PERSPECTIVE FOR REVIEW
OF CDSCO - B.A. / B.E. STUDY GUIDELINES
1. Applicability of this guidance document:
i
Prospective/Retrospective
: Whether
this document will have effect only on Drug Applications that are received
after its notification or data will be solicitated
for products that are already in the market.
ii
Applicable for:
o
All
products otherwise justified scientifically or
o
Products
that have been identified as problematic and all new products or
o
All
products (new or old) having characteristics identified as problematic or
o
All
new products or
o
All
new products otherwise justified scientifically or
o
All
new products having characteristics identified as problematic
iii
Applicability for post approval
changes in approved products :
Whether
the guidance document will be applicable for changes in the formulation and
manufacturing process that are made after approval.
If yes, do we
have the mechanism to ensure that all manufacturers disclose their true formula
and manufacturing process in the License application and will disclose all
subsequent changes made.
iv
Whether feasible to write in two
parts:
o
Certain
aspects as law
o
Elaborate
methodology as guideline
2.
Comparator
product:
How do we
define the Comparator product for comparing the bioavailability
? Should it be the :
o
Innovator
product marketed in the inventor country
o
Innovator
product marketed in
o
All
approved products
o
Product(s)
first approved in
o
Listed
reference products
·
Manufacturer
doing “Bridging Clinical Trials” in
·
If
this guidance is applicable for all new applications (whether for ‘New’ or
‘Old’ drugs), which one will be the comparator product for old drugs. For
example, if we solicit bioequivalence study for a marketing application for a
new gresiofulvin formulation (which is known to have
significant bioavailability problems), what will be the comparator product for
the same since we are not confident about the performance of formulations that
are already in the market)
3.
Ongoing
Survelliance:
4. Batch Size of Test Product:
o
Need
not be specified
o
Pilot
scale batch
o
Pilot
scale batch – at least 10,000 tablets
o
Pilot
scale batch, 1/10th the size of the proposed production batch or
100000 tablets which ever is more.
5. Fed state bioavailability studies:
o
Not
required
o
Required
in case of NDA and not SNDA
o
Required
in case the product has shown some food interaction
o
Required
for all modified release products
o
Required
unless both test & reference products are:
§
Rapidly
dissolving (BCS-I)
§
If
labeling indicates that the product is to be taken on empty stomach or no
mention of food effect
6. Design and conduct of study:
No. of volunteers/subjects :
o
Should
the number be defined such as – 12, 18, 24…
o
Statistically
significant number
o
Statistically
significant number but not less than 12
o
Not
less than 12
7. Subject selection:
o
Subjects
could belong to either sex
o
Subjects
should belong to either sex
8. Volume of fluid for ingestion of samples
o
At
least 150ml but should be constant for all
o
200
ml
o
240
ml
9.
Comparative
dissolution profile
Should we ask for :
o
Comparative
dissolution profile as complimentary to bioequivalence study.
o
Comparative
dissolution profile as complimentary to bioequivalence study, with
in-vitro-in-vivo correlation
o
Comparative
dissolution profile for Biowaivers only
10. Criteria for Biowaivers
:
Should we adopt
the Biopharmaceutical Classification of Drugs and give biowaivers
for BCS Class I drug (highly soluble and highly permeable drugs formulated as
Rapid dissolving formulations).
In case we go
ahead with the same,
·
Do
we ask for the manufacturer to prove that it is a Class I drug or scientific
publications providing proof of it being a Class I drug will be acceptable.
·
will it be feasible for manufacturers in our country to carry out the
permeability studies in Cell lines like CACO2 Cells.
11. Bioequivalence study in case of different
strength formulations
o
Highest
strength to be used
o
Only one strength required and choice should be based on analytical,
pharmacokinetic and safety grounds.
12.
Whether
the following need to be included in the Guidance document :
·
Requirements
for Clinical Centre conducting Bioavailability / Bioequivalence studies.
·
Details
regarding :
o
Bioanalytical method validation
o
In-Vitro
drug dissolution methodology
o
Biopharmaceutical
Classification System and Biowaivers
o
Statistical
methodology for Data evaluation
Proposed
Contents for the Bioavailability / Bioequivalence Guidelines
2.
Glossary
/ Terminology / Definitions
3.
Applicability
for :
o
o
NDA
o
SNDA
o
Post
approval changes
4.
Facilities
for conducting BA/BE Studies
5.
Design
and Conduct of Studies
A.
Orally
administered drug products
i
Pharmacokinetic
Studies
o
General
considerations
o
Study
design
o
Study
population
o
Bioanalytical methodology
o
Pharmacokinetic
parameters
o
Statistical
evaluation
ii
Pharmacodynamic Studies
iii
Comparative
Clinical Trials
iv
In-vitro
Studies
o
Dissolution
testing for immediate release products
o
Dissolution
testing for modified release products
B.
Non-oral
Drug Products
o
Dosage
forms for topical application
o
Dosage
forms for nasal administration
6.
Biowaivers
7.
Documentation
8.
Maintenance
of records of BA/BE studies
9.
Retention
of BA/BE samples
10.
Special
Topics
o
Food
effect bioavailability studies
o
Individual
and population bioequivalence
o
Narrow
therapeutic range drugs
Topics not
covered in the existing
Draft Guidelines on Bioavailability / Bioequivalence
1.
Bio-waivers
based on established scientific principles
2.
Applicability
for :
o
o
NDA
o
Post
‘Market Authorisation’ changes in formulations
3.
Design
and Conduct of BA / BE Studies for Non-Oral drug products
4.
Pharmacodynamic studies as means to evaluate BA/BE
5.
Comparative
clinical trials as means to evaluate BA/BE
6.
