Clinical Trials DESIGNS, METHODOLOGY, AND KEY ISSUES FOR RESEARCH ADVOCATES (PILOT PRESENTATION – NOVEMBER 21, 2019) 1
Featured Presenters Lynn Howie, MD Pardee UNC Health Care Elizabeth Frank, Ed.M. Breast Cancer Advocacy Group Dana Farber Cancer Institute 2
Capacity Building Training Series for Advocates Involved in Research Advocacy Series includes modules on: 1. Clinical Trials — Designs, Methodology, and Key Issues for Research Advocates 2. Patient Centered Outcomes Research (PCOR) — What is it and How is it Different to Traditional Clinical Trial Research 3. Patient-Report Outcomes — What Are They, and How Are They Measured 4. Ethical Issues and Informed Consent in Clinical Trials and PCOR 5. FDA Drug Approval Process — Traditional and Accelerated Approval, and Issues in Breast Cancer Drug Development 6. Novel Trial Designs in PCOR — Pragmatic Clinical Trials and Adaptive Designs 7. Use of Real World Evidence – Potential Uses and Limitations 3
Learning Objectives • What is a clinical trial? • What are the basic requirements and key elements of a well-designed clinical trial? • What is bias, how does it come up in trial design, and how can we minimize this? • What are the endpoints or outcomes used in clinical trials? • What questions are being answered in clinical trials? • How can advocates play a role in the design and conduct of trials? 4
Key Discussion Items for Today • Introduction to clinical trials and how advocates can be involved • Types of clinical trial • Endpoints/outcomes • Sources of bias • Key advocate questions • PCOR 5
What is a Clinical Trial? Any research study where one or more human participants are assigned prospectively to one or more health related interventions to evaluate the effects of those interventions on health-related outcomes. (WHO, NIH) 6
Why Conduct Clinical Trials? Is a new intervention safe and effective? www.thehastingscenter.org/briefingbook/clinical-trials/ 7
What are the Basic Requirements of a Clinical Trial? • Identify and ask important research question • Use rigorous methodology to answer the question of interest • Minimize risk to study participants • Includes patient/advocate input throughout the trial to ensure questions asked and ways of assessing are adequate and of value to future patients Requires adequate study planning 8
Research Advocate Involvement Across the Clinical Trial Continuum • Support discussions • Provide feedback • Serve on FDA advisory • Provide information with funders, sites & from patient & post-market about unmet needs IRBS community on sites, surveillance • Assess interest of • Support trial awareness investigators, & study committees patient community • Provide FDA Testimony & recruitment experience Develop Prepare Open Dissemin Conduct Analyze FDA Review Study Study Study -ate Study Data & Approval Concept Protocol Sites Results • Provide input on study • Serve on Trial Steering & • Prepare lay summaries • Co-author papers & design Data Monitoring • Assist in creating informed Committees posters • Provide peer support • Communicate with consent document & patient education material during consenting patient community 9
PICO/PICOTS Framework For Developing Research Questions • P atient population – Patient population/problem to be addressed • I ntervention – Exposure to be considered – treatments/ tests • C omparator – Control or comparison intervention treatment/ placebo/standard of care • O utcome – Outcome (endpoint) of interest • T iming – Duration of treatment and follow-up • S etting – Where the study is implemented Sackett D, Richardson WS, Rosenburg W, Haynes RB. How to practice and teach evidence based medicine. 2nd ed. Churchill Livingstone; 1997 10
PICO: Elements of Trial Design 11
Questions Advocates Should Ask About Patients Population ◦ Are the characteristics of the group being studied well defined? Sample ◦ Does the inclusion criteria reflect the characteristics of patients who will be treated in the real world? ◦ Is it large enough? 12
Questions Advocates Should Ask About Interventions • Why was this drug selected? (e.g., oral vs. IV, manufacturer) • Why was this dose selected? (e.g., might a lower dose be as beneficial and less toxic) • Why was this schedule selected? (e.g., length of time on treatment, patient convenience) • Are all of the procedures necessary? Scheduled conveniently for patients? Paid for by the trial ? 13
