-: So there's no longer a discrepancy.
So John holds the Daniel W. Foster M.D. professorship
in medical ethics.
He received his medical degree from Indiana University
and then he trained in psychiatry here,
and he joined our faculty in 1984.
So he's been here for awhile.
He now directs the program in Ethics and Science
in Medicine, and his Chief of the division of Ethics
in the Department of Psychiatry.
His research broadly, is in the areas
of clinical psychiatry, psychiatric education,
bio-ethics, and the philosophy of psychiatry,
and he's published widely in all of these area.
He co-founded the Association for the Advancement
of Philosophy in Psychiatry,
and other organizations as well.
His teaching has been recognized by numerous awards,
including a UT system's Regents Outstanding Teaching Award.
Since 1985, John served on the Parkland Hospital
and Health System Institutional Ethics Committee,
and until very recently when Janet took over,
he was the clinical ethics consultant to the hospital.
So his topic today is Corruption in Clinical Research.
Please join me in welcoming our own John Sadler.
(audience applauds)
-: Thanks Fred for that calm, varied,
and generous introduction.
Can everyone hear me okay this thing okay?
Very good.
So there is my title.
What got me interested in this particular topic was,
I thought the word corruption referring to clinical research
has been thrown around somewhat casual
and certainly rhetorical way
and that it poses a very serious charge
to those individuals to whom it is aimed, on the one hand.
And on the other hand, that there is almost no discussion
in the literature about what exactly we mean by corruption.
And so that's one of my objectives here,
is to develop a working definition of corruption in science.
And I'd like to contrast research corruption
from other kinds of undue influence in clinical research,
which we'll talk about very briefly,
and you probably can intuit on your own.
I'll provide some examples of what I consider
fairly transparent or obvious true research corruption.
And then move progressively toward more and more
ambiguous areas, as a way of testing my working definition,
in this arena.
And then finally, I'll describe the importance
of research corruption for evidence-based medicine,
public policy, and ordinary practice.
So this is the basic overview.
What is corruption?
Case examples and then the significance.
For those of you who have trouble at the back reading,
I'm not gonna cover the birth of big pharma,
which is really a cynical cartoon,
but the color one there on the bottom says,
"Nine out of 10 doctors on our payroll
"recommend this product."
That pretty much sums up the potential for corruption.
And with some ambivalence I present this,
what appears to be some sort of indictment
of the pharmaceutical industry,
and so I should acknowledge from the very beginning,
how dependent we all are on the pharmaceutical industry,
and medical device industry for providing
products that are instrumental in our care
and healing of our patients.
And so I think that acknowledgement is a given.
Needless to say though, that there are forces out and about
that can make the task of quality, informed patient care
more difficult and that's what my focus is today.
So corruption as I mentioned is often used
in finger pointing
and in popular public discourse.
It's also found its way into accusations
against clinical investigators and their institutions.
Our ordinary sense of corruption is a serious moral charge,
and as I said in my introductory remarks,
this is why we should be responsible.
And so that's sort of the ethics element of this.
Moreover, understanding corruption I think can help us
to be more critically-informed consumers
of clinical research, as I hope you will see and agree.
So what is corruption in clinical research?
And how can we define that?
Interestingly when you do a broad literature review
about corruption in scholarship of various stripes,
the bulk of the literature comes from social sciences.
And particularly from economics where as you might imagine
there's keen interest about
the function of corruption in economies.
And I'm not gonna go into much detail
about corruption in economics, other than to say
that scientific evidence
about the impact of corruption is mixed.
That's is it's mixed about whether corruption
is bad for economies.
Political science, law, and philosophy
are also key stakeholders
in the investigation of corruption.
One of the key notions is that you need a framework,
or standpoint, or point of view,
about what the proper functioning of the individual,
or the institution that you're suspecting of being corrupt.
So understanding proper function is one of the first steps.
So we think about this in terms of the political sphere.
What is it about democracy such that they can be corrupted.
So that's sort of a fundamental question
about political corruption.
So there's very little literature
about what counts as corruption in science
and even less in clinical research.
So again, those of you in the back who can't read
the 1938 Lucky Strike advertisement and it says,
"20,679 physicians say Luckys are less irritating
"because it's toasted to reduce irritation
"and protect against cough."
So what is corruption exactly?
Many terms get used in corruption
and one of the fundamental skills in philosophy
is to recognize that one word can mask a whole host
of different concepts.
And so one of the fundamental skills
and directions in doing philosophical inquiry
is to understand what senses a word means
and what multiple meanings are involved.
So corruption in clinical research has been used
to refer to conflict of interest and conflict of duty,
very familiar to us.
