This document discusses efficacy endpoints in oncology drug development. It begins with an introduction to endpoints used in early and late phase trials. Overall survival is discussed as the gold standard, but surrogate endpoints are also examined, including objective response rate, progression-free survival, and time to progression. Considerations for various surrogate endpoints like bias, validation, and data management are provided. The document reviews regulatory requirements and considerations for different cancer types and endpoints.
Presented at PhUSE 2013
The evaluation of efficacy in oncology studies, in particular for solid tumors, is pretty standard and well defined by several regulatory guidance (e.g. EMA and FDA), including some specific cancer type guidance (e.g. NSCLC from FDA).
Although some references will be also given for non-solid tumors, the paper will mainly focus on solid tumors efficacy
endpoints.
Overall Survival, Best Overall Response as per RECIST criteria, Progression Free Survival (PFS), Time to Progression (TTP), Best Overall Response Rate are some of the key efficacy indicators that will be discussed.
Emerging diagnostic technologies proving the clinical application through g...Lyssa Friedman
Next Generation Sequencing is an exciting new technology for diagnostics companies. But is it right for all products and for all companies? This presentation was delivered via Webinar for a IVD audience for Q1 Productions, March 25, 2014.
Seventh Annual Next Generation Dx SummitJaime Hodges
The Next Generation Dx Summit (www.nextgenerationdx.com), entering its seventh year, brings together more than 800 diagnostics professionals from across the world, providing comprehensive programming and valuable networking opportunities. Spanning from clinical diagnostics to business strategy, this year’s expanded program encompasses predictive cancer biomarkers, companion diagnostics, infectious disease, point-of-care, pharmacy-based diagnostics, cell-free DNA, commercialization, cancer immunotherapy, and reimbursement. With widespread coverage of all the most relevant diagnostics topics, the Next Generation Dx Summit promises to be a must-attend event to hear the latest announcements and developments in this rapidly evolving field.
Elaboración de recomendaciones en GPC. Sistema GRADEGuíaSalud
This document discusses the GRADE system for developing clinical practice guidelines and making recommendations. It outlines some of the limitations of existing guideline development processes, including lack of transparency. GRADE provides a transparent and structured framework with three key steps: 1) assessing the quality of evidence through systematic review, 2) evaluating the risk-benefit profile and considering patient values, and 3) determining the strength of recommendations based on the quality of evidence and risk-benefit analysis. Examples are given of how GRADE has been applied to make both strong and weak recommendations. The speaker argues that adopting GRADE would help address many of the existing problems in guideline development.
Jean Marc Nabholtz : Médicaments biologiques : Critères d’enregistrement et d...breastcancerupdatecongress
This document summarizes key criteria for drug registration and development of biological medicines. It discusses important considerations for clinical trial design such as asking meaningful questions, defining appropriate patient populations, sample size calculations, intent-to-treat analysis, and selecting appropriate primary and secondary endpoints. Guidelines from regulatory bodies like the EMA and FDA for evaluating cancer drugs are reviewed, including their perspectives on using progression-free survival or overall survival as primary endpoints. Examples of clinical trial results are provided to illustrate the use of different endpoints.
The document discusses survey results from clinical investigators and practicing oncologists on their use of adjuvant chemotherapy regimens for breast cancer patients. The most common regimens used were anthracycline-containing regimens like AC for node-negative patients and TAC for node-positive patients. More clinicians were using taxane-containing regimens like AC followed by paclitaxel or docetaxel-cyclophosphamide over time. Many clinicians had information on or used gene expression assays like Oncotype DX or MammaPrint to guide chemotherapy decisions.
TexRAD is software that analyzes textures in existing medical scans to provide prognostic information and risk stratification to clinicians. It does this by measuring fine, medium, and coarse textures in scans of tumors like those in the liver, lungs, and other organs. This additional texture information can help predict factors like cancer stage, metastasis risk, and prognosis. TexRAD requires no new scanning procedures and can analyze routine clinical images, providing more information to clinicians to guide patient care decisions.
Presented at PhUSE 2013
The evaluation of efficacy in oncology studies, in particular for solid tumors, is pretty standard and well defined by several regulatory guidance (e.g. EMA and FDA), including some specific cancer type guidance (e.g. NSCLC from FDA).
Although some references will be also given for non-solid tumors, the paper will mainly focus on solid tumors efficacy
endpoints.
Overall Survival, Best Overall Response as per RECIST criteria, Progression Free Survival (PFS), Time to Progression (TTP), Best Overall Response Rate are some of the key efficacy indicators that will be discussed.
Emerging diagnostic technologies proving the clinical application through g...Lyssa Friedman
Next Generation Sequencing is an exciting new technology for diagnostics companies. But is it right for all products and for all companies? This presentation was delivered via Webinar for a IVD audience for Q1 Productions, March 25, 2014.
Seventh Annual Next Generation Dx SummitJaime Hodges
The Next Generation Dx Summit (www.nextgenerationdx.com), entering its seventh year, brings together more than 800 diagnostics professionals from across the world, providing comprehensive programming and valuable networking opportunities. Spanning from clinical diagnostics to business strategy, this year’s expanded program encompasses predictive cancer biomarkers, companion diagnostics, infectious disease, point-of-care, pharmacy-based diagnostics, cell-free DNA, commercialization, cancer immunotherapy, and reimbursement. With widespread coverage of all the most relevant diagnostics topics, the Next Generation Dx Summit promises to be a must-attend event to hear the latest announcements and developments in this rapidly evolving field.
Elaboración de recomendaciones en GPC. Sistema GRADEGuíaSalud
This document discusses the GRADE system for developing clinical practice guidelines and making recommendations. It outlines some of the limitations of existing guideline development processes, including lack of transparency. GRADE provides a transparent and structured framework with three key steps: 1) assessing the quality of evidence through systematic review, 2) evaluating the risk-benefit profile and considering patient values, and 3) determining the strength of recommendations based on the quality of evidence and risk-benefit analysis. Examples are given of how GRADE has been applied to make both strong and weak recommendations. The speaker argues that adopting GRADE would help address many of the existing problems in guideline development.
Jean Marc Nabholtz : Médicaments biologiques : Critères d’enregistrement et d...breastcancerupdatecongress
This document summarizes key criteria for drug registration and development of biological medicines. It discusses important considerations for clinical trial design such as asking meaningful questions, defining appropriate patient populations, sample size calculations, intent-to-treat analysis, and selecting appropriate primary and secondary endpoints. Guidelines from regulatory bodies like the EMA and FDA for evaluating cancer drugs are reviewed, including their perspectives on using progression-free survival or overall survival as primary endpoints. Examples of clinical trial results are provided to illustrate the use of different endpoints.
The document discusses survey results from clinical investigators and practicing oncologists on their use of adjuvant chemotherapy regimens for breast cancer patients. The most common regimens used were anthracycline-containing regimens like AC for node-negative patients and TAC for node-positive patients. More clinicians were using taxane-containing regimens like AC followed by paclitaxel or docetaxel-cyclophosphamide over time. Many clinicians had information on or used gene expression assays like Oncotype DX or MammaPrint to guide chemotherapy decisions.
