NMPA IND Application

The journey of an innovative drug from discovery to final marketing is long, costly and risky. In this article, we introduce China NMPA IND application, which is an important issue for new drug R&D, to help pharmaceutical companies understand the requirements and process, and improve the passing rate of IND applications. ‍

Introduction of IND in China

IND (Investigational new drug) refers to a new drug that has not yet been approved for marketing and is undergoing various phases of clinical trials. IND application, which is for a new drug study, aims to provide data to the drug regulatory authority to prove the safety and reasonableness of the drug for conducting clinical trials, and clinical trials can be carried out only after approval is granted.

In recent years, China's policies have vigorously encouraged the research and development of innovative drugs. According to the 2023 Annual Drug Review Report, the IND applications accepted by NMPA in 2023 increased by 33.56% year-on-year.

Communication Meetings

In response to the newly revised Measures for the Administration of Drug Registration, in December 2020, NMPA issued Measures for the Administration of Communication and Exchange between Drug R&D and Technical Review.

Definition

The communication meeting refers to communication between the applicant and the review team of the Center for Drug Evaluation (CDE) during the technical review process of drug development and registration applications on issues such as key technologies that cannot be covered by the current drug development and evaluation guidelines. It is proposed by the applicant, discussed by the project manager of the Drug Review Center and the drug registration specialist designated by the applicant, and agreed to by the review team of the Drug Review Center.

Scope

Communication in the R&D process and technical review of registration and application of traditional Chinese medicines, chemical drugs and biological products.

Meeting mode and type

Mode: face-to-face meeting, video conference, teleconference or written reply.

Three types of meetings: Type I, Type II and Type III.

Applicants can apply for communication at different stages of clinical development on key technical issues, and each type of meeting is applicable to different situations.

(1) Type I

• Significant safety issues encountered during drug clinical trials
• Major technical problems in the development of breakthrough therapeutic drugs
• Other stipulated circumstances

(2) Type II

• Pre-application meeting for new drug clinical trials (Pre-IND meeting)
• Pre-application meeting for Phase II clinical trial/initiation of Phase III clinical trial for a new drug
• Pre-application meeting for marketing authorization of new drugs
• Risk assessment and control meeting

(3) Type III

Meetings other than those in Type I and II.

Meeting convening time

If it is determined that a communication meeting will be held, a Type I meeting will be held within 30 days after application, a Type II meeting will be held within 60 days after application, and a Type III meeting will be held within 75 days after application.

Pre-IND meeting

To apply for IND, you need to prepare three aspects of information: a pharmacy study (CMC), a drug non-clinical study, and a clinical study. We recommend that pharmaceutical companies conduct a Pre-IND meeting before formally submitting the information.

The Pre-IND meeting is a Type II meeting as mentioned above. Applicants can make full use of this meeting to discuss and solve potential problems, and better reach a consensus with the Commissioner for Registration of Pharmaceuticals on the queries in the drug development process, which will help to improve the passing rate of IND applications.

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Filing Information Requirements

After good communication with the CDE, you can formally submit application materials. According to the requirements of "Technical Guidelines for Phase I Clinical Trial Application of New Drugs", paper and electronic materials should be submitted, and the format and content should be organized and submitted according to the requirements of ICH Common Technical Document (CTD), as follows:

1. Introduction note and overall research plan

The introductory statement should include the name of the new drug, all active ingredients, pharmacological class, structural formula (if known), dosage form, formulation, route of administration, and the purpose of the clinical trial. If there is clinical experience with the investigational drug, a brief overview should be provided, including studies and marketing experience in other countries. If none, state "None" under the heading.

The overall research plan should summarize the design basis for the proposed clinical trial, primarily focusing on the intended indications, subject population, number of subjects, dosing regimen (dose, dosing interval, duration of administration, etc.), methods for evaluating drug safety, and risk control plans. It should also provide a risk justification based on available information for any anticipated safety issues (important identified risks, important potential risks, important missing information, etc.).

2. Researcher's manual

The researcher's manual is a summary of existing pharmaceutical, non-clinical, and clinical (if any) research data related to investigational drugs for human studies. It should include the following contents:

(1) Cover Page: Includes the drug name, name of the applicant, date of finalization or update, and version number.

(2) Table of Contents: Lists all primary and secondary headings along with the corresponding page numbers.

(3) A Confidentiality Statement

(4) Overview: Introduces the drug type, proposed indications, and pharmacological characteristics.

