Transcript Morris - Hauck ICD2 2012

6th Science & Standards Symposium
January 16, 2013
Istanbul
Overview: Continuing Equivalence
Roger L. Williams, M.D.
CEO and Chair, Council of Experts
Drug Price
Competition & Patent
Restoration Act
(Waxman-Hatch Act)
1984
Orphan Drug
Act
1983
Generic Drug
Enforcement Act
1991
Drug Export
Amendments
1986
Kefauver-Harris
Drug Amendments
1962
Original
Food and Drug
Act
1906
Prescription
Drug User
Fee Act
1992
Prescription Drug
Marketing Act
1987
Fair Packaging
and Labeling
Act
1966
FD&C
ACT
1938
Toxicological
Research
Responsibilities
1972
Food and Drug
Administration
Formed
1931
AN AGENCY WITH GROWING
CONSUMER PROTECTION RESPONSIBILITIES
US History
• 1902 Federal law: biologics (vaccines) be evaluated for
‘safety, purity, and potency’
• 1906 Food and Drugs Act added drugs other than biologics
• 1938 Food, Drug, Cosmetic Act created FDA and required
safety evaluation on new drugs before marketing based on
data in a New Drug Application (NDA)
• 1962 law added effectiveness requirement for approval of
an NDA
US History (continued)
• 1960’s FDA created Drug Efficacy Study Implementation (DESI)
to assess new drugs approved between 1938 and 1962
• 1960’s FDA permits marketing of ‘similars’ while
corresponding pioneer products undergo DESI reviews.
‘Similars’ came into market between 1938 and 1962
• 1970 FDA terminates marketing of ‘similars’ unless a) DESI
pioneer showed safety and efficacy; and b) ‘similar’
manufacturer submits Abbreviated New Drug Application
(ANDA) with formulation and manufacture information
US History (continued)
• The Supreme Court in the United States v. Generix Drug
Corporation supported FDA requirement for ANDA
• FDA finalized the 1977 Bioavailability/ Bioequivalence
(BA/BE) regulations (21 CFR 320)--pioneer shows BA in
NDA; ‘similars’ to DESI-effective pioneers show BE--US
first generics (only 1938-1962)
• 1984 generic law in the US (Waxman-Hatch) created a
generic approval system for all new drugs, including
those approved after 1962
Pioneer and Generic Drugs
Approval
IND/NDA
Patent/
Exclusivity
Expiration
Single
Manufacturer
Safety
Efficacy
Post-approval
Change
Additional
Manufacturers
Shelf-life
Specifications
Equivalence
Equivalence
Equivalence
Formulation, Quality, and Performance
Time
The Food and Drugs Landscape: White Papers
1977 FDA Regulations: Pioneer and Generic
PIONEER DRUG (NDA)
Requirements
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Chemistry
Manufacturing
Controls
Labeling
Testing
Preclinical/Clinical Studies
Bioavailability
GMPs/USP-NF
GENERIC DRUG (ANDA)
Requirements



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


Chemistry
Manufacturing
Controls
Labeling
Testing
Bioequivalence
GMPs/USP-NF
Generic vs. Pioneer Equivalence Concepts (CFR 320)
• Pharmaceutical Equivalence
–
–
–
–
–
Same active ingredient
Same strength
Same dosage form and route of administration
Comparable labeling
Meet compendial or other standards of identity, strength,
quality, purity and potency
• Bioequivalence
– In vivo measurement of active moiety (moieties) in biologic
fluid (blood/urine)
– In vivo pharmacodynamic comparison
– In vivo clinical comparison
– In vitro comparison
– Other
THEN: THERAPEUTIC EQUIVALENCE
APPROVED DRUG PRODUCTS WITH
THERAPEUTIC EQUIVALENCE
EVALUATIONS “Orange Book”
http://cdsmlweb1/ob/index.htm
Orange Book
“AB” Rating
 Identical active ingredients
 Dosage form
 Route of administration
 Strength
 Bioequivalance
 GMP’s
 Comparable Labeling
Figure 3. Brand vs. Generic % of Rxs:
1980 to 2008
% of Rxs
100%
90%
85.0%
% Brand
80%
Generic Rxs are more
widely used than
Brand Name Rxs
69.8%
70%
64.5%
57.6%
60%
50%
42.4%
40%
30.2%
30%
20%
15.0%
35.5%
% Generic
10%
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
0%
Compiled by PRIME Institute, University of Minnesota from data found in NACDS Chain Pharmacy Industry Profile, 1990 to 2009-2010
based on data from IMS Health, NDC Health, and NACDS Economics Department.
Why Did H-W Work (or Not)?
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‘Clay Feet’ of BE Testing (Levy)
Transitivity—no (A = B, C=B, but A doesn’t equal
C)
Individual BE
Add On Studies
Failed BE Studies
Narrow Therapeutic Range Drugs
Highly Variable Drugs
Recent Buproprion Case
Well….Maybe USP Dissolution Test?
Overview: WHO

