Article Gonadotrophin products: empowering patients to choose the product that meets their needs

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1 RBMOnline - Vol 15 No Reproductive BioMedicine Online; on web 1 May 2007 Article Gonadotrophin products: empowering patients to choose the product that meets their needs Nancy Weiss is the IVF Co-ordinator at the Palo Alto Medical Foundation Reproductive Endocrinology Department, Portola Valley, California. Nancy s life-long career has focused on women s health with the last 7 years dedicated specifically to reproductive health. Her special interests in patient-focused matters include advocacy, education, and compliance in the treatment of infertility. In 2006, she received an outstanding research award for research she presented at the Nineteenth International Conference for Nurses and Support Personnel in Reproductive Medicine. She is a member of the American Society of Reproductive Medicine. Nancy Weiss, RN N Weiss Portola Valley Women s Health Center, Palo Alto Medical Foundation, 3220 Alpine Road, Portola Valley, CA 94028, USA Correspondence: Tel: or (direct line); Fax: ; weissn@pamf.org Abstract Gonadotrophins are injected daily over several days in follicular stimulation protocols. To facilitate self-injection, various injection or reconstitution devices are available. It was investigated whether injection training enabled patients to choose their preferred device. Patients and their partners received nurse-led training about: powdered urofollitropin (Bravelle ) with needle-free reconstitution (Q-Cap ) and conventional needles and syringes for administration; follitropin beta (Follistim AQ) in a premixed, prefilled cartridge (Follistim AQ Cartridge) with a reusable injection device (Follistim Pen ); or follitropin alfa (GONAL-f ) in a disposable, premixed, prefilled injection device (GONAL-f RFF Pen). A total of 123 participants (81 women) attended the training and were asked to complete a questionnaire after training. More participants expressed a preference for a pen injection device than the needle-free reconstitution and conventional syringe (84.6% versus 5.7%; P < ). Of the 94 participants who preferred a particular device, more preferred the follitropin alfa prefilled pen (68.1%) than the follitropin beta cartridge and pen (24.5%; P < ) or urofollitropin with needle-free reconstitution device and conventional syringe (7.4%; P < ). It was concluded that nurse-led training classes empowered participants to choose a device that they considered most suitable to their needs. Keywords: follitropin alfa, follitropin beta, injector pen, in-vitro fertilization, ovulation induction, patient preference Introduction Gonadotrophins are used frequently for monofollicular stimulation in ovulation induction protocols and for multifollicular stimulation in women undergoing assisted reproduction treatments (Johnson et al., 2003). Various devices for reconstitution and injection have been developed that simplify administration and allow many patients to self-administer their gonadotrophin at home (Markle et al., 2002; Somkuti et al., 2006). Self-injection can, however, be daunting to both patients and their partners, and they will naturally have many questions as to how to administer these drugs. Indeed, personal experience suggests that a large proportion of consultation time is occupied by patients questions about injection technique. Providing education and training in the administration of injectable gonadotrophin products can, therefore, not only pre-empt many of these questions but also empower patients and may enable them to select a medication delivery system that best meets their needs. Selecting the most appropriate means of reconstitution and injection for each patient is important, as maximizing adherence and minimizing errors made during the self-injection process are essential for ensuring the success of ovarian stimulation (Markle et al., 2002). The need for gonadotrophin injection techniques that minimize pain, difficulty and stress to improve patient compliance with self-administration procedures has also been highlighted (Markle et al., 2002). Furthermore, there is evidence from other self-injected therapies that patient choice and involvement in treatment decisions may help to improve adherence (Greenfield et al., 1988). As educated consumers, patients will often have researched medication and available resource options prior to treatment (Sass, 2003). When deciding which preparation of FSH to use, the means of delivery is as important as any difference in efficacy or safety Published by Reproductive Healthcare Ltd, Duck End Farm, Dry Drayton, Cambridge CB3 8DB, UK

