> DR. CARA: \--whether children that were on growth hormone and
> discontinued actually ended up doing better in the long run than
> growth hormone patients that continued on therapy and actually
> completed the study.
>
> \[Pause.\]
>
> DR. CUTLER: I don\'t think we\'ve done the kind of dichotomous, you
> know, look that you\'re asking for. We have tried to look at a number
> of things as continuous variables\--quite a few things.
>
> DR. CARA: Your original slide\--I think it\'s number\--umm\--59\--you
> showed data for the individual patients\--final height SDS for
> individual patients.
>
> Now, this was for all final-height patients. I was wondering if you
> could show us a slide, or at least give us an idea, where the
> completers were, so that we could get a sense of how those two groups
> segregated out?
>
> DR. CUTLER: So, what you\'re really asking me is which of the eight
> patients who were the ones who discontinued early and then came back?
> Do I understand correctly?
>
> DR. CARA: Right. Yep.
>
> DR. CUTLER: We\'ll have to\--I\'ve forgotten that. We\'ll have to\--we
> would have to look that up. I think it could be done, if you\--
>
> DR. CARA: And do you have the actual heights? Not the standard
> deviation scores, but the actual heights attained for the males and
> females in the different studies?
>
> DR. CUTLER: I think we\--yeah. I think we can get that for you\--the
> gender effect, in actual heights.
>
> DR. CARA: While you\'re putting that slide up\--
>
> DR. CUTLER: Okay.
>
> DR. CARA: Why do you think\--
>
> DR. CUTLER: While we\'re getting that, Dr. Rosenfeld, I think, had a
> comment that he wanted to make about your question about the puberty.
>
> DR. ROSENFELD: I think Dr. Cara\'s earlier points are absolutely
> right, that one of the characteristics of Turner\'s syndrome is that
> because of the ovarian failure there is an increased length of
> potential treatment time. This isn\'t necessary the case in the Lilly
> group of patients, and your point is well taken.
>
> However, I think that very point serves to potentially underestimate
> the benefit from the Lilly study because, as Dr. Cutler\'s pointed
> out, the study design incorporated a relatively old group of patients.
> These children tended to fuse their epiphyses earlier than would have
> occurred if he had elected to choose to treat children, say, with the
> mean age of five. And the study design therefore served to mitigate
> some of the benefit that would have occurred.
>
> The waning effect that you describe, as you know, we\'ve seen in every
> growth hormone application, including growth hormone deficiency. And I
> think it was exaggerated in this study because these children were
> fusing the epiphysis.
>
> So I think your point\'s well taken, and I agree with it. And I think
> that\'s another reason why I tend to believe that the Lilly study
> design actually underestimates the potential for benefit in this group
> if treatment can be initiated at a more age-appropriate time.
>
> DR. CUTLER: I have the other slide that you wanted.
>
> Before I show this, I will say that the study was really not powered
> for sub-group analyses, and so there are going to be small numbers for
> many of these sorts of things. But there was not any apparent gender
> effect, and that\'s one of the reasons\--by presenting everything as
> standard deviation scores, you\'re able to combine males and females,
> and it seemed\--and actually, it was intended that that would be the
> case from the outset of the study. Because we knew it had relatively
> small numbers of females, but there was no major difference between
> the benefit between male and female; certainly no statistically
> significant differences.
>
> DR. CARA: Why do you think you enrolled such few numbers of females?
>
> DR. CUTLER: This is seen\--with the exception of Turner\'s, every
> indication\--and it\'s quite common that somewhere around two-thirds
> to three-quarters of referrals for short stature are males. And I
> don\'t really know the reason for that. I think we could speculate,
> but\--
>
> DR. BRAUNSTEIN: Dr. Worcester had a question.
>
> DR. WORCESTER: It goes back to the question of people dropping at. And
> I think you haven\'t looked at it, but I wanted to look at the next
> stage, then, of people coming back. Because, clinically, I assume
> that, particularly if there were finances and other things getting in
> the way, that you might see a number of children taking the product
> for awhile\--and, particularly, perhaps, those that did the best, not
> continuing and then going back.
>
> So I just wondered if you looked at all at the yo-yo effect of
> children on the hormones, off, and then back on\--particularly in
> light of your own description of the catch-down phase that happens
> when children are taken off.
>
> DR. CUTLER: Mm-hmm.
>
> This study did not have that capability built into it. So if you
> discontinued, you became a discontinued patient. You weren\'t eligible
> to re-enter. So I don\'t have any data on that question.
>
> But, obviously, the final-height data that we have will take into
> account whatever deceleration, to the extent that some of the patients
> did stop early, they conceivably may have had somewhat less benefit
> than if they had continued through to final height.
>
> DR. BRAUNSTEIN: Dr. Tamborlane?
>
> DR. TAMBORLANE: Yes, the other thing about this waning effect\--I
> mean, for the efficacy group, I mean half of them dropped out by three
> years. So you\'re just going to carry forward that data. So, you know,
> that might be just a statistical quirk, the way, you know, you\'re
> trying to analyze these things.
>
> DR. BRAUNSTEIN: Any other questions? Yes\--Dr. Watts.
>
> DR. WATTS: You anticipated the question from Dr. Cara, and you didn\'t
> answer it; that is, whether or not growth hormone treatment
> accelerates or changes the timing of puberty. And I would appreciate
> the answer.
>
> DR. CUTLER: Yes. There actually was not any effect on puberty for the
> regimens used in this study, in either of the two studies. And I
> think, actually, probably the most helpful would be 239, and then 242.
>
> We first looked at onset\--and, actually, these data have been
> published. And we did this is boys because there were so many more
> boys in the studies; the numbers of girls are so small\--I could show
> those if you want, as well.
>
> But this was published in the [Journal of Pediatrics]{.underline}. And
> we looked at this by looking at the age at which testis volume was
> first measured at over 4 ml\--and this would be just the 23 subjects
> who were pre-pubertal at baseline; and then the age at which
> testosterone first rose above 30 nanograms. That was measured every
> visit. And there were no significant differences in this.
>
> And then we looked at the rate at which progression occurred from the
> time of onset. And what we found is that the rate at which testicular
> volume increased, and the rate at which testosterone\--and I also
> could have done the clinical assessment of pubertal stage\--and there
> really was no difference at all between the growth hormone and
> placebo-treated groups, either in the time of onset or the rate of
> progression through puberty.
>
> DR. BRAUNSTEIN: Dr. Cara wanted to make a comment on this.
>
> DR. CARA: Yes. I think we have to be careful about how well you can
> assess the timing of puberty in children that are being seen every six
> months.
>
> I think the other issue is\--one is the actual appearance of the
> child, in terms of the actual onset of puberty. The other is bone-age
> advancement, which is ultimately the critical factor in terms of
> height gain and, ultimately, height attained.
>
> I\'d like to point out that in a study that we actually did with Lilly
> in growth hormone deficient patients, the onset of puberty was
> definitely earlier in children that had gotten growth hormone therapy.
> And what we deduced from the data was that it actually normalized the
> timing, whereas children with isolated growth hormone deficiency
> usually go into puberty late, growth hormone, if anything, normalized
> that timing.
>
> And in girls, it appeared to have more of a pronounced effect in terms
> of the actual timing and tempo of puberty, which may explain why in
> girls the response is not as significant as in boys.
>
> DR. BRAUNSTEIN: Dr. Grady?
>
> DR. GRADY: I just wanted to ask\--I mean, again, I\'m kind of worried
> about the risk-benefit ratio here, even if we think that benefit is an
> inch, a couple of inches in height.
>
> It seems to me that your indication is fairly broad. I mean, could we
> treat five-year-olds? You know, is a five-year-old capable of making
> any kind of informed decision about whether or not they want to commit
> to four or five years of a daily injection to make them a couple of
> inches taller?
>
> It seems unreasonable to me not to have some sort of an additional age
> criterion. And I wonder what you\'ve thought about that.
>
> DR. CUTLER: You know, I think I\'d like to\--I have my own personal
> opinion, and I do still go to clinic. But I think I\'d like\--Dr.
> Rosenfeld, you\'re closest to the microphone, so I think I\'d like
> just to have one of our consultants who does this every day comment on
> this\--I mean, their views about it.
>
> DR. ROSENFELD: Well, the age issue is a very tough issue. We don\'t
> currently employ an age cutoff. Or if we do, it\'s a very weak cutoff
> of two years for other growth hormone indications. And that\'s, in
> large part, because there\'s a recognition that a child typically, by
> the age of two years, establishes the percentile that he or she will
> grow on for the remainder of childhood\--at least until the time of
> puberty.
>
> I think your point is well taken that a five-year-old is hardly able
> to give an informed consent about growth hormone, but I don\'t know
> that that would be true at age six or seven, or eight or nine either.
> And I find it difficult to figure out how I\'m going to differentiate
> a five-year-old who\'s minus-2.8 standard deviations from Turner\'s
> syndrome who\'s minus-2.8, or a growth hormone deficiency patient
> who\'s minus-2.8 standard deviations.
>
> So, having batted this around at length with the consultants and with
> the people at Lille, we again felt that this was something that was
> best left to the domain of the practicing pediatric endocrinologist to
> make the judgment call that integrated the clinical setting of the
> patient, the particular growth parameters and laboratory parameters of
> the patient.
>
> DR. BRAUNSTEIN: Dr. Follman was next, then Dr. Goldstein.
>
> DR. FOLLMAN: I\'d like to come back to something that was brought up
> earlier as a comment Dr. Grady made, and it had to do with in the GDCH
> trial, the mean duration of treatment was different between the two
> groups.
>
> And in the document that\--in the FDA document, it looks like it\'s
> about a half-year longer for the Humatrope patients. And I think you
> said it the other way around. And then, also, if you look at E001, the
> mean duration of the measurement of final is about a year longer in
> the higher dose compared to the lower dose.
>
> So, if you\'re concerned about, you know, children getting taller as
> they grow older, and you\'re looking at final height at different
> stages\--or different times relative to randomization, it seems like
> there might be the potential for a bias there. So I was wondering if
> you had looked at that and, in fact, addressed the issue of whether
> the final height was really the final height\--you know, because it\'s
> occurring earlier in the lower-dose or placebo groups in your two
> studies.
>
> DR. CUTLER: Well, let me clarify first the point about duration.
> You\'re correct that the duration of the growth hormone treatment was
> longer. It was 4.6, I think, compared to 4.1 years. But the age at
> which their final height was measured by six months. So it was 18.6
> versus 19.1.
>
> So my earlier statement was correct, because I was referring to the
> age at which the final height was measured, not the duration of
> treatment.
>
> DR. FOLLMAN: Do you have a similar comment for E001, then?
>
> DR. CUTLER: Now, for the\--I don\'t actually happen to remember the
> age at which the final height was measured for E001. I\'ve looked at
> it, and I don\'t recall that they were discrepant. Does anybody have
> that number? Or we can get that for you, I suspect. But I don\'t have
> it right now.
>
> There were, as always in small numbers like this, there will be some
> imbalances in age at randomization and so forth. We can try to get
> that.
>
> DR. BRAUNSTEIN: Well, while we\'re looking that up\--
>
> DR. CUTLER: But I want to follow-up, though, because I don\'t really
> quite understand the concept that\--I want to be sure I understand the
> area where you\'re concerned that bias might be creeping in related to
> efficacy. And I also want to explain that when we\--when the ANCOVA
> determines this SDS difference, and we then express that in a
> corresponding centimeter way, we do do it at a single age of 18. And
> in terms of whether\--I guess the issue is whether one group might be
> nearer final height than the other. Is that the issue? That one group
> might still be growing more than the other in that last little bit of
> lingering growth?
>
> DR. FOLLMAN: Right. The concern was that, you know, you call it final
> height in the placebo group, and yet they\'re going to be growing a
> little longer, perhaps than the other group was.
>
> My real concern, I guess, was the mean duration was different. I was
> thinking that was related to the age at final height, and you\'ve told
> me that there\'s not really a concern there. If anything, the placebo
> group is a little older.
>
> DR. CUTLER: Yeah.
>
> DR. FOLLMAN: So that reason for my concern about bias isn\'t really\--
>
> DR. CUTLER: Yes, they were six\--and one of the things we did in the
> design is to have an interval of a year from the time treatment
> stopped before we measured that. So the age of that measurement for
> the placebo patients, that\'s the mean age, which involved some girls,
> was 19.1. Growth is very slow at that age. And I don\'t have the exact
> numbers, but some of the values that I\'ve looked at were height
> velocities like, you know, .2 millimeters a year kind of thing. They
> were\--many of these patients had really gotten to very slow rates at
> the point that final height was measured.
>
> DR. BRAUNSTEIN: Dr. Goldstein, you were next.
>
> DR. GOLDSTEIN: By way of background, I happen to be a board certified
> pediatrician, and practiced pediatrics for 16 years before joining the
> industry. As a point of\--and also, chaired the American Academy of
> Pediatrics\' Clinical Pharmacology Section for six years.
>
> As a point of information, issues such as consent that were raised
> before have, in many institutional review boards, been treated with
> assent rather than consent. And it is a concept that can be utilized
> effectively, certainly, as Dr. Rosenfeld said, by six to seven years
> of age. That\'s probably the bottom of the\--you know, I wouldn\'t go
> as far as five.
