Effective September 30, 2011 Please refer to the Pharmacy policy for the new coverage criteria

Transcription

1 Effective September 30, 2011 Please refer to the Pharmacy policy for the new coverage criteria Name of Policy: Growth Hormone and Insulin Like Growth Factor-1 (IGF-1) Analogues Policy #: 067 Latest Review Date: July 2010 Category: Surgery Policy Grade: Active policy for dates of service prior to September 30, 2011 but no longer scheduled for regular literature reviews and update. Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage: 1. The technology must have final approval from the appropriate government regulatory bodies; 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 3. The technology must improve the net health outcome; 4. The technology must be as beneficial as any established alternatives; 5. The improvement must be attainable outside the investigational setting. Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are: 1. In accordance with generally accepted standards of medical practice; and 2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient s illness, injury or disease; and 3. Not primarily for the convenience of the patient, physician or other health care provider; and Page 1 of 24

2 4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient s illness, injury or disease. Description of Procedure or Service: Growth hormone (GH), also known as somatropin, is synthesized in the anterior pituitary throughout life. Recombinant DNA technology has also allowed development of synthetic forms of growth hormone. Growth hormone binds to the surface of cells and stimulates the production of insulin growth factor-i (IGF-I). Insulin growth factor is responsible for many of the growth promoting effects attributed to growth hormone. Growth hormone stimulates all aspects of cartilage growth, and one of its major effects is to simulate the growth of the epiphyseal cartilage plates of long bones. Other body tissues respond to the metabolic effect of growth hormone with increases in bone width and the growth of visceral and endocrine organs, skeletal and cardiac muscle, skin, and connective tissue. It also plays a role in the distribution and metabolism of fat in the body. Growth hormone deficiency (GHD) may result from abnormalities in the hypothalamus, or from pituitary pathologic conditions. Some causes are genetic and some are acquired. Currently the U.S. Food and Drug Administration has approved growth hormone for use in the following pediatric conditions: growth hormone deficiency, Turner syndrome, and chronic renal insufficiency. Adults may have true growth hormone deficiency due to pituitary disease of known cause, i.e. pituitary tumor, pituitary surgical damage, hypothalamic disease, irradiation, or trauma. Adult GHD may also be reconfirmed childhood GHD. Adults seeking coverage for treatment with growth hormone should have non-refutable laboratory evidence of GHD. Anti-aging therapy with growth hormone has not yet been proven effective according to objective outcome criteria. (NEJM 348, #9) The FDA s position on the illegality of distributing growth hormone as an anti-aging treatment is conveyed in warning letters to Web sites marketing growth hormone. Penalties for distribution or provision of growth hormone for anti-aging purposes are substantial. Biosynthetic growth hormone initially became available for prescription use in the United States in Since 1985 recombinant growth hormone has been marketed (trade names: Genotropin, Humatrope, Norditropin, Nutropin, Saizen, Somatrem) for a variety of FDA-labeled indications. In July 2003, the FDA approved Humatrope for use in non-gh deficient short stature, defined by the manufacturer as a height standard deviation score (SDS) of 2.25 below the mean. This new indication for GH is the first indication that is based on short stature alone, without an underlying etiology. Primary insulin growth factor deficiency (IGFD) is a growth hormone resistant state characterized by lack of insulin-like growth factor-1 (IGF-1) production in the presence of normal or elevated levels of endogenous growth hormone. Severe primary IGFD includes persons with mutations in the GH receptor (GHR), post-ghr signaling pathway, and IGF-1 gene Page 2 of 24

3 defects. These persons are not GH deficient and would not respond adequately to exogenous GH treatment. The U.S. Food and Drug Administration (FDA) has approved two injectable drugs for the treatment of growth failure in children with primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. Both mecasermin (Increlex) and mecasermin rinfabate (Iplex) contain recombinant human insulin-growth factor-1 produced by recombinant DNA technology. In humans, IGF-1 is released in response to stimulation by GH and has a broad range of activity central to growth and metabolism. Under normal circumstances, GH binds to its receptor in the liver and other tissues and stimulates the synthesis of IGF-1. In target tissues, the type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IFG-1, leading to intracellular signaling, thus stimulating structural growth. The metabolic actions of IGF-1 stimulate the uptake of glucose, fatty acids, and amino acids, which lead to cell, tissue, organ, and skeletal growth. According to the product labeling, GH (Genotropin) is contraindicated in patients with Prader- Willi syndrome (PWS) who are severely obese, have a history of upper airway obstruction or sleep apnea, or have upper airway obstruction or sleep apnea, or have severe respiratory impairment. Also, there are warnings and precautions noted specifically for PWS patients treated with GH. Here have been reports of fatalities after initiating therapy with somatropin in pediatric patients with PWS syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Also, male patients may be at greater risk than females. Patients with PWS should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. Policy: Effective for dates of service on or after September 30, 2011: Refer to the Pharmacy policy for coverage criteria. Effective for dates of service prior to September 30, 2011: The administration of growth hormone meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when the following conditions are met: 1. Coverage is provided for growth hormone for children for the following indications: a. Children who have documented growth hormone deficiency as defined by having fallen 2 standard deviations off the predicted growth curve due to inadequate secretion of normal endogenous growth hormone as confirmed by one of the following tests and include a baseline bone age x-ray indicating delayed bone age and growth velocity chart: A provocation test, using insulin, arginine, oral levodopa, glucagon or clonidine. A plasma growth hormone level less than 10 ng/ml after stimulation. A plasma growth hormone level greater than 10 ng/ml on any one of these tests effectively excludes growth hormone deficiency (exception is listed in next bullet). Page 3 of 24

