Archived Policies - Prescription Drugs
Growth Hormone (GH)
This is not an all inclusive listing of all growth hormone preparations. Refer to the U.S. Food and Drug Administration (FDA) for all labeled indications of those growth hormones not listed on this policy.
NOTE: Check contract or legislative provisions which may mandate benefits.
Recombinant human growth hormone (rhGH) therapy is addressed by indications and may be considered medically necessary when the following specific criteria are met, listed on the table below and when:
NOTE: Off-label use of any FDA approved drugs that are not included in the medical necessity table below is considered not medically necessary OR may be considered experimental, investigational and unproven when:
NOTE: Certain rhGH are self injectables and therefore may be covered under a pharmacy benefit plan rather than the medical benefits.
MEDICALLY NECESSARY TABLE
If the FDA approved indication is:
Then the criteria for review includes the following for medically necessary consideration:
Growth hormone deficiency (GHD), in children
Supportive documentation for children with GHD:
NOTE: In children, GH therapy is typically discontinued when the growth velocity is less than 2.0 cm/year; when epiphyseal fusion has occurred; or when the height reaches the 5th percentile of adult height.
NOTE: Once GHD has been established in childhood no further documentation of need is required through age 18.
Short-stature, in children
NOTE: In patients with chronic renal failure undergoing transplantation, GH therapy is discontinued at the time of transplant.
Growth hormone deficiency (GHD), in adults
NOTE: Insulin Provocation is the preferred test for confirming GHD in most adults. It must be ONE of the TWO tests provided for documentation of GHD unless the test is contraindicated because the patient has history of seizures, coronary artery disease, or high risk of coronary artery disease.
NOTE: Only about 25% of children with documented GHD will be found to have GHD when tested as adults. Therefore, once adult height has been achieved, they should be re-tested ONE time as adults to determine if continuing GH replacement therapy is medically necessary.
NOTE: When a diagnosis of GHD is established for an adult, and therapy with GH is initiated, documentation may be requested at one to two year intervals to demonstrate that the patient is obtaining measurable clinical benefit from GH therapy.
NOTE: A physician should consider a trial of withdrawal of GH therapy for patients who do not have demonstrated clinical benefit.
Acquired immunodeficiency syndrome (AIDS) wasting
NOTE: GH therapy is discontinued when the loss is less than 10% of baseline weight loss.
Associated growth failure.
Severe burns, in children
Severe burns, in adults
3rd degree burns requiring promotion of wound healing.
Short bowel syndrome
Patients receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome, including dietary adjustments, enteral feedings, parenteral nutrition, and fluid and micronutrient supplements.
NOTE: For additional discussion of short bowel syndrome, see Medical Policy MED201.021, Intestinal Rehabilitation Therapy.
Recombinant human growth hormone (rhGH) therapy is considered not medically necessary, including but not limited to, the following conditions listed on the table below.
NOT MEDICALLY NECESSARY TABLE
If the FDA approved indication is:
Then the explanation for not medically necessary is:
Small for gestational age (SGA)
Pediatric patients born SGA who fail to show catch up growth by age two, as there are no established criteria for SGA or catch-up growth. However, in the data submitted to the FDA as part of the approval process, the mean height of enrolled patients was at least 2.0 SD below mean. Absence of catch-up growth was defined as a height velocity below 1.0 SD score, adjusted for age.
Non-GHD with short-stature (idiopathic short-stature [ISS])
Pediatric patients who are non-GHD with short-stature (also known as ISS), as studies have failed to demonstrate a significant impact of height on psychosocial morbidity. The American Academy of Pediatrics (AAP) has pointed out that there will always be a population of individuals considered short based on the normal distribution of height, regardless of how the bell-shaped curve may be altered by GH therapy.
Patients with partial GHD, as these patients do not meet the criteria required for GHD. Further lab testing of children without classic GHD to diagnose partial GHD, or other abnormalities of GH secretion or bioactivity, is not considered medically necessary. This includes overnight hospitalization of children for testing of spontaneous GH secretion.
Neurosecretory GH dysfunction
Patients with neurosecretory GH dysfunction, as these patients do not meet the criteria required for GHD. Further lab testing of children without classic GHD to diagnose partial GHD, or other abnormalities of GH secretion or bioactivity, is not considered medically necessary. This includes overnight hospitalization of children for testing of spontaneous GH secretion.
All Other Indications
Experimental, investigational and unproven applications for rhGH therapy include, but are not limited to, the following:
The following diagnostic tests for GHD are considered experimental, investigational and unproven:
NOTE: Somatropin (or somatropin recombinant) manufactured as Accretropin™, Asellacrin 2®, Asellacrin 10®, Bio-Tropin®, Protropin®, and Crescormon® has been discontinued and is no longer on the market.
NOTE: Refer to Medical Policy RX501.065 for coverage for Mecasermin Recombinant (Increlex ™ or Iplex/iPLEX ™), which is a recombinant insulin-like human growth factor.