2 32 when choosing between a highly purified, urine-derived FSH (ufsh) preparation or a highly pure recombinant human FSH (rfsh) preparation (Daya, 2003; Lunenfeld, 2004). This study assessed whether training can help patients choose an FSH delivery system that meets their needs. Patients and partners attended a nurse-led programme that used product information and interactive demonstrations to provide training in the preparation and administration of gonadotrophins. The training included both ufsh and rfsh, focusing on the different reconstitution and injection devices available. Patients and partners opinions about the training on three different FSH injection or reconstitution devices were then surveyed, and whether they had developed a preference for any particular device was evaluated. As far as is known, this is the first study in this field to assess the impact of nurseled training classes on participants choice of a gonadotropin injection device that they considered most suitable to their needs. Materials and methods Patients This was a prospective survey conducted at a single centre in the USA. Couples who attended the Portola Valley Women s Health Centre for ovulation induction or assisted reproduction treatment and who attended training classes on the use of injectable medications were recruited into the study between January 2006 and January All such couples were eligible for inclusion into the study, with no additional inclusion or exclusion criteria in place. Each patient and applicable partner signed informed consent to undergo a single cycle of ovulation induction or assisted reproduction treatment for the treatment of infertility. The informed consent also granted Portola Valley Women s Health Centre and associates permission to collect, compare and publish non-identifiable cycle outcome variables. This study was approved by Coast Independent Review Board. Training Participants were trained about the different gonadotrophins that can be used in a treatment cycle. For the different FSH products, participants received training about the differences between highly purified urine-derived products and recombinant products, and in the practicalities of preparation and administration of FSH, with a focus on the differences between the devices available. FSH products that require conventional needles and syringes for reconstitution/transfer of solution and administration were discussed (single-dose follitropin beta and multidose follitropin alfa, Table 1) or briefly demonstrated (single-dose follitropin alfa, Table 1). Three FSH products that needed injection or reconstitution devices were demonstrated in more detail (follitropin alfa prefilled pen, follitropin beta cartridge and pen, urofollitropin with reconstitution device, Table 1). All training in this study was provided by the same specialist nurse and took place in classes of two to five couples each. Each couple attended one class, which lasted approximately h. In the training classes, the training nurse provided interactive demonstrations and couples used training tools provided by the pharmaceutical companies that manufacture the products. All resource materials relating to the products that participants were later questioned about are detailed in Table 2. Assessment To avoid bias, trainees were not aware that their views would be surveyed until after completion of training. Immediately after the training class, patients and their partners were asked if they would complete a questionnaire to assess the effectiveness of the training classes, written materials and visual aids. Participants were also asked whether they had developed a preference for any FSH injection devices for future self-administration and to give the reason for that choice. The questions are listed in Table 3. Statistical methods The population of interest comprised all participants who completed the questionnaire. As is typical in trials utilizing participant questionnaires, some data were missing from these forms. In these cases, the missing data were assumed to be of a random nature, no values were recorded and were, therefore, not included in analysis of the question s response. Participant responses were presented as a percentage of the population of interest. Descriptive statistics (contingency tables) were used to summarize participants responses and chi-squared tests (Fisher s exact test where appropriate) were used to analyse if there was an association between the responses and the products demonstrated. The significance level was set at Statistical analyses were performed using JMP Version 6 Statistical Discovery software (SAS Institute, Inc, Cary, NC, USA). Results A total of 123 patients or partners who were attending for ovulation induction or assisted reproduction treatment participated in the FSH injection training study, 65.9% of whom were female (81/123). Questions were answered by the training class participants, and all data were included in the analyses. No one refused to complete the questionnaire. All patients attending injection training were preparing to use an injectable gonadotrophin, either immediately after training or at some point in the future if oral medications proved ineffective. All were intending to self-administer or administer with the assistance of their partner. None of the participants had undergone assisted reproduction treatment before and none had used FSH, but some had previously received a single injection of chorionic gonadotrophin (Ovidrel Prefilled Syringe, EMD Serono, Inc., Rockland, MA, USA). The participants perceptions of the training and resource materials are shown in Table 4. Almost all of the participants felt that that they had been given clear explanations about all three products demonstrated and provided with adequate written and visual training materials for all three injectable FSH devices.

