This document provides an overview of different types of clinical study designs, including observational studies and experimental studies. It discusses the key aspects and objectives of different phases of clinical trials, including:
1. Phase I trials which aim to determine safety and maximum tolerated dose of new therapies.
2. Phase II trials which provide preliminary evidence of efficacy through surrogate endpoints and further evaluate safety.
3. Phase III trials which are comparative effectiveness trials that use clinical outcomes like survival to compare new treatments to standard of care through randomized controlled designs.
Strategies for Managing Recurrent Ovarian Cancerbkling
When ovarian cancer returns, it's not uncommon to experience a range of emotions and feel overwhelmed. But it's important to remember that recurrent ovarian cancer can often be successfully treated. Dr. Shannon N. Westin, gynecologic oncologist and clinical investigator at MD Anderson Cancer Center, goes over the latest treatment options for recurrent disease.
Please share this webinar with anyone who may be interested!
Watch all our webinars: https://www.youtube.com/playlist?list=PL4dDQscmFYu_ezxuxnAE61hx4JlqAKXpR
Cancer care is increasingly tailored to individual patients, who can undergo genetic or biomarker testing soon after diagnosis, to determine which treatments have the best chance of shrinking or eliminating tumours.
In this webinar, a pathologist and clinical oncologist discuss:
● how they are using these new tests,
● how they communicate results and treatment options to patients and caregivers, and
● how patients can be better informed on the kinds of tests that are in development or in use across Canada
View the video: https://youtu.be/_Wai_uMQKEQ
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Report Back from San Antonio Breast Cancer Symposium (SABCS 2022)bkling
Curious about the latest developments in Early-Stage Breast Cancer and Metastatic Breast Cancer Research? Join us as Dr. Anne Blaes, the Division Director of Hematology/Oncology/Transplantation and Professor in Hematology/Oncology at the University of Minnesota, breaks down the most recent developments released at the annual San Antonio Breast Cancer Symposium regarding early-stage and metastatic breast cancer research.
Strategies for Managing Recurrent Ovarian Cancerbkling
When ovarian cancer returns, it's not uncommon to experience a range of emotions and feel overwhelmed. But it's important to remember that recurrent ovarian cancer can often be successfully treated. Dr. Shannon N. Westin, gynecologic oncologist and clinical investigator at MD Anderson Cancer Center, goes over the latest treatment options for recurrent disease.
Please share this webinar with anyone who may be interested!
Watch all our webinars: https://www.youtube.com/playlist?list=PL4dDQscmFYu_ezxuxnAE61hx4JlqAKXpR
Cancer care is increasingly tailored to individual patients, who can undergo genetic or biomarker testing soon after diagnosis, to determine which treatments have the best chance of shrinking or eliminating tumours.
In this webinar, a pathologist and clinical oncologist discuss:
● how they are using these new tests,
● how they communicate results and treatment options to patients and caregivers, and
● how patients can be better informed on the kinds of tests that are in development or in use across Canada
View the video: https://youtu.be/_Wai_uMQKEQ
Follow our social media accounts:
Twitter - https://twitter.com/survivornetca
Facebook - https://www.facebook.com/CanadianSurvivorNet
Pinterest - https://www.pinterest.com/survivornetwork
YouTube - https://www.youtube.com/user/Survivornetca
Report Back from San Antonio Breast Cancer Symposium (SABCS 2022)bkling
Curious about the latest developments in Early-Stage Breast Cancer and Metastatic Breast Cancer Research? Join us as Dr. Anne Blaes, the Division Director of Hematology/Oncology/Transplantation and Professor in Hematology/Oncology at the University of Minnesota, breaks down the most recent developments released at the annual San Antonio Breast Cancer Symposium regarding early-stage and metastatic breast cancer research.
How can immunotherapy be used to treat metastatic breast cancer? Ian Krop, MD, PhD, discusses the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 and hosted by the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Overview about evolution of the term Oligometastases,the paradigm and various states of oligometastases,treat options ,clinical trials and relevance in current clinical practice
This deals with the current paradigm of treatment of osteosarcoma. It is an honest effort to clear the prevailing confusion in the treatment of osteosarcoma. I would be happy to get anyone
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
How can immunotherapy be used to treat metastatic breast cancer? Ian Krop, MD, PhD, discusses the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 and hosted by the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Overview about evolution of the term Oligometastases,the paradigm and various states of oligometastases,treat options ,clinical trials and relevance in current clinical practice
This deals with the current paradigm of treatment of osteosarcoma. It is an honest effort to clear the prevailing confusion in the treatment of osteosarcoma. I would be happy to get anyone
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
The most ambitious definition of health is that proposed by WHO in 1948: “health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity.” but,
Practical definitions of health and disease are needed in epidemiology, which concentrates on aspects of health that are easily measurable and amenable to improvement.
