Clinical Trials Design

Clinical Trials Design
By:Martha A. Feldman, RAC
Drug & Device Development Co., Inc.

Purposes of conducting clinical studies
Types of clinical studies
Ethical considerations
Regulatory requirements
Monitoring
Database management issues
Statistical considerations
Reports for submissions or papers

Purposes of Clinical Studies
Further scientific knowledge
Prove concept
Evaluation of product features, capabilities
Obtain initial safety data
Substantiate claim/indication for use
Establish degree of efficacy or effectiveness
Compare with competitor product; marketing evaluation

Types of Clinical Studies
Prospective or retrospective
Blinded/masked or open label
Randomized or not
Active control or placebo
Normal subjects or patients
Actual or surrogate clinical endpoints
Statistically significant or “anecdotal”

Ethical Considerations
Human Subject Review: IRB, Declaration of Helsinki
Informed consent, community consent, waiver of consent
Use of placebos versus positive control
Use of normal subjects
Use of investigational material in addition to standard care
Vulnerable populations

Regulatory Considerations
Drug/Therapeutic Biologic Studies

Overall investigation Plan
Phase 1 - Normal subjects: usually < 50 subjects, at one facility, safety parameters
Phase 2 - Patients: about 50 - 100 subjects; at two sites; may do some dose-range assessment; safety and some initial efficacy
Phase 3 - Patients: few hundred to several thousand; multiple sites; main support study
Phase 4 - Patients (post-marketing): varies


Phase 1 Clinical Study
Normal subjects; occasionally use patients
See if/how pharmacokinetics data from animal studies extrapolates to human data
Document pharmacodynamic effects
Usually open label with ascending doses; establish dose-range
Build safety profile: monitor adverse effects

Phase 2 Clinical Study
Patients or people with clinical condition
Confirm dose range is similar in such people; if not, re-define range
Blinding, randomization, controls used
Strict entry criteria
Initial efficacy determination

Phase 3 Clinical Study
Few hundred to few thousand patients
Multiple sites
Blinding, randomization, controls, prospective
May have slightly broader entry criteria - age, severity of disease,
Continue developing safety and efficacy profiles

Post-marketing Study
Surveillance or study
Numbers to be negotiated
Parameters determined as a result of Phase 3 study
May involve labeling issues

Device Clinical Studies
“It Depends”
Steps in Investigation Plan
Proof of concept/Feasibility: < 5 subjects or patients; one site, safety and some effectiveness
Pilot study: 20-50 subjects; “test drive” protocol, case report forms, initial effectiveness and safety; two sites
Pivotal study: 50 - 500 subjects; multiple sites; main supporting study for claims

Proof of Concept/Feasibility Study
few patients (<5)
limited to one site
usually investigator-sponsored study
goal: prove concept, check instructions for use; early safety and effectiveness assessments


Pilot Study
More rigorous protocol
May be up to 50, but usually around 20 subjects
One or two sites
Company-sponsored study
“Test drive” protocol, comparison of use at two sites, safety and some effectiveness data; finalize training plan
Adjust final protocol for pivotal trial

Pivotal Study
The main study to support the submission
Subject number could be from around 100 to several hundred
Multicenter study; each site should enroll sufficient subjects for separate analyses
Should demonstrate device is independent of inventors


IVD Studies
May be done in two parts: collection of samples (may take > 1 year) and use of IVD (may take < 1month); separate protocols
Collection of samples may involve dozens of sites; testing phase may be at minimum of three sites
Study size may range for 100 (for some monitoring studies) to several thousand (for screening indication)
May enrich samples with stored, known, positive samples: special IRB and consent issues

Monitoring
At least one a year on-site
Between visits: by telephone, e-mail, FAX and courier services

Prestudy Activities
Investigator selection and qualification
Site qualification:
additional staff
sufficient number of subjects
laboratories, pharmacies
special needs
Conduct Pre-study site visit

Prestudy Site Visit
Meet investigator, coordinators, other staff
Review protocol, case report forms
Emphasize consent procedure, requirements
Review adverse event procedures
Review investigator documentation
Review Regulatory Notebook
Visit, as needed, labs, pharmacy, etc.
“Build” study team

