An Introduction to Clinical Trials: Type of Studies Design Issues • Non-experimental (Observational) – Case report Edgar R Miller III PhD, MD – Case series Welch Center for Prevention, Epidemiology and Clinical Research – Cross-sectional (survey) Johns Hopkins University – Case-control School of Medicine and Bloomberg School of – Prospective, observational (cohort) Public Health • Experimental – Randomized, clinical trial (RCT) 2 Study designs Advantages of Clinical Trials • Observational studies: • Often provides the strongest evidence in – Observe both exposures and outcomes support of cause-effect relationships • Experimental studies (clinical trials) – Assign exposures • Basis for clinical and public health policy – Observe outcomes • Minimize/eliminate bias and confounding 3 4 Randomized Clinical Trial Comparison of Study Designs Target Population Type of Study Design Cross- Case- Study Population Dimension Sectional Control Cohort RCT Estimate A - B - Prevalence RANDOMIZED Estimate - - A B Incidence Prove C B- B+ A Standard Treatment New Treatment Causality Generalizability A B+ B+ B Disease Disease Feasability A A B C 5 6 Core Elements of a Clinical Trial The Research Question • Research Question •Data • Critical in the design of a trial • Hypotheses • Analytical Issues • Types of questions: • Core Design • Interpretation of – Assessing efficacy of an intervention • Study Participants Results – Assessing the effectiveness of an intervention • Recruitment • Allocation • Masking (Blinding) • Treatment Groups 7 8 Types of Hypotheses Types of Hypotheses • Comparative Trial (a.k.a. Superiority Trial) • Equivalence (non-inferiority trial) – Objective: to demonstrate that a new therapy – Objective: to demonstrate that a new therapy (n) is superior to standard therapy (s) in terms (n) is no worse than standard therapy (s) in of incident outcome (I) terms of incident outcome (I) HO: In = Is HO: In > Is HA: In < Is (one tailed) or HA: In ≠ Is (two tailed) at HA: In = Is at some ∆, the maximum tolerable some minimally detectable ∆ judged to have clinical difference considered to be clinically acceptable significance 9 10 Basic Types of Design Parallel Study Design (PREMIER) A Parallel Randomization B ADVICE ONLY EST A A Cross-Over EST + DASH BB Primary End of Outcomes Intervention = Data Visit 11 (6 months) (18 months) Cross-Over Study Design 4 Control Diet Fruits-and-vegetables Diet DASH (OmniHeart) 2 0 Randomization Washout Washout to 1 of 6 -2 Period Period sequences 2–4 wk 2-4 wk -4 -6 * Screening/ Run-In Period 1 Period 2 Period 3 -8 Baseline 6 days 6 weeks 6 weeks 6 weeks -10 ** Data: -12 Baseline1234567 and 8 Participants Ate Their Own Food Intervention Week Conlin et al., Am J Hypertens, 2002 Participants Ate Study Food Blood Pressure Results Mixed Study Design (DASH-Sodium) (mmHg) Randomized Sequence Randomization Mean Change from Baseline in to Diet Each Diet Lower Intermediate Higher Sodium Sodium Sodium Systolic BP Baseline CARB PROT UNSAT Usual Diet Usual Diet DASH Diet All 131.2 -8.2 -9.5 -9.3 Lower Intermediate Higher Sodium Sodium Sodium HTN Only 146.5 -12.9 -16.1 -15.8 Run-in (11-14 days) Intervention (three 30-d periods in random order) PreHTN Only 127.5 -7.0 -8.0 -7.7 Diastolic BP 77.0 -4.1 -5.2 -4.8 Appel et al. 2005 16 Effect of Increased Sodium Intake on Systolic Blood Pressure in Two Diets: Results of the DASH- Factorial Design Sodium Trial* • Type of trial in which individuals are randomized to two or more therapies (example: Physician’s Health 135 American Diet Study: tested aspirin (ASA) and β-carotene +2.1 +6.7 +4.6 No β-carotene β-carotene Systolic 130 p<.0001 Neither β-carotene Blood No 10,000 ASA only Pressure +3.0 125 P<.0001 +1.3 ASA only Both 10,000 +1.7 DASH Diet ASA 120 65 100 140 10,000 10,000 20,00018 *Sacks et al, 2001 Approximate Daily Sodium Intake (mmol/day) The African American Study of Kidney Disease AASK Research Questions and Hypertension (AASK) Among African-Americans with early evidence of hypertension-related kidney disease: • Does aggressive blood pressure control to a target blood pressure below current recommendations retard the progression of kidney disease? • Do specific classes of anti-hypertensive medications retard the progression of kidney disease? Treatment Assignments Design of AASK (2:2:1 ratio of drug assignment) 3 X 2 Factorial Design • Randomized, active controlled trial with a 2 x 3 factorial design Metoprolol* Ramipril Amlodipine • Participants: 1,094 African-Americans MAP <92 20% 20% 10% with hypertension-related renal insufficiency MAP 102-107 20% 20% 10% • Planned follow-up of 2.5 to 5 years N 441 436 217 MAP = Mean Arterial Pressure; * = referent group Mean Arterial Pressure During Follow-up Composite Clinical Outcome 130 Declining GFR Event, ESRD or Death 