China
Africa
Explore chapters and articles related to this topic
Meta-Analysis of Dose-Response Relationships
Published in Christopher H. Schmid, Theo Stijnen, Ian R. White, Handbook of Meta-Analysis, 2020
Nicola Orsini, Donna Spiegelman
We assess the possible non-linear dose-response relationship (elevated mortality rates at the extremes of the age distribution), while taking into account confounders, by using restricted cubic splines with three knots at 42, 61, and 78 years (10th, 50th, and 90th percentile of the overall age distribution). Figure 18.9 shows similar average dose-response shapes estimated on individual and summarized data. Statistical tests for the overall association between age and mortality (individual data: = 38.6, p-value < 0.001; summarized data: = 19.14, p-value < 0.001) and departure from linearity (individual data: = 8.21, P = 0.004; summarized data: = 5.65, p-value = 0.018) are consistent under the two approaches.
Biostatistics
Published in Arkadiy Pitman, Oleksandr Sverdlov, L. Bruce Pearce, Mathematical and Statistical Skills in the Biopharmaceutical Industry, 2019
Arkadiy Pitman, Oleksandr Sverdlov, L. Bruce Pearce
Phase II is arguably one of the most important and challenging parts in the entire development process [97], because it bridges the exploratory (phase I) and the confirmatory (phase III) stages. Ideally, at the end of phase II we want to have a high probability of making the correct decision on whether to continue the development of the compound (by investing in large and expensive phase III pivotal trials), or stop the development. Some important research questions to be addressed in phase II are as follows [90]: Is there any evidence of the drug effect (“proof-of-concept”)?Which dose(s) exhibit(s) a response different from the control?What is the dose-response relationship?What is the “optimal” dose?
Dose–Response
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
A predetermined number of animals, at least 10 animals per dose and 10 doses per chemical, are selected. Groups of animals are subjected to increasing single doses of the test substance (the dose is calculated as milligrams of substance per kilogram of body weight [mg/kg]). The number of animals that expire within the group at the end of a predetermined time period (usually 24 to 96 hours) is converted to a percentage of the total animals exposed to the chemical. A dose–response relationship is constructed, and the 50% extrapolation is computed from the curve (see Figure 7.2).
Tebentafusp in advanced uveal melanoma: proof of principle for the efficacy of T-cell receptor therapeutics and bispecifics in solid tumors
Published in Expert Opinion on Biological Therapy, 2022
Alex W. Liu, Alexander Z. Wei, Ashray B. Maniar, Richard D. Carvajal
In the first-in-man phase I clinical trial of tebentafusp (Table 2), 84 patients with metastatic or unresectable melanoma who were HLA-A2 positive received treatment on either a weekly (n = 66) or a daily (n = 18) dosing schedule [43]. Nineteen of the 84 patients treated had advanced uveal melanoma, while the remaining 65 patients were predominantly cutaneous melanoma. Weight-based dosing determined a maximum tolerable dose (MTD) of 600 ng/kg on the weekly dosing schedule, with hypotension during the first 2 weeks of treatment as the observed dose limiting toxicity (DLT) occurring in 2 of 4 patients treated at 900 ng/kg. The recommended phase 2 dose (RP2D) for the weekly schedule was set at a flat dose of 50 mcg. Six patients achieved partial responses (PR), for an objective response rate (ORR) of 8.7%; however, there appeared to be a dose response relationship. Of the patients who received tebentafusp at a dose of 600 mg/kg or greater (n = 26), PRs were observed in approximately 15% of evaluable patients, including those refractory to CPIs. Furthermore, three of the six responses occurred in patients with uveal melanoma, representing a 16% response rate (RR) in this patient subset. A 1-year OS rate of 65% was observed, with similar rates for both uveal and non-uveal patients.
The impact of supportive care on survival in large animal models of total body irradiation
Published in International Journal of Radiation Biology, 2021
Karla D. Thrall, Saikanth Mahendra, Jamie Lovaglio, M. Keven Jackson
For the study reported here, the initial selection of irradiation doses for comparison of lethality with and without supportive care with the Gottingen minipig was based on a prior publication by Moroni et al. (2011b) indicating an estimated LD50 of 1.73 Gy using total body irradiation, bilateral 60Co exposures at a dose rate of 60 cGy min−1 with no provision for supportive care. The dose response relationship profile established under similar exposure conditions and under limited supportive care measures was used to estimate a somewhat higher LD50 value of 1.96 Gy. Provision of standard supportive care shifted the lethality to the right, and a LD50 value of 2.15 Gy was estimated. Thus, in the minipig, provision of antibiotics and fluids administered on a set regimen regardless of symptom or indication provided a DMF of 1.09 (LD50 under standard supportive care to LD50 under limited supportive care ratio).
An overview of regulations for bioequivalence assessment of locally acting orally inhaled drug products for the United States, Europe, Canada, and India
Published in Expert Opinion on Drug Delivery, 2021
Prajakta P. Patil, Atmaram P. Pawar, Kakasaheb R. Mahadik, Vinod L. Gaikwad
However, that are some recommendations specific to India, as listed below: The acceptance range stated for pharmacokinetic-bioequivalence studies does not apply to pharmacodynamic studies.The test and reference drug should not produce maximum response throughout the entire study as it may prove impossible to discriminate between the formulations given in doses required to produce the maximum response.The necessity for investigation of a dose-response relationship.The criteria for the identification of responders and non-responders must be clearly stated within the protocol. The prior screening must be used to exclude non-responders from the study.If the pharmacodynamic studies are not decisive, then clinical trials should be conducted.