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Designing Clinical Research Anita S. Kablinger, M.D. Associate Professor Departments of Psychiatry and Psychopharmacology.

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Presentation on theme: "Designing Clinical Research Anita S. Kablinger, M.D. Associate Professor Departments of Psychiatry and Psychopharmacology."— Presentation transcript:

1 Designing Clinical Research Anita S. Kablinger, M.D. Associate Professor Departments of Psychiatry and Psychopharmacology

2 Chapter 2: Conceiving the Research Question Research question : Addresses uncertainty Resolved by measurements

3 Successful Research Questions Require: scholarship, experience, mentor Mastering the Literature - Published literature -Attend meetings -Relationships with professionals Knowledge of New Ideas and Techniques Imagination

4 FINER Research Questions Feasible Number of subjects, technical expertise, affordable in time and money, manageable Interesting to the investigator Novel Confirms/ refutes/ extends previous findings, provides new findings Ethical No unacceptable physical risks or invasion of privacy Relevant Scientific knowledge, clinical and health policy, future research

5 Early Stage Outline Researcher clarifies plan Researcher discovers specific problems -Is research question finer ? Allows colleagues’ reactions

6 Chapter 3: Choosing the Study Subjects Study sample must be affordable in time and money Study sample must represent the target population

7 Inclusion Criteria Includes main characteristics of target population What factors are important to the research question? How should these factors be defined? Include demographic, clinical, geographic, and temporal characteristics

8 Exclusion Criteria Characteristics that may interfere with the data or randomization of the study Excessive exclusion may degeneralize the study

9 Clinical vs. Community Populations Clinical are often already hospitalized so study subjects are inexpensive, available, and easy to recruit BUT Their condition may be severe or extraordinary, so the data may be distorted and not representative of the population

10 Convenience Samples Subjects meet entry criteria Subjects are accessible Samples often selected consecutively Minimizes voluntarism –Volunteers are often healthier than the general population, so data may be distorted

11 Probability Samples Guarantee that every member in the population has a specific chance of selection for the study Types: -Simple random -Stratified random -Cluster -Systematic

12 2 Goals in Recruiting Study Subjects Representative Response rate affects validity of study Non-response subjects are often different than those that respond –Disease may be the cause of non-response Size Monitor recruitment progress Note when/ why potential subjects are lost

13 Chapter 7 Designing an Observational Study: Cohort Studies Cohort studies take place over time Descriptive vs. Analytic Prospective vs. Retrospective

14 Prospective Cohort Studies Strengths –Measures predictor before outcome occurs (Less bias, more accurate) Weaknesses –Expensive and inefficient for studying rare outcomes –Conditions present with symptoms before diagnosis

15 Retrospective Cohort Studies Strengths –Measures predictor before outcome occurs (Less bias, more accurate) –Less costly and time-consuming than perspective studies Weaknesses –Investigator has limited control over sampling design or data collection

16 Nested Case-Control Study Used for predictor variables that are expensive to measure and can be assessed at end of study Subjects from completed cohort study -Cases: Part of cohort that developed outcome -Controls: Part of cohort without outcome *M atching is optional but an unmatched design is preferable

17 Nested Case-Cohort Studies Random sample selected from original cohort regardless of outcomes Advantages: -Same control group for different studies -Information on risk factor prevalence

18 Nested Studies Strengths –Costly measurements are available –Variables are collected before outcome –Reduces bias from fatal cases and use of various populations Weaknesses –Observed association from confounded variable –Silent preclinical disease

19 Multiple Cohort Studies 2 different subject samples based on level of predictor variable May compare cohort study outcomes with census data Strengths –Feasible approach for studying rare exposure or potential hazards Weaknesses –Cohorts may differ –Data may be imprecise, incomplete, nonexistent

20 **Following the Entire Cohort Exclude those planning to move/ difficult to reach Obtain information for difficult follow up -Physician, close friends, SSN, Medicare # Periodic contact and repeated follow-up efforts

21 Chapter 8: Designing an Observational Study: Cross-sectional and Case-control Studies Cross-sectional Case-control Bias

22 Cross Sectional Study Simultaneous measurements No follow up Cause and effect inferred Predictor and outcome designated

23 Case Control Study One sample from cases (With outcome) One sample from controls (No outcome) Compares levels of predictor in cases vs. controls

