milan smid, md, phd tutorial: who prequalification programme for priority medicines, beijing, march,...
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Milan Smid, MD, PhD
Tutorial: WHO Prequalification Programme for Priority Medicines, Beijing, March, 2010
Demonstration of Bioequivalence
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
Reference Test
Pharmaceutical EquivalentProducts
Possible DifferencesDrug particle size, ..
ExcipientsManufacturing process
EquipmentSite 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 alternativesand if their bioavailabilities (rate and extent) afteradministration in the same molar dose are similar
to such degree that their effects, with respectto both efficacy and safety, will be
essential the same.
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
BIOEQUIVALENCEBIOEQUIVALENCE
Administrative and summarizing data (Modules I and II) incl. GMPAdministrative and summarizing data (Modules I and II) incl. GMPPharmaceutical data (Module III)Pharmaceutical data (Module III)
Preclinical dataPreclinical data(Module IV)(Module IV)
Innovative medicineInnovative medicineExperimental data/ LiteratureExperimental data/ Literature
Generic medicineGeneric medicineMultisource interchangeableMultisource interchangeable
Clinical dataClinical data(Module V)(Module V)
Bioequivalence – bridging innovators and generics
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
PD studies Clinicalstudies
In vitromethods
Bioequivalence study
ONLY EXCEPTIONAL!
or
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
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 StudyPlanning a BE Study Study SubjectsStudy 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
single dose, two-period, crossover
Golden standard study design
Reference (comparator)/Test (generic)
healthy volunteers
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Design of bioequivalence studies
non-replicate
Standard approach BE study
average bioequivalence
single administrationR and T
90% CI AUC and Cmax:80 – 125%
WHO Prequalification Programme for Priority Medicines, Beijing, March 2010
Planning a BE StudyPlanning a BE Study Study SamplesStudy 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 drugsNarrow therapeutic index drugsFood effectMeasurement of metabolitesModified release formulationsFixed combination productsDrugs 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 StudiesQuality 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
BTIFBioequivalence 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
BTIFBioequivalence 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 partCritical deviations in %
% critical deviation
Raw data not available
calculation errors
exclusion of QC for P&A
batch acceptance
manual re-integration notconsistent
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:
Same manufacturer and manufacturing procesLinear pharmacokineticsSame 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)
If a product concerns several strengths and:
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
CLASS IHighly permeableHighly soluble (very rapid dissolutionor profile comparison)EligibleCLASS IIIPoorly permeableHighly solubleEligible if veryrapidly dissolving
CLASS IIHighly permeablePoorly solubleEligible only if weak acids, highly soluble at pH 6.8,+dissolution
CLASS IVPoorly permeablePoorly soluble
Not eligible
Absorbed >85%
Solubility at pH 1-6.8
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:Lamivudine
Stavudine
Zidovudine
TB:
Levofloxacin
Ofloxacin
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
smidm@who.int
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