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Ben Thanks for provoking this fascinating discussion. There is one issue that has been picked up only indirectly. The question "Can RCTs help establish causation?" invites a "Yes!" or "No!" answer. However, dichotomising questions are a bit dodgy, because the world is more complicated than that usually. It might be more helpful to think of clinical trials as measuring instruments, rather than as determiners of the Truth. Then the question becomes "How accurate and precise are the results?" And, to answer the accuracy bit you need to assess the risks of bias, which is what many of the people who have entered this discussion have done. Framing the question as "Can RCTs help establish causation?" focuses attention on trial design, which in itself is not a bad thing (otherwise Stephen Senn would not have written books on the subject). However, the risks of bias also depend on factors outside the trial design. Thus the results from an RCT can be more or less trustworthy, depending on external information. For example, the results from an open pragmatic trial with a "usual care" control are at higher risk of bias (lower chance of causality) when there are no results from previous "explanatory" trials with rigororous randomization, appropriate placebo control, careful blinding, narrow inclusion criteria, and close followup. Michael -----Original Message----- From: Djulbegovic, Benjamin [mailto:[log in to unmask]] Sent: 30 January 2011 16:30 Subject: Re: Can RCT help establish causation? Dear all First, I want to thank many of you who responded either directly to me or to the entire group with the phenomenal line of thoughtful insights related to the question if RCT can establish causation. Once again, participation in this group has proved so rewarding – there is no question, big or small, theoretical or practical that goes unanswered at rather deep level. The immediate reason for my question was motivated by increasing number of writings in the philosophical literature that question feasibility of developing hierarchy of evidence- one of the most important contribution of EBM, I should add. While there are several lines of this critique, the most fundamental- and thus most important- is the claim that, in principle, the inferences drawn from RCTs are not epistemologically superior to observational studies. In particular, the criticism was leveled against RCT as the purported mechanism to establish causation (as randomization allows equal distribution of all known and UKNOWN confounders apart from the intervention of interest). The critics (in particular Worrall) has asserted that …”given that there are indefinitely many possible confounding factors...the probability that the groups are unbalanced ...is high" and hence inferences from RCTs are not epistemologically different from those drawn from the observational research. Some of you graciously sent me several papers refuting some of Worral’s critique (I am still reading some of the material you sent- so, some what I am writing here may still change), but most poignant repudiation of Worral’s criticism came from Stephen Senn. His paper (Senn, SJ. Baseline Balance and Valid Statistical Analyses: Common Misunderstandings, Applied Clinical Trials 2005; 14: 24-27) should be required reading for all EBMers (although after reading one will probably say, this is so obvious!, it certainly was an eye opener for me, not exactly someone who is in this business since yesterday!). As Stephen pointed out (proved), “there is no point worrying about the distribution of unmeasured covariates” as we can still draw the valid inferences based on information we have (what we do NOT know CANNOT be factored in the way we draw our conclusions or make our inferences). The same argument cannot apply to observational studies as we don’t have formal machinery (randomization) to draw the accurate inferences about the probability statements. Finally, several folks cogently argued that randomization is indeed the necessary (although not sufficient reason, as it may be subverted etc) to establish causation. This all indicate that indeed experimental, RCT design remains epistemologically superior to observational studies (no big news for the members of this group, but fundamentally really big news). Thanks again to all of you for the phenomenal discussion and contribution Ben djulbegovic