Bioequivalence Guidance Summary

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					Bioequivalence Guidance Summary                                                                                                                                         PHC331H1

 Bioequivalence Guidance Summary
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 Regulatory Body             FDA

 Study Design                Single Dose

 Drug Characteristics           Modified Release             Highly Variable Drug
                                Critical Dose Drug           Rapid Onset Drug
                                Long Half-life Drug          Non-Linear Kinetics



 Click here to check the FDA Guidance for Industry: Individual Product Bioequivalence Recommendations

 Standards for Bioequivalence
 Unless otherwise indicated by a specific guidance, this guidance recommends that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic range drugs remain
 unchanged for the bioavailability measures (AUC and Cmax) of narrow therapeutic range drugs. (1)
 *90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional PK Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2+ (1)




 Sampling Scheme Criteria
 We recommend that blood samples be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most drugs, we
 recommend that 12 to 18 samples, including a predose sample, be collected per subject per dose. This sampling can continue for at least three or more terminal half lives of
 the drug. The exact timing for sample collection depends on the nature of the drug and the input from the administered dosage form. The sample collection can be spaced in
 such a way that the maximum concentration of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can be estimated accurately. At least three to four
 samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear regression. (1) An adequate washout period (e.g., more than 5
 half lives of the moieties to be measured) would separate each treatment. (1)



 Fasting and/or Fed Required?
 we recommend a BE study under fed conditions for all orally administered immediate-release drug products, with the
 following exceptions:
 • When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permeability (BCS Class I)
 (see footnote 3), or
 • When the DOSAGE AND ADMINISTRATION section of the RLD label states that the product should be taken only on an empty stomach, or
 • When the RLD label does not make any statements about the effect of food on
 absorption or administration. (2)

 In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover study. Both treatments should be sprinkled on one of the soft foods mentioned in the labeling,
 usually applesauce. The BE data should be analyzed using average BE and the 90 percent CI criteria should be used to declare BE. If there are questions about other foods, the
 design, or the analysis of such BE studies, the sponsors and/or applicants should contact the Office of Generic Drugs.(2)




53132d11-91d5-47be-9872-5a2c3fd862ea.xls                                                                                                                    10/8/2011 - 11:57 AM
Bioequivalence Guidance Summary                                                                                                                                    PHC331H1

 Parent and/or Metabolite Required?
 For BE studies, measurement of only the parent drug released from the dosage form, rather than the metabolite, is generally recommended. The rationale for this
 recommendation is that concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is more reflective of
 metabolite formation, distribution, and elimination. The following are exceptions to this general approach.
 • Measurement of a metabolite may be preferred when parent drug levels are too low to allow reliable analytical measurement in blood, plasma, or serum for an adequate
 length of time. We recommend that the metabolite data obtained from these studies be subject to a confidence interval approach for BE demonstration. If there is a clinical
 concern related to efficacy or safety for the parent drug, we also recommend that sponsors and/or applicants contact the appropriate review division to determine whether
 the parent drug should be measured and analyzed statistically.
 • A metabolite may be formed as a result of gut wall or other presystemic metabolism. If the metabolite contributes meaningfully to safety and/or efficacy, we also
 recommend that the metabolite and the parent drug be measured. When the relative activity of the metabolite is low and does not contribute
 meaningfully to safety and/or efficacy, it does not have to be measured. We recommend that the parent drug measured in these BE studies be analyzed
 using a confidence interval approach. The metabolite data can be used to provide supportive evidence of comparable therapeutic outcome. (1)




 Blinding and Data Analysis
  Subjects with predose plasma concentrations:
 • If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements
 and calculations. We recommend that if the predose value is > than 5 percent of Cmax, the subject be dropped from all BE study evaluations.
 Data deletion due to vomiting:
 • We recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistical analysis if
 vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during the labeled
 dosing interval can be deleted. (1)




 Reference Product
 For ANDAs, we also recommend that the BE study be conducted between the test product and reference listed drug using the strength(s) specified in Approved Drug Products
 with Therapeutic Equivalence Evaluations (Orange Book). (1)




53132d11-91d5-47be-9872-5a2c3fd862ea.xls                                                                                                                10/8/2011 - 11:57 AM
Bioequivalence Guidance Summary                                                                                                                                  PHC331H1

 Combining Studies




 REFERENCES
 (1) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations. U.S. Department of Health and Human
 Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); March 2003. BP Revision 1.
 (2) Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services. Food and Drug Administration. Center
 for Drug Evaluation and Research (CDER); December 2002. BP.




