BASIC PRINCIPLES IN CLINICAL RESEARCH

Transcription

1 Bruce I. Gaynes, OD, PharmD BASIC PRINCIPLES IN CLINICAL RESEARCH Why research? Human intellect Curious Creative Comprehend 1

2 Why Research? Helps to answer questions in a systematic mechanism Critical to answer important questions in biomedical practice in a valid manner Advances our understanding of a particular topic or field of study Helps to provide the evidence required for pragmatic biomedical applications Evidenced Based Medicine Early 20 th century-medicine practiced based on the opinion of senior medical staff Personal preferences in large part guided medical practice style Middle 20 th century efforts begun to change style of medical practice to a more evidence based approach. Requires critical research to provide evidence that suggests a particular biomedical technique results in favorable and/or acceptable outcome. 2

3 EBM triad Find the best evidence for every day practice (Information mastery) Assess relevance before rigor. Is the evidence patient oriented? Evaluate information about therapies, diagnostic tests, and clinical decision rules. Is it true? Have at fingertips just in time information at the point of care using web based and/or handheld computer based information and tools for clinical decision making Evaluate expert-based information, including colleagues, CME, presentations, reviews and guidelines. Consider sponsorship Critically evaluate information from pharmaceutical representatives. No Free Lunch Understand basic statistics Medical evidence in government Medicare Used evidence based medicine to help guide reimbursement guidelines AHRQ Federal agency charged with studying comparative effectiveness of medical interventions including drugs Pre-ops in cataract surgery 3

4 The Value of Routine Preoperative Medical Testing before Cataract Surgery Volume 342: January 20, 2000 Oliver D. Schein, M.D., M.P.H., Joanne Katz, Sc.D., Eric B. Bass, M.D., M.P.H., James M. Tielsch, Ph.D., Lisa H. Lubomski, Ph.D., Marc A. Feldman, M.D., M.P.H., Brent G. Petty, M.D., Earl P. Steinberg, M.D., M.P.P., for The Study of Medical Testing for Cataract Surgery Background Routine preoperative medical testing is commonly performed in patients scheduled to undergo cataract surgery, although the value of such testing is uncertain. We performed a study to determine whether routine testing helps reduce the incidence of intraoperative and postoperative medical complications Conclusions Routine medical testing before cataract surgery does not measurably increase the safety of the surgery. 4

5 Medical devices-the evidence? Artificial hips- Generate billions of dollars for companies Typical a provider will use only one type Training Familiarity Allegiance to company Consideration to price, quality and performance? Establish registry- accumulate data on patient preferences and acceptance Provide patients and providers with objective information on cost and performance Companies uncooperative to conduct research Requires independent research initiative to provide required evidence Seven alternatives to evidence based medicine David Isaacs, Dominic Fitzgerald BMJ 1999;319: ( 18 December ) Personality influences in medical practice Basis of clinical practice Basis for clinical decisions Marker Measuring device Unit of meas. Evidence Randomised controlled trial Metaanalysis Odds ratio Eminence radiance of white hair Luminometer Optical density Vehemence Level of stridency Audiometer Decibels Eloquence (or elegance) silk tie, Armani suit Teflometer Adhesion score Diffidence Level of gloom Nihilometer Sighs Nervousness Litigation phobia level Every conceivable test Bank balance Confidence* Bravado Sweat test moisture level *Applies only to surgeons. 5

6 Providing the evidence Requires research Multiple, systematic approach to generate knowledge in which the thought processes are clearly logical, understandable, confirmable and useful thought or action process-key to research success Research as multiple systematic strategies Multiple research strategies exist to examine complex topics from multiple perspectives Categorize these strategies into two broad subsets or domains Inductive vs. deductive theory Describes approaches to a particular research question 6

7 Inductive research strategy Theory development and theory generating Often starts with a hunch or idea No a priori acceptance of truth Observational-general research concepts develop or evolve from observation of various phenomena Seek to reveal or uncover a concept based on observation of patterns Context: natural setting Inductive analysis Theory development The primary instrument used for gathering information is the investigator Watching Observing Reviewing Assimilating Discover or reveal multiple diverse perspectives or patterns Performed by single investigator examining phenomena embedded in a specific context. 7

8 Inductive analysis Inductive reasoning, analysis done in concert with data collection Iterative process data analysis is ongoing with data collection and builds from previous observations Involves checking out hunches through continued review of each new piece of data obtained Inductive analysis Analysis incrementally builds on ideas as they are generated in the field Continued analysis forms the basis from which how subsequent field observations are to be made What to observe next Which piece of information to explore further Formulation of a concept or theory amendable to deductive testing 8

