??????????? ???????????? :??????????? ???????????? 15 ???? 2009 ?.


???? ?????????????: :???? ?????????????: ???????? ? ???? ?????????? 50-60 ???. ?? (23 ???. – FDA) ????????? ?? $ 0,5-2 ????. (??. 50% ???????? ?? R&D) ???? ???????? - ? ??????? 80 ???????????? ?????????????????? 14,9 ??? ? 5 000 ????????? 90% ??????????, ????????? ?? ????????? 20 ??? – ??????? 10-? ?????????? According to a recent report from the .Tufts Center for the Study of Drug Development, 2007 Stephen Andrade. ACT, April 2003 Schmidt A., 2005


???? ???????????? ???????????? :???? ???????????? ???????????? ???? I ???? II ???? III ???? IV ???????????? ? ???????? ???????????? ??????? ????????????? ????????????? ??????????????? ?????????????


???? ???????????? ??????????: :???? ???????????? ??????????: ????????????? ???????? ????????????? ??????????????, ?????? ? ??????????? ????????????? ?????? ??????????? ??????????? ???????????? ??? ?????? ??????? ??????????? ????????. Evidence-Based Medicine Working Group. JAMA, 1994


???? ????????????: :???? ????????????: N Engl J Med 1999:341:709-17. RALES 1663 ??????? ??? , 2 ???? ?????????? ?????????? C????????????? ????????? ??????? ???? ?????????? ?????? ?? 27% ????? ????? ?????????????? ????????? ?? 17,7%


??????? ?? ?????????: :??????? ?? ?????????:


Slide 7:??????? (USD 5,2 ????. 2007) TOP 2 USA – TOP 3 GLOBAL ????????? (USD 4,0 ????. 2007) TOP 2 USA – TOP 3 GLOBAL ??????? (USD 2,8 ????. 2007) www.astrazeneca.com


???? ????????: :???? ????????: ???? ????????? ???????????? ???????? ???????? ?????? ????? ????, ??? ????? ? ????? ???????? ????? ??????????? ? 3-3,5 ???? ????, ?? ????????? ? ??????????????, ??????? ??????? – ??????????? ??????? ??? ????????????? ???????????! Woodstock P., BMJ 1999


???? ??????: :???? ??????:


???? ???????????: :???? ???????????: http://www.ich.org International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use


??????????? ???????????? :??????????? ???????????? Hulley & Cummings, 2001 ????????????????? ?????? ??????? ?????? ?????? ???? ???????????? ?????????? ???????????? ????????? ?????????? ???????????? ?????? ?????? ??? ??????? ???????????? ?????? ??????


???????? ????? :???????? ????? ??????????? ????????????: ???????????????? ?????????? ????, ??? ??????? ???????? ?? ???????. ??????????? ?????: ???????? ?????????? ?????????????, ????????? ? ???????? ??????????? ???????????? ???????????? ?????????? - ??????????? ??????????? ????????? ??????????, ??????????: ????? ????????? ?????????????????? ??????.


?????? ??????? ???????, ????????? ??????????? ?????? ? ?? :?????? ??????? ???????, ????????? ??????????? ?????? ? ?? ???????????? ?????????? ?????????? ??????? ? ???????????? ????? ???????? ? ???????? ???????? ?????


??????-???????? :??????-????????


????????? ???????????? :????????? ????????????


??? :???


??????? ??????????????? :??????? ??????????????? ????????? ? ????????


?????? ??????????????? :?????? ???????????????


??????????? ???????????? :??????????? ???????????? ????????? ? ? B ????? (????????????? / ?????????? / ?????????????? / ?????????? ????????????? ?????? ??????-???? ??????????) ???? ??????: P<0.0001 ???? ?2: P<0.0001 ???????? ????? ???????? ???????? ????????, ?? ????????? ??? ???????


Slide 20:????????????? ???? (Relative Risk ??? Risk Ratio) ????????? ????? ? ???????? ?????? ? ????? ? ??????????? ??????? ? ?????? ? ????? ?????? 56% ?????? ?? ???????, ?? ????????? ? ??????? ???????? ?? ?????? ?


