Images are from the National Library of Medicine Archives

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The Regulation of Drugs and Poisons
Images are from the National Library of Medicine
Archives
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1906 - Federal Pure Food and Drug Act
Dr. Harvey Wiley - Poison Squad
Upton Sinclair - The Jungle
United States Pharmacopeia
National Formulary
http//www.cfsan.fda.gov/lrd/fdahist.html
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1938 - Federal Food, Drug, and Cosmetics Act
elixir of sulfanilamide
diethylene glycol (diglyme)
Victims of Elixir Sulfanilamide poisoning--many
of them children being treated for sore
throats--were ill about 7 to 21 days. All
exhibited similar symptoms, characteristic of
kidney failure stoppage of urine, severe
abdominal pain, nausea, vomiting, stupor, and
convulsions. They suffered intense and
unrelenting pain.
Some Significant Amendments Durham-Humphrey Act
(1951) - prescriptions written and filled by
licensed practitioners Food Additives Act (1958)
- GRAS list Delaney clause
Kefauver-Harris or Drug Amendments Act (1962) -
thalidomide - mandate for safety and efficacy

Drug Abuse Control Amendments (1965) Medical
Device Amendments (1976) Antidrug Abuse Act
(1988) - control of anabolic steroids
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thalidomide
R - sedative, antinausea S - teratogen
A regulatory application for thalidomide is
currently under review by the Food and Drug
Administration (FDA) to confirm its efficacy and
safety for use in myeloma. Thalidomide is
approved in the US for the treatment of a
condition that develops in some people with
leprosy (a chronic infectious disease). In
addition to myeloma, thalidomide is being
evaluated in clinical trials as a treatment for a
variety of solid tumors and hematologic (blood)
cancers.
Thalidomide is an immunomodulatory agent (a drug
that affects the immune system). However, its
precise mechanism of action is unknown and under
investigation. Thalidomide appears to have
multiple actions, including the ability to
inhibit the growth and survival of myeloma cells
in various ways and to inhibit the growth of new
blood vessels (angiogenesis).
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Other Significant Legislation

• Hazardous Substances Labeling Act (1960)
• Comprehensive Drug Abuse Prevention Control Act
  (1970)
• hierarchy of Schedules
• http//www.addictions.org/schedules.html
• http//www.dea.gov/pubs/scheduling.html
• Caution Federal law prohibits the transfer of
  this drug to any person other
• than the patient for whom it was prescribed.
• Occupational Safety and Health Act (1970)

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FIFRA
The primary focus of FIFRA was to provide federal
control of pesticide distribution, sale, and use.
EPA was given authority under FIFRA not only to
study the consequences of pesticide usage but
also to require users (farmers, utility
companies, and others) to register when
purchasing pesticides. Through later amendments
to the law, users also must take exams for
certification as applicators of pesticides. All
pesticides used in the U.S. must be registered
(licensed) by EPA. Registration assures that
pesticides will be properly labeled and that if
in accordance with specifications, will not cause
unreasonable harm to the environment.
Toxic Substances Control Act (1976)

• Major Environmental Laws (from the EPA website)
• Clean Air Act (CAA)
• Clean Water Act (CWA)
• Emergency Planning Community Right-To-Know Act
  (EPCRA)
• Endangered Species Act
• Federal Insecticide, Fungicide and Rodenticide
  Act (FIFRA)
• Freedom of Information Act (FOIA)
• National Environmental Policy Act (NEPA)
• Occupational Safety and Health Act (OSHA)
• Oil Pollution Act of 1990 (OPA)
• Pollution Prevention Act (PPA)
• Resource Conservation and Recovery Act (RCRA)
• Safe Drinking Water Act (SDWA)
• Comprehensive Environmental Response,
  Compensation, and Liability Act (CERCLA or
  Superfund)
• Superfund Amendments and Reauthorization Act
• Toxic Substances Control Act (TSCA)

