Veterinary drugs- bioequivalence guidance

(THIS VERSION OF THE GUIDANCE REPLACES THE VERSION TITLED “BIOEQUIVALENCE GUIDANCE” THAT WAS MADE AVAILABLE ON OCTOBER 9, 2002. THIS DOCUMENT HAS BEEN REVISED TO UPDATE THE CONTACT INFORMATION AND TYPOGRAPHICAL ERRORS IN THE EQUATION) Section III.

A. of this guidance has been superceded by CDER’s guidance entitled “Bioanalytical Method Validation”. Any general questions regarding the application of the Bioanalytical Method Validation guidance to new animal drugs should be directed to Marilyn Martinez, Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, (240)276-8357, marilyn. [email protected] hhs. gov.

Any questions regarding analytical methods for tissue residues should be directed to Valerie Reeves, 7500 Standish Pl. , Rockville, MD 20855, (240)276-8207, valerie. [email protected] hhs. gov . THIS DOCUMENT IS INTENDED TO PROVIDE GUIDANCE FOR THE DESIGN AND ANALYSIS OF IN VIVO BIOEQUIVALENCE STUDIES. THIS REVISION TO THE VERSION THAT WAS MADE AVAILABLE IN APRIL 1996 ADDS AN ILLUSTRATIVE EXAMPLE OF HOW TO CALCULATE CONFIDENCE BOUNDS WHEN LOG TRANSFORMED DATA ARE USED. COMMENTS AND SUGGESTIONS REGARDING THIS GUIDANCE DOCUMENT SHOULD BE SUBMITTED TO THE DIVISON.

OF DOCKETS MANAGEMENT (HFA-305), FOOD AND DRUG ADMINISTRATION, 5630 FISHERS LANE, RM. 1061, ROCKVILLE, MD 20852. ALL COMMENTS SHOULD BE IDENTIFIED WITH THE DOCKET NUMBER (94D- 0401). ADDITIONAL INFORMATION ON THE 1996 GUIDANCE DOCUMENT CAN BE FOUND IN THE FEDERAL REGISTER (VOL. 61, NO. 102, MAY 24, 1996). COMMENTS WILL BE ACCEPTED AT ANY TIME. FOR QUESTIONS REGARDING THIS GUIDANCE DOCUMENT, CONTACT KEN J. HARSHMAN, CENTER FOR VETERINARY MEDICINE (HFV-104), FOOD AND DRUG ADMINISTRATION, 7500 STANDISH PLACE, ROCKVILLE, MD 20855. U. S. Department of Health and Human Services Food and Drug Administration Center for Veterinary Medicine (CVM).

November 8, 2006 BIOEQUIVALENCE GUIDANCE DOCKET NO. 94D-0401 THIS GUIDANCE DOCUMENT REPRESENTS THE AGENCY’S CURRENT THINKING ON THIS MATTER. IT DOES NOT CREATE OR CONFER ANY RIGHTS FOR OR ON ANY PERSON AND DOES NOT OPERATE TO BIND THE FDA OR PUBLIC. AN ALTERNATIVE APPROACH MAY BE USED IF SUCH APPROACH SATISFIES THE REQUIREMENTS OF THE APPLICABLE STATUTE, REGULATIONS OR BOTH. PREAMBLE IN 1996, THE CENTER FOR VETERINARY MEDICINE (CVM) REVISED A DOCUMENT ENTITLED “APRIL 1990 BIOEQUIVALENCE GUIDELINE. ” THE REVISED DOCUMENT, “BIOEQUIVALENCE GUIDANCE (FINAL) 1996”, WAS ISSUED IN FINAL FORM FOLLOWING NOTICE AND COMMENT.

MANY OF THE CHANGES IN THE “BIOEQUIVALENCE GUIDANCE (FINAL) 1996” WERE BASED UPON REPORTS FROM PANEL PRESENTATIONS AT THE 1993 VETERINARY DRUG BIOEQUIVALENCE WORKSHOP IN ROCKVILLE, MARYLAND, SPONSORED BY THE CENTER FOR VETERINARY MEDICINE (CVM), THE ANIMAL HEALTH INSTITUTE (AHI), THE AMERICAN ACADEMY OF VETERINARY PHARMACOLOGY AND THERAPEUTICS (AAVPT), AND THE Animal Drug Alliance1. Some new topics were introduced into the guidance as a result of issues IDENTIFIED IN THE REVIEW OF BIOEQUIVALENCE PROTOCOLS AND STUDIES. THE MAJOR NEW TOPICS IN THE GUIDANCE WERE AS FOLLOWS: 1. HIGHER THAN APPROVED DOSE BIOEQUIVALENCE STUDIES.

2. BIOEQUIVALENCE TESTING FOR MULTIPLE STRENGTH SOLID ORAL DOSAGE FORMS. 3. ASSAY CONSIDERATIONS FOR BIOEQUIVALENCE STUDIES. 4. AUC AND CMAX AS THE PIVOTAL PARAMETERS FOR BIOEQUIVALENCE DETERMINATION. 5. BLOOD LEVEL BIOEQUIVALENCE STUDIES TO BE ACCOMPANIED BY TISSUE RESIDUE DEPLETION STUDIES FOR GENERIC PRODUCTS FOR FOOD-PRODUCING ANIMALS. CVM HAS REVISED THE “1996 BIOEQUIVALENCE GUIDANCE” TO ADD AN ILLUSTRATIVE EXAMPLE OF HOW TO CALCULATE CONFIDENCE BOUNDS WHEN LOG TRANSFORMED DATA ARE USED. THE GUIDANCE HAS ALSO BEEN REVISED IN ACCORDANCE WITH FDA’S GOOD GUIDANCE PRACTICES (GGPS, FOUND IN THE FEDERAL.

