The document discusses key aspects of phase III clinical trials (RCTs) including:
1) Phase III trials require large sample sizes to further evaluate safety and effectiveness.
2) Study designs consider controls like placebo, active controls, and non-inferiority comparisons. Assay sensitivity and dealing with multiple analyses are also important.
3) Interim analyses allow evaluating safety and stopping early for efficacy but can increase chances of false positives. Intent-to-treat and final analyses include all randomized patients.
LBDA: Ask the Expert - Daniel Kaufer Live Webinar June 2016wef
Dr. Daniel Kaufer's live presentation made at the LBDA hosted webinar of June 15, 2016. Review additional material and event recording at www.worldeventsforum.net/lbda and lbda.org
Some types of studies require unblinded personnel at the site and a matching unblinded monitoring and study management team. This presentation provides a little background on blinding and then reviews best practices for unblinding.
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.
LBDA: Ask the Expert - Daniel Kaufer Live Webinar June 2016wef
Dr. Daniel Kaufer's live presentation made at the LBDA hosted webinar of June 15, 2016. Review additional material and event recording at www.worldeventsforum.net/lbda and lbda.org
Some types of studies require unblinded personnel at the site and a matching unblinded monitoring and study management team. This presentation provides a little background on blinding and then reviews best practices for unblinding.
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.
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
Final navigating multiple clinical trial requirements for the usBhaswat Chakraborty
The title of the given topic mainly asks for technical, ethical and strategic aspects of multiple clinical trials that would result in a successful approval of an NDA by the US FDA. Other than Phase I studies aimed at safety and tolerance in healthy subjects, usually one or two exploratory (Phase II) and multiple confirmatory (Phase III) studies are required. Studies in Phase III need to be designed to confirm the findings in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies provide an adequate basis for marketing approval. All clinical studies giving evidence of efficacy & safety must be adequate and well-controlled investigations entailing a valid comparison to a control and an accurate quantitative assessment of the drug’s effect. In rare situations, only a single, adequate and well-controlled study of a specific new use (that can be supported by information from other related adequate and well-controlled studies) will suffice for approval. However, when a single study is used, there should be hardly any room for study imperfections or non-supportive information.
In addition to addressing the strategies for multiple clinical trial requirements, the speaker would also discuss the documentation requirements and best practice on conducting effective clinical trials for the US to establish a roadmap for success and also a swift approval. Both documentation and best practices must contain a complete, entirely accurate, representation of study plans, conduct and outcomes. Incompleteness, lack of clarity, unmentioned deviation from prospectively planned analyses, or an inadequate description of how critical endpoint judgments or assessments were made, are seen to be common problems.
Root cause Analysis (RCA) & Corrective and Preventive action (CAPA) in MRCT d...Bhaswat Chakraborty
This presentation describes Identification & differentiation of Protocol deviation & violation; Different methods of RCA & best suitable method for Multiregional Clinical Trial; CAPA management and CAPA application to other trial sites/CRO/SMO/ Country that is involved in same trial (Strategic Management and application of CAPA in MRCT)
This presentation gives effective solutions to outliers issue in bioequivalence trials. It described what would be acceptable to Regulatory agencies as well as some new approaches.
Equivalence approches for complex generics DIA 11 april 2019 Bhaswat Chakraborty
This is a workshop that i gave a few days ago on bioequivalence of complex generics like peptides, polymers, liposomes, colloids, ophthamic and topical produtcts.
Clinical trials that are needed for efficacy & safety evidence of Medical devices include feasibility (pilot) and Pivotal trials. An extended battery of preclinical trials are also needed for high risk devices.
Writing Science papers for for publication requires something more thatn creativity. Target journals, content organization, wrting style, elegance and referencing are equally important.
Multidisc review of NDAs and BLAs nipicon 2018 Dr. ChakrabortyBhaswat Chakraborty
NDAS and BLAs cannot be authoritatively reviewed these days until experts from different disciplines act together like a team. This presentation give some foundational points and an illustrative example in that regard.
