Bioequivalence studies:
Regulatory Requirements on Conduct &
Documentation of BE.
Guidance & Experience.
Meeting on WHO Prequalification Programme on Priority
Essential Medicines, WHO/EMRO
6-7 June 2007, Cairo, EGYPT
Dr Lembit Rägo
Coordinator
Quality Assurance and Safety: Medicines (QSM)
Medicines Policy and Standards (PSM)
WHO Headquarters, Geneva, Switzerland
ragol@who.int
1
History. One of the medicine's
most celebrated clinical trials.
Wood engraving from 1885 showing a
young patient receiving an anti-rabies
vaccine developed by Louis Pasteur. A
physician administers the vaccine while
Pasteur, a chemist, looks on.
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What are the problems with BE studies (I)?
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BE studies – small scale clinical trials
Lack of appropriate regulations
Lack of ethical review/ review capacity
Local industries may not have the experience and
resources
Lack of regulatory capacity
 Lack of financial resources
 Lack of adequately trained human resources
Copying ICH GCP and other relevant documents from
ICH regions alone does not solve the problems
(regulations do not stand in vacuum…)
…
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What are the problems (II)?
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CROs increasing in middle-income developing countries
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Local CROs and branches of international CROs
Recent sever problems with CROs revealed by WHO
inspections (in the framework of WHO prequalification
programme) in some developing countries
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WHO Glossary
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Contract Research organization (CRO): A scientific organization
(commercial, academic or other) to which a sponsor may transfer
some of its tasks and obligations. Any such transfer should be
defined in writing.
Good Clinical Practice (GCP): A standard for clinical studies which
encompasses the design, conduct, monitoring, termination, audit,
analyses, reporting and documentation of the studies and which
ensures that the studies are scientifically and ethically sound and
that the clinical properties of the pharmaceutical product
(diagnostic, therapeutic or prophylactic) under investigation are
properly documented.
Good Laboratory Practice (GLP)*: A quality system concerned with
the organisational process and the conditions under which nonclinical health and environmental safety studies are planned,
performed, monitored, recorded, archived and reported
(OECD/WHO) *as applied to human bioanalysis studies
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Handbook for Good Clinical Research Practice (GCP)
World Health Organization 2005
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Structured as 14 principles, 115 pages
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Serves as and adjunct to WHO's GCP
from 1995, and subsequent ICH GCP
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Contains CD version with all major
reference documents as hyperlinks
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Bioequivalence studies
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Products to be prequalified usually multisource
(generic) products
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Therapeutic equivalence generally demonstrated by
bioequivalence study in CROs
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Findings of deficient and discrepant bioequivalence
data and non-compliance with norms and standards
for GCP (WHO) and GLP (WHO GPNPCL, and
OECD/WHO as appropriate)
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What resources are available to assist proper
conduct of BE studies from WHO (I)?
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Multisource (generic) pharmaceutical products: guidelines on
registration requirements to establish interchangeability (1)
Proposal to waive in vivo bioequivalence requirements for WHO Model
List of Essential Medicines immediate-release, solid oral dosage forms
(2)
Additional guidance for organizations performing in vivo bioequivalence
studies (3)
Guidance on the selection of comparator pharmaceutical products for
equivalence
assessment of interchangeable multisource (generic) products (4)
"Note to applicants on the choice of comparator products for the
prequalification project” (see WHO PQ web site - 5)
WHO Public Inspection reports of CROs (see PQ web site - 6)
WHO Training courses (see materials of previous courses on PQ web
site)
… advise to manufacturers applying for prequalification
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WHO Documents

