Bioavailability & Bioequivalence Studies For Drug Products

Day 1 Agenda
Bioavailability & Bioequivalence Studies 09.00 – 10.00 Global Generic Market Overview
Session I
for Drug Products
10.30 – 12.00 Bioavailability (BA) / Bioequivalence (BE) Definitions
Session II
ASEAN-EU Programme for Regional
Integration Support – Phase II (APRIS II) 14.00 – 15.00 Key Elements of BA / BE Study Designs
Session III
[Assistance to ASEC and Pharmaceutical
Product Working Group] 15.30 – 17.30 Key Elements of BA / BE Study Designs & Case Studies
Session IV
Kuala Lumpur, Malaysia

7 – 8 December 2009
2
2
Global Top 10 Best Sellers
Brand Company Medical Use Approved

Session 1
Lipitor Pfizer Cholesterol 1996
Advair GlaxoSmithKline Asthma 2000
Global Generic Market Overview Plavix Bristol-
Bristol-Myers Squibb Thrombosis 1997
Nexium AstraZeneca GI disorder 2000
Norvasc Pfizer Hypertension 1992
Remicade J&J Rheumatoid arthritis 1998
Enbrel Amgen Rheumatroid arthritis 1998
Zyprexa Eli Lilly Schizophrenia 1996
Diovan Novartis Hypertension 1996
Risperdal J&J Schizophrenia 1993
3 4
3
Global Pharmaceutical Manufacturing Global Pharmaceutical Growth Trend
Source: IMS Health MIDAS - 2005
18% 17%
16%
14%
12%
10% 9.7%
8% 7%
6%
4%
2%
0%
Overall Generic Drug Biotech
Market Growth Drugs
5 6
Growth Growth
Expiring Generic Prescription Drugs Expiring Generic Prescription Drugs
Category Drug Name Year Category Drug Name Year
Allergy • Singulair • 2012 Epilepsy • Depakote • 2008

Asthma
Genital Herpes • Valtrex • 2009
Bipolar Disorder • Depakote • 2008
• Lamictal • 2009 Heart Attack • Plavix • 2012
• Zyprexa • 2011
• Seroquel • 2012 Heartburn • Prevacid • 2009
Depression • Effexor XR • 2011 • Aciphex • 2009
• Lexapro • 2012 • Protonix • 2011
Diabetes • Actos • 2011 High Blood Pressure • Lotrel • 2007
• Avandia • 2012 • Norvasc • 2007
• Coreg • 2007
Enlarged Prostate • Flomax • 2010
7 8
• Toprol XL • 2007
Expiring Generic Prescription Drugs Global Generics Market
Category Drug Name Year • Leading Companies & Global Generics

High Cholesterol • Lipitor • 2011
Market Share
Insomnia • Ambien • 2007

Teva 18%
Migraine • Depakote • 2008 Others Sandoz 10%
• Topamax • 2009 50%
• Imitrex • 2009
Osteoporosis • Fosamax • 2008
Mylan
6%
Schizophrenia • Risperdal • 2008 Watson
Actavis = Ranbaxy
• Zyprexa • 2011 2% 6%
Stada = ratiopharm
9 3% 10
Source: BCC Report PHM009E Generic Drugs: The Global Market
Source: The US Generic Drugs Industry Overview, Themedica 2009

Top 8 Global Generic Markets, 2009
Account for 84% total global generics sales

• US
– US$ 33 bn
– 42% global sales Major Growth in:
– 79% of all approved drugs have generics • Respiratory
– Generic growth forecast
• 9.2%, 2010-
2010-2012 • CNS
• Germany • GI
• France • Anticancer
• UK
• Cardiovascular
• Canada
• Italy • Anti-infective
• Spain • Antiarthritics
11 • Japan 12
Global Generics Market
Year Market Size, US$ bn CAGR, %

2008 80
2009 84
2014 129.3 9
Highest growth rate in major markets:

• Japan
• 12.2% share
• US$ 5.4 9.6 bn (2009 – 2014)
13 14
Global Generic Trend Emerging Market Leaders
Generic production is growing at a faster rate than India China

innovative new drug production • Low cost • Low cost
Shift in generic production
• High quality • High quality
Away from the developed markets (U.S., Europe and Japan)
Significant growth regions:
India • Finished • API +
China
products intermediates
Southeast Asia
Brazil
Middle East
Russia
Mexico
15 16
Global Generics Market Summary Asia-Pacific Pharma Highlight
• Volatile time Key Market Trends & Outlook:

• Demand is increasing steadily due to healthcare cost control
• Fierce price competition slashed profit margins • 3rd largest pharma market globally:
• Major growth driver: blockbuster brands coming off patent – North America > Europe > Asia-
Asia-Pacific
• Rising stars: • Robust growth
– China, India, Eastern European countries, and Brazil – Asia-
Asia-Pacific Growth: 9% ~ 12% over 2006-
2006-2010
• Global generic market
– NA & Europe: 5 – 8%
– 2009 US$ 84 billion
– 2014 US$129.3 billion • Generic drug markets set to take off
– 9% Compound Annual Growth Rate (CAGR) – Patents US$20+ billion in sales expiring in 2008
• Generics penetration intensified: • Major emerging market for orphan drugs development
– Japan = 6%
– US = 10% • 2009 is likely to be extremely difficult, but Asia-
Asia-Pacific
– Germany = 18% pharma industry expected to hold up reasonably well
BCC Report, Generic Drugs: the Global Market, July 2009 17 18
Asia-Pacific Pharma Highlight Asia-Pacific Pharma Highlight
Key Market Trends & Outlook: • Example “Philippines”

– Estimated domestic pharma market:
• Key pharmaceutical markets:
bn, 2007 US$4 bn,
• US$2.61 bn, bn, 2012
– Australia, Japan, China, India, South Korea and Taiwan – International : local = 65 : 35, with about equal production volume
volume
– 6 Asia-
Asia-Pacific pharmaceutical leaders that have FDA • Double-
Double-digit yearly growth over the next 5 years
• Smaller, emerging markets: • 85% via drug stores
– Singapore, Malaysia and Vietnam • 15% via hospitals & clinics
– Top importers
• Outsourcing leading the way
• Switzerland: US$65 million, 12.4%
• Many regulatory changes in the past years • Germany: US$51 million, 9.8%
• ↑ reliance on IT technologies to streamline operations and • France: US$48 million, 9.3%
research • Australia: Us$46 million, 8.9%
• Ireland: US$37 million, 7.07%
• US: US$31 million, 5.1%
19 20
Asia-Pacific Pharma Highlight Asia-Pacific Pharma Highlight
• Example “Philippines” • Significant risks still remain

– Top drug categories, 2007, Pharmaceutical & Healthcare Association of the Philippines
• Calcium antagonists hypertension
– Will Asian companies (with a few exceptions, e.g. Japan
Non-narcotic analgesics pain relief
• Non- and Singapore) continue to be technological followers or
• Infant formulas nutrition free-
free-riders?
• Cephalosporins & combination infection • Most promising when combining these:
• Broad spectrum penicillin infection
– Cost of medicines in the Philippines high:
– Education + Quality of scientists
• 2nd highest in Asia next to Japan – IP law reform
• WHO report: medicines sold in the Philippines at 4 - 18 times – Market growth + competitiveness
higher than international counterparts
• More Filipinos go for Generics (2009 DOH report: 6/10) – Pricing control strategy & mechanisms
• Government actively promoting generics – Growing convergence with international regulatory
– Cheaper & Quality Medicines Act, 2008
21
standards 22
ASEAN Pharma Situation Asia-Pacific Generic Market
• Net importers of pharmaceuticals

Generic Pharma Market Comparison, by Frost & Sullivan
• Most with no capability for new drug development
• Major pharmacy: generic industry
Country Market Type CAGR%, 2001 - 7
• Regulatory situation:
– Most have drug regulatory system: laws, rules, agencies Malaysia Growth 12.5
– Limited human & financial resources for regulatory Philippines Growth 19.7
framework & capacities
– Gaps between regulation & actual enforcement Singapore Growth 10.6
– Problems:
• Substandard drugs Taiwan Mature 4.0
• Counterfeits
• Illegal drug outlets 23 24
Session 2 Why is Equivalence Important?
• General BA/BE Overview

– Scope The most expensive
– Glossary & Definitions
– Pertinent References drug is the one that
• ASEAN BA/BE Guidelines does not work !!
25 26
Pharmacokinetics Pharmacokinetics
• The application of kinetics to a Pharmakon (Greek word • Intravenous (IV) dosing study
to specify drugs and poisons) – Most comprehensive insight about a drug's inherent
• Integral in drug development, esp. biological properties pharmacokinetic properties
of a drug – Route of administration (ROA): greatest quantitative
• The time course and fate of drugs in the body potential
• Absorption, Distribution, Metabolism (biotransformation) • Permits a mass balance approach in
and Excretion (ADME) – Distribution
– Clearance
• Pharmacodynamics (response) + pharmacokinetics – Body processes associated with excretion and metabolic
elimination
– how the drug affects the body and how the body affects the drug
» e.g. renal, hepatic
27 28
Pharmacokinetics GI Factors Contributing to Oral BA
• Non-IV ROA’s
– Oral, inhalation, topical (e.g. patch, cream, gel..), rectal
– Oral, especially, introduces an uncertainty in absorption
• Most important property for systemic conditions
– Ability to deliver the active ingredient to the bloodstream
– Sufficient amount
– Cause the desired response
29 30
Pharmacokinetic Terminology Plasma concentration time profile
• AUC:
concentration-time curve ⇒ measure of
– area under the concentration- concentration
the extent of bioavailability
• Cmax: Cmax
– the observed maximum concentration of drug ⇒ AUC
measure of both the rate of absorption and the extent of
bioavailability
• tmax:
– the time after administration of drug at which Cmax is
Tmax time
observed ⇒ measure of the rate of absorption
31 32
Bioavailability Bioavailability
Pharmacokinetics
• The extent and rate at which its active moiety is • The property of a dosage form conc. vs time
Conc.(mg/L)
• Also called:
delivered from pharmaceutical form and – Physiologic availability
becomes available in the systemic circulation – Biologic availability
0.0
– Bioavailability 0 25
Time (h)
• Two essential features
– How fast the drug enters the systemic circulation: rate of absorption
• Theory basis:
• Cmax
– Intravenous administration = 100% bioavailability – How much of the nominal strength enters the body: extent of absorption
• AUC
• Therapeutic effect = Function of the drug concentration in a patient's blood
• Onset of Response
• Time-dependent Extent of Response
• Rate of Drug Absorption
33 • Extent of Drug Absorption 34
Factors Affecting Oral Bioavailability Comparative BA
• Patient idiocyncracy • Dosage-form-related • Why do we do BA comparison?

