Why Do Clinical Why Do Clinical Research?Research?

• Satisfaction of answering Satisfaction of answering important questions which will important questions which will improve the health of our improve the health of our patientspatients

• Status of researchersStatus of researchers

• Skill advancementSkill advancement

• Professional advancementProfessional advancement

• Salary and Job SecuritySalary and Job Security

What is Research?What is Research?

• Research is the endeavor to Research is the endeavor to discover new facts, discover new facts, procedures, methods, and procedures, methods, and techniques by the scientific techniques by the scientific study of a course of critical study of a course of critical investigationinvestigation

Clinical ResearchClinical Research

• Clinical research involves Clinical research involves working with human subjects working with human subjects to answer questions relevant to answer questions relevant to their well-beingto their well-being

• Patient oriented research is Patient oriented research is where the ‘rubber meets the where the ‘rubber meets the road’!road’!

‘‘How To Do’ ResearchHow To Do’ Research

• Start with defining the Start with defining the questionquestion

• Write down a clear aimWrite down a clear aim

• Divide the problem into Divide the problem into smaller, answerable questionssmaller, answerable questions

‘‘How To Do’ ResearchHow To Do’ Research

• Develop hypothesesDevelop hypotheses

• Decide what data is needed to Decide what data is needed to test the hypothesestest the hypotheses

• Refine the above and check the Refine the above and check the line of thoughtline of thought

Good ResearchGood Research• CLEARCLEAR

– Essential for both the problem and Essential for both the problem and the answerthe answer

• ACCURATEACCURATE

– Exactness and precision come Exactness and precision come from hard work and responsible from hard work and responsible efforteffort

• RELIABLERELIABLE

– If repeated will the answer be the If repeated will the answer be the same?same?

Good ResearchGood Research

• OBJECTIVEOBJECTIVE

– The researcher exposes all The researcher exposes all possible prejudices at the onset possible prejudices at the onset of the study design and strives to of the study design and strives to overcome themovercome them

– Will the research be untarnished Will the research be untarnished by personal gain, biases, vested by personal gain, biases, vested interests, etc?interests, etc?

Researcher QualitiesResearcher Qualities

• KnowledgeableKnowledgeable

• ObservantObservant

• LogicalLogical

• Open-mindedOpen-minded

• HonestHonest

• MotivatedMotivated

• IndependentIndependent

• FlexibleFlexible

• CarefulCareful

Researcher QualitiesResearcher Qualities

• CuriousCurious

• InquisitiveInquisitive

• Eager to learnEager to learn

• SkepticalSkeptical

• PerceptivePerceptive

• PersistentPersistent

• PatientPatient

• OriginalOriginal

• CreativeCreative

Getting StartedGetting Started

• Learn your subjectLearn your subject

• Read, Read, ReadRead, Read, Read

• Start general and then focusStart general and then focus

• Begin with the problemBegin with the problem

Getting StartedGetting Started

• Formulate the problem as a Formulate the problem as a research questionresearch question

• Reduce the question to a Reduce the question to a single unambiguous question single unambiguous question that is well-defined and that is well-defined and answerableanswerable

Stages in CreativityStages in Creativity• SENSESENSE

– Realize the need for a studyRealize the need for a study

• PREPAREPREPARE– Gather relevant informationGather relevant information

• INCUBATEINCUBATE– Think through the problemThink through the problem

• ILLUMINATEILLUMINATE– Imagine possible solutionsImagine possible solutions

• VERIFYVERIFY– Evaluate the solutions you have generatedEvaluate the solutions you have generated

HypothesisHypothesis

• Thesis is the position that you Thesis is the position that you believe represents truthbelieve represents truth

• Hypothesis is the foundation Hypothesis is the foundation on top of which you build your on top of which you build your thesisthesis

HypothesisHypothesis

• Hypothesis is a tentative Hypothesis is a tentative construct to be proved or construct to be proved or disproved according to the disproved according to the evidenceevidence

• The hypothesis is sometimes The hypothesis is sometimes expressed as a null hypothesisexpressed as a null hypothesis

A Good Hypothesis A Good Hypothesis Should:Should:

• Be testableBe testable

• Convey the nature of the Convey the nature of the relationship being testedrelationship being tested

• State exactly what variables State exactly what variables form this relationshipform this relationship

• Reflect all variables of interestReflect all variables of interest

• Be formulated early on in the Be formulated early on in the planning stageplanning stage

Study TypesStudy Types

• Will you test a hypothesis or Will you test a hypothesis or describe a phenomenon?describe a phenomenon?

