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Quick Start: How to Get a Clinical Research Project Started at UTHouston Medical School

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Title: Quick Start: How to Get a Clinical Research Project Started at UTHouston Medical School


1
Quick StartHow to Get a Clinical Research
ProjectStarted at UT-Houston Medical School
Kathleen A. Kennedy, MD, MPH Jon E. Tyson, MD,
MPH Robert E. Lasky, PhD
2
  • This PowerPoint presentation, provided by the
    Center for Clinical Research and Evidence-Based
    Medicine, is a brief outline of the steps
    involved in getting a clinical research project
    off the ground at UT-Houston.
  • More detailed information is available in the
    following textbooks
  • Hulley SB et al. Designing Clinical Research, 3rd
    ed, Lippincott Williams Wilkins, 2006.
  • Fletcher RH et al. Clinical Epidemiology The
    Essentials, 4th ed, Williams Wilkins, 2005.
  • Friedman LM et al. Fundamentals of Clinical
    Trials, 3rd ed, Springer-Verlag, 1998.
  • Investigators without prior training in clinical
    research methods should at least read the Hulley
    text before embarking on a clinical research
    project.

3
  • Additional training is available in the Clinical
    Research Curriculum (CRCA) courses, including
  • Introduction to Epidemiology Research
    (Observational Studies) offered in the fall of
    odd years
  • Clinical Trial Design (Interventional Studies)
    offered in the winter at the end of odd years
  • Clinical Research Ethics offered in the spring
    of odd years
  • Additional references are included (at the bottom
    of the page) for specific components in this
    outline.
  • Videotapes for CRCA lectures can be borrowed by
    contacting Claudette Ocampo at (713) 500-6708.

4
Steps in Launching a Research Project
Idea
Detailed Literature Review
Study Question
Detailed Study Protocol
Funding (if needed)
Approval from Physicians, IRB, Hospital
Implementation
5
Steps in Launching a Research Project
  • This process is almost always iterative, with
    multiple revisions and changes in the study
    question.
  • To avoid unnecessary delays, seek advice about
    the sample size requirements, costs, and
    acceptance by clinicians early in the process.

6
Stating the Question/Hypothesis
  • A research idea (for an observational or
    intervention study) should be structured into a
    well-built clinical research question or
    hypothesis with the following PICO components
  • Population of interest
  • Intervention to be tested
  • Comparison strategy
  • Outcome(s)

(Jump ahead or return to Components of Clinical
Research Proposal)
Richardson WS et al. The well built clinical
question a key to evidence-based decisions.
ACP Journal Club. 1995 123(3)A12-3. CRCA
Lectures 11/7/07 (Interventional Studies)
9/3/03 (Observational Studies)
7
Study Questions
  • The type of question determines the study design
    that should be used to answer the question.
  • The following slides elaborate the definitions
    and important study design features for each of
    the most common types of study questions.
  • These features increase the methodologic quality
    of the study designs lacking these features are
    more subject to bias.

Hulley textbook, Chapter 2 (Question)
8
Types of Study Questions
  • Therapy/Prevention/Intervention (skip ahead)
  • Diagnosis/Diagnostic Tests (skip ahead)
  • Etiology/Harm/Risk Factors/Mechanism of Disease
    (skip ahead)
  • Prognosis (skip ahead)
  • Descriptive/Prevalence (skip ahead)
  • Systematic Reviews (skip ahead)
  • Economic Evaluations (skip ahead)

9
Therapy/Intervention/Prevention Study
  • A study intended to evaluate the safety,
    efficacy, or effectiveness of an intervention,
    including educational or behavioral interventions
  • Could include healthy people, patients, or health
    care providers as subjects
  • Includes studies labeled as pilot, phase 2,
    preliminary or feasibility study

Hulley textbook, Chapters 10 11, (Clinical
Trials) Friedman LM et al. Fundamentals of
Clinical Trials, 3rd ed, Springer,1998. Jadad A.
Randomized Controlled Trials A Users Guide,
BMJ Books, 1998. CRCA Lectures 11/28/07,
12/5/07, 12/12/07 (from Clinical Trial Design
Course)
10
Therapy/Intervention/Prevention StudyDesign
Features
  • Prospective cohort study
  • Randomized allocation
  • If randomized, concealed allocation
  • If not randomized, steps taken to make sure the
    groups are as similar as feasible with respect to
    important prognostic variables at the start of
    the study

