Double‐blindness protects scientific validity

Bias is one of the major threats to scientific validity [1]. It may be defined as systematic error and it may occur throughout all phases of randomized clinical trials, from initial design to data reporting and interpretation. One of the established and fundamental principles for avoiding the problem of bias is to keep the study participants and the investigators blinded, or masked, to the identity of the assigned intervention. This is referred to as double-blind design. The underlying reasons for this type of bias are that participants and investigators often have preconceived notions, hopes and expectations that new interventions will be more beneficial, or possibly safer, than older comparisons or placebo. This bias in favor of new drugs is even stronger for manufacturers of new interventions, who, in addition, have a major commercial stake in the outcome of a trial. Knowing the intervention assignment can influence, unconsciously or consciously, a participant s reporting of symptomatic improvement and occurrence of adverse events. In a double-blind, placebo-controlled clinical trial of vitamin C for the treatment and prevention of the common cold, a sizable proportion of the blinded participants, mostly medical staff, broke the blind [2,3]. At the trial conclusion, all participants were asked whether they knew the identity of the blinded intervention that they were on. Interestingly, vitamin C had no benefit as compared to placebo for the common cold among those who said that they did not know which intervention they received. In contrast, vitamin C did significantly better than placebo among those participants who knew the identity of their treatment. This case illustrates the role that preconceived notions can have on the reported benefit of an intervention. Thus, whenever possible, study participants should be blinded to their assigned study medication. Investigators have similar and often stronger expectations and hopes. Investigator bias may occur during the collection, assessment and classification of data. Naturally, investigators as well as participants want to be part of a successful trial with important and clearly positive results. Let us not forget that there is no academic glory in negative trials. The placebo-controlled trial investigating the effect of zinc on taste disorders was first done single-blind; that is, the participants were unaware while the investigator was aware of the treatment assignment. The trial reported that zinc had a statistically significant benefit. However, the reported treatment responses were very subjective and, in addition, the investigator had a vested interest in a positive outcome. Thus, the identical trial was repeated with only one difference: the second trial was double-blind [4]. Perhaps not surprisingly, zinc showed no benefit over placebo in the second trial. There are good reasons to believe that this type of bias is much more pronounced in trials conducted by commercial sponsors. All drug trials should, ideally, have a double-blind design to avoid potential biases in data reporting, collection, assessment and classification. The term ideally does not mean that this principle exists only in a perfect but unrealistic world, and that doubleblinded designs can be easily avoided. Rather, it is an acceptance of the fact that there are situations in which a double-blind design is not possible. For example, it is not possible or ethically justifiable to blind a procedure or a lifestyle change. The use of sham treatments and procedures is infrequent, and many trialists object to their use. To avoid bias in these types of trials, investigators should select outcomes that are as objective as possible or, if appropriate, rely on a blinded third party for the assessment and/or classification of the outcomes. High-quality research has its price. Double-blindness admittedly introduces challenges, in terms of both efforts and cost. The alternative – open trial designs – may be much costlier to society if the trial findings are biased and lead to market introduction of ineffective or unsafe drug treatments. Some of the key steps are as follows: 1 The study medications need to be well matched for taste, color and odor. Poor matching could lead to unblinding of the investigators. An alternative in active controlled trials Correspondence: Curt D. Furberg, Professor of Public Health Sciences, Wake Forest University School of Medicine, WinstonSalem, NC 27157-1063, USA. Tel. : +1 336 716 3730; fax: +1 336 716 0395; e-mail: cfurberg@wfubmc.edu Journal of Thrombosis and Haemostasis, 6: 230–231