4 The assessment of sleep related growth secretion type of testing will no longer be an approved method, for coverage purposes, as evidence of growth hormone deficiency. Effective for dates of service on or after October 1, 2007 and prior to September 30, b. Children with congenital syndromes, i.e., Turner's syndrome or Prader-Willi, without associated growth hormone deficiency but with marked growth retardation due to the disease process (e.g., from Prader-Willi, along with confirmation of diagnosis, height is less than 3 rd percentile of normal growth). c. Children with Russell-Silver syndrome frequently show catch-up growth by age 2. If not they may benefit from growth hormone therapy. Effective for dates of service on after December 2, 2005 and prior to September 30, d. For children with documented small for gestational age and lack of catch up growth by age 2 and remains below 2 standard deviations off the predicted growth curve may benefit from growth hormone. e. Children with growth hormone deficiency due to chronic renal insufficiency prior to renal transplantation. f. Children with AIDS associated failure to thrive, including AIDS wasting. g. Short bowel syndrome h. Termination of growth hormone therapy should be determined by reaching final height as determined by the 5 th percentile of adult height or epiphyseal closure and/or growth velocity is less than 2 cm per year. 2. Growth hormone therapy for growth hormone resistance will need to be reviewed on an individual case basis. The administration of mecasermin (Increlex) and mecasermin rinfabate (Iplex) meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when the following conditions are met: Treatment of growth failure in children with severe primary insulin-like growth factor-1 deficiency (primary IGFD) OR with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH AND when ALL of the following criteria are met: The patient s height is 3 standard deviations below normal The basal insulin-like growth factor-1 level (IGF-1) is greater than or equal to 3 standard deviations below normal The patient has a normal or elevated growth hormone level Note: Severe primary IGF-1 deficiency includes patients with mutations in the GH receptor (GHR), post-ghr signaling pathway, and IGF-1 gene defects. Page 4 of 24

5 Sermorelin acetate meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when used as part of growth hormone stimulation testing or provocative testing; Effective for dates of service on or after April 5, 2007 and prior to September 30, Sermorelin acetate does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage when used as therapy in persons with growth hormone deficiency; Effective for dates of service on or after April 5, 2007 and prior to September 30, Human growth hormone for the treatment of idiopathic short stature does not meet Blue Cross and Blue Shield of Alabama criteria for medical necessity and is not covered; Effective for dates of service on or after August 21, 2003 and prior to September 30, The addition of Leuprolide Acetate (Lupron, Lupron Depot) to human growth hormone to artificially prolong the period of time prior to skeletal maturation does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage; Effective for dates of service on or after March 23, 2004 and prior to September 30, Mecasermin ((Increlex) or mecasermin rinfabate (Iplex) does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage for other indications, including but not limited to, the following diagnoses: Idiopathic short stature Secondary forms of IGF-1 deficiency due to GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory drugs Extreme insulin resistance Myotonic muscular dystrophy HIV-associated adipose redistribution syndrome (HARS) Growth hormone does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered not medically necessary for the treatment of children with short stature that is not secondary to documented growth hormone deficiency or as specified above. Adult growth hormone meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the treatment of adults with the following indications: 1. GHD in adults is confirmed when there is growth hormone response of less than 5 nanograms per ml (ng/ml) when measured by the RIA (polyclonal antibody) or less than 5 micrograms/liter (µg/l) to a provocation test of levodopa, arginine, clonidine or glucagon or to an insulin tolerance test (ITT). At the end of the coverage period, a new request must be resubmitted for coverage with the current criteria; Effective for dates of service on or after October 1, 2007 and prior to September 30, In cases other than AIDS wasting or cachexia or severe burns, the patient must be evaluated by an endocrinologist who agrees with or recommends growth Page 5 of 24