NOTE: See Description for recommended FDA labeled dosing.
Human growth hormone, also known as somatotropin, is synthesized in somatotropic cells of the anterior lobe of the pituitary gland. Beginning in 1985, recombinant GH (rhGH or somatropin) has been marketed for a variety of FDA-labeled indications. rhGH is also proposed for various non-labeled indications such as cystic fibrosis and treatment of older adults without documented GH deficiency.
A major point of controversy is what defines inadequate secretion of normal endogenous growth hormone and what constitutes growth failure. Prior to the availability of biosynthetic growth hormone (GH), GH was rationed to those children with classic growth hormone deficiency (GHD) as defined by a subnormal response (< 10 ng/ml) to GH provocation tests. However, the ready supply of GH has created interest in expanding its use to short-stature children without classic GHD, often referred to as:
Classic GHD is suggested when there is an abnormal growth velocity (typically below the 10th percentile) or height is more than 2.0 SD below the current population mean, in conjunction with a chronological age that is greater than the height age and bone age. In practical fact, interest in broadening the use of GH to non-GHD children has resulted in GH evaluation in many children who are simply below the 3rd percentile in height with or without an abnormal growth velocity.
However, these broadened patient selection criteria have remained controversial due to uncertainties in almost every step in the diagnosis and treatment process as outlined below:
There are many ethical considerations regarding GH therapy, most prominently the appropriate informed consent when therapy is primarily requested by the parent due to their particular psychosocial concerns regarding height.
The following table lists the approved FDA rhGH therapy drugs:
NOTE: Drug dosing recommendations in the Medical Policy follow FDA approved dosage in the product label. A prescription for doses that exceed the product label must be accompanied by citation of clinical studies that support a higher dose regimen.
Recommended FDA Labeled Dosage
Genotropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
Humatrope should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
Norditropin Nordiflex® (somatropin recombinant)
Norditropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
(somatropin rDNA orgin or somatropin recombinant)
Nutropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
Omnitrope should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
(somatropin rDNA orgin or somatropin recombinant)
Saizen should be administered subcutaneously (which is preferred, but intramuscular is acceptable) and injection sites rotated to avoid lipoatrophy:
Serostim® (somatropin rDNA orgin or somatropin recombinant)
Serostim should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
(somatropin rDNA orgin or somatropin recombinant)
Tev-Tropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
Valtropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
Zorbtive should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:
The following discussion focuses on the most controversial aspects of growth hormone (GH) use.
Laboratory diagnosis of growth hormone deficiency (GHD): Diagnosing growth hormone deficiency (GHD) in children remains an area of confusion and disagreement. As a result, guidelines remain vague. For example, both the 2003 American Association of Clinical Endocrinologists (AACE) guidelines and the 2000 consensus guidelines published by the Growth Hormone Research Society state that diagnosis is a multifaceted process involving clinical, auxological, radiological, and biochemical assessment. These guidelines provide an informed discussion of various measures, but no proposal of specific criteria.
Regarding biochemical testing alone, there is little agreement on specific criteria within the pediatric endocrinology community. Some of the reasons include:
These areas of uncertainty have led some investigators and clinicians to abandon the use of provocative testing as the sole diagnostic for GHD, and instead base diagnoses on a combination of clinical and diagnostic test information. These often include:
However, it should be noted that for the purposes of this policy, relying on auxological measurements alone is inadequate to document GHD. This policy is based on the premise that GH would be considered medically necessary as a replacement therapy for GHD, and not medically necessary when used as treatment of short-stature in the absence of GHD. For example, as discussed further below, treatment of short-stature without accompanying GHD is generally considered not medically necessary due to the lack of a functional impairment.
GH therapy in short-stature children without documented GHD: While GH therapy in patients with classic GHD is accepted, the use of GH in short-stature patients without GHD (as identified by standard provocation tests) is controversial. The controversy is related to difficulties in laboratory diagnosis of GHD:
Surveys of endocrinologists suggest that laboratory measures of GH secretion are of limited usefulness in the decision of whether to initiate therapy. The most useful criteria cited by endocrinologists appear to be abnormal height, growth velocity, and delayed bone age. However, there are inadequate outcome data in terms of final height to validate this approach. These surveys also suggest that GH treatment is sought primarily to treat the potential psychosocial morbidity of short-stature, and yet this outcome has not been studied in GH recipients. In addition, other studies have suggested that short-stature is only variably related to psychosocial morbidity. There has been one controlled trial that examined the behavior of children without documented GHD who were treated with GH due to idiopathic short-stature (ISS).
Across measures of behavior, including intelligence quotient, self-esteem, self-perception, or parental perceptions of competence, there were no significant differences between the control and treatment groups, either at baseline or after five years of GH therapy, coming from a 1996 study. The authors (Downie et al.) concluded that while there have been no demonstrated psychosocial benefits of GH therapy; likewise, there have been no documented psychosocial ill effects of GH treatment.
