Transcript Document 7288319

IV Pan-American Conference
BE PANDRH Working Group
Draft - Progress Report
Salomon Stavchansky PhD
Alcon Centennial Professor of Pharmaceutics
The University of Texas at Austin
College of Pharmacy
Austin, Texas 78712
[email protected]
PAHO -WHO. Dominican Republic March 2, 2005
Working Group
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Ricardo Bolanos
Silvia Giarcovich
Silvia Storpitis
Conrad Pereira
Lizzie Sanchez
Justina Molzon
Roger Williams
Regina Pezoa
*Helgi Jung
Lidiette Fonseca Gonzalez
*Ana Lucia Valle
Eugene Brown
Rosario D’Alessio
Sabbine Kopp – Kubel
Loreta Marquez
Irene Goncalves
Argentina
ALIFAR
Brazil
Health Canada
FDA - USA
FDA – USA
USP – USA
Chile
Mexico
Costa Rica
Guatemala
Jamaica
PAHO
WHO
FIFARMA
Venezuela
Genesis of PANDRH
The II Pan American Conference (November 1999)
established the Pan American Network for Drug
Regulatory Harmonization (PANDRH)
and rules and regulations for the Network and its
working groups.
According to those regulations, harmonized
proposals developed by the Working Groups are
to be presented at the Conferences for their
adoption or approval.
Mission of BA-BE PANDRH Working
Group
• to contribute to the development of
harmonized bioequivalence criteria for the
interchangeability of pharmaceutical
products in the Americas through the
promotion of technical bases to assure
interchangeability of multisource products,
within an international and a national
context, by proposing the establishment of
reference materials as comparators for
bioequivalence testing.
Regulatory Considerations
Pharmaceutical Quality
M ANUFACTURING
SAFETY
EFFICACY
Present NDA Regulatory Paradigm
CMC
M ANUFACTURING
Product release
Specifications
SAFETY
EFFICACY
PreClinical
Phase 1
Pre-Clinical and
Clinical Studies
in Humans
Phase 3
Phase 2
DISCOVERY
DEVELOPMENT
800 Million Dollars
DELIVERY
10 Years
Performance Tests
• Performance tests are measures that relate to drugproduct efficacy and safety
• What are the appropriate performance tests for a drug
product?
• Are performance tests necessary for control of drug
product quality?
• How do performance tests, surrogate markers and
specifications inter-relate?
•
What value can we expect from a performance test?
(Q of the product to its expiry date)
Public Health
ACCESS
POLICY
QUALITY
REGULATION
RISK TO BENEFIT
COST
CLEAR RECOMMENDATIONS
Present ANDA Regulatory Paradigm
Bioequivalence
Post Approval
Changes
cGMP’s
CMC
MANUFACTURING
SAFETY
?
EFFICACY
in vivo
?
in vitro
BCS
Factors to Consider for Bioequivalence
Requires a
Comparator
Product
Parent Compound
Metabolite(s)?
P’dynamic Response
SAMENESS
VARIABILITY
Single Dose
Multiple Dose
?
Highly Variable Drugs
Food effects
Narrow Therapeutic Index
Drugs w ith Long T50
Statistical
Test
Industry
Risk
Consumer
Risk
Background Documents
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Guidelines Published by the Food and Drug Administration
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Health Canada’s Guideline on Preparation of DIN Submissions
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WHO document (1999) entitled “Marketing Authorization of Pharmaceutical
Products with Special Reference to Multisource (Generic) Products: a
Manual for Drug Regulatory Authorities, Multisource (Generic)
Pharmaceutical Products: Guidelines on Registration Requirements to
Establish Interchangeability.”
•
ICH documents
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Note for Guidance on the Investigation of Bioavailability and
Bioequivalence, Committee for Proprietary Medicinal Products (CPMP), 26
July 2001 (CPMP/EWP/QWP/98)
•
WHO QAS/04.093 Draft Guidance – Working Document Revision #3,
September 13, 2004. Revision of the Multisource (Generic) Pharmaceutical
Products: Guidelines on Registration Requirements to Establish
Interchangeability
Therapeutic Equivalence of Multisource
Product
Therapeutic Equivalence can be assured when
the multisource product is:
pharmaceutically equivalent and
bioequivalent.
TE = PE + BE
The concept of interchangeability applies to:
1. - the dosage form and
2. - the indications and instruction for use.
COST
Equivalence Documentation
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Comparative bioavailability (bioequivalence) studies,
in which the active drug substance and/or one or
more metabolites is measured in an accessible
biologic fluid such as plasma, blood or urine.