(5) The Name and Physicochemical Properties of the New Drug

(6) Non-clinical Study Results: Includes pharmacological effects, toxicological studies, and non-clinical pharmacokinetic studies. If some studies have not been conducted or are not required, reasons and justifications need to be provided.

(7) Existing Clinical Research or Usage Data (if any): This can include domestic and international past clinical usage information or reference literature, such as human pharmacokinetics, efficacy, safety, and marketing status.

(8) Other information

(9) References

3. Clinical trial protocols

(1) Background of the study: brief description of the indications for the drug, clinical effectiveness and safety data available for the drug (if any)

(2) The purpose of the trial

(3) Number of subjects expected to participate

(4) Description of inclusion and exclusion criteria

(5) Dosing regimen

(6) Detection indicators, details of relevant tests that are essential to the evaluation of the safety of the subjects, such as vital signs of the subjects and necessary blood biochemical monitoring

(7) Principles for determining toxicity and criteria for suspension of the study

4. Pharmacy research information

For the pharmaceutical research data of a phase I clinical study in a new drug application, the information should follow the laws of drug development, focusing on pharmaceutical research related to the safety of the subjects in the planned study (such as the analysis of impurity profiles based on existing knowledge, methodological validation of specificity and sensitivity of relevant substances, analysis and control of impurities with potential genotoxicity, immunogenicity and immunotoxicity of new biological drugs, etc.).

Pharmaceutical research information for chemical drugs mainly includes pharmaceutical research information for active pharmaceutical ingredients, formulations, and placebos.

The clinical trial should be postponed if the following pharmaceutical issues arise:

• The chemical structure of the new drug or excipients in the formulation has known toxicity or is highly likely to be toxic
• The new drug cannot maintain stability throughout the entire planned phase I clinical trial
• The impurity profile of the new drug indicates potential toxicity, or impurities present above the identification threshold have not been adequately identified and their potential toxicity not evaluated
• There are biosafety issues related to animal-derived components
• The master cell bank or working cell bank has not been fully characterised

5. Pharmacological and toxicological information

(1) Non-clinical study overview: Summary information about completed non-clinical studies, listing each test in tabular form if applicable.

(2) Summary of pharmacological studies: Information on in vivo and in vitro pharmacological effects and mechanisms of action, secondary pharmacodynamic information, and studies on the relationship between pharmacodynamics and exposure.

(3) Summary of toxicological studies: The degree, severity, and duration of toxic reactions, dose-relatedness, reversibility, species and gender differences, with special attention to information on toxicity from repeated dosing, animal mortality, pathological examinations, local tolerance, and other specific issues requiring explanation.

(4) Summary of pharmacokinetics: Feasibility of analytical methods, pharmacokinetic/toxicokinetic parameters, absorption and tissue distribution, metabolism, excretion, and physiological changes caused by pharmacodynamic and toxicological issues, such as the effects of disease states, antibody formation, and cross-reactivity.

(5) Individual study reports: Provision of all obtained study reports on pharmacological effects, toxicological studies, and pharmacokinetics.

6. Description of previous clinical use experience

If there is prior clinical usage experience, the applicant should provide an overview of the relevant information.

(1) If the investigational drug has been previously studied or marketed in China or other countries, detailed information related to the safety and rationale for the proposed trial should be provided.

(2) All published literature related to the safety of the proposed trial and efficacy evaluation data for the intended indications of the investigational drug should be provided, including a list of references or key supportive literature related to the drug's prior clinical usage experience.

(3) A comprehensive evaluation of the proposed clinical study should be conducted based on existing information. This will help support the choice of dosage, duration of administration, drug combinations, and selection of the subject population for the clinical study.

7. Offshore research information

For the relevant studies conducted or being conducted abroad for the submitted product, both the original text and the Chinese translation materials should be provided. The Chinese translation must be consistent with the original content.

Acceptance, Review and Approval Process

According to the Measures for the Administration of Drug Registration issued on January 22, 2020, the approval process and working timeframe for IND applications are as follows:

• Applicant submits an application and relevant information
• Acceptance (formal review): 5 working days. If additional information is required, it should be completed within 30 working days
• Technical review: 60 working days. If the notification is not published on the CDE website after the deadline, the application will be approved by default
• Submission of a trial protocol
• Ethics committee review
• Conduct a clinical trial (to be implemented within three years of approval)

Proregulations deeply studies the review concept and technical requirements of NMPA and CDE, and provides one-stop IND applications services for pharmaceutical companies. If you are interested in our services or need more details, please contact us.