Developing a Research Study Protocol

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Developing a Research Study ProtocolFrom an
Idea to Implementation

• Sadaf Aslam, MD
• Clinical Research Instructor
• USF Health, Clinical and Translational Sciences
  Institute
• July 18th, 2012

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What do we need to know?

• Research terminology
• Basic study designs/research question
• Required elements of a research study protocol
• Identify and avoid common mistakes
• Understand PI, IRB and Institutional
  responsibility

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How is research defined?

• Research
• Systematic investigation including research
  development, testing and evaluation, designed to
  develop or contribute to a generalizable
  knowledge
• Human Subject
• A living individual about whom an investigator
  obtains data through intervention or interaction
  or through identifiable private information

Federal policy 45CFR46. 102(f)
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What is Clinical Research? Breaking the
Scientific Bottleneck
Basic Sciences Research Finding the cause of
disease Translational Research Making the
results applicable to the population
Clinical Research Patient oriented
research-studies on mechanisms of disease,
therapies and intervention, new technology and
includes clinical trials Epidemiological and
behavioral studies Outcomes and Health services
research (NIH )
Association of American Medical Colleges American
Medical Association
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Clinical Trials

• Any prospective studies designed to evaluate the
  safety and efficacy of new drug, device or any
  behavioral intervention mostly against a control
  -gold standard of clinical research
• Any biomedical and health related study that
  follows a predefined protocol either by
  observation or intervention involving human
  subjects

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Clinical Trial-Phases
Drug discovery
Preclinical
Animal and lab testing
Phase I
20-30 healthy volunteers, for dosage n safety
Phase II
100-300 patients for efficacy n side effects
Phase III
1000-3000, mostly multi-center, efficacy and
comparison with current t/m
FDA
FDA review n approval process
Phase IV
Post marketing and long term effects of drug
0 2 4 6 8
10 12 14 16
years
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All studies
Descriptive
Analytical
Experimental
Observational
Surveys cross-sectional
Qualitative case reports, case series
RCTs
Cohort
Parallel Group
Case Control
Cross over
Cross- sectional
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Getting started
The best time to contemplate the quality of
evidence from a clinical trial is before it
begins. Conceptualizing and designing good
clinical trials is never an accident but results
from careful planning Clinical
Trials A Methodologic Perspective by Steven
Piantadosi
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Main Steps 1 Formulating a research
question 2 Drafting a study Protocol 3
Regulatory submission and Approval 4
Implementation
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Research Question

• - A research question is the starting point
  of all studies and addresses the uncertainty an
  investigator has and is trying to find an answer
• - Forms the foundation of your study
• - Must be specified before starting the
  analysis

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Origin of a research question

• Published literature
• Scholarship
• Mentor
• New ideas and techniques
• Surroundings- clinical setting, grand rounds,
  journal clubs etc

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Types of Questions

• Background
• Generally ask what, when, how, where about
  the disease, disorder, or treatment
• Foreground
• Patient oriented questions cover specific
  aspects with interpretation of therapy, disease,
  prognosis, diagnostic, risk etc and give answers
  based on outcome

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A 30-year-old woman presents with progressive
weakness of both legs. She has difficulty in
walking, climbing stairs, and standing up from a
sitting position. A diagnosis is made of
"demyelinating disease of the central nervous
system" and intravenous methylprednisolone is
prescribed. The patient is informed that her
symptoms and test results will be monitored over
time. She wants to know what her chances are of
developing multiple sclerosis (MS) in the next
few years.
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A 37-year-old pregnant woman comes to the clinic
for a routine checkup. This is her second
pregnancy. She had her first child when she was
35 years old and had an amniocentesis at 18 weeks
to test for Down syndrome. The amniocentesis was
negative. She is currently 8 weeks pregnant and
would like to know of any abnormalities. An
ultrasound can be done in the first trimester for
diagnosing Down syndrome, but it is unknown if
the results are as reliable as the conventional
test of amniocentesis.
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In elderly patients with heart failure with an
ejection fraction of 40, is Quinapril effective
in reducing the need for re-hospitalization?
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Key Concept

• P- Population
• I- Intervention
• C- Control
• O- Outcome

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Examples of a research question

• Is omega 3 fish oil beneficial for health?
• Changing it to hypothesis (prove or disprove)
• We hypothesize that taking omega 3 fish oil is
  beneficial for health
• Improved hypothesis In post menopausal women, we
  hypothesize that women who take omega 3 fish oil
  will have a a lower risk of heart disease then
  those who dont take it.
• Research Question Does Omega 3 fish oil reduce
  the risk of CHD in post menopausal women?

