Clinical Trials_1_Fundamentals_Randomised Clinical Trials.pptx

Randomized Clinical trial
• Randomized clinical trials are scientific investigations that assess the safety and efficacy of
• New drugs or
• Therapies using human subjects.
• The results of these trials are highly valued as they provide crucial data for evidence-based medicine.
• Understanding the principles of clinical trials helps in assessing the validity and reliability of their results.
• This ppt provides an overview of key principles and aspects of clinical trial design, analysis, and reporting.
• The ppt also discusses factors that can introduce bias into study results, using a contemporary clinical trial as
an example.
• The reader is encouraged to refer later ppts for more in-depth discussions on specific topics related to
clinical trials.

Randomized Clinical trial?
• Clinical trials involve the evaluation of a
• new drug,
• device, or
• procedure on human volunteers.
• These trials serve various purposes, such as assessing the safety of a new drug in
• Healthy individuals or
• Evaluating treatment benefits in patients with a specific disease.
• Clinical trials can compare:
• New drug against existing drugs, placebo (dummy medication), or
• may not have a comparison arm.
• Many clinical trials are sponsored by pharmaceutical or biotechnology companies that are
developing the new drug.
• Some studies, particularly those involving older drugs in new disease areas, are funded by health-
related government agencies or charitable grants.

• In a randomized clinical trial, patients and trial personnel are kept unaware of which patients are
receiving the new drug or treatment.
• This blind random allocation helps minimize bias in the evaluation of the treatment throughout the trial.
• Clinical trials must be designed ethically, ensuring that patients are not deprived of standard treatments.
• Patients must provide voluntary consent and have a clear understanding of the trial's purpose before
participating.
• Guidelines have been established to ensure ethical conduct, patient rights, and safety in clinical trials.
• These guidelines also address the proper reporting of clinical trial results.
Cont..Randomized Clinical trial?

Types of blinding in RCT
• In randomized clinical trials, blinding refers to the process of concealing the treatment assignment from
certain individuals involved in the study. There are three common types of blinding:
1.Single-Blind: In a single-blind trial, either the participants or the investigators (those responsible for
administering the treatment and assessing outcomes) are unaware of the treatment assignment. This helps
prevent bias in the assessment of outcomes but allows participants or investigators to have knowledge of
the treatment.
2.Double-Blind: In a double-blind trial, both the participants and the investigators are unaware of the
treatment assignment. The treatment is administered in a way that keeps it concealed from everyone
involved until the end of the study. This helps minimize bias in both the administration of treatment and
the assessment of outcomes.
3.Triple-Blind: In a triple-blind trial, in addition to participants and investigators, the individuals responsible
for data analysis and interpretation are also unaware of the treatment assignment. This extends blinding to
the analysis stage and further reduces the potential for bias in the interpretation of results.
• Blinding is an important methodological technique in clinical trials to minimize bias and ensure the validity
of study results. It helps maintain the integrity of the research process and increases confidence in the
findings.

Cont.. Diff Types of blinding in RCT
Type of
Blinding
Description Purpose
Single-Blind
In a single-blind trial, either the participants or the
investigators (those responsible for administering the
treatment and assessing outcomes) are unaware of the
treatment assignment.
1. Preventing bias: Blinding the investigators helps minimize bias in the
assessment of outcomes, as their knowledge of the treatment assignment may
consciously or unconsciously influence their judgments.
2. Preserving participant blinding: Blinding the participants prevents them from
knowing the specific treatment they are receiving, reducing the potential for
biases related to expectations or beliefs about the treatment's efficacy.
Double-Blind
In a double-blind trial, both the participants and the
investigators are unaware of the treatment assignment.
The treatment is administered in a way that keeps it
concealed from everyone involved until the end of the
study.
1. Minimizing bias in treatment administration: Blinding the investigators
ensures they cannot consciously or inadvertently influence the treatment
delivery based on their knowledge of the treatment assignment.
2. Reducing bias in outcome assessment: Blinding the investigators prevents
their knowledge of the treatment from influencing the assessment of
outcomes, ensuring more objective and unbiased evaluation of treatment
effects.
Triple-Blind
In a triple-blind trial, in addition to participants and
investigators, the individuals responsible for data
analysis and interpretation are also unaware of the
treatment assignment.
1. Enhancing objectivity in data analysis: By blinding the individuals involved in
data analysis and interpretation, the potential biases related to their knowledge
of the treatment assignment are mitigated, promoting more objective and
unbiased analysis of the study results.
2. Strengthening result interpretation: Blinding data analysts reduces the
likelihood of biased interpretations based on their awareness of the treatment
groups. It helps maintain the integrity and credibility of the study findings.

Are there different types of clinical trials?
• The types of clinical trials can vary depending on the entity conducting the trial and their specific objectives.
Here are the key points regarding the different types of clinical trials:
1.Pharmaceutical Company Trials:
1. Evaluate new drugs or established drugs in disease areas for potential new licenses.
2. Focus on testing drug efficacy and safety.
2.Device Manufacturer Trials:
1. Aim to prove the safety and effectiveness of new medical devices.
3.Clinical Investigator Trials:
1. Conducted by independent investigators unrelated to pharmaceutical companies.
2. Explore various objectives, including:
1. Use of established or older drugs in new disease areas, often without commercial support.
2. Focus on research rather than profit generation.
3. Investigate optimal drug administration or withdrawal methods.
4. Determine the best treatment duration to maximize outcomes.
5. Assess the benefits of prevention strategies like vaccination or screening programs.
4.Different Types of Trials:
1. Trials are categorized based on specific research needs and objectives.
2. These categories help cover a wide range of areas and contribute to medical knowledge advancement

