Establishing the suitability of model-integrated evidence to demonstrate bioequivalence for long-acting injectable and implantable drug products: Summary of workshop.

On November 30, 2021, the US Food and Drug administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled "Establishing the Suitability of Model-Integrated Evidence (MIE) to Demonstrate Bioequivalence for Long-Acting Injectable and Implantable (LAI) Drug Products." This workshop brought relevant parties from the industry, academia, and the FDA in the field of modeling and simulation to explore, identify, and recommend best practices on utilizing MIE for bioequivalence (BE) assessment of LAI products. This report summerized presentations and panel discussions for topics including challenges and opportunities in development and assessment of generic LAI products, current status of utilizing MIE, recent research progress of utilizing MIE in generic LAI products, alternative designs for BE studies of LAI products, and model validation/verification strategies associated with different types of MIE approaches.

Indian experience with immunotherapy in sarcoma and gastrointestinal stromal tumors: a retrospective study.

Aim: To study the role of check point inhibitors (CPI) in sarcoma and gastrointestinal stromal tumors. Materials & methods: Retrospective data of 15 patients diagnosed with advanced sarcoma or gastrointestinal stromal tumors and treated with CPI. Results: 3/14 patients (21.4%) responded to treatment with a disease control rate of 42.8% (6/14). After a median follow-up of 14 months (range: 2-24 months), 11 (73.3%) patients progressed, the median progression-free survival was 4 months (95% CI: 1.7-6.3) and median overall survival was 14 months (95% CI: 2.6-25.7). Only one patient experienced a grade IV adverse event. Conclusion: Our data represent the first real-world application of CPI in sarcoma from India. We believe that CPI should be further evaluated in clinical trials.

Physiologically based absorption modeling to predict bioequivalence of controlled release and immediate release oral products.

Physiologically based absorption modeling was conducted to predict bioequivalence (BE) for immediate release (IR) and controlled release (CR) formulations. In case of the CR formulation of a BCS class 1 drug, sensitivity analyses were conducted to investigate the impact of gastrointestinal (GI) transit time and absorption scaling factors in caecum and colon on formulation PK. The regional absorption profiles of the test and reference formulations were compared to provide additional confidence on the BE predictions. For IR formulation of BCS class 2b drug, the sensitivity of dissolution rate, precipitation time and human permeability were evaluated. Finally for both cases, population simulations were conducted in crossover manner to investigate BE between formulations, and compared with the observed data. These case studies highlight the utility of absorption modeling in prediction of BE. Such modeling can be used for development of innovator and generic products, as well as to address questions arising during regulatory reviews.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study.

BACKGROUND: Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX. OBJECTIVE: This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy. METHODS: This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for > or =3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg i.v. or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg i.v. or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve. RESULTS: Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24-73 years), and the mean body weight was 69.7 kg (range, 43-98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events. CONCLUSIONS: Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX (P < or = 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumab's long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.

A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis.

OBJECTIVE: To assess the pharmacokinetics, safety profile, and efficacy of the fully human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody adalimumab (D2E7) in patients with long-standing, active rheumatoid arthritis (RA). METHODS: This was a randomized, double blind, placebo controlled study of single intravenous injections of ascending doses (0.5 to 10 mg/kg) of adalimumab in 5 cohorts of 24 patients each (18 adalimumab and 6 placebo in all cohorts except the 0.5 mg/kg cohort of 17 adalimumab, 7 placebo). A total of 120 patients participated (adalimumab 89, placebo 31). The clinical response was measured by changes in composite scores defined by the criteria of the European League Against Rheumatism (EULAR) and the American College of Rheumatology. RESULTS: Single doses of adalimumab showed a rapid onset of clinical effect (24 hours to 1 week), with peak efficacy at 1 to 2 weeks that was sustained for at least 4 weeks and for as long as 3 months in some patients. EULAR response was seen at least once during the 4 week period after drug injection in 29% of patients in the placebo group as well as in 41%, 78%, 72%, 89%, and 100% in the 0.5, 1, 3, 5, and 10 mg/kg groups, respectively. No dose related increases in adverse events were observed in the adalimumab patients compared with the placebo group. Adalimumab systemic drug exposure (AUC0-( )) increased linearly with an increase in dose. The mean total serum clearance was 0.012 to 0.017 l/h, and the steady-state volume of distribution ranged from 4.7 to 5.5 l. The estimated mean terminal half-life ranged from 10.0 to 13.6 days for the 5 cohorts, with an overall mean half-life of 12 days. CONCLUSION: Treatment with the fully human Mab adalimumab was safe and well tolerated when administered as a single intravenous injection at doses up to 10 mg/kg, and was associated with a clinically significant improvement in the signs and symptoms of active RA.