53132d11-91d5-47be-9872-5a2c3fd862ea.xls                                                                                                              10/8/2011 - 11:57 AM
                                                                                           BA/BE Guidelines Summary
Regulatory                                            FDA                                                                                 TPD                                                                                  EMEA
Body

                Unless otherwise indicated by a specific guidance, this guidance recommends         For drugs with uncomplicated characteristics, the following standards-obtained        AUC-ratio: The 90% CI for this measure of relative BA should lie within an
                that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic       in single dose cross-over comparative bioavailability studies-determine               acceptance interval of 0.80-1.25. In specific cases of a narrow therapeutic
                range drugs remain unchanged for the bioavailability measures (AUC and              bioequivalence:                                                                       range the acceptance interval may be tightened. In rare cases a wider
                Cmax) of narrow therapeutic range drugs. (1)                                        a) The 90% confidence interval of the relative mean AUCT of the test to               acceptance range may be acceptable if it is based on sound clinical
                [90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional PK           reference product should be within 80 percent to 125 percent.                         justification.
                Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2] (1)                          b) The relative mean measured Cmax of the test to reference product should be         Cmax-ratio: The 90% CI for this measure of relative BA should lie within an
                                                                                                    between 80 percent and 125 percent.                                                   acceptance interval of 0.80-1.25.
                                                                                                    These standards must be met on log transformed parameters calculated from             The data should be transformed prior to analysis using a logarithmic
Standards for                                                                                       • the measured data, and                                                              transformation. (1)
BE: Single                                                                                          • data corrected for measured drug content (percent potency of label claim)           PK Parameters: AUCt, AUCinf, Cmax, tmax, AEt, AEinf. For additional
Dose Studies                                                                                        Additional PK Parameters to report: AUCT, AUCI, AUCT, AUCT/AUCI, Cmax,                information t1/2 and MRT can be estimated. (1)
                                                                                                    Tmax, lambda. (1)                                                                     If appropriate to the evaluation the analysis technique for tmax should be non-
                                                                                                                                                                                          parametric and should be applied to untransformed data. (1)
                                                                                                                                                                                          For establishing bioequivalence, the 90% confidence interval should lie within
                                                                                                                                                                                          the acceptance interval (in most cases, 0.80 – 1.25), the borders being
                                                                                                                                                                                          included. The conclusion that products are bioequivalent is based on the overall
                                                                                                                                                                                          scientific assessment of the PK studies, not only on meeting the acceptance
                                                                                                                                                                                          range. (3)
                For steady-state studies, we recommend that the measurement of total                The 90% confidence interval of the relative mean AUCtau of the test to                Whenever multiple dose studies are performed it should be demonstrated that
                exposure be the area under the plasma, serum, or blood concentration-time           reference formulation should be within 80% to 125%.                                   steady state has been reached. (2)
                curve from time zero to time tau over a dosing interval at steady state (AUC0-      The relative mean measured Cmax at steady state of the test to reference              PK Parameters: AUCtau, Cmax, Cmin, fluctuation.
                tau), where tau is the length of the dosing interval. (1)                           formulation should be within 80% to 125%.
                PK Parameters: Cmin (concentration at the end of a dosing interval), Cav            The relative mean measured Cmin at steady state of the test to reference
                (average concentration during a dosing interval), degree of fluctuation [(Cmax-     formulation should not be less than 80%.
                Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] (1)                                        [met on both potency uncorrected and corrected data]

                                                                                                    PK Parameters: AUCtau, Cmax, Tmax, Cpd, Cmin, fluctuation.
Standards for
                                                                                                    For steady-state studies of drugs with uncomplicated characteristics, at least
BE: Steady                                                                                          three consecutive pre-dose concentration levels (Cpd) are required to provide
State Studies                                                                                       evidence of steady state. Generally, observations of Cpd for the test and
                                                                                                    reference products should be recorded at the same time of the day. One of
                                                                                                    these measurements could be taken based on the first sample of the study day
                                                                                                    in which a profile over the dosing interval is being established. Steady state is
                                                                                                    usually achieved when repeated doses of a formulation are administered over a
                                                                                                    period that exceeds five disposition half-lives of the modified-release form. (6)