6 hormone; Effective for dates of service on or after October 1, 2007 and prior to September 30, AIDS wasting or cachexia associated with AIDS as approved by the FDA for adults. AIDS wasting syndrome involves involuntary weight below 10% of ideal body weight (based on Metropolitan Life Height and Weight Tables) and one of the following: Chronic diarrhea (2 loose stools per day for more than 30 days) (AIDS related) Chronic weakness and documented fever for more than 30 days (intermittent or constant) (AIDS related) These conditions must be in the absence of a concurrent illness or condition other than HIV infection that would explain the findings. 4. Clinically documented hypopituitarism, hypothalamic-pituitary disease, history of cranial irradiation, or documented childhood-onset growth hormone deficiency as documented by adult testing for Somatotropin Deficiency Syndrome guidelines (some growth-hormone deficient children are found to be growth hormone sufficient in adulthood). 5. Severely burned patients to maintain nitrogen balance and promote wound healing. 6. Short-bowel syndrome Growth hormone does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational for the following uses: Constitutional delay of growth and development, skeletal dysplasias, osteogenesis imperfecta, Down s syndrome and other syndromes associated with short stature and malignant diathesis (e.g., Bloom syndrome, Fanconi syndrome), Noonan syndrome, infertility, obesity, short stature after renal transplantation Growth hormone is not considered medically necessary and is not covered as anabolic therapy, to enhance body mass or strength for professional, recreational, or social reasons, as an anti-aging treatment, or to increase muscle mass and decrease fat. Growth hormone is not medically necessary for chronic fatigue syndrome, fibromyalgia, or battered wife syndrome. See Policy #152 for additional information on the use of human growth hormone as inpatient intestinal rehabilitation therapy. Page 6 of 24

7 See Below for Prior Coverage Guidelines Related to Appropriate Dates of Service: The administration of growth hormone meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when the following conditions are met: Coverage is provided for growth hormone for children for the following indications: a. Effective for dates of service prior to October 1, 2007 and prior to September 30, 2011: Assessment of sleep-related growth secretions. Failure to achieve a plasma growth hormone level greater than 10 ng/ml when serial blood samples are obtained at 30-minute to 1-hour intervals over at least a 5-hour period while the patient is asleep. This may be accepted, for coverage purposes, as evidence of growth hormone deficiency even if provocation tests are normal. b. Effective for dates of service prior to December 2, 2005 and prior to September 30, 2011: Children with Russell-Silver syndrome frequently show catch-up growth by age 4. If not, they may benefit from growth hormone therapy. Adult growth hormone meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the treatment of adults with the following indications: 1. Somatotropin Deficiency Syndrome Effective October 1, 2002 as identified by an insulin growth factor IGF I below 90 ng/ml or a response to insulininduced hypoglycemia of less than 5 mcg/l when measured by RIA (polyclonal antibody). Predeterminations performed prior to October 1, 2002 will remain in effect until the approved time has elapsed for the use of growth hormone in adults. At the end of the coverage period, a new request must be resubmitted for coverage with the current criteria; Effective for dates of service prior to October 1, 2007 and prior to September 30, Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administer benefits based on the members' contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. Key Points: Growth hormone has been used to treat growth hormone deficient children for more than 35 years. Currently in the United States, about 20,000 children receive growth hormone therapy, and approximately 4,000 children are annually diagnosed as candidates for growth hormone therapy. Growth hormone deficiency may result from abnormalities in the hypothalamus or from pituitary pathologic conditions. Some causes are genetic, whereas others are acquired. The cause of the insufficiency is particularly important in determining appropriate treatment. Growth hormone treatment in children is generally begun with a dosage of growth hormone of 0.15 to Page 7 of 24

8 0.3 mg/kg per week, divided into daily or six times per week subcutaneous injections. Treatment is continued until final height or epiphyseal closure (or both) has been recorded. Bone age estimated from an x-ray of the left wrist and hand should be under taken as part of the routine evaluation of children with growth failure over one year of age and should be read by an experienced person. In the United States, an estimated total of 35,000 adults have growth hormone deficiency, and approximately 6,000 new cases of growth hormone deficiency occur each year. Adult growth hormone deficiency must be distinguished from physiologically reduced growth hormone secretion that occurs with aging. The growth hormone secretion rate decreases by an estimated 14% per decade after young adulthood; mean levels in older adults are less than half those of a young adult. The idea that growth hormone reduction in aging adults is a deficiency that should be treated is controversial. Doctors do not agree that it is necessary to replace growth hormone that otherwise healthy patients no longer produce. Only properly designed studies can resolve the controversy. Short-term studies can determine the effects of growth hormone therapy on bone strength, body composition, muscle strength, and physical performance. Long-term studies are needed to determine if growth hormone therapy results in better overall health for older adults. Long-term studies will also provide information on potential harmful effects of treating healthy adults with synthetic growth hormone for long periods of time and whether growth hormone therapy makes some chronic diseases worse such as hypertension, diabetes, or the likelihood of developing prostate cancer. An evaluation of adults for growth hormone deficiency should include provocative testing of growth secretion. The insulin tolerance test has been the validated study of choice. Because the test has an inherent risk of profound hypoglycemia, the study should be performed with caution. The insulin tolerance test is not recommended for patients older than 65 years of age. The growth hormone response to insulin-induced hypoglycemia is dependent on age, weight, and sex hormones, but most normal adults tested will have a peak growth hormone secretion above 5 ng/ml (RIA). Johannsson also reports on diagnosing severe GHD in adults has been to be a peak GH response to ITT of less than 3 µg/l. Many of the studies documenting the beneficial effects of GH replacement therapy in adults have included subjects with a peak GH response less than 5µg/L, however. Other tests have their specific value for defining severe GHD ranging between 16.5 and 20.3 for Arg-GHRH, depending on BMI, and less than 10µg/L for the GHRH-GHRP-6 stimulation test. Biller, et al, in a study performed to determine sensitivity and specificity for other diagnostic tests state that most patients in the United States that are tested for growth hormone deficiency do not undergo insulin tolerance testing. Their results demonstrate that a serum insulin growth factor provided less diagnostic discrimination than some other tests; a value below 77.2 microg/l was 95% specific for growth hormone deficiency. The arginine (ARG) plus growth hormone releasing hormone (GHRH) provides the best alternative to the insulin tolerance test (ITT). Hartman, et al, in their study proposed that adult growth hormone deficiency could be predicted with 95% accuracy with either the presence of three or more pituitary hormone deficiencies or a serum IGF-I concentration less than 84 microg/l. The positive predictive values (PPVs) for growth hormone deficiency of three PHDs, four PHDs, and serum IGF-I less than 84 microg/l were 96%, 99%, and 96% respectively. They concluded that for patients evaluated for adult Page 8 of 24

