Republic of the Philippines
Department of Health
Food and Drug Administration
QPIRA Training Workshop on Drug Registration for Human Use
Regulatory Requirements in
Bioequivalence Studies
Presented by:
Willison John E. De Luna
Pharmacist II
08 May 2014
1
Presentation Outline
- Definition of Terms
- Purpose of BE Study
- Regulatory Requirements and Legal Basis
- Conducting a BE Study
- Future Direction/s
2
Important Terminologies
3
Definition of Terms
Bioavailability
- the rate and extent to which the active
substance or therapeutic moiety is absorbed
from a pharmaceutical form and becomes
available at the site of action.
4
Definition of Terms
Bioequivalence
- if the bioavailabilities (i.e. rate and extent
of absorption) of the test and reference
formulation after administration in the
same molar dose are similar to such
degree that their effects, with respect to
both efficacy and safety, will be
essentially the same.
5
Definition of Terms
Bioequivalence Study
- a comparative bioavailability study
designed to establish the equivalence
between the test and reference
formulation.
6
Definition of Terms
Comparator Product
- is a drug product with which a multi-source
pharmaceutical product is intended to be
interchangeable in clinical practice.
- aka reference drug
7
Definition of Terms
Comparator Product
- Innovator product registered in the country
- Alternatively, the market leader or the
generic product registered after the
innovator
8
Definition of Terms
Comparator Product
ASEAN Selection Criteria
(as agreed in the 13th ACCSQ-PPWG Meeting)
• Innovator product, and multiple
manufacturing sites of the same innovator
registered in the country are acceptable as
the reference drug.
9
Definition of Terms
Comparator Product
• If the reference drug cannot be identified,
the choice must be made carefully and be
comprehensively justified by the applicant.
10
Definition of Terms
Comparator Product
• Order of Preference
– Approval in International Conference on
Harmonization (ICH) member and
associate member countries
– Pre-qualified by the World Health
Organization (WHO)
11
Definition of Terms
Generic Product
- aka
• Multisource pharmaceutical product
• “me too”
• copy drug
- is a pharmaceutical equivalent or
alternative that may or may not be
therapeutically equivalent.
12
Definition of Terms
Generic Product
• In the BE Study, this is the test drug
• Must be manufactured by a GMP-certified
manufacturer
• Should originate from a batch 1/10 of
production scale or 100,000 units
whichever is greater
• The batch where BE studies samples were
taken is called biobatch.
13
Definition of Terms
Pharmaceutical Equivalents
- are drug products containing the same
molar amount of the same API in the
same dosage form, and are intended to
be administered by the same route.
14
Definition of Terms
Pharmaceutical Alternatives
- if drug products contain the same molar
dose of the same AP moiety/ies but
differ in dosage form, and/or chemical
form (e.g. esters, salts).
- deliver the same active moiety by the
same route of administration.
15
Definition of Terms
Therapeutic Equivalents
- A medicinal product is therapeutically
equivalent with another product if it
contains the same active substance or
therapeutic moiety and, clinically shows the
same efficacy and safety as that product,
whose efficacy and safety has been
established.
- PE/PA + Satisfactory BE Study = TE
16
Definition of Terms
Interchangeable Pharmaceutical Product
- one which is therapeutically equivalent to
the comparator product and can be
interchanged with it in clinical practice.
17
Definition of Terms
Biowaiver
- applies to a regulatory drug approval
process when the dossier is approved based
on evidence of equivalence other than
through in vivo equivalence testing.
- Usually by in vitro multipoint comparative
dissolution testing (profile)
18
Definition of Terms
Biowaiver
• Comparative Dissolution Profile
– 12 units each of the test and reference drugs
– Taken at specified interval for each individual
dosage unit
– A graphic representation of the mean dissolution
profiles for the test and reference drugs in the 3
media at pH 1.2, 4.5 and 6.8, as per WHO Technical
Report Series No. 937, 2006.
