Transcript Main Title - University of Massachusetts Medical School

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The contents of this module are accurate at the
time of publication.
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Case
• Your patient is taking Gudaznu
• There is concern because of a news report
issued by the FDA
• The patient wants to talk to you
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Pharmaceutical Development
and Regulation
Name brands, generics
and the FDA
Objectives
– Describe key steps in the pharmaceutical
approval process
– Outline key laws and regulations impacting
pharmaceutical development
– Understand the differences between generic
and branded drug development
– Explain patents, exclusivity, and intellectual
property
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We return to our case…
You anticipate questions about the safety of
Gudaznu
You rarely prescribe the drug, but do have a
few patients taking it
You start to wonder yourself how it could have
been approved by the FDA
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Pharma and the FDA
Pharmaceutical Industry
Food and Drug Administration
Profit driven
Government
Research adds
expense
Protecting the public
health
Several stakeholders
Public is the client
These two missions can conflict with one another
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Overview of Pharmaceutical
Industry
2003
– Pharma spent $24.9 billion on promotion of
prescription drugs
• 2004
– Pharma employed over 291,000 in the U.S.; 450,000
world wide
• 2004-2005
– 3.6 billion U.S. prescriptions sold
• 2006
– Pharma spent $55.2 billion on R&D
– NIH spent $28.5 billion on R&D
IMS Health. Available at: www.imshealth.com; PhRMA. Available at: www.phrma.org; US Department of Labor. Career
guide to industries 2008. Available at: www.bls.gov/oco/cg Accessed February 27, 2008.
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U.S. Department of
Health
and Human Services
Food and Drug
Administration
Center for Biologics
Evaluation and
Research
Center for Devices
and Radiological
Health
Center for Drug
Evaluation and
Research
Center for Food Safety
and Applied Nutrition
Center for Veterinary
Medicine
National Center for
Toxicological Research
Food and Drug Administration. Available at: www.fda.gov. Accessed February 27, 2008.
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Federal Food, Drug,
and Cosmetic Act
Requires Safety
2006
1938
1906
Original Food and
Drug Act Passed
Prohibits misbranded or
adulterated drugs
1962
Kefauver-Harris
Drug Amendments
Requires Efficacy
Food and Drug Administration. Available at: www.fda.gov. Accessed February 27, 2008.
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What is a drug?
“Any product used to diagnose,
cure, mitigate, treat, or prevent a
disease.”
Food and Drug Administration. Available at: www.fda.gov. Accessed February 27, 2008.
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Stages of Drug Development and Review
The Drug Discovery, Development, and Review Process
Stage 2
Preclinical
Stage 3
Clinical Trials
10,000
compounds
250
compounds
6.5 years
IND submitted
Phase 1
20-100 volunteers
Stage 4
FDA Review
Phase 3
1,000-5,000 volunteers
5 compounds
Phase 2
100-500 volunteers
NDA submitted
Stage 1
Drug
Discovery
7 years
1
Stage 5
Post
Marketing
Trials
Phase 4
several
hundred to
several
thousand
FDA
approved
drug
1.5 years
Entire Life
Cycle
Government Accountability Office, Report to Congress; Food and Drug Administration, 2006
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Clinical Trial Phases
PHASE 1
First in Man
Safety and
Tolerability
PHASE 2
Proof of
Concept
PHASE 3
Large,
Multi-centered
PHASE 4
Measures Safety
in Large and
Varied
Populations
Usually PlaceboControlled &
Replicated
Dose Ranging
Tests Different
Delivery Methods
Primary Data to
Support Marketing
Approval in NDA
Pharmacokinetics
Safety/PK in
Special
Populations and
Risk Factors
Select Populations/
Short-Term
Can be Condition
of FDA Marketing
Approval
Food and Drug Administration. Available at: www.fda.gov. Accessed February 27, 2008.
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Business Model for Selecting
Targets for Drug Development
Common Strategy
“Blockbuster” drugs
Alternate Strategy
“Me too” drugs
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2004 Sales of “Me Too” Drugs
Smith A. 'Me-too' drugs can rake in sales. CNN/Money. 2005. Available at:
http://money.cnn.com/2005/07/27/news/fortune500/metoo/index.htm. Accessed February 27, 2005.
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FDA Approval of New Drug Applications
Number of New Medicines, Vaccines, and
Biologics Approved by the FDA
All NDA Approvals
New Molecular Entities
140
120
100
80
60
40
20
0
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Although the pharmaceutical industry has numerous drugs
approved per year, few are new molecular entities
Food and Drug Administration. Reports to the Nation, 1997 – 2005.
