Transcript Guidelines - World Health Organization

Demonstration of Bioequivalence
Milan Smid, MD, PhD
Tutorial: WHO Prequalification Programme for Priority Medicines, Beijing, March, 2010
 Proof of bioequivalence is required for
multisource interchangeable medicines
evaluated within WHO Prequalification
Programme
Why?
How?
Always?
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Why?
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
 Although medicines may contain same active ingredient in
the same strength and dosage form, after administration to
the organism due to pharmaceutical differences the release
and absorption of active moiety may be different.
Therapeutic effect is different.
 In vitro tests provide valuable information but are not
necessarily a reliable guide to the bioavailability or
therapeutic performance of the product.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Bioequivalence
Pharmaceutical Equivalent
Products
Reference
Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution specifications)
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Bioequivalence
Two medicinal products are bioequivalent if
they are pharmaceutical equivalents or alternatives
and if their bioavailabilities (rate and extent) after
administration in the same molar dose are similar
to such degree that their effects, with respect
to both efficacy and safety, will be
essential the same.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Innovative medicine
Experimental data/ Literature
Bioequivalence – bridging
innovators and generics
Clinical data
(Module V)
Generic medicine
Multisource interchangeable
Preclinical data
(Module IV)
BIOEQUIVALENCE
Pharmaceutical data (Module III)
Administrative and summarizing data (Modules I and II) incl. GMP
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Interchangeability
Concept of interchangeability includes the equivalence
of the dosage form as well as for the indications and
instructions for use.
Bioequivalent products can be substituted for each
other without any adjustment in dose or other additional
therapeutic monitoring.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
How?
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Demonstration of bioequivalence
Bioequivalence study
or
PD studies
Clinical
studies
ONLY EXCEPTIONAL!
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
In vitro
methods
Tested product
 GMP
 batch size
 pilot batch
 commercial batch
 not smaller than 100 000 units or 10 % of industrial batch size
(whichever is higher)
 difference regarding the content of the investigative
products (T and R) should preferably not be more than 5 %
 strength with the largest sensitivity to detect differences in
the two products
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Comparators for Prequalification Programme
 Lists of recommended comparators available on WHO
website.
 Innovator product with established Q,S, and E sourced
from well regulated market (ICH process countries).
 Other comparators must be justified. Recommended to
consult WHO.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Planning a BE Study
Study Subjects
 Selection of subjects
♦ description of volunteers; smoker, vegetarian, phenotyping….
♦ verifying health of volunteers ( e. g. ECG, clinical blood
chemistry, blood pressure…)
♦ number of volunteers depending on variability; at least 12 (EU:
healthy, 18-55y; FDA: both sexes, > 18y)
♦ randomisation
objective: minimising interindividual variability in order to
detect product differences!
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Design of bioequivalence studies
Golden standard study design
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Design of bioequivalence studies
Standard approach BE study
non-replicate
single administration
R and T
average bioequivalence
90% CI AUC and Cmax:
80 – 125%
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Planning a BE Study
Study Samples
 Sampling times
 appr. 3 – 4 to describe drug “input”
 appr. 3 sampling times around peak concentration
 appr. 3 – 4 to describe elimination
 sufficient to “describe” at least 80 % of total AUC - usually
~12– 18 samples
 wash-out-phase (not less than 5 half-lives)
 Minimum!
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Specific bioeqivalence situations
 Highly variable drugs
 Narrow therapeutic index drugs
 Food effect
 Measurement of metabolites
 Modified release formulations
 Fixed combination products
 Drugs with inherent toxicity
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Analytical methods
 FDA Guidance for Industry
– Bioanalytical method validation, May 2001
 ICH Guidance for industry
– Validation of analytical methods: definitions and
terminology, June 1995
– Validation of analytical procedures: methodology,
November 1996
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Quality of Bioequivalence Studies
Good Clinical Practice (GCP) is an international ethical and
scientific quality standard for designing, conducting, recording and
reporting trials that involve the participation of human subjects.
