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.
• 1906 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.
• 1938 Food, Drug and Cosmetic Act (FDC)
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Replaces the Pure Food and Drug Act of 1906.
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.
• 1962 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 (1975-1976)
• 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)
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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
Commisioner
Office of
External Affairs
Office of
Management and Systems
Office of AIDS and Special Health Issues
Office of Consumer Affairs
Office of Health Affairs
Office of Legislative Affairs
Office of Public Affairs
Office of Women's Health
Office of
Operations
Office of Policy
Center for Biologics Evaluation and Research
Center for Devices and Radiological Health
Center for Drug Evaluation and Research
Center for Food Safety and Applied Nutrition
Center for Veterinary Medicine
National Center for Toxicological Research
Office of Orphan Products Development
Office of Regulatory Affairs
Office of Information Resources
Management
Office of Management
Office of Planning and
Evaluation
Regulations Policy and
Management Staff
Policy Development and
Coordination Staff
Policy Research Staff
International Policy Staff
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
Discovery
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Pre-Clinical Trials
Animal Testing
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Investigational New Drug Application(IND)
Permission to Test in Humans
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Clinical Trials
Human Testing
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New Drug Application (NDA)
Permission to Market
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Market Launch
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:
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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:
– http://www.fda.gov