1. regulatory requirements
Bioequivalence-
regulatory requirements
Drs. Jan Welink
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, October, 2010

2. Guidance documents http://apps.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)

3. Guidance documents

4. Europe: http://www.emea.europa.eu
Guidance documents
Europe:
- Guideline on the investigation of bioequivalence
- Note for guidance on modified release oral and transdermal dosage form: section II.
- Question and answer documents
………………………………

5. Bioequivalence Pharmaceutical Equivalent Products
Reference
Test
Pharmaceutical Equivalent
Products
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence

6. Bioequivalence
Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:
- difference excipients
- difference manufacturing process
- other variables
drug performance?

7. Bioequivalence
Therapeutic equivalent does not necessarily imply bioequivalence:
- sensitivity
- different formulations (IR/CR)
- different active substance
equivalence?

8. Bioequivalence pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, Cmax)
acceptance criteria: comparative rate and extent of absorption

9. EXPERIMENTAL DESIGN

10. World Health Organization
Bioequivalence
World Health Organization
21 April, 2017
Important PK parameters
Cmax:
the observed maximum concentration of a drug
 measure of the rate of absorption
AUC:
area under the concentration-time curve
 measure of the extent of absorption
tmax:
time at which Cmax is observed
 measure of the rate of absorption
Note that bioequivalence standards are applied to the pharmacokinetic parameters AUC and Cmax but not to Tmax.

11. Plasma concentration time profile
World Health Organization
21 April, 2017
Cmax
AUC
This is an example of a plasma concentration time profile following extravascular administration of a drug. The parameters often used in bioequivalence assessments are here marked as AUC, Cmax and Tmax. For definitions, see next page.
Tmax
time

12. Bioequivalence IR formulations– single dose
Basic design considerations:
minimize variability not
attributable to formulations
minimize bias
goal: compare performance
2 formulations

13. Bioequivalence IR formulations– single dose
Golden standard study design:
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)

14. Bioequivalence IR formulations– single dose
Single dose, two-period crossover:
Subjects receive in Period I and II Test/Reference
Subjects:
Healthy volunteers
randomisation
Inclusion/exclusion criteria
Number of subjects

15. Bioequivalence – variability
Number of subjects: variability!!
Controllable variation:
- carry-over effects (use of other medicines etc.)
- time-factors (sampling time etc.)
- physiological factors (gastric emptying etc.)
Inescapable variation:
- subject difference (inter- and intra variability)
- formulations differences
- random error

16. Bioequivalence – variability
Number of subjects:
Number of subjects
Required sample size depends on intra-individual variability either known through reasonable literature or by means of a pilot study
“low” variability: ~ 12 – 26 volunteers
“high” variability: ~ can be up to 250 volunteers

17. Bioequivalence – Test/Reference
TEST formulation:
not smaller than units or 10 % of industrial batch size (whichever is higher)
Certificate of Analysis
Manufacturing date/expire date
Reference formulation:
Certificate of Analysis
Expire date

18. Bioequivalence – fast/fed
Administration of Test/Reference:
Procedure of drug intake:
time of administration (fasted or fed state)
liquid volume
traceability of administrations

19. Bioequivalence – fast/fed
Fasted state e.g.
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 (e.g.) water
Light standardized meal not before ~4 h post-dose

20. Bioequivalence – fast/fed
Standardized fluid and food intake (time, composition, amount)
Prohibition of alcohol
Restriction of xanthins (coffee*, tea, coke, chocolate, chewing gum, grapefruit….)
Standardized posture
Restriction of physical activities

21. Bioequivalence – fast/fed
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

22. knowledge drug substance
Sampling
Blood sampling:
Number of samples.
Sampling times (Cmax!).
knowledge drug substance
Time of sampling (extrapolated AUC max. 20%).
Washout phase long enough.

23. Sampling
Time of sampling (extrapolated AUC max. 20%).

24. Sampling
Washout phase long enough!.
At least > 5 times elimination half-life drug.
Wash-out-phase
must be long enough to avoid residual concentrations
closely related to the limit of quantitation
metabolites may be considered

25. Selection of strength/dose
4.1.6 Strength and dose
important for application consisting more strengths (extrapolation of BE data)
elaborate section which strength/dose should be applied
EMA guidance
depends on linearity in PK and solubility active substance
bracketing approach possible

26. Choice of the comparator:

27. Comparator Example of how a national DRA can select a comparator:
choose national granted innovator for which quality, safety and efficacy has been established (nationally authorised innovator)
choose WHO comparator product from the comparator list (WHO comparator product)
choose innovator product from well-regulated country (ICH et al. innovator)
if no innovator can be identified, choice must be justified

28. Choosing national comparator complex
Decision tree
Choosing national comparator complex
WHO provides criteria decision tree NO ?
YES ?
YES NO NO ?

29. Selection of a comparator for a single national market:
cannot be translated in case other countries are at stake
national comparator may be the national market leader
no problem in that market
but others!?

30. World Health Organization
EMA (Europe)
World Health Organization
21 April, 2017
Differentiate between use for single market or many countries!
EMA:
For an abridged application claiming essential similarity to a reference product, application to numerous Member States based on bioequivalence with a reference product from one Member State can be made.

