Short Course introduction for Clinical trials basics & Definations For Free copy contact Adham.m.elbasha@gmail.com

1. Clinical Studies Basics
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2. Interventional VS Non Interventional
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
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3. Content
• How to read a clinical trial.
• Overview on Drug Development Process.
• Phases Of Clinical Trials.
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4. How to read a Trial
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5. Important Data to Know
Orientation
Opportunity
Overview
Observation
Obtain
Offer
6 O
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6. Important Data to Know
Orientation
Opportunity
Overview
Observation
Obtain
Offer
Title
Publication
Name Of author
Affiliation of Author
Abstract
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7. Title
• The title alerts 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.
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8. Publication
• Where the study published?
• Published study in a well known journal makes it more reliable.
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9. Author
• Most papers are 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.
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10. Author
• Appear in the 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.
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11. Affiliation of author
• Corresponding Author: Full name and affiliation for the primary
contact author for persons who have questions about the research.
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12. Abstract
• Recently, the structured 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.
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13. Abstract
• The abstract should be a summary of the paper.
• Nearly all journals require that research papers include abstracts.
• The abstract appears following the title page.
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14. Important Data to Know
Orientation
Opportunity
Overview
Observation
Obtain
Offer
Objective
Design
Primary Endpoint
Secondary Endpoint
Number of Patient
Safety assessment
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15. Objective
• Tell “why did you do the study”; setting the scene or laying the
foundation or background for the paper.
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16. The development process
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17. Moving from the question to study design
Goals of study design:
1. Eliminate systematic error (Bias).
2. Minimize random error (Variability).
3. Maximize generalizability of study findings.
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18. Design
Interventional study:
• One or 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.
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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.
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20. Design
Prospective Study:
• Study in 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.
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21. Design
Retrospective Study:
• Study in 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.
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22. Design
Meta-analysis:
• It is common 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.
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23. Design
Meta-analysis:
• Meta-analysis is most 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
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24. Design
Review Articles
• Reflect current 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.
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25. Design
Confirmatory(Explanatory( study
• A controlled 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.
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26. Design
Longitudinal study
• A study 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.
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27. Design
Efficacy study
• Does the experimental treatment work under ideal condition?
Effectiveness
• Does the experimental treatment work under ordinary condition?
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28. Design
Placebo-controlled:
• The therapy under 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
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29. Design
Randomization:
• A study has 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.
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30. Design
• Simple Randomization
• Stratified Randomization
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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
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32. Design options
• Two group parallel trials
• Multiple group parallel trials
• Factorial designs
• Cross-over designs
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33. Design options
• Two group 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.
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34. Design options
• Two group parallel trials
• Multiple group parallel trials
• Factorial designs
• Cross-over designs
Eligible patients
Group1
Group 3
End of trialGroup 2
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35. Design options
• Two group 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.
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36. Crossover Trials
• Randomization is 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.
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37. Crossover Trials
• Cross-over trials 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.
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38. Design
Blinding:
• The goal of 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.
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39. Design
Open-label:
• Both the investigator 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.
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40. Design
Double-blind:
• Neither the patient 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.
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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.
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42. Interventional VS Non Interventional
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
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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.
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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.
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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
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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
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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
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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
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49. The FINER criteria
• Five principals guide the selection of a research question.
• The research should be:
Ethical
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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
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51. Primary Endpoint
• Study endpoints 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.
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52. Secondary Endpoint
• An additional 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.
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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.
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54. Endpoints Types
Clinical endpoint:
• An endpoint relating to the symptoms and/or course of a disease.
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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.
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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.
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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).
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58. Endpoints Types
• Single VS Multiple primary endpoints: depends on the scientific
question being evaluated.
• With multiple outcomes, will affect sample size needed to answer
each of the questions.
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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.
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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
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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.
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62. Number of patient
Population
• The entire collection of subjects that have something in common
and to which conclusions of studies are inferred.
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63. Number of patient
Sample
• Subset taken from a population, and is usually intended to be
representative of the population.
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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.
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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.
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66. Number of patient
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67. Safety Assessment
• How side effect being evaluated.
• Either side effects reported directly from the patient to the
investigator or by asking the patients if specific side effects occur.
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68. Important Data to Know
Orientation
Opportunity
Overview
Observation
Obtain
Offer
Problems &
Opportunities
behind conducting
study
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69. Problems & Opportunities behind 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.
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70. Important Data to Know
Orientation
Opportunity
Overview
Observation
Obtain
Offer
Inclusion criteria
Exclusion criteria
How study drug
administered?
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71. Inclusion criteria
• Inclusion criteria 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.
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72. Exclusion criteria
• Exclusion criteria 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
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73. How study drug administered?
• This section define how patient take the study drug or
intervention.
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74. Important Data to Know
Orientation
Opportunity
Overview
Observation
Obtain
Offer
1ry Endpoint
2ry Endpoint
Safety
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75. Results
• The “what did 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.)
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76. Important Data to Know
Orientation
Opportunity
Overview
Observation
Obtain
Offer The Main Conclusion
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77. The Main Conclusion
• Contains the summary of results of the trial.
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78. Statistical Significance
P Value & Confidence Interval
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79. Note
Statistical significance does not necessarily imply clinical significance.
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80. Null Hypothesis VS Alternative Hypothesis
Null Hypothesis
• There is no effect, no difference, no association between two
interventions.
Alternative hypothesis
• There is difference between two intervention.
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81. Hypothesis testing
Actuality
Investigator Reality
H0 True H0 False
H0 True Correct Type I Error
H0 False Type II Error Correct
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82. The logic of hypothesis 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).
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83. P Value
• The p 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.
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84. Confidence Interval
• Hypothesis testing (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.
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85. Confidence Interval
• A 95% CI is an interval generated by a process that is correct 95%
of time in containing the population parameter.
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86. Clinical studies
Phases of clinical trials
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87. Definition
• Clinical trials are 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.
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88. Drug Development Process
Drug
Discovery
Pre-Clinical
(Animals)
Phases Of Clinical Trials
1-2-3
Post Approval
Studies 4
10-15 years
FIH: First on Human
Phase 1
POC: Proof of Concept
Phase 2
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89. Drug Development Process
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90. Pre-clinical safety testing
Target Organs 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
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91. Toxicity studies
Acute
Determine effect of Overdose
Repeated Dose
Toxicity findings
Determine the
maximum duration
of the clinical studies
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92. Maximum human recommended starting dose
(MRSD)
No Toxicity
No Adverse drug reactions
Small Dose
Larger Dose
NOAEL
(No Observed
Adverse Event Level)
Toxicity
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93. Clinical aspects in FIH
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.
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94. Pharmacokinetics in FIH
Blood samples 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
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95. Phases of clinical trials
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.
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96. Proof of concept studies (POC)
Single Dose in
Patients
Dose Response
Pathophysiology
Safety
Efficacy
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97. Phases of clinical trials
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.
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98. Phases of clinical trials
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.
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99. Phases of clinical trial
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100. Phases of clinical trials
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.
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101. Other Classification of Clinical 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.
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102. Other Classification of Clinical 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.
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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.
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104. Adham El Basha