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WWII (League of Nations to UN, then WHO)
Ministries of Health
Clusters
No safety and efficacy
ICH: no generic drugs
Mid-1990s: Multi-Source Guidance
Mid-2000s: Update of Multi-Source Guidance
Mid-2000s: Biosimilar Guidance
Pre-qualification
Vaccine certification
Decision Tree for ‘Similars’ and Generics
Reference
Generic/Similar
No Study
Study
In Vivo
(BE Self Evident)
In Vitro
USPC©2001
15 Job #
7/20/2015 7:46:23 PM
In Vivo versus In Vivo
RISK
COST
In Vivo
Only
BCS 1
Highly Soluble
Highly Permeable
Rapidly
Dissolving
Bio
Problem
Drugs
BCS 2
Highly Soluble
Rapidly
Dissolving
Top 50
High Health Risk
USPC©2001
In Vitro
Only
16 Job #
7/20/2015 7:46:23 PM
BE/BCS Dissolution Proposal (Dr. Amidon)
BCS
Class
I
Drug Solubility
pH 1.2
Drug Solubility
pH 6.8
Drug
Permeability
High
High
High
Preferred Procedure
>85% Dissolution in 15 min; 30 min, f2., pH =
6.8.
15 min at pH=1.2, then 85% Dissolution in 30
min., pH = 6.8; F2>50; 5 points minimum; not
more than one point > 85%.
II-A
Low
High
High
II-B
High
Low
High
>85% Dissolution in 15 min., pH = 1.2.
II-C
Low
Low
High
15 min at pH=1.2; then 85% Dissolution in 30
min., pH = 6.8 plus surfactant*; F2>50; 5 points
minimum, not more than one point > 85%.
III
High
High
Low
>85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8.
IV-A
Low
High
Low
15 min. at pH = 1.2; then 85% Dissolution in 30
min., pH = 6.8,; F2>50; 5 points minimum.; not
more than one point > 85%.
IV-B
High
Low
Low
>85% Dissolution in 15 min., pH = 1.2.
IV-C
Low
Low
Low
15 min at pH=1.2; then 85% Dissolution in 30
min., pH = 6.8 plus surfactant*; F2>50; 5 points
minimum, not more than one point > 85%.
Dissolution
• About 70% of orally administered immediate release
essential medicines (WHO List) are “highly soluble” drug
products.
• Using dissolution criteria as “safe haven” base, it is
possible to develop drug products with acceptable
performance, as in MC <12>.
• There will be always instances where dissolution it self
may not be sufficient, and may require clinical or
bioequivalent study.
• To label product as “Bioequivalent” test results must be
compared with appropriate comparator
Going Further: Use of the Medicines Compendium
• Medicines Compendium
– General Chapter <12>
– Uses Dr. Amidon’s Proposal
– Orally Administered Non-Solution Dosage Forms
• Manufacturers
– Adopt in Private Specification for Regulatory Agency
– Manufacturers Give Acceptable Medicine Compendium
Monograph
What Would This ‘Further’ Look Like?
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Pharmaceutically equivalence
Highly soluble drug substance (API)
Meets Dr. Amidon’s Criteria
Then optimally bioavailable (O-BA)
– All O-BA are also BE
– No comparator product; no comparison studies
– Registration only
– No regulatory review
– Only pharmacopoeial monographs
– Periodic inspection to assure conformity
– Label OBA
All others: in vivo studies and CPP
What Can We Do Together

