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Bioequivalence protocol power point presentation

The document outlines the key elements that should be included in a bioequivalence study protocol. It discusses the study objective to show that the drug bioavailability from test and reference products is statistically equivalent. The study design may include crossover, parallel, or replicate designs. Important aspects covered include the study population, drug administration, sampling schedule, analytical methods, data analysis plan, and statistical evaluation of pharmacokinetic parameters to determine bioequivalence within the 80-125% range. In vitro dissolution and content uniformity testing should also be included to support the in vivo bioequivalence results.

Health & Medicine◦
BIOEQUIVALENCE PROTOCOL BY T.M.RASALA Assistant Professor Pharmaceutics Department Gururnanak college of pharmacy 4/6/2022 1
Elements of Bioequivalence Study Protocol 1.Title a. Principal investigator b. Project number and date 2. Study objective 3. Study design a. Design b. Drug Products i. Test products(s) ii. Reference product c. Dosage regimen d. Sample collection schedule 4/6/2022 2
e. Housing f. Fasting /Meals schedule g. Analytical methods 4. Study population a. Subjects b. Subject selection i. Medical history ii. Physical examination iii. Laboratory tests c. Inclusion/exclusion criteria i. Inclusion criteria ii. Exclusion criteria 4/6/2022 3
• Restrictions/prohibitions 5.Clinical procedures a. Dosage and Drug Administration b. Biological sampling schedule c. Activity of subjects 6.Ethical considerations a. Basic principles b. Institutional review board c. Informed consent d. Indication for subject withdrawal e. Adverse reaction and emergency procedures 4/6/2022 4
Facilities 8. Data Analysis a. Analytical validation procedure b. Statistical treatment of data 9. Drug Accountability 10.Appendix 4/6/2022 5
Study Objective: The objective for a bioequivalence study is that the drug bio availability from test and reference products are not statistically different when administered to patients are subjects at same molar dose under similar experimental conditions. 4/6/2022 6
Study Designs: For many drug products, the FDA, division of bio equivalence, office of generic drugs provides guidance for the performances of in- vitro dissolution and in-vivo bioequivalence studies  Generally three bioequivalence studies required for solid oral dosage forms including- 1. A fasting study 2. A food intervention study 3. Multi dose study 4/6/2022 7
1.Cross Over Study Design:  Two formulations, even number of subjects  Randomly divided into two equal groups  Each number of one group receive a single dose of the test formulation and each member of the other group receive the standard formulations. 4/6/2022 8 Subject Period 1 Period 2 1-8 Test Standard 9-16 Standard Test
2.Latin Square Design: 4/6/2022 9 More than two formulations Eg: A group of volunteers will receive formulations in the sequence.
3.Balance Incomplete Block Design:  More than 3 formulations  Latin square design will not be used because each volunteer may required drawing of too many blood samples.  If each volunteer expected to receive at least 2 formulations then such study can be carried out using BIBD. 4/6/2022 10
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4.Parallel Group Design:  Even number of subjects in 2 groups  Each receive a different formulation  No wash out necessary  For drugs with long half life 4/6/2022 12
5.Replicate Cross Over Study Design:  For highly variable drugs  Allows comparisons of within subject variances  Reduces the number of subjects needed  4-periods, 2-sequences, 2 formulations design(recommended)  3-periods, 3-sequences, single dose partially replicated 4/6/2022 13
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Difference between parallel group and cross over study design 4/6/2022 15
6. Pilot Study:  If the sponsor chooses in a small number of subjects  To access a variability, optimize the sample collection time intervals, and provide other Information Eg: Immediate release products: careful timing of initial samples-avoid a sub sequent finding that the first sample collection, occurred after the plasma concentration peak. Modified released products: To determine sampling schedule- Assess log time and dose dumping 4/6/2022 16
7. Analytical Methods:  Analytical methods used in an in-vivo bio availability, bio equivalence, or Pharmacodynamics studies must be validated for accuracy and sufficient sensitivity.  The analytical method for measurement of drug must be validated for accuracy, precision, sensitivity, specificity, and robustness. The use of more than one analytical method during a bio equivalence study may not be valid because different methods may yield different values. 4/6/2022 17
Subject Selection:  Healthy adult volunteers  Age 18-45years  Age/sex representation corresponding to therapeutic and safety profile weight with in normal limits  women-pregnency test period to first and last  Dose of study Selection Of Number Of Subjects:  Sample size estimated by  Pilot Experiments  Previous Studies  Published Data 4/6/2022 18
 Significance level desired usually 0.05  Power of study normally 80% or more  Minimum 16 subjects unless ethical justification  Allow for drop outs Exclusion Criteria:  H/o allergy to test drug  H/o liver or kidney dysfunction  H/o jaundice in past 6 months  Chronic diseases Eg: Asthma, Arthritis  Psychiatric illness 4/6/2022 19
Administration of drug products:  Administration of drug products to the should be based on randamization. After the administration of drug products, biood samples are withdrawn from the subjects at fixed time points.  It takes some to take a sample from each subject, and the total time difference between first and last subject range from 10 to 20 minutes depending upon the number of subjects and technicians in the study.  This 10 to 20 minutes difference would represent a substantial change in the drug concentrations observed in the blood. 4/6/2022 20