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Orphan Drug Act (1983, amended 1984) orphan
condition or disease - affecting lt200,000 in
U.S. 7 years of marketing rights after FDA
approval tax credits for clinical research
expenses assistance for FDA approval grant
support for clinical trials filing fee waivers
rare diseases
Tourettes syndrome acromegaly mumps muscular
dystrophy beta thalassemia sickle cell disease
Drug Price Competition and Patent Term
Restoration Act (1984)
The Food and Drug Administration Modernization
Act of 1997
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Chemical Weapons Convention (CWC)
international

• destruction and prohibition of chemical weapons
  and related facilities
• restrictions on international trade in toxic
  chemical and precursors

Schedules (3) Schedule 1 - chemicals posing a
high risk for use as chemical weapons little or
no use for peaceful purposes in commercial or
industrial trade chemicals that have already
been produced, stockpiled, or used as weapons
includes binary weapons Schedule 2 - chemicals
and precursors posing a significant risk because
of lethal or incapacitating properties these
are not produced in large quantities and may be
used to produced specific products such as
pharmaceuticals. Schedule 3 - similar to
Schedule 1 chemicals but produced in large
quantities for purposes not prohibited by the CWC.
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OPCW - Organization for the Prohibition of
Chemical Weapons
verification
Examples of Scheduled Chemicals
Schedule 2 toxics - amiton, PFIB, BZ
precursors - P connected to methyl- ethyl-
or propyl but no more carbons others
Schedule 1 toxics sulfur mustards
Lewisites nitrogen mustards
sarin, soman, etc.
arsines
Schedule 3 toxics precursors
phosgene, cyanogen chloride, HCN, chloropicrin
phosphorous oxychloride, di-,penta-chloride phosph
ites sulfur chlorides, thionyl chloride ethyl-,
methyl-, triethanolamines
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Agencies
10 Most Significant Health Achievements of the
20th Century
FDA DEA EPA DOT OSHA USDA CPSC FTC

• Vaccination
• Motor-vehicle safety
• Safer workplaces
• Control of infectious diseases
• Decline in deaths from coronary heart disease and
  stroke
• Safer and healthier foods
• Healthier mothers and babies
• Family planning
• Fluoridation of drinking water
• Recognition of tobacco use as a health hazard

CDC NIH NIST BATF
CDC Morbidity and Mortality Weekly Report (MMWR)
4/19/99
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Pre-Clinical Research
Clinical Studies
synthesis purification
high failure rates in Phase 3
formulation
industrial production
animal testing
Institutional Review Boards
NDA submitted
INDA submitted
PMA - medical devices
ANDA - generics
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Clinical Trials
population purpose
20-80 healthy volunteers
to determine safety and dosage
Phase I
100-300 patient volunteers
to evaluate effectiveness and side effects
Phase II
1000-3000 patient volunteers
to confirm effectiveness, study adverse effects,
and effects from long-term use
Phase III
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NDA Chemical Type
1 - New molecular entity 2 - New ester, new
salt, or other noncovalent derivative 3 - New
dosage form 4 - New combination 5 - New
formulation or new manufacturer 7 - Drug
already marketed, but without an approved NDA 8 -
OTC switch
Review Classification P - Priority Review -
Significant improvement compared to marketed
products, in the treatment,
diagnosis, or prevention of a disease. S -
Standard Review - Products that do not qualify
for priority review. O - Orphan Designation -
Pursuant to Section 526 of the Orphan Drug Act
(Public Law 97-414 as amended).
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Clinical trials are advertised in magazines,
newspapers, and online
for example - Alzheimers
Currently there are 147 clinical trials
recruiting or about to recruit

• Alzheimer's Disease Genetics Study
• A Comparison of Two Standard Therapies in the
  Management of Dementia With Agitation
• MRI of Alzheimer's Disease Imaging Amyloid
  Plaques in Persons With and Without Memory
  Problems
• Prevention of Alzheimer's Disease by Vitamin E
  and Selenium (PREADVISE)
• Development of NIC5-15 in the Treatment of
  Alzheimers Disease
• Comparative Efficacy, Safety, and Tolerability of
  Rivastigmine 10 and 15 cm2 Patch in Patients With
  Alzheimers Disease (AD) Showing Cognitive
  Decline
• Memantine for Agitation and Aggression in Severe
  Alzheimer's Disease
• Raloxifene for Women With Alzheimer's Disease
• Biomarkers and Early Alzheimer's Disease

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Toxicity Testing

• Underlying principles
• Effects produced in laboratory animals, when
  properly qualified, can be applied to humans.
• Exposure of experimental animals to high doses
  of toxic agents are a necessary and valid method
  for discovering potential hazards in humans.

