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Can One Predict Unpredictable?
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
Another well-known issue is not paying attention to safety signals in small phase I studies—it is in our best interest to confirm or reject them in phase II, before embarking on a long and expensive phase III program. Another piece of advice comes from our personal experience—we would never know it had we not experienced the nightmarish BLA submission described in Chapter 6. When going into a pivotal trial, we should make sure that we are going to test our drug against the same comparator that was used to get promising preliminary efficacy results.
Globally Optimal Adaptive Trial Designs
Published in Mark Chang, John Balser, Jim Roach, Robin Bliss, Innovative Strategies, Statistical Solutions and Simulations for Modern Clinical Trials, 2019
Mark Chang, John Balser, Jim Roach, Robin Bliss
To search an optimal design phase 3 trial, we not only need to have the estimate the effect size of the treatment, but also need to know the distribution of effect size or the posterior distribution of the effect size up per the data cumulated so far up to the phase 2 trials. Assume the calculated posterior is shown in Table 4.2 (the derivation will be discussed later). This posterior will serve as the prior for the pivotal trial to be designed (Table 4.3).
Regulatory and Policy Aspects of Platform Trials
Published in Zoran Antonijevic, Robert A. Beckman, Platform Trial Designs in Drug Development, 2018
Rasika Kalamegham, Ramzi Dagher, Peter Honig
Further characteristics of a persuasive clinical trial include: relatively broad patient inclusion criteria; diverse study populations with regards concomitant or prior treatment, disease stage, age, gender, race and other baseline demographics; multiple endpoints that measure different aspects of disease or disease burden each showing relevant and statistically significant benefits. Finally, it should be noted that the FDA guidance calls for a single pivotal trial to have a statistically very persuasive finding (i.e., very low p-value) to protect against Type I (False Positive) inferential error. In addition to the substantial experience in oncology, several non-oncology drugs have received initial full approval based on a single pivotal trial including ticagralor and prasugrel for cardiac event risk reduction following acute coronary syndrome (ACS) and both are excellent examples of a single pivotal trial that have the desired clinical and statistical features described above (9, 10).
Corneal cross-linking versus conventional management for keratoconus: a lifetime economic model
Published in Journal of Medical Economics, 2021
Richard L. Lindstrom, John P. Berdahl, Eric D. Donnenfeld, Vance Thompson, David Kratochvil, Chiang Wong, Heather Falvey, Grace Lytle, Marc F. Botteman, John A. Carter
The model individually simulated the disposition of 2,000 patients and 4,000 eyes. Baseline patient characteristics were consistent with those reported in the US multicenter clinical trials comparing CXL versus a sham control with riboflavin but without removal of the epithelium. This pivotal trial program was conducted in support of the US FDA new drug application (NDA no. 203324) for the iLink drug and device combination product that was approved by the FDA in 2016. The trials included N = 205 patients and demonstrated the effectiveness of CXL for stopping the progression of keratoconus. Key effectiveness outcomes include a decrease of 1.6 diopters for maximum keratometry and improved corrected distance visual acuity of 5.7 logMAR units observed over 12 months1.
Evolution of the inclusion/exclusion criteria and primary endpoints in pivotal trials of biologics and small oral molecules for the treatment of psoriasis
Published in Expert Review of Clinical Pharmacology, 2020
Shao-Hsuan Hsu, Tsen-Fang Tsai
The safety concern of current biologics was best reflected by their exclusion criteria in the pivotal trial designs. In short, patients with active tuberculosis, HBV/HCV/HIV infections, recurrent/disseminated zoster, psychiatric problems, significant cardiovascular problems, recent malignancies, and pregnancy were excluded. For the case of HBV, there is a trend to use HBV DNA positivity, and not only HBsAg positivity as exclusion criterion. Patients with latent tuberculosis were more fortunate and most trials allowed concomitant use of tuberculosis prophylaxis and the active treatment of the trials. In fact, a recent trial of risankizumab even allowed patients treated by risankizumab to receive tuberculosis prophylaxis under the discretion of the investigators. This is a welcome relaxation of the exclusion criteria of biologics. With the presence of effective or even curative anti-viral treatment, future studies should probably also include patients with HBV, HCV, and HIV infections. The safety of biologics during pregnancy is accumulating, and hopefully, women planning to become pregnant should also be allowed for the usage of biologics, probably with a biologic of a modified structure, like certolizumab pegol.
Novel Therapies for Sleep Apnea—The Implants Have Arrived!
Published in The Neurodiagnostic Journal, 2018
Edwin M. Valladares, Terese C. Hammond
The remedē® System received FDA approval to treat adult patients with moderate to severe central sleep apnea, which is broad and nonspecific to the type of central sleep apnea (Respicardia: remedē® 2010). Respicardia, Inc., recommends using selection criteria used during their pivotal trial. During the pivotal trial, patients were 18 years of age or older, with a conducted polysomnography (PSG) test within the last 40-days evidencing an Apnea-Hypopnea Index (AHI) of at least 20/hour, central apneas being at least 50% or higher of all apneas, ≥30 central apneas events throughout the night, and an obstructive apnea index (OAI) of 20%. Contraindications for device implantation are active infection and need for magnetic resonance imaging (MRI) (Respicardia: remedē® 2010). The pivotal study’s exclusion criteria also included phrenic nerve palsy, stage D heart failure, cerebrovascular event within the past 12 months, central sleep apnea secondary to opioids, and advanced renal disease (Costanzo et al. 2016). These criteria make the remedē® System potentially useful in treating patients with heart failure and low ejection fractions, in who adaptive servo ventilation (ASV) therapy is not recommended (Cowie et al. 2015).