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RANDOMIZED
CONTROLLED TRIALS
PRESENTED BY:
DR. NABEELA BASHA
CONTENTS
 INTRODUCTION
 STEPS IN CONDUCTING RCT
 TYPES OF RCT
 ETHICAL CONSIDERATIONS
 CONCLUSIONS
 REFERENCES
 PRE...
Upon People Science
INTRODUCTION
 Epidemiology is derived from the word “epidemic”
• Epidemiology is the study of the distribution and
determinants of health-related states and events in
specified populati...
CLASSIFICATION
1. Observational studies
a. Descriptive studies
b. Analytical studies
(i) Ecological
(ii) Cross-sectional
(...
EXPERIMENTAL STUDIES
• In the 1920s, “Experimental epidemiology” meant the study of
epidemics among colonies of experiment...
• Thus experimental studies involve some action, intervention or
manipulation such as deliberate application or withdrawal...
AIMS
• To provide “scientific proof” of etiological or risk factors
which may permit the modification or control of those
...
ADVANTAGES OF EXPERIMENTAL
RESEARCH DESIGNS
• Researcher ‘control’ over the intervention and over which
subjects receive a...
DISADVANTAGES OF EXPERIMENTAL
RESEARCH DESIGNS
• Problems in dealing with multiple causation; isolating
individual factors...
RANDOMIZED CONTROLLED TRIALS
• It is mainly in the last 35 to 40 years, determined efforts have
been made to use scientifi...
What is a Randomized Controlled Trial?
• RCT is widely regarded as gold standard for evaluating health
care technologies a...
Definition: (Stedman’s medical dictionary)
RCTs are quantitative, comparative, controlled experiments in
which investigato...
What is this method of carrying out scientific research,
and why is it so highly valued?
• A Randomized Controlled Trial i...
Progression of Study Design:
Clinical Research
The role of oxygen in retrolental fibroplasia RLF
among premature infants.
...
 I RCT: Gallinger Muncipal Hospital, Washington, DC
 II Collaborative Multi-centred Trial
 Confirmed the role of oxygen...
DESIGN OF RANDOMIZED CONTROLLED
TRIAL
Select suitable population
(reference or target)
Select suitable sample
(experimenta...
1. DRAWING UP A PROTOCOL
• Strict protocol
• Aims & objectives
• Questions to be answered
• Criteria of selection: Study &...
Preliminary test runs:
• Sometimes, before a protocol is completed, preliminary(pilot)
studies have to be made to find out...
2. SELECTING REFERENCE AND
EXPERIMENTAL POPULATION
a) Reference or target population:
 It is the population to which the ...
b) Experimental /Study Population:
• It is derived from the reference population.
• Ideally should be randomly chosen from...
The participants should fulfill the following criteria:
• They must give informed consent.
• Should be representative of t...
3. RANDOMIZATION
• “Heart" of a control trial.
• It is the statistical procedure by which the participants are
randomly al...
• Randomization eliminates “selection bias”
• Randomization is done only after the participant has entered
the study and i...
TYPES OF RANDOMIZATION
1. RANDOM ASSIGNMENT:
 Flip a coin
o “Heads”—Tx A
o “Tails”—Tx B
 Roll a six-sided dice
o Even nu...
2. BLOCK RANDOMIZATION:
• Subjects are divided into ‘blocks’ and randomization is carried
out in each blocks.
• Ex; for tw...
3. STRATIFIED RANDOMIZATION:
• It may be important to ensure that the treatment and control
groups are balanced on importa...
• A separate simple or blocked randomization schedule is
developed for each stratum.
4. MANIPULATION
• This refers to the deliberate application or withdrawal of the
suspected causal factor as laid down in t...
5. FOLLOW-UP
• Examination of groups at defined intervals of time under the same
conditions, in a standard manner, with eq...
6. ASSESSMENT
The final step in the outcome of the trial is in terms of:
a) Positive results: that is, benefits of the exp...
• Errors in assessment can lead to “Bias”.
• Bias can arise from three sources:
Subject variation
Observer bias
Evaluation...
Blinding :
• Blinding can be done in three ways –
(a) SINGLE BLIND TRIAL : The trial is so planned that the
participant is...
(C) TRIPLE BLIND TRIAL : This goes one step further. The
participant, the investigator and the person analyzing the data a...