It's been used to refer to research bias of various kind,
selection bias, confirmation bias, and so forth.
It's been used to refer to scientific fraud,
or the intentional fabrication, or falsification
of data, analysis, or conclusions.
And even sloppy, careless research practices
could be labeled as corruption as well.
So a clear understanding of corruption
should clarify the relationship of these ideas
to corruption proper.
The Harvard ethics scholar now retired, Dennis Thompson,
in referring to again, political corruption,
"corruption is a disease of the body politic".
So what makes the health of the body politic?
Analogously, what is it about science that can be corrupted?
So from this standpoint, science is a social enterprise
that aims to develop genuine, or more accurately,
credible knowledge about the world.
Speaking of using the term credible,
I acknowledge my long-term friend and colleague
Fred Grinnell, who's used this language
in his outstanding work in the science process.
Science has a particular set of methods,
but the purposes of understanding corruption,
I focus more on the social aspects of science,
as corruption is a social
rather than, more than a methodological phenomenon.
So the law scholar Hellman says that "most theories agree
"that corruption requires the violation of a normative
"standard, some benefit, personal or political,
"and some connection between the two."
So what is it about the social organization of science
that facilitates its goal of genuine credible knowledge
of the world?
That's where the the philosopher Helen Longino comes in,
from work that she did quite a few years ago now,
in examining the social features of science,
as well as the kinds of social values
that are embraced by science.
And in a certain sense, in a presumptive way,
the values of science are typically assumed,
and simply practiced and enacted.
I think you'll understand why here shortly.
So oftentimes and in science education in our school years
we are presented that science is defined by methods
or procedures like hypothesis testing or experimentation
and that sort of thing,
but science has many diverse methods.
So, if you consider for example, four examples
of sciences, clinical trials, ethnography
and cultural anthropology, evolutionary biology,
and quantum physics, few would dispute these
as legitimate science, but their methodologies
are barely comparable.
So what are the common features of science
and particularly the common social features
of science broadly speaking?
So I'm gonna talk about these in sorta
two lists or frameworks.
One is the social features or structures of science,
and then the social values of science.
So science can be characterized as a particular
kinda social enterprise or respects particular values
in meeting its goals.
So the social structure aspect centers around the task
of generating credible knowledge.
To this end, some of the structures involved include,
and again these are nothing esoteric or unfamiliar,
peer review, that is grants, journal editorial,
considerations, manuscript submissions, undergo peer review,
oftentimes blinded to avoid various sort of bias,
and that peers sit in judgment of each other.
Professional meetings, scientific meetings,
associate to compare their findings
and critique each others findings,
as we'll see in the next element or structure.
Criticism, that knowledge claims are tested
by peer-critical comments.
So, the fourth is continuity,
that is prior knowledge
is crucial in building new knowledge.
And so while it probably would be a distortion to say
scientific knowledge is cumulative in the sense that
it's never revised, or re-envisioned,
that would be untrue, but certainly all scientists
consider prior work in building their new observations,
testing, and conclusions.
And then the methodological core stated very broadly,
to address the very diverse methods in science.
Observation, evidence, and explanation are all key elements
in scientific methods.
So now we then turn to the social values
associated with science.
So the social values of science complement the task
of generating credible knowledge.
And I've listed five here, and I'm sure
there are others that we could consider.
But the five I've chosen is openness,
that is scientists exchange evidence, reasoning,
and methodologies, at least in the ideal.
And I should probably say, most of these social values,
like all values that are aspirational, have their limits
and their exceptions, but the basic idea is openness
as an ideal that scientists can freely exchange
their evidence, reasoning, and methodologies.
The second is equality of opportunity.
That is in principle, anyone willing and able
can participate in the scientific community.
What that means is the willing and able
is the contingency.
Not everyone is willing and able to write a grant,
or perform a laboratory experiment,
or conduct a social science investigation,
but if they are able to they can participate.
And 100 years ago, much of the science was done by
lone innovators in their basements conducting research.
Peer review is also a crucial value of science.
It's the stage where judgments of scientific worth
are made consensually,
with protections against abuse and power.
And so like for in the journal peer review arena,
the editor sort of monitors the peer-review process
for misuse, abuse, or unfairness, and has some check.
In turn the editor is accountable to an editorial board,
who may censure him or her depending on the quality
of their conduct.
Then finally criticism.
All aspects of scientific interests
are subject to criticism: methods, procedure,
evidence, interpretation, and background assumption.
And so that's one of the structurally,
as well as value-aspect distinct elements of science
is this eagerness, and indeed esteem for criticism,
because that's how we get closer to the truth.