TexRAD is software that analyzes textures in existing medical scans to provide prognostic information and risk stratification to clinicians. It does this by measuring fine, medium, and coarse textures in scans of tumors like those in the liver, lungs, and other organs. This additional texture information can help predict factors like cancer stage, metastasis risk, and prognosis. TexRAD requires no new scanning procedures and can analyze routine clinical images, providing more information to clinicians to guide patient care decisions.
The document discusses statistical considerations for clinical trial designs that aim to evaluate cardiovascular risk for new diabetes drugs per FDA guidance. It outlines the FDA guidance, which requires ruling out unacceptable increases in CV risk. It then discusses various possible trial designs for standalone trials, including traditional single-analysis designs, group sequential designs, and adaptive designs, noting pros and cons of each approach. The goal would be to rule out hazard ratios above 1.3 and 1.8 with sufficient power and type 1 error control.
The Business of Genomic Testing by James CrawfordKnome_Inc
This document summarizes the key findings from a survey of 13 early adopter institutions that have implemented next-generation genomic sequencing (NGS) technologies. The survey identified common drivers for adoption including demands from clinical colleagues, anticipated efficiency gains, and acquiring institutional expertise. It also explored barriers such as lack of informatics expertise and high costs. Respondents provided lessons learned such as NGS being more complicated than expected and the importance of multidisciplinary teams. Common measures of successful outcomes included growth in test volumes and expansion of testing menus. The document concludes with recommendations for professional organizations like the College of American Pathologists, including providing educational programs and testing standards.
This document provides an overview of Certis Oncology Solutions and their precision oncology approach using patient-derived xenograft (PDX) mouse models. Certis aims to improve cancer treatment outcomes by determining the best therapy for each individual patient's tumor through testing multiple drug therapies simultaneously in mice models. Their orthotopic PDX models are able to reliably metastasize and closely mimic a patient's tumor progression and response, providing more accurate and timely treatment recommendations compared to standard of care. Certis offers to establish immortalized tumor banks from patient samples that can be used for ongoing drug testing if initial therapies fail in order to continually improve treatment outcomes.
Technology Assessment, Outcomes Research and Economic Analysesevadew1
This document discusses technology assessment, outcomes research, and economic analyses in healthcare. It provides background on rising healthcare costs in the US and outlines a hierarchy for assessing new medical technologies from technical efficacy to patient and societal outcomes. Randomized controlled trials are described as the gold standard but limitations are noted. Alternative study designs like modeling and assessing intermediate outcomes are proposed when RCTs are not feasible. The document uses CT for appendicitis as an example to work through initial steps in outcomes research. It also discusses limitations and alternative outcomes like assessing the therapeutic value of diagnostic tests.
1) The document discusses improving outcomes and endpoints in cancer trials by better defining what is important to measure, making endpoints more understandable for patients, and advancing endpoints to reflect changes in trial design and treatments.
2) It notes that endpoints need to show clinically relevant benefits to patients, and that improvements in trial design should be accompanied by improvements in available endpoints.
3) Stakeholders including clinicians, patients, and regulators must work together to determine the best approach for research that ensures accountability and optimizes the use of resources.
Emerson et al-2013-journal_of_ultrasound_in_medicinelinhnguyen1927
Ultrasound imaging has not been fully integrated into PACS systems compared to other modalities like CT and MRI. A survey of ultrasound radiologists found that:
1) Only 53.2% rated their PACS experience for ultrasound as high, significantly lower than for CT (85.2%), MRI (84.4%), and radiography (83.2%).
2) Ultrasound-specific functions like displaying 3D volumes (0.9% rating) and managing data (29.8% rating) received much lower scores than basic functions like viewing black-and-white images (92% rating).
3) Most respondents felt ultrasound-specific functions needed to be implemented or improved in P
Care bundles involve grouping several evidence-based interventions together that are aimed at improving patient outcomes when implemented collectively rather than individually. The ventilator bundle includes interventions like DVT prophylaxis and head of bed elevation. Compliance with care bundles is measured using both process measures like completion rates of individual elements as well as outcome measures. Studies show care bundles can improve outcomes for conditions like sepsis when bundle elements are reliably completed for all applicable patients. Ongoing auditing of compliance and outcomes is needed to demonstrate the sustained impact of care bundles.
Evaluating the cost effectiveness of diagnostic tests ScHARR HEDS
Evaluating the cost-effectiveness of diagnostic tests requires modeling their accuracy, the downstream patient experiences and costs based on test outcomes, and calculating the incremental cost-effectiveness ratio compared to current practice. For new diagnostic tests for sepsis, models would estimate quality of life and costs for high, medium, and low risk groups under different testing strategies incorporating a risk assessment tool and more accurate but costly test. Additional complications in evaluating diagnostics include understanding complex patient pathways, limitations of available data, dependencies between tests, and imperfect reference standards.
Biostatistics in development of Medical Devices By T. Mudde - Clinquest (Qser...qserveconference2013
The document discusses guidelines and considerations for clinical investigations of medical devices, focusing on the role of biostatistics in evaluating safety and effectiveness. It outlines statistical aspects that should be addressed in a clinical investigation plan and protocol, including study objectives, design, analyses, and handling of issues like missing data and sample size calculations. Interactive aspects between biostatisticians and sponsors are also covered, such as balancing precision and bias in study design and choice of endpoints.
POC Breast 1 | 2007 - Systemic Therapy for Metastatic Diseasertp
The document discusses survey results from clinical investigators and practicing oncologists on their treatment recommendations and preferences for various cases of metastatic breast cancer. Key findings include:
- For premenopausal patients with metastatic breast cancer, most recommend monthly injections of leuprolide or goserelin rather than every 3 months.
- For patients progressing after 4+ years of adjuvant anastrozole, fulvestrant and exemestane were the most preferred first-line endocrine therapies.
- Most felt nab-paclitaxel has similar or better efficacy and safety compared to docetaxel-based regimens for metastatic disease.
- Options like bevacizumab, ca
- Telemonitoring for heart failure patients has been shown to reduce mortality rates by up to 36% and decrease hospitalization rates in studies such as TEN-HMS and the Cochrane review.
- The Hull model of telemonitoring in the UK involves a comprehensive system of care including home monitoring devices, community kiosks, and support from nurses and specialist clinics to closely manage heart failure patients.
- Further research and investment in telemonitoring technologies could help shift care from crisis management to proactive health maintenance and empowering patients to better self-manage their condition.
Utility of primary care based TIA electronic decision support: A cluster randomised controlled trial. Presented by Anna Ranta, Department of Neurology, MidCentral DHB, at HINZ 2014, 12 November 2014, 12pm, Plenary Room
This document discusses technology assessment, outcomes research, and economic analyses in healthcare. It provides background on rising healthcare costs in the US without clear improvements in health outcomes compared to other countries. The rationale for assessing new technologies and their impact is described. Key aspects of technology assessment are outlined, including technical efficacy, diagnostic accuracy, diagnostic impact, therapeutic impact, patient outcomes, and societal outcomes. Challenges with randomized controlled trials in assessing technologies are reviewed. The National Lung Screening Trial is presented as an example. Finally, computed tomography for appendicitis is analyzed as a hypothetical example of how modeling could be used to assess a technology when a randomized trial may not be feasible.