31. Prequalification program

32. EOI

33. Comparator lists
List of acceptable reference products for the prequalification project for reproductive health
List of acceptable reference products for the prequalification project for reproductive health

34. Guidance documents Comparator 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 are the ICH members European Union, Japan and USA; and the ICH observers Canada and Switzerland.
Note: some are not available in ICH

35. Guidance documents

36. Comparators
For the Prequalification Program:
* the comparator should be selected from the comparator list ( applicants_BE_comparator.htma)
* guidance on selection and the to be provided documents should be followed.
* if comparator is not available, information can be obtained at:

37. Statistical considerations

38. = bioavailability with pre-defined criteria for the rate
Bioequivalence
Bioequivalence:
= bioavailability with pre-defined criteria for the rate
and extent of absorption!!

39. 2 pharmaceutical products
Bioequivalence
2 pharmaceutical products
Reference
Test
Bioequivalent??

40. Statistical considerations
How similar is similar?

41. Statistical considerations

42. Statistical considerations
Statistical test should take into account…
The consumer (patient) risk of erroneously accepting bioequivalence (primary concern health authorities)
Minimize the producer (pharmaceutical company) risk of erroneously rejecting bioequivalence
Choice:
two one-side test procedure
confidence interval ratio T/R 100 (1-2)
 set at 5% (90% CI)

43. Non-inferiority studies
Choice:
two one-side test procedure
Superiority studies
A is better than B (A = active and B = placebo or gold-standard)
Conventional one-sided hypothesis test
Equivalence studies
A is more or less like B (A = active y B = standard)
Two-sided interval hypothesis
Non-inferiority studies
A is not worse than B (A = active y B = standard with adverse effects)
One-sided interval hypothesis

44. Statistical considerations
Average Bioequivalence:
two drug products are bioequivalent
‘on the average’ when the (1-2α)
confidence interval around the
Geometric Mean Ratio falls
entirely within %
(regulatory control of specified limit)

45. Statistical considerations
Some International Criteria
Country/Region
AUC 90% CI
Criteria
Cmax 90% CI
Canada (most drugs)
80 – 125%
none (point estimate only)
Europe
South Africa (most drugs)
75 – 133% (or broader if justified)
Japan (some drugs)
Some drugs wider than 80 – 125%
Worldwide
“acceptance range for Cmax may be wider than for AUC”

46. Statistical considerations
Sponsors have to use a validated software
E.g. SAS, SPSS, Winnonlin, etc.

47. Statistical considerations
BE Limits
The concept of the 20% difference is the basis of BE limits (goal posts)
If the concentration dependent data were linear, the BE limits would be %
On the log scale, the BE limits are %
The 90%CI must fit entirely within specified BE limits e.g %

48. Statistical considerations
Variables..:
Log transformation:
For all concentration dependent pharmacokinetic variables (AUC and Cmax)
Analysis of log-transformed data by means of ANOVA (analysis of variance)
includes usually formulation, period, sequence or carry-over, and subject factors
parametric test (normal theory)

49. Statistical considerations
The sources of variance in the model are
Product
Period
Sequence
Subject (Sequence)
Residual variance
These account
for all the inter-subject
variability
This estimates
Intra-subject
variability

50. Statistical considerations
The width of the 90%CI depends on
The magnitude of the WSV (ANOVA-CV (residual variance))
The number of subjects in the BE study
The bigger the WSV, the wider the CI
If the WSV is high, more subjects are needed to give statistical power compared with when the WSV is low

51. Statistical considerations80
100
125

52. Statistical considerations
why log-transformation:

53. Statistical considerations
Why parametric testing and not non-parametric:
Non-parametric testing can hide outlying values!
based upon test for normality, however these are insensitive and it concerns a small study
normally after log transformation AUC and Cmax are normal distributed
reason for non-normality should be explained

54. ‘Outliers’ Outliers Definition:
aberant/irregular values (e.g. no plasma concentration, ‘late’ high concentrations….)

55. Outliers
‘Outliers’
Explanation:
vomiting?
non-compliant volunteers?
bioanalytical failure?
individual pharmacokinetics?
protocol violations? ……

56. Outliers ‘Outliers’ Handling:
“…pharmacokinetic data can only be excluded based on non-statistical reasons that have been defined previously in the protocol.
Exclusion of data can never be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish between formulation effects and pharmacokinetic effects.

57. Regulatory requirements for BE studies
Bioequivalence:
Linear pharmacokinetics
Non narrow therapeutic drug
Non highly variable drug
Decision based upon parent drug data
Decision based upon plasma concentrations
Stereochemistry not an issue

58. BE studies for modified release formulations
Modified release (MR) oral dosage forms:

59. BE studies for modified release formulations
Modified release (MR) oral dosage forms:
Requested BE studies for enteric coated formulations:
single dose, two-period,
crossover, fasting
single dose, two-period,
crossover, fed
pH!
90% CI AUC and Cmax:
80 – 125%
90% CI AUC and Cmax:
80 – 125% or
not statistical
significant different

60. BE studies for modified release formulations
Modified release (MR) oral dosage forms:
Requested BE studies for controlled release formulations:
single dose, two-period,
crossover, fasting
multiple dose, two-period,
crossover, fasting
single dose, two-period,
crossover, fed
90% CI AUC and Cmax:
80 – 125%
90% CI AUC and Cmax:
80 – 125%;
Cmin and PTF!
90% CI AUC and Cmax:
80 – 125%
- dose dumping
- FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002)
- steady state conditions
- EU, not FDA

61. BE studies for modified release formulations
In case of more strengths:
type of formulation should be taken into account.
multiple unit formulations
single unit formulations

62. depends on drug substance!
Bioequivalence
Most submitted bioequivalence studies are:
Single dose studies.
Fasted conditions.
depends on drug substance!
Crossover design.
Non replicate.

63. Thank you for your attention
End
Thank you for your attention