TYPES OF RANDOMIZED
CONTROLLED TRIALS
BASED ON RANDOMIZATION:
1. Randomized controlled trials: where randomization is used...
BASED ON STUDY DESIGNS:
1. Concurrent parallel study design:
• In this design, comparisons are made between two randomly
a...
2. Factorial Design:
• Factorial design study may be more efficient than a parallel
design if there is an interest in stud...
3. Cross-over type of study designs:
• With this type of study design, each patient serves as his own
control.
• As before...
• The two groups are observed over time. Then the patients in
each group are taken off their medication or placebo to allo...
Split mouth design:
• Dental arches, quadrants, sextants, or individual teeth within
patients are randomized for treatment...
• It is often seen in trials that evaluate dental filling materials;
subjects would require two similar cavities on the op...
BASED ON USES:
1. Clinical trials
2. Preventive trials
3. Risk factor trials
4. Cessation experiment
5. Trial of etiologic...
1. CLINICAL TRIALS
WHO definition of a Clinical Trial:
Any research study that prospectively assigns human participants or...
EARLY TRIALS
• 1747 - James Lind study on scurvy patients
• 1796 – Edward Jenner experiment with cow pox
• 1881-1900 – Fin...
• 1945 – Water fluoridation study
• 1953 – first Randomized Controlled Trial on tuberculosis
patients
PHASES OF CLINICAL TRIAL
Traditionally, clinical trials of new therapies or devices pass
through the following phases:
1. ...
PHASE 0 ( Human microdosing studies):
• Phase 0 is a recent designation for exploratory, first-in-human
trials, also known...
PHASE I (dose ranging / dose escalating/ safety trial)
• Phase I trials are the first-stage of testing in human subjects.
...
PHASE II (Safety and intervention tolerance trial):
• Phase II trials are performed on larger groups (100-300) and
are des...
PHASE III
• Phase III studies are randomized controlled trials on large
patient groups (300–3,000 or more) and are aimed a...
PHASE IV ( Post-marketing or surveillance studies):
• Phase IV trials involve the post-launch safety surveillance and
ongo...
MULTICENTER TRIALS
• A Multicenter research trial is a clinical trial conducted at
more than one medical centre or clinic....
2. PREVENTIVE TRIALS
• To prevent or eliminate disease on an experimental basis.
• The most commonly occurring trials are ...
3. RISK FACTOR TRIALS
• It is a preventive trial of risk factors in which the investigator
intervenes to interrupt the usu...
4. CESSATION EXPERIMENTS
• An attempt is made to evaluate the termination of a habit,
which is considered to be causally r...
5. TRIAL OF ETIOLOGICAL AGENTS
• To confirm or refute an etiological hypothesis.
• Since most diseases are fatal, disablin...
6. EVALUATION OF HEALTH SERVICES
• To assess the effectiveness and efficiency.
• Since resources are limited and prioritie...
7. COMMUNITY INTERVENTION
TRIALS (CITs)
• CITs are usually carried out in hospitals or clinics, and are
usually directed a...
• Communities selected for entry to the study have to be similar
as much as is possible, especially since only a small num...
Typical examples of such trials include:
1. Evaluating the need for a service, i.e. Community
diagnosis(assessment or eval...
4. Evaluating the effectiveness and impact of the programme or
procedure (effectiveness or impact evaluation)
5. Relating ...
OTHER TRIAL DESIGNS:
 Efficacy and Effectiveness trials:
• An efficacy trial answers the question: "Does this interventio...
 Explanatory and Pragmatic trials:
• Explanatory trials: main purpose is to provide biological
information ( about the wa...
 Equivalency and Non – inferiority trials:
• Equivalence trial: A randomized clinical trial in which two
distinct agents ...
QUALITY ASSESSMENT OF RCT
• Various approaches used:
 Checklist approach
 Quality scoring system approach
• Quality scor...
CHECKLIST APPROACH
QUALITY SCORE APPROACH
Jadad AR, et al. Assessing the quality of reports on randomized clinical trials: Is blinding necess...
INITIATIVE TO IMPROVE QUALITY OF
REPORTING TRIALS
• The Consolidated Standards of Reporting Trials (CONSORT)
has become th...
• The main product of CONSORT is the CONSORT Statement,
which is an evidence-based, minimum set of recommendations
for rep...
• The CONSORT Statement comprises a 25-item checklist and a
flow diagram. The checklist items focus on reporting how the
t...