Compliance with this standard provides public assurance that the
rights, safety and well-being of trials subjects are
protected, consistent with the principles
that have their origin in the Declaration
of Helsinki, and that the
clinical trial data are credible.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BTIF
Bioequivalence Trial Information Form
http://who.int/prequal
Information for Applicants
Generics, ANNEX 7:
Presentation of Bioequivalence
Trial Information
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BTIF
Bioequivalence Trial Information Form
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Frequent GCP non-compliances
 No informed consent, complex language
 Ethics committee not independent
 Dosing procedure is inadequately documented, no drug
accountability
 Certificates of analysis are not consistent with study products or not
sufficiently detailed
 No testing on addictive substances performed
 Withdrawals are improperly documented
 Meals not standardized and not documented
 Storage of blood samples is not monitored
 Method of calculation of PK parameters is not specified
 Insufficient explanation of outliers
 Chromatograms not consistent with data
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Non-compliance
Bioanalytical part
Critical deviations in %
% critical deviation
Raw data not available
calculation errors
exclusion of QC for P&A
batch acceptance
manual re-integration not
consistent
forged peak
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Always?
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Bioequivalence
Cases when pharmaceutical equivalence is enough:
 Aqueous solutions
–
–
–
–
–
–
Intravenous solutions
Intramuscular, subcutaneous solutions
Oral solutions
Otic or ophthalmic solutions
Topical products prepared as solutions
Aqueous solution for nebulizer inhalation or nasal sprays
 Powders for reconstitution as solution
 Gases
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Bioequivalence may be proven for one strength
Immediate release (IR) oral dosage forms:
If a product concerns several strengths and:
 Same manufacturer and manufacturing proces
 Linear pharmacokinetics
 Same qualitative composition of different strengths (WHO)
 Same ratio between active substance and excipients, or same
excipients in case of low concentration active substance (less
than 5%)
 Similar dissolution profiles (WHO)
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BCS-based biowaiver
” BE studies may be exempted if the absence of
differences in the in vivo performance can be
justified by satisfactory in vitro data.”
Valid for oral immediate release dosage forms with
systemic action!
Biowaiver justification based on criteria derived from
the concepts underlying the Biopharmaceutics
Classification System
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Basis for BCS-based Biowaiver
Applications/Decisions
 WHO – Technical Report Series No. 937, May 2006
Annex 7: Multisource (generic) pharmaceutical products: guidelines on
registration requirements to establish interchangeability
Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO
Model List of Essential Medicines immediate release, solid oral
dosage forms
 FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence
studies for immediate release solid oral dosage forms containing
certain active moieties/active ingredients based on a
Biopharmaceutics Classification System” (2000)
 EU-guidance:“Note for Guidance on the Investigation of Bioavailability
andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BCS-based biowaiver
Biopharmaceutics Classification System (BCS)
dissolution (both formulation and API)
drug product 
drug substance in solution
membrane transport
 drug substance in the system
simplified mechanistic view on bioavailability
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BCS according to WHO
Solubility at pH 1-6.8
Absorbed
>85%
CLASS I
CLASS II
Highly permeable
Highly soluble
(very rapid dissolution
or profile comparison)
Eligible
Highly permeable
Poorly soluble
Eligible only if weak
acids, highly soluble
at pH 6.8,+dissolution
CLASS III
CLASS IV
Poorly permeable
Highly soluble
Poorly permeable
Poorly soluble
Eligible if very
rapidly dissolving Not eligible
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BCS-based Biowaiver Application Form
Active Pharmaceutical Ingredients (APIs) eligible for a BCS-based
biowaiver application are identified by the WHO Prequalification of
Medicines Programme.
It is not necessary to provide data to support the BCS classification
of the respective API(s) in the application i.e. data supporting the
drug substance solubility or permeability class.
Comparative dissolution of final product is necessary.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
WHO BCS-based biowaiver
Active substances selected for biowaiving by WHO
HIV/AIDS:
TB:
 Lamivudine
 Levofloxacin
 Stavudine
 Ofloxacin
 Zidovudine
 Ethambutol
 Isoniazid
 Pyrazinamide
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BCS-based Biowaiver Application Form
Designed to facilitate information exchange between the Applicant
and the WHO Prequalification of Medicines Programme if the
Applicant seeks to waive bioequivalence studies, based on the
Biopharmaceutics Classification System (BCS).
For further information, please study the respective WHO biowaiver
guidance documents. This form is not to be used, if a biowaiver is
applied for additional strength(s) of the submitted product(s), in
which situation a separate "Biowaiver Application Form: Additional
Strengths" should be used.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Information sources
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Guidance documents
http://who.int/prequal/
* Note to applicants on the choice of comparator products for
the prequalification project
* Guideline on generics
- Annex 7 (Multisource (generic) pharm. products: guidelines on
registration requirements to establish interchangeability)
- Annex 11 (Guidance on the selection of comparator pharm. products for
equivalence assessment of interchangeable multisource (generic)
products)
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Thank you for attention
[email protected]
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010