Teaching by stories, anecdotes and historical facts sept 25 2018Bhaswat Chakraborty
Many difficult principles in science and humanities can be taught best by a story (of its discovery), by an anecdote or some historical facts about them.
Orientation and Adaptation for Post-Graduate Pharmacy ProgramsBhaswat Chakraborty
PG Pharmacy programs are more focused and professionally oriented than the undergraduate counterpart. Many soft skills are required along with the curricular competence for excellence at the PG level.
Scientific integrity calls for some basic originality. Plagiarism can destroy this original creativity and ideation. This presentation defines plagiarism (stealing from others' works) and some of the creative and systematic remedies.
Best Practices to Risk Based Data Integrity at Data Integrity Conference, Lon...Bhaswat Chakraborty
Data integrity can be implemented using several approaches. One of the most effective ways to implement DI is a risk based approach. The speaker elaborates this.
There are several dimensions in Pharmaceutical ethics -- Practice-, research- and community oriented. This presentation mainly deals with Clinical research oriented Ethics.
Young pharmaceutical scientists are and can get involved in all aspects of new drug discovery and development. They have to be appropriately qualified, trained and experienced though,
This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
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.
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.
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
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
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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
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.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Are There Any Natural Remedies To Treat Syphilis.pdf
Integrated aspects of rct niper feb 2009 final
1. Integrated Aspects of Phase III
RCTs
Presented at the NIPER Symposium on Clinical Research and Training,
February 21-22, 2009
Dr. Bhaswat S. Chakraborty
Senior VP, Cadila Pharmaceuticals Ltd.
2. Contents
• Clinical Trials
– Regulatory phases
• Phase 3 Trials
• Data Requirements
• Study Design Considerations
• Controls
– Placebo, Active, NI
• Assay Sensitivity, Multiplicity of Analyses
• Interim Analysis
• Intent to Treat & Final Analyses
• Missing Data, Multiple Analyses & Assay Sensitivity
• Prediction of Success of a Trial
• Evidence Based Medicine
• Conclusions
2
6. Investigational New Drug
• The pharmaceutical industry begins talking to FDA prior to
submission of an IND
• Show FDA the results of preclinical testing in animals and any
prior human experience
• What is being proposed to do for human testing
• At this stage, the FDA decides whether it is reasonably safe
for the company to move forward with testing the drug in
humans
6
7. Phase 1
• Phase 1 studies are usually conducted in
healthy volunteers
• Goal:
– determine what the drug's most frequent side
effects are
– how the drug is metabolized and excreted
• The number of subjects typically ranges from
20 to 100
7
9. Phase 2
• Phase 2 begins if Phase 1 studies don't show unacceptable
toxicity
• Phase 1 → Safety; the emphasis in Phase 2 → Effectiveness
– Obtaining data on whether the drug works in people with a certain
disease or condition
• RCTs
– Gold standard for evidence of efficacy
– Patients receiving the drug vs patients receiving a placebo or a
different drug
– Randomized, well designed
• Safety continues to be evaluated
• N = a few dozen to about 300
9
10. Phase 3
• Phase 3 studies begin if evidence of effectiveness
is shown in Phase 2
• Phase 3: large-scale efficacy & safety studies
• Jointly decided by FDA & sponsor
• A is pre-NDA meeting with FDA is common, right
before a new drug application is submitted
• Gather more information about safety and
effectiveness
– different populations and different dosages
– using the drug in combination with other drugs
• N = several hundred to about ≥4,000 patients
10
12. Phase 4
• Postmarketing study commitments are called Phase 4
commitments
– Studies conducted after the FDA has approved a product
for marketing
• The FDA uses postmarketing study commitments to
gather additional information about a product's
– Safety (mainly)
– also efficacy or optimal use
12
15. Clinical Trials: Testing Medical Products in
Humans
• Clinical studies, test potential treatments in human volunteers
to see whether they should be approved for wider use in the
general population
– A treatment could be a drug, medical device, or biologic,
such as a vaccine, blood product, or gene therapy
– A new treatment may or may not be “better”
