Title: Quick Start: How to Get a Clinical Research Project Started at UTHouston Medical School
1Quick 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.
4Steps in Launching a Research Project
Idea
Detailed Literature Review
Study Question
Detailed Study Protocol
Funding (if needed)
Approval from Physicians, IRB, Hospital
Implementation
5Steps 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.
6Stating 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)
7Study 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)
8Types 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)
9Therapy/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)
10Therapy/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.
11Therapy/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
12Therapy/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
13Therapy/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
14Study 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)
15Study 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
16Study 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
17Study 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)
18Study 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.
19Study 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
20Prognosis 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)
21Prognosis 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
22Prognosis 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
23Descriptive/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
24Descriptive/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
25Systematic 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
26Systematic 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
27Economic 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)
28Economic 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
29Protocol 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.
30Components 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)
31Components 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).
32Final 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
33IRB/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)
34IRB/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
35IRB/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.
36IRB/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.
37IRB/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)
38Hospital/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.)
39Hospital/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
40Clinical 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.
41Clinical 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.
42CRU 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
43Getting 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)
44Getting 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)
45Data 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.
46Data 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)
47Spreadsheets
- 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
48Databases
- 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
49Databases
- 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
50Quality Control for Outcome Measures
- Error/variance might be reduced by
- Written procedures
- Training sessions
- Testing and certification of examiners
- Centralized reader
51Monitoring 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
52Dealing 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.
53Early 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
54Early 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.