• Observational Observational

– LongitudinalLongitudinal

– Cross-sectionalCross-sectional

• Randomized, double-blind, Randomized, double-blind, parallel group, placebo parallel group, placebo controlled trialcontrolled trial

Epidemiology Epidemiology vsvs RCT RCT• Epidemiology allows the study Epidemiology allows the study

of the real world and the of the real world and the development of hypothesis development of hypothesis regarding disease statesregarding disease states

• Randomized, controlled trials Randomized, controlled trials allow the rigorous testing of allow the rigorous testing of hypothesis in a well hypothesis in a well characterized manner that is characterized manner that is less real world in natureless real world in nature

Study DesignStudy Design• Study PopulationStudy Population

– AgeAge

– GenderGender

– Ethnicity/RaceEthnicity/Race

– Disease characteristicsDisease characteristics

– ExclusionsExclusions

– NumberNumber

– StratificationStratification

– RandomizationRandomization

Human SubjectsHuman Subjects

• The safety and rights of human The safety and rights of human subjects must be protectedsubjects must be protected

– Study DesignStudy Design

– Institutional Review BoardInstitutional Review Board

– Informed consentInformed consent

– Data Safety Monitoring/Medical Data Safety Monitoring/Medical MonitorsMonitors

Key QuestionsKey Questions• What is the main purpose of the What is the main purpose of the

trial?trial?

• What treatments will be used What treatments will be used and how? and how?

• What is the participant risk?What is the participant risk?

• What are the possible benefits?What are the possible benefits?

• How will patient safety be How will patient safety be monitored?monitored?

Key QuestionsKey Questions• Are there alternative treatments?Are there alternative treatments?

• Who is sponsoring the trial?Who is sponsoring the trial?

• What is the participant burden?What is the participant burden?

– How long and where?How long and where?

– What do the participants have to do?What do the participants have to do?

– Will there be any discomfort even if Will there be any discomfort even if there is no risk?there is no risk?

MethodsMethods

• Define methods carefullyDefine methods carefully

• Decrease variabilityDecrease variability

• Check Check reliability/reproducibilityreliability/reproducibility

• Are you testing what you think Are you testing what you think you are testing?you are testing?

MethodsMethods

• Try to ‘walk through’ the study Try to ‘walk through’ the study and consider as many likely and consider as many likely scenarios as possible.scenarios as possible.

• Try to design in any variations Try to design in any variations in treatment or data collection in treatment or data collection that you think will occur before that you think will occur before the study startsthe study starts

Operationalize Operationalize ConceptsConcepts

• Specify how you will Specify how you will repeatably and reliably repeatably and reliably measure the variables you are measure the variables you are using to answer the questionusing to answer the question

• An operational definition An operational definition specifies how your concepts specifies how your concepts will be observed and measuredwill be observed and measured

• This should allow your This should allow your research to be reproducedresearch to be reproduced

DataData• Data are the facts you measureData are the facts you measure• They should be carefully They should be carefully

recorded in an unbiased recorded in an unbiased mannermanner

• They should be measured in a They should be measured in a manner that minimizes random manner that minimizes random variationvariation

• They should be derived from They should be derived from the operational definitions you the operational definitions you have developedhave developed

Data ValidationData Validation

• Do the data make sense?Do the data make sense?

• Look critically at the dataLook critically at the data

– Highest and lowest valuesHighest and lowest values

– Data entry errorsData entry errors

– Distribution: Normal or skewedDistribution: Normal or skewed

• Check selected data entries Check selected data entries with original data formswith original data forms

Data InterpretationData Interpretation

• Do notDo not interpret/analyze data interpret/analyze data until after study is completeduntil after study is completed

• Do notDo not ‘unblind’ subjects until ‘unblind’ subjects until the study is completed other the study is completed other than for safety reasonsthan for safety reasons

• Do notDo not interpret/analyze data interpret/analyze data until after data has been until after data has been validated and the data set validated and the data set closedclosed

Data InterpretationData Interpretation

• Use the research question and Use the research question and hypotheses to guide analyseshypotheses to guide analyses

• Use a priori definitions for any Use a priori definitions for any sub-set analysessub-set analyses

• Exploration of epidemiologic Exploration of epidemiologic data sets is OK, but need to data sets is OK, but need to avoid data miningavoid data mining

Writing It UpWriting It Up• If you don’t write it, then it didn’t If you don’t write it, then it didn’t

happenhappen

• Order of writing:Order of writing:

– MethodsMethods

– ResultsResults

– IntroductionIntroduction

– DiscussionDiscussion

– AbstractAbstract

– TitleTitle

Writing It UpWriting It Up• After the first draft, new After the first draft, new

analyses will usually be analyses will usually be suggested by the process of suggested by the process of putting your ideas down on paperputting your ideas down on paper

