The Food and Drug Administration

1
Chapter 16

• The Food and Drug Administration

2
FDA Prehistory

• 1862, President Lincoln appointed first director
  of Department of Agriculture
• 1883 Request for petition to pass laws
  prohibiting adulteration misbranding of foods
  and drugs.
• For serious drinking, the drugstore was the place
  to go. Lydia E. Pinkham's Vegetable Compound, a
  popular nostrum for women, was depending on the
  formula, 15 to 20 percent alcohol (VU).

3
Advertising Cards

• A common method for medicine-makers to hawk their
  products was to provide druggists with
  postcard-sized advertisements with a picture on
  one side and a description of the glories of the
  product on the other.
• Ayer's Sarsaparilla
• Dr. Morse's Indian Root Pills
• Hires' Root Beer
• Lydia E. Pinkham's Vegetable Compound (First
  Card)
• Lydia E. Pinkham's Vegetable Compound (Second
  Card)
• Pond's Extract
• Rumford Yeast Powder
• Wells, Richardson, Co.'s Lactated Food

http//www.mc.vanderbilt.edu/biolib/hc/nostrums/ca
rds.html
4
The Jungle, Upton Sinclair, 1906

• with the hot weather there descended upon
  Packingtown a veritable Egyptian plague of flies
  there could be no describing this--the houses
  would be black with them. There was no escaping
  you might provide all your doors and windows with
  screens, but their buzzing outside would be like
  the swarming of bees, and whenever you opened the
  door they would rush in as if a storm of wind
  were driving them. (Chapter 10)

5
FDA History

• 1906 FDA formed, banned interstate commerce in
  adulterated misbranded food, drink, and drugs
• 1938 107 deaths of (primarily) children due to
  ingestion of Elixir of Sulfanilamide, a toxic
  combination of diethylene glycol and sulfa.
• gt1938 Federal Food, Drug and Cosmetic Act

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FDA Act 1938

• requiring that new drugs be shown to be safe
  before marketing.
• extending FDAs control to cosmetics and
  therapeutic devices.
• authorizing factory inspections and standards of
  identity for food staples.
• eliminating a requirement to prove intent to
  defraud in drug misbranding cases.
• adding court injunctions to the previous
  penalties of seizures and prosecutions

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Drug Testing Guidelines

• Chemical Composition
• Acute toxicity studies in two species
• Chronic toxicity studies with different doses in
  different species
• Observation of animals
• Pathological examination of animals
• Studies on the absorption and elimination of the
  chemical
• Study of interactions
• Knowledge of idiosyncrasies and untoward
  reactions

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FDA History Continued

• 1962 sale/use of thalidomide banned in U.S. based
  upon thousands of birth defects, primarily in
  Europe South America amendment for efficacy
  safety
• 1969 hearings re injuries (10,000) deaths
  (731) in a 10 year period heart valves,
  pacemakers, IUDs, (Nader)

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FDA History Continued

• gt 1976 Medical Device Amendments newgt review,
  oldgtgrandfathered, new equivalentgtgrandfathered
  
• gt1978 Good Manufacturing Practices
• gt1984 Medical Device Reporting
• gt1988 Device Recall/Rebuild
• gt1990 Safe Medical Devices

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FDA History Continued

• gt1992 Medical Device Amendments tracking,
  surveillance, reporting, refund, ..
• gt1997 Modernization Act public health is a
  responsibility shared by the entire health care
  community. The law directs the agency to carry
  out its mission in consultations and cooperation
  with all FDA stakeholders, including consumer and
  patient groups, the regulated industry, health
  care professionals, and FDAs regulatory
  counterparts abroad

13
Labeling

• FDA (also) regulates the labeling of products
  under its jurisdiction. This information, which
  must be rigorously truthful, well documented, and
  not misleading, plays a major role in protecting
  consumers and the public health. The
  FDA-regulated food label is helping shoppers eat
  a healthy diet the labeling of drugs and medical
  devices gives prescribers and patients reliable
  guidance about the safety and effectiveness of
  health care products.

14
Recent TV Ad (October 2001)

• (several photos of couples, )
• 3 bottles of male virility compounds!
• Free three month supply, 3 bottles!
• Simply pay 8.50 shipping and handling charges
  for each bottle!
• No health claims are made for these pills in
  accordance with FDA regulations.

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• A medical device is"an instrument, apparatus,
  implement, machine, contrivance, implant, in
  vitro reagent, or other similar or related
  article, including a component part, or accessory
  which is
• - recognized in the official National
  Formulary, or the United States Pharmacopoeia, or
  any supplement to them,
• intended for use in the diagnosis of disease or
  other conditions, or in the cure, mitigation,
  treatment, or prevention of disease, in man or
  other animals, or
• intended to affect the structure or any function
  of the body of man or other animals, and which
  does not achieve any of it's primary intended
  purposes through chemical action within or on the
  body of man or other animals and which is not
  dependent upon being metabolized for the
  achievement of any of its primary intended
  purposes."
• FDA Definition

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Is My Device a Medical Device?