A cohort study assembles subjects on the basis
of eligibility criteria and the presence or
absence of exposure status subjects are then
evaluated, usually prospectively, for the
presence or absence of the outcome of interest.
A clinical trial is a cohort study in which the
investigator, usually by random assignment,
determines the exposure or treatment status of
the subjects.
11
Therapy/Intervention/Prevention StudyDesign
Features (cont)
  • Patients, clinicians, and investigators masked to
    treatment to the extent feasible
  • Outcome evaluators masked to treatment to the
    extent feasible
  • Groups treated equally, apart from the treatment
    under investigation

12
Therapy/Intervention/Prevention StudyDesign
Features (cont)
  • Inter-observer reliability of the tests evaluated
    if a test or evaluation is being used
  • Follow-up of patients after treatment
    sufficiently long and complete to identify
    important benefits and hazards
  • Unbiased stopping rules for ending the study and
    a power calculation for the planned sample size
  • Intention-to-treat analysis (analysis of all
    patients in the group to which they were
    randomized) for management trials

13
Therapy/Intervention/Prevention StudyDesign
Features (cont)
  • For pilot studies, a clear and credible plan for
    a definitive study to address the study question
  • For drug or device studies, subjects in both
    groups provided all care that is considered to be
    routine and of proven benefit
  • For drug or device studies, evaluation in an
    appropriate spectrum of patients (like those in
    whom it would be used in practice)
  • Skip ahead to protocol writing

14
Study of Diagnosis/Diagnostic Test
  • A study intended to evaluate a diagnostic test
    with respect to whether the test provides
    reliable information about whether the subject
    has the disease or condition of interest
  • When the utility or benefit of a diagnostic test
    is evaluated as a management strategy, it should
    be categorized as a therapy/intervention/
    prevention study.

Fletcher textbook, Chapter 3 (Diagnosis) Hulley
textbook, Chapter 12 (Medical Tests) Users
Guides to the Medical Literature IIIAB.
Diagnostic Tests. JAMA 271389-391, 703-707,
1994 XVII Screening. JAMA 2812029-2034,
1999. CRCA Lectures 10/17/07 (Diagnosis),
10/24/07 (Screening)
15
Study of Diagnosis/Diagnostic Test Design Features
  • An independent masked comparison to a reference
    (gold) standard of diagnosis
  • An appropriate spectrum of patients (like those
    in whom it would be used in practice)
  • The reference standard applied to all patients
    regardless of the diagnostic test results
  • Inter-observer reliability of the tests evaluated
    if a test or evaluation is being used

16
Study of Diagnosis/Diagnostic Test Design
Features (cont)
  • The test (or cluster of tests) validated in a
    second, independent group of patients (preferable
    but not critical)
  • Skip ahead to protocol writing

17
Study of Etiology/Harm/Risk Factors/Mechanism of
Disease
  • A study intended to evaluate the etiology
    (cause), predictors, or risk factors for a
    disease or condition

Fletcher textbook, Chapter 11 (Cause) Hulley
textbook, Chapters 7 (Cohort Studies),
9(Cross-sectional and Case-Control Studies), and
9 (Causal Inference) Users Guides to the Medical
Literature IV. Harm. JAMA 2711615-1619,
1994. CRCA Lectures 9/12/07 (Prospective
studies) 9/19/07 (Case-control studies)
18
Study of Etiology/Harm/Risk Factors/ Mechanism of
Disease Design Features
  • Cohort, case-control, or cross-sectional
  • Clearly defined groups of patients, with measures
    to ensure that they are similar in all important
    ways other than exposure/treatment/ risk factor
    under investigation
  • Exposures/treatments/risk factors and outcomes
    measured in the same ways in both groups

A case-control study assembles subjects on the
basis of the presence or absence of the outcome
of interest subjects are then evaluated,
usually retrospectively, for the presence or
absence of the an exposure or exposures. A
cross-sectional study evaluates subjects at a
single time point for exposure and outcome
status.
19
Study of Etiology/Harm/Risk Factors/Mechanism of
Disease - Design Features (cont)
  • Assessment of outcomes objective and masked to
    exposure/treatment/risk factor to the extent
    feasible (for cohort studies and cross-sectional
    studies)
  • Assessment of exposure/treatment/risk factor
    that is objective and masked to the outcome, to
    the extent feasible (for case-control and
    cross-sectional studies)
  • Follow-up complete and long enough to answer the
    study question
  • Skip ahead to protocol writing

20
Prognosis Study
  • A study intended to evaluate the expected outcome
    for subjects with a particular condition or
    treatment, including studies that evaluate the
    risks associated with particular test
  • There should be no intention of drawing
    conclusions regarding a causal relationship
    between the condition and the outcomes. If
    causal inferences are to be made, it should be
    categorized as an etiology study type.

