Proof of Concept: Drug Selection? Or Dose Selection? Thoughts on Multiplicity Issues

Li, Qian H; Deng, Qi; Ting, Naitee

doi:10.1007/s43441-021-00299-4

Cited by 3 publications

(3 citation statements)

References 10 publications

(9 reference statements)

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“…In addition, it is important to generate a dataset supporting clinical proof-ofmechanism (POM), defined as evidence that a molecule reaches the desired target tissue and modulates its target and downstream biology in a manner and magnitude consistent with the therapeutic hypothesis [97]. Phase 2 trials subsequently support a clinical proof-ofconcept (POC), representing early evidence of clinical efficacy to enable decision-making on progression to larger, registrational phase 3 trials [98]. POM and POC are key de-risking steps in the development path of a new medicine, and each of these milestones is associated with an increased probability of future clinical success [99].…”

Section: Limitations and Opportunities For Flow Cytometric Techniques...mentioning

confidence: 99%

Applications of Flow Cytometry in Drug Discovery and Translational Research

Ullas,

Sinclair

2024

IJMS

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Flow cytometry is a mainstay technique in cell biology research, where it is used for phenotypic analysis of mixed cell populations. Quantitative approaches have unlocked a deeper value of flow cytometry in drug discovery research. As the number of drug modalities and druggable mechanisms increases, there is an increasing drive to identify meaningful biomarkers, evaluate the relationship between pharmacokinetics and pharmacodynamics (PK/PD), and translate these insights into the evaluation of patients enrolled in early clinical trials. In this review, we discuss emerging roles for flow cytometry in the translational setting that supports the transition and evaluation of novel compounds in the clinic.

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Section: Limitations and Opportunities For Flow Cytometric Techniques...mentioning

confidence: 99%

Applications of Flow Cytometry in Drug Discovery and Translational Research

Ullas,

Sinclair

2024

IJMS

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“…Efficacy can be tested by PoC studies designed for drug development to test if a new drug works. Those phase 1 or phase 2 studies actually look at efficacy after the safety of a new drug has been tested on healthy volunteers (3). The study by de Vries (1) appears to be an external pilot study as it was designed and conducted to test feasibility of all traits of a future full scale trial (4).…”

Section: To the Editormentioning

confidence: 99%

“…Effectiveness studies assess the potential effect that can be obtained in real-world settings (3). It has been reasoned that most clinical interventional trials occur on a continuum between these phases, as it is difficult to conduct a pure efficacy or pure effectiveness study in a real-world situation in heterogeneous patient categories (3).…”

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confidence: 99%

Proof of Concept, Feasibility, and Efficacy Trials

Chandelia

2022

Critical Care Medicine

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Iread with interest the article published in a recent issue of Critical Care Medicine by de Vries (1). I appreciate the novel concept and its implementation. The authors state that this is the "first study to investigate feasibility and efficacy. " However, I have concerns whether it would be correct to say that the study by de Vries (1) investigated efficacy. First, the study's primary and secondary outcomes are feasibility outcomes and not efficacy outcomes. The authors showed that a bedside titration ventilation algorithm is possible which can achieve diaphragm-protective ventilation without compromising lungprotective ventilation. Whether this novel intervention resulted in improved patient-/laboratory-centered outcomes was not the study's aim. The outcomes such as diaphragm anatomy, physiology, excursion or effect of intervention on patient mortality, length of ICU/hospital stay, and ventilator-free days would have been efficacy outcomes (written as limitation in the article) (2). Second, for proving efficacy, one needs to include an adequate sample size with adequate power to have robust statistic calculation. The authors used "proof of concept" (PoC) and "feasibility" interchangeably for design of study. Efficacy can be tested by PoC studies designed for drug development to test if a new drug works. Those phase 1 or phase 2 studies actually look at efficacy after the safety of a new drug has been tested on healthy volunteers (3). The study by de Vries (1) appears to be an external pilot study as it was designed and conducted to test feasibility of all traits of a future full scale trial (4). But, the study has prepared the base for future studies for which authors must be commended.The authors write they did "intention to treat" (ITT) analysis. They excluded one patient (who self extubated) after getting randomized to intervention arm. The authors analyzed 19 patients, whereas they randomized 20 patients in intervention arm. This goes against the principle of ITT. What the authors have done appears to be "modified ITT. " In modified ITT, one can exclude some patients assessed to be disqualified after randomization or who never started the treatment (the case in the study by de Vries [1]) (5). But, this approach seems justified as authors did not have any data on primary outcome for this excluded patient. However, we can expect that this will have effect on overall analysis of patient mortality, total hospital/ICU stay, and total ventilator days. This factor needs to be taken care of, if a large-scale trial is planned in future.The limitations of the study are not actually limitations in my opinion. These limitations come hand in hand with a feasibility study. Simply, the outcomes could have been: 1) whether participants (and how many) can be recruited, 2) whether intervention is applicable/feasible, and 3) the extent of missing data. For feasibility outcomes, there is no need to calculate the statistical significance of the results. Small sample size and restricted analysis are all traits of a feasibility ...

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Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa: a randomized double-blind placebo-controlled clinical trial

Alavi,

Prens,

Kimball

et al. 2024

British Journal of Dermatology

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Background Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies. Objective To explore the effects of spesolimab treatment in patients with HS. Methods This randomized, double-blind, placebo-controlled, proof-of-clinical-concept study was conducted at 25 centers across 12 countries from May 3, 2021, to April 21, 2022. Patients had moderate-to-severe HS for ≥1 year before enrollment. Patients were randomized (2:1) to receive a loading dose of 3600 mg intravenous spesolimab (1200 mg at Weeks 0, 1, and 2) or matching placebo, followed by maintenance with either 1200 mg subcutaneous spesolimab every 2 weeks from Week 4–10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at Week 12. Secondary endpoints were the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of zero, absolute change from baseline in revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥1 flare (all at Week 12), and patient-reported outcomes (PROs). Results In this completed trial, randomized patients (N=52) received spesolimab (n=35) or placebo (n=17). The difference (95% confidence interval) versus placebo in least squares mean are reported. At Week 12, the percentage change in total AN count was similar between treatment arms: −4.1% (−31.7, 23.4). There was greater numerical improvement in the spesolimab arm, as measured by IHS4: −13.9 (−25.6, −2.3); percentage change from baseline in dT count: −96.6% (−154.5, −38.8); and the proportion of patients achieving a dT count of zero: 18.3% (−7.9, 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 versus placebo. Spesolimab demonstrated a favorable safety profile, similar to that observed in trials in other diseases. Conclusions This exploratory proof-of-clinical-concept study supports the development of spesolimab as a new therapeutic option in HS. ClinicalTrials.gov identifier: NCT04762277.

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Proof of Concept: Drug Selection? Or Dose Selection? Thoughts on Multiplicity Issues

Cited by 3 publications

References 10 publications

Applications of Flow Cytometry in Drug Discovery and Translational Research

Applications of Flow Cytometry in Drug Discovery and Translational Research

Proof of Concept, Feasibility, and Efficacy Trials

Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa: a randomized double-blind placebo-controlled clinical trial

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