So with these background considerations of science,
we can now be more clear about what corruption might mean.
Hellman makes a frame that corruption involves
the purposeful violation of a normative standard
for personal or political gain,
and a connection between those two things.
And so the key term here is purposeful,
which we're gonna return to several times
throughout the rest of this lecture.
Another key term is normative, that is what's normal,
what's the normal standard that is being violated?
That keys back to what I said earlier,
what is it about science that can be corrupted?
And this is where then, the social and value structures
of science come in.
So corruption violates the normative, or social value
standards of science as previously described.
And particular incidents can be considered
against this framework, and that's what I'm gonna be doing,
in just a few short slides.
And it's likely that some aspects of scientific structure
and values can be corrupted, while other aspects may not be.
So here is my working definition.
The purposeful violation, corruption in science is,
the purposeful violation of, or interference with,
one or more of the social structures and values of science,
towards some personal or institutional gain.
These science structures are peer review, meetings,
criticism, continuity, observation,
evidence, and explanation.
The science values are openness, equality of opportunity,
peer review, epistemic freedom, and criticism.
So the purposefulness is not difficult, or excuse me,
is difficult to assess, as we'll see.
And corruption not surprisingly is not an either/or,
but it's an continuum, that scientific practices
can be greater, and lesser, or more, or less corrupt,
under this sort of definition.
And then finally, the corruption can be personal,
that is individual practitioners in science can be corrupt,
as well as institutions, as we'll see through our examples.
So I've conveniently listed in these and upcoming slides,
these features of science and my brief version
of my definition in the right, yellow frame, box there,
for y'alls reference.
And we'll have an opportunity
for some audience participation here shortly.
So lemme talk about then, some case examples of corruption
in clinical research science.
The first set that I wanna discuss, are fairly flagrant,
obvious, generic examples of corruption.
This case one, involves an investigator
who alters the data collected in favor of a hypothesis,
that is commits scientific fraud.
So applying this rubric of the structure
and values of science to this case,
the purposeful element we've sort of given you,
that the investigator, it's given that the behavior
is intentional, and the personal benefit is clear,
that is getting a potential more attractive publication,
given the fraud.
This behavior disrespects the central role
of evidence in science.
The secret nature of altering the data
undermines openness, as well as peer review,
and then this compromises the conduct
and value of criticism by sort of preemptively avoiding it.
Case two, again obvious example,
involves a pharmaceutical firm, who fails to register
a clinical trial at clinicaltrials.gov,
and then hides the study data when the study drug
is found to be ineffective, or inferior.
So in this context, tanking a study has a transparent,
financial motive, that is hiding efficacy,
or lack of efficacy data,
and therefore not interfering with sales.
Interferes with peer review, pretty obviously,
meeting, presentations, criticism,
continuity and explanations.
So this is a pretty profound corrupting act.
It undermines the scientific values of openness,
equality of opportunity, peer review,
epistemic freedom, and criticism.
And I think I failed to have mentioned
that epistemic freedom as the character.
Epistemic freedom is fancy way of saying
scientists are free to choose what they study
and how they do it, without outside interference.
And again, we can all think of limitations to this
and constraints on this, but at core,
this is a crucial scientific value.
As a third example of an obvious, or generic
example of corruption is case three.
Preparing a review article, a beginning investigator
copies large portions of text verbatim
from a prior review article in an obscure journal.
So the potential personal gain is clear.
This interferes with the continuity of science,
the appropriation of previous work without credit,
dispenses with the value of critically appraising past work.
Thus criticism is compromised, as is peer review,
and the secretive quotation disrespects openness as a value.
So again, these are fairly straightforward,
and not in any way problematic,
in terms of examples
of corruption as I've described them, at least in my view.
So now, as our second set of examples,
we're going to consider cases where
they may not be so clear cut and more ambiguous.
Case four is actually anonymized,
or somewhat anonymized, actual case.
A prominent child psychiatrist and clinical investigator
receives 1.6 million in pharma money over seven years.
Many of you know Marcia Angell from her years
at the New England Journal of Medicine.
In her article from the New York Review of Books
some years ago, she pointedly used this as a example
of corruption in clinical research.
So what I would say, is without more information
about this individual's conduct,
simply having a financial interest,
including a big one from pharma,
does not constitute corruption under my rubric.
That is, we don't really know for sure,
from the information that we have here,
if these, that this behavior necessarily interfered
with the social structures of science,
or the social values of science.
That has to do with the actual behavior of the investigator,
other than accepting large sums of money.