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Comparative pharmacodynamic studies in humans.
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Comparative clinical trials.
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Comparative in vitro tests
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In vitro dissolution tests in combination with the
Biopharmaceutics Classification System
Oral Drug Products for which in vivo documentation of
equivalence is considered especially important
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(a) Oral immediate release pharmaceutical products with systemic
action when one or more of the following criteria apply:
•
(i)
Indicated for serious conditions requiring assured therapeutic
response;
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(ii) Narrow therapeutic window/safety margin, steep dose-response
curve;
•
(iii) Pharmacokinetics complicated by variable or incomplete absorption
or absorption window, nonlinear pharmacokinetics, presystemic
elimination/high first-pass metabolism >70%;
•
(iv) Unfavorable physicochemical properties, e.g., low solubility,
instability, metastable modifications, poor permeability, etc.,
•
(v) Documented evidence for bioavailability problems related to the
drug or drugs of similar chemical structure or formulations;
•
(vi)
Where a high ratio of excipients to active ingredients exists.
Oral Drug Products for which in vivo documentation of
equivalence is considered especially important
•
(b) Non-oral and non-parenteral pharmaceutical products designed to
act by systemic absorption (such as transdermal patches, suppositories,
etc.).
•
(c) Sustained or otherwise modified release pharmaceutical products
designed to act by systemic absorption.
•
(d)
•
(e) Non-solution pharmaceutical products which are for nonsystemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc. application)
and are intended to act without systemic absorption. In these cases, the
bioequivalence concept is not suitable and comparative clinical or
pharmacodynamic studies are required to prove equivalence. This does
not, however, exclude the potential need for drug concentration
measurements in order to assess unintended partial absorption.
Fixed combination products
USA Present Statistical Criteria
• Comparison between test and reference product
• Use natural log transformation of Cmax and AUC
• Criterion: 90% confidence intervals about geometric
mean test/reference ratios for both Cmax and AUC must
fall within 80 – 125%
• Applies to all systemically acting drugs (i.e., not locally
acting) with measurable blood or urine levels without
regard to the drug’s inherent variability
• Same criteria used by pioneer firms to support
formulation changes
Some International Criteria
Country/Region
AUC 90% CI
Criteria
Cmax 90% CI
Criteria
Canada (most drugs)
80 – 125%
none
(point estimate only)
Europe (some drugs)
80 – 125%
75 – 133%
South Africa (most drugs)
80 – 125%
75 – 133% (or broader
if justified)
Japan (some drugs)
80 – 125%
Some drugs wider than
80 – 125%
Worldwide (WHO)
80 – 125%
“acceptance range for
Cmax may be wider
than for AUC”
Comparator Product
•
The innovator product is usually the most logical comparator product.
Quality, safety and efficacy have been well assessed.
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If an innovator product cannot be identified or is not available in the market.
– What to do?
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The selection of the comparator product is usually made at the national level
by the drug regulatory authority. A national drug regulatory authority has in
principle three options:
– choose the innovator product which has been established for quality,
safety and efficacy (international comparator), or to
– choose the market leader for which the pharmaceutical quality, safety
and efficacy has been established (national comparator), or
– in the case the above are not available, the drug regulatory authority is
encouraged to consider a product available on another market, that has
been assessed for quality, safety and efficacy, and/or was chosen by
another national or a regional regulatory authority (regional specific
comparator).
•
It should be noted that a possibility exists for significant differences to
emerge between comparator products used in different countries.
Criteria recommended for waiver of evidence of in vivo
bioavailability or bioequivalence
• When multisource pharmaceutical are to be administered
parenterally (e.g., intravenous, intramuscular, subcutaneous,
intrathecal administration) as aqueous solutions and contain the
same active substance(s) in the same concentration and the same
excipients in comparable concentrations;
• (b) When multisource pharmaceutical products are solutions for
oral use, contain the active substance in the same concentration,
and do not contain an excipient that is known or suspected to
affect gastro-intestinal transit or absorption of the active substance;
• (c)
When multisource pharmaceutical products are a gas;
• (d) When the multisource pharmaceutical products are powders
for reconstitution as a solution and the solution meets either
criterion (a) or criterion (b) above;
Criteria recommended for waiver of evidence of in vivo
bioavailability or bioequivalence
• When multisource pharmaceutical products are otic or ophthalmic
products prepared as aqueous solutions and contain the same
active substance(s) in the same concentration and essentially the
same excipients in comparable concentrations;
• (f) When multisource pharmaceutical are topical products
prepared as aqueous solutions and contain the same active
substance(s) in the same concentration and essentially the same
excipients in comparable concentrations;
• (g) When multisource pharmaceutical are inhalation products or
nasal sprays, tested to be administered with or without essentially
the same device, prepared as aqueous solutions, and contain the
same active substance(s) in the same concentration and essentially
the same excipients in comparable concentrations. Special in vitro
testing should be required to document comparable device
performance of the multisource inhalation product.
