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.
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.
INSTITUTIONAL REVIEW BOARD (IRB/IEC).pptxRAHUL PAL
The International Council on Harmonisation (ICH) defines an institutional review board (IRB) as a group formally designated to protect the rights, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup. IRBs can also be called independent ethics committees (IECs).
An IRB/IEC reviews the appropriateness of the clinical trial protocol as well as the risks and benefits to study participants. It ensures that clinical trial participants are exposed to minimal risk in relation to any benefits that might result from the research.
IRB/IEC members should be collectively qualified to review the scientific, medical and ethical aspects of the trial.
Per the FDA, an IRB/IEC should have:
At least five members.
Members with varying backgrounds.
At least one member who represents a non-scientific area (a lay member).
At least one member who is not affiliated with the institution or the trial site (an independent member).
Competent members who are able to review and evaluate the science, medical aspects and ethics of the proposed trial.
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Randomization is the process by which allocation of subjects to treatment groups is done by chance, without the ability to predict who is in what group. It is done in clinical trials. This presentation describes the methods of randmization used in clinical trials.
Cross over design, Placebo and blinding techniques Dinesh Gangoda
A crossover design is a modified randomized block design in which each block receives more than one 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 sequence contains all treatments under investigation.
A placebo is a dummy medicine containing no active substance.
This substance has no therapeutic effect, used as a control in testing new drugs.
Latin- ‘ I shall please’
INSTITUTIONAL REVIEW BOARD (IRB/IEC).pptxRAHUL PAL
The International Council on Harmonisation (ICH) defines an institutional review board (IRB) as a group formally designated to protect the rights, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup. IRBs can also be called independent ethics committees (IECs).
An IRB/IEC reviews the appropriateness of the clinical trial protocol as well as the risks and benefits to study participants. It ensures that clinical trial participants are exposed to minimal risk in relation to any benefits that might result from the research.
IRB/IEC members should be collectively qualified to review the scientific, medical and ethical aspects of the trial.
Per the FDA, an IRB/IEC should have:
At least five members.
Members with varying backgrounds.
At least one member who represents a non-scientific area (a lay member).
At least one member who is not affiliated with the institution or the trial site (an independent member).
Competent members who are able to review and evaluate the science, medical aspects and ethics of the proposed trial.
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Randomization is the process by which allocation of subjects to treatment groups is done by chance, without the ability to predict who is in what group. It is done in clinical trials. This presentation describes the methods of randmization used in clinical trials.
Cross over design, Placebo and blinding techniques Dinesh Gangoda
A crossover design is a modified randomized block design in which each block receives more than one 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 sequence contains all treatments under investigation.
A placebo is a dummy medicine containing no active substance.
This substance has no therapeutic effect, used as a control in testing new drugs.
Latin- ‘ I shall please’
Freshers in clinical research and regulatory affairs must go through this presentation. It will help you to understand the basis of clinical trial design as per European guidelines, which is the most preferred reference guideline. Initially, I also faced many problems to understand this concept. A student who is studying a clinical research diploma can also use this presentation for their basic understanding.
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
Clinical trials are the gold standard of evidence-based medicine. Properly designed clinical trials can lead to chance findings and potentially lead to erroneous conclusions.
Importantly, clinical trials can also be badly designed on purpose to increase the risk of false or chance findings leading to support misleading claims. Such techniques are frequently used by bad researchers and charlatans to substantiate their claims with biased clinical trials. It is therefore important to be weary of the limitations of clinical trials and understand how causal inference should be approach. In that presentation, I discuss the situations under which the risk of erroneous conclusions from clinical trials is increased and I discuss ways to identify and prevent bad clinical research.
The views expressed and presented in that presentation are my own views and may not represent the views of the National Institute for Health and Care Excellence.
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
This seminar is my attempt to discuss screening of anti-emetic drugs using different animal models. The materials used in the presentation is derived from different standard textbooks, internet and journals. Please feel free to suggest ways to improve it.
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.
This power point is my attempt to address the common yet serious issue of Polypharmacy.
Polypharmacy in elderly is a necessary evil. Although it is not always inappropriate, but the “inappropriateness” should be judged on a case to case basis.
Necessary tools should be used to avoid it.
And deprescribing is recommended to correct it as soon as it is labeled as a case of “inappropriate polypharmacy”.
Enantiomers are a part and parcel of modern Drug discovery and development. Chiral drugs are largely replacing their earlier racemic as and when found suitable. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
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MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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!!