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New Drug Application Approvals
by FDA in July 2007
Drug Name
and
FDA Appl. #
Active
Ingredients
NDA Chem.
Type *
Company
CHEMET
(NDA # 019998)
SUCCIMER
New molecular
entity
OVATION PHARMS
ALLEGRA
(NDA # 021909)
FEXOFENADINE
HYDROCHLORIDE
New formulation
SANOFI AVENTIS US
ATRALIN
(NDA # 022070)
TRETINOIN
New formulation
CORIA
EXELON PATCH
(NDA # 022083)
RIVASTIGMINE
New formulation
NOVARTIS PHARMS
CALOMIST
(NDA # 022102)
CYANOCOBALAMIN
New
manufacturer
FLEMING PHARMS
Food and Drug Administration. Available at: www.fda.gov/cder/rdmt. Accessed February 27, 2008.
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Prescription
Drug
User
Fee
Act
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Food and Drug Administration. PDUFA White Paper, 2005. Figure 4.
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Selected Drug Safety Provisions of the
FDA Amendments Act
New resources for drug safety
New authorities and enforcement tools
Active post marketing surveillance
Expanded clinical trials registration
New requirements for public disclosure
of trial results
Improvements in transparency and
communications with patients and physicians
Psaty B, Korn D. Congress Responds to the IOM Drug Safety Report—In Full. JAMA. 2007; 298:2185-2187.
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We return to our case…
Your FDA review helped you prepare to talk
to your patient
Together you and your patient decide to
discontinue the Gudaznu
You propose an alternative medication that
has similar properties, and comes in a
generic form
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We return to our case…
Your patient called back and was
concerned that a generic medication
would not control the symptoms as well as
Gudaznu
Your nurse has heard similar queries from
other patients
You take some time to review the process
of generic drug approval prior to calling
back your patient
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Hatch Waxman Act
Under Hatch-Waxman, the Abbreviated New Drug
Application (ANDA) process allows for the
acceleration of the FDA approval of generic
pharmaceuticals.
?
=
Food and Drug Administration. Available at: www.fda.gov/cder/ogd. Accessed February 27, 2008.
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Generics
Active ingredients
Dosage
Purity and quality
Manufacturer’s processing
Amount absorbed
Safety
Efficacy
Food and Drug Administration. Available at: www.fda.gov/cder/generics. Accessed February 27, 2008.
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Generics
Dong H, Hauck W, Gambertoglio J, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment
of hypothyroidism. JAMA. 1997; 227:1205-1213.
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Generics
Some question:
Bioequivalence = Therapeutic equivalence
Especially for drugs with narrow
therapeutic ranges
Food and Drug Administration. Available at: www.fda.gov/cder/generics. Accessed February 27, 2008.
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Generic Drug Review Process
Determine if application is acceptable
Bioequivalence Review
Application
submitted
to Office of
Generic
Drugs
Plant Inspection
Chemistry/Micro Review
FDA reviews
and decides if
product is
approved or
not approvable
Labeling Review
Generic manufacturers do not need to
complete the three phases of clinical trials
Food and Drug Administration. Available at: www.fda.gov/cder/generics. Accessed February 27, 2008.
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=
Generic substitution
=
Therapeutic substitution
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The Cycle of Innovation and
Competition
Branded company
innovates
Generics are
distributed;
branded company
loses revenue
Branded company
rewarded with
monopoly position
Patent expiration
opens market to
generic competition
Generic Pharmaceutical Association (GPhA).
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Patents and Drug
Exclusivity
•
Drug patents are granted by the Patent
and Trademark Office and can be granted
at any time during the development of a
drug
• Drug exclusivity refers to the exclusive
marketing rights granted to a drug upon its
approval by the FDA
Food and Drug Administration. Available at: www.fda.gov/cder. Accessed February 27, 2008.
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Marketplace
Branded
Patents and
Exclusivity
Generic
Generics
Entranceare
to
unable to gain
Marketplace
access to the
marketplace
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Generic
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Agreements Between Brand Name
and Generic Manufacturers
“Some brand-name companies
attempt to slow the sale of generic
drugs by paying generic drug makers
to stay off the market.”
Kaufman, M. 2006. Drug Firms’ Deals Allowing Exclusivity. The Washington Post. April 25, 2006; A12. Available at:
http://www.washingtonpost.com/wp-dyn/content/article/2006/04/24/AR2006042401508.html. Accessed October 2006.
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Drug Company Tactics for
Extending Patents
New drug delivery systems
(extended release, patch, solu-tab,
etc.)