In January 1997, the American Academy of Pediatrics (AAP) published a document that recommended the following patient selection criterion for children with short-stature (not associated with classic GHD): “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 argue 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."
GH therapy in small for gestational age (SGA) children: In 2001, one GH preparation (Genotropin) received FDA-approval for treatment of small for gestational age (SGA) children. This FDA-approval was based on four randomized, open-label controlled clinical trials. Patients were observed for 12 months before being randomized to receive 0.24 mg/kg/week or 0.48 mg/kg/week GH or no treatment for 24 months. After 24 months all patients received GH. In patients receiving the higher GH dosage of 0.48 mg/kg/wk, the patients' height improved from a baseline of -3.4 SD to -1.7 SD below the mean. In contrast, in the control group the SD score improved to a lesser degree, from -3.1 to -2.9 SD below the mean. The issues associated with this indication for GH are similar to those for other short-stature children without documented GHD. There are no documented functional impairments associated with short-stature and no data regarding final adult height in the control or treatment group. It should be noted that the dosage recommended for SGA children, 0.48 mg/kg/week, is a supraphysiologic dose. For example, in patients with documented GHD, in which the intent is to provide normal physiologic replacement levels of GH, the recommended dosage is only 0.24 mg/kg/week. There are very minimal data regarding the psychosocial outcomes of short- pediatric- or short-adult-stature related to intrauterine growth retardation, and how these outcomes may be affected by GH therapy. As noted above, there are inadequate data to document that short-stature youths have either low self-esteem or a higher than average amount of behavioral or emotional problems.
For both SGA children and short-stature children, an additional strategy to achieve target adult heights is to combine GH therapy with gonadotropin-releasing hormone (GnRH) analogs, which prolong the prepubertal growth period. The combined therapy is intended to increase the critical pubertal height gain by delaying the fusion of the epiphyseal growth plates, thus prolonging the period during which GH is active. This therapy has been suggested for children who are considered short when they enter puberty.
GH therapy in conjunction with GnRH therapy as a treatment of precocious puberty: Precocious puberty is generally defined as the onset of secondary sexual characteristics before eight years of age in girls and nine years in boys. Central precocious puberty is related to hypothalamic pituitary gonad activation, leading to increase in sex steroid secretion, which accelerates growth and causes premature fusion of epiphyseal growth plates, thus impacting final height. Children with precocious puberty are often treated with GnRH analogs to suppress the pituitary gonad activity, to slow the advancement of bone age, and to improve adult height. Several long-term studies have reported that treatment with GnRH analogs is associated with improved adult height in most cases, particularly in those with the most accelerated bone age progression at treatment onset, the shortest predicted height, and the greatest difference between the target height and the predicted height.
In contrast, patients with a slowly progressive form in which the predicted height does not change after two years of follow-up may not require any treatment. In another subset of patients, GnRH analog therapy may be associated with a marked deceleration of bone growth that may ultimately result in an adult stature that is less than the targeted mid parental height. GH may be offered to these patients in order to achieve the targeted adult height. There have been no randomized controlled trials comparing final adult height in those treated with GnRH analogs alone versus GnRH analogs combined with GH therapy, and the largest case series includes 35 patients. Case series suggest that GH is most commonly offered as an adjunct to GnRH analogs when the growth velocity drops below the 25th percentile for chronological age.
A series of comparative case series that have included final adult heights have been reported by the same group of investigators from Italy. This group of investigators is the only one to have reported final adult heights. The most recent reports focus on a group of 17 girls with precocious puberty and a growth velocity below the 25th percentile who was treated with a combination of GnRH and GH, and 18 girls who refused treatment with adjunctive GH. Those in the combined group attained a significantly greater adult height (161.2 +/- 4.8 cm) than the “control” group (156.7 +/- 5.7 cm). This small study is inadequate to permit scientific conclusions. Tuvemo and colleagues reported on the results of a trial that randomized 46 girls with precocious puberty to receive either GnRH analogs or GnRH analogs in addition to GH. Of interest, all the participants were adopted from developing countries; precocious puberty is thought to be common in such cross-cultural adoptions. Criteria for participation in this trial did not include predicted adult height or growth velocity. After two years of treatment, the mean growth and predicted adult height were greater in those receiving combined treatment compared to those receiving GnRH analogs alone. The absence of final height data limits interpretation of this trial.
As noted above, the not medically necessary status of other applications of GH for non-GH deficient short-stature children is based on the absence of a functional impairment associated with a less than predicted final adult height. While these same considerations may apply to using GH therapy as a component of therapy for precocious puberty, the experimental, investigational and unproven status of this indication is based on lack of final height data from controlled trials.
