"The definition of breakthrough is "it costs a packet" "  Now that, I like.. 

But I have to disagree on your method of science. Einstein's general relativity theory remains a theory despite the experimental results that concord with the predictions it makes. What these experiments do is fail to falsify the theory, so we stick with it. There are some things it cannot explain, which quantum theory does better, so we continue with two not compatible but very useful models to explain our world.

Such models and experiements should not be confused with the method employed in trials. Trials are not designed to test a theory (for example, a trial of betablockers is not testing the theory that there are biochemical receptors). The trial is there to establish which of one or more interventions is superior, if at all. No theory/modle is falsified by such experiments  - although beliefs (some cherished) can be dispelled. I suppose statisticians/epidemiologists have not helped our understanding by using the term hypothesis testing.

Kev



Dr Kev (Kevork) Hopayian, 
MD FRCGP
General Practitioner, Leiston, Suffolk,
General Practice Trainer, Leiston
Hon Sen Lecturer, Norwich Medical School, University of East Anglia
Primary Care Tutor, East Suffolk
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On 24 Jul 2014, at 20:49, Tom Jefferson <[log in to unmask]> wrote:

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

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Suite 250

3030 SW Moody Ave.

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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.


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