Transcript Clinical Trials- How Human Research is Done

Clinical TrialsHow Human Research is
Done
Eve Marie Holzemer, ANP
Administrative Director
Clinical Research Unit
Department of Neurology & Psychiatry
Saint Louis University
Disclosures
None to report
Objectives
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To discuss how history has had an
impact on how human research is
carried out
To discuss abuses in human research
throughout time
To detail current standards in human
research
To necessary elements to conduct
human research
History of Research
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Earliest recorded research was done in
the 12th century and involved human
dissections.
Experiments in the 1700’s involved
vaccinations.
Physicians used themselves or their
slaves as study subjects.
Conducted using deception or without
explaining dangers.
Medieval Times
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Began in the Middle East and spread to
Europe
Involved dismemberment and autopsy
Resulted in basic understandings of cause
and effect
“Humors” (liquid substances) were thought
to balance health and body temperature
Was proved to be wrong by research by
injecting hot liquids into the body to change
the temperature
Early 20th Century
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Saw progress of medicine
Began to think about a code of ethics
for study subjects.
Inoculations for yellow fever studies by
Walter Reed
History of Abuse
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Japan experimented with prisoner
vivisection, dismemberment, bacteria
inoculation, induced epidemics in
1932.
British army used Indian Army
soldiers to test if mustard gas
inflicted greater damage on Indian
skin compared to British skin.
Abuse continued
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In Maryland, Operation Whitecoat involved
the injection of infectious agents into human
subjects without their knowledge.
Sweden experimented on “retarded”
subjects to induce dental caries.
United Kingdom experimented on subjects
with bacterial agents without their knowledge
in the 50’s and 60’s.
Israel was involved in giving drinks with
uranium to research subjects without
knowledge.
Abuse in the United States
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Deliberately infecting people with deadly or
debilitating diseases.
Exposing people to biological and chemical
weapons.
Human radiation experiments.
Injecting people with toxic and radioactive
chemicals.
Surgical experiments
Interrogation/torture experiments
Tests involving mind-altering substances.
Research on Pregnant Women
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Immediately after WW II, Vanderbilt
University deceived 829 pregnant women
and involved in study to “improve the health
of their babies”.
Given “vitamin drinks” that were really
radioactive iron to determine how fast
radioisotope crossed the placenta.
Children died, women and children suffered
cancers and lifelong disabilities.
Other Surgical Experiments
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In 1840’s, surgical experiments were
performed on enslaved African women
without anesthesia.
Anesthesia was readily available at the
time.
Also performed experimentation on
fetuses of pregnant slaves.
Women died from infections, infants
dead at birth.
Abuse in Research
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Many studies were performed on
children and mentally disabled
subjects.
Many research subjects were poor
racial minorities or prisoners.
Many experiments were funded by the
United States government, CIA or U.S.
military
Surgical Research
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Herophilos (considered father of anatomy)
founded first medical school in Alexandria.
Performed surgery on 600 live prisoners.
Japanese physicians performed surgical
experiments on concentration camp
prisoners during WW II.
Amputations on condemned prisoners were
often carried out in Japan in 1944 and 1945
and often involved women and children.
Psychological Research
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Milgram experiment: done to see if subjects
were able to inflict electric shock on other
humans if under orders to do so. Used
deception.
The Stanford prison experiment: to induce
participants to become violent and abusive
of each other.
The Monster Study conducted in 1939 in an
attempt to induce stuttering.
Monster Study
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Was carried out in 1939 in Davenport Iowa
Involved 22 orphan children
Positive speech therapy given to half
Negative therapy and belittling given to other
half
Resulted in lifelong psychological effects
and retained speech problems
Experiment was kept hidden for fear of
ruining reputation of physician involved
Formally apologized for in 2001
Tuskegee Syphilis Experiment
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Conducted between 1932 and 1972 in
Tuskegee, Alabama.
Involved 399 impoverished AfricanAmerican sharecroppers with
diagnosed syphilis.
Was funded by the U.S. Public Health
Service.
Penicillin was found to be effective in
the treatment of syphilis in 1947’s.
Tuskegee Continued
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Study participants were not offered the
treatment.
Scientists prevented patients from
accessing syphilis treatment programs.
Numerous men died of disease, wives
contracted disease and children were
born with congenital syphilis.
Why Human Research is done
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To prove that one treatment is better
than another
To prove how safe a treatment is
To determine the dose of the treatment
To determine the side effects of the
treatment
Current examples
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By the mid 1980s, US cardiologists had
been doing RCTs for 20 years
yet…
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Their leaders recommended encainide
and flecainide for dangerous
arrhythmias following heart attacks
The basis for this recommendation
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Patients with these arrhythmias had very
high mortality
These drugs corrected the arrhythmias.
therefore….
Treatment must have a life-saving effect
Tens of thousands of patients were
treated with these drugs
The end result
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What about all those patients being
treated on the basis of that earlier
recommendation?
