Started At Ut Houston Medical School

Quick Start:How 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

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.

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.

Steps in Launching a Research Project

Idea

Detailed Literature Review

Study Question

Detailed Study Protocol

Approval from Physicians, IRB, Hospital

Implementation

Funding (if needed)

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.

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)

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)

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)

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)

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 StudyDesign Features

* A cohort study assembles subjects on the basis of eligibility criteria andthe presence or absence of exposure status; subjects are then evaluated, usually prospectively, for the presence or absence of the outcome of interest. Aclinical trial is a cohort study in which the investigator, usually by randomassignment, determines the exposure or treatment status of the subjects.

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 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

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

Therapy/Intervention/Prevention StudyDesign Features (cont)

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)

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 TestDesign Features

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 TestDesign Features (cont)

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)

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 orabsence of the outcome of interest; subjects are then evaluated, usuallyretrospectively, 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.

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

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)

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

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

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

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

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

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

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)

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

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 285:1987-1991, 2001.

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)

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).

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

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)

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

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.

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.

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)

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.)

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

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.

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.

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

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)

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)

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.

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)

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

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

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

Quality Control for Outcome Measures

Error/variance might be reduced by Written procedures Training sessions Testing and certification of examiners Centralized reader

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

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.

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

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.

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