Clinical TrialsDESIGNS, METHODOLOGY, AND KEY ISSUES FOR

RESEARCH ADVOCATES(PILOT PRESENTATION – NOVEMBER 21, 2019)

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Featured Presenters

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Lynn Howie, MDPardee UNC Health Care

Elizabeth Frank, Ed.M.Breast Cancer Advocacy Group

Dana Farber Cancer Institute

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 TraditionalClinical 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 CancerDrug Development

6. Novel Trial Designs in PCOR—Pragmatic Clinical Trials and Adaptive Designs

7. Use of Real World Evidence – Potential Uses and Limitations

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Learning Objectives• What is a clinical trial?

• What are the basic requirements and key elements of a well-designed clinicaltrial?

• What is bias, how does it come up in trial design, and how can we minimizethis?

• 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?

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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

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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)

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Is a new intervention safe and effective?

Why Conduct Clinical Trials?

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www.thehastingscenter.org/briefingbook/clinical-trials/

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

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Research Advocate Involvement Across the Clinical Trial Continuum

Develop Study

Concept

Prepare Study

Protocol

Open Study Sites

Conduct Study

Analyze Data

Dissemin-ate

Results

FDA Review & Approval

• Provide informationabout unmet needs• Assess interest of

patient community

• Provide feedbackfrom patientcommunity on sites,investigators, & studyexperience

• Serve on Trial Steering &Data MonitoringCommittees• Provide peer support

during consenting

• Support discussionswith funders, sites &IRBS• Support trial awareness

& recruitment

• Provide input on studydesign• Assist in creating informed

consent document &patient education material

• Serve on FDA advisory& post-marketsurveillancecommittees• Provide FDA Testimony

• Prepare lay summaries• Co-author papers &

posters• Communicate with

patient community

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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

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Sackett D, Richardson WS, Rosenburg W, Haynes RB. How to practice and teach evidence based medicine. 2nd ed. Churchill Livingstone; 1997

PICO: Elements of Trial Design

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Questions Advocates Should Ask About PatientsPopulation◦ 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?

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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 andless toxic)

• Why was this schedule selected? (e.g., length of time on treatment, patientconvenience)

• Are all of the procedures necessary? Scheduled conveniently for patients?Paid for by the trial ?

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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 stoppingrules for efficacy and futility?

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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 ofinterest?

• 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?

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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.

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Types of Clinical Trials

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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

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Cancer Therapy Trials• New drugs go through multiple

phases of evaluation

• Preclinical studies in animalmodels evaluate safety andhelp to identify possibletoxicities

• Advocates should ask about theevidence that was developedto move this drug to humans

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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

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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 initialevaluation of efficacy

• End points depend on whether single arm orcomparative◦ Can be ORR, PFS, or OS

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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 ofpatients

• End points usually PFS or OS

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NBCC Criteria for Clinical Trial CollaborationsStudy 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 inappropriateexclusion of specific populations

◦ Trial results are disseminated to the public in a timely fashion

Educated Patient Advocates involved from the beginning!

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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

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Clinical Trials Projects

• Herceptin (Trastuzumab): key collaboration in a clinical trial thatrevolutionized the treatment of HER2-positivebreast cancer

• BMN 673 PARP inhibitor (Talazoparib): changed the standardof care for patients with BRCA mutation

• Pfizer Paloma 3 CDK 4/6 inhibitor (Palbociclib): changed thestandard of care for patients with ER+/HER2- locallyadvanced and MBC

Phase 4 Trials• Trials used to evaluate long term safety

• Often include 1000s of people

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Endpoints/Outcomes

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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)

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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

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Interpretation of Endpoints

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Subjectivity

Reliability

Composite endpoint looking at pain or another symptom that triggers an

intervention

Progression free orDisease-free Survival

Overall survival

Overall SurvivalStrengths◦ 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

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

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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

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Objective Response Rate• Radiographic endpoint

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

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

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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

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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

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PROs and Quality of LifeAny 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 withcare or symptoms, adherence to prescribed medications or other therapy,and perceived value of treatment

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Sources of BiasAPPROACHES TO MINIMIZING

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Bias and Threats to Validity and Precision• Threats to Validity

(Systematic Error)

• Threats to Precision (Random Error)

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Threats to Validity (Systematic Error)• Selection bias

• Bias introduced by the selection of individuals, groups or data for analysis in such a waythat 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

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Akobeng 2008

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

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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

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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

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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 actuallyreceived

• 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 ITTis done first

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Treats to Precision (Random Error)• Inadequate study size

• Not powered to test study hypothesis for an individual study

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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?

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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?

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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?

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Key Advocate QuestionsADDITIONAL CONSIDERATIONS FOR ADVOCATES

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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

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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 afterlocal 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?

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Questions and Answers

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Patient Centered Outcomes Research

WHAT IS IT AND HOW IS IT DIFFERENT TO TRADITIONAL CLINICAL TRIAL RESEARCH

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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

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History of PCORIAuthorized 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

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PCORI Vision and Mission

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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 informationavailable 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

Patient Centered Outcomes ResearchPCOR 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.

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Examples of Patient-Centered Questions Addressed by PCOR

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“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?”

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

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Comparing Goals of Traditional Clinical Research and CER/PCORSTANDARD CLINICAL TRIAL (ONCOLOGY)

Drug A (SOC) vs. Drug B (new treatment)

Goal is for a new therapy to get to market

CER/PCOR

Variety of different types of studies and methodologies

Goal is to help patients/clinicians/health systems make decisions

◦ Understand treatment options

◦ How a therapy might affect a patient who doesnot meet trial eligibility

Compares existing interventions for which the evidence is

May or may not be associated with a new “product”

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PCOR and CER MethodsEncompasses a wide variety of types of research and methodologies◦ Randomized controlled trials

◦ Observational studies

◦ Pragmatic clinical studies

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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.

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Differences Between PCORI and Standard Clinical TrialsPrimary 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

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Breast Cancer Studies Funded by PCORIThe 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 Breast Conservation in DCIS(completed)

A study that looked at records from national databases to learn:• What patient traits, such as age or race, may affect a woman’s

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 Outcomes After Breast REConstruction (FABREC) (ongoing)

A study to comparing two ways to provide radiation to women who had a mastectomy with breast reconstruction (standard therapy vs. short-course higher dose therapy)

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ConclusionsClinical 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.

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Questions and Answers

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