9 growth hormone deficiency with an appropriate clinical history and either the presence of three or four additional pituitary hormone deficiencies or serum insulin growth factor-i less that 84 microg/l does not require growth stimulation testing for diagnosis of adult growth hormone deficiency. It is also recommended that other causes of low serum IGF-I should be excluded before applying the diagnostic criteria. Blackman, et al studied men and women years of age who were given growth hormone or placebo for 6.5 months. There was no change in muscle strength or maximal oxygen uptake during exercise in either group. These results confirmed an earlier study by Papadakis, et al. A study by Taafe et al evaluated 18 healthy men age who underwent progressive strength training for 14 weeks, followed by an additional 10 weeks of strength training plus either growth hormone or placebo. Resistance training increased muscle strength significantly, but the addition of growth hormone did not result in any further improvement. Scolapio, et al (1997), looked at the effects of parenteral growth hormone (GH), glutamine (GLN) supplementation, and a high carbohydrate low fat diet (HCLF) on gut adaptation in 8 patients with short bowel syndrome (SBS). The patients were treated for 21 days. The results showed that active treatment transiently increased body weight, improved electrolyte absorption, and delayed gastric emptying. However, there were no improvements in small bowel morphology, stool losses, or macronutrient absorption. Scolapio also published more results in 1999 on these same 8 patients. He reported that active treatment significantly increased body weight and lean body mass and decreased percent body fat. They felt the positive findings are most likely a reflection of increased extracellular fluid because all 8 patients developed peripheral edema on active treatment. Also, the positive effects were not sustained once treatment was discontinued. The authors did not advocate the use of this treatment. Szkudlarck, et al (2000), looked at 8 short bowel patients to see if GH with GLN and no change in diet improved intestinal function. The results showed that GH with GLN did not improve intestinal absorption of energy, carbohydrate, fat, nitrogen, net weight, sodium, potassium, calcium, or magnesium compared with placebo or baseline 5 days after treatment was terminated. Jeppesen, et al (2001), looked at the changes in body weight (BW) and composition, 24-h urine creatinine excretion, intestinal fatty acid absorption, and EFA status in relation to treatment with GH and GLN in 8 short bowel patients. The results showed that active treatment did not increase BW, lean body mass (LBM), fat mass (FM), and bone mass significantly compared with placebo. There were no changes in intestinal absorption of fatty acids and no changes in essential fatty acids measured in plasma phospholipids. Li-Ling and Irving (2001), did a review of published trials and found only a marginal, if any, benefit for SBS patients from administering GH alone or with GLN with or without a low-fat high-carbohydrate (fiber) diet. Seguy (2003) reported on 12 adult HPN- dependent patients with SBS who received daily low dose GH and placebo for two 3-week periods separated by a 1-week washout period. Patients were on an unrestricted hyperphagic diet. The results showed that treatment with GH increased intestinal absorption of energy, nitrogen, carbohydrates, and fat. Patients showed an increase in Page 9 of 24