This document discusses potential alternatives to the thorough QT study (TQT study) that is currently required by regulatory agencies to assess the potential for drugs to cause abnormal heart rhythms. Specifically, it summarizes:
1) A study that tested using pharmacokinetic/pharmacodynamic modeling of ECG data from first-in-human trials to detect QT effects as an alternative to the TQT study.
2) Issues that still need to be addressed for this alternative approach to be widely accepted, including demonstrating assay sensitivity without an active control.
3) Separate efforts to develop nonclinical assays to directly assess a drug's potential to cause abnormal heart rhythms, with the goal of moving proarrhyth
The document discusses randomized controlled trials and which statements about them are true. It states that option C, "Randomization reduces the risk of an imbalance in factors which could influence the clinical course of the patients," is true. Randomization helps balance both known and unknown prognostic factors between treatment groups in a randomized controlled trial.
This document contains rationales for questions from the 2007 ACR Diagnostic Radiology In-Training Exam. The rationales provide explanations for the correct answers to multiple choice questions related to diagnostic radiology topics including test sensitivity and predictive values, medical ethics, and radiation safety. Specifically, one rationale discusses how the positive predictive value of a diagnostic test increases as the prevalence of a disease increases in a population. Another rationale examines the ethical requirement for physicians to be honest with patients about medical errors or complications. A third rationale identifies radon exposure as contributing the most to background radiation levels in the US.
This document summarizes a medication utilization evaluation of topical tranexamic acid used in orthopedic surgeries at MultiCare Health System. A retrospective review was conducted of 42 patients who received topical TXA between July and October 2014. Results found low transfusion rates of 2.4% comparable to prior IV TXA studies. However, 3 patients who received topical TXA developed deep vein thromboses post-operatively, compared to none with IV TXA. Overall outcomes of length of stay and costs were similar to prior IV TXA patients. The evaluation recommends establishing consistent TXA documentation practices and providing surgeon education on results to optimize safe and effective use.
This document provides an outline for a presentation on electronic medical records (EMRs). It begins with defining the components of an EMR, including labs, admissions/discharge/transfer data, orders, radiology, notes, and billing. It then discusses the history and adoption of EMRs from the 1960s to present. The document reviews studies showing the effectiveness of EMRs in improving quality of care and achieving treatment standards. It also outlines how EMR data is structured in databases and data warehouses and describes common health data standards like ICD, CPT, LOINC, SNOMED, and HL7. The presentation covers meaningful use incentives and provides examples of using EMR data for research studies.
Nomograms provide more accurate predictions of patient outcomes than alternative approaches and should be used to inform treatment decisions. Nomograms discriminate better than risk groups by accounting for individual patient characteristics. Studies show nomograms make more accurate predictions than clinicians. Not using nomograms risks inferior decision making and can be unethical by not providing patients with personalized outcome estimates.
Temp Workers Safety Considerations with OSHABill Enos
The document discusses OSHA requirements and responsibilities for staffing agencies and host employers regarding temporary workers' safety and health. It outlines that:
1) Staffing agencies and host employers share joint responsibility for ensuring temporary workers receive proper training, protections, and a safe work environment according to OSHA standards.
2) Staffing agencies must verify temporary workers receive necessary safety training and protections from hazards at the host worksite. They must also keep records of all training received.
3) Host employers are primarily responsible for recording injuries or illnesses of temporary workers on their OSHA 300 log, as they generally provide day-to-day supervision of temporary workers.
The document discusses statistical considerations for clinical trial designs that aim to evaluate cardiovascular risk for new diabetes drugs per FDA guidance. It outlines the FDA guidance, which requires ruling out unacceptable increases in CV risk. It then discusses various possible trial designs for standalone trials, including traditional single-analysis designs, group sequential designs, and adaptive designs, noting pros and cons of each approach. The goal would be to rule out hazard ratios above 1.3 and 1.8 with sufficient power and type 1 error control.
The Business of Genomic Testing by James CrawfordKnome_Inc
This document summarizes the key findings from a survey of 13 early adopter institutions that have implemented next-generation genomic sequencing (NGS) technologies. The survey identified common drivers for adoption including demands from clinical colleagues, anticipated efficiency gains, and acquiring institutional expertise. It also explored barriers such as lack of informatics expertise and high costs. Respondents provided lessons learned such as NGS being more complicated than expected and the importance of multidisciplinary teams. Common measures of successful outcomes included growth in test volumes and expansion of testing menus. The document concludes with recommendations for professional organizations like the College of American Pathologists, including providing educational programs and testing standards.
This document provides an overview of Certis Oncology Solutions and their precision oncology approach using patient-derived xenograft (PDX) mouse models. Certis aims to improve cancer treatment outcomes by determining the best therapy for each individual patient's tumor through testing multiple drug therapies simultaneously in mice models. Their orthotopic PDX models are able to reliably metastasize and closely mimic a patient's tumor progression and response, providing more accurate and timely treatment recommendations compared to standard of care. Certis offers to establish immortalized tumor banks from patient samples that can be used for ongoing drug testing if initial therapies fail in order to continually improve treatment outcomes.
Technology Assessment, Outcomes Research and Economic Analysesevadew1
This document discusses technology assessment, outcomes research, and economic analyses in healthcare. It provides background on rising healthcare costs in the US and outlines a hierarchy for assessing new medical technologies from technical efficacy to patient and societal outcomes. Randomized controlled trials are described as the gold standard but limitations are noted. Alternative study designs like modeling and assessing intermediate outcomes are proposed when RCTs are not feasible. The document uses CT for appendicitis as an example to work through initial steps in outcomes research. It also discusses limitations and alternative outcomes like assessing the therapeutic value of diagnostic tests.
1) The document discusses improving outcomes and endpoints in cancer trials by better defining what is important to measure, making endpoints more understandable for patients, and advancing endpoints to reflect changes in trial design and treatments.
2) It notes that endpoints need to show clinically relevant benefits to patients, and that improvements in trial design should be accompanied by improvements in available endpoints.
3) Stakeholders including clinicians, patients, and regulators must work together to determine the best approach for research that ensures accountability and optimizes the use of resources.
Emerson et al-2013-journal_of_ultrasound_in_medicinelinhnguyen1927
Ultrasound imaging has not been fully integrated into PACS systems compared to other modalities like CT and MRI. A survey of ultrasound radiologists found that:
1) Only 53.2% rated their PACS experience for ultrasound as high, significantly lower than for CT (85.2%), MRI (84.4%), and radiography (83.2%).
2) Ultrasound-specific functions like displaying 3D volumes (0.9% rating) and managing data (29.8% rating) received much lower scores than basic functions like viewing black-and-white images (92% rating).
3) Most respondents felt ultrasound-specific functions needed to be implemented or improved in P
Care bundles involve grouping several evidence-based interventions together that are aimed at improving patient outcomes when implemented collectively rather than individually. The ventilator bundle includes interventions like DVT prophylaxis and head of bed elevation. Compliance with care bundles is measured using both process measures like completion rates of individual elements as well as outcome measures. Studies show care bundles can improve outcomes for conditions like sepsis when bundle elements are reliably completed for all applicable patients. Ongoing auditing of compliance and outcomes is needed to demonstrate the sustained impact of care bundles.