Cont….Are there different types of clinical trials?
Trial Type Objective Focus
Pharmaceutical Company
Trials
Evaluate new drugs or established drugs in disease
areas for potential new licenses
Testing drug efficacy and safety
Device Manufacturer
Trials
Aim to prove the safety and effectiveness of new
medical devices
Testing the safety and effectiveness of
medical devices
Clinical Investigator Trials
Conducted by independent investigators unrelated to
pharmaceutical companies
Exploration of various objectives, including:
- Use of established or older drugs in new disease
areas, often without commercial support
- Testing established or older drugs in new
disease areas without commercial support
- Focus on research rather than profit generation
- Investigating optimal drug administration
or withdrawal methods
- Determining the best treatment duration to
maximize outcomes
- Assessing the benefits of prevention
strategies like vaccination or screening
programs
Different Types of Trials
Trials are categorized based on specific research
needs and objectives
Covering a wide range of areas and
contributing to medical knowledge
advancement

Phases
• Clinical trials in the pharmaceutical industry follow a specific classification based on the four phases of drug
development (Phases I-IV). Here is a summary of each phase:
1.Phase I:
1. Tests the effects of a new drug in healthy volunteers or patients who are unresponsive to usual therapies.
2. Focuses on understanding how the drug is processed in the body (pharmacokinetics/pharmacodynamics) and
assessing immediate short-term safety at higher doses.
2. Phase II:
1. Examines dose-response relationships and potential benefits in a small group of patients with a specific disease.
2. Helps determine the appropriate dosage range for further studies.
3. Phase III:
1. Involves testing the new drug in a controlled manner with a large patient population.
2. Compares the drug against a placebo or standard therapy.
3. Crucial phase for establishing safety and efficacy before marketing approval.
4. Positive results in Phase III can lead to the drug being licensed for use in treating a specific disease.
4. Phase IV:
1. Also known as post-marketing studies, conducted after regulatory approval is granted.
2. Focuses on gathering additional safety information from a larger patient group to understand long-term safety
and potential drug interactions.
• These phases play a critical role in the development and evaluation of new drugs, ensuring their safety, efficacy, and suitability for specific diseases. Each phase provides important
insights into the drug's characteristics and contributes to its overall reputation in the market.

Phase Purpose Patient Population Study Design Key Focus
Phase I
Tests the effects of a new drug in
healthy volunteers or patients
unresponsive to usual therapies
Healthy volunteers or
unresponsive
patients
PK/PD, safety
Immediate short-term
safety, drug processing
Phase II
Examines dose-response
relationships and potential benefits
in a small group of patients with a
specific disease
Small group of
patients with the
disease
Assessing appropriate
dosage range, efficacy
Determine optimal
dosing, potential
benefits
Phase III
Tests the new drug in a controlled
manner with a large patient
population
Large patient
population
Comparisons against
placebo/standard
therapy, safety
Establish safety,
efficacy for marketing
approval
Phase IV
Conducted after regulatory
approval is granted; focuses on
gathering additional safety
information from a larger patient
group
Larger patient group
Long-term safety, drug
interactions
Post-marketing
surveillance, safety
monitoring

Steps in conducting a Randomized Controlled Trial (RCT)
1. Identify Research Question
o Clearly define the research question or hypothesis.
2. Develop Study Protocol
o Outline study design, selection criteria, intervention, control group, and outcomes.
o Determine sample size for statistical power.
3. Obtain Ethical Approval
o Seek approval from ethics committees or institutional review boards.
4. Randomize Participants
o Randomly assign participants to intervention or control groups.
5. Recruit Participants
o Identify and recruit eligible participants.
o Obtain informed consent.
6. Intervene and Control
o Administer intervention to the intervention group.
o Provide placebo or standard treatment to the control group.
7. Follow-up and Data Collection
o Monitor participants and collect data on predetermined outcomes.
8. Analyze the Data
o Utilize appropriate statistical methods to analyze the collected data.
9. Interpret the Results
o Assess statistical significance and clinical relevance of findings.
10. Report and Publish
o Prepare a comprehensive report adhering to reporting guidelines.
o Publish the findings in a peer-reviewed journal.

RCT-Trial design
• Clinical trials can be further categorized based on their design, which describes how patients are
randomized to different treatment groups. Here are some common trial designs:
1.Parallel-Group Trial:
1. Patients are randomly assigned to either the new treatment or the standard treatment.
2. The effects of each treatment are evaluated in separate, parallel groups.
3. This is the most common trial design.
2.Crossover Trial:
1. Patients are randomized to different sequences of treatments.
2. Each patient eventually receives all treatments in different orders, acting as their own control.
3. This design is useful when studying treatments with immediate effects or investigating individual patient
responses.
3.Factorial Trial:
1. Patients are assigned to multiple treatment-comparison groups.
2. Different treatments are tested simultaneously, allowing for the assessment of their individual and
combined effects.
3. This design helps study the interaction between treatments and their independent effects.
4.Cluster Randomized Trial:
1. Larger groups, such as patients under a specific practitioner or hospital, are randomized as a whole instead
of individual patients.
2. This design is employed when it is more practical or efficient to randomize groups rather than individual
participants.