BA-BE may be demonstrated by evidence obtained in
vitro in lieu of in vivo data. ( Waiver of in vivo Data)
• 1.- The drug product is in:
– the same dosage form
– in a different strength,
– is proportionally similar in its active and inactive
ingredients
– manufactured at the same site
• 2. Both drug products meet an appropriate in vitro test
approved by a Drug Regulatory Authority and/or
accepted reference pharmacopeias, or has
demonstrated in vivo – in vitro correlation ( e.g.,
correlation level A, etc)
BA-BE may be demonstrated by evidence obtained in vitro
in lieu of in vivo data. ( Waiver of in vivo Data)
• 3. Both drug products are proportionally similar in
their active and inactive ingredients.
• 4. The drug product is a reformulated product that is
identical, except for a different color, flavor, or
preservative that could not affect the bioavailability of
the reformulated product
• 5. Regulatory Authorities, for good cause, may
require evidence of in vivo bioavailability or
bioequivalence for any drug product
In Vitro Dissolution Profile Comparison.
Similarity Factor.
1
f 2  50 Log {[1 
n
n
2  0 .5
(
R

T
)
 t t ] x100 }
t 1
N = NUMBER OF SAMPLING TIME POINTS
Rt = REFERENCE VALUE (PRE CHANGE)
Rt = TEST VALUE ( POST CHANGE)
T = IS THE DISSOLUTION VALUE AT TIME t
f2 between 50 and 100 suggests similarity
also the average difference at any dissolution time point should not be
greater than 15% between products
f2 less than 50 doesn't necessarily mean lack of
similarity.
You may use a different method:
-- statistical analysis should be provided, e.g., 90% confidence intervals.
Special Consideration for Antiretroviral
Products
• At the present time, the BA-BE working group strongly
recommends that in the case of anti-retroviral drug
products, proof of pharmaceutical equivalence
and bioequivalence be required to infer
therapeutic equivalence. However, further
discussion is warranted.
Biopharmaceutics Classification System (BCS)
• BCS is a scientific framework for classifying drug substances (API’s)
based on their aqueous solubility and intestinal permeability.
•
•
•
•
Class 1: High Permeability
Class 2: High Permeability
Class 3: Low Permeability
Class 4: Low Permeability
-
High Solubility
Low Solubility
High Solubility
Low Solubility
• In addition, immediate release solid oral dosage forms are
categorized as having rapid or slow dissolution.
Basis of BCS
Dissolution of drug in vivo
SIMILAR IN VIVO DISSOLUTION
determines
Drug Concentration in
the Membrane Domain
SIMILAR IN VIVO ABSOPRTION
proportional
Intestinal Absorption
SIMILAR SYSTEMIC
AVAILABILITY
Drug
Permeability Class
Antipyrine
High (Potential IS candidate)
Caffeine
High
Carbamazepine
High
Fluvastatin
High
Ketoprofen
High
Metoprolol
High (Potential IS candidate)
Naproxen
High
Propranolol
High
Theophylline
High
Verapamil
High (Potential ES candidate)
Amoxicillin
Low
Atenolol
Low
Furosemide
Low
Hydrochlorthiazide
Low
Mannitol
Low (Potential IS candidate)
Methyldopa
Low
WHO Essential Drugs: Oral
WHO
325 Medicines
260 Drugs
123 Oral IR
US DRUGS
200 Drugs Products
141 Oral
43 On WHO List
Maximum Strength
Solubility mg/ml
Dose Number
clogP
LogP
pKa
Therapeutic Class
Kasim, N. A., et.al. Molecular Pharmaceutics, 1, 85, (2004)
Solubility Classification
Percentage of immediate-release oral drugs
80.0
High Solubility Drugs
70.0
WHO
US
60.0
50.0
40.0
30.0
20.0
10.0
0.0
Dose number ≤ 1.0
Solubility ≤ 0.1 mg/ml Solubility ≤ 0.01 mg/ml
Source: Amidon, G.L Personal Communication
No solubility
information
Solubility Conclusions
• Majority of Drugs (67%) are High
Solubility (Do<1)
• Similar on WHO and FDA lists
• A Dissolution BE test is the best test
What is the question?