– Meals & timing – Chemical nature of the drug – Comparison
– Age • Salts • Route of administration
• Acids
– Gender – Physical property of the • New vs. old formulation
– Disease drug • Generics vs. reference product
– Genetic traits • crystal structure – Obtain drug concentration profiles
– GI physiology • Particle size – Apply statistical analysis
– Formulation factors
– … • non-active ingredients
• manufacturing (e.g. tablet
hardness) variables
35 36
Typical Reformulation BA Study Typical Reformulation BA Study
• Objectives • Study design

– Comparing BA: Reformulation vs. Original product – Effects of formulation can be distinguished
– Determine their equivalence
– When comparing 2 formulations
• Primary endpoints
• Randomized two-period, two-sequence crossover
– Administer both the reformulated and the original products
study
– Determine the time-dependent concentrations of the
administered drug in the collected blood (or plasma/serum) of – Apply an adequate washout period between periods
each subject to avoid drug carryover effects
• Secondary endpoints – Tight control over all facets of the study
– Administer both the reformulated and the original products – Pay attention to subject’s fasting details:
– Determine the time-dependent concentrations of potentially
important metabolites (active and contributing to the product's • Time, fluid intake & frequency, meals, sequential
therapeutic response) in the collected blood (or plasma/serum) blood sampling…
of each subject – Analytical method validation
• Other exploratory endpoints 37 38
New Formulation Development BA

Typical Reformulation BA Study Modified Release
• Study population • What is a Delayed-release product?

– Usually healthy volunteers
– Preferably non-smokers – Does not release the actives immediately
– Some may be conducted in patients – Usually release the actives later
• Specific exclusion criteria
– Could exhibit an absorption lag time
– Commonly excluded: women of childbearing potential if there is
a potential risk
• Tools for assessing primary endpoints
– Validated analytical method
• Specific criteria for early withdrawal and discontinuation
– Include sufficient number of subjects to allow all phases of the
study to be completed successfully
– Subjects shall retain the right to discontinue the trial
– Reasons to discontinue:
• Adverse drug reactions, personal preferences…
– Report all withdrawals 39 40
New Formulation Development BA New Formulation Development BA
Modified Release Modified Release
• Purpose of the required studies – to determine if the • Study designs for modified-release products:
following conditions are met: – A single dose crossover comparison of
– The drug product meets the controlled release claims made
• A conventional, immediate release product, and
– The BA profile rules out the occurrence of what is called "dose
dumping“ • The modified release product
• Premature release of the drug from the dosage form • Ideally, also includes a solution or suspension of
– The formulation provides consistent performance between the same drug in the same strength
individual dosage units
– A single dose food-effect study
– The steady state performance, in comparison to an available
conventional product, is equivalent – A steady-state study
– Clinical studies are usually required if BA comparisons indicate
“difference”
41 42
Equivalence
What About Equivalence? Other Products with Same APIs
• Innovation product vs. Subsequent followers • Also called:

– Subsequent-
Subsequent-entry products
• First to Market = “Innovation” Product – Generic products
– Multisource products
• Need to prove:
– Quality
– Safety and efficacy
• Based on extensive clinical trials
• Expensive
• Time consuming
43 44
Equivalence Pharmaceutical Equivalence vs. BE
Which one is it? BE or TE or PE?
• Bioequivalence (BE): • Pharmaceutical Equivalence (PE) Criteria

– Products are pharmaceutically equivalent – Same amount of the same API
– Bioavailabilities (both rate and extent) after • May use different excipients
administration in the same molar dose are so similar
that their effects can be expected to be essentially – Same or comparable dosage form
the same – Same route of administration
• Therapeutic Equivalence (TE): – Same mfg process not necessary
– Pharmaceutically equivalent
– Same safety and efficacy profiles after • Is pharmaceutical equivalence enough for
administration of same dose
Generics?
45 46
Sometimes PE is NOT Enough Sometimes PE is Enough
• Therapeutic Equivalence (TE): • Aqueous solutions

– Must be pharmaceutically equivalent, and – Intravenous solutions
– Same safety and efficacy profiles after administration – Intramuscular, subcutaneous
of same dose – Oral solutions
– Otic or ophthalmic solutions
• PE ≠ TE – Topical preparations
– Pharmaceutical equivalence does not necessarily – Solutions for nasal administration
imply therapeutic equivalence • Powders for reconstitution as solution
– Why?
• Gases
– Differences in the excipients and/or the manufacturing
process differences in product performance
47 48
How to Assess Equivalence? Comparative BA for Generics – BE Studies
• Suitable methods: • The deductive inference concept - Central to BE

– Comparative pharmacokinetic studies testing
– Comparative pharmacodynamic studies 1. The reference drug product has established
– Comparative clinical trials acceptable safety and efficacy
– Comparative in vitro tests 2. Time-dependent drug concentrations in blood from
the reference product are intimately linked to its
therapeutic effects
3. Chemically equivalent and pharmaceutically
equivalent products are bioequivalent
4. Bioequivalent products by inference are considered
therapeutically equivalent
49 50
Comparative BA for Generics – BE Studies Bioequivalence
• A full array of trials usually not needed for the reference

product 90
• The generic product by inference is regarded as 80
Concentration (ng/mL)
therapeutically equivalent to the reference product 70
60
• Usually proven through single dose administrations Test/G eneric
50
– Designed to test inherent product absorption properties Reference/Brand
40
– Focus:
30
• Rate and extent of absorption of the active ingredient and/or 20
primary active metabolite(s) 10
– Generally specify healthy normal controls 0
0 5 10 15 20 25 30
Time (hours)
51 52
Bioequivalence
ASEAN BA BE Guidelines
Glossary & Definitions

53
ASEAN Generic Situation BA BE Definitions
• Generic Registration • Pharmaceutical equivalence

– Data usually not required – Medicinal products containing
• Non-
Non-clinical – The same amount of the same active substances
• Clinical
– In the same dosage forms
– Usually required
• Bioequivalent to Reference Product • Meet the same or comparable standards
– Similar bioavailability in systemic circulation • Pharmaceutical alternatives
– Similar rate/extent of availability of active ingredients – Medicinal products containing
• Same as RF
– Route of administration
– The same active moiety but
– Safety/efficacy profiles – Differ in chemical form (e.g., salt, ester, etc) of the
– Dosage form moiety, or
– Indications, Dosing regimen, Patient population – Differ in the dosage form, or
55 – Differ in strength 56
BA BE Definitions BA BE Definitions
• Bioavailability • What’s “essentially similar”?

– The rate & extent to which the active substance or – European Court of Justice 1998 Ruling
active moiety is absorbed from a pharmaceutical form – A medicinal product is essentially similar to an original
and becomes available at the site of action where it satisfies the criteria of having the same
qualitative and quantitative composition in terms of
• Bioequivalence active substances, of having the same
– Two medicinal products are BE if they are pharamaceutical form, and of being BE unless it is
pharmaceutically equivalent or pharmaceutical apparent in the light of scientific knowledge that it
alternatives and if their BA after administration in the differs from the original as regards to safety and
same molar dose are similar to such degree that their efficacy
effects, with respect to both efficacy and safety, will – Different salts, esters, ethers, isomers, complexes or
be essentially the same derivatives are now considered to be the same substance
unless they differ signioficantly in regard to safety or
57 efficacy in accordance with the “Generics” ruling 58
BA BE Definitions
• Therapeutic equivalence
– A medicinal product is therapeutically equivalent with
another product if it contains the same active ASEAN BA BE Guidelines
substance or therapeutic moiety and, clinically, shows
the same efficacy and safety as that product, whose
efficacy and safety has been established
Design & Conduct of Studies

59
BA BE Study Design & Conduct Study Design
• Follow ICH/EU regulations on Good Clinical • Comparative BA study designed to establish equivalence
Practice between test and reference products
• Usually single-
single-dose studies would suffice
• The rights, safety, and well-being of all trial
• However, make sure that
subjects must always be respected and should
– The formulation effect can be distinguished from other effects
be given special attention – If the # of formulations = 2
• Design of choice should include a two-
two-period, two-
two-sequence
crossover design
• Sampling plan should allow for adequate estimation of
the extent of absorption
– Best to carry out over a full 24-
24-hr cycle if the circadian rhythm
has a known effect on BA
61 62
Study Subjects Study Subjects
• Selection objective • When to consider including patients

– Minimize variability – The active has known adverse effects, and
– Permit detection of differences between products – Effects / risks unacceptable for healthy volunteers
• Usually healthy volunteers, both genders – Under suitable precautions & supervision
– Taking into consideration risk to women of childbearing – Must justify
potential
– 18 – 55 years • Consider genetic phenotyping
– Informed consent – Exploratory BA studies
– Normal weight range, BMI 18- 18-30 – All studies using parallel group design, or
• Asians: 18 – 25 – Crossover studies for safety or pharmacokinetics
– Use clinical lab tests to screen for suitability
– Non-
Non-smokers, no history of alcohol/drug abuse preferred
63 64
Study Conditions Study Conditions
• Standardization • Standardization
– Diet & Fluid intake – Dosing
• Avoid food & drinks that may interact with physiological functions
functions
• Generally one unit of the highest marketed strength
• Specify time of day for ingestion for oral drugs
• Constant volume of fluid, e.g., 150 ml min. • Smaller dose if adverse events too great
• Prior to & during each study phase – Other medicines
– Allow water as desired except for 1 hr before & after drug • Should not be allowed during a suitable period before
administration
& during the stidu
– Hot drink / juice OK after 3 hrs of drug administration
– Standard meals no less than 4 hrs after drug administration
– Exercise
– Preferably:
• Fasting during the night prior to administration of the products
65 66
Chemical Analysis Chemical Analysis Method Validation
• GLP standards • Two phases

– EMEA/OECD GLP SIX CHARACTERISTICS: – Prestudy phase
– WHO GLP 1. Stability • Verify the compliance of the 6 characteristics
– ISO/IEC 17025/1999 • stock solution – Study phase
• analytes • Apply validated methods to the actual analysis of
• Method criteria 2. Specificity samples from the biostudy
– Well-
Well-characterized 3. Accuracy • Confirmation of
– Fully validated & documented 4. Precision – Stability
5. Quantification limit – Accuracy
– Reliable results
6. Response function – Precision
– Satisfactory interpretation
• Biological sample reparation method should be
validated
67 68
More on Chemical Analysis Reference vs. Test Products
• Calibration required • Reference product selection must be justified

