History Why Are We Regulated?

Preamble of the Constitution " We, the people of the United States, in order to form a more perfect union, establish justice, insure domestic tranquility, provide for the common defense, promote the general welfare, and secure the blessings of liberty to ourselves and our posterity, do ordain and establish this Constitution for the United States of America.” Basis for regulation

History, continued: First Examples of Regulatory Action: In 1646, the General Court of the Massachusetts Bay Colony enacts the “Bread Act”. This act provides for: –traceability of bakers in the event of contaminated bread –annual inspections –shut-downs and/or fines and imprisonment In 1785, Massachusetts enacts the first general food adulteration law in the United States

History, continued: The Next 260 Years: –Thousands of useless cure-alls, elixirs, and machines are introduced to the general public. 1901: –Diphtheria Disaster 1902: –The Biologics Control Act is passed to insure the purity of serums vaccines, and similar products to prevent or treat human diseases.

History, continued: 1905: Upton Sinclair publishes The Jungle, which exposes U.S. meat-packing industry practices, such as casual meat inspection, and dramatizes many more graphic examples Pure Food and Drug Act –prohibits the sale of adulterated foods, drinks, and drugs –provides the beginning of what later became the Food and Drug Administration.

Food and Drug Administration, (FDA) Established in 1928, it is charged with protecting public health by ensuring that foods are safe and pure, cosmetics and other chemical substances harmless, and products safe, effective, and honestly labeled. In 1940, the FDA is transferred from the Department of Agriculture to the Federal Security Agency, which will become the Department of Health, Education, and Welfare in 1953 and the Department of Health and Human Services in 1980.

History, continued: 1937 Sulfanilamide Scare: –U.S. children die after treatment with sulfanilamide elixir containing diethylene glycol Food, Drug and Cosmetic Act (FDC) –Replaces the Pure Food and Drug Act of –Establishes requirements for identity, quality, and strength of drugs. –Extends coverage to include cosmetics and medical devices. –Requires manufacturers to prove safety of new drugs. –Mandates FDA review and approval of new drugs. –Controls the packaging and labeling of drugs. –Authorizes inspections and adds remedies of court injunction, seizure, and prosecution.

History, continued: 1962 Thalidomide Disaster –Britain and France remove thalidomide from the market. The Washington Post credits FDA researcher Frances Kelsey with having prevented thalidomide birth defects in thousands of U.S. infants Kefauver-Harris Amendment –Extends the authority of the FDA to regulate the approval of new drugs –Provides for greater assurance of safety –For the first time requires drug manufacturers to prove efficacy of new drugs before marketing them

History, continued: Early 1970’s: First implementation of GLP –New Zealand (1972) –Denmark (1973) US GLP –Implemented June 1979 Global –Organization for Economic Cooperation and Development (OECD) –Adopted May 1981 –Accepted as “International GLPs”

Events Leading to US GLPs Laboratory conditions found by FDA and EPA in mid-1970’s Testimony to US Senate Subcommittee on Health ( ) Flagrant research discrepancies noted at leading contract research laboratory, Industrial Biotest Corporation (IBT)

Sample FDA Observations Original autopsy records unavailable. Records of laboratory observations neither dated nor signed. Employees unable to account for discrepancies between raw data and final reports. Animals observed and recorded to be normal in appearance, appetite, and thirst, when in fact dead. FDA told that animal tissue examined histopathologically, when review indicated that samples were never collected.

FDA Conclusions Experiments were poorly conceived, carelessly executed, or inaccurately analyzed or reported. Technical personnel were unaware if the importance of protocol adherence, accurate observations, accurate administration of the test substance, and accurate record keeping and record transcription. Management did not assure critical review of data or proper supervision of personnel. Assurance could not be given for the scientific qualifications and adequate training of personnel involved in the research study.

