1. Why Do Clinical Research? Satisfaction of answering important questions which will improve the health of our patientsSatisfaction of answering important questions which will improve the health of our patients Status of researchersStatus of researchers Skill advancementSkill advancement Professional advancementProfessional advancement Salary and Job SecuritySalary and Job Security

2. What is Research? Research is the endeavor to discover new facts, procedures, methods, and techniques by the scientific study of a course of critical investigationResearch is the endeavor to discover new facts, procedures, methods, and techniques by the scientific study of a course of critical investigation

3. Clinical Research Clinical research involves working with human subjects to answer questions relevant to their well- beingClinical research involves working with human subjects to answer questions relevant to their well- being Patient oriented research is where the ‘rubber meets the road’!Patient oriented research is where the ‘rubber meets the road’!

4. ‘How To Do’ Research Start with defining the questionStart with defining the question Write down a clear aimWrite down a clear aim Divide the problem into smaller, answerable questionsDivide the problem into smaller, answerable questions

5. ‘How To Do’ Research Develop hypothesesDevelop hypotheses Decide what data is needed to test the hypothesesDecide what data is needed to test the hypotheses Refine the above and check the line of thoughtRefine the above and check the line of thought

6. Good Research CLEARCLEAR –Essential for both the problem and the answer ACCURATEACCURATE –Exactness and precision come from hard work and responsible effort RELIABLERELIABLE –If repeated will the answer be the same?

7. Good Research OBJECTIVEOBJECTIVE –The researcher exposes all possible prejudices at the onset of the study design and strives to overcome them –Will the research be untarnished by personal gain, biases, vested interests, etc?

8. Researcher Qualities KnowledgeableKnowledgeable ObservantObservant LogicalLogical Open-mindedOpen-minded HonestHonest MotivatedMotivated IndependentIndependent FlexibleFlexible CarefulCareful

9. Researcher Qualities CuriousCurious InquisitiveInquisitive Eager to learnEager to learn SkepticalSkeptical PerceptivePerceptive PersistentPersistent PatientPatient OriginalOriginal CreativeCreative

10. Getting 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

11. Getting Started Formulate the problem as a research questionFormulate the problem as a research question Reduce the question to a single unambiguous question that is well- defined and answerableReduce the question to a single unambiguous question that is well- defined and answerable

12. Stages in Creativity SENSESENSE –Realize the need for a study PREPAREPREPARE –Gather relevant information INCUBATEINCUBATE –Think through the problem ILLUMINATEILLUMINATE –Imagine possible solutions VERIFYVERIFY –Evaluate the solutions you have generated

13. Hypothesis Thesis is the position that you believe represents truthThesis is the position that you believe represents truth Hypothesis is the foundation on top of which you build your thesisHypothesis is the foundation on top of which you build your thesis

14. Hypothesis Hypothesis is a tentative construct to be proved or disproved according to the evidenceHypothesis is a tentative construct to be proved or disproved according to the evidence The hypothesis is sometimes expressed as a null hypothesisThe hypothesis is sometimes expressed as a null hypothesis

15. A Good Hypothesis Should: Be testableBe testable Convey the nature of the relationship being testedConvey the nature of the relationship being tested State exactly what variables form this relationshipState exactly what variables form this relationship Reflect all variables of interestReflect all variables of interest Be formulated early on in the planning stageBe formulated early on in the planning stage

16. Study Types Will you test a hypothesis or describe a phenomenon?Will you test a hypothesis or describe a phenomenon? ObservationalObservational –Longitudinal –Cross-sectional Randomized, double-blind, parallel group, placebo controlled trialRandomized, double-blind, parallel group, placebo controlled trial

17. Epidemiology vs RCT Epidemiology allows the study of the real world and the development of hypothesis regarding disease statesEpidemiology allows the study of the real world and the development of hypothesis regarding disease states Randomized, controlled trials allow the rigorous testing of hypothesis in a well characterized manner that is less real world in natureRandomized, controlled trials allow the rigorous testing of hypothesis in a well characterized manner that is less real world in nature

18. Study Design Study PopulationStudy Population –Age –Gender –Ethnicity/Race –Disease characteristics –Exclusions –Number –Stratification –Randomization

19. Human Subjects The safety and rights of human subjects must be protectedThe safety and rights of human subjects must be protected –Study Design –Institutional Review Board –Informed consent –Data Safety Monitoring/Medical Monitors

20. Key Questions What is the main purpose of the trial?What is the main purpose of the trial? What treatments will be used and how?What treatments will be used 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 monitored?How will patient safety be monitored?

21. Key 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? –What do the participants have to do? –Will there be any discomfort even if there is no risk?

22. Methods Define methods carefullyDefine methods carefully Decrease variabilityDecrease variability Check reliability/reproducibilityCheck reliability/reproducibility Are you testing what you think you are testing?Are you testing what you think you are testing?

