Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe.

Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.

Two innovative pharmaceutical forms of leuprorelin: results from 818 patients with advanced prostate cancer.

OBJECTIVES: This study set out to examine the efficacy and tolerability of two innovative implant forms of leuprorelin acetate in men with advanced hormone-dependent prostate cancer in everyday clinical practice. METHODS: Data were collected from 818 patients (from 273 centers across Germany) who were pretreated with slow-release luteinizing hormone-releasing hormone (LHRH) agonist formulations and who were about to be switched to the leuprorelin implants. Patients received three injections of 1- or 3-month leuprorelin implant and physicians were asked to complete a case report form specific to each of the three clinic visits. Documented parameters included laboratory measurements, such as testosterone and prostate-specific antigen (PSA) levels, adverse events, and patient- and physician-rated assessments of the therapy. RESULTS: Compared with baseline, a significant decrease in both testosterone and PSA levels were measured after the first and second injections of leuprorelin implant. These results were confirmed for both the 1-month and 3-month implants in separate analyses. Switching, without treatment interruption, from Trenantone® (Takeda Pharma GmBH, Aachen, Germany) to the leuprorelin implant resulted in a significant decrease in the mean serum testosterone concentrations (P < 0.05) and a nonsignificant increase in the proportion of patients reaching castrate testosterone levels, while the number of patients with PSA values ≤ 4 ng/mL significantly increased (P = 0.045). Similar results were obtained for patients previously treated with goserelin who switched to leuprorelin implant. For 94% of patients, treating physicians rated the efficacy of leuprorelin implant as "very good" or "good." Treatment with leuprorelin implant was well tolerated, with only 61 adverse events reported in 42 (5.1%) patients. Patients and physicians rated the tolerability of leuprorelin implant as "very good" or "good" in 95% and 91% of cases, respectively. CONCLUSIONS: These results confirm the efficacy, tolerability, and ease of use of the leuprorelin implants among a large population of men with advanced, hormone-dependent prostate cancer treated in a clinical practice setting.

Clinical development of two innovative pharmaceutical forms of leuprorelin acetate.

OBJECTIVES: Two innovative pharmaceutical forms of leuprorelin acetate have been developed as 1-month and 3-month implants for the treatment of advanced hormone-dependent prostate cancer. These products contain active substance dispersed homogeneously in a biodegradable polymer. Here we present the key results from the clinical development of these slow-release implant formulations of leuprorelin. METHODS: Two therapeutic studies of the 1-month implant were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Enantone) as the active control; and a single-arm study of the leuprorelin implant. For the 3-month implant, four therapeutic studies were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Trenantone) as the active control; a single-arm study of the leuprorelin implant; and two long-term studies with the 3-month implant administered twice, either 12 or 16 weeks apart. A pooled analysis of data from the comparator-controlled and single-arm studies of the 3-month implant was also conducted. The main inclusion criterion for all studies was histologically confirmed advanced prostate cancer, with primary endpoints based around successful testosterone suppression (≤0.5 ng/ml). RESULTS: In the comparator-controlled studies, both implants were as effective as the microspheres for achieving successful testosterone suppression and normalization of prostate-specific antigen (PSA) levels. Data from the single-arm and long-term studies were consistent with those from the comparator-controlled studies. In the pooled analysis, significantly more patients treated with the 3-month implant achieved successful testosterone suppression compared with the comparator (p ≤ 0.01). The safety profile of the implants in the comparator-controlled studies was similar to that of the prolonged-release microsphere formulation, and consistent with that of the luteinizing hormone-releasing hormone agonist class. CONCLUSIONS: The innovative 1-month and 3-month implants of leuprorelin acetate are at least as effective as leuprorelin acetate prolonged-release microspheres for achieving successful testosterone suppression and normalization of PSA in men with advanced hormone-dependent prostate cancer, with a comparable safety profile.

Biosimilar rhG-CSFs: how similar are they?

Biosimilars are more affordable copycat versions of originator biological products in much the same way as generics are copies of small molecule pharmaceuticals. However, while generics are approved on the basis of structural and pharmacokinetic equivalence, the intricate structure of biological medicinal products and the complex nature of their manufacturing process in living organisms impose a separate, and more stringent, regulatory approval process. The aims of this article are (a) to discuss key aspects of the development process and authorization requirements for biosimilars in Europe using published comparative physicochemical and clinical data for EU-approved recombinant human granulocyte colony stimulating factor (rhG-CSF) biosimilars, the most recent addition to the therapeutic category of hematopoietic growth factors, and (b) to demonstrate that the rigorous scientific evaluation process is designed to ensure that their clinical safety and efficacy is not compromised by the abbreviated development program.

Bioequivalence studies of omnitrope, the first biosimilar/rhGH follow-on protein: two comparative phase 1 randomized studies and population pharmacokinetic analysis.

This article discusses the bioequivalence of Omnitrope (Sandoz's rhGH biosimilar) and Genotropin (reference rhGH product), assessed in the first 2 clinical phase 1 studies conducted during the development of Omnitrope. Both of these phase 1 studies were randomized, double-blind, crossover studies, each involving 24 healthy volunteers who underwent pituitary somatrope cell down-regulation using octreotide. Three different formulations of recombinant human growth hormone (rhGH) were compared: Omnitrope lyophilisate, Omnitrope liquid and Genotropin (lyophilized powder for injection). Both pharmacokinetics (area under the curve [AUC], C(max), t(max) and t(1/2)) and pharmacodynamics (serum levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3 and non-esterified fatty acid) were assessed after a single subcutaneous injection of 5 mg rhGH. The 3 formulations had comparable pharmacokinetics and pharmacodynamics. All the 90% confidence intervals of the ratios of the least squares means for the pharmacokinetic and pharmacodynamic parameters AUC and C(max) were within the predefined FDA and EMEA acceptance range of 80%-125% for bioequivalence. In addition, a comparative population pharmacokinetic analysis further supports that Omnitrope lyophilisate, Omnitrope liquid and Genotropin can be regarded as equivalent in terms of pharmacokinetics. Therefore, Omnitrope lyophilisate was demonstrated to be bioequivalent to both Genotropin and the Omnitrope liquid formulation.