Introduction to the U.S. Food and Drug Administration (FDA)
1. U.S. drug administration agency
The U.S. Food and Drug Administration (FDA) , affiliated to the U.S. Department of Health, Education and Welfare, is responsible for the management of drugs, food, biological products, cosmetics, veterinary drugs, medical devices and diagnostic supplies nationwide. FDA consists of the Drug Administration, Food Administration, Veterinary Drug Administration, Radiological Health Bureau, Biological Products Bureau, Medical Devices and Diagnostic Supplies Bureau, National Toxicology Research Center, and regional work management agencies, that is, 6 bureaus (some publications also call it 6 center), a center and a regional governing body. The U.S. Food and Drug Administration has approximately 7,500 employees, including 1,143 employees at the FDA headquarters, including 350 employees at the Drug Administration.
The Drug Administration (also known as the Drug Evaluation and Research Center) is responsible for the approval of human drugs and has 8 divisions and several departments. 1. Drug Administration. It consists of four departments: drug information, information system design, administrative management and budget, and medical library. 2. Office of Drug Enforcement. It has seven departments including drug quality evaluation, drug label supervision, production and product quality, scientific research and investigation, and regulations. 3. Division of Pharmaceutical Standards. It has two departments: evaluation of commonly used drugs, drug marketing and advertising. 4． Drug Review Unit. It consists of five departments: cardiovascular-renal drugs, anti-tumor drugs, nutritional drugs, medical imaging surgery and dental drugs, gastrointestinal drugs and coagulation drugs. 5． Drug Evaluation Division II. It consists of three departments: anti-infectious drugs, metabolic and endocrine drugs, and antiviral drugs. 6． Division of Epidemiology and Biostatistics. It consists of two departments: Epidemiology and Investigation and Biostatistics. 7． Research Division. It consists of two departments: Research and Testing and Drug Analysis. 8. Division of Generic Drugs. It has two departments: generic drugs and bioequivalence.
The U.S. Food and Drug Administration is located in Washington, D.C., and Rockwell City, Maryland. It has a large organization with branches all over the country. In order to strengthen drug quality management, the FDA divided the country into six regions, namely the Pacific Region (San Francisco, Seattle, Los Angeles), the Southwest Region (Dallas, Denver, Kansas), and the Central and Western Region (Chicago, Minneapolis, Detroit), Northeast (Boston, New York, Buffalo), Mid-Atlantic (Philadelphia, Cincinnati, Newark, Baltimore), Southeast (Atlanta, Nashville, New Orleans, Orlando, San Juan de Puerto Rico) . Each district has a regional office, and there are several regional offices under the regional office. The Pacific Region is located in San Francisco, the Southwest Region is located in Dallas, the Midwest Region is located in Chicago, the Northeast Region is located in Boston, and the Mid-Atlantic Region is located in Philadelphia. , the seat of the southeastern district is Atlanta. The district office is responsible for supervising and inspecting food, drugs, cosmetics, equipment, blood banks, etc. in the region. Each region has set up a number of workstations according to work needs to ensure that the work surface can cover the scope of the region. There are currently 143 workstations in the United States. Regional offices, regional offices and workstations are all directly affiliated agencies of FDA at all levels. The size of the district depends on the workload. More than 65% of the drugs in the United States are produced in the Mid-Atlantic region, so the district is relatively strong. It has 525 employees, including 250 supervisors, which is about 100% of the supervisors at the FDA headquarters. 1/4 of the total, 150 analytical and inspection personnel.
The management of drugs in each state is carried out in accordance with local drug management regulations. The main tasks are: examination and registration of pharmacists, supervision and inspection of drug business departments and pharmacies, issuance or renewal of licenses, and revocation of illegal households. license, evaluate local pharmacy schools, review trainee pharmacies, etc.
2. Drug review in the United States
In the United States, it takes 8 to 10 years from development to approval and production of a new drug, costing US$65-80 million. It usually takes two years for the FDA to approve a new drug. On average, 2,000 new drugs are reviewed every year, and only 10% can be produced. U.S. drug applications are divided into three categories. 1. Investigational drug application p. New drug application; 3. Simplified New Drug Application. The average development and review cycle for a new drug is: 1 and a half years for preclinical research, 1 month for FDA safety review, 5 years for phase III clinical trials, and 2 years for FDA new drug review. Only 1/4 of the new drugs applied for have passed the review. It takes 17 years for a new drug to be patented before other pharmaceutical companies can copy it. Applications for the production of generic drugs must be approved by the Generic Drugs Division before using the simplified new drug application.
