Course Guide

Clinical trial essentialsfor medical imagers

Sponsoring Organizations:

Radiological Society of North America, Oak Brook, IL

National Cancer Institute, NIH, Bethesda, MD

Compiled and edited by

C. Carl Jaffe, M.D. NCI

Click here for 2011 full participating faculty list

Concepts addressed inthis course

How does a screening trial differ from a therapeutic trial?

How does a randomized control trial (RCT) differ from an observational trial?

Must the control arm of a therapeutic RCT always be a placebo?

What distinguishes Phase 1, 2, 3 and 4 trials?

Whatare ‘Phase 0’ trials and what role would imaging have in them?

What data do you need to determine a statistically valid study size?

When does a trial need a Data Safety Monitoring (DSM) board?

What functions do interim and futility analyses serve?

What are the definitions of type 1 and type 2 errors?

How do you constitute an imaging central reading review panel and how does it function?

What is the regulatory definition (e.g., FDA) of a “surrogate’ biomarker?

How do “prognostic”biomarkers differ from ‘predictive’ markers?

What happens if an ‘adverse event’ occurs to a study subject?

TABLE OF CONTENTS

Introduction......

Trials: their types......

Diagnostic Technology Assessment Trials......

Introduction to Therapy Clinical Trials......

Investigational Drugs and Devices......

Biases and Their Control......

Assessing predictive value of tests......

Imaging as a Measure of Therapeutic Response......

Ethics Considerations......

Monitoring of Clinical Trials: IRB, DSM, CTEP

Sponsorship and Economics of Imaging Trials......

Informatics Tools for Protocol Development......

Bibliography......

Required reading, in advance of the workshop......

Introduction

What are clinical trials?

A clinical trial is a carefully designed research process. Studies are done to find out whether promising approaches to disease screening, diagnosis, and treatment are safe and effective <

Information Resources

The National Cancer Institute’s (NCI) Web site, cancer.gov, provides access to a wealth ofinformation on clinical cancer care. The site contains informationfrom PDQ®, including the latest information about cancertreatment, screening, prevention, genetics, supportive care, andcomplementary and alternative medicine, as well as a registry ofcancer clinical trials thatis coordinated with clinicaltrials.gov. The latter provides a listing of trials that thekey medical publishers have agreed must have been pre-specified and announced, without which the trial resultswill not be published.

At the cancer.gov and the National Library of Medicine (NLM) websites clinical specialists review currentliterature from the medical journals, evaluate itsrelevance, and synthesize it into clear summaries, which are reviewed monthly and updated based on newinformation. Most information summaries appear in twoversions: 1) a technical version for the health professional and 2)a non-technical version for patients, their families, and the public.Many of the summaries are also available in Spanish.NCI also maintains a telephone helpdesk for patients seeking cancer care and clinical trials information at 1-800-4-CANCER. The NCI Website also includes approximately 100 fact sheets onvarious cancer-related topics, information on ordering NCIpublications, and educational features and news summariesconcerning the latest results from cancer clinical trials.

NCI’s clinical trials registry (PDQ) contains more than 1,800ongoing clinical trials, including information about studies aroundthe world. The trials listed in the NCI PDQ site are transferred and harmonized weekly with the clinicaltrials.gov website maintained by NLM. The latter site includes trials on a variety of diseases besides cancer.Although no single resource lists every cancer clinical trial beingconducted in the United States and abroad, PDQ is the mostcomprehensive cancer clinical trials registry. It containsinformation about trials sponsored by NCI, the pharmaceuticalindustry, and some international groups. Users can narrow theirsearch by multiple parameters, such as stage of disease, phaseof trial, treatment modality, and geographic location. PDQ alsocontains an archival file of more than 11,000 clinical trials that areno longer accepting patients, including contact information for theprincipal investigators of trials that may not yet be published inthe biomedical literature. Demographics and incidence of cancer by state and other parameters are accessible from the NCI SEER database.

The American Cancer Society (ACS) has a website that also provides information on cancer prevalence and other information that can be helpful in determining the import and relevance during the planning of a clinical trial.

