In the past 150 years, the US FDA has grown from a department under the US Patent Office to one of the largest consumer protection agencies in the world today. Its main task is to ensure that medical supplies can reach consumers as much as possible to save them. At the same time, it is necessary to ensure the safety and effectiveness of approved medical supplies.
IND (Investigational new drug, IND) application is a new drug research application. Before a new drug is used in human clinical trials, the applicant must submit a new drug research application IND to the FDA. The main purpose is to provide the FDA with data to prove that the drug is reasonable and safe for early clinical trials. In addition, for drugs that have not been approved by the FDA, U.S. law prohibits their intercontinental transportation and distribution in the United States. Therefore, for new drug applicants, an approved IND application is also a new drug applicant transporting drugs outside the country. State legal exemption for conducting clinical trials.
It is not difficult to apply for an IND in the United States. Every year the FDA receives thousands of new or ongoing IND applications. These applications may come from companies seeking to obtain marketing authorization for new drugs, or they may come from companies seeking to explore marketable drugs. For academic researchers on the effects of various diseases, INDs can be divided into two types: commercial INDs and research INDs. Commercial INDs are for registration purposes, while research INDs are not for registration purposes. They are mostly initiated by researchers, and it is difficult to define whether they should be classified as exploratory clinical trials or confirmatory clinical trials.
INDs can be divided into three types of applications: research IND, emergency IND and therapeutic IND.
Investigator IND (Investigator IND) applications are generally doctors, and sometimes pharmaceutical companies and other organizations with commercial purposes. Researchers are responsible for initiating and implementing these research contents, and are directly responsible for the distribution and management of drugs. After the applicant issues an IND application, the FDA has a 30-day review time limit for its review, that is, the FDA must notify the applicant whether the applicant can enter the clinic within 30 days; if the FDA does not raise any objections during this period, the I Phased clinical trials; however, if the FDA believes that clinical trials pose a safety risk, it has the right to issue a clinical hold notice to a research or research institution. Before further review, any human trials must be suspended until the applicant submits a complaint. Clinical Hold will be released only after sufficient explanations and answers are given to the question or defect.
Usually, the FDA issues a Clinical Hold in order to further evaluate the quality of investigational drugs and to ensure their safety before they are used in humans. The usual causes of Clinical Hold are as follows:
Insufficient information to prove the safety of the drug;
The impurity of the clinical trial batch is unqualified or the impurity information is not sufficiently characterized;
Insufficient research on master cell, working cell bank or virus bank;
The drug is unstable during the test;
Toxicology studies did not define “No Observable Adverse Effect Level” (NOAEL);
Non-clinical trial data cannot support the definition of the maximum human dose;
The clinical program design does not meet the specified goals;
The clinical research design lacks necessary safety monitoring, and/or the “trial suspension rule” is not defined or is insufficient;
Lack of researcher’s statement
The FDA review panel is generally composed of chemists, pharmacologists/toxicologists, clinicians, statisticians, and pharmacokinetics. Pharmacology and toxicology, clinical and other disciplines have completed relevant professional reviews and formed written opinions. The review department will make a comprehensive decision based on these professional reviews and arrive at a very clear result. Therefore, the entire review process is to follow the principle of scientificity, which is to evaluate whether there are enough data to support the entry of the project into clinical research from a scientific perspective.
If the applicant does not have enough time to complete a standard IND application process or the approval of the ethics committee, the applicant will apply to the FDA for an emergency use investigational new drug application EIND (Emergency use Investigational New Drug). The initiator of the EIND application is generally a doctor, and the application conditions are met. The following three points:
The drug is urgently needed by patients who are in serious or even life-threatening conditions;
There are no alternative treatment options;
Patients cannot obtain the drug through any existing clinical trials or through expanded use programs.
Under emergency conditions, the FDA will approve the use of the clinical drug before the complete IND application, but it still needs to complete the entire IND application process in a timely manner in the later stage.
The Treatment IND (The Treatment IND), also known as Expanded Use IND, refers to the situation where the access of experimental drugs and approved drugs for diagnosis, monitoring and treatment of patients’ diseases is restricted due to risk assessment and mitigation strategies (REMS) In the absence of suitable alternative therapies for the diagnosis, monitoring and treatment of diseases, the speed up of patients with severe diseases to obtain relevant drugs.
The FDA judges whether it meets the expanded use requirements based on the following conditions:
The patient has a serious or life-threatening disease and there is no satisfactory alternative therapy for diagnosis, monitoring and treatment of the disease;
The potential benefit of the patient’s use of the trial drug to treat the disease exceeds the reasonable possible risk;
The expanded use of experimental drugs will not affect the clinical research of drugs that are already on the market.
Life-threatening disease refers to a disease state that causes death within a few months of illness and premature death without intervention; and severe disease refers to a disease that has a major impact on daily behavior and function. The disease is often irreversible, persistent, and easy to relapse. There is no clear restriction on the type of disease, which provides a certain flexibility in decision-making, and aims to actually solve the unmet clinical needs of patients.
FDA usually grants one meeting for each milestone, such as Pre-IND meeting and Pre-NDA meeting. Pre-IND meeting refers to a meeting where applicants voluntarily submit an application for a meeting with the FDA before submitting an IND application; FDA encourages the holding but does not require it. The duration of the Pre-IND meeting is 60 days (counting from the date of receipt of the application), and the meeting will be held by telephone or face-to-face communication. The main purpose of the Pre-IND meeting is to review the animal test research required for the first human test and to reach an agreement on the test protocol. The Pre-IND meeting does not charge any fees, and the sponsor can request the FDA to give feedback on the drug development plan in the form of written feedback to reduce travel expenses and other expenses.
However, it is not necessary for all IND applications to hold a Pre-IND meeting, and it is not necessary to hold a Pre-IND meeting for simple clinical trials. However, for drugs that are expected to be used for the treatment of serious or life-threatening diseases, the drugs have new indications, there is no applicable latest guidance document, the initiators lack experience or doubts about drug development, and there are important pharmacological and/or toxicological signs FDA strongly recommends that the sponsors convene a Pre-IND meeting for the several situations where the drug is a new molecular entity (or multiple situations occur at the same time).
Any IND application requires the following three basic information:
Pre-clinical animal pharmacology/toxicology research and any previous human application experience may include data outside the United States;
Production information, including information on the composition, production process, manufacturer, stability, and production control of the drug product;
The clinical trial protocol, the researcher’s manual (to ensure that they are eligible to conduct the trial), the subject’s informed consent, the approval of the ethics committee (IRB), and any relevant IND regulations and regulations attached.
Reference materials:
1. The history and development of the system of expanding the use of drugs for clinical trials in the United States;
2. FDA communication meeting;
3. FDA’s IND application strategy
4. FDA
Medicilon’s IND Filing-innovative drug research and development
Medicilon’s IND Application Platform
Medicilon successfully held CFDA IND seminar in Seoul, South Korea
Medicilon sponsored the seminar on new drug preclinical research and IND application strategy
FDA's IND application strategy
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.
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