New Drug Clinical Trial Design Path: Phase I Clinical Trials.

Text . . . Yang Liuqing 1 background knowledge clinical trial, English clinical trial, not clinical experiment.
school medicine children's shoes must have more or less done a variety of experiments, whether it is chemical experiments, biological experiments or preparation experiments, pharmacological experiments, using the word "experiments."
so-called "experiments", the modern Chinese Dictionary is defined as doing or engaging in an operation or engaging in an activity to test a scientific theory or hypothesis, while "experiment" is to observe the result of something or the performance of something.
clinical trials are a series of trials to examine the effectiveness of new drugs for target patients, and this series of articles will talk about clinical trials of new drugs.
the process of new drug research and development mainly includes the discovery of seed molecules, cell activity evaluation, non-clinical pharmacological toxicology research, clinical trials and post-market safety supervision.
clinical trials cost/ time-consuming account for 60% to 80% of the total development of new drugs, can be described as the most cost-consuming stage of new drug development.
the FDA divides clinical studies into three phases, which are usually carried out on schedule, but can also overlap, and the FDA defines them as Phase IV clinical trials for clinical studies after new drug approvals are marketed.
ICHE8 also divides clinical trials into four phases for the purposes of clinical studies.
2006, the FDA published "Guidance for Industry, investigator and reviewers exploratory INDstudies", which proposes the concept of Phase 0 clinical trials with fewer subjects (?10 cases) and a shorter study cycle (?7 days) to explore the pharmacokinetics and pharmacology of new drugs in the human body to provide guidance for phase I clinical studies.
whether it is a Phase 0 clinical trial concept or a traditional trifraction clinical trial, the purpose of its staging is based on a philosophical view of risk control.
Phase I clinical usually use a small number (dozens of people) healthy volunteers as subjects, compared to the use of more patients as subjects of Phase II and a larger sample size of Phase III clinical trials, with low cost (less people), short time (many healthy subjects available) and low risk (health subjects body resistance is strong) and so on.
Phase 2I Clinical Trial Panorama 2.1 What (Who) Phase I Clinical Trials are the first in humans to evaluate human tolerance and pharmacokinetic tests of new drugs based on the basic success of animal pharmacological toxicology trials.
2.2 Why (Why) Phase I clinical trials are primarily designed to observe side effects as the dose of the drug increases in the body, the kinetic properties of new drugs in the human body, and the collection of early evidence of efficacy.
to observe the body's tolerance to new drugs, pharmacokinetics, and pharmacodynamics through Phase I clinical trials, and explore the maximum drug tolerable dose (Maximal Tolerable Dose, MTD), dose-restrictive toxicity (Dose-Limit Toxicity, DLT) to provide the basis for the development of the next Phase II and III clinical trials design and delivery protocols.
2.3 What to Do (What) Phase I Clinical lying answers two main questions: (1) what is the adverse reaction to the drug;
to answer the above questions, Phase I clinical needs to complete at least the following key studies: In addition, Phase I clinical can also simultaneously examine the human pharmacodynamics of new drugs, food effects, drug-to-drug interactions, etc.
2.4 How (How) trial sequence: one-dose tolerance tests, single-dose drug-based tests, multi-dose tolerance and pharmacokinetic trials are usually performed in turn.
for Phase I clinical trials conducted in patients, human tolerance tests and pharmatictest trials can be performed simultaneously.
design principle: Phase I clinical trials often use open, self-controlled trials.
but when the main adverse reactions lack objective indicators or it is not appropriate to determine the relationship between adverse reactions and drugs, randomized blindness and placebo-controlled trials are often used.
subjects: More healthy young men as volunteers.
but similar cytotoxic drugs (e.g. anti-tumor drugs) should use the patient as the subject.
sample size: generally 20-80 subjects.
next, we will focus on the design path of Phase I clinical trials.
phase 3I clinical human tolerance test designhuman tolerance test is to examine the tolerance of different doses of drugs in human stakes, through the test found the nature and dose of adverse reactions.
phase I clinical human tolerance tests are generally first to carry out single-dose exploration, on this basis to determine whether to carry out multi-dose tests.
tests can be open, baseline control, or randomized and blind methods can be used to improve the accuracy of observations.
the general design concept of phase I clinical human tolerance testing: several groups are set between the starting dose and the maximum dose, and the dose scans are taken from small to large groups until the maximum tolerable dose (MTD) is found or the maximum dose of the design is reached.
3.1 The starting dose is the drug dose that is first applied to humans during the transition from animal tests to human trials.
to determine the safe starting dose of Phase I clinical trials, pharmacological, toxicology, and pharmacomatic data for preclinical animals need to be fully understood. There are five main methods for determining the starting dose
. The selection of the initial dose of
should follow two main principles: (1) avoidtoxic reactions, and (2) the assessment objectives of phase I clinical human tolerance tests should be achieved quickly.
the maximum dose of 3.2 The maximum design dose usually has the following three methods (1) the maximum dose of the same drug, the same drug or similar structure of the drug;
the maximum dose range should include the expected effective dose.
the trial can be completed if the subject scored the maximum dose and there were no adverse reactions.
dose increased to the appearance of termination indicators or other serious adverse reactions, although the maximum dose is not reached, the trial should also be terminated.
