Transcript Guidelines - World Health Organization

Principles of Interchangeability
Testing
Alfredo García – Arieta, PhD
WHO Workshop on Assessment of Bioequivalence Data, 31 August – 3 September, 2010, Addis Ababa
WHO Guideline
 Annex 7 of WHO Technical
Report Series, No. 937, 2006
 Multisource (generic)
pharmaceutical products:
guidelines on registration
requirements to establish
interchangeability
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Additional Guidance
 Proposal to waive in vivo bioequivalence
requirements for WHO Model List of Essential
Medicines immediate release, solid oral dosage
forms (Annex 8)
 Additional guidance for organizations performing in
vivo bioequivalence studies (Annex 9)
 Guidance on the selection of comparator
pharmaceutical products for equivalence
assessment of interchangeable multisource
(generic) products (Annex 11)
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Additional Guidance
 http://apps.who.int/prequal/
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Bioequivalence Trial Information Form (BTIF)
Biowaiver Application Form: Biopharmaceutics Classification System (BCS)
Biowaiver Application Form: Additional Strengths
Note to applicants on the choice of comparator products for the
Prequalification Programme
• Recommended comparator products: medicines for HIV/AIDS and related diseases
• Recommended comparator products: anti-tuberculosis medicines
• Recommended comparator products: anti-malarial medicines
• Recommended comparator products: Reproductive Health medicines
• Recommended comparator products: Influenza-specific antiviral medicines
– General notes on Biopharmaceutics Classification System (BCS)-based
biowaiver applications
– Biopharmaceutics Classification System (BCS)-based biowaiver
applications: anti-tuberculosis medicines
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
European Union Guidelines
 Guideline on the investigation of bioequivalence (2010)
 Note for guidance on modified release oral and transdermal dosage form: section
II (1999).
 Question and answer documents
 Draft Guideline on the Validation of Bioanalytical Methods
 NfG on the clinical requirements for locally applied, locally acting products
containing known constituents (1995)
 Guideline on the requirements for clinical documentation for orally inhaled
products (OIP) including the requirements for demonstration of therapeutic
equivalence between two inhaled products for use in the treatment of asthma and
COPD in adults and for use in the treatment of asthma in children and
adolescents (2009)
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
US FDA Guidance for Industry
 Bioavailability and Bioequivalence Studies for Orally Administered
Drug Products — General Considerations (2003)
 Food-Effect Bioavailability and Fed Bioequivalence Studies (2002).
 Waiver of In Vivo Bioavailability and Bioequivalence Studies for
Immediate-Release Solid Oral Dosage Forms Based on a
Biopharmaceutics Classification System (2000)
 Extended Release Oral Dosage Forms: Development, Evaluation,
and Application of In Vitro/In Vivo Correlations (1997)
 Bioanalytical Method Validation (2001)
 Bioavailability and Bioequivalence Studies for Nasal Aerosols and
Nasal Sprays for Local Action (Draft 2003)
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Purpose of WHO Guidelines
 One of WHO’s constitutional functions is to provide
objective and reliable information and advice in the field of
human health, a responsibility that it fulfils in part through
its programme of publications
 The Organization seeks through its publications to
support national health strategies and address the most
pressing public health concerns of populations around the
world.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Recommendations for the National
Authorities
 The national health and drug regulatory authorities should
ensure that all pharmaceutical products subject to their
control conform to acceptable standards of safety,
efficacy and quality, and that all premises and practices
employed in the manufacture, storage and distribution of
these products comply with good manufacturing practice
(GMP) standards so as to ensure the continued
conformity of the products with these requirements until
they are delivered to the end-user.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Recommendations for the National
Authorities
 All pharmaceutical products, including multisource
products, should be used in a country only after approval
by the local authority
 Regulatory authorities should require the documentation
of a multisource pharmaceutical product to meet the
following:
– GMP;
– quality control specifications; and
– pharmaceutical product interchangeability.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Recommendations for the National
Authorities
 Multisource pharmaceutical products need to conform to
the same appropriate standards of quality, efficacy and
safety as those required of the innovator’s (comparator)
product.
