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

Disclosures None to report Disclosures None to report

Objectives n n To discuss how history has had an impact on how human Objectives n n 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 n n Earliest recorded research was done in the 12 th History of Research n n Earliest recorded research was done in the 12 th 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 n n n Began in the Middle East and spread to Europe Medieval Times n n n 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 20 th Century n n n Saw progress of medicine Began to think Early 20 th Century n n n 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 n n Japan experimented with prisoner vivisection, dismemberment, bacteria inoculation, induced History of Abuse n n 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 n n In Maryland, Operation Whitecoat involved the injection of infectious agents Abuse continued n n 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 n n n n Deliberately infecting people with deadly Abuse in the United States n n n n 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 n Immediately after WW II, Vanderbilt University deceived 829 pregnant Research on Pregnant Women n 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 n n In 1840’s, surgical experiments were performed on enslaved African Other Surgical Experiments n n 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 n n n Many studies were performed on children and mentally Abuse in Research n n n 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 n n Herophilos (considered father of anatomy) founded first medical school in Surgical Research n n 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 n n n Milgram experiment: done to see if subjects were able Psychological Research n n n 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 n n n n Was carried out in 1939 in Davenport Iowa Monster Study n n n n 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 n n Conducted between 1932 and 1972 in Tuskegee, Alabama. Involved Tuskegee Syphilis Experiment n n 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 1947’s.

Tuskegee Continued n n n Study participants were not offered the treatment. Scientists prevented Tuskegee Continued n n n 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 n n To prove that one treatment is better Why Human Research is done n n 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 n By the mid 1980 s, US cardiologists had been doing RCTs Current examples n By the mid 1980 s, US cardiologists had been doing RCTs for 20 years yet… n Their leaders recommended encainide and flecainide for dangerous arrhythmias following heart attacks

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

Why such stupid and lethal treatments? n n n Most illnesses get better (so Why such stupid and lethal treatments? n n n 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 n n n n Total mastectomy for breast cancer Swan Ganz catheter Other examples n n n n 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 n n Example: Placebo-controlled trial of shortcourse of AZT for International Research and Equipoise n n 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 n n Developed in 1947 in response to war crimes involving research. Nuremberg Code n n 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 n Developed for the Protection of Human Subjects in research in 1974. National Commission n 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 n n Established in 1979 in response to Tuskegee. Also established Office Belmont Report n n 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 n n Adopted in 1964 in Finland. Specifically addresses clinical research. Declaration of Helsinki n n 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 n n n Research is governed by rules established by Up to the Present n n n 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 n n n Not all projects using human subjects is human Scope of Guidelines n n n 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 1. Similar groups of treated Five scientific requirements for the evaluation of any treatment 1. Similar groups of treated and untreated patients n n 2. Cared for by clinicians who are “blind” to which treatment they are receiving n n 3. 4. 5. 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 n Multiple sources including: Federal funding n State funding n University Funding for Studies n Multiple sources including: Federal funding n State funding n University funding n Company funding n Pharmaceutical funding n Foundation or organization funding n

Studies being done for MG n n n www. clinicaltrials. gov Stem cell transplantation Studies being done for MG n n n 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 n n Phase 1: Done after animal studies, safety study of Phases of Studies n n 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 n n Is the standard developed for all countries, governments and Good Clinical Practice n n 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 n n n Committed Principal Investigator Experienced research team Dedicated infrastructure Available Essential Ingredients n n n Committed Principal Investigator Experienced research team Dedicated infrastructure Available study subjects Available and experienced regulatory bodies Thick skin

Lessons Learned n n n Study patients are unpredictable Expect the unexpected Don’t take Lessons Learned n n n 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 Most Important Ingredient FAITH

So, in the end…… n “…there are knowns; there are things we know. We So, in the end…… n “…there are knowns; there are things 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 also unknown unkowns—the ones we don’t know” DH Rumsfeld