In-vitro
drug release studies as means to evaluate BA/BE
7.
Maintenance
of records of BA/BE studies
8.
Retention
of BA/BE samples
9.
Special
Topics
o
Food
effect bioavailability studies
o
Individual
and population bioequivalence
o
Narrow
therapeutic range drugs
Documents
which may be consulted for drafting Bioavailability / Bioequivalence Guidelines
for
I. Indian Documents
|
||
|
1. |
Draft guidelines for Bioavailability / Bioequivalence
studies on conventional and extended release dosage forms. |
Draft BE Studies Document for Peer Review.doc |
|
2. |
GCP Guidelines (www.cdsco.nic.in) |
Indian Good Clinical Practices.htm |
|
II. WHO Documents (www.who.int) |
||
|
1. |
Multisource
(Generic) Pharmaceutical Products: Guidelines on Registration Requirements to
Establish Interchangeability. |
Multisource generics.htm |
|
2. |
Guidance on the selection of comparator pharmaceutical
products for equivalence assessment of interchangeable multisource
(generic) products |
Comparator.pdf |
|
III. USFDA
Documents (www.fda.gov) |
||
|
1. |
21CFR320: Bioavailability and bioequivalence
requirements |
21CFR320.htm |
|
2. |
Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products — General Considerations (Issued 10/2000) |
3615fnl.pdf |
|
3. |
Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products — General Considerations (Draft-Issued 7/2002) |
4964dft.pdf |
|
4. |
Statistical Approaches to Establishing Bioequivalence (Issued 2/2001) |
3616fnl.pdf |
|
5. |
Waiver of In Vivo Bioavailability and Bioequivalence
Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. (Issued 8/2000) |
3618fnl.pdf |
|
6. |
Bioanalytical Method Validation (Issued 5/2001) |
4252fnl.pdf |
|
7. |
Dissolution Testing of Immediate Release Solid Oral
Dosage Forms (Issued 8/1997) |
1713bp1.pdf |
|
8. |
Extended
Release Oral Dosage Forms: Development, Evaluation, and Application of In
Vitro/In Vivo Correlations (Issued
9/1997) |
1306fnl.pdf |
|
9. |
Food-Effect Bioavailability and Fed Bioequivalence
Studies (Issued 12/2002) |
5194fnl.pdf |
|
10. |
Bioavailability and Bioequivalence Studies for Nasal
Aerosols and Nasal Sprays for Local Action (Draft - Issued 6/1999) |
2070dft.pdf |
|
11. |
Bioavailability and Bioequivalence Studies for Nasal
Aerosols and Nasal Sprays for Local Action –
Statistical Information for In Vitro Bioequivalence Data (Draft - Issued 8/1999) |
2070stat.pdf |
|
12. |
In Vivo Bioequivalence Studies Based on Population and
Individual Bioequivalence Studies (Draft - Issued
10/1997) |
1716dft.pdf |
|
13. |
In Vivo Bioequivalence Studies Based on Population and
Individual Bioequivalence Studies - Bioequivalence Studies Data and Detailed Statistical
Methodology (Draft - Posted 02/1998) |
index.htm bioequiv.zip |
|
14. |
SUPAC-IR: Immediate-Release Solid Oral Dosage Forms:
Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In
Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation |
cmc5.pdf |
|
15. |
SUPAC-MR: Modified Release Solid Oral Dosage Forms
Scale-Up and Postapproval Changes: Chemistry,
Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo
Bioequivalence Documentation (Issued
06/1997) |
1214fnl.pdf |
|
16. |
SUPAC-SS:
Nonsterile Semisolid Dosage Forms; Scale-Up and
Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro
Release Testing and In Vivo Bioequivalence Documentation (Issued
5/1997) |
1447fnl.pdf |
|
IV. EMEA Documents
(www.eudra.org) |
||
|
1. |
Note For Guidance on the Investigation
of Bioavailability and Bioequivalence |
140198en.pdf |
|
2. |
Note For Guidance on Modified
Release Oral and Transdermal Dosage Forms: Section
II (PharmacoKinetic and Clinical Evaluation) |
028096en.pdf |
|
3. |
Note for Guidance on Fixed
Combination Medicinal Products |
024095en.pdf |
|
4. |
Note for Guidance on the Clinical
Requirements for Locally Applied, Locally Acting Products containing Known
Constituents |
023995en.pdf |
Comments on the Draft
Guidelines on Bioavailability / Bioequivalence
1.
Introduction
:
1.2 Justification
for an ER formulation – Not required
1.3 Need for Bioeq. Studies for ER products – Not required
1.4 Labelling requirements – Not required
Checklist
of activities for Auditors – May be given as an appendix
2.
Definitions
:
2.2 Bioequivalence
– Needs to be redefined
2.35 Bibliography
– Not required at this point
3. Organization :
3.1
Legal
identity – Appropriate statuatory body should be
defined
3.4 Documented
SOPs: List need not be given
3.6
No.
of Volunteers required has been mentioned as 12 which may not be statistically
appropriate.
It
has been mentioned (which need not be mentioned) that additional space for
should be provided:
§
Wet
chemical lab
§
Instrumentation
lab
§
Library
§
Computers
4.
Protocol
:
4.2 Objective
of the study – Reason for choosing the innovator product – Not required
4.3 Drug information : Not required
5.
Protocol
and study design for Extended release dosage forms :
5.1 Requirements
for studies – Need to be redefined
5.2.1 to 5.2.5 – Can be same as
for conventional dosage forms
5.2.14 Statistical
Analysis - Needs to be redefined
6.0
Methodology
- Needs to be redefined
9.0 In-vitro dissolution - Needs to be
redefined
13.0 Waiver requirements – Need to be redefined