Introduction: Although there are some recommendations in the literature on the assessments that should be performed in children on recombinant human growth hormone (rhGH) therapy, the level of consensus on these measurements is not clear. The objective of the current study was to identify the minimum dataset (MDS) that could be measured in a routine clinical setting across the world, aiming to minimise burden on clinicians and improve quality of data collection. Methods: This study was undertaken by the growth hormone (GH) scientific study group in GloBE-Reg, a new project that has developed a common registry platform that can support long-term safety and effectiveness studies of drugs. Twelve clinical experts from 7 international endocrine organisations identified by the GloBE-Reg Steering Committee, 2 patient representatives, and representatives from 2 pharmaceutical companies with previous GH registry expertise collaborated to develop this recommendation. A comprehensive list of data fields routinely collected by each of the clinical and industry experts for children with growth hormone deficiency (GHD) was compiled. Each member was asked to determine the: (1) importance of the data field and (2) ease of data collection. Data fields that achieved 70% consensus in terms of importance qualified for the MDS, provided <50% deemed the item difficult to collect. Results: A total of 246 items were compiled and 27 were removed due to redundancies, with 219 items subjected to the grading system. Of the 219 items, 111 achieved at least 70% consensus as important data to collect when monitoring children with GHD on rhGH treatment. Sixty-nine of the 219 items were deemed easy to collect. Combining the criteria of importance and ease of data collection, 63 met the criteria for the MDS. Several anomalies to the MDS rule were identified and highlighted for discussion, including whether the patients were involved in current or previous clinical trials, need for HbA1c monitoring, other past medical history, and adherence, enabling formulation of the final MDS recommendation of 43 items; 20 to be completed once, 14 every 6 months, and 9 every 12 months. Conclusion: In summary, this exercise performed through the GloBE-Reg initiative provides a recommendation of the MDS requirement, collected through real-world data, for the monitoring of safety and effectiveness of rhGH in children with GHD, both for the current daily preparations and the newer long-acting GH.

Growth hormone deficiency (GHD) due to an inadequate production or secretion of growth hormone (GH) has a reported prevalence of about 1 in 4,000 in children [1, 2], and the annual incidence rate for childhood-onset GHD is about 1 in 20,000 of the general population [3]. GH replacement therapy is highly effective for promoting growth in children with GHD. Although the first subject was treated with GH in the 1950s, therapy in children with GHD only became widespread after the advent of recombinant human growth hormone (rhGH) in 1985 [4].

With greater supply and use of daily rhGH in GHD, it has become clear that there is a wide variability in response to rhGH with a greater growth response in those with more profound GHD [5]. Over the last few decades, it has also become clear that GH has effects on a wide range of target organs [4, 6], and although daily rhGH therapy for GHD is a remarkably safe drug in childhood [7], concerns remain about the long-term safety profile of rhGH therapy in certain subgroups has been raised [4, 7, 8]. Given that some studies have raised the possibility of increased risk of cancer, cardiovascular morbidity, and impaired glucose homoeostasis, there is a sufficiently strong case for continued long-term surveillance [9, 10]. Another important reason for the need for ongoing surveillance is that rhGH has only been available for less than 40 years, and it may still be too early for a conclusive assessment of long-term safety. Furthermore, globally, rhGH is still a relatively new drug and there are new forms of rhGH, such as biosimilars and long-acting GH (LAGH), which are now available.

An assessment of the long-term safety of rhGH therapy has primarily relied on the use of pharmaceutical industry-initiated post-marketing surveillance registries, linked national datasets in individual countries, or by pooling these linked national datasets from individual countries [9]. The industry registries are usually expensive and unlikely to serve as tools for surveillance over the longer term especially as they lack suitable comparators and controls. On the other hand, studies that rely on linkage of routinely collected health care datasets pose their own challenges, as several countries do not have the resources or legislation that support this activity, and linked datasets can suffer from their own selection biases [11].