                                                                                                     Analysis of Tmax, lambda, and fluctuation should be carried out on the
                                                                                                     raw scale, while calculations for AUCX, AUCT, AUCtau, AUCI, Cmin, Cpd,
                                                                                                     and
                                                                                                     Cmax should use the logarithmic (ln) scale. (6)
                RAPID ONSET:                                                                         RAPID ONSET:                                                                         RAPID ONSET:
                An early exposure measure may be informative on the basis of appropriate             To date this standard has only been applied to two drugs, gel formulations of        Statistical evaluation of tmax only makes sense if there is a clinically relevant
                clinical efficacy/safety trials and/or pharmacokinetic/pharmacodynamic studies ibuprofen and tablet formulations of sumatriptan. This notice serves to clarify            claim for rapid release or action or signs related to adverse effects. The non-
                that call for better control of drug absorption into the systemic circulation (e.g., that bioequivalence standards for drugs for which an early time of onset or          parametric 90% confidence interval for this measure of relative bioavailability
                to ensure rapid onset of an analgesic effect or to avoid an excessive                rapid rate of absorption is important because of therapeutic or toxic effects (for   should lie within a clinically determined range.
                hypotensive action of an antihypertensive). In this setting, the guidance            example, an analgesic for rapid relief of pain) are as described in current TPD
                recommends use of partial AUC as an early exposure measure. We                       guidelines and policy statements. In addition, the relative mean AUCReftmax of
                recommend                                                                            the test to reference formulation should be within 80 to 125%, where
                that the partial area be truncated at the population median of Tmax values for       AUCReftmax for a test product is defined as the area under the curve to the
Rapid Onset     the reference formulation. We also recommend that at least two quantifiable          time of the maximum concentration of the reference product, calculated for
Drugs           samples be collected before the expected peak time to allow adequate                 each study subject. We reiterate that this notice applies to comparative
                estimation of the partial area. (1)                                                  bioavailability (bioequivalence) studies only. Submissions in support of
                                                                                                     comparative (superiority) claims, such that time to onset of effect is important,
                                                                                                     may need additional pharmacokinetic-pharmacodynamic or clinical data. (4)
              MODIFIED RELEASE:                                                                MODIFIED RELEASE (APPLIES TO SINGLE DOSE):
              For modified-release products submitted as ANDAs, the following studies are      PK Parameters: AUCX, AUCT, AUCI, AUCX/AUCI, AUCT/AUCI, Cmax, Tmax,
              recommended: (1) a single-dose, nonreplicate, fasting study comparing the        lambda. For formulations that are likely to accumulate
              highest strength of the test and reference listed drug product and (2) a food-   (i.e., AUCX/AUCI < 0.8), safety requires that steady-state studies be performed
Specifics for effect, nonreplicate study comparing the highest strength of the test and        in addition to the single-dose studies. Where the AUCX/AUCI ratio cannot
Modified      reference product (see section VI.A). Because single-dose studies are            be reliably determined, accumulation must be assumed to occur. (7)
Release Drugs considered more sensitive in addressing the primary question of BE (i.e.,
              release of the drug substance from the drug product into the systemic
              circulation), multiple-dose studies are generally not recommended, even in
              instances where nonlinear kinetics are present. (1)
              Extra PK parameters:
              • Lag-time (tlag) for modified-release products, if present (2)