>
> You all know what pediatrics is, and big people\'s doctors often call
> it, in a term of terribly ironic today, \"midget medicine.\" But to
> that end, having practiced and having seen this for that long, do we
> want to wait five years to find out whether we should have made a
> diagnosis, or should have referred the patient for treatment? In many
> instances\--and I think Dr. Grady quoted a figure of one in a
> hundred\--the pediatric is the first level of filtration before even
> the pediatric endocrinologist gets into this. I can\'t tell you how
> many mothers\--overanxious mothers or fathers I\'ve managed to delay
> successfully.
>
> But the point is that I would not want to wake up five years later, or
> 10 years later saying I wished I had. And many of my colleagues, I
> have no doubt, feel exactly the same way.
>
> The psycho-social consequences of this are to the child, to the family
> and to their respective communities are often only visible or, indeed,
> palpable years later. So it is a difficult decision that this
> committee makes, but I would certainly say that given all that we\'ve
> heard here today, I would certainly recommend approval.
>
> DR. BRAUNSTEIN: Dr. Grady, you had a\--no.
>
> DR. GRADY: No, I was just going to point out that if you double
> duration of treatment you double the amount of time for potential
> adverse effects, and you at least double the cost. If you\'re going to
> treat from ages five to 15 or 16, that\'s, you know, 10, 11 years\'
> duration. And, as far as I can figure, that\'s\--I mean, my cost
> estimates on the back of the envelope were quite a bit higher than
> were presented here. So we could be talking half a million bucks, say,
> for treating between five and 16 years.
>
> And that\'s just the cost of the drug. I don\'t know how much the
> doctor visits, and pediatric endocrine and all that\'s going to cost
> either.
>
> DR. CUTLER: I have just one piece of information that Dr. Follman
> wanted.
>
> The mean age at which the final height was measured in the
> dose-response study was 18.1 years in the low-dose group, and 17.8
> years in the higher-dose group. So they were very similar.
>
> And, if I might, I would like to make just one comment, Dr. Grady, to
> your points about the size of the population. I think the population
> prevalence is correctly stated at about 1 percent. But the numbers of
> children who will be treated\--all of us who work in this field quite
> confidently know will be much less. So a realistic\--if that\'s an
> important consideration, the estimates that Dr. Quigley has provided
> of about 40,000 children\--30 to 40\--from all manufacturers for this
> indication, five years, is our best estimate. It\'s a very realistic
> estimate. And that really amounts to 10 percent of the population, or
> about one in a thousand children, which we feel is a very responsible
> number to be treated with this condition.
>
> DR. BRAUNSTEIN: Dr. Schade?
>
> DR. SCHADE: Yeah, I just\--in listening to all this discussion, I\'m
> trying to really come to the issue that\--the problem that I\'m
> having, and that is: I feel that most people here believe that short
> stature does cause, or can cause, a very serious handicap
> psychologically and developmentally, and cause many problems. And
> we\'ve heard, I think, some very compelling testimony during the open
> session.
>
> And I also think that the data we\'ve seen, that growth hormone
> therapy does provide some increase in growth. Where I\'m having
> trouble is trying to come up with any data\--and Lilly seems to say
> \"We don\'t have any data,\"\--that if you do take a short child and
> you treat them with growth hormone, what percent, or how much decrease
> in the psychological burden are they achieving with this expensive
> treatment?
>
> In other words, it isn\'t that short stature is not a very serious
> handicap, it\'s what benefit, in real terms\--not height\--are we
> actually seeing with the growth hormone treatment? And that\'s where
> I\'m having a problem, with understanding why we should actually spend
> \$20,000 a centimeter, as one of the speakers mentioned\--whether
> that\'s correct, I don\'t know\--when we have\--at least Lilly has not
> even indicated that we are reducing by 10 percent the psychological
> trauma of being short. That\'s the problem I\'m having. Without any
> hard data in that area, how do we know whether it\'s worth it or not?
>
> Maybe Lilly can address my concern.
>
> DR. CUTLER: I think I\'d like Dr. Grumbach to\--just to make a
> comment, if you wish. I think this\--we\'ve told you the data that we
> have, and I can\'t go beyond the data. And I think it\'s better,
> perhaps, for one of the experts in the field who does this to share
> their perspective.
>
> I would say, maybe, before Mel begins though\--this is\--it\'s an
> issue that has been around, really, from the beginning of growth
> hormone therapy. It is not unique to this indication; that
> psychological benefit has not been shown conclusively for any of the
> indications. And so this is an issue that really reflects, I think, to
> the difficulty of studies in this field in developing children.
>
> DR. GRUMBACH: I think you\'ve hit on a very important point, and a
> very difficult question to answer.
>
> The studies that have been done are really\--are ambiguous. And let me
> just give you an example, just taking short kids, that if you go into
> the community and take a group of short children, and inquire about
> their own\--the psycho-social aspects, you\'ll find they don\'t differ
> very much from their colleagues. On the other hand, if you take the
> group of children that have been\--that come to see the pediatric, the
> pediatric endocrinologist, you get a very different point of view.
> Here, these are children that are handicapped, or disadvantaged by
> their height.
>
> Now, to find out\--to answer your question, we really have to get late
> adolescent and early-adult data about what\--in terms of outcome. I
> think it\'s really difficult, as one of the people who discussed this,
> to really get\--as one of, in the public arena\--to get children,
> really, necessarily to be able to convey how they feel about this.
>
> And the issue really comes down to those who feel disadvantaged that a
> form of treatment is available that will increase their height. But to
> be able to do this for a whole constituency, it\'s very difficult and
> it has not been done to my satisfaction.
>
> DR. BRAUNSTEIN: Thank you.
>
> Gordon, I wonder if you would comment on\--Dr. Guyda mentioned that
> there were seven deaths among patients with Prader-Willi syndrome. Do
> you know anything about that?
>
> DR. CUTLER: Yes. Prader-Willi, for those who are not familiar, is a
> syndrome where there is extreme obesity. And what I know is from a
> mailing, and I probably\--in fact, I think I should let the agency
> comment on this, because I have\--are you able to comment? There is a
> mailing that\'s come from\--to all physicians, or at least all
> endocrinologists about it, and this is all I know. But what I remember
> from the mailing is that these were respiratory, or sudden deaths, or
> deaths associated with the development of an acute respiratory
> infection in these massively overweight children. If you\'ve ever
> taken care of Prader-Willi, it\'s one of the most remarkable syndromes
> of obesity. I had one of my patients once drink a quart of barium when
> he went for x-ray. And they just have an insatiable appetite.
>
> And so these were directly related to the upper airway obstruction
> that can occur. And the recommendation that came out with these
> deaths, these patients need to be very carefully monitored for sleep
> apnea and so on at the time of considering growth hormone therapy, and
> to carefully be sure that there is not a predisposition to a
> respiratory event such as a sleep-apneic death, or sudden death.
>
> But, Rob, do you\--
>
> MR. PERLSTEIN: \[Off mike, inaudible\]
>
> DR. BRAUNSTEIN: Could you talk into the microphone?
>
> MR. PERLSTEIN: I can\'t add anything to what Gordon just said. The
> agency\'s aware of the mailing from Pharmacia, and agrees with it.
>
> DR. BRAUNSTEIN: Okay. We\'ll take just two more questions.
>
> Dr. Woolf has one, then Dr. Cara.
>
> DR. WOOLF: Am I correct or not that the ultimate height\--extra height
> from treatment is independent of the age that the child is treated?
> Not in SD units, but in inches and centimeters, since that\'s what
> counts to the kid?
>
> Does a younger child get more height, in absolute terms, when treated
> until puberty than a 21-year-old?
>
> DR. CUTLER: What we\'ve found is that if you look at the final height
> compared to the baseline height\--and I think it would be the same. I
> have it here in SDS, but I believe it would be the same in
> centimeters. I\'m not sure we\'ve done it exactly in centimeters\--is
> that baseline age was a statistically significant predictor, in that
> the younger that you begin treatment, the higher\--the greater the
> gain over your baseline prediction. And that fits, I think, with\--and
> others have actually found this in the observational studies.
>
> So I\--it\'s not quite correct that it\'s independent. The issue is
> that when you actually\--in our study, which is unique in having a
> placebo control, when you actually look for an interaction term, it is
> not significant. And what that means is that the placebo group also
> did somewhat better, relative to their prediction, the younger you
> started treatment\--the younger you put them into the study.
>
> DR. WOOLF: This gets back to Dr. Grady\'s concern of duration of
> treatment, the same benefit treating for three years, why treat for
> six?
>
> DR. CUTLER: Yeah\--and I think\--and maybe Dr. Quigley will want to
> comment\--but I think it means a lot to the child whether they\--since
> they catch up with their peers within a year or two, whether they, you
> know, spend their childhood very short and then catch up very late, or
> whether they have the opportunity to be more close to their peers
> during the period of development.
>
> DR. BRAUNSTEIN: Dr. Cara?
>
> DR. QUIGLEY: I would also just add that if you compare the GDCH data
> with the low-dose data in study E001, where the did start younger, and
> therefore get longer treatment, there was a greater effect.
>
> DR. GOLDSTEIN: Gordon, actually two quick questions.
>
> One is, in your GDCH, when you looked at IGF-1 levels across the study
> duration, pretty much everybody started at quite a low level; almost a
> level that would\--quote-unquote\--\"entitle\" them to growth hormone
> therapy based on growth hormone deficient criteria, if you use the
> recommendations that were proposed by Rosenfeld [et al]{.underline}.
> In the E001 study, it didn\'t look like the IGF-1 levels were that
> low. They were in the, I think, 81 nanograms per mil range or
> something like that?
>
> DR. CUTLER: Mm-hmm.
>
> DR. CARA: And it sounded like they were pretty normal. Is that
> accurate?
>
> DR. CUTLER: Can you give me the baseline data for the dose-response
> study? I just don\'t remember the actual number.
>
> I mean, I think you\'re probably correct on the numbers, and I\'m not
> sure that we did those particular numbers in SDS units.
>
> But if you\'ll give me\--it\'s a core slide. It would be, probably,
> about 50.
>
> DR. CARA: Well, I\'m just wondering why the difference.
>
> DR. CUTLER: Yeah.
>
> DR. CARA: If the populations were actually quite similar\--
>
> DR. CUTLER: We don\'t have IGF-1 on that particular\--
>
> DR. CARA: Okay.
>
> DR. CUTLER: I think that the key point is that if you look at the
> literature for many, many studies of this condition, the IGF-1\'s
> range between about minus-1 SDS at the high end, to about minus-1.7 or
> 8 at the low. So the mean of our group was probably near the lower
> end, but within the range that others have reported.
>
> DR. CARA: One of the things that we became aware of, and that parents
> actually mentioned\--especially in the Turner\'s syndrome
> patients\--was that there was concern about the size of hands and
> feet, as kids continued on therapy.
>
> Did you notice any unusual disproportion of hand, foot\--hand size or
> foot size?
>
> DR. CUTLER: No, this is the first I\'ve actually heard any mention of
> that. In terms of our\--at least as far as\--I mean, not the
> Turner\'s, but in terms of our study patients, there\'s been\--we
> didn\'t measure hand size, but no comments clinically that there was
> any change in hand or foot size that would be out of proportion to the
> rest of their growth.
>
> DR. BRAUNSTEIN: Dr. Follman?
>
> DR. FOLLMAN: One of the concerns that I think that we\'ve been asked
> to look at is whether the floodgates would be open, and that there
> would be a large number of children treated with this if it was
> approved as indicated.
>
> You have a model where you talked about 400,000 children would be
> eligible for this, and you anticipate only 40,000 would actually be
> treated. If you could briefly describe, you know, what assumptions, or
> how the model arrived at that number, I think it might be helpful.
>
> DR. QUIGLEY: Thank you. The model starts with the\--can I have that
> core slide back, too, please? No\--the core slide.
>
> The model basically starts from the prevalence of height below
> minus-2.25 standard deviation scores in the total population. So,
> starting with the total population under 2.25 standard deviation
> scores, we calculate 400,000 children, and that is between the ages of
> 7 and 15 years. And the fact that the number here is 2.25, and the 7
> to 15 year age group here is included underscore what the differences
> are between the model that we use and the model that\'s actually in
> the\--the numbers suggested in the FDA\'s document.
>
> We then used the model that Finkelstein and coworkers developed in
> their 1998 paper that looks at the way in which growth hormone is
> prescribed for this group of patients. And so starting with the total
> of 400,000, you lose probably 70 percent or more of them at the
> primary care physician level. So the numbers are whittled down very
> dramatically at the first level.
>
> At the second level, with respect to treatment recommendations by
> pediatric endocrinologists, there\'s another 74 percent or so\--74 or
> 75 percent taken off what\'s already reduced down to a quarter of what
> it was when we started. So another three-quarters is chopped off down
> here. And then at the insurer-reimbursement level, another 80 or 90
> percent goes down from the level you started with before. So that\'s
> how the numbers get down to 30 or 40 thousand out of the 400,000 we
> started with. And that\'s a well-validated model from the literature.
>
> DR. FOLLMAN: Of course, if this is approved as indicated, things might
> change\--in particular the selective referral might increase, and
> insurance might change as well\--insurance reimbursement might change.
>
> DR. QUIGLEY: Those assumptions were taken into account in coming up
> with the numbers that\--so these actually are numbers that include the
> assumption that this is an approved indication. So we\'ve built into
> that the fact that there will be higher rates of referral to the
> pediatric endocrinologists, higher rates of approval of
> recommendations for treatment, and higher rates of insurance with that
> model.
>
> DR. BRAUNSTEIN: Okay, thank you. We\'re going to take a 10 minute
> break then come back for the charge and then discussion of the
> committee, and we won\'t take a break later on.
