Transcript An Overview of the Pharmaceutical Development Process

Discovering New Medicinal
Drugs
Freddie Arocho-Perez, MS, MSSE
Senior Research Scientist
Inhalation Products and Medical Device
Development
Pharmaceutical Product Development, Inc. (PPDI)
Glossary
 FDA –
U.S. Food and Drug Administration
 API – Active Pharmaceutical Ingredient
 NCE – New Chemical Entity
 IND – Investigational New Drug
 IRB – Institutional Review Board
 NDA – New Drug Application
 GLP – Good Laboratory Practices
 cGMP – current Good Manufacturing
Practices
NCE/API Development

Medicinal chemists develop compounds based
on related substances.

Aspirin developed as synthetic form of willow bark
extract (salicin).
• Ibuprofen based-off aspirin
• C13H18O2

Acetaminophen
• C8H9NO2

Albuterol
• (C13H21NO3)2·H2SO4
NCE/API Development

S-ibuprofen:



Also known as “dexibuprofen”.
It is a non-steroidal anti-inflammatory drug (NSAID).
It is used as an anti-inflammatory agent and as
analgesic (painkiller).
NCE/API Development

(R)-Albuterol:



Albuterol is a bronchodilator that relaxes muscles in the airways and
increases air flow to the lungs.
Albuterol is used to treat or prevent bronchospasm in people with
reversible obstructive airway disease.
Asthma Treatment. Asthma is a breathing problem due to
widespread narrowing of the airways (bronchial tubes).
NCE/API Development

Tetrahydrocannabinol (THC) is the active
ingredient in marijuana. Marijuana increases
levels of dopamine in the brain.

Drug Discovery: Local Anesthetics from Cocaine


By altering the structure of cocaine, two new local
anesthetics were discovered (benzocaine and
novocaine).
Novocaine is used in the treatment of dental pain.
Product Development Cycle
Years
Pre
Phase Phase Phase NDA
clinical
I
II
III
Review
2-6
0.5-1
1-2
1.5-3 1-2.5*
Test
Animal
Subjects
Purpose Safety/
Efficacy
20 100
Safety/
Dose in
Healthy
100 - 1000 –
1000 10,000
Safety/
Effect on
Disease
Safety/
Effect/
Side
Effects
Success 5,000
5 into Human trials
Rate
Overall process takes 6-14.5+ years.
Review
Process
and
Approval
1
Phase I Studies
Pre
Phase Phase Phase NDA
clinical
I
II
III
Review
Years
2-6
0.5-1
1-2
1.5-3 1-2.5*
Test
Animal 20 100 - 1000 – Review
Process
Subjects
100
1000 10,000
and
Approval
Safety/
Safety/
Safety/
Purpose Safety/
Efficacy
Dose in
Healthy
Effect on
Disease
Effect/
Side
Effects
Success 5,000
5 into Human trials
Rate
Overall process takes 6-14.5+ years.
1
Phase I Studies
 Determine

Dose ranging on healthy individuals.
 Determine

tolerable dose.
potential side effects profile.
Side effects on healthy individuals help
determine impact on patients with disease.
 Discover
human pharmacology and drug
distribution.

Analysis of patient’s blood, urine and feces to
determine metabolites, API half-life and route
of elimination.
Phase I Studies
 Requires
IND be filed with the FDA.
 Clinical trial design approved by IRB.
 Limited number of test subjects used
(20-100).
 These studies use healthy, male
volunteers to determine the safety of the
product through dose-ranging studies.


Increasing doses are given to determine
potential side effects.
Subjects may be kept under observation.
Phase I Clinical Studies
Side Effects
Before
After
Phase II Studies
Pre
Phase Phase Phase NDA
clinical
I
II
III
Review
Years
2-6
0.5-1
1-2
1.5-3 1-2.5*
Test
Animal 20 100 - 1000 – Review
Process
Subjects
100
1000 10,000
and
Approval
Safety/
Safety/
Safety/
Purpose Safety/
Efficacy
Dose in
Healthy
Effect on
Disease
Effect/
Side
Effects
Success 5,000
5 into Human trials
Rate
Overall process takes 6-14.5+ years.
1
Phase II Studies
 Actual
product development for
commercial style product.

Tablets, creams, liquids, injectables, pMDI
 Assessing
activity of NCE/API on disease
state.

Main focus for determining if product is viable.
 Lab
scale still possible for clinical supplies.
Phase II Clinical Studies
 These
studies use test subjects with the
target disease to confirm the safety, dose
and efficacy of the drug product.
 Number of test subjects (both sexes)
increases for determination of efficacy
(100-1000).
 These studies will determine whether the
selected drug product actually works on
the target disease.
Phase III
Pre
Phase Phase Phase NDA
clinical
I
II
III
Review
Years
2-6
0.5-1
1-2
1.5-3 1-2.5*
Test
Animal 20 100 - 1000 – Review
Process
Subjects
100
1000 10,000
and
Approval
Safety/
Safety/
Safety/
Purpose Safety/
Efficacy
Dose in
Healthy
Effect on
Disease
Effect/
Side
Effects
Success 5,000
5 into Human trials
Rate
Overall process takes 6-14.5+ years.
1
NDA Submission
Pre
Phase Phase Phase NDA
clinical
I
II
III
Review
Years
2-6
0.5-1
1-2
1.5-3 1-2.5*
Test
Animal 20 100 - 1000 – Review
Process
Subjects
100
1000 10,000
and
Approval
Safety/
Safety/
Safety/
Purpose Safety/
Efficacy
Dose in
Healthy
Effect on
Disease
Effect/
Side
Effects
Success 5,000
5 into Human trials
Rate
Overall process takes 6-14.5+ years.
1
NDA Submission
 NDA has

2 major sections:
Chemistry, Manufacturing and Controls
• Discusses means of manufacturing and testing of
API and drug product.
• Outlines performance and stability of drug product.

