Bioequivalence lecture and Bioavialbilty
- 1. BIOEQUIVALENCE & BIOAVIALBILITY STUDIES Dr. Sadia Asim B. Pharm, MBA, Ph.D. (Fellowship) Director IBBPS, DUHS OJHA campus
- 2. Guidelines for BA/BE studies • WHO_TRS_996_annex09.pdf • Microsoft Word - BE-invivo-studies-guidance-QAS14-601_08 052015.doc (who.int) • Guideline o the Investigation of Bioequivalence (europa.eu) • Bioavailability and Bioequivalence Studies Submitted in ND As or INDs — General Considerations | FDA • 4964dft.PDF (fda.gov)
- 3. WHAT IS THE NEED OF BA/BE study? • Generic drugs are safe and effective alternatives to brand name prescriptions • Generic drugs can help both consumers and the government reduce the cost of prescription drugs • No clinical studies have been performed on patients with the Generic Product to support its Efficacy and Safety. • With data to support similar in vivo performance (Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.
- 4. NDA vs. ANDA • An abbreviated new drug application (ANDA) contains data that is submitted to the FDA for the review and potential approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, lower-cost alternative to the brand-name drug it references. • NDA, mean a new drug application, when the sponsor of a new drug believes that they have collected enough data on drug efficacy and safety to meet the FDA requirement for marketing approval, the sponsor submits the NDA application to the FDA.
- 5. NDA vs. ANDA Review Process Generic drug ANDA requirements Chemistry Manufacturing Controls Labelling Testing Bioequivalence Study (In Vivo, In vitro) Original Drug NDA requirements Chemistry Manufacturing Controls Labelling Testing Animal studies Clinical studies Drug registration Post marketing Surveillance
- 6. Generic is what??? • Same active ingredient (s) • Same route of administration • Same dosage form • Same strength • Same indications • Compares to reference listed drug (RLD
- 7. Bioequivalence (BE) Definition • Absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Source: CDER U.S. Food Drug Administration
- 8. Test methods for assessing bioequivalence • Comparative bioavailability(bioequivalence) studies -- In vivo measurement of the active moiety in biologic fluid • Comparative pharmacokinetic studies in humans(invivo) • In vitro dissolution tests
- 9. What are the study designs?? • Single-dose, two-way crossover, fasted • Single-dose, two-way crossover, fed • Single-dose, parallel, fasted (Long half-life) • Multiple-dose, two-way crossover, fasted • Parallel or crossover?, Fasted or Fed?, Single or Multiple?, Replicate or non replicate? • Washout: Duration of washout period for cross-over design, should be approximately greater than 5 times the plasma’s apparent terminal half-life. However, it should be adjusted accordingly for drugs with a complex kinetic model
- 10. Blood sample schedule Case # 1 Dosing: The dose will be administered on Day 1 of each Period after 10 hours fasting. Note: The dose will be a single dose of Eperisone HCI 50mg Tablet. Blood Sampling Time Points: 13 sampling points including one Pre-dose sample and 12 post dose samples at 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 4, 6, 8,10 and 12, hour after dosing the study drugs in each period. Total Blood Volume: Approximately 128 ml of blood will be collected in a study, including 16 ml blood at screening, 104 ml blood in both study periods (52 ml in each period) & 8 ml follow up samples. Further descriptions explained in section 12.8.
- 11. Study Activities Procedure/Activity Time points Screening Check-in day in P-I & P-II Dosing-Day-1 (P-1) Dosing-Day-2 (P-2) Post-Study (Follow-Up) Screening Informed Consent Forms (ICF) X Inclusion/Exclusion Assessment X X Physical Examination X X X X X Clinical Laboratory Investigations X X Health status Monitoring X X X X X Medical History X Participation Informed Consent Forms (ICF) X* (P-I only) Drug Administration X X Adverse Event Monitoring X X X Adverse Event Reporting X X X Compliance Test (ECG) X* (P-I only) Restrictions Compliance Check X X X Meal X X X Blood Sampling X X X X
- 12. How do make a sample collection schedule and the total volume of blood ??
