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Gheorghe Doros,1 Philip T Lavin,2 Michael Daley,3 Larry E Miller4 1School of Public Health, Boston University, Boston, 2Lavin Consulting LLC, Framingham, MA, 3OrthogenRx Inc., Doylestown, PA, 4Miller Scientific Consulting, Inc., Asheville, NC, USA Abstract: Although the concept of equivalence for drugs (generics) and biologics (biosimilars) has been readily adopted, the concept of equivalence or indistinguishable characteristics for class III medical devices has yet to be specifically addressed regarding a defined regulatory approval process in the US. In September 2015, GenVisc 850® (sodium hyaluronate), a hyaluronic acid approved for the treatment of knee osteoarthritis, was approved by the US Food and Drug Administration (FDA) based upon indistinguishable characteristics in comparison to an approved branded hyaluronic acid (Supartz®/Supartz FX™). The purpose of this paper is to review the methodology and report the main outcomes used to demonstrate clinical comparability of GenVisc 850 with Supartz/Supartz FX. The FDA approval was collectively attained using prospectively defined methods for preclinical, physical, and chemical testing, as well as noninferiority in clinical performance comparisons. Evidence from five randomized controlled studies of Supartz/Supartz FX vs saline control injections (used for Supartz approval), two randomized controlled trials of GenVisc 850 vs saline control injections, and one randomized controlled study of GenVisc 850 vs Supartz/Supartz FX provided evidence of safety for GenVisc 850. Efficacy was further assessed based on assessment of the same Supartz studies and three prospectively identified GenVisc 850 studies. A Bayesian network meta-analysis was used to demonstrate that the clinical efficacy of GenVisc 850 was noninferior to Supartz/Supartz FX and superior to saline control. Overall, safety of GenVisc 850 was similar to that of Supartz/Supartz FX and saline control injections, while efficacy of GenVisc 850 was noninferior to that of Supartz/Supartz FX and superior to saline control injections. Keywords: Food and Drug Administration, generic, substantially equivalent, biosimilar, indistinguishable, hyaluronic acid, knee, class III, medical device, osteoarthritis

Ahmad Haider,1 Aksam Yassin,2-4 Karim Sultan Haider,1 Gheorghe Doros,5 Farid Saad,4,6 Giuseppe MC Rosano7 1Private Urology Practice, Bremerhaven, 2Institute for Urology and Andrology, Segeberger Kliniken, Norderstedt, 3Department of Preventive Medicine, Men’s Health Program, Dresden International University, Dresden, Germany; 4Department of Urology, Gulf Medical University, Ajman, United Arab Emirates; 5Department for Epidemiology and Statistics, Boston University School of Public Health, Boston, MA, USA; 6Global Medical Affairs Andrology, Bayer Pharma AG, Berlin, Germany; 7Department of Cardiology, Centre for Clinical and Basic Science, San Raffaele-Roma, Rome, Italy Background/objectives: Long-term testosterone therapy (TTh) in men with hypogonadism has been shown to improve all components of the metabolic syndrome. In this study, we investigated the effects of long-term TTh up to 8 years in hypogonadal men with a history of cardiovascular disease (CVD).Patients and methods: In two urological clinics observational registries, we identified 77 hypogonadal men receiving TTh who also had a history of CVD. The effects of TTh on anthropometric and metabolic parameters were investigated for a maximum duration of 8 years. Any occurrence of major adverse cardiovascular events was reported. All men received long-acting injections of testosterone undecanoate at 3-monthly intervals.Results: In 77 hypogonadal men with a history of CVD who received TTh, we observed a significant weight loss and a decrease in waist circumference and body mass index. Mean weight decreased from 114±13 kg to 91±9 kg, change from baseline: −24±1 kg and –20.2%±0.5%. Waist circumference decreased from 112±8 cm to 99±6 cm, change from baseline: −13±0.3 cm. Body mass index decreased from 37±4 to 29±3, change from baseline: −8±0.2 kg/m2. Cardiometabolic parameters such as lipid pattern, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably. No patient suffered a major adverse cardiovascular event during the full observation time.Conclusion: In men with hypogonadism, TTh appears to be effective in achieving sustained improvements in all cardiometabolic risk factors and may be effective as an add-on measure in the secondary prevention of cardiovascular events in hypogonadal men with a history of CVD. Keywords: testosterone, long-term testosterone therapy, cardiovascular risk, hypogonadism, secondary prevention