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Description : Check out this medical PowerPoint presentation titled "Destination Clinical Research 2020: An Abbreviated Trip through History" by Janie Gardner, MS, CCRP, CIM.

This medical PowerPoint presentation tells us about the events in history that led to the drafting of ethical and regulatory guidelines for clinical research in the United States.

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Research 101sponsored by
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Conflict of Interest Disclosure Conflicts of Interest A Conflict of Interest occurs when an individual has an opportunity to affect educational content about healthcare products or services of a commercial interest with which she/he has a financial relationship. There is no conflict of interest for this presentation. Commercial Support No commercial support for this seminar Non-Endorsement of Products Non-applicable
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Destination Clinical Research 2020 An Abbreviated Trip through History Research 101 May 21, 2020 Janie Gardner, MS, CCRP, CIM Clinical Research Education
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Key Points The Science - Clinical Trial Study Design The Ethics - Protection of Human Subjects U.S. Regulations and Guidance ---Study Conduct Objectives: Recognize the events in history that led to the drafting of ethical and regulatory guidelines for clinical research in the U.S. Explain the major provisions of the national Research Act of 1974 - Include the impact on the ethical and regulatory considerations for clinical studies.
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Clinical Research is Research involving Humans To examine physical, mental and/ or behavioral attributes of an individual or group of people To collect information that contributes to our collective memory and general knowledge about individuals and groups of people
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Clinical Trials A special type of Clinical Research that evaluate the effects of an intervention on biomedical or health –related outcomes. The function of the controlled clinical trial is not the "discovery" of a new drug or therapy. The function of the formal controlled clinical trial is to separate the relative handful of discoveries which prove to be true advances in therapy from a legion of false leads and unverifiable clinical impressions, and to delineate in a scientific way the extent of and the limitations which attend the effectiveness of drugs.” William Thomas Beaver, MD PHARMA v. Robert Finch and Herbert Ley 1969
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Contributions to the “The Science” Study Design
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These early physician /investigators through their Curiosity, Observation and Documentation pioneered a rigorous research method for new treatments
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Problem: Daniel and his friends cannot eat the food ordered by the king First Documented Clinical Study (Daniel 1:5-16).
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First Novel Therapy Problem: Gunshot wounds (Guns used in battle for the first time in 16th century)
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First Novel Therapy Ambroise Pare 1537 Siege of Turin
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First Controlled Clinical Trial Problem: Sea Scurvy James Lind 1747
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First Controlled Clinical Trial Lind’s Experiment Twelve sailors with same symptoms of Scurvy Each pair received one of the following interventions Quart of cider a day 25 drops vitriol 3x a day 2 spoons of vinegar 3x a day Half pint of sea water a day Paste of garlic, mustard seed, dried radish and myrrh An orange and two lemons
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First Double Blind Controlled Clinical Trial Problem : The Common cold British Medical Research Council- 1943 – 44 Multi-center study to compare Patulin to placebo. Patulin a fungal metabolite (mycotoxin) from rotting apples (Penicillium patulum) was compared to placebo W. A. Hopkins, M.D. Bradford Hill, M.D. Army and Navy Trials “An Apple a Day…”
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First Randomized, Double -blind Controlled Clinical Trial 1948 Problem: Penicillin ineffective against Pulmonary Tuberculosis … tuberculosis was the most important cause of death ( 50% mortality) of young adults in Europe and North America. Study was to measure the efficacy of Streptomycin to treat Pulmonary tuberculosis Bradford Hill, M. D. Phillip D’Arcy Hart
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The randomized, double bind controlled trial is still considered the gold standard for today’s clinical investigations.
