CLINICAL TRIALS public health dentistry.pptx

clinical trials in detail

1. GOODMORNING 1

2. RANDOMIZED CONTROLLED TRIAL Presented by, Dr. Nitha Willy First year PG Department Of Oral Medicine And Radiology 2

3. Contents History Introduction Goal of RCT Applications of RCT Design of RCT Types of controls Classification of RCT Summary 3

4. HISTORY The first instance of random allocation of patients to experimental and control conditions is attributed to James Lind, a naval surgeon, in 1747. 4

5. Lind randomly assigned 12 sailors to 6 different treatments for scurvy . The two patients who were given lemons and oranges recovered most quickly, suggesting a beneficial effect of citrus. 5

6. The first RCT in medicine is credited to Sir A. Bradford Hill , an epidemiologist for England's Medical Research Council. The trial, published in the British Medical Journal in 1948 , tested whether streptomycin is effective in treating tuberculosis . 6

7. Randomized controlled trial is an epidemiological experiment to evaluate new preventive or therapeutic regimens. Subjects are randomly allocated to treatment and control groups. INTRODUCTION 7

8. Gold standard among epidemiological studies in terms of validity. Allow the investigators high degree of control over the study subjects and conditions Randomized controlled trial with double blinding is of very high validity . 8

9. GOAL OF RCT 9

10. APPLICATIONS OF RCT 10

11. DESIGN OF RANDOMIZED CONTROLLED TRIALS Drawing up a protocol Selecting reference and experimental populations Randomization Manipulation or intervention Follow –up Assessment of outcome 11

12. Drawing Up Protocol   It is conducted under a strict protocol. Prevents bias and reduces source of errors in the study. Preliminary or pilot test runs of protocol can be held so to see whether it contains any flaw. Final version of protocol should be agreed upon by all concerned before the trial begins. 12

13. The protocol specifies the aims and objectives of the study Criteria for the selection of study and control groups Size of sample The procedures for allocation of subjects into the study and control groups Treatments to be applied Standardization of working procedures and schedules Up to the stage of evaluation of outcome of the study 13

14. Selecting Reference And Study Population Reference /Target Population:  It is the population to which findings of the trial ,if found successful , are applicable .  e.g. whole population, population of school children, population of a city, industrial workers or social groups 14

15. II. Experimental /Study Population:  Derived from reference population .  Ideally, it should be chosen randomly from reference population so that it is representation of reference population. 15

16. Selection of study subjects  Inclusion & exclusion criteria : for determining who will or will not be included in the study must be spelled out with great precision, and in writing. To ensure the replicability by others. 16

17. Randomization a statistical procedure by which the participants are allocated to “Study” and “Control” groups. 17

18. RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL  is considered as research design par excellence and “GOLD STANDARD” amongst research designs with which results of other studies are often compared. 18

19. Theory of Randomization Randomization ensures each participant a known chance of being assigned to any of the groups. Why randomization…? • The intervention exhibits a real effect. • Generally minimizes the selection bias. • More or less confounders get equally distributed between the groups. 19

20. Manipulation: To manipulate the study group by withdrawal or reduction of the suspected causal factor (e.g. This may be a drug, vaccine etc.) As laid down in the protocol 20

21. Masking the intervention: Experimental and control interventions are made to look alike The taste, texture, color, flavor of the drug should be similar. In surgical trials that’s why sham surgery is performed in the control group 21

22. Follow up Examination of the experimental and control group subjects at defined intervals of time. Thus the follow up may be short or may require many years depending upon the study undertaken. 22

23. Assessment The final step is outcome of trials in terms of rates of outcome of interest in the intervention group, is compared with that of the control group. beneficial effects and adverse effects have to be compared. The comparison can be in terms of differences in mean, differences in proportions, relative risk, absolute risk reduction, number needed to treat, percentage change, median ratio or hazard ratio (HR). 23

24. Even if some participants have crossed over from intervention group to control group or from control group to intervention group, analysis should be done as randomized. This is known as intention to treat analysis . Appropriate statistical test of significance should be done to find out if the point estimate has occurred by chance or no. 24

25. Absolute Risk Reduction  (ARR) ARR = incidence rate of (bad) event or outcome in control group – incidence rate of the same event or outcome in the intervention group. 25

26. Number Needed to Treat (NNT) It indicates the number of patients who are to be treated in order to prevent one bad event or outcome. It is the inverse of Absolute Risk Reduction (ARR). The NNT is an important measure in clinical economics. If a clinical endpoint is devastating enough, drugs with a high NNT may still be indicated in particular situations. NNT =1/ARR 26