Is it advisable to grant bio-waivers
based on BCS and in vitro
Dissolution? If it is advisable,
when to grant the bio-waiver?
Waiver of in vivo studies…
Not waiver of bioequivalence
Immediate Release Products.
Solubility Considerations
•
highest dose strength of an IR product
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A drug substance is considered highly soluble when
the highest dose strength is soluble in 250 ml or
less of aqueous media over the pH range of 1-7.5
•
The volume estimate of 250 ml is derived from typical
BE study protocols that prescribe administration of a
drug product to fasting human volunteers with a glass
(about 8 ounces) of water.
PROPOSED DRUG CLASSIFICATION BY
G. AMIDON, et-al Pharm. Res. 12,3(1995)
HIGH PERMEABILITY I
HIGH PERMEABILITY II
HIGH SOLUBILITY
LOW SOLUBILITY
LOW PERMEABILITY
LOW PERMEABILITY
HIGH SOLUBILITY
LOW SOLUBILITY
III
IV
HIGH PERMEABILITY
EXTENT OF ABSORPTION
>>90%
HIGH SOLUBILITY
DOSE mg/ml/250 ml
Do= SOLUBILITY mg/ml
Do <1 HS
pH = 1 – 6.8 ?
Immediate Release Products.
Solubility Considerations
•
The permeability class boundary is based indirectly on
the extent of absorption (fraction of dose absorbed,
not systemic BA) of a drug substance in humans
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a drug substance is considered to be highly
permeable when the extent of absorption in
humans is determined to be 90% or more of an
administered dose.
Permeability Methods
• (1) in vivo intestinal perfusion studies in humans;
• (2) in vivo or in situ intestinal perfusion studies using
suitable animal models;
• (3) in vitro permeation studies using excised human or
animal intestinal tissues; or
• (4) in vitro permeation studies across a monolayer of
cultured epithelial cells.
Where are we going?
– Waiver of In Vivo Bioequivalence Study
Requirements
• Waiver Based on the Pharmaceutical Dosage
Form (Solutions)
• Waiver Based on the Biopharmaceutics
Classification System
• Waiver Based on the Dose. (Highest Strength
should be tested)
Waiver of in vivo BA and BE for IR products
based on BCS
• BCS Class 1:
- Highly Soluble (Highest dose soluble in 250
ml in water over pH range of 1.2 - 6.8
- Highly Permeable (Extent of absorption
greater than 85%)
- Rapidly dissolving (Basket at 100 rpm,
paddle at 50 rpm in 900 ml of pH
1.2, and 6.8 buffer)
• For a waiver of BE, the test and the reference
product should exhibit similar dissolution
profile, f2 criteria
Proposal Discussed with Professor Amidon
BCS
Class
Drug
Solubility
pH 1.2
Drug
Solubility
pH 6.8
Drug
Permeability
Preferred Procedure
I
High
High
High
>85% Dissolution in 15
min., pH = 6.8.
II-A
High
Low
High
>85% Dissolution in 15
min., pH = 1.2
High
>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%.
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%.
II-B
II-C
Low
Low
High
Low
Stavchansky’s Proposal
BCS
Drug Solubility
Class pH 1.2 and pH 6.8
I
II
III
and
IV
High
Low
Drug Permeability
Preferred Procedure
High
>85% Dissolution in
45 min., pH = 6.5
High
>85% Dissolution in
45 min., pH = 6.5
4 pt dissolution
profile, F2 > 50. If
needed, add
surfactant and
justify, use lowest
amount
I am not ready to endorse in
vitro dissolution in lieu of in
vivo studies
No Food-BE
studies, IR.
Forms, Class I
Intestinal Transporters
• Mrp2 Multidrug resistance associated protein 2
• Pept 1 Oligopeptide transporter
• Oatp 3 Intestinal organic anion transporting
polypeptide 3
• OCT 1 Organic cation transporter
• CNT Nucleoside transporter N1 (purine) N2
(Pyrimidine)
• MDR1 Multidrug resistance protein 1
• BCRP Breast cancer resistance protein
Metabolites and Bioequivalence
•
The Concentration-time profile of the parent drug is more sensitive to
changes in formulation performance than a metabolite, which is more
reflective of metabolite formation, distribution, and elimination.
•
When may Metabolite concentrations be necessary:
– The measurement of concentrations of therapeutically active
biotransformation product is essential if the substance studied is a prodrug.
