This document discusses clinical proof-of-concept (POC) trials in drug development. It defines POC as establishing whether a drug is reasonably likely to succeed based on early evidence of safety and efficacy. The document outlines goals of POC trials, decision criteria used, and strategies to improve probability of success such as better patient selection using biomarkers. It provides examples of oncology POC trials and discusses practical considerations for using patient selection approaches.
Real-World Evidence: The Future of Data Generation and UsageApril Bright
As data is captured through electronic health records, registries and unique device identifiers, the generation of evidence based on this data is expected to play a crucial role in informing orthopedic manufacturers’ decisions before and after regulatory approval. While regulators, payors, hospitals and manufacturers support this shift, they acknowledge that gaps remain in its optimal execution. Priority considerations include how to generate evidence to expedite regulatory market decisions, device indication expansion, postmarket studies, postmarket surveillance and reimbursement decisions. The National Evaluation System for health Technology Coordinating Center (NESTcc), an initiative of the Medical Device Innovation Consortium (MDIC), is leading the conversation with various stakeholders, including FDA and orthopedic device companies to support the sustainable generation of Real-World Evidence (RWE) using Real-World Data (RWD).
Good Clinical Practice Guidelines (ICH GCP E6).pptMohamed Fazil M
M. Pharmacy - Pharmaceutical Regulatory Affairs (MRA)
1st Semester - Clinical Research Regulations (MRA 103T)
Unit 4 - Clinical Research Related Guidelines: Good Clinical Practice Guidelines (ICH GCP E6)
THE PRINCIPLES OF ICH GCP
INSTITUTIONAL REVIEW BOARD/ INDEPENDENT ETHICS COMMITEE
Principal Investigator
Sponsor
Investigator's Brochure
Real-World Evidence: The Future of Data Generation and UsageApril Bright
As data is captured through electronic health records, registries and unique device identifiers, the generation of evidence based on this data is expected to play a crucial role in informing orthopedic manufacturers’ decisions before and after regulatory approval. While regulators, payors, hospitals and manufacturers support this shift, they acknowledge that gaps remain in its optimal execution. Priority considerations include how to generate evidence to expedite regulatory market decisions, device indication expansion, postmarket studies, postmarket surveillance and reimbursement decisions. The National Evaluation System for health Technology Coordinating Center (NESTcc), an initiative of the Medical Device Innovation Consortium (MDIC), is leading the conversation with various stakeholders, including FDA and orthopedic device companies to support the sustainable generation of Real-World Evidence (RWE) using Real-World Data (RWD).
Good Clinical Practice Guidelines (ICH GCP E6).pptMohamed Fazil M
M. Pharmacy - Pharmaceutical Regulatory Affairs (MRA)
1st Semester - Clinical Research Regulations (MRA 103T)
Unit 4 - Clinical Research Related Guidelines: Good Clinical Practice Guidelines (ICH GCP E6)
THE PRINCIPLES OF ICH GCP
INSTITUTIONAL REVIEW BOARD/ INDEPENDENT ETHICS COMMITEE
Principal Investigator
Sponsor
Investigator's Brochure
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.
This presentation is a brief overview of ICH-GCP guidelines. Although ICH-GCP is a very vast topic, still this presentation will cover almost all the points. The reader will be able to discuss about the roles and responsibilities of various personnel in clinical trials.
Regulation Governing Clinical Trials In India,USA and Europe. KapilKumar198
This presentation contain detailed information about the "Regulation Governing Clinical Trials In India,USA and Europe".And about the clinical trails and medical devices regulations in India.
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
An example of a successful proof of conceptETLSolutions
In this presentation we explain how to create a successful proof of concept for software, using a real example from our work in the Oil & Gas industry.
Post-launch experiences from a locally developed internal proof of concept im...Sebastian Schumann
Post-launch experiences from a locally developed internal
proof of concept implementation
- Service description
- Used technologies and integration challenges
- Lessons learned
Presented at the 2nd annual WebRTC Global Summit in London, UK
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.
