Bioavailability and bioequivalance studies and Regulatory aspects


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This presentation based on the BA & BE Studies on current FDA and EMEA status.

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Bioavailability and bioequivalance studies and Regulatory aspects

  2. 2. DEFINITION  Bioavailability Regulatory Definition (21 CFR 320.1(a)): “Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.”  Bioequivalence Regulatory Definition (21 CFR 320.1(e)): “Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”
  3. 3.  PHARMACEUTICAL EQUIVALENTS Pharmaceutical equivalents are drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients.  PHARMACEUTICAL ALTERNATIVES Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester.  THERAPEUTIC EQUIVALENTS Therapeutic equivalents are drug products that contain the same active substance or therapeutic moiety and, clinically show the same efficacy and safety.
  4. 4. REFERENCE PRODUCT  Identified by the Regulatory Authorities as “Designated Reference Product”  Usually the Global Innovator’s Product  Protected by a patent  Marketed under manufacturers brand name  Clinical efficacy & safety profile is well documented in extensive trials  All generics must be Bioequivalent to it
  5. 5. TEST PRODUCT For Oral solid forms for systemic action: a) The test product should usually originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified. b) The production of batches used should provide a high level of assurance that the product and process will be feasible on an industrial scale. In case of a production batch smaller than 100,000 units, a full production batch will be required. c) The characteristics and specification of critical quality attributes of the drug product, such as dissolution, should be established from the test batch, i.e. the clinical batch for which Bioequivalence has been demonstrated. d) Samples of the product from additional pilot and/or full scale production batches, submitted to support the application, should be compared with those of the BE study test batch, and show similar in vitro dissolution profiles when employing suitable dissolution test condition. e) Comparative dissolution profile testing should be undertaken on the first three production batches. f) If full scale production batches are not available at the time of submission, the applicant should not market a batch until comparative dissolution profile testing has been completed. For other immediate release pharmaceutical forms for systemic action, justification of the representative nature of the test batch should be similarly established.
  6. 6. REQUIREMENT OF BA & BE STUDIES  For IND/NDAs: To establish equivalence between: • Early & late clinical trial formulations • Formulations used in clinical trial & stability studies, if different • Clinical trial formulations & to-be-marketed drug product • Any other comparisons, if appropriate  ANDA for a generic drug product  Change in components, composition, &/or manufacturing process  Change in dosage form (capsules to tablet)
  7. 7. NDA VS. ANDA REVIEW PROCESS NDA Requirements ANDA Requirements 1. Chemistry 1. Chemistry 2. Manufacturing 2. Manufacturing 3. Controls 3. Controls 4. Labeling 4. Labeling 5. Testing 5. Testing 6. Animal Studies 7. Clinical Studies 6. Bioequivalence 8. Bioavailability
  8. 8. DESIGN AND CONDUCT OF STUDIES I. Pharmacokinetic Studies II. Pharmacodynamic Studies III. Comparative Clinical Studies IV. Dissolution Studies
  9. 9. PHARMACOKINETIC STUDY Pharmacokinetic Study a) Study b) Study c) Selection d) Study e) Statistical Design Population Criteria Condition evaluation
  10. 10. STUDY DESIGN The basic design of an in-vivo bioavailability study is determined by the following: • What is the scientific question(s) to be answered. • The nature of the reference material and the dosage form to be tested. • The availability of analytical methods. • Benefit-risk ratio considerations in regard to testing in humans.
  11. 11. STUDY POPULATION  The number of subjects to be included in the study based on an appropriate Sample size which is estimated by: • Pilot experiment • Previous studies • Published data  The number of subjects recruited should be sufficient to allow for possible withdrawals or removals (dropouts) from the study.  Significance level desired, usually 0.05  Power of the study, normally 80% or more  Minimum 12 subjects, unless ethical justification  if the drug product is intended for use in both sexes, the sponsor attempt to include similar proportions of males and females in the study.
  12. 12. SELECTION OF SUBJECTS  Healthy adult volunteers  Age: 18years or older  Age/Sex representation corresponding to therapeutic & safety profile  Non-smokers/without a history of alcohol or drug abuse Medical history/Clinical Lab test values must be within normal ranges  Weight within normal limits→ BMI (18.5-30 kg/m2)  Women: Women should be required to give assurance that they are neither pregnant, nor likely to become pregnant until after the study.  Drug use intended in Elders, the sponsor attempt to include as many subjects of 60yrs of age or older as possible.  Teratogenic Drugs→ Male volunteers  Highly toxic drugs: Patients with concerned disease (stable) eg. Cancer
  13. 13. STUDY CONDITION Selection of Blood Sampling Points/Schedules  For at least three elimination half-lives (cover >80% of AUC) • Absorption phase : 3-4 points • Around Tmax : 3-4 points • During elimination : 4 points  Intervals not longer than the half-life of the drug  If urine tested, collect it for at least 5 half-lives The lot Numbers of both reference listed products and the expiration date for the reference product would be stated. The drug content of the test product cannot differ from that of reference product by more than ± 5%.  The sponsor can include a statement of the composition of the test product and if possible a side-by-side comparison of the compositions of the test and reference product. Samples of the test and reference listed product must be retained for 5 years.