The Expert Committee
documents pass wide
international consultation
and are finally adopted by
the Committee composed
of outstanding inernational
technical experts
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1
1.1
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1.2
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2
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3.1
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3.2
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4
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5
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6.1
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6.2
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What is WHO doing re ETHICS?
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Operational Guidelines for Ethics Committees that Review
Biomedical Research (TDR/PRD/ETHICS/2000.1)
http://www.who.int/tdr/publications/publications/pdf/ethics.pdf
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Surveying and Evaluating Ethical Review Practices: a
complementary guideline to the Operational Guidelines for Ethics
Committees that Review Biomedical Research (PUB:
TDR/PRD/ETHICS/2002.1)
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http://www.who.int/tdr/publications/publications/pdf/ethics2.pdf
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CRO inspections - areas covered
Clinical
General organization, the protocol, protection of trial subjects,
responsibilities of the investigator, responsibilities of the
sponsor/monitor, record-keeping and handling of data, handling
and accountability for pharmaceutical products, quality
assurance for the conduct of a clinical trial
Bio-analytical
Apparatuses/material/reagents, SOPs, performance of the
study, test and reference items, storage and retention of records
and materials, quality assurance
PK analysis and statistics
Reporting
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Examples of findings
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Based on CRO inspections performed by WHO
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Inspections study-specific
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Team of 3 inspectors (2 WHO team + national inspector as
observer)
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Based on 6 CROs inspected
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Findings. General organization.
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Transfer of responsibilities from sponsor to CRO not
documented
Unclear procedure for assigning Subject ID (two subjects
assigned the same ID on the Attendance Sheet Form!)
No SOP for drug dispensing
No SOP for assigning study numbers
No trial site staff sample signature log for the study
Organization chart not readily available, no version date
No QC system to ensure accuracy and consistency in recording
and document control
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Findings. The protocol (II)
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Validity of screening tests?
No CRFs designed for the study (raw data not transferred to
CRFs)
Not included:
Name and address of sponsor
Description of trial site and information on investigators
Method and procedure of randomisation, randomisation
schedule and how it was established
Method and timing of subject allocation to investigational groups
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Findings. The Protocol, cont. (III)
Not included:
 Information to volunteers (informed consent)
 Procedures for maintaining subject identification code list
 Statistical justification for the number of subjects
 Method for measuring blood pressure - sitting or supine? And if
both, which value to use…
 Type of test tubes for blood sampling
 PK analysis; Method of calculating PK pararmeters, e.g. AUC,
how to deal with deviations from planned sampling times
 How to evaluate the results, including statistics and how to
handle withdrawals
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Responsibilities of the Sponsor/Monitor
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No monitors appointed by the sponsor. No
monitoring/audit reports available.
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No evidence of assessment of the trial site (labs,
equipment, staff, facilities)
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Audits performed by the sponsor, but scheduled after the
report was issued and no audits' reports available
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Issues with certificate of insurance subscribed by the CRO
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Record-keeping and handling of data
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No study or protocol number on ECGs to link them to the study.
Of 95 ECGs copied by inspectors, 43 appeared to have been
recorded from one subject, 21 from a second subject and 11 from
a third subject (i.e. in total 75 ECGs from 3 persons!).
For several subjects the "screening" and "follow up" ECGs
appeared to have been recorded from different subjects
No mention on ECG print outs of the identity of the equipment
used
Some ECGs had no date of birth of subject
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Doubts as to the authenticity of ECG documentation!
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Record-keeping and handling of data
(continued)
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No mention of name, batch no or expiry date of the in vitro diagnostic
serology test kit in source doc's or lab data
Discrepancies between Attendance Sheet Forms and CRF Screening
pages (screening visit dates)
Discrepancies between Volunteer Card and CRF (smoking/alcohol)
Unclear dosing time
Identical (actual) blood sampling times for two subjects!
Recordings of actual sampling times - same handwriting, however
initials of phlebotomists different at different sampling times!
Deviations from planned blood sampling times not reported
Inconsistencies in screening dates
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Record-keeping and handling of data (continued)
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Deliberate attempt to change subject code
Discrepancies between source documents and study report
Method/procedure of randomization not documented
No record of subjects screened
Source documents not kept
Original entry erased!
Type of tubes and anticoagulant used not documented
CRF (IPΦ) used was not specific to the study
Errors on the CRFs
Expiry date of medications not recorded on CRFs
Appearance of tablets incorrectly described
Missing: Lab data, ECG…
Final study report not signed by the monitor
…
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Bioanalytical. Test and reference items
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Batch numbers of reference substances used not
documented – were the batches used, those for which CAs
were available?
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Not possible to verify purity of reference substances used!
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Reporting.
(OECD GLP 2 & 9)
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Same or different stock solution for calibration/control
samples?
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Some zidovudine conc's were lamivudine conc's
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Discrepancy between concentration on chromatogram and
in study report
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Composition of buffer for sample preparation not in SOP
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Errors in the bioanalytical report
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Rounding errors
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What is WHO doing regarding Ethics?