This presentation is a brief overview of ICH-GCP guidelines. Although ICH-GCP is a very vast topic, still this presentation will cover almost all the points. The reader will be able to discuss about the roles and responsibilities of various personnel in clinical trials.
Regulation Governing Clinical Trials In India,USA and Europe. KapilKumar198
This presentation contain detailed information about the "Regulation Governing Clinical Trials In India,USA and Europe".And about the clinical trails and medical devices regulations in India.
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
An example of a successful proof of conceptETLSolutions
In this presentation we explain how to create a successful proof of concept for software, using a real example from our work in the Oil & Gas industry.
Post-launch experiences from a locally developed internal proof of concept im...Sebastian Schumann
Post-launch experiences from a locally developed internal
proof of concept implementation
- Service description
- Used technologies and integration challenges
- Lessons learned
Presented at the 2nd annual WebRTC Global Summit in London, UK
OTN tour 2015 Oracle Enterprise Manager 12c – Proof of ConceptAndrejs Vorobjovs
Why we are talking about this
How – minimal survival kit
Database provisioning:
Database provisioning
Pluggable database provisioning
Schema provisioning
Middleware provisioning:
New instance installation
Instance cloning
Integration provisioning
Restrictions
Conclusion
Q&A
Peteris Arajs
Technology Architecture Associate Manager at Accenture
More than 15 years experience in IT industry with main focus to:
- DB design, analysis, development and performance tuning
- Oracle eBusiness Suite
- Oracle Middleware
Also experienced in all stages of software development life cycle (SDLC) from business requirements and technical definitions to development, testing and production support.
Alex Nemirovskis
Technology Architecture Associate Manager at Accenture
More than 19 years experience in IT industry with main focus to:
- DB design, analysis, development and performance tuning
- DWH / ETL / BI / Analytics
- Oracle ADF
Also experienced in all stages of software development life cycle (SDLC) from business requirements and technical definitions to development, testing and production support.
VMworld 2015: Conducting a Successful Virtual SAN Proof of ConceptVMworld
In this session, Cormac Hogan and Julienne Pham of VMware take a comprehensive look at the setup, policy management, failure handling, and monitoring tools needed to perform a successful Proof of Concept. This session empowered attendees to go and implement their own VSAN POCs.
Proof of Concept with Real Application Testing 12cLuis Marques
Evaluate how certain real world database workload behaves on different I/O subsystem, processors and
architecture or the coexistence with other databases is the goal of a Proof of Concept. The need of testing
real production workloads to eliminate uncertainty with help of techniques like Workload Folding, Time
Shifting and Schema Remapping, this talk will produce evidence that exploring Real Application Testing
features in 12c leverage what can be accomplished by a Proof of Concept.
Speaker: Wendy Hill, Gap Strategies. Part of the MaRS Best Practices Series.This session, led by seasoned industry experts, will explore how to effectively set up your pre-clinical POC studies, address pre-clinical safety requirements and issues, and give you an overview of the manufacturing standards required for Phase I studies
More information: http://www.marsdd.com/Events/Event-Calendar/Best-Practices-Series/ind-05132008.html
Twiliocon Europe 2013: From PoC to Production, Lessons Learnt, by Erol Ziya &...eazynow
Here are the slides for the talk that myself (Erol Ziya - @eazynow) and Rob Baines (@telecoda) gave at the first Twiliocon Europe, providing tips for when moving from PoC to production based on our experiences in hibu labs. #twiliocon
PoC: Using a Group Communication System to improve MySQL Replication HAUlf Wendel
High Availability solutions for MySQL Replication are either simple to use but introduce a single point of failure or free of pitfalls but complex and hard to use. The Proof-of-Concept sketches a way in the middle. For monitoring a group communication system is embedded into MySQL usng a MySQL plugin which eliminates the monitoring SPOF and is easy to use. Much emphasis is put of the often neglected client side. The PoC shows an architecture in which clients reconfigure themselves dynamically. No client deployment is required.
