Randomized Controlled Trials Introduction to

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Randomized Controlled Trials

  • Introduction to

  • Sequence Generation

Critical Methodological Elements in RCTs

  • Randomization

  • Avoiding and handling exclusions after trial entry

  • Blinding

Excellent Familiarity with Blinding in the Scientific Community

  • Blinding embodies a rich history spanning several centuries

  • Most researchers worldwide understand blinding terminology, but . . .

    • confusion lurks beyond a general comprehension
    • terms such as “single-blind,” “double-blind,” and “triple-blind” mean different things to different people

Inflating the Importance of Blinding

  • Some investigators, readers, and editors overstate the importance of blinding

  • Indeed, some consider RCTs as high quality if “double-blind,” i.e. sine qua non of an RCT

  • A randomized trial can be methodologically sound and not be double-blind or, conversely, double-blind and not methodologically sound

Inflating the Importance of Blinding

  • Lasagna captured that notion long ago in 1955

  • "Let us examine the placebo somewhat more critically, however, since it and 'double blind' have reached the status of fetishes in our thinking and literature. The Automatic Aura of Respectability, Infallibility, and Scientific Savoir-faire which they possess for many can be easily shown to be undeserved in certain circumstances."

Inflating the Importance of Blinding

  • “Mefloquine Prophlaxis Prevents Malaria during Pregnancy: A Double-Blind, Placebo-Controlled Study”

    • Nosten et al. JID 1994; 169: 595-603.
    • “We report here a double-blind, placebo-controlled trial of . . .”
    • Not only did the authors not describe how they randomized, but any mention of randomization at all is difficult to find

Blinding Important, but Less Important than Widely Believed?

  • Unclear allocation concealment

    • ORs exaggerated by 33% (95% CI; 25%-40%)
  • Inadequate allocation concealment

    • ORs exaggerated by 41% (95% CI; 27%-52%)
  • Not double-blinding

    • ORs exaggerated by 17% (4%-29%)
  • Important, but also more difficult to successfully accomplish than allocation concealment

    • Side effects or even intervention effectiveness

Confused Terminology of Single, Double, and Triple Blinding Permeates the Literature

  • Physicians, textbooks, and journal articles vary greatly in interpretations and definitions

  • [Devereaux et al. JAMA 2001; 285: 2000-3]

  • Define “double-blind” inconsistently

    • Authors frequently fail to report their definitions clearly
  • When I use “double-blind”, participants, investigators, and assessors are blinded

  • In reporting RCTs, authors should explicitly state what steps were taken to keep whom blinded

  • Building upon once common double blindfold terminology (Lasagna) we further obfuscate . . .

Blinding or Masking

  • Different terms to describe the same procedures

  • “Masking” may be more appropriate semantics:

    • Participants with impaired vision
    • Less confusing with blindness an outcome
    • But more pc in all trials?
  • “Blinding” conveys strong bias prevention

  • Apparently, “blinding” terminology emerged when Benjamin Franklin et al. actually blindfolded participants when evaluating Mesmerism

  • Lasagna used the term “double blindfold” in 1955

Blinding or Masking

  • We prefer “blinding” because:

    • it rests on a long history
    • maintains worldwide recognition
      • If you use “masking” someone using PubMed in Asia or Africa may not know what you did
    • creates strong visual imagery
    • permeates the ICH guidelines

Final Thoughts on “Double”-Blinding: Beyond Overvaluation

  • Overrated – cannot always double-blind

  • Usually reduces differential assessment

  • May improve compliance and retention

  • May reduce biased supplemental care or treatment (co-intervention)

  • Without it, better to at least blind outcome assessments

    • except with “hard” outcomes, such as death


  • Principal bias reducing technique

  • Success depends upon successful implementation

  • Chance rather than choice eliminates selection bias

Assures Comparability

  • In observational studies, statistical methods allow investigators to control for confounding factors

    • Must be measurable
    • Must be measured

Assures Comparability (Cont.)

  • No statistical method can achieve comparability on unknown or unmeasured factors in analysis phase

  • Random allocation is the only known method to assure comparability

Hormone Replacement Therapy (HRT) and Coronary Heart Disease (CHD)

  • HRT decrease risk of CHD by 35% to 50%, according to 3 different meta-analysis of numerous observational studies

  • Especially strong for secondary prevention in women with CHD

Experimentation Trumps Observation*

  • RCT of hormone-therapy for secondary presentation of CHD

  • Relative hazard = 0.99; 95% CI 0.80 - 1.22

  • No effect of hormone therapy

  • Recent Women’s Health Initiative RCT in healthy women (JAMA 2002; 288: 321-333)

    • CHD: HR=1.29; 95% CI 1.02-1.63)

Randomized Controlled Trials

  • The methodologic standard of excellence for medical research

  • RCTs: gold standard in theory

    • Frequently a bronze standard in practice

Randomized Trials Require Methodological Rigor

  • Improperly conducted RCTs yield biased results

  • Researchers must devote assiduous attention to design and conduct of RCTs

  • Only properly conducted RCTs will fulfill their promise of minimizing bias

Randomization Depends Upon Two Interrelated Processes

  • Sequence generation

    • An unpredictable allocation sequence must be generated based on a random procedure
  • Allocation concealment

    • Strict implementation of that schedule must be secured through an assignment mechanism that prevents foreknowledge of treatment assignment

“Randomization” (Cont.)

