An article on FDA new drug registration process (NDA)

In the United States, it takes about 15 years for a common new compound to apply for marketing from its initial discovery Among them, the time for FDA to review is about 6-10 months The review of new drugs in the United States is stipulated in the FDCA (Federal Food, drug and Cosmetic Act) Although FDCA is considered by many to be the most complex of these laws, the most important provisions of the act on new drug review are quite simple First of all, FDCA stipulates that: articles used to diagnose, cure, alleviate and prevent human and other animal diseases; articles (except food) used to affect the structure or function of human or other animal bodies are drugs The FDCA also requires that any new drug be shown to be safe, effective and approved before it goes on the market New drug applications can be submitted to FDA if the following conditions are met: 1 New molecular entity (NME) 2 New chemical entity (NCE) 3 New base and new ester group of the same chemical composition of the original approved drug 4 New formula composition of the original approved drug 5 New indications of the original approved drug (including the use of prescription drug transferred to over-the-counter drug) 6 New dosage form, new route of administration, new specification (unit content) 7 New combination of two or more original approved drugs new drug registration Route 505 (b) - subchapter 505 of Chapter 5 of the federal food, drug and Cosmetics Act, namely act 505 The 505 act includes three applications for NDA: the first is 505b1: the applicant conducts all pharmaceutical research (complete new); the second is: 505b2: it is also the applicant who conducts all pharmaceutical research, but the difference is that part of the information is not completed by the applicant, or the research is not completed for the applicant, and the applicant has no right to quote (hybrid new, 505j: the preparation to be declared is the same as the existing one in API, dosage form, route of administration, label, quality, test and indication (generic, anda) 505j is the application way of Anda, which will not be discussed in detail in this paper There are many new drugs on the market every year in the United States Although there are different varieties and FDA's evaluation requirements for them are different, the evaluation framework is still the same, which can be roughly divided into the following steps: 1 Preclinical research The research on the safety and effectiveness of new drugs will eventually be carried out in human body, but before FDA allows the trial drug to be used in human body, it must be proved that the research on the drug is safe for human body If the drug sponsor can not prove the safety of the drug from the existing research data, domestic and other countries' use data, then the pre clinical research must be carried out At this stage, the FDA generally stipulates (at a minimum) that drug applicants must: (1) conduct pharmacological studies on the drug; (2) conduct acute toxicity tests on at least two kinds of animals; (3) conduct short-term studies of the drug for two weeks to three months in accordance with its intended use; It should be noted that once the preclinical study is completed, the animal test will not be completed Many longer and more specific studies, such as chronic and anti-cancer trials, will be carried out in the whole process of new drug application Preclinical studies are used to evaluate: pharmacological phenomena and mechanisms of action (MOA) drug toxicity characteristics and drug absorption, distribution, metabolism and excretion (ADME) of toxic target organs 2 Application for clinical trials of new drugs (ind) When the drug sponsor thinks that it has enough data to prove that the drug is safe, it is ready to submit the new drug clinical research application (ind) to FDA In essence, IND is just a suggestion, through which the drug sponsor obtains the FDA's permission to start the test on people In clinical research applications, drug applicants must submit materials in at least two areas First of all, it must publish the results of all preclinical studies to FDA, provide information on the composition of the drug, as well as the production and quality control procedures for the production of the drug Secondly, it must provide the plan of clinical research In the proposal, the clinical research that the drug sponsor hopes to prove the safety and effectiveness of the drug used in human body is described in detail There are also other materials related to clinical research, including the qualification of researchers (clinicians) According to the current regulations, FDA has 30 days to decide whether to allow the drug to be tested in humans, and FDA will also evaluate the clinical plan The clinical research plan should ensure that clinical subjects should not be exposed to unnecessary risks and have the hope to prove that the drug is safe and effective for human body If the FDA does not contact the sponsor within 30 days after the IND is submitted, the clinical trial can start However, it is best for the drug sponsor to contact the FDA before starting clinical research Once FDA makes a decision that clinical research should not start, it should be sent out within 30 days, delaying clinical trials until the relevant issues are resolved Generally speaking, FDA issues the notice of "clinical trial suspension" mainly for the following reasons: (1) the preclinical study fails to prove that the drug will be safe for human body; (2) the preclinical study fails to meet GLP and some other standards; (3) the proposed clinical study plan is incomplete and the clinical study is not safe If the applicant fails to conduct the planned clinical study within two years after applying