Operational Guidelines for Ethics Committees that Review
Biomedical Research (TDR/PRD/ETHICS/2000.1)
http://www.who.int/tdr/publications/publications/pdf/ethics.pdf

Surveying and Evaluating Ethical Review Practices: a
complementary guideline to the Operational Guidelines for Ethics
Committees that Review Biomedical Research (PUB:
TDR/PRD/ETHICS/2002.1)

http://www.who.int/tdr/publications/publications/pdf/ethics2.pdf
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BSC based bio-waiver: a long way from
concept to practice
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1995 FDA – SUPAC guidance
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1996 WHO – Interchangeability guideline - cautious and vague
attitude
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1999 WHO – "Blue book" – cautious recognition of BCS potential,
no change in reserved position
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2000 FDA – Guidance on BA and BE waiver based on BCS, deals
with INDs/NDAs, ANDAs and post-approval changes
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2001 EU – Note for guidance on BA and BE – takes BCS into
consideration
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2006 WHO – Interchangeability guideline and specific BCS
guideline proposing the implementation of BCS approach
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WHO Technical Report Series, No. 863, 1996
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Annex 9
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Multisource (generic) Pharmaceutical Products:
Guidelines on Registration Requirements to Establish
Interchangeability.
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WHO Technical Report Series, No. 863, 1996
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Annex 9, Part III – Tests for equivalence
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Section 13: In vitro dissolution
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Comparative in vitro dissolution studies may be useful in
the documentation of equivalence between two
multisource pharmaceutical products. However because
of the many limitations associated with the use of in vitro
dissolution in the documentation of equivalence it is
recommended in these guidelines that its application for
this purpose should be kept to a minimum.
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WHO Technical Report Series, No. 863, 1996
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Annex 9, Part III, Section 13: In vitro dissolution
In vitro dissolution testing … should be reserved for rapidly
dissolving drug products. When the multisource test and
reference products both dissolve with sufficient rapidity
(e.g. >80% in 15 minutes) their in vivo equivalence may be
presumed. Approval of multisource formulations by the
use of comparative in vitro dissolution studies should be
based on the generation of comparative dissolution
profiles rather than single-point dissolution tests …
Multiple dissolution test conditions and physiologically
relevant media are recommended.
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Chronology of BCS implementation
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1995 FDA – SUPAC guidance
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1996 WHO – Interchangeability guideline - cautious and vague attitude