Trial Design Description Application
Parallel-Group Trial
Patients are randomized to either the new treatment or
the standard treatment.
Most common trial design.
Crossover Trial
Patients are randomized to different sequences of
treatments, acting as their own control.
Studying treatments with
immediate effects.
Factorial Trial
Patients are assigned to multiple treatment-comparison
groups, testing different treatments simultaneously.
Assessing individual and
combined treatment effects.
Cluster Randomized
Trial
Larger groups (e.g., patients of a single practitioner or
hospital) are randomized as a whole instead of
individuals.
Practical for randomizing
groups efficiently.
Cont….RCT-Trial design

Here are some pneumonic to help remember the different randomized trial designs:
1.Parallel-Group Trial: "Pick One or Stay" - Patients are randomized to either pick the new treatment or stay
with the standard treatment.
2.Crossover Trial: "Come and Go, Repeat the Show" - Patients come and go through different sequences of
treatments, repeating the cycle to act as their own control.
3.Factorial Trial: "Four at Once, Combo Dance" - Patients are assigned to multiple treatment-comparison
groups, testing different treatments simultaneously to explore their combined effects.
4.Cluster Randomized Trial: "Groups United, Randomized Invited" - Larger groups, like patients of a single
practitioner or hospital, are united and randomized as a whole, rather than individuals.
Cont….Trial design RCT

Parallel-Group Trial
• Parallel group randomization involves randomizing participants into one or more arms or groups.
• Each arm should have an equal number of participants to ensure fairness and minimize bias.
• Participants in each arm receive the same treatment throughout the trial.
• The results obtained from each group are compared to assess the effectiveness of the different treatments.
• Any variability in the outcomes that cannot be explained is attributed to inherent differences between
participants.
• Covariates, such as age, weight, or disease severity, may be considered to explain variations in participant
variables.
• The parallel group design is the most commonly used design in clinical trials.
Advantages
• Can be applied to almost any disease.
• Any number of groups can be run simultaneously.
• Groups can be in separate locations
Disadvantages
• High variance brought on by loose connection to
control.
• In multiple treatment groups statistics may become
challenging.

Cross-Over Trial Design
• Cross-over randomization involves participants receiving a sequence of different treatments.
• Participants start each treatment at an equivalent point and serve as their own control.
• This design offers advantages such as low variance due to the same participant receiving both treatment and
control.
• Cross-over trials allow for the inclusion of multiple treatments.
• A washout period is necessary between treatments, during which participants do not receive any treatment.
• Participants in cross-over trials should have a stable and chronic disease.
• Cross-over trials require a smaller number of participants but for a longer period of time.
Advantages
• Low variance due to participant and control
being the same.
• Can include a number of treatments.
Disadvantages
• Requires a long-term illness as treatments are
applied one after the other.
• Carry over effects need to be avoided
(washout period must be sufficiently long).

Factorial Trial
• Factorial design assumes no interaction between the interventions.
• It involves evaluating two interventions compared to a control within a single trial.
• Each participant in the trial receives two different treatments: x and y, x and control, y and control, and
control and control.

Withdrawal Trials
 In a randomised withdrawal trial, participants initially receive a test treatment to which they respond for a specified
time.
 At the end of the specified time, participants are randomly assigned to either continue treatment with the test treatment
or switch to a placebo, which involves withdrawing the active therapy.
 Participants for this type of trial can be selected from various sources such as open single-arm studies, existing clinical
cohorts, active arms of controlled trials, or active control trials.
 The purpose of a randomised withdrawal trial is to assess the effect of the active treatment by comparing the group
receiving continued treatment with the group randomized to placebo.
 While withdrawal studies are particularly applicable to chronic diseases, they can also be used in other contexts
The objectives are:
• To assess response to the dose being stopped or
reduced.
• To determine if treatment is still required.
• To discontinue participants in a study that have not
responded to the medicine being studied.

Number of Centers in Clinical Trials
• Clinical trials can be categorized as single-center or multicenter studies based on the number of sites
involved.
• Single-center studies are primarily used for Phase I and II trials.
• Multicenter studies can be conducted at any stage of clinical development and offer several advantages.
Advantages of Multicenter Studies:
1. Efficient Subject Recruitment: Multicenter trials enable faster enrollment of an adequate number of
participants within a shorter time frame.
2. Enhanced Generalizability: Involving multiple centers allows for the evaluation of treatment effects across
diverse patient populations and healthcare settings.
Importance of Multicenter Studies:
3. Efficient Evaluation: Multicenter trials are effective in evaluating the efficacy and safety of new medications or
procedures by including a larger number of subjects.
4. Generalization of Findings: The effects of the treatment can be evaluated in various types of centers,
providing a stronger basis for generalizing the trial's findings.

Other classifications
Trial Type Objective Focus
Superiority Studies
Designed to demonstrate that a new drug is more effective
than the comparative treatment (placebo or current best
treatment).
Establishing the superiority of the new
intervention
Equivalence Studies Aim to prove that two drugs have the same clinical benefit.
Showing that the effect of the new drug is not
clinically different from the effect of the
current treatment
Noninferiority Studies
Intended to demonstrate that a new treatment is not
significantly weaker than the current treatment.
Establishing that the new intervention is not
inferior to the current standard
Exploratory Trials
First-time comparisons of a specific treatment, seeking to
identify key issues or explore the impact of a new drug in
specific subsets of patients.
Generating hypotheses and exploring the
impact of a new drug
Confirmatory Trials
Further trials conducted to confirm or validate previous
observations or treatment effects.
Providing additional evidence supporting the
efficacy and safety of a specific treatment
Trials with Both
Confirmatory and
Exploratory Aspects
Some trials can have elements of both confirmatory and
exploratory studies.
Primarily confirming a treatment effect while
also exploring additional hypotheses or
subgroup effects for confirmation

Why might clinical trial results not represent the true
difference?
• Clinical trial results may not always accurately represent the true difference between the new drug and
the comparative treatment. Several factors contribute to this potential discrepancy:
1.Bias:
• The trial may have been affected by systematic errors, leading to a deviation from the true treatment effect.
• Bias can occur during participant selection, data collection, analysis, or result interpretation.
• Predictable biases can distort the trial results.
2. Confounding:
• Unpredictable factors can contaminate or confound the relationship between the treatment and the outcome.
• These confounding factors are associated with both the treatment and the outcome, leading to a distorted observed
treatment effect.
• Proper study design and statistical analysis are crucial for addressing and controlling confounding factors.
3. Random Chance:
• Even in well-designed trials, the observed result may be due to random variation or chance alone.
• There is always a possibility of obtaining statistically significant results by chance.
• Statistical methods are used to determine the likelihood that the observed treatment effect is not merely a result of
random chance, but a true difference between treatments.