A major common limitation of all these approaches has been the lack of standardisation of data that were collected during the period of rhGH therapy in childhood. It is possible that this may have occurred due to a lack of consensus on the clinical outcomes that should be assessed during childhood rhGH therapy to assess its effectiveness and safety. These issues of inconsistency and outcome-reporting bias can be reduced with the development and application of an agreed standardised set of outcomes, known as core outcome sets [12]. A core outcome set relies on measures that can be simply and routinely collected in the real-world clinical setting so that they can be undertaken over the long term. For instance, if the annual change in height SDS is an agreed core outcome for rhGH therapy in GHD [5, 13], then sex, date of birth, dates of measurement, heights, and height reference standards would be the required minimum dataset (MDS). Although there are some recommendations in the literature on the assessments that should be performed in children on rhGH therapy [14‒16], the level of consensus on these measurements and their frequency for routine clinical practice is unclear.

The aim of the current study was to identify the MDS that could be measured in a routine clinical setting across the world. This exercise was undertaken through the involvement of a group of experts who form the GH scientific study group (SSG) in GloBE-Reg, a new project that has developed a common registry platform in close collaboration with clinicians, patients, and industry, which can support long-term safety and effectiveness studies for drugs that require such surveillance in children.

Twelve clinical experts from 7 international endocrine organisations identified by the GloBE-Reg Steering Committee, 2 patient representatives, and representatives from 2 pharmaceutical companies with previous GH registry expertise collaborated to develop this recommendation. All participants signed a conflict of interest declaration, and the exercise was supported by the GloBE-Reg SSG Development Grant. A comprehensive list of data fields routinely collected by each of the clinicians during routine clinical monitoring for children with GHD and data fields collected in previous post-marketing surveillance registries were compiled. Each participant was asked to determine the: (1) importance of the data field and (2) ease of data collection as part of routine clinical practice, using a traffic light grading system. The importance of the data field referred to the significance of the information to enable good clinical care of patient in terms of establishing the diagnosis, assessing efficacy, and monitoring for adverse events. The ease of data collection was based on the participants’ experience in how readily available the information was in routine clinical settings. Green represented a highly important and easy-to-collect data field, while red represented a field that was least important and most difficult to collect. Data fields that achieved 70% or greater consensus in terms of importance qualified for the MDS, provided that less than 50% of the respondents deemed the item difficult to collect. Preparations for the development of the finalised MDS took place over 4 months, including two teleconference meetings between the study group members. A final consensus meeting was held in Rome, just before the 60th Annual European Society of Paediatric Endocrinology (ESPE) meeting, where propositions and recommendations were considered by the participants before the finalised MDS recommendation was developed. The frequency of data collection was generated based on discussion and group consensus.

The comprehensive list of data fields compiled from all the sources generated a total of 246 items. Only 219 items were subjected to the grading system, as 27 items were removed due to redundancies. Of the 219 items graded, 111 items achieved over 70% consensus as important data to collect when monitoring children with GHD on rhGH treatment, 55 items achieved 50–70% consensus, and 53 items achieved less than 50% consensus as being important to collect (Fig. 1). Sixty-nine of the 219 items were deemed easy to collect. Combining the criteria of importance and ease of data collection, 63 met the criteria for the MDS. Of the 63 items, 7 items were designated as part of core data and some were merged into similar headings as indicated in Figure 2, resulting in a total of 39 items.

Fig. 1.

Consensus grading for the criteria of importance. Bold items indicate those fields that fulfilled the minimum dataset (MDS) criteria for both importance and ease of collection. *Indicate fields where there was a discrepancy between the level of consensus for importance and ease of collection. aCalculated parameters; bmerged into “associated conditions”; cmerged into “GH stimulation type”; dreplaced by “date of first start of GH therapy”; emerged into “gonadotropins” with free text; fmerged into “adverse events”; gmerged into respective treatment doses under therapy; honly 3 of 6 items required for each gender; ^part of core data.

Fig. 1.

Consensus grading for the criteria of importance. Bold items indicate those fields that fulfilled the minimum dataset (MDS) criteria for both importance and ease of collection. *Indicate fields where there was a discrepancy between the level of consensus for importance and ease of collection. aCalculated parameters; bmerged into “associated conditions”; cmerged into “GH stimulation type”; dreplaced by “date of first start of GH therapy”; emerged into “gonadotropins” with free text; fmerged into “adverse events”; gmerged into respective treatment doses under therapy; honly 3 of 6 items required for each gender; ^part of core data.

Close modal
Fig. 2.

