Literature analysis of the design and results of the First-In-Human clinical trials of drugs from 2009 to 2020 / 中国临床药理学与治疗学

AIM: Describe the general situation of the First-In-Human trials of the drugs, and summarize the design and results of the First-In-Human trials. METHODS: We searched the literature of the First-In-Human trials in 2009-2020 on PubMed and screened out the literature that met the research purpose. The basic information of the literature was collected. Data analysis was conducted to summarize relevant outcomes. RESULTS: A total of 559 First-In-Human trials were included in this study. The types of drugs included small molecule drugs (52.42%, 293/559), macromolecule drugs (45.62%, 255/559), and a small amount of cells and viruses (1.97%, 11/559) and so on. Regarding the determination of the starting dose, whether it was in macromolecules (23.86%, 21/88) or small molecules (30.15%, 41/136), No Observed Adverse Effect Level (27.68%, 62/224) was mainly used as the main reference basis, followed by preclinical research (21.88%, 49/224) and Minimal Anticipated Biological Effect Level (8.48%, 19/224), etc. In the dose escalation test, 50.19%(135/269) of the studies used the traditional standard 3+3 dose escalation method, followed by the accelerated titration method (7.06%, 19/269), and the improved 3+3 method (6.69%, 18/269), etc. CONCLUSION: The design of First-In-Human clinical trials has certain regularity in the content and results of the research design. In the subsequent trials, it is important to scientifically design the First-In-Human trials, and promote the safe and effective development of the First-In-Human trials of the drugs.

Considerations on the dose determination for first-in-human clinical trials with novel biopharmaceuticals / 药物评价研究

In the development process from the preclinical stage to the subsequent clinical phase,one critical risk controlling step is the determination of the first-in-human (FIH) dose.There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs,therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals.This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL,MABLE,and PK/PD model.The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe,although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented.It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product.Early communication between sponsors and regulators is always beneficial.

Considerations on the dose determination for first-in-human clinical trials with novel biopharmaceuticals / 药物评价研究

In the development process from the preclinical stage to the subsequent clinical phase,one critical risk controlling step is the determination of the first-in-human (FIH) dose.There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs,therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals.This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL,MABLE,and PK/PD model.The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe,although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented.It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product.Early communication between sponsors and regulators is always beneficial.

Post lumbar puncture headache: Case report of a serious adverse event in first-in-human study

A lumbar puncture can be used to measure the concentrations of drugs and/or pharmacodynamic biomarkers during clinical trials of central nervous system drugs. We report a case of a post lumbar puncture headache (PLPH) in a first-in-human study, which was reported as a serious adverse event. A 20-year-old man received 200 mg of the investigational product (IP) for 7 days and underwent a lumbar puncture for cerebrospinal fluid sampling before IP administration (Day 1, pre-dose) and after 7 days and multiple IP administrations (Day 7, 1 hour post-dose). After discharge on Day 8, the subject complained of headache, nausea, vomiting, neck stiffness, and numbness of the extremities. The symptoms occurred when he got up and disappeared after he remained in the supine position for several minutes. Five days later, he visited the neurology clinic of the main hospital. The neurologist recommended hospitalization for further evaluation and symptom management, and the subject was then admitted to the hospital. There were no abnormal findings in vital signs, laboratory results, or brain-computed tomography. His symptoms disappeared during the hospitalization period. It was important to distinguish whether the headache was IP-related or lumbar puncture-related. Therefore, knowledge of clinical characteristics and differential diagnosis of PLPH is paramount. Furthermore, if severe PLPH occurs, a consultation with a neurologist and imaging studies should be considered for a differential diagnosis of PLPH.

Comparative Study of First-in-Human Dose Estimation Approaches using Pharmacometrics

OBJECTIVE: First-in-human dose estimation is an essential approach for successful clinical trials for drug development. In this study, we systematically compared first-in-human dose and human pharmacokinetic parameter estimation approaches. METHODS: First-in-human dose estimation approaches divided into similar drug comparison approaches, regulatory guidance based approaches, and pharmacokinetic based approaches. Human clearance, volume of distribution and bioavailability were classified for human pharmacokinetic parameter estimation approaches. RESULTS: Similar drug comparison approaches is simple and appropriate me-too drug. Regulatory guidance based approaches is recommended from US Food and Drug Administration (FDA) and European Medicines Agency (EMA) regarding no-observed-adverse-effect level (NOAEL) or minimum anticipated biological effect level (MABEL). Pharmacokinetic based approaches are 8 approaches for human clearance estimation, 5 approaches for human volume of distribution, and 4 approaches for human bioavailability. CONCLUSION: This study introduced and compared all methods for first-in-human dose estimation. It would be useful practically to estimate first-in-human dose for drug development.

Broader Transparency on Risk-benefit Assessment of the Bial Trial in France.

On 11 January 2016, a Phase I trial of an experimental fatty acid amide hydrolase inhibitor for pain developed by Bial-Portela was halted after six healthy volunteers were admitted to the University of Rennes Hospital in France. One volunteer died and four suffered severe neurological injuries. It is a dreadful reminder of the Tenegero trial that also hospitalized six volunteers in 2006. Three major similarities were observed between the Tegenero and Bial trials. The first similarity is related to the dosing interval protocol. There is a lack of information about whether the multiple-dose regimen included adequate time intervals between individuals receiving the drug. The second similarity is on the dosing calculation that was based on the ‘no adverse effect level’ (NOAEL). The third similarity is observed in terms of how there was no prior publication of preclinical findings in the public domain before the start of both trials. There have been calls for the full release of the Investigation Medicinal Product Dossier and the Investigator’s Brochure, as these data are critical to maximize patient safety in the future and should outweigh considerations of commercial confidentiality. Likewise, it is necessary for the Brest Regional Ethics Committee to release its documents, which captured the risk-benefit assessment in approving the Bial trial, for external scrutiny.