1. Quick Start:
How to Get a Clinical Research Project
Started 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
Approval from Physicians, IRB, Hospital
Implementation
Funding (if needed)
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. 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”)
Stating the Question/Hypothesis
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. 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.
Study Questions
Hulley textbook, Chapter 2 (Question)
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 User’s Guide, BMJ Books, 1998.
CRCA Lectures: 11/28/07, 12/5/07, 12/12/07 (from Clinical Trial Design Course)
10. 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
Therapy/Intervention/Prevention Study
Design Features
* 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. 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
Therapy/Intervention/Prevention Study
Design Features (cont)
12. 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
Therapy/Intervention/Prevention Study
Design Features (cont)
13. 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
Therapy/Intervention/Prevention Study
Design Features (cont)
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 IIIA&B. Diagnostic Tests. JAMA 271:389-391,
703-707, 1994; XVII Screening. JAMA 281:2029-2034, 1999.
CRCA Lectures: 10/17/07 (Diagnosis), 10/24/07 (Screening)
15. 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
Study of Diagnosis/Diagnostic Test
Design Features
16. The test (or cluster of tests) validated in a
second, independent group of patients
(preferable but not critical)
Skip ahead to protocol writing
Study of Diagnosis/Diagnostic Test
Design Features (cont)
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 271:1615-1619, 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 272:234-237, 1994 .
CRCA Lectures: 9/26/07 (Causation); 10/3/07 (Risk and Prognosis)
21. Prognosis Study
Design 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 Study
Design 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 Study
Design 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 272:1367-1371, 1994.
CRCA Lectures: 1/16/08
26. Systematic Reviews
Design 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 277:1552-1557,
1997; XIIIB. Economic Analysis. JAMA 277:1802-1806, 1997.
CRCA Lectures: 2/13/02 (Quality of Life); 2/20/02 (Economic Evaluations)
28. Economic Evaluations
Design 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 Writing
Components 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 285:1987-1991, 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 273:408-412, 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 Started
Planning 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 Started
Preparation 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 Data
and 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.
