1. BENEFITS
   1. Provide credible evidence
      1. Statistical tests can verify
   2. Investigator control over sudy aspects/interventions
   3. Potentially impacts health care practice
   4. FDA requirement fore new drug entities
2. DISADVANTAGES
   1. More complicated study design and reporting needed for detailed methodology
   2. Published clinical trial is NOT always clinically useful information
      1. CONSORT statement
         1. Designed to improve quality of reporting clinical trials in medical
         2. helps get most accurate and unbiased results → checklist and flow chart
      2. Positive vs negative
         1. See negative results less in lit. Info can still be useful however
3. STRUCTURE
   1. Topic
4. Sections
   1. ABSTRACT
      1. Study overview
         1. May have a word limit
   2. INTRODUCTION
      1. Study rationale, purpose, objective
      2. Background info
         1. Literature review possible
   3. METHODS
      1. Controlled clinical trial
         1. PROSPECTIVELY determines difference in effect between two therapies
      2. TYPES
         1. historical controls
            1. aka "before and after studies"
            2. Rationale
            3. Compares results from new intervention with those from patients treated with paste intervention
            4. used with alternative therapy is unavail and placebo control considered unethical
            5. Advantages
            6. Only one group is needed for study
            7. useful for rare diseases or with high death rates
            8. Disadvantages
            9. Overestimating the effect of the intervention
            10. Not true randomization
            11. The participants and procedures may differ in new study vs the old study
            12. People healthier back then
         2. randomized control
            1. PREFERRED METHOD
            2. Advantages
            3. Minimize bias
            4. Can examine multiple interventions
            5. Can help determine CAUSE AND EFFECT relationships
            6. CONSORT guidelines promote study quality
            7. Disadvantages
            8. cant used to dermine impact of harmful interventions
            9. that would be unethical!
            10. Can be costly and labor intensive
            11. Obviously
            12. dropout can compromize randomization benefits
            13. Multicenter groups may not be comparable to individual clinician patient groups
            14. Commercial sponsors can affect the outcomes of clinical trials
            15. TYPES
            16. Placebo-controlled
            17. rationale
            18. to document changes in dependent outcome variables due to factors other than the treatment under study
            19. Placebo =
            20. no pharmacologically active ingredient
            21. Placebo effect =
            22. change in dependent variable due to factors other than treatment effects
            23. "feel improvement that is not part of the actual treatment"
            24. Hawthorne effect =
            25. Increase in performance due predominantly to being chosen for the study
            26. "better results when the participants are aware that you are studying them"
            27. Active-controlled
            28. Rationale
            29. To compare safety/efficacy of intervention with active ingredients
            30. Used when denying effective therapy is unethical
            31. If we tested warfarin, we cant just give placebo to the others
            32. subtypes
            33. Equivalence trials
            34. No significant difference in safety/efficacy between standard and alternative treatment
            35. Noninferiority trials
            36. Newer treatment is NO WORSE than another treatment
            37. Superiority trials
            38. to establish if the new treatment is better than the standard treatment
            39. common randomized/controlled trial designs
            40. Parallel design
            41. def.
            42. Fixed # of study participants randomized to one of N treatments, followed for some set times, and then discountinued
            43. Advantages
            44. MOST COMMONLY USED TRIAL DESIGN
            45. Not subject to carryover effects
            46. Not affected by natural history of disorder
            47. Potentially shorter trial duration
            48. Disadvantages
            49. Potential for unbalanced groups
            50. Between-patient variability
            51. Used to assess
            52. Effects when treatment is curative
            53. Therapeutic effects with prolonged treatment
            54. When effects of one treatment persist after therapy (carry over)
            55. Comparative efficacy of large #s of treatments
            56. Crossover design
            57. def.