>
> \[Off the record.\]
>
> DR. BRAUNSTEIN: Okay. Dr. Orloff will now give the charge to the
> committee.
>
> DR. ORLOFF: Is everybody back?
>
> DR. BRAUNSTEIN: Almost.
>
> **Charge to the Committee**
>
> DR. ORLOFF: First, from the FDA I\'d like to thank the speakers at the
> open public hearing for their statements. The open public hearing is,
> like the discussion by the Advisory Committee, an important aspect of
> this process for FDA\'s function with regard to decision-making.
>
> I\'ve got to catch my breath. I just had to run and fill a parking
> meter.
>
> \[Laughter.\]
>
> The charge to the committee, as people realize, is generally to go
> over the questions, and I will do that. I just wanted to make a couple
> of comments first.
>
> The first is that, as you will have noted, the questions cover a
> number of issues that have been discussed already. And we realize
> this. It\'s not unexpected. I guess it probably means we were on based
> with regard to our questions.
>
> I leave it up to the Chair and to the members to extend the discuss as
> they choose on the questions, or to deem them covered, as it were.
> That\'s up to you.
>
> And I remind you\--the committee, that is, and those present\--that
> perhaps more than the yea or nay vote tallies on questions that have
> yea or nay answers, FDA benefits from and relies upon the content of
> discussion around the issues. In other words, we are listening, and
> have been.
>
> The questions are our best efforts to get to the major points
> requiring comments. We also note that additional points have been
> raised, and they\'ve been heard by us.
>
> And then, finally, I want to just\--before I go to the questions\--I
> just want to raise one other issue that has not actually been raised
> here explicitly but may be in the back of some people\'s minds, and in
> the minds of those perhaps listening from the audience. And that is,
> to some extent it\'s kind of the flip side of the clinical
> significance question that\'s been asked and will be asked again, and
> that is whether the use of growth hormone in non-growth hormone
> deficient short stature represents \"cosmetic\" use of growth hormone
> and, as such, might be construed, were it to be approved and endorse,
> might be construed somehow as setting a broad precedent for cosmetic
> use of drugs.
>
> The first point I\'d like to say is that any decision that\'s made
> with regard to growth hormone in this instance will be based upon a
> judgment of a favorable balance of risk versus benefit for the
> proposed indication, and that would not, in our minds, be setting a
> broad policy with regard, generally, to the use of drugs for cosmetic
> purposes.
>
> I\'d also propose that it is not the purpose of this meeting to debate
> the merits of approvals of other drugs for what some\--usually those
> unaffected by the target condition\--might construe as cosmetic
> purposes. And I think it\'s safe to say that we should concede that
> once demonstrated to be safe and effective, the choice of whether to
> attempt therapy for, for example, baldness, or mild acne, or even
> overweight is up to doctors, patients and their families as they
> weight the potential benefits of the therapy against the potential
> risks.
>
> And I guess I said it before, but I\'ll just point it out one more
> time: that we don\'t see a regulatory stance favoring approval for the
> use of growth hormone putting this Division or the agency on a
> slippery slope toward blanket uses of\--cosmetic uses of growth
> hormone, as well as for other drugs.
>
> So, some of the questions\--I guess I\'ll go quickly over the ones
> that I think don\'t need much clarification, and pause to clarify some
> that I think do.
>
> \"Has the efficacy of human growth hormone, or Humatrope specifically,
> in non-growth hormone deficient short stature been sufficiently
> characterized?\" And I think it\'s worth our hearing the committee\'s
> opinion on, really, the matter of whether proof of principle of
> efficacy in this population has been provided. I realize there\'s been
> a lot of discussion about the absolutely magnitude of the effect
> observed, as well as what could be expected, depending upon a number
> of variables. Has proof of principle of efficacy been characterized?
>
> \"Is the dose regimen proposed supported by the results of the studies
> presented?\" And a very important point here that has been the subject
> of some discussion so far\--and I leave it again up to you to discuss
> it further if you like\--comment on the discussion by the sponsor of
> the importance of height augmentation in the target population, and on
> the conclusion that the expected effects are, indeed, meaningful. I
> wrote \"clinically meaningful,\" but I think \"clinically\" is a
> problematic term here. \"Meaningful\" is vague, but I think it\'s the
> best we\'ve got.
>
> \"Has the safety of Humatrope in non-growth hormone deficient short
> stature been sufficiently characterized? Specifically, do the results
> of the trials and the current knowledge of the safety profile of
> growth hormone in children support a favorable balance of risk versus
> benefit in this population?\" And also, something that wasn\'t
> elaborated on in great detail, I believe, by the company, we\'re
> interested in your thoughts on the proposal\--or the possibility,
> you\'d say, of long-term follow-up of these children as part of
> GeNeSIS; and what other suggestions you might have with regard to
> surveillance of the safety of this intervention in this population.
> And I know that the company is prepared, if need be, to give a little
> bit more explanation on, actually, the details of their GeNeSIS
> program, and on its present and future, I gather.
>
> \"Are the available data from the studies presented sufficient to
> guide the safe and effective use of Humatrope?\" And this is a
> distinction from \"Is there evidence of safety and efficacy?\" Do we
> know enough about how to treat kids who have non-growth hormone
> deficient short stature from the studies that have been done so
> far\--and whatever other knowledge people might bring to the
> clinic\--to guide the safe and effective use of Humatrope in this
> population?
>
> And some of the sub-parts of this question include: \"Is the
> restrictive height criterion that is proposed satisfactorily
> rationalized?\" Is it too high, is it too low? Do you have any
> comments on that.
>
> And perhaps more importantly, \"Are there additional criteria needed,
> such as pre-treatment height velocity, bone-age, chronological age,
> serum IGF-1 level, growth hormone receptor mutational studies, to
> avoid unnecessary or, as it were, potentially ineffective growth
> hormone therapy in children who have idiopathic short stature?\"
>
> I think it\'s also been noted\--and we noted\--that the range of
> responses observed in the trials, and thus expected in the clinic, is
> broad. Additionally, there\'s been a dose-response demonstrated. The
> question is\--and we\'d like to hear discussion on this, we do not
> expect definitive plans\--we\'d like to hear discussion on \"The need
> for information on the effective individualization of dose, age at
> initiation of therapy and duration of therapy on growth response and
> on safety.\"
>
> And what I\'m driving at here is the idea that, irrespective of what
> we\--the decision the FDA finally makes on this and, frankly,
> irrespective of what the advice of the committee is today: what more
> is needed going forward in this field? Perhaps you might\--some might
> judge that there are certain things that are absolutely needed before
> we could move forward with an approval. You\'re welcome to comment on
> that. But even if you recommend approval, I think it\'s quite clear
> that not all the questions about the safe and effective use of this
> intervention in this population have been answered by the studies to
> date. So, with the realization that further placebo-controlled trials
> in this area are not possible\--but, I believe studies as a generic
> term are possible\--what additional information needs to be gleaned
> from such studies?
>
> And, likewise, we\'d like to hear you\--or, following that we\'d like
> to hear you discuss the \"Need for information on potentially useful
> predictors of response, both pre-treatment and on treatment; for
> example, early growth or other bio-marker effects?\"\--again, to
> enhance the safe and effective use.
>
> And then, the last three questions are to \"Comment on the sponsor\'s
> overall risk management proposals,\" which I don\'t think have been
> broadly discussed as yet; and \"Any other concerns you have regarding
> safety and efficacy.\"
>
> And then, finally, the\--I guess for those who are watching this from
> afar\--and perhaps for the company a very important questions: \"Do
> you recommend that the use of growth hormone in non-growth hormone
> deficient short stature, as proposed by the sponsor, be approved by
> FDA?\"
>
> And I turn it back. Thank you.
>
> **Committee Discussion**
>
> DR. BRAUNSTEIN: Thank you, Dr. Orloff.
>
> I think what we\'ll do is we\'ll start with Dr. Follman, and ask him
> to respond to Question 1, and also A and B. And then we\'ll go around
> the room with the committee members. And then we\'ll start Question
> Number 2, with Dr. Grady.
>
> So\--Dr. Follman?
>
> DR. FOLLMAN: Thank you.
>
> So\--to begin, question 1 has to do with whether or not the drug seems
> to be efficacious in increasing height? And do I agree with the dose
> range that was proposed by the sponsor?
>
> The two studies that we\'ve looked at in detail today were both
> controlled studies and randomized studies. The first one was a
> placebo-controlled study. It was designed to compare the final height
> between the two groups.
>
> It had a lot of dropout which was somewhat concerning to me, and I
> think also to the sponsor and to the FDA as well; and it was subject
> to many different analyses. We heard discussion of the different
> cohorts that were used; the efficacy-evaluable; the final-height
> cohort. And there was a consistent message, I think, in the analyses
> there that the treatment effect seemed to be significant for a variety
> of analyses.
>
> The magnitude of the effect seemed to be about 3.5 centimeters, maybe
> and inch-and-a-half\--something like that.
>
> So I\'m willing to say that, on the basis of that\--even though there
> was a lot of dropout and we don\'t like that\--the treatment seems to
> b e effective in increasing final height.
>
> The second study, that looked at different doses and different dosing
> schedules of Humatrope also showed a benefit, in terms of the
> pre-specified primary endpoint, which was change in height velocity
> over the first two years of study. They also looked at final height in
> that study, even though it wasn\'t the primary analysis, and the
> results that they showed demonstrated a trend toward benefit towards
> the higher-dose group.
>
> So, in my mind, I think it\'s pretty clear that compared to the
> placebo the treatment is effective, and the estimate of effectiveness
> that we\'ve been bandying about\--1.5 inches, perhaps\--is probably a
> little underestimated if we take into account the E001 study, which
> shows larger benefits\--partly because, I think, the doses are given
> earlier and they\'re given at a more frequent rate.
>
> So, to Question 1.A, I think the answer is: yes, it\'s been shown that
> it works in this population.
>
> And if I have to comment on Question 1.B, what\'s meaningful increase
> in height, I think that\'s a very difficult question. When I first was
> looking at this, I thought, you know, an inch or two would be
> meaningful. If you\'re going from five feet to 5\'2\", I thought that
> would be worthy\--you know, that it would be worthwhile. And so
> my\--what I think is meaningful, I think, is on the rather low end of
> what\'s been discussed here today.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Grady?
>
> DR. GRADY: Well, I think the question we\'re discussing is: has the
> efficacy been well characterized and proven?
>
> And, you know, just to summarize what was just said, I think that
> we\'ve been shown that treatment with growth hormone can improve
> height, but that the effect is, I think, fairly small; on the average,
> about one-and-a-half inches; and that there\'s been no demonstration
> of the impact of this on quality of life.
>
> DR. BRAUNSTEIN: So, you\'re answers to this would be: yes, it\'s been
> shown to be efficacious, and the importance of height augmentation is
> open to question\--whether this is clinically significant because of
> quality of life issues. Is that right?
>
> DR. GRADY: Well, that, and I think\--I mean, I think all of us would
> agree that if you could change adult height from five feet to 5\'6\"
> we\'d be less concerned. But changing it from, you know, five feet to
> 5\'1-1/2\"\--there is more concern that that will translate into a
> real impact on, you know, a person\'s life.
>
> DR. BRAUNSTEIN: Okay. I think the efficacy has been demonstrated by
> the pivotal study, in comparison to the control group. I do think that
> a dose-response relationship has been shown by the European study, as
> well as some of the studies that have been reviewed by the meta
> analysis. So I do think that it is efficacious.
>
> In regards to\--and I think that the dose regimen proposed is
> supported by the results of the studies; and then certainly the higher
> dose seemed to give a higher effect than the lower dose.
>
> In regards to the clinical importance, I think this is the crux of the
> problem that many of us are having with this. Dr. Grady nicely brought
> out that there\'s no really good evidence that one-and-a-half inches
> or so is going to improve quality of life. I\'m also concerned about
> the resource allocation issues, about who\'s going to pay for this and
> the potential worsening of the drag on health care dollars over time.
>
> Nevertheless, I don\'t think that\'s really the charge of the
> committee. The charge of the committee is really to determine whether
> this is safe and efficacious, and clinically important.
>
> So my conclusion about the clinical importance is that it really has
> to be defined by the patient and the parents, and that this really
> requires a fully informed consent of both the patient and the parents,
> so that they know that this is going to be\--going to require six
> shots to seven shots a week; that the shots will be given for,
> potentially, 5 to 10 years\--obviously, the younger\--well, the data
> supports that the younger you start it the better the overall effect;
> that the individuals may not experience any improvement in height, or
> they may experience height improvement of one to, maybe, three
> inches\--some individuals had a spectacular response, but most did
> not.
>
> So, I think that when the patient and the parents are fully informed
> about this, and when they understand the resources that are going to
> have to be allocated, either from their pocket, or from other sources,
> that in the final analysis it\'s they, along with their physician, who
> should make the conclusion as to whether it\'s clinically meaningful
> or not.
>
> So, I do think that for some individuals one inch, one-and-a-half
> inches may be clinically meaningful. For others it won\'t be, but they
> have to make that decision.
>
> Dr. Cara?
>
> DR. CARA: In terms of the efficacy of Humatrope in non-growth hormone
> deficient short stature, I think it\'s been sufficiently
> characterized. I think that we\'ve tried to squeeze the data as much
> as we can. And the data is the data. And I think it just highlights
> the fact\--I think the study highlights just how difficult it is to do
> very long-term studies, even in very motivated patients, when such
> frequent follow-up, and such long-term care is required. It\'s not
> only hard for the endocrinologist, but obviously very difficult for
> patients.
