Developing a Rational Approach for the Use of Growth Hormone in Nonpediatric Patients

The development of a manageable medicalpolicy that ensures appropriateuse of recombinant human growthhormone (hGH) has been elusive. Sortingthrough the misconceptions, fads, cosmeticuses, and economics of this therapy is difficulteven for the most sophisticated medicalpolicy or pharmacy and therapeutics committees.An effective policy enables thequick identification of appropriate patientsusing minimal resources. A poorly structuredpolicy can create a hostile environmentin which extra resources are spent onmany members in an effort to prevent inappropriateuse by a few members. The followingarticle applies the principles ofethics, expert scientific input, and an appreciationof the economic impact eachapproved treatment regimen will place onthe healthcare system. The roundtable facultyfunctioned as a medical policy committee,and the sample policies are presentedto stimulate discussions within health plansto assess current growth hormone (GH)policies and challenge the standard of carewhile respecting the need to manage hGHproactively.

Medical Policy for Adults

Defining the appropriate adult hGHpatient population is controversial. Based onthe US Food and Drug Administration (FDA)labeling, published studies, and expert opinions,the panel stratified the potential usesinto 4 categories:

• Approved: FDA labeled indication
• Accepted: Use supported by numerous clinical trials published in peer-reviewedjournals; widely accepted use within the endocrinology community
• Possible: Medical rationale for use (lesspublished support) is that it improves outcomes
• No Medical Rationale: Uses described incase reports or fad uses; no clinical trialsavailable to support improvement in clinical outcomes

The objective of the committee was toprioritize uses that have documented clinicalbenefit in reducing morbidity and/ormortality. By employing the above criteria,the cosmetic uses of hGH were placed in thelowest categories. Table 1 summarizes thecurrent uses by category.

The uses in the approved and acceptedcategories are routinely incorporated inmany medical policies of managed careorganizations (MCOs). These categories representthe core of an inclusive medical policy.However, some health plans have chosento limit their definition of appropriate use toa subset of these clinical uses based on theirown review of the literature and the recommendationsof local endocrinologists. Thevariation in covered uses leads to confusionwithin the provider community and mayresult in additional time for the plan andendocrinologist to verify plan coverage andnavigate the prior authorization process. Inadult patients, accepted hGH therapyincluded treatment of growth hormone deficiency(GHD) resulting from pituitary disease,hypothalamic disease, irradiation ortrauma to the pituitary, and reconfirmedchildhood GHD. In addition, GH replacementtherapy for Turner syndrome, chronic renalfailure, Prader-Willi syndrome, acquiredimmune deficiency syndrome (AIDS) wasting,and short-bowel syndrome are supportedby significant clinical data. On theother hand, a host of other conditions wereconsidered inappropriate therapy, includingfibromyalgia, chronic fatigue syndrome, andobesity, among others. The treatment ofidiopathic short stature and isolated GHDwere considered gray areas–areas in whichtreatment would be possible, but would needto be considered on a case-by-case basis.

The diagnostic workup requirements toestablish GHD, as defined by medical policy,are often a source of considerable confusionand frustration. Documentation of GHD canbe convoluted based on the patient presentationand the sensitivity of the test specifiedin the policy. A previous article in this supplementdiscussed the benefits and challengesassociated with each test. Often MCOmedical policies specify the need for 2 testsor do not specify which tests are preferred.One health plan reported a pattern of someendocrinologists to require clonidine andlevodopa for their policy. Because of lowspecificity of these tests, a number ofpatients with questionable criteria havebeen approved. The concept of using a stringenttest (ie, a test that payers and providerscan rely on) is emerging. The insulin tolerancetest (ITT) and/or the arginine GHreleasinghormone (GHRH) tests currentlyfit this description. This case illustrates thatonly defining when to test and the number oftests in a medical policy is not sufficient; alist of which tests are acceptable for a diagnosisneeds to be included. Follow-up monitoringrequirements can also be confusing.Health plans waste resources because testingrequirements are not necessary, inappropriate,or place the member at undo risk.

Clearly, there is a need to develop evidence-based guidelines for the use of hGH inadults to ensure that the appropriatepatients are tested for GHD and receive hGHtherapy. The Figure displays an algorithmfor the assessment and treatment of GHD inadults, based on the workshop discussionand the clinical evidence presented in thissupplement.

When this algorithm is coupled with theuse categories listed in Table 1 and streamlinedtesting requirements, a degree of clarityemerges to provide an objectiveassessment of each potential GH patient.Limiting tests to only those with the greatestspecificity and removing testing requirements in those patients with the highestprobability of disease quickly identifiesappropriate patients. As with all algorithms,flexibility to manage specific situations needsto be included to accommodate patients withcontraindications to specific tests or an atypicalGHD presentation. Obtaining an insulinlikegrowth factor 1 (IGF-1) level at baselineis also recommended prior to starting therapy.Since IGF-1 levels are an effectivemethod to monitor the response to hGHtherapy, this baseline level provides a monitoringmechanism that is reliable and costeffective.

