Clinical Research PDF

Clinical Research Anthony T. Podany, Pharm.D., Ph.D. Associate Professor UNMC, College of Pharmacy November 7, 2023 About me BS Nebraska Wesleyan, Biochemistry 2004 Analytical Chemist, MDS Pharma Services, 2002-2011 PharmD., UNMC 2012 Clinical Pharmacology Fellowship, UNMC 2012-2014...

Clinical Research Anthony T. Podany, Pharm.D., Ph.D. Associate Professor UNMC, College of Pharmacy November 7, 2023 About me BS Nebraska Wesleyan, Biochemistry 2004 Analytical Chemist, MDS Pharma Services, 2002-2011 PharmD., UNMC 2012 Clinical Pharmacology Fellowship, UNMC 2012-2014 Assistant Professor, UNMC, 2014-2021 Associate Professor, UNMC, 2021- present PhD, UNMC, Clinical & Translational Research, 2022 PI, Phase II Study, since 2019 Outline Translational Science Spectrum Clinical Research Basics and Terminology Types of Clinical Research History of Human Subjects Research Clinical Trial Phases Pediatric Clinical Research Clinicaltrials.gov Review of real world protocol Translational Science Spectrum Phases of Translational Research https://victr.vumc.org/translational-research/ Clinical Research Clinical Research Clinical Research: the comprehensive study of the safety and the effectiveness of the most promising advances in clinical care. Clinical research is different than laboratory research. It involves people who volunteer to help us better understand medicine and health. JHU, www.hopkinsmedicine.org, accessed 01-NOV-2023 Types of Clinical Research JHU, www.hopkinsmedicine.org, accessed 01-NOV-2023 Clinical Trials JHU, www.hopkinsmedicine.org, accessed 01-NOV-2023 Clinical Research Basics What is clinical (human subjects) research? Department of Health and Human Services (DHHS) Definitions (45 CFR 46.102) In order for activities to be deemed human subjects research by the DHHS, they must meat the definition of “research” and involve one or more “human subjects” as defined by DHHS regulations. Research: “A systemic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” Clinical Research Basics DHHS Human Subjects Definition “A living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual; or (2) identifiable private information.” Examples of identifiable private information Names, SS #, bank account info, fingerprint, telephone #, home or email address, medical record # Indirect identifiers: Age, ethnicity, gender, city or state of residence, occupation, specific time, event or context of occasion Considered identifiable if combined with enough info to potentially identify a participant Clinical Research Basics Belmont Report Definition of Clinical Research “Any activity designed to test a hypothesis, permit conclusions to be drawn and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships).” Clinical Research Basics DHHS Definitions Continued Intervention: Includes both the physical procedures by which data are gathered (eg. blood draw) and manipulations of the subject (eg. drug) or the subject’s environment (eg. dark rooms) that are performed for research purposes Interaction: Includes communication or interpersonal contact (eg. questionnaires, interviews) between the investigator and subject Clinical Research Basics DHHS Definitions Continued Private Information: Includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (eg. medical record). Private information must be individually identifiable (eg. the identity of the subject is or may readily be ascertained by the investigator or associated with the information). Food & Drug Administration (FDA) FDA has its own set of definitions FDA guidelines need to be followed when using a drug or device in a research study "Human subject" means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient. https://www.hopkinsmedicine.org/institutional-review-board/guidelines-policies/guidelines/fda- ohrp#:~:text=Definition%20of%20Human%20Subject,(2)%20identifiable%20private%20information. History of Human Subjects Research History of Human Subjects Research US Public Health Service Syphilis Study ’32-’71 § Better known as the “Tuskeegee Syphilis Study” § Started in 1932 to Study the natural history of syphilis § Originally designed to make treatment available to African-American men with syphilis, even though there was no known effective treatment § Originally involved 600 Black men, 399 w/ syphilis § Participants were told they were being treated for “bad blood”, a term used to describe many local ailments, including syphilis § Provided free medical exams, free meals, and free burial insurance § Issues: 1. Men were recruited without their consent 2. Misinformation about procedures, ie spinal taps 3. Misinformed about study duration: 6 mo vs 40 years 4. After penicillin was proven an effective treatment in 1943, men were denied antibiotics and prevented treatment from military and local physicians 5. More than 100 men died as a result of non-treatment History of Human Subjects Research US Public Health Service Syphilis Study ’32-’71 § In 1972 associated press story about the study published § Assistant secretary for health and scientific affairs appointed an advisory committee to look at the study § Panel concluded the study was “ethically unjustified”…..”results were disproportionately meager compared to the known risks” § October 1972 the panel recommended halting the study § In 1973 the Secretary of the DHHS instructed the USPHS to provide all necessary medical care for the survivors of the study § 1973 class action law suit on behalf of participants and their families resulted in a $10M settlement § 1997 President Bill Clinton publicly apologized for the study History of Human Subjects Research US Food, Drug and Safety Act (1938) § Aka Food, Drug and Cosmetic Act § Tennessee Drug company marketed new sulfa wonder drug § 107 people died after taking sulfanilamide, a cold remedy that contained chemical analogue of anti-freeze. § This act enforces manufacturers to demonstrate drug safety. § Drugs must be labeled with adequate directions for use § Mandated pre-market approval for all new drugs § Prohibits false therapeutic claims History of Human Subjects Research Nuremberg Code (1947) § Result of the trial of Nazi doctors and scientists from WWII – no guidelines for human research § Created a set of ethical research principles for human experimentation § Guidelines: 1. Need for informed consent 2. Research should be based on prior animal work 3. Risks should be justified by anticipated benefits 4. Only qualified scientists must conduct research 5. Physical and mental suffering must be avoided 6. No research where death/severe injury is expected History of Human Subjects Research Nuremberg Code (continued) § Problems: 