So having a conflict of interest, as we all do
in our spheres of practice and research,
does not in itself constitute corruption.
It does however, raise questions about bias,
which is of course very important,
but is a different concept.
Case five, again the more ambiguous case,
and this is fiction.
Clinical investigator, although very familiar.
A clinical investigator with a $5,000 consultant contract
with Extra Pharmaceuticals is designing
a comparative effectiveness trial.
A junior colleague on his team is puzzled
why several Extra products are in the trial,
while some familiar standard drugs are not.
The senior investigator realizes with embarrassment
that he unintentionally is biased toward Extra products.
So I would argue, again under this rubric,
this is not corruption,
as any violation here is not purposeful or intentional.
This is where then the purposeful violation
does some of the work in helping us sort out
what is corruption and what isn't.
And indeed, the investigator's response
to this realization that he was biased
in his selection of drugs to test,
indicates that he's open to peer review and criticism,
self-observation, and evidence, all of which
are positive scientific values.
So this would argue in favor, or against this being
an example of Sadlerian corruption.
The third less obvious case, excuse me,
now we turn to cases where,
are even more ambiguous and challenging.
This is case six.
Dr. Distinguished is the chairman
of a prominent clinical department
in a prominent academic medical center.
Now 62 and the top of his game,
he has a long-standing relationship
with Extra Pharmaceuticals, through speaker's fees,
and advisory committee contracts
to the tune of 100K per year.
For these fees, he is involved in research design
of Extra's products, assisting in ghost-writing
the papers from the company's contract research organization
and serving as a nominal author
in their industry-sponsored publications.
His presentations are listed as promotional
and not as continuing medical education or CME.
So the question here is, are any aspects
of this research arrangement corrupt,
again under this rubric?
So here's the audience participation part.
We have time maybe for one or two comments,
very brief if you could keep them, from the audience,
regarding the question, is Dr. Distinguished
in some sort of corrupt situation here?
Anyone?
Man: Judging by the morays of Sloan Kettering
it is corruption.
John: Say more.
Man: If it's a prominent position there
the fact that it's a contract drug company,
researching cancer, paid a lot of money.
John: And so why though then?
Man: Clearly was more staff.
John: Beg your pardon?
Man: I'm not clear on that, but he was more staff.
John: I see.
Man: And the implication was that he was sort of
raising their drug trials, I'm not sure
that was ever proven.
John: Okay, other comments?
Okay so let's go on then to the analysis.
So Lessig, Light and others have considered
institutional corruption as, as they put it,
bending policy, or in this case research
in directions favorable to industry.
That's to say this bending doesn't necessarily mean
it pays for results, but pays for the direction
that research takes.
How it's promulgated and how it's promoted.
Dr. D in the lingo is a key opinion leader, or KOL,
for Extra Pharmaceuticals.
That is he's an influential leader in the field,
who can then advise the company,
and as we'll see, direct some,
or influence directions in research.
So is this a purposeful violation of the structural
values of science?
I would say it's not purposeful.
Indeed, key opinion leaders in industry
take special care to prevent the key opinion leader
from looking like a sell out.
As a key opinion leader though, Dr. D is in a position
to distort and direct research in practice interest
in directions favorable to Extra.
He may influence treatment guidelines, policies,
influence federal grant reviews, initiate topics
friendly to Extra in professional meetings, and so forth.
So this then is a more subtle version
of interfering with the structure and values of science.
Judgments of such bending of research practices
and policy require extraordinary scrutiny,
often requiring peeking behind closed doors
at proprietary practices,
and then, only in the context of a lawsuit
or a public demand.
This was actually the idea of tank, back oh 25 years ago,
when it was discovered that large numbers
of clinical trials sponsored by industry,
were being hidden because of negative results.
Those were discovered in the context of lawsuits
for adverse outcomes, where this information
then came to light of day in the public world,
leading to then further interest in this phenomenon.
So those sorts of disclosures can be accidentally important,
as well as directly important.
So regarding observation evidence and explanation,
key opinion leaders may shape what observations,
evidence, and explanations count, and which ones don't.
We'll see some examples of this shortly, further examples.
And as influential leaders in their field,
junior colleagues may be conflicted about criticizing
the key opinion leader's science,
worrying that recommendations, mentoring,
placement on study sections, and so forth,
and grant competitiveness, may be compromised.
Regarding the values of science, industry data,
procedures, and use of key opinion leaders are proprietary,
That is we don't get to find out what's going on,
undermining the value of openness,
peer review, and criticism.
More powerfully though, I think the use
of key opinion leaders interferes with epistemic freedom,
the idea that scientists can choose freely what to study.