A new drug application often has 5,000-100,000 pages of information. To facilitate review, FDA has developed a series of guidelines on the format and content of declarations. For example, the method verification and analysis data application guide stipulates that the applicant should prepare 4 samples, 2 of which will be sent to 2 laboratories designated by the Drug Evaluation Office, and the other 2 will be for backup. When sending samples, control substances for inspection (including miscellaneous reference substances) and uncommon reagents and materials should also be sent. The attached information should describe the reference substance purification method, spectrum and other calibration data. Another example is the new drug application submission method, which stipulates that two types of documents should be submitted. One is the complete permanent master file, and the other is the review document for each volume. Both documents should be accompanied by an application form and application letter.
The contents of the main file are: 1. Abstract; 2. Chemistry, manufacturing and quality inspection; 3. Non-clinical pharmacology and toxicology; 4. Human metabolic kinetics and bioavailability; 5. Microbiology; 6. Clinical data; 7. Statistical data. In addition, FDA has clear regulations on the paper size of declaration documents and the specifications and colors of folders for dividing files. Microfilm of specified specifications can also be used for the content of the master file to facilitate the review work and the storage of review data.
3. Drug Supervision in the United States
The FDA’s Drug Supervision Office has 150 staff. Fine division of labor. The main tasks of each department are: 1. Returns Department. Track the return information of pharmaceutical companies; 2. Counterfeiting Section. Clean up deceptive drug information; 3. Label Supervision Section. Manage the labels of commonly used drugs and prescription drugs; 4. Pharmaceutical and Product Quality Section. Among them, the Supervision and Evaluation Office reviews the supervision reports of regional institutes, the Policy Guidance Office reviews the policy nature of the reports, the Sterilization Drug Office focuses on supervising the production and quality of large infusions, and the Generic Drugs Office is responsible for supervising generic drugs; 5. Drug Quality Evaluation Department. Among them, the Product Investigation Office is responsible for reviewing the certification and issuance of insulin, etc. and formulating a national drug quality survey plan. The Drug Catalog Office is responsible for pharmaceutical factory registration and product catalog registration. The Legal Methods Research Office is responsible for studying disputes over statutory inspection methods. The Pharmaceutical Investigation Office is responsible for collecting data. Drug reporting information; 6. Research Section. Responsible for the review and investigation of new drug application materials, the Scientific Research Department consists of four departments: regulatory management, scientific research review, clinical research, and non-clinical research; 7. Regulations Section. Responsible for drafting relevant regulations and resolving disputes over the interpretation of regulations.
The supervision offices in each region have dedicated personnel responsible for the supervision of drugs, and the supervisors in the region are responsible for the supervision of drug production enterprises in the region. U.S. drug manufacturers must re-register with the FDA every year. Enterprises should apply for re-registration within one month after receiving FDA’s notice on re-registration. Companies should report changes to product catalogs to FDA every six months. Although foreign pharmaceutical companies exporting medicines to the United States are not required to register, they must undergo supervision and inspection and submit product catalogs. The imported product catalogs are used for customs inspection. Supervision of pharmaceutical factories is mainly to check whether the production activities of pharmaceutical factories are under control. That is, pharmaceutical factories should have a set of management measures that comply with the requirements of the Food, Drug, and Cosmetic Law and the current pharmaceutical production management regulations and should implement them. The regional office will make a supervision plan based on past supervision situations or reports and rework records. Generally speaking, pharmaceutical companies are inspected once every two years. Inspections are divided into comprehensive inspections and simple inspections. Comprehensive inspections are generally conducted every 3-4 years. The comprehensive inspection is relatively in-depth, and the main contents include: 1. Factory equipment, such as status markings, can easily cause unevenness or cross-contamination factors; 2. Personnel, such as training, quality and experience; 3. Materials, such as storage, standards and sampling, water supply; 4. Production operations; 5. Laboratory management, such as testing capabilities, instrument suitability tests, records and results; 6. Packaging and gold labeling, focusing on checking labels that may be confusing; 7. Records and reports, such as batch records and sales records; 8. Process validation, such as validation during process changes. After the comprehensive inspection, an inspection report should be written, and the conclusions of the report should be accurate and appropriate. The simple inspection only conducts a brief inspection of the pharmaceutical factory's facilities, representative batch records, etc., but strict inspections of packaging, labeling, and production processes should be carried out. Key processes for the production of APIs should also be inspected in accordance with the requirements of current pharmaceutical manufacturing practices. Key processes refer to phase changes during production, such as dissolution, crystallization, evaporation, etc.; phase separation, such as centrifugation, filtration, etc.; chemical changes, such as acetylation. Salt formation, etc.; condition adjustment, such as pH adjustment; application of materials; changes in particle size, such as crushing, etc.; improving uniformity, such as mixing and other processes.
