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Bioequivalence Study.pptxDiscusses bioequivalence study its applications & study designs
- 1. Bioequivalence Study Presenter: Dr.Pragya Pandey (JR-2) Department of Pharmacology & Therapeutics King George’s Medical University Lucknow, Uttar Pradesh, India. Email – drpragyakgmu@gmail.com
- 2. Contents • WHO definitionof bioequivalence • Need for bioequivalence study • Biowaiver • Methods • Prerequisites • Study designs • Flowchart • Summary
- 3. Specific learning objective Afterthe teaching learning session, audience shall be able to • Define bioequivalence study • Differentiate between biosimilars and bioequivalents • Enumerate applications of bioequivalence study • Understand study design for bioequivalence study
- 4. Abbreviations • CDSCO: CentralDrugs Standard Control Organisation • BCS: Biopharmaceutics Classification System • DCGI: Drug Controller General of India • FDA: Food and Drug Administration • API: Active Pharmaceutical Ingredient
- 5. Definition “Two pharmaceutical productsare bioequivalent, if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of rate and extent of absorption, after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same”. Ref: World Health Organization
- 6. Biosimilars • Biologics arelarge complex molecules made from living organisms • Biosimilars are made taking biologics as their reference product • Biosimilars are more complex and larger molecules compared to bioequivalents • Examples of biosimilars are monoclonal antibodies, insulin analogues
- 8. Need for bioequivalencestudy • Development of generic drugs • Development of different dosage form of a drug • For change in more appropriate marketed formulation of a drug • To monitor manufacturing processes of drug
- 9. Reference product • Referenceproduct should be the innovators product for which generic product is made • In absence of innovators product, Indian product approved by CDSCO can be taken as reference product • CDSCO releases list of approved reference product list
- 11. Test Product • Itis the representative of the product to be marketed • It originates from a batch of 1/10 of production scale or 100,000 units whichever is greater • If there are multiple strengths, bioequivalence of highest strength is established
- 12. Biowaiver • It meansin vivo bioavailability/bioequivalence studies can be waived • It is applicable when test drug & reference product are identical and belong to the class I & III of BCS • BCS provides surrogate evidence for in vivo bioequivalence study
- 13. Class I High Permeability HighSolubility Class II High Permeability Low Solubility Class III Low Permeability High Solubility Class IV Low Permeability Low Solubility Permeability Solubility Biopharmaceutics Classification System
- 14. Examples for biowaiver •BCS class I & III drugs • Prodrug is converted to active metabolite & the metabolite is of BCS class I & III • Minor changes to additives (colorant, flavoring) • Scale up changes
- 15. Advantages of Biowaiver •Reduces time of study • Simplifies protocol approval • Reduces human testing • Cost effective
- 16. Methods of bioequivalencestudies In-vivo method In-vitro method
- 18. Pre-requisites • Form 44– the application for the study • Form 12 – application for import of drug substances • Challan receipt as required • Details of the test drug and reference product • Details of manufacturer of reference product
- 19. Pre-requisites (cont.) • Documents:Study protocol, Informed consent form, Undertaking by investigator • Ethics committee approval • The study center should be registered under central licensing authority • Grant of permission from DCGI
- 22. Study designs Following typesof study designs are commonly used 1. Single dose 2 period/2 treatment cross-over design 2. Parallel study design 3. Replicate design
- 23. Cross over studydesign • Participants are treated with both reference & test drug • Washout period is provided in between the treatments • Useful in study of drugs used for chronic diseases • Used for drugs with shorter half life
- 24. Cross over studydesign (cont.) • Advantages include lesser chances of variations as participants serve as their own control & lesser no of participants needed • Disadvantages include longer study duration , more drop outs and difficult to follow up and complex study
- 25. Study Participants Randomization Reference Drug Test Drug Washout Period Reference Drug Test Drug Period 1Period 2 Single dose crossover study design
- 26. Parallel study design •It is the traditional & commonest study design • Participants are treated with either reference drug or test drug • Washout period is not needed in the study • Used for drugs with longer half life
- 27. Parallel study design(cont.) • Advantages include easy to implement study design and less chances of drop outs • Disadvantage is can cause inter individual variations
- 28.
- 29. Replicate study design •Participants are given both reference and test drug multiple times • There is a washout period in between the treatment periods • It can be partial or fully replicate study • It is done for drugs with high pharmacokinetic variability
- 30. Replicate study design(cont.) • Disadvantages include longer study duration, complex study and chances of more drop outs • Advantages include fewer participants needed and less chances of variations
- 31. Study Participants Randomization Reference Drug Test Drug Washout Period Reference Drug Test Drug Test Drug Reference Drug Period 1 Period2 Period 3 Replicate Study Design Washout Period
- 32. Single dose crossover study Parallel study Replicate study • Subjects might drop out more • Less number of subjects required • Lesser chances of inter - variations • Used for drugs with very long half life • No washout period • Less drop outs • More number of subjects required • Used for drugs with high pharmacokinetic variability
- 33. Study Conditions • Tominimize confounding factors standardization of study environment is ensured • Fasting condition: overnight pre dose fasting & 4 hours post dose for single dose study 2 hours predose & post dose for multiple dose study • Fed condition: high fat breakfast (50% of total caloric content) 15 min pre dose
- 34. Selection of participants •Healthy volunteers are commonly enrolled as participants • In case of drugs with high risk of side effects, patients can be included • Participants usually are of age 18-55 years • Either gender can participate based on study criteria • Women on oral contraceptives not included in study • Teratogenic drug study should not be done on females
- 35. Tests for bioequivalence •Plasma level study • Urinary excretion study • Pharmacological end-point study • Clinical end-point study • In vitro tests for solubility & permeability
- 36. Criteria for bioequivalence •The average bioavailability of test formulation should fall between 80- 125% range of the reference (80/125 rule) • The average bioavailability of test formulation should fall within ± 20% of the reference (± 20 rule)
- 37.
- 38. Characterization of referenceproduct Design of generic product Bio batch Bioequivalence study Manufacturing Process
- 39. DCGI JDCI DDCI ADCI DI ADI Head of CDSCO Supervisesdrug approval Approves drugs, clinical trials , licenses Heads offices at Mumbai, Dehradun & Baddi Head Medical Device Section & Technical Data Associate Division at Zonal & Sub-Zonal offices Ref: CDSCO Organogram
- 41. Summary • Bioequivalence issimilarity in rate & extent of absorption of two pharmacological products at same dose & under same conditions • Types of BE studies are in vivo and in vitro • Types of BE study designs are crossover, parallel and replicate • Bioequivalence can be tested by plasma level study, pharmacological end-point & clinical end-point study
- 42. References • Maiti R,Postgraduate topics in pharmacology.3rd ed. Paras Medical Publisher;2023. • Niazi S, Handbook of bioequivalence testing. Informa healthcare;2007. • Sarkar S, Srivastava V, Mohanty Postgraduate pharmacology.2nd ed. Paras Medical Publisher;2024.p.341-345
- 43. Questions • What isbioequivalence? • What is the need of bioequivalence study? • What is biowaiver? • What are the types of study designs for bioequivalence studies?
- 44.