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Keswick Safety Presentation-final2.ppt 6-19-00. Statement from the Growth Hormone Research Society. Keswick Hall Charlottesville, Virginia May 7 - 10, 2000. Critical Evaluation of the Safety of Recombinant Human Growth Hormone Administration. Background

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statement from the growth hormone research society

Keswick Safety Presentation-final2.ppt

6-19-00

Statement from the Growth Hormone Research Society

Keswick Hall

Charlottesville, Virginia

May 7 - 10, 2000

critical evaluation of the safety of recombinant human growth hormone administration
Critical Evaluation of the Safety of Recombinant Human Growth Hormone Administration
  • Background
  • Epidemiological and experimental data used to assess relationships of GH, IGF-I and cancer risk
  • Safety aspects
    • GH therapy in children
    • GH replacement in adults
    • Pharmacological GH treatment in adults
  • Closing remarks
participants
Robert Baxter

Bengt Åke Bengtsson

Sandra L. Blethen

Werner F. Blum

Bjorn Carlsson

Lena Carlsson

Paul V. Carroll

Jens Sandahl Christiansen

Peter E. Clayton

David R. Clemmons

Pinchas Cohen

Christopher T. Cowell

Gordon B. Cutler

Judith E. Fradkin

Joseph M. Gertner

Sue Hankinson

Raymond Hintz

Jörgen Isgaard

Gudmundur Johannsson

Jens Otto Lunde Jørgensen

Anne-Marie Kappelgaard

Irene Langbakke

Derek LeRoith

Barbara Lippe

Saul N. Malozowski

Thomas Maneatis

John P. Monson

Yoshikazu Nishi

Michael N. Pollak

Iain Robinson

Ron Rosenfeld

Daniel E. Salazar

Participants

Akira Shimatsu

Peter H. Sönksen

Peter Stein

Christian J. Strasburger

Elisabeth Svanberg

Anthony Swerdlow

Katsuhiko Tachibana

Hiroaki Takahashi

Jukka Takala

Toshiaki Tanaka

Michael O. Thorner

Greet van den Berghe

A.J. van der Lely

Patrick Wilton

Douglas Yee

background
Background
  • Lessons learned since recombinant human GH was introduced to the market in 1985
  • Unprecedented level of scrutiny has lasted more than 15 years because
    • Jacob Creutzfeld disease relationship to pituitary-derived GH
    • Potential association between GH and leukemia
    • GH was the second recombinant protein brought to market
epidemiological and experimental data used to assess relationships of gh igf i and cancer risk

Epidemiological and experimental data used to assess relationships of GH, IGF-I and cancer risk

epidemiological data
Epidemiological Data

Active acromegaly, a disease characterized by raised serum GH, IGF-I, and IGFBP-3 levels has been reported to be associated with

  • increased incidence of colonic neoplasia, although conflicting data exist
  • no increased incidence of breast or prostate cancers
epidemiological data7
Epidemiological Data

Recent epidemiological surveys, including case-control, as well as follow-up designs report

  • Serum IGF-I levels in upper normal range may be associated with increased risk of developing prostate cancer and breast cancer in premenopausal, but not postmenopausal women
  • High IGF-I and low IGFBP-3 levels in serum may be associated with increased risk of these two tumors, as well as risk of colon cancer
  • High serum IGFBP-3 levels alone have also been related to reduced cancer risk
epidemiological data8
Epidemiological Data

Consensus regarding background information

  • A cause-effect relationship between serum IGF-I and development of cancer has not been demonstrated
  • Serum IGF-I levels may be affected by additional factors other than GH status, including nutrition
experimental data
Experimental Data

Studies in vitro and in animal models

  • Most cells, including cancer cells, possess IGF-I receptors and respond to IGF-I with increased growth
  • IGF binding proteins (IGFBP) and IGFBP proteases also modulate cell growth, and over expression of IGF-I receptors induces tumor formation in animal models
  • No evidence that systemic administration of IGF-I to animalsstimulates tumor formation, although it can increase growth of some established tumors
experimental data10
Experimental Data