27. Median Ratio Clinical trials commonly record the length of time from study entry to a disease endpoint for the intervention group and the control group. These data are commonly depicted with a Kaplan – Meier curve (survival analysis) from which the median time (time at which 50% of cases are resolved) and the mean time (average resolution time) can be derived. The groups are compared by time to event analysis. 27

28. Median ratio  is calculated by dividing control group median time by intervention group median time. The mean time (the average resolution time) between the two groups can be compared based on the area under the Kaplan – Meier curve. 28

29. Hazard ratio (HR) Hazard ratio is a type of relative risk. The Cox proportional hazard model (by Sir David Cox) estimates the hazard ratio and its confidence interval. The hazard ratio is an estimation of the ratio of the hazard rate in the intervention versus the control group. The hazard ratio is equivalent to the odds that an individual in the group with the higher hazard reaches the end point first. 29

30. Controls are comparison groups. They are needed to defend the results of a trial(to counter balance). Is essential for evaluation of benefits of a particular agent or product. The choice of controls depends on many aspects. 30

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32. BENCH MARK CONTROL: A control which is commercially available product which has set a benchmark of its own. Find out whether the tested product is superior than a set benchmark Ex: Listerine mouth wash 32

33. POSITIVE CONTROL: It is an agent considered to be best and available agent NEGATIVE CONTROL: The type of control commonly employed to determine whether an agent provides activity over and above its vehicle. 33

34. PLACEBO CONTROL: Placebo control consists of a placebo(inert substance) Very similar to the test drug Counteract the placebo effect. 34

35. TYPES OF RANDOMIZED CONTROLLED TRIALS 35

36. TRIALS BASED ON RANDOMIZATION: Randomized controlled trials : where randomization is used for allocation of products and / or subjects. Non-randomized or “non-experiment” or quasi-experiment : those departing from strict randomization for practical purposes in such a manner that non-randomization does not seriously affect the theoretical basis of conclusions e.g. natural experiments, water fluoridation studies 36

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38. Superiority Design: Show that new treatment is better than the control or standard (maybe a placebo) Non-inferiority: Show that the new treatment Is not worse that the standard by more than some margin Would have beaten placebo if a placebo arm had been included (regulatory) 38

39. Equivalent design Trial with active (positive) controls The question is whether new (easier or cheaper) treatment is as good as the current treatment Must specify margin of “equivalence” or non- inferiority Can't statistically prove equivalency -- only show that difference is less than something with specified probability 39

40. BASED ON BLINDING Open trials Blinded trial . 40 Blinding is the concealment of group assignment to either the treatment or control Hiding the knowledge of particular treatment

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42. WHY DO WE DO BLINDING ? To reduce the following biases Information bias Investigator/Assessor bias Patient bias Statistician bias Interpretation bias 42

43. Tests for blinding: Asking participants to which group they belong If they do not know, they are asked to make a guess. 43

44. Types of RCT Clinical trials Preventive trials Risk factor trials Cessation experiments Trial of etiological agents Evaluation of health services 44

45. Preventive Trials: These trials are purported to prevent or eliminate disease on an experimental basis. The most frequently occurring type of preventive trials is vaccines and chemo- prophylactic drugs. 45

46. Risk factor trials: In this the investigator intervenes to interrupt the usual sequence in the development of disease for those individuals who have "risk factor" for developing the disease. Ex: Risk factors of coronary heart disease are elevated blood cholesterol, smoking, hypertension. Risk factor trials can be "Single factor" or "Multi factor" trials. 46

47. Cessation experiments: In this study, an attempt is made to evaluate the termination of a habit (or removal of suspected agent) which is considered to be casually related to a disease. If such action is followed by a significant reduction in the disease, the hypothesis of cause is greatly strengthened. Ex: cigarette smoking and lung cancer. 47

48. Trial of etiological agents : One of the aims of experimental epidemiology is to confirm or refute an etiological hypothesis. 48

49. Evaluation Of Health Services To assess the effectiveness and efficiency. Since resources are limited and priorities must be set for the implementation of a large number of activities. Eg : TB regimen in India – which demonstrated that “domiciliary treatment” of pulmonary tuberculosis was as effective as the more costlier “hospital treatment”. 49

50. COMMUNITY INTERVENTION TRIALS (CITs) CITs are usually carried out in hospitals or clinics, and are usually directed at a patient group with specific health conditions. In these types of studies, the major difference from the RCT is that the randomization is done on communities rather than individuals. 50

51. Typical examples of such trials include: Evaluating the need for a service , i.e. Community diagnosis Evaluating the design of a health service Evaluating the performance or efficiency of the process of delivery of the services Evaluating the effectiveness and impact of the programme or procedure Relating the outcome to the input and constraints of the programme including cost-benefit analysis. 51