3.3 dose-increasing design (climbing test) After the initial dose and the maximum dose have been determined, a dose increment scheme needs to be designed in order to carry out the dose-increasing climbing test. The determination of the
dose increment scheme takes into account factors such as the distance between the initial dose and the effective dose of pharmacoactiveias and toxic doses, the toxic and pharmacokinetic characteristics.
usually uses the Fyshrigmethod (improved Fibonacci method) to design a dose climbing scheme, i.e. when the reagent is n (g/m2), then the sequential doseist is 2n, 3.3n, 5n, 7n, and then increase disnumbered 1/3 of the previous dose.
is characterized by the rapid start of increment, the slower growth rate in the later stages, and the rapid termination of the tolerable clinical trial with reasonable speed and gradient, while ensuring the safety of the subjects.
the additional dose increase design and fixed proportion increment method, that is, the dose is increased according to the fixed proportion, but the clinical application is less.
for dose increase, but also according to the specific characteristics of the drug, the design of a more targeted dose increase program.
the basic principle of dose increase: the initial increase can be larger, and the later increment should be small.
the increase coefficient is too small, will increase the number of unnecessary subjects, the increase coefficient is too large, will increase the risk of the subject.
the dose of drugs with high safety or low toxicity can be increased by a large margin, and some can be multiplied, and the dose of drugs with low safety or toxicity should be small.
3.4 Maximum Tolerable Dose (MTD) Trial Design Phase I Clinical Human Tolerance Trial is aimed at determining the maximum tolerable dose in the human body.
, given the starting dose, the maximum dose, and the incremental dose, we design the experimental scheme to determine the maximum tolerable dose in the human body. There are generally two broad categories of methods for determining the maximum tolerable dose
: Rule-Based Trial Design and Model-Based Design.
A: Rule-Based Test Design (Rule-Based Designs) Key Points: No pre-estimated dose-toxicity curve; dose increments based on toxicity results at current dose levels; including traditional 3-3, accelerated titration, PGDE tests, etc.
B: Model-Based Design Key points: Build a dose-toxicity curve model before the subjects enter the group; during the trial, modify the dose-toxicity curve in real time using the subject toxicology data; require good biostatistical support to establish and correct the dose-toxicity curve; and model-based design includes: CRM, Modified CRM, EWOC, TITE-CRM, mTPI, Mixed-field, the main purpose of the
4I clinical human pharmacokinetics trial design Phase I clinical human pharmacokinetic test is to evaluate drug removal rate, predict the possible accumulation of drugs or their metabolites in human sons, potential drug-to-drug interactions, etc.
phase I clinical pharmacokinetic tests are generally conducted after human tolerance tests.
4.1 Trial design Phase I clinical pharmacokinetics trial design is generally randomly cross-controlled to reduce the impact of different trial cycles and individual differences on the results of the trial.
there are two main experimental designs: 2 dose two-cycle cross-test design, 3 dose 3-cycle 3 x 3 Latin cross-test design.
the following is an example of a 3-by-3 Latin cross-test design. basic requirements for
trial: Subjects: 9 healthy men.
grouping: randomly divided into three groups of 3 people.
dose: low, medium, high three doses, high dose must be close to or equal to MTD, medium dose should be close to or the same as the clinically proposed single dose, the three doses should be an iso-equivalent or equivalent relationship, in order to observe whether the concentration of different doses - blood drugs is linear.
two trial interval periods: 7 half-life test design scheme: In addition, pharmacokinetictests may consider adding the following tests: pre-test: before the formal pharmacokinetic test, you may consider conducting pre-tests of 2-4 people in order to identify possible problems, and provide reference for later test conditions, dose size, observation time, sampling frequency, etc., with a view to accurately reflect ingestthedes of drug kinetics in the human body.
effects of food: The pharmacokinetic test of oral solid preparations should examine the differences in pre- and post-meal pharmacokinetics, especially the effects of food on the degree of drug absorption.
5 multi-dose human tolerance and pharmacokinetic test after single-dose human tolerance and pharmacokinetic test, it is necessary to carry out multiple dose tolerance and pharmacokinetic tests, in order to examine the human tolerance of multiple drug administrations and whether there is a drug accumulation effect.
the basic requirements of the experiment: Subjects: Generally select 8-12 healthy subjects.
dosage: 1-3 doses are selected based on Phase II clinical trials.
the life of the drug: based on the half-life of single-dose pharmacokinetics.
6 Thinking Phase I Clinical Trial is the first time that a new drug has been applied to humans, the main purpose of Phase I clinical trial is to examine the tolerance and pharmacokinetic properties of healthy subjects to new drugs, and to provide reference for the treatment dose and possible side effects of the next Phase II clinical trial for patients.
although Phase I clinical trials in the entire clinical trial cycle of new drugs accounted for a relatively small, but the so-called "no complex, then must work at the beginning and end", a good Phase I clinical, as far as possible to find the characteristics of new drugs, for the next Phase II, III clinical trial design to provide a solid factual basis.
References: Phase 1, Phase 0 Clinical Trials: New Models for Clinical Research 2, Accelerated Titration Designs for Phase I3, Phase 1 Trial Design Is 3 s 3 The Best? 4, ICH E8. General Considerations 5, Research Review on Phase I Clinical Trials 6, FDA: Estimation of the maximum safe starting dose of the first dose in the human body7, comparative study of phase clinical trial design methods of the anti-tumor drug Bayes I, and research on drug clinical trials1 Phase 9, Innovative Drug Phase I Clinical Trial Program Design Discussion 10, Drug Clinical Trial Methodology 11, Clinical Trial Design and Analysis 12, New Drug Phase I Clinical Trial Dose Exploration and Determination 13, Anti-Tumor Drug Phase I Clinical Trial Design Method Overview.