CONSORT: checklist and flow diagram
ETHICAL ISSUES IN CLINICAL
TRIALS
Clinical trials should follow 3 principles:
• Beneficence: which require that good shoul...
CLINICAL EQUIPOISE (Freedman 1987):
There must be uncertainty as to the usefulness of the intervention
among those knowled...
INFORMED CONSENT:
• Informed consent of all study participants is essential.
The nature of informed consent may differ in ...
INSTITUTIONAL REVIEW
BOARD/INDEPENDENT ETHICS COMMITTEE
• Safeguards the rights, safety, and well-being of all trial
subje...
• Documents which should be submitted to a IRB/IEC:
 Trial protocol with amendments
 Written informed consent form
 Sub...
CONCLUSIONS
• “Gold standard” of research designs
• Individual patients are randomly allocated to receive the
experimental...
REFERENCES
• Park’s Textbook of Preventive And Social Medicine, K.
PARK . 23rd EDN
• Oxford Textbook of Public Health Vol ...
• http://annals.org/article.aspx?articleid=745807
• http://www.consort-statement.org/consort-statement/flow-
diagram
• htt...
PREVIOUS YEAR QUESTIONS
• How will you assess the quality of a randomized controlled
trial. (20 marks) (RGUHS SEPTEMBER-20...
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Randomized Controlled Trials

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Randomized Controlled Trials

  1. 1. RANDOMIZED CONTROLLED TRIALS PRESENTED BY: DR. NABEELA BASHA
  2. 2. CONTENTS  INTRODUCTION  STEPS IN CONDUCTING RCT  TYPES OF RCT  ETHICAL CONSIDERATIONS  CONCLUSIONS  REFERENCES  PREVIOUS YEAR QUESTIONS
  3. 3. Upon People Science INTRODUCTION  Epidemiology is derived from the word “epidemic”
  4. 4. • Epidemiology is the study of the distribution and determinants of health-related states and events in specified populations, and the application of this study to the control of health problems. ( John M. Last in 1988 )
  5. 5. CLASSIFICATION 1. Observational studies a. Descriptive studies b. Analytical studies (i) Ecological (ii) Cross-sectional (iii) Case-control (iv) Cohort 2. Experimental/Intervention studies a. Randomized controlled trials b. Field trials c. Community trials
  6. 6. EXPERIMENTAL STUDIES • In the 1920s, “Experimental epidemiology” meant the study of epidemics among colonies of experimental animals such as rats and mice. • In modern usage, experimental epidemiology is often equated with “Randomized controlled trials”. • Experimental or intervention studies are similar in approach to cohort studies expecting that the conditions in which study is carried out are under the direct control of the investigator.
  7. 7. • Thus experimental studies involve some action, intervention or manipulation such as deliberate application or withdrawal of the suspected cause or changing one variable in the causative chain in the experimental group while making no change in the control group, and observing and comparing the outcome of the experiment in both the groups. • This contrasts sharply with observational studies (descriptive, case control, cohort studies), where the epidemiologist takes no action but only observes the natural course of events or outcome.
  8. 8. AIMS • To provide “scientific proof” of etiological or risk factors which may permit the modification or control of those diseases. • To provide a method of measuring the effectiveness and efficiency of health services for the prevention, control and treatment of diseases and improve the health of the community.
  9. 9. ADVANTAGES OF EXPERIMENTAL RESEARCH DESIGNS • Researcher ‘control’ over the intervention and over which subjects receive any intervention. • Results are ensured. • Reliable and well-respected research design • Individual factors can be identified.
  10. 10. DISADVANTAGES OF EXPERIMENTAL RESEARCH DESIGNS • Problems in dealing with multiple causation; isolating individual factors may over-simplify complex issues. • Ethical issues. • Researcher bias and subjectivity in research design, methods and analysis. • Hawthorne effect upon groups being researched.
  11. 11. RANDOMIZED CONTROLLED TRIALS • It is mainly in the last 35 to 40 years, determined efforts have been made to use scientific techniques to evaluate methods of treatment and prevention. • An important advance in this field has been the development of an assessment method, known as Randomized Controlled Trial(RCT). • It is really an epidemiologic experiment.
  12. 12. What is a Randomized Controlled Trial? • RCT is widely regarded as gold standard for evaluating health care technologies as it allows us to be confident that a difference in outcome can be directly attributed to a difference in the treatments & not due to some other factor. • RCTs: Gold Standard
  13. 13. Definition: (Stedman’s medical dictionary) RCTs are quantitative, comparative, controlled experiments in which investigators study two or more interventions in a series of individuals who receive them in random order. The RCT is one of the simplest and most powerful tools in clinical research.