3 Table 1. FSH preparations discussed and/or demonstrated during the training classes. FSH medicinal Trade name and Reconstitution Administration product manufacturer Demonstrated and discussed Urine-derived follitropin Bravelle (Ferring Pharmaceuticals a ) Powder reconstituted using a Conventional needles and (urofollitropin) needle-free device (Q-Cap ) syringe Recombinant follitropin Follistim AQ (Organon USA Inc. b ) Premixed solution in a prefilled Reusable injection device beta cartridge (Follistim AQ (Follistim Pen ) Cartridge) Recombinant follitropin GONAL-f Revised Formulation Premixed solution Disposable, prefilled alfa Female (RFF) Pen (EMD Serono, injection device Inc. c ) Recombinant follitropin GONAL-f RFF 75 IU (EMD Powder and prefilled vials of Conventional needles alfa Serono, Inc. c ) diluent and syringes Discussed only Recombinant follitropin GONAL-f Multidose 450 IU Powder and prefilled vials of Conventional needles alfa (EMD Serono, Inc. c ) diluent and syringes Recombinant follitropin Follistim single-dose (Organon Premixed solution; conventional Conventional needles beta USA Inc. b ) needle to draw into the syringe and syringes a Ferring Pharmaceuticals, Suffern, NY, USA. b Organon USA Inc., Roseland, NJ, USA. c EMD Serono, Inc., Rockland, MA, USA. Table 2. Information about the specific training tools that were supplied by pharmaceutical companies and used during the FSH injection training classes. Follitropin alfa Follitropin beta Urofollitropin with prefilled pen cartridge and pen reconstitution device and conventional syringe Handouts Instructions for use of GONAL-f Follistim AQ cartridge. For use Step-by-step instructions for RFF Pen. When you need to only with Follistim Pen reconstitution and subcutaneous complete a dose with a new pen (instructions for cartridge administration of Bravelle (dosing chart) and pen) Multi-media aids Your guide to preparing and Your guide to patient-friendly A guide to administration (DVD) administering Serono fertility fertility treatment (DVD) products (DVD) Fertility Lifelines website Fertility Journey website 33

4 Table 3. Questions used to assess participants opinions on training and devices. Questions Pen devices Do you feel both pen devices were presented and explained in a thorough and clear manner? Did your injection trainer provide adequate written and visual information on both the pen devices? Did your injection trainer demonstrate the difference between each pen device? Did you prefer one pen device over another? If so what pen device and why? Did the colour of the pen device influence your decision? Did your trainer influence your decision? Needle-less mixing device and conventional syringe and needle Did your trainer demonstrate this device in a manner that would make it easy to use? Did your trainer provide adequate written and visual information for this device? Do you prefer this device over using injection pens? If so why? Possible answers Name of device and reason Reason Table 4. Participants perceptions of the demonstrations and resource materials used during FSH injection training classes (n = 123). Question Response Yes No Not stated Each pen device was presented and explained in a thorough and clear manner, n (%) 122 (99.2) 0 (0.0) 1 (0.8) Adequate written and visual material was provided for each pen device, n (%) 123 (100.0) 0 (0.0) 0 (0) The differences between each pen device were demonstrated, n (%) 122 (99.2) 0 (0.0) 1 (0.8) Needle-free mixing devices were explained in thorough and clear manner, n (%) 119 (96.7) 3 (2.4) 1 (0.8) Adequate written and visual material was provided for needle-free mixing devices, n (%) 119 (96.7) 4 (3.2) 0 (0) Note: rows may not total 100% due to rounding. 34 In total, 111 participants stated a preference for a particular device type. A significantly greater proportion of patients reported that they would prefer to use a pen device (n = 104, 84.6%) for administration of FSH rather than a device for needle-free reconstitution and conventional syringe (n = 7, 5.7%; P < ). Twelve patients (9.8%) were undecided or stated no injection device preference. Of the 111 participants who stated a preference, nine preferred the pen device but had no pen-type preference; four were undecided between pens; four failed to name the pen, leaving 94 participants who stated which product they preferred. A significantly greater proportion of these participants stated that they would rather use the follitropin alfa prefilled pen for FSH administration (n = 64, 68.1%) than the follitropin beta cartridge and pen (n = 23, 24.5%; P < ) or the urofollitropin with needle-free reconstitution device and conventional syringe (n = 7, 7.4%; P < ; Figure 1). The reasons given for the participants choices of FSH delivery device are shown in Figure 2. Of the 94 participants who stated a preference, 89 provided