What clinical data do I need to provide for the first clinical application of an innovative drug?

In recent years, with a series of adjustments in national policies, the development of innovative drugs has been accelerated unprecedentedly, and the number of new IND varieties declared every year has doubled

01

What is required for CTD data?

There are 5 modules in the CTD format file, which are Module 1~Administrative Management Information, Module 2~General Technical Document Summary, Module 3~Quality Research Information, Module 4~Non-clinical Trial Report, and Module 5~Clinical Research Report.

For the organization of CTD general technical documents, on the basis of clinical review, clinical summary, and clinical report, the content can be specific to the development plan (may include Phase I~III), development path, and development time in the clinical trial plan; clinical research plan Dose selection basis (including starting dose, maximum tolerated dose, grouping, dose escalation), blinding (including unblinding, evaluation indicators, subject selection), safety/tolerability evaluation, data analysis, adverse events , ethics, etc.

Figure 1.

Organizational diagram of the ICH-CTD general technical document

02

M4E guidelines on requirements for clinical phase I of new drugs

The clinical review and clinical summary in module 2 are the location of the clinical content of the application materials, and the content covered is not only for the clinical phase I of new drugs, so the first clinical application can be objectively described according to the content in M4E, that is, there is room for choice 's writing

A clinical review should:

1) Describe and explain the general idea of ​​drug clinical development, including key clinical study design decisions;

2) Evaluate the quality of study design and conduct, including a statement of compliance with Good Clinical Practice (GCP);

3) Briefly describe the clinical findings, including important limitations (such as lack of comparisons to specific relevant active comparators, or lack of information on certain patient populations, relevant endpoints, or combination therapy);

4) Provide benefit and risk assessments based on the conclusions of relevant clinical studies, including explaining how efficacy and safety results support proposed doses and target indications, and evaluating how to use labeling and other methods to optimize benefits and manage risks;

5) Propose special efficacy or safety issues encountered during development, and explain how these issues are evaluated and resolved;

6) discuss unresolved issues, explain why they do not affect approval, and provide a plan to address those issues;

7) Explain the basis for important or uncommon parts of the specification

The clinical summary is a detailed summary of all clinical information in the CTD

Figure 2.

ICH-CTD Module 2 Clinical Information Content

The organization of clinical research reports and related information in Module 5 is a recommended specific framework for organizing clinical research reports and related information, which can simplify the preparation and review of application materials and ensure the integrity of the materials; the layout of the report should be Determined by the primary purpose of the study; each study report should be described in only one section; if a study has multiple research purposes, the study should be cross-referenced in multiple sections; when no section or subsection is appropriate In the case of research reports or information, an explanation such as "not applicable" or "no research was conducted" should be provided

Figure 2.

ICH-CTD Module 5 Clinical Information Content

03

Important documents related to domestic regulations & guidelines

For Phase I clinical trials, CDE has successively issued "Guidelines for the Management of Phase I Clinical Trials of Drugs (Trial)", "Technical Guidance for Phase I Clinical Trials of New Drugs (Draft)", and "Clinical Related Materials for First Human Clinical Trials of New Anti-Tumor Drugs" Prepare Recommendations”, etc.

➣ "Technical Guidance for New Drug Phase I Clinical Trial Application"

In September 2016, the State Food and Drug Administration (CFDA) issued the "Technical Guidance for New Drug Phase I Clinical Trial Application (Draft)", which covers all the specific information required for IND submission.

The biggest background of the technical guidance is "to protect the rights and safety of research subjects, so as to ensure the quality of clinical trials to scientifically and fully evaluate the effectiveness and safety of drugs"

Figure 3.

"Technical Guidance for New Drug Phase I Clinical Trial Application (Draft)"

Relevant clinical content

➣ "Suggestions for the preparation of clinical data for the first-in-human clinical trial of new anti-tumor drugs"

In February 2018, in order to actively implement the "Opinions on Deepening the Reform of the Review and Approval System and Encourage the Innovation of Drugs and Medical Devices" jointly issued by the Central Office and the State Office, CDE specially organized and published the "Preparation of Clinical Relevant Materials for the Application for the First Human Clinical Trial of New Anti-Tumor Drugs" Recommendation"

The general requirements of the "Recommendation" are: In the clinical review with the plan as the core, it is recommended to provide the "General Research and Development Plan" to summarize the clinical research and development strategy at the same time, and include "Clinical Review Information", "Risk Control Plan" , "Investigator's Manual", "Informed Consent" and relevant materials of the ethics committee to support the trial protocol

Figure 3.
2

"Suggestions on the preparation of clinical data for the first human clinical trial application of new anti-tumor drugs"

clinically relevant content

04

summary

To sum up, it is the general direction of the information required for the first clinical application of innovative drugs
.
First of all, it should be noted that the above-mentioned items have a certain time limit for review, but the content and essence are actually unchanged
.
Secondly, a large amount of the first clinical data is based on the results of non-clinical trials.
Therefore, in order to better carry out clinical work, it is necessary to have a better understanding of non-clinical content and data
.
Finally, as a whole, the content introduced in this article is mainly based on preliminary understanding.
If you really want to understand the content of clinical data, in addition to participating in clinical related work, you also need to summarize, connect, and run through the program, process, and data.
, so that the effectiveness and safety of a drug can be deduced
.

References:

1.
M4(R4): Organization of General Technical Documentation for Registration Application of Drugs for Human Use.
CDE

2.
Validity of the Revised ICH M4E Guidelines on the Format and Structure of Optimizing Benefit-Risk Information - M4E(R2).
CDE

3.
Guidelines for the management of drug phase I clinical trials (trial implementation).
CDE

4.
New Drug Phase I Clinical Trial Application Technical Guidelines (Draft).
CDE

5.
Suggestions on the preparation of clinical data for the first human clinical trial application of new anti-tumor drugs.
CDE

6.
Consideration for writing the clinical research plan for the first human trial of new anti-tumor drugs.
CNKI