Critical evaluation of an article titled " Systematic review of basket trials, umbrella trials, and platform trials: A landscape analysis of master protocols"
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.
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/
Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences
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.
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/
Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences
you can know about the central composite design, historical design, optimisation techniques and also about the TYPES OF CENTRAL COMPOSITE DESIGN, BOX-BEHNKEN DESIGN, DATA COLLECTION, CRITICISM OF DATA, PRESENTATION OF FACTS, PURPOSE, OPTIMISATION PROCESS, DIFFERENT TYPES PRESENT IN IT AND THEIR CLASSIFICATION AND EXPLANATION.
the ppt describes in detail the translational research and path of the drug from lab to bed side, CONSORT guidelines, DCGI guidelines, CTR-I, the GCP principles, medical ethics, sample size estimation for RCT, RCT designs including cross over design and factorial design, Randomized permuted blocks, blinding and matching.
Webinar Series on Demystifying Phases in Clinical Trials & COVID-19 Updates organized by Institute for Clinical Research (ICR), NIH
Speaker: Dato Dr Chang Kian Meng, Haematologist from Sunway Medical Centre
More information, please visit: https://clinupcovid.mailerpage.com/resources/p9f2i7-introduction-to-phase-2-3-trial-s
Abbreviated New Drug Application [ANDA]Sagar Savale
An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's CDER, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product.
pharmacovigilance, adverse effects, causality assessment,methods, who-umc method with case study, FOR DOWNLOAD PPT MAIL ME ON iamgauravchhabra@gmail.com
you can know about the central composite design, historical design, optimisation techniques and also about the TYPES OF CENTRAL COMPOSITE DESIGN, BOX-BEHNKEN DESIGN, DATA COLLECTION, CRITICISM OF DATA, PRESENTATION OF FACTS, PURPOSE, OPTIMISATION PROCESS, DIFFERENT TYPES PRESENT IN IT AND THEIR CLASSIFICATION AND EXPLANATION.
the ppt describes in detail the translational research and path of the drug from lab to bed side, CONSORT guidelines, DCGI guidelines, CTR-I, the GCP principles, medical ethics, sample size estimation for RCT, RCT designs including cross over design and factorial design, Randomized permuted blocks, blinding and matching.
Webinar Series on Demystifying Phases in Clinical Trials & COVID-19 Updates organized by Institute for Clinical Research (ICR), NIH
Speaker: Dato Dr Chang Kian Meng, Haematologist from Sunway Medical Centre
More information, please visit: https://clinupcovid.mailerpage.com/resources/p9f2i7-introduction-to-phase-2-3-trial-s
Abbreviated New Drug Application [ANDA]Sagar Savale
An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's CDER, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product.
pharmacovigilance, adverse effects, causality assessment,methods, who-umc method with case study, FOR DOWNLOAD PPT MAIL ME ON iamgauravchhabra@gmail.com
This slide contains B.Pharm 8th Sem Biostatistics and research methodology, Unit-3.
Topic covered: Designing the methodology, Sample size determination and Power of a study, Report writing
and presentation of data, Protocol, Cohorts studies, Observational studies, Experimental studies,
Designing clinical trial, various phases.
Advances in Clinical Trial Design: Adaptive and Platform TrialsClinosolIndia
Advances in clinical trial design have led to the emergence of two innovative approaches: adaptive trials and platform trials. These designs offer flexibility, efficiency, and the potential to accelerate the development of new therapies.
Adaptive Trials:
Adaptive trials are designed to make real-time modifications to key aspects of the study, such as the sample size, treatment arms, or patient population, based on accumulating data during the trial. This adaptive approach allows researchers to make informed decisions and optimize the trial design as new information becomes available. Adaptive trials can be particularly beneficial when studying complex diseases or evaluating treatments with varying responses.
Advances in Clincal Trial Design- Adaptive and Platform TrialsClinosolIndia
Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages.
Irrespective of study design, the first step in the process of avoiding any type of bias is the proper definition and articulation of the research question.
Consequently, this step will lead to a number of questions that need to be adequately addressed by the investigator during the planning stage of research:
what kind of information are required to answer this question in the study in terms of exposure, outcome, and possible confounders?
what is the most appropriate method to collect these information?
how to achieve comparable accuracy of data collection between the study groups?
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.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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
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
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.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
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
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
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
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
4. Features Conventional trial Adaptive design
Design More rigid Flexible
Treatment arms Maximum two or three Many simultaneously
Hypothesis
Test the hypothesis under
consideration
Fit data into a hypothesis
Modifications
Not allowed without protocol
amendments
Pre-specified allowed
Phases Phases I–II well defined Seamless phase II/III design
Statistical analysis frequentists methods complicated Bayesian approach
Organization Much simple Complicated, requiring simulations
Interim analysis Not a routine Done routinely and frequently
Role of IDMC More once trial/phase is over Proactive role throughout the trial
Table: General Characteristics of conventional and adaptive design
5. Clinical trials are most commonly
based on a “one population, one
drug, one disease” strategy
Precision
medicine? Targeted
therapies?
Heterogenous
population?
Multiple
treatment?
Multiple
disease?
Advanced
cancers and
rare genetic
diseases?