  14. 14. What is this method of carrying out scientific research, and why is it so highly valued? • A Randomized Controlled Trial is an experiment or study conducted in such a way that as many sources of bias as possible are removed from the process. • Basically, scientific errors of the past have taught us where we can go wrong, drawing false conclusions from our research. RCTs are designed to eliminate these major errors. • For new programmes or new therapies, the RCT is the No.1 method for evaluation.
  15. 15. Progression of Study Design: Clinical Research The role of oxygen in retrolental fibroplasia RLF among premature infants.  First Case - Feb. 14, 1941, Dr. Clifford, Boston  Case Series - 1941 (Silverman 1980)  Ca-Co Study (53 RLF Children, 298 Normal Children)  Association was observed. Still, it was postulated that poor health of infants necessitated longer hours of oxygen. Poor health and no oxygen use caused RLF.
  16. 16.  I RCT: Gallinger Muncipal Hospital, Washington, DC  II Collaborative Multi-centred Trial  Confirmed the role of oxygen in the etiology of Retrolental Fibroplasia
  17. 17. DESIGN OF RANDOMIZED CONTROLLED TRIAL Select suitable population (reference or target) Select suitable sample (experimental or study) Make necessary exclusions Those not eligible Those who do not wish to give consent Randomize Experimental Control Manipulation & Follow-up Assessment
  18. 18. 1. DRAWING UP A PROTOCOL • Strict protocol • Aims & objectives • Questions to be answered • Criteria of selection: Study & control groups • Intervention to be applied • Standardization of working procedures • Schedules Strictly followed through the study
  19. 19. Preliminary test runs: • Sometimes, before a protocol is completed, preliminary(pilot) studies have to be made to find out the feasibility or operational efficiency of certain procedures or unknown effects or the acceptability of certain policies. • Sometimes it is useful to have a short test run of the protocol to see whether it contains flaws. • It is important that the final version of the protocol should be agreed upon by all concerned before the trial begins.
  20. 20. 2. SELECTING REFERENCE AND EXPERIMENTAL POPULATION a) Reference or target population:  It is the population to which the findings of the trial if found successful, are expected to be applicable.  It may be as broad as mankind or it may be geographically limited or limited to persons in specific age, gender, occupational or social groups.  E.g.: population of the whole city, school children, industrial workers etc
  21. 21. b) Experimental /Study Population: • It is derived from the reference population. • Ideally should be randomly chosen from the reference population. • It should have the same characteristics as target population. • It is also important to choose a stable population whose co- operation is assured to avoid loses to follow-up.
  22. 22. The participants should fulfill the following criteria: • They must give informed consent. • Should be representative of the population. • Should be qualified or eligible for the trial. E.g.: new drug : treatment of anemia.
  23. 23. 3. RANDOMIZATION • “Heart" of a control trial. • It is the statistical procedure by which the participants are randomly allocated into groups usually called the "study" and "control" groups. • It is an attempt to eliminate "bias" and allow for comparability.
  24. 24. • Randomization eliminates “selection bias” • Randomization is done only after the participant has entered the study and it can be done by using table of random numbers. • In other words, by random allocation, every individual gets an equal chance of being allocated into either group. • Finally, randomization guarantees that statistical tests of significance will be valid.
  25. 25. TYPES OF RANDOMIZATION 1. RANDOM ASSIGNMENT:  Flip a coin o “Heads”—Tx A o “Tails”—Tx B  Roll a six-sided dice o Even number—Tx A o Odd number—Tx B
  26. 26. 2. BLOCK RANDOMIZATION: • Subjects are divided into ‘blocks’ and randomization is carried out in each blocks. • Ex; for two treatments and a block size of four, two of every four consecutive patients would receive the experimental therapy and the other two would receive control therapy. EECC,ECEC, ECCE, CCEE, CECE,……..
  27. 27. 3. STRATIFIED RANDOMIZATION: • It may be important to ensure that the treatment and control groups are balanced on important prognostic factors that can influence the study outcome (e.g., gender, ethnicity, age, socioeconomic status). • Before doing the trial, the investigator decides which strata are important and how many stratification variables can be considered given the proposed sample size.
