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Are we using available evidence at the best? Nicola Magrini AIFA Spring Seminar 30 Marzo 2007.

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Presentation on theme: "Are we using available evidence at the best? Nicola Magrini AIFA Spring Seminar 30 Marzo 2007."— Presentation transcript:

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2 Are we using available evidence at the best? Nicola Magrini AIFA Spring Seminar 30 Marzo 2007

3 Contents of the presentation Are regulatory agencies using available evidence at the best? Are journals and the scientific community using evidence at the best? How are we presenting available evidence to prescribers? Conclusions

4 Are regulatory agencies using available evidence at the best? Surely NO

5 Why regulatory agencies are not using available evidence at the best Loose criteria for approval (scanty data or just a single trial sufficient for registration) Lack of transparency and lack of full access to existing information and knowledge Lack of laws and regulation protecting public interest giving full access in Europe (vs Freedom of Information Act in the US) False myths: GCP role and their usefulness (a solution worse than the problem?)

6 FDA approval process S. Okie NEJM 2005 Almost never are now requested 2 indipendent pivotal studies

7 How is FDA faring?

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9 Why regulatory agencies are not using available evidence at the best Loose criteria for approval (scanty data or just a single trial) Lack of transparency and lack of full access to existing information and knowledge Lack of laws and regulation protecting public interest giving full access in Europe (vs Freedom of Information Act in the US) False myths: GCP role and their usefulness (a solution worse than the problem?)

10 Lack of transparency/access to EMEA data: a recent example Torcetrapib, a nove antidyslipidemic drug (which also increases HDL levels) was shown to increase myocardial events in association with atorvastatin – FDA press release - trial not yet published Where are the data for a more detailed evaluation?

11 EMEA and … novel torcetrapib New anonymous product EMEA - Scientific Advice Background Package November 2006 Pp 1-224

12 Lack of transparency/access to EMEA data: a recent example Torcetrapib, a nove antidylipidemic drug (which also increases HDL levels) was shown to increase myocardial events in association with atorvastatin – FDA press release - trial not yet published Similar drugs are currently evaluated: how should they be studied? Why the scientific community was not involved in this debate? Several phase III Worldwide, Multicenter, Double-Blind, Randomized, Parallel, Placebo-Controlled Studies are proposed: but only with surrogate (LDL cholesterol) short- term (maximum 1 year) end-points Why EMEA is not changing its guideline for evaluating cholesterol drugs effectiveness? Why is EMEA so little present in the scientific journals?

13 Researchers contest how (regulatory agencies accept) new drugs are developed

14 Are journals and the scientific community using evidence at the best? Surely improving …

15 Available evidence and Journals: the achievements RCT registration (to reduce publication bias and outcome reporting bias) Improving post-publication criticism and the future of medical publishing (open access movement) Putting the latest clinical trials in the context of available evidence What this study adds / what is already known (BMJ) Speak badly of GCP

16 A great achievement to reduce publication and outcome reporting bias: RCT registration

17 Available evidence and Journals: the achievements RCT registration (against publication bias and outcome reporting bias) Improving post-publication criticism and the future of medical publishing (open access movement) Putting the latest clinical trials in the context of available evidence What this study adds / what is already known (BMJ) Speak badly of GCP

18 Papers and postpublication criticism R. Horton, JAMA 2002

19 An example of postpublication criticism flaws R. Horton, JAMA 2002

20 A structured format for discussion section? R. Horton. JAMA 2002

21 Available evidence and Journals: the achievements RCT registration (against publication bias and outcome reporting bias) The limits of post-publication criticism and the future of medical publishing (open access movement) Putting the latest clinical trials in the context of available evidence What this study adds / what is already known (BMJ) Speak badly of GCP

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23 RCT … improper without a systematic review Lancet, July 9, 2005

24 An interesting option: the latest trial and its metanalysis Lancet trial (alteplase in stroke) SITS-MOST, Lancet, 2007

25 BMJ (slight) improvement of latest trial and previous RCTs

26 Available evidence and Journals: the achievements RCT registration (against publication bias and outcome reporting bias) The limits of post-publication criticism and the future of medical publishing (open access movement) Putting the latest clinical trials in the context of available evidence Improve study results presentation and what this study adds / what is already known (BMJ) Speak badly of GCP