FDA Conclusions (continued) There was a disregard for the need to observe proper laboratory, animal care, and data management procedures. Sponsors failed to adequately monitor the studies performed by contract testing laboratories. Firms failed to systematically verify the accuracy and completeness of scientific data in reports of nonclinical laboratory studies before submissions to FDA.

Regulations Current Good Manufacturing Practices for Pharmaceuticals (cGMP) –Proposed by FDA February 13, 1976 –Published in final form in CFR September 29, 1978 –Effective March 28, 1979 Good Laboratory Practices (GLP) –Proposed November 1976 –Implemented June 1979 –Revised September 1987 –Minor change July 1991

1992 Prescription Drug User Fee Act Requires drug and biologics manufacturers to pay fees for applications and supplements submitted to FDA. Funds are to be used by FDA to hire more reviewers and thus speed up the approval process.

FDA Organization and Structure The FDA is one of eight agencies within the Public Health Service, which in turn is part of the Health and Human Services Department. FDA is headed by the FDA Commissioner, who is appointed by the Secretary of HHS.

FDA Organization and Structure

Classifications of FDA Regulated Products: Drug Product: A finished dosage form that contains an active ingredient, usually classified as a drug substance or biologic. Drug Substance: An active drug ingredient which is generally, but not limited to, a well-defined, characterized chemical entity prepared by controlled synthesis. Biologic: A blood product or an active drug ingredient which is generally a protein isolated from a biomass produced by a natural or recombinant organism. Device: Generally, but not limited to, a manufactured instrument or mechanical object used for medical purposes.

How the FDA Review a New Drug Application (NDA): The members of the FDA review team simultaneously apply their special technical expertise to the review of an NDA: Chemists focus on how the drug is put together, whether the manufacturing controls and packaging are adequate to insure the stability of the product, and whether the proposed labeling accurately reflects the effects of the drug. Pharmacologists evaluate the effects of the drug on laboratory animals in short-term and long-term studies. Physicians evaluate the results of the clinical tests -- including the drug’s adverse as well as therapeutic effects.

How the FDA Review a New Drug Application (NDA), continued: Statisticians evaluate the designs for each controlled study, the validity of statistical analyses, and the conclusions of safety and effectiveness based on the study data. Microbiologists evaluate the data on anti-infectives (antibiotics, antivirals, and antifungals). These drugs differ from others because they’re intended to affect microbes instead of patients. Other staff evaluate the rate and extent to which the drug’s active ingredient is made available to the body and the way it is distributed, metabolized, and eliminated. They determine whether the evidence supports the labeling for the recommended dosing regimen.

Regulatory Lifecycle of a Drug

Regulations and Guidelines Good Manufacturing Practices (GMP; also cGMP or CGMP): A set of regulations governing the methods used in manufacture, quality control, and quality assurance for the preparation of drug or medical device products. Good Laboratory Practices (GLP): A set of regulations governing the methods used in conducting nonclinical laboratory studies intended to support applications for research or marketing permits for FDA-regulated products. ISO 9000 Series Standards: A set of guidelines issued by the International Organization for Standardization (ISO) that describes standards for quality systems (for all industries, not just pharmaceuticals).

ISO 9000 Series Standards: ISO 9000: Clarifies the distinctions between the principal quality concepts and systems and provides guidelines for the selection and use of the series of standards. ISO 9001: Specifies a model for quality when compliance is to be assured during several stages, including design and development, production, installation, and servicing. ISO 9002: Specifies a model for quality assurance in production and installation. ISO 9003: Specifies a model for quality assurance in final inspection and testing. ISO 9004: Describes the elements of quality management and the quality system.

Control Systems: Implemented as a means of quality management for all aspects of pharmaceutical manufacturing. Designed to assure compliance with regulations. Examples include: –Document Control –Facility and Equipment Control –Material Control –Laboratory Control –Recordkeeping and Report Systems –Change Control

FDA on the Net: Contains introduction to FDA, organizational, and much other useful information (I used it as a source for this class). Documents, guidelines, news, headlines, and magazines on-line. Home page address: –