Blinding in Pharmacological Trials: the Devil Is in the Details
Total Page：16
File Type：pdf, Size：1020Kb
Downloaded from adc.bmj.com on February 6, 2014 - Published by group.bmj.com Leading article measures involve some subjectivity, and Blinding in pharmacological trials: becomes less so to reduce observer bias for objective criteria.7 However, even the devil is in the details then, the lack of participant or healthcare provider blinding can lead to other pro- 1 2 3 2 Mandy Wan, Mine Orlu-Gul, Helene Legay, Catherine Tuleu blems, such as differential attrition and cointervention bias, which can likewise influence the assessment of clinical trial While the methodological principle of science underpinning blinding is very outcomes.710 ‘blinding’ for minimising bias in randomised much pharmaceutical based, and may be controlled trials (RCT) is widely debated technical at times, but part of this paucity BLINDING WITH PLACEBOS and accepted, rarely is this depth of thinking of knowledge is undoubtedly due to a The use of placebo in RCTs would appear applied to its correct handling with respect certain lack of recognition for the as a seemingly simple experimental to design, reporting and analysis. Beyond pharmaceutical properties of a medicine. scheme. Such perception is so deeply fi the general comprehension of the de nition This article, written with clinicians in embedded that we often implicitly accept of the word, the practical aspects of estab- mind, presents a discussion on the prac- clinical trial reporting with rather loose lishing blinding in investigator-initiated tical considerations for blinding in paedi- descriptions of blinding procedures as pharmacological trials are often grossly atric pharmacological trials, with the aim 1 adequate indication for the success of underestimated, and very much an after- to facilitate paediatricians in improving blinding.23Rarely do we ask ourselves thought. The resulting inadequacy can the success and timely delivery of blinded 1 any questions concerning the placebo, nor lead to trial delayed and increased costs, RCTs in children. Furthermore, this do we think much, if at all, about the and can also potentially place the entire trial article aims to encourage detailed disclos- work involved in producing them. The at risk. ure of blinding methodology in clinical fact is that the seemingly simple concept It is worth nothing that reporting of trial reporting. does not necessarily hold true for obtain- blinding methodology is often absent or ing placebo supply. One cannot just pur- of low quality in published articles of 23 BLINDING chase matching placebo in an RCTs. Thus, in such context, when Blinding in clinical trials refers to the ‘off-the-shelf’ manner; its provision needs these fundamental details of trial design fi 23 process of withholding information about to be speci c to each trial and the chal- are inadequately reported, it becomes the assigned treatment from specificgroups lenge is in the word ‘matching’.To easier to see why it should be of no sur- of individuals. The first blinded experiment achieve its purpose, one must ensure the prise that there are, equally, very few pub- was conducted by Benjamin Franklin who placebo matches the sensory specifications lished commentaries addressing the literally blindfolded participants to shield to that of the medicine under test. The challenges of blinding that those embark- them from knowledge in their assessments ability to maintain blindness throughout ing on pharmacological trials face. So, it of the therapeutic claims made for applying the complete clinical trial must focus on would seem that little is available, at least mesmerism. Quite understandably, the use the visual aspects of the product, and in biomedical literature, to guide investi- of blindfolds is less favourable today. should also take into consideration the gators on this particular methodological Instead, identical-appearing treatments, be other human senses. The relative import- aspect. A review of RCTs published over it matching placebo or masked active com- ance of these specifications will very much fi 15 years in this journal identi ed only parator, are important tools in modern-day depend on the route of administration 176 RCTs in children involving pharma- 4 pharmacological research. and the dosage form concerned; this may ceutical interventions ; the authors sug- When performed correctly, blinding is include: shape, size, colour, texture, fi gested that dif culties in obtaining intended to minimise the occurrence of weight, taste, smell11 and not merely a adequate placebos without the collabor- conscious and unconscious bias in the ‘sugar pill’. ation of pharmaceutical companies may 4 conduct and interpretation of a trial until An appropriate source for supply would have contributed to the low