6. MASTER PROTOCOL
Master protocol is defined as a protocol designed with multiple sub-
studies, which may have different objectives and involves coordinated
efforts to evaluate one or more investigational drugs in one or more
disease subtypes within the overall trial structure
9. Single disease/ histology
Screening for biomarkers
Biomarker 1 Biomarker 2 Biomarker 3
Targeted
therapy 1
Umbrella trial
Control Targeted
therapy 2
Control Targeted
therapy 3
Control
10. Squamous cell lung cancer
Genomic screening
Sub-study assignment based on biomarker
Sub-study A
(Non-match)
Sub-study B
(PIK3CA
Mutation)
Sub-study C
(CDK4,
CCND1, 2, 3)
Sub-study D
(FGFR
mutation)
MEDI4736 GDC-0032 Palbociclib AZD4547
LUNG-MAP
CT CT CT
PFS and OS
11. Trial events
Time (ongoing)
Trialschema
Bm A
Bm B
Bm -ve
Investigational drug 1
Investigational drug 2
Std. of care-A
Stop because criteria for success are met
Recruitment
closed
Investigational drug 1 becomes new std. of care- A
Platform trial
Investigational drug 3
Std. of care-B
Stop for
futility
Investigational drug 4
Std. of care for bm -ve
Stratum continues to
enrol patients
Investigational drug 4
Std. of care-C
Bm C
13. Characteristics Conventional trial Platform trial
Scope
Efficacy of a single agent in a
homogeneous population
Evaluating efficacy of multiple agents in a
heterogeneous population
Duration
Finite, based on time required to
answer the single primary questions
Potentially long-term, as long as there are
suitable treatments requiring evaluation
No. of treatment
groups
Pre-specified and generally limited
Multiple treatment groups (number of
treatment groups and the specific
treatments may change over time)
Stopping rules
Entire trial may be stopped early for
success or futility or harm
Trial continues, with the addition of new
experimental treatment(s)
Allocation
strategy
Fixed randomization Response-adaptive randomization
Sponsor
support
Single federal or industrial sponsor
Multiple federal
or industrial sponsors or a combination
General Characteristics of conventional and platform trial
16. Challenges faced by
Master Protocols
Protocol
changes
Resources
Appropriate
communication
Innovative
statistical
analysis
Validity,
power
Trial
complexity
Ethics
Consent
17. Background: Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple
hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial),
offering enhanced efficiency and a more ethical approach to trial
evaluation. Despite the many advantages of these designs, they are infrequently used.
Methods: We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been
conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies
were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries.
Results: We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master
protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs
(n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not
randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was
205 participants (interquartile range, Q3-Q1 [IQR]: 500–90 = 410), and the median study duration was 22.3 (IQR: 74.1–42.9 = 31.1) months.
Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The
median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9
= 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). The majority of platform trials
were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform
trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835–255=1580), and the median study
duration was 58.9 (IQR: 101.3–36.9 = 64.4) months.
Conclusions: We anticipate that the number of master protocols will continue to increase at a rapid pace over the
upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design
methods to fields outside of oncology.
Keywords: Master protocols, Basket trials, Umbrella trials, Platform trials, Multi-arm, multi-stage design
ABSTRACT
(Structured and informative)
19. • Advancements in genomics, have improved the ability to differentiate
cancers by their genetic mutations
• Precision oncology: Therapies are selected to specifically target
cancers on the basis of their genetic mutations
• These innovative treatments are commonly referred to as targeted
therapies
20. • It is unrealistic to investigate the broad spectrum of genetic sub-
populations by conventional trial designs
• Thus, “master protocol” frameworks have been proposed to provide a
means of comprehensively and adaptively evaluating treatments from
the field of oncology
• General goals are improving efficiency and establishing uniformity
21. • Under a common infrastructure, the master protocol may be
differentiated into multiple parallel sub studies
• Master protocols may be tailored and adapted to suit the research
objectives of multiple clinical indications
• But they have not been well established in fields outside of oncology
22. • Thus, improved understanding and awareness of these research
designs are important for the research community
• Methodological summaries of master protocols to date have not been
comprehensive
• With the intent of improving literacy in this emerging field, this
comprehensive systematic literature review was conducted
(Rationale for the review well described)
23. To determine what trials have been conducted and proposed, for an
overall goal of improving the literacy in this emerging concept
OBJECTIVE
(SMART & good action verb is used)
25. Study design:
Systematic review
(Appropriate to answer the objective)
Protocol and registration:
(Not given)
26. Eligibility criteria:
Category Inclusion criteria:
Population Humans
Interventions No restrictions
Comparator No restrictions
Outcomes No restrictions
Study design
Basket trials
Umbrella trials
Platform trials
Other Peer-reviewed publications and conference abstracts with
results or published protocols in English language
Table 1. PICOS (population, intervention, comparator, outcomes,
study design) criteria
27. Mater protocol
Master protocols were defined as a single overarching protocol
that has been designed to be divided into multiple sub-studies that
could allow for evaluation of multiple interventional hypotheses
28. Basket trials
‘Basket trials’ were defined as any prospective clinical trials that
tested the utility (e.g., effectiveness, dosage, and safety) of
intervention(s) in a study population of multiple diseases with
common predictive biomarkers and/or other common predictive
patient characteristics that can be used to predict whether a
patient will respond to a specific intervention as the unifying
eligibility criteria
29. Umbrella trials
‘Umbrella trials’ were defined as any prospective clinical trials
that tested the utility of targeted interventions based on predictive
biomarkers or other patient characteristics or both
30. Platform trials
• ‘Platform trials’ were defined as any clinical trials that allowed
the intervention arm(s) to be dropped and the flexibility of
introducing new intervention(s) during the trial
• Platform trials are sometimes referred to as multi-arm, multi-
stage (MAMS) designs
31. Exclusion criteria:
Non-English language studies
(Eligibility criteria for selecting studies are given
but are not mutually exclusive)
32. Data sources:
Systematic searches were conducted on July 8, 2019, in:
• MEDLINE
• EMBASE
• Cochrane Central Register of Controlled Trials
• Bibliographies from included publications
• Trial registries (ClinicalTrials.gov and ISRCTN registry)
(Information of sources & last date searched given)
33. Search strategy:
• Developed on the basis of a review of key papers, including the Draft
Guidance of the US Food and Drug Administration (FDA)
• Search terms: “master protocols”, “basket trials”, “umbrella trials”,
“platform trials” and “adaptive trial designs”
34. No. Terms Hits Comments
1
(Master protocol or master trial protocol or trial master
protocol).mp.