REGISTER OF FEBRUARY 27, 1997, 62 FR 8961). WITH THE EXCEPTION OF THE ADDITION OF INFORMATION ON HOW TO CALCULATE CONFIDENCE BOUNDS WHEN LOG TRANSFORMED DATA ARE USED, MINOR REVISIONS MADE TO COMPLY WITH THE GGPS (E. G. , ADDITION OF A COVER SHEET), AND REVISIONS TO THE PREAMBLE, 2 3 THE DOCUMENT IS THE SAME AS THE DOCUMENT ISSUED IN 1996. IN SEPTEMBER 2000, FDA REVISED THE GUIDANCE TO CLARIFY SOURCES OF INFORMATION MORE CLEARLY.

IS (ARE) ABSORBED AND BECOME(S) AVAILABLE AT THE SITE(S) OF DRUG ACTION. THE GENERIC ANIMAL DRUG AND PATENT TERM RESTORATION ACT (GADPTRA) SIGNED INTO LAW ON NOVEMBER 16, 1988, PERMITS SPONSORS TO SUBMIT AN ABBREVIATED NEW ANIMAL DRUG APPLICATION (ANADA) FOR A GENERIC VERSION OF ANY OFF-PATENT APPROVED ANIMAL DRUG (WITH CERTAIN EXCEPTIONS NOTED IN THE LAW)

REGARDLESS OF WHETHER THE DRUG WAS APPROVED PRIOR TO 1962 AND SUBJECT TO THE National Academy of Sciences / National Research Council / Drug Effectiveness Study Implementation (NAS/NRC/DESI) REVIEW. BIOEQUIVALENCE STUDIES ARE USED IN A VARIETY OF SITUATIONS, MOST OFTEN WHEN A SPONSOR PROPOSES MANUFACTURING A GENERIC VERSION OF AN APPROVED OFF-PATENT PRODUCT.

A BIOEQUIVALENCE STUDY MAY ALSO BE PART OF A NEW ANIMAL DRUG APPLICATION (NADA) OR SUPPLEMENTAL NADA FOR APPROVAL OF AN ALTERNATIVE DOSAGE FORM, NEW ROUTE OF ADMINISTRATION, OR A SIGNIFICANT MANUFACTURING CHANGE WHICH MAY AFFECT DRUG BIOAVAILABILITY.

THE CENTER HAS CONCLUDED THAT THE TISSUE RESIDUE DEPLETION OF THE GENERIC PRODUCT IS NOT ADEQUATELY ADDRESSED THROUGH BIOEQUIVALENCE STUDIES. THEREFORE, SPONSORS OF ANADA’S FOR DRUG PRODUCTS FOR FOOD-PRODUCING ANIMALS WILL GENERALLY BE ASKED TO INCLUDE BIOEQUIVALENCE AND TISSUE RESIDUE STUDIES (21 USC 360 B (N) (1) (E)).

A TISSUE RESIDUE STUDY SHOULD GENERALLY ACCOMPANY CLINICAL END-POINT AND PHARMACOLOGIC END-POINT BIOEQUIVALENCE STUDIES, AND BLOOD LEVEL BIOEQUIVALENCE STUDIES THAT CAN NOT QUANTIFY THE CONCENTRATION OF THE DRUG IN BLOOD THROUGHOUT the established withdrawal period (21 USC 360 b (n) (1) (A) (ii)).

BIOEQUIVALENCE STUDIES (I. E. , BLOOD LEVEL, PHARMACOLOGIC END-POINT, AND CLINICAL END-POINT STUDIES) AND TISSUE RESIDUE DEPLETION STUDIES SHOULD BE CONDUCTED IN ACCORDANCE WITH GOOD LABORATORY PRACTICE (GLP) REGULATIONS (21 CFR PART 58). WHEREAS THE FOCUS OF THE GUIDANCE IS BIOEQUIVALENCE TESTING FOR ANADA APPROVAL, THE GENERAL.

PRINCIPLES ALSO APPLY TO RELATIVE BIOAVAILABILITY STUDIES CONDUCTED FOR NADA’S. SPONSORS SHOULD CONSULT WITH THE CENTER EARLY IN THE PRODUCT DEVELOPMENT PROCESS TO FACILITATE THE DESIGN OF STUDIES ADEQUATE FOR DRUG APPROVAL. THE CENTER URGES SPONSORS TO SUBMIT PROTOCOLS FOR REVIEW PRIOR TO CONDUCTING STUDIES.

7 II. GENERAL CONSIDERATIONS A. Selection of Reference Product for Bioequivalence Testing AS A GENERAL RULE, THE PROPOSED GENERIC PRODUCT SHOULD BE TESTED AGAINST THE ORIGINAL PIONEER PRODUCT. IF THE ORIGINAL PIONEER PRODUCT IS NO LONGER MARKETED, BUT REMAINS ELIGIBLE TO BE COPIED, THEN THE FIRST APPROVED AND AVAILABLE GENERIC COPY OF THE PIONEER SHOULD BE USED AS THE REFERENCE PRODUCT FOR BIOEQUIVALENCE.

TESTING AGAINST THE PROPOSED NEW GENERIC PRODUCT. IF SEVERAL APPROVED NADA’S EXIST FOR THE SAME DRUG PRODUCT, AND EACH APPROVED PRODUCT IS LABELED DIFFERENTLY (I. E. , DIFFERENT SPECIES AND/OR CLAIMS), THEN THE GENERIC SPONSOR MUST CLEARLY IDENTIFY WHICH PRODUCT LABEL IS THE INTENDED PIONEER. BIOEQUIVALENCE TESTING SHOULD BE CONDUCTED AGAINST THE SINGLE APPROVED PRODUCT WHICH BEARS THE LABELING THAT THE GENERIC SPONSOR INTENDS TO COPY.