23. Methods Try to ‘walk through’ the study and consider as many likely scenarios as possible.Try to ‘walk through’ the study and consider as many likely scenarios as possible. Try to design in any variations in treatment or data collection that you think will occur before the study startsTry to design in any variations in treatment or data collection that you think will occur before the study starts

24. Operationalize Concepts Specify how you will repeatably and reliably measure the variables you are using to answer the questionSpecify how you will repeatably and reliably measure the variables you are using to answer the question An operational definition specifies how your concepts will be observed and measuredAn operational definition specifies how your concepts will be observed and measured This should allow your research to be reproducedThis should allow your research to be reproduced

25. Data Data are the facts you measureData are the facts you measure They should be carefully recorded in an unbiased mannerThey should be carefully recorded in an unbiased manner They should be measured in a manner that minimizes random variationThey should be measured in a manner that minimizes random variation They should be derived from the operational definitions you have developedThey should be derived from the operational definitions you have developed

26. Data Validation Do the data make sense?Do the data make sense? Look critically at the dataLook critically at the data –Highest and lowest values –Data entry errors –Distribution: Normal or skewed Check selected data entries with original data formsCheck selected data entries with original data forms

27. Data Interpretation Do not interpret/analyze data until after study is completedDo not interpret/analyze data until after study is completed Do not ‘unblind’ subjects until the study is completed other than for safety reasonsDo not ‘unblind’ subjects until the study is completed other than for safety reasons Do not interpret/analyze data until after data has been validated and the data set closedDo not interpret/analyze data until after data has been validated and the data set closed

28. Data Interpretation Use the research question and hypotheses to guide analysesUse the research question and hypotheses to guide analyses Use a priori definitions for any sub- set analysesUse a priori definitions for any sub- set analyses Exploration of epidemiologic data sets is OK, but need to avoid data miningExploration of epidemiologic data sets is OK, but need to avoid data mining

29. Writing It Up If you don’t write it, then it didn’t happenIf you don’t write it, then it didn’t happen Order of writing:Order of writing: –Methods –Results –Introduction –Discussion –Abstract –Title

30. Writing It Up After the first draft, new analyses will usually be suggested by the process of putting your ideas down on paperAfter the first draft, new analyses will usually be suggested by the process of putting your ideas down on paper Put the paper away for a few weeks and then read it againPut the paper away for a few weeks and then read it again Ask mentors and colleagues to read the paper at the first draft stageAsk mentors and colleagues to read the paper at the first draft stage

31. Sending It In When writing the paper, have the journal you will submit to in mindWhen writing the paper, have the journal you will submit to in mind Pick journals that will match your paper’s topic and the quality and importance of your workPick journals that will match your paper’s topic and the quality and importance of your work Aim high and, if needed, go lowAim high and, if needed, go low Persist, Persist, PersistPersist, Persist, Persist

32. Clinical Research Drug Development

33. Preclinical/Laboratory StudyPreclinical/Laboratory Study –Cell culture in animal and human cells –Animal studies –Looking both at toxicity/carcinogenicity as well as effect, if relevant Develop Investigational New Drug application with FDA (IND)Develop Investigational New Drug application with FDA (IND)

34. Phase I Studies Assess drug safety and tolerabilityAssess drug safety and tolerability Healthy volunteers, then those with target diseaseHealthy volunteers, then those with target disease PharmacokineticsPharmacokinetics –Absorption –Metabolism –Excretion Dose escalationDose escalation 70% of new drugs pass this phase70% of new drugs pass this phase

35. Phase II Studies Assess drug efficacyAssess drug efficacy Usually randomized, controlled trials with smaller numbers up to several hundred subjectsUsually randomized, controlled trials with smaller numbers up to several hundred subjects Test different therapeutic strategiesTest different therapeutic strategies Use surrogate variables and are usually short termUse surrogate variables and are usually short term Only 1/3 get past phase IIOnly 1/3 get past phase II

36. Phase III Studies Large scale RCT to assess efficacy and safety of medicationLarge scale RCT to assess efficacy and safety of medication Several hundred to thousands of patients enrolledSeveral hundred to thousands of patients enrolled Classic randomized, placebo-controlled designClassic randomized, placebo-controlled design Long-term study design with real world outcome variablesLong-term study design with real world outcome variables Define package insert content and allow marketingDefine package insert content and allow marketing

37. Study Size and Adverse Events The size of the treatment group determines the likely frequency of adverse events (side effects) that can be detectedThe size of the treatment group determines the likely frequency of adverse events (side effects) that can be detected A good rule of thumb is that you can detect an adverse event rate that is one event in the number of subjects divided by three:A good rule of thumb is that you can detect an adverse event rate that is one event in the number of subjects divided by three: –A study with 100 patients will only detect AE’s that occur at a rate of 1/33 = 3%