number. Our all such opportunities for bias have be the original manufacturer of the medi- experience over the years has also high- passed. The biases associated with prior cine. After all, they would have manufac- fi lighted, among investigators, a de ciency knowledge of treatment assignment are tured placebo for their own marketing in the awareness of how pharmaceutical well known, and the benefits of blinding authorisation trials, and have all the ramification can constrain trial design and 37 56 have been presented elsewhere Indeed, required technical data on the manufactur- its validity. There is no denying that the it is acknowledged that the relevance of ing and analytical methods to support clin- blinding will vary according to the clinical ical trial application. However, for many 1National Institute for Health Research—Medicines for trial context. In general, blinding of parti- pharmaceutical companies, the little incen- Children Research Network–London & South East, cipants, healthcare providers and outcome tive to manufacture placebos on the com- Evelina London Children’s Hospital, Guy’s and St assessors is considered important in paratively limited quantity required by ’ Thomas NHS Foundation Trust, King s Health Partners, explanatory trials, where the primary most clinical trials is often disappointing London, UK; 2Department of Pharmaceutics, UCL focus is to determine the efficacy of an to the independent researchers.11213 School of Pharmacy, Centre for Paediatric Pharmacy 8 Research, London, UK; 3Faculté Des Sciences intervention under ideal circumstances. Even if one is fortunate enough to have Pharmaceutiques et Biologiques de Lyon, Université By contrast, in pragmatic trials, as in the agreed a supply, commercial influence over Claude Bernard, Lyon, France real-world delivery of care, blinding of protocol design, trial results and publica- Correspondence to Mandy Wan, National Institute participants and healthcare providers are tion can be somewhat disheartening.12 14 for Health Research, Medicines for Children Research sometimes considered not necessary, so as Short of compromising the study design Network—London & South East, Guy’s and St Thomas’ fi ’ ’ to render the ndings more applicable to with an unblinded trial, an alternative NHS Foundation Trust, St Thomas Hospital, St Thomas 8–10 House, 5th Floor, London SE1 7EH, UK; usual care setting. Blinding is also par- approach is to have the matching placebo [email protected] ticularly important when outcome manufactured elsewhere. While it would 656 Wan M, et al. Arch Dis Child September 2013 Vol 98 No 9 Downloaded from adc.bmj.com on February 6, 2014 - Published by group.bmj.com Leading article be logical to use the same ingredients copying goes, certain imprints or mark- encapsulation can potentially provide the (excipients) in the placebo formulation as ings on tablets are registered trademarks, solution to the problem. A sensible those in its active counterpart (without and therefore exclusive rights are approach would be to consider the double- the active drug), such approach does not bestowed upon the trademark owner, the dummy blinding strategy. With this always guarantee a satisfactory level of drug’s original manufacturer. approach, the comparator doesn’t need to blinding. First, blinding is particularly Consequently, third-party placebo manu- match the test product. Instead, a placebo challenging where the actual drug itself facturing is not always possible. matching the test product and a second has a characteristic taste or colour, neces- placebo matching the comparator product sitating the testing and addition of new BLINDING OF ACTIVE COMPARATORS are used. Although such a study design excipients to the placebo formulation in To many, over-encapsulation may appear may be more pragmatic, it does have some order to achieve sensory equivalent.15 16 to be the ubiquitous solution to blinding drawbacks. On the one hand, there are Second, and rather more problematically, solid oral formulations, and indeed, such considerable technical difficulties, as dis- is when such addition is unsatisfactory; in a technique can be very effective. As the cussed above, with manufacturing placebo these circumstances, it may be necessary term implies, over-encapsulation is basic- for liquid formulation. As two matching to reformulate the active treatment from ally hiding a tablet or capsule inside an placebos are now needed, this would its licensed form (eg, the addition of a opaque capsule shell (often involving the require additional research expense and new excipient to mask the taste of the addition of a backfilled excipient to time. On the other hand, the double- active drug), to what is in effect manufac- prevent rattling), so that the contents are dummy design requires participants to turing of a new product.