Consort diagram from the initial comprehensive list to the final minimum dataset (MDS).

Fig. 2.

Consort diagram from the initial comprehensive list to the final minimum dataset (MDS).

Close modal

There were three items which reached the threshold for being identified as important to collect but did not reach the threshold for ease of collection. These included HbA1c, other past medical history, and adherence. All participants agreed that HbA1c was important to collect for patients on long-acting rhGH but not daily rhGH, and in that situation, would be justifiable to be performed as part of routine clinical practice. Information on past medical history was considered important, but 62.5% felt that it was difficult to collect a comprehensive and directed past medical history. Similarly, although 90% of the participants agreed that information on adherence was very important to be collected, it was deemed difficult to collect by the majority (62.5%). One item, participation in previous or current trials, was considered important by 67% of the participants and difficult to collect by 87.5%.

All four items were examined on their individual merits and discussed by the study group with the overall consensus for inclusion in the MDS with the information on past medical history merged with information on previous surgery and information specifically on type 1 diabetes, under the heading of associated conditions, enabling formulation of the final MDS recommendation of 43 items (Table 1). Of these 43 items, 20 would only need to be completed once, 9 would not need to be completed more frequently than every 12 months. The remaining 14 could be completed at every visit; however, for the purpose of a registry, collecting information on long-term safety and effectiveness would not be required any more frequently than every 6 months while on therapy.

Table 1.

Finalised minimum dataset (MDS) for the GloBE-Reg GH therapy module for GH deficiency

DiagnosisTherapyClinician-reported outcomesAdverse events
Patient characteristics GH Anthropometry Has the patient experienced any discomfort (adverse events) which by your clinical judgement is related or possibly related to the drug? 
Gestational age Date of start of first GH therapy Height 
Delivery mode Date of start of current GH therapy Weight 
Birth weight GH dose Pubertal status 
Paternal height Adherence Genitalia stage (Tanner) 
Maternal height Date of end of GH therapy Pubic hair (Tanner) 
Associated conditions Reason for stopping therapy Testicular volume (mL) 
Past medical history Reinitiation of GH after FAH Breast stage (Tanner) 
Neoplasia or cranial tumour Other medications Menarche status 
Cranial or total body irradiation Thyroid hormone Biochemistry 
Chemotherapy Glucocorticoid IGF-1 
Traumatic brain injury Oestrogen TSH  
Pituitary or cranial surgery Testosterone Free T4  
Participation in other clinical trials Gonadotropins HbA1c  
Biochemistry/imaging at diagnosis DDAVP Imaging  
IGF-1 result  Bone age  
Type of GH stimulation test    
Peak GH test 1    
Peak GH test 2    
Priming test 1    
Priming test 2    
TSH    
Free T4    
HbA1c    
Bone age    
MRI pituitary    
DiagnosisTherapyClinician-reported outcomesAdverse events
Patient characteristics GH Anthropometry Has the patient experienced any discomfort (adverse events) which by your clinical judgement is related or possibly related to the drug? 
Gestational age Date of start of first GH therapy Height 
Delivery mode Date of start of current GH therapy Weight 
Birth weight GH dose Pubertal status 
Paternal height Adherence Genitalia stage (Tanner) 
Maternal height Date of end of GH therapy Pubic hair (Tanner) 
Associated conditions Reason for stopping therapy Testicular volume (mL) 
Past medical history Reinitiation of GH after FAH Breast stage (Tanner) 
Neoplasia or cranial tumour Other medications Menarche status 
Cranial or total body irradiation Thyroid hormone Biochemistry 
Chemotherapy Glucocorticoid IGF-1 
Traumatic brain injury Oestrogen TSH  
Pituitary or cranial surgery Testosterone Free T4  
Participation in other clinical trials Gonadotropins HbA1c  
Biochemistry/imaging at diagnosis DDAVP Imaging  
IGF-1 result  Bone age  
Type of GH stimulation test    
Peak GH test 1    
Peak GH test 2    
Priming test 1    
Priming test 2    
TSH    
Free T4    
HbA1c    
Bone age    
MRI pituitary    

