Human factors engineering and design validation for the redesigned follitropin alfa pen injection device.
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ABSTRACT:
SUBMITTER: Mahony MC
PROVIDER: S-EPMC4496816 | biostudies-other | 2015 May
REPOSITORIES: biostudies-other
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Project description:BackgroundSelf-administration of recombinant human follicle-stimulating hormone (r-hFSH) can be performed using injection pen devices by women undergoing assisted reproductive technology procedures. The objective of this study was to explore the use of the prefilled follitropin alfa pen in routine assisted reproductive technology procedures in Germany.MethodsThis prospective, observational study was conducted across 43 German IVF centres over a period of 1.75 years. Patients who had used the prefilled follitropin alfa pen in the current or a previous cycle of controlled ovarian stimulation completed a questionnaire to assess their opinions of the device.ResultsA total of 5328 patients were included in the study. Of these, 2888 reported that they had previous experience of daily FSH injections. Significantly more patients reported that less training was required to use the prefilled follitropin alfa pen than a syringe and lyophilized powder (1997/3081 [64.8%]; p < 0.001 'less' versus 'more' training). Significantly more patients rated the prefilled follitropin alfa pen as easier in terms of use (2321/3206, 72.4%; p < 0.001 'much more easy' versus 'less easy') and daily injection (2384/3262, 73.1%; p < 0.001 'much more easy' versus 'less easy') than existing injection methods. Approximately one third of respondents rated the prefilled follitropin alfa pen as easier to use than the follitropin beta pen with reloadable cartridges. The majority (3378/4024, 83.9%) of patients had a general preference for the prefilled follitropin alfa pen over other injection methods.ConclusionsIn this questionnaire-based survey, routine use of the prefilled follitropin alfa pen was well accepted and associated with favourable patient perceptions. Users of the pen found it easier to initially learn how to use, and subsequently use, than other injection methods. In general, the prefilled follitropin alfa pen was the preferred method for self-administration of gonadotrophins. Together with previous findings, the results here indicate a high level of patient satisfaction among users of the prefilled follitropin alfa pen for daily self-administration of r-hFSH.
| S-EPMC2949697 | biostudies-literature
Project description:Although the full primary structures of the alfa and beta subunits of reference r-hFSH-alfa and its biosimilars are identical, cell context-dependent differences in the expressing cell lines and manufacturing process can lead to variations in glycosylation profiles. In the present study, we compared the structural features of reference r-hFSH-alfa with those of five biosimilar preparations approved in different global regions outside Europe (Primapur®, Jin Sai Heng®, Follitrope®, Folisurge®, and Corneumon®) with respect to glycosylation, macro- and microheterogeneity, and other post-translational modifications and higher order structure. The mean proportion of N-glycosylation-site occupancy was highest in reference r-hFSH-alfa, decreasing sequentially in Primapur, Jin Sai Heng, Corneumon, Follisurge and Follitrope, respectively. The level of antennarity showed slightly higher complexity in Corneumon, Primapur and Follitrope versus reference r-hFSH-alfa, whereas Jin Sai Heng and Folisurge were aligned with reference r-hFSH-alfa across all N-glycosylation sites. Sialylation level was higher in Corneumon and Follitrope, but small differences were detected in other biosimilar preparations compared with reference r-hFSH-alfa. Jin Sai Heng showed higher levels of N-glyconeuramic acid than the other preparations. Minor differences in oxidation levels were seen among the different products. Therefore, in summary, we identified var ious differences in N-glycosylation occupancy, antennarity, sialylation and oxidation between reference r-hFSH-alfa and the biosimilar preparations analyzed.
