Transcript ALIMTA - Insynergy Pharmaceuticals

Regulatory Requirements for
Pharmaceutical Generics
MFPD Conference
Montreal June 21, 2010
Eric Ormsby
Therapeutic Products Directorate
Outline
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History of bioequivalence
Regulations to support generic drugs
Guidance relevant to generic drugs
Proposed changes to guidance
History of bioequivalence in
Canada
• Research done in HC labs in 60s indicated generics
could be accepted based on blood levels
• 1967 Harley Parliamentary report on drug costs
recommended compulsory licensing
• 1969 Amendment to the Patent Act allows
compulsory licensing
• First developed country to allow generics
• First generic => Valium (diazepam)
• Special Advisory Committee established in 1974 to
provide recommendations on scope and data
requirements
History con’t
• Expert Advisory Committee re-established for
1986-1993 and provided recommendations in
reports A, B, C
• Report A => Conduct and Analysis of
Bioequivalence Studies (1992)
• Report B => Modified-release Dosage
Formulations (1996)
• Report C => stayed as a report – complicated
PK drugs and PD studies
History con’t
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1989 Bio-international conference in Toronto
1990 Crystal City meeting on Bioanalytical validation
1993 Patent Act amended to respect existing patents
1995 Abbreviated New Drug Submission regulations
2002- present - Scientific Advisory Committee
established to provide recommendations on revisions
to guidances
• January 2010 – two guidances issued for
consultation => combines 11 guidances
Regulations
C.08.002.1.- Abbreviated New
Drug Submission (ANDS)
(1) A manufacturer of a new drug may file an ANDS for the
new drug where in comparison with the Canadian
reference product (CRP),
(a) the new drug is the pharmaceutical equivalent of the
CRP;
(b) the new drug is bioequivalent with the CRP, based on
the pharmaceutical and, where the Minister considers it
necessary, bioavailability characteristics;
(c) the route of administration of the new drug is the
same as that of the CRP; and
(d) the conditions of use for the new drug fall within the
conditions of use for the CRP.
C.08.002.1.(2)Regulation Con’t
• Safety and effectiveness
- evidence of pharmaceutical equivalence
- information on the CRP
- when needed bioavailability characteristics
that are bioequivalent with the CRP through
bioavailability, pharmacodynamic or clinical
studies
Canadian Reference Product
• Defined in regulation as
(a) a drug in respect of which a NOC is issued
pursuant to Section C.08.004 and which is marketed in
Canada by the innovator of the drug
(b) a drug, acceptable to the Minister, that can be
used for the purpose of demonstrating bioequivalence
on the basis of pharmaceutical and, where applicable,
bioavailability characteristics, where a drug in respect of
which a NOC has been issued cannot be used for that
purpose because it is no longer marketed in Canada, or
(c) a drug, acceptable to the Minister, that can be
used for the purpose of demonstrating bioequivalence
…. in comparison to a drug referred to in paragraph (a).
Pharmaceutical Equivalent
• Defined in regulations as:
a new drug that, in comparison with
another drug, contains identical amounts
of the identical medicinal ingredients, in
comparable dosage forms, but that does
not necessarily contain the same nonmedicinal ingredients.
Guidances
Use of Foreign Reference
Product
• Requirements for using a foreign reference
product instead of the product on the Canadian
market are given in the Policy entitled:
Canadian Reference Product
- must be simple dosage form
- drug must have simple PK
- other criteria such as dissolution testing,
labelling, manufacturer, etc
Identical medicinal ingredients
• What can be considered identical is defined
in the policy document entitled: Interpretation
of “Identical Medicinal Ingredient”
- hydrated forms are identical
- unsolvated and solvated forms are identical
with supporting data
- different complexes (esters, salts, etc) are
non-identical
- different isomers are non-identical
Bioequivalence
• Comparative bioavailability study
- almost always measured by collecting
blood levels over time after dosing in fasted
volunteers on two separate occasions the test
and reference formulations in a crossover
design
• Comparative pharmacodynamic study
- must be a measure which directly relates
to action of the drug (FEV1, acid reduction)
• Comparative clinical endpoint study
Biowaivers
• Solutions - these products do not need
bioavailability data only chemistry and
manufacturing data
• Proportional Dosage Forms
- only one strength in a dosage line
needs to show bioequivalence if they
are proportional
- must have similar dissolution rates
Proposed 2 new guidances
Guidance 1: Conduct of
Bioequivalence Studies
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GMP
GCP
A well designed study
Must control type I error at 5%
Validated bioanalytical method
Validated statistical methods and programs
Appropriate standards met
Food studies
• Currently: only fed study for complicated
kinetics and MR formulations
• Proposal: for certain IR formulations and for
all MR formulations
• Issue: no problems identified with current
standard but when innovator PM states food
effect or lack of one how should this be
applied to subsequent-entry product?