This exercise has demonstrated the wide variety as well as the level of consensus that exists within an international expert group in the field of rhGH therapy and has led to the development of an MDS which can guide clinicians towards routine, standardised collection of data as part of routine clinical practice. The MDS that has been developed should be sufficient to capture the crucial safety and efficacy information on the use of rhGH in children with GHD, while minimising the burden on clinicians, particularly in terms of time and effort of data entry. By restricting this MDS to the absolute minimum, it is also expected that the quality of data that are collected will be greater. By defining the MDS, the GloBE-Reg project also aims to encourage all registries to collect the same MDS, thus facilitating the sharing and exchange of data between different data sources over the longer term. The current exercise of developing a MDS for GHD has allowed the GloBE-Reg team to develop a process that can be applied to the monitoring of rhGH therapy for other indications such as small for gestational age, Prader-Willi syndrome, Turner syndrome, Noonan syndrome, skeletal dysplasia, and adult GHD. While the MDS will have several similarities to the one created for GHD, there will be a need for further involvement of experts in these specific areas.

Given that GHD was the first indication for daily rhGH therapy and knowledge of therapy outcomes has existed for over 4 decades, the exercise of creating an MDS was not particularly challenging. However, the exercise also revealed that it is possible that the MDS may vary depending on whether the rhGH is a daily or weekly preparation. For instance, daily rhGH therapy in GHD may be associated with reduced insulin sensitivity but does not lead to impaired glucose homoeostasis [17‒19]. However, the various newer LAGH preparations exhibit different pharmacokinetics and pharmacodynamics [20], necessitating potentially different safety considerations regarding insulin resistance [21], necessitating HbA1c monitoring [7]. To date, phase 3 studies of LAGH have shown comparable metabolic profile in fasting blood glucose concentrations, 2-h postprandial blood glucose, HbAlc, total cholesterol, triglycerides, and HOMA-IR to daily rhGH [22, 23], with all parameters being within the normal range, although the longer term metabolic consequences of LAGH remain unknown, hence the importance of collecting this information.

Information on past medical history and adherence, although can be challenging to systematically capture, may have implications on the safety and efficacy of rhGH therapy, respectively. Treatment with rhGH can adversely affect the blood glucose control of children with type 1 diabetes or growth response in those with ADHD on stimulant medication [24]. In some patients with a propensity to develop type 2 diabetes, the use of rhGH can increase their lifetime risk of developing glucose intolerance or frank diabetes [25]. Adherence to therapy is an important variable but is difficult to assess reliably [26‒29], and there is little consensus on how to report it [30]. A systematic review by Fisher and Acerini estimated the prevalence of non-adherence in children to vary from 5 to 82%, depending on the methods and definitions used [31]. Standardisation of the collection of this data field in routine clinical practice and related databases and registries will provide a more comprehensive assessment of effectiveness and burden of therapy with rhGH in children.

Knowledge of whether a patient was in a trial, previous or existing, was initially considered not to be important but retained in the MDS on further discussion. Knowing that a patient may be in a trial allows a future investigator to know that there may be further datasets that exist for a patient. A recently published study of a clinical cancer trial showed that 25% of participants had previously taken part in other research studies [32]. Co-enrolment of patients in studies, trials, and pharmacovigilance studies maximises opportunities for patients with rare conditions to participate in, and benefit from, clinical research but pose their own challenges [33, 34]. In the field of GHD, a patient with multiple pituitary hormone deficiency may have previously been in one or more efficacy trials of rhGH or may be on a concurrent trial of another form of endocrine replacement therapy. As such, the study group decided that the information on a patient’s participation in other clinical trial, whether current or previous, should be collected, without prejudice for or against co-enrolment. This will also align with one of the key functionalities of international registries, which is to facilitate research studies at participating centres as well as collaboration between centres globally.

While there was a high level of consensus on the collection of quality of life (QoL) measures among the study group, there was uncertainty on the tools that should be used in routine clinical practice for this purpose. Interest in health-related QoL measures has increased over the last 3 decades [35], and it is possible that their routine use in the clinical setting may improve communication and management [36]. In paediatrics and paediatric endocrinology, there is scarce experience of the routine use of patient-/parent-reported outcome measures in the clinical setting [37]. However, the EQ-5D tool is one of the most popular generic instruments [38, 39] that have been used. There are also other more specific tools that may be appropriate for rhGH therapy, such as the original 22-item Quality of Life in Short Stature Youth (QoLISSY) instrument [40], the revised short form of QoLISSY [41], and the Life Interference Questionnaire for GHD (LIQ-GHD) [42]. However, their use as well as utility in routine clinical practice requires further exploration.

