Biostat Methods STAT 5820/6910 Handout #6: Intro. to Clinical Trials (Matthews text)

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1 Biostat Methods STAT 5820/6910 Handout #6: Intro. to Clinical Trials (Matthews text) Key features of RCT (randomized controlled trial) One group (treatment) receives its treatment at the same time another group (control) receives its treatment Subjects are randomly assigned to each group Statistical comparison is made between groups Results will be generalized to larger population These RCT s have developed over the past 70 years or so, in parallel with field of statistics; previous to that time, assessment of treatment efficacy was largely empirical and anectdotal. Same principles apply to multi-group trials; here we ll assume treatment is a pill Key ethical issues (all related to statistical issues) 1. Treatment must not be known to be inferior Hippocrates: control is not necessarily a placebo because 2. Subjects must provide informed consent following WWII: informed as to consent cannot be 3. Subjects may withdraw 4. Sample size should be appropriate too few unable to settle RCT question

2 too many later participants unnecessarily exposed 5. Risks are reasonable in relation to anticipated benefits Clear eligibility criteria are established at beginning of trial have to be able to generalize to helps maintain statistical integrity Why random allocation? ethics: statistical: reduce sources of bias comparison of T vs. C is impossible if allocation is want to measure effect of treatment statistical: allows useful estimates Types of bias possible in RCT: 1. Selection bias enrollment decision influenced by knowledge of group assignment example: doctor knows a particular patient would receive treatment A if enrolled in study and is not comfortable with risks for this patient; may [subconsciously] discourage enrollment

3 only a potential problem in RCT when recruiters / enrollers intersect with allocators 2. Allocation bias one group has a disproportionate number of subjects with some characteristic that may be related example: coin-tossing method of allocation by chance puts most nonambulatory patients in control group when studying multiple sclerosis therapies avoid with allocation by stratification ( 4.5) or minimization ( 4.6) 3. Assessment bias assessors of patient condition know group assignment, and example: blood pressure is measured avoid with appropriate blinding and assessment protocols 4. Publication bias publications more likely to be accepted if even if no treatment effect, what % of trials will be significant? literature may overstate significance, so information there can be considered biased mostly an issue in meta-analysis (combining published [and unpublished] results) 5. Stopping rules may keep enrolling patients until instead: Recall previous class discussion (Handout #1) of sample size and power goal is to detect a difference of some magnitude of interest, making assumptions about unknown parameters; key to achieve this: (See examples and discussion coming up in Handouts #8 and 8a.)

4 Clinical trial phases (NIH: clinicaltrials.gov) I. treatment given to small group of people for first time evaluate determine identify II. treatment given to a larger group of people consider further evaluate III. treatment given to large groups of people confirm monitor compare to collect information to allow treatment to be used safely IV. after treatment has been marketed, study: treatment s effect in side effects from

5 Clinical trial s protocol : detailed action plan of study, before beginning how/why/when, adhering to scientific and ethical principles CONSORT Statement (consort-statment.org) began in 1993 Canadian workshop wanted to develop a scale to assess the quality of RCT reports, but found that led to a 1996 American-Canadian group to provide a clear set of guidelines for standards in reporting trials 2001 CONSORT Statement 2010 revision now in use (PLoS Medicine (3):e ) the most prominent medical journals endorse / require it reflects a high value

6 CONSORT 2010 checklist of information to include when reporting a randomised trial* Section/Topic Item No Checklist item Reported on page No Title and abstract 1a 1b Identification as a randomised trial in the title Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) Introduction Background and objectives 2a 2b Scientific background and explanation of rationale Specific objectives or hypotheses Methods Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons Participants 4a Eligibility criteria for participants 4b Settings and locations where the data were collected Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were actually administered Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed 6b Any changes to trial outcomes after the trial commenced, with reasons Sample size 7a How sample size was determined 7b When applicable, explanation of any interim analyses and stopping guidelines Randomisation: Sequence 8a Method used to generate the random allocation sequence generation 8b Type of randomisation; details of any restriction (such as blocking and block size) Allocation concealment mechanism 9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those CONSORT 2010 checklist Page 1 assessing outcomes) and how 11b If relevant, description of the similarity of interventions Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses Results Participant flow (a diagram is strongly 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome recommended) 13b For each group, losses and exclusions after randomisation, together with reasons Recruitment 14a Dates defining the periods of recruitment and follow-up 14b Why the trial ended or was stopped Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups Outcomes and estimation 17a 17b For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) For binary outcomes, presentation of both absolute and relative effect sizes is recommended Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) Discussion Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses Generalisability 21 Generalisability (external validity, applicability) of the trial findings Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Other information Registration 23 Registration number and name of trial registry Protocol 24 Where the full trial protocol can be accessed, if available Funding 25 Sources of funding and other support (such as supply of drugs), role of funders *We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see CONSORT 2010 checklist Page 2

7 CONSORT Statement 2010 Flow Diagram Enrollment Assessed for eligibility (n= ) Excluded (n= ) Not meeting inclusion criteria (n= ) Declined to participate (n= ) Other reasons (n= ) Randomized (n= ) Allocation Allocated to intervention (n= ) Received allocated intervention (n= ) Did not receive allocated intervention (give reasons) (n= ) Allocated to intervention (n= ) Received allocated intervention (n= ) Did not receive allocated intervention (give reasons) (n= ) Analysis Follow-Up Lost to follow-up (give reasons) (n= ) Discontinued intervention (give reasons) (n= ) Analyzed (n= ) Excluded from analysis (give reasons) (n= ) Lost to follow-up (give reasons) (n= ) Discontinued intervention (give reasons) (n= ) Analyzed (n= ) Excluded from analysis (give reasons) (n= ) From Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332. For more information, visit

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