Transcript Options for establishing bioequivalence

Multisource (generic) products
and Interchangeability
Training Workshop on Dissolution,
Pharmaceutical Product Interchangeability
and Biopharmaceutical Classification System.
Hotel Bratislava
1 Malyshko Street
Kyiv, Ukraine
Date: 25 to 27 June 2007
WHO Prequalification Programme
June 2007
Multisource (generic) products
and Interchangeability
Options for Establishing Bioequivalence
according to New WHO Guidance
Presenter:
Vinod P. Shah, Ph. D.
FIP Scientific Secretary
North Potomac, MD 20878, USA
E-mail: [email protected]
WHO Prequalification Programme
June 2007
Regulatory Authority
Mission
“Assure that
SAFE and EFFECTIVE
drugs are marketed in the
country and are available
to the people”
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Bioavailability and Bioequivalence
 BA and BE are generally required for approvals of
comparator and multisource drug products.
 BE based on blood level determination of Cmax and AUC
has become the most commonly used and successful
biomarker for safety and efficacy of the drug product.
 BE products can be substituted for each other without any
adjustment in dose or other additional therapeutic
monitoring.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Outline
 Definitions
 Documentation of Bioequivalence
 Study design
 Biowaiver
 Conclusion
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Bioequivalence
Two pharmaceutical products are bioequivalent if they are
pharmaceutically equivalent or pharmaceutical
alternatives, and their bioavailabilities, in terms of peak
(Cmax and Tmax) and total exposure (area under the curve
(AUC)) after administration of the same molar dose under
the same conditions, are similar as to such a degree that
their effects can be expected to be essentially the same.
Ref: WHO Technical report series, No. 937, 2006. Annex 7.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Bioequivalence
 What is Bioequivalence?
– Comparison of two products with respect to rate and extent of
drug availability.
 Why do Bioequivalence?
– For product approval and to use as a substitute for brand name
product (interchangeability)
 When do you do Bioequivalence?
– To establish BE between clinical batch and to-be-marketed batch
– To compare BA between the comparator and multisource products
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Multisource Pharmaceutical Product
 Therapeutic equivalence of a multisource product can be
assured when the multisource product is both
pharmaceutically equivalent / alternative and bioequivalent.
 Concept of interchangeability includes the equivalence of
the dosage form as well as for the indications and
instructions for use.
TE = PE + BE
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Biowaiver
The term biowaiver is applied to a regulatory drug
approval process when the dossier (application) is
approved based on evidence of equivalence other than
through in vivo equivalence testing.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Equivalence Test
A test that determines the equivalence between the
multisource product and the comparator product using
in vivo and/or in vitro approaches.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Pharmaceutical Equivalence
 Products are pharmaceutically equivalent if they contain
- the same molar amount of the same API,
- the same dosage form,
- if they meet comparable standards, and
- are intended to be administered by the same route.
 Pharmaceutical equivalent does not necessarily imply
therapeutic equivalence, as differences in the excipients
and/or the manufacturing process and some other
variables can lead to differences in product performance.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Approaches to Determine Bioequivalence
 Comparative pharmacokinetic studies in humans
- API and/or its metabolite measurement in biological fluid
such as blood, plasma, serum or urine to obtain PK
measures such as AUC and Cmax.