Fletcher textbook, Chapters 5 (Risk) and 6
(Prognosis) Hulley textbook, Chapter 7 (Cohort
Studies) Users Guides to the Medical Literature
V. Prognosis. JAMA 272234-237, 1994 . CRCA
Lectures 9/26/07 (Causation) 10/3/07 (Risk and
Prognosis)
21
Prognosis StudyDesign Features
  • Cohort study
  • A defined, representative sample of patients
    assembled at a common (usually early) point in
    the course of their disease
  • Follow-up of patients complete and long enough to
    answer the study question
  • Objective outcome criteria applied in a masked
    fashion (as feasible) for prognostic factors
  • Adjustment for important prognostic factors if
    subgroups identified

22
Prognosis StudyDesign Features (cont)
  • Validation of the predictors of outcome in an
    independent group (test set) of patients (not
    the group in which the predictors were defined)
    (preferable but not critical)
  • Skip ahead to protocol writing

23
Descriptive/Prevalence Study
  • A study that describes the characteristics of a
    population without testing a hypothesis about the
    population or its subgroups

Fletcher textbook, Chapter 4 (Frequency) CRCA
Lecture 9/5/07
24
Descriptive/Prevalence StudyDesign Features
  • Population described in sufficient detail for the
    study to be replicated
  • Subgroups (if used) described in sufficient
    detail for the study to be replicated
  • Delineation of disease status or condition
    described in sufficient detail for the study to
    be replicated
  • Inter-observer reliability of the tests evaluated
    If a test or evaluation is being used
  • Skip ahead to protocol writing

25
Systematic Reviews
  • A review of the literature using explicitly
    stated search methods and criteria for evaluation
    of methodologic quality
  • May or may not include summary statistical
    analyses (meta-analysis)

Hulley textbook, Chapter 13 (Secondary Studies
and Systematic Reviews) Users Guides to the
Medical Literature VI. Overviews. JAMA
2721367-1371, 1994. CRCA Lectures 1/16/08
26
Systematic ReviewsDesign Features
  • Focused clinical question
  • Explicit and thorough methods for searching the
    literature
  • Explicit and appropriate criteria for including
    and excluding studies in the review
  • All clinically important outcomes considered
  • Subgroups considered when appropriate
  • Skip ahead to protocol writing

27
Economic Evaluations
  • A study that includes an assessment of the costs
    of alternative health care strategies

Drummond MF et al. Methods for the Economic
Evaluation of Health Care Programmes, 2nd Ed,
Oxford, 1997. Users Guides to the Medical
Literature XIIIA. Economic Analysis. JAMA
2771552-1557, 1997 XIIIB. Economic
Analysis. JAMA 2771802-1806, 1997. CRCA
Lectures 2/13/02 (Quality of Life) 2/20/02
(Economic Evaluations)
28
Economic EvaluationsDesign Features
  • Comparison of well-defined alternative courses of
    action
  • Specified point of view
  • Clinically important outcomes considered
  • Valid evidence for the efficacy or accuracy of
    the alternatives
  • Identification and valid measurement of all
    relevant costs
  • Skip ahead to protocol writing

29
Protocol WritingComponents of a Clinical
Research Protocol
  • Background/Significance, including systematic
    review of the literature
  • Question or hypothesis (review PICO format)
  • Methods
  • Population (Inclusion/Exclusion Criteria)
  • Recruitment methods
  • Tracking of eligible non-enrolled subjects (for
    management trials)

Hulley textbook, Chapters 1 (Getting Started) and
3 (Study Subjects) Moher D et al. The CONSORT
Statement Revised Recommendation for Improving
the Quality of Reports of Parallel-Group
Randomized Trials. JAMA 2851987-1991, 2001.
30
Components of a Clinical Research Protocol
  • Methods (cont)
  • Procedures for group assignment
  • Study and control interventions if applicable
  • Management of Co-interventions and /or
    Confounding variables
  • Masking
  • Procedures for monitoring recruitment and
    protocol compliance