– Complete and accurate research
– Protection and well being of participants
• Ethics, consent, audit
– Documentation
15
16. Clinical Trials..
• Drug studies in humans can begin only after an
IND is reviewed by the FDA and a local
institutional review board (IRB)
• The board is a panel of scientists and non-
scientists in hospitals and research institutions
that oversees clinical research
16
17. Institutional (Ethical) Review
• IRBs approve the clinical trial protocols
– the type of people who may participate in the clinical
trial
– the schedule of tests and procedures
– the medications and dosages to be studied
– the length of the study
– the study's objectives
– other details
• IRBs make sure the study is
– acceptable
– participants have given consent
– Participants are fully informed of their risks
– researchers take appropriate steps to protect patients from
harm 17
18. Data
• There are legal and ethical reasons for reporting all
relevant data collected during the drug development
process
• Some reporting strategies already exist in the 1988
Guidelines, ICH E3 and E9
• Electronic Submissions and desktop review capabilities
will help all of us make better use of clinical data in
NDA’s
• There may be better strategies and these should be
considered
18
19. What does FDA Look for?
• FDA approves a drug application based on
– Substantial evidence of efficacy & safety from
“adequate and well-controlled investigations”
– A valid comparison to a control
– Quantitative assessment of the drug’s effect
• (21 CFR 314.126.)
• The design of cancer trials intended to support
drug approval is very important
19
20. Adequate and Well-Controlled
Studies
• Because the course of most diseases is variable, you need a control group,
a group treated just like the test group, except that they don’t get the drug,
to distinguish the effect of the drug from spontaneous change, placebo
effect, observer expectations
• 21 CFR 314.126 describes the following controls
– Placebo
– No treatment
– Dose response
– Active control
• Superiority of non-inferiority
– Historical
• Placebo, dose response or superiority are usually convincing studies
20
21. Adequate and Well-Controlled
Studies..
• Minimization of Bias: a unidirectional tilt favoring one group,
a non-random difference in how test and control group are
selected, treated, observed, and analyzed
– These are the 4 main places bias can enter
• Remedies:
– Blinding (patient and observer bias)
– Randomization (treatment and control start out equal)
– Careful specification of procedures and analyzes in a
protocol to avoid
• Choosing the most favorable analysis out of many (bias)
• Having so many analyses that one is favorable by chance
(multiplicity)
Source: RJ Temple, US FDA, Unapproved Drugs Workshop January 21
2007
23. Purposes of Active Trials
• The purpose of an active control trial
could be to demonstrate that a new
experimental treatment is either
• superior to the control
• equivalent to the control, or
• non-inferior to the control
• superior to a virtual placebo
23
24. Study Design: Approaches
• Randomised Controlled Trials (RCT) most preferred approach
– Demonstrating superiority of the new therapy
• Other approaches
– Single arm studies (e.g., Phase II)
• e.g., when many complete responses were observed or when
toxicity was minimal or modest
– Equivalence Trials
– No Treatment or Placebo Control Studies
– Isolating Drug Effect in Combinations
– Studies for Radiotherapy Protectants and Chemotherapy
Protectants
24
25. Randomized Clinical Trials
• Gold standard in Phase III
• Single centre CT
– Primary and secondary indications
– Safety profile in patients
– Pharmacological / toxicological characteristics
• Multi-centre CT
– Confirmation of the above
– Effect size
– Site, care and demographic differences
– Epidemiological determination
– Complexity
– Far superior to meta-analyzed determination of effect
25
26. Placebo Control Equality Trials
• No anticancer drug treatment in the control arm is unethical
• Sometimes acceptable
– E.g., in early stage cancer when standard practice is to give
