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# 2nd lect phases and types of the intervention research

  1. Dr. Eman M. Mortada Professor In public health and preventive medicine Basics of interventional research Phases and types
  2. Historical aspects of the clinical trials Drug Development Process Phases of the clinical trials Advantages and disadvantages of clinical trials Types of Clinical Trials Based on the unit being studied Types of clinical research studies based on the purpose Lecture Outline
  3. It is usually used to: 1- assess the efficacy of a new line of treatment (a new drug for example) or 2- to compare two types of treatments: surgical or medical RECAP: Clinical trials ❑ Clinical trials have the objective of finding the best intervention to prevent, and treat diseases Clinical trials are ”Gold standard” in epidemiological research & the best epidemiological study design to prove causation. Dr. Eman Mortada
  4. What are clinical trials? *Clinical trials involve A carefully and ethically designed prospective research study conducted on humans that is designed to to find better ways to prevent, diagnose, or treat a disease and add to medical knowledge Clinical Persons with clinical disease or persons at risk of clinical disease Trial An experiment Dr. Eman Mortada
  5. RECAP: Randomized Trial Design Time Defined Population New Treatment Current Treatment Improved Not Improved Improved Not Improved R A N D O M I Z E D Dr. Eman Mortada
  6. Clinical Trials in History Dr. Eman Mortada Significant Historical Events For Clinical Trials
  7. Early clinical trial James Lind’s Dr. Eman Mortada
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  9. Edward Jenner vaccinating for prevention of Smallpox (1796) Dr. Eman Mortada  Edward Jenner was an English country doctor who pioneered vaccination.  Jenner's discovery in 1796 that inoculation with cowpox gave immunity to smallpox, was an immense medical breakthrough and has saved countless lives.
  10. Dr/ Eman Mortada What is Smallpox?  In the 18th century smallpox was a very common serious, contagious disease and was a major cause of death.  There is no specific treatment for smallpox, and the only prevention is vaccination.
  11.  Jenner was given the opportunity, when a young milkmaid called Sarah Nelmes came to see him with sores on her hands like blisters.  Jenner identified that she had caught cowpox from the cows she handled each day.  He carefully extracted some liquid from her sores and then took some liquid from the sores of a patient with mild smallpox.  Jenner believed that if he could inject someone with cowpox, the germs from the cowpox would make the body able to defend itself against the dangerous smallpox germs which he would inject later.
  12.  Jenner approached a local farmer called Phipps and asked him if he could inoculate his son James against smallpox.  He explained to the farmer that if his theory was correct, James would never contract smallpox.  Surprisingly, the farmer agreed.  Jenner called his idea " vaccination"  from the word vaccinia  which is latin for  cowpox.
  13.  Clinical trials began in 1800 onward to proliferate and more attention was paid to study design. Lifespan Improvement John Snow and Cholera (1850) Dr. Eman Mortada
  14. 1- John Snow mapped cases of cholera to help give him clues about the cause. 2- Mapping of cases led John snow to suspect water from the Broad street pump as a cause of cholera. What did he do?
  15. Dr / Eman Mortada 15 1- He used chlorine in an attempt to clean the water 2- he removed the handle, thus ending the outbreak. Broad Street Pump
  16.  Placebos were first use in 1863  Goldberger relating pellagra to maize diet (1915) Pre-20th Century Medicine Dr. Eman Mortada
  17. The story of pellagra Dr/ Eman Mortada What is pellagra?
  18. What was the problem of pellagra? In 1914, pellagra was a common disease in the United States. It caused rashes, insanity and death. The story of pellagra An insect Or Bacteria/germs Dr/ Eman Mortada What did people think cause of pellagra?
  19. What evidence did Dr. Goldberger observe or collect about pellagra? Dr/ Eman Mortada Pellagra was common in the South, particularly in poor areas and institutions (such as mental hospitals, orphanages, and prisons). Many people in the South ate a poor diet, consisting of cornbread Staff at institutions (such as mental hospitals, orphanages, and prisons) did not have pellagra. Descriptive study Analytical study
  20. He generated a Hypothesis Pellagra might be a nutritional deficiency disease He tested that hypothesis Some prisoners fed a poor diet developed pellagra. When provided a better diet, they recovered. What did Dr. Goldberger conclude about the cause of pellagra? Dr. Goldberger concluded that pellagra was caused by a nutritional deficiency (poor diet). Dr/ Eman Mortada
  21.  The first trial using properly randomized treatment and control groups also featured double blind assessment was carried out in 1948 by the Medical Research Council, and involved the use of streptomycin to treat pulmonary tuberculosis.. First large-scale clinical trial using a properly designed randomized schema New Era of Medicine The idea of randomization was introduced in 1923.
