Hervé Dumas 1Serono International SA, 15 bis Chemin des Mines, Geneva, CH-1202, Switzerland , Paris Panayiotopoulos Serono International SA, 15 bis Chemin des Mines, Geneva, CH-1202, Switzerland, , Dorothy Parker Fast Forward Research Ltd, Crown House, Manchester Road, Wilmslow, Cheshire SK9 1BH, UK , Vincent Pongpairochana Laboratoires Serono SA, Patients Care Technologies, Coinsins, CH-1267, Switzerland

Abstract

Background: Recombinant human growth hormone (r-hGH) is used to treat: growth hormone deficiency in children and adults; children born small for gestational age; Turner's syndrome; and chronic renal failure. r-hGH is administered by daily subcutaneous injection and may be given using a number of different administration devices. The aim of this survey was, firstly, to identify which attributes of an r-hGH administration device are considered most important to physicians, teenage patients, parents of young children requiring GH and nurses who have experience of r-hGH administration, and, secondly, to determine how they rate existing devices in each of these key attributes.

Methods: The opinions of 67 individuals with experience in r-hGH administration were captured in discussion sessions. Parents, physicians and nurses were asked to rate 19 device attributes by completing a questionnaire, and to rank four different r-hGH administration devices (including a conceptual electronic device) in order of preference. Results: Reliability, ease of use, lack of pain during injection, safety in use, storage, and number of steps in preparation before use, during use and after were considered to be the five most desirable attributes of an r-hGH administration device. An electronic device was preferred to an automatic, multi-dose injection device, a needle-free injection device or a manual, ready-to-use, disposable injection device.

Conclusion: In the opinion of physicians, nurses and parents using r-hGH injection devices, an ideal device must combine reliability with simplicity, while delivering treatment with minimal pain. An electronic device, which combines many of the most useful features of existing devices with novel functions, was the preferred option for r-hGH administration.

 

Background

Approximately 1 in 4000 children are born every year with growth hormone deficiency (GHD) [1]. GHD causes short stature, low growth velocity, excess subcutaneous fat and delayed skeletal maturation [1], which have a considerable impact on physical and psychological functioning [2]. Adults with untreated GHD also have an increased cardiovascular risk [3]. Replacement therapy using exogenous GH has been used successfully since the 1950s to treat children (and more recently adults) with GHD [4,5]. Early preparations of GH were extracted from human pituitary glands, but its use was discontinued in 1985 following the diagnosis of four cases of Creutzfeldt-Jakob disease in patients who had received GH [6]. Later in the same year, the first recombinant form of human GH (rhGH) became available. Initially, r-hGH was produced using genetically engineered bacterial cells (Escherichia coli) [7], but in 1987 a mammalian cell-derived r-hGH preparation (produced by murine C127 cells) was introduced [8]. With the advent of a new, unlimited source of GH, researchers were able to explore the use of GH for other conditions associated with growth retardation or metabolic dysfunction. Today, GH is used to treat not only GHD in both children and adults [4,5] but also a number of other disorders, including Turner's syndrome [9], chronic renal failure [10], and children born small for gestational age [11].

To achieve optimal therapeutic results with GH, continuous, long-term adherence is essential. However, all existing r-hGH products are administered subcutaneously, usually on a daily basis, and this can lead to problems with adherence [12]. Therefore, it is important that devices used for r-hGH administration are convenient and acceptable to patients. In particular, a large proportion of the patients who require r-hGH therapy are children, so an r-hGH administration device must be child-friendly. The optimal device must be simple enough for a child to operate easily and safely. The option of a hidden needle or a needle-free device may also be particularly useful in making the administration of r-hGH more acceptable to children. The first commercially available preparations of r-hGH were injected using a standard syringe, but novel administration devices – pre-filled syringes, manual injector pens, auto-injectors, injectors with hidden needles and needle-free devices – have since been introduced in an attempt to increase dosing accuracy and adjustability, ease of use, convenience, adherence, simplicity, and patientfriendliness [13-21].