THE GENERIC SPONSOR SHOULD CONSULT WITH CVM REGARDING SELECTION OF THE APPROPRIATE REFERENCE PRODUCT BEFORE CONDUCTING THE BIOEQUIVALENCE STUDY. B. Criteria for Waiver of In Vivo Bioequivalence Study THE REQUIREMENT FOR THE IN VIVO BIOEQUIVALENCE STUDY MAY BE WAIVED FOR CERTAIN GENERIC PRODUCTS (21 USC 360 B (N) (1) (E)).

CATEGORIES OF PRODUCTS WHICH MAY BE ELIGIBLE FOR WAIVERS INCLUDE, BUT ARE NOT LIMITED TO, THE FOLLOWING: 1. PARENTERAL SOLUTIONS INTENDED FOR INJECTION BY THE INTRAVENOUS, SUBCUTANEOUS, OR INTRAMUSCULAR ROUTES OF ADMINISTRATION. 2. ORAL SOLUTIONS OR OTHER SOLUBILIZED FORMS. 3.

TOPICALLY APPLIED SOLUTIONS INTENDED FOR LOCAL THERAPEUTIC EFFECTS. OTHER TOPICALLY APPLIED DOSAGE FORMS INTENDED FOR LOCAL THERAPEUTIC EFFECTS FOR NON-FOOD ANIMALS ONLY.

4. INHALANT VOLATILE ANESTHETIC SOLUTIONS. IN GENERAL, THE GENERIC PRODUCT BEING CONSIDERED FOR A WAIVER CONTAINS THE SAME ACTIVE AND INACTIVE INGREDIENTS IN THE SAME DOSAGE FORM AND CONCENTRATION AND HAS THE SAME PH AND PHYSICO-CHEMICAL CHARACTERISTICS AS AN APPROVED PIONEER PRODUCT. HOWEVER, THE CENTER WILL CONSIDER BIOEQUIVALENCE WAIVERS FOR NON-FOOD ANIMAL TOPICAL PRODUCTS WITH CERTAIN DIFFERENCES IN THE INACTIVE INGREDIENTS OF THE PIONEER AND GENERIC PRODUCTS.

IF A WAIVER OF THE IN VIVO BIOEQUIVALENCE AND/OR THE TISSUE RESIDUE STUDY/STUDIES IS GRANTED FOR A FOOD ANIMAL DRUG PRODUCT, THEN THE WITHDRAWAL PERIOD ESTABLISHED FOR THE PIONEER PRODUCT WILL BE ASSIGNED TO THE GENERIC PRODUCT. 8 SPONSORS MAY APPLY FOR WAIVERS OF IN VIVO BIOEQUIVALENCE STUDIES PRIOR TO SUBMISSION OF THE ANADA’S.

C. Selection of Blood Level, Pharmacologic End-point, or Clinical End-point Study IN VIVO BIOEQUIVALENCE MAY BE DETERMINED BY ONE OF SEVERAL DIRECT OR INDIRECT METHODS. SELECTION OF THE METHOD DEPENDS UPON THE PURPOSE OF THE STUDY, THE ANALYTICAL METHOD AVAILABLE, AND THE NATURE OF THE DRUG PRODUCT.

BIOEQUIVALENCE TESTING SHOULD BE CONDUCTED USING THE MOST APPROPRIATE METHOD AVAILABLE FOR THE SPECIFIC USE OF THE PRODUCT. THE PREFERRED HIERARCHY OF BIOEQUIVALENCE STUDIES (IN DESCENDING ORDER OF SENSITIVITY) IS THE BLOOD LEVEL STUDY, PHARMACOLOGIC END-POINT STUDY, AND CLINICAL END-POINT STUDY.

WHEN ABSORPTION OF THE DRUG IS SUFFICIENT TO MEASURE DRUG CONCENTRATION DIRECT LY IN THE BLOOD (OR OTHER APPROPRIATE BIOLOGICAL FLUIDS OR TISSUES) AND SYSTEMIC ABSORPTION IS RELEVANT TO THE DRUG ACTION, THEN A BLOOD (OR OTHER BIOLOGICAL FLUID OR TISSUE) LEVEL BIOEQUIVALENCE STUDY SHOULD BE CONDUCTED.

THE BLOOD LEVEL STUDY IS GENERALLY PREFERRED ABOVE ALL OTHERS AS THE MOST SENSITIVE MEASURE OF BIOEQUIVALENCE. THE SPONSOR SHOULD PROVIDE JUSTIFICATION FOR CHOOSING EITHER A PHARMACOLOGIC OR CLINICAL END-POINT STUDY OVER A BLOOD-LEVEL (OR OTHER BIOLOGICAL FLUIDS OR TISSUES) STUDY. WHEN THE MEASUREMENT OF THE RATE AND EXTENT OF ABSORPTION OF THE DRUG IN BIOLOGICAL FLUIDS CAN NOT BE ACHIEVED OR IS UNRELATED TO DRUG ACTION, A PHARMACOLOGIC END-POINT (I. E. , DRUG INDUCED PHYSIOLOGIC CHANGE WHICH IS RELATED TO THE APPROVED INDICATIONS FOR USE) STUDY MAY BE CONDUCTED.

LASTLY, IN ORDER OF PREFERENCE, IF DRUG CONCENTRATIONS IN BLOOD (OR FLUIDS OR TISSUES) ARE NOT MEASURABLE OR ARE INAPPROPRIATE, AND THERE ARE NO APPROPRIATE PHARMACOLOGIC EFFECTS THAT CAN BE MONITORED, THEN A CLINICAL END-POINT STUDY MAY BE CONDUCTED, COMPARING THE TEST (GENERIC) PRODUCT TO THE REFERENCE (PIONEER) PRODUCT AND A PLACEBO (OR NEGATIVE).