• Put the paper away for a few Put the paper away for a few weeks and then read it againweeks and then read it again

• Ask mentors and colleagues to Ask mentors and colleagues to read the paper at the first draft read the paper at the first draft stagestage

Sending It InSending It In• When writing the paper, have the When writing the paper, have the

journal you will submit to in mindjournal you will submit to in mind

• Pick journals that will match your Pick journals that will match your paper’s topic and the quality and paper’s topic and the quality and importance of your workimportance of your work

• Aim high and, if needed, go lowAim high and, if needed, go low

• Persist, Persist, PersistPersist, Persist, Persist

Clinical ResearchClinical Research

Drug DevelopmentDrug Development

Drug DevelopmentDrug Development• Preclinical/Laboratory StudyPreclinical/Laboratory Study

– Cell culture in animal and human Cell culture in animal and human cellscells

– Animal studiesAnimal studies

– Looking both at Looking both at toxicity/carcinogenicity as well as toxicity/carcinogenicity as well as effect, if relevanteffect, if relevant

• Develop Investigational New Drug Develop Investigational New Drug application with FDA (IND)application with FDA (IND)

Phase I StudiesPhase I Studies• Assess drug safety and tolerabilityAssess drug safety and tolerability

• Healthy volunteers, then those with Healthy volunteers, then those with target diseasetarget disease

• PharmacokineticsPharmacokinetics

– AbsorptionAbsorption

– MetabolismMetabolism

– ExcretionExcretion

• Dose escalationDose escalation

• 70% of new drugs pass this phase70% of new drugs pass this phase

Phase II StudiesPhase II Studies• Assess drug efficacyAssess drug efficacy

• Usually randomized, controlled Usually randomized, controlled trials with smaller numbers up trials with smaller numbers up to several hundred subjectsto several hundred subjects

• Test different therapeutic Test different therapeutic strategiesstrategies

• Use surrogate variables and are Use surrogate variables and are usually short termusually short term

• Only 1/3 get past phase IIOnly 1/3 get past phase II

Phase III StudiesPhase III Studies• Large scale RCT to assess efficacy Large scale RCT to assess efficacy

and safety of medicationand safety of medication

• Several hundred to thousands of Several hundred to thousands of patients enrolledpatients enrolled

• Classic randomized, placebo-Classic randomized, placebo-controlled designcontrolled design

• Long-term study design with real Long-term study design with real world outcome variablesworld outcome variables

• Define package insert content and Define package insert content and allow marketingallow marketing

Study Size and Adverse Study Size and Adverse EventsEvents

• The size of the treatment group The size of the treatment group determines the likely frequency of determines the likely frequency of adverse events (side effects) that adverse events (side effects) that can be detectedcan be detected

• A good rule of thumb is that you A good rule of thumb is that you can detect an adverse event rate can detect an adverse event rate that is one event in the number of that is one event in the number of subjects divided by three:subjects divided by three:

– A study with 100 patients will only A study with 100 patients will only detect AE’s that occur at a rate of 1/33 detect AE’s that occur at a rate of 1/33 = 3%= 3%

Phase IV StudiesPhase IV Studies

• Compare drugs with other Compare drugs with other drugs on the marketdrugs on the market

• Define broader target Define broader target populationpopulation

• Monitor long-term efficacy and Monitor long-term efficacy and safetysafety

• Conduct health economics Conduct health economics assessment and quality of life assessment and quality of life studystudy

Reading Clinical Reading Clinical ResearchResearch

How to Approach RCT How to Approach RCT ReportsReports

Reading Clinical TrialsReading Clinical Trials

• ‘‘All that glitters is not gold’All that glitters is not gold’ by by Bengt and Curt FurbergBengt and Curt Furberg

• Just because a study is Just because a study is published in a journal does not published in a journal does not mean that it represents truthmean that it represents truth

• ‘‘Throwaways’ and Drug Throwaways’ and Drug company sponsored company sponsored newsletters have either no or newsletters have either no or limited peer reviewlimited peer review

Was the question stated Was the question stated A A Priori?Priori?

• Exploring data is acceptable to Exploring data is acceptable to define hypotheses, but cannot define hypotheses, but cannot definitively answer themdefinitively answer them

• Primary outcomes and limited Primary outcomes and limited secondary outcomes should be secondary outcomes should be carefully defined before study carefully defined before study commencescommences

Was the question stated Was the question stated A A Priori?Priori?

