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The definition of breakthrough is "it costs a packet" - and Sovaldi fits the picture. This kind of bullshit is replicated in the EU with so called early assessment to get better, innovative drugs earlier to patients who desperately need them. So the burden of proof is slowly being pushed back to phase IV or beyond which may be observational, subverting Galileo's methods. What we should always remember is that Einstein's general relativity theory (1915) was a theory and remained a theory until Eddington's natural experiment during the 1919 solar eclipse confirmed that gravitation could deflect starlight as the theory had put forward. The rise of observational data (even non comparative) is an involution, not an evolution. There are many culprits most of them in my profession (I am a physician) and they will be held to account. Greed and science do not mix. Nite from Rome. Tom. On 24 July 2014 17:10, Poses, Roy <[log in to unmask]> wrote: > 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] > -- Dr Tom Jefferson Medico Chirurgo GMC # 2527527 www.attentiallebufale.it