  22. Austin Bradford Hill Dr. Eman Mortada The father of modern RCTs
  23. Clinical Trials recently Dr. Eman Mortada
  24. Importance Of Clinical Trials Registration Dr. Eman Mortada All clinical trials should be registered before the enrolment of the first patient and all results made publicly available To ensure transparency, accountability and to increase public trust in the conduct of clinical research. Clinical trial registration and results reporting would help ensure unbiased public records on safety and efficacy of drugs.
  25. Drug Development Process Phases of Clinical Trials Dr. Eman Mortada
  26. Phases in the Development of Drugs Laboratory Research  Animal Studies  Clinical Trials  Clinical trials that involve new drugs go through a series of steps are conducted in several phases and each phase has a different purpose.  The steps include:  #1: Experiments in the laboratory  #2: Once deemed safe, go through 4 phases Dr. Eman Mortada
  27. Drug development timeline Dr. Eman Mortada
  28. 1- Preclinical trials It is tested on animals before being tested on human beings  It takes about 2-5 years on the average  To test drug safety  Pharmacokinetics and pharmacodynamics are tested ➢ Preclinical testing by clinical Pharmacologist Dr. Eman Mortada
  29. Pharmacodynamics vs Pharmacokinetic  What does the drug do to the body?  Investigate: - Physiological effects (blood glucose, electrolytes, kidney and liver function) - Mechanism of Drug action (molecular and cellular responses to drugs) - Relationship between drug concentration and effect (optimal dose)  What does the body do to the drug?  Investigate: - Absorption (bioavailability) - Distribution (circulation and tissue) - Metabolism (breakdown) - Excretion (kidney and liver) Pharmacodynamics studies Pharmacokinetic studies Dr. Eman Mortada
  30. Figure 1.1 Schematic representation of the pharmacokinetic and pharmacodynamic processes that link the administration of drugs to its effects Dose of drug administered Drug concentration In systemic circulation Drug in tissues or distribution Drug concentration at site of action Drug metabolized or excreted Pharmacokinetics Pharmacologic effect Clinical response Toxicity Efficacy Pharmacodynamics Absorption Distribution Elimination Distribution Dr. Eman Mortada
  31.  First in Man : Small number of healthy volunteers (20 to 25)  Objective: dose finding (DF). Start with a dose of about 1/10 to 1/5 tolerated animal dose  Slowly increase the dose to find a safe maximum tolerated dose or target dose based on pre-clinical exposure  If safe → try in a larger group of up to about 50 –75  No blinding  Performed by clinical pharmacologists  Centre has emergency care & facility for kinetics study  Takes 3 – 6 months [ 70% success rate] 2- Phase 1, Typical Characteristics Dr. Eman Mortada
  32. 3- Phase II  Objective: Safety and Efficacy (SE) =To determine if new drug has any beneficial activity and thus worthy of further testing / investment of resources.  Once a drug has shown to be safe, then it must be tested for efficacy.  First in patient [ different from healthy volunteer]  Early phase [20 – 200 patients with relevant disease]  Therapeutic benefits & ADRs evaluated  Establish a dose range to be used in late phase  Single blind, comparison with standard drug  Late phase [ 50 – 500]  Double blind  Compared with a placebo or standard drug  Takes 6 months to 2 years [ 35% success rate] ➢ Clinical testing by clinical Pharmacologist Dr. Eman Mortada
  33. 3- Phase II  Objective:  Safety and Efficacy (SE)  To determine if new drug has any beneficial activity and thus worthy of further testing / investment of resources. ➢ Clinical testing by clinical Pharmacologist Dr. Eman Mortada Once a drug has shown to be safe, then it must be tested for efficacy.