CONTROL. D. Species Selection A BIOEQUIVALENCE STUDY GENERALLY SHOULD BE CONDUCTED FOR EACH SPECIES FOR WHICH THE PIONEER PRODUCT IS APPROVED ON THE LABEL, WITH THE EXCEPTION OF “MINOR” SPECIES (AS DEFINED IN SECTION 514.

1 (D) (1) OF TITLE 21 OF THE CODE OF FEDERAL REGULATIONS) ON THE LABEL. E. Dose Selection DOSE SELECTION WILL DEPEND UPON THE LABEL CLAIMS, CONSIDERATION OF ASSAY SENSITIVITY, AND RELEVANCE TO THE PRACTICAL USE CONDITIONS OF THE REFERENCE PRODUCT.

A BLOOD LEVEL BIOEQUIVALENCE STUDY SHOULD GENERALLY BE CONDUCTED AT THE HIGHEST DOSE APPROVED FOR THE PIONEER PRODUCT. HOWEVER, THE CENTER WILL CONSIDER A BIOEQUIVALENCE STUDY CONDUCTED AT A HIGHER THAN APPROVED DOSE IN CERTAIN CASES. SUCH A STUDY MAY BE APPROPRIATE WHEN A MULTIPLE OF THE HIGHEST APPROVED DOSE ACHIEVES MEASURABLE BLOOD LEVELS, BUT THE HIGHEST APPROVED DOSE DOES NOT.

IN GENERAL, THE STUDY WOULD BE LIMITED TO 2-3X THE HIGHEST DOSE APPROVED FOR THE PIONEER PRODUCT. THE PIONEER PRODUCT SHOULD HAVE AN ADEQUATE MARGIN OF SAFETY AT THE HIGHER THAN APPROVED DOSE LEVEL. THE GENERIC SPONSOR SHOULD ALSO CONFIRM (E. G. , THROUGH LITERATURE) THAT THE DRUG FOLLOWS LINEAR KINETICS.

A HIGHER THAN APPROVED DOSE BIOEQUIVALENCE STUDY IN FOOD ANIMAL SPECIES WOULD BE ACCOMPANIED BY A TISSUE RESIDUE WITHDRAWAL STUDY CONDUCTED AT THE HIGHEST APPROVED DOSE FOR THE 9 PIONEER PRODUCT. FOR PRODUCTS LABELED FOR MULTIPLE CLAIMS INVOLVING DIFFERENT PHARMACOLOGIC ACTIONS AT A BROAD DOSE RANGE (E. G., THERAPEUTIC AND PRODUCTION CLAIMS), A SINGLE BIOEQUIVALENCE STUDY AT THE HIGHEST APPROVED DOSE WILL USUALLY BE ADEQUATE.

HOWEVER, MULTIPLE BIOEQUIVALENCE STUDIES AT DIFFERENT DOSES MAY BE NEEDED IF THE DRUG IS KNOWN TO FOLLOW NONLINEAR KINETICS. THE SPONSOR SHOULD CONSULT WITH CVM TO DISCUSS THE BIOEQUIVALENCE STUDY OR STUDIES APPROPRIATE TO A PARTICULAR DRUG.

F. Multiple Strengths of Solid Oral Dosage Forms THE GENERIC SPONSOR SHOULD DISCUSS WITH CVM THE APPROPRIATE IN VIVO BIOEQUIVALENCE TESTING AND IN VITRO DISSOLUTION TESTING TO OBTAIN APPROVAL FOR MULTIPLE STRENGTHS (OR CONCENTRATIONS) OF SOLID ORAL DOSAGE FORMS.

CVM WILL CONSIDER THE RATIO OF ACTIVE TO INACTIVE INGREDIENTS AND THE IN VITRO DISSOLUTION PROFILES OF THE DIFFERENT STRENGTHS, THE WATER SOLUBILITY OF THE DRUG, AND THE RANGE OF STRENGTHS FOR WHICH APPROVAL IS SOUGHT.

ONE IN VIVO BIOEQUIVALENCE STUDY WITH HIGHEST STRENGTH PRODUCT MAY SUFFICE IF THE MULTIPLE STRENGTH PRODUCTS HAVE THE SAME RATIO OF ACTIVE TO INACTIVE INGREDIENTS AND ARE OTHERWISE IDENTICAL IN FORMULATION. IN VITRO DISSOLUTION TESTING SHOULD BE CONDUCTED, USING AN FDA APPROVED METHOD, TO COMPARE EACH STRENGTH OF THE GENERIC PRODUCT TO THE CORRESPONDING STRENGTH OF THE REFERENCE PRODUCT.

G. Manufacturing of Pilot Batch (“Biobatch”) A PILOT BATCH OR “BIOBATCH” SHOULD BE THE SOURCE OF THE FINISHED DRUG PRODUCT USED IN THE PIVOTAL STUDIES (I. E. , BIOEQUIVALENCE STUDIES AND TISSUE RESIDUE STUDIES), STABILITY STUDIES AND THE VALIDATION STUDIES FOR THE PROPOSED ANALYTICAL AND STABILITY INDICATING METHODS (REFER TO CVM’S GUIDANCE NUMBER 42, “ANIMAL DRUG MANUFACTURING GUIDELINES”).

