On the relationship among American drug laws, Pharmacopoeia and orange peel book

At present, China is carrying out the reform of drug management laws and regulations, and has issued a new drug management law Drug consistency evaluation has been carried out in an all-round way At the same time, the new edition of Pharmacopoeia has been opened Our own "orange peel book" and "patent connection" systems are also in planning But we can not avoid that most of our reform contents are drawing lessons from the laws and regulations of drug management in the United States, even from their ideas, forms and methods So, what are the roles of US drug regulations, FDA, orange peel book and US pharmacopoeia in drug management? What are the legal and functional connections and differences between them? What role do they play in the formulation and formation of drug standards? This article attempts to do a simple analysis, mistakes, please correct! The first part of this paper briefly introduces the background of the object of discussion; the second part assumes the application process of a new drug and its generic drugs, trying to demonstrate the role of each subject; the third part analyzes the relationship and difference between them; the fourth part briefly describes the understanding of drug standards 1 Background, jurisdiction and legal orientation 1) USP-NF: USP was born in 1820 It was edited by 11 doctors in the United States at that time After 1880s, it became a nationally recognized drug standard publication At the beginning, the purpose of compiling USP was mainly to serve as the drug standard for clinicians and pharmacists, and also to fight against the harm of counterfeit drugs and adulterated drugs to the market and public health Before the first drug administration act of the United States in 1906, USP was recognized as the drug standard in the United States; until the Kefauver Harris act in 1962, USP was the drug standard in the United States Before 2002, USP was revised every 10 years, and since 2002, it has been revised every year The United States Pharmacopoeia has become one of the standards for the management, evaluation and measurement of drugs in many countries Especially in countries with weak or imperfect drug regulations, USP is often cited as the drug management regulations 2) FDA and Drug Regulations: in 1906, the United States first promulgated the drug management law, and the same year, FDA was established In 1927, FDA was officially established as the drug management agency of the government to enforce the law Since the enactment of biological products act in 1902, more than 20 laws or acts on drug administration have been enacted in the United States Among them, there are four parts that have changed the history of human medicine: the pure food and Drug Act of 1906: for the first time, drugs are managed in the form of legislation, which requires that the outer package of drugs should be consistent with the contents FD & C, federal food, drug and cosmetic act of 1938: in view of the poisoning of sulfonic acid tincture, the United States put forward safety requirements for new drug application and marketing for the first time, and recognized the role of USP in identifying "adulterated drugs" and "counterfeit drugs" Kefauver Harris amendment of federal food, drug and cosmetic amendment in 1962: due to the dolphin baby incident in the 1960s, the U.S Congress amended FD & C, proposed the concept of safe and effective modern drugs for the first time, and authorized FDA to conduct the whole process management (ind, NDA, phase I, II, III, GMP...) on drug research, development, production and marketing Hatch Waxman act of 1984: it puts forward a new concept of drug imitation and management method of generic drugs (simple new drug application anda, bioequivalence be, treatment alternative te, patent challenge, etc.) The bill has greatly reduced the cost of medicine for the American public The U.S FDA is now the world's largest government drug administration with more than 15000 employees and the world's largest scientific staff 3) Orange peel book: as early as 1970s, FDA has been looking for alternative evaluation methods of drug effectiveness At the end of 1970s, when the bioequivalence be method is becoming more and more mature, FDA has established more than 100 "approved drug products with therapeutic equivalence evaluations", whose cover is orange, so it is called "orange peel book" (2) In 1984, the U.S legislative reform of generic drugs, in order to facilitate the entry of generic drugs into the market, the U.S Congress required the FDA to publish "orange peel book" as a data and information platform with legal effect for drug substitution At the same time, it also becomes the data platform of drug patent connection system 2 Jurisdiction 1) Pharmacopoeia: the United States Pharmacopoeia is a collection and publication of FDA approved drugs in the form of monograph The United States Pharmacopoeia is divided into monograph and general chapters The data and data of APIs and preparations are edited according to the legal drug name: drug name, structural formula, molecular formula, CAS number, character, identification, inspection, content determination, packaging, labeling and other quality control items One of the purposes of compiling pharmacopoeia is to clearly define the active ingredients and detection methods of drugs, so as to avoid disputes and confusion in drug detection USP only defines the substance composition and test method of "drug", not the "safety" and "effectiveness" of drug The United States Pharmacopoeia is the maker of legal drug names 2) FDA and drug laws and regulations: the drug laws and drug regulations that FDA enforces cover and stipulate all matters related to drugs FDA is the administrative law enforcer of drug laws and regulations In terms of drugs, the first and only responsibility of FDA is to ensure the "safety" and "effectiveness" of drugs on the market In short, FDA regulates all matters related to drugs 3) Orange peel book: as an FDA approved drug efficacy alternative evaluation publication, orange peel Book discloses all information and data related to drug substitution In order to implement the hatch Waxman act of 1984, FDA published patent