Translating Clinical Guidelines Into Practice: The Effective and Appropriate Use of Human Growth Hormone

There are 9 recombinant human growth hormone (rhGH) products currently available for 10 US Food and Drug Administration—approved indications; each rhGH product is approved for 1 or more indications. Adult and pediatric patients with the various conditions for which rhGH is indicated, from idiopathic short stature (ISS) and growth hormone (GH) deficiency to short bowel syndrome and HIV/AIDS wasting, may benefit from rhGH treatment. In clinical practice, pediatric patients with GH deficiency or ISS make up the majority of the population receiving treatment with rhGH.

Most rhGH products are provided through specialty pharmacies that often have to balance the needs of the patient, their own utilization objectives, and the availability of the rhGH on formulary from a particular payer. Often, a payer will prefer only 2 or 3 rhGH products to cover all 10 indications. As such, managed care professionals need to be more informed about the options available and should be familiar with the different indications to help educate patients about treatment. Additionally, healthcare providers should endeavor to identify and manage the care of appropriate patients who would potentially benefit from rhGH therapy, and should be aware of formulary options. Because many of the patients are children and young adults, adherence to treatment is a concern; patient education on the importance of treatment adherence should be ongoing. Various mechanisms are in place (eg, prior authorization requirements and case manager follow-up) to help ensure that rhGH products are used, and used appropriately.

This publication includes highlights from a roundtable discussion by key opinion leaders (clinicians and managed care professionals) on how managed care policies and clinical guidelines on appropriate use of rhGH translate into real-world practice. Also discussed are the efficacy and safety of rhGH therapy for its pediatric indications, and the role of specialty pharmacies in managing patient access to therapy.

Am J Manag Care. 2013;19(14 suppl):S281-S289In a recent roundtable discussion, the contemporary medical utilization of recombinant human growth hormone (rhGH) and its managed care implications were discussed by a panel of clinicians (Peter A. Lee, MD, PhD, professor of pediatrics, Penn State College of Medicine, Hershey, PA; and Robert Rapaport, MD, Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes, and director, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai/Kravis Children’s Hospital, New York, NY) and managed care professionals (Gary M. Owens, MD, president, Gary Owens Associates, Ocean View, DE; and Jeffrey D. Dunn, PharmD, MBA, senior vice president, VRx, Salt Lake City, UT). The panel was moderated by Robert Navarro, PharmD, clinical professor, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL.

In a climate of healthcare reform, the panel’s discussion was intended to educate and inform managed care practitioners about the importance of balancing treatment accessibility with the responsible administration of rhGH among appropriate patients to optimize clinical outcomes.

Why Is Recombinant Human Growth Hormone Needed?

Treatment with rhGH is used in most cases to increase low levels of growth hormone (GH), an essential pituitary hormone and endogenous growth factor. GH acts directly on growth plates and the liver to stimulate the production of insulin-like growth factor I (IGF-I), which, along with GH, promotes normal body growth.^1-4 The secretion of GH is controlled by many factors, including growth hormone—releasing hormone, somatostatin, and ghrelin.³ Numerous identifiable and unidentified factors can lead to GH deficiency or an attenuation of GH effectiveness, with the net result being a shorter-than-expected stature and possible metabolic imbalances.

Random measurement of GH blood levels is not a reliable means of measuring GH levels because GH is secreted in a pulsatile fashion. A better method of measuring the function of the GH system is to measure serum insulin-like growth factor-1 (IGF-I) and insulin-like growth factor binding protein-3 (IGF-BP3) levels, because their daily levels are less variable.³ GH provocative testing can also be performed by administering agents that stimulate GH secretion (eg, L-dopa, clonidine, arginine, insulin, or glucagon) and measuring serial GH levels (eg, every 15 minutes for 1 hour). Because of the difficulty in differentiating normal and abnormal responses, these tests are not precise. However, their results, along with knowledge of the patient’s height, growth velocity, physical examination, screening test results, and IGF-I and IGF-BP3 levels, can provide enough evidence to diagnose or rule out GH deficiency.³ There is no single test that is diagnostic of GH deficiency, and clinicians are strongly encouraged to collect as much clinical information as feasible before making a diagnosis.

The list of conditions that may be appropriate for rhGH treatment is shown in the Table.^5-16 In clinical practice, pediatric patients with GH deficiency or idiopathic short stature (ISS) make up the majority of the population receiving treatment with rhGH; thus the focus of the roundtable discussion was the use of rhGH in these pediatric patients.¹⁷

In pediatric patients with GH deficiency or ISS, rhGH treatment is used to attain an adult height within the genetically expected range based upon parental heights. Appropriate dosing with rhGH will not allow patients to be taller than their genetic potential; however, rhGH can allow patients to reach their genetically determined adult height.