Schultz KF et al. Empirical evidence of bias.
JAMA 273408-412, 1995. CRCA Lectures 1/30/02
(Practical Aspects) 2/6/02 (Data Management)
31
Components of a Clinical Research Protocol
  • Methods (cont)
  • Outcomes (primary and secondary) with methods of
    assessment
  • Analysis plan (including sample size)
  • Procedures for safety monitoring and early
    termination
  • Limitations
  • References

Fletcher Textbook, Chapter 2 (Abnormality) Hulley
textbook, Chapters 4 (Measurements), 5 6,
(Sample Size and Power) CRCA lectures 10/10/07
(Measurement) 9/6/06-10/4/06 (Biostatistics for
Clinical Investigators Course).
32
Final Preparation
  • Present proposal to division/department
  • for practical advice and approval of procedures
    that impact patient management
  • should be done earlier in the process (before
    finalizing protocol) if problems are anticipated
  • Present to nursing staff
  • for practical advice
  • suggestions about flyers, reminders, preprinted
    order sheets

33
IRB/CPHS Approval
  • Approval required before enrollment begins
  • Required for all research (retrospective or
    prospective, observational or interventional)
  • Common (albeit controversial) definition of
    research any activity involving human subjects
    that is designed to yield generalizable knowledge

Hulley textbook, Chapter 14 (Ethical Issues)
CRCA Lectures 2/21/07-4/4/07 (Ethical Issues in
Clinical Research Course)
34
IRB/CPHS Approval Process
  • Expedited approval possible if
  • project does not affect patient management
  • no risk to patient confidentiality
  • no informed consent required
  • Full committee review (with or without informed
    consent)
  • for all other projects
  • See CPHS web page for official policies,
    application instructions, and web page for
    electronic submission

35
IRB/CPHS Approval Process
  • There is no longer a submission deadline.
    Proposals may undergo pre-review before
    submission to the committee. Committee meetings
    are held three times a month. Notification of
    decision is usually available the following week.
  • Approval with modifications is usually given at
    first review for proposals that are well-designed
    and well-written with no (or easily solvable)
    research ethics problems. Others are likely to
    be deferred until the following month.

36
IRB/CPHS Approval Process
  • Major considerations for committee
  • Risks to participants vs. benefits for
    participants and society
  • Consent process (should present risk/benefit
    information adequately and fairly and minimize
    potential for coercion)
  • Consent form must be translated into Spanish if
    applicable (after final approval).
  • All investigators must provide certificate of
    Education on the Protection of Human Subjects
    (available online) before beginning research.

37
IRB/CPHS Application Components
  • CPHS application (electronic)
  • Study protocol
  • Consent form
  • Letters of approval/cooperation (if applicable)
  • Recruitment materials
  • Survey/questionnaire forms
  • HIPAA form(s) (part of electronic application)
  • Pediatric Risk Assessment form (if applicable,
    part of electronic application)

38
Hospital/Facility Approval Process
  • Must be received before research can begin
  • Focuses primarily on costs to facility, potential
    public relations problems
  • For Memorial Hermann
  • Electronic application is submitted with CPHS
    forms
  • Takes weeks-months longer than CPHS approval
    (Contact Marianna Riggs 713 704-4256 at
    Memorial Hermann if there is a prolonged delay.)

39
Hospital/Facility Approval Process (cont)
  • For LBJ
  • Form is submitted directly to Harris County
    Hospital District.
  • Form, instructions, and contact information are
    available on line.
  • Cannot be submitted until CPHS approval has been
    obtained with approved consent forms in English
    and Spanish
  • Takes weeks-months longer than CPHS approval

40
Clinical Research Unit (CRU)formerly General
Clinical Research Center (GCRC)
  • NIH funds that can be used to provide support for
    unfunded investigator-initiated studies or to
    supplement funded studies
  • See CRU web page for details regarding
    eligibility and application procedures.
  • Submission deadline is the last Friday of the
    month. Scientific Advisory Committee meetings
    are held on the fourth Thursday of the next
    month. Notification of decision is usually
    available the following week.

41
Clinical Research Unit (CRU)
  • Application are now submitted online in
    conjunction with IRB submission.
  • Pilot grants have recently become available
    through the CCTS to support pilot clinical
    research projects conducted by junior faculty and
    fellows.