10 body weight, lean body mass, D-xylose absorption, insulin-like growth factor, and insulin-like growth factor binding protein and a decrease in GH binding protein. Concern exists among evidence based practitioners about the effects of the long term administration of growth hormone in adults. It may be potentially harmful; particularly with regard to the risk of cancer. In 152 healthy men, the relative risk of the subsequent development of prostate cancer was increased by a factor of 4.3 among men with relatively higher levels of serum growth hormone. Direct correlation has not been proven. The literature on the final effect of the addition of GnRH agonist (GNRHa) to growth hormone in growth hormone deficient children (GHD) is limited. Adan et al. reported that the combined treatment resulted in a normal adult height, albeit somewhat below target height. Hibi et al. Reported in 24 GHD children treated with GH and GNRHa the final height (FH) SD score was about 1 SD score higher than in a group of children on GH alone. The addition of Leuprolide Acetate to growth hormone to increase final height is not an FDA labeled indication or indicated as an off-label indication in the USP-Di. Testing is not an absolute necessity if there is radiologic evidence of pituitary stalk agenesis, empty sella, sellar or supra-sellar mass lesion, ectopic pituitary bright spot. Testing may also be optional for children with multiple pituitary hormone deficiencies, with a history of surgery or irradiation of the pituitary or hypothalamus. In an article published in Pediatrics, September 2004, Sanberg et al in a study that was designed to investigate the role of stature, across a wide range, on the peer relationships of children and adolescents in the general population. Results demonstrated that among grades 6-12 in a middleclass suburban school district minimal effects of height on measures of social functioning were detected despite substantial statistical power. In addition, there were no detected significant relationships between height and measures of friendship, popularity, or reputation with peers. It was concluded in this study that there was little support for the idea that extremes of stature, either short or tall, serve as a risk factor for poor social adjustment among youths in the general population. Therefore, arguments to support the broadening use of growth hormone to increase growth velocity and height should not be grounded in assumptions regarding the presumed psychosocial stresses associated with short stature and corresponding emotional or behavioral sequelae. There have been several recent articles on the laboratory diagnosis of growth hormone deficiency, including the provocation tests and the insulin-like growth factors. Some of these articles are highlighted below. Sizonenko, et al (2001), published a review paper on the diagnosis and management of growth hormone deficiency in childhood and adolescence. They noted that GHD is characterized by a combination of auxological, clinical, genetic, radiological, metabolic, and hormonal abnormalities. GHD is caused either directly by the total or relative absence of GH or by secretion of abnormal GH or indirectly by decreased levels of growth factors, which are GH dependent, such as insulin-like growth factor-i (IGF-I). The authors stated that GH stimulation Page 10 of 24

11 (provocative) tests play a critical role in the diagnosis of GHD. Tests should be performed in a standardized manner: in the morning after an overnight fast in the recumbent position and after placing an indwelling catheter 30 min before the test is started. Tests are usually done on an ambulatory basis. Their review of the literature showed at least 34 provocative tests and 189 different combination protocols. The most frequently used tests in the literature are clonidine, insulin-induced hypoglycemia, arginine, and glucagon with or without a B-blocker such as propanolol, and GHRH with or without arginine. Most studies showed considerable variability when the same tests were done on different days or when two different tests were done on the same day or different days. Also, the majority of single-agent tests generate a 10-20% false negative rate. For these reasons, they noted that it has generally been accepted that two abnormal tests should be used to confirm impaired GH secretion. In practice, the definition of GHD has not been based on a gold standard, but on the combination of height retardation, slow growth, and suboptimal levels of GH during two stimulation tests. Also, there has been research concerning the use of tests to assess IGF and IGFBP levels. IGF-1 and IGF-II are small polypeptide growth factors that are GH dependent. The levels vary with age, sex, and pubertal status. Also, nutrition, renal and liver function, diabetes mellitus and thyroid hormone status can all affect IGF levels. There have been problems with the methodology of measurement of IGF-1. Also, most of IGF-1 and IGF-II are bound to IGFBP3 in the circulation, so this level must be measured. There is no single GH dependent peptide measurement that can be used to diagnose GHD with acceptable accuracy. Combining data from GH, IGF-1 and IGFBP3 tests can improve specificity, but the application of multiple tests in routine clinical service is not likely to be acceptable. Boquette, et al (2003), evaluated the diagnostic value of IGF-1 and IGFBP-3 in GHD children and adults. There were 66 children (34 GHD and 32 ISS) and 92 adults (72 GHD with 34 childhood onset, 38 adult onset and 20 healthy volunteers). Also, the SDS for IGF-1 was calculated from 596 normal subjects and the SDS for IGFBP-3 was calculated from 350 normal subjects. They used ROC plots to show the best cutoff lines and the effects on corresponding sensitivities (S), specificities (Sp) and diagnostic efficiency values (DEF). The results showed that for children, an accurate diagnosis was obtained using IGF-1 SDS alone in GHD children 65%; ISS, 97%: AGHD-CO, 92%; AGHD-AO, 86%. An accurate diagnosis was obtained using IGFBP-3 SDS alone in GHD children 60%; ISS, 90%; AGHD-CO, 75%; AGHD-AO, 68%. Considering both, an accurate diagnosis was obtained in GHD children 60%; ISS 87%; AGHD- CO, 71%; AGHD-AO, 64%. The authors stated that there is a need to use cut-off lines expressed in SDS obtained using an appropriate statistical methodology for better characterization of the various clinical presentations. IGF-1 proved to be more useful because of its good diagnostic efficiency and accuracy in both children and adults, whereas IGFBP-3 did not significantly contribute to the diagnosis of GHD. Pandian and Nakamoto (2004) published a review article on the rational use of the laboratory for childhood and adult growth hormone deficiency. They noted that GH (measured by GH stimulation testing), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP3) are the most important biochemical tests for GHD. For the evaluation of possible childhood GHD, the most commonly used agents for the GH stimulation test include insulin, clonidine, arginine, or glucagon. However, no two assays for GH give the same results, as there are different forms of GH circulating at one time. So, differences in GH measurements may arise from differences in antibody specificity, differences in choice of reference preparation, Page 11 of 24