Studies in vitro and in animal models

No studies have evaluated direct (IGF-independent) effects of GH on tumor formation

  • In GH transgenic animals, specific activation of GH receptors with concomitant elevations in circulating IGF-I did not result in breast, colon or prostate tumor formation
epidemiological data gh replacement and cancer risk
Epidemiological DataGH Replacement and Cancer Risk
  • No data to suggest that IGF-I and IGFBP-3 modulate cancer risk in GH-treated patients
  • Patients with previous malignancies or history of radiation therapy carry significant risk for recurrence and second malignancy
  • Recommend measurement of serum IGF-I levels in patients receiving GH treatment; place of regular IGFBP-3 monitoring is not defined
  • Recommend that IGF-I level be maintained within appropriate age- and gender-related normal range in GH-deficient adults during long-term therapy
epidemiological data regulatory aspects
Epidemiological DataRegulatory Aspects
  • Current labeling for GH states that active malignancy is a contraindication for GH treatment. There are, however, no data to support this labeling.
  • Current knowledge does not warrant additional warning about cancer risk in the product label.
safety gh therapy in children
Safety - GH Therapy in Children

Recombinant human GH has been used in an estimated 50,000 children.

  • Significant adverse drug reactions rare
  • Large international databases have been useful in quantifying adverse events, and hence, addressing safety issues
  • Extended follow-up into adulthood of children who have discontinued GH treatment would be ideal - this may only be achievable in subset of patients
safety gh therapy in children malignancy risk
Safety - GH Therapy in ChildrenMalignancy Risk

Children receiving GH, who have had a malignancy, account for approximately 20% of patients enrolled in international databases.

  • Existing evidence does not indicate that GH treatment will increase tumor recurrence in those successfully treated for their primary lesion
  • In patients who have been rendered GH deficient by tumor and/or its treatment, timing of initiation of GH treatment must be decided on basis of individual case, once tumor treatment is completed and condition is in remission
safety gh therapy in children malignancy risk15
Safety - GH Therapy in ChildrenMalignancy Risk

All subjects who have had a malignancy and received treatment for it are at risk for a second malignancy.

  • No evidence that GH treatment increases risk of this process based on limited data available
  • No evidence that de-novo cancer and leukemia are increased in GH recipients
  • In view of continuing evolution of oncology treatments, ongoing surveillance of GH recipients with appropriate age-related controls is important
safety gh therapy in children malignancy risk16
Safety - GH Therapy in ChildrenMalignancy Risk

Certain patient groups who receive GH treatment carry an intrinsic risk of developing malignancies, including those with Neurofibromatosis type 1, Fanconi anemia, Downs and Bloom syndromes.

  • Although no evidence that GH replacement poses increased cancer risk, we recommend that such children be carefully monitored with regard to tumor formation
safety gh therapy in children benign intracranial hypertension
Safety - GH Therapy in ChildrenBenign Intracranial Hypertension
  • Has been reported in 1/1000 children receiving GH treatment; may be underestimate
  • Headache in children on GH treatment should be carefully evaluated
  • Fundoscopic examination should be performed before initiation of GH treatment and repeated when clinically indicated
safety gh therapy in children glucose metabolism
Safety - GH Therapy in ChildrenGlucose Metabolism
  • Reduction of insulin sensitivity is physiologic effect of GH, however, glucose homeostasis is maintained in vast majority of patients
  • Most available surveillance data do not demonstrate increased incidence of diabetes, either type 1 or type 2, associated with GH treatment
  • There are, however, subgroups of patients inherently at risk of developing diabetes - these should be carefully monitored
safety gh therapy in children glucose metabolism19
Safety - GH Therapy in ChildrenGlucose Metabolism
  • Diabetes mellitus is not contraindication to GH treatment in children
  • Diabetic care should follow standard clinical practice
safety gh therapy in children skeletal disorders
Safety - GH Therapy in ChildrenSkeletal Disorders
  • Some underlying disorders that are treated with GH therapy can be associated with slipped capital femoral epiphysis, scoliosis and avascular necrosis
  • No evidence these conditions are caused by GH treatment; however, scoliosis may be exacerbated when growth is accelerated
safety gh therapy in children interaction with other hormones
Safety - GH Therapy in ChildrenInteraction with Other Hormones
  • No compelling evidence that GH treatment has any adverse effect on pubertal development and gonadal function
  • GH can affect metabolism of thyroid hormones and cortisol
safety gh therapy in children gh treatment and intercurrent illness
Safety - GH Therapy in ChildrenGH Treatment and Intercurrent Illness
  • No data to support discontinuation of GH replacement treatment during illness
  • Risk of hypoglycemia should be considered in children with GH deficiency who discontinue GH treatment
safety gh therapy in children23
Safety - GH Therapy in Children

