This is “learning ” weekend for me, Kev
Working on the grant (what else is new?) and my 99% of perspiration is on welcome occasions being alleviated by reflection on thoughtful messages and remarks
by people like you…(I confess: when I get tired of writing, I log back on my e-mail, and the messages from the EBM folks never stop inspiring me…)
In thinking about your latest example, we may be talking about two different things: evidence vs. decision-making, which in clinical trial design paradigm translates
into explanatory trials (whose goal is to provide a scientific answer to a research question, typically focusing on the proof of a concept or mechanism etc ;‘Efficacy” question) vs. pragmatic trials (Which treatment of already proven efficacy is better?” ;“effectiveness
question). [Several years ago we used regret approach to tackle these issues; see:Hozo I, Schell MJ, Djulbegovic B. Decision-making when data and inferences are not conclusive: risk-benefit and acceptable regret approach. Semin Hematol. Jul 2008;45(3):150-159.]
In terms of application of Popper’s discourse of scientific method to clinical trials, Jeremy Howick informed me that Fisherian hypothesis testing and Popperian
falsificationism is identical. Fisher wrote it first, but Popper had not read Fisher (until much later, I believe) at which point Popper acknowledged the similarity… (I slightly edited Jeremy’s words, and if I am not quoting him accurately, I hope he can clarify)
Enjoy auburn leaves (is it already fall in England?)
Best
ben
From: Evidence based health (EBH) [mailto:[log in to unmask]]
On Behalf Of k.hopayian
Sent: Saturday, July 26, 2014 7:47 AM
To: [log in to unmask]
Subject: Re: Since when did case series become acceptable to prove efficacy?
Hi Ben,
Short reply: I respectfully disagree that a trial is an example of Popper's scientific method. Popper was concerned with
theory. Whether drug A is better than B is not a theory (although confusingly, the negation of that statement is called the null
hypothesis) in the sense that the biochemistry and pharmacology around those drugs have theories (such as drug receptors, enzyme action etc).
Slightly longer reply: Theories make predictions but not all predictions come from theories.
For example, the laws of physics are applied in engineering. Physics and engineering have theories. Engineers may design cars. Two cars may be compared for performance (acceleration, speed, efficiency etc). In comparing them, a manufacturer
may start with an idea (our cars are better than yours) but that would hardly count as a theory. [By the way, have car manufacturers ever ever started with a null hypothesis?:-)] The manufacturer's prediction may be proven wrong (and no doubt get buried in
company vaults, car manufacturers are so different to pharma, aren't they?) but no rejection of the theory of engineering is necessarily implied. Now if an engineer designed a car whose performance was beyond the boundaries predicted by the laws of thermodynamics,
that WOULD falsify theory.
It is a lovely sunny weekend here in Suffolk, with many shades of green and auburn leaves, so out I go. I hope your weekend is a good one too.
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
RCGP Clinical Skills Assessment examiner
NHS Senior Appraiser, East Anglia
In fact, clinical trial is a classic example of (Popper's) falsificationism paradigm...and does test hypothesis that one drug is better than the other ( Ho: A=B; Ha:A<>B, as postured by classic frequentist statistical approach). Statistical
evidence obtained this way connects one phenomena with others eventually corroborating ( or, rejecting) theories ( group of related principles and laws that were built by testing a number of hypotheses) such as those if beta-blockers effects are consistent
with biochemical drug-receptor theory...
Ps Steven Senn had a wonderful article some years ago about falsificationism in clinical trials...worth reading...
Sent from my iPad
( please excuse typos & brevity)
"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.
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
RCGP Clinical Skills Assessment examiner
NHS Senior Appraiser, East Anglia
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
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,
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)
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
--
--
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