Clinical
• Discusses studies performed, outcomes and
statistical analysis.
• Outlines safety and effectiveness of product.
Commercialization/Phase IV
Commitments
 Phase
IV is post-approval status.
 FDA may require additional studies
(pediatric), product enhancements or
increased patient monitoring postapproval.
 Annual report required to FDA on product/
process changes (minor and major)
General Conclusions
 The
pharmaceutical development process
is a long (6-14+ years) and complicated
procedure.
 4 basic parts:
• NCE/API development
• Product development
• API/Product performance/stability
• Clinical studies results
General Conclusions
 Extent
of study designs will depend on API
and previous history/information.
 Generic manufacturers bypass much of
the early development aspects (and
costs).
 Patents of 20 years can have significant
market loss due to development timelines.
Why is this process so
complicated???
Celebrex

Celebrex (Celecoxib) is a non-steroidal antiinflammatory drug (NSAID) developed by Pfizer,
Inc.
 It is used to treat symptoms of osteoarthritis and
rheumatoid arthritis, acute pain, and primary
dysmenorrhea (menstrual cramping).
 The use of NSAID is associated in some
patients with serious problems from stomach
ulcers, including bleeding.
 NSAID medications are also associated with
liver damage in some patients.
Accutane

Accutane is a prescription medication chemically
similar to Vitamin A, which is used to treat
serious forms of cystic acne.
 Accutane has been manufactured in the United
States by a division of Hoffmann-La Roche, Inc.
since 1982.
 Controversy over Accutane focuses primarily on
two areas of potential harm:


use by pregnant women is associated with certain
birth defects
use by teenagers is associated with depression and
possibly with suicidal behavior
Zyprexa
 Zyprexa
(olanzapine) is a “second
generation” antipsychotic medication
produced by Eli Lilly and Company.
 Was believed to offer effective treatment of
psychotic disorders without the significant
side effects of first generation
antipsychotic medications.
 Recent research has demonstrated that
significant numbers of users contract
diabetes, and precursor conditions such
as hyperglycemia (high blood sugar).
Fen Phen, Redux, and Pondimin

In the late 1990's, the drugs known as Fen
Phen, Redux, and Pondimin were frequently
prescribed to assist with weight loss.
 As many as twenty percent of people who took
those drugs suffered heart damage, including:


Damaged Heart Valves - The drugs are associated
with damage to the heart's aortic and mitral valves.
Primary Pulmonary Hypertension (PPH) - A condition
is caused by a narrowing of the blood vessels in the
lungs, which can cause high blood pressure and can
lead to heart failure.
Bush Signs Drug Safety Bill into
Law

On Sept. 2007, President Bush
signed into law a bill, giving the
U.S. Food and Drug Administration
broad new powers to ensure the
safety of prescription drugs used by
millions.
 Congress used the legislation as a
vehicle to reform the FDA’s
handling of drug safety, primarily as
a result of the withdrawal of the
painkiller Vioxx three years ago.
Overview of Inhalation
Therapy
Types of Diseases Treated
 Asthma



Beta agonists – albuterol, pirbuterol,
fomoterol, metaproterenol, isoproterenol,
epinephrine
Steroids – beclomethasone, flunisolide,
triamcinilone, mometasone, dexamethasone
Anti-inflammatory agents - Na cromolyn
– ergotamine
 Antibiotic – pentamidine (HIV/AIDS
compromised patients)
 Diabetic – insulin
 Migrane
Asthma in the U.S.

According to the Asthma and Allergy Foundation of
America (AAFA) on Jan. 2007, the 10 worst asthma
cities are:











Atlanta (last year: 4th)
Philadelphia (last year: 3rd)
Raleigh, N.C.
Knoxville, Tenn.
Harrisburg, Pa.
Grand Rapids, Mich.
Milwaukee, Wis. (last year: 5th)
Greensboro, N.C. (last year: 7th)
Scranton, Pa. (last year: 1st)
Little Rock, Ark.
Seattle ranks best (or, in this case, least bad) on the
group’s list of the 100 “most challenging places to live
with asthma”.
Current Inhalation Delivery
Systems
 Nebulizers
 Dry
Powder Inhalers
 Pressurized Metered Dose Inhalers
(pMDI)
Nebulizers


Nebulizers utilize a pressurized
air source and a capillary jet
system.
Drug is dissolved in purified
water and inhaled over 10-30
minutes.



Drug must be water soluble.
Not appropriate for use as portable
treatment for acute asthma attacks.
Equipment is normally bulky and
needs a power source.
Dry Powder Inhalers




Normally drug with micronized
lactose as a carrier.
Drugs can have issues with “solid
state” chemistry such as
agglomeration or oxidation.
Systems can have variable dosing
based on patient inspiration rate or
coordination issues.
High levels of dry powders can
have patient compliance issues
(i.e. gagging).
Pressurized Metered Dose Inhalers
(pMDI)
 Advantages:



Drug “protected” from direct environmental
factors, e.g. moisture, light, etc.
Multiple doses per unit.
Cheapest and most reproducible per dose
cost of inhalation therapies.
 Disadvantages:


Requires extensive formulation and device
development.
Loss of CFCs requires new development
strategies.