Bias
• Bias refers to systematic errors that can occur in clinical trials and deviate the trial-derived estimate from
the true treatment effect
Type of Bias Description Impact on Trial Results
Selection Bias
Occurs when the investigator's knowledge of the
treatment allocation influences subject selection.
Imbalance in baseline characteristics,
potentially favoring a treatment group
over the other.
Measurement Bias
Arises from the way outcome measurements are
collected, recorded, or assessed.
Over- or underestimation of treatment
effects due to knowledge of treatment
assignment.
Exclusion Bias
Results from excluding subjects from the statistical
analysis, often due to noncompliance or missing data.
Imbalanced exclusion between treatment
groups can distort the estimate of
treatment benefit or harm

Confounding
• Confounding refers to the distortion of the true relationship between treatment and outcome by another
factor that is associated with both the outcome of interest and treatment group assignment.
• It can obscure an existing treatment difference or create a false difference that doesn't actually exist.
• For example, if patients are assigned to treatment groups based on inherent differences, such as age, the
observed treatment effect may be influenced by these pre-existing differences rather than the actual
treatment effect.
• Randomization in conjunction with a large sample size is the most effective way to address confounding.
Randomization helps distribute both known and unknown confounding factors evenly between
treatment groups.
• Stratified randomization can be used if specific factors are known to potentially confound the trial,
ensuring a balanced representation of these factors across treatment groups.
• During the analysis stage, special statistical techniques such as stratified analysis and regression analysis
can be employed to further control for confounding factors.
• These techniques help account for the influence of confounders on the observed treatment effect.
• By employing randomization, large sample sizes, and appropriate statistical methods, researchers can
minimize the impact of confounding and obtain more reliable trial results.

Cont….Random Error
 Random error can still impact observed treatment effects in well-designed trials.
 It can result from sampling, biological, or measurement variations in outcome variables, which his called as sampling
error.
 Sampling error occurs when the trial sample produces a chance false result compared to the overall population.
 Reducing sampling errors can be achieved by increasing the patient group size or utilizing meta-analysis techniques that
combine results from smaller studies.
1.1 Statistical analyses:
• Statistical methods estimate the likelihood of measured
treatment effects reflecting the true effect.
• Statistical testing assesses the probability assuming no difference
between treatments.
• The P-value or false-positive rate represents this probability.
• A P-value below the critical value (e.g., 0.05) is statistically
significant, indicating strong evidence for a true difference.
• Conversely, a P-value above the critical value suggests the
observed difference may be due to random error or chance.
1.2 Statistical estimates:
• Point estimates summarize treatment differences as means or proportions.
• Measures of precision, like confidence intervals (CIs), provide a range likely
to contain the true treatment difference.
• A 95% CI means the range has a 95% probability of containing the true
value.
1.3 Multiple hypotheses and testing:
• Testing multiple hypotheses or conducting interim analyses can increase the
likelihood of observing statistically significant differences by chance.
• Comparing treatments for different outcomes or subpopulations may lead to
spurious results.
• Multiple testing during interim analyses can also contribute to false results.
• Careful trial planning is crucial to minimize these errors.

The CHARM program: an example of a randomized clinical trial
1.Objectives and endpoints:
1. What are the specific goals and objectives of the study?
2. What are the primary and secondary endpoints that will be used to measure the treatment's
effectiveness or safety?
2.Patient population and disease:
1. What patient population or specific disease condition is the drug intended to treat?
2. Are there any specific inclusion or exclusion criteria that should be used to select eligible patients
for the study?
3.Sample size determination:
1. How large should the sample size be to ensure the study has sufficient statistical power to detect a
clinically significant benefit?
2. Power calculations can help estimate the required sample size based on factors such as the
expected treatment effect size, variability, and desired level of significance.
4.Assessment of treatment benefits:
1. How can we evaluate the observed treatment benefits with confidence?
2. Are there potential sources of systematic errors or biases that need to be considered and
minimized?
3. What statistical methods and analysis techniques should be employed to account for confounding
variables and minimize the influence of chance?