Evaluating the cost effectiveness of diagnostic tests ScHARR HEDS
Evaluating the cost-effectiveness of diagnostic tests requires modeling their accuracy, the downstream patient experiences and costs based on test outcomes, and calculating the incremental cost-effectiveness ratio compared to current practice. For new diagnostic tests for sepsis, models would estimate quality of life and costs for high, medium, and low risk groups under different testing strategies incorporating a risk assessment tool and more accurate but costly test. Additional complications in evaluating diagnostics include understanding complex patient pathways, limitations of available data, dependencies between tests, and imperfect reference standards.
Biostatistics in development of Medical Devices By T. Mudde - Clinquest (Qser...qserveconference2013
The document discusses guidelines and considerations for clinical investigations of medical devices, focusing on the role of biostatistics in evaluating safety and effectiveness. It outlines statistical aspects that should be addressed in a clinical investigation plan and protocol, including study objectives, design, analyses, and handling of issues like missing data and sample size calculations. Interactive aspects between biostatisticians and sponsors are also covered, such as balancing precision and bias in study design and choice of endpoints.
POC Breast 1 | 2007 - Systemic Therapy for Metastatic Diseasertp
The document discusses survey results from clinical investigators and practicing oncologists on their treatment recommendations and preferences for various cases of metastatic breast cancer. Key findings include:
- For premenopausal patients with metastatic breast cancer, most recommend monthly injections of leuprolide or goserelin rather than every 3 months.
- For patients progressing after 4+ years of adjuvant anastrozole, fulvestrant and exemestane were the most preferred first-line endocrine therapies.
- Most felt nab-paclitaxel has similar or better efficacy and safety compared to docetaxel-based regimens for metastatic disease.
- Options like bevacizumab, ca
- Telemonitoring for heart failure patients has been shown to reduce mortality rates by up to 36% and decrease hospitalization rates in studies such as TEN-HMS and the Cochrane review.
- The Hull model of telemonitoring in the UK involves a comprehensive system of care including home monitoring devices, community kiosks, and support from nurses and specialist clinics to closely manage heart failure patients.
- Further research and investment in telemonitoring technologies could help shift care from crisis management to proactive health maintenance and empowering patients to better self-manage their condition.
Utility of primary care based TIA electronic decision support: A cluster randomised controlled trial. Presented by Anna Ranta, Department of Neurology, MidCentral DHB, at HINZ 2014, 12 November 2014, 12pm, Plenary Room
This document discusses technology assessment, outcomes research, and economic analyses in healthcare. It provides background on rising healthcare costs in the US without clear improvements in health outcomes compared to other countries. The rationale for assessing new technologies and their impact is described. Key aspects of technology assessment are outlined, including technical efficacy, diagnostic accuracy, diagnostic impact, therapeutic impact, patient outcomes, and societal outcomes. Challenges with randomized controlled trials in assessing technologies are reviewed. The National Lung Screening Trial is presented as an example. Finally, computed tomography for appendicitis is analyzed as a hypothetical example of how modeling could be used to assess a technology when a randomized trial may not be feasible.
This document discusses potential alternatives to the thorough QT study (TQT study) that is currently required by regulatory agencies to assess the potential for drugs to cause abnormal heart rhythms. Specifically, it summarizes:
1) A study that tested using pharmacokinetic/pharmacodynamic modeling of ECG data from first-in-human trials to detect QT effects as an alternative to the TQT study.
2) Issues that still need to be addressed for this alternative approach to be widely accepted, including demonstrating assay sensitivity without an active control.
3) Separate efforts to develop nonclinical assays to directly assess a drug's potential to cause abnormal heart rhythms, with the goal of moving proarrhyth
The document discusses randomized controlled trials and which statements about them are true. It states that option C, "Randomization reduces the risk of an imbalance in factors which could influence the clinical course of the patients," is true. Randomization helps balance both known and unknown prognostic factors between treatment groups in a randomized controlled trial.
This document contains rationales for questions from the 2007 ACR Diagnostic Radiology In-Training Exam. The rationales provide explanations for the correct answers to multiple choice questions related to diagnostic radiology topics including test sensitivity and predictive values, medical ethics, and radiation safety. Specifically, one rationale discusses how the positive predictive value of a diagnostic test increases as the prevalence of a disease increases in a population. Another rationale examines the ethical requirement for physicians to be honest with patients about medical errors or complications. A third rationale identifies radon exposure as contributing the most to background radiation levels in the US.
This document summarizes a medication utilization evaluation of topical tranexamic acid used in orthopedic surgeries at MultiCare Health System. A retrospective review was conducted of 42 patients who received topical TXA between July and October 2014. Results found low transfusion rates of 2.4% comparable to prior IV TXA studies. However, 3 patients who received topical TXA developed deep vein thromboses post-operatively, compared to none with IV TXA. Overall outcomes of length of stay and costs were similar to prior IV TXA patients. The evaluation recommends establishing consistent TXA documentation practices and providing surgeon education on results to optimize safe and effective use.
This document provides an outline for a presentation on electronic medical records (EMRs). It begins with defining the components of an EMR, including labs, admissions/discharge/transfer data, orders, radiology, notes, and billing. It then discusses the history and adoption of EMRs from the 1960s to present. The document reviews studies showing the effectiveness of EMRs in improving quality of care and achieving treatment standards. It also outlines how EMR data is structured in databases and data warehouses and describes common health data standards like ICD, CPT, LOINC, SNOMED, and HL7. The presentation covers meaningful use incentives and provides examples of using EMR data for research studies.
Nomograms provide more accurate predictions of patient outcomes than alternative approaches and should be used to inform treatment decisions. Nomograms discriminate better than risk groups by accounting for individual patient characteristics. Studies show nomograms make more accurate predictions than clinicians. Not using nomograms risks inferior decision making and can be unethical by not providing patients with personalized outcome estimates.
Temp Workers Safety Considerations with OSHABill Enos
The document discusses OSHA requirements and responsibilities for staffing agencies and host employers regarding temporary workers' safety and health. It outlines that:
1) Staffing agencies and host employers share joint responsibility for ensuring temporary workers receive proper training, protections, and a safe work environment according to OSHA standards.
2) Staffing agencies must verify temporary workers receive necessary safety training and protections from hazards at the host worksite. They must also keep records of all training received.
3) Host employers are primarily responsible for recording injuries or illnesses of temporary workers on their OSHA 300 log, as they generally provide day-to-day supervision of temporary workers.
Designing Adaptive Programs for Neuropathic Pain and the Product Revenue impl...therealreverendbayes
This document discusses optimizing clinical trial designs for neuropathic pain drug development programs. It presents statistical models to simulate Phase 2b and Phase 3 trials, estimate probability of success, and calculate expected net present value. Simulation results show that selecting the dose based on maximum utility rather than just efficacy, and optimizing Phase 2b and Phase 3 sample sizes can improve expected profit by up to 30% compared to default designs. Reducing the minimum patient exposure requirements from regulatory guidance also increases potential profit.