Clinical trials with children
Kaufman, M. Drug firms’ deals allowing exclusivity: makers of generics being paid to drop patent challenges, FTC review
finds. Washington Post. April 25, 2006;A12. Available at: http://www.washingtonpost.com/wpdyn/content/article/2006/04/24/AR2006042401508.html. Accessed October, 2006.
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Key Points
• New pharmaceutical development is time
consuming and costly
• Federal regulations have attempted to make
initial drug development and generic approval
faster
• Generic and prescription drugs are bioequivalent with few known exceptions
• Profit-making plays a large role in the entire
process
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Recommendations
Prescribers should:

Use generic medications when
available

Talk to your patients about the
equivalency of generic and brand
name drugs
•
•
•

•
Incorporate knowledge about the
necessary profit-drive of branded
companies into decision-making
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We return to our case…
You are able to make a convincing
argument to your patient
If the generic medication does not work well,
there are a number of other options available
You feel good that you are able to provide
information which may help your patients’
understanding of their treatment
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References
 Dong H, Hauck W, Gambertoglio J, et al. Bioequivalence of generic and brand-name levothyroxine products
in the treatment of hypothyroidism. JAMA. 1997; 227:1205-1213.
 Food and Drug Administration. PDUFA White Paper, 2005. Figure 4.
 Food and Drug Administration. Reports to the Nation, 1997– 2005.
 Food and Drug Administration. Available at: www.fda.gov. Accessed February 27, 2008.
 Food and Drug Administration. Available at: www.fda.gov/cder/rdmt. Accessed February 27, 2008.
 Food and Drug Administration. Available at: www.fda.gov/cder/generics. Accessed February 27, 2008.
 Food and Drug Administration. Available at: www.fda.gov/cder. Accessed February 27, 2008.
 Food and Drug Administration. Available at: www.fda.gov/cder/ogd. Accessed February 27, 2008.
 Generic Pharmaceutical Association (GPhA). Available at: http://www.gphaonline.org/AM/
 Government Accountability Office, Report to Congress; Food and Drug Administration, 2006.
 IMS Health. Available at: www.imshealth.com
 Kaufman, M. Drug firms’ deals allowing exclusivity: makers of generics being paid to drop patent challenges,
FTC review finds. Washington Post. April 25, 2006;A12. Available at: http://www.washingtonpost.com/wpdyn/content/article/2006/04/24/AR2006042401508.html. Accessed October, 2006.
 Moses H, Dorsey E, Matheson D, Thier O. Financial anatomy of biomedical research. JAMA. 2005; 294:13331342.
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References
 PhRMA. Available at: www.phrma.org.
 Psaty B, Korn D. Congress Responds to the IOM Drug Safety Report—In Full. JAMA. 2007; 298:2185-2187
 Smith A. 'Me-too' drugs can rake in sales. CNN/Money. 2005. Available at:
http://money.cnn.com/2005/07/27/news/fortune500/metoo/index.htm. Accessed February 27, 2005
 US Department of Labor. Career guide to industries 2008. Available at: www.bls.gov/oco/cg. Accessed
February 27, 2008.
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Resources
•
•
Consumer Reports Best Buy Drugs
http://www.consumerreports.org/health/best-buy-drugs/index.htm
•
•
Journal Watch
http://www.jwatch.org/
•
•
Medical Letter
http://www.medicalletter.org/
•
•
Medline (through the U.S. National Library of Medicine)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed
Attorney General Consumer and Prescriber Education Grant Program Initiated Resources
•
Brigham & Women's Hospital
http://www.rxfacts.org/
•
Georgetown University
http://www.pharmedout.org/
•
MGH Institute of Health Professionals
http://www.perxinfo.org/perx.html
•
University of Kentucky
http://www.cecentral.com/
•
University of North Carolina, Chapel Hill
http://harryguess.unc.edu/
•
University of Massachusetts Medical School/
Meyers Primary Care Institute
http://www.umassmed.edu/meyers/index.aspx
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Resources
Additional Learning Modules in This Series
 Communicating with Patients
 Evidence-Based Medicine (EBM)
 Organizational Influences on Prescribing
 Pharmaceutical Marketing
 Provider-Pharmaceutical Representative (PR)
Communication
 Links to Web-Access and Downloadable Versions Available at:
http://www.umassmed.edu/meyers/index.aspx
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Questions
1. A drug patent guarantees exclusive rights to the filing company for 10 years
post granting.
A. True
B. False
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Answer
1. B: False.
Patents last for 20 years from the date of filing.
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Questions
2. Which of the following is true?
A. Generic drugs undergo the same FDA approval process as name brand
drugs.