• QC samples should be run • Reference product selection must be approved by
• SOPs for all procedures the regulatory authority
– Pre-
Pre-established • Test product preparation based on GMP
– Report & justify all modifications – Report batch control results
– Modification requires revalidation – Oral solid forms
• Batch size, greater of the two:
– min 1/10 production scale, or
– 10,000 units
• Use the full production batch if < 100,000 units
69 70
Statistical Analysis
• 90% Confidence Interval

• Use ANOVA for pharmacokinetic data
• Normally evaluate average BE, not individual BE
ASEAN BA BE Guidelines
• Acceptance range for pharmacokinetic parameters
AUC ratio 0.80 – 1.25
Cmax ratio 0.80 – 1.25
Reporting
71
Reporting ASEAN BE Study Reporting Format
• Protocol • Comparative dissolution • Study title

• Conduct & evaluation profiles
– GCP regulations • Signed statement • Name of sponsor
confirming test product =
– EU guidelines
the one submitted for • Name & address of clinical laboratory
– ICH E3 guidelines authorization • Name & address of analytical laboratory
• Responsible investigators • Drop-
Drop-out & withdrawl of
• Study site subjects • Dates of clinical study (start, completion)
• Study period • Justification of data • Signature Page
deletion
• Name & batch # of – Name of Principal & Clinical investigators
• Analytical validation report
products used
• …. – Signature
• Product compositions
– Date
• Finished product spec
73 • List of other study personnel 74
ASEAN BE Study Reporting Format ASEAN BE Study Reporting Format
• Study Protocol • Pharmacokinetic Parameters & Tests

– Introduction – Definition & calculations
– Study objective
– Figures & tables
– Study treatments
– Study methods • Statistical Analyses
– Reference & Test product information • Results & Discussion
– Name, Batch number, Batch size of test product, Formulation,
Actives, Amount of actives, Expiry date, Finished product spec, • Conclusions
Comparative dissolution profiles
• Appendices
• Clinical & Safety Records
– Study protocol
• Assay Methodology & Validation
– Letter of approval of institutional review board /
– Assay method description
independent ethical committee
– Validation procedure & results 75 76
ACTR BE/BA Preparation ACTR BE/BA Preparation
Singapore Example Singapore Example - Biowaiver

• Fundamentals to ensure equivalent products • Justification required • BE studies usually not
– ↓ variability & bias • Comparative BA studies required
• Clinical study required – Solutions
– GxPs – Dosage form – Solutions for injection
– Solubility data – Powder for reconstitution
• Study design
– Dissolution profiles, across – Oral suspension
– Healthy volunteers
3 pH media – Topical products without
– Study subjects receive each formulation only once
– PK profile systemic effects
– Single dose, 2-
2-period, crossover, adequate washout
– Clinical consequences – Otic/
Otic/ ophthalmic products
• Pre-
Pre-submission strongly encouraged, work with
– Formulation consideration
regulatory authority in advance
– Verify RP choice prior to BE study
77 78
77 78
Outline
Sessions 3 - 4 • US FDA Example

– Key Elements of BA / BE Study Designs
• Design
Key Elements of BA / BE Study Designs • Subjects
- USFDA Examples - • Investigation Considerations
• Chemical Analysis & References
• Statistical Analysis
Biowaivers • Reporting
• Special Considerations & Case Studies
– Biowaivers
Case Studies – Food Effects
79 80
US FDA Generics Definition US FDA Generics Definition
Source: US FDA, http://www.fda.gov/cder/drugsatfda/glossary.htm
• A generic drug is the same as a brand name drug in

dosage, safety, strength, how it is taken, quality, • Therefore, a generic drug product must be
performance, and intended use. Before approving a
generic drug product, FDA requires many rigorous tests the same as brand drug in:
and procedures to assure that the generic drug can be Active ingredient
substituted for the brand name drug. The FDA bases
evaluations of substitutability, or "therapeutic
Strength
equivalence," of generic drugs on scientific evaluations. Dosage form
By law, a generic drug product must contain the identical Route of administration
amounts of the same active ingredient(s)
ingredient(s) as the brand
name product. Drug products evaluated as Quality
"therapeutically equivalent" can be expected to have Therapeutic effect
equal effect and no difference when substituted for the
brand name product.
81 82
Generics Approval Considerations

Determination based on Assumption
by the US FDA
Source: CDER, US FDA
• Therapeutic Equivalnce = Brand Name Drug - Generic Drug –

– Pharmaceutical equivalence + Bioequivalence NDA Submission: ANDA Submission:
• Chemistry • Chemistry
• When administered under conditions specified • Manufacturing • Manufacturing
• Controls • Controls
in the labeling, expected to have the same: • Labeling
• Labeling
− Clinical effect • Testing • Testing
− Safety profile • Preclinical/Clinical
• Bioavailability • Bioequivalence
83 84
FDA Requirements for Drugs US FDA Generics APPLICANT
Source: US FDA Brand Generic Review ANDA Refuse to

Receive
For reformulations of a brand-name drug or generic versions of a drug, Source: CDER, US FDA Letter
FDA reviews data showing the drug is bioequivalent to the one used in Application Review
the original safety and efficacy testing.
FDA evaluates the manufacturer's adherence to good manufacturing Acceptable N

practices before the drug is marketed. & Complete
FDA reviews the active and inactive ingredients used in the formulation Y
before the drug is marketed.
FDA reviews the actual drug product. Request for Plant Chemistry & Micro Labeling Bioequivalence
Inspection Review Review Review
FDA reviews the drug's labeling. PreApproval

N Inspection Results Chem/Micro N N Labeling BE N
OK? OK? OK? OK?
Manufacturer must seek FDA approval before making major Y Y Y Y
manufacturing changes or reformulating the drug.
Manufacturer must report adverse reactions and serious adverse health

effects to the FDA. Approval Not Bio Deficiency
Withheld until Approvable Letter
FDA periodically inspects manufacturing plants. Results APPROVED
Letter
Satisfactory ANDA
FDA monitors drug quality after approval. 85 86
APPROVED DRUG PRODUCTS - US Orange Book
Electronic Orange Book - • All FDA approved drug products listed

http://www.fda.gov/cder/ob/ (NDA’s, OTC’s & ANDA’s)
– Codes for therapeutic equivalence
“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
87 88
BE for Generics - US BE for Generics - US
• Why do we need BE? • When is BE needed?

– Therapeutic equivalence (TE) – Determine rate & extent of absorption of each
– Bioequivalent products can be substituted for each therapeutic moiety
other without any adjustment in dose or other • Potential generic products for which there is an
additional therapeutic monitoring existing, approved reference
– The most efficient method of assuring TE is to assure • Potential new drug products where adequate
that the formulations perform in an equivalent manner clinical studies have been conducted
– New salts
– New dosage forms
• Reformulated drug products
89 90
• Chemistry • Manufacturing Compliance Programs

• Components and composition – Purpose - To assure quality of marketed drug
• Manufacturing and controls products
• Batch formulation and records – Mechanisms - Product Testing
• Description of facilities • Surveillance
• Specs and tests • Manufacturing/Testing plant inspections
• Packaging • Assess firm’s compliance with good
• Stability manufacturing processes
91 92
General Considerations General Considerations

• Subject • Examples of subject using patients
– Usually healthy normal subjects – Clozapine
– Usually both genders • BE, steady state study
– Must use patients • Schizophrenic patients
• If safety risk to healthy normal subjects • Established regimens
– Pharmacokinetic (PK) variability determines # of – Etoposide
subjects • BE, first dose of treatment cycle
• Highly variable drug, # • Cancer patients
93 94

• Dosing • Method validation
– Single-dose studies – Bioanalytical methods must be validated
• Usually for immediate release drugs • Assay selectivity
• Considered most sensitive • Assay precision & accuracy
– Multiple-dose / steady-state studies • Stability of stored analytes in matrices
• Usually for modified released drugs, in addition to • Recovery of analytes & internal standard
single-dose studies • Assay limit of quantitation (LOQ)
• Potential analytical issues
• Usually have to deal with variability issues
95 96

• Statistics • Statistics
– Use ANOVA with 2 one-sided tests to analyze data – Bioequivalence criteria
– BE criteria • ANOVA two one-
one-sided tests procedure
• 90% confidence intervals of means – Test (T) not significantly less than Reference (R)
• Test/Reference ratio: 0.800 – 1.250 – R not significantly less than T
– Questions – Significant difference is 20% (α(α = 0.05 significance
level)
• What does this mean?
» T/R = 80/100 = 80%
• Can there be a 45% spread? » R/T = 80% (all data expressed as T/R so this
– Rounding not permitted (either up or down) becomes 100/80 = 125%)
97 98
BE for Generics - US Possible BE Results (90% CI)

Source: US FDA, http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_06_BioINequivalence.pdf
80% 125%
T/R (%)
99 100
US FDA’s BE Approaches
• Pharmacokinetic PK study – drug concentrations

measured in plasma
– INIVC (In vitro-in vivo correlation)
US FDA’s BE Approaches • PK study – drug concentrations measured in urine
• Acute pharmacological effect measured as a function of
time
– BE study with pharmacodynamic endpoints
• Well-controlled clinical trial in humans
– BE study with clinical endpoints
• Currently available in vitro test
– Must be acceptable to FDA
– Must ensure BA
BE Study Design Elements • Any other approach deemed adequate by FDA to
102
establish BA or BE
US FDA’s BE Approaches BE Study Design – USFDA
• INIVC (In vitro-in vivo correlation) • PK study – drug concentrations measured in

– Develop formulations with varying release rates urine
– Correlate in vitro dissolution with in vivo absorption – Appropriate when drug can not be reliably measured
in plasma
– In vivo studies may be waived if an IVIVC is established – Example: Alendronate Sodium tablets at 5, 10, 35,
• IV solutions 40, 70 mg
• Oral solutions • Plasma concentrations & redistribution from bone
• Non-BE strengths of solid oral dosage forms too low to be detected properly
• BCS Class I drugs • Food intake also significantly reduces BA
Drugs entering US market,
• DESI drugs with no BE issues 1938 – 1962, approved for • So, FDA asks for:
safety but not effectiveness – Single-dose fasting BE on the 70 mg strength
– Evaluate both internal & external predictability – Measure Alendronate in urine
103
– Biowaivers will be considered for the lower strengths 104
BE Study Design – USFDA BE Study Design – USFDA
• Acute pharmacological effect measured as a function of time • BE study with clinical endpoints
- BE study with pharmacodynamic endpoints – Drug products not systemically absorbed
– Basis for decision • Topical drug products
• Ability of corticosteroids to produce vasoconstriction or blanching • Locally acting GI drug products
in skin – Design characteristics
– Example: Topical Corticosteroid • Randomized
• Mometasone fluroate cream, 0.1% • Blinded
• Pilot study • Balanced
– Apply reference drug to arm • Parallel
– Obtain ED50 value of X minutes
– Patients receive:
• Pivotal study
• Test drug
– Apply test and reference drugs to both arms, multiple sites for X
minutes • Reference drug
– Apply reference drug for 0.5X and 2X minutes • Placebo
– Monitor blanching response of skin for 24 hours after removing drug – To ensure that patients respond to test and reference products
105 106
– Perform BE statistics
BE Study Design – USFDA BE Study Design – USFDA
• BE study with clinical endpoints • Currently available in vitro test