This document summarizes a webinar presentation about adaptive sample size re-estimation for confirmatory time-to-event trials. The presentation discusses a motivating lung cancer trial example and introduces a promising zone design where the sample size is increased only if interim results fall within a promising zone. It demonstrates the design, simulation, and interim monitoring capabilities of East®SurvAdapt software. Key aspects of the adaptive design methodology are discussed, including conditional power calculations, maintaining type 1 error control, and balancing sample size increases with trial duration.
¿Puede hacer ejercicio en el jardín? Suena extraño, pero en un jardín de la comunidad, puede mover 500 lbs de estiercol o plantar 30 arboles! Si quiere, trabajando en el jardín puede ser ejercicio excelente. Aquí hay consejo para hacer su ejercicio en el jardín a salvo y efectivo:
3D Printing Technology Publication Wm EnosBill Enos
3D printing technology has advanced rapidly, enabling the production of complex objects from digital models through additive layering of materials. This emerging technology challenges risk management and insurance underwriting by creating new types of products and applications across many industries. 3D printing uses a variety of materials and processes like extrusion, powder binding, photopolymerization, and lamination to construct objects layer by layer. The widespread adoption of 3D printing introduces new liability risks that insurance carriers must address as the technology continues to evolve.
The document discusses the importance of robust documentation in construction projects to defend against future construction defect claims. It states that thorough documentation collected during all stages of construction, such as photos, inspection reports, and test results, can prove that standard construction practices were followed and any issues were properly addressed. The document provides examples of different types of important documentation to collect, such as compliance documentation, as-built drawings, commissioning records, training materials, and warranty documents. It stresses maintaining and organizing all documentation for easy future access in the event of a legal claim.
Social classes are divisions in society based on wealth and access to resources. They arise due to economic inequalities between those who can afford basic needs and those who cannot. This leads to differences in healthcare, living standards, jobs, and education between upper and lower classes. Obamacare aimed to help lower classes by increasing access to healthcare and taxes on the wealthy. Examples in Mexico show stark contrasts between tall business buildings housing the rich versus small cramped huts for the poor. Social classes have existed for thousands of years and mirror the stratified society depicted in Brave New World.
This document discusses experiences with program-level modeling and simulation (M&S) of drug development programs. It presents a case study using M&S to optimize the design of a Phase 2 and Phase 3 clinical trial program for a neuropathic pain drug. The M&S evaluated factors like dose selection methods, Phase 2 sample size, and dose-response models. It found that maximizing clinical utility for dose selection and larger Phase 2 samples improved the probability of success and expected value compared to traditional methods. M&S allowed quantitative evaluation of design choices to better align with commercial objectives like expected net present value. The main challenges were time needed to develop simulation models and integrating inputs from different functions.
Brent Eastman is an experienced project manager with over 15 years of experience managing international programs and projects for the U.S. Department of State and other organizations. He has managed projects ranging from $25,000 to $35 million and led teams of over 100 staff members. Currently, he works as a project management consultant providing strategic advice and guidance to clients.
This document discusses best practices for managing payments to subcontractors in order to minimize financial risk. It recommends establishing thorough corporate payment protocols, carefully reviewing project-specific requirements, evaluating payment applications based on field observations, being aware of warning signs of subcontractor distress, and encouraging communication across departments. Developing and adhering to standardized, consistent processes can help ensure timely, fair payments while protecting the company's interests and preventing costly defaults.
D6 transforming oncology development with adaptive studies - 2011-04therealreverendbayes
This document discusses adaptive clinical trial designs, which allow modifications to trials based on interim data analysis. It provides an example of using a promising zone design for a phase 3 oncology trial testing a new treatment for metastatic non-small cell lung cancer. The design calls for an interim analysis when 50% of required events are reached, with the option to increase the sample size if results fall within a promising zone, defined as a conditional power between 30-90%, indicating the treatment may be beneficial. Simulations show this adaptive approach maintains high power even if the treatment effect is smaller than initially estimated.
3D Printing Technology White Paper June 22 2014 FinalBill Enos
3D printing technology has advanced rapidly, allowing for the production of complex objects from digital models through additive layering of materials. This disrupts traditional manufacturing and challenges risk management and insurance underwriting. 3D printing has applications in prototyping, finished goods production, medical devices, construction, automotive, aerospace and more. Issues include the ability to print firearms and concerns about regulating online distribution of 3D printable files. The technology continues to develop and may one day enable printing of entire organs for transplantation.
D1 design and analysis approaches to evaluate cardiovascular risk - 2012 eugmtherealreverendbayes
This document summarizes a presentation on approaches to evaluate cardiovascular risk in diabetes drug development. It discusses using meta-analysis and group sequential designs to integrate cardiovascular evaluation into clinical trials and potentially reduce patient exposure. It also compares options like conducting a single large outcome study, two separate cardiovascular outcome trials, or incorporating sub-studies into cardiovascular outcome trials. The presentation emphasizes planning for both non-inferiority and superiority assessments and considering operational aspects like maintaining trial blinding for interim analyses.
Adaptive Drug Development Programs for Phases 2 and 3 in Neuropathic Pain - 2...therealreverendbayes
- The document describes a simulation plan to investigate adaptive Phase 2b and Phase 3 development programs for neuropathic pain drugs. The simulation evaluates different Phase 2 sample sizes, numbers of doses, and adaptive designs based on probability of success, number of patients, and expected profit.
- The simulation models efficacy and safety dose response curves, nuisance and serious adverse events, Phase 2b and 3 trial designs, and a commercial model to calculate net present value. Initial results from the base case are presented.
Surrogate Endpoints: Are drug review processes flexible enough to expedite pa...CanCertainty
This document discusses the use of surrogate endpoints in cancer clinical trials as an alternative to overall survival. It provides background on what constitutes a valid surrogate endpoint and examples of endpoints that are not good surrogates. The document notes that validation of surrogate endpoints is often lacking, especially for early-stage cancers. An analysis of clinical trials found that the majority of trials for early-stage solid tumors use surrogate endpoints rather than traditional endpoints like overall survival. This increasing reliance on surrogate endpoints may impact regulatory reviews and reimbursement decisions in the future.
The document discusses treatment options for locally advanced cervical cancer. It summarizes several meta-analyses and clinical trials that show concurrent chemoradiation (CCT-RT) is the standard of care, rather than neoadjuvant chemotherapy followed by surgery (NACT+Surgery). While some older trials showed a benefit of NACT+Surgery, most recent evidence suggests it does not provide benefits and adds unnecessary morbidity compared to CCT-RT. The takeaway message is that in clinical practice, only standard guidelines accepted by major organizations like NCCN and NCI should be followed, and experimental treatments belong only in clinical trials.
This document summarizes key efficacy endpoints used in oncology clinical trials, including for solid tumors and non-solid tumors like acute myeloid leukemia. For solid tumors, the best overall response (BOR) is assessed using RECIST criteria to evaluate tumor shrinkage or progression based on target and non-target lesion measurements. Key time-to-event endpoints discussed include overall survival (OS), progression-free survival (PFS), and time to progression (TTP). For acute myeloid leukemia, response is assessed based on blood counts and bone marrow blast percentage according to International Working Group criteria, with endpoints like complete remission rate and event-free survival. Surrogate endpoints are also discussed.