9 Inductive - Deductive experimental rationale Inductive Observation Concepts Constructs Deductive Acceptance of construct Develop hypothesis Test hypothesis Refine hypothesis Retest hypothesis Deductive research strategy Purpose is to explain, predict or test a particular theory Begin with acceptance of a general principle or belief and apply that principle to explain a specific case or phenomena Context is in a controlled setting Experiment Randomization Quasi-experiment Case-control Pre-experiment, non-experiment No control Mechanism of verification Hypothesis testing 9

10 Structure of experimental research Concept/construct Statement of problem Theory/Research Question Aims/goals Design Subject selection Statistical assessment Data collection How, when and where Data analysis Reporting 10

11 Structure of experimental research Concept/construct Statement of problem Theory/Research Question Aims/goals Design Subject selection Statistical assessment Data collection How, when and where Data analysis Reporting Concepts vs. constructs Inductive reasoning is a fertile mechanism to develop theory Abstract A concept is the first level of abstraction that helps us communicate an observed phenomena Symbolic representation of an observable phenomena or referent Constructs Does not have an observable or directly experienced referent in shared experience. 11

12 Construct validity Assesses where the variable you are testing is indeed address by the experiment How well your ideas or theories are translated into measurable parameters Formulate a construct in a manner allow operationalization in a straightforward and unequivocal method Structure of experimental research Concept/construct Statement of problem Theory/Research Question Aims/goals Design Subject selection Statistical assessment Data collection How, when and where Data analysis Reporting 12

13 Statement of the problem Purpose Background information for work What are you attempting to examine Why is it important How will the results alter or change biomedical principle or clinical care? 13

14 Structure of experimental research Concept/construct Statement of problem Theory/Research Question Aims/goals Design Subject selection Statistical assessment Data collection How, when and where Data analysis Reporting Theory and the research question Form testable hypothesis Null vs. alternative Simple vs. complex Must be set a priori One or two tailed May not be always necessary Descriptive and/or observational studies Data collection for development of concepts/constructs 14

15 Pitfalls in the research question Assessment of the literature Understand previous studies? All references sources researched? Has the work been already studied? Literature bias Arrive at an (incorrect) opinion based review of a particular study References may be restricted to those that a support a particular author s work. Criteria for a good research question Is the study feasible? Number of subjects, expertise, time, scope Interesting to others? Novel? Confirms or refutes previous data Extends previous findings vs. provide new findings Ethical? Relevant? 15

16 Primary and secondary questions Research questions do have to limited to one objective Primary and secondary goals Exploratory goals Examine outcome of subgroups Retain a primary outcome and base other outcomes around this objective. The research question and stats 16

17 Research question and stats Ideal time to choose the type of statistical analysis for the study is during the planning of the study. Knowing you statistical plan is critical to how you collect your data Statistical design is important in sample size determination The most important criteria in the statistical analysis is a well defined research question Structure of experimental research Concept/construct Statement of problem Theory/Research Question Aims/goals Design Subject selection Statistical assessment Data collection How, when and where Data analysis Reporting 17

18 Choosing your study subject Choosing study subjects Sampling Specification Recruitment 18

19 Sampling Inherent bias in selection of various populations Results in externally invalid study conclusions Often is not considered as a determinant of study bias Two forms of sampling predominate: Probability and non-probability sampling Probability Sampling Uses random number sequences to assure that each potential subject has an equal chance to participate in the study Ensures fidelity in which the phenomena in a given population is represented Increase the external validity of the study 19

20 Probability sampling Simple random Use of random number table i.e. assign a number to all subjects undergoing cataract surgery then use a random number table to select a subset of patients for study participation Systematic Periodic, i.e. every third person Stratified Cluster Probability sampling Stratified Dividing the population into varies groups based on age, gender or disease category Take random sample from each strata Subsamples can be weighted to draw from subgroups less common in the population but of interest to the study 20

21 Probability sampling Cluster Random sampling of natural groups of individuals Seek clusters with relative heterogeneity May be categorized geographically or through socioeconomics Example: Suppose that the Department of Agriculture wishes to investigate the use of pesticides on farms. A cluster sample could be taken by identifying different counties in a state as clusters. A sample of these counties (clusters) would then be chosen at random, all farmers in those counties selected would be included in the sample. Non-probability sampling Consecutive sampling Take every patient in sequence that meets study criteria for enrollment over a specific time interval Conveniences sampling Taking patients who are accessible to your practice and easily available. Judgmental sampling Handpicking most appropriate potential subjects 21