- 13. Conditions where bioequivalence studies are necessary Oral drug formulations with systemic action when one or more of the following criteria apply • Narrow therapeutic window drugs e.g Aminoglycosides, digoxin, digitoxin, phenytoin, phenobarbital etc. • high first metabolism ( greater than 70), non-linear pharmacokinetics • unfavorable physicochemical properties e.g- low solubility/poor permeability
- 14. • Non-oral and Non-parenteral drug formulations designed to act by systemic absorption (transdermal patches, suppositories, etc.) • Sustained release formulations for systemic absorption • Fixed dose combinations for systemic absorption • Comparative clinical or pharmacodynamic studies )
- 15. Conditions where bioequivalence studies are not necessary 1) When new drugs are to be administered parenterally (eg IV, IM, SC, intrathecal administration etc) as aqueous solutions(excipients also should be the same) 2) When the new drug is a solution for oral use, and contains the active substance in the same concentration and does not contain an excipient. 3) Availability of Multiple strength of the drug, no need to perform BA/BE studies for the lower strength product.
- 17. PROCESSES INVOLVED IN CONDUCT OF BIOEQUIVALENCE & BIOAVAILABILITY STUDY
- 19. Process Flow 19 Step1 Step2 Step3 Step 4 Step 5 Requestor generate study request form & Sign Confidential Disclosure Agreement Protocol discussion & budget approvals & sign service agreement Project start Pre-study feasibility assessment IRB Approval NBC Approval DRAP Approval
- 20. Human Subject Recruitment Screening of Human Subject Human Subject selection Assign codes to Investigational products Randomizatio n of Subject
- 21. Literature survey & Resources evaluation Method Development in biological matrix Method Validation according to the FDA guidelines Bioanalytical protocol and Analytical Master File
- 22. ACTIVITIES INVOLVE IN SCREENING OF HUMAN SUBJECTS
- 23. Singing Screening Inform Consent Form for start screening process, after review form in common understandable language English, Urdu Sindhi, etc.
- 26. Breath Alcohol Test Weight And Height Measurement for BMI calculation (18.0-30.0Kg/m2)
- 27. Screening tests Types of Test Component Hematology RBC, Hemoglobin, Platelet Count, Prothrombin Time, Hematocrit and WBC Serum Chemistry ALT, AST, Alkaline Phosphatase, Urea, Serum Creatinine, Serum Albumin, RBS, Bilirubin, and BUN Serology Hep A, Hep B, Hep C, HIV Urine Analysis Urine DR Compliance Tests P-I (Breath Alcohol & ECG), P-II (Breath Alcohol) Follow up tests CBC, PT, Creatinine, BUN, LFT and Urine DR
- 28. B. DURING STUDY ACTIVITIES
- 29. Subjects (Check –in ) Sample Collection Sample Processing Sample Storage Sample Transportation Clinical Department Drug Administration
- 30. The clinical staff collect all the volunteers personal belongings and provide them a uniform along with an Identification Code in form of wrist band and hanging card and take the signatures on participation inform consent form. Subject Check-In process
- 31. Vital Sign and Adverse Event Monitoring
- 36. Sample Processing (separation of blood cells from plasma) Sample Storage at -80C freezer
- 37. Check-out procedure. Collect “follow up sample” and give study compensation items to volunteers.
- 39. C. POST STUDY ACTIVITIES
- 40. Data generation from clinical & Analytical department Submission of all final documents to Regulatory department BE ( Bio-equivalence) Report Preparation
- 41. Analysis of Data • Pharmacokinetic calculation: Cmax: The maximal observed plasma concentration. Tmax: Time when maximal plasma concentration is observed. T1/2 Half life AUC0-t: Area under the concentration-time curve from time zero until the last measurable concentration or last sampling time t, whichever occurs first. AUCt is estimated using the trapezoidal method. AUC0-inf: Area under the concentration-time curve from time zero to infinity.
- 42. Analysis of Data • Statistical calculation For the purpose of bioequivalence analysis: • AUC0-t • Tmax • Cmax considered as primary variables. Parametric 90% confidence interval based on the ANOVA of the mean Test/Reference ratios of AUCs, Tmax and Cmax will be computed.