69 Master protocol
2
(Platform trial or platform clinical trial or adaptive
platform trial or platform adaptive trial).mp.
42 Platform trial design
3
(Umbrella trial or umbrella clinical trial or adaptive
umbrella trial or umbrella adaptive trial).mp.
11 Umbrella trial
4
(Basket trial or basket clinical trial or adaptive basket trial
or basket adaptive trial).mp.
48 Basket trial
5 (Multi-arm multi-stage or MAMS).mp. 297 Multi-arm multi-stage design
6
((Multi-stage or multi stage or multistage) and (clinical
trial or randomized trial or randomised trial)).mp.
298
7 Adaptive clinical trials.mp. 108
General terms for adaptive trial
designs
8 Adaptive clinical trial.mp. 98
9 Adaptive design.mp. 675
10 Flexible trial design.mp. 2
Table S1. Search strategy Medline
35. No. Terms Hits Comments
11 (Bayesian clinical trial or bayesian adaptive).mp. 294
12 Adaptive group sequential design.mp.
13
Adaptive group sequential
design
13 Group sequential design.mp. 150
14 (Interim monitoring or stochastic curtailment or futility analysis).mp.
256
Interim monitoring and
stochastic curtailment
15 (Predictive probabilit* or conditional power or bayesian predictive
probabilit*).mp.
484
16 ((Predictive power or posterior probabilit*) and (interim monitoring
or interim analys*)).mp.
30
17 ((Sample size or sample-size) adj3 (reestimation or re-estimation or re
estimation)).mp.
144
Sample size re-estimation
18 ((Sample size or sample-size) adj3 (reassessment or re-assessment or
re assessment)).mp.
47
19 ((Sample size or sample-size) adj3 adjustment).mp. 103
20 ((Sample size or sample-size) adj3 modification).mp. 24
21 (Enrichment design or population enrichment or population
enrichment design or bayesian adaptive enrichment).mp.
111
Population enrichment
design
22 (biomarker design or biomarker adaptive or biomarker adaptive
design or biomarker adjusted).mp.
30
Table S1. Cont.
36. No. Terms Hits Comments
23 (Responsive adaptive randomization or responsive adaptive
randomisation or responsive adaptive allocation or adaptive allocation
or adaptive randomization or adaptive randomisation or response
adaptive).mp.
389 Responsive adaptive
randomization
24 (Play the winner or play-the-winner or pick the winner or pick-the-
winner or drop the loser or drop-the-loser).mp.
79
25 (Adaptive dose rang* or adaptive dose or bayesian dose).mp. 265
26 (Seamless design or adaptive seamless or operationally seamless or
operational seamless or inferentially seamless or inferential
seamless).mp.
49 Seamless design
27 ("Seamless 2-3" or "seamless 2 to 3" or "seamless 2/3" or "seamless
phase ii/iii" or "seamless phase 2/3").mp.
48
28 ("Seamless 1-2" or "seamless 1 to 2" or "seamless 1/2" or "seamless
phase i/ii" or "seamless phase 1/2").mp.
17
29 or/1-28 3339
30 Humans/ 17835321
31 Animals/ 6430856
32 (29 and 30) not 31 2288 Limiting to studies on
humans
33 limit 32 to english language 2232 English language
Table S1. Cont.
39. • Two reviewers (JJHP and MJZ) independently reviewed all abstracts
and proceedings identified in the literature searches
• Full-text publications of potentially relevant abstracts were then
retrieved and assessed for eligibility
Study selection:
40. • Two reviewers also screened the bibliographies of published
literature reviews on master protocols (JJHP and ES) and trial
registries (JJHP and LD)
• Discrepancies in study selection were resolved by discussion or,
when necessary, by a third investigator (KT or EJM)
(Process of selecting studies well stated)
41. • Two investigators (JJHP and ES) independently extracted using a
standardized, piloted data extraction form to record:
Study design elements
Patient characteristics
Outcomes
Trial registry
Data extraction:
42. Trial recruitment status
Phase
Randomization
Masking
Number of clinical centres
Sample size
Trial duration
Interventions
43. Control
Disease area
Age of population
Number of conventional diseases recruited
Key eligibility for stratification
Number of subgroups defined
Geographic location of the master protocols
44. • Method of data extraction from reports described
• Lists all variables for which data were sought
• Use of manual searching of bibliographies mentioned
45. Data synthesis:
• Meta-analysis was not conducted for this study
• Findings of this landscape analysis was presented descriptively
• Temporal trends of master protocols, geographical representation, and
trial and disease characteristics of each of the three master protocols
were reported
(well described)
47. Records identified
through database
searching (n=5869)
Additional records
identified through
other sources (n=140)
IDENTIFICATION
Records
screened
(n=6009)
SCREENING
Records
excluded
(n=5370)
48. Full text articles
assessed for
eligibility (n=639)
Full text articles excluded,
with reasons (n=424)
• Population : 0
• Interventions : 0
• Comparators : 0
• Outcomes : 0
• Study design : 333
• Other : 91
ELIGIBILITY
Included
publications
(n=214, 83 trials)
INCLUDED