– Computation of the similarity factor (f2)
19
Definition of Terms
Biopharmaceutics Classification System
(BCS)
• Based upon their aqueous solubility and
intestinal permeability
• 3 major factors for the BA of IR oral solid
dosage forms
- Aqueous solubility
- Intestinal permeability
- Dissolution
20
Definition of Terms
Biopharmaceutics Classification System
(BCS)
• Class 1: High solubility, High permeability
e.g. Paracetamol, Amoxicillin
• Class 2: Low solubility, High permeability
e.g. Phenytoin sodium, Ibuprofen
• Class 3: High solubility, Low permeability
e.g. Atenolol, Ethambutol HCl
• Class 4: Low solubility, Low permeability
e.g. Glibenclamide, Cefixime 21
Why is there a need to
conduct BE Studies?
22
Purpose of BE Studies
- To prove that products can be substituted
for each other without any adjustment in
dose or other additional therapeutic
monitoring
- The most efficient method of assuring TE
(therapeutic equivalence) is to assure that
the formulations perform in an equivalent
manner
→ thru BE Studies
23
Legal Basis for the Requirement
of BE Studies
24
Legal Basis
Administrative Order No. 67 s. 1989
- Revised Rules and Regulations on
Registration of Pharmaceutical Products
• Under Annex I - Specific Requirements:
“Bioavailability/Bioequivalence study for
certain drugs as determined by BFAD.”
25
Legal Basis
Bureau Circular No. 01 s. 1997
- Enforcement of the Requirement for
Bioavailability Studies for Registration
of Products Included in the List B’
(Prime) under Administrative Order No.
67 s. 1989
• Drugs requiring strict precaution in
prescribing and dispensing contained in
the List B’ (Prime) shall be required
bioavailability/bioequivalence studies.
26
Legal Basis
Bureau Circular No. 2006-008
- Lifting of Moratorium on the Conduct of
Bioavailability/Bioequivalence Studies
for Selected Pharmaceutical Products
• Requirement of BA/BE studies covers 11
drug molecules, in addition to Rifampicin.
• BFAD-prescribed format of a BE Study
Report
27
Legal Basis
Bureau Circular No. 2006-008
11 Drug Molecules:
- Atenolol - Nifedipine
- Diltiazem - Phenytoin
- Gliclazide - Propranolol
- Metformin - Pyrazinamide
- Metoprolol - Theophylline
- Nicardipine
28
Legal Basis
Administrative Order No. 2012-024
- Amendment of A.O. No. 50 s. 2001 Covering Fees
and Charges for Accreditation of Bioequivalence
Testing Centers and Private Testing
Laboratories, as well as, Audits and Inspections
• Bioequivalence testing center accreditation –
Php20,000 per year [from Php10,000 per year]
• GCP/GLP audit of bioequivalence testing center –
Php15,000 + transportation cost (with per diem of
each inspector if facility is outside Metro Manila)
[from Php5,000]
29
BA/BE Testing Center
Inspection & Accreditation
• Accredited bioavailability/bioequivalence testing
centers in the Philippines:
- CeDRES, Inc.
- DLSHSI-Center for Biopharmaceutical Research
- United Laboratories BA Unit
- UP Manila Toxicology BA Unit
(in the process of re-accreditation)
• Testing centers are inspected to determine their
compliance to GCP and GLP principles.
30
Legal Basis
FDA Circular No. 2013-0014
- List of Products Requiring Bioavailability/
Bioequivalence (BA/BE) Studies as Part of the
Application for Marketing Authorization in
Addition to Rifampicin and the 11 Products
Listed in Bureau Circular No. 2006-008
31
Legal Basis
FDA Circular No. 2013-0014
- Expansion of the requirement of BE
Studies to cover:
• BCS Class 4 drugs (low solubility, low
permeability)
• BCS Class 2 drugs (low solubility, high
permeability) not eligible for biowaiver
• Modified-release products for oral
administration designed to act systemically
• Subsequent generic products after the patent of
the innovator has expired (unless biowaiver can
be supported) 32
Legal Basis
FDA Circular No. 2013-0014
- Certain drug products may avail of biowaiver
based on the aqueous solubility and
intestinal permeability of the API, and
dissolution performance of the dosage form:
• BCS Class 1 drugs (high solubility, high
permeability)
• BCS Class 2 drugs (low solubility, high
permeability) with weak acidic properties
• BCS Class 3 drugs (high solubility, low
permeability)
33
Legal Basis
WHO Biowaiver Testing Procedure
- By multipoint comparative dissolution testing
- For drug products with BCS Class 1 APIs
• Rapidly dissolving: >85% dissolution is required
within 30 minutes in standard media at pH 1.2, 4.5 and
6.8 using paddle apparatus at 75 rpm or basket
apparatus at 100 rpm; comparison of the dissolution
profiles of the comparator and test drugs by f2 (>50);
or
• Very rapidly dissolving: >85% of the API is released
from the comparator and test drugs within 15
minutes; profile comparison is not required.
