1. World Health Organization
Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence
Planning a BE Study
Kiev, October 3 – 7, Dr. H. Potthast
Pt WHO consultant

2. Guidance Documents EU “Note for Guidance on the Investigation of
Bioavailability and Bioequivalence”
CPMP/EWP/QWP/1401/98 and related guidances and documents ( )
FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations” (Oct. 2000)
Canadian Guidance for Industry: “Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations used for systemic effects.” (1992
related guidances and current scientific discussion
Pt WHO consultant

3. Definitions
Bioavailability – rate and extent at which a drug substance... becomes available in the general system (product characteristic!)
Bioequivalence – equivalent bioavailability within pre-set acceptance ranges
Pharmaceutical equivalence  Bioequivalence
Bioequivalence  Therapeutic equivalence

4. Definitions
♦ „Two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives AND if their bioavailabilities after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same.“
[section 2.4 of the EU guidance on BA and BE]
 possible surrogate for full clinical/toxicological documentation

5. Definitions
♦ „A generic medicinal product shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.“
[new EU Directive 2004/27/EC: Art. 10.1]

6. Definitions
♦ ….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.
[Faassen et al. Clin Pharmacokinet 43 (2004)1117]
 what does the product do to the drug substance?
Pt WHO consultant

7. BE Objectives Bioequivalence Studies
in vivo comparison by means of volunteers serving as in vivo dissolution model
‘biological quality control’
 comparison of product characteristics in order to ensure therapeutic equivalence

8. Choice of Design Single-dose Studies  usually for IR drug products
Multiple-dose/steady-state Studies
usually for MR drug products in addition to single-dose studies
dose/time dependent pharmacokinetics (mainly BA studies!)
possible analytical problems
variability issues

9. Study Protocol

10. Study Protocol
„A document that describes the objective(s), design, methodology, statistical consideration and organisation of a trial. It usually gives the background and rationale of the trial …“
Ref.: ICH GCP Guidance

11. Study Protocol General Information/Title Page Title Protocol Number
Version Number/Date
Sponsor Details
Name, Address, Telephone
Monitor/Medical Personnel
Investigator Details
Principal Investigation, Medical Doctor
Other Laboratory/Institution Details
 Responsibilities!

12. Ethical Considerations
IEC / IRB: ICH Definition
An independent body of medical, scientific and non-scientific members
Responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by,
Among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects;
Independent “Risk-benefit” evalution

13. Ethical Considerations
Composition requirements ICH GCP
At least 5 members
At least one member whose primary area of interest is a non-scientific area
At least one member who is independent of the trial site
Members without conflicting interest
 Only those members independent of the investigator and the sponsor should review on a trial-related matter

14. Ethical Considerations
Additional US FDA requirement for IRB
composition:
Diverse backgrounds (race, gender, cultural, qualification)
Not entirely one gender
Special expertise may be invited but without voting rights

15. Ethical Considerations
Required documents
Protocol (signed at least by the principal investigator)
Patient Information Sheet/Consent Form
Investigator´s Brochure
Subject recruitement procedures (e. g. advertisements)

16. Ethical Considerations
Approval notification to Investigator
Timely written approval
Identification of study (title, protocol number, version, investigator, site)
Specify all items reviewed
Date & place of review
Trial/study related decisions
Reasons for modifications & disapprovals
Minimum information required by ICH-GCP:
Date of the meeting
Documents reviewed (versions & dates)
List of members

17. Study Protocol Protocol Development Definition of Responsibilities
Organisation, premises, personnel & QMS
Clinical phase
Bioanalytical phase
Statistics and reporting
Archival

18. Protocol Development Drug substance / Drug products
Knowledge of Particularities e.g.
pharmacokinetics (t1/2, peak concentration, metabolism…)
important side effects (acceptable for healthy volunteers?)
practicability of roughly anticipated measurement period and/or wash-out period (crossover study possible?)
concept of bioanalytical method available?
plasma concentrations sufficiently quantifiable (administration of more than one dosage form necessary?)

19. Protocol Development Drug Products Availability Certification
Content
In vitro dissolution
Preparation of investigative products per volunteer acc. to GMP
Protocol amendment for product details frequently necessary
(e. g. labeling)

20. 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!