If under these conditions treatments are administered to the the subjects in a seqential manner (such as teatment A to the first 6 volunteers, teatment B to volunteers 7 to 12, and teatment C to Volunteers 13 to18), the error between the time of administration and sampling will gradually increase from treatment group to treatment group. This is because of sequential administration of drug products to different treatments. 4/6/2022 21
Sampling:  The biological sample to be used in the study as to be decided before the commencement of a bioavailability study.  If the bioavailability of a given dosage form is to be evaluated by a blood level study, some estimate of the area under the serum concentration v/s time curve, peak serum concentration, time of peak concentration must be obtained from the study.  These factors can markedly influence the ‘apparent’ results obtained in a given study. 4/6/2022 22
 The sampling scheme should frequent enough to define the absorption phase, the peak, and the elimination phase during a drugs time course in the body.  The absorption rate, volume of distribution, elimination rate, all influence the apparent drug concentration one obtains in a given sample.  It is necessary to see that all these factors influence each dosage form equally. To estimate the AUC from the data, sampling as to be carried out till the concentration of the drug reaches the linear elimination phase. 4/6/2022 23
The amount of drug excreted in urine is obtained directly. In the case of a blood level study, the amount of drug in the body is estimated using pharmacokinetic parameters. The urinary excretion method has several disadvantages 1. Urinary excretion studies are not useful in estimating the drug absorption rate. 2. In some cases, the metabolites of the drug are also concentrated in the sample that interferes with the estimation of unchanged drug in the urine sample. 4/6/2022 24
Evaluation of data: Pharmacokinetic evaluation of the data for single dose studies, including a fasting study or a food intervention study, the pharmacokinetic analyses include calculation for each subject of the area under the curve to the last quantifiable concentration (AUC0 ) and to infinity (AUC0), tmax and Cmax .Additionally ,the elimination rate constant,k, the elimination half-life,t1/2, 4/6/2022 25
Statistical evaluation of the data:  Bioequivalance is generally determined using a comparision of population averages of a bioequivalance metric, such as AUC and Cmax.  This approach, termed average bioequivalence, involves for the ratio of averages of the test and reference drug products. 4/6/2022 26
Statistical Analysis For Average Bio equivalence:  Based on log transformed data  Point estimates of the mean ratios Test / reference for AUC and Cmax are between 80% -125%  AUC and Cmax 90% confident intervals must fit between 80%- 125%  Statistical model typically includes factors accounting for following sources of variations:  Sequence, subjects, nested in sequences, period in treatment 4/6/2022 27
Proposed And Contents Of An In vivo Bio equivalence Study Submission And Accompaning In vitro Data:  Title Page  Study Title  Name of sponsor  Name and Address of clinical laboratory  Name of Principal Investigator(S)  Name of Clinical Investigator  Name of Analytical Laboratory  Dates of Clinical Study  Signature of principal investigator(and date)  Signature of Clinical Investigator(and date) 4/6/2022 28
 Table Of Contents 1.Study Resume  Product Information  Summary of Bio equivalence study  Summary of Bio equivalence data  Plasma  Urinary Excreation  Figure of mean plasma concentration-time profile  Figure of mean cumulative urinary excreation  Figure of mean urinary excreation rates 2.Protocol And Approvals  Protocol  Letter of acceptance of protocol from fda  Informed consent form  Letter of approval of institutional review board 3.Clinical study  Summary of Study  Details of study  Demographic characteristics of the subjects  Subject assignement in the study 4/6/2022 29
 Mean physical characteristics of subjects arranged by sequence  Details of clinical activity  Deviation from protocol  Vital science of subjects  Adverse reactions report 4.Assay Methodology And Validation  Assay method discription  Validation procedure  Summary of validation  Data on linearity of standard samples  Data on interday precision and accuracy  Data on intraday precision and accauracy  Figure for standard curve for low/high ranges  Chromatograms of standard and quality control samples  Sample calculation 4/6/2022 30
4/6/2022 31 5. Pharmacokinetic Parameters and Tests • Definitions and calculaton • Statistical tests • Drug levels at each sampling time and harmacokinetic parameters • Figure of mean plasma concentration-time profile • Figure of individual subjects plasma concentrations- time profiles • Figure of mean cumulative urinary excreation • Figures of individual subject urinary excreation rates • Tables of individual subject data arranged by drug, drug/period, drug/sequence
 6.statistical analyses  statistical considerations  summary of statistical significance  summary of statistical parameters  analysis of variance,least squares estimates and least  squares means  assessment of sequence, period, and treatment effects  90% confidence intervals for the differences between  test and reference products for the log-normal- transformed  parameters of AUC0-t, AUC0-infinty, CMAX should be 80%-125 4/6/2022 32
 7. Appendices 4/6/2022 33 • Randamization schedulule • sample identification codes • Analytical raw data • Chromatograms of at least 20% of subjects • Medical records and clinical reports • Clinical facilities discription • Analytical facilities discription • Curricula vitae of investigators 8. Invitro testing • Dissolution testing • Dissolution assay methadology • Content uniformity testing • Cotency determination 9. Batch size and formulations • Batch record • Quantitative formulations
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