Design and Conduct Considerations for First‐in‐Human Trials

Shen, Jie; Swift, Brandon; Mamelok, Richard D.; Pine, Samuel O.; Sinclair, John; Attar, Mayssa

doi:10.1111/cts.12582

Cited by 107 publications

(87 citation statements)

References 46 publications

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“…Safety pharmacology/pharmacokinetic studies evaluate the impact of an investigational product on the respiratory, cardiovascular, and central nervous systems. The concern that a new therapy could result in an arrhythmia that was not detected in preclinical animal models is the underlying reason that initial cardiovascular assessments in early human studies often include an evaluation of a drug's potential for prolongation of the QT interval 12 …”

Section: Preclinical Drug Developmentmentioning

confidence: 99%

“…The dose range in animal studies should be broad enough that the no observed adverse effect level (NOAEL) is established, which should be greater than the maximum exposure expected to be used in humans. The NOAEL is the most common method for determining a safe starting dose for human trials, but it is not the only method 12 …”

Section: Preclinical Drug Developmentmentioning

confidence: 99%

“…Phase I studies are short (a participant may receive the candidate drug for days to weeks) and conducted at centers that specialize in Phase I trials. Only events (safety and efficacy) that occur frequently will be detected in Phase I studies due to their small number of subjects and short duration 12 . Because FIH studies are small and likely underpowered, some investigators have questioned whether inclusion of a placebo group is justified or useful 12,17 .…”

Section: Clinical Developmentmentioning

confidence: 99%

“…Only events (safety and efficacy) that occur frequently will be detected in Phase I studies due to their small number of subjects and short duration 12 . Because FIH studies are small and likely underpowered, some investigators have questioned whether inclusion of a placebo group is justified or useful 12,17 . Once Phase I is complete, approximately 70% of drug candidates move on to Phase II trials 18 …”

Section: Clinical Developmentmentioning

confidence: 99%

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Drug development for cystic fibrosis

Sanders

Chmiel

2021

Pediatric Pulmonology

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The first regulatory approval for a drug developed specifically for cystic fibrosis (CF) occurred in 1993, and since then, several other drugs have been approved. Median predicted survival in people with CF in the United States has increased from approximately 30 years to 44.4 years over that same period. Highly effective modulators of the cystic fibrosis transmembrane conductance regulator became available to approximately 90% of people with CF ages 12 years and older in the United States in 2019 and in Europe in 2020. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies advance, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in outcome measures has become more difficult as the health status of people with CF improves. Innovative approaches are required to continue to advance drug development in CF. This review provides a general overview of drug development from the preclinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF.

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Section: Preclinical Drug Developmentmentioning

confidence: 99%

Section: Preclinical Drug Developmentmentioning

confidence: 99%

Section: Clinical Developmentmentioning

confidence: 99%

Section: Clinical Developmentmentioning

confidence: 99%

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Drug development for cystic fibrosis

Sanders

Chmiel

2021

Pediatric Pulmonology

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“…The sample size of 10 participants per cohort is a commonly used number in early studies. 13 The steps recommended in the US Food and Drug Administration's Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers 14 were followed for the estimation of the starting dose. On normalizing the experimentally determined nontoxic dosage level for surface area, the most sensitive preclinical animal species examined was the dog.…”

Section: Single Ascending Dose Study Proceduresmentioning

confidence: 99%

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers

Naik

Steiner

Versavel

et al. 2020

Clinical Translational Sci

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Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage-dependent and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (C max ), area under the concentrationtime curve from predose to 24 hours postdose (AUC 0-24 ), time to C max (T max ), and terminal half-life (t1/2), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that C max and AUC increased with dose, T max was 1-2 hours, and t 1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady-state was achieved from day 5 onward. These data indicate that oral vixotrigine is well-tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.Neuropathic pain can arise from a lesion or disease of the somatosensory system, including peripheral fibers (Aβ, Aδ, and C fibers) and central neurons. 1 The signs and symptoms of neuropathic pain include allodynia, spontaneous paroxysmal pain, hyperalgesia, and, on occasion, causalgia or incessant burning pain. 2 The estimated prevalence of neuropathic pain in the general population is 6.9-10%. 3 Substantial impairment of quality of life is caused due to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. 1 Voltage-gated sodium channels (Navs) are complex transmembrane proteins responsible for the initiation and propagation of action potentials in neurons. 4 Gain-offunction changes produced by missense substitutions in the genes encoding Nav1.7-1.9 have been implicated in human pain syndromes through genetic studies. 5,6 Loss-of-function autosomal recessive mutations in the gene encoding the α-subunit of Nav1.7 result in congenital insensitivity to pain. 5,7 Sodium channel subtype Nav1.7 is expressed in peripheral sensory neurons innervating skin, viscera, and dorsal

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Imbalanced Randomization (Rationales for)

Sverdlov

Ryeznik

Wong

2021

Wiley StatsRef: Statistics Reference Online

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Most randomized controlled trials use balanced randomization to achieve approximately or exactly equal sample sizes per group. However, in some settings imbalanced (unequal) randomization designs may be more powerful, less costly, and/or more ethically appealing to study participants. This article examines some important statistical rationales for unequal randomization designs. It covers both two‐arm and multi‐arm trial designs with either fixed or response‐adaptive randomization.

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Design and Conduct Considerations for First‐in‐Human Trials

Cited by 107 publications

References 46 publications

Drug development for cystic fibrosis

Drug development for cystic fibrosis

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers

Imbalanced Randomization (Rationales for)

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