Cont….The CHARM program
CHARM Trials:
 CHARM (Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity) trials were conducted to
investigate the impact of candesartan, an angiotensin receptor blocker, on mortality and morbidity in patients with chronic
heart failure (CHF).
 The trials serve as an example for understanding trial design, analysis, and reporting processes.
Patient Population:
 Patients with CHF, a condition associated with a high risk of cardiovascular death and recurrent hospital admissions, were
included in the CHARM trials.
CHARM Program:
 The CHARM program consisted of three independent but parallel trials.
 The trials aimed to compare candesartan against a placebo in terms of mortality and morbidity outcomes among CHF patients.
Distinct and Complementary Patient Populations:
 The three patient populations enrolled in the trials were distinct but complementary.
 This approach allowed for evaluation of candesartan's effects across a broad spectrum of patients with heart failure.
Key Considerations:
 The CHARM trials emphasize the importance of thoughtful trial design, rigorous analysis, and comprehensive reporting to
generate valuable insights into treatment effects in specific patient populations

Objectives and Endpoints in the CHARM Trials
1. Objectives:
o Clear objectives are essential for a clinical trial and are measured by endpoints.
o The main objective of the CHARM program was to determine whether candesartan could reduce
mortality and morbidity in patients with symptomatic heart failure.
2. Primary Endpoint:
o The primary endpoint for the overall CHARM population was defined as the time from
randomization to death from any cause.
o In each component trial, the primary endpoint was the time to the first occurrence of
cardiovascular death or emergency hospitalization for the management of heart failure.
3. Ethical Justification:
o The CHARM trial was ethically acceptable as there was insufficient evidence supporting the use of
candesartan in patients with heart failure before the study.
4. Prespecified Objectives and Endpoints:
o The objectives and endpoints of the CHARM trials were clearly stated in advance.
o Conclusions regarding the effect of candesartan were based on these prespecified objectives and
endpoints.

Study Design in the CHARM Trials
1. Multicenter Design:
o The CHARM study was conducted at multiple centres and consisted of three separate
trials.
o Each trial had a two-arm design, with randomization, blinding, and placebo control.
2. Patient Allocation:
o Patients were allocated to different sub trials based on their left ventricular ejection fraction
(LVEF) and background use of angiotensin-converting enzyme (ACE) inhibitors.
o Patients with preserved LVEF (≥40%) were enrolled in the 'CHARM-Preserved' trial.
o Patients with LVEF <40% were divided into two additional trials: 'CHARM-Alternative' for
those with known ACE inhibitor intolerance and 'CHARM-Added' for those already on ACE
inhibitors.
3. Randomization:
o Randomization of patients into different subtrials helps minimize systematic bias and
confounding factors.
o This design allows for valid estimation of the effect of candesartan in distinct patient
populations with heart failure.

Patient Population in the CHARM Trials
1. Generalizability:
o Clinical trial results are applicable to patients similar to the study participants.
2. Aim of the CHARM Trials:
o The CHARM investigators aimed to assess the effectiveness of candesartan in a broad spectrum of
patients.
3. CHARM Study Population:
o Symptomatic heart failure patients (New York Heart Association class II-IV) were included.
o Minimum age requirement: ≥18 years.
o Exclusion criteria:
 Recent major events, such as myocardial infarction, stroke, or open-heart surgery within the
previous 4 weeks.
 Noncardiac diseases judged likely to limit survival for 2 years.
o Patients with contraindications to candesartan treatment were also excluded.
o All enrolled patients provided written informed consent.

Sample Size Calculation in the CHARM Trials
1. Importance of Sample Size:
 Sample size calculation aims to minimize random error and ensure the study has sufficient power to draw
meaningful conclusions.
2. Factors Influencing Sample Size Calculation:
o Statistical models and rules are used to calculate the sample size for different trial designs and endpoint types.
o Trial designs include parallel-arm trials, cluster randomized trials, factorial trials, and crossover trials.
o Endpoint types include continuous outcomes, binary outcomes, and time-to-event or survival outcomes.
3. Sample Size Calculation in the CHARM Program:
o The primary endpoint in the CHARM program was all-cause mortality.
o The assumed annual overall mortality in the placebo group was 8%.
o The program aimed for >85% power to detect a 14% reduction in mortality at a significance level of 0.05 using the
log-rank test.
o Each component trial independently determined its sample size based on the anticipated event rate for cardiovascular
death or hospital admission for CHF

• Conduct of the CHARM Trial
1. Study Recruitment and Coordination:
o The CHARM trials recruited patients from 618 sites in 26 countries.
o Uniform procedures and management were followed, coordinated through a single central unit.
2. Randomization and Blinding:
o Between March 1999 and March 2001, 7,599 patients were randomly assigned in a double-blind
fashion to candesartan or placebo.
o Randomization was stratified by site and component trial, with allocation concealment maintained.
o Neither doctors nor patients were aware of the assigned treatment during the trial.
3. Treatment Administration and Monitoring:
o Patients received an initial dose of either 4 or 8 mg of the study drug (candesartan or placebo).
o Dose adjustments were made based on the patient's clinical status, guided by provided algorithms for
managing hypotension or kidney dysfunction.
4. Follow-up and Data Collection:
o Visits were scheduled every 4 months, with a planned duration of at least 2 years.
o Discontinuations and patient follow-up for outcomes were recorded.
• All deaths and first CHF hospital admissions were adjudicated by an endpoint committee.

• Interim Monitoring
1. Independent Data and Safety Monitoring Board (DSMB):
o In the CHARM program, an independent DSMB was established to oversee patient safety and monitor trial
progress.
o The DSMB had access to all trial data through an independent statistical centre.
o Predefined stopping rules for efficacy and safety, particularly focused on mortality, were established.
2. Ensuring Transparency and Patient Safety:
o Pharmaceutical companies have a vested interest in trial outcomes, but independent oversight ensures
transparency and patient safety.
o The use of an independent statistical centre and a DSMB prioritizes patient safety and minimizes bias.
3. Data Analysis and Discussions:
o At predefined time points, the independent statistical centre analyses the existing data and discusses the results
with the DSMB.
o The DSMB ensures that the new drug being tested is not harmful and may recommend stopping the trial if
safety concerns arise.
o Conversely, if significant evidence of beneficial effects is found before the planned end of the trial, the DSMB
may recommend stopping the trial for efficacy.
4. Ethical Challenges and Balancing Priorities:
o Monitoring trial results poses ethical challenges, requiring a balance between individual ethics and the long-
term goal of obtaining sufficient data.
o The goal is to ensure patient safety while also obtaining reliable evidence of treatment efficacy.

