Designing Clinical Research

A course for pre-doctoral researchersJanuary 4-March 8, 2007

Winter Quarter

UC San Francisco School of Medicine

Thomas E. Novotny, MD, MPHJanuary 4, 2007

Course overview

Faculty and staff Dept. of Epid. and Biostat.

Name Role

Thomas E. Novotny, MD MPH Co-Director/group leader

Nancy Lane, MD Co-Director/group leader

Olivia de Leon Course Support

Allison Deneen Website Management and Communications

Course Objectives

• Acquire research skills • Produce a 5-page protocol for a

real study• Help others in the course (peer

review)• Provide feedback on the course • Have a multiplier effect

Types of Study

• Not the best choice for this course Mice, molecules Cost-effectiveness, meta-analysis Secondary data analysis Qualitative research

• Ideal A new observational study (or

experiment) involving humans that you will do this year

Structure of the course

• 10 weeks in length, Thursdays 4-7 PM Lecture 4-5:30 PM, break with sandwiches Small group 5:30-7:00 PM One excused absence permitted (attendance taken)

• Assigned readings; writing sections to be completed by Monday at 5 PM, sent to group leader by email

• Discuss the various sections of each other’s protocols in small groups each week

• Full protocol Due Noon, March 2 to Olivia by email (olivia@epi.ucsf.edu)

• Peer Review Thursday, March 8, 4-5:30 followed by evaluation and dinner meeting of John Snow Society at Kezar Pub

Additional Course Essentials

• On-line CHR Course prior to ethics lecture on January 25

https://www.researchonline.ucsf.edu/

• EndNote Classes in Library

• Designing Clinical Research, 3rd Edition, Hulley et al.

The research question

Thomas E. Novotny, M.D., M.P.H.January 4, 2007

Lecture 1

Designing Clinical Research for Pre-doctoral researchers

Sections of the study protocol

• Research question• Significance (background)• Study design• Study population and sampling• Variables and measurements• Statistical issues• Ethical issues• Quality control and data management

The research question

• All studies should start with a research question that addresses what the investigator would like to know

• Goal is to find an important research question that can be developed into a feasible and valid study plan

The research cycle

Develop research question

The research cycle

Develop research question

Design study

The research cycle

Develop research question

Design study

Implement study

The research cycle

Develop research question

Design study

Implement studyAnalyze results

The research cycle

Develop research question

Design study

Implement studyAnalyze results

Infer conclusions

The research cycle

Develop research question

Design study

Implement studyAnalyze results

Infer conclusions

The research question

• Format for descriptive study “In a population of [study population], what

is the prevalence (or mean, median, etc.) of [outcome variable]?”

• Most studies will have more than one research question

• The research protocol flows from the research question

The research question

• Usual format (analytic studies):

“In a population of [study population], is [predictor variable] associated with [outcome variable]?”

Examples of research questions

• In a population of injection drug users with HIV infection, is HAART use associated with fewer opportunistic infections?

• In a population of HIV-infected Croatian patients on HAART, is a Mediterranean diet associated with lower risk of dyslipidemia?

• In a population of Croatian merchant seaman, is unprotected sex with sex workers in African ports associated with HIV infection?

What is the research question in this abstract?

Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children. We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a randomized, double-blind study in Soweto, South Africa. At 6, 10 and 14 weeks of age, 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin (CRM197), and 19,914 received placebo…

Klugman KP, Madhi SA, Huebner RE, et al. A trial of 9-valent pneumococcal conjugate vaccine in children with and without HIV infection.

N Engl J Med 2003; 349:1341-8.

In a population of South African infants is immunization with a 9-valent pneumococcal conjugate vaccine associated with invasive pneumococcal disease?

In a population of [study population] is [predictor variable] associated with [outcome variable]?

Origins of a research question

• Mastering the literature Scholarship -- be a scholar and know the

literature Get a mentor

• Be alert to new ideas and techniques Importance of teaching

• Be imaginative

FINER characteristics

• Feasible

• Interesting to the investigator

• Novel

• Ethical

• Relevant

FINER characteristicsCriteria for feasibility

• Adequate number of subjects

• Adequate technical expertise

• Affordable in time and money

• Manageable in scope

FINER characteristicsCriteria for novelty

• Confirms or refutes previous findings

• Extends previous findings

• Provides new findings

FINER characteristicsCriteria for relevance

• To scientific knowledge

• To clinic, public health or health policy

• To future research directions

Problems and solutions:Research plan is not FINER

• Not feasible Too broad Not enough subjects available Methods beyond skill of investigator Too expensive

• Not interesting, novel or relevant

• Uncertain ethical suitability

Problems and solutions:Research plan is not feasible

• Too broad Smaller set of variables Narrow the question

• Not enough subjects available Expand inclusion criteria Modify exclusion criteria Add other sources of subjects Lengthen the time frame for entry into study Use strategies to decrease sample size

Problems and solutions:Research plan is not feasible

• Methods beyond skill of investigator Collaborate with colleagues who have skills Consult experts and review literature for

alternative methods Learn the needed skills yourself

• Too expensive Consider less costly study design

• Fewer subjects and measurements• Less extensive measurement• Fewer follow-up visits

Problems and solutions:Research plan is not FINER

• Not interesting, novel or relevant Consult with mentor Modify the research question

• Uncertain ethical suitability Consult with institutional review board

(ethics committee) Modify the research question

Problems and solutions

• Study plan is vague Write the research plan at an early stage Get specific in the 1 to 2-page study plan

• How the subjects will be sampled• How the variables will be measured

Problems and solutions: examples

• What is the relationship between depression and health?