Case Study: Lessons from Newell Rubbermaid's SAP HANA Proof of ConceptSAPinsider Events
View this session from Reporting & Analytics 2014. Coming to Las Vegas in November! www.reporting2015.com
In this session, Newell Rubbermaid guides you through the key elements that comprised its SAP HANA business case and proof of concept, including an emphasis on process improvement. Learn firsthand how Newell Rubbermaid:
· Identified which business processes were most likely to realize significant improvement as a result of utilizing SAP HANA
· Established a “current state” baseline and demonstrated a “projected state” that could be realized through the use of SAP HANA
· Determined which SAP BI tools to use based on specific reporting scenarios and end user requirements
Accelerating Innovation: Proof of Concept Gap Fund Program Best Practicesinnovosource
Review of best practices in University Proof of Concept (POC) Gap Funding Programs from the Mind the Gap Initiative and Report, a full program development guide for fund managers covering 82 translational research, proof of concept, and start-up gap funding programs
Introduction to pre clinical screening of drugsKanthlal SK
Various Techniques and Methods for screening of new chemical entities in preclinical aspects (both invitro & invivo) for effective and safe clinical usage.
2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van GoolAlain van Gool
Tutorial lecture explaining real case stories of oncology drug development, passing on lessons learned from my pharma days to an audience of research professionals.
Analyzing ASCO 2016: Developments, takeaways, and implications from the confe...Pharma Intelligence
In conjunction with a Key Opinion Leader, Dr. Peter Lee MD Chair, Department of Immuno-Oncology at City of Hope Comprehensive Cancer Center, CA, several Informa analysts discuss the major developments of the conference and key take-aways via a Webinar.
Watch our recording of Biomedtracker's Robert Jeng, Ph,D., Citeline's Allison Bruce, Scrip's Mary Jo Laffler, and Datamonitor Healthcare's Zachary McLellan as they download and debrief following the always-exciting ASCO weekend.
View and listen to the full webinar here https://www.youtube.com/watch?v=7yMsCb3R5X8
Edward B. Garon, MD, MS, Jamie E. Chaft, MD, and Matthew D. Hellmann, MD, prepared useful Practice Aids pertaining to lung cancer management for this CME/MOC/CE activity titled "Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Cancer Continuum: State of the Science and Implications for Practice." For the full presentation, monograph, complete CME/MOC/CE information, and to apply for credit, please visit us at http://bit.ly/2ATq0qp. CME/MOC/CE credit will be available until November 21, 2019.
Target Validation Academy Of Medical Sciences 1 Dec 2006Mike Romanos
An overview of the issues and approaches in selecting the best targets for drug discovery and validating them. Given at the Drug Discovery Forum held at the Royal Society, London and organised by the Academy of Medical Sciences
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
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
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
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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.
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
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
Contact us if you are interested:
Email / Skype : kefaya1771@gmail.com
Threema: PXHY5PDH
New BATCH Ku !!! MUCH IN DEMAND FAST SALE EVERY BATCH HAPPY GOOD EFFECT BIG BATCH !
Contact me on Threema or skype to start big business!!
Hot-sale products:
NEW HOT EUTYLONE WHITE CRYSTAL!!
5cl-adba precursor (semi finished )
5cl-adba raw materials
ADBB precursor (semi finished )
ADBB raw materials
APVP powder
5fadb/4f-adb
Jwh018 / Jwh210
Eutylone crystal
Protonitazene (hydrochloride) CAS: 119276-01-6
Flubrotizolam CAS: 57801-95-3
Metonitazene CAS: 14680-51-4
Payment terms: Western Union,MoneyGram,Bitcoin or USDT.
Deliver Time: Usually 7-15days
Shipping method: FedEx, TNT, DHL,UPS etc.Our deliveries are 100% safe, fast, reliable and discreet.
Samples will be sent for your evaluation!If you are interested in, please contact me, let's talk details.