                                                                                                                                                                                 HIGHLY VARIABLE DRUG:
                                                                                                                                                                                 A drug product is called highly variable if its intra-individual (i.e. within-subject)
                                                                                                                                                                                 variability is greater than 30%. A high CV as estimated from the ANOVA
                                                                                                                                                                                 model is thus an indicator for high within-subject variability. However, a
                                                                                                                                                                                 replicate design is needed to assess within-subject variability. (3)
                                                                                                                                                                                 90% CI of AUC ratio: In rare cases a wider acceptance range may be
                                                                                                                                                                                 acceptable if it is based on sound clinical justification.
                                                                                                                                                                                 90% CI of Cmax ratio: In specific cases of a narrow therapeutic range the
                                                                                                                                                                                 acceptance interval may be tightened. In certain cases a wider interval may be
Standards for
                                                                                                                                                                                 acceptable. The interval must be prospectively defined e.g. 0.75-1.33 and
BE: High
                                                                                                                                                                                 justified addressing in particular any safety or efficacy concerns for patients
variability
                                                                                                                                                                                 switched between formulations. (1)
drugs
                                                                                                                                                                                 The NfG states under 3.6.2 that ―With respect to the ratio of Cmax the 90%
                                                                                                                                                                                 confidence interval for this measure of relative bioavailability should lie within
                                                                                                                                                                                 an acceptance range of 0.80 – 1.25. In specific cases, such as a narrow
                                                                                                                                                                                 therapeutic range, the acceptance interval may need to be tightened.‖ The NfG
                                                                                                                                                                                 also states that ―In certain cases a wider interval may be acceptable. The
                                                                                                                                                                                 interval must be prospectively defined, e.g. 0.75 – 1.33, and justified
                                                                                                                                                                                 addressing
                                                                                                                                                                                 in particular any safety or efficacy concerns for patients switched between
                                                                                                                                                                                 formulations‖.
                                                                                                                                                                                 The possibility offered here by the guideline to widen the acceptance range of
                                                                                                                                                                                 0.80 – 1.25 for the ratio of Cmax (not for AUC) should be considered
                                                                                               NON-LINEAR KINETICS:
                                                                                               These requirements must be met in both the fasting and fed states except
                                                                                               where it has been demonstrated that food does not modify bioavailability at
                                                                                               doses within the range of strengths to be marketed. (8)
                                                                                               The following pharmacokinetic parameters should be calculated from single
                                                                                               dose studies: AUCX, AUCI, Cmax and, where possible, lambda. The following
                                                                                               parameters should be calculated from steady state studies: AUCtau, Cmax,
                                                                                               Cpd, and Cmin.
                                                                                               STANDARDS FOR NON-LINEAR KINETICS DRUGS:
Non-Linear                                                                                     Single Dose: Standards for bioavailability and bioequivalence are those
Kinetics                                                                                       described in Report A: "Bioavailability of Oral Dosage Formulations of Drugs
(Report C)                                                                                     Used for Systemic Effects".
                                                                                               Chronic Dose: For drugs requiring chronic dose studies the following
                                                                                               bioavailability and bioequivalence standards are required:
                                                                                               1. The 90% confidence interval of the relative mean AUCtau* of the test to
                                                                                               reference formulation should be within 80 to 125%.
                                                                                               2. The relative mean measured Cmax of the test to reference formulation
                                                                                               should be within 80 to 125%.
                                                                                               3. The relative mean measured Cmin of the test to reference formulation should
                                                                                               be within 80 to 125%.
                                                                                               AUCtau* is defined as the area under the plasma concentration- time curve
                                                                                               after several doses indicating
                                                                                               "pseudo" steady state. Because of the non-linearity, steady state may be
                  LONG HALF-LIFE DRUGS:                                                              LONG HALF-LIFE DRUGS:                                                               LONG HALF-LIFE DRUGS:
                  In a BA or pharmacokinetic study involving an oral product with a long half-life   This notice serves to clarify that for drugs which exhibit a terminal elimination   For drugs with a long half-life, relative bioavailability can be adequately
                  drug, adequate characterization of the half-life calls for blood sampling over a   half-life greater than 24 hours, bioequivalence standards in comparative            estimated using truncated AUC as long as the total collection period is justified.
                  long period of time. For a BE determination of an oral product with a long half-   bioavailability studies will be applied to AUC0-72h. For the purpose of             In this case the sample collection time should be adequate to ensure
                  life drug, a nonreplicate, single-dose, crossover study can be conducted,          bioequivalence assessment, it will not be necessary to sample for more than 72      comparison of the absorption process. (1)
                  provided an adequate washout period is used. If the crossover study is             hours post-dose, regardless of the half-life. Alternate designs such as parallel
                  problematic, a BE study with a parallel design can be used. For either a           studies could be considered. (3)
                  crossover or parallel study, we recommend that sample collection time be
                  adequate to ensure completion of gastrointestinal transit (approximately 2 to 3
Long Half-Life    days) of the drug product and absorption of the drug substance. Cmax and a
                  suitably truncated AUC can be used to characterize peak and total drug
                  exposure,
                  respectively. For drugs that demonstrate low intrasubject variability in
                  distribution and clearance, an AUC truncated at 72 hours (AUC0-72 hr) can be
                  used
                  in place of AUC0-t or AUC0-∞. For drugs demonstrating high intrasubject
                  variability in distribution and clearance, AUC truncation warrants caution. In
                  such
                  cases, we also recommend that sponsors and/or applicants consult the
                  appropriate review staff. (1)

                  CRITICAL DOSE DRUGS:                                                               CRITICAL DOSE DRUGS:                                                                CRITICAL DOSE DRUGS:
                  Unless otherwise indicated by a specific guidance, this guidance recommends        1. The 90% confidence interval of the relative mean AUC of the test to              [90% CI of] AUC-ratio: In specific cases of a narrow therapeutic range the
                  that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic      reference formulation should be within 90.0 to 112.0%; the relevant AUC or          acceptance interval may be tightened.
                  range drugs remain unchanged for the bioavailability measures (AUC and             AUCs                                                                                [90% CI of] Cmax-ratio: In specific cases of a narrow therapeutic range the
                  Cmax) of narrow therapeutic range drugs. (1)                                       as described in Guidelines A and B are to be determined.                            acceptance interval may need to be tightened. (1)
                                                                                                     2. The 90% confidence interval of the relative mean measured Cmax of the test
Standards for                                                                                        to reference formulation should be between 80.0 and 125.0%.
BE: Critical                                                                                         3. These requirements are to be met in both the fasted and fed states.
Dose Drugs                                                                                           4. These standards should be met on log transformed parameters calculated
                                                                                                     from the measured data and from data corrected for measured drug content
                                                                                                     (percent potency of label claim).
                                                                                                     5. Steady-state studies are not required for ―critical dose drugs‖ unless
                                                                                                     warranted by exceptional circumstances. If a steady-state study is required, the
                                                                                                     90% confidence interval of the relative mean measured Cmin of the test to
                                                                                                     reference formulation should also be between 80.0 and 125.0%. (6)