Turner's syndrome: Short-stature is almost universal in Turner's syndrome. Poor growth is evident in utero and further deceleration occurs during childhood and at adolescence. The mean adult height for those with Turner's syndrome is 58 inches (4 ft 10 inches). Unlike Prader-Willi syndrome, GHD is not seen. The FDA approvals for Humatrope and Nutropin were based on the results of randomized, controlled clinical trials that included final adult height as the outcome. A group of patients with Turner's syndrome given Humatrope at a dosage of 0.3 mg/kg/week for a median of 4.7 years achieved a final height of 146.0 +/- 6.2 cm (57.5 +/-2.25 inches)/compared to an untreated control group who achieved a final height of 142.1 +/- 4.8 cm (56 +/- 2 inches). The results with Nutropin were similar. While the data regarding Turner's syndrome are somewhat unique in that final height is known, the clinical significance of a mean increase in height of 3.9 cm (1.75 inches) is unknown. It should also be noted that earlier initiation of GH therapy might result in more significant increases in adult height.
GH therapy in older adults without documented GHD: The GH 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. However, mean GH levels in older adults are greater than age-matched adults with diagnosed GHD. Older individuals experience changes in body composition, loss of muscle mass, and decreases in bone mineral density that are similar to changes seen in adults with biochemically verified GHD. Based on these observations, GH therapy has been investigated in older adult without organic pituitary disease. The policy regarding this off label application is based on a 2001 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) assessment, which offered the following observations and conclusions:
In 1998 the AACE published clinical guidelines regarding GH use. Regarding the use of GH in adults, the AACE guidelines noted that "the benefits of GH supplementation in aging patients remain to be established." In 1997, the Growth Hormone Research Society published consensus guidelines for the diagnosis and treatment of adults with GHD. These guidelines state, "partial GH deficiency exists, but further research is needed to distinguish it from physiological causes of reduced GH secretion, e.g., aging. Furthermore, the benefits of treatment of partial GH deficiency remain to be established."
Only six small controlled trials with at least ten patients per treatment arm have examined the effect of GH therapy on older patients who may have partial GHD, as compared to younger populations. These trials used much higher doses than are currently recommended and suffered from potential bias due to disproportionate numbers of dropouts from adverse events. Bone mineral density outcomes were most often reported, but results did not show consistent time frame (within the time frame tested) and have not been related to fracture rates. Trials tended to report increases in lean body mass and decreases in fat mass in treated patients compared to controls. Not all improvements are statistically significant; different methods of measuring body composition across trials may be affected by GH-induced changes in extra cellular fluid, and may not be comparable.
It is not possible to prove effectiveness of GH treatment or lack thereof unless otherwise similar groups of treated versus non-treated patients are compared over a sufficient length of time to allow detection of any significantly and clinically different results. Limited results do not suggest marked improvement with GH therapy and, in general, are insufficient to permit conclusions regarding the effectiveness of GH at improving disability and quality of life in older populations.
GH therapy as a treatment of altered body habitus related to antiretroviral therapy for HIV infection: There has been research interest in the use of GH to treat the altered body habitus that may be a complication of antiretroviral therapy for HIV-infection. Body habitus changes, also referred to as the fat redistribution syndrome (or lipodystrophy), include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement or an increased dorsocervical fat pad ("buffalo hump"). However, there is minimal published literature regarding the use of GH for this indication. Letters to the editors and small case series dominate the literature. The largest case series was reported by Wanke and colleagues who treated ten HIV-infected patients (with fat redistribution syndrome) with GH for three months. The authors reported improved waist/hip ratio and mid-thigh circumference.
GH therapy for severe burns: Mortality was studied in a controlled trial of 54 adult burn patients who survived the first seven post-burn days. Those patients showing difficulty with wound healing were treated with recombinant human growth hormone (rhGH) and compared to those healing at the expected rate with standard therapy. Mortality of rhGH treated patients was 11% compared to 37% not receiving rhGH (p=0.027). Infection rates were similar in both groups. In a randomized, double-blind, placebo-controlled trial of 40 severely burned children, the length of hospital stay was reduced from a mean of 0.8 days per % total body surface area (TBSA) burned for the placebo group to 0.54 days per % TBSA burned for the treatment group (p<0.05). For the average 60% TBSA-burned patient, this approximates a length of stay reduction from 46 to 32 days. Singh et al. studied two groups of patients (n=22) with comparable third-degree burns; those who received GH had improved wound healing and lower mortality (8% vs. 44%). Demling et al. found significantly improved weight retention and wound healing time with GH or oxandrolone compared to standard treatment in 36 adults with severe burns.
Two phase III double-blind randomized controlled trials of GH treatment in adults following cardiac or abdominal surgery, multiple traumas, or acute respiratory failure found increased in-hospital mortality rates in patients who received GH. The potential for increased mortality prompted additional studies in critically burned pediatric patients. Ramirez et al. retrospectively studied 263 pediatric burn patients. Those treated with GH had no increase in mortality from matched patients who did not receive GH.
However, a randomized, controlled trial in 56 children with more than 40% TBSA found no benefit of GH alone compared to or in combination with propanolol. Another placebo-controlled trial found no benefit to GH with regard to length of hospitalization in 24 adult patients with severe burns.