Definitions of health states used by epidemiologists tend to be simple.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
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
Title: Sense of Taste
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 structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
2. Overview of the presentation
I. Introduction to clinical research
II. Types of clinical studies
III. Observational study designs
IV. Experimental study designs
3. Important issues in Study Design
• Validity: Truth
– External Validity:
• The study can be generalized to the population
– Internal Validity:
• Results are not due to chance, bias or confounders
– Symmetry Principle:
• Groups are similar
4. Important issues in Study Design
• Confounding: distortion of the effect of one risk factor by
the presence of another
• Bias: Any effect from design, execution, & interpretation
that shifts or influences results
– Confounding bias: failure to account for the effect of one or more
variables that are not distributed equally
– Measurement bias: measurement methods differ between groups
– Sampling (selection) bias: design & execution errors in sampling
5. Classification of Research Study Designs
Observational studies Interventional studies
1.
2.
3.
4.
5.
Case report/case-series
Case-control studies
Cross-sectional studies
Prospective (cohort)
Retrospective cohort
1. Controlled trials
a)
b)
c)
Parallel designs
Sequential designs
External controls
2. Studies with no controls
7. Aims of observational studies
• Evaluate the effect of a suspected risk factor
on an outcome (e.g. disease)
define 'exposure' and 'disease'
(exposure)
• Describe the impact of the risk factor on the frequency
of disease in a population
8. Characteristics of observational studies
No control over study
units
Can study risk factors that have serious
consequences
Study individuals in their natural
environment
Possibility of
confounding
9. Cross-sectional study
• Exposure and disease measured once, i.e. at
the same point in time
n
exposed ?
diseased ?
presentpast future
10. Cross-sectional study
• Random sample from population
– i.e. results reflect reference population
• Estimates the frequencies of both exposure
outcome in the population
and
• Measures both exposure & outcome at one
point in time
• Typical example is a survey
11. Cross-sectional study
• Can study several exposure factors and outcomes
simultaneously
• Determines disease prevalence
• Helpful in public health administration & planning
• Quick and low cost (e.g. mail survey)
• Limitations:
– Does not determine causal relationship
– Not appropriate if either exposure or outcome is rare
12. Cohort studies
• Follow-up studies: subjects selected on presence or
absence of exposure & absence of disease at one
point in time. Disease is then assessed for all subjects
at another point in time
• Typically
depending
initiation &
prospective but can be retrospective,
on temporal relationship between study
occurrence of disease
13. Prospective Cohort Study
with outcome
without
outcome
Exposed
Cohort
with outcome
without
outcome
Time
Unexposed
Onset
of study Direction of inquiry
Q: What will happen?
14. Cohort studies
• More clearly established temporal sequence
between exposure & disease
• Allows direct measurement of incidence
• Examines multiple effects of a single exposure
(nurses’ health study, oral contraceptives &
breast, ovarian cancers)
15. Cohort studies
• Limitations:
– time consuming and expensive
– loss to follow-up & unavailability of data
– potential confounding factors
– inefficient for rare diseases
16. Case-Control Study
• Retrospective
– Can use hospital or health register data
• First identify cases
• Then identify suitable controls
– Hardest part: who is suitable ??
• Then inquire or retrieve previous
– By interview
exposure
– By databases (e.g. hospital, health insurance)
17. Case-Control Study
• Diseased and non-diseased individuals are selected first
• Then past exposure status is retrieved
n
exposed ?
exposed ?
past
yes
no
disease
present future
18. Case-Control Study
• Good for rare disease (e.g. cancer)
• Can study many risk factors at the same time
• Usually low cost (though not always)
• Confounding likely
• Measures Odds Ratio (not Relative Risk !!)