– If an active metabolite is formed as a result of gut wall or other
presystemic metabolic process(es) and the metabolite contributes
meaningfully to safety and/or efficacy, it is recommended that both
the metabolite and the parent drug concentrations be measured.
– Measurement of a metabolite may be preferred when parent drug
levels are too low to allow reliable analytical measurement in blood,
plasma, or serum for an adequate length of time or when the parent
compound is unstable in the biological matrix.
•
It is important to note that measurement of one analyte, drug or metabolite,
allows the risk of making a Type-I error (the consumer risk) to remain at
the 5% level
Drugs with Long Half-Life
•
A single dose cross-over pharmacokinetic bioequivalence study provided an
adequate wash-out period is used.
•
If the cross-over study is problematic, a pharmacokinetic bioequivalence
study with a parallel design can be used.
•
sample collection time should be adequate to ensure completion of
gastrointestinal transit (approximately 2 to 3 days) of the drug product and
absorption of the drug substance.
•
Blood sampling up to at least 72 hours should be carried out, unless
shorter periods can be justified. However, subject variability should be low
•
The number of subjects should be derived from statistical calculations but
generally more subjects are needed for parallel study design compared with
cross-over study design.
•
Powering parallel studies depends on between-subject variability, not
within-subject variability
Highly Variable Drugs in the
Context of Bioequivalence
• To date, there is no regulatory definition
for these drugs or drug products. Any drug
whose rate and extent of absorption
shows large dose-to-dose variability
within the same patient
• Commonly understood to include those
drugs whose intrasubject coefficient of
variation (Cmax and/or AUC) is
approximately 30% or more
Concerns with HVD
• Resources - Cost of studies due to the
large number of subjects required for a
bioequivalence study to be able to pass
the “goalpost”
• Ethical concerns because exposing so
many healthy subject to drugs
• Potential failure of the reference product
Examples of Highly Variable Drugs
• atorvastatin, esomeprazole, pantoprazole,
clarithromycin, paroxetine (CR),
risedronate, metaxalone, itraconazole,
balsalazide, acitretin, verapamil,
atovaquone, disulfiram, erythromycin,
sulfasalazine.
Why Current 80-125% Criteria Are
Not Appropriate For HVDs
• dose-to-dose variability within a patient is much
larger than the width of the criteria
• HVDs are “wide therapeutic index” drugs – i.e.,
have shallow dose response curves, and wide
safety margins
• One Size Does Not Fit All !!!!!!
Recommendation for HVD
• The confidence interval reflects the degree of consumer
risk (Type I error) A reduction in the level of confidence
from 90% to 85%, implies a possible increase in the
consumer risk
• In contrast, the width of equivalence limits represents the
allowable boundary for the ratio (or difference) of the
means between products in comparison. Statistically,
widening the bioequivalence limits can be accomplished:
– through expansion of the allowable boundary or
– by scaling the criteria based on the high variability of the
reference product.
– by using sequential designs
Critical dose drugs
• "Critical dose drugs" are defined as those
drugs where comparatively small
differences in dose or concentration lead
to dose- and concentration-dependent,
serious therapeutic failures and/or adverse
drug reactions which may be persistent,
irreversible, slowly reversible, or life
threatening event
Factors to be Considered for
Critical Drugs
• serious dose-dependent adverse effects exist close to
the dosing range
• narrow therapeutic range or narrow tolerance range
• requirement for blood level monitoring to control and
individualize treatment; this is the standard of care or
normal condition of use
• dosing based on body weight, body surface area, or
other highly individualized dosing requirements
• serious clinical consequences of overdosing (toxicity) or
under-dosing (lack of effect)
• steep dose response relationship for efficacy and/or
toxicity
When to, and not to conduct Food Effect
• When both test product and Comparator product are
rapidly dissolving, have similar dissolution profiles,
and contain a drug substance with high solubility and high
permeability (BCS Class I) or
• When the Dosage and Administration section of the
Comparator product states that the product should be
taken only on an empty stomach, or
• When the Comparator Product label does not make any
statements about the effect of food on absorption or
administration.
When to, and not to conduct Food Effect
For complicated Drugs in Immediate-Release Dosage
Forms (e.g., narrow therapeutic range drugs (drugs with a
steep dose –response curve, critical drugs), highly toxic
drugs and drugs known to have non-linear
pharmacokinetics).
For Modified Release Products, Controlled Release Products
Recommendation:
Bioequivalence must be demonstrated under both
fasted and fed conditions.
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