This document discusses various types of clinical trial designs. It begins by defining clinical trials and describing key elements like the PICO framework. It then covers ways to reduce bias through randomization and blinding. The document categorizes clinical trials based on factors like number of centers, control groups, randomization, and blinding. It provides details on traditional study designs like parallel group designs and crossover designs. It also discusses special designs for small populations and miscellaneous designs. Overall, the document provides an overview of different clinical trial designs, methods to reduce bias, and ways to categorize trial types.
Clinical trials are conducted to test new drugs, treatments or medical devices in humans to assess their safety and efficacy. There are four main phases of clinical trials:
Phase I trials involve small groups of people to determine basic safety and dosing requirements. Phase II trials expand the testing to more people to determine efficacy and further evaluate safety. Phase III trials involve large groups of people to confirm effectiveness, monitor side effects, compare to commonly used treatments and collect information to allow safe use of the intervention. Phase IV trials occur after the intervention has been marketed to gather information on effects in various populations and any long-term side effects.
This document discusses various clinical trial designs including parallel, crossover, factorial, and adaptive designs. It describes key elements of clinical trial methodology such as randomization, blinding, placebos, and controls. The document also outlines how clinical trial designs are applied differently in each phase of drug development from Phase 0 microdosing to Phase III confirmatory trials. Key challenges in clinical trial design like controlling bias and complex statistical analysis of factorial designs are also summarized.
PPT on Sample Size, Importance of Sample Size,Naveen K L
This document discusses factors related to determining sample size for research studies. It defines key terms like sample size, population and importance of sample size. The selection of sample size involves planning the study, specifying parameters, choosing an effect size, and computing the sample size based on those factors. Sample size is influenced by expected effect size, study power, heterogeneity, error risk, and other variables. Dropouts from the sample during a study also impact sample size calculations. Proper determination of sample size is important for obtaining meaningful results and conducting ethical research.
1) Blinding in clinical trials refers to keeping trial participants, investigators, and assessors unaware of treatment assignments to prevent bias.
2) Potential benefits of blinding include less psychological or physical bias in participants, better compliance, and less bias in outcome assessments.
3) Types of blinding include non-blinded (where all know assignments), single-blinded (one group remains unaware), and double-blinded (participants, investigators, and assessors remain unaware). Placebos are often used to maintain blinding.
An observational study observes subjects without intervening. A cohort study follows groups over time to compare outcomes based on exposure. This document defines and provides examples of cohort studies. It describes their design, strengths like establishing temporality between exposure and outcome, and ability to study multiple outcomes from one exposure. Examples include Framingham Heart Study, Swiss HIV Cohort Study, and a Danish study on psoriasis and depression.
Randomization aims to equally distribute participant characteristics between treatment groups to prevent bias. There are several types of randomization including simple, block, and stratified block randomization. Blinding, such as double or triple blinding, helps prevent performance, detection, and other biases by keeping parties unaware of treatment assignments. Bias can still occur through factors like selection, performance, detection, laboratory, or sample size biases if randomization and blinding are not properly implemented.
Clinical trial designs can be categorized in several ways:
1. Based on the method used to allocate participants such as randomized controlled trials, non-randomized controlled trials, parallel group designs, crossover designs, and withdrawal designs.
2. Based on awareness of participants and researchers, such as blinded, unblinded, and double-blinded trials.
3. Based on the magnitude of activity being tested, such as superiority, inferiority, equality, and dose-response relationships.
Common trial types include pilot studies, which test experimental design on a small scale, and placebo-controlled trials, which compare an intervention to a placebo. Randomized controlled trials are considered the gold standard for assigning participants randomly to treatment or
Clinical trials are conducted to test new drugs, treatments or medical devices in humans to assess their safety and efficacy. There are four main phases of clinical trials:
Phase I trials involve small groups of people to determine basic safety and dosing requirements. Phase II trials expand the testing to more people to determine efficacy and further evaluate safety. Phase III trials involve large groups of people to confirm effectiveness, monitor side effects, compare to commonly used treatments and collect information to allow safe use of the intervention. Phase IV trials occur after the intervention has been marketed to gather information on effects in various populations and any long-term side effects.
This document discusses various clinical trial designs including parallel, crossover, factorial, and adaptive designs. It describes key elements of clinical trial methodology such as randomization, blinding, placebos, and controls. The document also outlines how clinical trial designs are applied differently in each phase of drug development from Phase 0 microdosing to Phase III confirmatory trials. Key challenges in clinical trial design like controlling bias and complex statistical analysis of factorial designs are also summarized.
PPT on Sample Size, Importance of Sample Size,Naveen K L
This document discusses factors related to determining sample size for research studies. It defines key terms like sample size, population and importance of sample size. The selection of sample size involves planning the study, specifying parameters, choosing an effect size, and computing the sample size based on those factors. Sample size is influenced by expected effect size, study power, heterogeneity, error risk, and other variables. Dropouts from the sample during a study also impact sample size calculations. Proper determination of sample size is important for obtaining meaningful results and conducting ethical research.
1) Blinding in clinical trials refers to keeping trial participants, investigators, and assessors unaware of treatment assignments to prevent bias.
2) Potential benefits of blinding include less psychological or physical bias in participants, better compliance, and less bias in outcome assessments.
3) Types of blinding include non-blinded (where all know assignments), single-blinded (one group remains unaware), and double-blinded (participants, investigators, and assessors remain unaware). Placebos are often used to maintain blinding.
An observational study observes subjects without intervening. A cohort study follows groups over time to compare outcomes based on exposure. This document defines and provides examples of cohort studies. It describes their design, strengths like establishing temporality between exposure and outcome, and ability to study multiple outcomes from one exposure. Examples include Framingham Heart Study, Swiss HIV Cohort Study, and a Danish study on psoriasis and depression.
Randomization aims to equally distribute participant characteristics between treatment groups to prevent bias. There are several types of randomization including simple, block, and stratified block randomization. Blinding, such as double or triple blinding, helps prevent performance, detection, and other biases by keeping parties unaware of treatment assignments. Bias can still occur through factors like selection, performance, detection, laboratory, or sample size biases if randomization and blinding are not properly implemented.
Clinical trial designs can be categorized in several ways:
1. Based on the method used to allocate participants such as randomized controlled trials, non-randomized controlled trials, parallel group designs, crossover designs, and withdrawal designs.
2. Based on awareness of participants and researchers, such as blinded, unblinded, and double-blinded trials.
3. Based on the magnitude of activity being tested, such as superiority, inferiority, equality, and dose-response relationships.
Common trial types include pilot studies, which test experimental design on a small scale, and placebo-controlled trials, which compare an intervention to a placebo. Randomized controlled trials are considered the gold standard for assigning participants randomly to treatment or
Here are the designs I would recommend for each case:
Case 1: N-of-1 design. This design is well-suited for testing the efficacy of a treatment for an individual patient, as in this case assessing L-arginine for a carrier of OTCD.
Case 2: Randomized withdrawal design. This minimizes time on placebo by giving all patients open-label treatment initially to identify responders, who are then randomized to continue treatment or placebo. This is appropriate given the reversible but relatively slow outcome.
Case 3: Delayed start design. This can distinguish treatment effects on symptoms from effects on disease progression, which is important given the primary endpoint of changes on the UPDRS scale for Parkinson
Clinical trials involve testing investigational drugs or treatments on human subjects to determine safety and efficacy. They progress through several phases, beginning with small pre-clinical trials on animals. Phase 1 trials involve 20-50 healthy volunteers to assess pharmacokinetics and safety. Phase 2 trials enroll 50-300 patient volunteers to further evaluate safety and dosage. Phase 3 trials are large randomized controlled trials of 250-1000+ subjects comparing the investigational treatment to standard treatment or placebo. If Phase 3 is successful, the results are submitted to regulatory agencies for approval to market the new drug. Post-marketing Phase 4 trials monitor long-term safety and efficacy.