We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
2. OutlineOutline
Exploratory Drug Development
Defining POC Defining POC
Improving Probability of Success with Greater
Emphasis on POCp
Improving POC Through Better Patient Selection
Practical Considerations of Patient Selection
Strategies
Summary/conclusion
3. Exploratory Drug Development- Phase I/IIExploratory Drug Development Phase I/II
P li i l
Phase I
(Fi t i
Phase II
(P f f Ph III R i t tiPre-clinical (First-in-
Human)
(Proof-of-
Concept)
Phase III Registration
• Evaluate safety/PK
E l i f
• Establish POC
Inform phase 3
Phase 1 Phase II
S f t Effi (
• Inform phase 2
• Early signs of
efficacy
• Inform phase 2
• Inform phase 3
Endpoints
• Safety
• PK
• Efficacy (response
rates, time-to-event)
Outcomes
• Dose/regimen for
Phase 2 and beyond
• Efficacy sufficient for
Phase 3/ registration
Design • Dose-escalation
• Single-arm
• Randomized
Patient
population
• Unrestricted
• Restricted to
indication
Sample size • 30-50 • 75-150
4. Success Rates from First-in-Man to
RegistrationRegistration
Kola & Landis (2004) Nature Rev Drug Disc
5. Success Rates by Phase of DevelopmentSuccess Rates by Phase of Development
Kola & Landis (2004) Nature Rev Drug Disc
6. Cost of Drug Development by PhaseCost of Drug Development by Phase
Roy A (2012) Manhattan Institute
7. Defining POCDefining POC
PhRMA recommendation:
“POC is the earliest point in drug development processPOC is the earliest point in drug development process
at which the weight of evidence suggests that it is
“reasonably likely” that the key attributes for success
are present and the key causes of failure absent”
Varies by person, project, candidate, etc…
8. Goals by end of PoCGoals by end of PoC
P li i l
Phase I
(Fi t i
Phase II
(P f f Ph III R i t tiPre-clinical (First-in-
Human)
(Proof-of-
Concept)
Phase III Registration
• Establish POC
Inform phase 3
We’d like to know
• Inform phase 3
We d like to know
Best dose and regimen (safety driven)
Indications
Administered in combination with what, if anything
Patients who will respond
Pfizer Confidential │ 8
Degree of efficacy
9. POC Essential ElementsPOC Essential Elements
Define essential elements of target product profile
Determine level of risk tolerance for POC Determine level of risk tolerance for POC
Low weight of evidence when consequences of being
wrong are benign and benefits of speed are high
High weight of evidence where consequences of wrong High weight of evidence where consequences of wrong
POC are severe
Determine which elements of POC are already
“reasonably likely” on basis of prior information
Determine which of the remaining elements are not
likely to be significant threats to the programlikely to be significant threats to the program
Determine which of the still remaining elements
cannot be practically evaluated or changed
10. Decision Criteria for POCDecision Criteria for POC
Based on outcome
Set required effect size (∆) lower reference value Set required effect size (∆), lower reference value
(LRV) below which, drug would not have value
HR TV HR MAV
HR ≤ 0.63 &
0.63 0.80 1.00
PFS
Hazard ratio
HR ≤ 0.63 &
Upper bound of 90% CI < 1 &
Upper bound of 50% CI ≤ 0.80
GO to phase III NO GO
HR≥ 0.80
Re‐evaluate
1-sided
significance
level of 0.10
and 80%
power
GO to phase III NO GO
11. Examples of Oncology POC TrialsExamples of Oncology POC Trials
Design
Randomized in same patient population as phase
III/registration
Standard-of-care (SOC) +/- Experimental compound
Experimental compound vs. SOC
Single- arm trial
Compare with historical controls
Endpointsp
Same as endpoints which will be used in phase III/Registration
Time-to-event (OS, PFS)
PFS typically favored due to shorter trial; need to correlate withyp y ;
registrational endpoint (usually OS)
Sample sizes
Typically based on 1-sided α 0.05, 80% poweryp y , p
75‐80 patients per arm of randomized study
12. Attrition of Last-Stage Drug DevelopmentAttrition of Last Stage Drug Development
Adapted from Arrowsmith 2011
13. Patient Selection Strategies to Reduce
Attrition in Phase 3Attrition in Phase 3
Advantages to using biomarker to identify
patients likely to benefitpatients likely to benefit
Smaller sample sizes required
More expeditious path to reach Go/No Go to phase 3
Less expensive
Avoids treating patients with little opportunity of benefitting
Success of biomarker selection dependent on: Success of biomarker selection dependent on:
Prevalence of marker
Effect size
Clinical performance of diagnostic assay
14. Patient Selection StrategiesPatient Selection Strategies
Prospectively select biomarker positive patients
Requires confidence that biomarker is predictive of Requires confidence that biomarker is predictive of
outcome
Need for clinical data in biomarker-negative patients
Enrich for biomarker positive patients in otherwise all-
comers trial
Retrospective analysis of response based on Retrospective analysis of response based on
biomarker
Efficacy signal may be diluted by biomarker-negative
patients
Adaptive designs to incorporate biomarker
information in Phase 2information in Phase 2
15. Patient Selection Strategies
Incorporation of stratified medicine approach leads to increase in
eNPV versus all-comers
Patient Selection Strategies
• Increased eNPV when patient selection used
prospectively (e.g. trastuzumab)
• Negative effects of eNPV when patient
selection used retrospectively (e.g.