Slide 21:0,4 0,6 0,8 1,0 1,2 1,4 1,6 RR=1 ???????? ??????????? RR=0,559 95% CI [0.4056-0.7721] ???? ? ???????? ?????? ?????????? 56% ?? ????? ? ???????????: ??????? ?????????? ? ????????? ??????? ???? ?? 100-56=44% ???????? ??????????: 96% CI ?? ???????? 1 ?????? ? ???????????? ? 95% ???????? ????? ????? ?????????? ?????? 33% (100-77) ??? ?? ????? ???? ??????????? ????: 59% (100-41)


Slide 22:???????? ?????????????? ????? (Relative Risk Reduction) ???? ???????? ????? ? ????????????????? ??????, ?? ????????? ? ??????????? ??????? ?????????? ? ??????? ???? ?? 44% vs ??????? ?


Slide 23:???????? ??????????? ????? (Absolute Risk Reduction ??? Risk Difference) ???????? ? ??????? ????? ????? ???????? ??????? ???????????????? ??????? ? ?????? ? ?? 12,6% ????, ??? ? ?????? ?


Slide 24:????? ????? ?????????? ARR, ????? ? ??? ???? RR / ARR?


Slide 25:NNT (Number Needed to Treat) ??????? ??????? ?????? ???????? ???????? A, ??? ?? ?? ????????? ? ?????????? ? ????????????? ???????? ?????? ???????????????? ??????? ???????? ??????? ??? ???????????? ??????, ??????? ?????? ?? ?????, ????????? ????????? ?????? ?? ????? ??????? ??????? ????? ????????????? ??? ?? ?????????


Slide 26:??????? ??? (???????? ????? – ???????????)


Slide 27:Wiysonge CS et al. Beta-blockers for hypertension. Cochrane Database Syst Rev 2007;(1):CD002003. Number needed to harm ??? ??????? ???? ???????? ?? ????????? ? ??????? (NNT=200) ??? ?? ?????????? ?? ?????????? ? ????? ???????????? ???????? (NNT=0, ?? ??? ?????? ?? ???????) ??? ??????????? ???? ???????? ?? ????????? ? ???? (NNH=180) ??? ??????????? ???? ???????? ?? ????????? ? ??????????? (NNH=65)


Slide 28:????????? ?????? (Odds ratio) ????????? ?????? ?????? ? ???????? ?????? ? ????? ? ???????????


Slide 29:????????? ?????? (Odds ratio) ????????? ?????? ?????? ? ???????? ?????? ? ????? ? ??????????? ??????????? ? ????????????? «??????-????????», ??? ??????????????? ???????


???? ???????? ????? - ?????????? :???? ???????? ????? - ?????????? ??????? ????????????? ????????? ????? ????????????, ?? ??? ?? ?????? ????????? ??????? ?????????? ??????!


?????????? :?????????? Chi-square test: RR=24/24=1 (?=1,0) Log-rank (Mantel-Cox) Test: HR=0,87 [0,33-0,93], ?=0,01


Canadian ?ooperative Study Group :Canadian ?ooperative Study Group Gent. Circulation 1980 0 0.5 1 2 3 ??????? ????????? ?????? 0.7 (95% CI 0.5 to 1.0) ???????????? ???????? ??????? ??? ???? ????????/?????? ? 585 ???????, ????????? ??????????? ???????


?????? 1: ?????????? ?? ?????? ???????? ? ?????????? ?? ????? :?????? 1: ?????????? ?? ?????? ???????? ? ?????????? ?? ????? Gent. Circulation 1980 0 0.5 1 2 3 ??????? ????????? ?????? 0.7 (95% CI 0.5 to 1.0) ???????????? ???????? ??????? ??? ?? ???


?????? 2: ?????????? ?? ?????? ???????? ? ?????????? ???? ?? ?????? :?????? 2: ?????????? ?? ?????? ???????? ? ?????????? ???? ?? ?????? Gent. Circulation 1980 0 0.5 1 2 3 ??????? ????????? ?????? 0.7 (95% CI 0.5 to 1.0) ???????????? ???????? ??????? ??? ??? ???


ISIS-2 :ISIS-2 ISIS-2. Lancet 1988;ii: 349–60.


???????? ????? (?=0,05) :???????? ????? (?=0,05) 95% 5% 5% 90% 5% 85% 1-? ????? 2-? ????? 3-? ????? 15%


Slide 38:In clinical trials EVERYBODY LIES


????????? ?? ?????? ??? ?????????? ??? ??????? ???: :????????? ?? ?????? ??? ?????????? ??? ??????? ???: ?????????? ?????????? ??????????? (? ???? ?????) ?????????? ??????????