B. Generic drugs have bioequivalence to name brand drugs.
C. Generic drugs must look the same as name-brand counterparts.
D. Generic manufacturers complete 3 phases of clinical trials before drug
approval.
E. Prescribers must increase the dose of generic drugs by at least 20% to
match the efficacy of name brand drugs.
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Answer
2. B: Generic drugs have bioequivalence to name brand
drugs.
Generic drugs need to prove bioequivalence for FDA approval, they do not
need to repeat the chemical pre-testing or the 3-phase sequence of clinical
trials required for approval of new biologic entities (choices A and D), nor is
there a requirement that they look similar to name-brand
counterparts. Some providers believe that they need to increase the dosing
of all generic medications to have the same effect of name-brand. This
theory has not been proven. While in uncommon instances a change in
dosing may be made, the arbitrary choice of greater than 20% is untrue.
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Questions
3. How can a pharmaceutical company extend the patent life of a drug?
A.
B.
C.
D.
Performing studies of a drug’s effectiveness on seniors.
Completing post-marketing studies of adverse events.
Designing a new drug delivery system.
Paying additional fees to the FDA.
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Answer
3. C: Designing a new drug delivery system.
Drug companies can extend patent life by designing a new drug delivery
system for a previously approved drug (such as liquid, extended release, etc)
or performing studies on children (not seniors). Sometimes the FDA will
require companies to complete (phase IV) post-marketing studies as a
requirement for initial approval, not for patent extension. All pharmaceutical
companies pay fees to the FDA as part of PDUFA.
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Questions
4. New molecular entities account for the majority of new FDA approvals in
recent years.
A. True
B. False
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Answer
4. B: False.
New molecular entities account for approximately 20-30% of FDA approvals
in recent years.
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Questions
5. Publicly traded pharmaceutical companies have a fiduciary responsibility
to be profitable.
A. True
B. False
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Answer
5. A: True.
Publicly traded pharmaceutical companies have a fiduciary responsibility to
be profitable.
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Questions
6. Phase III clinical trials have about how many human subject volunteers?
A.
B.
C.
D.
20 - 100
100 - 500
1,000 - 5,000
5,000 - 10,000
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Answer
6. C: 1,000 – 5,000.
Phase III clinical trials have about 1,000 to 5,000 human subject volunteers.
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Questions
7. A drug patent is issued when a new drug is approved by the FDA.
A. True
B. False
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Answer
7. B: False.
Drug patents are granted by the patent and trademark office and can be
granted at any time during the development of a drug.
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Questions
8. Phase IV clinical trials are:
A. Used to obtain additional patent life for a drug.
B. Mandated by the FDA after a drug has been approved for post- launch
safety surveillance.
C. Completed by generic companies interested in producing a similar drug.
D. Conducted to test drugs already approved for adult use for application
with children.
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Answer
8. D: Conducted to measure safety and learn about long
term risks of FDA approved drugs.
Phase four clinical studies, or post marketing studies are used to measure
safety in large and varied populations, as well as to test different delivery
methods or to determine if the product may be used to treat another
condition. The FDA can make phase four studies a condition of
approval. Please see question 3 regarding patent life extension and
question 2 regarding generic drug approvals. There is currently no type of
trial that fits the description in B.
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Questions
9. The FDA has sole responsibility for study design, patient recruitment, and
data analysis in clinical trials.
A. True
B. False
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Answer
9. B: False.
The sponsor and/or principal investigator of the trial (pharmaceutical
company, private entity, etc.) are responsible for design and management of
all aspects of the study.
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Questions
10. There is generally no difference in the safety or efficacy profile between a
branded drug and its generic therapeutic equivalent.
A. True
B. False
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Answer
10. A: True.
A generic manufacturer must prove that its drug has been produced with the
same standards as the branded drug to receive FDA approval. These
include the same active ingredients, dosage form, standards for purity and
quality, processes for manufacturing, and the same amount of drug absorbed
over time. With few exceptions, there is no difference between the safety or
efficacy profile. Generic drugs are equivalent to their brand name
counterparts.
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Questions
11. Did completing this module help you to understand the differences
between generic and branded drug development?
A. Yes, definitely
B. Yes, probably
C. Probably not
D. Definitely not
E. Not sure
12. Would you recommend this training module to a colleague?
A. Yes, definitely
B. Yes, probably
C. Probably not
D. Definitely not
E. Not sure
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Questions
13. Will you do anything differently in your practice as a result of this training
module?
A. Yes, definitely
B. Yes, probably
C. Probably not
D. Definitely not
E. Not sure
14. Please tell us about any changes you are considering or planning:
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