Breaking blind

But do the clinical-trial data submitted to the FDA even establish proof of principle Recall that the rather small differences found between drug and placebo in the trials submitted to the FDA could have been due to the breaking of blind on the basis of perceived side effects. It may simply be evidence of an enhanced placebo effect, rather than a true drug effect. As I noted in Chapter i, once side effects are taken into account, the difference between SSRI and placebo is not even statistically significant.30... 

Rules governing the imblinding of the trial must be given in the protocol. In the normal course of the trial, this occurs at the end of a stated period, although subjects may be maintained on open observation for a further period of time. The breaking of the blind is a serious matter, as it can spoil part or the whole of the trial. The occurrence of a major adverse event is the most frequent reason for imblinding and, in most circumstances, requires a discussion between sponsors and investigators. 

There is an ethical imperative, despite blinding, to protect the patient from harm. Therefore, it is most important that a system is developed to allow the blind to be broken in circumstances, for example, when a patient suffers a serious adverse reaction. The study protocol should describe those conditions under which the blind may be broken and the system itself should allow the breaking of the blind in a single patient, rather than the whole study. 

The book Science and Corporate Strategy DuPont R D, 1902-1980 by Hounshell and Smith (1988) presents a well-documented story of the long journey of nylon from discovery to the marketplace. A large number of people were involved. The effort received many lucky breaks, as well as entering and abandoning numerous blind alleys, and requiring dedication and determination when things looked bleak. The journey can be divided into a number of phases that overlap in time the exploration-discovery phase, the development phase, and the commercialization-business phases. 

Any final decisions regarding combinations should be made at the Blind Review stage prior to breaking the blind. 

The definition of a per-protocol set of subjects allows us to get closer to the scientific question by including only those patients who comply with the protocol to a defined extent. The per-protocol set, like the full analysis set, must be prespecified in the protocol and then defined at the patient level at the blind review, following database lock, but before breaking the blind. It must be noted, however, that the per-protocol set is subject to bias and further, tends to overestimate the treatment effect. For this reason it is usually used only as a secondary analysis, supportive hopefully of the findings based on the full analysis set. 

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 ... 

Gardner and Cowdry (1985) found an increase in dyscontrol in borderline patients taking alprazolam in a double-blind, placebo-controlled cross-over study. The dyscontrol included the following Overdose, severe Overdose, moderate Deep neck cuts Transverse wrist cuts Tried to break own arm Threw chair at child and Arm and head banging jumped in front of car. ... 

The blinded data was the only valid data. However, Eli Lilly ran roughshod over science by breaking the blind in providing its new evaluators data indicating what each of the patients were taking when they were found to have attempted suicide. Thus, when evidence-based ... 

Blindness can also be destroyed by accidental breaking of the randomization code. With good design and adequate safeguards, however, this should not occur. 

The G.D., according to what little I hear, is practically in the hands of the B.B. [the Jesuits] who have worked on their old principle of Divide et impera , and have succeeded in breaking it up, which is always their aim with Occult Orders. The wish to keep it on is not sincere on the part of at least one. It is only a blind to keep it in the hands of the B.B. 

Tubes can be replaced. Tube-side headers, channel covers, gaskets, etc., are accessible for maintenance and replacement. Neimer the shell-side baffle structure nor the blind gasket is accessible. During tube removal, a tube may break within the shell. When this occurs, it is most difficult to remove or to replace the tube. The usual procedure is to plug the appropriate holes in the tube sheets. 

Say you want to make a house more energy efficient (a JTBD). But instead of tackling this problem as a whole, you could use Heuristic Redefinition to visually break the problem into smaller pieces. You could focus on any number of relevant system components the house itself, its insulation, the sun outside, the surrounding trees, the windows, the shades or blinds, the awnings over the windows, major appliances, or the house s ventilation system. With this breakdown, you can see the whole system and begin to hone in on the part(s) that promise to yield the most innovation for the least amount of effort, time, and resources invested. 

Blinding should go beyond the observer and the observed. None of the investigators should be aware of treatment allocation, including those who evaluate endpoints, assess compliance with the protocol and monitor adverse events. Breaking the blind (for a single subject) should be considered only when the subject s physician deems knowledge of the treatment assignment essential in the subject s best interests. 

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