 In addition, reasonable assurance must be provided that
the multisource product is therapeutically equivalent and
interchangeable with the comparator product.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Clarification of two important concepts:
“Prescribability” and “Switchability”
 Bioequivalent products have efficacy and safety profiles similar to
that of the reference product.
 Bioequivalence is direct proof that the multisource product can be
used for new patients with the same benefit and risk:
“Prescribability” (new prescriptions, without any adjustment in dose
or other additional therapeutic monitoring)
 A patient already under treatment with the reference product can
generally be switch to the multisource product: “Switchability”
(additional prescriptions)
 Bioequivalence is also generally considered as indirect proof of
“switchability” between generics / multisource products
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
More terminology
 Bioequivalence = Therapeutic equivalence
– Biological equivalence
– More frequent in North-America
– Clinical or PD studies are also methods to show bioequivalence
in addition to PK studies
 Bioequivalence = Therapeutic equivalence demonstrated
by means of pharmacokinetic studies
– Bioavailability is equivalent.
– European Union
– Products showing equivalence with clinical or PD studies are
not considered as “generics”
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Types of in vivo bioequivalence studies
Sensitivity to detect differences
 Pharmacokinetic studies
 Pharmacodynamic studies and
 Comparative clinical trials
 In vitro studies
– In vitro studies are rarely validated as surrogate of BE
– But if validated, they are the most sensitive
• BCS Biowaiver, IVIVC, binding studies for cholestyramine…
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Clinical or PD variables are less sensitive
 Bioinequivalent products could be considered therapeutic
equivalent with clinical endpoints if such a study were
performed
– Bioequivalent: 90% CI of AUC and Cmax for T/R within 80-125
– Non-bioequivalent: 90% CI inside and outside of 80-125%
– Bioinequivalent: 90% CI completely outside of 80-125%
 Therapeutic equivalence can be concluded between
immediate release and prolonged release formulations
 Therapeutic equivalence can be concluded with different
drug substances (e.g. omeprazole, lansoprazole, etc.)
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Therapeutic equivalence
 Direct practical demonstration of therapeutic equivalence
in a clinical study usually requires large numbers of
patients.
 Such studies in humans can be financially daunting, are
often unnecessary and may be unethical
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Therapeutic equivalence vs. Bioequivalence
 For these reasons the science of bioequivalence testing
has been developed over the last 40 years.
 According to the tenets of this science, therapeutic
equivalence can be assured when the multisource
product is both pharmaceutically equivalent/alternative
and bioequivalent.
 Bioequivalence 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.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Definition of 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 to such a
degree that their effects can be expected to be
essentially the same.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Bioequivalence Basic Assumption
 If two pharmaceutical products produce an essentially
similar plasma concentration - time course in a given
subject, then, essentially similar concentrations at the
site(s) of action and essentially similar therapeutic
outcome will be obtained.
 Therefore, PK may be used instead of therapeutic result
in pharmaceutical products with systemic action
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
PK vs. PD / Clinical Endpoints
Evaluation of the in vivo performance
Formulation
Solution
PK parameters
Intestinal wall
Blood
Dose
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Clinical endpoints
Site of action
Effect
Ln Dose
Scope of the Bioequivalence Guideline
 This guidance is generally applicable to orally
administered multisource products, as well as to nonorally administered pharmaceutical products for which
systemic exposure measures are suitable for
documenting bioequivalence (e.g. transdermal delivery
systems and certain parenteral, rectal and nasal
pharmaceutical products).
