Download Over-the-Counter Drug Products

Over-the-Counter Drug Products
Over-the-Counter (OTC) drug products are those drugs that are available to consumers without a
prescription. There are more than 80 classes (therapeutic categories) of OTC drugs, ranging from acne
drug products to weight control drug products. As with prescription drugs, CDER oversees OTC drugs to
ensure that they are properly labeled and that their benefits outweigh their risks.
OTC drugs play an increasingly vital role in America's health care system by providing easy access to
certain drugs that can be used safely without the help of a health care practitioner. This enables
consumers to take control of their own health care in many situations. There are more than 100,000 OTC
drug products marketed, encompassing about 800 significant active ingredients. Most OTC drug products
have been marketed for many years, prior to the laws that require proof of safety and effectiveness before
marketing. For this reason, FDA has been evaluating the ingredients and labeling of these products as part
of "The OTC Drug Review Program." The goal of this program is to establish OTC drug monographs for
each class of products. OTC drug monographs are a kind of "recipe book" covering acceptable
ingredients, doses, formulations, and labeling. Monographs will continually be updated adding additional
ingredients and labeling as needed. Products conforming to a monograph may be marketed without
further FDA clearance, while those that do not, must undergo separate review and approval through the
"New Drug Approval System." The NDA system--and not the monograph system--is also used for new
ingredients entering the OTC marketplace for the first time. For example, the newer OTC products
[previously available only by prescription] are first approved through the NDA system and their "switch"
to OTC status is approved via the NDA system.
FDA's review of OTC drugs is primarily handled by CDER's Division of Over-the-Counter Drug
Products in the Office of Drug Evaluation V. However, scientists and regulators throughout CDER, the
Office of General Counsel, and other Centers within FDA are routinely asked to assist in this massive
effort. There is also an advisory committee, "The Nonprescription Drug Advisory Committee," which
meets regularly to assist the agency in evaluating issues surrounding these products.
The FDA Process for
Approving Generic Drugs
Gary J. Buehler, R.Ph.
Dale Conner, Pharm. D.
Director
Director, Division of
Bioequivalence
Office of Generic Drugs
Did you know that generic drugs...
• Are safe and effective alternatives to brand
name prescriptions
• Can help both consumers and the
government reduce the cost of prescription
drugs
• Are currently used in 50% of all
prescriptions dispensed
• Save an average of $50 for every
prescription sold
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
2
Hatch-Waxman Amendments
to FFD&C Act - 1984
• Considered one of the most successful
pieces of legislation ever passed
• Created the generic drug industry
• Increased availability of generics
• 1984
12% prescriptions were generic
• 2000 44% prescriptions were generic - yet only
8% of revenue for prescription drugs
• Compromise legislation to benefit both
brand and generic firms
Continued
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
3
Hatch-Waxman Amendments
to FFD&C Act - 1984
• Allowed generic firms to rely on findings
of safety and efficacy of innovator drug
after expiration of patents and
exclusivities (do not have to repeat
expensive clinical and pre-clinical trials)
• Allowed patent extensions and
exclusivities to innovator firms
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
4
NDA vs. ANDA Review Process
Brand Name Drug
NDA Requirements
Generic Drug
ANDA Requirements
1.
2.
3.
4.
5.
6.
7.
8.
1.
2.
3.
4.
5.
Chemistry
Manufacturing
Controls
Labeling
Testing
Animal Studies
Clinical Studies
Bioavailability
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
Chemistry
Manufacturing
Controls
Labeling
Testing
6. Bioequivalence
5
What are the requirements for
a generic drug?
• Labeling
• Chemistry/Microbiology
• Bioequivalence
• Legal
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
6
How do we assure the quality
of generic drugs?
• First 5 steps of review process are identical
to NDA process
• Bioequivalence for complicated products is
discussed with the same staff that reviewed
the brand product
• FDA has experience with the product
• Scientific literature published
• Product is known to be safe
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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APPLICANT
Generic
Drug
Review
Process
ANDA
Refuse to
Receive
Letter
Application Review
Acceptable
&
Complete
N
Y
Request for Plant
Inspection
N
Chemistry & Micro
Review
PreApproval
Inspection Results
OK?
Chem/Micro
N
OK?
Y
Approval
Withheld
until Results
Satisfactory
N
Labeling
Review
APPROVED
ANDA
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
Labeling
Bioequivalence
OK?
OK?
Y
Y
Not
Approvable
Letter
Bioequivalence
Review
N
Y
Bio
Deficiency
Letter
8
What are the requirements for
a generic drug?