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A critic calculated that more Americans
were killed by encainide and flecainide
than by the Viet Cong
Why such stupid and lethal treatments?
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Most illnesses get better (so that any Rx they
receive appears efficacious)
Patients with severe illnesses die (so that any lethal
Rx they receive escapes blame)
Today’s patients fare better than “Historical
Controls,” even when neither gets treated at all
Patients who comply with new treatments fare
better (even on placebos !)
The therapeutic recommendations of “Experts”
carry more weight than they deserve
Dead patients tell no tales
Other examples
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Total mastectomy for breast cancer
Swan Ganz catheter
Warfarin is superior to aspirin for prevention of
stroke in patients with intracranial stenosis
EC-IC bypass decreases the risk of stroke in patients
it carotid stenosis/occlusion
HRT decreases the risk of MI and stroke
ASA/Dipirydamole is better than clopidogrel for
stroke prevention
Anticoagulation improves the outcome of acute
stroke
International Research and
Equipoise
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Example: Placebo-controlled trial of shortcourse of AZT for women in Uganda (AIDS
clinical trial group 076 protocol)
Ugandan women are randomized to nothing
or treatment we already know is effective and
better
M. Angell (NEJM, 1997): When effective
treatment exists, a placebo may not be used
Must use best KNOWN treatment for control
group
Nuremberg Code
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Developed in 1947 in response to war crimes
involving research.
Includes ten points: voluntary consent,
purposeful research, animal experiments,
avoidance of unnecessary suffering,
avoidance of harm, benefit outweighs risk,
adequate preparation, qualified researchers,
liberty of human subject, study can be
stopped at any time.
National Commission
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Developed for the Protection of Human
Subjects in research in 1974.
Congress charged the National
Commission to identify basic ethical
principles of research.
Guidelines were developed, starting
with Belmont Report in 1979.
Belmont Report
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Established in 1979 in response to
Tuskegee.
Also established Office of Human
Research Protection.
Belmont Report principles include:
respect for persons, beneficence and
justice.
American Psychological Association
drafted code of ethics.
Declaration of Helsinki
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Adopted in 1964 in Finland.
Specifically addresses clinical
research.
Has undergone 6 revisions.
Fundamental principle is respect for
the individual, right of individual to selfdetermination, and recognition of
vulnerable groups.
Up to the Present
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Research is governed by rules established
by Dept of Health and Human Services
Known as Common Rule
Came into effect in 1981
Title 45, CFR 46 is baseline standard of
ethics
Governs all research done at academic
institutions regardless of funding
Scope of Guidelines
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Not all projects using human subjects
is human subject research
Must meet definition of human
research, which means involvement of
subject in experiment, manipulation of
environment and collection of data
Must protect vulnerable populations
Five scientific requirements for
the evaluation of any treatment
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Similar groups of treated and untreated
patients
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Cared for by clinicians who are “blind” to which
treatment they are receiving
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Formed by “drawing lots” (nowadays by randomization)
With treatment assignments totally outside the control of their
clinicians (concealed assignment)
Avoiding contamination of the control group by experimental Rx
Avoiding unequal co-intervention in either group with some other Rx
All the other elements of patient care remain
equal
Assessment and adjudication of outcomes by
“blind” observers
Avoiding attrition
Funding for Studies
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Multiple sources including:
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Federal funding
State funding
University funding
Company funding
Pharmaceutical funding
Foundation or organization funding
Studies being done for MG
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www.clinicaltrials.gov
Stem cell transplantation
Methotrexate for patients who are
prednisone dependent
Thymectomy vs prednisone
Rituxan (may reduce circulating plasma
cells and B cells)
Phases of Studies
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Phase 1: Done after animal studies, safety
study of drug in humans. Usually involves
20-80 people
Phase 2: Larger study, efficacy study. Drug
compared to placebo to see if it works
Phase 3: Larger study of several thousand.
Randomization. If drug works, can be
submitted to FDA for approval
Phase 4: Post-marketing studies to
determine if drug works in different groups
Good Clinical Practice
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Is the standard developed for all
countries, governments and
pharmaceuticals in the conduct of
human research trials
Is essential to ensure patient safety,
protocol implementation, quality
assurance and improvement
Essential Ingredients
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Committed Principal Investigator
Experienced research team
Dedicated infrastructure
Available study subjects
Available and experienced regulatory
bodies
Thick skin
Lessons Learned
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Study patients are unpredictable
Expect the unexpected
Don’t take anything for granted
Murphy’s law really does exist
A study can be stopped must faster
than it can be started
A brilliant idea does not necessarily
mean you will have a brilliant research
study
Most Important Ingredient
FAITH
So, in the end……
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“…there are known knowns; there are
things we know we know. We also
know there are known unknowns; that
is to say we know there are some
things we do not know. But there are
also unknown unkowns—the ones we
don’t know we don’t know”
DH Rumsfeld