  34. 3- Phase II  Double blind  Compared with a placebo or standard drug Dr. Eman Mortada First in patient [ different from healthy volunteer] Early phase [20 – 200 patients with relevant disease] Late phase [ 50 – 500] ❑ Therapeutic benefits & ADRs evaluated ❑ Establish a dose range to be used in late phase ❑ Single blind, comparison with standard drug  Takes 6 months to 2 years [ 35% success rate]
  35. 4- Phase III  Large scale, Randomised, Controlled trials  Multiple arms: 2 (control vs intervention) or more  Randomized treatment allocation  Target population: 250 – 1000 patients  Objective: to compare outcome to standard [Comparative Treatment Efficacy]  Takes a long time: up to 5 years [25% success] ➢ Clinical Trials by clinical Investigators Dr. Eman Mortada
  36. Essential elements of a clinical trial 1. Prospective  Subjects followed forward 2. Intervention  Prophylactic, diagnostic or therapeutic 3. Control  Compared to intervention group 4. Randomized  Equality of baseline characteristics 5. Blinded  Systematic bias Controlled Randomized Dr. Eman Mortada
  37. Approval must be gained:  Once a drug has proven satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life.  This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities like the U.S. Food And Drug Administration (FDA) so they can then grant the sponsor approval to market the drug, device or treatment. Dr. Eman Mortada
  38. New Drug Application (NDA)  By law, the FDA has 60 days to decide if there is enough information to continue with the NDA review.  By law, the FDA is required to make a final decision within 180 days.  In practice this timeframe often is lengthened (considerably) by mutual agreement.
  39. Thalidomide:  German pharmaceutical company Grünenthal.  Sold from 1957 to 1961 (40 different brands) in almost 50 countries.  To pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep.  Inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.  Approximately 10,000 children (1956-1962) were born with severe malformations, including Phocomelia (presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet). Why so strict?
  40. 5- Phase IV ✓ Starts immediately after marketing ✓ Phase four studies are frequently observational ✓ Report all ADRs (Adverse Drug Reactions) ✓ Helps to detect  rare ADRs  Drug interactions  Also new uses for drugs [Sometimes called Phase V] ➢ Post marketing Surveillance by Practicing Clinicians Pharmacovigilance: the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medicines, biological products, herbals and traditional medicines Dr. Eman Mortada
  41. Summary of phases Summary of phases Dr. Eman Mortada
  42. Timeline of Clinical Trials A typical timetable from test tube to patient  R&D and pre-clinical 5 years  Phase 1 6 months  Phase 2 2.0 years  Phase 3 5 years  NDA evaluation ongoing  Total 12.5 years Dr. Eman Mortada
  43. Intervention Trials  Gold standard for evaluating efficacy of therapeutic or preventive measures.  Provides strongest evidence for causality.  Reduces influence of other determinants of exposure and outcome (confounding) due to randomization.  Expensive, time-consuming.  Loss-to-follow up of patients and non-compliance might constitute major biases  Often based on volunteer samples, results may not be generalizable to the wider population  Ethical considerations (equipoise necessary) – believe new treatment is at least as good as old treatment or placebo. Advantages Disadvantages Dr. Eman Mortada
  44. ✓The principle of equipoise, provides the ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. ✓Clinically, we define equipoise as a lack of consensus within the expert clinical community on the preferred therapy. = equal ignorance of certainity Clinical equipoise
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  46. Types of Clinical Trials Dr. Eman Mortada
  47. Depending on: Community trials The community is the unit of study Field trials Healthy people are the unit of study Clinical trials Patients are the unit of study Types of Experimental Studies Unit of Study Dr. Eman Mortada
  48. 1- Community trials: Intervention directed at entire community :  Start by determining eligible communities and their willingness to participate.  Communities are randomized into two groups  Collect baseline measures of the problem to be addressed in the intervention and control communities.  The experimental group (will take the new vaccine) and the the control group (will not take the vaccine).  The participants will be followed to compare the level of occurrence of the disease in both groups.  Therefore, these groups should be similar as much as possible in all aspects except the treatment /intervention received. Dr. Eman Mortada
  49. Examples of community-level interventions  Immunization campaigns  Screening programmes delivered to residents of a geographic area  Mass educational programs  Health promotion programmes delivered to towns, schools  Services provided to primary care practice populations  Nutritional, environmental sanitation interventions:  dietary supplements Dr. Eman Mortada
  50. e.g.: Vitamin A Community Trial  450 Sumatran villages with high childhood mortality rates  Exposure = Vitamin A supplementation program vs. no intervention  Random allocation of intervention: 229 treatment villages, 221 control villages 1 Childhood mortality rate in exposed village 53 4.9 per 1000 10,919 R = = 0 Childhood mortality rate in control villages 75 7.3 per 1000 10,231 R = = Dr. Eman Mortada
  51. Limitations of Community Trials  Random allocation of communities is not practical  Only a small number of communities can be included  Other methods are needed to ensure any difference found can be attributed to the intervention rather than to any inherent differences between the communities studied Dr. Eman Mortada