24 Prevalence vs. Incidence Cross sectional studies provide prevalence (at given time) –Relative prevalence: Outcome prevalence by level of predictor Cohort studies provide incidence –Over period of time

25 Cross Sectional Studies Strengths -Fast and inexpensive -No loss from follow-up Weaknesses -Difficult to determine cause and effect

26 Serial Survey Series of cross sectional studies Inferences can be drawn but a single group is not followed over time May be used in cohort study to prevent learning effect on data

27 Case-Control Studies Used to compare risk factor prevalence –How often do predictor variables lead to disease? Cases (with disease) vs. controls (without) –Specified number of each, so incidence or prevalence of disease not determined Retrospective so may contain bias

28 Case-Control Studies Rare diseases Diseases with long latency Retrospective so can look at various predictor variables to determine cause of new outbreak

29 Case-Control Study Bias Control and case separate sampling -Sampling bias Retrospective predictor variable measurements -Differential measurement bias

30 Sampling Bias Not all affected are available for study - Undiagnosed, misdiagnosed, dead SOLUTIONS: 1.Hospital- or clinic-based controls 2.Matching 3.Population-based sample 4.Two+ control groups

31 Differential Measurement Bias Imperfect recall SOLUTIONS: 1.Data recorded before outcome 2.Blinding

32 Chapter 10 Designing an Experiment: Clinical Trials I Treatment applied Effect on outcome observed Causality demonstrated Mature research questions

33 Selecting Participants Entry criteria: Rate of outcome Treatment effectiveness Recruitable Follow up Generalizability Compliance Sample size and recruitment planning

34 Measuring Baseline Variables Fewer variables may be more efficient Spend time and money wisely Tracking information Participant description Measure risk factor and subgroup defining variables Material banks Initial outcome variable

35 Randomizing random assignment to interventions Treatment assignment must be random Blocked Stratified blocked –Guarantees even distribution of strong predictor in small sample

36 Applying Intervention Blinding -Co-intervention effects -Biased outcome assessment Choosing the intervention -Effectiveness, safety, blindness, generalizability, combinations Choosing the control -The control treatment should mimic the active treatment -Ethical co-intervention -Equivalence trials

37 Chapter 11 Designing an Experiment: Clinical Trials II Maximize follow up and adherence Measuring outcome Analyzing results Monitoring clinical trials Vulnerable populations Research misconduct

38 Maximize Follow up and Adherence Tolerable drug Daily dosage Pill counts and drug screening Easy, convenient, and interesting studies (“participant friendly”)

39 Clinical Trials Clinical relevance should be balanced with feasibility and cost Measurable variables: Outcome (Clinical) Risk of outcome (Surrogate)

40 Measuring Outcome Outcomes should be accurate and precise Continuous variables preferred over dichotomous Include outcome measures to detect adverse effects (See FDA website “Good Clinical Practices”)

41 Analyzing Results Dichotomous: chi squared Continuous: t test Intention to treat –Cross-overs covered, prevents bias, may underestimate results (results are conservative) –Preferred over per protocol Per protocol analyzes only evaluable –May differ from those that drop

42 Subgroup Analysis Comparing randomized subjects of trials Randomization measurements should be determined before treatment Post randomization factors should not be considered Subgroup size is problematic –May be too small to detect differences Different findings among subgroups

43 Monitoring Clinical Trials Prevent harmful intervention –Risks are greater than benefits Provide beneficial intervention Discontinue intervention when research question becomes unanswerable Before study begins, create guidelines and procedures for monitoring Monitor recruitment, adherence, randomization, blinding, follow up, outcome, adverse effects, potential confounders Who will monitor and how often Statistical monitoring methods

44 Committee Monitoring Intervention and continuation decisions should balance ethical responsibility with advancement of medical knowledge Committee should be composed of physicians, participant advocates, biostatisticians, and clinical trial experts with no connection to study

45 Options to Randomized Blinded Trials Factorial Design Randomization of Matched Pairs Group or Cluster Randomization

46 Factorial Design Answers two separate research questions Efficient and cost effective Interaction b/t treatments and outcomes Useful for studying two unrelated questions

47 Randomization of Matched Pairs Subject pairs with matching factors (ex. age, sex) Contrast treatment and control in two parts of the same individual at same time (ex. one eye is treated, other serves as control)

