Uploaded byAdham M. El Basha
Clinical Trials basics
The document provides a comprehensive overview of clinical study design, highlighting key concepts such as interventional vs. non-interventional studies, various study designs (longitudinal vs. cross-sectional, prospective vs. retrospective), and the importance of establishing endpoints. It also emphasizes the nuances of trial documentation, including the significance of title, authorship, abstract structure, and safety assessments. Additionally, it outlines data selection criteria, statistical analysis, and the implications of hypothesis testing in clinical research.
More Related Content
Similar to Clinical Trials basics
Clinical Trials basics
- 1. Clinical Studies Basics AdhamEl Basha Adham El Basha
- 2. Interventional VS NonInterventional Confirmatory VS Exploratory Efficacy VS Effectiveness Placebo VS Active control Longitudinal VS Cross-sectional Prospective VS Retrospective Parallel VS Crossover Simple VS Stratified Randomization Blinding Adham El Basha
- 3. Content • How toread a clinical trial. • Overview on Drug Development Process. • Phases Of Clinical Trials. Adham El Basha
- 4. How to reada Trial Adham El Basha
- 5. Important Data toKnow Orientation Opportunity Overview Observation Obtain Offer 6 O Adham El Basha
- 6. Important Data toKnow Orientation Opportunity Overview Observation Obtain Offer Title Publication Name Of author Affiliation of Author Abstract Adham El Basha
- 7. Title • The titlealerts the reader to the topic of your paper. • A well written or phrased title creates curiosity and draws readers to investigate the substance of your paper. • However, the main function of the title is to describe your research. Adham El Basha
- 8. Publication • Where thestudy published? • Published study in a well known journal makes it more reliable. Adham El Basha
- 9. Author • Most papersare written by one or two primary authors. • The remaining authors have reviewed the work and/or aided in study design or data analysis. • Byline should list only those persons who have participated sufficiently in the work. • Taking responsibility for the content, design, analysis and interpretation of the data. Adham El Basha
- 10. Author • Appear inthe byline, Usually just below the title. • Usually, the byline is limited to 6 persons. • Authors may explain the rationale for the order of authorship in a footnote. • Some journals list each author’s degrees. Adham El Basha
- 11. Affiliation of author •Corresponding Author: Full name and affiliation for the primary contact author for persons who have questions about the research. Adham El Basha
- 12. Abstract • Recently, thestructured abstract (an abstract that has 5 sections: (introduction, objective, methods, results, and conclusions) has become the standard for most research articles (whereas reviews, case reports, and certain other types of special articles have non structured abstracts). • The abstract must accurately reflect the content of the paper; nothing can be included in the abstract that does not appear in the body of the paper. • Therefore, it is best to write the abstract after you have written and carefully edited your paper. Adham El Basha
- 13. Abstract • The abstractshould be a summary of the paper. • Nearly all journals require that research papers include abstracts. • The abstract appears following the title page. Adham El Basha
- 14. Important Data toKnow Orientation Opportunity Overview Observation Obtain Offer Objective Design Primary Endpoint Secondary Endpoint Number of Patient Safety assessment Adham El Basha
- 15. Objective • Tell “whydid you do the study”; setting the scene or laying the foundation or background for the paper. Adham El Basha
- 16. The development process AdhamEl Basha
- 17. Moving from thequestion to study design Goals of study design: 1. Eliminate systematic error (Bias). 2. Minimize random error (Variability). 3. Maximize generalizability of study findings. Adham El Basha
- 18. Design Interventional study: • Oneor more groups of patients are submitted to an investigator- controlled intervention such as a drug, a procedure, or a treatment. Interest lies in the effect the intervention has on study subjects. Adham El Basha
- 19. Design Epidemiological Study /Non-interventional: • One or more groups of patients are observed and characteristics about the patients are recorded for analysis. No intervention is performed on patients in an observational study. Adham El Basha
- 20. Design Prospective Study: • Studyin which subjects are identified prospectively and followed up over time; the outcomes of interest have not yet occurred when the study begins; most commonly used in the context of a cohort study. Adham El Basha
- 21. Design Retrospective Study: • Studyin which subjects are identified after they have already developed or failed to develop an outcome; study goes back in time to determine the prior characteristics of the individuals. • Suitable when the difference between exposure and out come is too long or out come is rare. Adham El Basha