>
> I think that in my mind, the dose\--anything less than .37 as a
> recommended dose really does not work well. And I don\'t think it\'s
> advantageous to recommend a dosing range. I would simply go with the
> higher dose and recommend that the higher dose be used.
>
> I think that the safety has been demonstrated. And, personally, I
> don\'t have any problems with a higher dose. If you\'re going to use
> growth hormone, I would advise that, rather than starting with lower
> doses.
>
> In terms of the importance of the height augmentation, taking care of
> patients that I struggle over because of their short stature and my
> inability to do anything for them, I think that the demonstrated
> efficacy for the higher dose is significant. And what we\'re talking
> about is the difference between a young girl\--if we take the average
> response in the final heights of the patients, what it means is that
> for a young girl, treatment with growth hormone makes a difference of
> being 4\'10-12\" versus 5\'1\"-5\'1.3\". For a boy it means the
> difference between 5\'3-1/2\" and about 5\'6-1/2\". So, I think
> that\'s significant.
>
> At loser doses I don\'t think that the efficacy or the height
> augmentation is significant enough to warrant that dose.
>
> DR. TAMBORLANE: I also feel that the efficacy has been well
> established. I see the pivotal study as sort of the worst-case
> scenario, in view of the older age, the three times a week
> administration, and the lower dose. So that just\--it\'s strength was
> the placebo-control aspects; that the real dose finding experiment was
> the E001 study, where you\'re talking about two to three inches
> increase over predicted height. So I think that is a very efficacious
> response for just what Jose mentioned.
>
> As far as clinical meaningfulness, I think that we would be very
> remiss not to comment\--and Jose was just starting to get into
> that\--and the incredible dedication that families, and the debt we
> owe to families who participated in the pivotal study; the fact that
> they would agree to be in a placebo-controlled, three times a week
> injection regimen study just, really, speaks to how important this is
> to them, or was to them. And I think it\'s the same importance that
> most kids who have heights who are almost 3 standard deviations below
> the mean really feel the same way\--and we heard about that from the
> open public forum.
>
> DR. BRAUNSTEIN: Thank you.
>
> DR. SCHADE: Relative to the first question, I agree with the rest of
> the speakers. I think that the drug does\--that they have convincingly
> shown that you do gain height.
>
> Relative to the second issue about whether it\'s clinically
> meaningful, clearly, because of the\--there are dropouts in both
> studies, to some families it wasn\'t clinically meaningful. But,
> again, as my colleague points out, they may have been in a placebo
> arm, and that\'s always a concern in a clinical trial.
>
> What the question, I think, really says, or asks, relative to whether
> the sponsor has shown or suggested by the data that it\'s clinically
> meaningful, I really think there should be additional data on some
> type of benefit besides simply the height. Now, I agree that if the
> height was dramatic\--six inches\--you probably wouldn\'t have to show
> anything else. But because the height benefit is much smaller than
> that, I am concerned that here is a very expensive treatment, in which
> the benefits are not clearly shown.
>
> And I appreciate the argument that these benefits may be very
> difficult to show. On the other hand, I\'ve been\--and everybody on
> the table has been in clinical trials where you hire experts to try to
> get at these problems. And there are many ways to do that. And I
> believe that that part of the studies have not been adequate in order
> to show a real benefit here.
>
> DR. BRAUNSTEIN: Thank you.
>
> DR. Woolf?
>
> DR. WOOLF: I\'ll echo what everybody else has said about 1.A. I mean,
> the statistics are the statistics, and no matter how we slice it and
> dice it, the numbers come up the same, and Humatrope causes
> statistically significant increase in growth.
>
> To me the big issue is: is it clinically meaningful, and there I guess
> we have to say we have no really good data to support that. And I
> don\'t think I can answer this question without having some answers
> for some of the questions further down the list, like who should we
> select, and how should they be followed? And I think they go together.
>
> I would not like to see a blanket approval on the hope that someone
> could grow four or five inches and, in fact, only grow one\--even if
> it\'s informed consent.
>
> DR. BRAUNSTEIN: Dr. Gelato?
>
> DR. GELATO: Well, I would say the same to 1.A. I think that efficacy
> has been shown. I agree with Dr. Cara that I think if you\'re going to
> do this you should go to the higher dose, because I don\'t think there
> was much gain at the lower dose, particularly in this patient
> population.
>
> I also think that the study was hampered by the fact that these were
> older children. And if we look at the growth hormone deficiency
> experience it does certainly look like if you start earlier you get a
> better effect.
>
> And I\'m torn, as everyone else is, with the B part of this, in terms
> of what is clinically meaningful. And I\'m not sure that I can answer
> that either. I think for the child\--again, if someone\'s 4\'9\" I
> think it probably is clinically meaningful to be 5\'1\". So it\'s a
> very difficult call.
>
> And I agree that the studies really didn\'t help us answer that. So it
> either becomes an individual thing, or it\'s one where, as we get
> farther on, maybe it will become more apparent. But, in my own mind,
> I\'m still torn by that.
>
> DR. BRAUNSTEIN: Dr. Watts?
>
> DR. WATTS: I think the company has done everything possible to answer
> the questions raised by the previous committee. But I still have
> questions that weren\'t asked by the previous committee.
>
> Efficacy, in terms of height gain, I think is convincing. Whether or
> not that\'s the right measure of efficacy I think is the question. And
> it seems to me, with a drug that\'s expensive, with a condition that
> potentially affects, by the sponsor\'s estimates, 400,000 children,
> that it should be possible to be placebo-controlled trials looking at
> clinical endpoints. WE don\'t accept surrogate endpoints for agents
> that lower blood pressure, or cholesterol, or improve bone density. We
> want to see clinically meaningful results. And I don\'t think I can
> answer 1.B\--whether or not this statistically significant gain in
> height is clinically meaningful across the board. But if 1 percent of
> all the students in elementary school, and in middle school are below
> the 2.25 standard deviation level, it should be possible to recruit
> one out of a hundred of them, and have vans that go around to the
> schools and measure psychometric response to patients who are on
> placebo or on active therapy.
>
> And whether that\'s done as a requirement for approval, or as a Phase
> IV investigation, I think it\'s very important, if we\'re going to
> spend this much money on a treatment, that we know that it has a
> clinically meaningful effect.
>
> DR. BRAUNSTEIN: Dr. Worcester?
>
> DR. WORCESTER: I would agree with other people, that we certainly have
> seen in the studies we\'ve seen that the treatment is effective as
> measured. As I was reading in the material, and certainly as I\'ve
> been listening to things today, though, I have felt it was very much a
> case of where the statistics don\'t always translate to what it means
> for real human beings.
>
> I think the testimony we\'ve heard, and probably from everybody\'s own
> experience, we know the enormous hurt and pain of the stigma of
> extreme shortness. And I think the kind of changes we\'ve seen here
> don\'t address that. So I\'m leaning on the side of thinking that
> we\'ve heard that, clinically, this much change in height is not
> enough.
>
> I\'m particularly concerned that we have a product here where there\'s
> going to be a huge difference in individual\'s response, and so there
> will be a lot of disappointment. So I think we have to really look at
> the medication, plus social-economic issues.
>
> DR. BRAUNSTEIN: Okay. Thank you.
>
> We\'ll go on to Question 2, and we\'ll start with Dr. Grady. Yes, 2.A
> and B, also.
>
> DR. GRADY: Let me start off by saying that I think safety is, of
> course, a very important issue here, because what we\'re talking about
> is treating otherwise perfectly normal kids who are short, for five to
> maybe 10 years, at a time when they\'re young children, up until their
> pubertal\--potentially a critical time for later events.
>
> I think we have data from the treatment of children with growth
> hormone deficiency which is fairly reassuring. Clearly the best data
> for this specific indication would be from a placebo-controlled
> comparison. And there we have data from one trial in \'71 children
> with about\--way less than 50 percent follow-up.
>
> Nevertheless, if you look at that data, I find it a little bit
> bothersome. There was one death reported in the treated group versus
> none in the placebo group. There were five serious adverse events
> versus two. Three was this report of a desmoplastic tumor and
> Hodgkin\'s disease. And if you look at the adverse events, there was
> report of more flu-like syndromes, more infections, more pain
> syndromes, more bone disorders, lymphadenopathy, reproductive
> abnormalities, fungal and parasitic infections and surgical
> procedures.
>
> These weren\'t statistically different but they were fairly different.
> There was more than a twofold increase in those things in the treated
> group.
>
> And then we\'ve heard these other sort of concerns about issues that
> we have no data from these trials on, including, you know, pseudo
> tumor cerebrae and so forth; slipped capital femoral epiphysis, of
> which there was one report.
>
> So, I don\'t think we have really good data on safety. And I
> personally think we should have really data on safety because we\'re
> talking about treating what are otherwise perfectly normal
> children\--who are short.
>
> DR. BRAUNSTEIN: Okay. So you do not feel that the safety
> characteristics have been sufficiently characterized in this group of
> patients.
>
> DR. GRADY: No.
>
> DR. BRAUNSTEIN: Okay.
>
> DR. GRADY: And I realize that this would be a very difficult thing to
> do. On the other hand, I don\'t think it\'s been shown.
>
> DR. BRAUNSTEIN: And what about\--so do you feel the risk-benefit ratio
> is adverse?
>
> DR. GRADY: I don\'t\--I don\'t know how to answer that, because we
> know the benefit, in terms of, you know, a couple of inches of height.
> And we have otherwise very little information, I think, on, you know,
> quality of life-type benefits, and inadequate information on safety.
>
> DR. BRAUNSTEIN: And what about the proposal for long-term follow-up of
> these children as part of the GeNeSIS study?
>
> DR. GRADY: Umm\--well, I\'d kind of like to hear a little bit more
> about that. But, certainly, I think if we decide to approve this there
> should be an effort to gather long-term safety data. This is always a
> difficult thing to do because there\'s no good comparison group.
>
> DR. BRAUNSTEIN: What type of surveillance would you recommend?
>
> DR. GRADY: Umm\--you know, I think, at a minimum, there should be some
> sort of registry for patients using growth hormone for idiopathic
> short stature. Again, it\'s not a great way to get good information,
> because it\'s difficult to know what the comparison group is. But I
> think there should be some attempt, in addition to a registry, to have
> routine follow-up of at least the first cohort of patients for
> specific conditions.
>
> DR. BRAUNSTEIN: So do you think that should be a mandatory registry?
>
> DR. GRADY: Ahh\--I think there should at least be a mandatory
> registry, yes.
>
> DR. BRAUNSTEIN: Okay. Thank you.
>
> Okay. I think the safety has been reasonably well characterized. I am
> pleased that there\'s a lot of data out there in other conditions for
> which Humatrope, and other growth hormone preparations from other
> manufacturers, have been used. So I do think that we pretty much know
> the major problems associated with growth hormone. Clearly, as you
> increase the population of patients that are going to be exposed to
> this some small problems may come to the forefront, and we may see
> some problems that were not previously apparent.
>
> I do think that in regards to risk and benefit, again, because there
> is a dearth of information about the psychological, psycho-social
> benefits\--other than anecdotal information\--that it again comes down
> to a personal decision on the part of the patient and especially the
> parents, since this will be started during childhood in most
> individuals, to know what the potential benefits are or may not\--what
> benefits may not be there, and what the risks are, and to let the
> parents and the child say, \"Yes, the benefits or potential benefits
> outweigh the risks\" for that particular individual.
>
> As far as long-term follow-up is concerned, I think that the GeNeSIS
> system\--what I know about he GeNeSIS system seems to be very
> adequate. I do think, though, that because the risks in this
> population have not been as well characterized as we\'d like, and the
> benefits in this population have not been as well characterized as
> we\'d like, that there should be a mandatory registry, mandatory
> surveillance of these patients.
>
> And since Lilly has indicated that the distribution of the drug will
> be so tightly controlled, clearly they have the capacity to make this
> a mandatory part of the distribution of the drug, because people who
> do not provide the information or the follow-up information would not
> be able to get a renewal of the drug prescription.
>
> So I think that they have a perfect system in place to have a
> mandatory follow-up. And this, again, should be indicated to the
> parents on the front end, that this is a mandatory part of the whole
> program.
>
> Dr. Cara?
>
> DR. CARA: Bill corrected me\--the data \"are\" the data. I got stuck
> between the data are the data, and it is what it is.
>
> I also concur with Bill when he said that I think\--and as Ron also
> pointed out\--that we\'re probably looking at the worse-case scenario
> because we are, in fact, dealing with the older population of
> patients, significant dropout rates, and I still think that there are
> a lot of questions that need to be resolved, but we\'re definitely
> looking at a subset of patients that are probably the patients that
> are giving us a very minimal idea of what is possible.
>
> In terms of the questions: has the safety profile been sufficiently
> characterized? Yes, I think so. Based on what we know about growth
> hormone, previous experience with growth hormone, and the data that\'s
> been provided by the sponsor, I think that the safety profile has been
> sufficiently characterized.
>
> I think that there is a favorable balance of risk and benefit. I think
> the benefits outweigh the risks significantly. That doesn\'t mean to
> say that growth hormone treatment should be used cavalierly or
> indiscretionately. I think that monitoring is a good idea. And I think
> that the GeNeSIS system that\'s been proposed by the sponsor makes
> very good sense.