Share Solubility Data
 Share Permeability Data
 Medicine Compendium Monographs
 Manufacturers Make Optimally BA Products
 If Meet Criteria (Dr. Amidon), then OBA via Drug
Product Monograph and Inspection
 If Not Then Further Studies and Regulatory Review
 Who Benefits
– Patients and Practitioners
– Key Countries: India, China, Others
Dosage Form Performance Background

Science Basics
– Drug Bioequivalence, Office of Technology Assessment, July 1974
– Equivalence Approaches, Clinical Pharmacology and Therapeutics, R.
Williams, M. Chen, W. Hauck, September 2002

US Approaches
– FDA Guidance for Industry: Bioavailability and Bioequivalence Studies
for Orally Administered Drug Products—General Considerations, March
2003
– FDA Guidance for Industry: Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-release Solid Oral Dosage
Forms Based on a Biopharmaceutics Classification System, August
2000
– Understanding Bioequivalence (BE) and its Assessment: Current
Status and Further Work, R. Patniak, October 2008
– Additional Results for “Sequential Design Approaches for
Bioequivalence Studies and Crossover Designs.” W. Hauck, et.al.,
September 2010
Dosage Form Performance Background

Policy
— A Theoretical Basis for a Biopharmaceutic Drug Classification: The
Correlation of in Vitro Drug Product Dissolution and in Vivo
Bioavailability, Amidon, et. al, November 1995.
— The Role of Transporters in the Pharmacokinetics of Orally
Administered Drugs, Shugarts and Benet, September 2009
— Bioequivalence of Oral Products and the Biopharmaceutics
Classification System: Science, Regulation, and Public Policy, Amidon,
et. al., July 2011
— The BCS, BDDCS, and Regulatory Guidances, Benet et. al., January
2011
— The FDA Should Eliminate the Ambiguities in the Current BCS
Biowaiver Guidance and Make Public the Drugs for Which BCS
Biowaivers Have Been Granted, September 2010
Dosage Form Performance Background

World Health Organization Approaches
– WHO Technical Report Series, No. 937, Annex 7: Multisource (Generic)
Pharmaceutical Products: Guidelines on Registration Requirements to
Establish Interchangeability, 2006
– WHO Technical Report Series, No. 937, Annex 8: Proposal to Waive In
Vivo Bioequivalence Requirements for WHO Model List of Essential
Medicines Immediate-release Solid Oral Dosage Forms, 2006
– WHO Technical Report Series, No. 937, Annex 9: Additional Guidance
for Organizations Performing In Vivo Bioequivalence Studies, 2006
– WHO Technical Report Series, No. 902, Annex 11: Guidance on the
Selection of Comparator Pharmaceutical Products for Equivalence
Assessment of Interchangeable Multisource (Generic Products), 2002
– Molecular Properties of WHO Essential Drugs and Provisional
Biopharmaceutical Classification, Amidon, et. al., 2004
– Prediction of Solubility and Permeability Class Membership: Provisional
BCS Classification of the World’s Top Oral Drugs, Amidon et. al.,
September 2009
– Bioequivalence Regulations in Key Worldwide Generic Markets, I.
Kanfer, June 2006
Dosage Form Performance Background
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Opportunities and Challenges
– Continuing Equivalence, Is There an End to the Story?, Williams/Shah,
June 2008 (Toward Global Standards for Comparator Pharmaceutical
Products: Case Studies of Amoxicillin, Metronidazole, and Zidovudine
in the Americas, R. Loebenberg, April 2012
– Notes of the USP Scientific Conclave on Drug Product Continuing
Equivalence, August 2011
– Clay Feet, Gerhard Levy, 1995 and 1996