and data exclusive information of NDA on orange peel book In order to facilitate the implementation of bioequivalence evaluation, FDA publishes designated reference preparation (RLD) and standard preparation (RS) through orange peel book The subject matter and procedures of the patent challenge shall be subject to the information published in the orange book 3 Legal orientation 1) Pharmacopoeia: the US pharmacopoeia convention is responsible for the editing and publishing of USP USPC is a non-profit, independent body When the U.S Congress passed the federal food, drug, and cosmetic act in 1938, it confirmed that the U.S Pharmacopoeia is the "official compendium" (502 (E), FD & C act) related to drugs The U.S Congress recognized the drug content described in the U.S Pharmacopoeia, and recognized that the U.S Pharmacopoeia is in the identification of adulterated and counterfeit drugs Misbranding) The USP committee is an independent organization responsible for its own profits and losses The USP committee does not have the power of law enforcement The power of law enforcement of USP is vested in FDA and other relevant government agencies In connection with the USP dispute, Congress encouraged manufacturers and interested parties to negotiate with FDA for resolution (4) The most authoritative work of USP is drug naming In addition to the exclusive proprietary drug's own trade name, the names of other drugs are from the United States Pharmacopoeia, including the general name, chemical name, etc If the pharmacopoeia is used for naming, and the content of the drug does not conform to the Pharmacopoeia, it is referred to as "pseudo drugs" (FDCA 501 (b); 21 CFR 299.5 (c)) 2) Laws, regulations, FDA: the U.S Congress is responsible for legislation (laws) The FDA is a government agency under the U.S Department of health and human services (HHS), which is responsible for drug regulatory enforcement All laws are compiled as regulations in the code of federal regulations (CFR) Item 21 of the regulation set is the drug management regulations (actually drafted by FDA), commonly known as 21cfr, which is the administrative law enforcement basis of FDA FDA informs law enforcement methods and procedures in the form of published guidelines, as well as FDA's current understanding of regulations The guidance has no legal effect, no legal binding force, and FDA does not require compliance However, the industry generally only follows the guidance of FDA 21cfr covers all aspects of drug regulation in the United States, and also defines the respective roles of USP and orange peel book in 21cfr 3) Orange peel book: orange peel book is an official publication published by FDA in accordance with 21cfr314 regulations on information and data of drugs on the market The publication published information and data can affect the approval of drugs, legal proceedings and so on, but the orange book itself has no legal effect From the background, jurisdiction and legal position mentioned above, it can be seen that FDA and relevant drug laws and regulations are the legal sources of drug mandatory standards USP is one of the drug standards approved by Congress, or part of the drug standards As for why USP is not classified as FDA, this is related to USP and US drug regulations as well as the complex formation history of FDA, which will not be discussed here It should be emphasized that USP and orange peel book are not specially designed functions or departments for the implementation of laws and regulations, but modifications and adjustments based on existing facts for the implementation of laws and regulations So this system in the United States is not necessarily the most ideal drug regulatory system 2 Examples of drug application deduction Now let's start with a hypothetical drug, and deduce how American drug laws and regulations, FDA, USP, and orange book play their respective roles The following figure describes the drug formation process, and the following table lists the responsibilities of FDA, USP and orange book in the drug formation process Note to the author: 1) the red part of the form is the regulations (code of federal regulations) implemented by FDA 2) in order to explain the relationship between them, the author has made a lot of simplification to the application content and process of drugs III differences between drug regulations (FDA) and pharmacopoeia: according to the brief introduction of Chapter I and the hypothetical process of Chapter II, analyze the characteristics of FDA / drug regulations and pharmacopoeia: 1) static and dynamic The USP formulates the legal name of the drug After the FDA Approves the drug's listing (not counting before 1938), the USP Committee, in consultation and cooperation with the FDA and its manufacturers, promulgates the substance index and detection method of the drug FDA carries out dynamic management of the whole process from application to marketing according to drug management regulations FDA uses the government's approval and refusal of drug listing rights to force the actor to research, manufacture and sell drugs in accordance with the procedures and standards established by laws and regulations, so as to ensure the safety and effectiveness of drugs For example, the United States Pharmacopoeia prescribes the formulation of the drug in drug monograph and, if possible, the in vitro dissolution index of the drug However, when FDA audits anda, it allows generic drugs to change the formula or even the drug release principle As long as the bioequivalence index of generic drugs is equal to or similar to that of reference drugs, FDA may approve anda for marketing, or even approve anda challenge reference drugs The laws and regulations on which FDA reviews drugs will adjust with the understanding of diseases, the progress of medical and pharmaceutical technology, and the change of social cognition For example, if necessary, after a congressional hearing, change laws, change regulations (sometimes 21 CFR changes do not require a congressional hearing) 2) Pharmacopoeia focuses on the identification and determination of drugs, while FDA focuses on the evaluation and evaluation of drugs and processes 3) Pharmacopoeia of chemistry and pharmacy mainly confirms and standardizes the