That is, what gets researched is driven by what's funded.
And if the funded is shaped by a relatively small number
of influential individuals
then that constrains epistemic freedom.
This building of epistemic freedom, or excuse me,
bending of epistemic freedom occurs by the use
of financial influence.
What's funded is bent to pharma interest,
or other medical industries.
Just as an example of how this works,
in 2015, the ratio of industry sponsorship
of clinical trials, compared to NIH-funded clinical trials,
was six to one.
So the pre-pondering proportion of clinical research,
or excuse me clinical trials today,
is done under industry sponsorship, again,
limiting epistemic freedom, as well as perhaps,
distorting the direction and content
of scientific questions.
So in conclusion, by my criteria Dr. D is complicit
in institutional corruption of clinical research,
the latter on a grand scale, as will be seen in otherwise,
later in the lecture.
Dr. D's bending of science may not be purposeful,
but accidental, an unintended consequence.
However, industry's bending of science
is quite purposeful, as Sismondo's paper below,
listed below, attests.
Case seven, again these are more subtle cases.
Van Spall and colleagues published a systematic review
of the use of exclusionary criteria in selecting
randomized clinical trial participants.
In 12% of the studies sampled, at the end was 283,
exclusion criteria were not reported.
Unreported exclusionary criteria were more likely
to be in industry-sponsored trials,
significant at the .001 level.
Reasons for exclusion included, gender, age,
socio-economic factors, medical comorbidities,
use of other medications.
Rationales for exclusion criteria in publications
where absent in 37% of these studies.
So again, here's the audience participation part.
Again brief comments.
Do unreported exclusionary criteria represent
corruption in science?
Again by the rubric on the right.
What do you all think?
Dave you're nodding your head yes.
You wanna say a little bit about that?
What your thinking is.
Dave: You wanna make sure
(indistinct response from audience member)
possible complications.
-: Good, good, other comments?
Okay so let's move on to my analysis.
RCTs use exclusionary criteria for a variety of reasons,
some are legitimate, even essential
to the conduct of research, while others are not.
The most common reasons for using exclusionary criteria
include, that specified populations are more likely
to show treatment signal compared to populations
with multiple confounding variables.
Fewer confounding variables and a smaller end,
makes for less expensive and often easier to conduct study.
Excluding some subjects on the basis of clinical interest
or importance of core subjects,
can be another reason why.
But exclusionary criteria can also have
adverse effects on the quality of the science.
Excluding children, women, elderly,
people with comorbidities in other fields,
compromises the generalizability of the research.
I think this is fairly well known and appreciated.
In clinical practice, the research findings,
when implemented in clinical practice,
may place some patients,
who fall outside of study criteria, at risk,
in that no one knows the adverse effects and interactions
of the study drug in the excluded population,
all we have are best estimates.
And then the social justice issues,
not everyone is an adult male, but adult males
are the primary participants and beneficiaries
of clinical research.
So the use of exclusionary criteria in itself,
do not undermine social structures and values of science,
and indeed, you could argue in some ways are facilitating
in the conduct of research.
But then perhaps a more pointed question is,
is non-disclosure of exclusionary criteria,
is that corrupt?
That is not mentioning or disclosing exclusionary criteria
in a research publication or publications,
is that corrupt?
So the rationales for withholding disclosure
of exclusion criteria are many and seldom discussed.
These could include, space saving
of journal editorial space.
And so you may chuckle at that, but journal editors
really have to pay attention to this.
They run on strict economic schedules.
They only get so many pages per issue.
And article length is a crucial consideration
in the numbers of the papers that they can publish,
in a purely practical way.
A second would be, and this is very common,
the exclusionary criteria are published in another,
previously published paper,
and they may, or may not be referenced within that.
So oftentimes clinical trials are conducted
with multiple publications coming outta the same,
or inter-related set of protocols,
and exclusionary criteria for the subject population
may be published in earlier papers.
Sometimes exclusionary criteria can be withheld
to increase sales, that is to create the illusion
of false generalizability.
That's the more cynical reason.
And if the latter, that is to increase sales,
were true, which again would be very difficult to ascertain,
because of the proprietary nature of the intent
of those practices,
that is it would be hard to determine purposefulness.
If the latter were true, then it would mean
the purposeful violation,
and violate multiple structures and values of science,
and therefore be a corrupt practice.
But this would be very difficult to demonstrate
as I suggested.
Regardless, withholding disclosure of exclusionary criteria
for any reason, erodes some scientific values,
openness, peer review, and constrains criticism.
And so really helps us to understand
the kinds of compromises that clinical investigators,
as well as journals,
and the general scientific enterprise has to do.