Routine, Interim Visit
Review regulatory notebook
Verify consent procedures followed
Ensure study eligibility criteria met
Compare data entries on CRFs and source data
Check investigational product accountability
Check for unreported adverse events
Resolve queries

“For Cause” Visit
Possible reasons
too little/too much enrollment
much greater number adverse events
badly completed case report forms
new coordinator/investigator needing training
results “too good”
Monitor has concerns about investigator or coordinator compliance with regulations

Close-Out Visit
Regulatory Notebook is complete
Supplies accountability checks out
All queries resolved
No unreported, unresolved adverse events
All patient follow-up completed
Investigator’s report done
Files prepared for FDA inspections and for storage

Database Management Issues
Programming for the case report entries
Developing a data entry plan; data entry verification plan
Generating queries for the monitors to have coordinators resolve
Entering amended data; database clean-up
Data editing plan
Closing database; data validation plan; send to statistician
Developing tables for the reports, submissions, etc.

Statistical Considerations
Developing hypotheses
Calculating sample size requirements
Developing plan for interim analysis, if needed, and for final analysis (including sub-analyses)
Determining how interim analysis results impact sample size
Perform analysis and data evaluation
Write statistical report

Sponsor Reports - Submissions
Adverse event reports
Use of investigational product without consent
IRB withdrawal of approval
Annual reports
Updating submissions with each advance in the investigational plan (e.g., study completion or termination)

Investigator Reports
Withdrawal of IRB approval
Use of product without consent
Adverse events - to sponsor and IRB
Study status reports; study close-out report
For device studies: malfunction, repair or replacement

Other Reports
Publications, posters, presentations
can review manuscript for proprietary information
cannot stop the publication of negative results
off-label use: company may not promote it, but can distribute articles written by health care practitioners
References

Code of Federal Regulations, Title 21
Part 50 - Informed Consent
Part 56 Institutional Review Boards
Part 312 - Investigational New Drug, antibiotic, Biotechnology-Derived Product regulations
Part 812 - Investigational New Device regulations
FDA Guidance Document on Good Clinical Practices, January 1988
ICH Guidance Document E6 - Good Clinical Practices
More References

Clinical Trials Design.ppt

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Increasing Complexity of Clinical Trials

Increasing Complexity of Clinical Trials

Definitions:
Procedures: include lab & blood work, routine exams, x-rays & imaging, questionnaire & subjective assessments, invasive procedures, heart assessment, etc.

Protocol: the clinical-trial design plan
Enrollment rate: the percentage of volunteers meeting the increasing number of protocol eligibility criteria (percentage screened who were then enrolled)

Retention rates: the percentage of volunteers enrolled who then completed the study; declining retention rates mean that firms must enroll more patients initially and/or recruit more patients during the trial.

Increasing Complexity of Clinical Trials
During the last decade clinical trial designs and procedures have become much more complex, demanding more staff time and effort, and discouraging patient-enrollment and retention

Unique Procedures per Trial Protocol (Median)
Total Procedures per Trial Protocol (Median)
Clinical-Trial Staff Work Burden (Measured in Work-effort Units)
Length of Clinical Trial (Days)
Clinical-Trial-Participant Enrollment Rate
Clinical-Trial-Participant Retention Rate

Increasing Complexity of Clinical Trials.ppt

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Clinical Protocol Development

CLINICAL PROTOCOL DEVELOPMENT

What’s The Question?
What is the study hypothesis?

What’s The Question?
* What’s the outcome?
* What’s the intervention?
* When and for how long?
* For whom?
* How many participants are needed?
* How can we optimize potential benefit (and what we learn) while minimizing potential harm?