  28. 28. • A separate simple or blocked randomization schedule is developed for each stratum.
  29. 29. 4. MANIPULATION • This refers to the deliberate application or withdrawal of the suspected causal factor as laid down in the protocol. Eg : drug, vaccine, dietary component, habit • Manipulation creates an independent variable (drug, vaccine, new procedure) whose effect is then determined by the measurement of the final outcome, which constitutes the dependant variable (incidence of disease, survival time, recovery period).
  30. 30. 5. FOLLOW-UP • Examination of groups at defined intervals of time under the same conditions, in a standard manner, with equal intensity, same circumstances, same time frame. • Follow-up can vary from a short period to many years. • Over the years, there may be loss of subjects from either group due to a number of reasons. This is called as “attrition”.  Death  Migration  Loss of interest
  31. 31. 6. ASSESSMENT The final step in the outcome of the trial is in terms of: a) Positive results: that is, benefits of the experimental measure such as reduced incidence or severity of the disease, cost to the health service or other appropriate outcome in the study and control groups. b) Negative results: that is, adverse effects, severity and frequency of side effects and complications, if any including death.
  32. 32. • Errors in assessment can lead to “Bias”. • Bias can arise from three sources: Subject variation Observer bias Evaluation Bias • Randomization cannot guard against these sort of bias. • To avoid the above situations, “Blinding” is done.
  33. 33. Blinding : • Blinding can be done in three ways – (a) SINGLE BLIND TRIAL : The trial is so planned that the participant is not aware whether he belongs to the study group or control group (B) DOUBLE BLIND TRIAL : The trial is so planned that neither the doctor nor the participant is aware of the group allocation and the treatment received
  34. 34. (C) TRIPLE BLIND TRIAL : This goes one step further. The participant, the investigator and the person analyzing the data are all "blind". Ideally, of course, triple blinding should be used; but double blinding is the most frequently used method when a blind trial is conducted.
  35. 35. TYPES OF RANDOMIZED CONTROLLED TRIALS BASED ON RANDOMIZATION: 1. Randomized controlled trials: where randomization is used for allocation of products and / or subjects. 2. 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. 36. BASED ON STUDY DESIGNS: 1. Concurrent parallel study design: • In this design, comparisons are made between two randomly assigned groups, one group exposed to specific treatment, and the other group not exposed. • Patients remain in the study group or the control group for the duration of the investigation.
  37. 37. 2. Factorial Design: • Factorial design study may be more efficient than a parallel design if there is an interest in studying more than one intervention at a time. • In addition to efficiency, an advantage to this design is that one might derive suggestions of differential effect of treatment in the presence or absence of the other treatment.
  38. 38. 3. Cross-over type of study designs: • With this type of study design, each patient serves as his own control. • As before, the patients are randomly assigned to a study group and control group. The study group receives the treatment under consideration. The control group receives some alternate form of active treatment or placebo.
  39. 39. • The two groups are observed over time. Then the patients in each group are taken off their medication or placebo to allow for the elimination of the medication from the body and for the possibility of any "carry over" effect. • After this period of medication (the length of this interval is determined by the pharmacologic properties of the drug being tested), the two groups are switched. Those who received the treatment under study are changed to the control group therapy or placebo, and vice versa.
  40. 40. Split mouth design: • Dental arches, quadrants, sextants, or individual teeth within patients are randomized for treatment. • Not applicable for systemic therapies, only to evaluate site- specific therapies.
  41. 41. • It is often seen in trials that evaluate dental filling materials; subjects would require two similar cavities on the opposite side before entering the trial. • The test material can then be compared in the same environment as the control material.
  42. 42. BASED ON USES: 1. Clinical trials 2. Preventive trials 3. Risk factor trials 4. Cessation experiment 5. Trial of etiological agents 6. Evaluation of health services 7. Community intervention trials
  43. 43. 1. CLINICAL TRIALS WHO definition of a Clinical Trial: 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 outcomes. Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.
