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Pharmogenology: The Industrial New Drug Development Process
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
It is necessary to do a full dose-ranging study prior to selection of the dose levels used in the carcinogenicity studies. This is done to establish an upper dose that is sufficiently high as to be intoxicating yet not so great as to induce excessive mortality and thus decrease the high dose population necessary to elicit and observe the incidence of tumorgenicity. It usually requires a full year for comprehensive tissue preparation, examination, and reporting after the study is completed and the animals have been sacrificed. The histopathology studies are best performed by experts in animal pathology.
Dose Ranging Studies and Dose Determination
Published in Emmanuel Lesaffre, Gianluca Baio, Bruno Boulanger, Bayesian Methods in Pharmaceutical Research, 2020
Phil Woodward, Alun Bedding, David Dejardin
Dose ranging studies are a critical part of drug development to determine the range of doses that determine the therapeutic window, defined as the difference between the minimal dose providing benefit and the maximum safe dose. In order to correctly determine the therapeutic window, dose response studies are carried out. These studies will ideally model the dose response relationship to determine not only the therapeutic window but also the optimal dose for a future study. The dose response is also critical if, at a later stage of development, a dose adjustment is needed. Generally, the determination of dose, and thus a dose ranging study, is carried out differently in oncology than in other therapeutic areas. In oncology, dose determination is carried out in a Phase I dose escalation trial, which will determine the dose to take into Phase III, thus obviating the need for Phase II. However, outside oncology the dose determination is done in a Phase II dose response study. In the next two sections, we will detail first dose finding studies in non-oncology situations and then in oncology studies. Since generic dose ranging methods apply more broadly to all therapeutic areas we cover the non-oncology studies first. We then go on to describe methods specific to dose escalation designs in oncology.
Bayesian Probability of Success for Go/No-Go Decision Making
Published in Mani Lakshminarayanan, Fanni Natanegara, Bayesian Applications in Pharmaceutical Development, 2019
The above posterior distributions serve as priors for predicting results of the next clinical trial. Step 1 of POS calculation is finished. Step 2, the design of the future study, is a parallelly randomized double-blind dose-ranging study with 150 subjects per arm. Steps 3–6 can be implemented in R using the codes below.
Investigational drugs in clinical trials for macular degeneration
Published in Expert Opinion on Investigational Drugs, 2022
Michael J Tolentino, Andrew J Tolentino
Avacincaptad pegol is an anti-C5 aptamer that directly inhibits membrane attack complex formation. A phase II/III randomized controlled dose ranging study GATHER1 trial was a 2-part study. Part 1 randomized patients to 1,2, mg Avacincaptad pegol and sham. Part 2 randomized patients to 2 mg, 4 mg of Avacincaptad pegol and sham. The 2 and 4 mg dosed patients achieved a 27.3% (p value = 0.0072) and 27.8% reduction (p value = 0.0051), respectively, in the mean rate of GA growth as compared with the sham group [135] CNV was reported in the fellow eyes of 10 participants (3.5%), in the study eye of 3 participants (2.7%) in the sham cohort, 1 participant (4%) in the Avacincaptad pegol 1 mg cohort, 6 participants (9%) in the 2 mg cohort and in 8 participants (9.6%) in the 4 mg cohort. No endophthalmitis occurred in any of the arms. A second confirmatory phase III trial is underway (GATHER2).
Upadacitinib for moderate-to-severe atopic dermatitis, in adults and adolescents 12 years and older: review of international and Japanese populations
Published in Expert Review of Clinical Immunology, 2023
Mitsumasa Kishimoto, Gautam A. Deshpande, Sho Fukui, Yoshinori Komagata, Manabu Ohyama, Shinya Kaname
The application for a new indication for upadacitinib in AD in Japan is primarily supported by four pivotal phase III studies: two mono-therapy studies (M16-045 and M18-891) [11] and two studies with upadacitinib used in combination with TCS (M16-047 and M17-377) [12,13]. Study M17-377 was conducted only in Japan. A phase II dose-ranging study (Study M16-048) is also included as supportive data for the dosing recommendation [49]. After the approval of upadacitinib for AD in Japan, a head-to head study (M16-046) was also reported, comparing upadacitinib and dupilumab [49]. A tabular overview of the pivotal clinical studies is shown in Table 6.
Chronic cough: Investigations, management, current and future treatments
Published in Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, 2021
I. Satia, M. Wahab, E. Kum, H. Kim, P. Lin, A. Kaplan, P. Hernandez, J. Bourbeau, L. P. Boulet, S. K. Field
High dose nebulized sodium cromoglycate reduced cough frequency by 31% in patients with idiopathic pulmonary fibrosis (IPF), but not in patients with RCC.103 The mechanism of action is unclear, but has been reported to reduce c-fiber activity by an orphan g-protein coupled receptor, GPR35.104 A phase 2 b 12-week study dose-ranging study is currently underway.