Health economic modelling in the diagnostics development processcheweb1
This document discusses the use of health economic modelling in the diagnostics development process. It highlights the need for early decision modelling to efficiently design clinical research studies for new diagnostics. Decision modelling can also be used to assess the potential clinical impact and cost-effectiveness of diagnostics across different stages of the validation process. The document describes an example of decision modelling used to help design the OPTIMA trial, which evaluated multiple biomarker tests for stratifying breast cancer treatment. Close collaboration between different stakeholders is important for effective diagnostics evaluation.
This document summarizes an introduction to clinical trials presented by Jan B. Vermorken. It outlines the process of moving new cancer therapies from the laboratory to clinical trials, including preclinical testing requirements, phases of clinical trials (I-III), response criteria, and considerations for trials of non-cytotoxic agents. It also discusses the roles and functions of ethics committees in overseeing clinical trials to protect participants.
The document provides an introduction to clinical trials for cancer drug development. It discusses moving potential new therapies from preclinical testing in animal models through the different phases of clinical trials in humans. Phase I trials determine safety and dosing, phase II screens for anti-tumor activity, and phase III tests for efficacy in larger patient populations through randomized controlled trials. Ethical review and informed consent are required throughout the clinical trial process to protect patient safety and rights.
Management Of Recurrent Ovarian Ca (ROC)
The document discusses the management of recurrent ovarian cancer. It provides details on the incidence and patterns of recurrence for ovarian cancer. For patients with platinum-sensitive recurrent ovarian cancer, the standard treatment is second line chemotherapy. Several chemotherapy regimens are discussed including carboplatin with paclitaxel, gemcitabine, or pegylated liposomal doxorubicin. For partially platinum-sensitive recurrent ovarian cancer, the OVA-301 trial showed improved overall survival with the combination of carboplatin and pegylated liposomal doxorubicin compared to carboplatin alone. Management of recurrent ovarian cancer aims to prolong survival, delay progression,
Controversies in the management of rectal cancersAjeet Gandhi
Management of rectal cancers have undergone a huge paradigm shift over the last decade. One the one hand, it has opened up new avenues; it also has thrown up new challenges and controversies
The document discusses adjuvant and neoadjuvant treatment options for renal cell carcinoma (RCC), including targeted therapies. It notes that localized RCC may be treated with adjuvant therapy after nephrectomy or neoadjuvant therapy to downsize tumors before surgery. Several ongoing clinical trials are investigating adjuvant targeted therapies for RCC. Neoadjuvant targeted therapies aim to downsize or downstage primary tumors but may also accelerate metastasis, and there is no way to predict individual responses. Outcomes of cytoreductive nephrectomy combined with targeted therapy in metastatic RCC depend on prognostic risk factors.
This document summarizes the findings of a large study conducted by the National Cancer Center Network (NCCN) and National Oncologic PET Registry (NOPR) on the impact of positron emission tomography (PET) on cancer management. The study analyzed over 130,000 patient scans from 1,891 PET facilities. It found that in 38% of cases, PET led to a change in the referring physician's intended patient management approach, such as changing or adjusting therapy. The study demonstrates the utility of PET in cancer evaluation and treatment decision making.
2014-10-22 EUGM | WEI | Moving Beyond the Comfort Zone in Practicing Translat...Cytel USA
1. The document discusses moving beyond conventional practices in translational statistics to obtain more robust and clinically meaningful results from clinical studies.
2. Several methodology issues are discussed, including how to define primary endpoints when there are multiple outcomes, how to handle dropouts and competing risks, and how to quantify treatment contrasts in a model-free way.
3. Alternative approaches are proposed for various types of studies, such as using restricted mean survival times instead of hazard ratios for survival analyses and performing meta-analyses for evaluating safety issues using large amounts of data.
CDISC journey in solid tumor using recist 1.1 (Paper)Kevin Lee
This document summarizes the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines for evaluating tumor response in clinical trials. It introduces the three types of oncology studies, defines target and non-target lesions, and describes how lesion measurements are used to determine complete response, partial response, stable disease, progression disease, and not evaluable responses. It also discusses how RECIST 1.1 data are organized in CDISC SDTM and ADaM domains, and provides an example of how these domains can be used to evaluate tumor response and analyze outcomes like objective response rate, progression-free survival, and time to progression.
This document summarizes the current state of targeted therapies for metastatic renal cell cancer. It discusses several front-line standard of care options including sunitinib, pazopanib, and bevacizumab with interferon. Ongoing areas of investigation mentioned include more potent VEGF inhibitors, biomarkers of response and resistance, alternative dosing schedules, and immunotherapy combinations with targeted agents.
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.
1. The document discusses various clinical and pathological factors that can help predict outcomes for prostate cancer patients undergoing surgery, such as cancer volume, Gleason grade, clinical stage, and PSA levels.
2. Nomograms and statistical models have been developed using these factors to predict chances of cancer recurrence, pathologic stage, and disease progression.
3. However, some factors like clinical stage may have limited predictive value. Ongoing research aims to improve predictive accuracy by addressing issues like PSA standardization and biopsy upgrading.
Postoperative nomograms can predict outcomes like biochemical recurrence and prostate cancer-specific mortality with high accuracy (c-index >0.8) based on pathological features from the radical prostatectomy specimen. However, preoperative models aim to predict pathological outcomes like Gleason score in order to determine the need for intensified treatment or active surveillance. Improving preoperative nomograms remains an area of ongoing research.
Dr. Hager 2016 Presentation The Challenges of Achieving Early Efficacy in Cli...Dr. Martin Hager, MBA
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Therapeutic Area Standards –Reflections on Oncology standards and what is ne...Angelo Tinazzi
This document discusses CDISC standards for oncology clinical trials and opportunities for improvement. It notes that CDISC has incorporated domains for tumor response assessment but questions remain around implementing RECIST criteria and capturing prior cancer therapies. The document suggests areas where CDISC oncology standards could provide more guidance, such as trial design elements like unlimited treatment cycles, capturing exposure modifications, and providing more support for non-solid tumor response assessments. Overall, it examines current CDISC oncology standards and identifies examples of additional clarity and domains that could better meet the needs of oncology clinical research.
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This document discusses standards for colposcopic treatment of precancerous cervical lesions. It summarizes current European standards agreed through a Delphi process, including that 85% of excisional treatments should contain CIN2+, 100% of cases should have a pre-treatment colposcopy, 80% of excised lesions should have clear margins, and documentation of the squamocolumnar junction. The document evaluates data on factors like excision length, margin status, and HPV testing after treatment. It discusses modifying standards based on discussions, including recording excision length, margin involvement, and HPV/cytology outcomes post-treatment. The conclusions are that additional treatment standards may be needed despite existing Delphi standards, and
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1) Modern techniques like IMRT and 4D radiotherapy allow for better treatment planning and delivery while avoiding nearby organs.