                  Subjects with predose plasma concentrations:                                       The analyses should include all data for all subjects (see Section 3.4, "Drop-      The method of analysis should be planned in the protocol. The protocol should
                  • If the predose concentration is ≤ 5 percent of Cmax value in that subject, the   outs and Withdrawal of Subjects from a Study") on measured data.                    also specify methods for handling drop-outs and for identifying biologically
                  subject‘s data without any adjustments can be included in all pharmacokinetic      Supplementary analyses may also be carried out with selected points or              implausible outliers. Post hoc exclusion of outliers is generally not accepted. If
                  measurements and calculations. We recommend that if the predose value is >         subjects initially excluded from the analyses. Such exclusions must be justified.   modelling assumptions made in the protocol (e.g. for extrapolating AUC to
                  than 5 percent of Cmax, the subject be dropped from all BE study evaluations.      It is rarely acceptable to exclude more than 5 percent of the subjects or more      infinity) turn out to be invalid, a revised analysis in addition to the planned
                  Data deletion due to vomiting:                                                     than 10 percent of the data for a single subject-formulation combination. (1)       analysis (if this is feasible) should be presented and discussed. (1)
                  • We recommend that data from subjects who experience emesis during the
                  course of a BE study for immediate-release products be deleted from statistical                                                                                   Under 3.6.3 the NfG states that ―Post-hoc exclusion of outliers is generally not
                  analysis if vomiting occurs at or before 2 times median Tmax. In the case of                                                                                      accepted‖ but at the same time acknowledges that ―the protocol should also
                  modified-release products, the data from subjects who experience emesis any                                                                                       specify methods for identifying biologically implausible outliers‖. Unbiased
                  time during the labeled dosing interval can be deleted. (1)                                                                                                       assessment of results from randomised studies requires that all subjects are
Data to Analyze                                                                                                                                                                     observed and treated according to the same rules that should be independent
                                                                                                                                                                                    from treatment or outcome. In consequence, pharmacokinetic data can only be
                                                                                                                                                                                    excluded based on non-statistical reasons that have been either defined
                                                                                                                                                                                    previously in the protocol or, at the very least, established before reviewing the
                                                                                                                                                                                    data. Acceptable explanations to exclude pharmacokinetic data or to exclude a
                                                                                                                                                                                    subject would be protocol violations like vomiting, diarrhoea,
                                                                                                                                                                                    analytical failure, etc. The search for such explanations must apply to all
                                                                                                                                                                                    subjects in all groups independently of the size of the observed
                                                                                                                                                                                    pharmacokinetic
                                                                                                                                                                                    parameters or its outlying position. 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
                We recommend that blood samples be drawn at appropriate times to describe The duration of blood or urine sampling in a study should be sufficient to                The sampling schedule should be planned to may justify post-hoc estimation of
                                                                                                                                                                                    pharmacokinetic effects. Exceptional reasonsprovide an adequate data
                the absorption, distribution, and elimination phases of the drug. For most drugs, account for at least 80 percent of the known AUC to infinity (AUCI). This period Cmax and to cover the plasma concentration time curve long enough to provide
                we recommend that 12 to 18 samples, including a predose sample, be                is usually at least three times the terminal half-life of the drug. To permit     a reliable estimate of the extent of absorption. This is generally achieved if the
                collected per subject per dose. This sampling can continue for at least three or Calculation of the relevant pharmacokinetic parameters, from 12 to 18 samples AUC derived from measurements is at least 80% of the AUC extrapolated to
                more terminal half lives of the drug. The exact timing for sample collection      should be collected per subject per dose. There may be considerable               infinity. If a reliable estimate of terminal half-life is necessary, it should be
Sampling
                depends on the nature of the drug and the input from the administered dosage inaccuracies in the estimates of the terminal disposition rate constant if the         obtained by collecting at least three to four samples during the terminal log
Scheme
                form. The sample collection can be spaced in such a way that the maximum          constant is estimated from linear regression using only a few points. To reduce linear phase. (1)
Criteria
                concentration of the drug in the blood (Cmax) and terminal elimination rate       these inaccuracies it is preferable that four or more points be determined during
                constant (λz) can be estimated accurately. At least three to four samples can     the terminal log-linear phase of the curve. (1)
                be obtained during the terminal log-linear phase to obtain an accurate estimate
                of λz from linear regression. (1)
                An adequate washout period (e.g., more than 5 half lives of the moieties to be     The interval should be the same for all subjects and, to account for variability in Subsequent treatments should be separated by adequate wash out periods.
                measured) would separate each treatment. (1)                                       elimination rate between subjects, normally should be not less than 10 times
Washout                                                                                            the mean terminal half-life of the drug. (generally, the interval between study
                                                                                                   days should not exceed four weeks). (1,7)