GH therapy to prevent growth delay in children with severe burns: Children with severe burns show significant growth delays for up to three years after injury. GH treatment in 72 severely burned children for one year after discharge from intensive care resulted in significantly increased height in a placebo-controlled, randomized, double-blinded trial. One study reported found that GH treatment in severely burned children during hospitalization resulted in significantly greater height velocity during the first two years after the burn compared to a similar group of untreated children.
GH therapy in conjunction with optimal management of short bowel syndrome: Short bowel syndrome is experienced by patients who have had half or more of the small intestine removed with resulting malnourishment because the remaining small intestine is unable to absorb enough water, vitamins, and other nutrients from food. The FDA label for Zorbtive indicates growth hormone has been shown in human clinical trials to enhance the transmucosal transport of water, electrolytes, and nutrients. The FDA-approval for Zorbtive was based on the results of a randomized, controlled, phase III clinical trial in which patients dependent on intravenous parenteral nutrition who received Zorbtive (either with or without glutamine) over a four week period had significantly greater reductions in the weekly total volume of intravenous parenteral nutrition required for nutritional support. However, the effects beyond four weeks were not evaluated nor were the treatment location (inpatient vs. outpatient) identified.
Several published studies have also demonstrated improved intestinal absorption in short bowel syndrome patients receiving parenteral nutrition. However, studies have noted the effects of increased intestinal absorption are limited to the treatment period. Specialized clinics may offer intestinal rehabilitation for patients with short bowel syndrome; GH may be one component of this therapy. Inpatient intestinal rehabilitation is considered separately in another policy.
Other Indications: GH therapy has been investigated for use in the treatment of cystic fibrosis, idiopathic dilated cardiomyopathy, and juvenile idiopathic arthritis. No randomized clinical trials (RCTs) were identified to sufficiently demonstrate the appropriateness of GH therapy in these conditions.
Ding and colleagues randomized 48 patients with chronic severe hepatitis B to evaluate growth hormone with lactulose versus no growth hormone. The authors noted clinical improvement in 90% of patients; however, this study focused on intermediate short-term outcomes and no conclusions can be drawn from the study. Therefore, chronic infectious disease is added to the investigational coverage statement on anabolic therapy for catabolic illness.
The policy was updated on several topics: Prader-Willi syndrome, Noonan’s syndrome, Turner’s syndrome, cystic fibrosis, lipodystrophy, advanced aging, inflammatory bowel disease, ISS, short bowel syndrome, children with tall parents, and children with GHD, as a result of a search of peer reviewed literature through January 2012.
Safety of GH treatment: The largest study published to date on safety of GH treatment includes data on 54,996 included in a postmarketing surveillance registry established by Genetech, Inc. (Bell, 2010). The study from Bell et al. was initiated due to concerns about long-term safety of GH, in particular, cases of de novo leukemia in patients without risk factors. The most common indications for GH use among children in the database were idiopathic GHD (42.5%), ISS (17.8%), organic GH deficiency (15.2%), and Turner’s syndrome (9.3%). As of January 1, 2006, a total of 4,084 adverse events (6.2%), including 1,559 (2.4%) serious adverse events and 174 (0.3%) deaths, had been reported. Investigators assessed 19 of 174 deaths (11% of deaths) as related to GH treatment. Twelve of the 19 GH-associated deaths were due to neoplasms (0.1% of children in the registry), and the other seven deaths were each due to a different cause. Overall, intracranial malignancies of non pituitary origin were reported in 243 patients; 44 were new-onset malignancies. In addition, extracranial malignancies, including leukemia, were reported in 87 patients; 63 were new-onset extracranial malignancies. The authors reported that 36 new-onset malignancies (intracranial and extracranial combined) occurred in individuals without risk factors; 29 of the 36 cases were confirmed as being enrolled in the registry. The rate of new-onset malignancy did not exceed the rate expected in the general population (standard incidence ratio=1.12, 95% CI: 0.75 to 1.61). The results of this study provide some evidence that the rate of malignancies was not increased in patients treated with GH. However, the registry study lacked a concurrent comparison with untreated patients to compare actual rates of malignancy and other adverse events.
GH treatment for various indications
Prader-Willi Syndrome: Use of GH therapy for patients with growth failure due to Prader-Willi syndrome is an FDA approved indication. Most patients with this syndrome have hypothalamic dysfunction and GHD. Numerous studies have shown patient improvements with use of GH. For example, a recent randomized study reported by Fensten involving 42 infants and 49 children showed that GH treatment significantly improved height, body mass index (BMI), head circumference, and body composition (Fensten, 2008). Recently, deaths have been reported in Prader-Willi patients who are being treated with GH. A number of these deaths occurred in children with morbid obesity, respiratory or sleep disorders. Airway obstruction has been hypothesized as a potential cause; however, the exact role of GH is not certain. Because of this, many specialists now recommend sleep studies and correction of underlying airway obstruction before initiating GH treatment in these patients.