Because rhGH is an expensive treatment option, and because it is being administered for conditions that may not be life threatening, it can be difficult to balance the needs of the patient with the economic realities of the healthcare system. Payers may focus on the short-term costs of rhGH therapy, as the long-term benefits may be difficult to directly quantify. While the primary benefits are taller stature for age and adult height within the normal range within genetic expectations, there may be other long-term benefits associated with rhGH therapy. For example, a recent study by Chaplin et al (2011) indicated that long-term treatment with rhGH in children with GH deficiency or ISS improved self-esteem as well as stability and mood outcome measures.¹⁸

The Advent of the Specialty Pharmacy

The Orphan Drug Act of 1983 was designed to encourage the development of treatments for rare diseases.¹⁹ Several drugs approved under the Orphan Drug Act are different formulations of rhGH. A 2011 survey of health plan pharmacy directors and medical directors revealed that 92% of plans classified treatment for GH disorders with rhGH as a specialty pharmaceutical.²⁰ In addition, the directors surveyed stated that most rhGH products (83%) required prior authorization (PA). The main reasons for a PA were to verify an indication (60%) or to drive utilization of a preferred product (28%).²⁰

All current rhGH products have the same mechanism of action, but have different FDA-approved indications. Commonly, rhGH products are used interchangeably for the different indications. As previously discussed, pediatric patients with GH deficiency or ISS make up the majority of the population receiving treatment with rhGH.¹⁷ Clinical guidelines for the use of GH in children state that there are no observable differences in the outcomes of therapy among the different products, though there may be patient and parent preferences for particular injection devices.²¹ Health plans may restrict the number of rhGH products to 2 or 3 “preferred” products. This means that specialty pharmacists and clinicians must be familiar with dosing recommendations for the different indications to help ensure adherence to the correct dosing.

Current Indications for Recombinant Human Growth HormoneGrowth hormone deficiency

GH deficiency occurs when the body does not produce enough GH. The etiology may be congenital or acquired, but in the majority of pediatric cases it is unknown (ie, idiopathic). Congenital GH deficiency can be the result of a number of gene mutations involved in the GH-pituitaryhypothalamic axis. Anatomic abnormalities (anencephaly or prosencephaly, optic nerve hypoplasia/septo-optic dysplasia, or vascular malformations) may also lead to GH deficiency. Acquired GH deficiency may result from neoplasms, cysts, inflammatory or infiltrative processes, head trauma, surgery, radiation, or chemotherapy. Even though the preceding is an expansive list, in many cases, the cause of GH deficiency in most children is unknown. Severe GH deficiency is characterized by short stature, slow growth, and delayed skeletal maturation, with reduced secretion of GH in response to provocative stimulation.⁶

Dosing of rhGH is adjusted based upon response, with the goal of allowing pediatric patients to attain their genetically estimated adult height. With the exception of Serostim and Zorbtive, all rhGH medications are approved to treat GH deficiency.^8-13,15

Growth failure due to chronic renal insufficiency

Children with chronic kidney disease may develop severe growth failure. The combination of energy malnutrition, water and electrolyte disturbances, metabolic acidosis, anemia, and hormonal disturbances affecting the somatotropic and gonadotropic hormone axes may all be involved in the etiology of growth failure.⁶

Carefully monitored, timely treatment with rhGH allows these pediatric patients the opportunity to catch up to normal height levels, and a majority of these patients achieve normal adult height.^11,22

HIV/AIDS-related wasting and/or cachexia

HIV/AIDS-related wasting often has a multifactorial etiology, including abnormalities of the GH—IGF-I axis.⁶

Treatment with GH may be of benefit to some patients by counteracting the wasting that is part of the progression of this condition.¹⁴

Idiopathic short stature

By definition, an individual is classified as having ISS if their height is 2.25 standard deviations (or more) below the mean height for a given age, sex, and population group in the absence of systemic, endocrine, nutritional, or chromosomal abnormalities.⁶

Treatment with rhGH increases height and growth velocity in children with ISS.^8,9,11,12