The document presents information on the Declaration of Helsinki (DoH), including its history, development, scope, and basic ethical principles for medical research involving human subjects. It notes that the DoH is a cornerstone document developed by the World Medical Association that has undergone several revisions since 1964 to update principles for ethical human research. The summary provides an overview of the key topics covered in the document.
The document discusses various types of clinical trial designs including observational studies, uncontrolled experiments, non-randomized controlled trials, and randomized controlled trials. It provides examples of different randomized controlled trial designs such as parallel group trials, crossover trials, and cluster randomized trials. Factorial and Latin square designs are also summarized. The key advantages and disadvantages of randomized controlled trials are outlined.
Choice of control group in clinical trialsNagendra SR
To describe the general principles involved in choosing a control group for clinical trials intended to demonstrate the efficacy of a treatment and to discuss related trial design and conduct issues.
This document discusses various types of biases and errors that can occur in epidemiological studies, including random error, systematic error, random misclassification, bias, and confounding. It provides definitions and examples of these terms. Specific types of biases covered include selection bias, information bias, and confounding. Methods for controlling biases discussed include randomization, restriction, matching, stratification, standardization, and blinding.
Randomization is a key process in clinical trials that assigns participants to treatment groups in a way that limits bias. It aims to balance groups so they are similar in all ways except for the intervention received. Common randomization methods include coin tossing, random number tables, and computer generation of sequences. Block and stratified randomization can help produce balanced groups with comparable characteristics. Blinding of participants, investigators, and assessors is important to prevent biases from influencing outcomes. Inclusion and exclusion criteria define who can participate in a clinical trial based on factors like age, sex, disease characteristics, and medical history.
CROSSOVER STUDY DESIGN, DESIGN OF PHARMACOKINETIC STUDIES, FACTORS INFLUENCING BIOAVAILABILITY STUDIES, STUDY DESIGN, PARALLEL DESIGN, CROSS-OVER STUDIES, LATIN SQUARE DESIN, TWO-PERIOD CROSSOVER STUDY DESIGN, BALANCED INCOMPLETE BLOCK DESIGN (BIBD), REPLICATE CROSSOVER STUDY DESIGN , DIFFERENCE BETWEEN PARALLEL AND CROSSOVER STUDY DESIGN.
This document discusses post-marketing surveillance (PMS), which involves monitoring the safety of pharmaceutical drugs and medical devices after they have been approved and released on the market. PMS is important because pre-approval clinical trials involve limited numbers of patients and cannot detect all potential adverse effects. The document outlines the history of PMS, sources of PMS information, benefits of PMS systems, methods of surveillance including spontaneous reporting and cohort studies, and how manufacturers can establish PMS procedures and systems to gather feedback on their products.
This document outlines a clinical research protocol template. It begins with an introduction section defining clinical research and clinical trials. It then describes the purpose and contents of a clinical research protocol, including sections for objectives, background/rationale, study design, eligibility criteria, treatments, assessments, data collection and analysis, monitoring, ethics and regulations. The protocol template provides guidance on the level of detail needed for each section to clearly explain the research question, methodology, and procedures to ensure scientific validity and participant safety.
Post-marketing surveillance (PMS) monitors drug and medical device safety after market release using approaches like spontaneous reporting databases, prescription monitoring, and health records. PMS identifies potential safety issues through data review and helps detect rare or long-term adverse effects not seen in pre-market clinical trials which have limited patient populations and durations. PMS provides additional safety and efficacy information on marketed products and allows monitoring of special patient groups. Common PMS methods include spontaneous reporting, observational studies, randomized trials, and active surveillance networks.
Phase 1 clinical trials are the first studies conducted in humans of a new drug or treatment. They aim to determine the drug's safety and tolerability, identify the maximum tolerated dose, and understand the drug's pharmacokinetics. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent phase 2 and 3 trials to further evaluate efficacy.
Randomisation is a process that randomly assigns participants in a clinical trial to treatment groups in order to prevent bias. It distributes characteristics of participants evenly across groups and ensures comparability. Common randomisation methods include simple randomisation using a coin flip or computer generation, block randomisation which assigns participants in blocks to balance group sizes, and stratified randomisation which divides participants with prognostic factors into subgroups before randomisation. Bias can still occur if the randomisation process is not properly implemented or if those involved in the trial are aware of participant group assignments.
Institutional review board by akshdeep sharmaAkshdeep Sharma
The Institutional Review Board/Independent Ethics Committee (IRB/IEC) serves as an independent body that reviews and approves clinical trials to protect participant safety and rights. The IRB/IEC consists of at least five members with diverse qualifications to evaluate scientific and ethical aspects of trials. The IRB/IEC's responsibilities include reviewing trials, providing continuing oversight, ensuring informed consent, and maintaining records for regulatory review.
Blinding in clinical trials refers to keeping participants and investigators unaware of treatment group assignments after randomization. This helps reduce performance bias and ascertainment bias. Blinding is accomplished through placebos, sham interventions, and coding of group assignments. It is important for subjective outcomes but not always possible, and sometimes must be purposefully broken.
The document discusses the role of placebos in clinical trials. It defines placebos as inert substances with no therapeutic value used as dummy medicines. Placebos are used in clinical trials to compare effects to active drugs and exclude placebo responders. The placebo effect is psychological and based on expectations. Mechanisms involve neurobiological and psychological factors. Guidelines state placebos can only be used when no alternative exists and risks are justified, with informed consent and risk monitoring. A placebo washout period terminates prior drug effects to observe the trial drug's effects. Problems include imperfect placebos, impure placebos, selection bias, and overestimating placebo effects.
This document provides an overview of different study designs used in clinical research. It describes descriptive studies like case reports, case series, and cross-sectional studies which aim to describe characteristics of populations. Analytical studies like case-control and cohort studies assess associations between exposures and outcomes. Experimental studies like randomized clinical trials allocate exposures to subjects. Biases like selection bias, information bias, and confounding are discussed. An example of a cross-sectional study design assessing hypertension prevalence is provided.
The mission of the Clinical Trials Registry-India (CTRI) is to ensure that all clinical trials conducted in India are prospectively registered, i.e. before the enrolment of the first participant. Additionally, post-marketing surveillance studies, BA/BE studies as well as clinical studies as part of PG thesis are also expected to be registered in the CTRI. The vision of the CTRI is to ensure that every clinical trial conducted in the region is prospectively registered with full disclosure of the trial data set items. While this register is meant primarily for trials conducted in India, the CTRI will also accept registration of trials conducted in other countries in the region, which do not have a Primary Registry of its own, provided ethics approval (in English) is available and the study has not begun enrolling. The Clinical Trials Registry- India (CTRI), hosted at the ICMR's National Institute of Medical Statistics (http://icmr-nims.nic.in), is a free and online public record system for registration of clinical trials being conducted in India that was launched on 20th July 2007 (www.ctri.nic.in). Initiated as a voluntary measure, since 15th June 2009, trial registration in the CTRI has been made mandatory by the Drugs Controller General (India) (DCGI) (www.cdsco.nic.in). Moreover, Editors of Biomedical Journals of 11 major journals of India declared that only registered trials would be considered for publication1, 2.