42
CRU Approval Process
  • Approval with modifications is usually given at
    the first review for proposals that are
    scientifically meritorious, well-designed, and
    well-written. Others are likely to be deferred
    until the following month.
  • Major considerations for committee
  • Scientific merit
  • Appropriate use of the CRU

43
Getting the Study StartedPlanning for Study
Procedures
  • Study procedures should be detailed in writing to
    ensure consistency among personnel and over time
    (should deal with all plausible contingencies).
  • Level of detail should be greatest and tolerance
    for error lowest for the study and control
    interventions and for the determination of the
    primary outcome variable.
  • Modify written procedures as needed when problems
    arise during the study.

Hulley textbook, Chapter 17 (Implementing Study)
44
Getting the Study StartedPreparation for Data
Collection
  • Data analysis and data collection should be
    driven by hypotheses.
  • Use analysis plan to design data collection.
  • Data definitions should be detailed in writing to
    ensure consistency among personnel and over time.
  • Level of detail should be greatest and tolerance
    for error lowest for key data items, especially
    outcome variables.

Hulley textbook, Chapter 16 (Data Management)
45
Data Collection
  • Collect data items needed for important baseline
    characteristics (population description) and
    analysis of primary and secondary outcomes.
  • Select a limited number of predictor/risk
    adjustment variables that can be accurately
    determined on all or most subjects.
  • Avoid the temptation to collect more data than
    you need or more than you can carefully collect.
  • Put more effort into accuracy and completeness of
    limited data items.

46
Data Entry Tips
  • Every data item should have an answer (include
    other, not applicable, permanently missing)
    so that an item is not left blank.
  • Use procedures to check for missing data on an
    ongoing basis.
  • Use procedures to identify or prevent implausible
    responses as data are entered.

Hulley textbook, Chapter 15 (Questionnaires and
Data Instruments)
47
Spreadsheets
  • Often used as substitutes for databases,
    particularly for small studies
  • Simpler to set up than databases
  • Easy to do relatively simple calculations
  • Data entry errors are easy to make, especially
    with a large number of subjects.
  • Sorting is possible but can be risky.
  • Can be exported into statistical programs

Online module on use of Excel CRCA Computer
Course
48
Databases
  • More complex to set up
  • Allow data entry forms that resemble paper forms
  • data entry more convenient
  • Multiple options for control of data entry
  • validation rules
  • required entry
  • look-up tables
  • radio buttons, checkboxes, etc

Online module on use of Access CRCA Computer
Course
49
Databases
  • Include definitions and instructions on form as
    feasible.
  • Test forms before using on study subjects.
  • Easier sorting/selecting even for complex sorting
    criteria
  • Automatic record saving
  • Can be exported into statistical programs

50
Quality Control for Outcome Measures
  • Error/variance might be reduced by
  • Written procedures
  • Training sessions
  • Testing and certification of examiners
  • Centralized reader

51
Monitoring Adherence
  • Poor protocol adherence results in a bias toward
    the null.
  • Monitor protocol adherence on an ongoing basis.
  • Goals for adherence
  • Very high in efficacy/explanatory trial
  • Real world in management trial

52
Dealing with Missing Dataand Loss to Follow-up
  • Nonadherent participants generally have worse
    outcomes than adherent participants, even if the
    treatment is placebo.
  • Survival analysis is useful only if survival is
    the outcome of interest and if the reason for
    withdrawal/censoring is unrelated to the
    intervention.
  • Plan procedures to minimize loss to follow-up.
  • Plan for competing events eg, death before
    outcome evaluation.

53
Early Termination
  • Reasons for early termination
  • For small/medium trials
  • None (exception if mortality difference is
    clearly demonstrated, unlikely with small sample
    sizes)
  • For large trials
  • Therapy more effective than projected
  • Adverse effects outweigh potential benefits
  • No realistic expectation of a difference

54
Early Termination
  • Statistical adjustments must be made for each
    interim analysis (will increase sample size or
    decrease power).
  • Decisions for early termination should be made
    with great caution.
  • Consider impact on credibility and acceptance of
    results.
  • Consider impact on usual practice.

55
  • Individual help is also available for CRCA
    participants through the Research Support
    Services in the Center for Clinical Research and
    Evidence-Based Medicine.
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