34
Legal Basis
WHO Biowaiver Testing Procedure
- For drug products with BCS Class 3 APIs, a
biowaiver can be considered only if both the
comparator and test drugs are very rapidly
dissolving:
• >85% of the API is released from the comparator and
test drugs within 15 minutes in standard media at pH
1.2, 4.5 and 6.8 using the paddle apparatus at 75 rpm
or basket apparatus at 100 rpm; profile comparison is
not required.
35
Legal Basis
WHO Biowaiver Testing Procedure
- For drug products with BCS Class 2 APIs
with weak acidic properties (i.e. high
solubility in pH 6.8 but not in pH 1.2 or
4.5, and with high permeability), a
biowaiver can be considered if the test
drug is rapidly dissolving:
36
Legal Basis
WHO Biowaiver Testing Procedure
Rapidly dissolving
• >85% of the API is released within 30
minutes in standard media at pH 6.8 using the
paddle apparatus at 75 rpm or basket
apparatus at 100 rpm; and
• Exhibits similar dissolution profile by f2 (>50)
with the comparator drug in buffer media at
all 3 pH values (pH 1.2, 4.5 and 6.8).
37
Legal Basis
FDA Circular No. 2013-0014
Other Provisions:
- For studies conducted abroad:
• Copy of valid Certificate of Accreditation of
the testing center demonstrating
compliance to Good Clinical Practice (GCP)
and Good Laboratory Practice (GLP)
principles shall be provided.
• The accreditation certificate shall be issued
by the governing drug regulatory authority
or a third party accrediting body.
38
Legal Basis
FDA Circular No. 2013-0014
Other Provisions:
- Use of comparator drug from multiple
manufacturing sites may be allowed provided
in vitro equivalence can be demonstrated.
- A list of comparator drugs shall be determined
by FDA.
- Report submission shall follow the ASEAN
Bioequivalence Study Reporting Format.
39
Legal Basis
FDA Circular No. 2013-0014
Other Provisions:
- Implementation time frame:
• From 01 July 2013 – BCS Class 4 drugs
• From 01 January 2014 – All remaining
product categories
40
Legal Basis
Also provided for in:
ASEAN Common Technical Dossier (ACTD)
- Part II: Quality
• Section P9: Product Interchangeability/
Equivalence Evidence
ASEAN Common Technical Requirements
(ACTR)
- ASEAN Guidelines for the Conduct of
Bioavailability and Bioequivalence Studies
41
Legal Basis
Other relevant laws and regulations:
• Bureau Circular No. 2006-008-A
- Amendment of/Supplemental guidelines to
Bureau Circular No. 2006-008
• Bureau Circular No. 13-A s. 1999
- Moratorium on the Conduct of
Bioavailability/ Bioequivalence Studies for
Pharmaceutical Products Included in the
List B’ (Products with Reported Problems
on Bioavailability/ Bioequivalence
42
How are BE Studies
conducted?
43
Conducting a BE Study
1. Preparation of study protocol
2. Approval of the study protocol by the
Institutional Review Board
(IRB)/Independent Ethics Committee
(IEC)
44
Conducting a BE Study
• Investigators should have appropriate
expertise, qualifications and competence to
undertake a proposed study and should be
familiar with pharmacokinetic theories
underlying bioavailability/bioequivalence
studies.