  44. 44. EARLY TRIALS • 1747 - James Lind study on scurvy patients • 1796 – Edward Jenner experiment with cow pox • 1881-1900 – Finlay and Reeds experiment to elucidate the mosquito-borne nature of yellow fever • 1915 – Goldberger’s classical study inducing pellagra by diet deficient in nicotinic acid
  45. 45. • 1945 – Water fluoridation study • 1953 – first Randomized Controlled Trial on tuberculosis patients
  46. 46. PHASES OF CLINICAL TRIAL Traditionally, clinical trials of new therapies or devices pass through the following phases: 1. Phase I clinical trial 2. Phase II clinical trial 3. Phase III clinical trial 4. Phase IV clinical trial
  47. 47. PHASE 0 ( Human microdosing studies): • Phase 0 is a recent designation for exploratory, first-in-human trials, also known as human microdosing studies. • Phase 0 trials gives no data on safety or efficacy. • Distinctive features include administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather data on agent’s Pharmacodynamics and Pharmacokinetics.
  48. 48. PHASE I (dose ranging / dose escalating/ safety trial) • Phase I trials are the first-stage of testing in human subjects. • Normally a small group of 20-100 healthy volunteers will be recruited. • These trials are conducted in an inpatient clinic, where the subject can be observed by full-time medical staff until several half-lives of the drug have passed.
  49. 49. PHASE II (Safety and intervention tolerance trial): • Phase II trials are performed on larger groups (100-300) and are designed to assess the activity of the therapy, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. • Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA is specifically designed to assess dosing requirements, whereas Phase IIB is specifically designed to study efficacy.
  50. 50. PHASE III • Phase III studies are randomized controlled trials on large patient groups (300–3,000 or more) and are aimed at being the definitive assessment of the efficacy of the new therapy. • They are the most expensive, time-consuming and difficult trials to design and run. • Phase III should be designed and conducted to a high standard, with precise quantitative results on efficacy and safety.
  51. 51. PHASE IV ( Post-marketing or surveillance studies): • Phase IV trials involve the post-launch safety surveillance and ongoing technical support of a drug. • This is designed to detect any rare or long-term adverse effects over a much larger patient population and timescale than was possible during the clinical trials. • Such adverse effects detected by Phase IV trials may result in the withdrawal or restriction of a drug.
  52. 52. MULTICENTER TRIALS • A Multicenter research trial is a clinical trial conducted at more than one medical centre or clinic. • Reasons for Multi-center Trials : 1. To recruit necessary number of subjects within a reasonable time. 2. May assure a more representative sample of the study or target population 3. Enables investigators with similar interest and skills to work together on a common problem
  53. 53. 2. PREVENTIVE TRIALS • To prevent or eliminate disease on an experimental basis. • The most commonly occurring trials are that of vaccines and chemo prophylactic drugs. Eg: Trial of whooping cough vaccines, Caries vaccine. • Preventive trials involve larger number of subjects and long span of time to obtain results, hence are associated with greater number of practical problems in their organization and execution
  54. 54. 3. RISK FACTOR TRIALS • It is a preventive 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; often this involves risk factor modification. • Can be either “single factor” or “multi factor”. • E.g.: The WHO promoted trial on primary prevention of coronary heart disease was largest preventive trial.
  55. 55. 4. CESSATION EXPERIMENTS • An attempt is made to evaluate the termination of a habit, which is considered to be causally related to a disease. • If it results in significant reduction of the disease, the hypothesis of cause is strengthened. E.g. Smoking & lung cancer
  56. 56. 5. TRIAL OF ETIOLOGICAL AGENTS • To confirm or refute an etiological hypothesis. • Since most diseases are fatal, disabling or unpleasant human experiments to confirm etiological hypothesis are rarely possible. Ex: Development of retrolental fibroplasia (RLF) in premature babies exposed to oxygen
  57. 57. 6. 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”.
  58. 58. 7. 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. • However, randomized experiments are also sometimes done in the community. • In these types of studies, the major difference from the RCT is that the randomization is done on communities rather than individuals.
  59. 59. • Communities selected for entry to the study have to be similar as much as is possible, especially since only a small number of communities will be entered. • Very often, blinding is not possible in these types of studies, and contamination and co-interventions become serious problems. • Contamination occurs when individuals from one of the receive the intervention from the other experimental group.
  60. 60. Typical examples of such trials include: 1. Evaluating the need for a service, i.e. Community diagnosis(assessment or evaluation of needs) 2. Evaluating the design of a health service (design evaluation) 3. Evaluating the performance or efficiency of the process of delivery of the services (efficiency or process evaluation)
  61. 61. 4. Evaluating the effectiveness and impact of the programme or procedure (effectiveness or impact evaluation) 5. Relating the outcome to the input and constraints of the programme (system evaluation) including cost-benefit analysis.
