Persistence With Growth Hormone Therapy in Pediatric Patients | Page 3

Published Online: February 19, 2014
Bradley S. Miller, MD, PhD; Deborah Rotenstein, MD; Larry C. Deeb, MD; John Germak, MD; and Tami Wisniewski, MPH
In the current study, patients who were most persistent with GH therapy (ie, those who reached the category of final height achieved) attained a statistically significant increase in linear growth with a final HSDS of –0.6 compared with –2.1 at baseline. This result is consistent with increasing linear growth patterns to near-adult height in prepubertal children with GHD or MPHD from other large patient registry databases.7,18 Current analyses of data from the ANSWER Program showed that patients who reached final height achieved were the most persistent with GH therapy and achieved a corrected HSDS of −0.3 compared with a baseline corrected HSDS of −1.8; that indicates that these patients, on average, had reached an adult height consistent with their genetic height potential. This result compares favorably with published target adult or genetic HSDS values within normal standards (±0.5) for North American adults and children.13,19 The fact that children in the final-height-achieved group had the slowest HV in the period prior to discontinuation but had the highest percentage in the normal adult height range also provides evidence that final height achieved was the primary reason for discontinuing therapy. Although MPHD patients in the final-height-achieved group had a longer duration of treatment, overall persistence was similar between patients with IGHD or MPHD, regardless of the reason for discontinuation.

The second-most common reason for patients discontinuing GH therapy was insurance issues; patients in this category were less persistent with GH treatment. Although patients discontinuing GH for insurance issues did not achieve height outcomes comparable to those of patients in the other categories, a shorter duration of treatment in this cohort may be a factor in their decreased height outcomes. However, even at the same duration of treatment at year 3, children in the final-height-achieved group attained greater HSDS and corrected HSDS than children in insurance-issues group and the other group; the final-height-achieved group also had the highest percentage of patients reaching an HSDS greater than −2. These results could imply that patients in the insurance-issues and other categories may already have had some adherence challenges related to insurance or other reasons. We were unable to evaluate the long-term effects of interrupted GH therapy in this cohort due to a lack of follow-up data once these patients were discontinued from the registry.

Additionally, although the baseline HSDSs for groups characterized by reason for discontinuation were comparable, there did appear to be differences in the mean age and proportion of males in the insurance-issues group compared with the other 3 groups. For these reasons, it is difficult to conclude that ultimate adult height values would differ among these groups. However, given the younger baseline age and bone age of the insurance-issues group, it might be expected that these patients would have shown a better growth response, which was not the case either at the last visit or after 3 years of treatment.

With pediatric patients it is difficult to conduct appropriately powered clinical studies with rigorous objective measures to assess the effect of adherence or persistence with GH therapy on long-term height outcomes. Studies of the effect of adherence and persistence on growth outcomes among patients with IGHD or MPHD are difficult because databases that monitor GH utilization in this population may include different dosing regimens (ie, weight based, fixed, pubertal, not following US Food and Drug Administration dosing guidelines) or fail to record data (ie, auxologic, dosing, adherence, reasons for discontinuation, gaps in therapy) in registry or claims databases. Infrequent patient visits to the specialist can also lead to inadequate data entry related to adherence and persistence. Such data would enable more effective analyses of large sample sizes and calculations of adherence and persistence using standardized methods.8 In the present study, we were limited to analyzing patient- and physician-reported data as a means to determine rates of persistence with GH treatment in pediatric patients with IGHD or MPHD.

Other factors correlating with the level of adherence to GH therapy are patient motivation,11,17 psychological/emotional problems,11,17 social and daily living problems,11,17 patient/caregiver understanding of the consequences of noncompliance with prescribed treatment,20,21 appropriate training of patients and caregivers in administration of GH,21 family socioeconomic status and parental educational level,22 choice of drug-delivery device,23,24 and technical- handling issues with the delivery device.5,9,10,17,25 In addition, it is likely that healthcare system factors impact adherence and persistence (eg, insurance prior authorization and recertification processes, medication-delivery issues, access to pediatric specialists). Increasing recognition of the factors that affect adherence and persistence with GH treatment has led to renewed interest in the development of clinical practice strategies that could help children and their families overcome these challenges.17 Improved communication between providers, insurance carriers, and specialty pharmacies could raise provider awareness of issues that impact patient adherence and persistence, and allow providers to address these barriers.