48 Group or Cluster Randomization Assigning by group (ex. family, sports team) Answers questions about public health programs More feasible and cost effective than individual assignments Complicated analysis

49 Within Group Designs May be used in time-series studies Time series studies: Participants are their own control for evaluating treatment effects –Disadvantage: Lack of concurrent control group –Efficacy is optimistic b/c learning effects, regression to the mean, secular trends –Repeatedly starting and stopping therapy to establish treatment effects

50 Cross-over Design Each person is their own control so requires fewer participants Due to carry over effects: Study duration doubled Complex analysis and interpretation –Carry over effects: Influence of intervention outcome after treatment has stopped –Use washout period to diminish carry over effect Use when limited number of subjects and unproblematic carry over effects

51 FDA Approval “Good Clinical Practices” on FDA website Preclinical involves animals Phase I: Unblended and uncontrolled with small number of human volunteers Phase II: Small random blind trials of diff doses Phase III: Large trials to test hypothesis Phase IV: Large studies after drug approval

52 Study Implementation Anita S. Kablinger MD Associate Professor Departments of Psychiatry and Pharmacology

53 Outline of Presentation Addressing Ethical Issues Designing Questionnaires and Data Collection Instruments Data Management Implementing the Study Community and International Studies Writing and Funding a Research Proposal

54 Chapter 14: Addressing Ethical Issues Ethical Principles IRB Informed Consent Scientific Misconduct Conflict of Interest Authorship Confidentiality

55 Ethical Principles Respect for persons- Informed consent, confidentiality Beneficence- Sound research design, risks are acceptable in comparison to benefits Justice- Vulnerable populations should not be targeted, equitable access to the benefits of research

56 Federal Regulations Ensure Protection of Subjects (OHRP) Institutional Review Board Approval Minimal risks Reasonable risks when compared to possible benefits Equitable participant selection Informed consent Confidentiality

57 IRB Lack research expertise –Research design, scientific merit, protocol adherence Investigator must uphold ethical research IRB reviews include: –Exemptions: surveys or observations, existing records, normal educational practices –Expedited: minimal risk, minor changes in approved research

58 Informed Consent Nature of research project Study procedures Risks, benefits, and alternatives Including medical, psychosocial, economic realms Confidentiality Voluntary participation assurance Comprehensible consent forms Subjects who lack decision-making capacity

59 Vulnerable Populations Avoid vulnerable populations unless problem under study is especially prevalent within that specific population Vulnerable populations should not be used unless necessary –These populations involve additional informed consent requirements –Children, prisoners, pregnant women, fetuses, and embryos, people with impaired decision- making capability

60 Research Misconduct Includes fabrication, falsification, plagiarism May lead to incorrect results Undermines public confidence and support Investigators should have access to all data, statistical analysis, and publishing rights –Sponsor should not veto or censor publication Conflicts of interest

61 Conflicts of Interest Blinded studies and peer review prevent bias in conflicts of interest Any conflicting interests should be disclosed and situations leading to conflicts of interest should be avoided Dual roles for clinician-investigator and financial conflict of interests may impair objectivity of study and undermine public trust

62 Dual Roles Physicians should always uphold patient welfare Data and safety monitoring boards that make study termination decisions should not include researchers Randomized blinded studies without controls should have equitable protocols for both groups in the study Principle of Nonmaleficence: Effective therapies should be provided to controls

63 Authorship Criteria for authorship to avoid questionable contribution and responsibility –Substantial contributions –Drafting or revising the article –Give final approval of article Honorary and ghost authorships

64 Chapter 15: Designing Questionnaires and Data Collection Instruments Questionnaires Interviews

65 Questionnaire Format Questionnaires should include purpose of study and how data will be used Instructions on answering should be provided –Include instructions throughout where format changes Wording: Clear, simple, neutralVisual analog scales Branching scales

66 Questionnaire Questions Questions should be mutually exclusive Avoid assumptions in questions Questions should cover one concept (avoid “and,” “or”) Include “other” or “none of the above” if questions are not exhaustive Group questions from same subject groups together and include heading

67 More Questions Use series of questions with scores to measure abstract concepts In questions with lists, use “yes” or “no” so each option requires a response Open-ended questions: Better for determining concept understanding but qualitative analysis is time consuming and subjective Close ended questions: More standardized, quicker and easier to analyze but may influence participants’ answers