Managing the Transitional Patient

The transitional population is uniquebecause persons of the same age may beclassified as pediatric, adult, or transitional.The definition of a transitional patientincludes those who received hGH as a childfor a pediatric indication and those whosehGH therapy was stopped upon reachingepiphyses fusion. This definition excludespatients diagnosed with GHD later in life andrecognizes these individuals as adults.Childhood-onset GHD because of anatomicaldamage to the pituitary, irradiation, ortrauma, or the presence of panhypopituitarismis sufficient to consider continuinghGH therapy into adulthood (Table 2).However, the panel could not reach a consensusas to whether isolated GHD, longtermrenal insufficiency, or the presence ofTurner syndrome or Prader-Willi syndromewere compelling indications for the use ofhGH in transitional patients. Other grayareas for the use of hGH in transitionalpatients include the treatment of shortbowelsyndrome and AIDS wasting.

The primary issue is determining whichindividuals with known GHD in childhoodshould be tested for ongoing treatment. As inthe adult population, if a patient exhibits atleast 3 pituitary hormone deficiencies, thenprovocation testing would not be clinicallynecessary; however, magnetic resonanceimaging (MRI) and IGF-1 data should beobtained to establish baseline information ofthese patients. If only 1 or 2 pituitary deficienciesare present, provocation testing iswarranted, preferably an ITT or arginine-GHRH. Then, an MRI should be performedas part of the workup for anterior pituitarydisease, and an IGF-1 level should beobtained for baseline purposes.

Transitional patients already have a significantrisk for osteopenia, an increase ofvisceral fat, and decreased muscle mass.Consequently, they exhibit many of the featuresof adult GHD. Indeed, the metaboliceffects of GHD are thought to be similar intransitional and adult patients with GHD.Patients with Prader-Willi syndrome andTurner syndrome, approved indications forhGH until epiphyses fusion, should receivean evaluation of need before approval tocontinue for the transitional patients.Duration of therapy for transitional patientsis not clear. Periodic testing using IGF-1 issuggested to determine the continued needfor hGH therapy.

Conclusion

Developing an evidence-based hGH medicalpolicy for nonpediatric patients is a complexprocess. In addition, medical andprescription policies are never static. Thereis a continual need to balance evolving scientificinformation and an ever-increasingrequirement to manage increasing medicalcosts. Practice patterns vary across the country,and an assessment of the plan's providernetwork prescribing practices is a startingpoint. Understanding the patient with GHdeficiency that is routinely rejected providesan initial focus for policy revision or providereducation. Overly restrictive policies mayactually increase the long-term cost to thehealth plan as the metabolic complications ofGHD develop. Broad policies, on the otherhand, may yield lower than expected clinicaloutcomes, resulting in an increased cost tothe plan with no measurable improvement inclinical outcomes.

Because of emerging medical evidencehighlighting the deleterious impact of GHDover a lifetime, payers and providers arebeginning to recognize the importance ofhGH therapy not only in the well-establishedpediatric setting but also in the treatment oftransitional patients and adults. Transitionalpatients and adults with GHD are at anincreased risk for metabolic disturbancesthat can increase morbidity and mortalityand, in turn, long-term health plan costs. Asthe evidence is examined, the long-termbenefit of this therapy may be the resolutionof metabolic complications and an improvementin the quality of life for members withGHD. It is paramount for providers and payersto agree on which transitional and adultpatients are appropriate for coverage andtreatment. A consensus is starting to emergeamong payers and providers on which transitionaland adult patients should be testedfor GHD, which provocation tests are mostappropriate, and who ultimately shouldreceive hGH therapy.

A secondary consideration should begiven to the approval process used by healthplans. Various treatment approval forms areused by MCOs and specialty pharmacies todocument an appropriate diagnosis. Some ofthese tools could actually limit the presentationof the clinical situation or requireunnecessary tests resulting in less-than-optimalMCO decisions.

In addition, gaps exist in providers'knowledge of health plan reimbursementpolicies for hGH therapy. To overcome theseimpediments to quality cost-effective care,an efficient means for clear and consistentcommunication between payers and providersis clearly needed. Ideally, evidence-basedguidelines should drive the use of hGHin transitional patients and adults to achievethe goal of balancing ethical and compassionatecare for these patients with themounting need to restrain payer and memberprescription costs. A policy based onFDA-approved and extensively documenteduses may appear adequate but, in reality,may deprive therapy for individuals with anatypical presentation of GHD. The processmust include a mechanism for a physicianspecialist to exercise professional judgmentbecause the diagnostic process is not alwaysclearly defined. An open dialogue betweenmedical directors and endocrinologistsforms the foundation for a successful policythat meets the needs of the GH populationand respects the financial burden this treatmentplaces on the MCO. The resulting policywill clearly define appropriate patientsand minimize provider, payer, and memberfrustration.

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