1999 WHO – "Blue book" – cautious recognition of BCS potential, no
change in reserved position

2000 FDA – Guidance on BA and BE waiver based on BCS, deals with
INDs/NDAs, ANDAs and post-approval changes

2001 EU – Note for guidance on BA and BE – takes BCS into
consideration

2006 WHO – Interchangeability guideline and specific BCS guideline
proposing the implementation of BCS approach
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WHO Technical Report Series, No. 937, 2006
Annex 7
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Multisource (generic) pharmaceutical products: guidelines
on registration requirements to establish interchangeability.
Intended to provide recommendations to sponsors and
national regulatory authorities on in vivo and vitro
requirements to assure interchangeability of
multisource medicinal products without compromising
quality, safety and efficacy.
http://www.who.int/medicines/publications/pharmprep/TRS_
937.pdf
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WHO Technical Report Series, No. 937, 2006
Annex 7
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Section 9: In vitro testing
Over the past three decades, dissolution testing has
evolved into a powerful tool for characterising the
quality of oral pharmaceutical products. The
dissolution test … is now emerging as a surrogate
equivalence test for certain categories of orally
administered pharmaceutical products. For these
products (typically solid oral dosage forms containing
APIs with suitable properties) a comparative in vitro
dissolution profile similarity can be used to document
equivalence of a multisource with a comparator product.
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WHO Technical Report Series, No. 937, 2006
Annex 7
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Section 9: In vitro testing
9.1 In vitro testing and the Biopharmaceutical Classification
System
9.1.1 Biopharmaceutics classification system
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High solubility
High permeability
9.1.2 Determination of dissolution characteristics of
multisource products in consideration of a biowaiver
based on BCS
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Very rapidly dissolving
Rapidly dissolving
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WHO Technical Report Series, No. 937, 2006
Annex 7
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Section 9: In vitro testing
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9.2 Qualification for a biowaiver based on BCS
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9.2.1 Dissolution criteria for biowaivers based on the BCS
according to the properties of active pharmaceutical
ingredients
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WHO Technical Report Series, No. 937, 2006
Annex 8
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Proposal to waive in vivo bioequivalence requirements for
WHO Model List of Essential Medicines immediate-release,
solid oral dosage forms".

Intended to give national regulatory authorities
information on orally administered APIs on WHO Model
List of Essential Medicines whether biovaiwer can be
granted for generic formulations.

http://www.who.int/medicines/publications/pharmprep/TRS_9
37.pdf
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WHO Technical Report Series, No. 937, 2006
Annex 8
WHO revisions to the criteria for BCS classification
 High solubility: max 250ml at 37C over pH 1.2-6.8
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FDA - pH 1-7.5
EMEA - pH 1-8, preferably 1, 4.6 and 6.8
Highest strength (dose): according to Essential Medicines
List (14th EML 2005)
Permeability: absorbed at least from 85%
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FDA - 90% or more
EMEA – linear and complete absorption
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WHO Technical Report Series, No. 937, 2006
Annex 8
WHO extensions to the scope of application of biowaiver
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Class I APIs classification criteria relaxed - both solubility and
permeability
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Class II weak acidic APIs eligible for biowaiver, if
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soluble in 250 ml or less at pH 6.8
rapid dissolution at pH 6.8
similar dissolution profiles (f2) to comparator at pH 1.2, 4.5 and 6.8
Class III APIs eligible for biowaiver, if very rapid dissolution
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BCS according to WHO
Solubility at pH 1-6.8
Absorbed
>85%
CLASS I
Highly permeable
Highly soluble
(very rapid dissolution
or profile comparison)
Eligible
CLASS II
Highly permeable
Poorly soluble
Eligible only if the
D:S at pH 6.8 is 250ml or
lower*
CLASS III
Poorly permeable
Highly soluble
Eligible if very
rapidly dissolving
CLASS IV
Poorly permeable
Poorly soluble
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Not eligible
WHO Technical Report Series, No. 937, 2006
Annex 8
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3 Tables of APIs
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non-complementary orally administered EML APIs
complementary EML APIs
newly /2005/ classified APIs
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In case of incomplete data APIs classified conservatively
("worst case" approach)
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Potential risks, indications (EML) and comments included
to support risk assessment and decision making
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WHO Technical Report Series, No. 937, 2006
Annex 8
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Conclusions
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QUALITY first, only then BE
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For many developing country manufacturers BE studies a
"bottleneck"
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Need to start implementing BSC based biowaiver in PQ
Programme step-by-step

Need for additional guidance and training re BE and
BSC/dissolution based biowaiver
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