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Should postmenopausal women receive hormones?

• Population postmenopausal women
• Predictor hormones
• Outcome ?
• Changing it to hypothesis (prove or disprove)
• We hypothesize that taking hormones is
  beneficial for postmenopausal women

Ref Designing Clinical Research by Dr. Stephen
Hulley
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Improved Research Question

• Does estrogen treatment prevent
• heart attacks in postmenopausal women?
• Population postmenopausal women
• Predictor estrogen treatment vs none
• Outcome heart attacks

Improved hypothesis In post menopausal women, we
hypothesize that women who take estrogen
treatment will have a a lower risk of heart
disease than those who dont take it.
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Cohort design

• Population
• - 5000 women age 55 and above living in the Tampa
  Bay Area
• Predictor
• - Post-menopausal estrogen at baseline
• Outcome
• - Follow-up 5-year incidence of heart attacks

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Case-control design

• Population
• - Cases 100 women with heart attacks at TGH ED
• - Controls 100 women matched age and
  demographics TGH ED
• Predictor
• - Post-menopausal estrogen intake
• Outcome
• - Heart attack in Cases vs controls

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Cross-sectional design

• Population
• - 2000 women age 55 seen at Womens Health
  Center
• Predictor
• - Taking post-menopausal estrogen?
• Outcome
• - History of heart attack?

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Characteristics of a Research Question in Context
of a Study Design FINER

• Feasible
• Interesting
• Novel
• Ethical
• Relevant

Designing Clinical Research by Stephen Hulley
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Criteria for Feasibility

• Adequate number of subjects
• Knowledge and expertise
• Adequate resources regarding time and money
• If manageable in scope

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Criteria for Interesting

• Depends on your passion, motivation
• Something to be an expert in
• Finding the truth and making a difference

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Criteria for Novelty

• Comes from thoroughly reviewing the literature
• Confirms or refutes previous findings
• Extends previous findings
• Provides new findings
• How to find Novelty?
• Mastering the published literature-resources-
  EBM, Medline Ovid, pubmed
• Perform systematic reviews and meta-analysis

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Critically reviewing literature!!

• Introduction Why did they initiate the
  research?
• Methods What did they do?
• Results What did they find?
• Discussion What do the results mean?

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Purpose of Thorough Literature Search

• Places others work in the context of its
  contribution to the topic and provides critical
  review
• If the research question is significant and the
  work is original and important
• Identifies new ways to interpret and find any
  gaps in previous research
• Identify areas of prior research to prevent
  duplication of effort
• Helps formulate your own research question and
  study

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Working with Literature

• Find -types, resources, skills, knowledge
• Manage reading, keeping track, annotation
• Use research topic, question, justification,
  design, method
• Review writing background section, working on
  style n tone

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Criteria for Ethical

• Respect for human subjects
• Respect for confidentiality
• Respect for informed consent
• Respect for beneficence and justice

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Criteria for Relevance

• To add on to scientific knowledge
• To benefit clinic, public health or health policy
• For future research directions

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The research cycle
Formulate a research question
Publish
Literature search Systematic Review
Infer conclusions
Answer? Yes
Answer? No
Analyze results
Design study
Implement study
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Step 2 Drafting a study protocol
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Protocol

• A study protocol is a formal document which
  leads to a systematic approach about the modes to
  conduct a study based on ethical, scientific and
  organizational grounds
• A document that describes the objective, design,
  methodology, statistical consideration and
  organization of a trial (ICH definition)