40 Lower BP Goal (Achieved: 128/78) Lower BP (Achieved: 128/78) 120 Usual BP Goal (Achieved: 141/85) 35 Usual BP (Achieved: 141/85) 30 Low vs. Usual: RR=2%, (p=0.85) 110 25 20 100 15 MAP (mm Hg) MAP % with Events % with 10 90 5 0 80 0 6 12 18 24 30 36 42 48 54 60 0 4 12 20 28 36 44 52 60 Follow-Up Time (Months) Follow-up Month 23 24 RR=Risk Reduction, adjusted for baseline covariates Main Clinical Composite Outcome Declining GFR Event, ESRD, or Death 40 Amlodipine Ramipril 35 Metoprolol 30 Ramipril vs. Metoprolol 25 RR = 22%, p = 0.042 20 15 Metoprolol vs. Amlodipine: 10 RR= 20%, p=0.17 %withEvents 5 Ramipril vs. Amlodipine: RR= 38%, p=0.004 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up Month RR = Risk Reduction25 RR = Risk Reduction, Adjusting for Baseline Covariates Study Participants Study Participants: Example Target Accessible Population • Target Population -> Healthy Elderly Population • Accessible Population -> Retired Teachers Study Samples • Study Sample -> Volunteer Teachers who respond to mass mailing 27 28 Study Participants Enrollment Criteria • Inclusion Criteria • Ideal ‘Accessible’ Population – characteristics of accessible population – high risk for disease • Exclusion Criteria – candidates for treatment – considerations related to: – representative of target population • adherence to therapy – feasibility considerations • follow-up • recruitment • safety • follow-up •ethics • high quality data 29 30 Common Recruitment Strategies Comments on Recruitment • General mailings • Screenings – Licensed drivers – Worksite • Recruitment begins with design – Voters – Community • Response rate is always lower than – Employee paychecks • Physician Referral • Targeted mailings • Medical Record Review expected – HMO enrollees • Internet / WWW • Required resources are more than – AARP members – Clinical trial registries • Mass media – Banner ads expected – Radio – Social networks – TV ads • Dedicated personnel are necessary – Newspapers – Posters/flyers 31 32 Recruitment “Funnel” More Comments on Recruitment (Example: VITAL Pilot Study) • Recruitment period is often longer than expected 4,774 Mailed Invitations • Implement several strategies to identify best 43% 2,034 Questionnaires Returned source 38% • Prepare back-up strategies 765 Interested After Initial Mailing • Monitor recruitment 41% –Early 323 Randomizable after Second Mailing (7% cumulative) – Often 297 Randomized – Locally 33 34 Allocation Why randomize? • Random – stratified • Two critical reasons: – blocked – to eliminate selection BIAS • Non-Random – to reduce/avoid CONFOUNDING from known and, more importantly, unknown confounders – haphazard – systematic 35 36 Masking (Blinding) Masking (Blinding) • Single Blind Single Double Triple – Observers (persons who collect outcome Masked Masked Masked variable) do not know treatment assignment Outcome XX X • Double Blind Assessor(s) – Study participants AND observers do not know Participant X X treatment assignments • Triple Blind Data X – Data interpreters, study participants, and Interpreter observers do not know treatment assignments37 38 Problems with selecting Selection of Groups active treatment group • Active Treatment Group • Many Candidate treatments – observation studies, animal models, or • Comparison Group theoretically based – Placebo (no active therapy) – Usual care (referral back to personal MD) • Strong evidence rarely exists to guide – Active control group (provision of standard selection of intervention therapy) 39 • Dose/intensity are uncertain 40 Problems with standard of Comparison Group care approach • Placebo – used in setting of: • Efficacy of ‘Usual care’ often not tested – No standard therapy OR – Standard therapy but risk of not providing it • Variations in standard of care are common: is minimal – across providers – between experts and providers • Usual care OR active control – common – secular trends occur 41 42 Data Outcome Variables • Baseline data • Principal outcome – Determine eligibility – most important variable after – Describe study participants randomization code – Define subgroups – specified in hypothesis – Address confounding – determinant of sample size • Measures of Adherence • Secondary Outcomes • Outcome Variables – relevant to research question 43 44 Desirable Features of Surrogate Outcomes Outcome Variable • Definition: a laboratory measurement • clinically relevant or physical sign used as a substitute • easy to measure for a clinically meaningful outcome • little measurement error –random error – leads to imprecision • Types: physiologic variable, clinical –systematic error – leads to bias risk factor, or sub-clinical disease • masked (blinded) ascertainment 45 46 Advantages of Surrogate Advantages of Surrogate Outcomes Outcomes (continued) • Surrogate