(精选)An update from the JSM 2006 - Seattle教学课件.pptVIP

Apologize for over-emphasizing my own work; the spirit is to present to you a series of successful case studies using a particular tool – hazard spline regression – that you might also find useful. Testing what is ”too much”… The two tests can be written: H01: μT - μR ≤ -Δ versus H11: μT - μR ≥ -Δ And then… H02: μT - μR ≥ Δ versus H12: μT - μR ≤ Δ Testing what is ”too much”… The testing parameter Δ was chosen by the FDA to be Δ=log(1.25) Both of the two tests are carried out with a 5% level of significance Thus, there is a maximum 5% chance of declaring two products bioequivalent when in fact they are not TOST has some drawbacks: drugs which small changes in dose → BIG change in clin. response, test limit too narrow for high variability products, doesn’t address individual BE (“Can I safely switch my patient’s formulation?”) Models for the outcomes… They suggest modeling data from the two period, two Rx cross-over via a linear mixed model: Let Yijk be the (log-transformed) response obtained from Subject k, in period j, in sequence i, taking formulation l If we assume no carry-over effects the model resembles: Yijk= μi + λj + πl + βk + εijkl where μi, λj, and πl are fixed; βk, εijkl are random Models for the outcomes… So to estimate πT – πR we are supposed to take: ? [(Y21-Y22)-(Y11-Y12)] which in expectation is equal to the treatment difference Yij is the sample mean from the i,j’th cell above Group Period 1 Period 2 1 (RT) μ1 + λ1 + πR μ1 + λ2 + πT 2 (TR) μ2 + λ1 + πT μ2 + λ2 + πR * μ parameters could likely be dropped Some general comments… Guidelines from the FDA on methodology are very specific in this field (e.g. numerical method for AUC, “goal posts” for determining BE, distributional assumptions, etc) Interesting history of how these regulations came about/evolved: - 75/75 rule (70’s): 75% of subjects’ individual ratios of T to R must be ≥ 0.75 to prove BE - 80/20 rule (80’s): set up H0 such that the two formulation