12 and differences in diluents/matrix effects. In light of this method-to-method variability, it is not possible to define universal cutoff values for GH responses. It is recommended that laboratories and kit manufacturers obtain and publish clinical cutoffs that are individualized for the specific GH assay used. The authors also discussed IGF-1 and IGFBP3. They noted that IGF-1 may not be a perfect test, as the measured level may not represent the true target tissue level. Also, it may have much biologic variability, the levels vary widely with age and sex, and the current assays may be calibrated too high. They stated that IGF-1 may not be sensitive and specific for the diagnosis of GHD, but may be useful when added to other clinical information. IGFBP3 is age dependent, as the level increases from childhood through puberty, then decreases gradually. For adult and childhood GHD, the diagnostic sensitivity of IGFBP3 is low. For childhood GHD, the specificity may be up to 98% when a cutoff of 2 SD is used. They also noted that extremely low levels of IGF-1 or IGFBP3 may help confirm a diagnosis of GHD in a high risk patient. Cianfarani, et al (2005), reported on the use of IGF-1 and IGFBP-3 to diagnose GHD. The authors stated that the sensitivity of assays of both of these is inadequate to exclude the diagnosis of GHD based on normal values of these two. They stated that the specificity of both measurement is > 90%, so subnormal concentrations support the diagnosis of GHD. They also stated that combining the evaluation of growth velocity with IGF-1 measurement leads to sensitivity and specificity > or = 95%. Cole, et al (2004) reported on how the GH provocation test result affected response to GH treatment in children with GHD. They looked at 337 prepubertal GHD patients with a GH provocation test result < 20 mu/l. They found that the test was a valuable predictor of growth response in the first year of treatment. Nagel, et al (1997), looked at the association between pituitary size and severity of GHD. They evaluated 91 MRIs done on children with short stature. There were 4 sub-groups of patients: severe, isolated GHD (n = 21); partial, isolated GHD (n = 22); multiple pituitary hormone deficiency (n = 13); neurosecretory dysfunction (n = 10); non-classifiable diagnosis (n = 13); idiopathic short stature (n = 9); and intrauterine growth retardation (n = 3). Pituitary height was measured and hypoplasia was assumed when PHT was < -2 SDS. The results showed that patients with ectopic posterior pituitary, missing stalk, and hypoplastic anterior pituitary suffer from severe isolated GHD or multiple pituitary hormone deficiency. So, the pituitary height is significantly correlated with GH secretion in several types of short stature. The American Association of Clinical Endocrinologists (AACE) Growth Hormone Task Force issued a 2003 update of medical guidelines for GH use. They discussed the GH provocation tests and measurements of IGF-1 and IGFBP-3. They stated that after an overnight fast, a wellstandardized protocol using a limited number of agents, such as arginine, clonidine, glucagon, insulin, or levodopa should be used. An experienced team should monitor the test and be careful with using insulin or glucagon in a young child. In a child with clinical criteria for GHD, a peak GH concentration <10 µg/l supports the diagnosis. However, this level may need to be adjusted with newer monoclonal-based assays and recombinant human GH reference preparations are used. For IGF-1 and IGFBP-3, reference ranges (standardized for age and sex) are necessary. Values more than 2 SD below the mean for IGF-1 or IGFBP-3 strongly suggest an abnormality in the GH axis, if other causes of low IGF have been excluded. Also, normal values for IGF-1 Page 12 of 24

