However, not everybody is blinded to the treatment assignment. On the Sponsor side, the clinical trial material (CTM) management group is usually unblinded and has full access to the treatment assignments - because they need to make sure that the correct drugs (active or control) are packaged, labeled, shipped, and dispensed. CTM group will track the inventory at the study sites to make sure the study materials are available at all open sites.
The drug safety group or pharmacovigilance group (PVG) may also request for full access to the treatment assignment and they claim the full access to the treatment assignment is needed for serious adverse event reporting.
It is true that the regulations require the drug safety group to report the 'serious and unexpected suspected adverse reaction (SUSAR)' to regulatory agencies, investigators, and IRBs/ECs.
- 21CFR 312.32 IND safety reporting
- Directive 2001/20/EC of the European Parliament and of the Council
- Breaking the Blind in Clinical Trials & Reporting to Health Authorities, Investigators & IRBs/Ethics Committees
- Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
- Safety assessment in Clinical Trials and Beyond
"(i) Serious and unexpected suspected adverse reaction. The sponsor must report any suspected adverse reaction that is both serious and unexpected. The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as:
(A) A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);
(B) One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture);
(C) An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group."
EU has similar regulations. According to EU directive "on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use"
Article 17 Notification of serious adverse reactions 1. (a) The sponsor shall ensure that all relevant information about suspected serious unexpected adverse reactions that are fatal or life-threatening is recorded and reported as soon as possible to the competent authorities in all the Member States concerned, and to the Ethics Committee, and in any case no later than seven days after knowledge by the sponsor of such a case, and that relevant follow-up information is subsequently communicated within an additional eight days. (b) All other suspected serious unexpected adverse reactions shall be reported to the competent authorities concerned and to the Ethics Committee concerned as soon as possible but within a maximum of fifteen days of first knowledge by the sponsor. (c) Each Member State shall ensure that all suspected unexpected serious adverse reactions to an investigational medicinal product which are brought to its attention are recorded. (d) The sponsor shall also inform all investigators.
It is true that the drug safety group needs the treatment assignment information to assess the causal relationship of a SUSAR event to the study drug. If a SUSAR occurs in a placebo group, the event will then not be required to be reported.
Unlike the STM group, the drug safety group only needs the treatment assignment for individual subjects at the time when a SUSAR is reported. It is concerning that the drug safety group is given full access to the treatment assignment for all subjects. Drug safety group personnel sometimes can accidentally communicate the treatment assignment information outside the drug safety group (to the investigator and to the blinded study team) and causing the accidental unblinding of the subject.
I just read the FDA’s review document for a Merck product and noticed the review comments mentioning that drug safety staff should be blinded during the study. Given the potential accidental unblinding caused by drug safety staff, it is prudent to restrict drug safety staff’s access to the randomization codes for ongoing blinded studies.
I just read the FDA’s review document for a Merck product and noticed the review comments mentioning that drug safety staff should be blinded during the study. Given the potential accidental unblinding caused by drug safety staff, it is prudent to restrict drug safety staff’s access to the randomization codes for ongoing blinded studies.
However, the drug safety group should be given emergency access to the randomization codes. In the situation a SUSAR is reported, drug safety personnel who are handling the SUSAR reporting can log into the interactive response technology (IRT) including interactive web response (IWR) and interactive voice response system (IVR) systems, and obtain the randomization information and treatment assignment for the individual subject with SUSAR reported.
In summary, the drug safety group or PVG should not be given full access to all randomization codes, but should be provided in a controlled way the access to treatment information for individual subjects who have SUSAR reported.
Clinical trials are usually designed as double-blinded studies whenever the blinding is feasible to avoid the conscious and unconscious bias in safety and efficacy assessment. The drug safety group or pharmacovigilance group (PVG) may also request full access to the treatment assignment. They claim full access to the treatment assignment is needed for serious adverse event reporting.
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