Noonan syndrome

Noonan syndrome is a genetic condition that afflicts 1 in 1000 to 2500 live births.²³ It is characterized by proportionate postnatal short stature (among some but not all), dysmorphic facial features, chest deformities, and congenital heart disease (most commonly pulmonary valve stenosis and hypertrophic cardiomyopathy). Some children may also develop mild mental retardation, cryptorchidism, and clotting disorders. Mutations of the tyrosine phosphatase nonreceptor type 11 gene have been observed in some patients, but how these mutations result in short stature remains unclear.⁶

Treatment with rhGH can increase the patient’s height, but not all patients with Noonan syndrome have short stature and some will reach normal adult height without treatment.¹⁰ As with other indications, better outcomes may occur with earlier initiation and longer duration of GH treatment.³

Prader-Willi syndrome

Prader-Willi syndrome is a rare genetic condition. Those affected have an uncontrollable craving for food that leads to obesity and retarded growth that may result in short stature. Other hormonal balances are also present.⁶

Patients with Prader-Willi syndrome show increased growth rates when given rhGH.^8,12

Short bowel syndrome

Short bowel syndrome is a rare condition in which the patient has lost approximately two-thirds or more of his or her small intestine, usually as a result of trauma, cancer, thrombosis, radiation, or other cause. These patients are generally dependent on parenteral means to receive their nutrition.⁶

Treatment with rhGH is designed to increase transmucosal transport of water, electrolytes, and nutrients and thereby decrease parenteral nutrition requirements.¹⁶ At present, only 1 rhGH product (Zorbtive) is approved for short bowel syndrome. With rhGH therapy, reduced weekly parenteral nutrition requirements have been observed.¹⁶

Small-for-gestational-age infants

Small for gestational age (SGA) occurs in about 3% of infants at birth. By the age of 2 years, most infants will experience sufficient growth to normalize their height, but it is estimated that approximately 8% of SGA infants will remain short throughout childhood and as adults.^3,6

Although most of these pediatric patients do not show evidence of decreased GH secretion, rhGH treatment results in catch-up growth among the 8% who have not caught up spontaneously, commonly to within the normal height range for age, and results in adult height within the normal range for sex.^8-10,12

Short stature homeobox-containing gene deficiency

Short stature homeobox (SHOX)-containing gene deficiency results in short stature. Absence of the SHOX gene may occur with Turner syndrome or as a separate condition. During fetal development, the SHOX gene appears to be involved in the regulation of bone growth, and under normal circumstances, individuals have 2 copies of the SHOX gene.^3,6

Children with SHOX gene deficiency may have short stature and develop mesomelic disproportion of the limbs and Madelung deformity.²⁴ Patients with SHOX gene deficiency do not have low GH levels, but treatment with rhGH can increase their height.⁹

Turner syndrome

Turner syndrome is a disorder in females defined by the complete or partial absence of the second X chromosome.²³ Although most (>90%) of Turner syndrome conceptions are aborted spontaneously, they do account for about 1 in 2000 to 2500 live female births. A common feature of Turner syndrome is severe short stature during both childhood and adulthood. The average height of untreated women with Turner syndrome is 4 feet, 8 inches.^3,6

Treatment with rhGH does increase the height of these patients,^8-12 and most can reach normal height with proper treatment.10 Norditropin is the only rhGH product with an approved dose of up to 67 mcg/kg/day in patients with Turner syndrome.¹⁰

Implementing Utilization Management of Recombinant Human Growth Hormone: Balancing Access and Appropriate Use

There are several guidelines issued by professional societies regarding the diagnosis and management of the various conditions that may benefit from rhGH treatment,^21,25-28 with more in development (eg, MCG, formerly the Milliman Care Guidelines).²⁹ Historically, treatment guidelines published by clinical organizations have heavily emphasized the clinical aspect of optimal disease management. As the sector of specialty pharmacy continues to grow amid a climate of rising healthcare expenditures, managed care authorities have turned to stringent cost-containment strategies that balance rhGH treatment accessibility with responsible administration among the most appropriate patients and treatment candidates to maximize patient outcomes while moderating the use of limited resources. Many payers will limit the number of rhGH products available to 2 or 3 products because of financial arrangements, as all products have the same mechanism of action. In other words, because these drugs are thought to be clinically equivalent, this is an instance in which the indications of a particular medication are not relevant to which drug is preferred by the plan and subsequently prescribed. In a survey of managed care providers, 77% stated that they have preferred products to treat GH disorders.²⁰ Specialty care pharmacists, along with clinicians, need to balance the needs of the patient with the rhGH products available from that patient’s provider.