– Example: Topical Acne Gel, Tretinoin, at 0.025, 0.05 – Applicable: locally acting drug products
& 0.1% • Nasal sprays, suspensions
• FDA asks for: • Oral cholestyramine suspensions, tablets,
– BE studies with clinical endpoints on the 0.025% & 0.1% capsules
strengths
– So that the endpoints relevant to the healing of lesions
• Biowaiver granted on the 0.05% strength
– Why? All strengths were proportionally similar
107 108
BE Study Designs Summary - USFDA BE Study Designs Summary - USFDA
(21 CFR 320.24) (21 CFR 320.24)
FeV1 Albuterol
Blanching Study
Topical • Single-dose, two-way crossover, fasted
• In vivo measurement of active moiety Corticosteroid
or moieties in biologic fluid • Single-dose, two-way crossover, fed

Long Half-Life (wash-
• In vivo pharmacodynamic comparison • Alternatives out)
Amiodarone,
– Single-
Single-dose, parallel, fasted Etidronate
• In vivo limited clinical comparison Topicals
Nasal Highly Variable
– Single-
Single-dose, replicate design Drugs
• In vitro comparison Suspensions
Questran - Binding – Multiple-
Multiple-dose, two-
two-way crossover, fasted
• Any other approach deemed Studies
Nasal Solutions- – Clinical endpoint study
appropriate by FDA Sprayer Evaluation Less Sensitive
Propofol - Droplet Size Clozapine (Patient
Topicals
109 Nasal Suspensions Trials) 110
Chemotherapy Trials
Summary - US FDA BE Types of Solid Oral Dosage Form

Simple Solid Oral Dosage Form US FDA Orange Book
• BE study to compare test vs. reference product • Capsule • Tablet, chewable

– Rate & extent of BA • Capsule, Delayed-
Delayed- • Tablet, coated particles
– At site of action Release pellets (DR) • Tablet, DR
• Capsule, DR • Tablet, DR, orally
• Compare plasma concentration for systemically
• Capsule, Extended-
Extended- disintegrating
available drugs Release (ER) • Tablet, effervescent
• BE study uses metrics Cmax & AUC • Granule • Tablet, ER
– 90% CI of test/reference ratios must be within 80 – • Granule, DR • Tablet, for suspension
125% • Powder, EF • Tablet, orally
• Compare Test and Reference Tmax values • Suspension disintegrating
• Suspension, ER • Troche/lozenge
– Evaluate differences clinically
• Tablet
111 112
Biowaivers Guidelines
• EU Guidelines
– EMEA BA/BE 2001. Note for guidance on the investigation of
bioavailability & bioequivalence
• US Guidelines
Biowaiver – FDA SUPAC-IR 1995. Immediate release solid oral dosage forms. Scale-
up & post-approval changes
– FDA IVIVC 1997. Extended release oral dosage forms: development,
The regulatory acceptance of in vitro testing as evaluation & application of in vitro/in vivo correlations
– FDA BCS 2000. Waiver of in vivo bioavailability (BA) & bioequivalence
a reliable surrogate for an in vivo BE study studies for immediate release solid oral dosage forms based on a
Biopharmaceutics Classification System
– FDA BA/BE 2003. Bioavailability & bioequivalence studies for orally
administered drug products – general considerations
• WHO Guidelines
– The WHO Guidance: Multisource (generic) pharmaceutical products:
guidelines on reegistration requirements to establish interchangeability.
Latest revision 2005a
114
BE Biowaivers for Generics - US BE Biowaivers for Generics - US
Biowaivers – IV Solutions Biowaivers – Oral Solutions

• Parenteral solution intended for injection, or an • Oral generics can contain different excipients, but
otic or ophthalmic solution • Must not contain an excipient that will significantly
• Both Actives & Inactives must be of the same affect absorption of the active
amounts as the reference drug • Inactives should not present safety issues
• Data requested by the FDA:
– Same composition as the reference drug
– Data needed for a biowaiver request:
• CMC
• Labeling
115 116
• Formulation
BE Biowaivers for Generics - US Biowaiver Based on BCS
Biowaivers – Solid Oral Dosage Forms A biowaiver based solubility and permeability
• Acceptable in vivo BE must be established for one consideration of active pharmaceutical
strength ingredient, as well as dissolution profile
– Usually the highest strength similarity of the multisource (e.g., test, generic)
• Must have acceptable dissolution for all strengths and the comparator (e.g., name brand,
reference) product in pH 1.2, 4.5 and 6.8
• Strengths must be proportionally similar to the
media.
bio-strength
Source: WHO Technical Report Series, No. 937, 2006, Page: 347-390.
117 118
Biophamaceutics Classification System of

Absorption Pathway Drug Substance
• BCS
– Scientific framework for classifying drug substances based on their
Membrane Absorbed Liver aqueous solubility and intestinal permeability
Dissolution Drug at
Drug in Transfer Extraction Systemic – When combined with the dissolution of the drug product, the BCS takes
Solid the
Dose Solution Metabolic Circulation into account three major factors that govern the rate and extent of drug
Sites absorption from IR solid oral dosage forms: dissolution, solubility,
Plasma and intestinal permeability
Portal Conc.
Vein • BCS Classification of Drug Substances:
Solubility – Class 1: High Solubility – High Permeability
Permeability Metabolism • Pre-requisite for requesting FDA biowaivers EMEA Position:
– Class 2: Low Solubility – High Permeability Class I & III might be
eligible for biowaivers
– Class 3: High Solubility – Low Permeability Vet Products
– Class 4: Low Solubility – Low Permeability
119 120
Biophamaceutics Classification System of Biophamaceutics Classification System of
Drug Substance Drug Substance
• If two drug products, containing the same drug, have

Solubility High
the same concentration time profile at the intestinal Low
membrane surface Drug Substance
they will have the same rate and extent of availability at the High
Permeability
site of action Low
• If two drug products have the same in vivo
dissolution profile under all luminal conditions Very Rapid
Drug Product Dissolution Rapid
they will have the same rate and extent of availability at the
site of action Slow
VPShah-Ukraine-07
121 122
Dissolution Characteristics
Very rapidly dissolving 85% in 15 min

Rapidly dissolving 85% in 30 min
Slowly dissolving 85% in 30+ min
• To quality for biowaivers, both the generic and

reference products must have similar dissolution
profile in all 3 media – pH 1.2, 4.5 & 6.8
123 124
BE Biowaivers for Generics - US BE Biowaivers for Generics - US
• BCS Class 1 Drugs – FDA Biowaiver Requirements: • BCS Class 1 Drugs – FDA Biowaiver Example:
– Ofloxacin tablets at 200, 300, 400 mg
Highly • An amount of drug comparable to the highest strength
• Solubility > 400 mg/250 ml
soluble • Must be soluble in 250 ml of solution
• Over a wide pH range
• Oral bioavailability > 95%
• Can be established via in vivo or in vitro methods
• Dissolution rapid at pH 1.2, 4.5, & 6.8
Highly
permeable
Rapidly • At 0.1N HCl pH 1.2, pH 4.5, and pH 6.8 buffers
dissolving • 900 ml
conditions • Use paddles at 50 rpm, or basket at 100 rpm
125 126
BE Biowaivers for Generics - US BE Biowaivers for Generics - EU
Biowaivers – DESI Drugs Biowaivers – Immediate Release Vet Products

• In vivo BE studies for solid oral dosage forms • Class I BCS Active Substance
must meet the following: – Very rapid in-vitro dissolution for both the test &
– Approved in the US before 1962 reference products
– DESI expert panel has determined it to be efficacious – Excipients do not have relevant impact on BE
– No BE issues • Class III BCS Active Substance
– Have acceptable dissolution data – Very rapid in-vitro dissolution for both the test &
reference products
– Excipients qualitatively the same + quantitatively very
similar
> 85% within 15 min.
127 128
BE for Generics - US
Food Effects on BA – Potential Mechanisms:

• Delay gastric emptying
• Stimulate bile flow
Case Studies • Change GI pH
• Increase splanchnic blood flow
• Change luminal metabolism of a drug substance
• Physically or chemically interact with a dosag form or a
drug substance
Meals high in total calories & fat more likely to affect

the GI physiology higher impact on BA
Food Effects
2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies
130
Drug Products where FDA requests Fed BE Studies

Drug Products where FDA requests Fed BE Studies • Immediate-release drug products (IR)
• Immediate-release drug products – Safety concern
• Modified-release drug products • When a drug should not be given on an empty stomach
– Labeling requirement
• When the FDA-approved label contains statements
about effect of food on absorption or administration
2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies 2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies
131 132
Drug Products where FDA requests Fed BE Studies For Single-dose Fed BE Studies
• Modified-release drug products (MR) • Most solid oral drugs
– Delayed-release – Both fasting & fed BE should be included
– Extended-release • High fat, high calorie meal recommended
– Compare potential for dose-dumping – Calories from fat: at least 50%
– Not necessary to conduct fed BE for all strengths of MR – Total calories: 800 – 1000 Kcal
products
• Drug given timing: ≤ 30 min of consuming a
high-fat meal
2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies 2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies
133 134
Fasting Considerations • FDA’s recommendation for test meals for Food-effect BA

