What core trials are included in the Phase I clinical phase of innovative drugs?

Phase I clinical trials are the results of verification of the druggability of innovative drugs, and also the beginning of verification of whether a product can finally be turned into a drug
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For Phase I clinical trials, most non-clinical practitioners stay in the superficial concept of "healthy subjects, dozens of cases, tolerance, safety", but they don't know much about the actual operation and specific content of this stage.

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Here, based on years of project participation experience and learning of guiding principles, the author summarizes the core trials and their contents in Phase I clinical phase, hoping to enable readers to explore the specific work of Phase I clinical phase clinical development
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01 Introduction to Phase I Clinical Trials Phase I clinical trials in the traditional sense are preliminary clinical pharmacology and human safety evaluations, and are based on a large number of laboratory non-clinical studies to begin the human trials of new drugs
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Its purpose is to understand the dose response and toxicity; to carry out preliminary safety evaluation, to study the human body's tolerance and pharmacokinetics of new drugs, and to provide a preliminary dosing scheme; the subjects are generally healthy volunteers, and in special cases Patients were also selected as subjects under certain circumstances; the methods were open, controlled, randomized, and blinded; the number of subjects was 20-30
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To introduce the content of Phase I clinical trials, it is necessary to start with how to apply for it
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In January 2018, the drug regulatory department issued the "Technical Guidelines for the Application of Phase I Clinical Trials of New Drugs".
In the guidelines, the clinical work first requires the introduction of the overall research plan, that is, the design basis of the clinical trial plan.
The main contents include the proposed indications, subjects.
Population, number of subjects, dosing schedule, drug safety evaluation method, risk control plan,
etc.
Here, we focus on the results of non-clinical studies and the design of clinical protocols
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? Non-clinical research results This part is mainly divided into three parts, namely pharmacology, toxicology and pharmacokinetics
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Pharmacology should include the results of completed non-clinical trials to suggest efficacy
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Toxicology should list safety pharmacology tests, single-dose toxicity tests, repeated-dose toxicity tests, genotoxicity tests, reproductive toxicity tests, carcinogenicity tests and other toxicity tests; if some studies have not been performed or need not be performed , need to explain the reasons and basis
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Non-clinical pharmacokinetics should include drug absorption, distribution, metabolism and excretion (ADME)
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? The clinical trial protocol mainly includes the following information: 1) Research background, briefly describe the indications of the drug, and briefly describe the existing clinical efficacy and safety data of the drug (if any); 2) The purpose of the trial; 3) Expected participation 4) Description of inclusion and exclusion criteria; 5) Description of dosing schedule, including duration, starting dose, dose escalation schedule and termination conditions, dosing schedule and description of the basis and method for determining the first dose; 6 ) Detection indicators, relevant trial details that are critical to subject safety evaluation, such as subjects' vital signs and necessary blood biochemical monitoring; 7) Toxicity determination principles and trial suspension criteria for study termination
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The protocol includes three parts in turn, namely the single-dose tolerance test protocol, the single-dose pharmacokinetics test protocol, and the continuous-dose pharmacokinetics test protocol
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PS: Now, some small clinical trials of food and drugs are usually done during Phase I clinical trials
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Figure 1.
1 "Technical Guidelines for New Drug Phase I Clinical Trial Application" 02 First Clinical Trial & MRSD Domestic application for Phase I clinical trial is not necessarily the first clinical trial application of a drug, but the content of the first clinical trial of a drug can better reflect the sponsor's concern for the variety overall control and development strategy
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The first clinical trial is one of the important milestones in the process of innovative drug development.
It is the first time to explore whether a new compound can be turned into a drug in the human body, and the first time to verify the relevance of all animal data obtained before this to the human body
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It is a clinical trial with the highest safety risk when species differences have not been fully clarified
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Before the clinical trial, the choice of the starting dose is the first question.

