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
• 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
Raymond Hintz
Akira Shimatsu
Bengt Åke Bengtsson
Jörgen Isgaard
Peter H. Sönksen
Sandra L. Blethen
Gudmundur Johannsson
Peter Stein
Werner F. Blum
Jens Otto Lunde Jørgensen
Christian J. Strasburger
Bjorn Carlsson
Anne-Marie Kappelgaard
Elisabeth Svanberg
Lena Carlsson
Irene Langbakke
Anthony Swerdlow
Paul V. Carroll
Derek LeRoith
Katsuhiko Tachibana
Jens Sandahl Christiansen
Barbara Lippe
Hiroaki Takahashi
Peter E. Clayton
Saul N. Malozowski
Jukka Takala
David R. Clemmons
Thomas Maneatis
Toshiaki Tanaka
Pinchas Cohen
John P. Monson
Michael O. Thorner
Christopher T. Cowell
Yoshikazu Nishi
Greet van den Berghe
Gordon B. Cutler
Michael N. Pollak
A.J. van der Lely
Judith E. Fradkin
Iain Robinson
Patrick Wilton
Joseph M. Gertner
Ron Rosenfeld
Douglas Yee
Sue Hankinson
Daniel E. Salazar
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 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 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 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
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
animals stimulates tumor formation, although it can
increase growth of some established tumors
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
• 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
• 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
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
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 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 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
• 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
• 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 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
• 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
• 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
• 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 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
• 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 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
• 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 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
• 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 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
• 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 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
• 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 GHtreated hypopituitary adult
Safety - GH Replacement in Adults
Cancer 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
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 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 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 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 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 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 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 GH
replacement in patients receiving intensive care
treatment for critical illness, or during period of less
severe illness or in relation to surgery
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