20. Case Selection
•
•
Define source population
Cases
– incident/prevalent
– diagnostic criteria (sensitivity
Controls
+ specificity)
•
– selected from same population as cases
– select independent of exposure status
21. Control Selection
•
•
Random selection from source population
Hospital based controls:
–
–
convenient selection
controls from variety of diagnostic groups
other than case diagnosis
avoid selection of diagnoses related to
particular risk factors
limit number of diagnoses in individuals
–
–
22. Summary of Observational Studies
Characteristic Cross-
sectional
Case-Control Cohort
Sampling Random
sample:
population
Purposive
sample:
diseased/non-
diseased
Purposive
sample:
Exposed/non-
exposed
Time One point Retrospective Prospective
Causality Statistical
association
Screening for
many risk factors
Testing one (or
few) risk factors
Frequency
measure
Prevalence None Incidence
Risk
parameter
Prevalence
(risk) ratio,
odds ratio
Odds ratio Relative risk,
odds ratio
23. What is a clinical trial ?
A clinical trial tests potential interventions in
humans to determine if the
and
intervention
represents
adopted for
an advance should be
general use
FDA 2003
24. What do clinical trials test ?
•
•
Clinical trials test research hypotheses
Good clinical trials test specific research
hypothesis
• A clinical research hypothesis is a
in
carefully
formulated assumption developed order to
test its logical consequences
26. What is a Phase I trial ?
•
•
First evaluation of a new therapy in humans
Classical Goals:
Identify dose limiting toxicities (DLT)
Identify maximum tolerated dose (MTD)
Assess pharmacokinetics (PK)
Assess pharmacodynamic (PD) endpoints
27. Dose Limiting Toxicity (DLT)
• Toxicity described by standardized grading
criteria considered unacceptable because
of severity or irreversibility
• What is considered unacceptable varies
from situation to situation
DLT is specified for each trial protocol•
28. Maximum Tolerated Dose (MTD)
• Dose associated with unacceptable toxicity
(DLT) in a pre-specified proportion of
patients (sometimes defined inconsistently)
Generally the dose at which ≥ 33%
patients experience unacceptable
toxicity (eg. DLT in ≥ 2 out of 6 pts)
MTD: 1 dose level below DLT•
29. Principles of Phase I trial design
•
•
Start with a safe starting dose
Minimize number of patients treated at sub-
therapeutic doses
Escalate doses rapidly in absence of toxicity
Escalate dose slowly in presence of toxicity
•
•
30. Selection of starting dose
Based on pre-clinical (animal) toxicity data
1/10th LD10 (0.1 MELD10) if mouse
most sensitive species
•
3rd1/ TDL (0.33 DETDL) if dog most
sensitive species
• Conservative dosing based on other
studies if data suggest human tissues
more sensitive and PK data show a steep
dose/toxicity curve
31. Classical Phase I Trial Design
Conventional 3 + 3 design
3-6 pts per cohort
Starting dose 0.1 MELD
Dose escalation using modified
Fibonacci series
100%-66%-50%-40%-33%
MTD achieved
Previous dose level is RPTD
32. Problems with 3 + 3 design
Empirical and traditional method
Lacks solid statistical foundation
May take too many or too few patients
Takes a long time for dose escalation
•
•
•
•
• Starting dose may significantly under or
overestimate ‘safe’ dose
• Early dose levels far away from optimal and/or
therapeutic doses thus exposing substantial
proportion of patients to low, suboptimal and
ineffective doses
33.
34. Summary of phase I trial designs
• Phase I clinical trials
drug development
are the gateway for all new cancer
• The traditional 3+3 design though safe, treats large
numbers below therapeutic doses and takes a long time
for escalation
• Alternative phase I designs enable a higher proportion of
patients to be treated at or near MTD, but at an
increased risk of Grade 3-4 toxicities within a shortened
time span
35. What is a phase II trial ?
Primary goal is to establish efficacy / activity
"Proof-of-principle" for preliminary evidence of efficacy
Generally relies on surrogate end-points
Mostly single arm studies
May be randomized ("pick-a-winner")
Suggests further potential (for phase lll testing)
Documents additional safety information
36. Objectives of phase II trials
1. To define antitumor activity
2. To further demonstrate safety
3. To gain new insights into the pharmacokinetics,
pharmacodynamics & metabolism of drugs
4. To evaluate biologic correlates which may predict
response or resistance to treatment and/or toxicity
38. Summary of Phase II studies
• Phase ll trials are exploratory studies and rarely are
definitive
• Efficient to exclude inactive therapies
• Results must be interpreted cautiously, in the
the availability of other therapies
context of
• Estimate clinical activity and provide further safety
information – important in the "go/no go" decision
• Require confirmation in pivotal phase lll trials
39.