2) Several randomized clinical trials found that a shorter, hypofractionated course of radiotherapy was not inferior to standard radiotherapy in terms of local recurrence or toxicity.
3) Partial breast irradiation techniques are being studied as a way to further reduce treatment volumes and time for selected low-risk patients.
1. Geneva Branch
EFFICACY ENDPOINTS IN ONCOLOGY
– IS01
Bruxelles 13-16/10/2013
Angelo Tinazzi
Cytel Inc., Wilmington Del. USA
Succursale de Meyrin – Geneva – Switzerland
angelo.tinazzi@cytel.com
2. Geneva Branch
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Efficacy Endpoints in Oncology
Disclaimer
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
The information contained in this
presentation is based on personal
research of the author and does not
necessarily represent Cytel Inc..
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Efficacy Endpoints in Oncology
Introduction
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Oncology Endpoints in Drug Development
Early Phase
Safety and Evidence of Drug Activity
Identification of possible indications
Late Phase
Seeks for Clinical Benefit
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Efficacy Endpoints in Oncology
Introduction
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Key Requirements for Drugs Approval
Demonstration of efficacy with acceptable safety in
adeguate and well-controlled studies
Benefits/Risks asssessment
Longer Life
Better Life (Quality)
Safety
Cost
“Clinical Trials Enpoints for the Approval of Cancer Drugs and Biologics”
Guidance for Industry, FDA, May 2007
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Efficacy Endpoints in Oncology
Overall Survival (OS)
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Definition Time from randomization until death
from any cause
Pros • Measure of direct benefit
• Easy to measure (Unbiased)
Cons • It may require large population and follow-up
• It includes deaths unrelated to cancer
• It may be affected by crossover or subsequent
therapies
Censor • Last date subjects was seen alive
The «Gold» standard for demonstrating clinical benefit
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
History of (FDA) Drugs Approval
‘70: Objective (tumor) Response Rate (ORR)
‘80: More evidence of clinical benefit:
Survival, QoL, Physical functioning, Tumor-
related symptoms
’90: use of Surrogate endpoints predicting
clinical benefits
1992: FDA adopted accelerated drug approval
J. McCain, "The Ongoing Evolution of Endpoints in Oncology," 2010.
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
A surrogate endpoint is an alternative endpoint that if validated
allows inference on the effect of an intervention on a true
endpoint often requiring a shorten observaion period
Surrogate ‘efficacy’ endpoints in oncology aim to replace OS,
the endpoint to ‘predict’
Primary endpoints in randomized controlled
trials of treatments for advanced breast
cancer 2000-2007)
Endpoints used for
basis of oncology drug
approvals
(FDA 1990–2002)
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
The concept of Tumor Response and Progression in Solid Tumors
Standard set of Criteria (RECIST)
Identification and Classification of Tumor Lesions
Measurable (Target) vs Non Measurable (Non-Target)
Periodicity (e.g. CT-Scan every 6 or 8 weeks)
Response evaluated vs Baseline (baseline assessment prior
to study entry)
A 30% decrease in the sum of all lesions measurement (mm)
Progression evaluated vs Nadir (best response prior to current
assessment)
A 20% increase in the sum of all lesions’ measurements (mm)
An increase / prgression of any non-target lesion or new lesion identified
after study entry determines also the progression
9. Geneva Branch
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
The concept of Tumor Response and Progression in Solid Tumors
Standard set of Criteria (RECIST)
Identification and Classification of Tumor Lesions
Measurable (Target) vs Non Measurable (Non-Target)
Periodicity (e.g. CT-Scan every 6 or 8 weeks)
Response evaluated vs Baseline (baseline assessment prior
to study entry)
A 30% decrease in the sum of all lesions measurement (mm)
Progression evaluated vs Nadir (best response prior to current
assessment)
A 20% increase in the sum of all lesions’ measurements (mm)
An increase / prgression of any non-target lesion or new lesion identified
after study entry determines also the progression
10. Geneva Branch
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
The concept of Tumor Response and Progression in Solid Tumors
Standard set of Criteria (RECIST) - Cont
5 Overall Response Criteria
CR – Complete Response
PR – Partial Response
SD – Stable Response
PD – Progressive Disease
NE – Not Evaluable
Best Overall Response as the best response (criteria) assessed since the
subject is on-study (on-treatment)
• P Therasse et al, "New response evaluation criteria in solid tumors: Revised RECIST
guideline (version 1.1)," European Journal of Clinical Oncology, pp. 45: 228-247, 2009.
• MB Mayakuntla, PM Nidamathy, "RECIST and programming challenges," in IASCT, 2012.
• Ji Yu, P Slagle, "Objective tumor response and RECIST criteria in cancer clinical trials," in
MWSUG, 2011.
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
The concept of Tumor Response and Progression in Solid Tumors
EUROPEAN JOURNAL OF CANCER 45 ( 2009 ) 228 –247
Lesion Baseline Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4
T1 (mm) 10 10 5 7 10
T2 (mm) 25 15 5 5 5
T3 (mm) 15 15 15 15 20
(Sum of Lesion mm) 50 40 25 27 35
(Response Target Lesions) SD PR PR PD
NT1 NA Stable Stable Stable Stable
New Lesion NA No No No No
PRSD PR PDPRSD PD
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
The concept of Progression and Response
PD
PR
PR
SD
Decrease with
respect to baseline...
…but also increase
with respect to prior
reduction showing
the «re-growth» of
the tumor and
therefore the
possible failure of
the treatment
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
The concept of Progression and Response
PD
PR
PR
SD
data respT;
set SOLD;
by USUBJID VISITNUM;
retain NADIR BASE;
if first.USUBJID then do;
NADIR=.;
BASE=SOLDMM;
end;
PCTBASE=((SOLDMM-BASE)/BASE)*100;
PCTNADIR=((SOLDMM-NADIR)/NADIR)*100;
if SOLDMM=0 then NTRESP=‘CR’;
else if PCTNADIR>20 then NTRESP=‘PD’;
else if abs(PCTBASE)>30 then NTRESP=‘PR’;
else SOLDMM ne . Then NTRESP=‘SD’;
else NTRESP=‘NE’;
output;
NADIR=min(NADIR,SOLDMM);
run;
Timepoint SOL
DMM
BA
SE
PCTB
ASE
NA
DIR
PCTN
ADIR
NTRE
SPT
Baseline 50
Timepoint 1 40 50 -20 50 -20 SD
Timepoint 2 25 50 -50 40 -37.5 PR
Timepoint 3 27 50 -46 25 8 PR
Timepoint 4 35 50 -30 25 40 PD
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Definition Time from randomization until radiolagical
tumor progression
Pros • Requires smaller sample size
• Not affected by crossover or subsequent
therapies
• Based on objective and quantitative assessment
Cons • Measurement may be subject to bias
• Requires frequent radiologic assessment (e.g.