Figure S1. Study flow chart
50. Trial ID Study ID Year Title
Basket trials
AcSe´ NCT02304809 2014
Phase 2 Study Assessing Secured Access to Vemurafenib
for Patients With Tumors Harboring BRAF Genomic
Alterations (AcSé)
Ado-trastuzumab Basket
trial
Li 2017 2017
Ado-trastuzumab emtansine in patients with her2 mutant
lung cancers: Results from a phase ii basket trial
Ado-trastuzumab Basket
trial
Li 2018 2018
A multi-histology basket trial of adotrastuzumab
emtansine in patients with her2 amplified cancers
Ado-trastuzumab Basket
trial
NCT02675829 2016
Trial of Ado-Trastuzumab Emtansine for Patients With
HER2 Amplified or Mutant Cancers
AGADIR NCT03915678 2019
Atezolizumab Combined With Intratumoral G100 AnD
Immunogenic Radiotherapy in Patients With Advanced
Solid Tumors (AGADIR)
ALCHEMIST NCT02193282 2014
Erlotinib Hydrochloride in Treating Patients With Stage
IB-IIIA Non-small Cell Lung Cancer That Has Been
Completely Removed by Surgery (An ALCHEMIST
Treatment Trial)
Table S6. List of included studies: Basket trials
51. ALCHEMIST NCT02201992 2014
Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell
Lung Cancer That Has Been Removed by Surgery and ALK
Fusion Mutations (An ALCHEMIST Treatment Trial)
ALCHEMIST NCT02595944 2015
Nivolumab After Surgery and Chemotherapy in Treating Patients
With Stage IB-IIIA Non-small Cell Lung Cancer (An
ALCHEMIST Treatment Trial) (ANVIL)
Bardia 2019 Bardia 2018 2018
Efficacy of sacituzumab govitecan (anti-trop- 2-sn-38 antibody-
drug conjugate) for treatment-refractory hormone-receptor positive
(hr+)/her2- metastatic breast cancer (mbc)
Trial ID Study ID Year Title
Basket trials
Basket of
Basket
NCT03767075 2018
A Modular Multi-Basket Trial to Improve Personalized Medicine
in Cancer Patients (Basket of Baskets) (BoB)
BeGIN NCT03872427 2019
Testing Whether Cancers With Specific Mutations Respond Better
to Glutaminase Inhibitor, CB-839 HCl, Anti-Cancer Treatment,
BeGIN Study
BLU-667
Basket Trial
Iams 2018 2018 Stop fretting the target: Next-generation ret inhibitors have arrived
BLU-667
Basket Trial
NCT03037385 2017
Phase 1 Study of the Highly-selective RET Inhibitor BLU-667 in
Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and
Other Advanced Solid Tumors
Table S6. Cont.
52. Table S7. List of included studies: Umbrella trials
Trial ID Study ID Year Title
Umbrella trial
Bardia 2019 Bardia 2019 2019
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-
Negative Breast Cancer.
Bardia 2019 Cardillo 2015 2015
Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38
Antibody-Drug Conjugate: Characterization and Efficacy in
Pancreatic, Gastric, and Other Cancers.
Bardia 2019 NCT01631552 2012 Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers
Bardia 2019 Starodub 2015 2015
First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38
Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse
Metastatic Solid Tumors.
BATTLE Kim 2011 2011 The BATTLE Trial: Personalizing Therapy for Lung Cancer
BATTLE NCT00409968 2006
BATTLE Program: Umbrella Protocol for Patients With Non-Small
Cell Lung Cancer (NSCLC)
BATTLE NCT00410059 2006
BATTLE Program: Erlotinib in Previously Treated Subjects With
Advanced NSCLC
BATTLE NCT00410189 2006
BATTLE Program: Erlotinib in Previously Treated Subjects With
Advanced NSCLC
BATTLE NCT00411632 2006
BATTLE Program: Tarceva and Targretin in Patients With Advanced
Non-Small Cell Lung Cancer (NSCLC)
53. Table S8. List of included studies: Platform trials
Trial ID Study ID Year Title
Platform trials
ALIC4E Butler 2018 2018 A trial like alic4e: Why design a platform, response-adaptive, open,
randomised controlled trial of antivirals for influenza-like illness?
ALIC4E ISRCTN27908921 2015 Antivirals for influenza-like illness? Are they effective?
CREATE NCT01524926 2012 CREATE: Cross-tumoral Phase 2 With Crizotinib (CREATE)
CREATE Peron 2019 2019 A multinational, multi-tumour basket study in very rare cancer types: The
european organization for research and treatment of cancer phase ii 90101
'create' trial
CREATE Schoffski 2017 2017 Activity and safety of crizotinib in patients with advanced clear-cell
sarcoma with MET alterations: European Organization for Research and
Treatment of Cancer phase II trial 90101 ‘CREATE’
CREATE Schoffski 2018 2018 Crizotinib in patients with advanced, inoperable inflammatory
myofibroblastic tumours with and without anaplastic lymphoma kinase
gene alterations (European Organisation for Research and Treatment of
Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-
randomised phase 2 trial.
CREATE Schoffski 2018B 2018 Activity and safety of crizotinib in patients with alveolar soft part
sarcoma with rearrangement of TFE3: European Organization for
Research and Treatment of Cancer (EORTC) phase II trial 90101
‘CREATE’
54. Fig. 2 Trends of master protocols over time. This figure illustrates the accumulating
number of basket (white), umbrella (gray), and platform (black) trials over time.