• Most sensitive & discriminating form of BE test designs and Fed BE studies
• Required for ALL systemically available drug unless – Use meal conditions expected to provide the greatest effects on GI
safety concerns physiology so that systemic drug availability is maximally affected
• Example: Mefloquine HCL Tablets 250mg – A high-fat & high-calorie meal is recommended
– ROA: Oral – Meal calorie breakdown should be included in the study report:
– Type of study: Fed • Protein: 150
– Design: Single-dose, parallel design in-vivo • Carbohydrate: 250
– Subjects: General population, normal healthy males & females • Fat: 500-600
– FDA comment: – If the test meal’s caloric breakdown is significantly different, the
• Fasting BE not recommended sponsor should provide a scientific rationale for this difference
– Mefloquine known to cause GI problems under fasting – In NDAs, the sponsor can choose to conduct food-effect BA studies
– Analyte to measure: Mefloquine in plasma using meals with different combinations of fats, carbohydrates, and
– BE based on: 90% CI, Mefloquine proteins for exploratory or label purposes. However, one of the
– Dissolution methods database available from FDA meals for the food-effect BA studies should be the high-fat, high-
135 136
calorie test meal described above
Case Study – Food Effects Case Study – Food Effects
• Food Prolongs Absorption Rate • Food Prolongs Absorption Rate

– Typically seen in: – Example: Lamivudine
• Highly soluble, highly permeable, rapidly absorbed
drug substances Clinical • Fed state absorption, Tmax:
Tmax: 3.2 hr
• Major mechanism pharmacology • Fasted state absorption, Tmax:
Tmax: 0.9 hr
– Delayed gastric emptying finding • Fed state Cmax:
Cmax: 40% lower than in fasted
– Example: Lamivudine state
• No significant AUC difference
Labeling on May give with or without food
Dosage &
Administration
137 138
• Food Decreases Absorption • Food Decreases Absorption

– Major mechanisms – Example: Didanosine
• Instability in gastric acids
Clinical • Cmax reduced by 46%
• Physical/chemical binding with food components pharmacology • AUC reduced by 19%
• Increased first-
first-pass metabolism & cleanrace finding
– May lead to decreased efficacy Labeling on Dosage • Should be taken on an empty stomach
& Administration
– Example: Didanosine
Labeling on • Unstable in acid solution
Description • Protected by enteric coating
Labeling on • Administer once daily on an empty stomach
Precautions
139 140
• Food Increases Absorption • Food Increases Absorption

– Major mechanisms – Example: Isotretinoin
• Inhibition of first-
first-pass effect
Clinical • Cmax more than doubled
• Physicochemical / physiological effects pharmacology • AUC more than doubled
• Increased bile release finding • Tmax also prolonged
• Longer gastric residence time Labeling on Dosage • Should always take with food
& Administration • Failure to take with food will significantly decrease
– Food may affect efficacy and/or safety
absorption
– Example: Isotretinoin,
Isotretinoin, Efavirenz • Practitioners should question patients about compliance
with food instructions before adjusting doses upward
141 142
• Food Increases Absorption • No effects

– Example: Efavirenz – Major mechanisms
• Relatively insensitive to changes in the GI tract
Clinical • AUC increased by 22%, Cmax increased by 39% with a
pharmacology high fat, high calorie meal
• Rapidly, completely absorbed
finding • AUC increased by 17%, Cmax increased by 51% with a • Well-
Well-absorbed from both large & small intestine
low fat, normal calorie meal
– Example: Finasteride
Labeling on Dosage • It is recommended that XXXX be taken on an empty
& Administration stomach, preferably at bedtime
• Taking XXXX with food may lead to increased adverse
events
143 144
Case Study – Food Effects
• No Food Effect
– Example: Finasteride
Clinical • BA not affected by food

Case Study
pharmacology
finding
Labeling on Dosage • Can be administered with or without meals

& Administration
Albuterol Metered-dose Inhaler

145
Case Study – Albuterol Inhaler Case Study – Albuterol Inhaler
• Objective • Design
– Randomized, double-
double-blind, balanced, crossover
– Determine the potency of each generic albuterol MDI – Placebo inhalers used to maintain blinding of inhaler & doses
actuation relative to Ventolin administration – Reference Ventolin MDI: 90 µg/actuation
µg/actuation
• Drugs: – 1 treatment on each of 4 study days
– A histamine bronchoprovocation procedure was initiated 1.25 hr
– Generic drugs: albuterol metered-
metered-dose inhalers prior to and 15 min after treatment
– Reference drug: Ventolin (Glaxo Wellcome)
Wellcome) • Subjects
– Adult patients, 18 – 65 yrs, n = 24
– Nonsmoking
– Clinically screened for mild-
mild-to-
to-moderate asthma
• FEV1, > 60% of predicted; and provocative concentration of
histamine causing a 20% fall in FEV1 [PC20], ≤ 8 mg/mL
mg/mL at
screening
147 148
Geometric mean PC20 (±
Case Study – SEM) measured 30 to 45 min
Case Study – Albuterol Inhaler after test MDI dosing
Albuterol Inhaler
Mean effects of the generic
• Measurements (Norton) and Ventolin MDIs on
– Primary outcome: histamine PC20, measured after treatment PC20
• Results
– Significant dose-
dose-effect relationship (p < 0.0001)
– Not significant: • Significant dose-response
• Deviation from parallelism of the Generic & Reference dose-
dose- Relationship (p < 0.0001)
response curves (p = 0.95)
• 1 puff Generic = 1.01 puffs Reference
• Differences in overall mean response between the Generic &
Reference (p = 0.68)
– Estimation The same results express
• 1 actuation of Generic equivalent to 1.01 puffs of Reference as activity ratio (± SEM)
• CI 90% R/T = 0.69 – 1.50 Source:
• Conclusion Stewart B A et al. Demonstration of In Vivo
Bioequivalence of a Generic Albuterol
– Generic is bioequivalent to Reference Metered-Dose Inhaler to Ventolin.
149 Chest 2000;117:714-721 150
Case Study –
Albuterol Inhaler
Top: Relationship between s/b and
difference between response to
test and Ventolin MDIs
Case Study
Estimated potency of test inhaler

relative to the Ventolin MDI and its
90% CI
Source:
Stewart B A et al. Demonstration of In Vivo
Bioequivalence of a Generic Albuterol
Generic IR Tablets
Metered-Dose Inhaler to Ventolin.
Chest 2000;117:714-721 151
Generic IR Tablets Generic IR Tablets
Source: Alt et al 2004, Rote Liste 2004 Source: Alt et al 2004, Rote Liste 2004
• Reference drug product • Data

– Sotalex® – API = BCS Class 1
Sotalex® tablets C & D
• BA 90%, rapidly absorbed
– API - antiarrhythmic:
antiarrhythmic: sotalol HCl
• In vitro/in vivo: high permeability
• Generic drug products – In vitro dissolution profiles conducted in 0.1N HCl and pH 4.5 &
– 80 & 160 mg IR tablets 6.8 phosphate buffers, paddle, 75 rpm
• Dissolved >85% in 15 min in all media
– API - antiarrhythmic:
antiarrhythmic: sotalol HCl
– Excipients in the generic: well established and in amounts
common in IR tablets, and unlikely to affect the absorption
• High conc. (0.755g/200 ml) mannitol may lead to lower
absorption
• But the amount of mannitol present is below 1/3 of the
concentration that would accelerate small intestine transit
153 time 154
Generic IR Tablets References

Source: Alt et al 2004, Rote Liste 2004
• Regulatory decision on biowaiver • US FDA Individual Product BE

– Germany: accepted Recommendations Dissolutions Methods
• In compliance with the EMEA, BA/BE 2001 Database
• USA: acceptance expected – http://www.fda.gov/Drugs/GuidanceComplianceRegul
atoryInformation/Guidances/ucm075207.htm
155 156
Day 2 Agenda
09.00 – 10.00 Special Considerations for BA / BE Study Designs, part 1

Session 1
Session I
Case Studies
10.30 – 12.00 Special Considerations for BA / BE Study Designs, part 2
Session II
Special Considerations
Special Considerations for BA / BE Study
Designs, Part 1
14.00 – 16.30 BA / BE Study Design Workshop
Session III
Case Studies
157 158
Model of Oral Dosage Form Performance Endogenous Drug BE
• Endogenous products are not covered by the general

BA/BE Guidance documents
Pharmacokinetic Clinical/PD – FDA Guidances on KCl and levothyroxine
Dosage Form Measurement Measurement
Performance • Require special considerations
– Case by case
Dosage Drug in Site of Therapeutic
• Examples of endogenous drug products:
Solution Gut Wall Blood – Ursodiol
Form Activity Effect
– Iron products
– Calcitriol
– KCl
– Estradiol
– Progesterone
– Testosterone
– FSH
Source: US FDA Dose ln Dose – Levothyroxine
159 160
Model of Oral Dosage Form Endogenous
Endogenous Drug BE
Drug Performance
• Potential issues
– Differentiation between endogenous & exogenous Dosage Form Body Pharmacokinetic Clinical/PD
Measurement Measurement
sources Performance Production Feedback
– Assay sensitivity
– Feedback impact Dosage Drug in
Gut Wall Blood
Site of Therapeutic
Form Solution Activity Effect
– Circadian rhythm
– Baseline correction & methods of correction
– Moving baselines
– Need for special population
Source: US FDA Dose ln Dose

161 162
Case Study Blakesley Study Design
• LT4 Drug products:

–Levo-
Levo-t (Sandoz,
Sandoz, generic) vs. Synthroid (Abbott, brand)
BE of Levothyroxine (LT4 ) • 36 healthy volunteers (18M, 18F)

The Blakesley Study • Fasting, open-label, randomized, three-period,
crossover; 42 to 54 days between periods
Blakesley V, et al. Thyroid. 2004;14:191-200 • LT4 doses administered
–Regimen A: 600 µg (12 x 50 µg Synthroid)
FDA Citizen Petition No. 2003P-0387 –Regimen B: 450 µg (9 x 50 µg Synthroid)
–Regimen C: 400 µg (8 x 50 µg Synthroid)
Synthroid)
163 164
Blakesley Study Results BE Studies Comparison
Blakesley V, et al. Thyroid. 2004;14:191-200. Petition to the FDA Docket No. 2003P-0387
8
Regimen A: 600 µg Dose
Regimen B: 450µg Dose
Regimen C: 400µg Dose AUC0-48 .6 .8 1.0 1.25 1.4
T4 Concentration (mg/dL)
Sandoz L-T4
4 vs. Synthroid
Endogenous hormone
correction
2 Sandoz L-T4
vs. Levoxyl
0 8 16 24 32 40 48
0 .8
Time (hours) 1.25
0 12 24 36 48 60 72 84 96
Time (hours) Range of Bioequivalence
165 166
Approved LT4 Products What’s This Petition All About?