1. Little impact on research done in the US – thought to condemn Nazis 2. No strength of the law behind it 3. Only applied to non-therapeutic human subject research Code has influenced the drafting of current DHHS regulations History of Human Subjects Research Declaration of Helsinki (1964) § Code of ethics developed by the World Medical Association (now known and WHO) § Broader than Nuremberg Code § Geared towards therapeutic medical research § Recommended informed consent § Precursor to IRB requirement § Journals required all published research to follow Declaration’s guidelines History of Human Subjects Research The National Research Act (1974) § Culmination of hearings by US Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Purpose of The National Commission: 1. Identify basic ethical principles underlying the conduct of human subject research 2. Develop guidelines to ensure conduct of human subject research in accordance with those principles History of Human Subjects Research The National Research Act (continued) § 45 CFR 46 – “Regulations for the Protection of Human Subjects of Biomedical and Behavioral Research”; Issued by the Department of Health, Education and Welfare (later renamed DHHS) § Revisions made in late 1970’s and early 1980’s § By 1991, 16 other federal agencies/departments applied 45 CFR 46 to research they fund/conduct § Referred to as the “Common Rule” History of Human Subjects Research The Belmont Report (1979) § Issued by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research § Purpose: resolve ethical problems that surround the conduct of human subject research § One principle does not outweigh another; each has equal weight History of Human Subjects Research The Belmont Report The three principles: 1. Respect for Persons – treat people as autonomous creatures and not a means to an end; provide extra protection for those with limited autonomy Requires informed consent Requires respect of privacy of research subjects History of Human Subjects Research The Belmont Report The three principles: 2. Beneficence – minimize harm and maximize benefit Requires use of the best possible research design to maximize benefit and minimize harm Requires researchers to be able to perform the procedures and manage the risks Prohibits research without a favorable risk-benefit ratio History of Human Subjects Research The Belmont Report The three principles: 3. Justice – treat all people fairly and ensure burdens and benefits are shared equitably Requires equitable selection of research subjects Requires avoidance of exploitation of vulnerable populations or populations of convenience (ie pregnant women; children; incarcerated populations) History of Human Subjects Research International Conference on Harmonization - ICH (1990) § Joint regulatory/industry project to improve process of developing new products between Japan, Europe and United States § Allows for international research studies to follow same rules/regulations § Conference convenes to update regulations § Established “Good Clinical Practices” Good Clinical Practice (GCP) Known as GCP’s Misnomer – they are rules/regulations for the conduct of research Sometimes called “Good Research Practices” Standard for the design, conduct, performance, monitoring, analyses and reporting of research Even though established for drug studies, they dictate appropriate conduct for all research Clinical Trials Clinical Trial Phases Phase I: Unblinded studies of a small number of healthy volunteers to test safety of treatment (can sometimes use people with the disease, eg. oncology) Is the medicine safe, and what is the right dose? Typically 20 – 100 subjects Few sites Study length, typically days to weeks. Clinical Trial Phases Phase II: Randomized studies of relatively small number of people with the disease to test dose ranges and/or efficacy of treatment Does the new medication work, and what are the side effects? Typically 100 – 300 subjects Up to ~30 sites Study length, typically one month to a year. Clinical Trial Phases Phase III: Randomized studies of large number of people with the disease to test efficacy of treatment on pre-selected outcomes Is the new medication more effective than existing therapies? Typically, 100’s to 1000’s of subjects – real world population Multiple sites, often multiple countries Study length, typically 6 months to years. Clinical Trial Phases Phase IV: Large experimental studies or observational studies conducted after treatment has been approved by the FDA to assess performance of treatment (called Post- Market Studies) Is the new medication safe and effective over the long term? Typically, 100’s to 1000’s of subjects Multiple sites, often multiple countries Study length, typically 6 months to years. Pediatric Clinical Research Pediatric Clinical Research Conducting pediatric clinical research is more complex than adult studies. Pediatric population perceived as a vulnerable patient population. Decision making capacity may be immature Lives are subject to the authority of others Underlying dissent may be masked for fear of upsetting authority figures Their rights and interests may be undervalued by society Pediatric Clinical Research Informed consent is based upon the Belmont Report ethical principle “respect for persons” Standards of consent include: Information should be provided to the subject so that they may decide whether to participate Information should be presented so that it is easily understandable (8th grade level). The potential subject should understand that consent is voluntarily given and can be withdrawn at any time Difficult to do in a pediatric population Researchers work with child’s guardian to meet the informed consent standards to the best of their ability. Age of consent in the US is typically 18 For teenagers, often written assent is required along with consent from parents. Adults who serve as legal guardians must provide consent for younger subjects CITI Program Collaborative Institutional Training Initiative (CITI) Training needs of colleges, universities, healthcare institutions, technology and research organizations, and governmental agencies CITI Training Clinicaltrials.gov Website and online database of clinical research studies and information about their results. Purpose: to provide information about clinical research studies to the public, researchers, and health care professionals. Listed studies are not reviewed or approved by US government. Relies on sponsors or investigators to submit and update information about studies. Includes studies from all 50 states, and over 200 countries. Clinicaltrials.gov www.clinicaltrials.gov Clinicaltrials.gov