Someone asked an interesting question on the IRBForum today. Under what circumstances
should the blinding for a trial be broken when an unexpected Serious Adverse Event (SAE)
occurs? The questioner did mention the International Conference
on Harmonisation (ICH) guidelines which read as follows:
When the sponsor and investigator are blinded to individual patient treatment (as
in a double-blind study), the occurrence of a serious event requires a decision on
whether to open (break) the code for the specific patient. If the investigator breaks
the blind, then it is assumed the sponsor will also know the assigned treatment for that
patient. Although it is advantageous to retain the blind for all patients prior to final
study analysis, when a serious adverse reaction is judged reportable on an expedited
basis, it is recommended that the blind be broken only for that specific patient by the
sponsor even if the investigator has not broken the blind. It is also recommended that,
when possible and appropriate, the blind be maintained for those persons, such as
biometrics personnel, responsible for analysis and interpretation of results at the
study's conclusion.
There are several disadvantages to maintaining the blind under the circumstances
described which outweigh the advantages. By retaining the blind, placebo and comparator
(usually a marketed product) cases are filed unnecessarily. When the blind is eventually
opened, which may be many weeks or months after reporting to regulators, it must be
ensured that company and regulatory data bases are revised. If the event is serious,
new, and possibly related to the medicinal product, then if the Investigator's Brochure
is updated, notifying relevant parties of the new information in a blinded fashion is
inappropriate and possibly misleading. Moreover, breaking the blind for a single patient
usually has little or no significant implications for the conduct of the clinical
investigation or on the analysis of the final clinical investigation data.
However, when a fatal or other "serious" outcome is the primary efficacy endpoint
in a clinical investigation, the integrity of the clinical investigation may be
compromised if the blind is broken. Under these and similar circumstances, it may be
appropriate to reach agreement with regulatory authorities in advance concerning serious
events that would be treated as disease-related and not subject to routine expedited
reporting. Clinical Safety Data Management: Definitions And Standards For
Expedited Reporting. E2A, page 9.
www.fda.gov/cder/guidance/iche2a.pdf
This is excellent advice. In particular, I support their comment about how breaking the
blind for a single patient usually doesn't have any significant implications on the
scientific validity of the study. Sometimes researchers get hung up over running the
"perfect" research study and let that unduly interfere with other important considerations.
Another consideration is that the research subjects themselves should have the option of
breaking the blind. For example, a research subject is about to undergo an unexpected surgery
and needs to know about the drug being administered in the clinical trial because one of the
two drugs being studied thins out the blood and increases the risk of the operation.
You don't want to break the blind for any old reason, but if the patient has a legitimate
reason to know, we should respect that. Patients who volunteer for a research study cede a
lot of their autonomy when they join. They let a random flip of the coin decide which
treatment they get and in most cases, they are kept in the dark about that treatment they get
until the study is over. There are good reasons why we ask patients to sacrifice this much
autonomy, but we should recognize that it is indeed a sacrifice and we should respectfully
return that autonomy early to the patient when there is a good medical justification.
In a perfect world, the rules under which the blinding might be broken should be specified
in the research protocol.
A final consideration is that any data safety and monitoring board should have access to
unblinded data, especially in trials where SAEs occur frequently.
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Safeguarding patients in clinical trials with high mortality rates. Freeman BD,
Danner RL, Banks SM, Natanson C. Am J Respir Crit Care Med 2001: 164(2); 190-192.
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