Answering the Question
* Response variable selection and measurement
* Defining the intervention
* Study design
* Eligibility criteria
* Sample size estimate
* Patient management procedures
* Monitoring for safety and benefit
* Data analysis approaches
Response Variable Selection
* “Dose ranging”
* Biologic activity
* Biomarker
o Understand mechanism
o Surrogate outcome
* Toxicity
* Condition/vector/gene interaction
* Feasibility for larger study
* Clinical outcome

Response Variable Criteria
* Well defined
* Stable
* Reproducible
* Unbiased
* Ascertainable in all participants
* Adequately address study hypothesis

Defining the Intervention
* Dose/dosing schedule
* Vector
* Route of delivery
* Method of preparation

Study Design
* Uncontrolled
* Controlled
o Before/after
o Historical
o Concurrent, not randomized
o Randomized

Comparing Treatments
* Fundamental principle
o Groups must be alike in all important aspects and only differ in the intervention each group receives
o In practical terms, “comparable treatment groups” means
“alike on the average”
* Randomization
o Each participant has the same chance of receiving any of the
interventions under study
o Allocation is carried out using a chance mechanism so that neither the participant nor the investigator will know in advance which will be assigned
* Blinding
o Avoidance of conscious or subconscious influence
o Fair evaluation of outcomes

Non-randomized Trials May Be Appropriate
* Early studies of new and untried therapies
* Uncontrolled early phase studies where the standard is relatively ineffective
* Investigations which cannot be done within the current climate of controversy (no “clinical equipoise”)
* Truly dramatic response

Advantages of Randomized Control Clinical Trial
1. Randomization "tends" to produce comparable groups
2. Randomization produces valid statistical tests

Disadvantages of Randomized Control Clinical Trial

1. Generalizable Results?
o Participants studied may not represent general study population.
2. Recruitment
o Hard
3. Acceptability of Randomization Process
o Some physicians will refuse
o Some participants will refuse
4. Administrative Complexity
Study Population
Subset of the general population determined by the eligibility criteria
General population
Eligibility criteria
Enrollment
Study sample
Eligibility Criteria
* State in advance
* Consider
o Potential for effect of intervention
o Ability to detect that effect
o Safety
o Ability for true informed consent

Sample Size (1)
* The study is an experiment in people
* Need enough participants to answer the question
* Should not enroll more than needed to answer the question
* Sample size is an estimate, using guidelines and assumptions

Sample Size (2)
* Approaches for early phase studies
o Dose escalation schemes
o Decision that intervention is unlikely to be effective in ?x% of participants
o Decision that intervention could be effective in ?x% of participants
* Standard ways of estimating for phase III
Sample Size (3)
* Assumptions depend on
o Nature of condition
o Desired precision of answer
o Availability of alternative treatments
o Knowledge of intervention being studied
o Availability of participants

Regular Follow-up
* Routine Procedures (report forms)
o Interviews
o Examinations
o Laboratory Tests
* Adverse Event Detection/Reporting
* Quality Assurance
Contingency Plans
* Patient management
* Evaluation and reporting to all relevant persons and groups
* Data monitoring plans
* Protocol amendment or study termination
Data Analysis (1)
* Occurrence of event
* Time to event
* Mean level of response
* Duration of response
Data Analysis (2)
* Intention-to-treat
* Explanatory
* Subgroups
* Adjusted vs. Unadjusted

Data Analysis (3)
* Specify in advance
o Primary
o Secondary
o Other
o Statistical approach
* Exploratory

Clinical Protocol (1)
* Background/Justification
--Where we are in the field
--What the study will add that is important
* Objectives
--Primary hypothesis
--Secondary hypotheses
--Other
Clinical Protocol (2)
* Study Design and Methods
--Type of study, comparison
--Inclusion and exclusion criteria
--Description of intervention (what, how)
--Concomitant therapy
--Examination procedures (baseline, follow-up, outcome assessment)
--Intervention assignment procedure

Clinical Protocol (3)
* Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria

Clinical Protocol (4)
* Statistics
--Sample size
--Stopping guidelines
--Analysis plans
* Participant protection issues
Summary
* Protocol lays out who, what, why, when, where, how
* Safeguards participants
* Safeguards study integrity
* Midcourse changes are often appropriate (even necessary)

Clinical Protocol Development.ppt

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