Randomization and blinding are critical components of the clinical trial from the start (design) to the end. Randomized, controlled, and double blinded trial (RCT) has been the ideal clinical trial design. Inappropriate randomization and blinding (or potential unblinding) affect the integrity for the clinical trial. If the patient or investigator is aware of the treatment assignment, there will be conscious or unconscious biases in assessing efficacy, safety, or patient-reported outcome. With available software and computer programs, generating randomization schedule is relatively easy. Ten years ago, I wrote a paper on “Generating randomization schedule using SAS programming” to show how easily the randomization can be generated. With the interactive response technologies (IRT) including interactive voice response system (IVRS) and interactive web response system (IWRS), implementation of the randomization can also be easily managed. However, maintaining the blinding during the study may not be as easy as we thought.
I still remember the time when I was one of the randomization team members in PPD. After we generated the randomization schedule, we had to put the randomization schedule into an envelope and sealed with signatures. Then we had to put the envelope into a locked security box in a secured randomization room. In order to get the randomization schedule, at least two statisticians had to be present in order to open the security box.
While the actual randomization schedule is locked and secured, the randomization information or treatment assignment concealment can still be compromised by what happened at the site, how the patient and investigator guess the treatment assignment, and how the unblinded personnel communicate with the blinded team members.
There are many factors that can cause the potential unblinding. Here are some examples:
- Guess treatment assignment by the experience of adverse events and side effects. Suppose an intravenously administered drug can cause more headaches than Placebo, a patient with headache may guess he/she is on treatment group and not on Placebo. While this guess may not be 100% accurate, majority of patients may guess their treatment assignment correctly. In a book by Chow et al, ‘Design and analysis of clinical trials: concepts and methodologies’, an example about challenge in maintaining blinding was described “beta-blocker (e.g., pro-pranolol) have specific pharmacologic effects such as lowering blood pressure and the heart rate and distinct adverse effects such as fatigue, nightmares, and depression. Since blood pressure and heart rate are vital signs routinely evaluated at every visit in clinical trials, if a drug such as propranolol is known to lower blood pressure and the heart rate, then preservation of blindness is a huge challenge and seems almost impossible” In a large scale study (BHAT study), at the conclusion of the trial, patients, investigators, and clinical coordinators were asked to guess the patient’s treatment assignment, 79.9%, 69.6%, and 67% of patients, investigators, and clinical coordinators respectively guessed correctly the patient was on Propranolol and 42.8%, 58.6, and 70.6% of patients, investigators, and clinic coordinators respectively guessed correctly that the patient was on Placebo.
- Guess treatment assignment by improvement or no improvement in efficacy. If there is a prior knowledge that an treatment is effective (lack of equipoise), the investigator or patient can guess which treatment the patient is on based on the lack of effect.
- Guess treatment assignment by knowing the blood concentration of the drug or analytes. If a treatment is for augmentation purpose, a patient could have his/her blood sample tested to know whether or not the concentration for augmented drug is increased or not, then guess which treatment group he/she is on.
- In double-blinded studies, there are always some unblinded groups. These groups could include global drug safety for safety monitoring, laboratories that measure drug concentration or biomarkers, study drug supplies, site unblinded pharmacist… all of these groups could potentially reveal the treatment assignment to other study team unintentionally.
- For a study with DMC that involved a third party to prepare the unblinded data for DMC, treatment concealment could potentially be compromised during the information exchange with the blinded study team. This is critical for studies with adaptive designs where the patient data needs to be constantly reviewed and analyzed. An interesting example was discussed by Janet Witts regarding an awkward situation in an adaptive design where the DMC knew the event rate by treatment assignment and the sponsor didn’t.
There is a dilemma when we develop the informed consent form. On the one hand, we are required to put into the informed consent form as much information as we can. On the other hand, the more information we put into the informed consent form, the more likely we enable the patients to guess their treatment assignment (based on their experience of side effects or perceived efficacy).
Ideally, in double-blind trial, it is a good practice to evaluate for both the subjects and investigators whether or not blinding / masking has been preserved. However, in real world, it is rare in double-blinded clinical trials to include formal assessment about how good the blinding has been preserved. If assessment of blinding becomes a routine, I think that many studies will show that subjects / investigators guessed correctly more frequently than they should have done by chance alone. Part of the reason this assessment has not been done often is perhaps the difficulty to explain the study results if the blinding is found to be compromised. It will be extremely difficult to assess the magnitude of the impact on the safety and efficacy evaluation if the blinding / treatment assignment concealment is compromised.
- Blinded trials taken to the test: an analysis of randomized clinical trials that report tests for the success of blinding
- Blinding, unblinding, and the placebo effect: An analysis of patient’s guesses of treatment assignment in a double-blind clinical trial
- Can keeping clinical trial participants blind to their study treatment adversely affect subsequent care?