The Scientist as a Responsible Member of Society:

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The Scientist as a Responsible Member of Society:
A Personal Perspective on Research Integrity
Constantine G. Lyketsos, MD, MHS
Elizabeth Plank Althouse Professor, Johns Hopkins University
Chair of Psychiatry, Johns Hopkins Bayview
[email protected]
Presentation overview
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Definitions-why are we here?
Why am I giving this talk?
More on integrity
A few personal vignettes
WHILE MY FOCUS IS ON HUMAN
RESEARCH, THE KEY MESSAGES APPLY
TO ALL MEDICAL RESEARCH
Purpose of medical research
• Prevent, cure, or treat disease and
related human conditions
• Make the lives of our patients better
Johns Hopkins is a special place
For me, research on humans
necessitates a commitment to help
participants access the best possible
care at the same time
I am also their doctor
Definitions: human subjects
research (CFR Title 45; Part 46)
(f) Human subject means a living
individual about whom an investigator
(whether professional or student)
conducting research obtains:
(1) data through intervention or interaction
with the individual, or
(2) identifiable private information.
http://ori.hhs.gov/education/products/mass_cphs/training_staff/RCReng/RCRCo
mmonRule.htm#46.102#46.102
Research misconduct
Johns Hopkins Definition
… means fabrication, falsification, or plagiarism in
proposing, performing, or reviewing research, or in
reporting research results.
a) Fabrication is making up data or results and recording or reporting them.
b) Falsification is manipulating research materials, equipment, or processes, or changing or omitting
data or results such that the research is not accurately represented in research records or reports.
c) Plagiarism is the appropriation of another person's ideas, processes, results, or words without giving
appropriate credit.
d) Research misconduct does not include honest error or honest differences of opinion.
e) Research misconduct includes the destruction of, absence of, or accused person's failure to provide
research records accurately documenting the questioned research.
Forms of misconduct
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Falsification
Obfuscation
Fabrication
Supression
Plagiarism
Self-plagiarism
Ghost writing
http://en.wikipedia.org/wiki/Scientific_misconduct
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Bare assertions
Improper authorship
Misappropriation
Bibliometric inflation
• Violation of ethical
standards regarding
human and animal
experiments
Why research misconduct?
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Career advancement
Money
Competitiveness
Laziness
Ability to get away with it
Why me?
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Investigator
Research mentor
Former IRB member and chair
Research misconduct investigator
•Son of George C. Lyketsos
George C. Lyketsos, MD, FRCPsych
11 January 1917- 20 August 2011
• Professor of Psychiatry, National
Kapodistrian Univeristy of Athens,
1974-1989
• Medical Director, Dromokaition
Mental Hospital, 1947-1985
• Lived through the transition to
modern psychiatry
Human subject researcher
in an era before regulation
Dromokaition Mental Hospital
• Bequest of major philanthropist 1887
• Where thousands of patients lived,
some for decades
• Where new therapies for mental
illness where introduced in Greece
• Where community placement of
most patients took place by the
1980s
• This was largely unregulated
research
The introduction of ECT to Greece:
from The Story of My Life (GCL, 1998)
The first patient finds himself
And then the time came for the great trial…of ECT in a patient. Thinking of those
days I am surprised by my confidence. I had no doubt things would go well. I chose
for the trial patient X who had been lost to the world…nobody had shown any
interest in him for many years…That morning in March 1946…(the staff) brought X.
He was catatonic…We laid him down on a sofa and placed the electrodes on his
temples which we had already rubbed with salted water… I pressed the button for
10ths of seconds. A jerk followed… I increased the intensity…I pressed the button
for a longer duration and after a few seconds the seizure happened. We became
scared as the patient turned blue. We fell onto him to provide artificial respiration.
Quickly, breathing returned and we took him to the ward where he fell asleep. Later
we visited him. He had awakened and was active… I asked him “How are you?”
and he ANSWERED “fine.” This gave us courage and we repeated the ECT after
two days. After that we were able to communicate enough to find out who his
relatives where who came to visit. He is the phenomenon and I think he still lives at
Dromokaition. In total he had ten ECT. It did not cure him, but he was able to live at
the level of social life of a developed psychiatric hospital.
Tidbits of the ECT story
• Built their own machines (“cost 10 gold
sovereigns to build and sold for 11”)
• Offered to most every patient
• Consent was obtained when families
available or patients could discuss (no
documentation)
About 30% of patients improved and left the
hospital within the next year
Outcomes of ECT therapy
• Schizophrenia: N=75, 6-12 treatments
– 12 (16%) full remission (mostly catatonic)
– 17 (23%) partial remission
– 46 (61%) no change—mostly “demented”
• Affective disorder: N=25
– 18 (72%) full remission
– 6 (24%) partial remission
– 1 (1%) no change
Lyketsos GC, Arkalides N. The therapeutic method via electric shock at Dromokaition Therapeuterium. Results
of 100 cases. (Experience of over 4,000 treatments.) Kliniki 1 December 1946
Other examples of Dromokaition research
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Observational studies
EEG research
Frontal leucotomies
Ancient Greek Drama therapy
Rehabilitation methods
None of our contemporary
processes followed
• Research happened
• Patients were helped
• Advances occurred
How is that possible?
INTEGRITY
Definitions: integrity
1. firm adherence to a code of especially
moral or artistic valuesINCORRUPTIBILITY
2. an unimpaired condition:
SOUNDNESS
3. the quality or state of being complete:
COMPLETENESS
http://www.merriam-webster.com/dictionary/integrity
But what is integrity really?
• An attitude
• A state of mind
• A commandment
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Must be cultivated and honed
Occurs in a context
A team sport: you are not alone
Modeling critical to its development
Measuring integrity
• Choice of research we conduct
– Why is the study important?