Questions have been raised about the value of testing for GHD before treatment in these patients. The majority of patients with Prader-Willi syndrome are GH deficient. A number of recent clinical studies on use of GH in Prader-Willi syndrome were reviewed. In none of these studies were patients selected for treatment based on presence or absence of GH, nor were results reported separately for those with or without GHD (and thus no differential impact was noted). One older study did describe a series of Prader-Willi syndrome patients treated with GH that were GH deficient (Lindgren, 2008). However, the FDA approval is for those with Prader-Willi syndrome and growth failure, thus this “growth failure” indication is added to the policy statement. Information from the product label indicates that the height SD score for Prader-Willi syndrome children in the clinical studies was -1.6 or less (height was in the 10th percentile or lower).
Noonan’s Syndrome: In 2007, the FDA approved the use of GH (Norditropin) for treatment of short-stature in children with Noonan’s syndrome. This approval was based on a comparative study of 21 children that showed improvement in height and growth velocity in those with short-stature due to Noonan’s syndrome (FDA, 2012).
Turner’s Syndrome: In 2007, a Cochrane review identified four RCTs (total n=365) evaluating GH for treating Turner’s syndrome (Baxter, 2007). Studies included children who had not yet achieved final height, treated for at least six months, and compared GH to placebo or no treatment. Only one trial reported final height, so findings on this outcome could not be pooled. A pooled analysis of two trials found that short-term growth velocity was greater in treated than untreated children (mean difference [MD], three cm per year, 95% CI: two to four cm per year).
Cystic Fibrosis: Since the use of GH is not FDA approved for this indication, this use remains considered experimental, investigational and unproven. A systematic review by Phung et al. identified ten controlled trials evaluating GH for treating patients with cystic fibrosis (Phung, 2010). One study was placebo-controlled, eight compared GH therapy to no treatment and the remaining trial compared GH alone to glutamine or glutamine plus GH. In one study, patients were treated with GH for four weeks and in the other studies, duration of treatment ranged from six months to one year. There were insufficient data to determine the effect of GH on most health outcomes including frequency of intravenous antibiotic treatment, quality of life, and bone fracture. Data could be pooled, however, on frequency of hospitalizations although the authors did not report the number of studies included in their meta-analyses. In trials with a duration of at least one year, there was a significantly lower rate of hospitalizations per year in the group receiving GH therapy (pooled effect size=-1.62, 95% CI: -1.98 to -1.26). The authors commented that GH is a promising therapy for treatment of cystic fibrosis, but there are a number of important research questions that must be answered; in particular, there is a need for high-quality studies on health outcomes.
Lipodystrophy: Since the use of GH is not FDA approved for this indication, this use remains considered experimental, investigational and unproven (FDA, 2012). The coverage statement is unchanged. However, some studies have demonstrated the efficacy of GH treatment to reduce visceral adipose tissue and to improve peripheral fat wasting as part of body habitus changes and metabolic abnormalities commonly observed in HIV patients. Macallan (2008) reported that if GH is effective in reducing visceral fat, the effects are short-lived.
Advanced Aging: Although advanced age or symptoms of aging are not among approved indications for GH therapy, rhGH and various GH-related products are aggressively promoted as anti-aging therapies. Well-controlled studies of the effects of GH therapy in endocrinologically normal elderly subjects report some improvements in body composition and a number of undesirable side effects in sharp contrast to the major benefits of GH therapy in patients with GHD. Since the use of GH is not FDA approved for this indication, this use is considered experimental, investigational and unproven (FDA, 2012).
Inflammatory Bowel Disease: Since the use of GH is not FDA approved for this indication, this use remains experimental, investigational and unproven. This coverage statement is unchanged. Studies have not clarified patient selection or long-term use during GH treatment of patients with inflammatory bowel disease (FDA, 2012).
GH Use in Children with Idiopathic Short-Stature (i.e., without documented GH deficiency or underlying pathology)
Is GH effective at increasing the adult height of children with idiopathic short-stature? Several meta-analyses have been published (Deodati, 2011). Most recently, Deodati and colleagues identified three RCTs and seven non-RCTs. To be included in the meta-analysis, studies needed to include pre-pubertal children with initial short-stature (more than two standard deviations [SD] below the mean) and peak GH response greater than 10 ug/L. In addition, participants needed to have no previous growth hormone therapy and no comorbid conditions that could impair growth. Adult height was defined as a growth rate of less than 1.5 cm/year or bone age was 15 years in females and 16 years in adults. The primary efficacy outcome was the difference between groups in adult height; this was measured as an SD score (SDS, also known as a z-score). The investigators considered a mean difference in height of more than 0.9 SD scores (about six cm) to be a satisfactory response to GH therapy. Only one of the RCTs was placebo-controlled, and that study had a high dropout rate (40% in the treated group and 65% in the placebo group).