Petition to the FDA Docket No. 2003P-0387
Complaint:
BE Class Reference Drug Mfg Name
• The mean bioavailability of the generic
AB1 Unithroid Stevens Sandoz product is, on average, 12.5%
AB2 Synthroid Abbott greater than that of Synthroid after baseline
correction
AB3 Levoxyl Jones
• But based on FDA’s criteria for BE, Sandoz
BX levothyroxine was allowed to be labeled as
Not interchangeable bioequivalent to both Synthroid and Levoxyl
167 168

• Statistics • Statistics
– Use ANOVA with 2 one-sided tests to analyze data – Bioequivalence criteria
– BE criteria • ANOVA two one-
one-sided tests procedure
• 90% confidence intervals of means – Test (T) not significantly less than Reference (R)
• Test/Reference ratio: 0.800 – 1.250 – R not significantly less than T
– Questions – Significant difference is 20% (α(α = 0.05 significance
level)
• What does this mean?
» T/R = 80/100 = 80%
• Can there be a 45% spread? » R/T = 80% (all data expressed as T/R so this
– Rounding not permitted (either up or down) becomes 100/80 = 125%)
169 170
BE for Generics - US Possible BE Results (90% CI)

Source: US FDA, http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_06_BioINequivalence.pdf
80% 125%
T/R (%)
171 172
Why is the Question Important? US FDA Generics Definition
• Are patients getting therapeutically equivalent

prescriptions when substitution occurs at the • Therefore, a generic drug product must be
dispensing pharmacy? the same as brand drug in:
– Rx: no substitution Active ingredient
– Rx: brand name only Strength
– Rx: dispense as written Dosage form
– Too complex for clinicians & pharmacists Route of administration
Quality
Therapeutic effect
173 174
Generics Approval Considerations

Study Design: Basic design consideration
by the US FDA
Source: CDER, US FDA
Brand Name Drug - Generic Drug – • When comparing performance of two products
NDA Submission: ANDA Submission:
• Chemistry • Chemistry
– Minimize variability not attributable to formulations
• Manufacturing • Manufacturing
– Minimize bias
• Controls • Controls
• Labeling • Labeling
• Testing • Testing
• Preclinical/Clinical
• Bioavailability • Bioequivalence
175 176
Study Design: Basic design consideration Overview of BE Study Designs
• BE of a generic equivalent, G, of name brand TEST drug & REFERENCE drug
drug N
Modified Release
• Study Design
Immediate Release Extended Release Delayed Release
– Healthy subjects (Controlled Release) (Enteric Coated)
– Two treatments
• One for G Single Dose Fasting Single Dose Fasting
• One for N Single Dose Fed Single Dose Fed
– Two sequences
AUC AUC
• G- N Cmax Cmax
Tmax Tmax
• N-G λz (Kel)
λz (Kel) Terminal elimination rate constant
177 T1/2 Time to half peak concentration T1/2 178
Case Study EFFUDEX

http://www.efudex.com/index.jspf
EFFUDEX
5-FU
FDA Citizen Petition 2004P-0557

179 180
EFFUDEX EFFUDEX
• Effudex • FDA denied Valeant’s CP & approved of Spear’s

– Fluorouracil Topical Treatment of Solar or Actinic Keratoses & ANDA for a generic flurouracil cream 5%
Superficial Basal Cell Carcinoma (5% strength) product, April 11, 2008
• Indications – “…it has not been the Agency’s policy to require that
– Multiple actinic / solar keratosis BE be shown in every indication if drug release from
– Superficial basal cell carcinomas the dosage form and appearance at the site or sites
• Citizen Petition 2004P-
2004P-0557 filed by Valeant,
Valeant, December of activity has been demonstrated…”
2004, asking the FDA not to approve of ANDA for – “If a study demonstrated efficacy for a 5-5-FU
generic versions unless formulation to treat Actinic Keratoses,
Keratoses, this would
– BE is established for each different site of action for each
provide assurance that the formulation would
indication penetrate the skin sufficiently to treat sBCC.”
sBCC.”
– BE is established in the most difficult condition to treat • Valeant sued FDA on April 25, 2008
181 – Requested to suspend approval of Spear’s ANDA 182
EFFUDEX Case Study
• FDA, Assoc. Commissioner for Policy and

Planning issued an administrative order staying Colazal
the approval of generic fluorouracil cream 5% Balsalazide Disodium
until May 30, 2008
– Due to “outstanding questions regarding this approval
that the Agency must consider"
• Spear suspended all further sales and shipment
• October 2009, the U.S. District Court for the
Central District of California upheld FDA’s
position FDA Citizen Petition No. CP 2005P-1461
183 184
Local Acting Oral Drugs Local Acting Oral Drugs
Colazal – CP 2005P-
2005P-1461 by Salix Colazal – CP 2005P-
2005P-1461 by Salix
• API = Balsalazide disodium: • API = Balsalazide disodium

– Orally administered – locally acting GI product • Salix’ citizen petition to the FDA to require all generic
ANDAs to include efficacy & safety data from comparative
– Enzymatically cleaved in the colon Mesalamine (anti- clinical trials:
inflammatory) – FDA to establish guidance on BE standards for oral, locally acting
– Indications – reduce inflammation associated with GI drugs prior to approval of any generic ANDAs
ulcerative colitis – In vivo BE to use ulcerative colitis patients in remission instead of
normal health subjects
• Site of action: colon – In vivo BE to include specific analyte (N-Acetyl-5-Aminosalicylic acid
in plasma) measurement in adults and pediatrics
– In vivo BE to use a fed, a sprinkling and a fasting study
– In vivo BE to include pharmacokinetic studies in the pediatric
population and measure plasma levels of balsalazide, mesalamine,
& N-acetyl -5-ASA
185 186
Local Acting Oral Drugs Interchangeable or Not?

Colazal – CP 2005P-
2005P-1461 by Salix
• API = Balsalazide disodium • Let’s walk down the history lane…

• FDA’s conclusion the CP on December 28, 2007 – 1938: Food, Drug & Cosmetic Act
– Both fasting & fed studies should be conducted for BE, as a result of – Prior to 1962, proven safe but not necessarily effective
labeling changes – 1950s: generics started to appear
– Other requests denied
– 1960s: Thalidominde disaster
• Solubility
– 1962: Kefauver Harris Drug Amendments Act, S&E
• Mechanism of release
• Ability to measure plasma concentrations and relation of plasma
• Cost of medicine went up
concentrations to release at the site of action – 19702: Generics found to have BA problems
• Sensitivity of clinical studies to detect differences in product – 1984: Hatch–
Hatch–Waxman ActAct
performance • ANDA for generics
• ANDAs for generics approved on Dec 28, 2007 • BE required
– 80 – 125%
187 188
Price of Medicine vs. Generic Availability Interchangeable or Not?
Source: FDA, retail sales data from IMS Health
• Let’s walk down the history lane…
– 1986 FDA public hearing on BE determination method
• Conclusion: 80 – 125% rule satisfactory and clinically acceptable, but
• Both pro- & anti- camps agreed acceptable bioavailability variation for
generic
– Most meds: 11%
– Critical dose meds: 5%
– 1989 generics submissions scandal: S&E of generics rejuvenated
• FDA employees bribed to expedite approval
• Fraudulent submissions to the FDA for approval of generic drugs &
GMP violations
• extensive FDA inspections
• Hundreds of generic drug applications reexamined
– including narrow therapeutic index drugs: aminophylline tablets
– Only 27 samples (1%) failed to comply
– Only 5 of those (all aminophylline tablets) failed to meet USP standards
189 – None of the defects deemed to pose a public health hazard 190
Interchangeable or Not? Interchangeable or Not?
• Let’s walk down the history lane… • Let’s walk down the history lane…
– Joint guidelines by the FDA & EMEA on BA/BE – What did the end users say about generic substitution?
• Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products - General Considerations • Physicians, pharmacists and patients
• Other data may be needed beyond BE assurance • Pharmacists
– Analytical methods validation – Supported the use of generic drugs
– In vitro/in vivo correlation – Quality, price and supplier consistency
• FDA letter to health practitioners • Patients
– “Products evaluated as therapeutically equivalent are expected to
have equivalent clinical effect whether the product is a brand name
– 72% accepted generics on pharmacist’
pharmacist’s recommendation
name
or a generic drug product – 76% agreed on generics on doctor’
doctor’s suggestion
– It is not necessary for the health care provider to approach any one • Physicians
therapeutic class of drug product differently from any other class,
class,
when there has been a determination of therapeutic equivalence by by
– Only 17% could correctly identified FDA’
FDA’s BE standards
FDA for the drug products under consideration.”
consideration.” 191 192
– Conflicting findings on differences in brand – generics substitution – FDA’s philosophy
• 1997 US Case – FDA looked at all approved generics: • PMS - one of the best mechanisms to protect patients from
– AUC: 3.25% (SD, 2.97) to 3.47% (SD, 2.84) problems
– Cmax: 4.29% (SD, 3.72) • FDA adverse event alert & maintenance system to update drug
• 1984 - 1986 US Case: labeling, reevaluate approval or marketing
– AUC: 3.5% – The Spontaneous Reporting System
• 1995 - 1996, UK Case: » Computerized database – early warning system for adverse
events
– UK Medicines Control Agency (MCA) examined 2427 generics
» Adverse drug reactions primarily reported by health
– 228 deficiencies
professionals
– MCA requested 84 product quality improvements in labelling,
» 1960s - January 1997, serve as an early warning system for
packaging, methods of analysis, and products specifications
adverse drug reactions not detected during prermarketing
testing. This system has been replaced by the Adverse Events
193
Reporting System 194
– FDA’s philosophy – FDA’s philosophy
• FDA adverse event alert & maintenance system to update drug • FDA adverse event alert & maintenance system to update drug
labeling, reevaluate approval or marketing labeling, reevaluate approval or marketing
– The Adverse Events Reporting System
– FDA Therapeutic Inequivalence Action Coordinating Committee
» Replacing the above
(TIACC)
» Electronic submission
» What can the TIACC do?
» International compatibility
– MedWatch » Remove inequivalent products from the market
» For both health professionals & the public » Evaluate and change the TE rating of products
» Voluntary reporting of serious AE » Recommend a grandfathered product to submit a new drug
– FDA Therapeutic Inequivalence Action Coordinating Committee application
(TIACC) » Test and evaluate BE/dissolution relationship
» To identify and evaluate reports of therapeutic failures and » Recommend appropriate dissolution specifications for narrow
toxicity that could indicate that one product is not equivalent to therapeutic drugs
another similar product
» A mechanism for timely follow up on reports of therapeutic » Evaluate toxicity profile of injectables and mandate appropriate
inequivalence and full-scale investigation controls…
195 196
From Brand to Generics
• Let’s walk down the history lane… • Anti-arrhythmics (e.g., Amiodarone)