            58. Participants assigned to one treatment and then switched to alternate treatment at some point
            59. general
            60. Order of treatment should be random to avoid confounding of results
            61. Advantages
            62. Each person serves as his own control
            63. Less variability b/w treatment groups
            64. Sample sizes are much smaller → less costly
            65. Disadvantages
            66. Carry over effects
            67. Disease course can change over the study period → effects interpretation of the results
            68. Data analysis much more affected by patient dropouts
            69. Lose 2 patients instead of 1
            70. Utilized when
            71. When trial has SHORT term carry over effects
            72. Treatment PERIOD does not alter difference between treatment effects
            73. A baseline measurement cannot be made
            74. Treatment does not result in an ↑ dropout rate
   4. Study Population
      1. Terms
         1. Target population
            1. Pop which investigator desires to generalize
         2. Study population
            1. Population under study, population from which SAMPLE is drawn
         3. Sample
            1. Subset of the population under study
         4. Pic
            1. Topic
      2. Participant selection
         1. Need to make sure that they represent the target population
      3. Inclusion/Exclusion criteria
         1. Must be clearly defined
            1. INCLUDE those who would benefit from intervention
            2. INCLUDE population that will support hypothesized results
            3. EXCLUDE those who may be harmed
            4. EXCLUDE those who will not comply
         2. Typically adderss
            1. Pregnant, lactation, comorbid, renal and hepatic function
         3. Direcly correlate with study results
      4. Blinding
         1. def.
            1. Treatment status for experimental and control groups is concealed from patients and/or investigators
         2. Advantages
            1. ↓ possible bias
         3. Disadvantages
            1. double bind are more difficult to conduct
            2. Potential ethical issues with triple blind
            3. What happens if adverse rxn occurs and no1 knows what they are taking
            4. Risk of bias with single and unblinded
            5. Difficult to mask adverse event unique to a specific treatment arm
         4. Types
            1. No Blinding
            2. investigator and participator are aware of the treatment
            3. Simpler and may reflect clinical practice more accurately
            4. Single blind
            5. Either investigator or participator (but not both) know about the treatment
            6. May provide better care to the patient
            7. Double blind
            8. Neither if them know what the treatment is
            9. GOLD STANDARD
            10. Triple blind
            11. participator, investigator and personnel do not know what the treatment is
         5. Double dummy technique
            1. used
            2. to maintain blind in which each API treatment has a placebo identical to it
            3. rationale
            4. Needed when the API has a different rout of administration
            5. Ex. Tylenol..testing to see how sprinkles vs liquid works
            6. To make the taste or smell of treatment
      5. Random Assignment/randomization
         1. Goal
            1. to balance intervention and groups by providing study objects with equal chance to be in any treatment group
         2. Advantages
            1. Minimizes potential for bias
            2. Promotes comparable study groups
            3. Ensures researchers dont create significantly different groups
            4. ensures that statistical difference is due to the treatment and NOT external factors