  • Crucially, allocation concealment shields those who admit participants to a trial from knowing upcoming assignments

Quality of Reports of Randomized Trials

  • Reviewed 2000 randomized trials of all treatments for schizophrenia

    • Only 4% (n=80) of the trials clearly described the methods of allocation

Reporting of Method of Randomization

  • Review of 122 RCTs of selective serotonin uptake inhibitors in patients with depression (Hotopf et al. 1997)

    • Only 1 trial report included details of the method of randomization

Allocation Methods

  • Whim

  • Judgement

  • Chance

  • The quasi- simulated “Randomized” approach

Allocation Methods (Cont.)

  • Alternate assignment

  • Chart number

  • Date of birth

  • “Randomization was achieved by rotating the three medications after each was used for a week.”

Stopping Smoking in Pregnancy: Effect of a Self-help manual in Controlled Trial Summary. For medical reasons, encouraging women to stop smoking during pregnancy and post partum has high priority. Many smokers want to stop smoking but decline clinical treatment when it is offered. The aim of this study was to find a method which was accepted by a large number of smokers, had a high success rate and, at the same time,

  • “Women were randomized . . . born on days 1-10 of every month formed the control group (n=231), and those born on days 11-31 formed the treatment group (n=492). ”

Nifedipine in the Treatment of Severe Preeclampsia We conducted a randomized clinical trial in which patients with severe preeclampsia between 26-36 weeks of gestation receive either nifedipine (10-30 mg sublingually, then 40-120 mg/day orally; N= 24) or hydralazine (6.25-12.5 mg intravenously, then 80-120 mg/day orally; N= 25)

  • “We conducted a randomized controlled trial. . . ”

  • “Subjects were assigned to the nifedipine or hydralazine group according to the week of the month.”

The use of Histoacryl for Episiotomy Repair Summary. Histoacryl-tissue adhesive (B. Braun Melsungen AG W. Germany) was used in place of skin sutures (2/0 chromic catgut, Ethicon Ltd, Edinburgh, Scotland) for episiotomy repair in a group of 20 women. This group was compared with two groups of women undergoing first and repeat episiotomy. Variables analysed included pain in the episiotomy site, pain while walking, sitting, sleeping, lying down, breast-feeding, micturating and defaecating. The Histoacryl group was superior with regard to all the variables. This simple,

  • “Groups 1 and 3 (first episiotomy repair) were selected randomly, by registration number; group 1 odd and group 3 even numbers.”

Two Problems

  • Non-random

  • Difficult to conceal anyone assigning or referring patients know in advance the next assignment

    • Decide eligibility
    • Time their referral

Sequence Generation (Cont.)

  • Table of random numbers?

  • preferable & recommended

    • Random
    • Reproducible - can be checked
    • Easier (not widely recognized)
  • Same can be said for most computer random number generators

Types of Sequence Generation

  • Simple randomization

  • Replacement randomization

  • Blocked (random permuted blocks) randomization

  • Stratified randomization

Type of Sequence Generation (Cont.)

  • Simple

    • Perfectly unpredictable
    • Large sample sizes, generate groups of relatively similar sizes
    • Small sample sizes, will sometimes generate groups that differ quite substantially in sizes (5% will result in an imbalance in size greater than 1.96 √ ; N = total study size)
    • Probably used less frequently than should be

The Difference (T-C) and Total Size for 96 Unrestricted Trials

Power reduction as the proportion on new treatment is increased

Restricted Randomization

  • Biased–coin – alters probability of assignment

  • Restricted shuffled – essentially one large block the size of the study (random allocation rule)

  • Minimization – several prognostic factors

  • Blocked (balanced)

    • Probably the most common restricted approach

Blocked Randomization

  • Every ?B? number of participants, the group sizes are the same

  • At least two good properties

    • Similar group sizes at the end of the trial
    • Similar group sizes throughout the study, which reduces variability due to a time trend in the prognosis of participants and is helpful for interim analyses

Blocked Randomization

  • If the block size is unraveled, and if treatment assignments become known after allocation, a sequence can be discerned from the pattern of past assignments

  • Some future assignments could then be accurately anticipated and bias introduced, regardless of the effectiveness of allocation concealment