Final Data Analysis
1. Intention-to-Treat Analysis:
o Intention-to-treat analysis considers all randomized patients, including those who discontinued or changed treatment,
reflecting real-world treatment scenarios.
o In the CHARM program, all analyses were performed using intention-to-treat analysis.
2. Statistical Tests and Models:
o Time-to-event endpoints were analyzed using the log-rank test and displayed on Kaplan-Meier plots by treatment.
o The Cox proportional hazards model was used to estimate the hazard ratio and assess the treatment effect of candesartan against
placebo.
o Covariate-adjusted Cox regression models were fitted to account for baseline factors that might affect prognosis.
o Subgroup analyses were conducted using tests for heterogeneity to explore possible interactions between treatment and selected
baseline variables.
3. Importance of Prespecified Analyses:
o Statistical analyses are typically prespecified in the trial protocol to ensure credibility and address the issue of multiple testing.
o The principal statistical test for the primary endpoint, as prespecified in the sample size calculation, should be applied.
4. Subgroup Analysis Considerations:
o Subgroup analyses can be performed, but it should be recognized that significant effects seen in subgroups do not provide
definitive evidence of differential effects unless the trial was initially powered to assess those specific subgroups.
5. Study Design Limitation:
o CHARM was designed and powered to assess the effects of candesartan on specific endpoints in different populations of heart
failure patients.
o It was not specifically designed to evaluate the differential effects of candesartan in diabetic participants compared to other heart
failure patients.

Trial Reporting
1. Publication and CONSORT Guidelines:
o The results of the CHARM program were published in four reports, following the CONSORT statement and
reporting guidelines.
o The CONSORT guidelines ensure transparent and comprehensive reporting of randomized controlled trials.
2. Trial Profile and Baseline Characteristics:
o A trial profile was provided to describe the flow of participants through each stage of the trial, including
enrollment, randomization, treatment allocation, follow-up, and analysis.
o Baseline characteristics of patients, including demographic information, risk factors, medical history, and
treatment, were displayed in appropriate formats for each component trial and the overall program.
3. Presentation of Results:
o Results of prespecified primary endpoints and relevant secondary endpoints were presented in tables and figures.
o Key findings of the CHARM program included the reduction in all-cause mortality and cardiovascular deaths with
candesartan treatment.
o The hazard ratios, confidence intervals, and P-values were reported to assess the significance of the treatment
effect.
4. Subgroup Analysis:
o Separate articles were published to report the effects of candesartan on cardiovascular death or CHF
hospitalization in different populations of heart disease patients (CHARM-Preserved, -Added, and -Alternative).

1. Randomized clinical trials are crucial for advancing medical care by providing reliable evidence on treatment efficacy
and safety.
2. Valid trial results require minimizing bias and maximizing precision through appropriate study design, rigorous data
analysis, and transparent reporting.
3. Key considerations in trial design include defining hypotheses, selecting outcome measures, and defining the study
population.
4. Minimizing systematic errors and considering potential biases or confounding factors enhance the reliability of trial
findings.
5. Statistical analyses assess treatment effects, address random errors, and provide measures of treatment effect and
precision.
6. Interpretation of statistical measures should consider potential biases and confounding factors.
7. Ethical considerations prioritize patient safety and minimize harm to participants during trial conduct.
8. Trials should be designed to answer research questions while ensuring participant well-being.
9. Successful implementation of randomized clinical trials relies on careful planning, rigorous execution, and meticulous
reporting.
10. Adherence to established guidelines and best practices ensures the generation of high-quality evidence that informs
medical decision-making and improves patient outcomes.
Randomised clinical Trials: Summary

MCQs
 Which of the following is a primary characteristic of a randomized clinical trial?
a) Observational design
b) Non-randomized treatment allocation
c) Blinding of participants
d) Convenience sampling
Answer: b) Non-randomized treatment allocation
 What is the purpose of randomization in an RCT?
a) To ensure equal distribution of confounding factors
b) To select a homogeneous study population
c) To guarantee blinding of participants
d) To increase the statistical power of the study
Answer: a) To ensure equal distribution of confounding factors

Cont…MCQs
 What is the primary goal of blinding in an RCT?
a) To minimize bias in outcome assessment
b) To increase participant recruitment
c) To simplify data analysis
d) To ensure equal treatment allocation
Answer: a) To minimize bias in outcome assessment
 Which of the following is an example of an open-label RCT?
a) Single-blind RCT
b) Double-blind RCT
c) Triple-blind RCT
d) Non-blind RCT
Answer: d) Non-blind RCT

Cont…MCQs
 What is the purpose of an intention-to-treat analysis in an RCT?
a) To assess treatment adherence
b) To exclude non-compliant participants
c) To analyze only participants who completed the study
d) To maintain randomization and preserve real-world conditions
Answer: d) To maintain randomization and preserve real-world conditions
 In an RCT, which of the following best describes the control group?
a) Receives a placebo or standard treatment
b) Is not included in the study design
c) Represents the general population
d) Is randomly selected from a different population
Answer: a) Receives a placebo or standard treatment

Cont…MCQs
 What is the purpose of sample size calculation in an RCT?
a) To estimate the duration of the study
b) To determine the number of participants needed
c) To identify potential confounding factors
d) To assess treatment compliance
Answer: b) To determine the number of participants needed
Which type of bias occurs when participants are aware of their treatment assignment in an RCT?
a) Selection bias
b) Measurement bias
c) Reporting bias
d) Performance bias
Answer: d) Performance bias