Although recent reviews have focused on nonadherence as a major factor that can influence the outcome of GH therapy,9-13,17 results from our study suggest that GH therapy is also often discontinued because of insurance issues that are independent of personal or medical reasons. The effects of insurance-mandated brand switches during the course of pediatric GH treatment are poorly understood, but a recent survey of physicians found that such switches may contribute to decreased adherence and increased patient anxiety.26 Switching to a different GH product may lead to worse growth outcomes due to the possibility of dosing errors and patient confusion, new potential for immunogenicity, and adverse effects such as injection site pain or burning.26

Changes in insurance coverage for GH therapy can be due to a change of carriers, an insurance company switch to approval through a pharmacy benefit manager, a change in the insurance criteria for GH approval, a retrospective review of previously approved cases with new approval criteria, or a change in insurance criteria for stopping therapy. When an insurance carrier changes, a new coverage application is required and the child may no longer qualify based on the new carrier’s coverage criteria. If an insurance company rejects a patient’s treatment, physicians and family members may then need to become involved in a time-consuming appeals process; this may cause a lack of persistence or early termination of therapy, leading to worse growth outcomes.

A lack of follow-up data and a lack of height-outcomes comparisons for patients who discontinued therapy with somatropin injection after receiving GH treatment for the same length of time are limitations of this analysis. Individuals may have continued therapy on another GH drug and achieved comparable height outcomes; currently, however, there is no way to track patients who are enrolled in different manufacturer-based registries. Future research is needed to explore the impact of therapy discontinuation on long-term height outcomes in children treated with GH. Improving payer processes so that GH therapy will continue to be approved, while minimizing mandated switches to a different GH product, may help ensure adherence and persistence with GH therapy and optimize growth outcomes.26 Improvements in the approval and formulary-change processes could include notifying patients and providers about impending formulary changes and changes in coverage criteria, educating patients and families about the importance of persistence in order to achieve ultimate height outcomes, developing industrywide insurance guidelines for the approval and continuation of GH therapy, and creating similar application forms and appeals processes among insurers.

Take-Away Points

This analysis of the ANSWER Program registry—an observational, noninterventional study—provides reasons for lack of persistence with growth hormone (GH) therapy and the effect on outcome in pediatric patients with GH deficiency (GHD), including those with idiopathic GHD and multiple pituitary hormone deficiency.
  •  A change in insurance coverage was the second-most common reason for discontinuation of GH therapy. 

  • Patients who discontinued therapy because of insurance issues were least persistent with therapy. 

  • Pediatric patients discontinuing therapy for any reason other than achievement of final height had worse height outcomes, consistent with a shorter duration of treatment.
Author Affiliations: From Department of Pediatrics (BSM), University of Minnesota, Minneapolis, MN; Pediatric Alliance (DR), Pittsburgh, PA; Department of Medical Humanities and Social Sciences, Florida State University (LCD), Tallahassee, FL; Novo Nordisk Inc (JG, TW), Princeton, NJ.

Funding Source: Novo Nordisk Inc, Princeton, NJ.

Author Disclosures: Dr Bradley reports attending a paid scientific advisory board meeting at Novo Nordisk, receiving phase 4 safety and efficacy registry grants from Novo Nordisk, and presenting data from this paper at an Academy of Managed Care Pharmacies meeting in 2011; Dr Rotenstein reports receiving payment from Novo Nordisk for speaking engagements. Ms Wisniewski and Dr Germak report employment at Novo Nordisk and ownership of Novo Nordisk stock.

Authorship Information: Concept and design (BSM, LCD, DR, TW, JG); acquisition of data (BSM, JG); analysis and interpretation of data (BSM, LCD, DR, TW, JG); drafting of the manuscript (BSM, LCD, DR, TW, JG); critical revision of the manuscript for important intellectual content (BSM, LCD, JG); statistical analysis (JG); provision of study materials or patients (BSM).

Address correspondence to: Bradley S. Miller, MD, PhD, Department of Pediatrics, University of Minnesota Amplatz Children’s Hospital, MMC 8952D, E Bldg MB671, 2450 Riverside Ave, Minneapolis, MN 55454. E-mail: mille685@umn.edu.
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