???????????? COMET :???????????? COMET ?????? ?????? ????????? 2-? ??? ? ??????? ??? ?????????? ??? ??????? ???????????? – 33,9% ???????????? – 39,5% (?=0,0017) ?????????? «??? ?????? ?????? + ??? ??????????????» ? ??????????? ??????? ???????? ???????? ?????????? (p=0,122). Remme WJ et al. J Am Coll Cardiol 2007;49:963–71.


Slide 41:KOL: ?????????? ?? ????????? ? ???????????? ?????????? ??????? ?????????? ??????? ??? ?? 14,2%! ????: ? ????? 14 ??????? ?? 100 ???? ?????? ?????????? ? ??????? ??????????!


Slide 42:Remme WJ et al. J Am Coll Cardiol 2007;49:963–71. MERIT-HF Study Group. Lancet 1999;353:2001–7. ???. ????? ???????????: ?? ????? ???? ???????? ?? ????? ??????: ???? ????????? ?? ??? ? ???????? ? ?????? ??? ?????? ?? 5,6% ????, ? NNT=17. ?? ???? ?? ?????? 100 ???????, ??????? ???????? ? ??? ?? ??? ????????????? ????????? ???????? ?????? ???????? ? ???.


Slide 43:Remme WJ et al. J Am Coll Cardiol 2007;49:963–71. MERIT-HF Study Group. Lancet 1999;353:2001–7. ???. ????? ???????????: ?? ????? ???? ???????? ?? ????? ??????: ???? ????????? ?? ??? ? ???????? ? ?????? ??? ?????? ?? 5,6% ????, ? NNT=17. ?? ???? ?? ?????? 100 ???????, ??????? ???????? ? ??? ?? ??? ????????????? ????????? ???????? ?????? ???????? ? ???. ?? ???? ??? ????????? ????? ???? ??????????? ???????! ?????? ?????? ?????????? ??? ?? ?????? ?? ?????? ???????? ????? (?????????? + ??????????????)? ?????? ? ???????????? ?????????? ??? ???????? ?????? ? ???????????? MERIT-HF ? ?????? ??? ????????? ?????????? ????????? ? 3 ???? ????, ??? ? ???????????? COMET ? ?????? ? ???????????? MERIT-HF ??????? ???? ????????? ? ????????? ?? «??????» ??? ?????????? 155 ??, ? ? ???????????? COMET ?????? 78 ???


???????? ? ??????????????? :???????? ? ??????????????? Andersson B., et al. J Card Fail 2001;7:311–317. ??????????? ??????? 50 ?? 3 ???? ? ????? 14 22 08 08 300 200 100 0 ??????????? ???????? CR/XL 100 ?? ??????????? ???????? CR/XL 200 ?? ??????????? ??????? 50 ?? ??????????? ??????? 50 ?? ????? ??????, ? ??????????? ???????? 200 ?? 1 ??? ? ????? ???????????? ????????? ? ?????? ????? (?????/?) ??????????? ???????? 100 ?? 1 ??? ? ????? MDS: ??????? ???? 100-150 ?? – ??? ??????? ?? ?????????? MERIT-HF: ??????? ???? 200 ?? – ???????? ?????????? ?? 34%


????? ??? ??????????? :????? ??? ??????????? 5,6%


COMET :COMET 5,6% 7,5 ???.


COPERNICUS :COPERNICUS ?????????? ??????? 8 ???.


?????? ???????????? ???????????? :?????? ???????????? ???????????? ? ????? ?????? ? ??? ??????? ??????: «???????? ?? ??? ????????? ????????? ??????? ????-??????? ??? ??? ????????? ???? ????????? ????-?????????? ? ?????????? ?????????????? ??????????, ??????? ?????????? ?????? ?????????» ?? ?????? ??????, ????? ??????? ?????, ?????????? ?? ???????????????: ????????? ???????? ???????????, ?? ???? ?? ???? ????????????? ???, ??? COMET ?????????????????: ????? ??????? ???? ??? ??????? ?????, ??? ??????. ??? ?? ????? ?????????. Eric Topol Ake Hjalmarson, PI of MERIT-HF


Slide 49:In clinical trials EVERYBODY LIES, but do it CORRECTLY!