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Scope of the Bioequivalence Guideline
 Systemic action
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Oral Immediate Release or Modified Release Products
Transdermal products with systemic action
Certain parental products (e.g. prolonged release),
Rectal, nasal, etc. with systemic effect
 Local action
– Inhalation products
• For systemic safety (FDA, Canada, EU)
• Lung deposition (total and pattern of deposition in EU) as surrogate of efficacy
– Nasal products
• For systemic safety (nasal suspensions in FDA draft guidance)
– Gastrointestinal tract (certain drug specific guidance in FDA webpage)
• For systemic safety + in vitro dissolution
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Therapeutic equivalence
with Clinical or PD endpoints
 Systemic action, but no measurable concentrations
 Products for local action
– Except solutions with the same composition (Q1+Q2)
– PD design for cutaneous corticosteroids (skin blanching assay)
• In addition Q1+Q2 in EU
– PD design for bronchodilators
• Bronchoconstriction or Bronchodilation
– Clinical variables required in other cases
• No FDA model for Inhaled Corticosteroids (NOe)
• Dermatopharmacokinetics and Dermal Microdyalisis for cutaneous?
– In vitro acceptable in very few cases (e.g. sevelamer)
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Excluded Products from Bioequivalence
Guidelines
 For yet other classes of products, including many
biologicals such as vaccines, animal sera, products
derived from human blood and plasma, and products
manufactured by biotechnology, the concept of
interchangeability raises complex considerations that are
beyond the scope of this document, and these products
are consequently excluded from consideration.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Biowaiver
 Proportional formulations
– Bioequivalence has been shown with one strength (most sensitive strength)
– Same manufacturing process
– Similar dissolution profile
 Certain dosage forms (e.g. oral solutions
– For some classes of product, including – most evidently – parenteral
formulations of highly water-soluble compounds, interchangeability is
adequately assured by implementation of GMP and evidence of conformity
with relevant pharmacopoeial specifications.
 BCS Biowaivers
– In selected cases, in vitro comparison of dissolution profile of the
multisource product with that of the comparator product, or dissolution
studies, may be sufficient to provide indication of equivalence.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Biowaiver for certain dosage forms
 Pharmaceutical equivalence may be enough in case of:
– Oral aqueous solutions (excluding active excipients)
– Aqueous Intravenous solutions (similar excipients)
– Aqueous Intramuscular / Subcutaneous solutions (similar excipients and
viscosity)
– Oily Intramuscular / Subcutaneous solutions (same oil)
– Aqueous Otic / Ophthalmic solutions
– Cutaneous solutions (if same Qualitative and Quantitative composition)
– Nasal Solutions (if same Q1 and Q2 + in vitro testing for device
performance)
– Powders / Granules for reconstitution as solution
– Gases
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
4. When equivalence studies are not necessary
 The following types of multisource pharmaceutical product are
considered to be equivalent without the need for further
documentation:
No Propofol
No Docetaxel
 (a) when the pharmaceutical product is to be administered
parenterally (e.g. intravenously, subcutaneously or intramuscularly)
as an aqueous solution containing the same API in the same molar
concentration as the comparator product and the same or similar
excipients in comparable concentrations as in the comparator
product.
 Certain excipients (e.g. buffer, preservative and antioxidant) may be
different provided it can be shown that the change(s) in these
excipients would not affect the safety and/or efficacy of the
pharmaceutical product
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Section 4 b
 (b) when pharmaceutically equivalent products are
solutions for oral use (e.g. syrups, elixirs and tinctures),
contain the API in the same molar concentration as the
comparator product, and contain essentially the same
excipients in comparable concentrations.
 Excipient(s) known to affect gastrointestinal (GI) transit, GI
permeability and hence absorption or stability of the API in
the GI tract should be critically reviewed;
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Section 4 c - d
 (c) when pharmaceutically equivalent products are in the
form of powders for reconstitution as a solution and the
resultant solution meets either criterion (a) or criterion (b)
above;
 (d) when pharmaceutically equivalent products are gases;
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Section 4 e
 (e) when pharmaceutically equivalent products are otic or
ophthalmic products prepared as aqueous solutions and
contain the same API(s) in the same molar concentration
and essentially the same excipients in comparable
concentrations.