Trials: their types

Trial types can be classified as:

  • Treatment
  • Prevention
  • Screening
  • Diagnostic
  • Genetics
  • Quality-of-life

Screening Trials

The ultimate goal of screening is to reduce the burden of advanced disease. For many types of disease,detection and treatmentof the disease at an early stage can result in animproved outcome.Single arm trials can be useful for determining if a new screening test can detect disease earlier, e.g., before it is symptomatic, and for determining the feasibility of screening. Non-invasive ways to detectdisease at an early stage include body fluids and imaging. Randomized control trials (RCT)composed of a screened group and a control group is the most reliable method for determining whether earlier detection translates into a reduction in disease morbidity or mortality.

Diagnostic Trials

Diagnostic testsare conducted to determine whether cancer is present, where it islocated and its stage.Some diagnostic trials compare two or more techniques todiagnose cancer and determine whether one technique is superior. Genetic tests are being evaluated as diagnostictools to further classify cancersso as to direct therapies orimprove treatments for people with specific genetic changes.

The Clinical Trial Protocol

Clinical trials follow strict scientific guidelines. These guidelinesclearly state the study’s design and who will be able to participatein the study (patient eligibility). Every trial has principal investigator(s). The principal investigatorprepares a plan for the study (a protocol) which describes the clinical trialin complete detail.The protocol explains what the trial will do, how the study will becarried out, and why each part of the study is necessary. Itincludes information on:

  • The importance and rationalethat justifies the study
  • A statistically justified cohort size (for each arm)
  • Eligibility criteria (requirements mayinvolve type of cancer, general health, age, prior therapy)
  • The intervention or therapy being tested (e.g. drug dosage, etc.)
  • What tests participants will have and how often (a ‘patient calendar’)
  • What information will be gathered about the participants and how their privacy will be protected
  • The participants options if they choose to withdraw
  • Areadable consent form(at an eighth-grade readability level)
  • The endpoints (primary and secondary) and correlative studies
  • Methods of analysis
  • Regulatory requirements and reporting obligations

Diagnostic Technology AssessmentTrials

Some trials are primarily focused on imaging technology endpoints such as sensitivity for disease detection or staging, etc. The trial design and its elements with thus encompass:

Scope of the diagnostic technology assessment process:

– Developmental level of technology

– Performance of technology, as measured byspecific metrics.

Developmental stages of imaging technology

  • Stage I (Discovery): Establishment oftechnical parameters and diagnosticcriteria.
  • Stage II (Introductory): Early quantificationof performance in clinical cohorts, usuallyin single institution studies.
  • Stage III (Mature): Comparison to othermodalities in large, prospective, multi-institutionalclinical studies (efficacy ).
  • Stage IV (Disseminated): Assessment ofperformance in the community at large

setting (effectiveness).

Endpoints for diagnostic test evaluation

  • Diagnostic performance (sensitivity, specificity, measures ofaccuracy and predictive value)
  • Intermediate process of care:

–Diagnostic thinking/decision making

–Therapeutic thinking/decision making

  • Patient outcomes: Quality of life,satisfaction, cost, mortality, morbidity

Studies of diagnostic performance are

  • Needed in all phases of diagnosticmodality evaluation.
  • Should incorporate the assessment ofintra- and inter-reader variability.

Facetsof the effect on process of care include:

  • Effects on choice of further diagnosticworkup; impact on utilization and cost.
  • Effects on patient management, such asdecision to undergo surgery or to administration of specific types of therapy.
  • Techniques relatively easy to carry out.

Assessing impact on process of care

  • Has important methodologic limitations:

– Confounding by temporal and institutionalfactors.

– Reproducibility of results?

– Generalizability of results?

– Need to take into account accuracy ofdiagnosis and appropriateness of care.

Empirical studies of patient outcomes are more feasible for early occurring outcomes.

Are subject to confounding by treatment for longer-termoutcomes.

Magnitude of the effect could be verysmall, especially for distant outcomes.

Randomization is usually needed.

However use of randomization leads to inefficientdesigns for studying accuracy.

Introduction to Therapy Clinical Trials

Phases of Clinical Trials

Treatment (therapy) trials are usually classified as one of four phases, each designed to answer different research questions.