Despite these advances in r-hGH administration device design, there is still scope for improvement. None of the current devices are pain-free, and developments that reduce pain or the patient's perception of pain (psychological pain) are also likely to increase adherence and acceptance of therapy. In addition, it may be possible to improve existing features or to introduce new, useful features, such as pre-set dosing programmed by the physician, administration/cartridge replacement reminder alarms or adjustable injection speeds. Some of these functions may help to improve adherence but would need to be incorporated in a way that did not compromise the simplicity of the device.

The aim of this survey was, firstly, to identify which attributes of an r-hGH injection device are considered most important by physicians, teenage patients, parents and nurses who have experience of GH administration, and, secondly, to determine how these participants rate existing devices in each of these key attributes, and to use this to identify any unmet needs in GH injection devices.

Methods

Individuals were recruited for this survey in France, Germany, Italy, the UK and the USA. Participants included prescribing physicians (endocrinologists and paediatric endocrinologists, no more than two from the same hospital, with recent experience of treating patients aged under 18 years with r-hGH), nurses involved in patient training and support (community- or hospital-based, no more than two from the same hospital), teenage patients (aged between 13 and 15 years) self-injecting r-hGH using a delivery device, and parents injecting their children (aged under 14 years) with r-hGH. Recruitment of patients/parents was facilitated with the assistance of medical professionals (in Europe) or patient associations (in the USA). Group discussions involving three to six individuals were conducted to assess opinions relating to r-hGH administration device attributes. These discussions lasted 2–3 hours, were audio and video recorded, and were viewed by up to five experts in a professional viewing room. Where participants were unable to attend group discussions (e.g. issues with geographical logistics), individual face-to-face interviews were carried out (audio-recorded). During these discussions and interviews, participants were made aware of the current device options, asked to brainstorm their desired alternative devices and to suggest improvements.

Physicians, nurses and parents were also asked to complete a questionnaire assessing which attributes they felt to be the most important in a device for r-hGH administration. The participants first spontaneously identified the key device attributes that were important for them. These attributes were then compared with a pre-existing list and the participants were free to add extra attributes from this list, if they wished. The participants were then asked to score each of the selected attributes. A total of 19 attributes were assessed to evaluate the importance of ergonomics, functionality and the psychological impact of such a device: number of steps in preparation, no need for reconstitution, ease of releasing trapped air, automatic injecting, drug pre-loaded, disposable device, multi-dose, ease of use, reliability, pain during injection, level of noise during injection, design aspects, position of release button, size, weight, level of physical strength required to operate, ease of grip, ease of storage, safety in use and in storage. Each attribute was rated from 0 (not important at all) to 10 (extremely important). The questionnaire also asked participants to rank the performance of existing rhGH injection devices that they had used previously for each of these attributes, from 0 (not well at all) to 10 (extremely well). It was not considered appropriate for the younger patients to complete a questionnaire, so only the questionnaire results of parents, nurses and physicians are presented below under Results. The children's views were expressed spontaneously and key aspects were probed for (e.g. their views on ease of use, size, etc.). These children were also asked to produce drawings of desired features/ new devices during the group sessions.

Three r-hGH administration devices were demonstrated during the discussion sessions: an automatic, multi-dose injection device (one.click™, Serono, Geneva, Switzerland), a needle-free injection device (cool.click™, Serono, Geneva, Switzerland) and a manual, ready-to-use, disposable injection device (FlexPen®, Novo Nordisk, Dublin, Ireland). The concept of an electronic device was also introduced. Devices were ranked in order from 1 (preferred choice) to 4 (least preferred choice). In addition, individual and consensus opinions relating to the attributes of each device were captured during these discussions. Mean scores were calculated for each attribute assessed in the questionnaire. Mean scores were also calculated for each attribute, grouped by participant type or by country.