Tuesday, July 05, 2016

Some Blinding Techniques in Clinical Trials

In randomized controlled clinical trials, the blinding is one of the key components. The purpose of the blinding to the treatment assignment is to avoid the conscious or unconscious biases in assessing the efficacy and safety endpoints, therefore, to maintain the integrity of the study. How much important of the blinding? Look at the investigator initiated studies, early phase trials – many of them had positive results, but later was demonstrated untrue.

In terms of the blinding technique, researchers should look for 3 qualities: it must successfully conceal the group allocation; it must not impair the ability to accurately assess outcomes; and it must be acceptable to the individuals that will be assessing outcomes. In some clinical trials, not all these three qualities can be met.

Based on how the blinding is maintained, the clinical trials can be categorized as open-label study, single-blind study, and double-blind study.

The open label study (may be called 'open study' in EU countries) is a study with both the investigator and the subject knowing the treatment the subject is receiving. The open label study can be a study without any control group or can be a randomized, controlled, open label study.

The single blind study is a study with investigator knowing the treatment assignment and with the subject not knowing which treatment he/she is receiving.

The double blind study is a study with both investigator and subject not knowing which treatment the subject is receiving.

  • The blinding is defined based on whether or not the investigator and subject know the treatment assignment, however, in industry, additional parties who are involved in the managing and conducting the clinical trials may also be blinded to the treatment assignment. For example, in double-blind studies, the study team on the sponsor side, the CRO, and vendors are usually also blinded.

  • There is an extended term ‘triple blind study' which is defined as a double-blind study in which, in addition, the identities of those enrolled in the study and control groups and/or the details about the nature of the interventions (experimental medications), are withheld from the statistician(s) who conduct the analysis of the data. Since the study statisticians (with exception of the DMC statisticians) are part of the study team and usually remain blinded to the treatment assignments during the study, the ‘double blind study’ is usually operated as a triple blind study in practice. This is why we rarely see the term ‘triple blind study’ is actually used in clinical trials.

  • In practice, for a single blind study, it is usually better to be conservative to treat the single blind study as if a double blind study for the study teams.
The blinding is usually easy to operate if the investigational products are pills. The pills for investigational products and the control products can be manufactured to be identical in size, color, smell,...   There are clinical trials where the comparison involves different route of drug administrations, different type of surgical procedures, or different devices. In these situations, the blinding of the treatment assignments seems to be impossible. However, this may not be entirely true. There are still some techniques or approaches that can be employed to have certain levels of the blinding to minimize the biases in assessing the efficacy and safety endpoints. 

Using sham treatment: Sham treatment is an inactive treatment or procedure (usually a medical procedure) that is intended to mimic as closely as possible a therapy in a clinical trial. Sham treatment is given to the subjects in the control group to mimic the investigational treatment group. With the use of the sham treatment, a seemly impossibly blinded study can now be blinded. Here are some examples that sham treatment is used in the study. 

Separating the treating physician and the evaluation or examining physician: in clinical trials where a separate physician other than the treating physician or investigator is employed to assess the efficacy or safety. The treating physician and the examining physician are separate and do not communicate about the assessment results. Treating physician can be unblinded to treatment assignment, but the examining physician is blinded. Therefore, the blinding is maintained. This type of arrangements is useful and necessary in neurological trials especially in multiple sclerosis trials where many subjective scales are used. In EMA (2006) GUIDELINEON CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS FOR THE TREATMENT OF MULTIPLESCLEROSIS, the following is described:
“As several subjective decisions and assessments will have to be performed, with a considerable risk of bias, all possible efforts should be done to keep the design double blind. In cases where double blind is not possible (some active comparator trials, some easily unblinded treatments,...) a blind observer design with a blinded examining physician different than the treating physician may be used. All measures to ensure reliable single blind evaluation should be guaranteed (i.e. patches that cover injection sites to hide reddening or swellings, education of examining physicians,…).”
Similarly, in FDA's guidance for industry "Rare Diseases: Common Issues in Drug Development", it stated: 
...As another example, effective blinding of treatments can reduce concern about bias in the subjective aspects of an assessment, as can conduct of endpoint evaluation by people not involved in other aspects of the trial (e.g., radiologists, exercise testers).

 Some of the examples are: 

Central reader with the blinded clinical data: using central reader for image endpoints where the central reader is blinded to the clinical data to avoid the biases. Additional blinding can also be employed through blinding of the baseline image and the subsequent images so that the changes (for example the tumor size) assessed by the central reader can be more reliable.

FDA (2015) Guidance for Industry Clinical Trial Imaging Endpoint Process Standards
"In unblinded clinical trials, clinical information may bias a site-based image interpretation because the expected relation of clinical features to outcome is known and, therefore, local reading will raise concern about potential unblinding. A centralized image interpretation process, fully blinded, may greatly enhance the credibility of image assessments and better ensure consistency of image assessments. Some imaging modalities also may prove vulnerable to site-specific image quality problems, and a centralized imaging interpretation process may help minimize these problems. For example, the National Lung Screening Trial’s experience with computed tomography of the chest suggested that centralized image quality monitoring was important to the reduction of imaging defects (Gierada, Garg, et al. 2009). Hence, a centralized image interpretation process may be used to help control image quality as well as to provide the actual imaging-based endpoint measurements."
"In a time-sequential presentation, a subject’s complete image set (from baseline through the follow-up evaluations) is shown in the order in which the images were obtained. In this process (unless prespecified and justified in the charter), the reader does not initially know the total number of time points in each subject’s image set.
 In a hybrid, randomized image presentation, a subject’s complete image set (or only the postbaseline images) are shown fully randomized. After the read results have been locked for each time point, the images are shown again in known chronological order for re-read. Changes in any of the randomized assessments are tracked and highlighted in the final assessment. In within-subject-control trials (e.g., comparative imaging), images obtained before and after the investigational drug should be presented in fully randomized unpaired fashion and in randomized paired fashion in two separate image evaluations. The minimum number of images in each randomized block necessary to minimize recall should be considered."
Firewall to prevent the sponsor from performing the aggregate analysis: Building a firewall between the sponsor and the Data Monitoring Committee is a technique that is necessary to make sure that the study integrity is maintained. The firewall between the sponsor the investigator/clinical research organization can also be implemented in an open label study or single-blind study so that the sponsor is prevented to access the cumulative data for the primary efficacy endpoint for analysis. The primary efficacy endpoint information is accessible to the investigator and the CROs, but withheld from the sponsor. While the investigator and CRO may have some biases due to knowing the treatment assignment, but the biases from the sponsor side may be prevented.

Additional reading:

1.      Kenneth F Schulz, David A Grimes (2002) Blinding in randomised trials: hiding who got what
2.      Karanicolas et al (2009) Blinding:Who, what, when, why, how?
3.      Brennan C. Kahan et al (2015) Blinded Outcome Assessment Was Infrequently Used and Poorly Reported in Open Trials
4.      Brennan C Kahan (2014) Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials
5.      FDA Clinical Trial Endpoints for the Approval of NonSmall Cell Lung Cancer Drugs and Biologics Guidance for Industry
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