Metabolites
• Currently: unclear when metabolites can be
used to determine BE
• Proposal: BE to be determined on the drug
which was formulated, if not possible then
metabolite, preferably a primary metabolite.
Metabolite must be justified and stated in
protocol (can use metabolite as a covariate)
• Why: It is the formulated drug that is being
absorbed
Guidance 2:
Standards
• All standards in one document
• No complicated vs uncomplicated drugs
• Offer points to consider for
pharmacodynamic studies
Bioequivalence intervals
• These have been redefined with
increased precision from e.g. 80% to
80.0%
• Only affects rounding off
Potency Correction
• Currently: BE must be shown in both the
observed data as well as after potency
correction
• Proposal: Only require analysis on observed
concentrations … but potency content should
be within 5% of reference
• Why: 5% rule should keep test and reference
formulations comparable
Steady-state studies for MRs
• Currently: steady-state study required
when accumulation is indicated in
single-dose study
• Proposal: remove requirement
• Why: steady-state does not give any
better comparison of the two
formulations
The basic standard for most
drugs
• The 90% confidence interval for the
mean geometric ratio of AUCt must be
between 80.0-125.0% , and,
• Mean geometric ratio of Cmax must be
between 80.0-125.0%
Critical Dose Drugs
• The 90% confidence interval for the
mean geometric ratio of AUCt must be
between 90.0-112.0% , and,
• The 90% confidence interval for the
mean geometric ratio of Cmax must be
between 80.0-125.0%
• Fed and fasted states
• Any drugs need to be added to list????
Combination products
• Each drug in a combination must meet
its own standard
Time to onset important
• The 90% confidence interval for the
mean geometric ratio of AUCt and
Cmax must be between 80.0-125.0% ,
and,
• Mean geometric ratio of AUCreftmax must
be between 80.0-125.0%
• Is there a better measure for rate????
Long Half-life drugs
• terminal elimination half-life >24 hours
• The 90% confidence interval for the
mean geometric ratio of AUC0-72 must
be between 80.0-125.0% , and,
• Mean geometric ratio of Cmax must be
between 80.0-125.0%
Non-linear drugs
• Currently: draft guidance states what dose to
use and that fed and fasted studies should be
run, non-linearity determined from literature
• Proposal: same only for highly soluble drugs
possible waiver for fed study
• Why: the fed study does not provide any
addition information for a non-linear highly
soluble drug
• Do we need a fed study at all ????
Highly Variable Drug Products
• HVDP has greater than 30% intra-subject CV
• Should we allow a wider bioequivalence
interval for HVDP?????
• Some issues:
- HVDP or a Highly Variable Study
- should the single study determine BI
- influence of outliers
Endogenous substances
• Adjustment for baseline based on the
average of three pre-dose concentrations
• negative results set to zero
• Positive values found after a negative value
past Cmax should also be set to zero
• Analysis of distribution of zeros between
formulations suggested
Urine data
• Unchanged drug only
• 90% CI for relative mean AeT should be
within 80.0 and 125.0 %
• Relative mean Rmax should be within
80.0 and 125.0 %
• Are these appropriate????
Thank you for your attention…
Send comments on guidances and
other issues to
[email protected]
Hope to receive many thoughtful
comments and proposals