52. OTHER TRIAL DESIGNS: Efficacy and Effectiveness trials: An efficacy trial answers the question: "Does this intervention work under optimal conditions?" An effectiveness trial answers the question: "Does this intervention work under usual conditions?” 52

53. Explanatory trials: Efficacy trials are sometimes called explanatory trials Main purpose is to provide biological information ( about the way the drug acts and the way body reacts to them) Pragmatic trials: Effectiveness trials are also known as pragmatic trials. Which aims to test procedures under the condition in which they would be applied in practice. 53

54. Equivalence trial : A randomized clinical trial in which two distinct agents are compared head-to-head against each other, and sometimes, but not always, against an inert agent (a placebo) as well. Non – inferiority trial: A clinical trial that shows that a new treatment is as good as the standard treatment 54

55. QUALITY ASSESSMENT OF RCT Various approaches used: Checklist approach Quality scoring system approach 55

56. SUMMARY • “Gold standard” of research designs • Individual patients are randomly allocated to receive the experimental treatment (intervention group) or the standard treatment (control group) • Maximizes the potential for attribution • Good internal validity • May lack generalisability due to highly selected participants • Can be costly to set up and conduct, ethical issues 56

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59. “BETTER HEALTH OUTCOMES FOR ALL WHEN PATIENTS PARTNER WITH RESEARCHERS” 59

60. CLINICAL TRIALS Presented by, Dr. Nitha Willy First year PG Department Of Oral Medicine And Radiology 60

61. CONTENTS Introduction Types of clinical trials Phases of clinical trials Importance of clinical trials Types of randomized clinical trial designs 61

62. Clinical trials are scientific investigations that examine and evaluate safety and efficacy of different therapies in human subjects. Clinical Trials 62

63. 63 The World Health Organization (WHO) definition for a clinical trial is: “ any research study that prospectively assigns human participants or groups of humans to one or more health related interventions to evaluate the effects on health outcome.”

64. 64 Usually medical or clinical studies Constitute the last step of the research process Investigations are carefully conducted following a pre- determined research protocol Human subjects volunteer to participate Last for about 5-7 years Approval of relevant governing and ethical committees is essential

65. Types Of Clinical Trials 65

66. Prophylactic Trials/Prevention Trials : look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning e.g immunization 66

67. 67 Therapeutic/ Treatment Trials : test new treatment, new combinations of drugs or new approaches to surgery or radiation therapy

68. 68 Risk factor trials : eg . proving the etiology of a disease by inducing it with the agent in animals or withdrawing the agent( e.g.smoking ) through cessation.

69. Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. Diagnostic trials usually include people who gave signs or symptoms of the disease or condition being studied. 69

70. 70 Screening (Early Detection) Trials : test the best way to detect certain disease or health conditions.

71. 71 Quality of Life Trials( or Supportive Care Trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness

72. Clinical trials help to find out if: treatments are safe treatments have any side effects new treatments are better than the standard available treatments Clinical trials show us what works (and what doesn’t) in medicine and health care. They are the best way to learn what works best in treating diseases like cancer . 72

73. Clinical trials are designed to answer 2 important questions: Does the new treatment work in humans? Is the new treatment safe?  73

74. PHASES OF CLINICAL TRIALS Clinical trials used in drug development are sometimes described by phase. These phases are defined by the Food and Drug Administration (FDA). 74

75. Clinical trials involving new drugs are commonly classified into four phases(I,II,III,IV). 75

76. PHASE 0: Officially named as an exploratory investigational new drug study and also known as a “ microdosing ” study . 76

77. Phase 0 studies do not re- place formal Phase I drug safety testing and do not offer any possibility of patient benefit. Intended to speed drug development as part of the FDA Critical Path Initiative by quickly weeding out ineffective drugs early in the development process . (No therapeutic or diagnostic intent.) 77

78. PHASE I: Initial studies to determine the metabolism and pharmacologic actions of the agent in humans the side effects associated with increasing doses to gain early evidence of effectiveness test a new drug or treatment in a small group of healthy people ( 20 -50) 78 20 -50

79. 79 PHASE I/II (Device – Pilot): Some trials combine Phase I and Phase II , and test both efficacy and toxicity (safety, dosage levels, and response to new treatment).