• http//www.fda.gov/MedicalDevices/DeviceRegulation
  andGuidance/default.htm

Contains overviews, marketing information, search
terms, etc.
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Special Terms

• 510k Premarket notification
• Exemptions equivalent to pre 1976 devices or
  other approved devices
• IDE investigational device exemption
• PMAA premarket approval application
• GLP good laboratory practices
• GMP good manufacturing practices
• Design Control
• IRB Institutional review board

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Device Classification Class I

• Not life sustaining
• No risk
• No fixed standards
• 510k (some) gt registration gt listing gt GMP
  (some) gt Record keeping
• Tongue depressors, stethoscopes, screwdrivers,

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Device Classification Class II

• Not life sustaining, but must meet
  control/performance standards
• 510k gt IDE gt PMAA gt Registration gt Record
  keeping
• Sphygmanometer, powered wheelchairs, drapes,
  infusion pumps

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Device Classification Class III

• Life sustaining
• 510k gt IDE gt data!!! gt PMAA gt Registration
  gt Record Keeping
• Data techniques must include failure mode
  analysis, animal test, toxicology studies, human
  trials (IRB), PDP (product development protocol.)

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FDA approval?

• One or more years
• Now you will be monitored

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Registration

• (All US (foreign optional)) (manufacturer or
  preparer or processor or propagator of device)
  must register yearly with FDA get a device
  registration . (30 days change)

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Listing

• All manufacturers must list w FDA all devices
  they market (q 6 mo.)
• All manufacturers must supply FDA with all
  labeling advance copy of new labeling.

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Registration Listing

• traceability recallability
• FDA may force recall, fines, reparations, repair,
  
• FDA may inspect devices, records, labeling,
  documentation, licenses, laboratories, premises,
  etc at virtually any time.
• FDA requires reporting of adverse events (MAUDE
  system.)

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The 510k substantial equivalency process See
http//www.fda.gov/cdrh/devadvice/314.html
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Related 510ks

• Special minor modification of current device
• Abbreviated guidance/control/consensus in place

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Declaration of Conformance to a Recognized
Standard

• ID of standards that were met
• ID of any variations (alternate steps)
• ID of any standards not applicable

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Premarket Approval

• Class 3, ensures adequate review
• Fairly fixed format/content, includes standards,
  investigations, samples, all relevant data

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Investigational Device Exemptions

• Must have IRB approval(s) equitable risk
  selection, informed consent (documented),
  adequate safety controls, privacy/confidentiality
  
• Investigator is RESPONSIBLE
• No fixed format

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Good Laboratory Practices

• 1978 laws requiring GLP and laboratory audit and
  inspection procedures by the FDA
• Must have records for audit, proof of
  maintenance, evaluation, inspection, etc.

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Good Manufacturing Practices

• FDA requirements regarding manufacturing of
  medical devices
• Auditable records must be kept re
  input/output/QA/record keeping/standards/inspectio
  ns/etc
• FDA may inspect/fine/etc.

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Human Factors

• Guidance document (1996) Do it by design. see
  http//www.fda.gov/cdrh/humfac/doit.html
• General discussion/guidance re the design of
  medical devices
• May become a required part of device
  documentation

33
Design Controls

• See http//www.fda.gov/cdrh/comp/designgd.html
• General guidance document regarding the
  application of design controls/methods that can
  properly address risk management, design
  development planning, interfaces, design cycles,
  etc.

34
Software

• If part of a device, generally must meet same
  minimum standards as the device.
• If standalone (say drug calculator) same general
  levels I no risk, II some, esp. if in
  radiation therapy machines, III life sustaining
• 8-20 of all deaths are software related.
• FDA has published guidelines, can inspect

35
FDA Inspections

• Access to everything but sales/pricing/financial
  data
• Close/fine/recall/etc. powers
• Cooperate! Keep up to date on regulations! Have
  a good QA program

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Drugs

• FDA has even more say here.
• All drugs must be tested on at least 2 properly
  chosen animal models (thalidomide). (Generally do
  test tube toxicity test first, then animals.)
• Testing on humans must go through three or more
  stages under IRB control. Testing must stop if
  there is any untoward event.
• Powers fine, recall, inspect, etc.

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Animals?

• Chimpanzees, cats, dogs, mice/rats, primates,
  rabbits, pigs, sheep, ferrets, woodchuck,
  armadillo, guinea pigs, lobsters, chinchillas,
  electric eels, opossums, angler fish, axolotl,
  slugs, pigeons, shark, zebra fish, tropical fish,
  trout, goldfish, C elegan, fruit fly, etc.

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Drug testing in Humans

• Under IRB approval (Informed consent)
• Phase 1 small cohort, 20-80 people, look for
  major problems, safety, tolerance, dose limiting
  toxicities, mode of entry, dose range
• Phase 2 100 - 300, look for dosing concerns,
  look for minor problems, efficacy, safety
• Phase 3 1000-3000 develop and prove statistics
  on efficacy, safety, tolerance, possible other
  uses.

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FDA Approval?

• Screen 5000 compounds gt 5 trials gt 1 drug.
• Blind/Double blind studies
• High cost of development (360M), giving rise to
  mathematical modeling simulation
• Penalties! 100M fine Abbott Labs Q/A.
• .questions?