  52. Field trial Clinical trial In healthy population On patients Often prophylactic Often therapeutic (including prevention of sequelae) For primary prevention For secondary and tertiary prevention 2- Field trials ❑ Involve people who are disease-free but presumed to be at risk ❑ Data collection – “in the field” in the general population Dr. Eman Mortada
  53. Dr. Eman Mortada Real examples: CATCH -Coordinated Approach To Child Health (formerly known as the Child and Adolescent Trial for Cardiovascular Health) The largest school-based field trial ever sponsored by the National Institutes of Health. Designed to prevent sedentary behavior, poor dietary choices, and tobacco use through changes at the elementary school level The trial demonstrated positive changes in the school food service and physical education program, as well as in students' cardiovascular health behaviors. Examples of field trial Go to the readings for details
  54. Caries Fluoride Study Dr. Eman Mortada  This was a controlled trial conducted to determine if increasing fluoride levels in drinking water would reduce children's dental caries. Two experimental units, the towns of Newburgh and Kingston in New York State, were assigned to a treatment (fluoridation) arm and a control (unfluoridation) arm, respectively. What is the IV, DV &type of this trial IV: fluoridation DV: dental caries &type of this trial: community trial
  55. Bicycle helmet campaign You want to test whether a public awareness campaign about bicycle safety at elementary schools will increase bicycle helmets use among school-aged children. To test this intervention, you identify 12 elementary schools, half of which will be randomly assigned to participate in a school-wide bicycle helmet awareness program. The other 6 schools will serve as controls and will receive no special intervention. Research assistants will determine the percentage of bicyclists wearing helmets at standard locations in neighborhoods of each of the schools before and after the intervention. Dr. Eman Mortada What is the IV, DV &type of this trial IV: bicycle helmet awareness program DV: percentage of bicyclists wearing helmets &type of this trial: community trial
  56.  One of the largest trial ever conducted was the MRFIT Study in the US  It was a primary prevention trial to test the effect of multiple interventions to reduce the risk of premature coronary heart disease (CHD)  in 12,866 men, age 35–57, with one or more of three risk factors (hypertension, hyperlipidemia, or cigarette smoking) without a prior history of CHD. Dr. Eman Mortada The Multiple Risk Factor Interventional Trial (MRFIT) What is the IV, DV & unit of study?
  57.  The trial was conducted in 22 clinical centers in the United States, screening 356,222 men for the desired study population.  Six thousand four hundred and twenty eight participants were assigned to the intervention group, and 6,438 were assigned to the usual care group. Active follow-up was obtained for 6 years, and more than 25 years of surveillance has occurred. Dr. Eman Mortada IV: bicycle helmet awareness program DV: risk of premature coronary heart disease &type of this trial: field trial
  58. Test new treatments, combinations of drugs, surgical approaches, or radiation therapy Find ways to prevent diseases; include medicines, vaccination, or lifestyle change Test the best way to detect specific diseases or health conditions Come up with better tests or procedures for diagnosing a disease or health condition Explore ways to improve the comfort and quality of life of people with a chronic illness (also known as supportive care trials) Types of Clinical Trials Based on the purpose
  59. 1. Treatment Trials They test  New treatments  New combination of drugs  New approaches to Surgery  New Radiation therapy Possible benefit: Early access to new treatments Possible risk: Occurrence of unknown side effects For the most part, "clinical trials" have been concerned with evaluating therapeutic agents, mainly drugs. Dr. Eman Mortada
  60. Types of Treatment Trials Pharmaceutical (treatment, biological, synthetic). Device (prosthesis, sensory aids). Procedure (surgery, laser, radiological). Behavior change (smoking cessation, dietary modification, exercise). Other (counseling, information provision). Dr. Eman Mortada
  61. 2. Prevention Trials They try to find better ways to prevent disease in people and to prevent disease recurrence using  Medicines  Vaccines  Vitamins  Minerals The most frequently occurring type of preventive trials are the trials of vaccines and chemo-prophylactic drugs. Dr. Eman Mortada
  62. ➢ A type of preventive trial is the trial of risk factors in which the investigator intervenes to interrupt the usual sequence in the development of disease for those individuals who have "risk factor" for developing the disease. ➢ For example the major risk factors of coronary heart disease are elevated blood cholesterol, smoking, hypertension and sedentary habits. Risk Factor Trial Dr. Eman Mortada
  63. 3. Screening Trials  To find out the best way to detect certain diseases or conditions Possible benefit: Detecting disease at an earlier stage, resulting in improved outcomes Possible risks: Discomfort Dr. Eman Mortada
  64. Screening can be defined as: The early detection of disease in individuals who do not show any signs of disease (preclinical) to prevent worsening of the existing disease. Dr / Eman Mortada 10/25/2021 Screening is an important aspect of secondary prevention.