Issues related to GH treatment in patients with non-GH deficient disorders

  • Monitoring glucose homeostasis in Turner syndrome and glucose homeostasis and lipid profiles in chronic renal failure should be undertaken at intervals determined by standard clinical practice
  • In patients with chronic renal failure treated with GH who receive renal transplant, assessment of graft function and surveillance for development of malignancy should be carried out according to routine nephrology guidelines
safety gh replacement in adults glucose metabolism
Safety - GH Replacement in AdultsGlucose Metabolism
  • Prevalence of diabetes mellitus (DM) increased in hypopituitary adults
  • Metabolic actions of GH include insulin antagonism
  • THUS, recommend that glucose metabolism be assessed in all patients before and during GH replacement
  • DM (or impaired glucose tolerance) not a contraindication to GH replacement; care of diabetes in GH-replaced adults should follow standard guidelines, but intensified monitoring of metabolic control is advocated in early phase of GH replacement of such patients
safety gh replacement in adults glucose metabolism25
Safety - GH Replacement in AdultsGlucose Metabolism
  • Eye examination is indicated in case of overt diabetes and should be conducted in accordance with standard guidelines
  • Stable background retinopathy should not lead to discontinuation of GH replacement
  • Development of pre-proliferative changes and presence of proliferative retinopathy are contraindications to GH replacement
safety gh replacement in adults fluid retention
Safety - GH Replacement in AdultsFluid Retention
  • Symptoms related to fluid retention may be encountered especially in early phase of GH replacement
  • This partly reflects a GH-induced, dose-dependent normalization of tissue hydration
  • Monitoring of hydration during GH replacement should include body weight measurement, patient interview and clinical examination
safety gh replacement in adults fluid retention27
Safety - GH Replacement in AdultsFluid Retention
  • In the case of persistent symptoms attributable to fluid retention, reduction of GH dose should be considered
  • Increased awareness of such symptoms and signs are recommended in patients with congestive heart failure
safety gh replacement in adults interaction with other hormones
Safety - GH Replacement in AdultsInteraction with Other Hormones
  • Growth hormone increases extrathyroidal conversion of T4 to T3 - thyroid function should be monitored in all patients
  • GH may decrease serum total cortisol concentrations by decreasing circulating cortisol binding globulin
safety gh replacement in adults interaction with other hormones29
Safety - GH Replacement in AdultsInteraction with Other Hormones
  • Even though clinical implications for these observations are uncertain, increased awareness of glucocorticoid status is recommended in all patients
  • Possibility that overt ACTH insufficiency may be unmasked during GH replacement (as a result of inhibition of 11bHSD1) should be considered
safety gh replacement in adults heart function and lipoproteins
Safety - GH Replacement in AdultsHeart Function and Lipoproteins
  • Increased prevalence of cardiovascular disease in active acromegaly cannot be extrapolated to GH-replaced hypopituitary adult
  • Monitoring of cardiovascular function should follow standard of care for normal population
safety gh replacement in adults heart function and lipoproteins31
Safety - GH Replacement in AdultsHeart Function and Lipoproteins

GH replacement in adults is known to increase serum levels of lipoprotein(a).