>
> I would extend that to\--I\'m not sure how you can enforce, but to try
> to enforce pediatric endocrinologists that are treating patients with
> non-growth hormone deficient short stature to provide at least a
> yearly update on the patients that they are treating, in terms of
> safety profile, in terms of their overall evaluation of efficacy, and
> whatnot. I think that that would make a lot of sense.
>
> There are still a lot of questions that we have, but I don\'t think
> that the GeNeSIS sort of monitoring regiment proposed by the sponsors
> is going to answer those. I think those will be done by separate
> clinical studies.
>
> DR. BRAUNSTEIN: Dr. Tamborlane?
>
> DR. TAMBORLANE: Yes. As far as the safety profile, I think we have
> abundant experience with growth hormone in a variety of circumstances,
> over many years. So I think the safety profile is reasonably well
> characterized. In fact, I would contend that the argument from the
> company, as far as\--you know, that growth hormone has been used for
> various indications related to growth augmentation not related to
> treatment of underlying disease is actually, from a safety viewpoint,
> even more of a problem with the other conditions. Growth hormone
> deficiency, renal failure, Turner\'s syndrome\--I have more safety
> concerns with use of growth hormone say, for instance, in Turner\'s
> syndrome than I would have in a non-growth hormone deficient child.
>
> And I think the data that I saw actually supported the idea that there
> were fewer adverse effects, and I think that would be expected.
>
> Now, the couple years I\'ve been on the committee I\'ve always enjoyed
> Dr. Grady\'s comments. However, I have to say, I could just envision a
> deja-vu from 10 or 15 years ago, if this committee was talking about a
> weight reduction medication for children who were overweight, and Dr.
> Grady\'s mother saying that, you know, these are perfectly healthy
> children except they\'re fat.
>
> You know, so I really don\'t\--I\'m not sure that these severe growth
> hormone\--or short stature patients really fit into that category. And
> I think I would tend to weigh on the idea that we may not have
> discovered all of the psycho-social implications of being severely
> growth impaired at that age, but that they are, in fact, real
> problems.
>
> DR. BRAUNSTEIN: And what about the follow-up?
>
> DR. TAMBORLANE: I think the\--you know, all the companies have routine
> sort of post-marketing surveillance. I don\'t understand the legal
> implications of mandatory involvement and follow-up. I mean, I think
> under HIPAA rules, you know, does the patient have to agree to be part
> of a registry to get the medication? You\'d have to explain that to
> me. I don\'t know that it has to be mandatory.
>
> I think the way that it is, where it\'s worked very efficiently with
> pediatric endocrine practices, where the companies actually help
> support the process and the data get collected.
>
> DR. BRAUNSTEIN: Okay.
>
> Dr. Schade?
>
> DR. SCHADE: Yeah, it\'s always a pleasure to disagree with Bill.
>
> I think we\'re all a product of our experiences, and I\'m an adult
> endocrinologist, and I\'ve sort of lived through the rezolin era, in
> which the FDA approved the drug, and not until we used it in thousands
> of patients with diabetes did we really see some adverse events that
> then resulted in withdrawal of the drug.
>
> My concern is that the use of growth hormone in the population we\'re
> talking about is a major change in numbers. All of a sudden we\'re
> going from several limited populations to a huge population that will
> always be huge because it\'s defined as a statistical standard
> deviation below the mean. So we\'re never going to reduce that
> population, and so we\'re always going to be dealing with 400,000
> individuals or more, depending on how big a world you want to treat.
>
> The other thing that influenced me besides that type of history is:
> growth hormone use in adults\--in fact, as in the elderly\--has
> recently been looked at, and is still being looked at. And in those
> individuals, although the dosages and the size of the individuals are
> different, there have been problems, and adult endocrinologists are
> concerned with those problems.
>
> So I think there is a potential to run into several types of problems
> when you give, basically, an individual with normal growth hormone
> levels\--and we can argue that\--but we\'re adding a hormone that\'s
> already there, rather than a hormone to growth hormone-deficient
> individuals, that you can get into problems. And you don\'t see these
> problems until you start treating thousands of individuals, and then
> all of a sudden you start seeing some problems that you didn\'t see
> before.
>
> I guess I\"m concerned about the numbers we\'re seeing in the clinical
> trials. I would have much preferred numbers in the thousands. When
> we\'re dealing with a population of 400,000 individuals that are
> potential for treatment. And whether we end up with 40,000, or 100,000
> people, depending on the algorithm you want to use, we\'re still
> talking about hundreds of thousands of individuals. And to have
> clinical trials that only have hundreds of people in there, rather
> than a couple thousand, to me is difficult for me to understand.
> Because, certainly, it can\'t be a recruitment issue; not when
> there\'s 400,000 individuals there that are potentially treatable.
>
> So I\'m concerned that we haven\'t looked at enough individuals in
> order to define the hazards of this drug. So whatever the FDA decides,
> I believe that close monitoring is absolutely required, because I am
> concerned you will start seeing a significant risk profile once you
> start treating the numbers of individuals that I think are going to be
> treated with this medication if this drug is approved for that
> purpose.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Woolf?
>
> DR. WOOLF: Let me echo what my esteemed colleague on the right has
> said.
>
> We\'re now proposing to treat growth hormone-sufficient children with
> growth hormone for perhaps a decade. And we really don\'t know\--at a
> time when they\'re growing. And we really don\'t know, down the road,
> what will happen to these kids. I doubt whether the growth hormone
> will initiate new tumors, but kids who already have tumors could their
> spread be worse? Could this child with Hodgkin\'s, who was missed six
> months earlier\--that Hodgkin\'s get accelerated by virtue of the
> growth hormone treatment? I mean, I have no idea. I don\'t know if
> anybody else has.
>
> Certainly, in the small context of the clinical trial I think the
> safety was demonstrate. But when it gets out into the field, I don\'t
> know. Certainly it\'s reassuring, from other growth hormone
> indications, that it doesn\'t appear to be serious\--there were some
> problems with the adults that were overdosed, and many of those went
> away.
>
> But tumor genesis still persists. So, for that reason, I think doing
> whatever is legally possible to have as much of a mandatory registry,
> with follow-up\--assuming that it\'s HIPAA-compliant, and compliant
> with other regulations\--would be very beneficial, and it would need
> to be done for decades.
>
> DR. BRAUNSTEIN: So, do you\--is your response about the current
> knowledge of the safety profile\--do you think that that\'s\--
>
> DR. WOOLF: I think what we have is fine. What we don\'t have\--we
> don\'t know what we don\'t know.
>
> DR. BRAUNSTEIN: Let me go back also to Dr. Schade just to have you
> define that.
>
> Do you think, with the current knowledge, that the safety profile
> gives a favorable balance of risk and benefit?
>
> DR. SCHADE: Well, I only believe that\'s true if you\'re defining
> benefit as growth. I would prefer that question be growth, rather than
> benefit, because we\'ve already have the discussion and argument: what
> benefit means. So, right now, I don\'t think we have the data to
> answer that question in the affirmative. But if you want to change the
> benefit to the word \"growth,\" then I would agree. But if you don\'t,
> then I cannot\--I would not say we have the data to answer that
> \"yes.\"
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Gelato?
>
> DR. GELATO: I think, in terms of safety profile, we do know a lot
> about growth hormone. We certainly know a lot about the effects of
> growth hormone in growth hormone-deficient children\--and adults,
> actually. And there it seems to be safe, and there\'s a lot of
> long-term follow-up.
>
> I agree with what has been said by Dr. Schade and Dr. Woolf, that in
> sufficient patients it may be something different. And certainly there
> are some indications that it may be. However, I think what was
> presented is somewhat reassuring, because there wasn\'t anything that
> at least looked like an immediate red flag.
>
> But I do agree that whatever surveillance goes on should be mandatory,
> simply because now you are going to be going out to a much larger
> population, treating potentially many more children, and we really
> don\'t know what\'s going to come down the line in 10 or even 15 years
> from this therapy.
>
> DR. BRAUNSTEIN: Dr. Watts?
>
> DR. WATTS: My answer to 2.B is: yes, there is a need for a registry or
> some type of very long-term follow-up.
>
> My answer to 2.A is: no. In looking at the data that we have, there
> were 80 patents enrolled in the higher-dose growth hormone group in
> E001, and 13 who were followed to final height. And there\'s no
> placebo group in that study.
>
> In the placebo-controlled trial, which was a lower dose, we have 10
> placebo subjects who were followed to final height. And the comparison
> is not with normal healthy children, the comparison for adverse
> effects is with patients receiving growth hormone for other
> indications.
>
> And so even in the short term, I\'m not convinced that we have
> adequate data on safety for this indication. And I\'m not sure that we
> know that right dose. In looking at the height response, it appeared
> to me that at least half the children who received the lower dose of
> growth hormone did quite well, and I would love to see a dose
> escalation study to find out how many children\--while we\'re told
> that there are no predictors of response, but in a larger trial it
> might be possible to establish either predictors of response, or find
> out who would have a maximum height response to a lower dose and which
> children need a higher dose, and what safety issues emerge when
> treating large number of children with a higher dose\--things like
> insulin resistence, changes in glucose metabolism that we don\'t know
> about.
>
> DR. BRAUNSTEIN: Dr. Worcester?
>
> DR. WORCESTER: I would answer the question by saying in this
> particular situation we can\'t possible have enough safety information
> because we\'re looking at marketing this to a very large number of
> healthy people, at a very important stage of their development, in
> terms of both pre-puberty and very young. So I think the safety
> standards have to be high, even though I think the beginning
> information that we have today looks promising, but I would only think
> it looks promising for the reasons that other people have said.
>
> And obviously you would expect me, then, to go on to say that
> long-term follow-up, with as much information as possible, is
> certainly going to be necessary. So I certainly support a mandated
> registry\--and not just while people are being treated, but also 10
> years after, to see any long-term impact.
>
> The other issue that I brought up earlier, and could not be addressed
> because of the kind of studies we had today, I think we\'re going to
> see a lot of people\--a lot of children\--in and out of treatment. And
> so the yo-yo impact I think is a whole other issue that we haven\'t
> even mentioned, except for my question today. And that\'s something
> else to watch for.
>
> DR. BRAUNSTEIN: Good. Thank you.
>
> DR. GOLDSTEIN: May I comment?
>
> DR. BRAUNSTEIN: Umm-I need a ruling on that\--since you\'re not a
> voting member of this.
>
> DR. GOLDSTEIN: Right.
>
> DR. BRAUNSTEIN: Dr. Goldstein has requested to offer a comment. Can we
> hear his comment, without a vote?
>
> DR. GOLDSTEIN: The comment I would make would be in response to Dr.
> Schade, particularly. There were\--I don\'t recall the number, but in
> a hundred or two in these studies\--in these rigorously conducted
> studies over a long period of time\--if we were to wait to approve
> this until \"adequate\"\--quote-unquote\--safety data were obtained,
> as a practical matter the cost of mounting a study of thousands of
> patients of this prior to approval would make it, in a word,
> impractical.
>
> I think the alternative of a careful monitoring system, such as
> GeNeSIS and the very careful pharmacovigilance and other activities
> that Lilly is renowned for is likely to provide a lot of the data over
> the coming period of time, as to be able to reassure the committee.
>
> So I think that\'s a reasonable balance.
>
> Thank you for permission to comment.
>
> DR. BRAUNSTEIN: Thank you, Dr. Goldstein.
>
> Dr. Follman?
>
> DR. FOLLMAN: Yes\--in terms of the safety- benefit ratio, I would
> say\--I would vote in favor of a favorable risk-benefit for Humatrope.
> I think it\'s been sufficiently characterized in these studies. You
> know the studies have small numbers. We don\'t really see anything
> alarming there. If you also take into account the other studies in
> which this has been studied, I\'d have to say that it\'s been
> sufficiently characterized.
>
> Of course, you know, the concern I think a lot of us have is that
> these are relatively small populations and now we\'re talking about
> broadly\--broadening it quite a bit, so it will be tens of thousands
> of patients who potentially get this. And in a situation like that,
> things that weren\'t detectible earlier because the studies were
> relatively small, now have a chance to be detectible. And I think
> it\'s important, as has been mentioned earlier, to have a monitoring
> program\--if it\'s approved.
>
> DR. BRAUNSTEIN: Thank you.
>
> Okay, I\'ll start with Question Number 3: are the available data from
> the studies presented sufficient to guide the safe and effective use
> of Humatrope in patients with NGHDDS?
>
> And I feel the answer to that is yes, based not only on the small
> studies done by the sponsor, and the meta analysis, but also because
> the large experiences available from other patients who have short
> stature that is not due to growth hormone deficiency; so\--the
> Turner\'s patients, Prader-Willi, renal insufficiency patients,
> etcetera, as well as the growth hormone deficient patients. I think
> that a lot has been learned from those patients.
>
> And so I do think that it\'s reasonable to suggest a .37 dose, with
> six to seven shots a week. And, over time, I\'m sure, as we learn more
> about this, that would be modified.
>
> The sponsor has proposed a restrictive height criterion for treatment
> eligibility. Is this proposal satisfactorily rationalized?
>
> Ahh\--I think so. And the reason why I\'m hesitating is because we\'re
> dealing with a statistical issue here. And clearly, if we treat the
> entire population who is in the first percentile, we\'re still going
> to have huge populations in the first percentile, because by
> definition there\'s always going to be somebody who\'s going to be at
> the lower end of the curve.
>
> But I do feel that, taking into account the learned society\'s
> recommendation that less than 2 standard deviations be considered
> short, and the need to be even more conservative, the sponsor has
> justified their choice of minus-2.25 standard deviations.
