Clinical Trials DESIGNS, METHODOLOGY, AND KEY ISSUES FOR RESEARCH ADVOCATES (PILOT PRESENTATION – NOVEMBER 21, 2019)

1 Featured Presenters

Lynn Howie, MD Pardee UNC

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 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 & recruitment experience • Provide FDA Testimony

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 design Data Monitoring • Co-author papers & • Assist in creating informed Committees posters consent document & • Provide peer support • Communicate with patient education material during consenting patient community

9 PICO/PICOTS Framework For Developing Research Questions • Patient population – Patient population/problem to be addressed • Intervention – Exposure to be considered–treatments/ tests • Comparator – Control or comparison intervention treatment/ placebo/standard of care • Outcome – Outcome (endpoint) of interest • Timing – Duration of treatment and follow-up • Setting – 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 Endpoints/Outcome Measures • How an endpoint is measured affects its reliability • The more interpretation, the more susceptibility to bias • Frequency of assessment can affect the interpretation of the endpoint and the possible magnitude of benefit • Confidence in the tools being used such as assessments for patient reported outcomes

29 Interpretation of Endpoints

Reliability

Composite endpoint Progression free or Overall survival looking at pain or another Disease-free Survival symptom that triggers an intervention

Subjectivity

30 Overall Survival Strengths ◦ Direct measure of benefit ◦ Least prone to bias as there is no interpretation of the event (death is yes/no) ◦ Event timing is known to the day (date of death) ◦ Includes information regarding drug safety as deaths due to drug toxicity are included in the assessment Limitations ◦ Last event in a disease’s natural history which leads to larger and longer trial ◦ Requires a randomized controlled trial as comparisons with historical controls are limited ◦ May be confounded by cross over (patients in the comparator arm going on to receive the therapy later) depending on the magnitude of effect and the availability of subsequent therapies if unequal between arms

31 Surrogate Endpoints Goal is to identify an outcome measure associated with clinical benefit that can lead to smaller, shorter trials

32 Surrogate Endpoints • Many endpoints in oncology are based on radiographic assessment • Progression free survival/time to progression are the times from study randomization to the growth of tumor beyond a predefined threshold • Response rate is the degree to which an agent shrinks a tumor

33 Objective Response Rate • Radiographic endpoint

• Composite endpoint: proportion of those with a partial or complete response with treatment

• Critical to understanding the clinical importance of ORR is to document the duration of response, location of the response, and the relationship between response and symptoms

34 Progression Free Survival (PFS) & Time to Progression (TTP) • Used in patients who have active disease • Not affected by crossover or confounded by subsequent therapy • Subject to assessment bias in open label studies • Frequent assessment/balanced timing of assessments needed • Definitions vary study to study PFS ◦ Includes death ◦ Better correlation with overall survival ◦ Preferred regulatory endpoint TTP ◦ Deaths censored at the time of death ◦ Acceptable when majority of deaths not cancer related

35 Disadvantages of Surrogate Endpoints • Relevance may be questionable • False negative: drug is affecting real outcome but not affecting surrogate • For example, drug does not improve pathologic complete response rate, but improves disease free survival and overall survival • False positive: change in surrogate may lead to opposite change expected in outcome • For example, drug improves bone density but leads to higher fracture rate • For example, drug may cause patients tumors to shrink, but does not change OS • Correlation w/ true endpoint may be low, or high but not generalizable to new interventions (not causative) • Harms may not emerge until later

36 PROs and Quality of Life Any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. (FDA) • Health related quality of life (HRQOL), symptoms, function, satisfaction with care or symptoms, adherence to prescribed medications or other therapy, and perceived value of treatment

37 Sources of Bias APPROACHES TO MINIMIZING

38 Bias and Threats to Validity and Precision • Threats to Validity (Systematic Error) • Threats to Precision (Random Error)

39 Threats to Validity (Systematic Error) • Selection bias • Bias introduced by the selection of individuals, groups or data for analysis in such a way that proper randomization is not achieved, • Confounding by indication or allocation bias • Bias that arises from a systematic difference in how participants are assigned to treatment groups and comparison groups in a clinical trial