the reason for their preference, ease of use, simplicity and reliability of the dosing mechanism and a design to minimize the chance of dosing errors were the three most common reasons stated for selection. More than two-thirds of the participants who considered ease of use as a reason for FSH device preference (n = 37/52; 71.1%) preferred the follitropin alfa prefilled pen to other devices (P > 0.05). Of the patients who stated the dosing mechanism as a reason for FSH device preference, 63.2% (n = 24/38) preferred the follitropin alfa prefilled pen, 34.2% (n = 13/38) preferred the follitropin beta cartridge and pen and 2.6% (n = 1/38) preferred the urofollitropin with needle-free reconstitution device. Almost all of the 23 patients who considered that minimizing the chances of error was important in their choice of FSH delivery device chose to use the follitropin alfa prefilled pen (follitropin alfa prefilled pen, n = 22/23, 95.7%; follitropin beta cartridge and pen, n = 1/23, 4.3%; P = 0.004). Factors that were less important in device selection were trainer influence, the shelf life of the product and whether the device was ready to use or not. Although participants were asked whether the colour of the device influenced their decision, few said that it had (follitropin alfa prefilled pen, n = 9/64, 14.1%; follitropin beta cartridge and pen, n = 1/23, 4.3%; P > 0.05). In addition, most participants (n = 87, 92.6%), when asked whether the trainer influenced their decision, stated they were not influenced (follitropin alfa prefilled pen, n = 58/64, 90.6%; follitropin beta cartridge and pen, n = 22/23, 95.7%; urofollitropin with needle-free reconstitution device, 7/7, 100%; P > 0.05).

5 Figure 1. The proportion of participants who stated a preference for a specific FSH administration device after completion of injection training (n = 94). Figure 2. The reasons stated by patients for selection of a specific FSH-administration device (n = 89; participants were able to state more than one reason). Discussion This study shows that training on the use of three different injectable FSH products enabled the majority (90.2%) of participants to select the delivery device most suitable to their needs. Of the participants who expressed a preference for an FSH delivery method, 93.7% preferred to use a pen device rather than a needle-free reconstitution and conventional syringe method. The follitropin alfa prefilled pen was the most popular FSH injection device and was chosen by 68.1% of those participants who expressed a preference for a particular device. In comparison, the follitropin beta cartridge and pen was chosen by 24.5% of participants and the urofollitropin device (for needlefree reconstitution but with a conventional syringe for injection) was selected by 7.4% of participants. The most common reasons given for selection of the follitropin alfa prefilled pen were that it was considered to be easy to use and had a simple and reliable dosing mechanism with minimal perceived chances of error. These results agree with studies that have assessed the use of injection devices during assisted reproduction treatment. For example, women who were self-injecting follitropin beta for ovarian stimulation found a pen device easier to use, more convenient and less painful than injections using conventional syringes and needles (Platteau et al., 2003). In another study of women undergoing ovulation induction, the follitropin alfa prefilled pen was more convenient for patients to use when compared with prior therapy using conventional vials or ampoules and syringes (Somkuti et al., 2006). Ease of use is also recognized as an important feature in injection devices used to deliver other hormonal therapies. Thus, an earlier study of recombinant human growth hormone injector devices showed that reliability, overall ease of use and, specifically, the number of steps involved in preparation, administration and, following use, were three of the five most desirable attributes of delivery devices for growth hormone among patients, parents, physicians and nurses (Dumas et al., 2006). 35

6 36 From these results, it is clear that minimizing the chance of error is also a key consideration for participants. The importance of minimizing such error was shown by a study of women undergoing IVF cycles: 15% of these women made errors when preparing or administering human chorionic gonadotrophin injections and errors were associated with lower pregnancy rates (10% versus 27%) (Markle et al., 2002). Although gonadotrophin use was not investigated as part of this study, prefilled injector pens such as the follitropin alfa prefilled pen may help to reduce administration errors. As well as facilitating patient choice, as shown in this study, there is evidence across many therapeutic areas that increasing patient information