for the ind, or the clinical trial of the IND is suspended for more than one year, FDA will list the ind as "inactive status" Once the IND is placed in an "inactive state," all clinical investigators must be notified and returned to the applicant or immediately destroyed in accordance with 21 CFR 312.30 Ind can be divided into the following two categories: ① commercial ind refers to a new clinical trial applied for the purpose of applying for new drug listing The applicants of ind usually cooperate with enterprises There is a situation in commercial ind called "exploratory ind" or "screening ind", which is the first application document submitted to support the first phase 1 clinical study of new drugs ② Non commercial ind (non commercial ind) non commercial ind is a study conducted by doctors themselves The purpose of this study is to study the effect of drugs on specific populations or to provide unapproved drug treatment for patients without drugs Non commercial ind includes investigatorind / research ind The ind application package mainly includes 9 parts: ① first page letter, FDA 1571 form; ② contents; ③ introduction and overall research plan; ④ researcher manual; ⑤ clinical research program; ⑥ chemical, production and quality control information; ⑦ pharmacological and toxicological information; ⑧ existing human clinical experience; ⑨ additional information; In the ind declaration package, relevant original and complete research reports, such as toxicology research report, shall also be submitted 3 Clinical trials if the FDA Approves the ind application, clinical trials (studies involving human subjects) can start Phase 1 clinical: strictly control the drug in a small number of healthy volunteers, about 20-80 cases In this stage, we mainly obtain the basic safety data and pharmacological information of the drug The subjects were generally healthy volunteers Phase 2 clinical trials: the trial drug was administered to a small number of subjects, about 100 to 200 cases These patients are suffering from diseases that the drug is designed to treat This stage further provides the safety data of the drug, which is used for the first indication of the proposed use and the effectiveness of the test drug If the sponsor of the drug can conclude from the use of the drug or previous clinical studies that the drug is safe for clinical use, the first phase clinical or even the second phase clinical in some cases can be omitted Phase 3 clinical: there are hundreds to thousands of participants, focusing on the safety and effectiveness of the drug The trial drug was carried out among more subjects who were suffering from diseases such as treatment, diagnosis, prevention and so on Prior to the start of this phase of the study, the sponsor must submit data from phase I and phase II clinical trials to FDA to show that the drug is reasonably safe, effective, and has a favorable benefit / risk ratio End of phase IIa meeting (eop2a) after the completion of phase II clinical trial, FDA strongly recommends that the applicant propose eop2 meeting before starting phase III critical clinical trial The eop2a meeting takes place after the clinical trial obtains the dose-response relationship in the proposed indication, including the effect of dose range on safety, biomarkers and conceptual verification; it usually takes place after the completion of phase I clinical trial and the first batch of patient exposure response trial and before phase IIB (such as patient dose range trial) and phase III clinical effectiveness safety trial It can help the applicant to find the best dose, save cost and maximize the success rate of later clinical trials In order to make full use of the eop2 meeting to communicate with FDA, the applicant shall submit a meeting file package to FDA one month before the meeting: 1 Meeting request & meeting information (60 days): y or N 2 Date, time and participants 3 Summarize all the latest data (clinical, CMC, pharmacology / toxicology, etc.) 4 Propose phase III development plan 5 Propose possible drug labels 6 Q & a 4 After the clinical trial of new drug application (NDA), the drug applicant can submit an NDA to apply for approval of the drug for sale in the United States According to the treatment characteristics of drugs, FDA can be divided into "standard review (SR)" and "priority review (PR)" in the review procedure For the "new drugs that can significantly improve the treatment, diagnosis or disease prevention compared with the listed drugs", FDA reviews the very important NDAs within 6 months, and the standard review time of new drugs is 10 months According to the relevant provisions of the manual of policies and procedures (MAPPS), FDA can adopt the "priority review", and the review time is shortened from 10 months to 6 months NDA review is the most rigorous and time-consuming process, and only a small proportion of trial drugs are finally allowed to enter the market In addition, FDA encourages drug innovation and expedites the review of new drugs used to treat serious or life-threatening diseases or unmet clinical treatment needs, such as AIDS, Alzheimer's disease, heart failure, tumor, epilepsy, depression and diabetes, through FastTrack Once a drug is compliant with fast track, FDA must make a decision within 60 days After the new drugs are approved, the label of the drugs may be changed, including new information about the side effects of the drugs Drug applicants need to submit safety changes, and doctors or patients can also report serious adverse events related to drugs to FDA Drugs that cause more serious than expected side effects should be withdrawn from the market if necessary NDA application fee - PDUFA PDUFA is the prescription drug filer payment act, according to which FDA collects a certain amount of