Phase1Phase 1 / Phase2 / Phase3 / Phase4
Number of
participants / 15-30 subjects / Less than 100 subjects / 100 or more / Large subject numbers
Purpose / • To find a safe dosage
• To decidehow the
agentshould be
given
• To observehow theagentaffects the
human body / • To determineif the agent orintervention
has an effecton a
particular disease
• To see howthe agent orintervention
affects thehuman body / • To comparethe new
agent orintervention
(or new useof a
treatment)with the
currentstandard / • To further
evaluate thelong-termsafety andeffectiveness
of a newtreatment

Recently, a new special purpose Phase 0 trial structure has been defined: new class of trial has bee defined ca

Phase 0 trials
Number of participants: about a dozen
Purpose and Method: Using micro-doses to determine if ‘targeted’ therapeutic agents reach the intended tissue. In early therapeutic development efforts, ‘Phase 0’ human clinical trials often use image-able, nuclear-tagged molecular compounds.

The following outlinecourtesy of Dr Tony Shields

Most therapeutic (e.g., drug) trials involve treatment of advanceddisease.

Are often done with palliative intent, which are the simplest to perform.

Trials done with curative intent are generally adjuvantstudies after surgery for solid tumors or chemotherapyfor leukemia/lymphoma and use regimens proven effective in advanced disease, but require large phase II and III trials.

Prevention trials may include vitamin and hormonaltherapies.

– Require extremely large patient populations and years to complete.

Clinical Therapeutic Studies

  • Surgery is the backbone of effective treatment for mostsolid tumors and is usually done with curative intent.
  • Radiation can be done with curative or palliative intent and these protocols use radiation with curative intent, either asprimary therapy or adjuvant treatment.
  • Chemotherapy trials generally use new drugs withpalliative intent and may include single agents or complex combinations (usuallythe latter). Successful use of new agents in the advanced setting can leadto use earlier in therapy.

Sources of new protocol ideas

Arise from: 1) Extension of pre-clinical cellular or animal laboratory work 2) Inspired by a unique patient or series of patients 3) A new imaging instrument is available 4) A new imaging probe is available 5) New software or hardware have improved anolder instrument 6) A common problem or disease seen at yourinstitution 7) A device or pharmaceutical company suggests a protocol

Design basics: you must critically evaluate:

– Feasibility coordinated with other research programs

– Adequate space

– Personnel availability/ commitment

– Competing protocols for patients or protocol complements other studies

– Can include patients enrolled in another protocol

– Will include a similar tumor type as an ongoing protocol with different eligibility

Protocol synopsis should address:

• Study objectives

• A basic description of the study design

• The number of subjects to be enrolled

• Summary of inclusion and exclusion criteria

• The dosage regimen or device utilization plan

• Planned study procedures

• The planned methodology for statistical analysis

Design: Objectives

• The primary objective is key: it will drive yourdesign, statistics, and accrual goals

• Secondary objectives may include relatedmeasures of results (e.g. overall vs.progression free survival)

• Secondary objectives may look at completelydifferent issues (e.g. cost analysis)

• Make sure the main objective is one that isclinically or scientifically meaningful

• Correlative studies are often included to expand the base of science knowledge of the disease

Statistical vs. Clinical Significance

• A good study will have validity that is both: Statistical– probability that a finding is true; and Clinical– the contribution that the finding makes an impact on medicalpractice

Design: Endpoints

• Should be an identifiable clinical changeindicating attainment of the goal

• Needed to define data and assess resultsin a consistent manner

• Must be objective and measurable

Design: Study Population

• Is the total number of subjects needed for clinicaland statistical significance taking into account: 1) Inclusion/ exclusion criteria 2) Demographic criteria 3) Diagnostic methods to determine clinicaleligibility

Pitfalls in Protocols: Eligibility

• Write eligibility carefully-- or it will come back to bite you

• Do not include unnecessary conditions that you willbe tempted to ignore, such as limits on:

– acceptable labs

– co-morbid conditions

– prior malignancies

– prior treatments

– results from standard imaging techniques(“measurable disease”)

• Conversely, make sure you include limits that would otherwise prevent enrollment of patients who would be endangered by the study or give uninterpretable results

Screening Procedures Prior to Study Entry

• Make sure the timing of procedures is appropriate

– if screening is done too far in advance of enrollment; lab or imagingmay have changed.