I mentioned earlier that the scientific values
and structures are ideals and can't always be fully met.
Oftentimes for practical reasons as well as too often
for corrupt reasons.
So withholding the publication of exclusionary criteria
may not be frankly corrupt.
It probably doesn't represent the best science either.
So now we turn to case eight.
Some of you may remember Charles Seife,
who gave ethics grand rounds here several years ago.
Very interesting.
He's a professor of Journalism at NYU,
and enlisted an army of graduate students
to conduct this research.
In an analysis of publicly-available documents
from 1998 to 2013, Charles Seife's team
looked for evidence of impact of FDA citations
of ethics violations in clinical research.
Some of you may, or may not be aware
that the FDA monitors clinical research
and oftentimes will cite investigators for ethics violations
that are publicly available, although rarely publicized.
They looked for publications resulting
from the offending research and of ones connected
to one or more publications.
57 projects were found, which were censured by the FDA.
Of those 73 publications linked to the 57,
only three acknowledged the FDA's censure in any way,
that is in a later scientific publication.
The other papers were published without acknowledgement
of research misconduct by authors or journal editors.
So does the failure by authors and editors,
to acknowledge FDA-identified research misconduct,
does that constitute corruption,
under by yellow-box rubric?
Comments.
Yes Chet.
Chet: The question
(indistinct response from audience member)
John: Yeah so you're getting at the purposefulness of it.
Chet: Absolutely.
John: So I think it's a relevant consideration,
I'm sure we'll talk about.
Other comments before I move on?
Yes Jim.
Jim: I think under the continuity,
(indistinct response from audience member)
John: Could you say a little bit more.
Why is that?
Jim: Well so study was done.
FDA censured the study.
Study's built upon that prior study,
but the whole picture was not brought forth
in those later studies.
So for continuity you might--
John: So the readers of that research
may have a false confidence, I'm sort of leading you here,
but they have a false confidence about the credibility
of the findings.
Is that fair to say?
Okay, very good.
So perhaps a prior question, before we get into
whether this is corrupt or not, should be addressed.
Is disclosure of research misconduct important
to the scientific enterprise?
I would argue yes.
Misconduct undermines the potential
for peer review and criticism.
It provides potentially false knowledge
for later investigators to build upon.
Dr. Wagner's point about undermining continuity.
It also undermines equality of opportunity,
in that investigators who play by the rules
are disadvantaged compared to those who do not.
Is the violation purposeful?
This is the hard part.
It's impossible to say.
And one of the questions when Seife was here,
we asked did you your studies get a sense
of whether this was, this withholding of these FDA censures,
was it intentional and meticulously over sought?
And he couldn't answer.
They just didn't have the information.
They did ask FDA staff, if they knew anything
about the reasons for these omissions,
and the FDA staff did not know,
even the fact that this information was being withheld,
in the vast majority of the cases.
So corruption, open question.
So this is sort of a summary slide.
So corruption in clinical research,
relation to other concepts and practices.
So in the left column, likely to be corruption
is research fraud, falsifying data, failure to register
clinical trial at clinicaltrials.gov, hides trial data,
use of key opinion leaders to bend treatment guidelines
and prioritize research funding, significant plagiarism.
Likely not corruption, sloppy, careless data collection,
naive mistakes, simple conflict of interest,
doesn't count as corruption in this view,
and investigator-initiated oversight journal
publication retraction, also probably doesn't qualify.
We didn't give an example of that,
but it's another good example of likely not corruption.
Excessive delay, in terms of unclear, excessive delays,
or failure to publish negative results of a clinical trial,
we'll talk about some examples here,
conflict of interest with consistent,
industry-favorable outcomes, may be unclear,
and failure to disclose exclusion criteria.
So how common is corruption under this definition?
Short answer, unknown.
The cases have identified a variety of ways
that science can be corrupted.
No taxonomy exists to lump them together and count them.
However, there is some research on the commonality
of two kinds of research corruption,
fraud and disclosure.
And we'll consider these very briefly.
For fraud, Fanelli in 2009 did a meta-analysis
of all scientific citation databases, scientific journals,
gray literature, and internet search engines,
yielding eight studies.
They were specifically directed to falsification
and fabrication research misconduct,
and other kinds were excluded.
About 2% of scientists self-admitted
to at least one instance of fabrication
or falsification of data.
About 14% of scientists reported colleagues'
fabrication and falsification.
Trend toward biomedical and pharmacologic researchers
was greater than in other areas of science, interestingly.
Self reports in social science in general
are often time likely to under estimate.
However, the threshold was at least one.