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? Maximum recommended starting dose MRSD When determining the MRSD, all preclinical data should be considered in order to achieve the goal of avoiding adverse effects and rapidly reaching Phase I clinical trials
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Before a new compound enters clinical trials, the applicant should complete a series of preclinical studies
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These include: pharmacodynamic studies, animal pharmacokinetic studies (absorption, distribution, metabolism and excretion), toxicology and toxicokinetic studies
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Published in 2012, the Guidelines for Estimating the Maximum Recommended Starting Dose of Drugs for First-Time Clinical Trials in Healthy Adult Volunteers provides a strategy for determining the maximum recommended starting dose for clinical trials of new drugs in adult healthy volunteers: 1) Available relevant The NOAEL of animals is converted into HED, and divided by the appropriate safety factor to obtain MRSD; 2) The exposure and pharmacokinetic parameters of relevant animals can be converted into human pharmacokinetic parameters, and the expected human body can be calculated according to the predicted human biological activity exposure.
biological effect dose
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In general, investigators should use a lower starting dose
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In addition, for drugs for which the predictability of preclinical data is uncertain, it may be more appropriate to use the lowest expected biological effect dose as the initial human dose
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The determination of the maximum recommended starting dose for the first clinical trial should be jointly discussed by multiple departments and multiple disciplines, and all preclinical data and previous clinical experience and data of similar compounds or compounds with the same mechanism of action should be combined, and reliable scientific judgments should be used to ensure that.
Subject safety and rationality of trial design
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Applicants are encouraged to discuss issues related to the maximum recommended starting dose for the first clinical trial of the drug with the reviewing agency
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03 It is recommended to conduct phase I clinical trials in the early stage.
The earliest phase I clinical trials are usually single-dose dose escalation studies (that is, the so-called single-dose escalation).
Food, drugs, and material balance, etc.
; here are several clinical trials recommended in the early stages of the "Technical Guidelines for Clinical Pharmacology Research of Innovative Drugs"
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? Single/multiple dose escalation studies Single dose escalation (SAD) studies and multiple dose escalation (MAD) studies usually include safety tolerability evaluation and PK evaluation
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Among them, the single/multiple administration dose escalation PK study is the earliest study to explore the PK characteristics of innovative drugs in humans and to correlate the relationship between exposure and drug safety (sometimes including drug efficacy), which can be combined in tolerability studies
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SAD studies can obtain data on the safety and tolerability, PK characteristics, dose ratio characteristics, and linear range of innovative drugs at different doses within a wide dose range
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MAD studies can obtain data on the safety and tolerability, PK characteristics, dose proportional characteristics, linear range, time dependence, and accumulation degree of innovative drugs under multiple administrations of different doses
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Through early clinical PK studies, it is possible to explore and understand the relationship between the administered dose and drug exposure in vivo, evaluate the rationality of drug formulations, and guide formulation optimization
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In order to understand the exposure-effect relationship earlier and better, it is recommended to investigate the PK/PD of drugs in a wider dose range as much as possible in SAD and MAD studies, so as to provide a basis for the selection of subsequent clinical research programs
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Early SAD and MAD studies are usually conducted in healthy volunteers
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Sometimes, SAD and MAD studies can select patients for study based on the characteristics of the drug, the characteristics of the indication, and the clinical needs
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? Food Effect Study Food effect study examines changes in in vivo exposure of innovative drugs after subjects eat a meal, and the effects of different types of diets on exposure compared with no meal
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The results of food effect studies can be used to support the design of subjects' medication and diet type or timing in subsequent clinical studies, and ultimately to guide the writing of instructions
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In particular, it is pointed out that whether changes in food-induced exposure can ultimately have a significant impact on clinical drug use needs to be comprehensively evaluated in combination with the safety and efficacy results of clinical studies and the analysis of the exposure-effect relationship.