III. BLOOD LEVEL STUDIES BLOOD LEVEL BIOEQUIVALENCE STUDIES COMPARE A TEST (GENERIC) PRODUCT TO A REFERENCE (PIONEER) PRODUCT USING PARAMETERS DERIVED FROM THE CONCENTRATIONS OF THE DRUG MOIETY AND/OR ITS METABOLITES, AS A FUNCTION OF TIME, IN WHOLE BLOOD, PLASMA, SERUM (OR IN OTHER APPROPRIATE BIOLOGICAL FLUIDS OR TISSUES).

THIS APPROACH IS PARTICULARLY APPLICABLE TO DOSAGE FORMS INTENDED TO DELIVER THE ACTIVE DRUG INGREDIENT(S) TO THE SYSTEMIC CIRCULATION (E. G. , INJECTABLE DRUGS AND MOST ORAL DOSAGE FORMS). GENERALLY, THE STUDY SHOULD ENCOMPASS THE ABSORPTION, DISTRIBUTION, AND DEPLETION (ELIMINATION) PHASES OF THE DRUG CONCENTRATION VS TIME PROFILES. A. Assay Consideration A PROPERLY VALIDATED ASSAY METHOD IS PIVOTAL TO THE ACCEPTABILITY OF ANY PHARMACOKINETIC STUDY.

SPONSORS SHOULD DISCUSS ANY QUESTIONS OR PROBLEMS CONCERNING THE ANALYTICAL METHODOLOGY WITH CVM BEFORE UNDERTAKING THE BIOEQUIVALENCE STUDIES. THE ANADA SUBMISSION SHOULD CONTAIN ADEQUATE INFORMATION NECESSARY FOR THE CVM REVIEWER TO DETERMINE THE VALIDITY OF THE ANALYTICAL 10 METHOD USED TO QUANTITATE THE LEVEL OF DRUG IN THE BIOLOGICAL MATRIX (E. G. , BLOOD).

THE FOLLOWING ASPECTS SHOULD BE ADDRESSED IN ASSESSING METHOD PERFORMANCE: 1. CONCENTRATION RANGE AND LINEARITY THE QUANTITATIVE RELATIONSHIP BETWEEN CONCENTRATION AND RESPONSE SHOULD BE ADEQUATELY CHARACTERIZED OVER THE ENTIRE RANGE OF EXPECTED SAMPLE CONCENTRATIONS.

FOR LINEAR RELATIONSHIPS, A STANDARD CURVE SHOULD BE DEFINED BY AT LEAST 5 CONCENTRATIONS. IF THE CONCENTRATION RESPONSE FUNCTION IS NON-LINEAR, ADDITIONAL POINTS WOULD BE NECESSARY TO DEFINE THE NON-LINEAR PORTIONS OF THE CURVE. EXTRAPOLATION BEYOND A STANDARD CURVE IS NOT ACCEPTABLE. 2. LIMIT OF DETECTION (LOD) THE STANDARD DEVIATION OF THE BACKGROUND SIGNAL AND LOD SHOULD BE DETERMINED. THE LOD IS ESTIMATED AS THE RESPONSE VALUE CALCULATED BY ADDING 3 TIMES THE STANDARD DEVIATION OF THE BACKGROUND RESPONSE TO THE AVERAGE BACKGROUND RESPONSE.

3. LIMIT OF QUANTITATION (LOQ) THE INITIAL DETERMINATION OF LOQ SHOULD INVOLVE THE ADDITION OF 10 TIMES THE STANDARD DEVIATION OF THE BACKGROUND RESPONSE TO THE AVERAGE BACKGROUND RESPONSE. THE SECOND STEP IN DETERMINING LOQ IS ASSESSING THE PRECISION (REPRODUCIBILITY) AND ACCURACY (RECOVERY) OF THE METHOD AT THE LOQ. THE LOQ WILL GENERALLY BE THE LOWEST CONCENTRATION ON THE STANDARD CURVE THAT CAN BE QUANTIFIED WITH ACCEPTABLE ACCURACY AND PRECISION (SEE ITEMS 5. AND 6. BELOW).

4. SPECIFICITY THE ABSENCE OF MATRIX INTERFERENCES SHOULD BE DEMONSTRATED BY THE ANALYSIS OF 6 INDEPENDENT SOURCES OF CONTROL MATRIX.

THE EFFECT OF ENVIRONMENTAL, PHYSIOLOGICAL, OR PROCEDURAL VARIABLES ON THE MATRIX SHOULD BE ASSESSED. EACH INDEPENDENT CONTROL MATRIX WILL BE USED TO PRODUCE A STANDARD CURVE, WHICH WILL BE COMPARED TO A STANDARD CURVE PRODUCED UNDER CHEMICALLY DEFINED CONDITIONS. THE COMPARISON OF CURVES SHOULD EXHIBIT PARALLELISM AND SUPERIMPOSABILITY WITHIN THE LIMITS OF ANALYTICAL VARIATION ESTABLISHED FOR THE CHEMICALLY DEFINED STANDARD CURVE.

5. ACCURACY (RECOVERY) THIS PARAMETER SHOULD BE EVALUATED USING AT LEAST 3 KNOWN CONCENTRATIONS OF ANALYTE FRESHLY SPIKED IN CONTROL MATRIX, ONE BEING AT A POINT 2 STANDARD DEVIATIONS ABOVE THE LOQ, ONE IN THE MIDDLE OF THE RANGE OF THE STANDARD CURVE (“MID-RANGE”) AND ONE AT A POINT 2 STANDARD DEVIATIONS BELOW THE UPPER QUANTITATIVE LIMIT OF THE STANDARD CURVE. THE ACCURACY OF THE METHOD, BASED UPON THE MEAN VALUE OF 6 REPLICATE INJECTIONS, AT EACH CONCENTRATION LEVEL, SHOULD BE WITHIN 80-120% OF THE NOMINAL CONCENTRATION AT EACH LEVEL (HIGH, MID-RANGE, AND LOQ).