Cont…MCQs
 Which of the following is a common outcome measure in an RCT?
a) Convenience sampling
b) Incidence rate
c) Confidence interval
d) Reliability coefficient
Answer: b) Incidence rate
 In an RCT, what is the purpose of the placebo group?
a) To ensure participant blinding
b) To establish the superiority of the intervention
c) To assess the baseline characteristics of the participants
d) To measure the natural course of the disease
Answer: d) To measure the natural course of the disease

Cont…MCQs
• Which of the following is an example of an efficacy outcome in an RCT?
a) Participant satisfaction
b) Quality of life
c) Disease remission
d) Healthcare costs
Answer: c) Disease remission
• Which of the following is a potential disadvantage of using a crossover design in an RCT?
a) Increased sample size requirements
b) Potential carryover effects
c) Limited generalizability
d) Inability to blind participants
Answer: b) Potential carryover effects

Cont…MCQs
• Which of the following is a limitation of using historical controls in an RCT?
a) Increased cost of the study
b) Reduced statistical power
c) Lack of blinding
d) Inability to measure treatment adherence
Answer: b) Reduced statistical power
• What is the purpose of a washout period in a crossover RCT?
a) To allow participants to adapt to the treatment
b) To minimize carryover effects from previous treatments
c) To assess treatment side effects
d) To ensure blinding of participants
Answer: b) To minimize carryover effects from previous treatments

Cont…MCQs
• Which of the following statements about cluster randomized trials is true?
a) Participants are randomly assigned to the intervention or control group.
b) Individual-level data is analyzed in the intervention group only.
c) Clusters, rather than individuals, are randomized to treatment groups.
d) The primary outcome measure is participant satisfaction.
Answer: c) Clusters, rather than individuals, are randomized to treatment groups.
• What is the purpose of an interim analysis in an RCT?
a) To assess the safety of the intervention
b) To evaluate the recruitment rate
c) To monitor the study's progress and make early stopping decisions
d) To adjust the sample size based on observed effect sizes Answer:
c) To monitor the study's progress and make early stopping decisions

Cont…MCQs
• In an RCT, which of the following is a potential source of allocation bias?
a) Inadequate blinding of participants
b) Unequal distribution of confounding factors
c) Measurement errors in outcome assessment
d) Incomplete follow-up of participants
Answer: b) Unequal distribution of confounding factors
• Which type of bias is most likely to occur if participants drop out of an RCT and their data are not
included in the analysis?
a) Attrition bias
b) Reporting bias
c) Observer bias
d) Recall bias
Answer: a) Attrition bias

Cont…MCQs
Which of the following is an example of a pragmatic trial design?
a) Non-inferiority trial
b) Phase I dose escalation trial
c) Exploratory pilot trial
d) Cluster randomized trial
Answer: d) Cluster randomized trial
Which of the following is an example of an adaptive trial design?
a) Stepped-wedge design
b) Factorial design
c) Sequential parallel comparison design
d) Pre-post design
Answer: c) Sequential parallel comparison design

Cont…MCQs
What is the purpose of a run-in period in an RCT?
a) To establish a baseline measurement before randomization
b) To assess treatment side effects
c) To identify participants suitable for the study
d) To minimize attrition during the trial
Answer: a) To establish a baseline measurement before randomization
 Which of the following is a characteristic of a crossover design in an RCT?
a) Participants receive multiple treatments simultaneously.
b) The control group receives a placebo.
c) Each participant serves as their own control.
d) Randomization occurs at the cluster level.
Answer: c) Each participant serves as their own control.

Cont…MCQs
 In an RCT, the term "efficacy" refers to:
a) The effectiveness of the intervention in routine clinical practice.
b) The potential benefits of the intervention under ideal conditions.
c) The participant's satisfaction with the intervention.
d) The cost-effectiveness of the intervention.
Answer: b) The potential benefits of the intervention under ideal conditions.
 Which of the following is an example of a non-inferiority trial?
a) A trial comparing a new drug to a placebo.
b) A trial comparing two drugs to determine which one is superior.
c) A trial comparing a new drug to an established drug.
d) A trial comparing different dosages of the same drug.
Answer: c) A trial comparing a new drug to an established drug.

Cont…MCQs
 What is the primary purpose of randomization in an RCT?
a) To ensure an equal distribution of confounding variables between treatment groups.
b) To determine the sample size required for the study.
c) To enhance blinding of participants and investigators.
d) To allocate resources effectively during the trial.
Answer: a) To ensure an equal distribution of confounding variables between treatment groups.
Which of the following is a potential disadvantage of using a placebo-controlled design in an RCT?
a) Potential unblinding of participants and investigators.
b) Increased risk of contamination between treatment groups.
c) Limited ability to assess treatment effects.
d) Difficulty in recruiting participants.
Answer: c) Limited ability to assess treatment effects.

Cont…MCQs
Which of the following is a potential source of selection bias in an RCT?
a) Inadequate blinding of participants.
b) Unequal distribution of confounding factors.
c) Measurement errors in outcome assessment.
d) Incomplete follow-up of participants.
Answer: b) Unequal distribution of confounding factors.
 In an RCT, which of the following is a potential source of detection bias?
a) Inadequate participant blinding.
b) Unequal distribution of confounding factors.
d) Incomplete follow-up of participants.
Answer: c) Measurement errors in outcome assessment.

