Functional Unblinding in Double-blind, Randomized, Controlled Trials (RCTs)

Earlier this month, FDA advisory committee declined to endorse Lykos Therapeutics’ application to market its psychedelic drug MDNA, also known as ecstasy, as a treatment for post-traumatic stress disorder (PTSD). The panel voted 9-to-2 against the treatment when asked if data showed MDMA’s effectiveness, and 10-to-1 against when asked if the benefits of MDMA outweighed its risks. Both of Lykos Therapeutics’ pivotal studies (MAPP1 study and MAPP2 study) are positive. With relatively small sample sizes, both studies showed highly statistically significant results that MDNA-assisted therapy is highly efficacious in individuals with severe PTSD. The failure in earning the endorsement from FDA advisory committee was not due to the study results, but due to the concerns about the study design and the study conduct, specifically, potential abuse, functional unblinding, and expectation biases. Functional Unblinding was one of the sticky issues discussed during the advisory committee meeting. 

Functional unblinding refers to the situation in a clinical trial or research study where individuals involved (such as participants, investigators, or assessors) gain access to information that reveals the identity of the treatment or intervention being administered. Functional unblinding can happen inadvertently due to various reasons, such as unintended disclosure of treatment details (accidental unblinding), observation of side effects specific to a treatment, or recognition of differences between treatment groups. Clinical trial sponsors usually implement strict procedures to prevent accidental unblinding and manufacture the matched control treatments/using double-dummy technique to prevent recognition of differences between treatment groups. 

However, functional unblinding due to side effects (or treatment emergent adverse events (TEAEs)) may occur with any investigational drug. If the treatment group (or investigational drug) can cause significantly more side effects, study participants, investigators, or assessors can guestimate which treatment group the study participants are assigned to. For example, IGIV causes headache events; niacin causes red or flushed skin, sotatercept causes telangiectasia, bleeding events, and increased hemoglobin levels,... participants or investigators may be able to guesstimate if the participants are receiving the investigational drug based on these unique side effects (adverse events). 

Functional unblinding is an especially important issue in psychedelic drug (such as Lykos' therapeutics's MDNA) clinical trials. In FDA's guidance for industry (June 2023) "Psychedelic Drugs: Considerations for Clinical Investigations", 'functional unblinding' was discussed as the following. It raised the functional unblinding issue and provided some solutions for preventing/handling the functional unblinding: 

Functional unblinding is a critical concern in clinical trials where the investigational drugs have unique and distinctive side effects. Functional unblinding can introduce bias (consciously or unconsciously), affect participant behavior, influence how outcomes are measured and interpreted, and compromise the objectivity of the study's outcome.

If functional unblinding is suspected, it is difficult for sponsors to demonstrate that the functional unblinding does not occur. One approach to investigate/assess the functional unblinding is to employ questionnaires before the study unblinding to ask the participants and investigators which treatment group they think the participants are receiving. However, I see no or very few sponsors doing this. I described this in an earlier post "Assessing potential unblinding due to imbalance in side effects through exit questionnaires".

Clinical Trial Design: Double-Blind Fixed Duration Trial with Long-term Double-Blind Various Treatment Duration

The randomized, double-blind, parallel-group design is the most common type of design for clinical trials (especially the confirmatory clinical trials). This type of design can be further classified into clinical trials with a fixed treatment duration or with various treatment durations. For clinical trials with a fixed duration, all patients are treated with study drugs for a fixed duration (for example, 16 weeks, 24 weeks, 52 weeks,...) and the primary efficacy endpoint will be estimated at the end of the fixed duration (for example, change from baseline in xxx measure at week 16, week 24, or week 52,...). For clinical trials with various durations such as event-driven study design, patients are treated with study drugs for various durations - the early enrolled patients may receive the study drugs for a much longer time than those later enrolled patients, and patients will stay in the study and receive the study drugs if no protocol-defined event occurs until the required number of events for the study has occurred and the entire study is closed. The event can be Clinical Worsening Event, MACE, Exacerbation, Hospitalization, Progression-free survival, Death,...

In the informed consent form, patients who participate in the clinical trial will be informed how long they may be treated with the experimental drug or placebo. The ethical issue arises if patients are randomly assigned to the placebo group and treated with placebo for a prolonged period of time.     

Lately, we saw several clinical trials with a hybrid approach containing a double-blind fixed duration and then followed by a double-blind various duration. The primary efficacy endpoint was measured at the end of the fixed duration (i.e., week 52 for INBUILD and ISABELLA trials and week 24 for STELLAR trial). The double-blind various duration was added to the trial to collect the information for secondary and exploratory endpoints that need a longer exposure time. The double-blind various duration depends on the enrollment speed and the timing of patients entering into the study. Early-enrolled patients will stay in the study much longer than the later-enrolled patients. The slower the enrollment speed is, the longer the double-blind various duration takes. 

INBUILD study: Nintedanib in Progressive Fibrosing Interstitial Lung Diseases 

For each patient, the trial consisted of two parts: Part A, which was conducted during the first 52 weeks, and Part B, which was a variable treatment period beyond week 52 during which patients continued to receive either nintedanib or placebo until all the patients had completed Part A. 

The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based on efficacy and safety data over 52 weeks.

The primary analysis of this study will therefore be performed once the last randomized patient reaches the Week 52 Visit (Visit 9 at the end of Part A). At that time, a database lock will occur and all the data will be unblinded. Efficacy and safety analyses will be performed on the data from Part A of the trial to assess the benefit-risk of nintedanib over 52 weeks. In addition, data collected in Part B of the trial (after 52 weeks) and available at the time of data cut-off for the primary analysis will be reported together with data from Part A (i.e. over the whole trial).

Once the benefit-risk assessment of nintedanib over 52 weeks is confirmed to be positive, all patients receiving trial medication in Part B will be offered open-label treatment with nintedanib in a separate study.

Trial 1199.247 i.e. Part B will continue until all patients have been switched to open-label nintedanib or completed the Follow-up Visit. A final database lock will then occur and Part B data collected between the data cut off for the primary analysis and the final database lock will be reported together with data from Part A i.e. over the whole trial.

ISABELLA Studies: GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis

See the paper: Rationale, design and objectives of two phase III, randomised, placebo controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2)

In each study, approximately 750 subjects will be randomized 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or matching placebo, once daily, in addition to local SOC. SOC is defined as either pirfenidone or nintedanib, or neither pirfenidone nor nintedanib (for any reason). Treatment will continue for at least 52 weeks (subjects will continue to receive randomized treatment until the last patient reaches 52 weeks in the study). A follow-up visit will be conducted 4 weeks after the end-of-study visit (figure 1 below).

STELLAR Study: Sotatercept in Pulmonary Arterial Hypertension

According to Acceleron's ATS 2021 INTERNATIONAL CONFERENCE ACCELERON INVESTOR AND ANALYST CALL, the STELLAR study was designed as the following:

The double-blind fixed duration is 24 weeks and the primary efficacy endpoint (6MWD) is measured at week 24. The double-blind various duration had a cap at 72 weeks, i.e., the maximum duration for the period is 72 weeks). Patients can be in the long-term double-blind treatment period for 0 (the last enrolled patient) to 72 weeks (early enrolled patients). 

Randomization Using Envelopes In Randomized, Controlled, and Blinded Clinical Trials

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