Basket trial
(B2225)
Platform trial
(STAMPEDE)
57. Master
protocol ID
Registry Trial status
Ph
ase
Rando
-mized
(Y/N)
Masking
Total
N
Proposed
trial
duration
(mo)
Interv-
ention
types
No of
interv
en-
tion
Contro
l: Y/N
Basket trials
AcSe´ NCT02304809 Recruiting II No Open label 500 90.9 Drugs 1 No
Ado-
trastuzumab
Basket trial
NCT02675829 Recruiting IIA No Open label 100 35.9 Drugs 1 No
AGADIR NCT03915678
Not yet
recruiting
II No Open label 247 47.9 Drugs 1 No
ALCHEMIST
NCT02201992;
NCT02193282;
NCT02595944
Recruiting III Yes Open label 1542 118.8 Drugs 3 Yes
Bardia 2019 NCT01631552
Active, not
recruiting
I/II No Open label 500 81.8 Drugs 1 No
Basket of
Basket
NCT03767075 Recruiting II No Open label 1000 4.0 Drugs 1 No
BeGIN NCT03872427
Not yet
recruiting
II No Open label 108 20.0 Drugs 1 No
Table S9. Trial characteristics of master protocols
58. Master protocol
ID
Registry Trial status
Ph
ase
Rando
-mized
(Y/N)
Masking
Total
N
Proposed
trial
duration
(mo)
Interv-
ention
types
No of
interv
en-
tion
Contro
l: Y/N
Umbrella trials
BATTLE-1 NCT00409968
Active, not
recruiting
(results
published)
II Yes Open label 250 167.7 Drugs 4 No
BATTLE-2 NCT01248247
Active, not
recruiting
(results
published)
II Yes Open label 334 95.8 Drugs 4 No
CheckMate 370 NCT02574078
Active, not
recruiting
I/II Yes Open label 342 41.3 Drugs 5 Yes
FOCUS4
ISRCTN90061
546
Completed/
published
II/
III
Yes
Double
blind
384 58.8 Drugs 5 Yes
FUTURE NCT03805399 Recruiting
Ib/I
I
No Open label 140 46.9 Drugs 7 No
Genomics
Enabled Medicine
for Melanoma
NCT02094872
Active, not
recruiting
II Yes Open label 47 46.9 Drugs 19 Yes
LUNG-MAP NCT02154490 Recruiting
II/
III
Yes Open label 10000 93.8 Drugs 5 Yes
Table S9. Cont.
59. Master
protocol ID
Registry Trial status
Ph
ase
Rando
-mized
(Y/N)
Masking
Total
N
Proposed
trial
duration
(mo)
Interv-
ention
types
No of
interv
en-
tion
Contro
l: Y/N
Platform trials
ALIC4E
ISRCTN279089
21
Completed
"N
A"
Yes Open label 675 39.0 Drugs NR Yes
EBOLA NCT02380625 Terminated II Yes Open label 150 35.9 Drugs 3 Yes
FRACTION
NCT02935634;
NCT02750514;
NCT02996110
Recruiting II Yes Open label 1004 68.3 Drugs 5+ Yes
GBM AGILE NR Recruiting
II/
III
Yes NR NR -- Drugs NR Yes
I-SPY2 NCT01042379
Recruiting/pub
lished
II Yes Open label 1920 128.8 Drugs 18 Yes
INSIGhT NCT02977780 Recruiting II Yes Open label 280 50.8 Drugs 3 Yes
LEAP NCT03092674
Suspended
(Unscheduled
safety data
review)
II/
III
Yes Open label 1670 67.8 Drugs 4+ Yes
Table S9. Cont.
61. Disease characteristics of master protocols
• Most studies were in adult populations (n = 69/83)
• Nearly all were in the field of oncology (n = 76/83)
62. Master protocol ID
Disease
area
Type of
population
Age
eligibility
(yr)
Number
of
diseases
Key eligibility
criteria for
stratification
Number
of
subgroups
Basket trials
AcSe´ Oncology Adults ≥18 11+ Biomarkers 11
Ado-trastuzumab Basket
trial
Oncology Adults ≥18 4+ Biomarkers 4
AGADIR Oncology Adults ≥18 6 Tumour type 6
ALCHEMIST Oncology Adults ≥18 1
Biomarkers and
treatment history
3
Bardia 2019 Oncology Adults ≥18 16 Biomarker 16+
Basket of Basket Oncology Adults ≥18 2+ Biomarkers 6
BeGIN Oncology Mixed ≥18 4+ Biomarkers 4+
BLU-667 Basket Trial Oncology Adults ≥18 4+
Biomarkers and
treatment history
6
Table S10. Disease characteristics of master protocols
63. Master protocol ID
Disease
area
Type of
population
Age
eligibility
Number
of
diseases
Key eligibility
criteria for
stratification
Number
of
subgroups
Basket trials
CLUSTER
Hereditary
Periodic
Fevers
Mixed 1mo or
older
3 Disease type 3
TNT0009 Basket Trial
Complement
-Mediated
Disorders
Adults
18yr or
older
4 Biomarkers 3
64. Master protocol ID
Disease
area
Type of
population
Age
eligibility
Number
of
diseases
Key eligibility
criteria for
stratification
Number
of
subgroups
Umbrella trials
BATTLE-1 Oncology Adults ≥18 1
Biomarkers and
tumour type
4
BATTLE-2 Oncology Adults ≥18 1
Biomarkers and
tumour type
NR
CheckMate 370 Oncology Adults ≥18 1 Biomarkers NR
FOCUS4 Oncology Adults ≥18 1
Biomarkers and
tumour type
5
FUTURE Oncology Adults ≥18 1 Biomarkers 4
Genomics Enabled
Medicine for Melanoma
Oncology Adults ≥18 1 Biomarkers 19
LUNG-MAP Oncology Adults ≥18 1
Biomarkers and
tumour type
5
BATTLE-1 Oncology Adults ≥18 1
Biomarkers and
tumour type
4
Table S10. Cont.
