prequalification of medicines programme bioequivalence assessment update · pdf...
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Prequalification of Medicines Programme
Bioequivalence Assessment Update
Dr. John Gordon
Joint UNICEF / UNFPA / WHO Meeting with Manufacturers
Copenhagen, September 23-25, 2013
Joint UNICEF / UNFPA / WHO Meeting with Manufacturers
Copenhagen, September 23-25, 2013 2 |
Overview
Bioequivalence (BE) guidelines
In vivo bioequivalence study designs
Biowaivers • BCS-based biowaivers • Additional strength biowaivers
Zinc sulfate
Bioanalytical methods
Comparator products
Joint UNICEF / UNFPA / WHO Meeting with Manufacturers
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Primary BE Guidance
“Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability". In: Fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization. WHO Technical Report Series, No. 937, 2006, Annex 7
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Under revision
Annex 7 – under revision – National regulatory authorities (NRAs) – Manufacturers / Contract Research Organizations – WHO Prequalification Programme (PQP)
Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products – under revision
– National regulatory authorities (NRAs) – Manufacturers / Contract Research Organizations – PQP provides lists of PQP Comparator products on website
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Additional PQP BE-related guidances on PQP website
General notes on Biopharmaceutics Classification System (BCS)-based biowaiver applications (October 2012)
BCS-based biowaiver applications for Reproductive Health (RH) products (January 2013)
Guidance on Bioequivalence studies for reproductive health medicines (April 2013)
Questions & Answers on zinc applications (August 2013)
Questions & Answers on magnesium sulfate injection applications (September 2013)
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Typical in vivo BE Design Single-dose administration
Cross-over (within-subject) comparison
Healthy volunteers
Administration with or without food – Fasted study is the norm
Thoroughly validated bioanalytical method
Data from parent compound used for BE decision
Analysis should be carried out on the logarithmically transformed AUCT and Cmax data
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In vivo BE Study Design
Administration of products under fasted or fed conditions?
Fasted conditions – Study conducted under fasted conditions the norm – Comparator product labeling (SPC)
• Specifies fasted conditions • Does not specify fasted/fed for administration • States that either fasted or fed administration
Fed conditions – If specified in comparator product labeling (SPC)
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In vivo BE Study Design
Administration of products under fasted or fed conditions?
Fed conditions – If specified in comparator product labeling (SPC) – Type of meal to be consumed
• high-fat, high-calorie meal • “standard” or typical breakfast
Administration under both fasted and fed conditions – Not generally necessary for immediate-release products – Required for modified-release products
• e.g., didanosine enteric coated tablets
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In vivo BE Study Design
Crossover Design – Each subject administered both test and comparator – Within-subject comparison – Preferred
Parallel Design – Each subject administered test or comparator – Between-subject comparison – Only recommended for extremely long half-life drugs – Consult WHO – e.g., medroxyprogesterone depot injection
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Alternative in vivo BE Study Designs
Unknown variability – Estimates of intra-subject CV not available – Pilot Study – Two-stage group sequential two-way crossover design
• Details of statistical plan in protocol • Overall Type 1 error must be preserved
– Adjusted level of significance resulting in CIs higher than 90%
Studies of this type submitted in 2012-2013 – Malaria, Tuberculosis, Neglected Tropical Diseases
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Alternative in vivo BE Study Designs
High variability in Cmax – Intra-subject ANOVA-CV of ≥ 30% – Replicate design
• Estimation of variability based on replicate administration of comparator product
• Widening of acceptance criteria for Cmax based on estimated variability
– “scaled” acceptance criteria
Studies of this type submitted in 2012-2013 – HIV/AIDS, Malaria, Reproductive Health
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Biowaivers
Surrogate approaches for demonstrating safety and efficacy of products in lieu of conducting in vivo bioequivalence studies
Biopharmaceutics Classification System (BCS) – based biowaivers
– Suitable for products containing eligible APIs
Additional strengths biowaivers – Suitable for additional strengths in a product line when one of
the strengths has been proven bioequivalent to the comparator
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BCS-based Biowaivers eligible APIs
Medicines for HIV/AIDS and related diseases
– Abacavir sulfate (Class III) – Emtricitabine (Class I) – Lamivudine (Class III) – Stavudine (Class I) – Zidovudine (Class I)
Three (3) products pre-qualified based on biowaiver in 2012-2013
Anti-tuberculosis medicines – Ethambutol (Class III) – Isoniazid (Class III) – Levofloxacin (Class I) – Moxifloxacin HCl (Class I) – Ofloxacin (Class I) – Pyrazinamide (Class III)
Five (5) products pre-qualified based on biowaiver in 2012-2013
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BCS-based biowaiver for RH products
BCS-based biowaiver applications for Reproductive Health (RH) products (January 2013)
– Data available on the RH APIs is not sufficient to allow for accurate classification
– PQP has invited interested manufacturers to submit the data necessary to accurately classify an API(s) as a part of a BCS-based biowaiver application for a finished pharmaceutical product (FPP) containing that API(s)
• Solubility data across pH range (1.2-6.8) • Data on absorption / permeability
– Class I and III APIs are eligible
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BCS-based biowaivers for paediatric strengths
BCS-based biowaivers are meant to compare two products of equivalent strength
For many pediatric strengths of e.g., HIV/AIDS medicines, there are no equivalent strength comparator products
PQP, in consultation with experts in the area, is exploring the scientific basis for accepting biowaivers for pediatric strengths of products whose adult strengths are eligible for a BCS-based biowaiver.