                we recommend a BE study under fed conditions for all orally administered           For uncomplicated drugs in immediate-release dosage forms, if there is a            Subjects should preferably be fasting at least during the night prior to
                immediate-release drug products, with the                                          documented serious safety risk to subjects from single-dose administration of       administration of the products. If the Summary of Product Characteristics of the
                following exceptions:                                                              the drug or drug product in the absence of food, then an appropriately designed     reference product contains specific recommendations in relation with food
                • When both test product and RLD are rapidly dissolving, have similar              study conducted in the presence of only a sufficient quantity of food to prevent    intake related to food interaction effects the study should be designed
                dissolution profiles, and contain a drug substance with high solubility and high   the toxicity may be acceptable for purposes of BE assessment. (5)                   accordingly. (1)
                permeability (BCS Class I) (see footnote 3), or
                • When the DOSAGE AND ADMINISTRATION section of the RLD label states                                                                                           The recommendations concerning food intake in the SPC are not sufficient for
                that the product should be taken only on an empty stomach, or                                                                                                  regulatory decisions on the adequacy of bioequivalence studies. Preferably, the
                • When the RLD label does not make any statements about the effect of food                                                                                     following conditions should be considered separately when the SPC
                on                                                                                                                                                             recommends administration of the substance together with food intake:
Fasting vs.     absorption or administration. (2)                                                                                                                              1. If the recommendation of food intake in the SPC is based on
Fed: Single                                                                                                                                                                    pharmacokinetic properties such as higher bioavailability, then a
Dose            In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover                                                                                 bioequivalence study under fed conditions is generally required.
                study. Both treatments should be sprinkled on one of the soft foods mentioned                                                                                  2. If the recommendation of food intake is intended to decrease adverse events
                in the labeling, usually applesauce. The BE data should be analyzed using                                                                                      or to improve tolerability, a bioequivalence study under fasting conditions is
                average BE and the 90 percent CI criteria should be used to declare BE. If                                                                                     considered acceptable although it would be advisable to perform the study
                there are questions about other foods, the design, or the analysis of such BE                                                                                  under fed conditions.
                studies, the sponsors and/or applicants should contact the Office of Generic                                                                                   3. If the SPC leaves a choice between fasting and fed conditions, then
                Drugs.(2)                                                                                                                                                      bioequivalence should preferably be tested under fasting conditions as this
                                                                                                                                                                               situation
                                                                                                                                                                               will be more sensitive to differences in pharmacokinetics.
                                                                                                                                                                               The composition of the meal should be described and taken into account, since
                                                                                                                                                                               a light meal might sometimes be preferable to mimic clinical conditions,
                We recommend that food-effect BA and fed BE studies be performed for all                                                                                       Different modified release formulations of the same sensitive to differences in
                                                                                               A second or subsequent market entry MR formulation should be compared with especially when the fed state is expected to be less drug substance may differ
                modified release dosage forms.                                                 the Group I or II MR product with which bioequivalence is claimed. Both         with respect to food interaction. Hence, the influence of food on the
                                                                                               formulations should be administered as single doses. The objective of these     bioavailability of oral modified release formulations must be investigated for
Fasting vs.                                                                                    studies is to evaluate the bioequivalence of the test and reference drug        safety and efficacy purposes. (2)
Fed: Modified                                                                                  products under both fasting and fed conditions. However, safety of the subjects
Release                                                                                        may require that an investigation be conducted after the administration of an
                                                                                               appropriate meal at a specified time before taking the drug. In this case,
                                                                                               manufacturers should consult with Health Canada before undertaking the study.
                                                                                               (7)

                                                                                                   CRITICAL DOSE:
                                                                                                   In general BE should be demonstrated under both fasted and fed conditions.

Fasting vs.                                                                                        For complicated drugs in immediate-release dosage form [#5.2] and drugs in
Fed: Critical                                                                                      modified-release dosage forms [#5.3], if there is a documented serious safety
                                                                                                   risk to subjects from single-dose administration of the drug or drug product in
Dose
                                                                                                   either the absence or presence of food, then an appropriately designed study
                                                                                                   conducted in the indicated condition of use (fed or fasted state) may be
                                                                                                   acceptable for purposes of BE assessment. (5)

                                                                                                   If possible, the study should be conducted in such a way that the subject is not
                                                                                                   aware of which product is administered. Furthermore, the person checking for
                                                                                                   adverse reactions and the person conducting the analysis of samples must not
Blinding                                                                                           know which product was administered. Other individuals involved in the
                                                                                                   administration of the drugs, the surveillance of the patients, or the analysis of
                                                                                                   plasma (or blood, or serum) data should not know which product was
                                                                                                   administered. (1)

