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Reflect on the consequences of not using controls. The first modern silicone implants (Dow Corning’s Silastic mammary prosthesis) were placed in 1962. In 1984, a jury awarded $2 million to a recipient who complained of problems resulting from the implants. Award after award followed, the largest being more than $7 million. A set of controlled randomized trials was finally begun in 1994. The verdict: Silicon implants have no adverse effects on recipients. Tell this to the stockholders of bankrupt Dow Corning.
Use positive controls.
5 Dr. Good told his wife he was an author—it was the only way he could lure someone that attractive to his side. Dr. Hardin is still searching for an explanation for his own good fortune.
CHAPTER 3 COLLECTING DATA 35
There is no point in conducting an experiment if you already know the answer.6 The use of a positive control is always to be preferred. A new anti-inflammatory should be tested against aspirin or ibuprofen. And there can be no justification whatever for the use of placebo in the treatment of a life-threatening disease (Barbui et al., 2000; Djulbegovic et al., 2000).
Observers should be blinded to the treatment allocation.
Patients often feel better solely because they think they ought to feel better. A drug may not be effective if the patient is aware it is the old or less-favored remedy. Nor is the patient likely to keep taking a drug on schedule if he or she feels the pill contains nothing of value. She is also less likely to report any improvement in her condition, if she feels the doctor has done nothing for her. Vice versa, if a patient is informed she has the new treatment, she may think it necessary to “please the doctor” by reporting some diminishment in symptoms. These sorts of behavioral phenomena are precisely the reason why clinical trials must include a control.
A double-blind study in which neither the physician nor the patient knows which treatment is received is preferable to a single-blind study in which only the patient is kept in the dark (Ederer, 1975; Chalmers et al., 1983; Vickers et al., 1997).
Even if a physician has no strong feelings one way or the other concerning a treatment, she may tend to be less conscientious about examining patients she knows belong to the control group. She may have other unconscious feelings that influence her work with the patients, and she may have feelings about the patients themselves. Exactly the same caveats apply in work with animals and plants; units subjected to the existing, lessimportant treatment may be handled more carelessly and may be less thoroughly examined.
We recommend you employ two or even three individuals, one to administer the intervention, one to examine the experimental subject, and a third to observe and inspect collateral readings such as angiograms, laboratory findings, and x-rays that might reveal the treatment.
Conceal Treatment Allocation
Without allocation concealment, selection bias can invalidate study results (Schultz, 1995; Berger and Exner, 1999). If an experimenter could predict the next treatment to be assigned, he might exercise an unconscious bias in the treatment of that patient; he might even defer enrollment of a
6 The exception being to satisfy a regulatory requirement.
36 PART I FOUNDATIONS
patient he considers less desirable. In short, randomization alone, without allocation concealment, is insufficient to eliminate selection bias and ensure the internal validity of randomized clinical trials.
Lovell et al.  describe a study in which four patients were randomized to the wrong stratum; in two cases, the treatment received was reversed. For an excruciatingly (and embarrassingly) detailed analysis of this experiment by an FDA regulator, see http://www.fda.gov/cber/review/etanimm052799r2.pdf.
Vance Berger and Costas Christophi offer the following guidelines for treatment allocation:
• Generate the allocation sequence in advance of screening any patients.
• Conceal the sequence from the experimenters.
• Require the experimenter to enroll all eligible subjects in the order in which they are screened.
• Verify that the subject actually received the assigned treatment.
• Conceal the proportions that have already been allocated (Schultz, 1996).
• Conceal treatment codes until all patients have been randomized and the database is locked.
• Do not permit enrollment discretion when randomization may be triggered by some earlier response pattern.
Blocked Randomization, Restricted Randomization, and Adaptive Designs
All the above caveats apply to these procedures as well. The use of an advanced statistical technique does not absolve its users from the need to exercise common sense. Observers must be kept blinded to the treatment received.
TO LEARN MORE
Good  provides a series of anecdotes concerning the mythical Bumbling Pharmaceutical and Device Company that amply illustrate the results of inadequate planning. See also Andersen  and Elwood .