How will you eliminate Bias in Clinical Trials – DNB Theory

METHODS TO ELIMINATE BIAS IN CLINICAL TRIALS: RandomizationAllocation ConcealmentBlinding (Masking) Bias:1,2 Bias may be defined as a systematic error, or “difference between the true value and that actually obtained due to all causes other than sampling variability.” Bias “kills” the scientific value of the study bias A. Randomization and allocation concealment Actual assignment that can be followed by masking/blinding subjects as to their assigned groupProspective evaluation periodOutcome evaluation during which outcome assessors can be masked as to the subjects’ assigned group RANDOMIZATION The process by which each subject has the same chance of being assigned to either intervention or control. It begins with the sequence generation process, and extends until the subjects are assigned to their groups. What follows sequence generation is allocation concealment, so that until the subjects are assigned to their respective groups, this assignment remains a secret, and no external influence must be made to alter the original assignment. The successful implementation of randomization is dependent on allocation concealment. Importance of randomisation: Reduces many types of Bias: Investigator related or patient relatedAdds Validity to Statistical Tests: differences between intervention and control groups should behave like differences between two random samples from the population Minimizes Confounding: Randomization tends to produce groups that are similar in terms of both known and unknown prognostic factors. (Confounding factor- something that can independently affect the outcome in a trial, unrelated to the intervention being given) Ethical aspects: Randomisation ensures a fair distribution of patients, and gives each patient an equal chance of being either in the control or test group.Produces groups similar with respect to known or unknown risk and confounding Types of Randomisation: Simple randomisation: Toss a coin, Random digit table Easy to implement, but unequal distribution of subjects may occur Random permuted blocks: to equalize the number of subjects on each treatmentStratified Permuted Block randomisation: stratum is first defined, following which block randomisation is performed within each stratumPlay the winner designTwo armed bandit designAdaptive minimisation ALLOCATION CONCEALMENT IN CLINICAL TRIAL Allocation concealment refers to preventing the next assignment in the clinical trial from being known. It ensured correct implementation of the sequence generated by randomisation. In an RCT, a system must be in place to ensure that subjects and investigators, do not know to which group a subject will be allocated before that subject is entered into the study. The use of Sequentially Numbered, Opaque, Sealed Envelopes (SNOSE) is an economical and straightforward means of assuring allocation concealment Consider the following scenarios3: Scenario 1: Consider the investigator knows the group to which the next patient will be assigned; that investigator may try to influence the assignment, resulting in the randomisation being broken, and the trial ends up being non-randomised. Scenario 2: Consider the subject learns of the assignment into the placebo group; the subject may refuse to take the medication or may even drop out of the trial. Both the above scenarios result in loss of randomisation and introduction of bias. Inadequate allocation concealment may result in deciphering of the randomisation code. Examples of Methods of Deciphering Allocation Concealment: Holding translucent envelopes up to bright lights to reveal upcoming assignment (even using the hot light in a radiology department for more opaque envelopes)Opening unsealed assignment envelopes, or well-sealed, opaque envelope in advance of consentOpening unnumbered envelopes until desired allocation foundDetermining different weights of the assignment envelopes (eg, the heavier envelope means intervention group)Asking a central randomization center for the next several assignments all at onceDeciphering assignments to active drug or placebo based on appearance of drug container labels Allocation concealment vs Blinding (Masking) Masking only refers to the prevention of knowledge of assigned groups and the allocation sequence after actual allocation. The goal of masking is to prevent ascertainment bias. Allocation concealment refers to the prevention of knowledge of upcoming assignment from the time of generation of the randomized sequence up until actual allocation. Types of Bias - eliminate bias BLINDING Blinding refers to the concealment of group allocation from one or more individuals involved in a clinical research study, most commonly a randomized controlled trial (RCT). More the number of parties ‘blinded’ in a clinical trial, the better it is. Blinding in a surgical trial is more difficult, tricky and at times unethical, when compared to medicines, which can easily be blinded with a placebo medication. Blinding is completely different from Allocation Concealment- this is done to eliminate selection bias during the process of recruitment and randomization Why Blind? In order to reduce performance and ascertainment bias after randomizationThe purpose of blinding is to prevent differential treatment of the groups later in the trial or the differential assessment of outcomes, which may result in biased estimates of treatment effects. Levels of blinding: Single blinded trial: Participant/subject does not know whether he is getting the test drug or control drug. If participants are not blinded, knowledge of group assignment may affect their behaviour in the trial and their responses to subjective outcome measures. This can be minimised by blinding the participants. Double blinded trial: Both the participant and the investigator is unaware of the group assignment. Avoids the clinicians showing differential attitude towards patients receiving either the test or the control medication. Triple blinded trial: Participant, Investigator and the Data collectors/Statisticians are unaware of the group assignment. Ensures unbiased data collection and analysis, as there may be a subconscious effort to see a positive result with a new drug. Blinding would reduce this. When is blinding not possible? Surgical interventions being compared to medical management- ethical blinding may not be possible, eg concealment of incisions/scars. Sham surgeries are done in animal experiments, but may not be ethically possible in human participants.Data collectors may not be possible to be blinded in certain situations, eg research involving highly contagious or infectious disease If blinding is not possible Standardize the treatment of the groups (apart from the intervention)Consider an expertise-based trial designUse objective, reliable outcomes if possibleConsider duplicate assessment Acknowledge the limitations To conclude, Blinding is an important methodologic feature of RCTs to minimize bias and maximize the validity of the results. Researchers should strive to blind as many parties involved in a trial, as possible. Extra Resources - https://www.slideshare.net/PROFSATYA1/bias-in-clinical-research-satya-slideshare 1. Gerhard T. Bias: Considerations for research practice. American Journal of Health-System Pharmacy. November 2008:2159-2168. doi:10.2146/ajhp070369 2. Pannucci C, Wilkins E. Identifying and avoiding bias in research. Plast Reconstr Surg. 2010;126(2):619-625. doi:10.1097/PRS.0b013e3181de24bc 3. Paradis C. Bias in Surgical Research. Annals of Surgery. August 2008:180-188. doi:10.1097/sla.0b013e318176bf4b

METHODS TO ELIMINATE BIAS IN CLINICAL TRIALS:

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