What safety data support is needed for the clinical advancement of innovative drugs?

TextMedicine Crazy

The three attributes of medicines are safe, effective, and quality controllable
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"Safety" is the foundation, "effectiveness" is the value, and "quality controllable" is the guarantee; without the foundation of safety, the latter two are 0

So, for innovative drugs, what data are needed to prove their safety? What safety data are needed to support the continuous advancement of clinical practice and the formulation of its program? Based on the experience of the new drug varieties developed by the author and the further sorting out of the ICH guidelines, the author summarizes it as follows
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Nonclinical safety studies required for marketing approval

Nonclinical safety studies required for marketing approval

According to the ICH guideline - "Guideline M3(R2) for Non-clinical Safety Research Supporting Drugs for Clinical Trials and Marketing", the non-clinical safety tests required for drug marketing approval usually include: pharmacology tests, general toxicology tests , toxicokinetics and non-clinical pharmacokinetics tests, reproductive toxicity tests, genotoxicity tests, and drugs with special reasons for concern or intended for long-term use, carcinogenicity tests are also required
.

According to the principle of case-by-case analysis, other non-clinical tests should be conducted to evaluate phototoxicity, immunotoxicity, juvenile animal toxicity and dependence,

Based on the author's own experience, the above-mentioned toxicological tests seem to be very numerous.
Judging from the current domestic review standards, usually a new drug will not complete the above items, but select different items at different stages to support the product's development.
The clinical process, after all, most non-clinical trials are very time-consuming-labor-consuming
.

Further narrowing down the scope, such as safety pharmacology experiments, general toxicology experiments, pharmacokinetics, reproductive toxicity, and genetic toxicity, are usually required items, and can be reasonably arranged according to the project development time

Figure 1.
1 "Guidelines M3(R2) for Nonclinical Safety Research Supporting Drugs for Clinical Trials and Marketing"

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What safety data does the application doss require the sponsor to provide?

What safety data does the application doss require the sponsor to provide?

What standard of safety data evidence does an innovative drug have? It requires scientific evaluation + compliance review; it is the basis for the guarantee of “safety-effective-quality controllable” drugs after being reviewed by the State Drug Administration, and it is also the basis for new drugs.
important basis for developing programs
.

So, what kind of documents does the national drug review department need from pharmaceutical companies? This has to talk about an important guiding principle of ICH "Organization of General Technical Documents for Registration of Pharmaceuticals for Human Use: M4"

M4 is a general format document that has been agreed upon during the preparation of application materials submitted to regulatory agencies; general technical documents can be organized in the following five modules
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Module 1 is a regional requirement, while modules 2, 3, 4 and 5 are unified

Figure 2.
1 Organizational diagram of the ICH-CTD general technical document

For safety-related trial studies in M4, the focus was on "Nonclinical review and nonclinical summary of Module 2" and "Organization of Module 4"
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The related content mainly focuses on the ICH guideline "General Technical Documentation for Registration of Pharmaceuticals for Human Use: Safety-M4S (R2)"

Figure 2.
2 ICH-Security-M4S (R2)

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What are the preliminary safety tests?

What are the preliminary safety tests?

As mentioned above, the development of clinical trials of new drugs is inseparable from the support of toxicological data and the scientific summary of the conclusions of "administration dose-administration route-test protocol-test results-test analysis" in the process of safety evaluation
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In the early safety-toxicology content research of an innovative drug, the pre-requisites usually include safety pharmacology, single-dose toxicity, repeated-dose toxicity, genotoxicity, reproductive toxicity, and toxicology research; in the later stage of development, corresponding to complete the previous work, as well as carry out some toxicological tests required for the process and final listing, such as carcinogenicity, phototoxicity, immunotoxicity,

Figure 3.
1 Some examples of toxicological data from ICH guidelines

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Safety test pre-items are introduced one by one

Safety test pre-items are introduced one by one

The above-mentioned safety-related non-clinical trials, combined with the author's own experience and ICH guidelines, will be introduced one by one
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➣ Safety Pharmacology

➣ Safety Pharmacology

Pharmacological tests can be divided into three categories: primary pharmacodynamics tests, secondary pharmacodynamics tests and safety pharmacology tests
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Safety pharmacology, mainly to study the potential undesired adverse effects on physiological function when the drug is in the therapeutic range or above the therapeutic range, that is, to observe the drug's effects on the central nervous system, cardiovascular system and respiratory system (core combination).
) influence
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At the same time, additional and/or supplementary safety pharmacology studies (eg, studies on the urinary system, autonomic nervous system, gastrointestinal system, and other organs and tissues) are conducted as needed

Purpose of safety pharmacology test:

Identify unexpected pharmacodynamic properties of the test substance that may be related to human safety; Evaluate adverse pharmacodynamic and/or pathophysiological effects of the test substance observed in toxicological and/or clinical trials; Research has observed Mechanisms of proposed and suspected adverse pharmacodynamic effects
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PS: The safety pharmacology core combination trial should generally follow the GLP specification, and the supplementary and supplementary trials should follow the GLP specification as much as possible
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Safety pharmacology studies can be performed as part of general toxicity studies, in which case GLP guidelines should be followed
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Primary pharmacodynamic trials do not have to follow GLP guidelines
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➣ Single-dose toxicity

➣ Single-dose toxicity

Acute toxicity, that is, a single-dose toxicity test in a broad sense, refers to the toxic reaction produced within a certain period of time after a single or multiple administration of a drug within 24 hours; while the narrow-sense single-dose toxicity study is to investigate a single administration.
Acute toxic reaction after the test substance
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Drugs intended for use in humans typically require single-dose toxicity studies
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The single-dose toxicity test is of great significance for the preliminary elucidation of the toxic effects of drugs and the understanding of their toxic target organs
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The information obtained from the single-dose toxicity test has important reference value for the dose design of the repeated-dose toxicity test and the selection of the initial dose of some drugs in clinical trials, and can provide some information related to acute poisoning caused by human drug overdose
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After administration, generally continuous observation for at least 14 days, the interval and frequency of observation should be appropriate, so as to observe the emergence time and recovery time of toxic reactions, animal death time,
etc.
If the toxic reaction appears slowly or recovers slowly, the observation time should be appropriately extended
.

PS: Chemical drugs—the test substances should be samples with relatively stable process, purity and impurity content that can reflect the quality and safety of the samples to be used in clinical trials and/or marketing samples (generally should be samples of pilot scale or above).
)
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The test substance should indicate the name, source, batch number, content (or specification), storage conditions, validity period and preparation method, etc.
, and provide a quality inspection report
.
The solvent and/or excipients used in the test should be marked with the name, standard, batch number, validity period, specification and production unit, etc.
, and meet the test requirements
.

➣ Repeated dose toxicity

➣ Repeated dose toxicity

Repeated-dose toxicity test is the most comprehensive, most informative, and most clinically significant toxicology test in non-clinical drug toxicology research
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When evaluating the results, a comprehensive evaluation should be carried out in combination with the pharmaceutical characteristics of the test substance, the results of pharmacodynamics, pharmacokinetics and other toxicological tests, and the results of clinical trials that have been obtained
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The evaluation of repeated administration toxicity test results should ultimately be implemented in the clinical adverse reactions of the test substance, clinical toxicity target organs or target tissues, safety margins, clinical indicators that need to be tested, and necessary clinical monitoring or rescue measures
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Available data information:

Predict the clinical adverse reactions that may be caused by the test substance, including the nature, extent, dose-effect and time-effect relationship, and reversibility of adverse reactions; determine the toxic target organs or target tissues of repeated administration of the test substance; The dose level at which clinical adverse reactions were observed (NOAEL); the initial dose of the first clinical trial (First in Human, FIH) was estimated to provide a safe dose range for subsequent clinical trials; and a reference for clinical adverse reaction monitoring and prevention
.

Repeated dosing, the shortest duration is 2 weeks, which can usually support clinical development trials with a dosing duration of no more than 2 weeks; clinical trials with longer dosing durations should be supported by repeated-dose toxicity studies with at least the same duration of dosing; A 6-month rodent trial and a 9-month non-rodent trial usually support clinical trials with dosing durations longer than 6 months
.

Figure 4.
1 Recommended duration of repeated-dose toxicity studies to support clinical trials

PS: Generally, normal, healthy and sexually mature animals are selected, and the weight difference of the same sex should be within 20% of the average body weight
.
The age of the animals should be determined according to the test period and the clinical population.
Generally, rats are 6 to 9 weeks old, Beagle dogs are 6 to 12 months old, and monkeys are 3 to 5 years old.
The age of the animals should be as close as possible, and the start of administration should be indicated.
Animal age
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The number of animals in each dose group is generally not less than 15 animals/sex for rodents (10 animals in the main test group and 5 animals in the recovery group), and generally not less than 5 animals/sex for non-rodents (3 animals in the main test group and 5 animals in the recovery group).
2 only)
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➣ Genotoxicity

➣ Genotoxicity

Genotoxicity assays, which can be defined as in vitro and in vivo assays for the detection of compounds that induce genetic damage through different mechanisms; these assays enable risk identification of DNA damage and its fixation
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Fixation of DNA damage in the form of genetic mutation, extensive chromosomal damage, or recombination is generally considered to underlie heritable effects and is one of the links in the multistage developmental process of malignant tumors
.
Changes in chromosome number are also associated with tumorigenesis and may suggest the possibility of aneuploidy in germ cells
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Compounds that are positive in assays detecting these classes of damage are potential human carcinogens and/or mutagens
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Since a correlation between exposure and carcinogenicity of certain compounds has been established in humans, and it is difficult to demonstrate a similar correlation for genetic diseases, genotoxicity tests are mainly used for carcinogenicity prediction
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In addition, genotoxicity test results may have important implications for the analysis of carcinogenicity test results
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A panel of genotoxicity assays (both in vivo and in vitro) detects carcinogens primarily through direct mechanisms of genetic damage, such as most known human carcinogens
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The most important combination is "Option 1" in the ICH guidelines, and its items are:

A bacterial reverse mutation assay, the Ames assay; a cytogenetic assay for chromosomal damage (in vitro metaphase chromosomal aberration assay or an in vitro micronucleus assay), or an in vitro mouse lymphoma Tk gene mutation assay; an in vivo assay Genotoxicity assays, usually chromosomal damage assays using rodent hematopoietic cells, are used to detect chromosomal aberrations in micronucleus or metaphase cells
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➣ Reproductive toxicity

➣ Reproductive toxicity

Reproductive and Developmental Toxicity (DART) The purpose of the DART trial is to reveal the effects of drugs on mammalian reproduction that are relevant for human risk assessment
.
Where appropriate, a set of trials should include observations of a complete life cycle (ie, from conception of the first generation to conception of the next generation) and detect immediate and potential adverse effects
.
For this purpose, reproductive toxicity studies and interpretation of the results should be carried out in combination with all other available pharmacological and toxicological data to determine whether the potential reproductive toxicity (risk) to humans is greater than, less than or equal to other toxicities.
performance
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Most new drug development uses a three-stage single trial design:

Fertility and Early Embryo Development Test (FEED - Stages A and B); Two Species Embryos-Fetal Development Test (EFD - Stages C and D); Perinatal Development Test (PPND - Stages C to F)
.
However, different combinations of these experimental designs can be performed to reduce animal use
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Combination trials should better simulate clinical exposure periods, especially for drugs with long half-lives
.
A commonly used combination trial design is a combined fertility and EFD trial (phases A to D), plus a separate PPND trial (phases C to F)
.

➣ Toxicokinetics

➣ Toxicokinetics

Toxicokinetics is an extension of pharmacokinetics in the assessment of systemic exposure, as part of a nonclinical toxicity study, or as a supportive study specifically designed to assess the systemic exposure of a drug
.
Toxicokinetic measurements are usually combined in toxicity studies, so they are also called concomitant toxicokinetics
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The emphasis is on interpreting toxicity test results rather than characterizing the underlying pharmacokinetic parameters of the test substance
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Toxicity studies that can be effectively supported by toxicokinetic information include single- and repeated-dose toxicity, reproductive toxicity, genotoxicity, and carcinogenicity studies
.
Toxicokinetic information is also valuable for the evaluation of proposed changes in the clinical route of administration
.

The overall research purpose of toxicokinetics is to know the degree and duration of systemic exposure of the test substance at different dose levels in the toxicity test, and to predict the potential risk of the test substance in human exposure; the main purpose is to describe the systemic exposure of animals and Its relationship to the dose and time of the toxicity study; a secondary objective, to describe the correlation between the exposure achieved in the toxicity study and the toxicity findings, in order to evaluate the correlation between these results and clinical safety
.
Common parameters used to assess exposure in toxicokinetic studies are plasma (whole blood or serum) AUC, Cmax and C(time)
.

The main value of toxicokinetic studies in safety evaluation is reflected in the following aspects
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Describe the systemic exposure of the test substance and/or its metabolites in the toxicity test and its relationship with the dose and time of toxicity; such as pregnancy status); to evaluate the rationality of species selection and drug regimen for nonclinical toxicity studies
.
Improve the predictive value of animal toxicity test results for clinical safety evaluation
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Evaluating the target site toxicity (such as liver or kidney toxicity) caused by the accumulation of the test substance according to the exposure can help to provide quantitative safety information for subsequent safety evaluation
.
Comprehensive drug efficacy and exposure and toxicity and exposure information guide human trial design, such as initial dose, safety range evaluation, etc.
, and guide clinical safety monitoring according to the degree of exposure
.

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summary

summary

The above content, that is, the author summarizes part of the non-clinical safety evaluation of new drug pre-clinical development & pre-marketing development based on my own experience and sorting out the ICH guidelines
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The development of innovative drugs is the joint crystallization of all disciplines and their professionals.
Without decades of continuous learning and experience accumulation, it is difficult to achieve overall control of project development
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Although there are hundreds of IND registration applications in China every year, there are not many technicians with real project development and overall control
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In order to better understand the development of a new drug, we have to develop branches and leaves on the basis of this specialty, we have to continuously combine theory with actual combat, and then better understand the technical characteristics of innovative drugs based on clinical value.

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References:

1.
http:// CDE official website

3.
"Guidelines for non-clinical safety research to support clinical trials and marketing of drugs M3 (R2)"

4.
ICH guideline "S1A: Guidance on the necessity of drug carcinogenicity testing"

5.
Drug carcinogenicity test S1B

6.
S2(R1): Guidelines for human genotoxicity testing and analysis of results

7.
The official website of the Food and Drug Administration https://