 Certain excipients (e.g. preservative, buffer, substance to
adjust tonicity or thickening agent) may be different
provided their use is not expected to affect safety and/or
efficacy of the product
Device: volume, handling
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Section 4 f
 (f) when pharmaceutically equivalent products are topical
products prepared as aqueous solutions and contain the
same API(s) in the same molar concentration and
essentially the same excipients in comparable
concentrations;
Different excipients probably
have different absorption
enhancing effect
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Section 4 g
Salbutamol solution
for nebilisation with or
without benzalconium
 (g) when pharmaceutically equivalent products are
aqueous solutions for nebulizer inhalation products or
nasal sprays, intended to be administered with essentially
the same device, and contain the same API(s) in the same
concentration and essentially the same excipients in
comparable concentrations.
 The pharmaceutical product may include different
excipients provided their use is not expected to affect
safety and/or efficacy of the product.
Toxicity of preservatives:
Chlorobutanol and benzalconium
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Section 4
 For situations (b), (c), (e), (f) and (g) above, it is incumbent
upon the applicant to demonstrate that the excipients in
the pharmaceutically equivalent product are essentially
the same and in concentrations comparable to those in
the comparator product or, where applicable (i.e. (e) and
(g)), that their use is not expected to affect the safety
and/or efficacy of the product.
 In the event that this information cannot be provided by
the applicant and the drug regulatory authority does not
have access to the relevant data, it is incumbent upon the
applicant to perform appropriate studies to demonstrate
that differences in excipients or devices do not affect
product performance.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Bioequivalence cannot be assumed
 Pharmaceutical equivalent does not necessarily Pharmaceutical Equivalent Products
imply therapeutic equivalence
Test
Reference
 Differences in:
– Raw materials
• Drug (e.g. particle size, polymorphism, etc.)
• Excipients (e.g. grade)
– Formulation / composition
• Q1 and Q2 (effect on in vivo dissolution and absorption)
– Manufacturing process (e.g. dry vs. wet granulation)
– Equipment
– Site of Manufacturing
– Batch size
 May affect the bioavailability of pharmaceutical
equivalents or pharmaceutical alternatives.
 Then, bioequivalence has to be demonstrated
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Possible Differences
Drug particle size, ...
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
Bioequivalence / Comparative
Bioavailability is required
 In vivo documentation of equivalence is needed when there is a
risk that possible differences in bioavailability may result in
therapeutic inequivalence.
 When the innovator develops a new formulation
– During the drug-development process (before approval)
– As a variation of the marketed product after approval
 When the innovator develops a new dosage form
– Line extension
 When a multisource (generic) product is applied for marketing
authorisation
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Interchangeability
 The concept of interchangeability includes the
equivalence of the dosage form as well as of the
indications and instructions for use.
– If BE is shown, it is equivalent in all indications if used
according to the instructions of use.
– Some indications may be protected by patent
– Interchangeability
• If both products in the same dosage form in some countries (e.g. USA)
• Between capsules and tablets (e.g. Canada)
• All oral immediate release dosage forms (e.g. EU)
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Final concepts
 Average Bioequivalence:
– ABE compares population mean values of AUC, Cmax, …
 Population Bioequivalence:
– Proposal to compare population mean values and total variability
– To improve assurance of prescribability. Not used.
 Individual Bioequivalence:
– Proposal to compare mean values, intra-subject variability and subject-byformulation interaction.
– To improve switchability. Not used.
– Aggregate criterion more permissive than ABE
– Unnecessary. SxF interaction mostly an artifact
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Summary
 Average Bioequivalence ensures a
similar biopharmaceutical quality or in
vivo performance.
– This may require more than one study
• Fasted state
• Fed state
 Then, it is assumed that the multisource product can be used
instead of the reference in all type of patients
– Elderly, Children
– Renal / Hepatic impairment.
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa
Thank you very much for your attention!
WHO Workshop on Assessment of Bioequivalence Data
31 August – 3 September, 2010, Addis Ababa