And so that's interesting as a threshold
because there's no requirement for a pattern.
So those investigators who admitted to at least one
could have done it once,
or could have done it dozens of times,
by the structure of this study.
Self-admissions they found had decreased over the years
of the study period.
It was unclear why.
And up to 34% of the surveyed scientists
admitted to other kinds of questionable research practices.
So then the second element is about how common is corruption
under my definition,
is non-disclosure of negative clinical trial results.
I mentioned in the late 1990s,
investigators and clinicians became increasing aware
of pharma's withholding of negative results,
resulting in studies to examine how common
this practice was.
Knowledge of withholding emerged
from public lawsuit disclosures
and investigator complaints of gag rules.
Those of you that have been around long enough
may remember some of these examples.
In 1999, NIH established clinicaltrials.gov,
intended to serve as a registry.
It went public in 2000.
In 2005, this trend went international,
the idea of clinical research registries.
So countries around the world now have clinical trial
particular registrations, but other drug trials
may be required as well.
And in 2007, the FDA, the Food and Drug Administration
Amendments Act mandated that sponsor/investigator
registration with clinicaltrials.gov,
that they do so register their clinical trials
with one year.
And then this set the stage then for compliance.
And I don't have time to talk about this,
but there are a number of key studies
looking at compliance with registration
with clinicaltrials.gov.
And I've listed the key studies there,
but in general the studies document poor compliance,
both in terms of registering at all,
as well as registering within the time,
the recommended time frame.
So my conclusions, oh good my timing is good,
corruption under my definition, or any definition,
is difficult to study, with complex variables
and the need for big data.
Nevertheless, the studies I reviewed,
indicated that while under reporting
of clinical research data is still too common,
probably clinical research misconduct
is still too uncommon,
modest progress is made in improving matters.
The practicing clinician still faces enormous barriers
to access to current clinical trial safety
and red-lighted data.
So even, I imagine very few of you
doing active clinical work
have consulted clinicaltrials.gov
to look at clinical research data
anytime within the past week, month, or even year.
Outright fraud, while seemingly large in absolute numbers,
when considered in the context of millions
of scientific studies published,
is still a very small phenomenon.
And in that sense, in a real sense, has little impact
on the general credibility of science practice.
But what about the significance
of clinical research corruption?
The literature discusses, and I agree,
that the withholding of negative results,
undermines the clinical evidence base
and the viability of evidence-based medicine.
However, I think this undermining of the past
and present validity of our evidence base
is under appreciated
by almost everyone, including practitioners.
The harm to patients of false, biased,
or incomplete clinical knowledge is unknown,
but hard to imagine that these factors
do not make substantial contributions
to adverse events and poor outcomes.
Moreover, the public perception of corrupt science
could easily undermine confidence in medicine,
political support, and funding.
Thank you for your attention.
(audience applauds)
(audience member speaks indistinctly)
-: Sure.
Mac, yes.
Mac: So I have one question
that I wanted your thoughts on.
It has to do with this whole idea about key opinion leaders
directing the course of where science goes.
And I think you made a very clear point
that if this is influenced by payments,
whether it's performance--
(audience member coughs)
or otherwise, that it would be corruption.
But I think more often, key opinion leaders
direct science in particular ways based
more on their own personal beliefs and ideas,
that may be based on their own data whatever,
and less often because of an external influence.
And I'm not sure that that's any different,
but I'm interested in your thoughts about that.
-: Well first of all, I hope I didn't use direct,
key opinion leaders direct, because I don't think
it's that intentional.
I would say they influence.
And so first of all, then, so then the question is,
do they do this out of their own personal interest
rather than financial or other interests.
And I would say, well sure.
But, I'm a psychiatrist and we all know in psychiatry
that people do stuff for multiple reasons.
Mac: Right, but my question I guess is,
is that different and is it not corruption
if you're not really paying attention
to what all the data shows,
as compared with just steering it in the direction that,
you know, you've had a hypothesis about.
-: I think it's, the corrupting aspect of it
has to do with the financial drivers.
And so a good example in my field,
is if you think about the evidence base
for psychiatric drugs, medications,
versus the evidence base for psychotherapies.
Now both of them have robust evidence base,
but the order of magnitude of clinical research
supporting pharmaceutical interventions
is probably 10 to 50x for psychotherapy.
And there's a whole variety of reasons for that,
not all of which are potentially corrupt,
but the whole point, the distinction is,
psychotherapies have no political clout,
they have no advocates on Capitol Hill for funding.
They don't have advocates on Capitol Hill saying,
fund basic science in psychotherapy,
as opposed to basic science in neuroscience.