- 22. Design Meta-analysis: • It iscommon to find that several trials have attempted to answer similar questions about clinical effectiveness. • Often many of the individual trials will fail to show a statistically significant difference between treatments. • However, when the results from individual studies are combined using appropriate techniques (meta-analysis), significant benefits of treatment may be shown. • Systematic review methodology is at the heart of meta-analysis. Adham El Basha
- 23. Design Meta-analysis: • Meta-analysis ismost often used to assess the clinical effectiveness of healthcare interventions; it dopes this by combining data from two or more randomized control trials. • Meta-analysis of trials provides a precise estimate of treatment effect, giving due weight to the size of the different studies included • The validity of the meta-analysis depends on the quality of the systematic review on which it is based Adham El Basha
- 24. Design Review Articles • Reflectcurrent thinking on a particular topic, and influence how individual physicians practice. • Are usually written by an expert or a group of experts in the field. Adham El Basha
- 25. Design Confirmatory(Explanatory( study • Acontrolled study in which a hypothesis is stated in advance. • Intended to provide firm evidence in support of claims. Exploratory study • Should have a clear and precise objective. • May require a more flexible design. Adham El Basha
- 26. Design Longitudinal study • Astudy in which research subjects are assessed at several different times. Cross sectional study • A study in which a single group of research subjects are assessed at a single time. Adham El Basha
- 27. Design Efficacy study • Doesthe experimental treatment work under ideal condition? Effectiveness • Does the experimental treatment work under ordinary condition? Adham El Basha
- 28. Design Placebo-controlled: • The therapyunder evaluation is compared with a placebo, a substance that has no pharmacological effect. Active-controlled: • The therapy under evaluation is compared with an agent that has known efficacy Adham El Basha
- 29. Design Randomization: • A studyhas greater validity if the allocation to treatment is as random as possible. • In a randomized trial, chance is used to assign a person to either the study group or the control group. • A randomization mechanism (often a computer program) is employed so that any one individual enrolled in the trial has an equal chance of being assigned to either the study group or the control group. Adham El Basha
- 30. Design • Simple Randomization •Stratified Randomization Adham El Basha
- 31. Design Parallel group design: •The different treatments are given at the same time and each patient receives only one treatment; the cohort studies mentioned previously are parallel group studies Crossover design: • Patients are started on one treatment and crossed over to the other treatment; this design is commonly used for pharmacokinetic studies Adham El Basha
- 32. Design options • Twogroup parallel trials • Multiple group parallel trials • Factorial designs • Cross-over designs Adham El Basha
- 33. Design options • Twogroup parallel trials • Multiple group parallel trials • Factorial designs • Cross-over designs Eligible patients Group1 Group 2 End of trial With a parallel study, the possibility always exists that some unrecognized difference between the group A and group B patients will affect the results. Adham El Basha
- 34. Design options • Twogroup parallel trials • Multiple group parallel trials • Factorial designs • Cross-over designs Eligible patients Group1 Group 3 End of trialGroup 2 Adham El Basha
- 35. Design options • Twogroup parallel trials • Multiple group parallel trials • Factorial designs • Cross-over designs Eligible patients Group1 treatment A Group 2 Treatment B End of trial Group1 treatment B Group 2 Treatment A Each patient serves as his own control. Adham El Basha
- 36. Crossover Trials • Randomizationis used to determine the order in which the patient receives each treatment, i.e. treatment A followed by B, or treatment B followed by A. • One advantage of using a cross-over design is that it reduces the between patient variability, because the comparison of treatment A versus B is made on the same patient. • Thus, sample sizes are smaller than for a parallel group trial design. Adham El Basha
- 37. Crossover Trials • Cross-overtrials cannot be used in the situation where patients can only receive one treatment (such as surgery), and are appropriate only for chronic conditions. • An analysis of a cross-over trial should investigate if patient outcome is influenced by the order in which treatments are given and if the effects of the first treatment carry over into the period of the second treatment. Adham El Basha
- 38. Design Blinding: • The goalof the blinding design of a study is to eliminate bias by preventing either the investigators or the patients, or both, from learning who is receiving the control medication and who is receiving the study medication. Adham El Basha