| S-EPMC9223809 | biostudies-literature
Project description:PURPOSE: Evaluation of patients' ease of use of the redesigned, disposable, ready-to-use follitropin alfa pen during controlled ovarian stimulation for assisted reproductive technology. METHODS: This single-center, observational, open-label, single-arm study recruited infertile normo-ovulatory women (aged 18-45 years). Nurses trained patients to self-administer recombinant human follicle-stimulating hormone daily using the follitropin alfa pen (300 IU, 450 IU, and 900 IU). Before treatment, patients completed Questionnaire A. Following self-administered treatment, on stimulation days 5-6 and 7-8 (within a day of receiving recombinant human chorionic gonadotropin), patients completed Questionnaire B. Nurses completed an ease-of-learning/teaching questionnaire. The primary endpoint was proportion of patients rating the pen as "easy/very easy" to use (Questionnaire B) on the final visit before recombinant human chorionic gonadotropin. Secondary endpoints included: proportion of patients rating the follitropin alfa pen as easy to learn, use, prepare, deliver, and dispose of (Questionnaires A and B). Proportions (95% confidence intervals [CIs]) were provided for primary and secondary endpoints. Adverse events were reported descriptively. RESULTS: Eighty-six patients received recombinant human follicle-stimulating hormone. Of the 72 patients who had completed the overall assessment questions, 66 (91.7%; 95% CI =82.7%-96.9%) found the pen "easy" to use. Also, 70/86 (81.4%) patients "strongly agreed/agreed" that, overall, it was easy to learn how to use the pen; 72/86 (83.7%) "strongly agreed/agreed" that easily understandable, verbal information was provided; and 70/86 (81.4%) were confident about using the pen correctly. In total, 24/26 nurses (92.3%; 95% CI =74.9%-99.1%) rated the pen as easy to use. Clinical pregnancy rate/patient/cycle/embryo transfer was 37%. Twenty-six ovarian hyperstimulation syndrome events were reported (none severe; 16 patients [19%]); of these, 13 occurred at embryo transfer. CONCLUSION: In this observational study, patients had a high acceptance of the redesigned follitropin alfa pen, with most finding it very easy/easy to use. Assisted reproductive technology nurses found the pen very easy/easy to teach.
| S-EPMC4051799 | biostudies-other
Project description:INTRODUCTION:Recombinant human luteinizing hormone (r-hLH) is used in a fixed-ratio combination with recombinant human follicle-stimulating hormone (r-hFSH) for the stimulation of follicular development. OBJECTIVE:The objective of this article was to conduct a review of safety data to evaluate the risks of r-hFSH/r-hLH treatment. METHODS:Data were retrieved from the Global Safety Database (Merck KGaA, Darmstadt, Germany) including reports from healthcare professionals, patients, health authorities, clinical trials, non-interventional studies, and the literature. Reports of important risks (identified and potential) as per the risk management plan applicable at the time of data retrieval were obtained up to December 2017. The estimated patient exposure to r-hFSH/r-hLH in the post-marketing setting was 427,012 treatment cycles. Nine hundred patients received r-hFSH/r-hLH during company-sponsored clinical trials (pre- and post-marketing). RESULTS:We identified 72 case reports describing important risks related to r-hFSH/r-hLH use, including 46 cases of ovarian hyperstimulation syndrome (10.8 per 100,000 treatment cycles) and 24 of hypersensitivity reaction (5.6 per 100,000 treatment cycles). No thromboembolic events were reported. One congenital anomaly, not suspected to be related to r-hFSH/r-hLH use, was reported during a clinical trial; the event was resolved by corrective surgery. Two fatal cases were identified; one case of recurrent malignant melanoma (suspected to be related to r-hFSH/r-hLH use) and one case resulting from complications of ovarian hyperstimulation syndrome. CONCLUSION:Cumulative reporting rates of important identified and potential risks of r-hFSH/r-hLH during a 10-year surveillance period demonstrate the benefit-risk balance is positive. This post-marketing surveillance and continued surveillance of safety events should provide reassurance about the use of r-hFSH/r-hLH in clinical practice.
| S-EPMC6426819 | biostudies-other
Project description:BackgroundAfter a subcutaneous injection fluid might leak out of the skin, commonly referred to as leakage or backflow. The objective was to examine the influence of needle design and injection technique on leakage after injections in the subcutaneous tissue of humans and pigs.MethodLeakage data were obtained from a post hoc analysis of clinical trial data and from a pig study. Data from the clinical study were used to determine leakage as a function of injection volume, speed and region. Data from the pig study were used to determine leakage as a function of needle wall thickness, needle taper, injection angle, and wait time from end of injection to withdrawal of needle from skin.ResultsLeakage volume was positively related to injection volume. Injections in the abdomen caused less leakage than thigh injections. A 32G needle caused less leakage than a 31G and a 32G tip (tapered) needle, and a "straight in" 90° needle insertion angle caused less leakage than an angled (~45°) insertion. Wait times of minimum 3 seconds caused less leakage than immediate withdrawal of the needle after injection. Needle wall thickness and injection speed did not influence leakage.ConclusionsLeakage will be minimized using a thin needle, using 90° needle insertion in the abdomen, injecting maximum 800 µL at a time, and waiting at least 3 seconds after the injection until the needle is withdrawn from the skin.
