I read an article by Clark et al “Envelope use and reporting in randomized controlled trials: A guide for researchers”. The article reminds me of the old times when envelopes were the popular ways for randomization and blinding (treatment concealment). In the 1990s and 2000s, for randomized, blinded clinical trials, the concealed envelope is the only way for the investigator to do the emergency unblinding (or code breaking) and sometimes the way to administer the randomization for single-blinded studies.
In Berende et al (2016, NEJM) “Randomized Trial of
Longer-Term Therapy for Symptoms Attributed to Lyme Disease”, the
study protocol described the following procedure for "unblinding of randomization" where sealed envelopes were used.
I used to be an unblinded statistician to prepare the randomization
schedule (including the randomization envelopes) for clinical trials. The
following procedures will need to be followed:
- Based on the study protocol, develop the randomization specifications describing randomization ratio, stratification factors, block size, the number of randomization codes, recipients of the randomization schedule, or code-break envelopes
- Generate the dummy randomization schedule for the study team to review and approval
- Replace the random seed to generate the final randomization schedule (a list of all randomized assignments)
- Prepare the randomization envelopes (randomization number, stratification factors outside the envelope, and treatment assignment inside the envelope)
- QC the randomization envelopes (to make sure that inside/outside information matches the randomization schedule
- Shipping and tracking
For double-blinded studies, both the investigator and the
patient are blinded to the treatment assignment. The randomization schedule
will usually be sent to a third party (for example, the pharmacist) who is
unblinded to the treatment assignment and can prepare the study drug for dispensing
or administration. The third-party (for example, the pharmacist) must not be
involved in other aspects of the clinical trial conduct. The concealed envelopes
can be sent to the investigators for emergency unblinding. If there is a medical emergency requiring the
unblinding of an individual subject, the investigator can open the code
break envelope to reveal the treatment assignment for the specific subject.
For single-blinded studies, the investigator is unblinded to
the treatment assignment and the patient is blinded to the treatment assignment.
The randomization schedule and/or the randomization envelopes can be sent to
the investigators.
Nowadays, randomization through envelopes is obsolete.
The randomization procedures are integrated into the overall CTM (clinical trial material) management process through the IRT (interactive response technologies). In the last 20 years, the randomization process has shifted from randomization envelopes
-> IVRS (interactive voice response system) -> IWRS (Interactive Web
Response System) - > IRT.
With IRT, the randomization schedule will be sent to the IRT
vendor and uploaded into the IRT system. The study team members can be assigned different levels of access to the IRT system depending on their roles in the
study. The investigators and pharmacovigilance personnel can be granted the emergency
access code for them to gain the access to the treatment assignment in IRT when necessary.
However, in some situations, randomization envelopes may still
the best way for implementing the randomization.
In a study by Chetter et al “A
Prospective, Randomized, MulticenterClinical Trial on the Safety and Efficacy
of a Ready-to-Use Fibrin Sealant as an Adjunct to Hemostasis during Vascular
Surgery”, the randomization occurred in the operation room and only after
the target bleeding site (TBS) was identified after the surgical procedure.
There would not be ideal for the surgeon (the investigator) to log into the IRT
system to obtain the treatment assignment information. The better approach
would be for the surgeon or surgeon’s assistant to open the randomization envelope to
obtain the treatment assignment information in the operation room. The
randomization procedure was described as the following in the paper:
Randomization
In the Primary Study, patients were randomized 2:1to treatment with FS Grifols or MC after the identification of the TBS during the procedure. Treatment group assignments were generated by the randomization function of the statistics software and communicated using sealed opaque envelopes. Due to the obvious differences between the 2 treatments, blinding of investigators was not possible following randomization
Additional Reads:
- Kennedy et al (2017) Subversion of allocation concealment in a randomised controlled trial: a historical case study
- Deng and Graz (2002) Generating Randomization Schedules Using SAS Programming
- Park et al (2012) Rapid, easy, and cheap randomization: prospective evaluation in a study cohort
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