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