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Clinical Trials- How Human Research is Done


Clinical Trials-How Human Research is Done Eve Marie Holzemer, ANP Administrative Director Clinical Research Unit Department of Neurology & Psychiatry – PowerPoint PPT presentation

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Title: Clinical Trials- How Human Research is Done

Clinical Trials-How Human Research is Done
  • Eve Marie Holzemer, ANP
  • Administrative Director
  • Clinical Research Unit
  • Department of Neurology Psychiatry
  • Saint Louis University

  • None to report

  • To discuss how history has had an impact on how
    human research is carried out
  • To discuss abuses in human research throughout
  • To detail current standards in human research
  • To necessary elements to conduct human research

History of Research
  • Earliest recorded research was done in the 12th
    century and involved human dissections.
  • Experiments in the 1700s involved vaccinations.
  • Physicians used themselves or their slaves as
    study subjects.
  • Conducted using deception or without explaining

Medieval Times
  • Began in the Middle East and spread to Europe
  • Involved dismemberment and autopsy
  • Resulted in basic understandings of cause and
  • 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

Early 20th Century
  • Saw progress of medicine
  • Began to think about a code of ethics for study
  • Inoculations for yellow fever studies by Walter

History of Abuse
  • 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
  • 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
    50s and 60s.
  • Israel was involved in giving drinks with uranium
    to research subjects without knowledge.

Abuse in the United States
  • Deliberately infecting people with deadly or
    debilitating diseases.
  • Exposing people to biological and chemical
  • Human radiation experiments.
  • Injecting people with toxic and radioactive
  • Surgical experiments
  • Interrogation/torture experiments
  • Tests involving mind-altering substances.

Research on Pregnant Women
  • 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
  • In 1840s, 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Conducted between 1932 and 1972 in Tuskegee,
  • Involved 399 impoverished African-American
    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 1947s.

Tuskegee Continued
  • Study participants were not offered the
  • Scientists prevented patients from accessing
    syphilis treatment programs.
  • Numerous men died of disease, wives contracted
    disease and children were born with congenital

Why Human Research is done
  • To prove that one treatment is better than
  • To prove how safe a treatment is
  • To determine the dose of the treatment
  • To determine the side effects of the treatment

Current examples
  • By the mid 1980s, US cardiologists had been
    doing RCTs for 20 yearsyet
  • Their leaders recommended encainide and
    flecainide for dangerous arrhythmias following
    heart attacks

The basis for this recommendation
  • Patients with these arrhythmias had very high
  • 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
  • What about all those patients being treated on
    the basis of that earlier recommendation?
  • A critic calculated that more Americans were
    killed by encainide and flecainide than by the
    Viet Cong

Why such stupid and lethal treatments?
  • 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)
  • Todays 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
  • 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

International Research and Equipoise
  • Example Placebo-controlled trial of short-course
    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
  • 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
  • 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
  • Established in 1979 in response to Tuskegee.
  • Also established Office of Human Research
  • Belmont Report principles include respect for
    persons, beneficence and justice.
  • American Psychological Association drafted code
    of ethics.

Declaration of Helsinki
  • Adopted in 1964 in Finland.
  • Specifically addresses clinical research.
  • Has undergone 6 revisions.
  • Fundamental principle is respect for the
    individual, right of individual to
    self-determination, and recognition of vulnerable

Up to the Present
  • 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
  • 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
  • Must protect vulnerable populations

Five scientific requirements for the evaluation
of any treatment
  • Similar groups of treated and untreated patients
  • Formed by drawing lots (nowadays by
  • With treatment assignments totally outside the
    control of their clinicians (concealed
  • Cared for by clinicians who are blind to which
    treatment they are receiving
  • 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
  • Assessment and adjudication of outcomes by
    blind observers
  • Avoiding attrition

Funding for Studies
  • Multiple sources including
  • Federal funding
  • State funding
  • University funding
  • Company funding
  • Pharmaceutical funding
  • Foundation or organization funding

Studies being done for MG
  • Stem cell transplantation
  • Methotrexate for patients who are prednisone
  • Thymectomy vs prednisone
  • Rituxan (may reduce circulating plasma cells and
    B cells)

Phases of Studies
  • 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
  • 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
  • Committed Principal Investigator
  • Experienced research team
  • Dedicated infrastructure
  • Available study subjects
  • Available and experienced regulatory bodies
  • Thick skin

Lessons Learned
  • Study patients are unpredictable
  • Expect the unexpected
  • Dont take anything for granted
  • Murphys law really does exist
  • A study can be stopped must faster than it can be
  • A brilliant idea does not necessarily mean you
    will have a brilliant research study

Most Important Ingredient

So, in the end
  • 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
    unkownsthe ones we dont know we dont know
  • DH Rumsfeld
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