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BCS-based biowaivers for paediatric strengths
The principles involved for the API – Only applicable for eligible APIs on PQP list – Additional solubility criterion to account for smaller fluid volume
in pediatric stomach e.g., 50 mL
The requirements for the FPP – Excipient comparisons conducted on a proportional scale – Comparative dissolution studies in media of at least 3 pHs
• Single and multiple unit comparisons
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BCS-based Biowaivers
Guidance documents – General notes on Biopharmaceutics Classification System
(BCS)-based biowaiver applications • October 2012
– Annex 7 • 2006
Application form – Biowaiver Application Form: Biopharmaceutics Classification
System (BCS) • 2008
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Additional Strengths Biowaiver
Guidance – Annex 7 – Annex 1 of PQP Quality Guideline
Application form – Biowaiver Application Form: Additional Strengths
• May 2012 • Comparative in vitro dissolution: Studies comparing different strengths
of the test product – Reference strength: Strength with demonstrated in vivo
bioequivalence
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Zinc Sulfate Tablets
Questions & Answers on zinc applications (August 2013) – The absorption of zinc is sensitive to many factors that affect
either GI status or the availability of the zinc through interactions such as complexation
Biowaiver – Primary pathway to approval for safety & efficacy
Acceptability study
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Zn biowaiver requirements
Evidence demonstrating excipients do not negatively impact zinc absorption
– Typical tablet diluents and disintegrants not expected to impact • e.g., microcrystalline cellulose or colloidal anhydrous silica
– Sweeteners & flavours problematic – Evidence from
• Literature • In vitro studies (comparative absorption data)
Zinc from the proposed product is proven to be completely in solution after one (1) minute using the solubility test described in Q&A
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Analytical Method Validation
Complete validation is necessary to produce confidence in the data set
All procedures including handling and storage should be validated
EMA guidance ‘Guideline on Bioanalytical Method Validation’ (2011)
New USFDA and Japanese guidelines
Note: Incurred sample reanalysis (ISR) expected
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Comparator (Reference) Products
Comparator products should be obtained from a well regulated market with stringent regulatory authority i.e., from countries participating in the International Conference on Harmonization (ICH)
Countries officially participating in ICH – ICH members: European Union, Japan and USA – ICH observers: Canada and EFTA as represented by
Switzerland – Other countries associated with ICH (through legally binding
mutual recognition agreements) include Australia, Norway, Iceland and Liechtenstein.
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Comparator Products
If WHO comparator product cannot be located from ICH-associated markets, consult PQP
– Assistance identifying pharmaceutical distributors – Identification of alternate markets for sourcing particular
products
There are instances when a comparator is not available in the ICH region
– e.g., Terizidone 300mg • Terivalidin 250 mg (Sanofi-Aventis, South Africa)
– e.g., Artesunate + Amodiaquine 100 mg + 270 mg FDC • Coarsucam (Sanofi-Aventis)
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Comparator Products
Complete documentation required as per website – Purchase – Shipping – Storage & handling
Check website regularly for updated lists as change is sometimes necessary
– For example: pyrazinamide • Previously: Pyrazinamide <Lederle> by Riemser Arzneimittel
– Withdrawn from market • Current: Pyrafat by Fatol
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Conclusions
Prequalification Programme constantly evolving
Check website regularly for updates – Guidance
• Including advice on the design of bioequivalence studies for specific APIs
– Application forms – Comparator information
Consultation with programme – Scientific advice
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Contact
Website: www.who.int/prequal
Email:
Dr Matthias Stahl Medical Officer, Head of Assessments Telephone: +41-22-791-3717 Email: [email protected]
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