Educating Investigators to Understand When to Break the Blind

Investigators are sometimes eager to open a subjects blinding code when they perceive a medical emergency. Informing investigators about expected adverse events can forestall these requests.

According to the ICH Guideline for Good Clinical Practice (4.7), the investigator should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding . . . .

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Situations that might warrant breaking the code are usually defined in the protocol (a serious adverse event, for example). Still, some investigators understand breaking the blind as a compulsory step to be followed with any serious adverse event, even if knowledge of the study drug is not relevant to the treatment of the adverse event.

Examining an event that occurred in Spain suggests some ways to avoid unnecessary code-breaking. An investigator phoned the sponsor asking to open a subjects blinding code. The subject was in a double-blind Phase 2 study for the treatment of benign prostatic hyperplasia. The therapies being compared were two different doses of a new alpha blocker, a marketed alpha blocker, and placebo.

An adverse event in SpainThe CRAs story. I was in my office when the phone rang. It was Dr. X, who sounded as though he were in a state of great panic.

Subject MJO received the first dose four hours ago, and now he is having postural hypotension, said Dr. X. His blood pressure is dropping every second, and now it is 101/65. I need to know immediately what drug he is taking, he demanded. Is there any particular treatment for this event?

The standard treatment as for any postural hypotension, I said. There is no need to open the blind.

My response did not calm the doctors anxious demands. Well, I need to know the drug anyway. In the event of a cardiac arrest, the emergency personnel will need to know all the medications he was taking. And even if theres no emergency, Id like to tell the subject what he was taking, he said firmly.

I will need to discuss this with the project manager in charge of the study, I said, but Dr. X was not to be delayed.

Look, his blood pressure is dropping to 91/60! he said. He is sick and dizzy. There is no time for discussionIm opening the code.

I did not argue further. The blinding code was opened, and revealed the standard treatment. Dr. X administered intravenous fluids, as for any postural hypotension. One hour later, the subject had recovered.

The project managers story. At my office here in the UK, I got a voice mail message from the CRA. I thought it was crazy to break the code, but by then it was too late; the code was broken. What could I do?

The urge to unblind
Why did this investigator want to open the blind even though there was no antidote for the new drug and the expected adverse reaction would have to be treated like any other alpha blocker postural hypotension? Perhaps the investigator had his doubts about the study drug. Sometimes it is hard for a clinical research associate to explain the meaning of events to a project manager who comes from a different medical/scientific culture. The difference in perspective can lead to misunderstanding, investigator lack of confidence, and project manager misinterpretation of an adverse event. The investigator might have been embarrassed about referring the subject to another doctor without knowing the study treatment. Not knowing the name of the drug that caused the adverse event might have made the investigator feel uneasy in front of the subject.

Investigators have a legitimate reason to open the blind when the study drug is likely to have a significant effect on clinical management of the subject, as in the case of a serious adverse event. Without adequate information about what adverse events they might expect, investigators could believe that any adverse event could become serious.

Consequences of breaking the blind for one subject
Whether or not a medical emergency warrants breaking the blind, unblinding has several consequences.

• Subsequent assessment of that subject may be affected by the investigators (or sponsor staffs) knowledge of the treatment received.
• The subject will generally be included in an intent-to-treat analysis, but will usually be excluded from the evaluable subject or protocol-compliant analysis, even if the subject continues and completes the study normally. Therefore, by breaking the blind we lose data.²
• If the open blinding disclosure code is not quickly forwarded to the data manager, the subjects data may be inappropriately included in evaluable subject analyses.³
• Finally, blocking is used to try to ensure that each site has subjects on all study treatments. When the randomization code is based on small blocks, breaking the blind for one subject may reveal information about the treatment of other subjects. The study cited in this article used a block size of four, with one subject in each block receiving each treatment. Knowing what our unblinded subject was receiving tells everyone that the other subjects in the block were receiving something else. (Sponsors are often secretive about the block size to make this detective work harder for investigators.)

How to avoid unblinding
Taking a few precautions in advance can decrease the likelihood of anxious calls like the one in our example.

First, provide information to the investigators about the adverse events that might occur and the treatment required. If you refresh this information at every opportunity, you will improve your investigators confidence in their ability to handle expected adverse reactions without opening the blind.

If a medical emergency does arise, urge the investigators to make every effort to consult the studys clinical manager before opening the blinding code.

In case a clinical trial subject is treated by physicians other than the investigator, the investigator should describe on the clinical records the treatment to follow in case of an expected adverse reaction. This might stop physicians not familiar with the clinical study from requesting permission to break the blind.

References
1. Guideline for Good Clinical Practice, International Conference on Harmonisation, Federal Register 62 (901) 2569125709 (9 May 1997; also available from EMEA, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK, or www.eudra.org/humandocs/PDFs/ICH/013595en.pdf).

2. Sally Hollis and Fiona Campbell, What is Meant by Intention to Treat Analysis? Survey of Published Randomised Controlled Trials, British Medical Journal, 319, 670674 (1999).

3. K.F. Schulz et al., Blinding and Exclusions after Allocation in Randomised Controlled Trials: Survey of Published Parallel Group Trials in Obstetrics and Gynaecology, British Medical Journal, 312, 742744 (1996).

Eduardo Ayala, MD, is supervisor clinical research associate with Pfizer Global Research and Development, Ave. Europa, 20-B Parque Empresarial La Moraleja, 28108 Alcobendas, Madrid, Spain, +34 91 490 9479, fax +34 91 490 9712, e-mail: Eduardo_Ayala@sandwich.pfizer.com.Neil MacKillop, MD, is senior director, Pfizer Global Research and Development, Sandwich, United Kingdom.