- 39. Design Open-label: • Both theinvestigator and the patient know who is receiving the treatment drug and who is receiving the control (placebo or comparative medication). Single-blind: • The patient does not know which treatment is being received, but the investigator knows. Adham El Basha
- 40. Design Double-blind: • Neither thepatient nor the investigator knows who is receiving the treatment drug and who is receiving the control. • Provides the most reliable data. • More complicated to initiate and conduct than other study designs. Adham El Basha
- 41. Design Combination of blinds: •In some 2-part trials, patients may begin in a double-blind design for one part of a trial and then switch to a single-blind or open- label design for another part of the trial. Single blind washout period: • The investigators gives a placebo to patients at the beginning of the study to eliminate any pervious effect of any product. Adham El Basha
- 42. Interventional VS NonInterventional Confirmatory VS Exploratory Efficacy VS Effectiveness Placebo VS Active control Longitudinal VS Cross-sectional Prospective VS Retrospective Parallel VS Crossover Simple VS Stratified Randomization Blinding Adham El Basha
- 43. Ascertainment of endpoints •Every clinical trial has a primary question or questions that the trial is being conducted to evaluate. • These primary questions, as well as any secondary and tertiary questions, are clearly defined and stated in advance. • These objectives correspond to a study endpoint(s) for each participant. • Endpoints are the post-randomization measurement required to address the intervention trial objectives. Adham El Basha
- 44. Ascertainment of endpoints •Have to be clearly defined and reproducible. • Specified in advance, before ever see the data from trial. • Wide range: binary, continuous, ordinal, counts, time to event or length of survival, actual level, change from baseline. • In general, collect more data rather than less. • Example: better to collect blood pressure, not binary hypertension. Adham El Basha
- 45. Choosing the question •Good questions arise from both clinical experience and pervious research. • How do we begin the search for a good question? – Master the literature – Be alert to new ideas and techniques – Keep your imagination roaming – Learn from leaders and mentors Adham El Basha
- 46. The FINER criteria •Five principals guide the selection of a research question. • The research should be: Feasible Adequate number of patients Adequate technical expertise Affordable in time and money Manageable in scope and scale Adham El Basha
- 47. The FINER criteria •Five principals guide the selection of a research question. • The research should be: Interesting Study Interesting problems So you can continue the trial Adham El Basha
- 48. The FINER criteria •Five principals guide the selection of a research question. • The research should be: Novel Confirming, refuting, or extending previous findings Pursuing new questions Adham El Basha
- 49. The FINER criteria •Five principals guide the selection of a research question. • The research should be: Ethical Adham El Basha
- 50. The FINER criteria •Five principals guide the selection of a research question. • The research should be: Relevant To scientific knowledge To clinical and health policy To future research Adham El Basha
- 51. Primary Endpoint • Studyendpoints are the measurements for what the trial is setting out to prove, and they are directly tied to the study hypothesis. • The main measurement of the study. Adham El Basha
- 52. Secondary Endpoint • Anadditional measurement of the study. • Trials may have one or more 2ndry endpoints. • 2ndry endpoints are designed to evaluate aspects of the therapy under study. • Moa, safety, ..Etc. Adham El Basha
- 53. Endpoints Types Hard endpoint: •A study endpoint that is definitive with respect to the disease process and requires no subjectivity in its measurement; can be directly quantified. • Example: all cause mortality, myocardial infraction confirmed by WHO criteria. Soft endpoint: • A study endpoint that requires subjective assessment or that may not relate strongly to the disease. • Example: level of pain, feeling better. Adham El Basha
- 54. Endpoints Types Clinical endpoint: •An endpoint relating to the symptoms and/or course of a disease. Adham El Basha
- 55. Endpoints Types Surrogate endpoint: •Surrogate endpoints are laboratory measurements or clinical sign or intermediate markers used as a substitute for a clinically meaningful endpoint. • Measure changes in an intermediate factor in the main pathway that determines clinical outcome. Adham El Basha
- 56. Endpoints Types Surrogate endpoint: •Advantage: can shorten the length and cost of RCT; further our understanding of pathophysiology (intermediate marker) • Disadvantage: utility depend on strength of association between surrogate and primary clinical outcome. • Changes of intervention on surrogate marker must accurately predict changes in clinically meaningful endpoint. Adham El Basha