38. Phase IV Studies Compare drugs with other drugs on the marketCompare drugs with other drugs on the market Define broader target populationDefine broader target population Monitor long-term efficacy and safetyMonitor long-term efficacy and safety Conduct health economics assessment and quality of life studyConduct health economics assessment and quality of life study

39. Reading Clinical Research How to Approach RCT Reports

40. Reading Clinical Trials ‘All that glitters is not gold’ by Bengt and Curt Furberg‘All that glitters is not gold’ by Bengt and Curt Furberg Just because a study is published in a journal does not mean that it represents truthJust because a study is published in a journal does not mean that it represents truth ‘Throwaways’ and Drug company sponsored newsletters have either no or limited peer review‘Throwaways’ and Drug company sponsored newsletters have either no or limited peer review

41. Was the question stated A Priori? Exploring data is acceptable to define hypotheses, but cannot definitively answer themExploring data is acceptable to define hypotheses, but cannot definitively answer them Primary outcomes and limited secondary outcomes should be carefully defined before study commencesPrimary outcomes and limited secondary outcomes should be carefully defined before study commences

42. Was the question stated A Priori? Multiple hypothesis testing can lead to false associationMultiple hypothesis testing can lead to false association P <0.05 is subverted if there are 20 looks at the dataP <0.05 is subverted if there are 20 looks at the data

43. Is the question relevant? Does the answer clarify whether the treatment will help patients to:Does the answer clarify whether the treatment will help patients to: –Feel better –Live longer –Have less complications of illness Are the endpoints real world or merely surrogatesAre the endpoints real world or merely surrogates How can one generalize the findings?How can one generalize the findings?

44. How is improvement quantified? Are the outcomes relevant?Are the outcomes relevant? Do the measures used make sense?Do the measures used make sense? Is the magnitude of the difference relevant to patient care?Is the magnitude of the difference relevant to patient care? Is the study ‘over-powered’?Is the study ‘over-powered’?

45. Are the outcomes relevant? Quality of lifeQuality of life MortalityMortality Health economicsHealth economics Surrogate markers of clinical outcomeSurrogate markers of clinical outcome Surrogate biologic markersSurrogate biologic markers

46. How are adverse events measured? Side effects are characterized as:Side effects are characterized as: –Severe: Treatment must be stopped, or patient hospitalized, or dies, or develops cancer, or has congenital anomaly in child –Moderate: Dosage must be reduced, usually leads to discomfort, temporary disability, or reduction in functioning –Mild: No change in treatment. Limited discomfort or dysfunction

47. How are adverse events measured? AE’s are characterized as to whether or not they are related to the medication:AE’s are characterized as to whether or not they are related to the medication: –Definitely –Likely –Probably –Possibly –Not associated

48. Are the patients representative? This is most problematic in pediatrics where we often have to extrapolate from adult studiesThis is most problematic in pediatrics where we often have to extrapolate from adult studies Gender, age, and race can all alter outcomesGender, age, and race can all alter outcomes Disease classification and severity can alter outcomesDisease classification and severity can alter outcomes High risk patients are usually excludedHigh risk patients are usually excluded

49. Where the groups initially comparable? Even in studies of 150-200 subjects substantive imbalance can occur between treatment groupsEven in studies of 150-200 subjects substantive imbalance can occur between treatment groups Was stratification used to ensure balance?Was stratification used to ensure balance? Did the treatment group start out sicker so that they likely would improve more than the placebo group?Did the treatment group start out sicker so that they likely would improve more than the placebo group?

50. Excluded Subjects? Intent to treat analyses should be reportedIntent to treat analyses should be reported Two unacceptable reasons to exclude subjects are:Two unacceptable reasons to exclude subjects are: –After randomization where they do not meet entry criteria –Because they did not take the medication

51. Do you need a statistician to read the study? In clinical trials, design should allow relatively straightforward presentation of resultsIn clinical trials, design should allow relatively straightforward presentation of results Effect size and relevance are more important than P valuesEffect size and relevance are more important than P values

52. Do you need a statistician to read the study? Consider the number of patients who would have to be treated to avoid the outcome being preventedConsider the number of patients who would have to be treated to avoid the outcome being prevented Subgroup analyses should be avoided unless defined a prioriSubgroup analyses should be avoided unless defined a priori

53. Economic Analysis “Of course our drug is more expensive, but we need to convince clinicians to use it more”“Of course our drug is more expensive, but we need to convince clinicians to use it more” Does the medication reduce direct or indirect costs or both?Does the medication reduce direct or indirect costs or both?

54. Economic Analysis Be sensitive to relationship between the authors and the sponsorBe sensitive to relationship between the authors and the sponsor Be careful if soft assumptions are usedBe careful if soft assumptions are used Beware of analyses based on the clinical trial setting and not the real worldBeware of analyses based on the clinical trial setting and not the real world Beware indirect evidence with surrogate markersBeware indirect evidence with surrogate markers