Today, any researcher who plans to conduct a trial involving human participants, of any intervention such as drugs, surgical procedures, preventive measures, lifestyle modifications, devices, educational or behavioral treatment, rehabilitation strategies as well as trials being conducted in the purview of the Department of AYUSH (http://indianmedicine.nic.in/) is expected to register the trial in the CTRI before enrollment of the first participant. Trial registration involves public declaration and identification of trial investigators, sponsors, interventions, patient population etc before the enrollment of the first patient. Submission of Ethics approval and DCGI approval (if applicable) is essential for trial registration in the CTRI. Multi-country trials, where India is a participating country, which have been registered in an international registry, are also expected to be registered in the CTRI. In the CTRI, details of Indian investigators, trial sites, Indian target sample size and date of enrollment are captured. After a trial is registered, trialists are expected to regularly update the trial status or other aspects as the case may be. After a trial is registered, all updates and changes will be recorded and available for public display.
Siro Clinical Research Institute
Post Graduate Diploma in Clinical Research
www.siroinstitute.com
www.siroclinpharm.com
Table of contents
-Definition of CRF
-What is CRF
-Types & Methods of filling of CRF
-CRF Input team
-CRF Approval team
-Review team
-Facts about CRF
-Purpose of CRF
-CRF Development process & Guidelines
-Elements of CRF
-CRF Design
-CRF completion checklist
-CRF Design tools
-CRF use
-GCP connection
The document discusses clinical trials and their various phases. It begins by defining a clinical trial and noting they systematically study new drugs in human subjects to determine safety and efficacy. It then describes the various phases of clinical trials - phase I examines safety and dosing in small groups, phase II assesses efficacy and further evaluates safety in larger groups, and phase III tests effectiveness compared to standard treatments in large patient populations. The document provides details on trial designs, methods to reduce bias, and goals and considerations of each phase of clinical drug testing.
This document provides an overview of clinical trial design. It discusses the typical phases of clinical trials including:
- Phase I which focuses on safety and dose escalation
- Phase II which screens for therapeutic activity and further evaluates toxicity
- Phase III which uses a proper control group to further evaluate efficacy and monitors long-term safety
It also describes various study designs including randomized controlled trials, parallel designs, cross-over designs, and cohort studies. Key aspects of each design like advantages, disadvantages, and implementation are covered. The document provides a comprehensive yet concise primer on clinical trial methodology.
Here are the designs I would recommend for each case:
Case 1: N-of-1 design. This design is well-suited for testing the efficacy of a treatment for an individual patient, as in this case assessing L-arginine for a carrier of OTCD.
Case 2: Randomized withdrawal design. This minimizes time on placebo by giving all patients open-label treatment initially to identify responders, who are then randomized to continue treatment or placebo. This is appropriate given the reversible but relatively slow outcome.
Case 3: Delayed start design. This can distinguish treatment effects on symptoms from effects on disease progression, which is important given the primary endpoint of changes on the UPDRS scale for Parkinson
Clinical trials involve testing investigational drugs or treatments on human subjects to determine safety and efficacy. They progress through several phases, beginning with small pre-clinical trials on animals. Phase 1 trials involve 20-50 healthy volunteers to assess pharmacokinetics and safety. Phase 2 trials enroll 50-300 patient volunteers to further evaluate safety and dosage. Phase 3 trials are large randomized controlled trials of 250-1000+ subjects comparing the investigational treatment to standard treatment or placebo. If Phase 3 is successful, the results are submitted to regulatory agencies for approval to market the new drug. Post-marketing Phase 4 trials monitor long-term safety and efficacy.
The document presents information on the Declaration of Helsinki (DoH), including its history, development, scope, and basic ethical principles for medical research involving human subjects. It notes that the DoH is a cornerstone document developed by the World Medical Association that has undergone several revisions since 1964 to update principles for ethical human research. The summary provides an overview of the key topics covered in the document.
The document discusses various types of clinical trial designs including observational studies, uncontrolled experiments, non-randomized controlled trials, and randomized controlled trials. It provides examples of different randomized controlled trial designs such as parallel group trials, crossover trials, and cluster randomized trials. Factorial and Latin square designs are also summarized. The key advantages and disadvantages of randomized controlled trials are outlined.
Choice of control group in clinical trialsNagendra SR
To describe the general principles involved in choosing a control group for clinical trials intended to demonstrate the efficacy of a treatment and to discuss related trial design and conduct issues.
This document discusses various types of biases and errors that can occur in epidemiological studies, including random error, systematic error, random misclassification, bias, and confounding. It provides definitions and examples of these terms. Specific types of biases covered include selection bias, information bias, and confounding. Methods for controlling biases discussed include randomization, restriction, matching, stratification, standardization, and blinding.
Randomization is a key process in clinical trials that assigns participants to treatment groups in a way that limits bias. It aims to balance groups so they are similar in all ways except for the intervention received. Common randomization methods include coin tossing, random number tables, and computer generation of sequences. Block and stratified randomization can help produce balanced groups with comparable characteristics. Blinding of participants, investigators, and assessors is important to prevent biases from influencing outcomes. Inclusion and exclusion criteria define who can participate in a clinical trial based on factors like age, sex, disease characteristics, and medical history.
CROSSOVER STUDY DESIGN, DESIGN OF PHARMACOKINETIC STUDIES, FACTORS INFLUENCING BIOAVAILABILITY STUDIES, STUDY DESIGN, PARALLEL DESIGN, CROSS-OVER STUDIES, LATIN SQUARE DESIN, TWO-PERIOD CROSSOVER STUDY DESIGN, BALANCED INCOMPLETE BLOCK DESIGN (BIBD), REPLICATE CROSSOVER STUDY DESIGN , DIFFERENCE BETWEEN PARALLEL AND CROSSOVER STUDY DESIGN.
This document discusses post-marketing surveillance (PMS), which involves monitoring the safety of pharmaceutical drugs and medical devices after they have been approved and released on the market. PMS is important because pre-approval clinical trials involve limited numbers of patients and cannot detect all potential adverse effects. The document outlines the history of PMS, sources of PMS information, benefits of PMS systems, methods of surveillance including spontaneous reporting and cohort studies, and how manufacturers can establish PMS procedures and systems to gather feedback on their products.
This document outlines a clinical research protocol template. It begins with an introduction section defining clinical research and clinical trials. It then describes the purpose and contents of a clinical research protocol, including sections for objectives, background/rationale, study design, eligibility criteria, treatments, assessments, data collection and analysis, monitoring, ethics and regulations. The protocol template provides guidance on the level of detail needed for each section to clearly explain the research question, methodology, and procedures to ensure scientific validity and participant safety.
Post-marketing surveillance (PMS) monitors drug and medical device safety after market release using approaches like spontaneous reporting databases, prescription monitoring, and health records. PMS identifies potential safety issues through data review and helps detect rare or long-term adverse effects not seen in pre-market clinical trials which have limited patient populations and durations. PMS provides additional safety and efficacy information on marketed products and allows monitoring of special patient groups. Common PMS methods include spontaneous reporting, observational studies, randomized trials, and active surveillance networks.
Phase 1 clinical trials are the first studies conducted in humans of a new drug or treatment. They aim to determine the drug's safety and tolerability, identify the maximum tolerated dose, and understand the drug's pharmacokinetics. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent phase 2 and 3 trials to further evaluate efficacy.
Randomisation is a process that randomly assigns participants in a clinical trial to treatment groups in order to prevent bias. It distributes characteristics of participants evenly across groups and ensures comparability. Common randomisation methods include simple randomisation using a coin flip or computer generation, block randomisation which assigns participants in blocks to balance group sizes, and stratified randomisation which divides participants with prognostic factors into subgroups before randomisation. Bias can still occur if the randomisation process is not properly implemented or if those involved in the trial are aware of participant group assignments.