no treatment
– Add-on design (also for adjuvants)
• all patients receive standard treatment plus either no
additional treatment or the experimental drug
– Placebos preferred to no-treatment controls because they
permit blinding
– Unless very low toxicity, blinding may not be feasible
because of a relatively high rate of recognizable toxicities
26
27. Reasons for Active Control
1. Ethics – For trials involving mortality or serious morbidity
outcome, it is unethical to use placebo when there are
available active drugs on the market
2. Assay sensitivity – In trials involving psychotropic drugs,
placebo often has large effect. An active control is sometime
used to demonstrate that the trial has assay sensitivity
3. Comparative purpose – To show how the experimental drug
compares to another known active drug or a competitor
27
28. Non-Inferiority Trials
• New drug not less effective by a predefined
amount, the noninferiority (NI) margin
– NI margin cannot be larger than the effect of the
control drug in the new study
– If the new drug is inferior by more than the NI
margin, it would have no effect at all
– NI margin is some fraction of (e.g., 50 percent) of
the control drug effect
28
29. Drug or Therapy Combinations
• Use the add-on design
– Standard + Placebo
– Standard + Drug X
• Effects seen in early phases of development
– Establish the contribution of a drug to a standard
regimen
– Particularly if the combination is more effective
than any of the individual components
29
30. What to Measure?
• Primary outcome measure: The health parameter measured
in all study participants to detect a response to treatment
• Secondary outcomes measure: Other parameters that are
measured in all study participants to help describe the effect of
treatment
• Baseline variables: The characteristics of each participant
measured at the time of random allocation.
– This information is documented to allow the trial results to
be generalised to the appropriate population/s
– Specific characteristics associated with the patient’s
response to treatment (such as age and sex) are known as
prognostic factors
30
31. What to Measure? E.g., Cancer
Trials
• Time to event end points
– Survival
– Disease free survival
– Progress (of disease) free survival
• Objective response rates
– Complete
– Partial
– Stable disease
– Progressive disease
• Symptom end points
• Palliation
• QoL
31
32. Cancer Trials – End Points
Endpoint Evidence Assessment Some Advantages Some Disadvantages
Survival Clinical benefit • RCT needed • Direct measure of • Requires larger and
• Blinding not benefit longer studies
essential • Easily measured • Potentially affected by
• Precisely crossover therapy
measured • Does not capture
symptom benefit
• Includes noncancer
deaths
Disease-Free Surrogate for • RCT needed • Considered to be • Not a validated survival
Survival (DFS) accelerated • Blinding clinical benefit by surrogate in most settings
approval or preferred some • Subject to assessment
regular • Needs fewer bias
approval* patients and shorter • Various definitions exist
studies than survival
32
33. Interim analysis
after each new response or group of responses
an interim analysis is performed
⇓
enough evidence to stop the trial
or
continue the trial
→ continuous sequential or group sequential analysis
33
34. Why Interim Analyses?
• Ethics: superiority of a treatment
• Safety: inferiority of a treatment /
toxicity of a treatment
• Economy: costly therapy
no clinically relevant difference in
effect between treatments
34
35. False Positives in Interim Analyses
Interim analysis for a trial in non-Hodgkins lymphoma; n=130,
IA after enrolment of each 25 patients
Response Rate Response Rate
CP CVP
Analysis 1 3/14 5/11 1.63
Analysis 2 11/27 13/24 0.92
Analysis 3 18/40 17/36 0.04
Analysis 4 18/54 24/48 3.25 0.05<P<0.1
Analysis 5 23/67 31/59 4.25 0.016<P<0.05
CP=Cytoxan-prednisone
CVP=Cytoxan-vincristine-prednisone
Source: Stuart J. Pocock, Clinical Trials
35
36. Interim Analysis of Data
2 Looks 3 Looks
How many times can
0.05
0.05
you look into the
data?