– Would you put your mother in your study?
• How we look after our participants
– How would you consent your sister/brother?
– How would you monitor your ill child?
• How we report our findings
Personal vignettes
• DIADS/CATIE/CITAD-placebo/vulnerable
• ADAPT-crisis in a prevention trial for AD
• DBS for AD-pushing the envelope
• Mrs. F-my patient in 3 studies
• Mrs. H-from participant to patient
35.5 million people have dementia today
The number of living cases doubles every 20 years
115.3 million people with dementia by 2050—NEW CASES
7/12/2016
Alzheimer’s
Disease International
World Alzheimer’s Report, September 21, 2009
22
NPS are universal in dementia
Steinberg et al, Int J Ger Psychiatry 2008
Treating NPS is a high priority
• High utilization of treatments based on
findings in general psychiatry
– Antipsychotics, antidepressants, etc
• Little controlled research
• Safety concerns
• We undertook placebo controlled RCTs
The issues
• Vulnerable population
• Placebo controls
The CATIE-AD Study
Sertraline for the Treatment of Depression in Alzheimer Disease
Rosenberg, Paul B. M.D.; Drye, Lea T. Ph.D.; Martin, Barbara K. Ph.D.; Frangakis, Constantine Ph.D.;
Mintzer, Jacobo E. M.D., M.B.A.; Weintraub, Daniel M.D.; Porsteinsson, Anton P. M.D.; Schneider, Lon
S. M.D.; Rabins, Peter V. M.D., M.P.H.; Munro, Cynthia A. Ph.D.; Meinert, Curtis L. Ph.D.; Lyketsos,
Constantine G. M.D., M.H.S.; For the DIADS-2 Research Group
Author Information
From the Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University School of Medicine (PBR, PVR, CGL); Department of
Health Policy and Management (PVR), Department of Mental Health (CGL), Center for Clinical Trials
(BKM, CF, CLM), Johns Hopkins Bloomberg School of Public Health; Johns Hopkins Bayview Medical
Center (PBR, CGL), Baltimore, MD; Department of Neurosciences (JEM), Medical University of South
Carolina and Ralph P Johnson VA Medical Center, Charleston, SC; Division of Medical Psychology
(CAM), Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
Medicine; Department of Neurosciences (JEM), Medical University of South Carolina; Section of
Geriatric Psychiatry (DW), University of Pennsylvania and Mental Illness Research, Education and
Clinical Center (MIRECC), Philadelphia Veterans Affairs Medical Center; AD-CARE Program (APP),
Department of Psychiatry, University of Rochester School of Medicine and Dentistry; Departments of
Psychiatry, Neurology, and Gerontology (LSS), University of Southern California Keck School of
Medicine.
Received April 16, 2009; revised June 25, 2009; accepted July 7, 2009.
Send correspondence and reprint requests to Paul B. Rosenberg, M.D., Department of Psychiatry and
Behavioral Sciences, Johns Hopkins Bayview Medical Center, 5300 Alpha Commons Drive #447,
Baltimore, MD 21224. e-mail: [email protected]
Alzheimer Disease Anti-inflammatory
Prevention Trial (ADAPT)
• Primary prevention RCT with two outcomes:
– Incident Alzheimer Disease (AD)
– Cognitive Decline
• Treatments vs. placebo
– Conventional NSAID (naproxen 225 BID)
– Selective COX-2 inhibitor (celecoxib 200 BID)
• Six sites: Baltimore, Boston, Phoenix,
Rochester, Seattle, Tampa/Sarasota
• N=2422 aged 70+ with history of AD-like
dementia in 1o relative: 437 at JHU
ADAPT in crisis
• Dec 2004—adenomatous polyps prevention trials suggest
increased risk of cardiovascular events with celecoxib (OR~2.5)
• Two similar trials stopped Dec 17
• ADAPT DSMB met week before and recommended continuation
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WHAT TO DO IN ADAPT?
Took the risk seriously especially in prevention trial
Considered re-consent and continuation, esp naproxen arm
Logistics got in the way: media effects on participants, concerns
about IRB review process, FDA hold on celecoxib trials
• ENROLLMENT AND TREATMENTS STOPPED
• FOLLOWUP CONTINUED
Did we make the right decision?
• Stopped a trial mid-stream largely for
pragmatic reasons
• Interfered with an experiment that may
have identified a preventive therapy
• We may never know
Patient to research participant
Mrs. RF
• Married, artist in her 80s; healthy
• Closely connected with husband-agent
• First seen as outpatient for depression
• Did well on antidepressants
• Developed AD dementia
• Requested research participation
• ADRC, GSI RCT, apathy Rx RCT
Research participant to patient
Mrs. EH
• ADAPT participant—her mother had AD
• During ADAPT followup diagnosed MCI
• Asked to become my patient
• Continues in ADAPT
• Several complex clinical issues
The issues
• My own patient in my own research
• Triage of what’s the right study
• Communication, disclosure, oversight
The next plunge
Final words: threats to integrity
Excessive focus on process
• Uses up resources and energy
• Gives the wrong signal that the process
assures integrity
Research Integrity
• An attitude
• A state of mind
• A commandment
•
•
•
•
Must be cultivated and honed
Occurs in a context
A team sport: you are not alone
Modeling critical to its development
Johns Hopkins is a special place
For me, research on humans
necessitates a commitment to help
participants access the best possible
care at the same time
I am also their doctor
In Memoriam
George C. Lyketsos
1917-2011
pictures after age 90
“Pepper” with his family
age 94, a month before he passed
Panel Discussion
• Joseph Carrese, M.D., M.P.H.
• David Hellmann, M.D.
• Cynthia Rand, Ph.D.
• Sheila Garrity, J.D., M.P.H., M.B.A.,
– Moderator
7/12/2016
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