11 6. PRECISION THIS PARAMETER SHOULD BE EVALUATED USING AT LEAST 3 KNOWN CONCENTRATIONS OF ANALYTE FRESHLY SPIKED IN CONTROL MATRIX, AT THE SAME POINTS USED FOR DETERMINATION OF ACCURACY.

THE COEFFICIENT OF VARIATION (CV) OF 6 REPLICATES SHOULD BE ± 10% FOR CONCENTRATIONS AT OR ABOVE 0. 1 PPM (0. 1 ? G/ML). A CV OF ± 20% IS ACCEPTABLE FOR CONCENTRATIONS BELOW 0. 1 PPM. 7. ANALYTE STABILITY STABILITY OF THE ANALYTE IN THE BIOLOGICAL MATRIX UNDER THE CONDITIONS OF THE EXPERIMENT (INCLUDING ANY PERIOD FOR WHICH SAMPLES ARE STORED BEFORE ANALYSES) SHOULD BE ESTABLISHED. IT IS RECOMMENDED THAT THE STABILITY BE DETERMINED WITH INCURRED ANALYTE IN THE MATRIX OF DOSED ANIMALS IN ADDITION TO, OR INSTEAD OF, CONTROL MATRIX SPIKED WITH PURE ANALYTE.

ALSO, THE INFLUENCE OF 3 FREEZE-THAW CYCLES AT 2 CONCENTRATIONS SHOULD BE DETERMINED. STABILITY SAMPLES AT 3 CONCENTRATIONS SHOULD BE STORED WITH THE STUDY SAMPLES AND ANALYZED THROUGH THE PERIOD OF TIME IN WHICH STUDY SAMPLES ARE ANALYZED. THESE ANALYSES WILL ESTABLISH WHETHER OR NOT ANALYTE LEVELS HAVE DECREASED DURING THE TIME OF ANALYSIS.

8. ANALYTICAL SYSTEM STABILITY TO ASSURE THAT THE ANALYTICAL SYSTEM REMAINS STABLE OVER THE TIME COURSE OF THE ASSAY, THE REPRODUCIBILITY OF THE STANDARD CURVE SHOULD BE MONITORED DURING THE ASSAY. A MINIMAL DESIGN WOULD BE TO RUN ANALYTICAL STANDARDS AT THE BEGINNING AND AT THE END OF THE ANALYTICAL RUN. 9.

QUALITY CONTROL (QC) SAMPLES THE PURPOSE OF QC SAMPLES IS TO ASSURE THAT THE COMPLETE ANALYTICAL METHOD, SAMPLE PREPARATION, EXTRACTION, CLEAN-UP, AND INSTRUMENTAL ANALYSIS PERFORM ACCORDING TO ACCEPTABLE CRITERIA. THE STABILITY OF THE DRUG IN THE TEXT MATRIX FOR THE QC SAMPLES SHOULD BE KNOWN AND ANY TENDENCY FOR THE DRUG TO BIND TO TISSUE OR SERUM COMPONENTS OVER TIME SHOULD ALSO BE KNOWN.

DRUG FREE CONTROL MATRIX, E. G. , TISSUE, SERUM, ETC. THAT IS FRESHLY SPIKED KNOWN QUANTITIES OF TEST DRUG, SHOULD BE ANALYZED CONTEMPORANEOUSLY WITH TEST SAMPLES, EVENLY DISPERSED THROUGHOUT EACH ANALYTICAL RUN.

THIS CAN BE MET BY THE DETERMINATION OF ACCURACY AND PRECISION OF EACH ANALYTICAL RUN (ITEMS 5 AND 6). 10. REPLICATE AND REPEAT ANALYSES SINGLE RATHER THAN REPLICATE ANALYSES ARE RECOMMENDED, UNLESS THE REPRODUCIBILITY AND/OR ACCURACY OF THE METHOD ARE BORDERLINE.

CRITERIA FOR REPEAT ANALYSES SHOULD BE DETERMINED PRIOR TO RUNNING THE STUDY AND RECORDED IN THE METHOD SOP. 11. SUMMARY OF SAMPLES TO BE RUN WITH EACH ANALYSIS 12 A. ACCURACY ESTIMATE (ITEM 5) B. PRECISION ESTIMATE (ITEM 6) C. ANALYTICAL SYSTEM STABILITY (ITEM 8) D. ANALYTE STABILITY SAMPLES (ITEM 7) B. General Experimental Design Considerations.

1. DOSING BY LABELED CONCENTRATION THE POTENCY OF THE PIONEER AND GENERIC PRODUCTS SHOULD BE ASSAYED PRIOR TO CONDUCTING THE BIOEQUIVALENCE STUDY TO ENSURE THAT FDA OR COMPENDIAL SPECIFICATIONS ARE MET. THE CENTER RECOMMENDS THAT THE POTENCY OF THE PIONEER AND GENERIC LOTS SHOULD DIFFER BY NO MORE THAN ±5% FOR DOSAGE FORM PRODUCTS.

THE ANIMALS SHOULD BE DOSED ACCORDING TO THE LABELED CONCENTRATION OR STRENGTH OF THE PRODUCT, RATHER THAN THE ASSAYED POTENCY OF THE INDIVIDUAL BATCH (I. E. , THE DOSE SHOULD NOT BE CORRECTED FOR THE ASSAYED POTENCY OF THE PRODUCT). THE BIOEQUIVALENCE DATA OR DERIVED.