And so that's how the bending of,
bending influence and the subtle mechanisms
of financial corruption work.
And so then we have this lamentable situation,
is we have a very safe and effective
set of psychotherapy modalities, who have a much poorer
evidence base than medications, which as we all know,
and especially in my field, there are lots of adverse
aspects of psychiatric drug treatment.
Does that answer your question?
Mac: Yes, or I mean, again I still think
that there's an enormous amount of bias
that the opinion leaders have based on getting the grant
refunded that steers science in directions
that not necessarily are based
on what pharmaceutical companies influence is,
like in my hypothesis and my body of work
are all based on this set of facts.
Somebody else has information that's contrary to that.
A lotta times that gets steered in a direction
that I don't think is necessarily favorable
to the ultimate outcome.
-: Yeah so then you think about key opinion leaders
are the ones who make up study sections.
Mac: Correct.
-: There you go.
So other comments?
Questions?
Yes Fred.
Fred: So I can think of several examples where
clinical research was carried out that one might think
was corrupt in some ways and was for the purpose
of personal gain, but led to major discoveries
that were of clinical importance to science and medicine.
-: Yes, every cloud has a silver lining.
Fred: So I'm wondering about putting the two of them
in the same category.
You can corrupt, the person could be corrupt.
-: So you're thinking the out--
Fred: Corrupt--
-: Corruption depends on the outcome.
Fred: Well I don't know if it does or not.
But they way you're, if you're talkin' about corrupting
the scientific record, then a person can behave
and behaviors that is extraordinarily corrupt,
without actually, while advancing the scientific record.
-: Yeah my worry about that is, so I think again,
every cloud has a silver lining.
And so, of course corrupt research
might turn out useful information,
but the idea of basing judgments of corruption on outcomes,
looks to me like an invitation to politicize
what corruption is which I don't want scientists
to have to deal with.
Man: Can you give us an example?
Fred: Yeah so lemme give you an example.
Albert Kligman.
There's a big discussion now about Kligman
in the dermatology community.
He's the discoverer of Retin-A.
And much of his research was going on at a time
when working with prisoners was acceptable.
And he was doing all kinds of experiments
for drug companies with prisoners
that led to his significant enrichment.
And a lotta people would look at those experiments
and say he really didn't care at all
about who he was working on, what he was doing,
that the experiments themselves were unethical.
But one of the outcomes of his research
was the discovery of Retin-A.
So the dermatology up until this year
has always had a Kligman Lecture at the annual meeting.
And sort of the younger dermatologists,
have decided that Kligman was not a good model.
And they've now, that lecture's no longer gonna take place,
as of this year.
-: That's interesting.
Fred: But the point is, that he was operating
at a time when normatively,
it was okay to do research on prisoners, it's not now.
The experimental designs he was using
were specifically for the drug industry
and the federal government as well,
to advance questions that, using sort of things
that had no value, the role of the prisoners,
but one of the side effects was the discovery of Retin-A.
So you tell me, he's corrupt it sounds like.
But it's not clear that the science
that he was doing is, had the same effect--
-: So tell me though, how he was corrupt, under my rubric.
Fred: For personal gain.
I mean if you think about that idea.
-: Okay yeah.
Man: Can you show the definition of corruption
again John because I don't think.
Tom: It's manipulation of science
and not just doing good science, is that right?
-: Well it's on the right column.
Go ahead Tom, say more.
Tom: Understanding of the definition
you were saying earlier, your talk was something
along the lines of manipulation of the truth,
or of the science, method for personal gain,
or for profit, not doing bad science,
or for personal reputation and gain.
Does that, I may have misunder, read your--
-: Right.
Yeah I have to think about that more Fred.
Man: Because of what was done in Nazi Germany
was considered normal within Nazi Germany,
but other people decided it was not normative.
And we've had discussions about
you know the data that comes from that,
and how to use it and so on.
But what about the Tuskegee Airmen too that kind of studies?
You look at those, we would say they're corrupt
and then you're back to issues around normative too.
Are we talking descriptively or prescriptively?
-: Well I think your point, that's a good point
in that for some research to be misconduct
doesn't mean it has to be corrupt.
Because that's the broader, more generic notion
of corruption, rather than the very focused,
restricted one that I'm tryin' to aim at here.
So, Nazi Germany practices were unethical research,
for a whole variety of reasons, perhaps not these reasons.
Man: But research with prisoners
has a similar kind of issue.
-: Exactly, yeah, yeah.
I'm afraid we're outta time everybody.
Thank you for your attention and thoughtful comments.
(audience applauds)