- 57. Endpoints Types Composite Endpoints •Having multiple endpoints within a trial increases the possibility of achieving a significant result for one of them by chance alone. • Another problematic feature with multiple endpoints is that the endpoints may give conflicting results (showing a significant difference for some but no significant difference for others). Adham El Basha
- 58. Endpoints Types • SingleVS Multiple primary endpoints: depends on the scientific question being evaluated. • With multiple outcomes, will affect sample size needed to answer each of the questions. Adham El Basha
- 59. Number of patient •Size of the Study Population: • “N” is used to describe the entire study population. • “n” is used to describe a group within the entire population. Adham El Basha
- 60. Number of patient ITT:(More statistically rigorous) • The outcomes for all patients are analyzed based on the treatment arm to which they were randomized, regardless of whether they received the treatment or completed the study; also known as full analysis Protocol analysis: (more accurately) • The outcomes are analyzed only for those patients who had a pre- specified minimal exposure to the regimen and who did not have any major protocol violations; also known as observed cases or evaluable patients analysis Adham El Basha
- 61. Number of patient •Large sample sizes reduce biases and errors in the clinical trial, and are necessary to detect significance and increase the power. • Statisticians determine the optimum sample size based on several factors, include: 1. The rate at which the event occurs in the control group. 2. The magnitude of effect that is expected( or desired). 3. The desired probability of detecting significance for a specific effect. Adham El Basha
- 62. Number of patient Population •The entire collection of subjects that have something in common and to which conclusions of studies are inferred. Adham El Basha
- 63. Number of patient Sample •Subset taken from a population, and is usually intended to be representative of the population. Adham El Basha
- 64. Number of patient Prevalence •It is the number of individuals with a given disease at a given point in time divided by the population at risk at that point in time. Adham El Basha
- 65. Number of patient Incidence •It is the number of new cases that have occurred during a given interval of time divided by the population at risk at the beginning of the time interval. Adham El Basha
- 66. Number of patient AdhamEl Basha
- 67. Safety Assessment • Howside effect being evaluated. • Either side effects reported directly from the patient to the investigator or by asking the patients if specific side effects occur. Adham El Basha
- 68. Important Data toKnow Orientation Opportunity Overview Observation Obtain Offer Problems & Opportunities behind conducting study Adham El Basha
- 69. Problems & Opportunitiesbehind conducting study • The reason behind conducting this trial. • What is the added value of the results of the trial. • How this trial will benefit future patients. Adham El Basha
- 70. Important Data toKnow Orientation Opportunity Overview Observation Obtain Offer Inclusion criteria Exclusion criteria How study drug administered? Adham El Basha
- 71. Inclusion criteria • Inclusioncriteria are characteristics that the prospective subjects must have if they are to be included in the study. • Inclusion criteria determine which patients in the population may benefit from the results of this trial. Adham El Basha
- 72. Exclusion criteria • Exclusioncriteria are those characteristics that disqualify prospective subjects from inclusion in the study. • Strongly Justified Reasons for Exclusion: – Unable to provide informed consent – Placebo or intervention would be harmful – Lack of equipoise (intervention harmful) – Effect of intervention difficult to interpret • Potentially Justified Reasons for Exclusion: – Individual may not adhere – Individual may not complete follow up – Individuals do not have reliable information Adham El Basha
- 73. How study drugadministered? • This section define how patient take the study drug or intervention. Adham El Basha
- 74. Important Data toKnow Orientation Opportunity Overview Observation Obtain Offer 1ry Endpoint 2ry Endpoint Safety Adham El Basha
- 75. Results • The “whatdid you find” • Report on data collection and/or recruitment • Participants (demographic, clinical condition, etc.) • Present key findings with respect to the central research question • Secondary findings (secondary outcomes, subgroup analyses, etc.) Adham El Basha
- 76. Important Data toKnow Orientation Opportunity Overview Observation Obtain Offer The Main Conclusion Adham El Basha
- 77. The Main Conclusion •Contains the summary of results of the trial. Adham El Basha
- 78. Statistical Significance P Value& Confidence Interval Adham El Basha
- 79. Note Statistical significance doesnot necessarily imply clinical significance. Adham El Basha
- 80. Null Hypothesis VSAlternative Hypothesis Null Hypothesis • There is no effect, no difference, no association between two interventions. Alternative hypothesis • There is difference between two intervention. Adham El Basha
