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Operational Characteristics of Proof-of-Concept Trials with Biomarker-Positive and -Negative Subgroups
Published in Nusrat Rabbee, Biomarker Analysis in Clinical Trials with R, 2020
In addition to the cutoff for the biomarker positivity (negativity), I assume that the prevalence of the marker-positive population is known at the time of designing the clinical trial. While it is generally assumed that treatment effect in BM+ group is higher, clear evidence does not exist that the agent is not active in the biomarker-negative subgroup. Hence, the justification for doing a confirmatory trial in the marker-positive subgroup needs to be established. Alternatively, the PoC study will guide us to do the confirmatory trial in all subjects.
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
For instance, suppose we are designing a confirmatory trial to demonstrate superiority of the new drug over a placebo. The analysis objective is formulated as: “To reject the null hypothesis of no treatment difference at the 5% significance level (one-sided P-value < 0.05)”. Therefore, for the design objective, we would require that the study sample size n should be such that there is, say, 90% probability of achieving the analysis objective (one-sided P-value < 0.05), if the true mean treatment difference equals some clinically meaningful value Δ > 0.
Sample Size Calculations for Phase III Trials in Oncology
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Sample size calculation is one of several crucial points when researchers plan a new trial because the number of patients directly relates to the feasibility of the study (e.g., how many investigators can actually enroll patients, or can the investigators acquire the necessary funding). In addition, designing trials that are too large or too small (relative to the objective) may be considered unethical [1]. Especially in phase III clinical trials (sometimes defined as a therapeutic confirmatory trial [2]), it is important to assure high probability (statistical power) to confirm an assumed difference in each study hypothesis as a statistically significant difference, if such a difference exists.
Patient-reported outcomes validated in phase 3 clinical trials: a targeted literature review
Published in Current Medical Research and Opinion, 2023
Antonia Morga, Silvia Dibenedetto, Rocco Adiutori, Jun Su
While appropriate use of PRO data can support medical labelling claims, clinical trials that have not selected an appropriate PRO measure, or one that has not been properly validated, may have subsequent PRO-based labelling claims declined5,11. The US Food and Drug Administration (FDA) specifies that PRO data can support labelling claims if the PRO instrument is well-defined, reliable, used in accordance with the instrument’s documented measurement capability, and validated in the target population1. Guidance from Europe also indicates that PRO validation should preferably take place ahead of their inclusion in a phase 3 confirmatory trial8. However, early PRO instrument validation can be challenging since the outcomes and measures that are most important for the target population are often selected late in the clinical trial program12. For this reason, PRO analyses tend to be more prominent in post-marketing, observational research, rather than pre-approval clinical trial programs12, limiting their inclusion in labelling claims and availability of patient-reported information to healthcare providers, patients, and other stakeholders. Omission of PRO data creates an incomplete picture, particularly for patients deciding whether to start treatment, for whom information about the user experience is particularly meaningful.
TRICALS: creating a highway toward a cure
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Ruben P.A. van Eijk, Tessa Kliest, Christopher J. McDermott, Kit C.B. Roes, Philip Van Damme, Adriano Chio, Markus Weber, Caroline Ingre, Philippe Corcia, Mònica Povedano, Evy Reviers, Michael A. van Es, Ammar Al-Chalabi, Orla Hardiman, Leonard H. van den Berg
In order to improve the translational power of exploratory to confirmatory trials, the follow-up duration of exploratory trials should be increased to at least 6 months and indicate a response in biomarkers of target engagement, or in multiple clinical endpoints, prior to initiation of a confirmatory trial. As showing a therapeutic benefit on mortality is required by European regulators for market authorization (25), the follow-up duration of confirmatory trials should be increased to at least 12 months in order to design trials with feasible sample sizes (27). Halting or slowing motor neuron degeneration may be slow, and take time to manifest in trial endpoints. The power to quantify a survival benefit can be improved by employing the Joint Modeling Framework (14). In addition, remote digital technology can help to further define the real-world functional benefits of a therapeutic intervention (13,27,28), whereas extensive training on outcome measures as organized by TRICALS and Northeast ALS Consortium (NEALS) may warrant quality control and minimize endpoint variability (5,15).
Atezolizumab for the treatment of colorectal cancer: the latest evidence and clinical potential
Published in Expert Opinion on Biological Therapy, 2018
Gonzalo Tapia Rico, Timothy J. Price
In September 2017, the FDA granted pembrolizumab accelerated approval for the treatment of adult and pediatric patients with unresectable or metastatic refractory MSI-H/dMMR solid tumors including breast, prostate, bladder, endometrial, thyroid and other gastrointestinal cancers. This was the FDA’s first-ever tissue/site-agnostic approval. Pembrolizumab has also been approved for patients with MSI-H/dMMR mCRC following progression on standard chemotherapy agents. These approvals were based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm studies [37–41]. Of those 149, 90 patients had mCRC, while the remaining 59 patients had 1 of 14 other tumor types. The ORR with pembrolizumab was 39.6%, including 7.4% CR and 32.2% PR. Among patients who responded to pembrolizumab, 78% had durable responses for at least 6 months or longer. Among the 90 mCRC patients, the ORR was 36% (95 CI 26–46%) lasting up to almost a year [38]. The accelerated approval for pembrolizumab in this setting is contingent, however, on the results of a confirmatory trial.