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Thanks, Tom. Could not agree more. But it seems like there is little protest about this paradigm shift, your work, of course, excepted. Re: "trials are for regulators" - but in the US, the regulators apparently decided they don't need so many trials. The FDA designated Sovaldi/ sofosbuvir as a "breakthrough" therapy, which apparently allows approvals based on much more limited evidence, although the evidence behind that "breakthrough" designation itself was not clear. See: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm377888.htm On Thu, Jul 24, 2014 at 10:45 AM, Tom Jefferson <[log in to unmask]> wrote: > Roy and all evidencers. > > The scientific method of Galileo has been subverted before our very eyes. > > Galileo observed, described and then produced a hypothesis or theory which > he then proceeded to test with an experiment. This model has served us well > in the last 400 years with a few exceptions (the already cited penicillin > for example). > > What we now witness is a fundamental subversion of the order (I am not > going to call it a paradigm shift) of things. Observations are fact, > case-controls, case series, cohorts (even retrospective and datalinked > ones) are being held out as proof. Trials are for regulators, they say. > > The origin of all this is complex and partly known. In the Tamiflu story > as we began uncovering the extent of reporting bias affecting the clinical > trials that had been used to make policy and justify stockpiling, decision > makers turned to observational evidence (of universally recognised poor > quality) as props for their unchangeable policies. > > It is a sad parable of the world we live in. > > Best wishes, > > Tom. > > > On 24 July 2014 16:33, Valerie King <[log in to unmask]> wrote: > >> Agree Roy. >> >> >> >> Don’t think we can assume, based on these case-series in highly selected >> populations, that the “eradication” rate is >=90% or that SVR is a good >> surrogate. Also, although the studies were registered with SVR24 as primary >> outcome the FDA let them give SVR12 as part of the “breakthrough” >> designation so we don’t even have a particularly good surrogate. >> >> >> >> Virtually all of the subjects in published studies had very positive >> treatment prognosis anyway. Over half of subjects had HCV genotype 2 which >> is the easiest to treat no matter what drug used. And there is certainly >> more than a hint in several of the studies of substantial relapse rates >> after SVR24 achieved (e.g. ~9% in NUTRINO.) I honestly think that most >> people are listening to the marketing drumbeat on this drug and not reading >> the papers for themselves. I’d be happy to have these drugs be the >> breakthrough that most people seem to think that they are, but in my >> opinion, currently there are a lack of data to support that position. >> >> >> >> Cheers, >> >> Valerie >> >> >> >> *Valerie J. King, MD, MPH* >> >> Professor of Family Medicine, and >> >> Public Health & Preventive Medicine >> >> Director of Research >> >> Center for Evidence-based Policy >> >> Oregon Health & Science University >> >> Mailstop MDYCEBP >> >> Suite 250 >> >> 3030 SW Moody Ave. >> >> Portland, OR 97201 >> >> Voice: 503-494-8694 >> >> Fax: 503-494-3807 >> >> [log in to unmask] >> >> www.ohsu.edu/policycenter/ >> >> Twitter: @drvalking >> >> >> >> >> >> >> >> *From:* Evidence based health (EBH) [mailto: >> [log in to unmask]] *On Behalf Of *Poses, Roy >> *Sent:* Thursday, July 24, 2014 07:08 >> >> *To:* [log in to unmask] >> *Subject:* Re: Since when did case series become acceptable to prove >> efficacy? >> >> >> >> But it is not clear that SVR is a good surrogate marker. >> >> >> See: >> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961025-4/fulltext >> >> and the Cochrane review it references: >> >> http://www.ncbi.nlm.nih.gov/pubmed/24585509 >> >> As an aside, given that hep C infection is a chronic problem and bad >> effects from it occur long after original infection, it is extremely >> strange that no one has ever thought to do a good RCT with long term follow >> up to assess clinical outcomes of ANY hepatitis C treatment. >> >> >> >> On Wed, Jul 23, 2014 at 4:54 PM, Djulbegovic, Benjamin < >> [log in to unmask]> wrote: >> >> But, if eradication of viral load is greater than 90% ( and we accept >> viral load as a good surrogate marker), would then single arm study be >> justified? >> >> Ben >> >> Sent from my iPhone >> >> (Please excuse typos & brevity) >> >> >> On Jul 23, 2014, at 4:50 PM, "Poses, Roy" <[log in to unmask]> wrote: >> >> That seems reasonable, but certainly does not apply to this particular >> clinical situation and article. >> >> >> >> On Wed, Jul 23, 2014 at 4:47 PM, Steve Simon, P.Mean Consulting < >> [log in to unmask]> wrote: >> >> On 7/23/2014 9:39 AM, Poses, Roy wrote: >> > I still don't see why case-series without any control groups are now >> > regarded as credible ways to evaluate efficacy of therapy??? >> >> I cannot comment on this particular example, but in general you can >> safely dispense with a control group when there is close to 100% morbidity >> or mortality in that control group. In such a setting, any improvement is >> painfully obvious and does not need a rigorous design or fancy statistical >> analysis. Also, it is pretty difficult and probably unethical to randomly >> assign half your patients to be in a group that has 100% morbidity or >> mortality. >> >> Steve Simon, [log in to unmask], Standard Disclaimer. >> Sign up for the Monthly Mean, the newsletter that >> dares to call itself average at www.pmean.com/news >> >> >> >> > > -- > Dr Tom Jefferson > Medico Chirurgo > GMC # 2527527 > www.attentiallebufale.it > -- Roy M. Poses MD FACP President Foundation for Integrity and Responsibility in Medicine (FIRM) [log in to unmask] Clinical Associate Professor of Medicine Alpert Medical School, Brown University [log in to unmask]