Lastly, it was clear from the exercise that a large proportion of measures, such as dual X-ray absorptiometry, for instance, that were considered to be important to collect by the expert group were not considered to be easy to collect in routine clinical practice. The study did not ascertain the underlying hurdles, but it is possible that some may relate to the burden of routinely performing that assessment or a lack of clarity on the timing or frequency of that assessment within the context of the ongoing management of the child with GH deficiency who is receiving rhGH. The MDS that has been developed does not preclude a centre from undertaking a more comprehensive assessment if it is clinically justified and the resources are available.

In summary, this study performed through the GloBE-Reg initiative provides a recommendation of the MDS requirement, collected through real-world data, for the monitoring of safety and effectiveness of rhGH in children with GHD, both for the current daily preparations and the newer LAGH. Further work needs to be undertaken to assess whether this MDS is sufficient to assess the core outcomes that are considered important for rhGH therapy in GHD. Furthermore, similar exercises need to be performed for the other indications of rhGH therapy.

Ethical approval is not required for this study in accordance with the UK Policy Framework for Health and Social Care Research guidance. The study was a consensus recommendation from the GloBE-Reg GH scientific study group members for which data fields to be collected in the registry database, and did not involve patient or patient data. The GloBE-Reg registry database itself has ethics approval from the West of Scotland Research Ethics Committee (REC reference 22/WS/0074, IRAS Project ID 314283), with written informed consent obtained from all participants and/or carers prior; all documents are openly available on the GloBE-Reg website, https://globe-reg.net.

All members of the GloBE-Reg GH SSG signed a declaration of interest in the registry, information which is openly available on the GloBE-Reg website, https://globe-reg.net. E.C. received education support grant from Sandoz and Merck. R.H. is a member of the advisory boards for Novo Nordisk, Sandoz, and Merck. A.R.H. has received consultancy fee from Ascendis. R.H. has received consultancy fees from Sandoz, Novo Nordisk, Lumos Pharma, and Pfizer/Opko. J.H. has received consultancy fees from Novo Nordisk, Ascendis, Pfizer, BioMarin, and Ipsen. G.J. has received consultancy fees from Ascendis Pharma, Astra Zeneca, Novo Nordisk, Pfizer, Sandoz, and Shire. A.A.L.J. has received independent research grant from BioMarin and consultancy fee from Novo Nordisk. B.S.M. has received consultancy fees from AbbVie, Ascendis Pharma, BioMarin, Bristol-Myers Squibb, EMD Serono, Novo Nordisk, Orchard Therapeutics, Pfizer, and Tolmar, as well as research grants from Alexion, AbbVie, Adrenas Therapeutics, Aeterna Zentaris, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, and Spruce Biosciences. L.S. has received consultancy fees from Novo Nordisk, Pfizer, Merck, Sandoz, and Ascendis. S.F.A. has received consultancy fees from Novo Nordisk and Sanofi, unrestricted education grant from Novo Nordisk and Neurocrine Biosciences, as well as speaker honorarium from Ipsen. The other authors declare no competing interests.

S.C.C. receives funding support from NHS Research Scotland. The GloBE-Reg project is grateful to GenSci and Novo Nordisk for an unrestricted research support grant and to Pfizer for a research collaboration grant.

S.C.C. compiled, analysed the data, and wrote the initial manuscript and subsequent revisions. S.C.C., J.B., M.C., E.C., J.-H.C., X.D., C.G., R.H., J.H., A.R.H., R.H., G.J., A.A.L.J., B.S.M., S.R., L.S., X.T., D.V., M.W., and S.F.A. contributed to the initial data field compilation, the grading process, participated in the discussion meetings, and revision of the manuscript. S.F.A. conceived of, designed the study, and revised the manuscript.

The data that support the findings of this study are openly available on the GloBE-Reg website, https://globe-reg.net. Further enquiries can be directed to the corresponding author.

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