>
> Are additional criteria needed, such as pre-treatment height velocity,
> bone-age, chronologic age, serum IGF-1 levels?
>
> And I think the answer to that is yes, and I would make this part of
> the mandatory follow-up program. We want to get as much
> data\--oxyological, biochemical, bone-age data as possible, because
> over time we may be able to use that database to better define how the
> drug should be used, and in what group of patients the drug should be
> used.
>
> So I advocate actually requiring that information on the front end,
> before starting a patient on therapy, and then collecting that
> information periodically while the patient\'s on therapy, until it is
> deemed that we have a sufficient amount of information to know how to
> use the drug effectively and safely.
>
> C\--the range of responses observed in the trials, and thus expected
> in the clinic, is broad. Additionally, a dose-response is evident.
> Please discuss the following: 1) the need for information on effective
> individualization of dose; age at initiation of therapy; and duration
> of therapy and gross response and on safety.
>
> I think the data with this group of patients, as well as with other
> groups of patients, is that the younger the patient the better the
> response after you initiate therapy. When should one stop the therapy?
> You know, I think that, certainly, you know, the broadest response
> would be: when final height is reached. But I think that there
> probably should be careful observation of changes in height velocity,
> and determination of when the response to growth hormone is so low, in
> terms of a decrease in height velocity, that it no longer is
> reasonable to continue the growth hormone.
>
> So, although I don\'t know what that number is, and it hasn\'t been
> defined, this is something that I hope will come out of a mandatory
> registry and follow-up type of study.
>
> Then, number 2: the need for information on potentially useful
> predictors of response, both pre-treatment and on treatment; early
> growth or bio-marker effects, again, to enhance safe and effective
> use.
>
> And I agree that we need to collect more information on these
> patients, although I wouldn\'t demand that that information be
> collected before the drug was approved for more general use. I am a
> bit concerned that in this group of individuals with idiopathic short
> stature, non-growth hormone deficient short stature, that there\'s a
> group of individuals who have growth hormone resistence. And we need
> to be able to define those individuals, because it would be
> anticipated that those individuals would not respond to growth
> hormone, and we need to be able to define those, either by growth
> measurements, height velocity, IGF-1 response to growth hormone, or
> other parameters, and we\'re only going to be able to define that
> sub-group by doing those types of studies.
>
> Dr. Cara?
>
> DR. CARA: My answer to Question Number 3 is: yes. As a practicing
> pediatric endocrinologist, I don\'t think that we\'re going to see the
> thousands of patients that people have been concerned about. I think
> that my experience has been that, in general, parents are more
> interested in finding out if there\'s a problem or not, and are very
> willing to initiate therapy, but are also very relieved when their
> children are actually fine and don\'t need any treatment whatsoever.
>
> Of course, to a large extent that\'s at the discretion of the
> endocrinologist. But I trust most pediatric endocrinologists, being
> one myself.
>
> So my answer to Question Number 3 is yes. 3.A\--I think it\'s a good
> idea to have some criteria for initiation of therapy, and I think that
> the criteria that the sponsor provided is helpful\--specifically in
> relationship to the degree of short stature, especially when we
> consider that the degree of short stature was probably one of the
> better predictors of ultimate response to growth hormone therapy.
>
> 3.B\--are additional criteria needed? My answer is yes, but of course
> it\'s somewhat arbitrary, since we really don\'t have any idea of what
> pre-treatment criteria may ultimately define the response to growth
> hormone.
>
> Personally, I would like to see IGF-1 levels in the less than 50th
> percentile range for age, which comes up to above the 50th percentile
> but no greater than the 90th percentile on therapy\--or 97th
> percentile on therapy; appropriate treatment monitoring, in terms of
> safety issues. Keeping\--again keeping the IGF in the upper end of
> normal but not exceeding the normal range I think is a good idea,
> especially when many of these youngsters have low IGF-1 levels to
> begin with. I think using IGF as a criteria for pre-treatment and then
> efficacy of therapy is also very helpful.
>
> It\'s helpful to have bone-age, chronological age and other serum
> markers, but I don\'t know that, other than height velocity, whether
> any of those other markers are truly helpful in making a decision.
> It\'s sort of the patient in toto that we have to be looking at, and
> not relying on a specific marker.
>
> So, to summarize, I would recommend the height criteria that\'s been
> proposed by the sponsor. I would like to see an IGF-1 level below the
> 50th percentile for age, and a pre-treatment height velocity that\'s
> below the 50th percentile for age, as well.
>
> 3.C\--I don\'t know that there is such a thing as individualization of
> dose when it comes to growth hormone therapy. We\'ve generally tended
> to use the recommended dosages, .3 to .375 for most individuals. And I
> think that we\'ve felt fairly comfortable doing so. Ideally, I would
> expect a response to growth hormone therapy of a minimum of 50 percent
> increase above basal growth rates, so that that might be a way that we
> can evaluate the growth response. But I would be very hesitant about
> increasing doses further beyond the .37 dose recommendation. Again,
> I\'ve commented before on lower doses, and I don\'t think that they
> are really work discussing any further.
>
> 3.C.2\--again, having been in the growth field for quite a while, and
> having looked at a variety of predictors of response\--and being
> frustrated at not finding any, I don\'t know that looking for
> potential predictors is really going to be entirely helpful. That
> said, I\'m also not very comfortable with a notion of committing a
> child to seven to ten years of growth hormone treatment without having
> some sort of justification for it, or treatment efficacy that I can
> then use to say, yes, this is working, makes any sense either.
>
> In my own view, I think an increase of 50 percent above basal baseline
> rate of growth is a useful indicator. And, again\--well, having any
> additional markers, I think, is\--well, it\'s going to be very
> difficult to determine those. That\'s the bottom line.
>
> DR. BRAUNSTEIN: Dr. Tamborlane?
>
> DR. TAMBORLANE: As far as the data as far as safe and effective use of
> Humatrope, I don\'t know if this has come up yet. I certainly haven\'t
> heard it, but this issue about data about safety, I just want to
> follow up a little on that\--is that, you know, there are, as far as I
> understand, literally thousands of youngsters who are classified as
> idiopathic short stature, non-growth hormone deficient short stature,
> that have been followed for years within the current registries\--I
> mean, the Genentech registry and the other registries. So there is a
> tremendous amount of exposure. It\'s not just these 80 patients who
> were followed for a number of years. And nothing has certainly jumped
> out, to my knowledge, about safety. So, again, that\'s why I just want
> to fill in some of the\--why I felt the safety profile was pretty
> good.
>
> As far as\--I thought the height criteria was reasonable. Remember,
> the height criteria\--minus-2.25 is, you know, the cut line. And when
> you do that, then you come up with a mean of 2.7 standard deviations.
> So, I mean, I think that\'s a very reasonable way to try to limit the
> available population and that, you know, one of the safeguards as far
> as this floodgate sort of thing.
>
> As far as additional criteria, I\'d have to think about this a little
> more, but I think that probably the one that I would be most in favor
> of is sort of an age criteria that the E001 when five years of age and
> up, so you have efficacy data in that age group. I think, as a
> pediatric endocrinologist, we know there\'s a lot of shifting of
> growth percentiles during the first two to three years of life. So I
> would hate to think that we would be treating a two-year-old who was
> more than .25 standard deviations below the mean. So I think a five
> year cutoff seems like a reasonable place as a starting point for
> discussion.
>
> As far as IGF-1, you know we\'ve heard, and it\'s been our experience,
> that none of these are great predictors. So that\'s what\--I\'d just
> go with age.
>
> As far as what other trials\--I think that the registry is very
> important. I think that we\'re only scratching the surface, as far as
> dose response characteristics. I think maybe\--again, trying to add
> something to the discussion\--what we may have if this is approved, in
> treating patients, and with the pivotal study showing proof of concept
> that it works, you may not\--obviously, you have to go to final
> height. So you could do a series of dose responses, and looking at
> different ages, and you may just need response over the first two
> years, and that might actually be your surrogate marker, rather than a
> biochemical surrogate marker to show relative efficacies of different
> dosing regimens at different ages.
>
> DR. BRAUNSTEIN: Dr. Schade?
>
> DR. SCHADE: Well, in answer to the first question, I\'m concerned
> whether we have sufficient information to guide the safe and effective
> use of Humatrope. For example, since we\'re suddenly using it, or may
> be using it in large numbers, I have seen no data, for example,
> whether this drug is safe in a type-I diabetic. I have seen no data
> that this drug does not significantly augment insulin resistence in
> the obese child with a BMI greater than 35, and that\'s of great
> concern because, at least in my state, and probably throughout the
> U.S., childhood obesity has become an epidemic.
>
> So, I\'m concerned if you make a general statement, whether w e have
> the information available for safe and effective information on how to
> treat, I have no idea how to treat a type-I diabetic who happens to be
> in the short stature category.
>
> So, I think if we focus on certain populations that were in the
> clinical trials we may, but I didn\'t hear any data on two categories
> that I mentioned, and I could probably think of others. So I\'m
> concerned about that first question.
>
> And I think the height issue, I would agree that the company\'s
> recommendation is rational and statistically okay. And I really don\'t
> have any problem.
>
> I\'m also concerned\--and I expressed it this morning, and I\'m not
> arguing that it may not be difficult\--but I\'m very concerned that
> mechanistically we seem to have no way to predict who is going to
> respond, or whether the degree of response is proportional to some
> surrogate markers. And I didn\'t see any data on, for example, growth
> hormone levels after the injection. In many substances that we inject,
> different people characteristically have different responses. I
> didn\'t see any free fatty-acid data, which now has become a real
> problem relative to insulin resistence and causing insulin resistence.
>
> I think we should look much more thoroughly at finding surrogate
> markers, either relative to adverse events, or to response to growth.
> I think if we don\'t do that, if we say, \"Well, we can\'t find
> anything,\" we\'ll end up treating many, many people with a huge
> degree of responsiveness, and that\'s of concern. Because I think what
> we ought to be doing is targeting the people who grow more than 1.5
> inches. And if we simply say we can\'t do that, we\'ll never do that.
>
> So, I\'m a little concerned about the mechanism of responsiveness,
> that we haven\'t really had studies looking at that in any detail. And
> I would strongly recommend to the FDA that studies be initiated. I\'m
> not saying hold up approval. That\'s not the issue. But I\'m saying,
> when we\'re talking about treating up to 400,000 individuals, that if
> we don\'t have some handle on who\'s going to respond, we are going to
> be not only wasting a lot of resources, but basically causing a lot of
> children to take a lot of injections for no reason.
>
> So I have some major concerns about all of these questions, and
> whether we really have adequate numbers\--adequate amount of data to
> really guide the physician in using this drug in an intelligent
> manner.
>
> I have problems with the concept of\--quote\--\"letting the private
> physician or family make the ultimate decisions.\" They can do that,
> but they need the data, and they need the information on which to make
> those decisions, and I just don\'t believe we have them\--or at least
> I haven\'t seen them presented today.
>
> DR. BRAUNSTEIN: Dr. Woolf?
>
> DR. WOOLF: What I\'m about to say is probably heretical.
>
> Yes, I agree with the height\--that height restrictions should be
> there, but use of a 2.25 SD criteria is arbitrary. By definition of
> the pediatric societies, an SD below 2.0 is short stature.
>
> If, in fact, short stature is associated with psycho-social issues,
> then 46 percent of the short children will not be eligible for
> treatment. So I would submit that if we\'re going to treat because
> there are issues, that we treat to an SD of 2.0, rather than 2.25. And
> that\'s probably heretical, at least from what we have heard today.
>
> Now, I\'m not saying that it is beneficial. That hasn\'t been proven.
> And I\'ve said that before. But if it is beneficial, then roughly half
> the children will not be eligible for treatment.
>
> I would try to get as much information as possible on these kids.
> We\'re talking about having a mandatory or a near mandatory registry,
> and with only a couple hundred kids we may not have the information
> that we could have if we have thousands of children. So I\'d like to
> get as much information as possible using the current state of the
> art\--and I think the state of the art will jump light years
> ahead\--and we\'ve talked very briefly about this during a break, with
> DNA chips, and looking at responses and who are responsive, and what
> kind of path. And that may be down the road, not in the not too
> distant future. At least I hope it would be.
>
> We have no evidence that going higher is better, and the .375 mg dose,
> I think, is certainly acceptable.
>
> We don\'t know who will respond. Not everybody has response, and I
> would like to put a criteria on the continued use of the drug, that it
> will be discontinued if the response is less than x\--and I don\'t
> know what x is\--so that we don\'t have somebody take ten years\'
> worth of treatment who will not respond\--who does not appear to
> respond substantially, but exposes them to whatever the risks of
> long-term treatment are.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Gelato?
>
> DR. GELATO: Well, I believe that we do have evidence that can guide us
> to use the Humatrope in these children. I think that the height
> criterion\--the way they\'ve set it is fine. I\'m actually comfortable
> with the fact that we\'re not going to be treating every short child,
> because I think we need to get some information, and maybe this will
> help us do it.
>
> I think that we should have additional criteria. I think a
> pre-treatment height velocity would be important. And IGF-1 level
> would be other information, and the fact that the child has had
> provocative testing, I think, all should be collected. I\'m not sure
> that it should necessarily be a criterion for therapy. But I do think
> we should get as much information as possible.
>
> I don\'t know\--I guess my feeling about individualizing the dose is
> that if you have a young child and you\'re treating them and all of a
> sudden you see that the IGF-1 level has jumped out of the normal range
> to something higher, then I think, you know, one should cut back.