panitumumab)
Trusheim et. al. 2011
16. Evolution of Non-Small Cell Lung Cancer
TreatmentTreatment
Martin Reck , et. al., The Lancet, Volume 382, Issue 9893, 2013, 709 - 719
Reck et. al. 2013
18. Practical considerationsPractical considerations
Need for sufficient patient samples
CLIA-certified assays needed for patient selection CLIA-certified assays needed for patient selection
Establishment of cut-offs for biomarker expression
Prevalence of biomarker-positive population Prevalence of biomarker positive population
Evidence for correlation between biomarker
expression and outcomep
Seemless decision points if adaptive trial design
used
Prevent extended slowing or stopping of enrollment
during study
19. Summary and ConclusionsSummary and Conclusions
High cost of attrition in phase 3 setting is shifting
emphasis to better design of phase 2 trialsemphasis to better design of phase 2 trials
Establishing appropriate POC in exploratory
development critical for improving probability of
success in phase 3
Recent shift in oncology drug development toward
f ti ti t l ti i tt t tfocus on prospective patient selection in attempts to
address poor overall success rates
Adaptive study designs being considered to Adaptive study designs being considered to
efficiently use biomarker data
Practical considerations need to be addressed to
ensure success
20. ReferencesReferences
Arrowsmith J. Phase II failures: 2008-2010. Nat Rev Drug Disc (2011);10:1
Cartwright ME, Cohen S, Fleishaker JC, et. al. Proof of concept: a PhRMA position paper with
recommendations for best practice. Nature (2010);87;278
DiM i JA H RW G b ki HG Th i f i ti ti t f d DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug
development costs. J Health Econ (2003);22:151
Gatzemeier U, Pluzanska A, Szczesna A, et. al. Phase III study of erlotinib in combination with
cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva lung cancer
investigation trial. J Clin Oncol (2007);25;1545
G G S C G f Giaccone G, Herbst RS, Manegold C, et. al. Gefitinib in combination with gemcitabine and
cisplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 1. J Clin Oncol
(2004);22:777
Herbst RS, Giaccone G, Schiller JH, et. al. Gefitinib in combination with paclitaxel and carboplatin
in advanced non-small cell lung cancer: a phase III trial- INTACT 2. J Clin Oncol (2004);22:785
Herbst RS, Prager D, Hermann R, et. al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-
774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung
cancer. J Clin Oncol (2005);23:5892
Kola I and Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Disc
(2004);3:711
Reck M, Heigner DF, Mak T, et. al. Management of non-small-cell lung cancer: recent
developments. Lancet (2013);382:709
Roy SA. Stifling new cures: The true cost of lengthy clinical drug trials. Project FDA (2012).
Manhattan Institute for Policy Research. http://www.manhattan-institute.org/html/fda_05.htm
Trusheim MR Burgess B Hu SX et al Quantifying factors for the success of stratified medicine Trusheim MR, Burgess B, Hu SX, et.al. Quantifying factors for the success of stratified medicine.
Nat Rev Drug Disc (2011);10:817