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When food-induced changes in exposure have a significant impact on clinical medication, it is necessary to clarify in the labeling whether the patient can take the medication at the same time as diet or the time window between medication and diet
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If the preparation to be marketed is different from the preparation used in clinical studies, it is recommended to pay attention to the food impact of the preparation to be marketed
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? Substance balance research Material balance research examines the absorption, metabolism and excretion characteristics of innovative drugs in the human body, and clarifies the metabolism/elimination pathways and time courses of prototype drugs and their metabolites in the human body.
The results of clinical drug safety and efficacy are of great significance
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The results of mass balance studies have an important reference for drug interaction studies and exploratory/confirmative clinical study design, and provide a basis for the necessity of studies in people with hepatic/renal insufficiency
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It is recommended to focus on new metabolites found in human mass balance studies not observed in animal experiments and metabolites at disproportionately high concentrations in other species
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Mass balance studies can be carried out using radioisotope tracers or other suitable methods
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Figure 3.
1 Technical Guidelines for Clinical Pharmacology Research of Innovative Drugs , the estimation of parameters, and the content of the research report are further introduced
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? Single and multiple dose escalation PK studies should be designed to optimize information acquisition, minimize subject exposure to insignificant study doses, and optimize studies based on subject safety considerations designed to avoid unnecessary risk exposure
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The study design should be based on the safety and efficacy information of existing non-clinical and similar drugs, focusing on the following contents: test population; route of administration; initial dose, maximum dose/exposure, dose escalation; longest dose.
Drug duration, dosing rate/frequency; subject dosing interval in the same dose group; risk control plan; what needs to be assessed before entering the next dose group or study; sample size per dose group ; Accumulation of multiple doses; Sampling design; Evaluation indicators, evaluation methods and evaluation frequency of safety and/or efficacy effects,
etc.
? Estimation of pharmacokinetic parameters The main PK parameters of single dose escalation PK study are: Tmax, Cmax, AUC(0-t), AUC(0-∞), Vd or Vd/F, Kel, t1/2 , MRT, CL or CL/F, urine/fecal excretion rate (if applicable),
etc.
The results of studies on the corresponding PK parameters should be provided on a case-by-case basis
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In addition to the above parameters, multiple dose-escalation PK studies also include Cmin,ss, Cmax,ss, Cav,ss, AUC0-τ, steady-state fluctuation coefficient (DF), accumulation factor,
etc.
Each PK parameter should provide arithmetic mean, standard deviation, degree of variability, geometric mean, maximum, minimum, etc.
according to the data distribution
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For Tmax, the median and range should be provided
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The results of studies on the corresponding PK parameters should be provided on a case-by-case basis
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• Study Report The study report should provide the design rationale for key clinical study design considerations, such as the selection of the study population, sample size, dose, and estimated exposure levels (if any)
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The research report and appendix should provide the subjects' individual and average blood drug concentrations, drug-time curves (including semi-logarithmic plots), PK parameters, etc.
, and analyze the dose-exposure proportional relationship
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If PD indicators are collected in the study, appropriate PK/PD correlation analysis should be performed, or, where appropriate, PK/PD analysis should be reported as a separate analysis
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In the case of sufficient study data, analysis can be performed for one or more of the following factors that may affect PK, such as age, gender, race, body weight, liver/renal insufficiency, genetic polymorphism, dietary effects, drug interactions etc.

_ The research report should be able to achieve the research purpose, make a preliminary summary of the PK characteristics of innovative drugs in humans, analyze the dose-exposure ratio relationship, drug accumulation in vivo and exposure-effect, etc.
, and provide a reference for subsequent clinical research
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For more PK research content, please refer to "Technical Guidance for Pharmacokinetic Research on Single and Multiple Administration Dose-escalation Pharmacokinetics of Innovative Chemical Drugs"
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05 Summary In summary, the author summarizes the core trials and specific contents of the Phase I clinical stage of innovative drugs based on his own experience in participating in the project and on the basis of learning the guiding principles
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The development and results of phase I clinical trials usually have obvious guiding significance for the horizontal and vertical development of a variety, and can reflect the development potential of the variety to a certain extent
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Especially under the current domestic innovative drug development model in China, the requirements for Phase I clinical trials are more reflected in the operation of clinical resources and the seamless connection of project development
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However, this often reflects another problem, that is, the current domestic phase I clinical trials are mostly fast-copy development of me-too varieties, biased towards SOP, and additional or even innovative clinical development strategies are rarely added to the trials.
, and this idea will be further introduced into Phase II and III, and may eventually be able to be marketed quickly, but it is difficult to find the potential advantages of the drug in the clinical process
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This so-called potential clinical advantage is likely to be achieved by only a few small clinical trials, but few sponsors are often willing to try it
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Therefore, for the development strategy of phase I clinical trials, it is necessary to further add some combined research designs and nested research designs to better and more comprehensively understand and develop varieties, so as to achieve a certain level in each small trial.
innovation, and ultimately achieve a true understanding and innovation of Phase I clinical trials
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Reference materials: 1.
"Administrative Measures for Communication and Exchange of Drug Development and Technical Review" 2.
"Technical Guidelines for Application for Phase I Clinical Trials of New Drugs" 3.
"Guidelines for Estimating the Maximum Recommended Initial Dose of Drugs for First Clinical Trials in Healthy Adult Volunteers" 4.
"Technical Guiding Principles for Clinical Single and Multiple Administration Dose-escalation Pharmacokinetic Research of Innovative Chemical Drugs" 5.
"Technical Guiding Principles for Clinical Pharmacological Research of Innovative Drugs" 6.
"Technology for Food Impact Research in the Process of New Drug Development" Guiding Principles 7.
Technical Guiding Principles for Human Bioavailability and Bioequivalence Research of Innovative Drugs 8.
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