Akobeng 2008

40 Some Additional Sources of Bias • Attrition bias • Occurs when there are systematic differences between the groups in the loss of participants from the study. • Performance bias • Systematic differences in the care provided to participants to intervention and control group or protocol deviations. • Reporting bias • Systematic differences between reported and unreported findings

41 Controlling Bias: Allocation Concealment • Masking (or Blinding) Participants: • Participant doesn’t know which intervention she’s receiving

• Masking (or Blinding) Providers: • Provider does not know which intervention participant is receiving

42 Controlling Bias: Allocation Concealment (continued) • Masking (or blinding) the outcome assessor • Investigators assessing outcomes not knowing which intervention participant is receiving • Key for subjective outcomes such as: ◦ Reading imaging results ◦ Assessing whether tumor response • “Double masked”study: both participants and outcomes assessors and/or providers are masked

43 Controlling Bias in Analysis of Results • Count every enrolled person • Minimize lost to follow-up • Intention-to-treat (ITT) analyses: • Primary analysis • Everyone counted as part of assigned group, regardless of which intervention is actually received • Failure to do ITT destroys randomization, and study is effectively an observational study • Non-ITT analysis (as-treated, or per protocol) is a viable option as long as ITT is done first

44 Treats to Precision (Random Error) • Inadequate study size • Not powered to test study hypothesis for an individual study

45 Blinding

Questions Advocates Should Ask ◦ Many blinded trials require a placebo to be added to control interventions. Will this cause undue inconvenience to patients and to care providers? ◦ When and how will patients and their clinicians learn what treatment they received?

46 Randomization

Questions Advocates Should Ask ◦ Can a historical control be used? ◦ Can an observationally-enriched random control design be used? ◦ Can a 2:1 (or 3:1) randomization scheme be used? ◦ Will patients be allowed to cross-over?

47 Stratification Questions Advocates Should Ask ◦ What patient factors could impact the outcomes? ◦ Are they of interest in and of themselves? If yes consider stratifying; if no use randomization and assess differences among groups after the fact. ◦ What is the impact on power of adding stratification variables? ◦ Is there enough power to assess the impact of the stratification variables?

48 Key Advocate Questions ADDITIONAL CONSIDERATIONS FOR ADVOCATES

49 What Should Advocates Watch-Out For? Clinical Trials that don’t Serve Patient Agenda ◦ Test clinically irrelevant marginal difference ◦ Ignores patient related outcomes or quality of life ◦ Trial that is conducted without rationale (conducting a phase 3 despite negative phase 2) ◦ No strict publication criteria regardless of the results ◦ No evidence of patient advocate involvement ◦ Clinical trials that don’t return results to patient ◦ Clinical trials without plans for data sharing

50 Questions To Ask About the Trial • What is the standard of care outside the trial? Is this one of the arms (control arm) of the trial? • Is no intervention (e.g., active surveillance for low risk tumors or in the adjuvant setting after local treatment) an option? Is this an option in the trial? • What phase of clinical trial is it? • What is the primary hypothesis the trial wants to test? • Is it a randomized trial? • What are the side effects to expect from each arm? • What will the trial measure? Will it record quality of life? • What are the extra burdens a patient will face? • What are the plans for returning/sharing the trial results?

51 Questions and Answers

52 Patient Centered Outcomes Research WHAT IS IT AND HOW IS IT DIFFERENT TO TRADITIONAL CLINICAL TRIAL RESEARCH

53 Learning Objectives • What patient-centered outcomes research (PCOR) is • What comparative effectiveness research (CER) is • What PCORI is and the type of research it conducts • How PCOR/CER differs from traditional clinical trials

54 History of PCORI Authorized by Congress in 2010 as an independent agency to be a nonprofit, nongovernmental organization to identify research questions important to patients and fund research designed to answer those questions Idea was for an agency that focused on Comparative Effectiveness Research to determines ”what works best” for patients, caregivers and health systems

