The definition and legislative process of American generic drugs

1、 In 1888, the American Pharmaceutical Association (APhA) issued the "national formula" to protect brand drugs In 1906, the United States passed the pure food and Drug Act, which gave the government the right to interfere in the production and sale of drugs Establish FDA In 1928, there was a debate about the substitution of generic drugs for brand drugs In the endless article debates, brand drugs took the upper hand Finally, it was determined that the substitution of generic drugs for brand drugs was a "fraud" In 1938, through FDCA, the United States formally had new drug regulations Before a new drug is put on the market, the drug manufacturer must provide the FDA with the evidence of safety test and obtain the approval of FDA before it is put on the market However, there is no management of generic drugs after the patent expires (because generics are not "new drugs") From the independence of the United States to the Second World War, the pharmaceutical industry in the United States was basically monopolized by European pharmaceutical companies In the American Civil War, the first World War and the Second World War, the United States relied on "infringing" drugs to meet the demand of war drugs In the early days of the United States, there was the act on the use of property of hostile countries in wartime Specifically for the pharmaceutical industry, the Act allows us companies to produce drugs in wartime under the patent of a hostile country This is the prototype of the legal identity of generic drugs After the end of World War II, many people invested in the generic industry and made a lot of money by imitating European patent drugs Because such generic drugs do not belong to new drugs and are not under the management of FDCA in 1938, FDA has adopted a one eye open and one eye closed attitude It was an era of real medicine, fake medicine and generic medicine In order to regulate the pharmaceutical market, the Durham Humphrey amendment act of 1951 divides drugs into prescription drugs and over-the-counter drugs APHA has adopted an alternative with a legal nature: unless generic drugs are the only drugs on the market, the drug prescription must indicate the specific brand drugs and the generic drugs of specific manufacturers This scheme limits the market of inferior generic drugs, but also limits the development of high-quality generic drugs Before 1951, the competition of generic drugs was mainly the competition of commercial brands For example, Merck's morphine, Squibb's morphine, Johnny's morphine and so on They are not the inventors of morphine, and they have no patent protection There is no regulation (as long as it complies with the USP), what kind of morphine Merck should be, and what kind of morphine Squibb should be After the end of World War II, the pharmaceutical industry in the United States and drug research in various universities have made a leap forward development, gradually developing new drugs in the United States and accumulating their own patents Since the 1960s, the number of new drug development and drug patents in the United States has surpassed that in Europe, making it one of the world's largest pharmaceutical R & D, production and sales countries At the same time, the U.S patent system began to play a role, and American new drug manufacturers gradually gained profits through patent monopoly Generic medicine has gradually changed from imitating "brand" to imitating patent The real dispute between patent drugs and generic drugs began U.S Senator Kefauver devoted himself to the anti-monopoly cause after he failed to run for vice president in the 1950s To win the public opinion, he set his opponent as a pharmaceutical giant He not only advocated the substitution of generic drugs for patent drugs, but also advocated shortening the time of patent protection (or even proposed to abolish the drug patent system), forcing the cost of patent drug disclosure and reducing the drug price Kefauver used his position as chairman of the anti business monopoly Committee of Congress to hold frequent congressional hearings on drug prices and drug quality, forcing drug giants to testify frequently The big guys in the pharmaceutical industry hate and fear him The thalidomide incident in 1962 led to the Kefauver Harris amendment, which first proposed that drugs on the market must be "safe and effective" In addition, a series of scientific regulations (ind, NDA, phase I, phase II, phase III) have been made for the research, production and marketing of drugs, which is historically called "the Bible of modern drug laws and regulations" In the subsequent "efficacy reassessment" project (DESI) for drugs launched in 1938-1962, the concept of simplified new drug application (anda) was proposed for the first time That is to say, generic drugs can refer to the original NDA's literature data in the form of "literature NDA" to submit generic drug applications However, the FDA's attitude on whether generic drugs can directly refer to FDA declaration data of NDA has been unclear Therefore, many generic drugs must repeat animal experiments and clinical studies to confirm the "safety and effectiveness" of drugs During this period, the market entry of new drugs in the United States lagged behind, the market entry of generic drugs was blocked, and the drug price rose From 1965 to 1967, the social security act reform was carried out in the United States The government launched Medicare and Medicaid plans, which urgently needed cheap drugs to enter the market Can generic drugs reduce the cost of drug use? Can generic drugs replace original drugs? How can generic drugs replace original drugs? All of these are directly related to the success of social security reform in the United States, and whether the government can afford Medicare and Medicaid So generics and patent drugs were one of the hot topics among politicians of that era 2、 Now we often use FDA's "orange book" for blue book, green book and orange book, but the origin of orange book is very dramatic FDA first has a public "blue book" to record the list of generic drugs in question, which can be understood as "the list of generic drugs" There is no doubt that patent drugs create obstacles for imitated drugs to enter the market Haddad, a New York lawyer who lost his campaign to become governor of Brooklyn, turned