In the three RCTs (total n=115), the mean adult height (primary efficacy outcome) was -1.52 SDS for treated children and -2.30 SDS for untreated children. The difference between groups significantly favored the treated group; mean difference=0.65 SDS (about 4 cm), 95% CI: 0.40 to 0.91 SDS, p<0.001. The mean adult height in the seven non-randomized studies was -1.7 SDS for treated children and -2.1 SDS for untreated children. The mean difference between groups was 0.45 SDS (3 cm), 95% CI: 0.18 to 0.73 and was statistically significant favoring the treated group, p<0.001. Although GH treatment resulted in a statistically significant increase in adult height in the treated group, according to the a priori definition of a satisfactory response, the difference was not clinically significant. Moreover, there was a lack of high-quality placebo-controlled RCTs.
In 2009, a Cochrane review of RCTs evaluating GH therapy for idiopathic short-stature in children and adolescents was published (Bryant, 2009). A total of ten RCTs met eligibility criteria, which included being conducted in children who had normal GH secretion, normal size for gestational age at birth, and no evidence of chronic organic disease. In addition, studies needed to compare GH treatment to placebo or no treatment and provide GH treatment for at least six months. Three studies were placebo controlled and the other seven compared GH therapy to no treatment (Deodati, 2011). Unlike the Deodati review described above, studies were not required to report final adult height. Nine out of ten studies in the Cochrane review were short-term and reported intermediate outcomes. A pooled analysis of three studies reporting growth velocity at one year found a statistically significantly greater growth velocity in treated compared to untreated children. The weighted mean difference (WMD) was 2.84 (95% CI: 2.06 to 2.90). Five studies reported height SDSs, but there was heterogeneity among studies and their findings were not pooled. These data suggest that GH has an effect on height in children with ISS in the short-term but that evidence on GH’s effects on adult height is extremely limited.
In summary, recent systematic reviews have found that GH treatment may result in increases in height gain for children with ISS, but the difference in height gain may not be clinically significant. The absolute difference in height in these studies is in the range of 3-4cm, and children treated with GH remain below average in height, with heights that are between one and two SDs below the mean at the end of treatment. These studies do not follow treated patients long enough to determine the ultimate impact of GH on final adult height.
What is the impact of GH treatment on self-esteem and quality of life in children with ISS? Advocates of GH therapy often cite the potential psychosocial impairments associated with short-stature. However, several RCTs have addressed this topic, and they have not found better self-esteem, psychological functioning, or quality of life in children treated with GH compared to controls. These studies are described briefly below:
In 2004, Ross and colleagues published findings on psychological adaptation in 68 children with ISS without GH deficiency (Ross, 2004). Children (mean age, 12.4 years) were randomized to receive GH therapy (n=37) or placebo (n=31) three times per week until height velocity decreased to less than 1.5 cm per year. At baseline and then yearly, parents and children completed several psychological instruments including the Child Behavior Checklist (CBCL) and Self-Perception Profile (SPP). No significant associations were found between attained height SDS or change in height SDS and annual changes in scores on the CBCL. There were no significant differences between groups on any CBCL summary scales in years one and two, but in year four, there were significantly higher scores on the CBCL summary scales in the group receiving GH treatment. There were no significant differences between groups on the SPP at any follow-up point. In conclusion, short-stature in this study was not associated with problems in psychological adaptation or self-concept.
Theunissen and colleagues in the Netherlands published a trial in 2002 in which 40 prepubertal children with ISS were randomly assigned to GH treatment (n=20) or a control group (n=20) (Theunissen, 2002). Parents and children were interviewed at baseline and at one and two years to obtain information on health-related quality of life (HRQOL) and children’s self-esteem. At the two year follow-up, satisfaction with current height was significantly associated with improvement in children’s reported health-related quality of life, social functioning, and other psychosocial measures. However, satisfaction with height did not differ significantly between the treatment and control groups. The data from this study do not support the hypothesis that GH treatment improves HRQOL in children with ISS.
In summary RCTs have not found that short-stature is associated with psychological problems, in contrast to the expectations of some advocates. In addition, the available trials have not reported a correlation between increases in height and improvements in psychological functioning.
In light of the published research on the impact of GH on health outcomes for children with ISS, and because this group of children is healthy (i.e., no identified pathology or hormone deficits) and thus should avoid unnecessary exposure to long-term medical treatment, GH treatment for children with ISS is considered not medically necessary.