| S-EPMC4928216 | biostudies-literature
Project description:INTRODUCTION:We incorporated patient feedback from human factors studies (HFS) in the patient-centric design and validation of ava®, an electromechanical device (e-Device) for self-injecting the anti-tumor necrosis factor certolizumab pegol (CZP). METHODS:Healthcare professionals, caregivers, healthy volunteers, and patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or Crohn's disease participated in 11 formative HFS to optimize the e-Device design through intended user feedback; nine studies involved simulated injections. Formative participant questionnaire feedback was collected following e-Device prototype handling. Validation HFS (one EU study and one US study) assessed the safe and effective setup and use of the e-Device using 22 predefined critical tasks. Task outcomes were categorized as "failures" if participants did not succeed within three attempts. RESULTS:Two hundred eighty-three participants entered formative (163) and validation (120) HFS; 260 participants performed one or more simulated e-Device self-injections. Design changes following formative HFS included alterations to buttons and the graphical user interface screen. All validation HFS participants completed critical tasks necessary for CZP dose delivery, with minimal critical task failures (12 of 572 critical tasks, 2.1%, in the EU study, and 2 of 5310 critical tasks, less than 0.1%, in the US study). CONCLUSION:CZP e-Device development was guided by intended user feedback through HFS, ensuring the final design addressed patients' needs. In both validation studies, participants successfully performed all critical tasks, demonstrating safe and effective e-Device self-injections. FUNDING:UCB Pharma. Plain language summary available on the journal website.
| S-EPMC5778191 | biostudies-literature
Project description:Recombinant follicle-stimulating hormone (FSH) (follitropin alfa) and biosimilar preparations are available for clinical use. They have specific FSH activity and a unique glycosylation profile dependent on source cells. The aim of the study is to compare the originator (reference) follitropin alfa (Gonal-f®)- with biosimilar preparations (Bemfola® and Ovaleap®)-induced cellular responses in vitro. Gonadotropin N-glycosylation profiles were analyzed by ELISA lectin assay, revealing preparation specific-patterns of glycan species (Kruskal-Wallis test; p < 0.05, n = 6) and by glycotope mapping. Increasing concentrations of Gonal-f® or biosimilar (1 × 10-3-1 × 103 ng/ml) were used for treating human primary granulosa lutein cells (hGLC) and FSH receptor (FSHR)-transfected HEK293 cells in vitro. Intracellular cAMP production, Ca2+ increase and ?-arrestin 2 recruitment were evaluated by BRET, CREB, and ERK1/2 phosphorylation by Western blotting. 12-h gene expression, and 8- and 24-h progesterone and estradiol synthesis were measured by real-time PCR and immunoassay, respectively. We found preparation-specific glycosylation patterns by lectin assay (Kruskal-Wallis test; p < 0.001; n = 6), and similar cAMP production and ?-arrestin 2 recruitment in FSHR-transfected HEK293 cells (cAMP EC50 range = 12 ± 0.9-24 ± 1.7 ng/ml; ?-arrestin 2 EC50 range = 140 ± 14.1-313 ± 18.7 ng/ml; Kruskal-Wallis test; p ? 0.05; n = 4). Kinetics analysis revealed that intracellular Ca2+ increased upon cell treatment by 4 ?g/ml Gonal-f®, while equal concentrations of biosimilars failed to induced a response (Kruskal-Wallis test; p < 0.05; n = 3). All preparations induced both 8 and 24 h-progesterone and estradiol synthesis in hGLC, while no different EC50s were demonstrated (Kruskal-Wallis test; p > 0.05; n = 5). Apart from preparation-specific intracellular Ca2+ increases achieved at supra-physiological hormone doses, all compounds induced similar intracellular responses and steroidogenesis, reflecting similar bioactivity, and overall structural homogeneity.
| S-EPMC6667556 | biostudies-literature
Project description:BackgroundRecombinant human follitropin alfa (r-hFSH) is used for ovarian stimulation as part of medically assisted reproduction. There is a risk for ovarian hyperstimulation syndrome (OHSS) with r-hFSH treatment, and an increased risk for thromboembolic events in the presence of pregnancy with OHSS.ObjectivesTo report the frequency of OHSS and thromboembolism with originator follitropin alfa (GONAL-f) based on the Global Safety Database of Merck KGaA, Darmstadt, Germany and a systematic review of published data.Data sourcesReports of OHSS and thromboembolism were obtained from the Global Safety Database of Merck KGaA, Darmstadt, Germany from 20 October 1995 to 19 October 2018. The systematic review was based on MEDLINE and Embase searches from inception to 19 October 2018.Study eligibility criteriaPatients receiving GONAL-f for ovulation induction or ART, with a starting dose within the range included in the prescribing information and providing information on the occurrence of OHSS and/or thromboembolism.Study appraisal and synthesis matchesIn the Global Safety Database of Merck KGaA, Darmstadt, Germany there were an estimated 16,525,975 treatment cycles since 20 October 1995; 1110 reported cases of OHSS and 80 reported cases of thromboembolic events (reporting rates 6.7 and 0.48 per 100,000 treatment cycles, respectively). The systematic review identified 45 studies (5186 patients exposed to GONAL-f; 5240 treatment cycles). There were 272 reports of OHSS (5190 [5.19%] per 100,000 treatment cycles), including 10 cases of severe OHSS (191 [0.19%] per 100,000 treatment cycles).LimitationsThere may be the potential for under-reporting of safety outcomes in the literature, and under-reporting is a well-known phenomenon in spontaneous reporting databases.Conclusion and implications of key findingsOur analyses demonstrate low rates of OHSS and thromboembolism with GONAL-f.