Lessening the Chances of Deciphering with Blocked Designs

  • Long block lengths are more difficult to decipher than short block lengths (12 better than 4)

  • Randomly vary the block lengths throughout the trial

  • Consider the importance of blocking when your trial is not double-blinded


Epidemiologic Study Designs

The First Real Randomized Trial

  • Realization of selection bias problems with alternate allocation

  • Hill looked for opportunities to employ proper randomization

  • Pertussis vaccine trial; pilot in 1944; completed in 1950

  • Streptomycin for tuberculosis; initiated later; published in the BMJ in 1948

During the Emergence of Modern Epidemiology (around 1950)

  • Sir Austin Bradford Hill, Sir Richard Doll and colleagues conducted:

    • A case-control study of lung cancer
    • A cohort study of smoking and lung cancer
    • The first RCT in medicine, streptomycin for treatment of TB

Chemotherapy for Carcinoma of the Esophagus*

  • A meta-analysis of 8 non-randomized studies found a 68% reduction in death (OR=0.32, 95% CI 0.24 - 0.42)

  • A meta-analysis of 12 RCTs found a 4% reduction in death

  • (OR=0.96, 95% CI 0.75 - 1.22)

  • *Bhansali et al. Ann Oncol 1996;7:355-9.

Systematic Review of Randomized vs Non-Randomized Evidence*

  • On average, non-randomized studies result in overestimates of effect

  • That bias can, however, go in either direction

  • That bias can be as large or larger than the effects of worthwhile interventions

  • *Kunz R. and Oxman AD. BMJ 1998;317:1185-90.

  • The patients in each group were then randomly assigned to receive 10 mg of benazepril or placebo once daily.

  • Randomization was balanced for disease severity at each center.

  • “The study (AIDS Clinical Trials Group protocol 229) was a randomized, double-blind, phase 2 trial of three treatment regimens”

We tested topical intravaginal clindamycin phosphate at concentrations of 0.1, 1.0, and 2.0% in the treatment of 62 women with symtomatic bacterial vaginosis in a propective, randomized, double-blind, placebo-controlled trials.

  • “. . . prospective, randomized, double-blind, placebo-controlled trial.”

  • Design - A prospective randomized, controlled trial.”

    • We conducted a prospective, double-blind, randomized study involving 49 European hospitals.

Objective--To study the possible pathophysiological implications of long continued dietary sodium restriction in pregnancy Design--Longitudinal prospective randomized study of the effects of a low sodium diet compared with unrestricted sodium intake in pregnacy. Setting--Academic Department of Obstetrics and Gynaecology at Sint Radboud Hospital, Nijmegen, The Netherlands.

The Term Prospective Trial Is a Pleonasm

  • Trial used increasingly in combination with prospective

  • A PubMed search "prospective trial" yielded 507 hits for the period 1999-2001

    • Prospective is a pleonasm (superfluous)
  • “Because all trials are prospective by definition; the only way to do a retrospective trial is for the investigator to travel back in time with a box of pills.”

    • Letter in The Lancet, Sept 2002 by Martijn B Katan, Netherlands

Advantages of Randomized Trials

  • First and foremost, the only effective method known to control selection bias

  • Controls confounding bias without adjustment

  • Facilitates effective blinding in some trials

  • Theoretically attractive — many statistical methods assume random assignment

  • Maintains advantages of cohort studies

Disadvantages of Randomized Trials

  • May be complex and expensive

  • Prohibitively difficult and expensive with low incidence outcomes

  • May lack representativeness - volunteers may differ from population of interest

  • Ethical challenges of experimental research

  • Sometimes impossible or impractical to conduct

  • Frequently slight allocation concealment while stressing sequence generation

  • Without adequate allocation concealment, however, even random unpredictable sequences can be subverted

  • Basically, equates to no allocation concealment (perhaps a little concealment if the bulletin board is up 5 flights of stairs)

  • Those responsible for admitting participants could detect the upcoming allocations and then channel them based on prognosis

  • Bias easily introduced

Type of Sequent Generation

  • Replacement randomization

    • Prepare sequence for size N
    • Check it for a prespecified inequality based on criteria delineated 2 priority
    • If inequality sufficiently large, then generate a whole new sequence to replace prior sequence – iterate
    • Intuitively, may seem inappropriate but appropriate and has good properties
      • Simple random sequence
      • Similar group sizes

Stratified Randomization

  • Stratify on prognostic risk factors at entry; balance within each stratum


  • Not usually recommended

    • Adds complexity
    • Does not yield any commensurate gain in a large trial since the factors would be relatively balanced
    • Can deter collaborators
    • Can deter entering Ps during busy times

Stratified Randomization (Cont.)

  • Recommended as follows:

    • In small trials for which participant factors are well known to influence outcomes
    • In multicenter RCTs: stratify on center

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