to work on New York's generic alternative legislation (he had previously written an article attacking the price monopoly of tetracycline) With the support of the then governor of New York and Congressman Kefauver, Haddad launched a large-scale "generic drug investigation" and issued a military order to the New York state legislature to replace the "green paper" with New York State generic drugs in a short time Martin Seife, FDA's director of generic drugs, told Haddad: the U.S military has been purchasing generic drugs to replace original drugs to reduce the cost of military drugs FDA technically endorsed for the military and made a list of generic substitutes (the rudiments of be and Ba carried out by FDA) Seife gave part of the list to Haddad At a hearing in New York State, Haddad asked the FDA to hand over the list The FDA denied that there was only a negative list of "Blue Books" and no replacement list Haddad showed the evidence and pointed out the exact location of the FDA office building where the lists were kept In this case, New York state passed the New York "drug substitution list" which contains 800 drugs provided by Haddad group, which is the famous New York "green book" In a congressional hearing, the FDA recognized the legality of the New York green paper The FDA's troubles came one after another Every state in the United States began to make its own "green paper", requiring FDA to identify and approve it Therefore, the FDA proposed to the Congress to publish the evaluation of the equivalence of listed drugs to unify the national drug substitution standards, which is the origin of "orange peel book" In a congressional hearing, Kennedy, then FDA director, said: "it's a political decision.. To agree to a drug replacement." By the end of the 1970s, the debate between patent drugs and generic drugs in the United States had been heated After Reagan was elected president in 1982, he carried out deregulation and advocated reducing government interference in business From 1965 to 1983, generic drugs have been fighting with patent drugs for 18 years, and the proportion of prescription of generic drugs is only 19% After 18 years of fighting, the U.S government still has to pay high fees to patent drug dealers for Medicare and Medicaid every year Congress, the government, and the public are throwing their grievances at the FDA Patent druggists and copycat druggists say nothing about FDA regulations In this context, in 1984, the drug price competition and patent period Compensation Act was introduced, and generic drugs appeared as "slimming" With the data support of "orange peel book", FDA soon came up with a new standard and method of "simple new drug application" States in the United States soon passed their own generic substitution laws, giving generic drugs a green light to enter the market New generic manufacturers are camped in Brooklyn, New Jersey and Connecticut In 1989, there was a "generic drug scandal" in the United States Once again, generics are in the abyss People began to doubt the generic drug standards and rules formulated by FDA In response to the public opinion, the FDA sampled 2500 samples of 30 drugs Results the qualified rate was more than 99% In order to prevent the recurrence of scandals, in 1990, the data integrity policy verification system and the corresponding application oath system for generic drugs, the application avoidance system for generic drugs, etc were established To sum up, the definition of generic drugs in American laws and regulations has gone through three stages, which is essentially a process of concept transformation from "chemical imitation" to "pharmacology imitation": 1 Before 1962, there was no clear regulation on generic drugs The US pharmacopoeia is the standard, which is in line with the US pharmacopoeia The label is consistent with the content, and generally does not constitute the crime of "fake drugs" We call it "chemical imitation" 2 From 1962 to 1984, the management of generic drugs and new drugs in the same class required that generic drugs should be developed, produced and applied to 100% generic patent drugs 3 In 1984, the hatch Waxman act formulated detailed rules for the entry of generic drugs into the market, emphasizing the treatment substitution based on bioequivalence, that is, the management of "pharmacological generic" 3、 The definition of generic drugs can replace therapeutic generic drugs can replace original drugs, so what kind of generic drugs are qualified? How to define generic drugs based on original drugs? The standard of the national regulation set of the United States is: compared with the target drug, the application drug should have the following characteristics: the same active ingredient, the same drug dosage form, the same drug action intensity, the same treatment route, the same disease comes from: 21 CFR 314.92 Anda 505 (J) the official ppt diagram of the FDA of the United States is as follows: the FDA emphasizes that 5 is the same, 3 is equivalent However, in patent litigation, the court judge's understanding of things is often more effective than the 21cfr and FDA text regulations In 2008, Janssen & Janssen and Apotex filed a lawsuit on generic drugs The judge asked FDA officials, what is "generic drugs"? The FDA official replied, "the essence of a significant difference in the rate and ext to which the active recipient or active mobility in pharmaceutical equivalent or pharmaceutical alternatives become available at the site of drug action when administered at the same molecular dose under simple conditions in an appropriately designed study." It's a detour! "There is no significant difference in the distribution rate and degree of active components or active bodies in pharmaceutical equivalents or pharmaceutical substitutes when the drug is administered at the same molar dose under similar conditions and under the condition that the substances in the active parts can be measured in a reasonably designed experiment." (that is to say, if the design is reasonable and there is no significant difference between the release rate and release degree of the two comparison objects, it is anda = NDA!) To use the language of the Federal Circuit, “[g]eneric drug companies are not required to conduct their own independent clinical trials to prove safety and efficacy, But can instead rather on the research of the pioneer pharmaceutical companies,