| S-EPMC7595967 | biostudies-literature
Project description:This cost-effectiveness analysis was conducted from the patient's perspective alongside a randomized controlled trial comparing corifollitropin alfa with follitropin beta for a single stimulation cycle. Only unit costs paid by patients are included in this analysis. The incremental cost-effectiveness ratio was calculated. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were also performed. Baseline characteristics (except for the number of follicles and frozen embryos), treatment outcomes and complications were similar in the two groups. The live birth rate was comparable between the two groups, but the mean total cost per patient was higher for the corifollitropin alfa strategy (€4293) compared with the follitropin beta strategy (€4086). Costs per live birth were €13,726 and €12,511, respectively. The difference in effect between corifollitropin alfa and collitropin beta was three fewer live births, and the difference in costs was €24,048. The probability of live birth after the first and second embryo transfers and the proportion of patients who had no more frozen embryos available after non-achievement of live birth in the first or second transfer influenced the comparative cost-effectiveness of the two strategies. PSA showed that a corifollitropin alfa strategy would be rejected in up to 27.4% of scenarios. Follitropin beta 300 IU/day was more cost-effective than corifollitropin alfa 150 ?g in women aged 35-42 years weighing ? 50 kg undergoing in-vitro fertilzation/intracytoplasmic sperm injection.
| S-EPMC7235613 | biostudies-literature
Project description:BackgroundFollicle-stimulating hormone (FSH) and luteinizing hormone (LH) both have a role to play in follicular development during the natural menstrual cycle. LH supplementation during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) is used for patients with hypogonadotropic hypogonadism. However, the use of exogenous LH in COS in normogonadotropic women undergoing ART is the subject of debate. The aim of this study was to investigate characteristics of infertile women who received the 2:1 formulation of follitropin alfa and lutropin alfa (indicated for stimulation of follicular development in women with severe LH and FSH deficiency) in German clinical practice.MethodsA 3-year, multicentre, open-label, observational/non-interventional, post-marketing surveillance study of women (21-45 years) undergoing ART. Primary endpoint: reason for prescribing the 2:1 formulation of follitropin alfa and lutropin alfa. Secondary variables included: COS duration/dose; oocytes retrieved; fertilization; clinical pregnancy; ovarian hyperstimulation syndrome (OHSS).ResultsIn total, 2220 cycles were assessed; at least one reason for prescribing the 2:1 formulation was given in 1834/2220 (82.6%) cycles. Most common reasons were: poor ovarian response (POR) (39.4%), low baseline LH (17.8%), and age (13.8%). COS: mean dose of the 2:1 formulation on first day, 183.1/91.5 IU; mean duration, 10.8 days. In 2173/2220 (97.9%) cycles, human chorionic gonadotrophin was administered. Oocyte pick-up (OPU) was attempted in 2108/2220 (95.0%) cycles; mean (standard deviation) 8.0 (5.4) oocytes retrieved/OPU cycle. Fertilization (≥1 oocyte fertilized) rates: in vitro fertilization (IVF), 391/439 (89.1%) cycles; intracytoplasmic sperm injection (ICSI)/IVF + ICSI, 1524/1613 (94.5%) cycles. Clinical pregnancy rate: all cycles, 25.9%; embryo transfer cycles, 31.3%. OHSS: hospitalization for OHSS, 8 (0.36%) cycles, Grade 2, 60 (2.7%), and Grade 3, 1 (0.05%).ConclusionsIn German routine clinical practice, the most common reasons for using the 2:1 formulation of follitropin alfa and lutropin alfa for women undergoing ART were POR, low baseline LH, and age. Severe OHSS incidence was low and similar to that reported previously.
| S-EPMC3902060 | biostudies-literature