The pre-approval supervision procedure for drugs is that the review office first seeks the opinions of the regional institute before approval. The region may recommend not approving or deferring approval based on the situation at hand. If the approval is postponed, the pharmaceutical factory may need to be inspected again to verify the production facilities of the new product. Conduct a comprehensive comparative demonstration of clinical trial batch samples and production scale products at the time of application. If process changes are discovered during the inspection, the pharmaceutical manufacturer should submit a supplementary application for approval. Characteristics of the clinical trial batches were obtained and computerized by the Pharmaceutical Analysis Laboratory in St. Louis and a regional laboratory in New York for future review. The characteristics of the test batch include appearance, size, internal and external color, spectrum, differential thermal analysis and other data. For generic pharmaceuticals, the characteristics should be consistent with those of the production-scale product. However, it should not be completely consistent with the characteristics of the invention's products.
State pharmaceutical agencies inspect drug business units and pharmacies at least once a year, use a simple checklist, and re-register once a year. The registration of pharmacists is also updated once a year. One of the conditions is that they must receive more than 10 hours of continuing pharmacy education in the past year.
4. U.S. drug legislation
The U.S. Congress passed the Food and Drug Act in 1906 - the "Drug Administration Regulations." At that time, drug management was not strict enough, and only random inspections were adopted to prohibit interstate trading of adulterated or counterfeit drugs. In 1912, Congress passed an amendment that explicitly prohibited exaggerated claims on drug labels.
In 1935, pharmacists discovered the antibacterial effect of sulfonamides, and various sulfonamide tablets and capsules came out one after another.
In 1937, Watkins, the chief pharmacist of an American pharmaceutical company, used diethylene glycol and water as solvents to prepare an oral liquid preparation with complete color, aroma and taste in order to make it convenient for children to take it - namely, sulfonamides (containing grains and volatile oils or The preparation of the main drug is an alcoholic solution, referred to as liquor), and no animal testing was conducted (which was allowed by U.S. law at the time). In 1938, 107 people died from sulfonamide poisoning. Later animal tests proved that sulfonamide itself was not toxic, and it was industrial diethylene glycol that caused poisoning and death. The U.S. Federal Court fined the pharmaceutical company $1,688 for using diethylene glycol instead of alcohol in the liquor, adulteration, and false labeling. Watkins, the chief pharmacist, also committed suicide in guilt and despair. This was the "sulfonamide preparations" incident that shocked the United States at that time. The U.S. pharmaceutical regulatory authorities are aware that there are major loopholes in the regulations for clinical trials and marketing of new drugs, and must revise regulations and strengthen safety testing. The revised regulations require that new drugs must be safe. Before changing the dosage form of an old drug and entering the market, the prescription should be submitted to the FDA for review, and labels and advertising must also be strictly reviewed. In 1962, Congress revised the regulations and believed that drugs must not only be safe, but also effective. At the same time, strict regulations were added to the approval of new drugs and 412 types of drugs were eliminated. After this, various states complained that control was too strict and the approval time for new drugs was too long. Congress revised the Drug, Food, and Cosmetic Regulations in January 1979. This regulation stipulates that all drug varieties, pharmaceutical factories, and wholesalers that are manufactured and sold must be submitted for registration review and approval. At the same time, a drug quality standard system, a drug regulatory inspector system, adverse drug reaction reports, etc. are stipulated to monitor drug quality. The current "Food, Drug, and Cosmetic Act" in the United States Chapter 9, Section 902.