68 Questionnaires: Additional Information Emotionally neutral questions at beginning, sensitive ones in middle, personal at end –Use introductions for questions about undesirable behavior Set the time frame and quantify responses –Determine if average or extremes in behavior is more important for study –Recent brief time frames increase recall but responses may not be typical –Longer time frames make recall difficult and bias toward recent behavior may result

69 Questionnaire Editing Check for internal consistency to guarantee acceptable summing or averaging of scores 1) Draft made from focus group interviews 2) Critical review of draft 3) Pretest new questions or questionnaires

70 Developing Instruments for Study List variables to be collected and measured in study Existing measures for each variable Best to not modify unless necessary –Changes prevent comparison to previous studies with same instrument Make draft Revise to simplify and clarify –Check for length and ambiguity –Shorten to exclude any unnecessary variables (Think ahead to data analysis and presentation) Pretest and validate –Face validity, gold standard, predictive validity

71 Questionnaires vs. Interviews Questionnaires: –Efficient for simple questions, less expensive and time consuming for research staff, standardized –Less likely to be completed by people of limited literacy or lower education so results may be biased Interviews: –Complicated questions, more costly and time-consuming, less uniform, answers may be influenced by interviewer or participant/ interviewer relationship –Should be as standardized as possible Wording, nonverbal signals, tone of voice, probing Both are subject to imperfect memory Both are affected by tendency to give socially acceptable answers

72 Chapter 16: Steps in Data Management Define each variable Set up the study database Test data management procedures before the study begins Enter the data-identify and correct errors Back up the dataset regularly Create a dataset for analysis Archive and store database and results

73 Chapter 17: Implementing the Study Pretesting (pilot studies) Less stimulating than design or analysis Either can lead to a change in protocol once study begins Quality control measures: train the team, certify the team, regular meetings, performance review

74 Chapter 18: Community Studies Research outside the academic setting designed to meet the needs of the community –Answers questions of local or regional importance –May be more generalizable –Can help local economy and self-sufficiency

75 Chapter 19: Writing and Funding a Research Proposal Protocol: Detailed written plan of study Proposal: Written document to receive funding –Contains the protocol, the budget and other administrative and supporting documentation

76 Proposal Writing Guidelines Decide where proposal will be sent Follow specific guidelines, requirements, process of each agency Find model proposal specific to agency of interest Written criticisms of successful and unsuccessful proposals submitted to agency Contact scientific administrators to review proposal draft Organize team, assign leader –Organization and delegation –Authority/ accountability chart including all members of research team Timetable and periodic meetings –Research plan and timetable –Work from outline Review, pretest, and revise repeatedly

77 Proposal Elements Title, abstract, table of contents Budget with budget justification, biosketches of investigators, resources –Rebudgeting usually acceptable, increased funding may not be Specific aims, significance, preliminary studies, and previous work of investigators –What has been accomplished, what are the problems, what needs to be done in the field under study Methods, statistical section, timetable –Special attention to methods because they will be scrutinized Ethical issues, consultants, references and appendices

78 Scientific Methods Give special attention to this section Serves as manual for future studies Should contain table of contents Should contain general overview –Diagram may be helpful Includes subjects and measurements Includes pretest plans, data management, quality control

79 Methods Sections Overview of design (time frame and nature of control) Study subjects (selection criteria, recruitment plans) Measurements (intervention, outcome variables) Pretest plans Statistical issues Quality control Timetable and organizational chart

80 More Scientific Methods Statistical Section Analysis plans Null hypothesis, statistical test, sample size, power estimate Involve statistician in writing or editing this section

81 Human Subjects Section Address ethical issues Include children, women, minorities involved in study Risk and benefit presentation Obtaining informed consent Use and value of each consultant, with letter of consent and biosketch Arrangements with collaborating institutes with letters of agreement addressed to investigator References Appendices as needed for technical and supporting material

82 Funded Research Government (NIH) –Funding is general and determined by peer review –Summary statement of criticisms and comments –Resubmission should begin with quotes from summary statement with corresponding responses and proposal changes Private nonprofit (Foundations) –Funding is specific and determined by executive process Private for profit (Drug companies, Med equipment suppliers) –Establish right to publish Intramural resources –Local research funds from the universities for their own researchers

83 Acknowledgments Hulley, Stephen, et. al. Designing Clinical Research, 2 ND ed. Lippincott Williams & Wilkins. Philadelphia. 2001


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