27 How to improve study results presentation (I): some issues (from BMJ editorial board 2004) (Wilson T, Sackett D, Altman D) Researchers prefer relative measures Clinical decision need absolute measures (how many patients will benefit from the intervention) A reader needs thrre types of information to make sense of relative measures: –The context –The results –The implications

28 An example: For the patients included in the present study (baseline characteristics), the control group (receiving standard therapy …) showed an event rate of XX,X%, the tretament has produced a reduction in the event rate of YY,Y% (ARR), which correspnds to a NNT of ZZZ (with a 95% CI …) which means a relative risk reduction of VV% (RRR) How to express benefits and risks (II) some issues (from BMJ editorial board 2004) (Wilson T, Sackett D, Altman D)

29 Context: meningococcal septicaemia has a high mortality. Despite intrevenous antibiotics about 10% die. Results: Wondermycin is better than penicillin and reduces rates by 20% Implications: The NNT for patients in ITU is 50: for every fifty people with meningococcal septicaemia in ITU treated with wondermycin in place of penicillin one more would survive. Cost implications: in the UK a course of wondermycin in ITu would cost £300 whilst penicillin would cost £15. This represents a £ for every life saved. How to improve study results presentation (III): an example with all essential informations (Wilson T, Sackett D, Altman D: BMJ editorial board 2004)

30 How to put the latest trial in the context of available knowledge: BMJs WIAK & WTSA

31 Available evidence and Journals: the achievements RCT registration (against publication bias and outcome reporting bias) The limits of post-publication criticism and the future of medical publishing (open access movement) Putting the latest clinical trials in the context of available evidence What this study adds / what is already known (BMJ) Speak badly of GCP

32 GCP: gold or bronze standard?

33 GCP: drop them? Grimes DA et al. Lancet 2005

34 Are journals and the scientific community using evidence at the best? Surely improving … tough often below the optimal standard

35 GRADE G rades of R ecommendation A ssessment, D evelopment and E valuation What is the essential information to do more good than harm?

36 BMJ, 2004

37 GRADE – qualità delle evidenze e forza delle raccomandazioni 1. Choose and rate the clinically relevant outcomes 2. Evaluate the quality of evidence and define a balance-sheet 3. Evalute the benefit/risk ratio also considering: Feasibility Feasibility Access Access Costs Costs 4. Define the strength of the recommendaion (strong or weak)

38 GRADE – quality of evidence dimensions to be considered Tipe of study Tipe of study Quality of study: Quality of study: Consistency: etherogeneity or variability across studies Consistency: etherogeneity or variability across studies Directness: transferabilty (external validity) Directness: transferabilty (external validity) Comments Critical appraisal - often done through accompanying editorial and letters Critical appraisal - often done through accompanying editorial and letters Putting the latest trial into the context of available evidence Putting the latest trial into the context of available evidence Discuss the problems of patients selection and transferabilty Discuss the problems of patients selection and transferabilty COMMENT: For most drug approved the available evidence base does not allow an evaluation considering all the dimensions recommended by GRADE

39 Sono le linee-guida ATP-III evidence-based? Lancet 20 january 2007

40 Methodological quality of cholesterol guideline: NCEP ATP-III Multidisciplinary Panel Systematic Review Benefits and harms quantified for each recommendation Grading of the recommendations Transferability and implications Full disclosure of Conflict of interests NO YES YES/NO NO YES/NO ?

41 LG ATP-III – dove sono le evidenze? Lancet 20 january 2007

42 How are we presenting available evidence to prescribers? Improving but … mostly in format for researchers

43 Important achievements … for researchers Clinical evidence & Cochrane SR

44 Do we need more explicit formats? See Prescrire

45 Should we tell prescribers the whole story?

46 Is the New York Times more informative than scientific journals about FDA decisions? Why is EMEA surrounded by silence?

47 NEJM

48 Regulators and Newspapers: NYT and NEJM who is leading the game?

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51 NY Times 8 febbraio 2005

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53 NY Times 18 febbraio 2005

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55 Conclusions

56 Conclusions (1) A single study should be put in the context of available knowledge Protocols should be registered and made accessible Formats and ways of presenting RCT results to prescribers should be encouraged We should try to have a symmetry of information between producers (researchers and industry) and final users (doctors and patients)

57 Conclusions (2) Priorities Improve/change present laws to improve transparency and access Improve our knowledge brokering capacity Create network of indipendent researchers to perform pragmatic, simple large scale RCTs in a real practice setting Scientific Journals and newspapers should have a common approach and similar objectives


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