FDA's IND application strategy

An Investigational New Drug Application (IND) is the US FDA’s approval for drugs that have not yet been approved for marketing and require clinical trials. In addition, the U.S. federal government prohibits intercontinental transportation and distribution of drugs that have not been approved by the FDA in the U.S. Therefore, for sponsors to transport drugs to other states for clinical trials, the IND is also applying for an exemption from this legal provision. .

The FDA receives many IND applications every year, and the number of IND applications that Chinese companies apply to the FDA is also considerable. However, most of the IND applications of Chinese companies have already started clinical trials in China or even after they are on the market, or after clinical trials have been initiated in Australia. The FDA declares INDs, and there are few cases that directly declare INDs to FDA to carry out the first clinical trials.

So, under what circumstances do I need to submit an IND application? When a new drug or biological agent completes pre-clinical research and prepares to start a clinical trial, an IND application is required. It is also necessary to submit an IND application when new indications, important label changes, dosage forms, administration routes, or patient groups (such as children, gender) of approved drugs or biological preparations occur.

Preparation before IND application

Before submitting an IND application, the applicant needs to conduct a series of preclinical studies on the drug to prove that the drug is safe to use in human trials. At the same time, the applicant should also determine whether the drug does have pharmacological activity. When the pre-clinical research proves that the drug can be further developed into a marketed product, the applicant should collect necessary data and information in a limited early clinical trial to prove that the drug does not cause unreasonable risks to the human body. Once such drug data is determined (or corresponding to animal test data) and a report is generated, the applicant can begin to prepare the IND application.

The time required for IND application preparation is related to whether the product’s characteristic information, non-clinical trials and clinical trial data are adequately prepared. Many applicants who submit an IND for the first time underestimate the time required to submit a well-designed and operational IND. In fact, it may take two years or more to prepare from the discovery of a clinically-qualified drug candidate A complete IND application. Ideally, applicants should carefully study the IND-related guidance documents and forms on the FDA’s official website to better design products to meet the requirements.

Generally speaking, the IND application package should include three levels of information:

1) Animal pharmacology/toxicology research: pre-clinical data should fully prove that the drug is safe for the first human trial. It mainly involves research on pharmacodynamics, pharmacokinetics, toxicology, etc. The core content is safety evaluation, such as GLP toxicology test. The FDA observes the safety window based on key toxicological research data and decides whether to accept the clinical trial protocol.

2) CMC data (production information): including information on the composition, production process, stability and production control of the drug product, the purpose is to fully prove that the manufacturer can continuously produce and provide stable and uniform quality test samples.

3) Clinical trial protocol and researcher information: FDA’s criterion for deciding whether to allow clinical trials is to assess whether there is an unacceptable risk to the subjects. The clinical plan submitted in the United States is an executable plan that includes many details, and it needs to be confirmed through multiple communications with the CRO and doctors. In addition, the supervisor (professionals or doctors) of clinical trials should have the qualifications to engage in clinical trial-related work. It also includes the informed consent form of the subject, and that the test should be under the supervision of the Institutional Review Board (IRB) and comply with the relevant provisions of the IND regulations.

IND review

After the applicant submits the IND, the FDA’s project supervisory manager will act as the supervisory liaison and forward the IND application to the review team. Usually the review team is composed of chemists, pharmacologists/toxicologists, clinicians, statisticians and pharmacokinetics. If the medicine includes medical equipment, the review staff of the Center for Equipment and Radiological Health (CDRH) should also be consulted .

After the FDA receives an IND application, it must notify the applicant whether it can enter the clinic within 30 days. During this period, the FDA needs to review the safety of the IND to ensure that subjects will not be exposed to unreasonable risks. Since the FDA may require the applicant to provide additional detailed information or declarations, it is recommended that the applicant organize an internal IND working group within the company to conduct full discussions within 30 days in order to resolve IND-related issues in a timely manner.

If the applicant receives a notification from the FDA (usually by phone or e-mail, and then the FDA will send a “Safe to Proceed” notification), then clinical research can be conducted, and the IND is “activated” status.

How to respond to the “clinical trial suspension” order

If the FDA believes that a clinical trial poses a safety risk, it has the right to issue a clinical hold notice to a research or research institution and inform the reason. The clinical trial suspension can be a full or partial suspension. The FDA has issued a regulation (21CFR312.42) for issuing a notice of suspension of clinical trials for research involving drugs and biological products.

Generally, the applicant needs to supplement the information and submit a written complete response to the questions raised by the FDA within 30 days. Once the complete response to the clinical trial defect is received, the FDA will re-examine the submitted content within 30 days. If the FDA If the problem has been resolved, the applicant will be notified that the clinical trial can continue (Off Hold).

The usual reasons for “clinical trial suspension” are as follows:

1) Insufficient information to prove the safety of drugs;

2) The impurity of the clinical trial batch is unqualified or the impurity information is not sufficiently characterized;

3) Insufficient research on master cell or working cell bank or virus bank;

4) The drug is unstable during the test;

5) Toxicology studies have not defined “No Observable Adverse Effects Level” (NOAEL);

6) Non-clinical trial data cannot support the definition of the maximum human dose;

7) The clinical plan design does not meet the specified goals;

8) The clinical research design lacks necessary safety monitoring, and/or the “trial suspension rule” is not defined or is insufficient.

9) Lack of researcher’s statement (FDA Form 1572).

IND update

Once an IND is in the “active” state, it will become an updatable document. As an applicant of the IND, it is necessary to update the IND at any time, such as research data, new agreement documents, agreement document revisions, safety reports, new technical information, new validity data, and other related information. Most file updates are completed by submitting IND revisions, such as the following types:

1) Protocol amendment (21 CFR 312.30);

2) Information revision (21 CFR 312.31);

3) Safety report (21 CFR 312.32);

4) Annual report (21 CFR 312.33);

5) Reply to FDA information request.

TIPS for IND application

The preparation and submission of an IND application is an important step in the drug development process, and each applicant should not underestimate it. Once the IND application is “activated”, the applicant and clinical investigator assume full responsibility for the clinical trial and face many laws, regulations and regulatory requirements. Failure to meet the duties or requirements may result in the termination of the IND or the disqualification of the clinical investigator. Therefore, the planning and preparation of early clinical trials is crucial for the successful application of IND and the execution of clinical trials.

A few days ago, senior consultants Michelle Rose and Amanda Ceres of Halloran, an internationally renowned consulting company, summarized some common tips in order to help companies with IND applications.

1) Have an overall understanding of the final product during drug development;

2) Reasonably arrange the timetable for the pre-clinical drug trial meeting, so as to prepare sufficient data to support decision-making, and do not ignore official feedback;

3) The non-clinical trial data should be able to fully support the design of the clinical plan;

4) Establish a stable communication relationship with the FDA to improve the success rate of the project;

5) The application is best to comply with the FDA’s approval habits, and do not let the FDA dig into the information that may be hidden in the IND application;

6) Potential problems arising during or after the IND review should be made public and transparent, otherwise the credibility of the application will be affected.