Nominal Pvalue
Nominal Pvalue
0.03
0.03
o pocock
o ob+fle
0.01
0.01
o fle+har+ob
0.0
0.0
1 2 1 2 3
Look Look
4 Looks 5 Looks
Type 1 error at kth
0.05
0.05
test is NOT the same
Nominal Pvalue
Nominal Pvalue
as the nominal p
0.03
0.03
value for the kth test
0.01
0.01
0.0
0.0
1 2 3 4 1 2 3 4 5
Look Look
36
37. Considerations for IA
– Stopping rules for significant efficacy
– Stopping rules for futility
– Measures taken to minimize bias
– A procedure/method for preparation of data for analysis
– Data has to be centrally pooled, cleaned and locked
– Data analysis - blinded or unblinded?
– To whom the interim results will be submitted?
• DSMB
• Expert Steering Group
– What is the scope of recommendations from IA results?
– Safety? Efficacy? Both? Futility? Sample size
readjustment for borderline results?
37
38. Equality Designs
(e.g., 2-Sample, Parallel)
H0 : Є = 0 HA : Є ≠ 0
Reject H0 when
p1— p2
ˆ ˆ
> z/2
√p1(1—p1)/n1 + p2(1— p2)/n2
ˆ ˆ ˆ ˆ
Where p1— p2 are true mean response rates
ˆ ˆ
from Test & Control
38
39. Superiority/Non-Inferiority Designs
(e.g., 2-Sample, Parallel)
H0 : Є ≤ δ HA : Є > δ … Superiority
H0 : Є ≥ δ HA : Є < δ … Non-Inferiority
Reject H0 when
p1— p2 – δ
ˆ ˆ
> z
√p1(1—p1)/n1 + p2(1— p2)/n2
ˆ ˆ ˆ ˆ
39
40. Survival Data – The Kaplan-Meier Estimator
1.0
0.75
Survival
0.50
0.25
~35% Patient will
survive beyond 0.8
years
0.0
Time (Year)
0.0 0.2 0.4 0.6 0.8 1.0 40
41. Include all Patients: ITT
• It can be justified to look at data and drop the
“outliers”, poor compliers, inappropriately
entered patients
• It is even plausible and acceptable as an
academic principle
• But if not rigorously planned, such exclusion
can lead to bias
• Even when planned, it can lead to imbalances
that also introduce bias
41
42. Intent-to-Treat Principle
• All randomized patients
• Exclusions on prespecified baseline criteria permissible
– also known as Modified Intent-to-Treat
• Confusion regarding intent-to-treat population: define and agree upon in
advance based upon desired indication
• Advantages:
– Comparison protected by randomization
• Guards against bias when dropping out is realted to outcome
– Can be interpreted as comparison of two strategies
– Failure to take drug is informative
– Refects the way treatments will perform in population
• Concerns:
– “Difference detecting ability”
42
43. Per Protocol Analyses
• Focuses on the outcome data
• Addresses what happens to patients who remain on therapy
• Typically excludes patients with missing or problematic data
• Statistical concerns:
– Selection bias
– Bias difficult to assess
43
44. Intent to Treat & Per Protocol
Analyses
• Both types of analyses are important for approval
• Results should be logically consistent
• Design protocol and monitor trial to minimize exclusions
• Substantial missing data and poor drug compliance
weaken trial’s ability to demonstrate efficacy
44
45. Missing Data
• Protocol should specify preferred method for
dealing with missing primary endpoint
– ITT
• e.g., treat missing as failures
• e.g., assign outcome based on blinded case-by-case
review
– Per Protocol
• e.g., exclusion of patients with missing endpoint
45
46. Multiple Analyses
• The two main problems introduced by multiple analyses are
– firstly, the increased probability of detecting intervention
effects where none exist (“false positives” owing to
multiple comparisons — type I errors)
– secondly, the limited capability (“power”) of trials to detect
a true treatment effect in secondary outcomes if not enough
participants are enrolled to show a statistically significant
difference in these outcomes (“false negatives” — type II
errors)
46
47. Assay Sensitivity
• The critical question is whether a non-inferiority trial, for
example, could distinguish the control from placebo and shown
an effect of the non-inferiority margin
• If it could
– the trial is said to have said to have “assay sensitivity”
• If a trial a trial has assay sensitivity
– then if C-T < M, T had an effect
• If the trial did not have assay sensitivity
– then even if C-T < M, we have learned nothing
• If you don’t know whether the trial had assay sensitivity, finding no
difference between C and T means
– Both drugs were effective
– Neither drug was effective
Source: RJ Temple, US FDA, Unapproved Drugs Workshop 47
48. Assay Sensitivity: Major Problem in NI
• In a non a non--inferiority trial, the trial itself does not show
the study’s ability to distinguish active from inactive therapy.
