Blinded independent central review (BICR) is a process used in clinical trials, in which a group of independent experts review trial data, like radiographic images, to review assessments without access to information on patients’ treatment assignments. BICR of radiographic images is frequently conducted in oncology trials to address the potential bias of local evaluation by investigators (INV) of endpoints such as progression-free survival (PFS) and objective response rate (ORR).

What is the aim of BICR?

The BICR process serves several purposes. These include:

• Reducing bias: An investigator can be influenced in his or her assessment by prior knowledge of the treatment assignment in the case of an open-label study or patient toxicities. Blinded review enhances objectivity.
• Reducing measurement variability across sites and readers: Tasking a small number of central reviewers with expertise in a specific area with reviewing imaging may lead to more accurate and reliable assessments compared to local site reads. This is particularly important in multi-center trials.
• Ensure standardization: Centralized review ensures the standardized application of response criteria (e.g., RECIST 1.1, iRECIST).
• Improved data quality: Centralized monitoring allows for regular quality control, helping to identify issues such as inconsistent imaging techniques or poor-quality scans.
• Enhanced regulatory confidence: Regulatory agencies like the FDA and EMA often prefer or require BICR for pivotal oncology trials, in particular for open-label studies or those with higher bias risk. This strengthens the credibility of primary endpoints derived from tumor assessments.

What are the limitations of BICR?

While the BICR process can help achieve the above aims, there are limitations. For example:

• Operational complexity, time, and cost considerations: BICR requires a lot of coordination between multiple stakeholders (sponsors, imaging CROs, radiologists, adjudicators), resources, and logistics (e.g., reader’s training and data blinding, transfer, storage, and tracking).
• Informative censoring: BICR may introduce bias due to informative censoring, which results from having to censor unconfirmed locally determined progressions. Indeed, once a patient has progressed according to the local assessment, s/he might discontinue the study, and further imaging is unlikely to occur. As a result, determining the BICR progression time may be impossible. This type of censoring will be informative: patients who progress according to local review (but not according to central review) will be more likely to progress by the next scheduled scan than patients who have not been determined to progress by local review. One alternative to this issue is to request at least one additional scan beyond progression assessed by investigators. Even though it may be required in protocol, it may be difficult to implement.
• Regulatory agencies often expect BICR in pivotal oncology trials, in particular for open-label studies. However, inconsistencies between local and central results can complicate data interpretation and submission.

How is BICR data used?

As the primary endpoint (e.g., PFS-BICR): All patients need to be reviewed by BICR either in real time or by regular batch to be agreed upon.

For sensitivity analysis: All patients need to be reviewed by BICR either in real time or by regular batch (to be agreed upon) or as retrospective BICR. Retrospective BICR can be implemented only if the trial is positive based on local assessments (INV). Ideally, images should be collected and archived even after progression, to allow for retrospective BICR, if needed.

As an audit tool: In such context, only a random subset of patients can be reviewed and concordance between BICR and INV assessed on this subset of patients.

Practical aspects in BICR implementation

Imaging Charter

The Imaging Charter needs to be written in accordance with the protocol to ensure consistent methodology between investigators and independent review assessments.

Readers involved need to be specified in the charter; in general, two primary readers and one adjudicator are involved.

Adjudication paradigms should be detailed, in particular:

• Are the primary readers compared at the patient level or visit level?
• Which criteria are used to consider whether assessments from primary readers are different? For example:
  • At the patient level: the date of progression and/or best response are different
  • At the visit level: the sum of diameters on target lesions > xx mm

The choice of criteria impacts the number of cases that go to adjudication. Indeed, studies have shown that discrepancies between two readers can be substantial. For example, in lung cancer trials using RECIST 1.1, the average discrepancy rate at the patient level was around 59.2%,1 with adjudications often required to resolve differences. These discrepancies may stem from medically justifiable differences in interpretation or from errors, both of which can affect trial outcomes. Training and monitoring by a Central Imaging vendor can mitigate a large portion of the commonly encountered reading errors and therefore reduce variability.

• If adjudication occurs, which reader is the accepted one? (e.g., one of the primary readers (forced adjudication) and/or a new reader by adjudication (open adjudication, less common)).
• If adjudication does not occur, which reader is the accepted one? (e.g., reader 1 as default).
• The timing of readers and adjudication should be defined in the Charter (e.g., real-time review or review only once the patient discontinues the treatment, adjudication only once per patient or once per study, etc.).

Data transfers

The independent review must remain independent; imaging results should not be shared from the site to the BICR or vice versa.

The timing/frequency of the transfer to be defined:

• If only adjudication data are included, there might be a greater backlog for the tracking of BICR events.

Data reconciliation. Review of general consistency between the INV and BICR:

• Check whether patient populations, set of scans, visits, dates, and method of assessments (if needed) are consistent between BICR and INV datasets.
• Visits with Investigator Tumor Assessment but Missing BICR Assessment

Concordance between the INV and BICR results can be assessed during data review and at time of analysis.

• For PFS: Concordance of Occurrence and Timing of disease progression
• For ORR: Concordance of occurrence of Complete Response/Partial Response

Impact of tracking events and prediction of analysis timing

When the primary endpoint is PFS-BICR, interim or primary analyses are triggered by the number of BICR-assessed events. In such context:

• Monitoring BICR events may be more challenging than INV events. Indeed, it is hardly ever real-time event monitoring, there is some backlog for the review and adjudication time is to be considered.
• For event projections:
  • PFS-INV can be used as a first surrogate; if observed concordance is relatively high, it should provide relatively good estimate. The study team could consider estimating the BICR-assessed number of events based on an estimated ratio of investigator-assessed events (e.g., xx% of INV events).
  • Adjudication must be initiated early, to ensure that the number of BICR-assessed events are accurate. However, in some instances, the study may have pending adjudications at the time of data transfer for event projection.
  • BICR readers should read the full set of scans done up to a certain cutoff date and then transfer the data. Predictions can also be made for each reader separately if the adjudication is not yet completed.

Final takeaways

BICR enhances the objectivity and regulatory credibility of oncology trial endpoints by minimizing bias and standardizing radiographic assessments.

However, its implementation introduces operational challenges, may add complexity around data analysis with the risk of informative censoring, data interpretation in case of poor concordance between INV and BICR and prediction of analysis timing.

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