  14. 14. Fasting or fed conditions  Fasting state: • A single dose study should be conducted after an overnight fast (at least 10 hours), with subsequent fast of 4 hours following dosing. • For multiple dose fasting state studies, when an evening dose must be given, two hours of fasting before and after the dose is considered acceptable.  Fed State:  Required when: • Drug recommended with food • Modified release product • Assessment of Cmax and Tmax difficult with fasting state study  Requires consumption of a high fat food, 30 minutes before dosing  Provide 800-1000 kcals with about 50% of calories derived from fat.  Fat- 500-600, Proteins - 150, Carbohydrate- 250 Kcal  Ethnic & cultural variation considered  Specified in protocol In general BE Study conducted under fasting condition. 1. Where the SmPC recommends intake of the reference medicinal product on an empty stomach or irrespective of food intake, BE study conducted under fasting condition. 2. Where SmPC recommends intake of RMP only in fed state, BE Study conducted under fed state. 3. For specific formulation both study recommended, unless product taken only in fasting or fed state. Where information is required in both Fasting and fed state, it is acceptable to conduct either; a. Two separate two-way cross-over OR, b. A four way cross-over study
  15. 15. STEADY STATE/ MULTIPLE DOSE STUDIES  Long elimination half life→ Accumulation in the body  Toxic drugs requiring multiple dose therapy  Some Modified-release drugs  Combination products  Drugs inducing own metabolism  Drugs showing non-linear pharmacokinetics  Disadvantages: • Difficult to conduct • Costly • Longer monitoring • Longer exposure to drug
  16. 16. PARAMETERS IN MULTIPLE DOSING STUDIES Cmaxss AUCss Cminss Fluctuation: Cmax - Cmin
  17. 17. CHARACTERISTICS TO BE MEASURED  Evaluations of BA/BE will be based upon the measured concentrations of the active drug substance(s) in the biological matrix.  The measurements of an active or inactive metabolite may be necessary: a)where the concentrations of the drug(s) may be too low to accurately measure in the biological matrix, (b) limitations of the analytical method, (c) unstable drug(s), (d) drug(s) with a very short half-life or (e) in the case of prodrugs.  Racemates should be measured using an achiral assay method.  The plasma-time concentration curve is mostly used to assess the rate and extent of absorption of the study drug. This include Cmax, Tmax, AUC0-t and AUC0-∞.  Pharmacokinetic Parameters measured are: • Plasma conc. and time points • Subject, period, sequence, treatment • Cmax, Tmax, AUC0-t ,AUC0-∞ • Partial AUC only for early exposure of drug content.  For steady state studies: • Swing • Cav • Cmin • Degree of fluctuation Measurement of Individual enantiomers in BE Studies is recommended if 1. Exhibit different Pharmacodynamic characteristics 2. Exhibit different Pharmacokinetics characteristics 3. Primary efficacy and safety activity resides with minor enantiomers 4. Nonlinear absorption is present
  18. 18. STATISTICAL EVALUATION  Primary concern of bioequivalence is to limit Consumer’s & Manufacturer’s risk • Cmax & AUC analysed using ANOVA • Tmax analysed by non-parametric methods  Use natural log transformation of Cmax and AUC  Calculate 90% confidence interval for this GMR for Cmax  Similarly calculate GMR for AUC Criteria for bioequivalence • To establish Bioequivalence, the calculated 90% confidence interval for AUC and Cmax should fall within the bioequivalence range, usually 80-125%. • Tighter limits for permissible differences in bioavailability may be required for drugs that have: I A narrow therapeutic index. II A serious, dose-related toxicity. III A steep dose/effect curve, or IV A non-linear pharmacokinetics within the therapeutic dose range.