55 PCORI Vision and Mission

Vision Patients and the public have information they can use to make decisions that reflect their desired health outcomes Mission PCORI helps people make informed healthcare decisions, and improves healthcare delivery and outcomes, by producing and promoting high-integrity, evidence-based information that comes from research guided by patients, caregivers, and the broader healthcare community. Goals • Substantially increase the quantity, quality, and timeliness of useful, trustworthy information available to support health decisions • Speed the implementation and use of patient-centered outcomes research (PCOR) evidence • Influence clinical and healthcare research funded by others to be more patient-centered

56 Patient Centered Outcomes Research PCOR is research that helps people and their caregivers communicate and make informed health care decisions, allowing their voices to be heard in assessing the value of health care options.

57 Examples of Patient-Centered Questions Addressed by PCOR

“Given my personal characteristics, conditions and preferences, what should I expect will happen to me?”

“What are my options and what are the potential benefits and harms of those options?”

“What can I do to improve the outcomes that are most important to me?”

“How can clinicians and the care delivery systems they work in help me make the best decisions about my health and healthcare?”

58 Comparative Effectiveness Research Comparative effectiveness research (CER) attempts to compare the benefits and harms of existing alternative strategies for diagnosing, treating, or preventing disease in patients.

59 Comparing Goals of Traditional Clinical Research and CER/PCOR

STANDARD CLINICAL TRIAL (ONCOLOGY) CER/PCOR

Drug A (SOC) vs. Drug B (new treatment) Variety of different types of studies and methodologies Goal is for a new therapy to get to market Goal is to help patients/clinicians/health systems make decisions ◦ Understand treatment options ◦ How a therapy might affect a patient who does not meet trial eligibility Compares existing interventions for which the evidence is May or may not be associated with a new “product”

60 PCOR and CER Methods Encompasses a wide variety of types of research and methodologies ◦ Randomized controlled trials ◦ Observational studies ◦ Pragmatic clinical studies

61 Pragmatic Clinical Trials “Designed for the primary purpose of informing decision-makers regarding the comparative balance of benefits, burdens and risks of a biomedical or behavioral health intervention at the individual or population level” (Califf and Sugarman 2015)

(1) an intent to inform decision-makers (patients, clinicians, administrators, and policy-makers), as opposed to elucidating a biological or social mechanism; (2) an intent to enroll a population relevant to the decision in practice and representative of the patients or populations and clinical settings for whom the decision is relevant; (3) either an intent to (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial or (b) measure a broad range of outcomes.

62 Differences Between PCORI and Standard Clinical Trials Primary stakeholders: Company looking to get a drug to market vs. Patients, Caregivers and Health Systems looking for data to improve decision-making Comparative effectiveness: Drug to market may or may not be comparative to other standard therapies at the time of approval vs. PCORI looking to compare available treatment/intervention A to available treatment/intervention B to better understand the best course of action

63 Breast Cancer Studies Funded by PCORI

The WISDOM Study (ongoing) Testing two types of screening schedules: one based on a woman’s risks and one based on age Impact of Radiation Therapy on A study that looked at records from national databases to learn: Breast Conservation in DCIS • What patient traits, such as age or race, may affect a woman’s (completed) risk of getting another DCIS or breast tumor in the other breast • How likely it is that a woman who had treatment for DCIS will have a mastectomy if she has a second breast cancer The COMET Study (ongoing) Comparing treatment options for women with low-risk ductal carcinoma in situ (DCIS) Study of Radiation Fractionation on A study to comparing two ways to provide radiation to women who Outcomes After Breast had a mastectomy with breast reconstruction (standard therapy vs. REConstruction (FABREC) (ongoing) short-course higher dose therapy)

64 Conclusions Clinical trials are the primary way that the safety and efficacy of new interventions are evaluated PCOR is research that helps people, caregivers, clinicians and health systems make health care decisions. Advocate engagement happens throughout the spectrum of clinical trials and in all types of patient-centered outcomes research.

65 Questions and Answers

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