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Pediatric growth hormone deficiency (pGHD) affects 1 in 3,500–4,000 children in the United Kingdom and United States. (Guidelines 2010) (Lindsay , et al. 1994) Until recently, treatment required daily injections, but now weekly treatments are available.
Recently approved somatrogon injections, with a prolonged growth hormone (GH) half-life, showed comparable efficacy to daily somatropin injections at 12 months (Deal, et al. 2022) The trial met its primary goal of non-inferiority although the somatrogon group reported a higher percentage of serious and severe events as well as injection site. The statistical significance of these events was not assessed. (Deal, et al. 2022).
Adherence to growth hormone therapy is essential for its success (Maggio, Vergara und Porcelli 2018) . A phase 3 clinical trial found no difference in adherence between weekly and daily treatment. (Deal, et al. 2022)
For conditions like osteoporosis or diabetes weekly administration improves adherence compared to daily dosing. (Iglay, et al. 2015) (Qiao, et al. 2016) However, adherence challenges for children and in particular adolescents are multifactorial and differ from adults. (Maggio, Vergara und Porcelli 2018) (Taddeo, Egedy und Frappier 2008) (Gomez, et al. 2022) Factors improving adherence include supportive family and friends, rapid medication effect, and patients understanding of the condition’s importance. Adherence is negatively affected by therapy complexity, and side effects. (Taddeo, Egedy und Frappier 2008) Specifically for growth hormone treatments, Maggio et al. found highest adherence among 10-13 year olds (∼96%), lower in children under 10 (∼92%) and lowest in those over 14 years (86%) with adherence decreasing over time (Maggio, Vergara und Porcelli 2018)
In recent years, pharmaceutical companies have developed new devices to reduce pain and wastage and enhancing adherence; like the electronic auto-injector device, easypod™, which improves convenience and enables accurate monitoring of treatment adherence for both family and physicians. (Maggio, Vergara und Porcelli 2018) (Alcon Saez, et al. 2022) (Foo, et al. 2019)
In the cost-effectiveness analysis Rivolo et al. compared the use of daily GH (dGH) versus weekly GH for pediatric GHD treatment in Ireland (Rivolo, et al. 2023). The study utilized clinical data from the somatrogon phase 3 clinical trial with 224 prepubertal children with GHD, impaired height and height velocity (HV), and no prior GH treatment. They were treated for 12-month in an open-label, randomized, active-controlled, parallel-group design (Deal, et al. 2022). The study provides valuable economic insights. However, despite its strengths there are concerns about the methodology, the assumptions underlying it, and therefore the reliability of the results.
Clinical data – efficacy and safety
The phase 3 clinical trial comparing somatrogon to somatropin in children aimed for non-inferiority (not superiority) and achieved its primary efficacy endpoint without statistical significance. (Deal, et al. 2022) Rivolo et al. used the 1-year efficacy in HV (difference of 0.33 cm, 95% CI: −0.24, 0.89) as major outcome, extrapolating it until age 18/19. They applied the same yearly reduction in HV standard deviation scores (HVSDS) for the quality of life calculation. These assumptions led to a near adult height difference of 2.85 cm between somatrogon and somatropin patients at treatment end, not supported by any long-term efficacy data.
Surprisingly, the authors did not include differences in adverse events in their analysis due to their low incidence in the somatrogon trial. However, the somatrogon group had higher rates of serious (2.8% vs. 1.7%) and severe events (8.3% vs. 5.2%) injection site pain (39.4% vs. 25.2%) and injection site erythema (8.3% vs. 0%. Temporary discontinuation was also higher with somatrogon (, 2.6% vs. 1.7%).
Safety data is very important for assessing adherence, particularly among adolescents. Excluding it from the analysis is debatable, given that the non-significant efficacy difference in this 12-months non-inferiority trial was used as the main outcome of the analysis and extrapolated for up to age 18/19.
Adherence
The authors used data from Maggio et al. (2018) to link somatropin adherence over time with HV (Maggio, Vergara und Porcelli 2018). However, Maggio et al. showed a correlation between adherence and growth velocity (R= 0.325, p =0.044), but no correlation between final height and adherence (R= −0.067, p = 0.683), with improvement in height mostly related to parental height target (R =0.487, p = 0.002). (Maggio, Vergara und Porcelli 2018) They also showed that adherence decreases with duration of treatment (R= −0.453, p = 0.003), which was used to estimate linear reduction over time for somatropin.
For somatrogon adherence, 4% higher adherence rate for somatrogon at the end of year, the authors relied on expert opinions since “somatrogon adherence is not currently available in the real world”. This contradicts clinical trial data showing 99.4% adherence for somatrogon and 99.7% for somatropin after 1 year. (Deal, et al. 2022).
We agree that adherence in clinical trials may not reflect adherence in real world. However, given the adverse events and temporary discontinuation rates reported in the phase 3 trial, a similar adherence rate should be used in the cost effectiveness analysis.
Utilities
Quality of life were applied HtSDs gains over time with an additional utility gain applied to weekly injection versus daily injection. Both utility values were sourced from studies on adult patients (the latter from a study in adult diabetic patients). In this study Boye et al. estimate the added utility associated with weekly injection to be 0.023, while also reporting a reduction in utility of -0.011 related with injection site reactions (Boye, et al. 2010). However, Rivolo et al did not include the disutility associated with injection site reactions.
We encourage the authors to include adverse events and report the reduced utility associated with these for an unbiased analysis.
Finally, since quality of life was assessed in the phase 3 clinical trial comparing somatragon to somatropin, with data published in 2020 (Brod, Lee und Rasmussen 2020), we recommend utilizing this data to understand the utility values associated with HtSDs and differences between the treatments.
Wastage
The analysis includes wastage estimates, comprising device setting and adherence, to compare costs between treatment options. Other studies have emphasized the importance of wastage with GH therapies and the impact of new devices, like Miniquick pens, in reducing wastage (Pollock, Kappelgaard und Seitz 2015).
However, Rivoli et al.’s simple wastage calculation, based on the average mg/kg/day resulted in higher wastage for Miniquick pens, contradicting existing literature. Therefore, their analysis overlooks advancements in device technology over time and the option to switch pen types for different dosages.
Conclusion
In conclusion, the cost-effectiveness analysis comparing somatrogon treating GHD in children and adolescents may present misleading results regarding benefits, harms, and costs. Assumptions regarding long-term efficacy, safety, and quality of life appear biased in favor of somatrogon, and the wastage analysis overlooks device innovations aimed at improving convenience and adherence. More long-term data is needed to accurately assess the impact of once-a-week treatment on adherence, efficacy, and quality of life. This will allow a thorough evaluation of the treatment's benefits and potential challenges over time.
Transparency
Declaration of funding
No funding was received to produce this article.
Declaration of financial/other relationships
The authors received compensation from Merck KGaA, a manufacturer of somatropin. We affirm that this compensation did not influence the content of the submitted letter, which is solely based on our professional expertise and research findings.
AESARA the employer has received compensation from Merck for consulting services. Our work involves conducting research in Health Economics and Outcomes Research (HEOR) and providing expert analyses.
Acknowledgements
None stated.
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