65. Master protocol ID
Disease
area
Type of
population
Age
eligibility
Number
of
diseases
Key eligibility
criteria for
stratification
Number
of
subgroups
Platform trials
ALIC4E Influenza Mixed
At least
1yr
1
Disease type and risk
factors
NR
EBOLA Ebola Mixed
6mo or
older
1 Disease type NR
FRACTION Oncology Adults
18 yrs or
older
3 Biomarkers 12
GBM AGILE Oncology NR NR 1
Biomarkers and
tumour type
6
I-SPY2 Oncology Adults
18yr or
older
1
Biomarkers and
tumour type
3
INSIGhT Oncology Adults
18yr or
older
1
Biomarkers and
tumour type
4
LEAP Oncology
Adults
(older)
60yr or
older
1 Biomarkers NR
ALIC4E Influenza Mixed
At least
1yr
1
Disease type and risk
factors
NR
Table S10. Cont.
67. Geographic representation of master protocols
Fig 4. Geographical representation of master protocols. This figure illustrates
the accumulating number of basket (white), umbrella (gray), and platform
(black) trials over time
n=44/83
FUTURE, GBM
AGILE, TRUMP
AND VE BASKET
68. Table S11. Geographic location of master protocols
Master protocol ID
N of
centers
involved
LMICs
involved
Countries
Basket trials
AcSe´ NR No France
Ado-trastuzumab Basket trial 1 No US
AGADIR 10 No France
ALCHEMIST 1349 No US
Bardia 2019 12 No US
Basket of Basket 3 No France, Spain, and UK
BeGIN 1 No US
69. Table S11. Cont.
Master protocol ID
N of
centers
involved
LMICs
involved
Countries
Umbrella trials
BATTLE-1 1 No US
BATTLE-2 2 No US
CheckMate 370 133 No US
FOCUS4 18 No UK
FUTURE 1
Yes
(China)
China
Genomics Enabled Medicine
for Melanoma
8 No US
LUNG-MAP 1004 No US, Canada
70. Table S11. Cont.
Master protocol ID
N of centers
involved
LMICs
involved
Countries
Platform trials
ALIC4E 39 No
Belgium, Croatia, Czech Republic, Denmark, France,
Greece, Hungary, Ireland, Lithuania, Netherlands,
Norway, Poland, Spain, Sweden, Switzerland, United
Kingdom
EBOLA NR
Yes (West
Africa)
Guinea, Sierra Leone, Liberia
FRACTION 50 No
US, Australia, Austria, Canada, France, Italy, Spain,
Switzerland
GBM AGILE NR Yes (China) US, Australia, China
I-SPY2 24 No US
INSIGhT 10 No US
LEAP 508 No US
71. • In line with objectives
• PRISMA flow diagram given
• Tables are self-explanatory
• Footnotes are given
• Fig 4. labelling is not proper
72. To their knowledge, this is the first landscape analysis of master
protocols
STRENGTH
74. CONCLUSIONS
• Number of master protocols, especially in the last five years, has
increased dramatically and is anticipated to continue over the coming
years
• Master protocols, particularly platform trials, have the potential to
improve the efficiency across the broad spectrum of clinical trial
research
(In line with objective and derived from study results)
75. RECOMMENDATIONS
• Improved approach to standardized nomenclature and database
indexing is essential to improve the identification and retrieval of these
study designs
• Efforts are needed to improve the awareness and technical expertise of
master protocols to investigators in fields outside of oncology and in
geographic regions outside of high-income countries
(Derived from conclusion, specific and doable)
76. FUNDING:
This study was not funded
DECLARATION OF INTERESTS:
Authors declare that they have no competing interests
ETHICS APPROVAL:
Not applicable
77. What did I learn?
• Adaptive designs
• Master protocol
Basket trial
Platform trial
Umbrella trial
A clinical trial design that offers pre-planned opportunities to use accumulating trial data to modify aspects of an ongoing trial while preserving the validity and integrity of that trial (ACE steering committee)
.They add a review–adapt loop to the linear design–conduct–analysis sequence
The purpose is to make clinical trials more flexible, efficient and fast. Due to the level of flexibility involved, these trial designs are also termed as “flexible designs.”
Flexibility here does not mean that the trial can be modified any time at will. The modification and adaptations have to be pre-planned and should be based on data collected from the study itself.
Not all changes in the design after study initiation are considered adaptive design. The FDA defines some types of changes as reactive revisions. A reactive revision is a change that was made due to unplanned findings during an interim analysis or revisions based on information that is received from a source external the study. Thus, it is imperative to consider the possible outcomes for each interim analysis when planning the protocol and to write out, as thoroughly as we can, the next steps that will be taken for each of the outcomes. If the revisions to a study design are not incorporated into the protocol at the outset, reactive revision could invalidate a study.
Interim analysis—A statistical analysis or review of accumulating data from an ongoing trial (interim data) to inform trial adaptations (before the final analysis), which may or may not involve treatment group comparisons
Frequentist inference is a type of statistical inference that draws conclusions from sample data by emphasizing the frequency or proportion of the data.
Bayesian analysis based on bayseian Interpretation of probability which is based on element of belief. Bayes theorem based on conditional probability.
in which the clinical trial infrastructure is created to test
a single treatment in a homogeneous population.
There has been increasing interest in efficient trial
Strategies designed to evaluate multiple treatments and
combinations of treatments, in heterogeneous patient
populations, with the capability to add new treatments
in the future and eliminate investigational treatments
lacking efficacy
Precision medicine (PM) is a medical model that proposes the customization of healthcare, with medical decisions, treatments, practices, or products being tailored to a subgroup of patients, instead of a one‐drug‐fits‐all model. In precision medicine, diagnostic testing is often employed for selecting appropriate and optimal therapies based on the context of a patient’s genetic content or other molecular or cellular analysis
Effective treatments for such diseases (sepsis, alzheimers, demetia, stroke) will likely require combining treatments to affect multiple targets in complex cellular pathways and, perhaps, tailoring treatments to subgroups defined by genetic, proteomic, metabolomic, or other markers.