PARAMETERS SHOULD NOT BE NORMALIZED TO ACCOUNT FOR ANY POTENCY DIFFERENCES BETWEEN THE PIONEER AND GENERIC PRODUCT LOTS. 2. SINGLE DOSE VS MULTIPLE DOSE STUDIES A SINGLE DOSE STUDY AT THE HIGHEST APPROVED DOSE WILL GENERALLY BE ADEQUATE FOR THE DEMONSTRATION OF BIOEQUIVALENCE.

A SINGLE DOSE STUDY AT A HIGHER THAN APPROVED DOSE MAY BE APPROPRIATE FOR CERTAIN DRUGS (REFER TO THE SECTION ON DOSE SELECTION). A MULTIPLE DOSE STUDY MAY BE APPROPRIATE WHEN THERE ARE CONCERNS REGARDING POORLY PREDICTABLE DRUG ACCUMULATION, (E. G. ,A DRUG WITH NONLINEAR KINETICS) OR A DRUG WITH A NARROW THERAPEUTIC WINDOW.

A MULTIPLE DOSE STUDY MAY ALSO BE NEEDED WHEN ASSAY SENSITIVITY IS INADEQUATE TO PERMIT DRUG QUANTIFICATION OUT TO 3 TERMINAL ELIMINATION HALF- LIVES BEYOND THE TIME WHEN MAXIMUM BLOOD CONCENTRATIONS (CMAX) ARE ACHIEVED, OR IN cases where prolonged or delayed absorption2 exist. The determination of prolonged or DELAYED ABSORPTION (I. E. , FLIP-FLOP KINETICS).

MAY BE MADE FROM PILOT DATA, FROM THE LITERATURE, OR FROM INFORMATION CONTAINED WITH FOI SUMMARIES PERTAINING TO THE PARTICULAR DRUG OR FAMILY OF DRUGS. 3. SUBJECT CHARACTERISTICS ORDINARILY, STUDIES SHOULD BE CONDUCTED WITH HEALTHY ANIMALS REPRESENTATIVE OF THE SPECIES, CLASS, GENDER, AND PHYSIOLOGICAL MATURITY FOR WHICH THE DRUG IS APPROVED. THE BIOEQUIVALENCE STUDY MAY BE CONDUCTED WITH A SINGLE GENDER FOR WHICH THE PIONEER PRODUCT IS APPROVED, UNLESS THERE IS A KNOWN INTERACTION OF FORMULATION WITH GENDER.

AN ATTEMPT SHOULD BE MADE TO RESTRICT THE WEIGHT OF THE TEST ANIMALS TO A NARROW RANGE IN ORDER TO MAINTAIN THE SAME TOTAL DOSE ACROSS STUDY SUBJECTS. THE ANIMALS SHOULD NOT RECEIVE ANY MEDICATION PRIOR TO TESTING FOR A PERIOD OF TWO WEEKS OR MORE, DEPENDING UPON THE BIOLOGICAL HALF-LIFE OF THE ANCILLARY DRUG.

13 4. FED VS FASTED STATE FEEDING MAY EITHER ENHANCE OR INTERFERE WITH DRUG ABSORPTION, DEPENDING UPON THE CHARACTERISTICS OF THE DRUG AND THE FORMULATION. FEEDING MAY ALSO INCREASE THE INTER- AND INTRASUBJECT VARIABILITY IN THE RATE AND EXTENT OF DRUG ABSORPTION. THE RATIONALE FOR CONDUCTING EACH BIOEQUIVALENCE STUDY UNDER FASTING OR FED CONDITIONS SHOULD BE PROVIDED IN THE PROTOCOL.

FASTING CONDITIONS, IF USED, SHOULD BE FULLY DESCRIBED, GIVING CAREFUL CONSIDERATION TO THE PHARMACOKINETICS OF THE DRUG AND THE HUMANE TREATMENT OF THE TEST ANIMALS. THE PROTOCOL SHOULD DESCRIBE THE DIET AND FEEDING REGIME WHICH WILL BE USED IN THE STUDY.

IF A PIONEER PRODUCT LABEL INDICATES THAT THE PRODUCT IS LIMITED TO ADMINISTRATION EITHER IN THE FED OR FASTED STATE, THEN THE BIOEQUIVALENCE STUDY SHOULD BE CONDUCTED ACCORDINGLY. IF THE BIOEQUIVALENCE STUDY PARAMETERS PASS THE AGREED UPON CONFIDENCE INTERVALS, THEN THE SINGLE STUDY IS ACCEPTABLE AS THE BASIS FOR APPROVAL OF THE GENERIC DRUG.

HOWEVER, FOR CERTAIN PRODUCT CLASSIFICATIONS OR DRUG ENTITIES, SUCH AS ENTERIC COATED AND ORAL SUSTAINED RELEASE PRODUCTS, DEMONSTRATION OF BIOEQUIVALENCE IN BOTH THE FASTED AND THE FED STATES MAY BE NECESSARY, IF DRUG BIOAVAILABILITY IS HIGHLY VARIABLE UNDER FEEDING CONDITIONS, AS DETERMINED FROM THE LITERATURE OR FROM PILOT DATA.

A BIOEQUIVALENCE STUDY CONDUCTED UNDER FASTED CONDITIONS MAY BE NECESSARY TO PASS THE CONFIDENCE INTERVALS. A SECOND SMALLER STUDY MAY BE NECESSARY TO EXAMINE MEAL EFFECTS. CVM WILL EVALUATE THE SMALLER STUDY WITH RESPECT TO THE MEANS OF THE PIVOTAL PARAMETERS (AUC, CMAX). THE SPONSORS SHOULD CONSULT WITH CVM PRIOR TO CONDUCTING THE STUDIES.

