Download Clinical Trial Design and Methodology

Clinical Trial
Design and Methodology
Gary J. Kelloff, MD
International Clinical Trial Workshop
Punta Del Este, Uruguay
March 24–26, 2011
Protocol Development Outline
• Phase I, II, and III: their goals and rationale
• Therapeutic roles: prevention, cure, palliation
• Roles of different modalities: surgery, radiation, chemotherapy,
combinations
• Steps in development of a therapeutic trial
• Ways to speed protocol writing
• Choice of primary and secondary objectives
• Appropriate inclusion and exclusion criteria
• Treatment and evaluation schedule
• Assessment of toxicity and reporting AEs
• Scheme for dose modification
• Measurement of outcome, recurrence, response, or survival
Clinical Studies
• Phase I Trials are designed to determine safety and
appropriate doses or approaches to further trials
— 10 to 30 patients
• Phase II Trials are to determine if the new drug or
treatment is efficacious against a given tumor type
— 14 to 200 patients
• Phase III Trials
— Compare the old standard treatment to the latest
experimental therapy
— These are generally national/international trials and
involve hundreds of patients
Historical Cytotoxic Clinical Development Plan
(“More is Better”)
Phase I
— Escalate in cohorts of 3–6 patients from a very conservative dose
(10% of murine LD10) to the highest dose that results in less than
33% incident of dose-limiting toxicity
— More recently, acceptance of smaller cohorts and more rapid
escalation
— Treat six patients at final (maximally tolerated) dose
— Assume that dose should be based on body surface area (BSA)
Historical Cytotoxic Clinical Development Plan
(“More is Better”)
• Phase II — disease A
— Enroll 20 patients with disease A
— If a minimum number of responses (e.g., >1) observed,
then treat another 20
Goal is to either prove drug is inactive, or gain some data to
support hypothesis that drug is active
• Phase II — disease B (as above)
• Phase II— disease C (as above)
Phase I Studies of Noncytotoxic
Antineoplastic Agents
• Drug expected to be active at less than MTD
• Optimal dose cannot be established in Phase I studies,
even with biomarkers
• Definition of optimal dose requires a controlled
Phase II study
• Phase I can only define safety, pharmacokinetics, and
potential relationship of dose and pharmacokinetics to
biomarkers
Design of Phase I Studies:
Noncytotoxic Agents
• Define prospectively what biomarkers (including toxicity and
plasma concentrations) will be used to terminate study
—Use only readily measurable biomarkers, no serial
tumor biopsies
• Consider studying higher doses (e.g., two-fold), unless limited
by toxicity
• Study a sufficient number of patients at those dose levels
planned for future (dose-ranging) Phase II studies
Clinical Therapeutic Studies
• Most therapeutic trials involve treatment of advanced disease
— Done with palliative intent
— Simplest to perform
• Trials done with curative intent are generally adjuvant studies
after surgery for solid tumors or chemotherapy for
leukemia/lymphoma
— Done with palliative intent
— Require large Phase I and II trials
• Prevention trials may include vitamin and hormonal therapies.
— Require extremely large patient populations and many
years to complete
Clinical Therapeutic Studies
• Surgery is the backbone of effective treatment for most solid
tumors.
— Usually done with curative intent
Radiation can be done with curative or palliative intent
— Most protocols are radiation with curative intent, either as
primary therapy or adjuvant treatment
• Chemotherapy trials generally use new drugs with palliative
intent
— May include use of new agents or complex combinations
(usually the latter)
— Successful use of new agents in the advanced setting can
lead to their use earlier in therapy
Sources of a New Protocol
• Extension of preclinical laboratory work
• Inspired by a unique patient or series of patients
• A new drug or imaging instrument is available
• A common problem or disease seen at your institution
(listen to the questions clinicians ask)
• A device or pharmaceutical company suggests a protocol to
you
Design: The Basics
• Evaluate study protocol idea with colleagues
— Feasibility
— Coordinated with other research programs
— Adequate space
— Personnel availability commitment
• Competing protocols for patients?
• Protocol complements other studies
— Can include patients enrolled in another protocol
— Will include a similar tumor type as an ongoing protocol,
but with different eligibility
— Utilizes or complements laboratory work
Decision to Proceed
Am I strongly motivated
to undertake this research?
Am I qualified?
Do I have enough time?
Is the facility
Suitable?
Can I assemble an
effective study
team?
?
Is the patient
population
adequate?
Is expected funding
adequate?
Is the study
plan
acceptable?