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The Ethics Protecting Human Subjects
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“The Ethics” Protection of Human Subjects In the previous examples “patients/subjects” were not informed that they were involved in experimental treatments. Prior to the twentieth century, research ethics were primarily governed by physicians’ conscience and professional codes of conduct. Patients expected that the treatment or intervention was for therapeutic purposes
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Early U.S. Court Cases Carpenter V. Blake 1871 Earliest significant contribution to human subject protections The Carpenter court held that a doctor who departs from the usual, established method of treatment is liable for any resulting problems. Fortner v. Koch 1935 For the first time, the court recognized that some human experimentation must be permitted – specifically , Therapeutic Research, experiments that could potentially benefit the patient. The court imposed two important limits on such experimentation, namely that the subject must consent and that the procedure not deviate too much from established practice.
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The Berlin Code of Ethics 1900 “Prussian Standards” First regulations by a state authority for human experimentation Became a part of physician employment contracts Binding under German law In the meantime – in Europe
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Guidelines for New Therapy and Human Experimentation' “Reich Instructions” 1931 Expanded on the Berlin Code of Ethics No experimentation on patients who were poor or socially disadvantaged. Proportionality of risk and benefit must be respected, and that experiments should first be done in animals. Experimentation with dying persons not permissible, and Made the head of the institution personally and professionally responsible for the design, implementation and review of human experimentation
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The earlier human protection directives were reversed and laws were passed to control reproduction and achieve racial cleansing. 1) Sterilization Act of 1933 Protect the Hereditary Health of the German People 2) Reich Citizenship law 3) Nuremberg Laws of 1935 Safeguard Marital Health Rise of Adolf Hitler and the Third Reich 1933
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Euthanasia Program “life unworthy of life” 1939 This program authorized doctors to identify and destroy those who were “undesirable” in the population. In Berlin, a state organization was formed, which allowed doctors to examine hospital and clinic records. Between 1939 and 1941, doctors sentenced 70,000-100,000 Germans to death through their experiments in “perfecting methods of group killings” Public forced a shut down of the domestic euthanasia program – Hitler set up the death camps
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Nazi Doctors’ Trial1946U.S.A. V. Karl Brandt, et al Prosecution of 23 doctors and administrators participating in war crimes and crimes against humanity in the form of medical experiments and medical procedures inflicted on prisoners and civilians without their consent The specific crimes charged included more than twelve series of medical experiments concerning the effects of and treatments for high altitude conditions, freezing, malaria, poison gas, sulfanilamide, bone, muscle, and nerve regeneration, bone transplantation, saltwater consumption, epidemic jaundice, sterilization, typhus, poisons, and incendiary bombs.
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“Permissible Medical Experiments” (Nuremberg Code) Considered the basic text of Modern medical ethics for human experimentation First INTERNATIONAL document that advocated for informed consent and voluntary participation and imposed limits on how experiments could be conducted. Compliance and enforcement left to the investigator
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#1 The voluntary consent of the human subject is absolutely essential The experiment should aim at positive results for society that cannot be procured in some other way. It should be based on previous knowledge (like, an expectation derived from animal experiments) that justifies the experiment. The experiment should be set up in a way that avoids unnecessary physical and mental suffering and injuries. It should not be conducted when there is any reason to believe that it implies a risk of death or disabling injury. The risks of the experiment should be in proportion to (that is, not exceed) the expected humanitarian benefits. Preparations and facilities must be provided that adequately protect the subjects against the experiment’s risks. 8. The experiment should be conducted only by scientifically qualified persons. The human subjects must be free to immediately quit the experiment at any point when they feel physically or mentally unable to go on. 10. Likewise, the medical staff must stop the experiment at any point when they observe that continuation would be dangerous. Nuremberg Code
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Post Nuremberg ---1947 – 1974 Novel therapies and experiments continued to be performed on unsuspecting US populations by researchers without consent including those populations that we would now consider “vulnerable”. Pregnant Women Children Mentally disabled Prisoners Military personnel Elderly Terminally ill Infants Especially egregious were the experiments on the US population and military by the Atomic Energy Commission.
