Blinding and Unblinding

All statutory and/or company regulations or codes relevant to blinding or unblinding must be strictly adhered to. 

The sequence of blinding and unblinding must be carefully planned prior to startup or shutdown. The point in the startup-shutdown program at which each blind is to be inserted or removed should be clearly defined in the operating procedure (153). 

Likewise, the possibility of reverse flow from the column into 

A checklist of all the blinds to be installed or removed should be made. Whenever a blind is installed or removed, the operator witnessing the operation or removal should mark the date and time and initial the checklist (153). 

The pressure and temperature ratings as well as the material specifications of each blind should be checked to ensure compatibility with the column or line. There were cases of slip plates that corroded right through (210 Fig. 11.4a). In other cases, slip plates bowed due to excessive pressure (210 Fig. 11.46). 

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Extreme caution must be exercised when cracking flanges for blinding and unblinding (153, 210). The specific precautions must follow the safe handling procedures of the chemicals involved, and any statutory or company requirements. 

Cracking flanges must not be authorized without a written permit issued by a supervisor responsible for safety. The permit must list any specific precautions unambiguously. Breakdown of communication has caused several accidents during blinding and unblinding. In some cases (7), explosions resulted. 

Interim reviews of the data are an essential requirement to minimise risk during dose-escalation studies. After each study day, or certainly after a predefined number of volim-teers have received the next dose increment, the investigator, nurses, study physician and preferably one or two other experienced physicians who are not intimately involved with the study should meet to review the data. When the study is being conducted in a CRO, a sponsor company physician and a limited number of other personnel should participate by tele- or video-conference if not in person. A decision to stop, modify or continue dose escalation should be made jointly between the Principal Investigator at the CRO and the sponsor s physician. Such reviews should be conducted with maintenance of the double-blind and steps should be taken to avoid inadvertent unblinding, such as by coding of subject numbers. The data that should be reviewed are listed in Box 4.12. 

The ED plan will enumerate which studies are to be performed in healthy volunteers and which in patients. As the first studies progress, the information generated needs to be constantly evaluated while still blinded, and of course on unblinding after database lock at the end of each study. The decision to proceed to the patient population should take into account how well the studies have actually achieved their objectives. 

Acute Aspirin Therapy for AF-associated Stroke A combined analysis of the 1ST and CAST trials indicated a 21% RRR (95% Cl —5 to 41) in the frequency of early recurrent stroke associated with acute aspirin therapy compared to placebo in patients with AF. No difference in early mortality or sICH was found. This finding was largely driven by the relatively large (about 25% RRR) benefit observed in the unblinded 1ST, compared to the smaller benefit (5% RRR) observed in the double-blinded CAST. 

Swartzman, L. C. 8c Burkell, J. (1998). Expectations and the placebo effect in clinical drug trials why we should not turn a blind eye to unblinding, and other cautionary notes. Clin. Pharmacol. Ther., 64, 1-7. 

As far as possible, the study should be conducted under double-blind conditions. Sometimes, pharmacological effects, desired or undesired, tend to unblind the study but even in these circumstances the identity of treatment will be unknown to subjects and observers at the time of dosing and before onset of effects, thereby minimising bias. Specified persoimel, such as the pharmacist, bioanalyst and pharmacokineticist, may need to know the treatment allocation code... 

Are there clear instructions for reporting of adverse events and serious adverse events (SAEs) There should be full instructions for the reporting of SAEs (including addresses and fax numbers), with time limits. It should be clear that these rules also apply to SAEs that occur in subjects who have finished the study. All SAEs that come to the knowledge of the trialist should be reported unless the protocol provides guidance or time limit when the authors can justify that the occurrence of the SAE could not be related to the treatment received in the clinical trial. In a blinded study, there should be clear instructions on when and by whom the code for a particular study subject should be unblinded in an emergency. 

Data tables produced for the DMC should contain separate summaries by treatment group, with the treatment groups labelled A and B (partially blinded). A separate sealed envelope or a password-protected electronic file should be provided to the members with decodes for A and B to enable the DMC members to be completely unblinded. This may seem an elaborate process, but it protects against inadvertent unblinding. 

There is one final opportunity to revisit the proposed methods of statistical analysis prior to the breaking of the blind, or in an unblinded trial, before the statistics group have seen study data. This so-called blind review usually takes place around the time of database lock and the following lists some of the aspects of analysis that would generally be considered ... 

In addition to manufacturing both the test drug and the comparator drug, these materials need to be blinded. A trial may be called a double-blind study when neither the subjects nor any of the people concerned with their evaluation and care know which treatment the subjects are receiving. While double-blind trials predominate, in some cases a single-blind trial is conducted if it is not possible to blind the subjects (or sometimes the investigators). When trials are conducted in which everyone knows what treatment a subject is receiving, the trial is said to be unblinded. 

Clozapine has been used to treat benign essential tremor refractory to the usual drugs (propranolol, primidone, alprazolam, phenobarbital, and botulinum toxin) in a randomized, double-blind, crossover study in 15 patients with essential tremor (58). Responders with more than 50% improvement after a single dose of clozapine 12.5 mg, compared with placebo, subsequently received 39-50 mg unblinded for a mean of 16 months. Tremor was effectively reduced by a single dose of clozapine in 13 of 15 patients sedation was the only adverse effect reported. 

The execution of an interim analysis should be a completely confidential process because unblinded data and results are potentially involved. All staff involved in the conduct of the trial should remain blind to the results of such analyses, because of the possibility that their attitudes to the trial will be modified and cause changes in the characteristics of patients to be recruited or biases in treatment comparisons. This principle may be applied to all investigator staff and to staff employed by the sponsor except for those who are directly involved in the execution of the interim analysis. Investigators should be informed only about the decision to continue or to discontinue the trial, or to implement modifications to trial procedures. 

Clinical trial sponsors also have the obligation to report safety information to investigators and ethics committees in a timely fashion. Ethics committees can be informed in an unblinded fashion within the same timeframe as the regulatory authorities, or in reasonable, regular intervals (commonly quarterly). The investigators can be updated periodically in a blinded fashion, provided that no compelling safety reason to unblind have emerged. 

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