improves patient satisfaction and adherence to treatment (DiMatteo, 1994; Heisler et al., 2002; Schattner et al., 2006). Favourable physician patient relationships and effective communication have also been shown to lead to improved psychological and physical health outcomes (Heszen- Klemens and Lapinska, 1984; Greenfield et al., 1985, 1986; Evans et al., 1987; Kaplan et al., 1989; Stewart, 1995; Faller, 2003). The mechanism by which such patient-centred approaches result in improved self-management is poorly understood. The beneficial effects may be explained by increasing patients understanding of their disease and its treatment, or by improving their motivation (Wolpert and Anderson, 2001) or self-confidence (DiMatteo, 1994; Senecal et al., 2000). It is, however, clear that active participation in treatment decision making empowers patients and increases feelings of self-efficacy, increasing their belief in their own capability to perform and influence events (Orth et al., 1987; Kaplan et al., 1989; Mahler and Kulik, 1991; Faller, 2003; Arora et al., 2005). Furthermore, shared decision-making strategies provide an opportunity to encourage patients to take greater responsibility for their own treatment (Arora et al., 2005). There is evidence to support the strong desire of female patients to be involved in decision making: a survey by Davey et al. (2002) showed that women prefer to take an active role in consultations and share decision making equally with healthcare professions. The novel questionnaire used in this study was designed according to clinical experience. Its primary aim was to capture the effectiveness of nurse-led training, in order to determine if training gave participants sufficient knowledge and confidence to select a preferred injection device. The questionnaire focused on FSH products, as the injection of FSH plays a greater role in fertility treatment than other gonadotrophins. Thus, FSH is administered daily, for a longer period (generally days during a treatment cycle for ovulation induction or assisted reproduction treatment) and in greater quantity (by total IU administered) than either human menopausal gonadotrophin or human chorionic gonadotrophin. Only injection or reconstitution devices were included in the questionnaire, as standard reconstitution of FSH vials and injection using conventional syringe and needle is generally reserved for the end of treatment to avoid partially using a new cartridge or prefilled pen of FSH. This method of reconstitution and injection, therefore, constitutes a very small portion of the total number of FSH doses administered. The responses to the current questionnaire show the value of injection training, which included interactive demonstrations and the use of written and visual resource aids, in providing patients with the confidence to assert a product preference. This would reduce patients needs to rely on their practitioners choices of therapy, which can be the case if adequate training is not provided (N Weiss, unpublished observation). It is hoped that the results presented here could be useful to other healthcare workers, by indicating the features that are of specific concern to patients when selecting a means of preparing and administering FSH. The next stage of this investigation would be to assess if patients were satisfied with their chosen means of injection devices after they have experienced using the devices as part of their treatment. Although not part of the original study, a future study of this type is under consideration. In conclusion, comprehensive nurse-led training in the preparation and use of injectable FSH products enabled the majority of participants to choose their preferred method of administration with significant differences in preference between the different FSH devices. The follitropin alfa prefilled pen was the most popular injector device, as it was considered to be easy to use, had a simple, reliable dosing mechanism and minimized the chance of making a dosing error. Acknowledgements Assistance with data analysis was provided by Julie Hubbard of EMD Serono, Inc. The author would also like to thank Caudex Medical for their assistance in the preparation of the manuscript. References Arora NK, Ayanian JZ, Guadagnoli E 2005 Examining the relationship of patients attitudes and beliefs with their self-reported level of participation in medical decision-making. Medical Care 43, Davey HM, Barratt AL, Davey E et al Medical tests: women s reported and preferred decision-making roles and preferences for information on benefits, side-effects and false results. Health Expectations 5, Daya S 2003 Methodologic pitfalls in assessing the efficacy of recombinant follicle-stimulating hormone versus human menopausal gonadotropin in assisted reproduction. 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