40. What is a phase III trial ?
Comparative Trials with or without controls
Primary goal is to establish actual clinical value
Survival (OAS, EFS,PFS) are primary endpoints
Compares new treatment to current standard of care
Randomized (with allocation concealment) to minimize bias
May be sometimes placebo controlled and even blinded
41. Phase III Study Designs
•
•
•
Comparative Studies
Experimental Group vs
Establishing a Control
Control Group
1.
2.
3.
Historical
Concurrent
Randomized
• Randomized Control Trial
standard
– Eliminates several sources
(RCT) is the gold
of bias
42. Why Control Group
• To allow discrimination of patient outcomes
caused by experimental intervention from
those caused by other factors
– Natural progression of disease
– Observer/patient expectations
– Other treatment
• Fair comparisons
– Necessary to be informative
43. Type of Controls
• External
– Historical
– Concurrent, not randomized
lnternal and concurrent•
–
–
–
–
No treatment
Placebo
Dose-response
Active (Positive) control
• Multiple
– Both an Active and Placebo
– Multiple doses of test drug and of an active control
44. Randomized Control Trial
• Patients assigned at random to either standard arm
(control arm) or treatment arm (experimental) arm
• Equal chance of getting randomized to either
randomization
arm in 1:1
• Neither patient nor physician can influence this chance
• Eliminates several known & unknown biases
• Considered to be “Gold Standard”
45. Comparing Treatments
Fundamental principle•
• Groups must be alike in all important aspects and only differ in the
treatment each group receives
• ln practical terms, "comparable treatment groups" means
"alike on the average"
• Randomization
• Each patient has the same chance of receiving any of the
treatments under study
• Allocation of treatments to participants is carried out using a
chance mechanism so that neither the patient nor the physician
know in advance which therapy will be assigned
• Blinding
•
•
Avoidance of psychological influence
Fair evaluation of outcomes
46. Commonly Used Phase III Designs
•
•
•
•
•
•
•
•
•
Parallel Group
Run-in designs
Withdrawal
Group/Cluster
Randomized Consent
Cross Over
Factorial Large Simple
Equivalence/Non-inferiority
Sequential
47.
48. Phase IV trials
• Post-marketing surveillance studies
• Assess long-term toxic effects & risk-benefit ratio
• Optimize use of the drug / device / intervention
• Study specific patient population i.e children
50. • Levels of evidence: U.S. Preventive Services Task
Force (USPSTF)
• Level I: Evidence obtained from at least one properly
designed RCT
• Level II-1: Evidence obtained from well-designed controlled
trials without randomization
• Level II-2: Evidence obtained from well-designed cohort or
case control analytic studies, preferably from more than one
center or research group.
• Level II-3: Evidence obtained from multiple time series with
or without the intervention. Dramatic results in uncontrolled
trials might also be regarded as this type of evidence.
• Level III: Opinions of respected authorities, based on clinical
experience,descriptive studies, or reports of expert
committees.
51. Categories of recommendation:
• Level A: Good scientific evidence suggests that the benefits of the clinical
service substantially outweigh the potential risks. Clinicians should discuss the
service with eligible patients.
• Level B: At least fair scientific evidence suggests that the benefits of the
clinical service outweighs the potential risks. Clinicians should discuss the
service with eligible patients.
• Level C: At least fair scientific evidence suggests that there are benefits
provided by the clinical service, but the balance between benefits and risks are
too close for making general recommendations. Clinicians need not offer it
unless there are individual considerations.
• Level D: At least fair scientific evidence suggests that the risks of the clinical
service outweighs potential benefits. Clinicians should not routinely offer the
service to asymptomatic patients.
• Level I: Scientific evidence is lacking, of poor quality, or conflicting, such that
the risk versus benefit balance cannot be assessed. Clinicians should help
patients understand the uncertainty surrounding the clinical service.
52. NCCN Categories of Evidence and Consensus
•Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the
intervention is appropriate.
•Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the
intervention is appropriate.
•Category 2B: Based upon lower-level evidence, there is NCCN consensus that the
intervention is appropriate.
•Category 3: Based upon any level of evidence, there is major NCCN disagreement that the
intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference
•Preferred intervention: Interventions that are based on superior efficacy, safety, and
evidence; and, when appropriate, affordability
•Other recommended intervention: Other interventions that may be somewhat less
efficacious, more toxic, or based on less mature data; or significantly less affordable for similar
outcomes
•Useful in certain circumstances: Other interventions that may be used for selected patient
populations (defined with recommendation)
53.
54. Research: A Big Challenge
CONCEIVE
CONDUCT
COMMUNICATE
Understanding of research study designs & principles helps