Cont…MCQs
 What is the purpose of a control group in an RCT?
a) To provide a reference point for comparison with the intervention group.
b) To ensure that participants adhere to the study protocol.
c) To monitor adverse events associated with the intervention.
d) To enhance blinding of participants and investigators.
Answer: a) To provide a reference point for comparison with the intervention group.
 In an RCT, blinding is primarily used to:
a) Enhance participant recruitment.
b) Ensure equal allocation of participants to treatment groups.
c) Minimize bias in outcome assessment.
d) Determine the statistical power of the study.
Answer: c) Minimize bias in outcome assessment.

Cont…MCQs
Which of the following is an example of an adaptive trial design?
a) Non-inferiority trial
b) Factorial design
d) Pre-post design Answer:
What is the purpose of a run-in period in an RCT?
a) To establish a baseline measurement before randomization
b) To assess treatment side effects
c) To identify participants suitable for the study
d) To minimize attrition during the trial
Answer: a) To establish a baseline measurement before randomization

Cont…MCQs
Which of the following is a potential advantage of using a cluster randomized trial design?
a) Reduced risk of contamination between treatment groups
b) Enhanced blinding of participants and investigators
c) Improved generalizability to real-world settings
d) Increased statistical power
Answer: c) Improved generalizability to real-world settings
In an RCT, what is the purpose of randomizing treatment allocation?
a) To ensure each participant receives their preferred treatment
b) To minimize the risk of bias and confounding
c) To match participants based on similar characteristics
d) To evaluate the cost-effectiveness of different treatments
Answer: b) To minimize the risk of bias and confounding

Cont…MCQs
Which of the following is a potential limitation of using historical controls in an RCT?
a) Increased cost of the study
b) Reduced statistical power
c) Lack of blinding
d) Inability to measure treatment adherence
Answer: b) Reduced statistical power
Which of the following is an example of a surrogate outcome measure in an RCT?
a) Participant satisfaction
b) Quality of life
c) Blood pressure
d) Disease remission
Answer: c) Blood pressure

Cont…MCQs
Which of the following is a potential disadvantage of using a single-blind design in an RCT?
a) Participants may have biased expectations
b) Investigators may have biased assessments
c) Difficulties in recruiting participants
d) Increased risk of selection bias
Answer: b) Investigators may have biased assessments
Which of the following is a characteristic of a pragmatic trial design?
a) High degree of control over the intervention and study conditions
b) Focus on efficacy under ideal conditions
c) Emphasis on understanding the underlying mechanisms of the intervention
d) Evaluation of effectiveness in real-world settings
Answer: d) Evaluation of effectiveness in real-world settings

Cont…MCQs
Which of the following statements about blinding in an RCT is true?
a) Blinding is necessary for both participants and investigators.
b) Blinding is only necessary for participants, not investigators.
c) Blinding is only necessary for investigators, not participants.
d) Blinding is not essential in an RCT.
Answer: a) Blinding is necessary for both participants and investigators.
 In an RCT, what is the purpose of ethical approval?
a) To determine the study's statistical power
b) To ensure participant recruitment and retention
c) To protect the rights and welfare of the participants
d) To guarantee publication in a peer-reviewed journal
Answer: c) To protect the rights and welfare of the participants

Cont…MCQs
What is the purpose of a pilot study in the context of RCTs?
a) To evaluate the long-term effects of an intervention.
b) To establish the efficacy of a new treatment.
c) To assess the feasibility of conducting a larger-scale trial.
d) To measure the treatment effect size accurately.
Answer: c) To assess the feasibility of conducting a larger-scale trial.
Which of the following is a potential disadvantage of using a cluster randomized trial design?
a) Increased risk of selection bias.
b) Limited ability to control confounding variables.
c) Difficulties in blinding participants.
d) Higher cost compared to other designs.
Answer: b) Limited ability to control confounding variables.

Cont…MCQs
What is the purpose of a data monitoring committee (DMC) in an RCT?
a) To ensure participant recruitment and retention.
b) To analyze the trial data and interpret the results.
c) To monitor participant safety during the trial.
d) To provide statistical consultation for the study.
Answer: c) To monitor participant safety during the trial.
Which of the following is a potential advantage of using a factorial design in an RCT?
a) Simplified study protocol.
b) Reduced sample size requirements.
c) Increased statistical power.
d) Elimination of confounding variables.
Answer: c) Increased statistical power.

Cont…MCQs
In an RCT, what is the purpose of an inclusion criterion?
a) To ensure participant safety during the trial.
b) To determine the appropriate sample size for the study.
c) To define the target population for the intervention.
d) To identify potential confounding variables.
Answer: c) To define the target population for the intervention.
Which of the following is a potential source of attrition bias in an RCT?
a) Inadequate participant blinding.
b) Incomplete follow-up of participants.
d) Unequal distribution of confounding factors.
Answer: b) Incomplete follow-up of participants.

Cont…MCQs
What is the purpose of a placebo in an RCT?
a) To serve as an active treatment for the control group.
b) To enhance blinding of participants and investigators.
c) To elicit a psychological response in participants.
d) To ensure ethical considerations are met.
Answer: b) To enhance blinding of participants and investigators.
Which of the following is a potential disadvantage of using an open-label design in an RCT?
a) Increased risk of selection bias.
b) Potential unblinding of participants and investigators.
c) Limited ability to control confounding variables.
d) Difficulty in recruiting participants.
Answer: b) Potential unblinding of participants and investigators.

Cont…MCQs
What is the purpose of a control group in an RCT?
a) To provide a reference point for comparison with the intervention group.
b) To ensure that participants adhere to the study protocol.
c) To monitor adverse events associated with the intervention.
d) To enhance blinding of participants and investigators.
Answer: a) To provide a reference point for comparison with the intervention group.

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