Institutional review board by akshdeep sharmaAkshdeep Sharma
The Institutional Review Board/Independent Ethics Committee (IRB/IEC) serves as an independent body that reviews and approves clinical trials to protect participant safety and rights. The IRB/IEC consists of at least five members with diverse qualifications to evaluate scientific and ethical aspects of trials. The IRB/IEC's responsibilities include reviewing trials, providing continuing oversight, ensuring informed consent, and maintaining records for regulatory review.
Blinding in clinical trials refers to keeping participants and investigators unaware of treatment group assignments after randomization. This helps reduce performance bias and ascertainment bias. Blinding is accomplished through placebos, sham interventions, and coding of group assignments. It is important for subjective outcomes but not always possible, and sometimes must be purposefully broken.
The document discusses the role of placebos in clinical trials. It defines placebos as inert substances with no therapeutic value used as dummy medicines. Placebos are used in clinical trials to compare effects to active drugs and exclude placebo responders. The placebo effect is psychological and based on expectations. Mechanisms involve neurobiological and psychological factors. Guidelines state placebos can only be used when no alternative exists and risks are justified, with informed consent and risk monitoring. A placebo washout period terminates prior drug effects to observe the trial drug's effects. Problems include imperfect placebos, impure placebos, selection bias, and overestimating placebo effects.
This document provides an overview of different study designs used in clinical research. It describes descriptive studies like case reports, case series, and cross-sectional studies which aim to describe characteristics of populations. Analytical studies like case-control and cohort studies assess associations between exposures and outcomes. Experimental studies like randomized clinical trials allocate exposures to subjects. Biases like selection bias, information bias, and confounding are discussed. An example of a cross-sectional study design assessing hypertension prevalence is provided.
The mission of the Clinical Trials Registry-India (CTRI) is to ensure that all clinical trials conducted in India are prospectively registered, i.e. before the enrolment of the first participant. Additionally, post-marketing surveillance studies, BA/BE studies as well as clinical studies as part of PG thesis are also expected to be registered in the CTRI. The vision of the CTRI is to ensure that every clinical trial conducted in the region is prospectively registered with full disclosure of the trial data set items. While this register is meant primarily for trials conducted in India, the CTRI will also accept registration of trials conducted in other countries in the region, which do not have a Primary Registry of its own, provided ethics approval (in English) is available and the study has not begun enrolling. The Clinical Trials Registry- India (CTRI), hosted at the ICMR's National Institute of Medical Statistics (http://icmr-nims.nic.in), is a free and online public record system for registration of clinical trials being conducted in India that was launched on 20th July 2007 (www.ctri.nic.in). Initiated as a voluntary measure, since 15th June 2009, trial registration in the CTRI has been made mandatory by the Drugs Controller General (India) (DCGI) (www.cdsco.nic.in). Moreover, Editors of Biomedical Journals of 11 major journals of India declared that only registered trials would be considered for publication1, 2.
Today, any researcher who plans to conduct a trial involving human participants, of any intervention such as drugs, surgical procedures, preventive measures, lifestyle modifications, devices, educational or behavioral treatment, rehabilitation strategies as well as trials being conducted in the purview of the Department of AYUSH (http://indianmedicine.nic.in/) is expected to register the trial in the CTRI before enrollment of the first participant. Trial registration involves public declaration and identification of trial investigators, sponsors, interventions, patient population etc before the enrollment of the first patient. Submission of Ethics approval and DCGI approval (if applicable) is essential for trial registration in the CTRI. Multi-country trials, where India is a participating country, which have been registered in an international registry, are also expected to be registered in the CTRI. In the CTRI, details of Indian investigators, trial sites, Indian target sample size and date of enrollment are captured. After a trial is registered, trialists are expected to regularly update the trial status or other aspects as the case may be. After a trial is registered, all updates and changes will be recorded and available for public display.
Siro Clinical Research Institute
Post Graduate Diploma in Clinical Research
www.siroinstitute.com
www.siroclinpharm.com
Table of contents
-Definition of CRF
-What is CRF
-Types & Methods of filling of CRF
-CRF Input team
-CRF Approval team
-Review team
-Facts about CRF
-Purpose of CRF
-CRF Development process & Guidelines
-Elements of CRF
-CRF Design
-CRF completion checklist
-CRF Design tools
-CRF use
-GCP connection
The document discusses clinical trials and their various phases. It begins by defining a clinical trial and noting they systematically study new drugs in human subjects to determine safety and efficacy. It then describes the various phases of clinical trials - phase I examines safety and dosing in small groups, phase II assesses efficacy and further evaluates safety in larger groups, and phase III tests effectiveness compared to standard treatments in large patient populations. The document provides details on trial designs, methods to reduce bias, and goals and considerations of each phase of clinical drug testing.
This document provides an overview of clinical trial design. It discusses the typical phases of clinical trials including:
- Phase I which focuses on safety and dose escalation
- Phase II which screens for therapeutic activity and further evaluates toxicity
- Phase III which uses a proper control group to further evaluate efficacy and monitors long-term safety
It also describes various study designs including randomized controlled trials, parallel designs, cross-over designs, and cohort studies. Key aspects of each design like advantages, disadvantages, and implementation are covered. The document provides a comprehensive yet concise primer on clinical trial methodology.
This document outlines the key steps in conducting a clinical trial:
1. Drawing up a detailed research protocol that serves as the trial's operating manual.
2. Selecting and screening participants according to eligibility criteria to identify the study population. Sample size is also calculated.
3. Randomly allocating the study participants into experimental and control groups through a process like randomization to reduce bias.
This document discusses bioequivalence studies. It defines bioequivalence as when two drug products reach systemic circulation to the same relative extent, with their plasma concentration-time profiles being identical without statistically significant differences. It describes the analytical methods, pharmacokinetic evaluation, and statistical evaluation used in bioequivalence studies. It also discusses study designs such as parallel designs, crossover designs, and fasting versus fed conditions that can be used in bioequivalence studies.
1) Clinical trials involve prospectively assigning human participants to health interventions to evaluate effects on outcomes. They aim to carefully and ethically answer precisely framed questions.
2) Clinical trials are classified into phases based on goals, with Phase 0 trials involving small doses and numbers of participants to assess safety.
3) Randomization, blinding, inclusion/exclusion criteria, and sample size are important design considerations to reduce bias and ensure results reflect the interventions rather than other factors. Statistical analysis then determines if any effects seen are real or due to chance.
This document discusses key considerations for clinical trial design, size, and study population. It outlines common trial designs like parallel group, crossover, and factorial designs. Appropriate study design and adequate sample size are important to achieve study objectives and answer key questions. Sample size calculations should account for the primary endpoint, expected treatment effect, variability, type I and II errors. Selection of subjects and controls also impacts trial validity. An independent data monitoring committee provides trial oversight.
1) The document discusses a lecture on evidence-based medicine (EBM) and critical appraisal.
2) EBM involves integrating the best available research evidence with clinical expertise and patient values. It includes formulating clinical questions, searching for evidence, appraising research, and applying the evidence to patient care.
3) The lecture reviews the principles of EBM and critical appraisal, including how to formulate answerable clinical questions using the PICO framework, search for evidence, and appraise different types of research studies.
The document discusses techniques used in clinical trial design such as randomization, blinding, and study design. Randomization techniques include simple, restricted, stratified, and adaptive randomization to control for bias and variability. Blinding (single, double, triple) aims to eliminate subjective bias by withholding treatment information from patients and investigators. Study design determines objectives and compares new treatments parallel to current treatments through randomized parallel group designs. Proper selection and randomization of patients represents the target population.