– The Orange Book Designation – Uncertain combination impact exists:
• A = substitutable • Advanced age
– No known/suspected BE problems • Current diseases
– The second letter = the dosage form
• Concomitant drug therapy on bioequivalence
» AT = BE, topical dosage as compared to the topical
dosage form of the reference drug – Best to start on the Brand name medicines first
» AB = Actual or potential BE problems have been – Avoid presumed BE dosage forms
resolved with adequate in vivo and/or in vitro evidence – Switch and continue with generics used in the titration to
• B = non-interchangeable an effective antiarrythmic response
– NOT being therapeutically equivalent
– BC, BD, BE, BN, BP, BR, BS, BT, BX, where the second
letter indicate the dosage form 197 198

From Brand to Generics From Brand to Generics
• Anticoagulants (e.g., Warfarin) • Antiepileptics (Phenytion, Carbamezapine)

– Conflicting views from the guidelines issued by the FDA – Generic substitution can be approved only if safety and
and the health practitioners (the Institute for Clinical efficacy are not compromised
Systems Improvement) – Avoid switching between formulations except when
– BE results suggest both S & E to initiate therapy with the medically necessary
generics – Monitor blood levels closely at the time of any known or
• Patients take a single warfarin product whenever suspected switch to a different formulation
possible – Adjust & readjust medication doses accordingly
• Followed by additional monitoring after substitution of – Avoid unilateral switch by pharmacists to different
one warfarin product for another products
– Timely detection of patient’s anti-
anti-coagulation response
199 200
From Brand to Generics From Brand to Generics
• Thyroxine • Highly variable drugs

– First approved product: Synthroid (Levothyroxine), 1955 – Medicines demonstrating a high variability in
– Recommended: pharmacokinetic parameters a challenge in BE testing
• Obtain a thyroid stimulating hormone (TSH) level • Could be due to high intra-subject variability
within eight to twelve weeks of changing a • Examples:
levothyroxine dose or brand and every six to twelve – Propafenone IR
months thereafter – Verapamil
– Nadolol
• Current 80 – 125% standard suitable?
– A new specific FDA guidelines for this category
201 202
Interchangeable or Not?
From Brand to Generics Session 2
• Brand-generic substitution concerns and questions

– One single regulatory acceptance range (80 – 125%) for • ASEAN Status Summary
all drug products?
– The use of single dose studies in BE studies, while all • Special Considerations for BA / BE Studies
drugs are usually used in multiple doses – Good Laboratory Practice (GLP) in a Nutshell
– Extrapolation of BE in normal healthy volunteers – Good Clinical Practice (GCP) in a Nutshell
applicable to all patients populations?
– Inter-
Inter-relationship & Conduct
– BE studies performed on a small number of subjects
only…
– Different generic BE versions of a branded reference
product
• Assumption is the generics are freely interchangeable
• Where’s the data to suggest this? 203 204
ASEAN Survey Result ASEAN GCP Status
• Survey on Requirement of GCP, GLP & BE Study • 5 out of 9 countries have GCP regulation:
Report in AMS, 2008,
2008, reported at the 4th Meeting of − 4 of the 5 countries have National GCP guideline &
ASEAN BA/BE Taskforce Vientiane, 18 February 2008 mechanism for authorization of clinical trials, including
• 9 AMS participated BE studies and related Guidance or SOPs
– Brunei
− 5 countries are in line with ICH GCP (E6)
– Cambodia GCP Requirements for BE Center − 1 of the 5 countries is also in line with FDA Guidance
– Indonesia GLP Requirements for BE Center
– Lao PDR − 2 of the 5 countries are also in line with EMEA Note
BE Study Report
– Malaysia for Guidance on Clinical Practice as well as WHO
– Philippines Handbook for Good Clinical Research Practice
– Singapore • 4 countries do not have GCP regulation
– Thailand
– Vietnam 205 206
ASEAN GLP Status BE study reports received in the past 6 months
• GLP guidance in line with

– ISO 17025
70
– OECD
60 66
– WHO GLP
50
• 4 of the 5 conduct GLP inspection 40
30
30
25 25
20
10 13 2
0
Indonesia Malaysia Philippines Singapore Thailand Vietnam
207 208
ASEAN BE Study Report Format ASEAN GLP
• In line with international standards • Definition

• FDA – A quality system concerned with the organisational
• WHO TRS 937 process and the conditions under which non-
non-clinical
• ICH E3 health and environmental safety studies are planned,
performed, monitored, recorded, archived and
reported
• GLP standards
– EMEA/OECD GLP
– WHO GLP
– ISO/IEC 17025/1999
209 210
GLP in a Nutshell GLP Comparison
Topic FDA OECD

Scope For nonclinical lab studies For nonclinical safety testing &
Nonclinical health & environmental
•Food & color additives safety studies
Adequate Facility Qualified Personnel
•Animal food additives
Protocols •Pharmaceutical products
•Human/animal drugs
Proper Documentation •Pesticide products
•Medical devices for human
& Archiving •Cosmetic Products
use
Effective SOPs •Biological products •Vetirinary drugs
•Electronic products •Food additives, feed additives
Accurate Data Specifications
•Industrial chemicals
Suitable Test
Systems
211 212
GLP Comparison GLP Comparison
Topic FDA OECD Topic FDA OECD

Testing A person who actually conducts The persons, premises and Quality Any person or A defined system, including
a nonclinical laboratory study, operational unit(s)
unit(s) that are
Facility Assurance organizational element, personnel, which is
i.e., actually uses the test article necessary for conducting the non- non-
in a test system. Testing facility Unit
includes any establishment
clinical health and environmental except the study director, independent of study
required to register under safety study. For multi-
multi-site studies, designated by testing conduct and is designed to
section 510 of the act that those which are conducted at more
than one site, the test facility
facility management to assure test facility
conducts nonclinical laboratory
studies and any consulting comprises the site at which the perform the duties management of compliance
laboratory described in section Study Director is located and all relating to quality with these Principles of
704 of the act that conducts individual test sites, which
such studies. Testing facility individually or collectively can be
assurance of nonclinical Good Laboratory Practice
encompasses only those laboratory studies
considered to be test facilities.
operational units that are being
or have been used to conduct
nonclinical laboratory studies.
213 214

Study The individual The individual responsible Principal Principal Investigator means an individual
who, for a multi-
multi-site study, acts on behalf
Director responsible for the for the overall conduct of Investigator
of the Study Director and has defined
overall conduct of a the nonclinical health and responsibility for delegated phases of the
study. The Study Director's responsibility
nonclinical laboratory environmental safety study for the overall conduct of the study cannot
study be delegated to the Principal
Investigator(s);
Investigator(s); this includes approval of
the study plan and its amendments,
approval of the final report, and ensuring
that all applicable Principles of Good
Laboratory Practice are followed.
215 216

Test Any animal, plant, Any biological, chemical or Batch Batch means a specific Batch means a specific quantity
System microorganism, or subparts physical system or a combination quantity or lot of a test or or lot of a test item or reference
thereof to which the test or thereof used in a study control article that has been item produced during a defined
control article is administered characterized according to cycle of manufacture in such a
or added for study. Test Sec. 58.105(a). way that it could be expected to
system also includes be of a uniform character and
appropriate groups or should be designated as such.
components of the system Test Any food additive, color An article that is the subject of a
not treated with the test or Article additive, drug, biological study
control articles product, electronic product,
Specimen Any material derived from a Any material derived from a test medical device for human
test system for examination system for examination, analysis, use, or any other article
or analysis or retention subject to regulation
217 218

Control Any food additive, color Any article used to provide Study The date the protocol is The date the Study Director signs
Article additive, drug, biological a basis for comparison with Initiation signed by the study director the study plan
product, electronic product, Date
medical device for human
the test item
Study The date the final report is The date the Study Director signs
use, or any article other than Completion signed by the study director the final report
a test article, feed, or water Date
that is administered to the
test system in the course of a
nonclinical laboratory study
for the purpose of
establishing a basis for Source: Comparison Chart of FDA and EPA GLP Regulations and OECD
comparison with the test Principles of GLP. US FDA June 2004
article
219 220
GCP Overview Goals of GCP
• GCP is defined as a standard for the design, • Protect the rights, safety and welfare of humans
conduct, performance, monitoring, auditing, participating in research
recording, analysis and reporting of clinical trials • Aassure the quality, reliability and integrity of
or studies data collected
• GCP compliance provides public assurance that • Provide standards and guidelines for the
the rights, safety and well-being of human conduct of clinical research
subjects involved in research are protected • GCP = Ethics + Quality Data
221 222
Basis for Ethical Conduct of Clinical Research Basis for Ethical Conduct of Clinical Research
• The Nuremberg Code (1947)

• The Nuremberg Code (1947) – Voluntary participation
• The Declaration of Helsinki (1964) – Informed Consent
– Minimization of risk
• The Belmont Report (1979)
• ICH GCP E6
• ISO 14155
• Other International GCP Guidelines
223 224
• The Nuremberg Code (1947) • The Nuremberg Code (1947)

• The Declaration of Helsinki (1964) • The Declaration of Helsinki (1964)
– Well-being of subject takes precedence • The Belmont Report (1979)
– Respect for persons – Respect for Persons
– Protection of subjects health and rights • Informed consent
– Special protection for vulnerable populations • Protection of vulnerable populations
– Beneficence
• Non-malfeasance
– Justice
• Fairness
225 226
• The Nuremberg Code (1947) • The Nuremberg Code (1947)

• The Declaration of Helsinki (1964) • The Declaration of Helsinki (1964)
• The Belmont Report (1979) • The Belmont Report (1979)
• ICH GCP E6 • ICH GCP E6
– GCP is an international quality standard that is provided • ISO 14155
by the International Conference on Harmonisation (ICH) – ISO 14155: Clinical Investigation of Medical Devices for
– Goals: Harmonize technical procedures and standards; Human Subjects
improve quality; speed time to market • Assists sponsors, monitors, and clinical investigators in
the design and conduct of device clinical investigations
• Assists regulatory bodies and ethics committees in
227 their roles of reviewing clinical investigational plans228
13 Principles of ICH GCP 13 Principles of ICH GCP
• Ethics: • Data quality and integrity:

– Ethical conduct of clinical trials
– Benefits justify risks
– Accurate reporting, interpretation, and verification
– Rights, safety, and well-being of subjects prevail – Protects confidentiality of records
• Protocol and science: • Investigational Products
– Nonclinical and clinical information supports the trial
– Conform to GMP’s and used per protocol
– Compliance with a scientifically sound, detailed protocol
• Responsibilities: • Quality Control/Quality Assurance
– IRB/IEC approval prior to initiation – Systems with procedures to ensure quality of every
– Medical care/decisions by qualified physician aspect of the trial
– Each individual is qualified (education, training, experience) to
perform his/her tasks
• Informed Consent:
– Freely given from 229 230
GCP Responsibility Chain GCP In a Nutshell
• Sponsors • Protection of the rights of subjects

• Clinical Investigators (CIs)
• Good documentation
• Independent Ethics Committees (IECs)
– Institutional Review Boards (IRBs) • Monitoring
• Contract Research Organizations (CROs)
• Research nurses
• Clinical Research Coordinators (CRCs)
• Clinical Research Associates (CRAs)
• Medical monitors
• Data entry personnel
• Others
231 232
ICH GCP IRB Responsibilities (ICH 3.1)
• Chapter 1 - Glossary • IRB is required to

• Chapter 2 - Principles of ICH GCP – Review informed consent, protocol, advertisements,
and the Investigator's Brochure.
• Chapter 3 - Institutional Review Board
– Submit documents:
• Chapter 4 - Investigator • Subject recruitment procedures
• Chapter 5 - Sponsor • Written information provided to subjects
• Chapter 6 - Protocol and Amendments • Information about subject compensation
• Chapter 7 - Investigator’s Brochure • Investigator's current CV and/or other documents
evidencing qualifications
• Chapter 8 - Essential Documents
233 234
IRB Composition (ICH 3.2) IRB Composition - US
• IRBs required composition: • Additional FDA requirements on IRB (56.107a-f):

– At least five members – One scientific member
– One non-scientific member – Diversity in race, gender, cultural backgrounds
– Varying backgrounds - not composed of only one
– One member not affiliated with the institution profession
– Members involved in the protocol not have a – Members qualified to assess the acceptability of the
voting role protocol with institutional SOPs & professional
practice standards
– Members with a conflicting interest cannot vote for
protocol approval
235 236
Investigator Agreements (ICH 4.1) Investigator Resources (ICH 4.2)
• Investigators required to maintain a list of • Investigators to demonstrate potential for recruiting

appropriately qualified persons to whom the required number of patients within the agreed
significant trial-related duties have been recruitment period
delegated. – Retrospective data
– Patient database analysis
237 238
Subject Medical Care (ICH 4.3) Protocol Compliance (ICH 4.5)
• Investigators required to • Investigators (or their designees) to document

– Inform subjects when medical care is needed for an and explain any deviation from the approved
intercurrent illness
protocol
– Make every reasonable effort to ascertain the
reason(s)
reason(s) for subject early withdrawal (although the
subject is not obliged to give a reason)
• ICH recommendation
– Investigators inform the subject’s primary physician
of trial participation (with the subject’s permission)
239 240
Investigational Product (ICH 4.6) Informed Consent (ICH 4.8)
• ICH allows the delegation of study drug • ICH allows the delegation of the informed
dispensing, patient counselling, and drug consent process to a designee
accountability to a designee
• ICH requires the person conducting the
informed consent process to sign and
date the consent form
• ICH requires that the subject receive a
signed and dated copy of the consent
form. FDA only requires that a copy be
provided
241 242
Informed Consent Records and Reports (ICH 4.9)
• ICH requirements but not required by the US • Investigators (or designees) required to:
FDA: – Document explanations for discrepancies between
data in the CRFs and the source documents
– Discussion of trial treatments and probability of
random assignment – Initial, date and explain (if necessary) all CRF
changes/corrections. CRF designees must be
– Subject responsibilities documented
– Anticipated payment, if any, to the subject – Endorse & retain records of all CRF changes
– Important potential risks and benefits of alternative made by the Sponsor
treatment
– Authorization to access medical records by regulatory
authorities (FDA and foreign)
243 244
Records and Reports (ICH 4.9) Sponsor QA/QC (ICH 5.1)
• Retention of “essential documents” for at least

two years after the approval of a marketing • Sponsors to secure agreement from all
application in an ICH region or until there is no involved parties to ensure direct access of
pending or contemplated applications in an ICH study records to foreign regulatory authorities
region or development is formally discontinued
245 246
Record Keeping (ICH 5.5) Compensation (ICH 5.8)
• Sponsors to inform Investigators in writing of:

• Sponsors to provide insurance or indemnify
– Study record retention requirements the investigator against claims arising from
– Notification of when records are no longer the trial
needed
247 248
Financing (ICH 5.9) IRB Review (ICH 5.11)
• Financial aspects of the trial to be documented • Sponsors to obtain a statement from

in an agreement between the Sponsor and Investigators that their local IRB is organized and
Investigator operates according to GCP and applicable laws
• No specific requirements on the investigator’s and regulations
financial disclosure
249 250
Supplying IP (ICH 5.14) FDA Inspections on GCP & GLP
• Sponsors to obtain documentation of IRB • What Piques FDA’s Interest?

approval prior to shipping investigational product – Proper protocol approval?
to an Investigator – Was the approved protocol followed by the
investigator? By whom, in which steps?
– Accountability for the test product
– Informed consent obtained properly?
– Source document match the data submitted?
– Monitor’s accountability & communication
251 252
FDA Inspections on GCP & GLP
• Common Reasons for Warning Letters – Failure Session 3

in the following areas:
– Informed consent issues
– IRB/EC approval & issues BA / BE Study Design Workshop
– Protocol deviations
– Reporting of AE
– Study records
– Investigator responsibilities (e.g., lack of control)
– Regulatory documentation
253 254
Session 3 Outline BE Basic Considerations
BA / BE Study Design Workshop • Key Objective:

– Compare product performance
• Delegations will be grouped into various working
teams • Minimize variability
• Each team will be asked to design a BA / BE study • Minimize bias
scheme for a specific drug product
• Team presentation & discussion
255 256
BE General Study Design When to Consider Multiple Dosing?
• Single-dose, two-period, crossover • Drug is too potent/toxic for administration in

• Healthy volunteers healthy volunteers
– Patients / no interruption of therapy
• Subjects receive each formulation once
• For extended/modified release products
• Adequate washout (ER/MR)
– Accumulation using recommended dosing interval
– In addition to single-
single-dose studies
• Non-linear pharmacokinetics at steady-state
(e.g., saturable metabolism)
• Assay not sufficiently sensitive for single-dose
study
257 258
Crossover vs. Parallel Designs Fasted or Fed?
• Testing suitable for Crossover Designs: • Fasted design preferred

– Intra-
Intra-subject comparison – Minimize variability not attributable to formulation
– Lower variability
– Better able to detect formulation differences
– Generally fewer subjects required
• Parallel design possible in: • Usually use Fed design when
– Drug with very long half-
half-life – Significant gastrointestinal (GI) disturbance caused by
– Crossover design not practical fasted administration
– Watch out: – Product labeling restricts administration to fed state
• Have enough subjects
• Have adequate sample collection
• Completion of Gastrointestinal transit / absorption process
• 72 hours normally sufficient
259 260
Questions?
Contact your speaker:

Wen Schroeder, RAC
President
SEKI Cosmeticals USA
261

Bioavailability & Bioequivalence Studies For Drug Products

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Bioavailability & Bioequivalence Studies For Drug Products

Diunggah oleh

Hak Cipta:

Format Tersedia

Day 1 Agenda

Kuala Lumpur, Malaysia

Global Top 10 Best Sellers

Brand Company Medical Use Approved

Expiring Generic Prescription Drugs Expiring Generic Prescription Drugs

Category Drug Name Year Category Drug Name Year

Allergy • Singulair • 2012 Epilepsy • Depakote • 2008

Category Drug Name Year • Leading Companies & Global Generics

Insomnia • Ambien • 2007

Source: The US Generic Drugs Industry Overview, Themedica 2009

Account for 84% total global generics sales

Year Market Size, US$ bn CAGR, %

Highest growth rate in major markets:

Global Generic Trend Emerging Market Leaders

Generic production is growing at a faster rate than India China

• Volatile time Key Market Trends & Outlook:

Asia-Pacific Pharma Highlight Asia-Pacific Pharma Highlight

Key Market Trends & Outlook: • Example “Philippines”

• Example “Philippines” • Significant risks still remain

ASEAN Pharma Situation Asia-Pacific Generic Market

• Net importers of pharmaceuticals

• General BA/BE Overview

Pharmacokinetic Terminology Plasma concentration time profile

Factors Affecting Oral Bioavailability Comparative BA

• Patient idiocyncracy • Dosage-form-related • Why do we do BA comparison?

• Objectives • Study design

New Formulation Development BA

• Study population • What is a Delayed-release product?

• Innovation product vs. Subsequent followers • Also called:

• Bioequivalence (BE): • Pharmaceutical Equivalence (PE) Criteria

Sometimes PE is NOT Enough Sometimes PE is Enough

• Therapeutic Equivalence (TE): • Aqueous solutions

• Suitable methods: • The deductive inference concept - Central to BE

Comparative BA for Generics – BE Studies Bioequivalence

• A full array of trials usually not needed for the reference

Glossary & Definitions

ASEAN Generic Situation BA BE Definitions

• Generic Registration • Pharmaceutical equivalence

• Bioavailability • What’s “essentially similar”?

Design & Conduct of Studies

Study Subjects Study Subjects

• Selection objective • When to consider including patients

Chemical Analysis Chemical Analysis Method Validation

• GLP standards • Two phases

• Calibration required • Reference product selection must be justified

• 90% Confidence Interval

AUC ratio 0.80 – 1.25

Cmax ratio 0.80 – 1.25

• Protocol • Comparative dissolution • Study title

ASEAN BE Study Reporting Format ASEAN BE Study Reporting Format

• Study Protocol • Pharmacokinetic Parameters & Tests

Singapore Example Singapore Example - Biowaiver

Sessions 3 - 4 • US FDA Example

• A generic drug is the same as a brand name drug in

Generics Approval Considerations

• Therapeutic Equivalnce = Brand Name Drug - Generic Drug –

Source: US FDA Brand Generic Review ANDA Refuse to

FDA evaluates the manufacturer's adherence to good manufacturing Acceptable N

FDA reviews the drug's labeling. PreApproval

Manufacturer must report adverse reactions and serious adverse health

FDA monitors drug quality after approval. 85 86

APPROVED DRUG PRODUCTS - US Orange Book

Electronic Orange Book - • All FDA approved drug products listed