C. Pharmacokinetic and Statistical Considerations in Study Design 1. SAMPLING TIME CONSIDERATIONS THE TOTAL NUMBER OF SAMPLING TIMES NECESSARY TO CHARACTERIZE THE BLOOD LEVEL PROFILES WILL DEPEND UPON THE CURVATURE OF THE PROFILES AND THE MAGNITUDE OF VARIABILITY ASSOCIATED WITH THE BIOAVAILABILITY DATA (INCLUDING PHARMACOKINETIC VARIABILITY, ASSAY ERROR AND INTERPRODUCT DIFFERENCES IN ABSORPTION KINETICS). THE SAMPLING TIMES SHOULD ADEQUATELY DEFINE PEAK CONCENTRATION(S) AND THE EXTENT OF ABSORPTION.

THE SAMPLING TIMES SHOULD EXTEND TO AT LEAST 3 TERMINAL ELIMINATION HALF-LIVES BEYOND TMAX. THE SPONSOR SHOULD CONSULT WITH CVM PRIOR TO CONDUCTING THE PIVOTAL BIOEQUIVALENCE STUDY IF THE ASSAY IS UNABLE TO QUANTIFY SAMPLES TO 3 HALF-LIVES. MAXIMUM SAMPLING TIME EFFICIENCY MAY BE ACHIEVED BY CONDUCTING A PILOT INVESTIGATION.

THE PILOT STUDY SHOULD IDENTIFY THE GENERAL SHAPES OF THE TEST AND REFERENCE CURVES, THE MAGNITUDE OF THE DIFFERENCE IN PRODUCT PROFILES, AND THE NOISE ASSOCIATED WITH EACH BLOOD SAMPLING TIME (E. G. , VARIABILITY ATTRIBUTABLE TO ASSAY ERROR AND THE VARIABILITY BETWEEN SUBJECTS, FOR PARALLEL STUDY DESIGNS, OR WITHIN SUBJECTS, FOR CROSSOVER STUDY DESIGNS).

THIS INFORMATION SHOULD BE APPLIED TO THE DETERMINATION OF AN OPTIMUM BLOOD SAMPLING 14 SCHEDULE. DEPENDING UPON THESE VARIABILITY ESTIMATES, IT MAY BE MORE EFFICIENT TO CLUSTER SEVERAL BLOOD SAMPLES RATHER THAN TO HAVE SAMPLES WHICH ARE PERIODICALLY DISPERSED throughout the duration of blood sampling. 3 2. PROTEIN BINDING IN GENERAL, PRODUCT BIOEQUIVALENCE SHOULD BE BASED UPON TOTAL (FREE PLUS PROTEIN BOUND) CONCENTRATIONS OF THE PARENT DRUG (OR METABOLITE, WHEN APPLICABLE).

HOWEVER, IF NONLINEAR PROTEIN BINDING IS KNOWN TO OCCUR WITHIN THE THERAPEUTIC DOSING RANGE (AS DETERMINED FROM LITERATURE OR PILOT DATA), THEN SPONSORS MAY NEED TO SUBMIT DATA ON BOTH THE FREE AND TOTAL DRUG CONCENTRATIONS FOR THE GENERIC AND PIONEER PRODUCTS. SIMILARLY, IF THE DRUG IS KNOWN TO ENTER BLOOD ERYTHROCYTES, THE PROTOCOL SHOULD ADDRESS.

THE ISSUE OF POTENTIAL NONLINEARITY IN ERYTHROCYTE UPTAKE OF THE DRUG ADMINISTERED WITHIN THE LABELED THERAPEUTIC DOSING RANGE. THE BIOEQUIVALENCE PROTOCOL OR COMPLETED STUDY REPORT SHOULD PROVIDE ANY INFORMATION AVAILABLE FROM THE LITERATURE REGARDING ERYTHROCYTE UPTAKE AND PROTEIN BINDING CHARACTERISTICS OF THE DRUG OR DRUG CLASS, INCLUDING THE MAGNITUDE OF PROTEIN BINDING AND THE TYPE OF BLOOD PROTEIN TO WHICH IT BINDS.

3. SUBJECT NUMBER PILOT STUDIES ARE RECOMMENDED AS A MEANS OF ESTIMATING THE APPROPRIATE SAMPLE SIZE FOR THE PIVOTAL BIOEQUIVALENCE STUDY. ESTIMATED SAMPLE SIZE WILL VARY DEPENDING UPON.

WHETHER THE DATA ARE ANALYZED ON A LOG OR LINEAR SCALE. USEFUL REFERENCES FOR SAMPLE SIZE estimates include Westlake4, Hauschke5, and Steinijans6. 4. CROSS-OVER AND PARALLEL DESIGN CONSIDERATIONS A TWO-PERIOD CROSS-OVER DESIGN IS COMMONLY USED IN BLOOD LEVEL STUDIES. THE USE OF CROSS-OVER DESIGNS ELIMINATES A MAJOR SOURCE OF STUDY VARIABILITY: BETWEEN SUBJECT DIFFERENCES IN THE RATES OF DRUG ABSORPTION, DRUG CLEARANCE, AND THE VOLUME OF DRUG DISTRIBUTION. IN A TYPICAL TWO-PERIOD CROSS-OVER DESIGN, SUBJECTS ARE RANDOMLY ASSIGNED TO EITHER SEQUENCE.

THIS DOCUMENT IS INTENDED TO PROVIDE GUIDANCE FOR THE DESIGN AND ANALYSIS OF IN VIVO BIOEQUIVALENCE STUDIES. THIS REVISION TO THE VERSION THAT WAS MADE AVAILABLE IN APRIL 1996 ADDS AN ILLUSTRATIVE EXAMPLE OF HOW TO CALCULATE CONFIDENCE BOUNDS WHEN …

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