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Clinical Endpoint Bioequivalence Studies for Locally Acting Drugs

Clinical Endpoint Bioequivalence Studies for Locally Acting Drugs. Dena R. Hixon, M.D. Associate Director of Medical Affairs Office of Generic Drugs . Systemic Drugs. Delivered to the bloodstream for distribution to site(s) of action in the body BE determined with PK studies

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Clinical Endpoint Bioequivalence Studies for Locally Acting Drugs

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  1. Clinical Endpoint Bioequivalence Studies for Locally Acting Drugs Dena R. Hixon, M.D. Associate Director of Medical Affairs Office of Generic Drugs

  2. Systemic Drugs • Delivered to the bloodstream for distribution to site(s) of action in the body • BE determined with PK studies • Relatively short studies • Relatively little variability in results • Relatively small number of subjects

  3. Locally-Acting Drugs • Not intended to be absorbed into the bloodstream • Delivered directly to sites of action in the skin, mouth, eyes, ears, nose, vagina, urinary tract, or gastrointestinal tract

  4. Locally-Acting Drugs • Topical acne creams, lotions, or gels • Topical or vaginal antifungal creams or suppositories • Oral lozenges for oral candidiasis • Ophthalmic drops for conjunctivitis • Otic drops for external otitis • Oral vancomycin for pseudomembranous colitis • Nasal sprays for rhinitis • Orally inhaled products for asthma

  5. BE of locally-acting drugs • PK studies are not adequate • Pharmacodynamic (PD) studies for topical steroids • Most require clinical endpoint studies • Combination products may require both PD and clinical endpoint studies

  6. Clinical endpoint studies • 3-arm comparative trials of generic vs. reference listed drug (RLD) vs. placebo • Treatment of an approved indication in a patient population according to the labeled dosing of the RLD. • Trial design and endpoints similar to NDA

  7. Clinical endpoint studies • Both generic and RLD must be statistically superior to placebo (p<0.05) in order to assure that the study is sensitive enough to show a difference between products. • Same established BE requirements as for other types of BE studies

  8. Challenges of clinical endpoint studies • Clinical endpoints more variable than PK but must meet the established BE limits • May require several hundred patients • Study duration may be several weeks depending upon the approved labeling • Very expensive to conduct • May present more safety concerns than PK studies

  9. Challenges of clinical endpoint studies • Unknown inter-subject variability within reference population • Difficulty in achieving consistency between studies • study design • study population • bioequivalence endpoints • Some products require multiple studies

  10. Dermatologic drugs • Antifungals and other anti-infectives • False negative baseline cultures lead to exclusion of many patients • Acne products • Multiple endpoints • Often small effect size and low power to demonstrate BE • Topical acyclovir • Confusion about indications and endpoints

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