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).
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
• Pond's Extract
• Rumford Yeast Powder
• Wells, Richardson, & Co.'s Lactated Food
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)
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.
• =>1938 Federal Food, Drug and Cosmetic Act
FDA Act 1938
• requiring that new drugs be shown to be safe
before marketing.
• extending FDA’s 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
Drug Testing Guidelines:
1. Chemical Composition
2. Acute toxicity studies in two species
3. Chronic toxicity studies with different doses in
different species
4. Observation of animals
5. Pathological examination of animals
6. Studies on the absorption and elimination of the
chemical
7. Study of interactions
8. Knowledge of idiosyncrasies and untoward
reactions
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The Crystaldyne Pain Reliever, 1996
Similar to The Stimulator
The Stimulator is essentially an electric gas barbecue grill igniter outfitted with finger grips.
When pressed against the skin, the devices sparks and causes a small electric shock. Makers of
the device claim it can relieve headaches, back pain, arthritis, stress, menstrual cramps, earaches,
sinus, nosebleeds, flu and other ailments.
Because of its medical claims, the Stimulator is considered a medical device. The manufacturers,
however, have not complied with any FDA regulations that govern the marketing of medical
devices. The companies have submitted no information to FDA showing that the device is either
safe or effective...
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)]
FDA History Continued
• => 1976 Medical Device Amendments
[new=> review, old=>grandfathered, new
equivalent=>grandfathered]
• =>1978 Good Manufacturing Practices
• =>1984 Medical Device Reporting
• =>1988 Device Recall/Rebuild
• =>1990 Safe Medical Devices
FDA History Continued
• =>1992 Medical Device Amendments [tracking,
surveillance, reporting, refund, ..]
• =>1997 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 FDA’s regulatory
counterparts abroad…
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.
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.
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
Is My Device a Medical Device?
• http://www.fda.gov/cdrh/devadvice/11.html#start
• http://www.fda.gov/cdrh/devadvice/313.html
• http://www.fda.gov/cdrh/devadvice/3132.html#class_1
• http://www.fda.gov/cdrh/devadvice/3132.html#class2
• http://www.fda.gov/cdrh/devadvice/3132.html#class2
• http://www.fda.gov/cdrh/devadvice/3131.html#proceed
Special Terms
• 510k Premarket notification
• IDE – investigational device exemption
• PMAA – premarket approval application
• GLP – good laboratory practices
• GMP – good manufacturing practices
• Design Control
• IRB Institutional review board
Class 1
• Not life sustaining
• No risk
• No standards
• 510k (some) => registration => listing =>
GMP (some) => Record keeping
• Tongue depressors, stethoscopes*,
screwdrivers, …
Class 2
• Not life sustaining, but must meet
control/performance standards
• 510k => IDE => PMAA => Registration =>
Record keeping
• Sphygmanometer, powered wheelchairs,
drapes, infusion pumps
Class 3
• Life sustaining
• 510k => IDE => [data!!!] => PMAA =>
Registration => Record Keeping
• Data & techniques must include failure
mode analysis, animal test, toxicology
studies, human trials (IRB), PDP (product
development protocol.)
FDA approval?
• One or more years
• Now you will be monitored…
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)
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.
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.)
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.
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.
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.
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.
FDA Approval?
• Screen 5000 compounds => 5 trials => 1
drug….
• Blind/Double blind studies…
• High cost of development ($360M), giving
rise to mathematical modeling &
simulation…
• Penalties! $100M fine – Abbott Labs Q/A.
http://www.apexbioscience.com/products.htm
For more detailed information on PHP, click
here)
Indications:
Nitric Oxide-induced shock
Other proprietary applications
Status:
Established patent position
Proved NO scavenger concept in sheep,
dog, pig, and mouse models
Completed Phase 1 safety study and initial
Phase 1/2 patient trial for NO-induced shock
Completed continuous infusion and dose
escalation (Phase 2) clinical trial
Randomized, controlled Phase 3 trial to
commence in 2001