22 Conveniences/judgmental sampling-disadvantages Introduces sampling bias/sample error sample is not representative of the entire population. biggest disadvantage when using a convenience sample Systematic bias may stem from sampling bias This refers to a constant difference between the results from the sample and the theoretical results from the entire population. A consequence of having systematic bias is obtaining skewed results. Limitation in generalization and inference about the entire population Since the sample is not representative of the population, the results of the study cannot speak for the entire population. This results to a low external validity of the study. Specification of the subject pool Inclusion criteria Demographic Clinical Geographic Temporal Exclusion criteria A likelihood of being lost to follow-up Transpiration issues Clinical barriers Drug interactions Inability to understand and sign the consent Language barriers 22

23 Recruitment Advertising, referrals, patient databases Recruit enough subjects to meet sample size recruitment Recruit in a unbiased fashion May require contacting individuals not known to the research team. Ready to start? Formulate your question. Who cares?-you Why does your research matter to YOU? Experience of learning something about the universe no one else knows! FINER Feasible Interesting Novel Ethical Relevant 23

24 Success in research Topic is interesting and relevant TO YOU The outcome is obtainable It is based on a hypothesis Involves systematic investigation How will your research be framed? Association? Are you looking for a correlation? Do you wish to make a prediction? Are you simply describing something? Do you wish to perform an experiment? 24

25 Step 1. Pick a topic The topic! Cataract I am interested in learning if a particular new drug entity impacts risk for cataract 25

26 Step 2. Is your question or investigation best answered by inductive design (hypothesis generation) or hypothesis testing (a clinical study or experiment)? Clinical Research Non-experimental: No randomization No controls No hypothesisinductive design Case series Observational studies Clinical Research Experimental: Randomization Controls Serial measurements Hypothesis drivendeductive design Randomized, placebo controlled clinical trial 26

27 The cataract question I am interested in learning if a particular new drug entity impacts risk for cataract I am interested in learning if a particular new drug entity impacts risk for cataract Drug entities known? Seeking to find specific drug entities? Hypothesis testing (deductive) Hypothesis generation (inductive) 27

28 Step 3: What type of measurement scale will you use? How are you going to measure your outcome? Important in determination of the type of statistical test that will be used in your analyses Nominal- male or female Ordinal- poor, average, good, excellent Interval no true zero Ratio-true zero Continuous measurement variables (interval or ratio) enhance study power permitting a smaller sample size. What is your study design? Cohort Study subjects over a period of time Lengthy, requires large sample size Provides data on relative risk and incidence Cross sectional One measurement, short duration, provides data on prevalence and correlation Case control Gives an assessment of association-odds ratio No information on prevalence, incidence or relative risk Nested case control 28

29 Study design Randomized Clinical trial-a true experiment Gold standard Can be applied to test any type of clinical intervention Not limited to drug studies Produces the strongest evidence for cause and effect Research criteria Inclusion/exclusion criteria Selection of controls Time frame Prospective/retrospective/cross-sectional Is the disorder rare or unusual Case control Is there a working hypothesis Has this been done before? 29

30 Summary Start with a hypothesis-finer Literature search Outcome? Is it easily measured? Study Framework- Association-case control, cross sectional Correlation- cross sectional Descriptive Experimental Are you testing a new or different treatment? Randomized clinical trial 30

31 Example 1 An ophthalmologist observes a number of infants who present with an unusual form of cataract. During questioning of the mothers during the infant examination the ophthalmologist finds that 90% of these infants had been born to mothers who acknowledge a severe URI during pregnancy. The physician suspects the cataract is related to a recent viral pandemic that occurred in the community during past 12 months. How would you design a study to test this hypothesis? Example 2. What is the long-term effects of phacoemulsification with intraocular lens implantation on IOP? Too general-try to focus: What is the effect of phamacoemulisifcation on facility of outflow? What is the change in angle configuration following cataract surgery in relation to IOP? What percentage of those with end stage glaucoma have had cataract surgery within the past 1, 5 or 10 years? Is the effect of cataract surgery on IOP durable? 31

32 Bibliography DePoy, E and Gitlin LN. Introduction to Research. 1993, CV Mosby Hulley SB and Cummings SR. Designing Clinical Research. 1988, Williams and Wilkins. If we knew what it was we were doing, it would not be called research, would it? - Albert Einstein 32