            5. Guarantees validity of statistical results
         3. Disadvantages
            1. Can lead to unequal numbers in treatment groups
            2. Ethical considerations
            3. You CANNOT NOT treat an asthmatic
            4. Typically not possible with rare diseases
            5. Would take lots of time and $ to do this
         4. Intervention vs control
            1. Intervention
            2. NEW therapy under investigation
            3. Control
            4. Therapy used in trial to measure difference in effect compared to study treatment
            5. Ideally should come from same target population as intervention
            6. Intervention-control group comparisons
            7. Statistical analysis
            8. Want P value less than 0.05 to be significant
            9. Unbalanced allocation
            10. Unequal # of subjects in intervention group compared to control
            11. Ex. 2:1 allocation
            12. Usually happens to gather more data on the therapeutic group compared to the control
         5. Common randomization protocols
            1. Simple random assignment
            2. General
            3. uses outcome of random event to determine participant placement
            4. Ex. Day of week, birthday, random number table
            5. Advantages
            6. Easy, minimizes selection bias
            7. Disadvantages
            8. # of subjects can be unbalanced, especially in small groups
            9. Potential for reduced ability to detect differences and loss of trial credibility
            10. Stratification
            11. General
            12. Subjects have equal probability of being distributed within treatment groups
            13. Groups contain similar proportion of CONFOUNDING Variables
            14. Advantages
            15. Breaks trial into "smaller trial" and reduces variability in groups comparisons
            16. Disadvantages
            17. Cannot stratify for all variables that may affect study
            18. May not stratify for confounding variables found during the course of study
            19. Block randomization
            20. General
            21. Subjects have equal probability of being distributed EVENLY within blocks of equal size
            22. Advantages
            23. ensure similar participation numbers in experimental and control groups
            24. Maintains balance in confounding factors if a block/group needs to leave the study early
            25. Disadvantages
            26. Data analysis is more complicated
            27. Investigators may be able to predict the next allocated treatment
            28. TYPES
            29. nonstratified
            30. Block size is chosen (4,8,16,24)
            31. Number of patients in each is proportional within the block
            32. Stratified
            33. subjects are grouped into homogenous blocks on the basis of a variable
            34. NOT the intervention variable
            35. Should be influencing the outcome
            36. Ex. Blocks of eight stratified by age and sex
   5. Bias
      1. Def.
         1. Systematic error presented into some aspect of study by experimental design or methods that promotes one outcome over the other
      2. TYPES
         1. Publication bias
            1. Inclination to publish more trials with positive results and omit those with negative results
         2. Investigator bias
            1. Investigator interpretations favor treatment results that are expected or desired and reject other treatment results
         3. Selection sampling bias
            1. When participants selected are not equally balanced or objectively represented
            2. Results in attributes that are over/under represented
            3. TYPES
            4. Study population charac.
            5. ex. Of the birthing room
            6. Those who chose special room volunteered for the experience
            7. Had lower complications
            8. Those in the standard room probably had complications before or were older
            9. Run-in-phase
            10. Short term period (2-4 weeks) prior to study initiation to assess incidence of a predetermined outcome defined by investigators
            11. Problem =
            12. May end up with more motivated group and not reflect the patient population
            13. Subject recruitment
            14. Sending out letters to recruit for participants in raffle
            15. Had more motivated students = bias
   6. RESULTS
      1. Subject demographics
         1. Dropout/compliance
      2. Data analysis methods
         1. TYPES
            1. Intention to treat (ITT)
            2. Data analysis based on ALL study participants randomized (including those that dropped out
            3. Advantage
            4. Provides more realistic estimate of safety and efficacy of GENERAL population
            5. Disadvantage
            6. The dropout can BIAS the trial results
            7. Modified Intention to Treat
            8. allows some exclusions if they are unlikely to bias the results
            9. Advantage
            10. Useful when outcomes are not measured in all participants
            11. Disadvantage
            12. Not clearly defined and lack of guidelines can introduce bias
            13. Per-protocol method
            14. Data analysis is based on only those who COMPLETED the trial
            15. Advantage
            16. Accurate estimate of treatment effects on participants who fully comply with protocol and finish
            17. Disadvantage
            18. Study dropout due to adverse effects may cause overestimation of results
      3. Study Outcomes
         1. Primary Endpoint
            1. The outcome the clinical trial is specifically trying to measure
            2. Composite endpoint
            3. Combination of end points into one main endpoint
            4. Ie. Look at mortality, stroke AND MI
            5. Does not hold as much weight as the primary end point
         2. Secondary Endpoint
            1. Results results of less interest that might contribute supporting evidence
         3. Subgroup analysis
            1. Evaluation of subsets of results based on specific demographics (age, disease)
            2. Prequisites
            3. Clinical trial should be well designed
            4. Multiple subgroup analysis should be avoided
            5. Primary endpoint should be statistically significant
            6. Subgroup should be designed PRIOR to trial initiation
         4. Ancillary vs adjunctive therapies
            1. Ancillary
            2. Additional therapy that is NOT equally distributed between groups
            3. Ex. Allowed to take other meds for additional BP control
            4. Adjunctive
            5. additional theray that can affect study outcomes but is distributed EQUALLY between the groups
            6. Ex. All patients told to get on a diet during trial
   7. IX Discussion/Comments/Conclusion
      1. Study strengths/limitations
      2. Comparison to previous trial results
   8. X Acknowledgements
      1. Author information/qualifications of researchers
   9. XI References
      1. Peer reviewed, $$ support