  62. 62. 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?" • Efficacy trials are sometimes called explanatory trials, whereas effectiveness trials are also known as pragmatic trials.
  63. 63.  Explanatory and Pragmatic trials: • Explanatory trials: main purpose is to provide biological information ( about the way the drug acts and the way body reacts to them). • Pragmatic trials: which aims to test procedures under the condition in which they would be applied in practice.
  64. 64.  Equivalency and Non – inferiority trials: • 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. If two agents work equally well, the treatment that is less expensive, better tolerated, or more easily administered, may be preferable to use. • Non – inferiority trial: A clinical trial that shows that a new treatment is as good as the standard treatment.
  65. 65. QUALITY ASSESSMENT OF RCT • Various approaches used:  Checklist approach  Quality scoring system approach • Quality scores are complicated and tend to vary depending on the instrument used –so, not encouraged
  66. 66. CHECKLIST APPROACH
  67. 67. QUALITY SCORE APPROACH Jadad AR, et al. Assessing the quality of reports on randomized clinical trials: Is blinding necessary? Controlled Clin Trials1996;17:1-12. URL: http://www.bmjpg.com/rct/chapter4.html 59
  68. 68. INITIATIVE TO IMPROVE QUALITY OF REPORTING TRIALS • The Consolidated Standards of Reporting Trials (CONSORT) has become the gold standard for reporting the results of RCTs. • CONSORT encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomized controlled trials.
  69. 69. • The main product of CONSORT is the CONSORT Statement, which is an evidence-based, minimum set of recommendations for reporting randomized trials. It offers a standard way for authors to prepare reports of trial findings, facilitating their complete and transparent reporting, and aiding their critical appraisal and interpretation.
  70. 70. • The CONSORT Statement comprises a 25-item checklist and a flow diagram. The checklist items focus on reporting how the trial was designed, analyzed, and interpreted; the flow diagram displays the progress of all participants through the trial.
  71. 71. CONSORT: checklist and flow diagram
  72. 72. ETHICAL ISSUES IN CLINICAL TRIALS Clinical trials should follow 3 principles: • Beneficence: which require that good should result, harm should be avoided, or that benefits should justify the expected risk or harm • Respect for rights: including the free choice of the subject and protection for those diminished autonomy • Justice: which require an equal distribution of burden and benefits
  73. 73. CLINICAL EQUIPOISE (Freedman 1987): There must be uncertainty as to the usefulness of the intervention among those knowledgeable about the intervention. Individual investigators or doctors may have personal beliefs about the benefits of a new intervention. Those beliefs may prevent those investigators from participating in or entering into a clinical trial.
  74. 74. INFORMED CONSENT: • Informed consent of all study participants is essential. The nature of informed consent may differ in different countries and cultures, but the concept of individual choice to join or not join a trial must be universal (Nuremberg Code 1949; World Medical Association 2000 etc).
  75. 75. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE • Safeguards the rights, safety, and well-being of all trial subjects. • Composition: • Should include: at least five members at least one member whose primary area of interest is in non-scientific area at least one member who is independent of the institution/trial site
  76. 76. • Documents which should be submitted to a IRB/IEC:  Trial protocol with amendments  Written informed consent form  Subject recruitment procedure  Written information provided to the subjects  Investigator’s brochure  Available safety information  Information about payments and compensation
  77. 77. CONCLUSIONS • “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.
  78. 78. REFERENCES • Park’s Textbook of Preventive And Social Medicine, K. PARK . 23rd EDN • Oxford Textbook of Public Health Vol 2. – The Methods of Public Health. Fifth Edn. Detels, Beaglehole, Lansang, Gulliford. • Essentials of Public Health Dentistry (Community Dentistry), Soben Peter. 5th EDN • Essentials of Dental Public Health. Daly, Batchelor, Treasure, Watt. 2nd EDN
  79. 79. • http://annals.org/article.aspx?articleid=745807 • http://www.consort-statement.org/consort-statement/flow- diagram • http://www.ebbp.org/course_outlines/randomized_controlled_t rials/ • http://medical- dictionary.thefreedictionary.com/equivalence+trial
  80. 80. PREVIOUS YEAR QUESTIONS • How will you assess the quality of a randomized controlled trial. (20 marks) (RGUHS SEPTEMBER-2005) • Clinical trials. (10 marks) (M.D.S Degree examination, 2000) • Double blind trials. (10 marks) ( M.D.S.Degree examination, 1995)

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