This document provides an overview of ICH guidelines E9 through E12, which provide statistical and clinical trial design guidance. E9 discusses statistical principles for clinical trials, including trial context, scope, design techniques to avoid bias, sample size considerations, and data analysis. E10 covers choice of control groups in clinical trials and describes placebo, no treatment, dose-response, and active controls. E11 provides guidance for clinical trials in pediatric patients, including issues around timing, formulations, study types, age classifications, and ethical considerations. E12 relates to clinical evaluation by therapeutic category.
This document discusses different types of epidemiological studies, with a focus on experimental studies and randomized controlled trials (RCTs). It describes the key features of RCTs, including that they: (1) involve randomly allocating subjects into study and control groups to receive or not receive an intervention, (2) aim to control for confounding factors through randomization, and (3) are considered the gold standard for evaluating interventions due to their ability to minimize bias. The document outlines the basic steps in conducting an RCT, from developing a protocol to randomization, intervention, follow-up, assessment and analysis. It also discusses types of RCTs and their importance in evaluating treatments, prevention, risk factors and more.
This document provides an overview of clinical trials. It defines a clinical trial and explains that they are conducted under controlled conditions to evaluate potential therapies. It describes the different phases of clinical trials from early safety testing to post-marketing studies. Key aspects of clinical trial design are discussed, including randomization, blinding, controls and study populations. Reasons for terminating a trial early are also mentioned.
How to scientifically conduct a clinical professional research trial? In the current era of Collaborate or parish, we need to keep this design in our mind.
Enjoy
@copyLeft
guia estatístico JAMA para metodologia de pesquisa
Table of contents:
1. The Intention-to-Treat Principle
2. Noninferiority Trials
3. Sample Size Calculation for a Hypothesis Test
4. Interpretation of Clinical Trials That Stopped Early
5. Cluster Randomized Trials
6. Case-Control Studies
7. Decision Curve Analysis
8. Gatekeeping Strategies for Avoiding False-Positive Results in Clinical Trials With
Many Comparisons
9. Multiple Comparison Procedures
10. Pragmatic Trials
11. Equipoise in Research
12. The Propensity Score
13. Dose-Finding Trials
14. Odds Ratios—Current Best Practice and Use
15. Evaluating Discrimination of Risk Prediction Models
16. Time-to-Event Analysis
17. The Stepped-Wedge Clinical Trial
18. Mendelian Randomization
19. Bayesian Analysis: Using Prior Information to Interpret the Results of Clinical Trials
This document discusses surgical audit and research. It defines audit as the systematic analysis of surgical care quality including procedures, treatments, complications, and patient outcomes and quality of life. Research is defined as determining the safety and effectiveness of medical treatments and technologies. The key differences between audit and research are that research can involve experiments while audit only reviews existing care, and research aims to increase medical knowledge while audit aims to identify opportunities to improve care quality. The document also outlines types of studies, sample sizes, biases, statistical analysis methods, levels of evidence, and the Cochrane Collaboration.
This document provides an overview of clinical trials and the role of statistics within clinical research. It discusses how clinical trials allow researchers to systematically study medical treatments and make evidence-based inferences about a treatment's effects. The document outlines the key elements of clinical trials, such as using a control group, randomization, blinding, and informed consent. It also discusses the history of clinical trials and how they became the preferred method for medical research due to providing a standardized and ethical way to study human subjects compared to observational studies. Finally, the document addresses some of the ethical considerations around clinical trials, such as balancing patient welfare with gaining scientific knowledge.
ich guidelines for clinical trials, scientific approach ppt.pptxJyotshnaDevi4
The document outlines the ICH guidelines for conducting clinical trials. It describes the objectives to promote common understanding and evaluation of foreign clinical trial data. Clinical trials should follow scientific principles and protect subjects. Trials generally proceed through four phases, starting with small healthy volunteer studies (Phase I) to evaluate safety, followed by exploratory efficacy studies (Phase II), then confirmatory efficacy and dosing studies (Phase III), and finally post-marketing studies (Phase IV). Special populations like children, pregnant women, and those with organ impairment require unique consideration. Proper study design, conduct, analysis and reporting are emphasized.
The document discusses various threats to valid causal inference from clinical trials, including chance findings, small effect sizes, repeated testing of ineffective treatments, inflation of type 1 error from multiple analyses, non-completion and selective publication of trials, deviations from scientific standards like lack of a comparator, and biases in meta-analyses. It provides examples of how these threats can lead to overstating evidence of effectiveness even when no true causal effect exists. Careful trial design and analysis is needed to avoid these issues and properly assess causality.
Experimental epidemiology with special reference to RCT - Harimu.pptxDrHarimuBargayary
The document discusses experimental epidemiology and randomized controlled trials. It begins by defining experimental epidemiology as involving experimentation through intervention in groups to measure effects. It describes the basic steps of RCTs as drawing up a protocol, randomization, intervention/manipulation, follow-up, and outcome assessment. It provides details on sample size estimation, selection of reference and experimental populations, randomization techniques, blinding, analysis approaches, and types of RCTs including clinical trials.
Randomized Control Trials
Enigma of Blinding Unraveled
Introduction
RCT
Steps in a RCT
Allocation Concealment
Bias in RCT
Phases in RCT
Types of RCT
Study Designs of RCT
Blinding
Methods of Blinding in different trials
Assessment of Blinding
Un-blinding
Current Scenario of Blinding
CONSORT
Conclusion
References
The document discusses key concepts in analyzing clinical trials, including:
- Intention-to-treat analysis, which analyzes all participants based on initial treatment assignment regardless of compliance, and measures effectiveness. This is the recommended primary analysis method.
- Per-protocol analysis, which only includes compliant participants, and measures maximum efficacy. This undermines randomization.
- Measures of effect size such as relative risk, absolute risk reduction, relative risk reduction, and number needed to treat, which are used to assess clinical significance beyond just statistical significance.
- The importance of assessing both statistical and clinical significance of trial results, where clinical significance considers the minimum clinically meaningful effect.
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Obesity is one of the most common factor which underlies the pathophysiology of many other non- communicable diseases. In recent years, its prevalence has blown out of proportions. The term GLOBESITY signfies that. Newer pharmacological developments will definitely play a crucial role in containing this epidemic.
This seminar is my attempt this interesting topic with all the latest data I could collect on the internet.
Pharmacogenetics and pharmacogenomics is an upcoming branch in therapeutics. Various pharmacogenomic tests are currently available to aid in actual clinical practice. It has shown to have promising results in personalized medicine It is my attempt to compile the basic concepts from various books, articles, and online journals. Please feel free to comment.
HIV AIDS is one of the most dreadful of all diseases. Newer drugs and drug combination are coming quite frequently. Attempts to design an HIV vaccine is also underway.
This seminar is my attempt this interesting topic with all the latest data I could collect on the internet.
GPCRs are the most dynamic and most abundant all the receptors. The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. GPCRs are responsible for every aspect of human biology from vision, taste, sense of smell, sympathetic and parasympathetic nervous functions, metabolism, and immune regulation to reproduction. GPCRs interact with a number of ligands ranging from photons, ions, amino acids, odorants, pheromones, eicosanoids, neurotransmitters, peptides, proteins, and hormones.
Nevertheless, for the majority of GPCRs, the identity of their natural ligands is still unknown, hence remain orphan receptors.
The simple dogma that underpins much of our current understanding of GPCRs, namely,
one GPCR gene− one GPCR protein− one functional GPCR− one G protein −one response
is showing distinct signs of wear.