• Must follow the ICH E6: Harmonized
Tripartite Guideline on Good Clinical Practice
– Main principle: Protection of the welfare of human
subjects
45
Conducting a BE Study
3. Recruitment and screening of subjects or
volunteers before they participate in the
study
46
Conducting a BE Study
Subject/Volunteer Criteria
- Not less than 12
- Healthy male and/or female
- BMI: 18-30
- 18-55 years old
- Can give informed consent
- Screened by lab tests, medical history
- Without history of smoking and
drug/alcohol abuse
47
Conducting a BE Study
4. Administration of test and reference
products by the subjects in separate
periods with random assignment
• Usually single dose, two-period, two-
sequence, cross-over, randomized design
• Washout period
• ≥ 5 half-lives of the drug; min. 7 days
48
n=12
Subject Group Period I Period II
Group 1 (n=6) Reference Test Drug
Sequence: Drug Washout
Reference then Period
test drug (around 7
days)
Group 2 (n=6) Test Drug Reference
Sequence: Test Drug
then reference
drug
49
Conducting a BE Study
5. Taking of biological samples
(blood/urine) and analyzing for drug
concentration levels
50
Conducting a BE Study
Sampling
- adequate estimation of Cmax and AUC
- long enough to provide a reliable estimate of
drug absorption
AUC0-t: at least 80% AUC0-inf
- should continue for at least 3 or more
terminal t1/2 of the drug
- at least 1-2 sampling points before Cmax, 2
points around Cmax, and 3-4 points should be
obtained during the terminal log-linear phase
if need to estimate of terminal t1/2
51
Concentration-Time Curve
90
80
Concentration (ng/mL )
70
60
Test/Generic
50
Reference/Brand
40
30
20
10
0
0 5 10 15 20 25 30
Time (hours)
52
Conducting a BE Study
6. Pharmacokinetic (PK) parameters are
obtained from resulting concentration-
time curve
• Area under the curve (AUC)
• Cmax
• Tmax
53
Basic Pharmacokinetic (PK)
Parameters To Be Assessed
• AUC = area under the curve (shows the
extent of absorption)
– AUC0-t - from time zero to time t (referring
to the last sampling point)
– AUC0-inf - from time zero to time infinity
• Cmax = maximum plasma concentration
(reflects the rate and extent of
absorption)
54
Basic Pharmacokinetic (PK)
Parameters To Be Assessed
• Tmax = time of achieving maximum
plasma concentration (reflects the rate
of absorption)
• T1/2 = half-life; the time it takes for the
body to decrease the concentration of
the drug by 50%
55
Concentration-Time Curve
56
Concentration-Time Curve
57
Concentration-Time Curve
58
Conducting a BE Study
7. PK parameters are then statistically analyzed
to determine if the test and reference products
yield comparable values
– Involves the calculation of CI for the ratio
(or difference) between the test and
reference product PK variable averages
– Limits of the observed CI must fall within
the predetermined range for the ratio (or
difference) of the product averages
59
Acceptance Criteria
for BA/BE Studies
• Accepted ranges for the main PK
characteristics are:
AUC-ratio: 0.8 – 1.25, 90% CI
Cmax-ratio: 0.8 – 1.25, 90% CI
60
Conducting a BE Study
8. Reporting of results
- Recommended format is divided into two main
parts: clinical and analytical data
- Clinical aspect should give the complete
documentation of the protocol, conduct and
evaluation complying with GCP.
- Analytical report should include the results for
all standard and control samples,
chromatograms, validation of the bioanalytical
procedure, etc.
61
Biowaiver for In vivo BA/BE Studies
• Examples:
– IV solutions for injection
– Gases
– Topical solutions
– Oral solutions
– Different proportional strength of an oral
solid dosage form with demonstrated BE
62
Dose Proportionality in Immediate
Release Oral Dosage Form
• For a product with several strengths, BE study
may be done on only 1 strength and is
acceptable under these conditions:
– The products are manufactured by the
same manufacturer and process;
– The drug has been shown to be linear over
the therapeutic dose range;
– The qualitative composition of the different
strengths is the same (except in the case of
flavors/colors);
63
Dose Proportionality in Immediate
Release Oral Dosage Form
– The ratio between amounts of API and
excipients is the same or;
– In case of preparations containing a low
concentration of the active substance (less
than 5%), the ratio between the amounts of
excipients is similar
– The dissolution profile should be similar
for additional strengths and the strength of
the batch used in BE study
64
What is the future
direction of the regulation?
65
Future Direction
• BE Study Requirement shall cover
products with systemic action other
than oral solid dosage forms such as:
– Orally inhaled powders
– Transdermal patches
– Nicotine chewing gums
66
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