Clinical Trials- How Human Research is Done

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Clinical Trials-How Human Research is Done

• Eve Marie Holzemer, ANP
• Administrative Director
• Clinical Research Unit
• Department of Neurology Psychiatry
• Saint Louis University

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Disclosures

• None to report

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Objectives

• 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

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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
  dangers.

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Medieval Times

• 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

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Early 20th Century

• Saw progress of medicine
• Began to think about a code of ethics for study
  subjects.
• Inoculations for yellow fever studies by Walter
  Reed

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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.

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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.

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Abuse in the United States

• 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.

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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.

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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.

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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

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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.

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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.

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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
  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

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Tuskegee Syphilis Experiment

• Conducted between 1932 and 1972 in Tuskegee,
  Alabama.
• 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.

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Tuskegee Continued

• 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.

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Why Human Research is done

• 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

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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

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The basis for this recommendation

• 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

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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

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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

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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
  stroke

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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

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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.

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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.

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Belmont Report

• 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.

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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
  groups.

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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

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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
  data
• Must protect vulnerable populations

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Five scientific requirements for the evaluation
of any treatment

• Similar groups of treated and untreated patients
• Formed by drawing lots (nowadays by
  randomization)
• With treatment assignments totally outside the
  control of their clinicians (concealed
  assignment)
• 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
  equal
• Assessment and adjudication of outcomes by
  blind observers
• Avoiding attrition

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Funding for Studies

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

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Studies being done for MG

• 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)

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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

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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

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Essential Ingredients

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

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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
  started
• A brilliant idea does not necessarily mean you
  will have a brilliant research study

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Most Important Ingredient

• FAITH

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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