21. Study Subjects Selection of subjects
Safe contraception for women (cave: interferences of contraceptives with investigative drug excluded?)
Phenotyping of volunteers (cave: possible side effects with “poor metabolisers” may cause drop-outs; variability reduction/explanation)

22. Study Subjects Selection of subjects
participation of healthy volunteers (“in vivo model”)
reasonable inclusion and exclusion criteria (protocol and CRFs)
comprehensive verbal and written information
volunteers´ insurance
reimbursement

23. Study Subjects Number of subjects
Required sample size depends on variability either known through reasonable literature or by means of a pilot study
“low” variability: ~ 12 – 20 volunteers
“high” variability: ~ 24 – 26 volunteers

24. Study Subjects Number of subjects ctd.
Required sample size depends on the expected mean difference between the test and reference formulation
For sample size calculation see literature data (e. g. Eur J Drug Metab Pharmacokinet 30 (2005) 41; J Biopharm Stat 13 (2003) 529; Stat Med 18 (1999) 93 …)
Consideration of possible withdrawals

25. Study Subjects Subject withdrawals
subject must adhere to study requirements but …
they are free to break of at any time
definition of “drop-outs” in the protocol (reason, reimbursement policy, handling of data, follow-up…)
concomitant medication
reporting

26. Study Design Crossover-design “latin square” / balanced / randomized
Intra-individual comparison!
Parallel group design
Replicate design
Volunteer
Period 1
Period 2 1 A B 2 …

27. Standardisation Procedure of drug intake
time of administration (fasted or fed state)
liquid volume
traceability of administrations
cave: e.g. granules, suspensions liquid formulations!
(require ‘method sheet’)

28. Standardisation
Standardised fluid and food intake (time, composition, amount)
Prohibition of alcohol
Restriction of xanthins (coffee*, coke, chocolate, chewing gum, grapefruit)
Standardized posture
Restriction of physical activities …
*cave: withdrawal may cause headache

29. Standardisation Fasted state
Confinement of subjects at least 10 h prior to drug administration
Last food intake ~10 h prior to drug intake
No food or fluids ~2 h prior to drug intake
Drug administration with ~ ml xanthine-free liquid
Light standardized meal not before ~4 h post-dose

30. Standardisation Fed state
Define time of drug administration and food intake, (e. g. drug intake within 30 min. before, immediately before or after the standardised meal)
High fat meal may serve to investigate the „worst case“ scenario

31. Study Samples Sampling number of samples sampling times (Cmax!)
time of sampling (extrapolated AUC max. 20 %)
wash-out-phase (3 – 4 half-lifes)
 knowledge of basic pharmacokinetics of the particular
drug substance is inevitable!
objective: characterisation of ‚drug input‘!
(see e.g. sect. 3.1 of the EU guidance 1401/98)

32. Study Samples Number of samples
sufficient to “describe” at least 80 % of total AUC
usually ~12 – 18 samples

33. Study Samples Sampling times appr. 3 – 4 to describe drug “input”
appr. 3 sampling times around peak concentration
appr. 3 – 4 to describe elimination
 Minimum!

34. Study Samples Wash-out-phase
must be long enough to avoid residual concentrations
closely related to the limit of quantitation
metabolites may be considered

36. Sampling Blood withdrawal equipment (consider bioanalytical method)
Preparation of plasma or serum
cooling
centrifugation
aliquotation
labeling
freezing
transport…

37. Bioanalytical Method The protocol should state
the bioanalytical method/detection
the limit of quantitation (1/10 of the expected peak concentration should be measurable)
the validation concept
whether metabolites are to be considered

38. Calculations The protocol should state (-among others-)
the transfer of bioanalytical results for biostatistical calculations
the handling of missing data
the handling of digits

39. Calculations The protocol should state (-among others-)
calculation procedure/methods
primary characteristics
possible consideration of differences of drug content
acceptance ranges

40. Adverse Events Definitions and handling/information
Evaluation of seriousness
Evaluation of relation to investigative drugs
Treatment (cave: concomitant drug intake should be testet a priori for possible analytical interferences)

41. Study protocol
?ANY MORE QUESTIONS?