>
> I think that there should be criteria in place for, if the is not
> responding\--and I would certainly defer to Dr. Cara for what he
> suggested in terms of growth velocity\--that the growth hormone should
> be discontinued. I think this will help us try to define who should be
> treated, what an adequate response may be, and maybe trying to define
> those people who have growth hormone resistence and may not be
> candidates for this.
>
> I think, as Dr. Schade said, we should try to get as much information
> as we can on these children. If it\'s free fatty-acids, insulin
> resistence\--whatever we can get\--to try to help us better understand
> what the therapy maybe doing, and what some of the potential problems
> may be down the line. So I\'m in favor of trying to collect what we
> can that\'s reasonable.
>
> The other thing I\"d like to say is that I also agree with an age
> restriction. And I probably would not treat children under the age of
> seven.
>
> DR. BRAUNSTEIN: I\'m sorry?
>
> DR. GELATO: I would not treat children under the age of seven.
>
> DR. BRAUNSTEIN: Okay\--so we have \"under five,\" by Dr. Tamborlane;
> \"under seven\" by you\--right? Okay.
>
> Dr. Watts?
>
> DR. WATTS: In all due respect to Dr. Tamborlane and to Dr. Grady\'s
> mother, I\'ve been thinking about this issue of drugs to treat
> childhood obesity, and if the response was in weight loss what the
> response here is to height, I\'m not sure the answer would be quite so
> easy. Because this is a change in height of 2 to 4 percent of adult
> height. And an agent that reduced weight in obese children by 2 to 4
> percent, that had limited safety data might not be something to
> embrace.
>
> DR. TAMBORLANE: I was afraid you\'d figure that one out.
>
> \[Laughter.\]
>
> DR. WATTS: Yes. And if you\'re aware of registry data on thousands of
> children who\'ve received growth hormone for this indication, that may
> reassure you, but I haven\'t heard anything about such data, and my
> comments and concerns about safety are limited to the information that
> I have heard here.
>
> For 3.A, I think that this is an arbitrary and logical height
> limitation, but if the real reason for treating short stature is
> because of psycho-social issues, it seems to me that it should be
> limited to short children who have psycho-social issues, and not just
> short children.
>
> I don\'t know that I can tell you any additional criteria for
> treatment, other than a lower age limit\--something along five to
> seven. But I think the studies listed here are studies that should be
> done as part of the work-up of a child who is going to be receiving
> growth hormone treatment.
>
> Need for information on useful predictors\--I\'ve mentioned; that as
> an adult endocrinologist, my answer to the overall question, \"Are the
> available data sufficient to guide the safe and effective
> uses?\"\--no. From what I\'ve heard today, I\'m not sure of the dose
> to use; I\'m not sure which children to treat; I\'m not sure what to
> monitor; and I\'m not convinced of safety.
>
> DR. BRAUNSTEIN: Dr. Worcester?
>
> DR. WORCESTER: I didn\'t have very much to say, but answering the
> first one, in terms of height criteria\--I certainly would not want
> the population that this would be marketed for to be broadened at this
> stage, so I like the limitation.
>
> In terms of additional criteria, I certainly hope the follow-up
> studies would help us answer this much more wisely in a pretty short
> time. But right now I don\'t what age to say, but I certainly would
> think there should be a minimum age at which the treatment would be
> started.
>
> And then my response to the wide range of individual responses to the
> product would be that what we need is very good guidance for the
> families making decisions about this, so that there\'s very realistic
> expectations. And I think that\'s as important as looking at the next
> couple questions.
>
> DR. BRAUNSTEIN: Thank you.
>
> Dr. Goldstein, I\'ve been informed that you can participate in the
> discussion. So, do you have any comments on these questions?
>
> DR. GOLDSTEIN: I would have prepared, Dr. Braunstein, but not
> expecting to be called upon\--we\'ve heard\--and everything I\'d
> probably wanted to say has either become moot at this point, or has
> been said by others, so\--
>
> DR. BRAUNSTEIN: Great.
>
> DR. GOLDSTEIN: \--thank you.
>
> DR. BRAUNSTEIN: Okay.
>
> Dr. Follman?
>
> DR. FOLLMAN: In answer to Question 3, I think the data are sufficient
> to guide the safe and effective use of Humatrope in these patients.
>
> The criterion that the sponsor has suggested of minus-2.25 seems, you
> know, arbitrary to me but, you know, what wouldn\'t be, in a way?
> These are\--this was used as the inclusion criterion in the pivotal
> study, and it\'s more restrictive than the inclusion criteria used in
> E001. So\--you have to come up with some guidance, and they\'ve
> proposed something, and I can\'t think of a reason why we should pick
> a different number.
>
> In regards to 3.B, I think additional criteria would be useful. I\'m
> not exactly sure what that would be. I had a concern I mentioned
> earlier about the stability of the standard deviation score, and so I
> don\'t\--I wouldn\'t want a patient to be\--to get this without some
> historical or some trajectory data on that person.
>
> Then age restriction had also been proposed here, and I would\--you
> know, that sounds good to me. I don\'t really know the area that well,
> but I would think additional criteria would be helpful.
>
> In terms of individualization of dose, I think this is an extremely
> difficult thing to try and do for this condition and this kind of
> endpoint. If you\'re looking at something such as high blood pressure
> you can try and individualize the dose; you can evaluate rather
> quickly. Here what you\'re aiming for is probably height at 18 years,
> and so how can you individualize that dose based on outcomes from a
> person until you wait 18 years.
>
> I think it\'s going to be difficult to do a trial, you know, in the
> future, to try and answer this question, to look at different doses
> for different subgroups. And so I think this is a very difficult
> issue.
>
> In terms of predictors of response, I think that\'s also somewhat
> difficult, but one thing that\'s been suggest that sounds promising
> would be to look at the early response\--say, over a year or two.
>
> DR. GRADY: I just want to thank you for this opportunity to uphold my
> reputation.
>
> I think that we don\'t have sufficient data to guide safe and
> effective use. I think that the height criterion is not nearly
> restrictive enough. It basically uses a descriptive statistical
> descriptive term to define around about 1 percent of all children as
> having idiopathic short stature and potentially needing treatment for
> that.
>
> I think that the additional restrictions the company has modeled
> depend only on the physician\'s discretion, and the discretion of an
> insurance company\--which certainly could change over time to prevent
> what could be 400,000 or\--400,000 children, to cut that number down
> to about 40,000.
>
> I also think that this is a descriptive cutoff based on standard
> deviations. If we think of any other situation in which we do that,
> it\'s always correlated with some real outcome. You think of a
> t-score. Well, the reason we choose more negative than minus-2.5
> t-scores for treatment of low bone density is because that\'s
> correlated with increased risk for fracture. And here we have no
> similar data on the correlation of this cutoff with any real outcome.
>
> Certainly the response to growth hormone seems to be continuous over a
> wide range of short stature. So, I also think that we need more
> information to individualize this. It seems\--the one-size-fits-all
> seems inadequate to me. I certainly agree that we should have some age
> restriction, and I agree with, probably seven. I think we should also
> not\--suggest that this treatment not be used for kids with
> constitutional growth delay, because it seems that those kids do catch
> up adequately on their own.
>
> And I think that there should be criteria developed for stopping
> treatment in the course of one or two years if it seems ineffective.
> Continuing treatment that requires six, seven injections a week, and
> costs a whole lost of money just seems inappropriate for 10 years with
> no estimate of response.
>
> \[Pause.\]
>
> DR. BRAUNSTEIN: Oh\--Dr. Schade, on Number 3, are the available data
> from the studies presented sufficient to guide the sage and effective
> use of Humatrope in patients with the syndrome\--with non-growth
> hormone deficient short stature?
>
> We just need a yes or no on that one?
>
> DR. SCHADE: Ahh\--I don\'t believe so.
>
> DR. BRAUNSTEIN: Okay.
>
> And, Dr. Woof? Yes or no?
>
> DR. WOOLF: No.
>
> DR. BRAUNSTEIN: Okay. Thank you.
>
> Okay, the next two questions, we don\'t need to go around, but I\'m
> going\--since we\'ve discussed a lot of these things\--we will\--I do
> want the committee to chime in on whether they have any comments
> concerning these.
>
> The first one is: please comment on the sponsor\'s risk-management
> proposals.
>
> And I\'ll remind you that what was presented is that to avoid
> inappropriate prescribing, they propose restrictive label; a specific
> description of appropriate patient population; physician education;
> limited marketing only to pediatric endocrinologists; no
> direct-to-consumer marketing; and a controlled distribution process.
>
> In regards to the issues\--the risk of lack of thorough diagnostic
> evaluation prior to initiation of treatment\--again, the restrictive
> labeling proposal should take care of part of that. Physician
> education should take care of part of that. And the marketing to
> pediatric endocrinologists.
>
> And then, finally, in regards to emergence of new adverse events, they
> propose the post-marketing studies and the pharmacovigilance that they
> have in place for this.
>
> Are there any comments from members of the committee regarding these?
>
> Yes\--Dr. Tamborlane?
>
> DR. TAMBORLANE: I meant to ask this before, but\--the issue about
> pediatric endocrinologists. You know, as you know, there\'s not enough
> pediatric endocrinologists, and there are major areas that are
> unserved by pediatric endocrinologists. So I assume you would not
> exclude adult endocrinologists who are taking care of children for
> growth disorders.
>
> How does that work?
>
> DR. QUIGLEY: That\'s correct. If you\'re in an area where the only
> population\--where the population is served only by an adult
> endocrinologist, there are occasional, rare instances where we do
> qualify and allow those physicians to prescribe.
>
> Could I also take the opportunity just to help to clarify something
> for Dr. Watts, while I have a second?
>
> DR. BRAUNSTEIN: Yes.
>
> DR. QUIGLEY: Because Dr. Watts, you indicted that you didn\'t\--that
> we didn\'t present the data on the thousands of patients that have
> received treatment. And, in fact, maybe I didn\'t make it clear, but
> within the two current registries\--the National Cooperative Growth
> Study, here in the United States, and the Kabi International Growth
> Study, which is global\--there are close to 9,000 patients with this
> condition who\'ve received treatment over the 15 years or so that
> these registries have been running, equating to approximately 300,000
> years of patient exposures.
>
> So I just wanted to be clear, because maybe I didn\'t make that clear
> in the presentation.
>
> DR. BRAUNSTEIN: Dr. Worcester?
>
> DR. WORCESTER: Yes, I wanted to comment on a couple things.
>
> Of course, I was delight to see that there would not be
> direct-to-consumer advertising. But then hearing that there is a
> webpage actually scared me even more than direct-to-consumer
> advertising, in terms of how families with medical issues probably use
> the web information now, more than even watching television.
>
> So if we\'re going to have a product like this, I would certainly hope
> the FDA would watch that website and make sure it was appropriate.
>
> And then, of course, it won\'t be surprising to anybody that I\'m also
> concerned about most of the medical education for physicians, which
> are going to play such a crucial role in terms of the gatekeepers for
> this being industry sponsored. I would certainly want to see a much
> wider range of medical education on such an important and
> controversial product.
>
> DR. BRAUNSTEIN: And, to be fair, they do, in the booklet, indicate
> that they will sponsor, with unrestricted grants, CME programs for
> physicians.
>
> Yes\--Dr. Goldstein?
>
> DR. GOLDSTEIN: I\'m afraid a case of staircase wit, and I would now
> like to take advantage of your invitation to make one, I think
> important, comment.
>
> I would urge that you not gauge this by age five, six or seven. There
> is\--or anything like it. There is so much variability in children,
> and to do it by age is rather like prescribing by Young\'s rule, or
> Clark\'s rule, or things that went out 40 years ago. Or, if you have
> surface area data available, prescribing in kilos or pounds.
>
> It would be much better to select an objective criterion, such as SDS
> and the like, and settle on that\--not age. Many, many five-year-olds
> that I\'ve seen are bigger, or have different body characteristics, or
> have other disorders that make them look like an eight-year-old, much
> less a seven-year-old.
>
> So, age is not where I would set my marker.
>
> DR. BRAUNSTEIN: Okay.
>
> Dr. Woolf?
>
> DR. WOOLF: I have a question for the sponsor, and that has to be with
> vetting of the person who is permitted to write the prescription. Does
> it have to be a board certified endocrinologist? A board eligible
> endocrinologist? Somebody who practices pediatric endocrinology but
> who has never been specialized?
>
> I mean, how do you restrict prescribing privileges, and who is the
> keeper of that key?
>
> DR. QUIGLEY: Prescribers need to be endocrinologists\--board
> certified. Mm-hmm.
>
> DR. BRAUNSTEIN: Yes\--Dr Cara?
>
> DR. CARA: I just wanted to comment regarding the risk-management and
> additional concerns.
>
> I think, as somebody that\'s been involved with growth hormone for
> awhile, I think growth hormone is probably one of the most scrutinized
> drugs currently available on the market. And I can understand a lot of
> the concerns that have been raised regarding the use of growth
> hormone.
>
> That said, I can almost guarantee you that anybody\--either parent or
> physician\--that is interesting in getting growth hormone can probably
> now get it. So that the\--I think this is a unique opportunity to be
> able to develop a program of not only treatment, but also monitoring
> to make sure that growth hormone is indeed used efficaciously, and
> used within appropriate clinical guidelines so that we do avoid the
> surreptitious use of the drug by\--quote-unquote\--\"potential
> abusers.\"
>
> So I would take this opportunity to put the sponsor within the
> responsibility of developing educational programs, perhaps even a web
> page\-- educational web page\--for physicians or for patients that can
> be monitored by the FDA. I think those sorts of things are critical,
> but I think especially the concept of being able to now monitor the
> actual treatment of these children who are now being managed
> haphazardly is something that really needs to be looked at.
