2024 PPCR Lecture 1 PDF

PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH INTRODUCTION TO CLINICAL TRIALS Felipe Fregni, MD, PhD, MPH, MEd PPCR Program Director Professor of PMR, Harvar...

PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH INTRODUCTION TO CLINICAL TRIALS Felipe Fregni, MD, PhD, MPH, MEd PPCR Program Director Professor of PMR, Harvard Medical School Associate Professor of Epidemiology, Harvard T.H. Chan School of Public Health Farr's Law In 1840, William Farr concluded from from mortality from smallpox in England and Wales - 1838 and 1839: "Epidemics appear to be generated at intervals in unhealthy places, spread, and go through a regular course, and decline...If the latent cause of epidemics cannot be discovered, the mode by which it operates may be investigated" A normal bell-shaped curve explains epidemics: Acceleration and decellaration are similar. Importance Confirmed by large epidemics from various of History in Science parts of the world over several centuries CATTLE PLAGUE (RINDER¬ PEST) - PROJECTION 1865 He projected peak was near instead of a catastrophic prediction of that time  Using the Farr's Law - example on AIDS epidemics - JAMA paper - Bregman 1990) FARR'S LAW WITH COVID-19 FARR'S LAW WITH COVID-19 BRIEF HISTORY OF CLINICAL TRIALS "The past does not repeat itself, but it rhymes". Mark Twain  In 1937, sulfanilamide tablets was produced as more palatable liquid version, with a sweet raspberry taste By mid-October, the AMA had received numerous reports: –Severe abdominal pain –Nausean and vomiting –Renal failure –Death 105 people in 15 states died, including 34 children Sulfanilamide The compound used to dissolve the tablets was diethylene glycol, a deadly Cold Syrup poison related to antifreeze  1959, thalidomide to relieve morning sickness and insomnia When the link between thalidomide and malformations were discovered, the FDA discovered that 2.5 million tablets of thalidomide were distributed to 1,270 U.S. physicians as samples Thalidomide  NUMBERS OF THALIDOMIDE 200,000 Americans received the drug 10,000 Birth defects  “The Tuskegee study of untreated syphilis in the negro male”. U.S Public Health Service (USPHS)- Alabama and the Tuskegee Institute - between 1932 and 1972 Hundreds of African American males didn’t receive proper and standard care for syphilis, with the intention to document the natural course of syphilis infection if it was left untreated. Tuskegee Study But we learned the lessons and now we are "safe"...aren't we? WHAT LESSONS WE LEARNED FROM THESE TRAGEDIES? First Student Participation We have seen a number of tragedies in the past that resulted in a number of deaths and also in morbidity, so how to conciliate the search for innovation and new treatments with the main CLASSROOM Hippocratic Oath: GOOGLE Primum non nocere/ first do no harm PHYSICIAN VS. RESEARHCER HAT "First do no harm". Hippocratic Oath Primum non nocere DISCUSSION Solutions TRAGEDIES IN CLINICAL MEDICINE Lessons Learned MILESTONES OF ETHICS IN CLINICAL RESEARCH "Relativity applies to physics, not ethics". Albert Einstein  1948: The Nuremberg ETHICAL PRINCIPLES Code Motivation: Nazi Experiments Nuremberg Code describes 10 basic principles of ethical conduct of human experimentation Pivotal principles: –Voluntary consent of the subject must be obtained –Prior animal experimentation to determine risk must be performed –Investigators must be qualified medical personnel Adopted by the United Nations in 1948 ETHICAL PRINCIPLES 1964: Declaration of Helsinki Motivation: Thalidomide Tragedy Outlines basic principles of human experimentation Requires informed consent of study subjects Describes ethical approval and review of research ETHICAL PRINCIPLES 1976: The Belmont Report Motivation: Tuskegee Study Three basic principles of medical research were identified: –Autonomy (informed consent) –Beneficence (always doing good, no harm) –Justice (equal and fair selection of subjects) Importance of rules and regulations Even though and even now some still complain about the regulations/IRB/ethical committees, you can see how they were important to avoid more disasters, but should we still be attentive to other potential "disasters"? What is the importance of regulations (is there any tradeoff)? Discussion Case Discussion  Death of an 18-year-old research subject in a gene replacement study at U Penn in 1999 - Jesse Gelsinger - fatal immunological reaction –Raised concerns about financial relationships, informed consent process, and interests on the part of biomedical researchers that could compromise the safety of research subjects Continued Problems in Human Based Research STUDENTS COMMENTS STUDENTS COMMENTS STUDENTS COMMENTS  POLL: AFTER READING THE CASE STUDY, IF YOU WERE THE PRINCIPAL INVESTIGATOR IN THIS CASE, WHAT WOULD YOUR DECISION BE? 1) Halt the study as it is too risky for subjects 2) Continue study planning based on potential individual benefits 3) Continue study planning based on the benefits for the society that this study can bring GO TO GOOGLE CLASSROOM What went wrong? Preparing for next week Definition of Systematic search Prepare for next topic/Research and flow chart weeks for review questions After well defined PICOS, data collection and follow the strategy for bias assessment Defining PICOs systematic search - help in OH and material STUDY PHASES "Prior to penicillin and medical research, death was an everyday occurrence. It was intimate." Katherine Dunn Study Phases Preclinical Animal Testing Phase I Phase II Safety Safety and Efficacy Phase III Phase IV Effectiveness Post-marketing survellaince  100.0% 80.0% What is the rate 60.0% of success? 40.0% 20.0% 0.0% II III A al al D o ov ov to It N pr pr II to e Ap Ap as e III as Ph o to e Ph It as A e D Ph as N Ph Probability of Success (per phase and overall) Source: Brandy Betz - Seeking Alpha  STUDY PHASES Consists on completing a rigorous animal testing previous to application before the FDA for an Investigational New Drug (IND). Most drugs that undergo animal testing don’t make it to human experimentation. Preclinical Phase  STUDY PHASES Main goal: determine pharmacokinetic and pharmacodynamics parameters of the drug and its safety in human subjects. Group of 20 – 80 healthy volunteers. The main parameter to determine progression to Phase I is proof of safety, mainly no severe toxic effects. Phase I  STUDY PHASES Main goal: efficacy of the medication on a given population. The study in a group of diseased patients, which can range from a dozen to 300. The study should be controlled. This phase continues to evaluate for drug safety and short-term side effects. Phase II  STUDY PHASES The main goal of this phase is to assess effectiveness and safety. “Real-life” conditions emulated in heterogeneous populations or compared against the standard of care. The number of patients can range from several hundreds to 3000 – 10.000. Phase III  STUDY PHASES Known as post-marketing survey. After the drug is approved by the FDA and put in the market. Post-marketing surveillance and commitment studies allow the FDA to collect further information on safety, efficacy and tolerability profile. Phase IV Second Student Participation How to ensure that your systematic review will come up with strong and unbiased conclusions? CLASSROOM GOOGLE Thank you!