The decision to proceed or stop can be made at many points in
protocol development
Integration: Professional Complement
The Study Team
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Investigators
Clinician specialists
Study coordinator
Technical assistants
Nurses
Data Manager
Clerical support
Pharmacists
Accountants
Investigator Role
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Leader of the study team
Selects members and delegates tasks
Directs study activities
Evaluates performance
Bears final responsibility
– Patient safety & welfare
– Quality control
– Integrity and scientific merit of findings
Write the Protocol
• A previous protocol can be a solid guide
• Check with clinical trials office and local IRB/ethics
committee for generic informed consent
• FDA: “Guidance for the Format and Content of the Clinical
and Statistical Sections of New Drug Applications”
• Harness the full potential of the team by asking for
feedback from colleagues and ask for appropriate previous
protocols, grants, and manuscripts
• Look at protocols from other institutions or cooperative
groups
Template for the Study
1. Title Page
2. Synopsis (1–2 pages)
3. Table of Contents
4. Introduction—background, rationale, and toxicity
5. Objectives
6. Eligibility Criteria
7. Procedures for Patient Entry on Study
8. Methodology and Study Schedule
9. Adverse Events and Treatment Modifications
10. Data and Safety Monitoring
11. Statistics and Data Analysis
Protocol Synopsis
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The study objectives
A basic description of the study design
The numer 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
• (1 to 2 pages)
Basic Maxims
• All clinical trials should have one or more specific
scientific goals
— The design of the trial should be adequate to
address at least one such goal—Primary endpoint
• Newer (“targeted”) oncology drugs should be
developed like non-oncology drugs
— Old (cytotoxic) oncology drugs were different (and
in some ways easier), because of the maxim that
“more is better”
Basic Maxims (cont)
• Developing newer oncology drugs does not require
that one understand historical oncology designs
— In fact, this may be an example of “less is better”
• Do not try to answer too many questions at the same
time
• Do not skimp on sample size if the questions is
important
— If the question is not important, why do the study
at all?
Design: Objectives
• The primary objective is key: it will drive your design,
statistics, and accrual goals
• Secondary objectives may include related measures
of results (e.g., overall vs. progression free survival)
• Secondary objectives may look at completely
different issues (e.g., cost analysis)
• Make sure the main objective is one that is clinically
or scientifically meaningful
Statistical vs. Clinical Significance
• A good study will yield both
• Statistical significance
– Probability that a finding is true
• Clinical significance
– The contribution a finding makes to medical practice
Design: Endpoints
• Should be an identifiable clinical change indicating
attainment of the goal
• Needed to define data and assess results in a
consistent manner
• Must be objective and measurable
Design: Study Population
• Total number of subjects needed for clinical and
statistical significance
• Inclusion/exclusion criteria
• Demographic criteria
• Diagnostic methods to determine clinical eligibility
Pitfalls in Protocols: Eligibility
• Write eligibility carefully
• Do not include unnecessary conditions that you will be
tempted to ignore, such as limits on:
— Acceptable laboratory values
— Co-morbid conditions
— Prior malignancies
— Prior treatments
— Results from standard imaging techniques
(“measurable disease”)
• Make sure you eliminate patients who are too sick or complex
to really evaluate
Study Calendar
TASK
Baseline Visit
Day 2
Day 7
X
X
Day 14
Screen to Eligibility X
Obtain informed consent before labs X
Vital signs X
EKG X
X
X
Patient history X
Hematology and Serum Chemistry X
X
X
X
X
X
ASSESSMENT: Pain X
X
X
X
Inflammation X
X
X
X
Adverse Event X
X
X
X
Urinalysis X
PHYSICAL EXAM: Complete X
Brief
Dispense Medications X
X
Retrieve unused meds and containers X
X
X
Data Collection
• Data collection and management of a clinical trial
currently accounts for up to 60% of the overall
clinical trial process
• Pressure to test, approve, and market new drugs
faster than ever so the documentation process
relevant to the clinical trial is now being
automated, which can cut the time of the trial by
two-thirds
Electronic Case Report Forms
• Streamlines the clinical trial process by capturing,
authoring, processing, and managing the clinical
documentation
• By standardizing, controlling, and securing
clinical trials-related content, companies can now
reduce the costs of data acquisition and clean up
during trials, and make data so much more
accessible
Protocol Review
Protocol Review Committee will assess:
– Scientific and clinical rationale
– Competing protocols and prioritization
– Ability to accrue patients
– Statistical review
– Treatment plan and safety (this group will have the
better expertise than the IRB)
– Use of Cancer Center resources (funding)
Institutional Review Board/
Ethics Committee
• Safeguards the rights, safety and well-being of all
trial subjects
• Reviews protocol amendments, recruitement
procedurs, payment & compensation to the
subject and PI’s qualifications
Protocol Review
• Institutional Review Board or Human Investigation
Committee includes:
– Physicians, scientists, statisticians, lay public
– Less likely to include radiologists
• Will assess:
– Safety — but may have limited expertise for your
specific protocol
• Hopefully, your IRB/Ethics Committee has developed
standard wording for common issues such as risks of
standard procedures, confidentiality issues, treatment
of side effects or problems.