13 and IGFBP-3 can be found in children with GHD. The clinician must integrate all available data (clinical, auxologic, radiologic, and biochemical) when making a diagnosis. There is no consensus on the use of priming with sex steroids before GH provocation tests. In July 2003, the Food and Drug Administration (FDA) approved the use of Humatrope, a biosynthetic hormone, to treat children with idiopathic short stature who are >2.25 SD below the mean in height. The approval was based on two randomized, multicenter trials, with approximately 300 children with ISS. The first trial was a randomized, double-blind study in 71 children treated three times weekly for a mean duration of 4.4 years. The mean final height in 33 patients showed GH treated patients exceeded placebo by 1.5 inches. In the second study, patients were treated with one of three increasing doses of GH, divided six times weekly, for an average duration of 6.5 years. The mean final height exceeded that predicted at baseline by approximately three inches. The long-term consequences of treating otherwise healthy children with GH remains uncertain. After the FDA s approval of the new indication for GH in children without GH deficiency, the AACE issued another statement on GH use in short children. They continue to recommend responsible use of GH. They advocate GH be administered and monitored by pediatric or adult endocrinologists. They stated there is limited information on long-term effectiveness and safety of this treatment in short children. They recommend that this treatment be individualized and carefully monitored and that risks, benefits, and costs be reviewed to make well-informed decisions. There have been several recent articles on the use of GH to treat ISS, its effects, and outcomes. Some of these articles are highlighted below. Finkelstein, et al (2002), did a systematic review of controlled and uncontrolled studies from to determine the effect of GH on short and long-term growth in idiopathic short stature. They looked at growth velocity and height SD score at baseline and 1 year to evaluate short-term effect of GH. There were ten controlled trials (434 patients) and 28 uncontrolled trials (655 patients) who met the criteria. The results showed that the GH treated group had increased growth velocity at one year and an average gain in adult height of approximately 4 to 6 cm. However, this corresponds to more than $35,000 per inch gained in adult height. Leschek, et al (2004), published the results of a randomized, double-blind placebo-controlled trial which was used to determine the effect of GH on adult height in peripubertal children. Initially, three were 68 subjects (53 males, 15 females, age 9-16 years) with marked, idiopathic short stature. The subjects received either GH or placebo three times per week until they were near adult height. At study termination, 33 patients (48.5%) had adult height measurements after a mean treatment duration of 4.4 years. The results showed the adult height was greater in the GH treated group by a mean of 3.7 cm (0.51 SDS). The authors noted that adult height was available in only 33 of 68 subjects. The mean height velocity was significantly greater in the GH treated group during the first 2 years of therapy, but changed little during the last 3 years. They cautioned that their observations do not imply that GH should be routinely used to treat children with idiopathic short stature and that any benefit from an increase in height must be weighed against the risk of adverse events, cost, and discomfort of GH injections. This study was supported in part by Eli Lilly and Company, the maker of Humatrope. Page 13 of 24

14 Ross, et al (2004), published a separate report on the psychological adaption of the children in the above Leschek study. These authors stated that it remains to be determined whether GH treatment significantly impacts adaptation, psychosocial function, or quality of life in children with ISS. Weise and Nahata (2004) published a review of articles from looking at the indication, pharmacology, efficacy, and adverse effects of human growth hormone in children with ISS. They reported that GH has been found to have a modest efficacy in improving final height in children with ISS. However, the specific patient population that would benefit, the optimal dosage regimens, and the long-term adverse effects are unknown. Quigley, et al (2005), also looked at the safety of GH treatment in children with ISS. They reviewed 5 studies and looked at the rates of adverse events. They reported that GH appears safe, but the studies were not powered to assess the frequency of rare GH-related events, and longer-term follow-up studies are warranted. In 1997, the American Academy of Pediatrics (AAP) published a document that recommended the following patient selection criteria for children with short stature not associated with classic GH deficiency: Therapy with GH is medically and ethically acceptable in patients whose extreme short stature keeps them from participating in basic activities of daily living and who have a condition for which the efficacy of GH therapy has been demonstrated. In addition, the AAP noted: Numerous considerations agree against widespread administration of GH therapy to other short children. First, the therapy s risk benefit ratio in this population is not established. There could be unknown long-term risks, and the treatment could result in either no increase or only an insignificant increase in final adult height Even if the clinical data show a positive risk benefit ratio, however, the benefits of GH therapy will inevitably remain somewhat elusive. Individual children may escape the stigma of being very short, but a group of very short children will always exist. On a broader scale, the best therapy for these children would be a campaign against the current prejudice against short people instead of an implicit medical reinforcement of such prejudice. Sermorelin acetate, also marketed as Geref, is an analogue of growth hormone-releasing hormone that can be used for diagnosis or treatment of idiopathic growth hormone deficiency. Sermorelin is suitable for use as a diagnostic tool when given along with conventional tests. Once daily sermorelin 30µg/kg is effective in promoting growth in prepubertal children with idiopathic growth hormone deficiency, although it appears to be less effective than growth hormone prepared by recombinant DNA technology (somatropin). Typically, provocative tests of growth hormone secretion with pharmacological stimuli, such as insulin, glucagon, levodopa, clonidine, arginine or propranolol, are used to confirm growth hormone deficiency. The minimum normal peak serum growth hormone response to these tests has been arbitrarily set at 10 µg/l. However, these provocative tests have a number of limitations including sparse normative data, unclear mechanism of action and high variability of growth hormone response. Because of the variable responses with these conventional tests, it is Page 14 of 24