Patient-centric factors must also be considered to further drive optimal medication utilization. For example, patients who travel frequently will likely benefit from a product that does not require refrigeration. Ease of use may also improve patient adherence.

A 2010 study that assessed the potential time involvement, required weekly administration steps, and utilization costs of daily rhGH administration found that pen devices with a greater time demand were associated with increased opportunity costs and net expenditures.³⁰ Another economic study examined the amount of waste that accumulates when using different products and found that the waste ranged from 14.3% to 19.5% with vial or syringe delivery products compared with 1.0% to 1.1% with pen delivery systems.³¹

Another concern with rhGH treatment is patient adherence. Because most patients taking rhGH are children and young adults, adherence can be an issue for some patients. Studies have observed that poor adherence to rhGH may impede the benefits of treatment.32 Efforts to regularly educate patients on the importance of compliance with treatment should be encouraged by all parties (see sidebars).

Inappropriate use of recombinant human growth hormone

Owing to its anabolic and lipolytic properties, rhGH has also been used inappropriately for athletic performance enhancement and “anti-aging” purposes. In the managed care setting, the inappropriate use of rhGH is generally very rare and most often will lead to reimbursement being discontinued.

If there is some suspicion that the patient is obtaining rhGH for nonmedical use or with the intention of providing the product to another person, medical professionals are encouraged to provide information about the risks associated with the use of rhGH in normal adults. Persons known to take GH (or anabolic steroids) include military personnel, police officers, firefighters, students, body builders, wrestlers, athletes, and anti-aging customers. The inappropriate use cancer, diabetes, hypertension, arthralgia, edema, carpal tunnel— like syndrome, and psuedotumor cerebri.³³

Conclusion

Specialty pharmacies are the most common means of dispensing rhGH. Given that all 9 rhGH products contain the same active molecule and managed care professionals generally consider the products therapeutically interchangeable, to reduce costs, most payers limit the number of preferred rhGH formulations to only a few that cover all of the indications for which rhGH can be prescribed. It can be difficult to balance the needs of the patient with the economic realities of the healthcare system. Payers may focus on the short-term costs of rhGH therapy, as the long-term benefits may be difficult to directly quantify. While the primary benefits are taller stature for age and adult height within the normal range within genetic expectations, there may be other long-term benefits associated with rhGH therapy. Thus, when rhGH treatment is appropriate, it is imperative that specialty pharmacists and clinicians help patients understand the importance of adhering to treatment, and work with payers to choose a treatment regimen that is suitable for the lifestyle of the patient and covered by managed care policies. In other words, specialty care pharmacists and clinicians need to balance the needs of the patient with managed care considerations. In situations where rhGH therapy is not deemed necessary by payers, there are methods in place for clinicians to seek clarification and/or reconsideration. Moving forward, these treatments may come under further scrutiny as payers make efforts to limit the costs while still providing care to those who really need it.Author affiliations: VRx, Salt Lake City, UT (JDD); Division of Pediatric Endocrinology, Department of Pediatrics, Hershey Medical Center, Hershey, PA; Department of Pediatrics, Penn State College of Medicine, Hershey, PA (PAL); Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL (RN); Gary Owens Associates, Ocean View, DE (GMO); Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai/Kravis Children’s Hospital, New York, NY (RR).

Funding source: Funding for the development of this supplement was provided by Novo Nordisk; the opinions expressed are those of the authors and not necessarily those of Novo Nordisk.

Author disclosure: Dr Lee reports board membership with the Pediatric Endocrine Society and employment with Hershey Medical Center and Penn State College of Medicine. Dr Lee also reports serving as a consultant/advisory board member for and receiving honoraria from Novo Nordisk, and serving as a speaker for AbbVie. Dr Navarro reports serving as a consultant for Astra-Zeneca, Forest, Ironwood, Novo Nordisk, and Pfizer. Dr Owens reports serving as a consultant/advisory board member for Eli Lilly and Company, Pfizer, and Teva. Dr Rapaport reports serving as a consultant/advisory board member for EMD Serono, Inc, Novo Nordisk, and Sandoz. Dr Dunn reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship information: Concept and design (PAL, GMO); acquisition of content (PAL, RN); analysis and interpretation of data (JDD, PAL, RR); drafting of the manuscript (JDD, RR); critical revision of the manuscript for important intellectual content (JDD, PAL, RN, GMO, RR); supervision (GMO); and participation in content development (RN).

Address correspondence to: Robert Navarro, PharmD, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, P.O. Box 100496, Gainesville, FL 32610. E-mail: robert@navarropharma.com.

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