  19. 19. I. Two-Period Crossover Design 2 formulations, even number of subjects, randomly divided into 2 equal groups First period , each member of one group receive a single dose of the test formulation; each member of the other group receive the standard formulation Subjects Period 1 Period 2 1-8 T S 9-16 S T
  20. 20. II. Latin Square Design  More than two formulations  A group of volunteers will receive formulations in the sequence shown
  21. 21. III. Balance Incomplete Block Design (BIBD)  More than 3 formulations, Latin square design will not be ethically advisable  Because each volunteer may require drawing of too many blood samples  If each volunteer expected to receive at least two formulation, then such a study can be carried out using BIBD
  22. 22. IV. Parallel-Group Design Even number of subjects in two groups Each receive a different formulation No washout necessary For drugs with long half life Treatment A Treatment B 1 2 3 4 5 6 7 8 9 10 11 12
  23. 23. V. Replicate Crossover-study design For highly variable drugs  Allows comparisons of within-subject variances  Reduce the number of subjects needed Four-period, two-sequence, two-formulation design (recommended) OR Three-sequence, three-period, single-dose, partially replicated Period 1 2 3 Group 1 T R T Group 2 R T R 4 R T
  24. 24. VI. Pilot Study  If the sponsor chooses, in a small number of subjects  To assess variability, optimize sample collection time intervals & provide other information, Validate analytical methodology.  Example: • Immediate-release products: careful timing of initial samples→ avoid a subsequent finding that the first sample collection, occured after the plasma concentration peak  Can be appropriate, provided its design & execution are suitable & sufficient number of subjects have completed the study
  25. 25. BIOWAIVERS– In vitro studies ,i.e. dissolution studies can be used in place of in vivo bioequivalence under certain conditions ,called BIOWAVIERS. 1. The drug product differs only in strength of active substance, provided the following condition hold ; a) Pharmacokinetics are linear. b) The qualitative composition is same. c) The ratio between active substance and excipient is same. d) Both product are produced by same manufacturer at same site with same manufacturing process. 2. The drug has been slightly reformulated or manufacturing method has been slightly modifies by same manufacturer in ways that can be argues irrelevant for BA. 3. The product meets following requirement :
  26. 26. a) The product is in form of solution or solublised form ( elixir, syrup) etc. b) The product contain active ingredient in same conc. as approved drug. c) The product contain no excipient known to significantly affect absorption of active ingredient. d) The product is administered by inhalation as gas or vapor. e) The product is for oral administration but not intended for absorption ( antacid or radio opaque medium ). f) The product is intended for topical administration (ointment, creams, gels etc,) for local effect.
  27. 27. PHARMACODYNAMIC STUDY  Measurement of effect on a Patho-physiological process as a function of time, after administration of 2 different products  Necessity: 1. Quantitative analysis in plasma or urine not possible with sufficient accuracy & sensitivity 2. Drug concentrations are not surrogate endpoints e.g. Topical formulations without systemic absorption 3. In situations of ‘Superiority Claims’  In case only Pharmacodynamic data is collected→ other methods tried & why they were unsuitable should be mentioned.
  28. 28. COMPARATIVE CLINICAL STUDIES  Necessity: • Both pharmacokinetic & pharmacodynamic parameters not properly measurable or not feasible • Mention which methods were tried & found unsuitable  Statistical principles to be considered: • No. of patients→ Variability of assessed parameters & acceptance range Much higher than BE studies
  29. 29. FOLLOWING CRITICAL POINTS NEED TO BE DEFINED IN ADVANCE, ON CASE TO CASE BASIS:  Clinical end points (Target parameters)→ intensity & onset of response  Size of equivalence range→ case-to-case basis (dependings on natural course of disease, efficacy of available treatments, target parameter)  Statistical confidence interval  Placebo included when appropriate  Safety end-points in some cases
  30. 30. DISSOLUTION STUDIES 1. Suitable to confirm unchanged product quality with minor changes in formulation / manufacturing after approval→ SUPAC ( Scale-Up & Post- Approval Changes) 2. Different strengths of drug manufactured by same manufacturer where: • Qualitative composition is same • Ratio of active ingredients & excipients is same • Method of manufacture is same • BE study has been performed on 1 strength • Linear pharmacokinetics 3. Assess batch-to-batch quality  More than 1 batch of each formulation tested
  31. 31. Design should include:  Individually testing of at least 12 dosage units of each batch →Mean & Individual results with Sd or SE  Measurement of percentage of content released at suitably spaced time points(eg. At 10, 20 & 30 mins or appropriate for complete dissolution)  Dissolution profile in atleast 3 aqueous media with pH range of 1.0-6.8 Or 1.0-8.0 wherever necessary  Conduct tests on each batch with same apparatus & on same or consecutive days
  32. 32. Dissolution testing should be carried out in:  USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the following dissolution media: • 0.1N HCl or Simulated Gastric Fluid USP without enzymes • a pH 4.5 buffer • a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes  For capsules and tablets with gelatin coating • Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used
  33. 33. DOCUMENTATION • With respect to the conduct of bioequivalence/bioavailability studies following important documents must be maintained: A) Clinical Data : • All relevant documents as required to be maintained for compliance with GCP Guidelines . B) Details of the analytical method validation including the following: a. System suitability test b. Linearity range c. Lowest limit of quantization d. QC sample analysis e. Stability sample analysis f. Recovery experiment result
  34. 34. C) Analytical data of volunteer plasma samples which should include the following: a. Validation data of analytical methods used, b. Chromatograms of all volunteers, c. Inter-day and intra-day variation of assay results, d. Details including chromatograms of any repeat analysis performed, e. Calibration status of the instruments . D) Raw data E) All comments of the chief investigator regarding the data of the study submitted for review. F) A copy of the final report