Assay ability to distinguish active from inactive therapy
• Assay sensitivity must, therefore, be deduced or assumed,
based on
1. historical experience showing sensitivity to drug effects
2. a close evaluation of study quality and, particularly
important
3. the similarity of the current trial to trials that were able to
distinguish the active control drug from placebo
• In many symptomatic conditions, such as depression, pain,
allergic rhinitis, IBS, angina, the assumption of assay
sensitivity cannot be made
Source: RJ Temple, US FDA, Unapproved Drugs Workshop January 48
2007
49. Data Safety and Monitoring Board
(DSMB)
• All trials may not need a DSMB
• DSMB Membership
– Medical Oncologist, Biostatistician and Ethicist
• Statistical expertise is a key constituent of a DSMB
• Three Critical Issues
– Risk to participants
– Practicality of Periodic Review of a Trial
– Scientific Validity of the Trial
49
51. Conclusion: Effect of Expertise
Trial Success Based on Centre Expertise
100
90
80
70
Success (%)
60
50
40
30
20
10
0
0 0.2 0.4 0.6 0.8 1
Probability of Expertise
Source: Unpublished Results, D. Chakraborty, University of Toronto
52. Conclusions
• Randomized Phase 3 Clinical Trials are very sophisticated and
complex
• Principal Investigators’, Monitoring Teams’, Biostatisticians’,
DSMB’s … all roles are important – Phase 3 Trials are team effort
• Phase 3 RCTs provide for the main evidence of efficacy and safety
• Clinical data is very complex (confounded, censored, skewed, often
fraught with missing data point), therefore, proper hypothesization
and statistical treatment of data are required
• Prospective RCTs are usually the preferred approach for evaluation
of new therapies
52
53. Conclusions
• Clinically meaningful margins must be well defined in Control trials
prospectively
– Superiority and non-inferiority margins must not be confused
• Two or one-sidedness of α should also be prospectively defined
• Power must be adequate
• Variance must be analysed using the right model
• Strategy for dealing with multiple end points must be prespecified
– Too many end points ot tests will increase the false positive (α) error
• Sometimes (e.g., in equality trials) statistically significant results may not be
medically significant
• Data censoring or skewed data must be well defined
– E.g., time to event data
53
54. Conclusions
• Randomisation and blinding offer a robust way to remove bias in end-point estimations
• Data must be accurately captured without any bias and analysed by prospectively
described methods
• Interim analysis should carefully plan ‘ spending’ function and the outcome
measure to be analyzed
• Final analysis should be done carefully, independently and meaningfully (medical as
well as scientific)
• Choose clinically relevant delta
• Design, conduct, and monitor trials to minimize missing data and poor compliance to drug
• Analysis
– Both intent-to-treat and per protocol analyses should be conducted
– Sensitivity analyses
• Outstanding medical and statistical issues must be brought to the fore
• Trial success can be predicted in many cases using Bayesian models
54