1. Regulation documentation requirements
Saila Antila, PhD
WHO consultant
Training workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence, Kiev

2. Guidelines
WHO:
Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products / Regulatory Support Series, No 5 (WHO/DMP/RGS/98.5)
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3. Guidelines (continues)
EMEA (EU)
Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98
Note for Guidance on Modified Release Oral and Transdermal Dosage Forms: Section II (Pharmacokinetic and Clinical Evaluation) CPMP/EWP/280/96
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4. Guideline (continues)
Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations (FDA, March 2003)
Guidance for Industry: Bioequivalence Guidance (FDA, October 9, 2002)
Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations Used for Systemic Effects (Canada, 1992)

5. Immediate release product
Preparations showing a release of the active substance(s) which is not deliberately modified by a special formulation design and/or manufacturing method
tablets
capsules

6. Immediate release product
usually a single dose study in fasting state is adequate
if the application contains several strengths of the active substance, bioequivalence study only with one strength may be acceptable dissolution profiles with each strength
if food enhances or interferes with drug absorption, a bioequivalence study in fed state should be performed

7. Immediate release product
if label indicates ’should be administered in fed or fasting state’ then bioequivalence study should be performed accordingly
a single dose study at a higher than approved dose may be appropiate for certain drugs ( difficulties in bioanalytics)

8. The amount of bioequivalence studies with preparations containing several strengths
if the application contains several strengths of a immediate release oral dosage form bioequivalence study only with one strength may be acceptable. The following conditions should be fulfilled:
the products are manufactured by the same manufacturer and process
qualitative composition of the different strength is the same
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9. The amount of bioequivalence studies with preparations containing several strengths
ratio between amounts of active substance and excipients is the same (or in case of preparations containing low concentration of the active substance; <5 %; the ratio between amount of excipients is similar)
the dissolution profiles of the test products are similar
the drug input should be linear over the therapeutic dose range

10. Modified release formulations
EMEA
Prolonged release formulations
Delayed release formulations
WHO, FDA
Extended (controlled, prolonged, sustained) release
tablets, capsules, granules, pellets or suspension

11. Modified release formulations
single dose, non-replicate cross-over study in fasting conditions
bioequivalence study under fed conditions (to ensure absence of dose dumping)
multiple dose study

12. Modified release forms (Prolonged and delayed release formulations) Food effect
As different modified release preparations may differ with respect to food, the influence of food should be investigated (the effects on efficacy and safety)
Predefined high fat meal immediately before dosing

13. Modified release forms Food effect (EMEA)
Food affects absorption-> should perform a 2-way randomized single-dose study
after fasting
with food
Food has no affect-> should perform a 2-way randomized single-dose study

14. Modified release formulations essentially similar to a marketed one
if two products differ in their release controlling excipients or mechanism but show similar in vitro dissolution profiles these products can be considered belonging to same category of pharmaceutical form and are considered essentially similar after showing bioequivalence
if the products differ in their release controlling excipients or mechanism and show different dissolution profiles then clinical trials should be considered

15. Prolonged release formulations (essentially similar to a marketed one)
Single and multiple dose studies
the test formulation exhibits the claimed prolonged release characteristics of the reference
the active drug substance is not released unexpectantly from the test formulation (dose dumping)
performance of the test and reference product is equivalent after single dose and at steady state
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16. Prolonged release formulations (essentially similar to a marketed one) (continues)
food effect is comparable for both formulations after high fat meal

17. Prolonged release formulation: (essentially similar to a marketed one)
Many strengths
Single unit:
single dose study in fasting conditions with each strength
multiple dose study with the highest strength if the pharmacokinetics is linear, the quality of the products is the same etc.

18. Prolonged release formulation (essentially similar to a marketed one)
Many strengths
Multiple unit:
linear pharmacokinetics and the composition of the lower strengths are proportional to that of the highest strength, the formulation contains identical beads or pellets and dissolution profiles are acceptable
single dose study under fasting conditions with the highest strength

19. Modified release formulation vs. immediate release formulation
new indications  clinical studies
bioavailability should be investigated (rate and extend of absorption, fluctuations, variability, dose proportionality, risk of unexpected release characteristics)
rate and extend of absorption from a modified release formulation should be evaluated with an immediate release formulation (reference product) following single and repeated dosing

20. Modified release formulation vs. immediate release formulation
AUC, Cmax, Cmin, fluctuation
inter-individual variability of modified release formulation should not exceed variability of immediate release formulation

21. Modified release formulation vs. immediate release formulation
dose proportionally
linear pharmacokinetics: modified release formulation and immediate release formulation at one dose level following multiple dose administration
non-linear pharmacokinetics: modified release formulation and immediate release formulation at the highest and lowest dose level following multiple administration

22. Delayed release formulation
Gastro-resistant formulations (entero-coated formulations)
post-prandial bioequivalence studies are necessary
similar statistical procedures as for immediate release formulations