All constitute a collection of trials or substudies that share key design components and operational aspects to achieve better coordination than can be achieved in single trials designed and conducted independently
The ability to use a single infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and/or disease populations in multiple substudies speeds up drug development and makes it more efficient
Thus , mp is a unifying design that includes multiple subgrps or sub studies, with pts having same or diff ds and that employ one or multiple drugs to treat it.
Mp facilitates screening and pt accrual.
Saves time by 18% (117 weeks – 96-102 weeks)
Saves cost (12-15%) (dollar 11.2M --- 9.5M)
A MP DESIGNED to test a single ind or combo in diff pop defined by disease stage, or histology, genetic or other biomarkers
Usually early phase, single-arm sub-studies
Design: often single stage or Simon two-stage with futility stopping
Usually 20-30 patients per “basket” or molecular sub-study
Could drugs that target specific gene alterations cause responses across a wide variety of diseases? Could drugs work based on genomics rather than the site of origin of the cancer?
Studies rare types (broad eligib crit), smaller sample size req, when tt already approved for one tumor type – it can be extrapolated to diff tumor immediately
PIC 2:
Unlike traditional clinical trials which focus on patients with a single cancer histology, the core organizing principle of basket trials is concentrated on a specific genomic alteration found in the tumor, regardless of where the cancer originated. A basket trial tests the effect of one drug (Drug A/B/C) that targets the same genomic alteration (Mutation A/B/C) across a variety of tumor types.
HYMAN ET AL: A total of 120 patients with refractory cancer who harbored BRAF mutation received vemurafenib. In NSCLC patients after multiple-line therapy, the ORRs were 42% with a disease control rate (DCR) of 84%.
This rate compares favorably with the 7% ORR reported for standard second-line docetaxel in molecularly unselected patients.
The DCR was 62% in a cholangiocarcinoma cohort, which was also better than second-line chemotherapy (49.5%).
study demonstrated that histology-independent, biomarker-selected basket studies are feasible and can serve as tools for developing molecular-targeted cancer therapies
Erdheim-Chester disease or LCH had significant clinical benefits from vemurafenib . Thus, this basket trial established a standard of care for these rare cancers with BRAF mutation.
A protocol with more than one targeted therapy studied for a single disease. Patients are divided into multiple parallel treatment arms, receiving different drugs or drug combinations. Such studies usually include a control arm. Umbrella design studies may include multiple doses of the same drug for dose-finding purposes
Lung-MAP is a Phase 2/3 umbrella trial enrolling patients with advanced LUSC
June 2014, Lung-MAP originally had four biomarker-driven substudies and one nonmatch substudy
Patients with genomic alterations that qualify for multiple substudies are assigned to treatment based on a weighted-randomization algorithm that gives preference to molecular targets of lowest prevalence.
If no actionable marker was detected, they were enrolled to the non-match sub-trial, allowing all eligible patients to be treated
Since June 16, 2017 all of these five original sub-studies have been closed .
March 2015: FDA approved nivolumab in same patient population (SOC)
Oct 2017: 1,400 patients registered
As of June 2018, over 1700 patients have been accrued to the screening component. Nine substudies have activated; the original 5 are completed/closed and 4 are currently accruing. Completed studies evaluated taselisib for phosphoinositide 3-kinase mutations, palbociclib for cell-cycle gene alterations, AZD4547 for fibroblast growth factor receptor alterations, rilotumumab and erlotinib for c-MET+ tumors, and durvalumab. The results to date demonstrate the feasibility of the Lung-MAP trial platform and the ability to simultaneously accrue and evaluate therapies in rare prevalence patient populations.
currently, four new sub-studies (S1400F, S1400G, S1400I and S1400K) are a part of the Lung-MAP trial and are open for accrual
Instead of “intervention-focused” designs, platform trials are more “disease-focused” because they allow for more efficient evaluation of multiple interventions in a perpetual manner
Because there are usually multiple candidates in a given research area, intervention-focused approaches can result in multiple, independent trials being conducted with redundant infrastructures being created for shorter-term evaluation and the larger number of patients being randomized to standard of care or placebo
Multiarm CT: If a therapeutic discovery is made after a clinical trial begins, regardless of whether they are two-arm or multiarm studies, a new trial may be needed to determine its efficacy
CHALLENGES: POP DRIFT, BLINDING?, TYPE 1 ERROR, RESOURCES
(Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2
I-SPY 2 is a clinical trial for women with newly diagnosed locally advanced breast cancer [8].
regimens that show a high Bayesian predictive probability of being more effective than standard therapy will graduate from the trial with their corresponding biomarker signature
RCB: RESIDUAL CANCER BURDEN / PCR: PATHOLOGIC COMPLETE RESPONSE (tumour disappeared completely)
If predictive probabilities for an experimental agent reach a pre-determined level of efficacy in one or more molecular subtypes, it is declared a success (“graduates”)
Based on the participant's tumor subtype, outcome and treatment received, the predictive probabilities of the agent in the various subtypes are updated in real time.
I-SPY 2’s adaptive randomization engine assigns a participant to a study arm; it gives greater weight to arms that have been successful in the participant's tumor subtype.
The defining characteristic of all ADs is that results from interim data analyses are used to modify the ongoing trial, without undermining its integrity or validity
smooth and continuous, with no apparent gaps or spaces between one part and the next.
fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, n in faster time frames, n with more certainty, n and at lower costs”
Operationally: faster …. (by cutting out the ‘white space’ between Ph II and Ph III, using the same operational infrastructure )
Ineferentially: lower cost
Since we can combine Phase 2 and Phase 3 data in an adaptive seamless design, we can use data from the Phase 2 trial to inform Phase 3:
More efficiently use patient data to infer strong conclusions
Reduce the number of patients who must be enrolled at Phase 3, thus saving time and money
Improve selection of target doses and participants in Phase 3
Investigate possible covariates between short-term endpoints derived from Phase 2 and long-term clinical outcomes in Phase 3
Continue to follow patients on terminated treatment groups from Phase 2 throughout Phase 3, providing more information on time effects of treatment as well as safety
Change or cut treatments during the study, resulting in patients having a greater chance of receiving safe and efficacious treatment.