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First Federal Policy for Protection of Human Subjects 1953 The first U.S. Federal policy for the protection of human subjects was put into place for research conducted at the Clinical Center, NIH. This system is the model for the current IRB system. NIH Policy 1966 It required prospective review of human subjects research, taking into account the rights and welfare of the subjects involved, the appropriateness of the methods used to secure informed consent, and the risks and potential benefits of the research.
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Declaration of Helsinki 1964 Many in the medical community saw the Nuremberg Code as imposing strict legal obligation on Doctors. World Medical Association prepared recommendations as a guide to every physician in biomedical research involving human subjects. Informed consent requirement based on whether the research was considered Therapeutic or Non-therapeutic.
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Obedience to Authority Study Stanley Milgram Yale University Deception in Research
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"Tuskegee Study of Untreated Syphilis in the Negro Male” 1932- 1972 Based on finding of the Oslo Study of the natural history of 2000 cases of untreated syphilis 1890 – 1910 and follow up 1921 – 1928
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National Research Act 1974 Three major provisions Office of Protection from Research Risks (OPRR) in the NIH 2. Promulgated 45 CFR 46 Public Welfare Regulations for the Protection of Human Subjects National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research* - Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research
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45 CFR 46 Public Welfare Protection of Human Subjects National Research Act required DHEW to adopt the 1966 NIH policy for protecting human subjects as part of the public welfare regulations. The 1974 regulations at 45 CFR 46 were amended and re-issued in 1981 with provision that they only applied to federally funded research Oversight of federally funded human research was assigned to Office of Protection from Research Risks in the NIH 1991 45 CFR 46 subpart A was adopted by 17 federal agencies – called the “Common Rule”
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Regulations and Guidance
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Good Clinical Practice Is comprised of the FDA Regulations and guidance documents, the ICH guidelines for good clinical practice and ethical codes of conduct in clinical trials such as the Declaration of Helsinki and the Belmont Report Is a standard for the design, conduct, performance, monitoring, recording, analysis and reporting of clinical trials Ensures the rights, safety and welfare of subjects are protected and the integrity of the study data is maintained
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Good Clinical Practice in Clinical Trials Concurrent to the drafting of ethical guidelines and regulations , authorities began to recognize the need for controlling medical therapies early in the 20th Century Predecessor office to the current Food and Drug Administration (FDA) was the Chemistry Division, a scientific department, in the Department of Agriculture established in 1862. Major function was to test pesticides and other agricultural products (included preservatives in foodstuffs)
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FDA consumer oversight function of food and drug products began in 1906 The role of the FDA as a consumer protection agency has evolved and expanded “FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.”
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Turn of the Century in the United States 1900 “Adulterated Foods” “Patent Medicines” trade Publication of “The Jungle”
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Adulterated Foods “…investigate the character of food preservatives, coloring matters, and other substances added to foods, to determine their relation to digestion and to health, and to establish the principles which should guide their use." Common Additives/ Preservatives Borax Copper Sulfate Sulfuric Acid Potassium Nitrite Benzoic Acid Alum Formalin Chemistry Division, Department of Agriculture
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The Patent Medicine Trade Outrageous Advertising “Secret” Ingredients
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“Brain Tonic”
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The Jungle Sinclair wrote how diseased, rotten, and contaminated meat products were processed, doctored by chemicals, and mislabeled for sale to the public. …how workers would process dead, injured and diseased animals after regular hours when no meat inspectors were around – or paid them off
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The Pure Food and Drug Law of 1906 LANDMARK LEGISLATION The federal government assumed permanent and comprehensive ( law enforcement) responsibility for the health and safety of the American food and drug supply for the first time. First U.S. Consumer Protection law of the 20th Century
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“…to realize that six human beings, all of them my patients, one of them my best friend, are dead because they took medicine that I prescribed for them innocently, and to realize that that medicine which I had used for years in such cases suddenly had become a deadly poison in its newest and most modern form, as recommended by a great and reputable pharmaceutical firm in Tennessee: well, that realization has given me such days and nights of mental and spiritual agony as I did not believe a human being could undergo and survive” A.S. Calhoun, MD Sulfanilamide Disaster 1937
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Food, Drug and Cosmetic Act of 1938 The only remedy for such a situation ( Sulfanilamide Disaster) is the enactment by Congress of an adequate and comprehensive national Food and Drugs Act which will require that all medicines placed upon the market shall be safe to use under the directions for use. ...“ Required “substantial” evidence that a new drug was safe for use and be reported to the FDA* Required a FDA approval of new drug for market *Doesn’t specifically require animal testing in the law: however animal testing has become the default standard for the FDA and the agency will generally ask for toxicity test results using at least two species of animals
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Thalidomide Tragedy 1957 – 1961 Synthesized in Germany and marketed over the counter in 1957 as a sedative under the trade name Kevadon. Distributed in 46 countries -------wildly popular as the only non-barbiturate sedative available An Australian obstetrician discovered that the drug also alleviated morning sickness. He started recommending this off-label use of the drug to his pregnant patients, setting a worldwide trend.
