Milan Smid, MD, PhD Tutorial: WHO Prequalification Programme for Priority Medicines, Beijing, March, 2010 Demonstration of Bioequivalence

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?


Why?


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.


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)


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.


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


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.


How?


Demonstration of bioequivalence

PD studies Clinicalstudies

In vitromethods

Bioequivalence study

ONLY EXCEPTIONAL!

or


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


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.


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!


Design of bioequivalence studies

single dose, two-period, crossover

Golden standard study design

Reference (comparator)/Test (generic)

healthy volunteers


Design of bioequivalence studies

non-replicate

Standard approach BE study

average bioequivalence

single administrationR and T

90% CI AUC and Cmax:80 – 125%


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!


Specific bioeqivalence situations

Highly variable drugsNarrow therapeutic index drugsFood effectMeasurement of metabolitesModified release formulationsFixed combination productsDrugs with inherent toxicity


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


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.


BTIFBioequivalence Trial Information Form

http://who.int/prequal

Information for Applicants

Generics, ANNEX 7:

Presentation of Bioequivalence Trial Information


BTIFBioequivalence Trial Information Form


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


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


Always?


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


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:


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


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


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


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


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 BCS-based biowaiver

Active substances selected for biowaiving by WHO

HIV/AIDS:Lamivudine

Stavudine

Zidovudine

TB:

Levofloxacin

Ofloxacin

Ethambutol

Isoniazid

Pyrazinamide


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.


Information sources


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)


Thank you for attention

[email protected]

Documents

Milan Smid, MD, PhD Tutorial: WHO Prequalification Programme for Priority Medicines, Beijing, March, 2010 Demonstration of Bioequivalence