                For ANDAs, we also recommend that the BE study be conducted between the            • a drug product that has been issued a notice of compliance pursuant to            A 'Reference Product' must be an 'innovator' product. (1)
Reference       test product and reference listed drug using the strength(s) specified in          section C.08.004 of the Food and Drug Regulations, and is currently marketed
Product         Approved Drug Products with Therapeutic Equivalence Evaluations (Orange            in Canada by the innovator, or
                Book). (1)                                                                         • a drug product acceptable to the Director. (1)
              For BE studies, measurement of only the parent drug released from the dosage          Determination of bioequivalence should be based on data for the parent drug.      In most cases evaluation of bioavailability and bioequivalence will be based
              form, rather than the metabolite, is generally recommended. The rationale for                                                                                           upon the measured concentrations of the parent compound. In some situations,
              this recommendation is that concentration-time profile of the parent drug is          Waiver of the measurement of the parent drug will not be considered, unless       however, measurements of an active or inactive metabolite may be necessary
              more sensitive to changes in formulation performance than a metabolite, which         concentrations of the parent drug cannot be reliably measured, e.g., if the       instead of the parent compound. Such situations include cases where the use
              is more reflective of metabolite formation, distribution, and elimination. The        parent drug is not detectable due to rapid biotransformation or limitations in    of a metabolite may be advantageous to determine the extent of drug input, e.g.
              following are exceptions to this general approach.                                    available assay methodology. In such instances, the use of metabolite data        if the concentration of the active substance is too low to be accurately
              • Measurement of a metabolite may be preferred when parent drug levels are            may be acceptable. The measured metabolite should be a primary (first step)       measured in the biological matrix (e.g. major difficulty in analytical method,
              too low to allow reliable analytical measurement in blood, plasma, or serum for       and major one, and appropriate scientific justification for a waiver of the       product instable in the biological matrix or half-life of the parent compound too
              an adequate length of time. We recommend that the metabolite data obtained            measurement of the parent drug and the use of metabolite data should be           short) thus giving rise to significant variability.
              from these studies be subject to a confidence interval approach for BE                provided. The choice of using the metabolite instead of the parent drug is to be
              demonstration. If there is a clinical concern related to efficacy or safety for the   clearly stated, a priori, in the objective of the study in the study protocol.      Bioequivalence determinations based on metabolites should be justified in
Metabolites   parent drug, we also recommend that sponsors and/or applicants contact the                                                                                                each case bearing in mind that the aim of a bioequivalence study is intended to
              appropriate review division to determine whether the parent drug should be            For the purpose of this guidance, a pro-drug is to be treated as a ‗parent drug‘. compare the in vivo performance of test and reference products. In particular if
              measured and analyzed statistically.                                                  That is, if the substance released from the dosage form is absorbed intact and metabolites significantly contribute to the net activity of an active substance and
              • A metabolite may be formed as a result of gut wall or other presystemic             is reliably measurable in the systemic circulation, it should be used in the        the pharmacokinetic system is non-linear, it is necessary to measure both
              metabolism. If the metabolite contributes meaningfully to safety and/or efficacy,     assessment of bioequivalence. It is not generally considered necessary to           parent drug and active metabolite plasma concentrations and evaluate them
              we also recommend that the metabolite and the parent drug be measured.                measure both                                                                        separately. (1)
              When the relative activity of the metabolite is low and does not contribute           parent drug and metabolite levels for the purpose of bioequivalence
              meaningfully to safety and/or efficacy, it does not have to be measured. We           assessment. However, quantitation of metabolite levels may sometimes be             According to the guideline, the only situations where metabolite data can be
              recommend that the parent drug measured in these BE studies be analyzed               helpful, e.g., to explain extreme values caused by metabolic changes within a used to establish bioequivalence are:
              using a confidence interval approach. The metabolite data can be used to              subject. In those rare situations where use of drug concentrations in urine is      1. ―If the concentration of the active substance is too low to be accurately
              provide supportive evidence of comparable therapeutic outcome. (1)                    justifiable for the assessment of relative bioavailability, only parent drug        measured in the biological matrix, thus giving rise to significant variability‖.
                                                                                                    concentrations may be used. That is, use of metabolite concentrations in urine Comments. Metabolite data can only be used if the Applicant presents
                                                                                                    is two or more studies have been completed, they may be pooled if (3 - DRAFT) convincing, state-of-theart arguments that measurements of the parent
                                                                                                    If not considered acceptable in the assessment of bioequivalence. certain
                                                                                                    requirements are met.
                                                                                                    a) The same protocol must be used for all studies.
                                                                                                    Specifically, this means that the same analytical method is to be used, the
                                                                                                    blood samples drawn at the same time, and the same lots of the same
                                                                                                    formulations used.
                                                                                                    b) Two consistency tests must be done on the studies to ensure that pooling is
Combining                                                                                           meaningful.
Studies                                                                                             The first test is the test of equality of the residual mean squares. Take the ratio
                                                                                                    of the residual from the first study to the residual for each of the other studies.
                                                                                                    (For each ratio, the smaller of the two residuals must be used as the
                                                                                                    denominator.) This ratio is compared to an F statistic, using the degrees of
                                                                                                    freedom associated with the residuals. If the ratio is greater than the 5% F
                                                                                                    value, the studies may not be combined. The second test is the formulation by
                                                                                                    study interaction and is carried out as shown in Table 7-A. (1)


Sources:
              (1) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally (1) Guidance for Industry: Conduct and Analysis of Bioavailability and      (1) Committee for Proprietary Medicinal Products (CPMP) - Note for Guidance
              Administered Drug Products — General Considerations. U.S. Department of          Bioequivalence Studies - Part A: Oral Dosage Formulations Used for Systemic on the Investigation of Bioavailability and Bioequivalence.
              Health and Human Services, Food and Drug Administration, Center for Drug         Effects. Health Products and Food Branch Guidance Document (1992).          CPMP/EWP/QWP/1401/98. London, 26 July 2001.
              Evaluation and Research (CDER); March 2003. BP Revision 1.