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Thalidomide Tragedy In 1960 the FDA was petitioned to approve distribution in the US. Dr. Francis Kelsy held up the application for over a year –by then reports of the birth defects were being associated with Thalidomide use.
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Kefauver – Harris Amendment to the Food Drug and Cosmetic Act 1962 For a new drug application: the amendment Required Manufacturers to provide substantial proof of “Efficacy” through well controlled clinical trials Codified the informed consent requirement Set the rules for investigations Required the FDA specifically approve marketing applications Required adverse events be reported Laid the ground work for the New Drug Regulations
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Investigational Drug Regulations 1963 21 CFR 312 IND Application Regulations 21 CFR 314 New Drug Application for market approval
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Many other amendments through the years (24)1951 Durham Humphrey Act1976 Medical Device Amendments 1983 Orphan Drug Act 1992 Prescription Drug User Fee Act2003 Pediatric Research Equity Act Food Drug and Cosmetic Act
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1981FDA and OHRP regulations were harmonized to the extent allowed by statute.199145 CFR 46 Subpart adopted as the “Common Rule” Helpful to Remember! OHRP has regulatory oversight clinical research funded or supported by the federal government. (45 CFR 46) FDA has regulatory oversight of clinical investigations of FDA regulated products regardless of the source of funding. 21 CFR 11, 50, 54, 56, 312, 314, 812, 814
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International Conference on Harmonization Guidance Documents 1996
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Efficacy (E) - 20 GuidelinesConcerned with the design, conduct, safety and reporting of clinical trials. E8 GENERAL CONSIDERATIONS FOR CLINCIAL TRIALS The Guideline provides an introduction to clinical development, quality design of clinical studies and a focus on those factors critical to the quality of the studies.E6 (R2) GOOD CLINCIAL PRACTICE Outlines expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs. GCP E6 covers aspects of monitoring, reporting and archiving of clinical trials, and incorporates addenda on Essential Documents and on the Investigator's Brochure. The revised guidance updates and improves approaches to clinical trail design, conduct, oversight, recording and reporting including standards regarding electronic records and essential documents.E2 PHARMACOVIGILANCE E2A – Clinical Safety Data management: Definitions and Standards for Expedited Reporting International Conference on Harmonization Guidance Documents
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Useful Resources Nuremburg Code Declaration of Helsinki Belmont Report https://www.hhs.gov/ohrp/international/ethical-codes-and-research-standards/index.html Compare OHRP and FDA regulations https://www.fda.gov/science-research/good-clinical-practice-educational-materials/ comparison-fda-and-hhs-human-subject-protection-regulations Milestones in FDA History https://www.fda.gov/about-fda/fdas-evolving-regulatory-powers/milestones-us-food-and-drug-law- history