- 81. Hypothesis testing Actuality Investigator Reality H0True H0 False H0 True Correct Type I Error H0 False Type II Error Correct Adham El Basha
- 82. The logic ofhypothesis testing • If we find difference between two groups: • First we assume that there is no real difference between the two groups (Null hypothesis) • Then we calculate if we can see the observed or larger difference just by chance(P Value) • If P is small we reject the idea that there is no difference (reject Null Hypothesis) • If P is high the observed difference is a chance finding (we don’t reject the null hypothesis). Adham El Basha
- 83. P Value • Thep value is the probability of seeing the observed (or more extreme) outcome if the null hypothesis is true. • Significance level is commonly set to be 0.05 or less. Adham El Basha
- 84. Confidence Interval • Hypothesistesting (P Value) answer the question of whether the treatment is likely to have a non-zero effect with yes or no. • The CI is based on the idea that if the same study done with different sample, the results would not be identical but would spread around the true value but unknown value. Adham El Basha
- 85. Confidence Interval • A95% CI is an interval generated by a process that is correct 95% of time in containing the population parameter. Adham El Basha
- 86. Clinical studies Phases ofclinical trials Adham El Basha
- 87. Definition • Clinical trialsare experiments done in clinical research. • Designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison. • Clinical trials generate data on safety and efficacy. Adham El Basha
- 88. Drug Development Process Drug Discovery Pre-Clinical (Animals) PhasesOf Clinical Trials 1-2-3 Post Approval Studies 4 10-15 years FIH: First on Human Phase 1 POC: Proof of Concept Phase 2 Adham El Basha
- 89. Drug Development Process AdhamEl Basha
- 90. Pre-clinical safety testing TargetOrgans to assess Cardiovascular Neuromuscular Respiratory Others As Needed We Check Dose Dependence & Potential for reversibility Other Toxicity Studies Genotoxicity Carcinogenicity Local tolerance Photo toxicity Reproductive toxicity Adham El Basha
- 91. Toxicity studies Acute Determine effectof Overdose Repeated Dose Toxicity findings Determine the maximum duration of the clinical studies Adham El Basha
- 92. Maximum human recommendedstarting dose (MRSD) No Toxicity No Adverse drug reactions Small Dose Larger Dose NOAEL (No Observed Adverse Event Level) Toxicity Adham El Basha
- 93. Clinical aspects inFIH Single Dose in Healthy Volunteers Main Outcomes Safety Pharmacokinetics Pharmacodynamics Specific FIH Issues Route and Rate of Administration: Oral – Syrup – Injection – Suppositories. Endpoints: Adverse Events – Physiology – PK & PD – Efficacy. Adham El Basha
- 94. Pharmacokinetics in FIH Bloodsamples at different intervals This Allows us to Estimate C max T max AUC T ½ Population Pharmacokinetics profile Relate Pharmacokinetics profile to toxicity and physiological response Adham El Basha
- 95. Phases of clinicaltrials Phase 1 Goal of Phase 1 trials: Determine safe dose for further clinical studies Study pharmacokinetics of the drug Phase 1 trials are the first-in-human trials. Testing within a small group of people (20–80) to evaluate safety, determine safe dosage ranges, and begin to identify side effects. Adham El Basha
- 96. Proof of conceptstudies (POC) Single Dose in Patients Dose Response Pathophysiology Safety Efficacy Adham El Basha
- 97. Phases of clinicaltrials Phase 2 Establishing the efficacy of the drug, usually against a placebo. Testing with a larger group of people (100–300) to see if it is effective and to further evaluate its safety. The gradual increase in test group size allows less-common side effects to be progressively sought. Adham El Basha
- 98. Phases of clinicaltrials Phase 3 Final confirmation of safety and efficacy. Testing with large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely. Adham El Basha
- 99. Phases of clinicaltrial Adham El Basha
- 100. Phases of clinicaltrials Phase 4 Post marketing studies delineate additional information, including the treatment's risks, benefits, and optimal use. As such, they are ongoing during the drug's lifetime of active medical use. Adham El Basha
- 101. Other Classification ofClinical Trial 1. Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes. 2. Screening trials test the best way to detect certain diseases or health conditions. 3. Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. 4. Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. Adham El Basha
- 102. Other Classification ofClinical Trial 5. Quality of life trials (supportive care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness. 6. Compassionate use trials or expanded access trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. Adham El Basha
- 103. The study protocol •Clinical trials MUST have a written protocol • Communicates the design and organization of study • Written in advance and changed only in minor ways after the study begins. • Major medical journals require that a trial be registered before enrollment begins. Adham El Basha
- 104.