Validity: TUMORAL HETEROGENETY (bias)
Power: sample size not reached?
Resources: apt infrastructure, money?
Consents. Informed consent documents used in novel clinical trials are often overly cumbersome and confusing for both patients and investigators in large part because the trials themselves are so complicated and difficult to explain
through standardization of procedures in the development and evaluation of different interventions
to include standardized trial operational structures, patient recruitment and selection, data collection, analysis, and management
The second part is the aim of the study
Protocol articles will only be considered for proposed or ongoing research that has not yet started the final data extraction stage of the review at the time of submission, and should provide a detailed account of the hypothesis, rationale and methodology of the study.
Systematic Reviews requires the submission of a populated PRISMA-P checklist for all study protocols.
Systematic Reviews encourages prospective registration of systematic reviews in PROSPERO or Open Science Framework and encourages registration of scoping and other types of review in other relevant registration platforms.
THAT HAVE BEEN PROPOSED, ONGOING, ALREADY CONDUCTED
In umbrella trials, the single disease study population is stratified into multiple subgroups on predictive biomarkers or other characteristics or both
, but the MAMS designs that do not allow flexibility of adding new arms during the trial are not truly platform trials
MEDLINE: MEDLARS ONLINE( medical literature analysis and retrieval system online):1946: mesh [pubmed:1996]
EMBASE : EXCERPTA MEDICA DATABASE : 1947 [EMTREE]-ELSEVIER-NETHERLANDS
COCHRANE :UK, 1993
International Standard Randomised Controlled Trial Number: IS A numeric system for the identification of RCTS worldwide. Simplifies identification of trials and provides a unique no. used to track all publications and reports resulting from each trial.
Recognized by who and ICMJE
Conventional: based on or in accordance with what is generally done or believed
Other sources: hand searches of bibliographies and trial registries
Screening criteria?
Thirty-four trials were available only through trial registries, and three trials were in the
pre-recruitment phase (NCT03339843, NCT03915678, and NCT03872427)
The first master protocol conducted was a basket trial called the Imatinib Target Exploration Consortium Study B2225 which started in 2001.
This was followed by the platform trial STAMPEDE, which was first proposed in 2005 for advanced prostate cancer. Results have been published , 2017
NCT03003195 was the exception as a proposed vaccine basket trial
UMBRELLA TRIALS HAVE NARROW IQR COMPARED TO OTHER TWO (MORE DISPERESED)
SAMPLE SIZE DIST IS DIFF IN ALL THREE TRIALS
OUTLIERS IN UMB
Umb req larger sample size compared to basket coz they are confirmatory whereas basket exploratory (less sample size)
Two basket trials conducted outside oncology
The hereditary periodic fever syndromes are autoinflammatory diseases that mostly present in childhood and are characterized by recurrent, self-limiting, seemingly unprovoked episodes of fever and systemic inflammation that occur in the absence of autoantibody production or identifiable infection.
CLUSTER: 2017
UPMC: univ of Pittsburgh medical centre
Remap: random, embedded, multifactorial adaptive platform trial
Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE (ALIC4E)
Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial
OUT OF 83 , 44 studies have been conducted in US
Other high-income countries such as the UK (n = 25), France (n = 23), Spain (n = 17), and Canada (n = 13) were the next most common countries.
There were no master protocols observed from low-income countries, although the EBOLA (NCT02380625) trial had been proposed for Guinea, Sierra Leone, and Liberia
Two upper-middle-income countries, Brazil and Mexico, were involved in the DIAN-TU platform trial (NCT0760005), but these countries accounted for only three of 36 study sites
China, an upper-middle-income
country, has centers participating in
GBM AGILE : ADAPTIVE GLOBAL INNOVATIVE LEARNING ENV FOR GLIOBLASTOMA
this was offset by our rigorous approach that had strong supplemental searching strategies inclusive of several search terms on adaptive trial designs.
Coz in this article no studies represent developing countries
It is a general statement
Mixing of diff types of control will affect the comparability
Low adherence to treatment may introduce bias coz those who left may have more depression, anxiety etc
National Health and Medical Research Council (NHMRC) is Australia's peak funding body for medical research,
Excluded those without internet access
Who’s mast ct protocol could speed up development of covid therapies (4th mar)
Fda has stated from the ebola outbreak lessons: the feasibility and desirability to meet the demands of emerging public health crises, rare ds, cancer subtypes
On April 17, 2020 the National Institutes of Health (NIH) announced the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership to develop a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines.
ACTIV brings NIH together with its sibling agencies in the Department of Health and Human Services, including the Biomedical Advanced Research and Development Authority (BARDA), Centers for Disease Control and Prevention (CDC), and the U.S. Food and Drug Administration (FDA); other government agencies including the Department of Defense (DOD) and Department of Veterans Affairs (VA); the European Medicines Agency (EMA); and representatives from academia, philanthropic organizations, and numerous biopharmaceutical companies
Develop a collaborative, streamlined forum to identify preclinical treatments.
Establishing a steering committee with relevant expertise to set criteria for and rank potential candidates submitted by industry partners for testing
Designing, launching, and openly sharing master protocols with agreed-upon endpoints, sampling, and analysis for evaluating candidates
Specializing in different populations and disease stages
Leveraging infrastructure and expertise from across NIH and non-NIH networks and clinical research organizations
Using a single control arm to enhance trial efficiency
