Unblinding

Complaints, product recall and emergency unblinding - complaints and recall procedures... 

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. 

Shaner (1988)45 Time spent in SE Incidence of intubation, Unblinded study... 

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. 

Unfortunately, many clinical studies evaluating the efficacy of dietary supplements are flawed. Some of the flaws in the studies include non-randomization, being unblinded, lack of standardized products, small sample sizes, short treatment durations, and poorly defined inclusion and exclusion criteria. Many studies do not give detailed information about the dietary supplement used. When an herb is studied, the following information should be described plant species, part(s) used, product form (e.g., powdered crude herb, aqueous extract, ethanol extract, or aqueous alcohol extract) with stated proportions of water to alcohol, specifically extracted fractions, and quantities or concentrations used [48]. 

Unblinding. If the patient or physician are unblinded due to rapid improvement of the disease or an ADR they may be led to expect ADRs with the active treatment. 

The phase-three results were unblinded in March 2003 and overall, for all types of metastatic brain cancer, were reported as nonpositive, showing the drug to have efficacy but not at the statistical level set at the beginning of the trial by Alios Therapeutics Inc. for a successful phase-three trial. The subset analysis for the different types of metastatic cancer to brain, however, showed that breast cancer patients had a 100% increase in survival. The 500 plus patient trial also demonstrated RSR 13 to be extremely safe, confirming our early design feature of using a known antilipidemic drug, clofibrate, as a substructure. An NDA for RSR 13 with trade name efaproxaril was reviewed by the PDA on a fast track review for use in treatment of metastases of breast cancer to brain. 

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... 

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. 

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. 

Sealed codes used for unblinding a study subject... 

Non-randomized concurrent clinical trials initially assign participants to a control or test group in a non-random fashion. These trials are run concurrently, but are unblinded. This introduces a danger that the control and intervention groups are not strictly comparable. 

It is good practice to pre-specify in the protocol, or certainly in the statistical analysis plan, the statistical method to be used for analysis for each of the endpoints within the confirmatory part of the trial. This avoids the potential for bias at the analysis stage, which could arise if a method were chosen, for example, which maximised the treatment difference. As a consequence changing the method of analysis following unblinding of the study in an unplanned way, even if there seem sound statistical reasons for doing so, is problematic. Such a switch could only be supported if there was a clear algorithm contained within the statistical analysis plan which specified the rules for the switch. An example of this would be as follows ... 

In most cases, safety monitoring wUt be the major task for a DMC. Even if the safety parameters monitored are not directly related to efficacy, a DMC might need access to unblinded efficacy information to perform a risk/benefit assessment in order to weigh possible safety disadvantages against a possible gain in efficacy. ... 

There will also be at least one other statistician involved closely with the activities of the DMC and this is the statistician who supplies data tables to the committee for their deliberations. This statistician should also not be otherwise involved in the trial as they will potentially be supplying unblinded information to the DMC and attending their meetings. In the way that these things tend to be organised these days this individual may be part of a CRO that is providing this service (and potentially other services) to the sponsor. See Pocock (2004) and the FDA guideline for further discussion on this and related points. The DMC should also receive details of individual SAEs, usually in the form of narratives and these will often be supplied directly from the sponsor. These patients can be unblinded by the independent statistician if this has not already been done. 

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. 

Maintaining the blind is critical in these re-evaluations, otherwise a price in terms of the type I error, a, may need to be paid as looking at unblinded data could be viewed as a formal interim comparison of the treatments. There may... 

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