GH Use in Small for Gestational Age (SGA) Children: A meta-analysis of RCTs evaluating GH treatment for children born SGA was published in 2009 (Maiorana, 2009). Four trials with a total of 391 children met the eligibility criteria (birth height or weight below two SDS and initial height less than two SDS). The GH dose ranged from 33 to 67 ug/kg in the RCTs, and the mean duration of treatment was 7.3 years. Mean adult height in the four studies was -1.5 SDS in the treated group and -2.4 SDS in the untreated group. The adult height in the treated group was significantly higher than that of controls; mean difference=0.9 SDS (5.7 cm), p<0001. There was no difference in adult height between the two doses of 33 and 67 ug/kg per day. The authors commented that it is unclear whether the gain in adult height associated with GH treatment “is of sufficient clinical importance and value to warrant wide-spread treatment of short children born SGA…”
There are very minimal data regarding the psychosocial outcomes of short-pediatric or adult-stature related to intrauterine growth retardation and how these outcomes may be affected by GH therapy. As noted above, data are inadequate to document that short-stature youths have either low self-esteem or a higher than average number of behavioral or emotional problems.
For both SGA children and short-stature children, an additional strategy to achieve target adult heights is to combine GH therapy with GnRH analogs, which prolong the prepubertal growth period. The combined therapy is intended to increase the critical pubertal height gain by delaying the fusion of the epiphyseal growth plates, thus prolonging the period during which GH is active. This therapy has been suggested for children who are considered short when they enter puberty (Saggese, 1995; Pasquino, 2000; Tanaka, 1999).
GH use in children with “genetic potential” (i.e., lower than expected height percentiles based on parents’ height): No randomized or non-randomized studies were identified that evaluated the efficacy, safety, and/or psychosocial impacts of treating this group of children with GH therapy.
GH Therapy in Conjunction with Optimal Management of Short Bowel Syndrome: A 2010 Cochrane review identified five RCTs evaluating GH therapy for treating short bowel syndrome (Wales, 2010). Studies evaluated GH with or without glutamine treatment. The primary outcome was change in body weight. A pooled analysis of three small trials (total n=30) found a statistically significant difference in weight change when patients were treated with GH or placebo (MD, 1.66 kg, 95% CI: 0.69 to 2.63, p=0.0008).
General Practice Guidelines and Position Statements
In 2010, the National Institute of Health and Clinical Excellence (NICE) in the U.K. issued guidance on human GH for growth failure in children (NICE, 2010). NICE recommends GH as a possible treatment for children with growth failure who have any of the following conditions:
In 2009, the American Association of Clinical Endocrinologists issued updated guidelines on GH use in growth hormone-deficient adults and transition patients (Cook, 2009). Evidence-based recommendations include the following:
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Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
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The following codes may be applicable to this Medical policy and may not be all inclusive.
J2940, J2941, S9558
ICD-9 Diagnosis Codes
042, 253.2, 253.3, 253.5, 253.7, 259.1, 579.3, 593.9, 764.9, 758.6, 783.40, 783.41, 783.42, 783.43, 799.4, 759.81, 941.30 to 941.39, 942.30-942.39, 943.30 to 944.39, 945.30 to 945.39, 946.3, 949.3
ICD-9 Procedure Codes
ICD-10 Diagnosis Codes
B20, E23.0-E23.7, E30.1, K91.2, N28.9, P05.00-P05.9, Q87.1, Q96.0-Q96.9, R62.0-R62.59, R64, T20.30xA-T20.39xS, T22.30xA-T22.39xS, T23.301A-T23.399S, T24.301A-T24.399S, T25.311A-T25.399S, T30.0
ICD-10 Procedure Codes
3E013VJ, 3E033VJ, 3E043VJ, 3E053VJ, 3E063VJ
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The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
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9/15/2012 Document updated with literature review. Coverage remains conditional based on meeting growth hormone deficiency criteria; clarified use in growth failure when used for Prader-Willi syndrome, inflammatory bowel disease, and advanced aging; and coverage added for Noonan’s syndrome. Treatment of children with “genetic potential” (i.e., lower than expected height percentile based on parents’ height) included as experimental, investigational and unproven. Clarified and expanded explanation of each FDA approved rhGH drug and their indication(s). CPT/HCPCS code(s) updated.
8/1/2007 Document updated with literature review.
3/23/2005 Document updated with coverage change.
6/1/2004 Document updated with coverage change.
12/1/2003 Document updated with literature review.
2/2002 CPT/HCPCS code(s) updated (with bit changes).
6/2001 CPT/HCPCS code(s) updated (with bit changes).
1/2000 Document updated with literature review.
2/1998 Document updated with literature review.
5/1996 Document number changed.
4/1993 Document updated with literature review.
9/1990 New medical document.
|Title:||Effective Date:||End Date:|
|Human Growth Hormone (GH)||07-15-2018||06-14-2019|
|Growth Hormone (GH)||04-15-2017||07-14-2018|
|Growth Hormone (GH)||02-15-2016||04-14-2017|
|Growth Hormone (GH)||07-15-2015||02-14-2016|
|Growth Hormone (GH)||09-15-2012||07-14-2015|
|Growth Hormone (GH)||08-01-2007||09-14-2012|
|Growth Hormone (GH)||03-23-2005||07-31-2007|
|Growth Hormone (GH)||12-01-2003||03-22-2005|