SCIENTIFIC ADVISORY COMMITTEE ON BIOAVAILABILITY AND BIOEQUIVALENCE
RECORD of PROCEEDINGS
Teleconference
November 6, 2003
| Therapeutic Products Directorate Note: Until such time as final
recommendations are made and policy is developed and published, current
bioequivalence requirements remain unchanged. |
Committee Members Present: Dr. J. Thiessen (Chair),
Dr. R. Herman, Dr. F. Jamali, Dr. R. Nair,
Dr. E. Palylyk-Colwell, Dr. W. Racz, Dr. K. Renton,
Dr. W. Riggs, Dr. D. Sitar, Dr. F. Varin,
Mr. S. Walker
Regrets: Dr. A. Donner
Health Canada (HC) Scientific Advisory Committee Working Group
Members:
M.M. Bernard (BMORS), L. Carter (CTSAP), L. Cockell (DBE),
M. Davis (SAC Secretariat Officer, PB), E. Ormsby (PB),
C. Pereira (SAC - BB Scientific Advisor, PB),
C. Simon (DBE)
HC Observers: L-N Cui (DBE), C. Ficker (DBE),
J. Gordon (DBE), A. Makinde (DBE), S. Stojdl (DBE),
A. Tam (DBE), P. Wielowieyski (DBE)
Abbreviations for Health Canada Directorates, Bureaux, Divisions and
other terms used in this record:
BA = Bioavailability
BB = Bioavailability & Bioequivalence
BE = Bioequivalence
BMORS = Bureau of Metabolism, Oncology and Reproductive Sciences
CTSAP = Clinical Trials & Special Access Programme
DBE = Division of Biopharmaceutics Evaluation (BPS)
HC = Health Canada
HPFB = Health Products and Food Branch
PB = Policy Bureau
SAC = Scientific Advisory Committee
TPD = Therapeutic Products Directorate
| Discussions during this teleconference centered on a draft policy
statement on the use of metabolite data in bioequivalence studies
and associated questions posed by HC to the SAC members. This record
summarizes the final outcome and consensus reached by the members. |
Item 1 - Opening remarks, (Jake Thiessen)
Item 2 - Presentation of HC questions (Eric Ormsby)
The draft policy was introduced. It reflects current practice, although
we do not have a published policy on the use of metabolite data in bioequivalence
studies. Statements in current guidelines are not clear. Several questions
remain to be resolved.
Item 3 - Deliberation (Jake Thiessen)
Before addressing the draft policy and specific questions raised by the
TPD, the Chair invited general comment on the issue. Some of the comments
were:
- With unstable drugs such as acetylsalicylic acid, it may be necessary
to measure the metabolite/breakdown product, in this case salicylic
acid.
- Parent compound is the best if it can be measured (even if it is a
pro-drug)
- Measurement of the parent compound may be a problem when the drug
has very short half-life, where concentrations of the parent drug are
too low to be measured reliably.
- Use of metabolite data may be acceptable if it reduces variability
with highly variable drugs i.e. it may improve the quality of the bioequivalence
assessment.
- If the parent drug can be satisfactorily assessed, then it should
be the choice
Item 4 - Final recommendations (Jake Thiessen)
- What is meant by "reliably measurable"? This question
includes the issue of duration, i.e., if the parent drug concentrations
can be measured for just 2 hours, is that an adequate length of time?
No consensus was reached on a definition of "reliable" in
this context. It was suggested that if a company claimed that a drug
was not reliably measurable they would have to provide an acceptable
justification for the claim.
It was suggested that the analytical method used should be able to cover
80% of the AUCinf expected based on literature data.
The method should be able to provide drug concentration versus time
profiles that allow valid calculation of the relevant kinetic parameters/bioequivalence
metrics.
State-of-the-art technology should be used where possible. Older validated
methods could be used if they suited the purpose of bioequivalence assessment.
- How to deal with situations where 'bracketing' studies must be
done, i.e., studies on high and low strengths where it may be possible
to measure parent drug with the high dose but not with the low dose?
Is it acceptable to use the parent in one case and the metabolite in
the other?
It is acceptable to use the parent drug with the high dose and a metabolite
with the low dose if the parent cannot be reliably measured after the
low dose.
It was reiterated that the analyte to be studied must be established
a priori
- Under what, if any, circumstances would use of metabolite data
be acceptable even though the parent drug concentrations are measurable?
This question was not specifically addressed. However, from the discussion
it may be concluded that an acceptable a priori justification for the
use of metabolite data instead of parent drug data could be provided
even though the parent drug is measurable. For example, the parent drug
concentrations may be measurable but too low to allow valid calculation
of the relevant kinetic parameters /bioequivalence metrics.
- If metabolite data is to be used, does it have to be an active
metabolite? If so, why?
The metabolite does not have to be an active one. It should be a
primary (first step), major metabolite. In addition if there is a
choice between two primary metabolites, one being the precursor of
an active species and the other not, either metabolite may be used.
- If metabolite data is to be used, does it have to be a major metabolite?
(If so, what is meant by 'major')? Or can any primary metabolite
be used?
Any primary (first step) metabolite can be used. A major metabolite
(one present in the largest quantities) would presumably be easier
to measure and would have the highest reliability in testing differences
between the products.
- How to deal with submissions where both parent and metabolite
data have been provided but the protocol does not specify which moiety
is to be used for bioequivalence assessment?
If the use of metabolite data instead of parent drug data has not
been adequately justified a priori and stated clearly in the protocol,
the parent drug data should be used.
- Are there cases where it would be necessary to base the BE determination
on BOTH parent and metabolite data? For example, one author suggests
that the parent/metabolite ratio is important in assessment of BE for
amiodarone.
The committee did not have time to discuss this question specifically.
However, the discussions did not present any compelling reasons to
ever measure both parent and metabolite concentrations in the assessment
of bioequivalence.
The committee agreed with the wording of the draft policy statement
with the following exception:
In paragraph 3 the sentence
"The choice of using the parent drug or a metabolite is to
be clearly stated, a priori, in the objective of the study
in the study protocol."
should be changed to read:
"The choice of using the metabolite instead of the parent drug
is to be clearly stated, a priori, in the objective of the
study in the study protocol."
Item 5 - Announcements/next meeting (Eric Ormsby)
A stakeholder workshop and SAC meeting are being tentatively arranged
for June 2004. The topics for the meeting have not yet been decided.
Item 6 - Adjourn (Jake Thiessen) 3:05 PM
Prepared by: Marilyn Davis & Conrad Pereira (2004-01-28)
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