              (2) Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence         (2) DRAFT GUIDANCE FOR INDUSTRY: Use of Metabolite Data in                        (2) Committee for Proprietary Medicinal Products (CPMP) - Note for Guidance
              Studies. U.S. Department of Health and Human Services. Food and Drug                  Comparative Bioavailability Studies. Health Products and Food Branch,             on Modified Release Oral and Transdermal Dosage Forms: Section II
              Administration. Center for Drug Evaluation and Research (CDER); December              2004/05/05.                                                                       (Pharmacokinetic and Clinical Evaluation). CPMP/EWP/280/96 28 July 1999.
              2002. BP.
                                                                                                    (3) NOTICE TO INDUSTRY: Bioequivalence Requirements for Long Half-life            (3) CHMP EFFICACY WORKING PARTY) THERAPEUTIC SUBGROUP ON
                                                                                                    Drugs. file 05-113899-750. June 22, 2005.                                         PHARMACOKINETICS (EWP-PK): Questions & Answers on the Bioavailability
                                                                                                                                                                                      and Bioequivalence Guideline; EMEA/CHMP/EWP/40326/2006; London, 27
                                                                                                                                                                                      July 2006
                                                                                                    (4) NOTICE TO INDUSTRY: Bioequivalence Requirements for Drugs for Which
                                                                                                    an Early Time of Onset or Rapid Rate of Absorption Is Important (rapid onset
                                                                                                    drugs). 05-113913-859. June 22, 2005.
                                                                                                    (5) GUIDANCE FOR INDUSTRY: Bioequivalence Requirements: Comparative
                                                                                                    Bioavailability Studies Conducted in the Fed State. Health Products and Food
                                                                                                    Branch. 05-114865-164. July 21, 2005.
                                                                                                    (6) GUIDANCE FOR INDUSTRY: Bioequivalence Requirements: Critical Dose
                                                                                                    Drugs. Health Products and Food Branch. 06-112871-930. June 7, 2006.

                                                                                                    (7) GUIDANCE FOR INDUSTRY: Conduct and Analysis of Bioavailability and
                                                                                                    Bioequivalence Studies - Part B: Oral Modified Release Formulations. Health
                                                                                                    Products and Food Branch Guidance Document. 1996.
(8) Report on Bioavailability of Oral Dosage Formulations of Drugs Used for
Systemic Effects. Report C: Report on Bioavailability of Oral Dosage
Formulations, Not in Modified Release Form, of Drugs Used for Systemic
Effects, Having Complicated or Variable Pharmacokinetics. Expert Advisory
Committee on Bioavailability. Health Protection Branch, December 1992.
Canadian BA/BE Drug Classification System
Critical Dose Drugs
Cyclosporine                  C - Critical Dose Drug
Digoxin                       C - Critical Dose Drug
Flecainide                    C - Critical Dose Drug
Lithium                       C - Critical Dose Drug
Phenytoin                     C - Critical Dose Drug
Sirolimus                     C - Critical Dose Drug
Tacrolimus                    C - Critical Dose Drug
Theophylline                  C - Critical Dose Drug
Warfarin                      C - Critical Dose Drug

Drugs with Non-Linear Kinetics
Acetylsalicylic acid          C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Acyclovir                     C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Carbamazepine                 C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Cephalosporins                C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Disopyramide                  C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Fluorouracil                  C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Glucocorticosteroids          C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Griseofulvin                  C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Levodopa                      C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Phenytoin                     C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Propranolol                   C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Rifampin                      C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Valproic acid                 C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Verpamil                      C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
FDA Special Guidances/Exceptions: Bioequivalence
FDA Special Guidances:
Clozapine                   Steady-state study in patients required at 100 mg. See http://www.fda.gov/CDER/GUIDANCE/6077fnl.
Potassium Chloride          Steady-state study required. See http://www.fda.gov/CDER/GUIDANCE/old195fn.pdf

FDA Exceptions:
The following drugs are defined by the 2008 FDA Orange Book as, "DRUG PRODUCTS WHICH
MUST DEMONSTRATE IN VIVO BIOAVAILABILITY
ONLY IF PRODUCT FAILS TO ACHIEVE ADEQUATE DISSOLUTION"
Source: http://www.fda.gov/cder/orange/obannual.pdf
w.fda.gov/CDER/GUIDANCE/6077fnl.pdf
ANCE/old195fn.pdf

				
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