Questions Advocates Should Ask About Comparisons (or Controls) • Will patients on the comparator/control arm receive an appropriate standard of care? If not, why not • Can patients cross-over to receive the experimental therapy? • Are there adequate early stopping rules for efficacy and futility? 14
Questions Advocates Should Ask About Outcome Measures • Are these the outcomes that are most important to the relevant patients? • What are appropriate surrogate markers to allow for faster results? • Are the proposed measures reliable and valid? • Is the power appropriately proportioned if there are multiple outcomes of interest? • How long will it take to get results? ◦ Are there reasonable (AND valid) surrogate markers that can be used that will allow the results faster? 15
Trials Providing High Quality Evidence • Patients are similar to those who would be offered the therapy in everyday practice • Examine clinical strategies and complexities that are more likely to be seen in clinical practice. • Assess benefit and harm • Work to minimize bias • Have adequate power to address key outcomes/endpoints of interest. • Directly compare interventions. • Include all important intended and unintended effects including adherence and tolerability. 16
Types of Clinical Trials 17
Types of Clinical Trials In Oncology • Treatment trials (Phase I-IV studies) evaluating new therapies • Cancer care delivery studies • Comparative effectiveness research • Cancer prevention studies • Observational studies 18
Cancer Therapy Trials • New drugs go through multiple phases of evaluation • Preclinical studies in animal models evaluate safety and help to identify possible toxicities • Advocates should ask about the evidence that was developed to move this drug to humans 19
Phase 1 Trials • First in human studies to assess safety and preliminary efficacy • Multiple doses of drug evaluated to assess toxicity and response • People included in these studies may have different tumor types • Primary outcomes: dose limiting toxicity and objective response rate 20
Phase 2 Trials • Drug dose identified • Study population relatively homogeneous (e.g. all participants have a similar type of cancer) • Can be single arm or comparative • Small numbers of patients as an initial evaluation of efficacy • End points depend on whether single arm or comparative ◦ Can be ORR, PFS, or OS 21
Phase 3 Trials • Large cohorts of similar patients randomized to treatment A vs. treatment B • Compare a new treatment with the standard treatment • Can take many years and include hundreds to thousands of patients • End points usually PFS or OS 22
NBCC Criteria for Clinical Trial Collaborations Study must be…. ◦ Designed to answer important, novel questions ◦ Designed with appropriate/meaningful endpoints ◦ Designed to deal with patient costs ◦ Conducted in an ethical manner including: ◦ Well described informed consent process ◦ Appropriate patient educational materials ◦ Independent DSMB ◦ Designed to address NBCC’s concerns about the inclusion of a diverse population and no inappropriate exclusion of specific populations ◦ Trial results are disseminated to the public in a timely fashion Educated Patient Advocates involved from the beginning! 23
Research Advocates’ in TAILORx • Input on clinical design and resulting protocol • Two advocate members of on the Steering Committee • One advocate member of the Data Safety Monitoring Board • Developed outreach plan to create awareness of trial • Provided input on all patient education materials • Trial results provided evidence needed to eliminate chemotherapy and the sequela of toxicity for thousands of women with node negative, ER-positive early breast cancer 24
Clinical Trials Projects • Herceptin (Trastuzumab): key collaboration in a clinical trial that revolutionized the treatment of HER2-positive breast cancer • BMN 673 PARP inhibitor (Talazoparib): changed the standard of care for patients with BRCA mutation • Pfizer Paloma 3 CDK 4/6 inhibitor (Palbociclib): changed the standard of care for patients with ER+/HER2- locally advanced and MBC
Phase 4 Trials • Trials used to evaluate long term safety • Often include 1000s of people 26
Endpoints/Outcomes 27
Commonly Used Endpoints In Oncology Trials • Overall Survival (OS) • Endpoints based on assessment of tumor burden • Objective Response Rate (ORR) • Time To Progression (TTP) • Progression Free Survival (PFS) • Disease Free Survival (DFS) • Endpoints based on symptom assessment • Newer accepted endpoint: pathologic complete response rate (neoadjuvant studies) 28
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