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Outline of a study protocol

• Title
• Abstract/synopsis
• Background/significance/rationale
• Objectives/specific aims/research question
• Study design/Methodology/Procedures
• Informed consent process-confidentiality
• Overall Management Plan
• References

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1 Title

• Consistency across all documents
• 2 Abstract/Synopsis
• Abstract- question, rationale, convenient
  reminder of the specifics of proposal for
  everyone specially some non scientific reviewers

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3. Background/Introduction

• A Known
• B Unknown
• C Research question- How the new information
  may add to what is already known Why this
  research needs to be carried out-Justification
  for the study
• D Experimental approach-follows from question
  what you will do about your question

Broad
A
Narrow
B
C
D
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Example of Writing a Background Section
Title The Effect of Dietary Omega-3 Fatty Acids
on Coronary Atherosclerosis Ingestion of fish or
other sources of Omega-3 fatty acids has been
called a comprehensive strategy toward the
prevention of atherosclerosis (1). Hundreds of
epidemiologic studies, studies of mechanisms of
action, and studies in experimental animals have
shown that dietary intake of Omega-3 fatty acids
has anti atherosclerotic potential
(19).. However, only a few clinical trials
have shown that Omega-3 fatty acids have
cardiovascular benefit in humans To test the
hypothesis that consuming Omega-3 fatty acids for
2 years leads to less progression and more
regression of coronary atherosclerosis, as
assessed by coronary angiography, we will conduct
a randomized, double-blind, placebo-controlled
study in patients with coronary atherosclerosis.
April 1999 Annals of Internal Medicine Volume
130 Number 7 Clemens von Schacky, MD Peter
Angerer, MD Wolfgang Kothny, MD Karl Theisen,
MD and Harald Mudra, MD
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4. Objectives

• Objective is the research question that needs to
  be answered based on the rationale or hypothesis
• Each objective should have a corresponding
  discussion in the statistical section

Primary Objective To evaluate the effect of
omega 3 fish oil in reducing the risk for CHD in
post menopausal women Secondary Objective To
assess the effects of the Omega 3 fish oil with
respect to 6 months and 12 months development of
variables such as glucose, lipids, hormones, and
BMI
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5. Design and Methods Section

• Study design/methods
• Sample size
• Study subject selection/population
• Statistical Analysis Plan
• Data collection methods and Data management

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a) Study design/Methods

• Descriptive What is average number of servings
  of omega-3 fish oil per week in the diet of
  patients with a history of CHD ?
• Analytical Is there an association between fish
  oil and risk of developing CHD?
• Clinical trial Does treatment with omega 3
  capsules reduce the incidence of CHD in diabetic
  patients?

• Randomization /Blinding
• Process of recruitment
• Flow chart
• Methods of measurement

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b) Sample Size

• Provide the rationale for the sample size and the
  clinical justification
• If sample size shows certain level of power and
  effect size (If phenomenon is rare, effect size
  will be small and more subjects are needed)
• Sample size/power analysis

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c) Study Population /Selection of Subjects

• Define Inclusion and exclusion criteria
• If the selected population is appropriate to
  answer the RQ

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d) Statistical Plan
Details of the plan- statistical test to test
each hypothesis/expected data/ Coding
Plan for any missing, spurious and unused
data Procedures for reporting deviations from
the original statistical plan Software you will
be using for analysis
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e) Data collection/management and access

• How the data collected will be analyzed to
  determine the health outcomes
• Validity and reliability of the data collecting
  instrument
• Describe the sources of the data in case of chart
  reviews

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6. Informed consent
Requires all essential elements and its a
process
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Confidentiality

• Must comply with the data protection act
• Privacy and confidentiality (PHI- maintained by
  the covered entities)
• De-identification of the data
• In case of any communicable disease how to limit
  the reporting requirements

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7. Overall Project management

• Duration of your study and time line
• Handling and storage of data
• Reporting to participants, sponsors, community
• Reporting of any conflict of interest
• Identify any planned ways to present your results

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List all the references used in the background
section or in the protocol text at the end of the
protocol-use NIH format or endnote
8. References
Attachments and Appendices
Budget , PIsCV, certification, Data collection
forms, request to access data, Site agreement,
ICF, HIPAA waiver, amendments
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Step 3 Regulatory Submission and Approval