• Does eating red meat cause cancer?

• Does lowering serum cholesterol prevent heart disease?

• Do contraceptive vaginal sponges prevent HIV infection?

Anatomy of Clinical Research

Physiology of clinical research: How it works

Using measurements in a sample

to draw inferences about

Phenomena (variables) in a population

Predictor* Outcome

Confounding variables*

Effect Modifiers*

Types of variables

*Generally categorized as exposures

The research question

• In descriptive studies:

“In a population of [study population], what is the prevalence of [outcome variable]?”

• In analytic studies:

“In a population of [study population], is [predictor variable] associated with [outcome variable]?”

Types of clinical studies

• Studies with no variables Case studies, case series, editorials,

opinions, reviews

• Studies with single variables Descriptive studies and surveys

• Studies with ≥2 variables Experiments Observational studies Meta-analyses and systematic reviews

Hierarchy of clinical study types

Descriptive studies

Experimental studies

Cohort Case-control Cross-sectional

Observational studies

Analytic studies

Predictor variable(independent)

Outcome variable(dependent)

Variables

Hulley’s Research Question (1993)

Should postmenopausal women receive hormones?

Hulley’s Research Question (1993)

Should postmenopausal women receive hormones?

Subjects: postmenopausal women

Predictor: “hormones”

Outcome: ?

Improved Research Question

Does estrogen treatment prevent heart attacks in postmenopausal women?

Subjects: postmenopausal women Predictor: estrogen treatment vs none Outcome: heart attacks

FINER?

Feasible

Interesting

Novel

Ethical

Relevant

Need to specify design

• Observational study Cross-sectional Case control Cohort

• Randomized clinical trial Surrogate endpoints Endpoints of primary interest

Cohort design

Subjects 5000 women age 55+ living in the Bay Area

Predictor: Taking post-menopausal estrogen at

baseline?

Outcome: Subsequent 5-year incidence of heart attacks

Cross-sectional design

Subjects 2000 women age 55+ seen at SFGH

Predictor: Taking post-menopausal estrogen?

Outcome: History of heart attack?

Case-control design

Subjects Cases: 100 women with heart attacks in the

SFGH ED Controls: 100 women with trauma in the SFGH

ED

Predictor: Taking post-menopausal estrogen?

Outcome: Cases vs controls

Ethical?

• Equipoise (uncertain whether benefits or harms predominate)

Benefits of hormone Rx • Reduce menopausal symptoms• ? Prevent fractures• ? Prevent CHD• ? Prevent Alzheimer’s Disease• ? Improve quality of life

Harms • ?Venous thrombo-embolism• ? Breast cancer

Relevant?

• Premarin/Prempro: #1 in sales• Decision faced by half the population

THE PAST THE PRESENT

Cases

Controls

Yes

Yes

No

No

Breast Cancer

No breast cancer

Received HRT?

Making a research plan

1. Define the research question

2. Develop the research plan• List the elements of the study

• Identify published references on your question

3. Write a background and significance section (history of previous work, rationale, importance)

4. SOCO...single, over-riding communication objective.

Study plan

• Research question• Significance (background)• Study design• Study population and

sampling

• Variables and measurements

• Statistical issues

• Ethical issues• Quality control and data

management

• What is the focus of the study?• Why is it important?• How will you study it?

• Who are the research subjects and how are you going to select them?

• What measures will be done?• What will the size of the study

be and how will you analyze it?• Are there ethical issues?• How will the study be managed

to assure high quality results?

Background and significance

• Build on experience

• Be alert to new ideas

• Be alert to new technologies

• Be knowledgeable about the strengths and

limitations of earlier research

• Know what you want to communicate at the

end

Developing background and significance section for a protocol

• Same role as introduction in a paper• Puts the research question in context• Describes the rationale for the study• What is known about the topic to be studied• Why is the research question important?• What type of answer will be the study

supply?

Background and significance

• Cites previous research that is relevant (including the investigator’s own work)

• Indicates the strengths and weakness (or problems) of previous studies and what questions remain unanswered

• Be clear how the results of the proposed studies will help lead to resolution of uncertainty and influence public health policy or clinical practice

Finding pertinent literature

• Use End Note or a similar program• Check format of references from journal’s

instructions to authors and include them as you write protocol

• Keep copies of all references handy• Search PubMed• Personal communications (who and when)• Unpublished data (best to avoid)

Examples from students