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Hiranandani Hospital in Powai, Mumbai, is a premier healthcare institution that has been serving the community with exceptional medical care since its establishment. As a part of the renowned Hiranandani Group, the hospital is committed to delivering world-class healthcare services across a wide range of specialties, including kidney transplantation. With its state-of-the-art facilities, advanced medical technology, and a team of highly skilled healthcare professionals, Hiranandani Hospital has earned a reputation as a trusted name in the healthcare industry. The hospital's patient-centric approach, coupled with its focus on innovation and excellence, ensures that patients receive the highest standard of care in a compassionate and supportive environment.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
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Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
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Muscles of Mastication by Dr. Rabia Inam Gandapore.pptx
Designs of clinical trials
1. Designs of Clinical Trials
Dr. Prashant Shukla
Junior Resident
Dept of Pharmacology
2. Contents
Definition
Bias- ways to reduce it.
Classification of clinical trials
Individual designs:
Traditional Study designs
Study designs for small populations
Miscellaneous trials
2/18/2015 2
3. Clinical Trials
(As per the revised Schedule ‘Y’ of the
Drugs & Cosmetic Act 2005).
122-DAA. Definition of Clinical trial
It is a systematic study of new drug(s) in
human subjects to generate data for
discovering and/or verifying the clinical,
pharmacological, and/or adverse effects
with the objective of determining their
safety and/or efficacy of the new drugs.
2/18/2015 3
4. Key elements of Clinical Trials
The acronym PICO is used by health
professionals to convey all elements of
the clinical scenario in an orderly
fashion:
P - Patient, Population of patients,
Problem
I - Intervention (a therapy, test)
C - Comparison (another therapy,
placebo)
O - Outcome (survival, response)2/18/2015 4
5. Bias
Bias is a systematic error contained in
the study design, conduct or
interpretation of a study. Whereas
extensive lists of particular bias forms
exist, there are two basic forms of bias:
1. Selection bias occurs if study
populations are selected in an
erroneous way that comparison
groups are not comparable.
2. Information bias occurs if
measurements are different between2/18/2015 5
6. Techniques to avoid bias
The two most important techniques are:
1. Randomisation of subjects.
2. Blinding of subjects as well as
investigator.
3. Monitoring of clinical trial.
4. Checking original source documents.
5. Source data verification.
6. Clinical data management.
7. Quality control (QC) and Quality
assurance (QA) procedures.
2/18/2015 6
7. Randomisation
It aims to obviate systematic differences
between groups due to factors other than
intervention.
It gives each patient a known (or equal)
chance of being assigned to any of the
groups.
The most common methods of
randomisation are:
1. Simple randomization
2. Blocked randomization
3. Stratified randomization
4. Cluster randomization2/18/2015 7
9. TYPES OF CLINICAL TRIALS
Superiority Trials: compare a std
treatment or intervention with a new or
alternative approach anticipated to be
more effective.
Inferiority Trials: An alternative therapy
(perhaps one that is cheaper, less toxic or
easier to administer) is suggested to
replace the standard provided its efficacy
is no worse than the std.
Equivalence: Test treatment is required to
be neither less nor more efficacious than
2/18/2015 9
10. Did investigator
assign exposure?
Experimental study Observational study
Analytical
study
Random allocation Comparison group?
YES
NO
Descriptiv
e study
NO
YES
RCT
Non-
rando
mize
d
YE
S
NO
Cohort
Study
Case-
control
Cross-
sectiona
l2/18/2015 10
11. How to categorize clinical
trials?
Number of participating centers:
1. Single center vs Multicenter
2. National vs International
Control group:
1. Non comparative
2. Historical controls
3. Concurrent controls
4. “Self” controls
2/18/2015 11
12. How to categorize clinical
trials?
Randomization:
1. Non- randomized
2. Simple randomized
3. Balanced (stratified) randomized trials
4. Cluster randomized trials
Blinding (Masking):
1. Open label or non- blinded trial
2. Single blinded
3. Double blinded
4. Triple blinded
5. Double dummy
2/18/2015 12
13. How to categorize clinical
trials?
Purpose:
1. Treatment trials
2. Prevention trials
3. Screening trials
4. Quality of life trials
5. Compassionate use trials
6. Genetics trials
2/18/2015 13
14. How to categorize clinical
trials? Trial format:
1. Traditional designs for clinical trials
A. Parallel group trials
B. Cross over trials
C. Factorial design
D. Add on design
E. Randomized withdrawal design
F. Early escape design
2. Special Design issues for small clinical
trials
A. N- of- 1 design
B. Sequential design
C. Decision analysis- based design
D. Adaptive design
E. Risk based allocation design2/18/2015 14
15. How to categorize clinical
trials?
Trial format (contd.):
3. Miscellaneous Designs
A. Cluster randomized design
B. Enrichment design
C. Placebo Challenging design
D. Blind Reader design
E. Trial with Zelen’s design
F. Trial with Wennberg’s design
G. Trial with Comprehensive cohort design
H. Design using historical controls
I. Rolling design
2/18/2015 15
16. Factors to consider in selecting a
clinical trial design
2/18/2015 16
Study population and indication
Treatment duration
Carry over effects
Cost and logistics
Patient convenience
Statistical considerations
17. Role of Placebo in Clinical trials
No standard treatment exists.
Standard treatment is ineffective.
Standard treatment is inappropriate for
the particular clinical trials.
The placebo is reportedly effective in
treating the disease.
The disease is mild and lack of
treatment is not considered to be
medically important.
2/18/2015 17
18. Role of Placebo in Clinical
trials...
The placebo is given as an add-on
treatment to an already existing
regimen that is not sufficient to treat
patients.
The disease process is characterized
by frequent spontaneous
exacerbations and remission(e.g.,
peptic ulcer).
“Escape clauses” or points are
2/18/2015 18
19. Run in period
Before randomization of patients a run-in (or lead-in)
period of placebo, no active treatment, dietary control,
or active maintenance therapy is usually employed.
Advantages:
1. It acts as a washout period to remove effects of
previous therapy.
2. It can be used to obtain baseline data and to
evaluate if patient fulfills study entry criteria.
3. It can be used as a training period for patients,
investigators, and their staff.
4. It helps in identifying placebo responders.
5. It provides useful information regarding patient
compliance.
6. It can be used to estimate and compare the
magnitude of possible placebo effects between
groups. 2/18/2015 19
21. Parallel Group Design
• It is of two types:
1. Group comparison parallel design: In this
method, efficacy of treatment is using
two groups (Treatment vs Control group).
2. Matched pair parallel design: In this
method, pairs of subjects are formed
possessing the same characteristics and
who might be expected to respond
similarly to the treatments.
2/18/2015 21
22. Group comparison Parallel
Design
Treatment Group/ Arm Control Group/ Arm
• Most common clinical design.
• Complete randomized design in which each
patient receives one and only one treatment in
a randomized fashion.
2/18/2015 22
Exp.
Drug
23. Group comparison Parallel
Design
Advantages:
a) It’s simple and easy to implement.
b) It is universally acceptable.
c) It is applicable to acute conditions.
d) Analysis is less complicated and
interpretation is straight forward.
Disadvantages:
a) It does not into account the inter-
individual variability.
2/18/2015 23
24. Matched Pair Parallel Design
Pair A Pair B Pair C Pair D
• In this method, pairs of subjects are formed
possessing the same characteristics and who
might be expected to respond similarly to the
treatments.
• Matching of patients is done before
randomization. 2/18/2015 24
25. Matched Pair Parallel Design...
Advantages:
a) Requires small study population.
b) Can reduce variability from treatment
comparison (compared with parallel froup
designs).