>
> DR. BRAUNSTEIN: Great.
>
> Are there any other comments or concerns on the part of the committee
> regarding safety and efficacy that has not been already stated by the
> committee members?
>
> Dr. Watts?
>
> DR. WATTS: After Dr. Quigley\'s comments, I\'ve looked back in my
> material, and I confess I can\'t interpret these data.
>
> Slide 81 and 82 are the registry data, and one is expressed as
> \"adverse events per 100,000 treatment years,\" which is a denominator
> I have trouble dealing with. And the other is \"Even rates are
> reported as percent of total events,\" rather than percent of
> population. But it\'s looking to me like there\'s 13 percent diabetes,
> and other numbers that I have trouble\--
>
> DR. QUIGLEY: May I clarify for Dr. Watts? Yes.
>
> In the Kabi International Growth Study, the event rates discussed here
> as rate per 100,000 treatment years because of the very low rate of
> events\--of occurrence of events. So, as you can see here, this is 3.5
> thousand patients with idiopathic short stature\--their term for what
> we call non-growth hormone deficient short stature, compared with a
> similar number of patients with Turner\'s syndrome\--substantially
> greater numbers than patients with chronic renal insufficiency, or
> small-for-gestational-age, two currently approved non-growth hormone
> deficient conditions.
>
> So the information that we have from this global study is that the
> rates of adverse events in this patient population are similar to or
> lower than the other non-growth hormone deficient populations.
>
> Can I have the next slide, please? The KIGS data. Sorry that\'s\--oh,
> yes. Sorry. No, this is the right one. NCGS.
>
> This is a little confusing to understand, and it\'s made further
> confusing because we\'ve actually left off two columns from the
> original table, just to try to shrink the amount of data that was on
> the table. There is an additional column here of \"organic growth
> hormone deficiency,\" and an addition column here of \"other growth
> disorders.\"
>
> The key points to understanding it are that, again, to note that there
> is a substantial number of patients\--5.5 thousand\--compared with 3.5
> thousand with Turner\'s syndrome, and just in the hundreds with
> chronic renal insufficiency. So substantially greater exposure in this
> patient population than the other two non-growth hormone deficient
> populations in this table.
>
> The way the data are expressed is that this number here represents the
> percentage of patients within the patient database that this condition
> occupies. And then these\--so these numbers, if you add in the other
> two columns, would add up to 100 percent across the row. They don\'t
> add up to a hundred percent because you don\'t have the other two
> columns. But what\'s obvious is that all of these numbers here, for
> all adverse events in the various sub-types are lower than the 17
> percent that this patient groups represents within the total database.
>
> Does that help clarify?
>
> DR. WATTS: Not really What I\'m interested in is how many children
> treated with growth hormone for this disorder develop diabetes, or
> scoliosis, or\--
>
> DR. QUIGLEY: Develop\--
>
> DR. WATTS: \--or slipped capital femoral epiphysis.
>
> DR. QUIGLEY: The actual, absolute numbers.
>
> DR. WATTS: The percentage.
>
> DR. QUIGLEY: This is\--
>
> DR. WATTS: That\'s the percentage of adverse events that were
> diabetes, as I read the table.
>
> DR. QUIGLEY: No. That\'s the percentage of the cases of diabetes that
> occurred within this patient population. There were actually only
> something in the order of\--
>
> DR. MacGILLIVRAY: 27.
>
> DR. QUIGLEY: Yes.
>
> DR. MacGILLIVRAY: 27 total out of 33,000.
>
> DR. QUIGLEY: Right.
>
> DR. MacGILLIVRAY: And of that 27 patients, 25 percent fell into the
> IGHD, and 8 percent fell into renal insufficiency. So it was
> percentage of the patients who got diabetes, and there was 27
> type-I\'s.
>
> DR. WATTS: What I\'m interested in is how these patients do compared
> with the general population, not how they do compared with chronic
> renal insufficiency.
>
> DR. QUIGLEY: Okay.
>
> DR. WATTS: And the way the data are displayed in this table and the
> previous one doesn\'t help me very much.
>
> DR. QUIGLEY: So you\'re asking\--
>
> DR. WATTS: I get the sense that the numbers are very low\--
>
> DR. QUIGLEY: They\'re very low\--
>
> DR. WATTS: \--but it\'s late in day and I\'m calculator dependent, and
> I\'m not sure.
>
> DR. QUIGLEY: They\'re low, and they\'re no greater than the population
> base rate\--for diabetes, at least.
>
> DR. BRAUNSTEIN: Okay. So the last statement was: they\'re no greater
> than the population based anticipated\--I mean, if you just look at
> patients with non-growth hormone deficient short stature not receiving
> growth hormone, they have the same risk of developing these things? Is
> that\--
>
> DR. QUIGLEY: The same risk as the general population; the general
> pediatric population or\--in fact, lower\--I mean, certainly no
> greater than the general pediatric population, unselected for disease.
>
> DR. BRAUNSTEIN: Okay. Thank you.
>
> Any other questions about safety, efficacy?
>
> \[No response.\]
>
> Then we\'ll go on to the final question, and then I\'ll try to
> summarize what\'s been said.
>
> Do you recommend that the use of growth hormone in non-growth hormone
> deficient short stature, as proposed by the sponsor, be approved by
> the FDA?
>
> Dr. Cara, you start.
>
> DR. CARA: Yes.
>
> DR. TAMBORLANE: Yes.
>
> DR. SCHADE: Ahh-yes, with the addition that the follow-up comments be
> included, that additional things need to be added relative to
> monitoring.
>
> DR. BRAUNSTEIN: Dr. Woolf?
>
> DR. WOOLF: Yes, provided that it\'s discontinued for non-responders.
>
> DR. GELATO: Yes, with some of the additional criteria that we talked
> about: height velocity and age. And also that it be discontinued if
> children are not responding appropriately\--increase in height
> velocity.
>
> DR. BRAUNSTEIN: Dr. Watts?
>
> DR. WATTS: I think if these are the best data that you can get, then
> the answer is yes. But if you think you can get data on hard
> endpoints, then I think those data should be forthcoming, because the
> potential expenditure for this is considerable.
>
> DR. BRAUNSTEIN: Dr. Worcester?
>
> DR. WORCESTER: I\'m voting no. I\'m worried about the medicalization
> of shortness, and that it would actually increase the problem of the
> stigma.
>
> DR. BRAUNSTEIN: Thank you.
>
> DR. FOLLMAN: I vote yes.
>
> DR. BRAUNSTEIN: Dr. Grady?
>
> DR. GRADY: No.
>
> DR. BRAUNSTEIN: And I vote yes.
>
> **Summary**
>
> DR. BRAUNSTEIN: So let me try to summarize the committee\'s responses.
> I\'m probably not going to do it justice, but I\'ll try anyway.
>
> Question Number 1: \"Has the efficacy of Humatrope in non-growth
> hormone deficient short stature been sufficiently characterized?\" The
> answer was a uniform, unanimous \"yes\" on that.
>
> \"Is the dose-response regiment proposed supported by the results of
> the studies?\" And the answer to that was \"yes.\"
>
> \"Comment on the discussion by the sponsor of the importance of height
> augmentation in target population on the conclusion that the expected
> effects are clinically meaningful.\" And this is the area that had the
> greatest amount of discussion. It was pointed out that the studies
> that were performed\--the pivotal study that was performed\--probably
> underestimated the effect because older children were utilized.
>
> One of the major problems is that there\'s no quality of life data
> that is sufficient for us to judge whether the clinical benefits of
> the height augmentation is really clinically significant.
>
> The dose does appear to be okay. The majority of the group felt that
> the highest dose\--the .37\--was appropriate.
>
> And, in regards to whether it is a clinically meaningful response,
> three members of the panel felt that the answer was \"yes,\" and five
> had a very large question mark, and one felt that the definition of
> \"clinically meaningful\" really must be defined by the patient and
> the family.
>
> For Question Number 2: \"Has the safety of Humatrope in non-growth
> hormone deficient short stature been sufficiently characterized?\"
> Basically, there were three out of 10 of the committee who felt that
> it had not been sufficiently characterized in this group of patients.
>
> \"Do the results of the trials and the clinical knowledge of the
> safety profile of growth hormone in children support a favorable
> balance of risk and benefit?\" And, again, because many members of the
> committee were unsure about the overall benefit in regards to quality
> of life, and whether it reduces some of the stress on short kids and
> short adults, as to whether there was a reasonable risk-benefit
> profile\--but I think the majority of the committee felt that\--felt
> fairly secure that the drug is reasonably safe.
>
> \"Please comment on the proposal for long-term follow-up of these
> children as part of the GeNeSIS system? What other surveillance of the
> safety of this intervention, if any, are recommended?\" With one
> exception, nine members\--well, nine members of the committee said
> that a mandatory registry and follow-up of these patients be
> instituted. One individual felt that it should not be mandatory.
>
> Question Number 3: \"Are the available data from the studies presented
> sufficient to guide the safe and effective use of Humatrope in
> patients with non-growth hormone deficient short stature?\" There were
> two members of the panel that did not feel that the data was
> sufficient. There were, by my count, four members of the panel that
> felt that it was sufficient; and one\--there was a question mark.
>
> \"The sponsor has proposed a restrictive height criterion for
> treatment eligibility. Is this proposal satisfactorily rationalized?\"
> Three members of the panel felt that it wasn\'t satisfactorily
> rationalized; that included one member who felt that if one is going
> to treat short stature, and short stature is defined by the learned
> societies\--Pediatric Endocrine Society, for instance\--as being less
> than 2 standard deviations below the mean, that that\'s the criterion
> that should be used. The other two felt that minus-2.25 was not
> sufficiently rationalized, and the other seven members of the voting
> committee felt that it was.
>
> \"Are additional criteria needed, such as pre-treatment height
> velocity, bone-age, chronologic age, serum IGF-1 level?\" And, here,
> the committee did not take a specific vote. One member of the
> committee suggested that requirements be, in addition to the height
> standard deviation being less than 2.25 standard deviations below the
> mean, that also the IGF values should be less than the 50th
> percentile, and the pre-treatment height velocity be less than the
> 50th percentile.
>
> Others, including myself, felt that a variety of data should be
> collected on these patients, but that it does not\--that information
> was not necessary to\--as necessary criteria for institution of
> therapy; that therapy could be instituted based on the bone\--based
> upon the height being less than 2.25 standard deviations below the
> mean. But the other information that was suggested included
> pre-treatment height velocity, bone-age, chronologic age, serum IGF-1
> level, and provocative tests for growth hormone; and certainly that
> information should be compared to the information derived from the
> follow-up studies while the patients are on treatment.
>
> 3.C\--\"The range of responses observed in the trials, and thus
> expected in the clinic, is broad. Additionally, a dose-response is
> evident. Please discuss the following: 1) the need for information on
> effective individualization of dose, age at initiation of therapy and
> duration of therapy, and growth response, and on safety.\" Several
> members of the committee felt that there should be an age limitation;
> that is an age below which growth hormone should not be initiated. One
> member of the committee felt that it should not be initiated for
> anybody less than five years; two members of the committee felt that
> age seven years was reasonable; and another member of the committee
> felt that a minimum age should be established, but wasn\'t quite sure
> what that should be.
>
> Another criterion that was suggested was that during therapy the IGF-1
> levels should be kept at the upper limit of normal. Two members of the
> committee felt that that was appropriate, but there was not vote taken
> on that particular issue.
>
> How long should the therapy be given? One member of the committee felt
> that the therapy should be given for five years and no longer. Another
> member of the committee felt that patients with constitutional growth
> delay should not be treated, especially if their predicted height is
> going to be sufficiently well into the normal range as to indicate
> that they\'ll eventually be normal-sized adults.
>
> Under C.2\--the need for information on potentially useful predictors
> of response, both pre-treatment an on treatment; early growth or
> biochemical effects, again, to enhance safe and effective use\--the
> members of the committee that commented on this all said that, yes, we
> want predictors of response, we just don\'t know what they are;
> although one member said that there should be at least a 50 percent
> increase in growth during the first year for there to be considered to
> be a response.
>
> Another member of the committee felt that therapy should be clearly
> discontinued if there is no response, but did not define what that
> response was.
>
> In regards to sponsor\'s risk management proposals, they appear to be
> appropriate, with the caveats that the follow-up information be a
> mandatory requirement, and that this should be easily instituted,
> since the distribution of growth hormone will be so tightly controlled
> to pediatric endocrinologists or endocrinologists taking care of short
> kids in underserved areas.
>
> And then, finally, as far as a recommendation to the FDA on whether
> growth hormone should be approved for the use in non-growth hormone
> deficient short stature as proposed by the sponsors, there were eight
> members of the committee that felt that it should, and two members of
> the committee that voted no.
>
> So, unless there are any other comments from the committee or Dr.
> Orloff\--Dr. Orloff, do you want to have any closing comments?
>
> DR. ORLOFF: Just to thank everyone for their time and efforts, and
> we\'ll proceed from here.
>
> DR. BRAUNSTEIN: Great.
>
> Well, thank you all for attending, and thank you to Lilly and to
> members of the committee, as well as to the public representatives.
>
> \[Whereupon, at 4:50 p.m., the meeting was adjourned.\]
>
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