More radiologists should join PRC and IRBs
Design: Adequate Accrual
• Plan for accrual management; prepare remedies
for contingencies
— All communication must be IRB approved
• Consider communication of protocol to
physicians and practice groups
• Include talking points showing the merits of
research
• Consider publicity for potential patients through
brochures, posters, newsletters, the web (IRB to
approve all recruiting/publicity)
Design: Compliance and Discontinuance
• Ensure special measures are defined to monitor
subject compliance
• Include procedures for subjects lost to follow-up
• Define criteria for voluntary and involuntary
dismissal
Design: Protocol Revisions
• Despite careful planning — they occur
— Certain aspects of the plan may be
unworkable in practice
— Circumstances change (adverse event,
shortage of subjects)
• Implement when a change will reduce risk to
subjects
• One-time deviations may be allowed
Role(s) Changes During Study
enrollment decisions with PI
subject recruitment
obtaining informed consent
(M.D., R.N., P.A.)
collaborating with
industry
patient scheduling
(R.N., P.A.)
patient compliance
clinical data
management
coordinating study
documentation
supplies management
Enrollment Decisions
• Initial intake interview
• Take the medical history
• Alert to medical barriers to participation, conditions
listed in the exclusion criteria
• Warning signs that the patients may be unable to or
unwilling to comply with the study procedural
requirements
• Identify uncooperative attitudes or problems that may
prevent adherence to study schedules — will reduce
instances of poor compliance later in the study
Integration:
Good Clinical Practice Source Documentation
• First — a clinical observation is recorded
• Supports study’s findings
• Legally valid raw data
• Establishes an audit trail
• Tells the complete story of the subject
Good Trial Files
• Treat the files as “gold” and ensure that they do
not get lost or destroyed prematurely
• Once the study has ended, the PI is required to
keep study-related documents until the sponsor
tells them it is no longer necessary (10+ years
possible, depending on drug’s approval path)
• Documents should be retained until at least two
years after the last approval of a marketing
applicatio.
Documentation for Adverse Events
• An adverse experience (also called event, AE) is any untoward
medical occurrence in a trial subject who has been administered
a pharmaceutical product
• AE may have no relationship to the treatment
• Prompt report to the sponsor
• If AE alarming the PI must report it immediately; 21 CFR Part
312.64 (b)
• In an imaging study one may limit AE to those that occur for a
short time after time after the procedure (e.g., 2 hours)
• For therapeutic trials usually report AE for up to 30 days after
treatment
Safety Reporting
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Laboratory abnormalities may also be classified as AEs
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Good documentation needed to summarize medical
occurrence of SAE:
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Results in death
Is life threatening
Requires in-patient hospitalization
Prolongs existing hospitalization
Results in persistent or significant disability or
incapacity
– Is a congenital anomaly/birth defect
When in doubt report it !!!!
Dose Modifications for Chemotherapy
Regular schemes for dose modifications are needed for
chemotherapy trials when patients experience adverse
events
— Dose modifications schemes can be complex when
multiple agents are being used
— They need to take into account the timing, severity,
and recovery from the toxicity
— They need to indicate which patients should be
removed from the study, while keeping those who
may benefit from a lower dose
Imaging Response to Treatment
• For resectable or curable disease imaging may be limited to
detection or recurrence
— In some cases, recurrence is documented by biopsy
— In some cases, imaging alone is adequate proof of
progression. Central review is rare
• In advanced disease
— Imaging may be involved with the primary or secondary
endpoint. Main endpoints:
• Survival
• Response (e.g., partial or complete response rate),
central review may be needed
• Progression-free survival
• When measuring response, local reviewers involved in patient
care have a bias to read scans in the patient’s favor
Conclusions
Careful planning of clinical trials is essential to their
successful conduct.
Make sure that you have thoughtfully defined:
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Objective
Endpoints
Design
Eligibility
Pre-study procedures
Study calendar
Treatment
Dose adjustment
Data collection forms
Conclusions
During the trial make sure that you have adequate:
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Accrual
Consenting
Use of an eligibility checklist
Treatment compliance
Data collection
Reporting adverse events
Documentation
Accurate outcome measurements