• Descriptive Animal Toxicity Tests
• acute
• subacute
• subchronic
• chronic

• fertility and reproductive - phase 1
• teratogenic - phase 2
• perinatal and postnatal - phase 3
• multigenerational reproduction
• mutagenic
• others

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Estimates of the cost to develop 1 successful
therapeutic agent range from 300x106 to 800x106.
For Pharmaceutical Companies
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• All pharmaceuticals (2006)
• Active INDs 14,117
• NDAs received 123
• priority NDA approved 21
• median FDA review time 6 mons
• standard NDA approved 80
• median FDA review time 12 mons

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The 400 Best Big Companies in Drugs Biotechnolgy
Forbes 2007
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Chemical Engineering News, 12/4/2006
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Top 10 Therapies 2006
cholesterol triglyceride reducers antiulcerants
antidepressants antipsychotics all other
antineoplastics erythropoietins antiepileptics cal
cium antagonists, plain oral antidiabetics platele
t aggregation inhibitors
Data from Chemical Engineering News, 12/4/2006
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Top Pharma Companies by Prescription Drug Sales
Pharmaceutical Executive October 14, 2007
http//www.pharmexec.com
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TOP 10 Brand-Name Drugs (June 2006)
59.7 billion in sales
Brand Name
Drug Name
Indication
Lipitor Plavix Nexium Seretide Zocor Norvasc Zypre
xa Risperdal Aranesp Enbrel
Atorvastatin Clopidogrel Esomeprazole Fluticasone-
salmeterol Simavastatin Amlodipine Olanzepine Risp
eridone Darbepoetin alfa Etanercept
Hypercholesterolemia Atherosclerotic
events Ulcers, reflux disease Asthma Hypercholeste
rolemia Hypertension Schizophrenia Schizophrenia A
nemia Rheumatoid Arthritis
Data from Chemical Engineering News, 12/5/06
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TOP 10 GENERICS (2006)
Worlds TOP 10 Drugs (2006) Forbes
Lipitor HYCD/APAP (Merck) Toprol-XL Norvasc Amoxic
illin HYCD/APAP (WTS) Synthroid Nexium Lexapro Alb
uterol
Lipitor Plavix Nexium Advair Zocor Norvasc Zyprexa
Risperdal Prevacid Effexor
Pharmacy Times May 2007 http//www.pharmacytimes.c
om/article.cfm?ID4629
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Patents Ending in 2006
Brand Name
Compound
Indication
Zocor Zoloft Pravachol Ambien Zofran Lamasil
Simvastatin Sertraline Pravastatin Zolpidem On
dansetron Terbinafine
Hypercholesterolemia Depression Hyperlipidemia
Insomnia Chemotherapy-induced nausea Fungal
infections
Data from Chemical Engineering News, 12/5/05
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Issues
An Industry in Transition - Chemical and
Engineering News - June 2006
life-cycle management plans
"evergreening." This refers to the filing of
additional patents or other legal maneuvers,
often undertaken shortly before the original
patent expires.
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re-investigations of rejected candidates
http//pubs.acs.org/cen/pharma/8425introtext.html
- June 2006
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Issues
of drug-able disease-related targets
(300-1500) maybe only 180-190 for small molecule
drugs
promiscuous drugs
phenotypic cell- and organism-based approach vs.
reductionist target- and mechanism-based
strategies
target validation (must be done in humans)
knock-out mice RNAi
technique in which a double-stranded RNA
fragment called a short interfering RNA (siRNA)
is used to degrade a messenger RNA and thus
silence the gene that the mRNA is helping to
translate into protein.
http//pubs.acs.org/cen/pharma/8425introtext.html
- June 2006
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RISK ASSESSMENT
pharmacovigilance
Which quadrant is most likely to evoke
government regulation?