• Department Review/ Scientific Review
• IRB review-process
• Site approval
• COI Review

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Scientific Review Focus

• Research question
• Study design/methodology
• Systematic review
• Research team is qualified
• Background and rationale
• Sample size
• Subject selection
• Statistical plan
• Ensure the protection of human rights and welfare
  through study design

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IRB Review Focus

• Protection of rights and welfare of human
  subjects
• Risk/ benefit analysis
• Adverse event reporting plan
• Human subject selection/vulnerable population
• Privacy and confidentiality
• Informed consent process
• Monitoring and data safety management
• Subjects participation with payments
• Continuing reviews
• Consistency across study
• Conflict of interest

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Top Ten Problems which IRB Finds in your
Application

• Inconsistency-numbers, Inclusion/exclusion,
  funding, study procedures
• Shared responsibility- documents, application not
  read by dept chair
• Writing and language- copying and pasting from
  grants or other templates
• Too much or too less info-differentiate b/w SOC
  and research,
• Poorly written consent forms- not using templates
• Risk/benefit
• Compensation for t/m of adverse events
• Conflict of interest
• Research team
• Continuing reviews

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Overview of a research process
MORE studies
Dissemination of results
Data Analysis Final reports
Implementation
Data Collection
Safety monitoring
Informed consent
Recruitment n Enrollment
Approval
Ethical and COI review
Planning
IRB/COI
Scientific Review
Officials and dept
Protocol Development
Research Question
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Finally! points to remember

• Writing a protocol is a team effort
• Takes time and would lead to many drafts
  initially
• Involve your mentor, statistician, medical
  writer, data analyst from the start
• Review all relevant literature critically
• Expect multiple reviews from OCR, sponsors, and
  IRB
• Your draft version and date are very important,
  use footer with short title and date
• If any amendments to the IC or protocol, change
  to either requires IRB review and approval
• Follow templates posted on the websites

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Few points to consider

• Do you still need IRB review?
• If you are using existing data
• If you are collecting biological specimens for
  research through a non invasive procedures
• If you are writing for publication
• If your research involves greater than minimal
  risk, what kind of IRB review is required?
• Is there any study population that needs special
  consideration when planning the recruitment of
  human subjects?

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Few More Points to Consider

• What reports are you expected to submit to the
  IRB once your study is approved?
• Any unanticipated problem needs reporting to the
  IRB chair and sponsor
• Immediate reporting using AE reporting form in
  case of AE
• Annual progress report/continuing reviews
• Final report after the study is complete
• Major deviation from the protocol

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USF Regulatory/ Ethics/COI
Research support Sadaf Aslam-813-250-2205 Scientif
ic Review Committee under CTSI Benjamin
Djulbegovic-813-974-9178 Sadaf Aslam-813-250-2205
USF Health Office of Clinical Research (OCR)
Catherine Jahrsdorfer-813-396-9172 TGH OCR
Jennifer Cooper 813-844-4236 Conflict Of
Interest Camille McWhirter- 813-974-6676
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Finding Funding sources
USF Office of Research DSR- USF Internal
Grants http//www.research.usf.edu/sr/internal_aw
ards/summaries.htm USF Health Office of Clinical
Research NIH, NSF, non profit organizations http
//www.grants.gov/ National Science Foundation
http//www.nsf.gov/funding/ Congressionally
Directed Medical Research Program
http//cdmrp.army.mil/ Centers for Disease
Control http//www.cdc.gov/od/pgo/funding/grants/f
oamain.shtm Department of Defense DoD information
and links
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• Education and Training
• COM courses on Clinical Research Methods
• GMS-6875-Ethical and Regulatory aspect of
  clinical research
• Online certificate course on Clinical Research
  Methods
• COPH -Clinical Research related course
• PHC 6017-Design and conduct of clinical trials
• IRB offers several training courses for new
  investigators
• Health Sciences Shimberg library
• http//library.hsc.usf.edu/
• Look for monthly COM events

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But why think, why not try the
experiment? John Hunter, 1775