– if evaluation must be done just prior to the start you may need torepeat lab and imaging.

– generally, imaging can be done up to 4 weeks before treatment andlabs within 7- 14 days.

– insurance will often not cover imaging if too frequent

– screening that is not part of standard of care may need to be paid forby the study.

Consent procedure:

Make sure patient and investigator sign consent beforestarting protocol or pre-enrollment screening procedures thatare not part of standard of care. The consent should be readable at an eighth-grade level. It may contain components for opt-in or opt-out sub-consent signatures involving correlative studies or data-sharing that are not part of the primary endpoint.

Study StructureDetermines

• In a diagnostic trial how the test will be verified– type of treatment for each group– duration of treatment– if more than one treatment, the order in whichtreatments will be administered

• Phase II Design

– all patients receive same treatment or procedure

– compare to historic controls

– imaging trials may compare to a “goldstandard” of pathology or clinical follow up

• Two Group Studies

– Parallel: each group receives a differenttreatment or procedure from all other groups

– Crossover: each group receives a differenttreatment order from all other groups

Data Collection

Create a table that defines the clinical test sequence in a study calendar

• Data collection and management of a clinicaltrial currently accounts for up to 60% of theoverall clinical trial process

• Industry is pressured to test, approve, andmarket new drugs faster than ever so theyare now automating the documentationprocess relevant to the clinical trial and cancut the time of the trial by two-thirds

Electronic Case Report Forms (CRFs) and Remote Data Capture (RDC)

• Streamlines the clinical trials process bycapturing, authoring, processing andmanaging the clinical documentation

• By standardizing, controlling and securingclinical trials-related content, the companiescan now reduce the costs of data acquisitionand clean up during trials, and makes data much more accessible

• Internet-based Clinical Trials(RDC)

Has been recently introduced to replace paper-based processes. Clinical sites are beginning to embracethis but it often requires them toretrain staff, but leads to more rapid datacapture from electronic records and datasharing, and has potential privacy implications.

Design: Budget

• All protocols cost money, even if it is just your owntime but include regulatory and review costs, physicians and nurses recruiting patients, reimbursement of patient expenses and modest compensation, physicians and nurses to follow-up results of treatment orimaging, laboratory tests that are not part of the standard of care, data management costs, imaging costs: machine time, tech support, supplies that are not part of standard of care. Some of these costs may be hidden and notexplicitly charged, but they are all real

• The protocol is the tool to develop the budget– look at all the tests on the study calendar; is hospitalization needed (just drawing blood can be expensive) cost of data collection, validation, and analysis. It identifies all study - plan related costs: time: staff spends with subjects & on protocol, varies; procedures: cost per subject;overhead: dictated by institutional guidelines; divide costs into up front costs for evaluation and review of theprotocol: IRB charges etc., figure per patient costs. You may need to separately charge for procedures if theyare expensive (e.g., image guided therapy, extra scans etc.)

• Develop potential sponsors

– Internal seed money

– Grants from funding institutions, such as NIHprogram announcements, unsolicited

investigator initiated grants, SBIR grants or Industry such as pharmaceutical manufacturers,

medical device companies, contract research organizations

Pre-study Documents

Laboratory’s accreditation certificate

Current laboratory ranges

Form FDA1572 completed for all investigators (establishes their registration as investigators)

Primary Investigator(PI) and Co-investigator CVs

Financial Conflict of Interest Statements

Radiation Safety Application

IND number, if investigational drug

IDE number, if investigational device

IRB Submission Form

CancerCenter Submission Form

HIPAA compliance documentation

Informed consent

Protocol

Protocol Review

FDA review

• Required for investigational device unless it has “no significant risk”

• Always required for investigational drug

CancerCenter Protocol Review Committee (PRC)

Includes: Medical oncologists; Surgeons; Radiation oncologists; Radiologists (not always - but participation ishighly recommended); Statisticians; Nurses; Data managers