every 6 weeks) and same or similar among
treatment arms
• In some settings can be difficult to validate
Censor • Last date radiological tumor assessment
Time to Tumor Progression (TTP)
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Progression Free Survival (PFS)
A variant of TTP where deaths are also counted as events
In some protocols Death as event can be limited if occurred
within ‘xx’ weeks from last tumor assessment (e.g. 12 weeks)
Applicable to study with patients with advanced cancer
Disease Free Survival (DFS)
Same as PFS but it assumes patients are disease-free
at study entry
Applicable to study testing adjuvant therapies with
patients where the disease (cancer) was previously
surgically removed
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Time to Treatment Failure (TTF)
Time from randomization to discontinuation of
treatment for any reason
TTF not reccomended as regulatory endpoint for
approval; «a regulatory endpoint should clearly
distinguish the efficacy of the drug from toxicity,
patient or physichian withdrwal or patient intolerance»
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Definition Proportion of patients with tumor size reduction
of a predefined amount and for a minumim time
period. FDA has defined ORR as the sum of
Complete and Partial Responses
Pros • Can be assessed in single-arm studies
• Can be assessed earlier and in smaller studies
• Effect attributable to drug, not natural history
Cons • Not a direct measure of benefit
• Only a subset of patients who benefit
Objective Response Rate (ORR)
Response Duration (DR)
Time from first assessment of CR or PR until date of
progression or last tumor assessment
Applicable only to patients with ORR
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Efficacy Endpoint – Example 1
Responder
Progressing
RAN SD SD PR CR PD
Response Duration
ORR
OS
PFS TTP
Death /
Alive
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Efficacy Endpoint – Example 2
Non Responder
Non Progressed
Death
RAN SD SD SD Off TRT
OS
TTP
Death
PFS
TTF
20. Geneva Branch
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Sensitivity Analysis in Tumor Response based endpoint
Use of Per Protocol Population
Include clinical progressions
Different Censoring/Event Date Methods
Backdating event date when tumor assessment is not performed within the
pre-defined interval
Censoring at the date of subsequent cancer therapy if occurred before
progression
Use of Independent Review of Tumor Endpoints
Can minimize bias in readiographic interpretation of the radiological
findings (investigator)
Often Primary endpoints in non-blinded studies
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Modified Response / PFS Criteria
e.g. Prostate Cancer according PCWG2 criteria
Where disease progression is defined as the presence of at
least one of the following conditions:
Bone Lesions Progression
Soft-Tissue Lesions Progression (RECIST)
Presence of Skeletal Events
HI Scher, "End Points and Outcomes in Castration-Resistant Prostate Cancer: From Clinical
Trials to Clinical Practice," J Clin Oncol, 2011.
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Other endpoints: Time to symptom progression (TTSP)
e.g. TTSP in Lung Cancer Trials as per the Lung Cancer
Symptom Scale (LCSS)
Symptomatic progression defined as an increase
(worsening) of the average symptomatic burden index
(ASBI, i.e., the mean of the six major lung cancer
specific symptom scores [fatigue, pain, dyspnoea,
cough, anorexia and hemoptysis])
The worsening is defined as an at least 10% increase
of the scale breadth (i.e., at least 10 mm increase on
the 100 mm scale) from the baseline score.
Hollen PJ, Gralla RJ, Kris MG, et al. Quality of life assessment in individuals
with lung cancer: Testing the lung cancer symptom scale (LCSS). Eur J Cancer.
1993;29A(1):51-8..
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Quality of Life
Only used in support of primary endpoints
Several ‘validated’ questionnaires available for
different indications
http://groups.eortc.be/qol/eortc-modules
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Duration of Complete Response in Leukemia
Considered established endpoint of clinical benefit in leukemia
Less infection
Less Bleeding
Less use of blood product support (e.g. transfusion)
D Cheson et al, "Revised Recommendations of the International Working Group for Diagnosis,
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in
Acute Myeloid Leukemia," Journal of Clinical Oncology, pp. Vol 21, No 24: pp 4642-4649, 2003
25. Geneva Branch
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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Efficacy Endpoints in Oncology
Regulatory Requirements
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
FDA Clinical Trial Endpoints for the Approval of Cancer
Drugs and Biologics (2007)
General regulatory requirements for efficacy
Detailed description of endpoints and how these can
be used in various clinical settings
Pros and Cons
Protocol and SAP design requirements
Data Collection for Tumor Measurement
Issue to consider in PFS analysis
Progression and Censore Date
How to handle Missing Data
Lesions evaluation
Sensitivity Analysis
++ Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Cancer Drugs and
Biologics, FDA, 2011
Cancer Drug Approval Endpoints
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/CancerDrugs/ucm094586.htm
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Efficacy Endpoints in Oncology
Regulatory Requirements
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
EMA Guideline on the evaluation of anticancer medical
products in man
Guidance on all stages of clinical drug development for
the treatment of malignancies
The current version of the guidance cover also non-
cytotoxic compounds and additional indication for
exploratory studies.
Completed by a set of specific appendices covering
methodologial aspects related
Methodological Consideration for using Progression Free Survival
(PFS) and Disease Free Survival (DFS) in confirmatory trials
Confirmatory Studies in Haematological Malignancies
Condition specific Guidance such as NSCLC, Prostate
The EMA is also planning to provide an additional
appendix for Quality of Life/Patient Reported Outcome.
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Efficacy Endpoints in Oncology
Data Management Issues
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Tumor Response
Missing Assessments
Consistent Lesions Reporting
Type, Site
Assessment of method used
Disappeared Tumor Lesions (0mm)
Consisteny between lesions details (sum of diamaters
for target lesions) and overall response
Independent Review Committee
Keep follow-up up-to-date
CDISC SDTM 3.1.3 Tumor Response Domains
++ • Overcoming Difficulties in Implementing RECIST criteria, PhUSE 2013, G. Ruhnke
• CDISC Journey on Solid Tumor Studies using RECIST 1.1., PhUSE 2013, K. Lee
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ORR Analysis with proportion and %CI
Efficacy Endpoints in Oncology
Analysis
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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Survival Analysis
Unadjusted (Kaplan Meier & Log-Rank Test)
SAS Proc LIFETEST
Adjusted (Cox proportional hazards regression model)
SAS Proc PHREG
Selection of covariates to be used depends on the indication and
treatment setting. E.g. type and/or response to prior therapy
Examples of other possible covariates
Efficacy Endpoints in Oncology
Analysis
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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Survival Analysis
Efficacy Endpoints in Oncology
Analysis
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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Subgroup Analysis with Forest Plot
Efficacy Endpoints in Oncology
Analyisis
Bursac, Z, "Creating Forest Plots from Pre-computed Data using PROC SGPLOT and Graph Template Language,“
In SAS Global Forum, 2010
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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Efficacy Endpoints in Oncology
Analyisis
Tumor Shrinkage with Waterfall Plot
NJ Pandya, "Waterfall Charts in Oncology Trials - Ride the Wave,"
In PharmaSUG, 2012
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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Efficacy Endpoints in Oncology
Conclusions
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Analysis
Data Management
Conclusions
Despite its complexity, “stable” standards exist for
efficacy evaluation
Use of efficacy indicators may be different from an
indication to another
Managing, deriving and analyzing efficacy endpoints
in oncology requires a clear understanding of the
disease
The use of efficacy endpoints in drug approval may
change again with the idea of targetting the therapies
based on molecular profiling
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New Geneva offices – November 2012
Efficacy Endpoints in Oncology
Questions