23. Oral solution
bioequivalence study is not required if the product is in aqueous solution and contains active substance in the same concentration as an oral solution currently approved and the excipients in the product do not affect gastrointestinal transit, absorption and in vivo stability of the active substance
if the solution has to be tested against immediate release formulation, a comparative bioavailability study is required

24. Fixed combination products
bioequivalence should be assessed of individual active substance separately (new combination) or as existing combinations
design a way that drug-drug interactions should be detected

25. Bioequivalence study is not needed
The product is
a parenteral solution
aqueous intravenous solution containing same active substance in the same concentration
aqueous or oily intramuscular or subcutaneous solution containing same active substance and same comparable excipients
gas for inhalation

26. Bioequivalence study is not needed
locally applied product (oral, nasal, inhalation, ocular, dermal, rectal vaginal etc) without systemic absorption  pharmacodynamic or clinical studies are required (note: if the product has systemic effects a BE study is required)

27. Immediate release form Bioequivalence study is needed, in vitro dissolution is not enough:
Properties of the active substance:
narrow therapeutic index
absorption is not complete and/or small bioavailability
poor water solubility of the drug
risk of bioinequivalence
risk of therapeutic failure or adverse drug reaction

28. Transdermal drug delivery system
bioequivalence should be assessed after single dose and after multiple dose administration
the site of application should be the same body area for both test and reference product
multiple strengths-> bioequivalence study with the highest strength
proportionality in the formulation
there is an acceptable in vitro test
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29. Transdermal drug delivery system (continues)
intraindividual variability should be assessed (replicate design)
if products with different release mechanism are compared, a replicate design is required (formulation interaction)
the products should have the same or less degree of local irritation, adhesiveness to skin, phototoxicity, sensitization and similar systemic adverse event profile compared to the reference drug

30. Non-linear pharmacokinetics
if pharmacokinetics is non-linear, extrapolating the results from one bioequivalence study to other strengths is not possible
drugs that exhibit nonlinear pharmacokinetics at steady state (saturable metabolism, active secretion) -->multiple dose study
if the pharmacokinetic system is non-linear, plasma concentrations of the parent drug and the metabolite should be measured and analysed separately

31. Narrow therapeutic window
examples of narrow therapeutic drugs: digoxin, litium, warfarin, theophylline
drug concentrations or pharmacodynamics are monitored
Cmax and AUC confidence intervals % unless otherwise justified
the applicant should consider additional tests and controls to ensure interchangeability of the products
(Ctox/Cther < 5)

32. Highly variable drugs
drugs and drug products exhibiting intra-subject variability greater than 30 % CV for AUC and Cmax (CV=coefficient of variation)
number of subjects required for a study with highly variable drugs is higher than normally
ethical concerns of exposing large number of healthy volunteers to the studies
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33. Highly variable drugs (continues)
replicate designs often used to reduce the sample size
sample size may reduce up to 50 %
takes longer time to finalize the study
drop-outs may increase
group sequence design
useful when uncertainty about the estimates of variability
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34. Highly variable drugs (continues)
no regulatory definition for these drugs
ICH has not accepted bioequivalence as a topic
several proposals in the literature
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35. Highly variable drugs (continues)
Regulatory approaches in different regions:
EMEA: Cmax in certain cases e.g % provided that there is no safety concerns
South Africa: CI % for Cmax except for narrow therapeutic drugs
Canada: a limit is placed only on the means (point estimate) for Cmax. The sponsor may add more subjects, if random variation or a larger than expected relative difference
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36. Highly variable drugs (continues)
Japan: wider limits allowed for less potent drugs
dissolution rates should be equivalent,
log AUC and Cmax log(0.9)-log(1.11),
total number of subjects 20 or pooled sample size 30
USA: CI %

37. Test product (oral)
test product used in bioequivalence studies should be indentical to the projected commercial pharmaceutical product
composition and quality characteristics (including stability) should be the same
manufacturing methods should be the same
test product should preferably be from the industial scale

38. Test product (oral)
pilot or production batches may be used provided that they are not smaller than 1/10 of the expected full production batch
EMEA (EU): batch size at least units or 1/10 of the production batch whichever is higher (unless otherwise justified)

39. Test product (oral)
certificate of analysis of the test product should be included in the documentation
batch numbers and expiry dates should be provided in the bioequivalence study documentation

40. Test product (oral)
the content of the active drug substances between the test and reference product should not differ more than ±5 %

41. Reference product
innovator product (full chemical, biological, pharmaceutical, pharmacological, toxicological and clinical data)
EMEA (EU): the innovator product must be from a EU country

42. Reference product WHO:
the innovator product should be obtained from a well regulated market (such as Australia, Canada, European Union member states, Japan, USA, Switzerland)
a generic product should not be used as an innovator

43. Reference product WHO:
when the innovator product is not available, the market leader may be used as reference product provided its efficacy, safety and and quality has been established

44. Reference product
galenic development: innovator products are not exactly the same as those with full quality, safety and efficacy -> should still used as reference product
fixed dose combinations should not be used as comparators unless full clinical trials establishing the safety and efficacy of the product