  65. Benefits of screening 1. Magnitude of disease can be precisely assessed, where pre-symptomatic cases are not missed. . Dr / Eman Mortada 10/25/2021
  66. Benefits of screening 2. Early detected cases can be effectively controlled, with better prognosis, no or minimal consequences and less burden on health services. Dr / Eman Mortada Important assumption in epidemiology: The Earlier the diagnosis the better the prognosis 10/25/2021
  67. Common screening Tests General medical examination ( check ups)  Blood cholesterol for heart disease  Fasting blood sugar for diabetes  Blood pressure for hypertension e.g.: Preemployment medical examination Tuberculin test to screen for exposure to tuberculosis Dr / Eman Mortada 10/25/2021
  68. Cancer screening 1. Pap smear to detect potentially precancerous lesions and prevent cervical cancer 2. Mammography and breast self examination to detect breast cancer 3. Colonoscopy and fecal occult blood test to detect colorectal cancer 4. One is the digital rectal examination (DRE), in which the examiner inserts a gloved, lubricated finger into the rectum to examine the adjoining prostate. The other is the prostate-specific antigen (PSA) blood test, which measures the concentration of this molecule in the blood Dr / Eman Mortada 10/25/2021
  69. Disadvantages of screening Screening is not always free of risk Dr / Eman Mortada Not 100% accurate test. Detected cases may be actually free of the disease False positive Test may misdiagnose actually diseased persons False negative 10/25/2021
  70. False Positives  Stress and anxiety caused by a “False Positive” screening result.  Unnecessary investigation and treatment  Monetary expense Risk in Screening Dr / Eman Mortada 10/25/2021 False Negatives • A false sense of security caused by false negatives, which may even delay final diagnosis and delayed intervention
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  72. 4. Diagnostic Trials  To find better tests for diagnosis of a disease  To find better procedures for diagnosis of a disease Dr. Eman Mortada
  73. 5. Quality of Life Trials  Also called Supportive care trials  Often employed for the chronically ill patients  They explore the ways to improve the quality of life Dr. Eman Mortada
  74. Examples of clinical trials  Physicians Health Study (PHS)  Risks and benefits of aspirin and beta carotene in the prevention of cardiovascular disease and cancer  Started recruitment of US male physicians in 1982  2x2 factorial structure  Primary endpoint: total mortality  Secondary endpoint: myocardial infarction Dr. Eman Mortada
  75. ❑ Approval of relevant governing and ethical committees is essential ❑ Clinical trials are research studies involving people ❑ Constitute the last step of the research process includes preliminary laboratory research and animal testing Lecture Summary ❑ Used to find better ways to prevent, detect, and treat disease Dr. Eman Mortada
  76. Recommended readings  1. Friedman LM, Furberg CD, and DeMets DL. Fundamentals of Clinical Trials. 4th Edition. 2010. Chapter 1.  2. straightforward and useful overview of randomized controlled trial, including details of different randomization methods Dr. Eman Mortada
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  78. What did you learn today? ▪ ___________________________ ▪ ___________________________ ▪ ___________________________ ▪ ___________________________ ▪ ___________________________ ▪ ___________________________ ▪ ___________________________ ▪ ___________________________
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