Disadvantages:
a) The prognostic characteristics are not
easily defined.
b) Patient recruitment is slow.
c) When the number of co-variates is large,
this design is difficult to implement.2/18/2015 25
26. Cross over design
A crossover design is a modified
randomized block design in which each
block receives >1 treatment at different
dosing periods.
A block can be a patient or a group of
patients. Patients in each block receive
different sequences of treatments.
A crossover design is called a complete
crossover design if each sequence2/18/2015 26
27. Cross over design...
Group A Group B
WASH OUT PERIOD WASH OUT PERIOD
2/18/2015 27
Drug A
Drug B
Drug B
Drug A
RANDOMIZATION
28. Cross over design...
Crossover designs may be used in clinical
trials in the following situations where
1. Objective measures and interpretable
data for both efficacy and safety are
obtained.
2. Chronic (relatively stable) disease are
under study.
3. Prophylactic drugs with relatively short
half-life are being investigated.
4. Relatively short treatment periods are
considered.
5. Baseline and washout periods are2/18/2015 28
29. Cross over design...
Advantages:
1. It allows a within-patient comparison
between treatments, since each patient
serves as his or her own control.
2. It removes the interpatient variability from
the comparison between treatments.
3. With a proper randomization of patients
to the treatment sequences, it provides
the best unbiased estimates for the
differences between treatments.
2/18/2015 29
30. Cross over design...
Disadvantages:
1. Carry- over effects: The residual
influence of treatments on subsequent
treatment periods. Avoided by wash out
period.
2. Order effects: Order in which the tt are
administered affects the outcome.
3. Period effects: The diff. between the
study periods.
4. Drop-outs can be higher.
2/18/2015 30
31. Concept of Wash-out effects
AKA carry over / residual effects.
It is the rest period between 2 treatment
periods.
It permits the effect of previous treatment
to wane off.
It should be long enough for the treatment
effect to wear off so that there is no
carryover effect of previous treatment to
next.
It depends upon the nature of the drug.
2/18/2015 31
32. Williams design
When there are more than two treatments
to be compared, a complete crossover
design is called William’s design.
I. William’s design with three treatments
ACB BAC CBA
BCA CAB ABC
II. William’s design with four treatments
ADBC BACD CBDA DCAB2/18/2015 32
33. Split person design
2/18/2015 33
• Occasionally, it is possible to administer the
two interventions at the same time.
•Very similar to that of the cross-over trial,
except there is no equivalent to the periods or
to the wash-out although a carry-over (now
termed carry-across) effect is likely to be
present.
Drug A Drug B
Split Mouth Design
34. Split person design...
2/18/2015 34
Drug A Drug B
Psoriasis patient
• Occasionally, it is possible to administer the
two interventions at the same time.
•Very similar to that of the cross-over trial,
except there is no equivalent to the periods or
to the wash-out although a carry-over (now
termed carry-across) effect is likely to be
present.
35. Split person design...
• Occasionally, it is possible to administer the
two interventions at the same time.
•Very similar to that of the cross-over trial,
except there is no equivalent to the periods or
to the wash-out although a carry-over (now
termed carry-across) effect is likely to be
present. 2/18/2015 35
Drug A Drug B
Paired Organs
36. 2/18/2015 36
Factorial designs
2× 2 Factorial design
•Used when it is desired to study the influence
of a number of factors on the treatments
compared as well as their interaction with
different treatments.
+
Drug A Drug B Drug
A+B
Neither Drug
37. Factorial designs...
Uses:
1. Make efficient use of clinical trial
subjects by evaluating two treatments
with same no. of individuals.
2. Influence of a number of factors can be
studied together which might require
many trials if done individually.
3. Establish dose-response
characteristics of the combination of A
and B when efficacy of each has been
previously established.2/18/2015 37
38. Factorial designs...
Advantages:
1. A greater precision can be obtained in
estimating the overall main factor effects.
2. Interaction between different factors can be
explored.
3. Additional factors can help to extend validity
of conclusions derived.
Disadvantages:
1. Difficult to analyse.
2. Large designs require large no of subjects.
3. Between subjects design lacks statistical2/18/2015 38
39. Add- on Design
Group A Group B
• A placebo-controlled trial of an experimental
intervention is tested with people already receiving an
established, effective treatment.
2/18/2015 39
+ +
Std. treatment Std. treatment
Exp.
Intervention
40. Add- on Design...
Uses:
1. Add on design is especially useful for
testing of an experimental interventions
that have mechanism of action different
from that of established effective
treatment.
2. It can be used for long term studies of
treatments of conditions like heart
failure since established treatment is
life saving and is not being denied.
2/18/2015 40
41. Randomized Withdrawal
Design
• Here, individuals who respond (+)ly to an experimental
intervention are randomized to continue receiving that
intervention or to receive a placebo.
• Return of symptoms in placebo group causes
withdrawal of subject from that group.
2/18/2015 41
WITHDRAWN
FROM STUDY
Exp.
Intervention
42. Randomized Withdrawal
Design...
Advantage: This trial design minimizes
the amount of time that individuals
receive a placebo.
Disadvantages:
1. Carry over effects.
2. Difficulties in assessing whether the
underlying disease process is still
active.
3. Long lag times to adverse events if
2/18/2015 42
43. Early escape design
Intervention Arm Placebo Arm
• Participants are removed from the study if
symptoms reached a defined level or they fail to
respond to a defined extent.
• The patient could then be switched over to
another
therapy, including the test treatment if
2/18/2015 43
Exp.
Intervention
Predefined negative
efficacy criterion
44. Early escape design...
Advantages:
1. It minimizes an individual’s duration of
exposure to a placebo.
2. Ethically justifiable.
Disadvantages:
1. Complex statistical analysis.
2. Difficulties in assessing whether
underlying disease is active or not (like
Randomised withdrawal design).
2/18/2015 44
46. Study designs for small
populations
Defined as <50 possible patients recruited
in 5years with multicentre∕ multinational
recruitment.
1. Rare diseases
2. Unique study populations (e.g. Astronauts)
3. Individually tailored therapies
4. Environments that are isolated
5. Emergency situations
6. Public health urgency
7. Restricted resources coupled with an
important need
2/18/2015 46
47. N- of- 1 Design
They are cross over trials in which one
participant receives the experimental
and the control interventions.
Typically the number of pair of
interventions varies from two to seven.
The number of interventions is not pre
specified so that the clinician and the
patient can decide to stop at will.
2/18/2015 47
48. N- of- 1 Design...
Indications:
1. If an RCT has shown that some
patients are unresponsive to treatment.
2. If there is doubt about whether a
treatment is really providing benefit to
the patient.
2/18/2015 48
49. Decision Analysis based
Design
Outcome Intervention A Intervention B
Beneficial
outcome
1. Utility (0-1)
2. Probability
1. Utility (0-1)
2. Probability
Adverse
Outcome
1. Utility (0-1)
2. Probability
1. Utility (0-1)
2. Probability
•Utility are numeric values assigned to each outcome
which reflects the “desirability of the event”.
• Probability are the “chances of event to occur”.
•Decision analysis combines the probability with utility to
calculate an “expected utility”.
2/18/2015 49
50. Decision Analysis based
Design...
Thus decision analysis is used during the
planning phase to structure the question.
One obtains best estimates of for each
probability and utility.
Sensitivity analysis is done where
potential important values (utility and
probability) are changed over a likely
range to create a model structure.
This design is dependent upon on the
assumptions made about parameter
values and model structure.2/18/2015 50
51. Adaptive design
2/18/2015 51
These designs are used when an RCT
clearly begin to favour one intervention
over another.