• Same active ingredient(s)
• Same route of administration
• Same dosage form
• Same strength
• Same conditions of use
Compared to reference listed drug (RLD)
- (brand name product)
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
9
Labeling
• “Same” as brand name labeling
• May delete portions of labeling
protected by patent or exclusivity
• May differ in excipients, PK data and
how supplied
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
10
Chemistry
• Components and composition
• Manufacturing and controls
• Batch formulation and records
• Description of facilities
• Specs and tests
• Packaging
• Stability
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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Manufacturing Compliance
Programs
• Purpose - To assure quality of
marketed drug products
• Mechanisms - Product Testing
– Surveillance
– Manufacturing/Testing plant inspections
– Assess firm’s compliance with good
manufacturing processes
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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APPROVED
DRUG PRODUCTS
WITH
THERAPEUTIC EQUIVALENCE EVALUATIONS
23rd EDITION
THE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER
SECTION 505 OF THE FEDERAL FOOD, DRUG, AND
COSMETIC ACT.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
OFFICE OF GENERIC DRUGS
2003
Electronic Orange Book -
http://www.fda.gov/cder/ob/
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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“Orange Book”
Book
• All FDA approved drug products listed
(NDA’s, OTC’s & ANDA’s)
– Therapeutic equivalence codes
 “A” = Substitutable
 “B” = Inequivalent, NOT Substitutable
– Expiration dates: patent and exclusivity
– Reference Listed Drugs/brand drugs
identified by FDA for generic companies
to compare with their proposed products
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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Definition of Bioequivalence
Pharmaceutical equivalents whose rate
and extent of absorption are not
statistically different when
administered to patients or subjects
at the same molar dose under similar
experimental conditions
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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Purpose of BE
• Therapeutic equivalence (TE)
• Bioequivalent products can be
substituted for each other without any
adjustment in dose or other additional
therapeutic monitoring
• The most efficient method of assuring
TE is to assure that the formulations
perform in an equivalent manner
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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Model of Oral Dosage Form
Performance
Dosage
Form
Drug in
Solution
Clinical/PD
Measurement
Pharmacokinetic
Measurement
Dosage Form
Performance
Gut Wall
Blood
Dose
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
Site of
Activity
Therapeutic
Effect
ln Dose
17
Clinical/PD Response
Clinical/PD Dose-Response
Log Dose
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
18
Plasma Conc.
Plasma Concentration-Dose
Dose
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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Approaches to Determining
Bioequivalence (21 CFR 320.24)
• In vivo measurement of active
moiety or moieties in biologic
fluid
FeV Albuterol
Blanching Study
• In vivo pharmacodynamic
Topical Corticosteroid
comparison
Topicals
• In vivo limited clinical
Nasal Suspensions
comparison
Questran - Binding Studies
• In vitro comparison
Nasal Solutions-Sprayer
1
• Any other approach
deemed appropriate by FDA
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
Evaluation
Propofol - Droplet Size
20
Study Designs
• Single-dose, two-way crossover, fasted
• Single-dose, two-way crossover, fed
• Alternatives
– Single-dose, parallel, fasted
– Single-dose, replicate design
– Multiple-dose, two-way
crossover, fasted
– Clinical endpoint study
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
Long Half-Life (wash-out)
Amiodarone, Etidronate
Highly Variable Drugs
Less Sensitive
Clozapine (Patient Trials)
Chemotherapy Trials
Topicals
Nasal Suspensions
21
Waivers of In Vivo Study
Requirements
• Definition
• Criteria (21 CFR 320.22)
– In vivo bioequivalence is self-evident
– Parenteral solutions
– Inhalational anesthetics
– Topical (skin) solution
– Oral solution
– Different proportional strength of product
with demonstrated BE
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
22
Statistical Analysis
(Two One-sided Tests Procedure)
• AUC and Cmax
– 90% Confidence Intervals (CI) must fit
between 80%-125%
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
23
Statistical Analysis
80 - 125 %
• What does this mean?
• Can there be a 46% difference?
• What is a point estimate?
• What is a confidence interval?
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
24
Statistical Analysis
• Bioequivalence criteria
– Two one-sided tests procedure
• Test (T) is not significantly less than
reference
• Reference (R) is not significantly less than
test
• Significant difference is 20% ( = 0.05
significance level)
– T/R = 80/100 = 80%
– R/T = 80% (all data expressed as T/R so
this becomes 100/80 = 125%)
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
25
Possible BE Results (90% CI)
80%
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
T/R (%)
125%
26
Narrow Therapeutic Range (NTI)
Drugs
• Drug Products that are subject to
therapeutic drug concentration or
pharmacodynamic monitoring
– Examples are: Digoxin, Lithium,
Phenytoin, Warfarin
• Traditional bioequivalence limit of 80125% is unchanged for these
products
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
27
Contacting the OGD
Contact: Office of Generic Drugs
FDA/CDER (HFD-600)
7500 Standish Place
Rockville, MD 20855
phone: 301-827-5845
Web site:
www.fda.gov/cder/ogd/index.htm
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
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