 Comparative PD studies in humans
 Comparative clinical trials and
 Comparative in vitro tests
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
When Equivalence Studies are
Not Necessary
 Parenteral preparations – aqueous solutions
 Solutions for oral use
 Powders for reconstitution as a solution
 Gases
 Otic or ophthalmic products prepared as aqueous solutions
 Topical products prepared as solutions
 Aqueous solutions for nebulizer inhalation or nasal sprays
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
When Equivalence Studies are Necessary
 Oral Immediate Release products
–
–
–
–
Critical use medicines
Narrow therapeutic range drug products
Documented BA or BE problems related to API
Scientific evidence suggesting polymorphs of API, excipients,
and/or process affecting BA
– Non-oral, non-parenteral products designed to act systemically
 Oral Modified Release products
 Fixed-combination products with systemic absorption
where at least one of the API requires an in vivo study
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
In Vivo Studies
 In vivo documentation of equivalence through either
- Comparative Pharmacokinetic study
- Comparative Pharmacodynamic study
- Comparative Clinical trial
 In vivo documentation of equivalence is needed when
there is a risk that possible differences in bioavailability
may result in therapeutic inequivalence.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Choice of Comparator Product
 Nationally authorized innovator
 WHO Comparator product
 ICH et al. innovator product
 Well selected comparator product
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WHO Prequalification Programme
June 2007
Pharmacokinetic Study - Pilot Study
 Generally performed in a smaller number of subjects
- To validate analytical methodology
- To assess variability
- To optimize sample collection time intervals,
 In case of modified release dosage form
– To determine the lag time and
– To assure that there is no dose dumping.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Pharmacokinetic Bioequivalence Study
 Crossover study design (T and R products) in 24-36 subjects
 Average BE based on 2 products, 2 period, 2 sequence
 Study protocol with adequate washout period,
12 to 18 samples (3 or more terminal half lives)
 Sample analysis (Bioanalytical method validation)
 PK analysis – Cmax and AUC
 Log transformed AUC and Cmax data analyzed by ANOVA
 90% Confidence Interval on geometric mean ratio of T and R product,
must be within BE limits of 80-125%
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
IR and MR Products
 Products marketed as
– single strength
– multiple strengths
 Do all strengths need to be studied for BE?
 BE study need to be carried out for only highest strength
 Lower strength(s) can get biowaiver based on
– dose proportional formulations and
– dissolution profile comparison (similarity factor f2)
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Modified Release Products
Bioequelence Studies
 Single dose study is considered more sensitive in assessing the
drug product quality – release of the drug substance from the drug
product into circulation
 A multiple-dose study for MR dosage form is not generally
recommended
Study Requirements:
 A single dose fasting study comparing highest strength of
multisource and comparator (T and R) products
 A single dose food-effect study comparing highest strength of
multisource and comparator (T and R) products
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Bioequivalence Study
 How long should you collect blood samples in BE study?
– In general for 3 or more terminal half lives
– For long half life drugs for 72 hours
 What should be measured in BE studies - Parent drug
and/or metabolites?
– In most cases parent drug only.
 What should be measured in BE studies - Enantiomers or
racemic mixtures?
– In most BE studies racemic mixture (racemates) only.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Bioequivalence Study
Why do they fail?
 Bioinequivalent products
 Not sufficient subjects/power (Highly variable drugs)
 Highly variable formulations
 Problems with bioanalytical method
 Problem with multiple parameter measurements
 Outliers
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Pharmacodynamic Studies
 PD measures are more variable than PK measures
– more subjects needed
 PD measures are subject to placebo effect
 Response measured should be phrmacological or
therapeutic effect relevant to efficacy and/or safety
 Methodology must be validated for precision, accuracy,
reproducibility and specificity
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Clinical Trials
 When PK or PD studies can not be performed, clinical
trials has to be performed to demonstrate equivalence
between multisource and comparator formulations.
- Clinical trial requires large number of subjects
- Methodology for establishing equivalence has not yet
evolved extensively as for PK BE trials
- The same statistical principles of confidence interval
approach should be used (as for PK studies).
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
In Vitro Methods
 BCS approach for biowaivers
 Biowaivers for lower strength(s) preparations* based on
dose-proportionality of formulations
–
–
–
–
Immediate release formulations
Extended release formulations – beads in a capsule
Extended release tablets
All requiring dissolution profile comparison
* Requires BE study on highest strength
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
World Health Organization
Multisource (generic) pharmaceutical products:
guidelines on registration requirements
to establish interchangeability
WHO Technical Report Series, No. 937, 2006
Annex 7, Pages 347-390
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Thank You
WHO Prequalification Programme
June 2007