Advantage: Over time more patients will
be assigned to the more successful
treatment.
Disadvantages:
1. In most trials, patients are
heterogeneous with respect to
important prognostic factors.
52. Adaptive design
2. It does not protect against bias
introduced by changes in the types of
patients entering into trial overtime.
Adaptive designs can be of two types:
1. Sequential designs
2. Rolling designs
2/18/2015 52
53. Sequential Design
Here the participants are sequentially
enrolled in the study and are assigned a
treatment (usually at random).
The efficiency, safety and efficacy of the
experiment is improved by changing the
rules as the study progresses.
Various for sequential designs are:
1. Up & down methods (Most Common)
2. Stochastic approximation methods
3. Maximum likelihood methods
4. Bayesian methods
2/18/2015 53
54. Sequential Design...
2/18/2015 54
Abandon the
Study
If low dose is ineffective
and
High dose is effective
If low dose is effective
and
High dose has ADRs
If both low dose and
High dose are ineffective
Low
dose
High
dose
Up & down method
55. Sequential Design...
Problems with sequential designs:
1) Uncertainty of sample size.
2) Duration of trial cannot be stipulated in
advance.
3) Resources (funding).
2/18/2015 55
56. Rolling design
• Design that can roll on continually by
introducing new treatment options
from the evidence accumulated, dropping
those of either proven efficacy or if found
not to be effective.
• Make use of intermediate endpoints (in
contrast to the traditionally used
endpoints that require longer patient
follow-up).
2/18/2015 56
57. Intervention A Intervention B Control Group
2/18/2015 57
Discontinue
Intervention B
Subsequent
recruitment favours
beneficial profiles
Randomized
recruitment to
control arm
continues
Drug A Drug B Std.
drug
58. Risk based Allocation Design
• This design allows individuals at higher risk or
with greater disease severity to benefit from a
potentially superior experimental treatment.
•Advantages: Ethically more justifiable.
•Disadvantage: It is a non-randomized design.
2/18/2015 58
Individuals with higher
risk or greater disease
severity
Individuals with lesser
risk or lesser disease
severity
Potentially superior
Experimental treatment
Relatively inferior
Experimental treatment
60. Cluster Randomized Design
Cluster/ Group A Cluster/ Group B Cluster/ Group C
• For assessment of non-therapeutic
interventions such as lifestyle intervention or
new educational programs for smoking
cessation.
• Randomization can be performed on intact
social units- family, school, worksites, athletic
teams, etc.
•Randomization is done at cluster level rather2/18/2015 60
Intervention A Intervention B Intervention C
61. Cluster Randomized Design...
Although the trials adopt a cluster
randomization, the analysis of data
completely ignores this fact and uses
subject as the unit of analysis.
Thus, the unit of analysis may not be
necessarily the same as the unit of
randomization.
2/18/2015 61
62. Enrichment Design
Enrichment
phase
Randomizatio
n phase
• Phase of manipulation of dose levels of a
therapeutic agent for identification of patients
with drug efficacy is Enrichment phase.
• The patients with drug efficacy identified at
enrichment phase are randomized to receive
either efficacious dose of drug or matching
placebo. 2/18/2015 62
63. Placebo Challenging design
For treatment of erection dysfunction, a
design that consists of a :-
1. “Titration phase” for achieving optimal
dose and
2. “Crossover active treatment phase”
with two placebo challenges (i.e., pre-
and post-treatment) is often
considered.
Design of this kind is a placebo-
challenging design.2/18/2015 63
64. Placebo Challenging design..
1. In-clinic
evaluation
(double-blind
placebo-
challenging)
2. Three-month
home treatment
3. In-clinic
evaluation (double-
blind
placebo- 2/18/2015 64
Titration phase
Active drug
Active drug
Placebo
Placebo Active drug
Active drug
65. Blinded reader designs
A clinical trial for evaluation of medical
imaging products with blinded imaging
evaluation is said to have a blinded reader
design.
It is not feasible to blind the investigators
who administer the investigational medical
imaging agents.
So effectiveness of medical imaging drug
products should be evaluated based on the
images by readers (usually trained
radiologists) obtained with the
investigational agents or controls under2/18/2015 65
66. Trial with Zelen’s design
Here, the patients are randomised before
they give consent to participate in the trial.
Those who are allocated to standard
treatment group are not told that they are
part of the trial.
Those who are allocated to the experimental
intervention group are told that they are part
of the trial. If they refuse to participate in the
trial, they are given the standard treatment
but analysed as if they had received the
experimental intervention.2/18/2015 66
67. Trial with Zelen’s design...
Advantages:
1. Almost all eligible individuals are
included in the trial.
2. Allows the evaluation of true effect of
experimental intervention in patients.
Disadvantages:
1. Open trials.
2. The statistical power of the study gets
compromised if large no of patients
choose the standard treatment.
2/18/2015 67
69. Trial with Zelen’s design...
There is ethical concerns of not telling
patients that they have been randomised
to receive the standard treatment.
So, the original Zelen’s design can be
modified by informing participants of the
group to which they have been allocated
and by offering them opportunity to switch
the group.
Disadvantages:
1. Lack of blinding 2/18/2015 69
71. Trial with Wennberg’s design
In this design, eligible individuals are
randomised to:
1. “Preference group” where patients can
choose between exp. or std. treatment at
will.
2. “RCT group” where patients are
randomised between both arms.
Rarely used.
They are likely to be more frequently used
as consumer participation in healthcare
decisions and research is increasing.2/18/2015 71
72. Trial with Wennberg’s design...
2/18/2015 72
Preference Group RCT Group
ELIGIBLE INDIVIDUALS
Std.
drug
Exp.
drug
Std.
drug
Exp.
drug
73. 2/18/2015 73
Trial with comprehensive cohort
design
• A comprehensive cohort trial is a study in
which all participants are followed up,
regardless of their randomisation status.
1. If a person agrees for RCT, he is
randomised to one of the study
interventions.
2. If a person does not agree for RCT, he is
given his intervention of choice and
followed up as if he were a part of a cohort
study.
•At the end, the outcomes of RCT and cohort
study are compared to assess their similarities
74. Trial with comprehensive cohort
design
2/18/2015 74
Outcomes of Cohort studies and RCT group are then
compared
Cohort Group RCT Group
ELIGIBLE INDIVIDUALS
Std.
drug
Exp.
drug
Std.
drug
Exp.
drug
75. Designs using historical
controls
Very rarely, a new treatment is given to all
patients and result are compared with the
past (historical controls).
It is almost always unacceptable even for
disease like leukaemia because:
1. Standards of diagnosis and treatment
change with time
2. Severity of some diseases fluctuates
An exception to this rule is the case-
control study
2/18/2015 75
76. Factors in choosing clinical trials
designs
1. Chronology of events: Chronological
effects may be very important in any trial
design, but particularly in cross over
design.
2. Subject convenience: Lengthy trials
requiring multiple visits and involving
washout periods may compromise patient
compliance.
3. Trial cost: Very lengthy trials may not be
routinely feasible due to prohibitive costs2/18/2015 76
77. Trial designs phase wise
Phase I CT: All patients receive the drug,
thus an unblinded, open label trial is
suitable.
Phase II through III CT: Parallel designs,
Cross over, Factorial designs are most
commonly used.
Phase IV CT: Non experimental
(observational) designs- These include
epidemiologic designs such as case
control or cohort studies.2/18/2015 77
78. 2/18/2015 78
Knowledge is the root and practice is the
bough and there is no bough without a
root behind it, although roots may be
found which can as yet boast no
boughs.
Moses
Maimonides
Thank you for your patience!!