• Multiple hypothesis testing can Multiple hypothesis testing can lead to false associationlead to false association

• P <0.05 is subverted if there P <0.05 is subverted if there are 20 looks at the dataare 20 looks at the data

Is the question Is the question relevant?relevant?

• Does the answer clarify Does the answer clarify whether the treatment will help whether the treatment will help patients to:patients to:– Feel betterFeel better– Live longerLive longer– Have less complications of illnessHave less complications of illness

• Are the endpoints real world or Are the endpoints real world or merely surrogatesmerely surrogates

• How can one generalize the How can one generalize the findings?findings?

How is improvement How is improvement quantified?quantified?

• Are the outcomes relevant?Are the outcomes relevant?

• Do the measures used make Do the measures used make sense?sense?

• Is the magnitude of the Is the magnitude of the difference relevant to patient difference relevant to patient care?care?

• Is the study ‘over-powered’?Is the study ‘over-powered’?

Are the outcomes Are the outcomes relevant?relevant?

• Quality of lifeQuality of life

• MortalityMortality

• Health economicsHealth economics

• Surrogate markers of clinical Surrogate markers of clinical outcomeoutcome

• Surrogate biologic markersSurrogate biologic markers

How are adverse events How are adverse events measured?measured?

• Side effects are characterized as:Side effects are characterized as:

– SevereSevere: Treatment must be : Treatment must be stopped, or patient hospitalized, or stopped, or patient hospitalized, or dies, or develops cancer, or has dies, or develops cancer, or has congenital anomaly in childcongenital anomaly in child

– ModerateModerate: Dosage must be reduced, : Dosage must be reduced, usually leads to discomfort, usually leads to discomfort, temporary disability, or reduction in temporary disability, or reduction in functioningfunctioning

– MildMild: No change in treatment. : No change in treatment. Limited discomfort or dysfunctionLimited discomfort or dysfunction

How are adverse events How are adverse events measured?measured?

• AE’s are characterized as to AE’s are characterized as to whether or not they are whether or not they are related to the medication:related to the medication:

– DefinitelyDefinitely

– LikelyLikely

– ProbablyProbably

– PossiblyPossibly

– Not associatedNot associated

Are the patients Are the patients representative?representative?

• This is most problematic in This is most problematic in pediatrics where we often pediatrics where we often have to extrapolate from adult have to extrapolate from adult studiesstudies

• Gender, age, and race can all Gender, age, and race can all alter outcomesalter outcomes

• Disease classification and Disease classification and severity can alter outcomesseverity can alter outcomes

• High risk patients are usually High risk patients are usually excludedexcluded

Where the groups initially Where the groups initially comparable?comparable?

• Even in studies of 150-200 Even in studies of 150-200 subjects substantive imbalance subjects substantive imbalance can occur between treatment can occur between treatment groupsgroups

• Was stratification used to ensure Was stratification used to ensure balance?balance?

• Did the treatment group start out Did the treatment group start out sicker so that they likely would sicker so that they likely would improve more than the placebo improve more than the placebo group?group?

Excluded Subjects?Excluded Subjects?

• Intent to treat analyses should Intent to treat analyses should be reportedbe reported

• Two unacceptable reasons to Two unacceptable reasons to exclude subjects are:exclude subjects are:

– After randomization where they After randomization where they do not meet entry criteriado not meet entry criteria

– Because they did not take the Because they did not take the medicationmedication

Do you need a statistician to read the Do you need a statistician to read the study?study?

• In clinical trials, design should In clinical trials, design should allow relatively allow relatively straightforward presentation straightforward presentation of resultsof results

• Effect size and relevance are Effect size and relevance are more important than P valuesmore important than P values

Do you need a statistician to read the Do you need a statistician to read the study?study?

• Consider the number of Consider the number of patients who would have to be patients who would have to be treated to avoid the outcome treated to avoid the outcome being preventedbeing prevented

• Subgroup analyses should be Subgroup analyses should be avoided unless defined a prioriavoided unless defined a priori

Economic AnalysisEconomic Analysis

• ““Of course our drug is more Of course our drug is more expensive, but we need to expensive, but we need to convince clinicians to use it convince clinicians to use it more”more”

• Does the medication reduce Does the medication reduce direct or indirect costs or direct or indirect costs or both?both?

Economic AnalysisEconomic Analysis• Be sensitive to relationship Be sensitive to relationship

between the authors and the between the authors and the sponsorsponsor

• Be careful if soft assumptions Be careful if soft assumptions are usedare used

• Beware of analyses based on Beware of analyses based on the clinical trial setting and the clinical trial setting and not the real worldnot the real world

• Beware indirect evidence with Beware indirect evidence with surrogate markerssurrogate markers