  • Clinical implications - if any - are uncertain and should be weighed against beneficial effects of GH replacement on other cardiovascular risk factors
  • Measurement of lipoprotein(a) not recommended as standard procedure in hypopituitary patients
safety gh replacement in adults cancer risk and tumor recurrence
Safety - GH Replacement in AdultsCancer risk and Tumor Recurrence
  • Increased incidence of certain malignancies has been reported in hypopituitary adults, but no evidence that it is associated with GH replacement
  • Current recommendations for cancer prevention and early detection in general population should be implemented in GH-treated hypopituitary adult
safety gh replacement in adults cancer risk and tumor recurrence33
Safety - GH Replacement in AdultsCancer Risk and Tumor Recurrence
  • To date no evidence to suspect that GH replacement influences recurrence rate or regrowth of pituitary/peripituitary neoplasms
  • Standard clinical practice requires regular pituitary imaging in patients with history of pituitary pathology
  • Baseline imaging study recommended in all patients before instituting GH replacement therapy
safety pharmacological gh treatment in adults
Safety - PharmacologicalGH Treatment in Adults

ICU Trials

  • Power of placebo-controlled trials has been demonstrated with intensive care unit (ICU) studies, which showed that mortality was doubled in severely ill patients treated with high doses of GH
  • These studies have refuted clinical practice beliefs that high-dose GH is beneficial in this situation
safety pharmacological gh treatment in adults35
Safety - PharmacologicalGH Treatment in Adults

ICU Trials

  • Two placebo-controlled clinical trials (522 ICU patients) demonstrated that mortality increased from 19% (placebo-treated) to 42% (GH-treated)
  • Prolonged stay ICU patients following complications from open heart or abdominal surgery, multiple accidental trauma or those with acute respiratory failure were included
safety pharmacological gh treatment in adults36
Safety - PharmacologicalGH Treatment in Adults

ICU Trials

  • Supraphysiological doses of GH (5.3-8 mg or 0.07-0.13mg/kg per day) were administered
  • Most common causes of death were multi-organ failure, septic shock and uncontrolled infections
  • Baseline patient characteristics, severity of illness and diagnostic category did not explain increased mortality
safety pharmacological gh treatment in adults37
Safety - PharmacologicalGH Treatment in Adults
  • Any GH treatment, other than replacement in those who have GH deficiency, should be considered as pharmacological
  • In specific conditions where pharmacological GH treatment is being considered, standard safety data should be collected and protocols for new drug development should be followed
  • Detrimental outcome of high dose GH treatment in ICU patients cannot be extrapolated to other conditions, which may potentially benefit from GH treatment
safety pharmacological gh treatment in adults38
Safety - PharmacologicalGH Treatment in Adults
  • At present, not recommended that pharmacological GH treatment be initiated in adult ICU patients
  • In patients receiving pharmacological (in contrast to replacement) GH treatment, cessation of GH treatment should be considered when patient is critically ill
  • ICU trials should not discourage new studies of GH treatment in groups who may benefit from GH
  • Pharmacological doses used in such trials should be minimum effective dose for relevant endpoint
safety pharmacological gh treatment in adults39
Safety - PharmacologicalGH Treatment in Adults

GH levels and critical illness

  • GH-IGF system is dysregulated in critical illness
  • Not known whether this has effect on outcome in such patients, nor whether GH-deficient adults, including those receiving replacement therapy, are at higher risk for adverse outcomes when critically ill
safety pharmacological gh treatment in adults40
Safety - PharmacologicalGH Treatment in Adults

GH levels and critical illness

  • GH deficiency in adults and children, however, is frequently part of a more extensive pituitary deficiency including adrenocortical deficiency, which should be considered during critical illness in such patients
  • No data to support discontinuation of appropriate GHreplacement in patients receiving intensive care treatment for critical illness, or during period of less severe illness or in relation to surgery
closing remarks
Closing Remarks
  • Extensive data collected on large numbers of children and adults treated with GH indicate that, for current approved indications, GH is safe
  • Nevertheless, this workshop highlighted a number of areas where ongoing surveillance of long-term safety of GH replacement is important (cancer – glucose homeostasis – high dose pharmacological GH treatment)
    • Appropriately designed follow-up studies using adequate epidemiological tools and untreated controls are required