80. PHASE II: Controlled clinical studies to evaluate the effectiveness of the agent for a particular indication or indications in patients with the disease or condition under study to determine the common short- term side effects and risks . The study drug or treatment is given to A selected group of patients (100 – 300). 80 100 – 300

81. PHASE II/III : Some trials combine Phase II and Phase III, and test for both efficacy and overall benefit-risk relationship. The new treatment is compared to a standard treatment regimen. 81

82. PHASE III (DEVICE – PIVOTAL) to evaluate the overall benefit-risk relationship and provide an adequate basis for physician labeling . Compares new agent/test article against commonly used agents/test articles. The study drug or treatment is given to a large group of patients (1000 – 3000) 82 1000 – 3000

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84. PHASE IV: Post-marketing studies designed to monitor the effectiveness of the approved intervention in the general population to collect information about any adverse effects associated with widespread use. 84 1000+

85. IMPORTANCE OF CLINICAL TRIALS Doctors and other healthcare professionals and patients need evidence from clinical trials to know which treatments work best. Without this evidence, there's a risk that people could be given treatments that have no advantage, waste resources, and might even be harmful. 85

86. Ethical issues in Clinical trials Ethical considerations are very important in the design of clinical trials. No patient should be denied appropriate treatment as a result of participation in an experiment. The intervention being tested must be acceptable in the light of current knowledge. 86

87. Types Of Randomized Clinical Trial Designs 87

88. Concurrent Parallel Study Design Classical clinical trial approach Two study groups 88

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90. Cross-over Type of Study Design  Will patient do better on drug A or drug B?  Removes “patient effect” reducing variability and increasing precision of estimation  Needs to determine appropriate length of washout period.  “Period” effects : Progression of disease, Dropout 90

91. Run in design Assign all eligible patients a placebo to be taken for a “brief” period of time. Patients who are “judged” compliant are enrolled into the study. This is often referred to as the “Placebo Run-In” period. 91

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93. Factorial Design  Evaluates  multiple factors simultaneously  Major concern: interaction of interventions  Patients must be willing and able to take any of the treatment combinations may be hard to determine 93

94. Cluster Design  Groups or clusters randomly assigned, not individuals. E.g. : villages, classrooms , platoons Examples: Community trials on fluoridation of water Smoking cessation intervention trial 94

95. Sequential Design: A large statistical literature for classical sequential designs Developed for industrial setting Modified for clinical trials 95

96. SUMMARY Trials are the primary way that researchers determine if a new form of treatment or prevention, such as a new drug, diet, or medical device, is safe and effective in people. 96

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99. Presented by, Dr. Nitha Willy First year PG Department Of Oral Medicine And Radiology NON- RANDOMIZED CONTROLLED TRIAL 99

100. Contents Definition Goal Source of bias When is it appropriate to use a non- randomized trial design? Reasons for the use of nonrandomized studies Disadvantages of the nonrandomized clinical trial Summary 100

101. Definition A study where participants have been assigned to the treatment, procedure, or intervention alternatives by a method that is not random. The investigator defines and manages the alternatives. Participants may choose which group they want to be in, or they may be assigned to the groups by researchers. 101

102. The ultimate goal  of the evaluation of healthcare interventions is to produce a valid estimate of effectiveness, in terms of both internal and external validity. 102

103. 103 Internal validity - the extent to which the results of a study can be reliably attributed to the intervention under evaluation External validity - the extent to which a study’s results can be generalized beyond the given study context.

104. SOURCES OF BIAS IN NRCT Selection Bias : will be introduced when participants chosen for one intervention have different characteristics from those allocated to the alternative intervention (or not treated). 104

105. 105 Systematic Bias : When faced with a patient who may be eligible to receive a given intervention, the decision to treat will be influenced by some factor that in turn is related to the treatment outcome. This introduces systematic bias leading to either over- or underestimates of treatment effects, depending on the treatment decision mechanism.

106. Attrition bias : will occur if there are dropouts Detection bias : if the assessment of outcomes is not standardized and blinded Performance bias : if there are errors and inconsistencies in the allocation, application and recording of interventions. 106

107. When is it appropriate to use a non- randomized trial design? The first is when an RCT would be ideal but practical considerations make a high-quality RCT infeasible. When the act of random allocation may reduce the effectiveness of the intervention When there are legal or political obstacles to random allocation 107

108. REASONS FOR THE USE OF NONRANDOMIZED STUDIES The only ethical way to conduct an investigation . The only ones possible in certain investigations that require the implementation of treatments that may affect people's lives. Usually less expensive. 108

109. reduce the threats to external validity that limit the value of RCTs results. Does not require the extensive planning and control often involve more providers and settings, making the results more generalisable the lack of randomization often facilitates recruitment of a larger proportion of eligible patients 109

110. DISADVANTAGES OF THE NONRANDOMIZED CLINICAL TRIAL The potential for bias from confounding. The direction of this bias is unpredictable from study to study. The results of these trials must be evaluated in a larger context, and internal and external validity may be best assessed through the replication of results in a variety of clinical settings 110

111. SUMMARY Uses natural groups or assigns participants to groups using a non-random procedure. While nonrandomized studies are cheaper, more easily carried out, and can be done retrospectively, inferences from them are generally more suspect than are those from randomized studies . 111

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