15 recommended that at least 2 provocative tests be performed to confirm the diagnosis of growth hormone deficiency. Intravenous sermorelin appears to be a rapid and relatively specific test for the diagnosis of growth hormone deficiency. False positive growth hormone responses (peak growth hormone levels < 10 µg/l in patients without growth hormone deficiency) are seen in fewer children after sermorelin than after conventional provocative tests. Data in adults indicate that the combination of sermorelin and arginine is a more reliable, reproducible and age-dependent test of growth hormone deficiency than sermorelin alone. This test merits evaluation in children with growth hormone deficiency. For diagnostic testing sermorelin acetate is given intravenous 1 mcg/kg as a single dose in the morning following an overnight fast. Venous blood samples for growth hormone determinations should be drawn 15 minutes before and immediately prior to sermorelin administration. Samples of venous blood for growth hormone determinations are drawn at 15, 30, 45, and 60 minutes after sermorelin administration. Increlex The FDA s approval of Increlex was based upon the results of five Phase III clinical studies, with patients enrolled on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal GH secretion. Patients (n=71) were given Increlex, 0.06 to 0.12 mg/kg subcutaneous twice daily. Data from the five clinical studies were pooled for global efficacy and safety analysis. Patients were treated for an average of 3.9 years, up to 11.5 years. The results showed a statistically significant increase in growth rate over an 8 year period in response to therapy. Compared to pre-treatment growth patterns, children gained an additional inch per year for each year of therapy over 8 years. The side effects were mild-to-moderate in nature and included hypoglycemia (42%), injection site lipohypertrophy, and tonsillar hypertrophy (15%). Three subjects developed intracranial hypertension. According to the FDA approved product labeling, Increlex is indicated for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency or with GH gene deletion who have developed neutralizing antibodies to GH. It is not intended for use in individuals with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Increlex treatment. Increlex is not a substitute for GH treatment. Contraindications to Increlex include patients with closed epiphyses, active or suspected neoplasia, allergy to mecasermin or one of the inactive ingredients, growth failure associated with other identifiable causes (e.g., Prader Willi Syndrome, Russell-Silver syndrome, Turner syndrome, Noonan syndrome, or chromosomal abnormality), or chronic illness (e.g., diabetes, cystic fibrosis). Iplex Iplex contains rhigf-1 and insulin-like growth factor binding protein-3 (rhigfbp-3). The primary effect of IGFBP-3 in humans is to regulate the release of IGF-1 to target tissues as needed. It has a longer half-life than Increlex and seeks to reduce the adverse events associated with unbound levels of free IGF-1. Page 15 of 24

16 The FDA s approval of Iplex was based on two cohort studies of subjects who had primary IGFD due to GH receptor deficiency (Laron syndrome), GH gene deletion with neutralizing antibodies to GH, or primary IGFD of unknown etiology. In the first cohort, subjects (n=16) received up to 1 mg/kg daily for 12 months and the mean height velocity increased from 3.4 cm/year pre-treatment to 6.4 cm/year at 12 months. In the second cohort, (n=9), subjects received up to 2 mg/kg daily for 6 months, and the mean height velocity increased from 2.0 cm/year pre-treatment to 8.3 cm/year at 6 months. Patients were treated an average of 10.4 months. Safety information beyond one year of treatment is limited. The most common treatment-related adverse events were mild hypoglycemia, headaches, and tonsillar and/or adenoid hypertrophy. According to the FDA approved product labeling, Iplex is indicated for the treatment of growth failure in children with severe primary IGF-1 deficiency or with GH gene deletion who have developed neutralizing antibodies to GH. It is not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Iplex treatment. Iplex is not a substitute for GH treatment. Contraindications to Iplex include patients with closed epiphyses, active or suspected neoplasia, allergy to mecasermin rinfabate or any of the excipients in Iplex, or IV administration. In summary, both Increlex and Iplex have been shown to be effective; however, there are no studies comparing the efficacy of Increlex with Iplex. In addition, Increlex requires twice daily injections, may cause hypoglycemia, and requires product refrigeration. Iplex requires once daily injection, may cause hypoglycemia, and must be kept frozen and thawed for 45 minutes before use. There is one recently published study on the use of rhigf-1 to treat short children with severe IGF-1 deficiency. This study was supported by Genentech, Inc. and Tercica, Inc. It is summarized below. Chernausek, et al (2007), reported on an open label study that examined the long-term efficacy and safety of recombinant human IGF-1 (rhigf-1) therapy for short children with severe IGF-1 deficiency. They looked at 76 children with IGF-1 deficiency due to GH insensitivity that were treated with rhigf-1, 60 to 120 micrograms/kg SC twice daily, for up to 12 years. The results showed that height velocity increased from 2.8 cm/year on average at baseline to 8.0 cm/year during the first year of treatment and was dependent on the dose administered. Height velocities were lower during subsequent years, but remained above baseline for up to 8 years. However, the growth response was less than that attained in GH deficient children receiving GH therapy. The adverse events included hypoglycemia (49%), injection site lipohypertrophy (32%), and tonsillar/adenoidal hypertrophy (22%), and intracranial hypertension (4%). March 2010 Update Growth hormone for patients with short-bowel syndrome should be limited to patients receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome. Specialized nutritional support may consist of a high-carbohydrate, low-fat diet adjusted for individual patient requirements. Optimal management may include dietary adjustments, enteral feedings, parenteral nutrition, fluid, and micronutrient supplements. Page 16 of 24