One of the primary concerns when considering a clinical study in oncology is how to ensure that the findings are reliable, objective, and acceptable to the regulators. The solution usually involves blinding, and eventually, when necessary, unblinding. Blinding limits the possibility of bias by keeping patients and researchers unaware of the treatment they receive or administer. However, blinding becomes much more difficult in oncology, because outcomes depend on imaging, side effects are unique, and treatments like immunotherapy or CAR-T don’t fit into a standard model. In view of this, sponsors frequently have to decide between practical viability and scientific rigour.

Let’s examine why this is important and how we could get past these challenges.

Why blinding matters in oncology?

In oncology, since subjective outcomes such as progression-free survival are typical, blinding is essential to the credibility of the study. Here is how:

• It minimises investigator and patient biases.
• It makes safety and efficacy data more reliable.
• Blinding is seen by regulators as an indication of sound trial design.

Where is the challenge? On scans, tumour shrinking is obvious. Distinct toxicities, such as colitis in immunotherapy or cytokine release syndrome in CAR-T, often identify the treatment arms. Sometimes, patients may tell when they are receiving “the real drug.”

Sponsors must therefore view blinding as a strategy rather than a checkbox.

Types of blinding in a clinical study in oncology

Selecting the appropriate blinding strategy in clinical study in oncology is essential because each type has distinct purposes and outcomes in cancer trials. Oncology requires adaptability, and each blinding type has its role: 

• Single-blind: In a single-blind study, investigators are aware of the treatment administered, whereas patients are blinded. This method works well in situations when careful investigator monitoring is essential for safety.
• Double-blind: Double-blind testing is the most effective way to minimise bias. The data is more reliable and credible because both patients and researchers are unaware of the treatment procedures. 
• Double-dummy: Double-dummy tests are useful for evaluating treatments with different routes or timings, such as oral pills vs. IV infusions. In matched arrangements, each group is given both an active treatment and a placebo.  
• Central-blinded imaging review: It’s particularly crucial in critical trials because regulatory decisions are based on imaging results. Here, scans are reviewed by impartial radiologists who are unaware of the therapy assignment. 
• Assessor-blind: Responses are reviewed by impartial adjudicators or lab personnel who are unaware of the treatment allocation. When a full double-blind is not feasible, this helps achieve a balance.

These blinding types clearly highlight the importance of adaptability. When choosing the optimum trial design, sponsors must consider both practical feasibility and scientific reliability. 

Use cases in oncology by trial phase

The methods used for blinding change as the research project goes on. Sponsors usually use the following strategy at various stages:

Early-Phase: Usually open-label (phase I/IIa)

Early-phase oncology studies (Phase I/IIa) commonly employ an open-label design, where patients and researchers both know the drug being delivered. A phase I trial’s main objective is to determine a new drug’s maximum tolerated dose (MTD) or optimal biological dose (OBD). For this approach, an open-label design is essential since it allows for real-time monitoring and the management of severe adverse effects. 

Mid-Phase: (Phase IIb) (A mix of blinded and open-label)

Through selective unblinding, the trial team may inform a patient’s treating physician about treatment allocation during a significant adverse event, enabling well-informed decisions for patient management. This is an important ethical factor, particularly for highly hazardous medications. For instance, basket trials for uncommon cancers may be open-label in general, but blinded reviewers still examine the tumour scans to maintain data objectivity.

Late-Phase: Registrational Trials (Phase III)

Phase III oncology trials concentrate on concrete clinical outcomes that are significant to patients and regulatory agencies, as opposed to previous stages that could use intermediary indications. One notable example is the use of blinded independent central review of imaging endpoints in PD-1 inhibitor trials to build credibility with the FDA and EMA.

Special cases in clinical studies in oncology

Regulators such as the FDA understand that randomised controlled trials (RCTs) are not always practical or acceptable for every situation, notably in oncology. In some “special situations,” such as rare cancers or where providing a placebo would be unethical, single-arm, open-label trials may be eligible for regulatory approval. Such trials ensure equitable access to a potentially life-saving treatment by giving the experimental medication to every participant. In addition to respecting patient liberty, the single-arm technique provides a chance to receive a novel therapy.  

Impact on bias and data integrity

Endpoints in oncology are particularly susceptible to bias because:

• Progression-free survival (PFS): Tumour measurements become arbitrary and subject to interpretation unless researchers employ an independent blinded evaluation
• Patient-reported outcomes (PROs): Patients may unintentionally distort outcomes if they are aware of their treatment.
• Investigator bias: Clinical judgement and even dropout rates may be impacted by knowledge of treatment allocation.

Blinding is more than just statistics; it’s what persuades regulators that the advantages you’re demonstrating are genuine and not merely the result of bias or assumptions.

Challenges of blinding in oncology trials

The challenges of blinding in oncology, however, are numerous since it is more difficult to disguise treatment assignments due to the nature of cancer medicines and trial designs. The following are some of the major challenges: 

• Differential toxicities: A lot of cancer medications have very identifiable adverse effects. For instance, CAR-T treatments may result in cytokine release syndrome, whereas immune checkpoint inhibitors may cause immunologically related colitis. 

• Differences in formulation: It make difficult to maintain blinding when one medication comes as an intravenous infusion and another comes as an oral pill. Trials frequently employ a double-dummy strategy to prevent bias, requiring each patient to receive both a tablet and an infusion (one of which is a placebo). Despite its effectiveness, this method makes trials more complicated and puts more strain on patients. 

• Drug supply logistics: Double-dummy designs increase the need for distribution, packaging, and production. It is expensive and logistically difficult for placebos to match active treatments in evaluation and administration, particularly for international, multi-centre trials with disparate regulatory requirements.

• Operational requirements: Sites in blinded cancer studies must strictly follow procedures, which demands intensive training. Sponsors must also invest in monitoring and retraining throughout the trial’s life.

• Emergency unblinding: In cancer, patient safety is the top priority. Especially in immunotherapy research, severe adverse events frequently necessitate investigators to break the blind right away to inform clinical judgments. 

Do you want to learn more about key operational challenges in oncology clinical trials? Click here.

When and why unblinding occurs

Even with meticulous trial design, unblinding is unavoidable; what matters is how you respond to it.

• Planned unblinding: Under tight protocol, carried out during interim analyses or at the final database lock.
• Emergency unblinding: Particularly important for immunotherapies, where prompt action could save lives.

Here, balance is crucial. It is pertinent to establish protocols in advance, rely on impartial supervision, and record each occurrence. Regulators seek confirmation that unblinding was appropriate and did not jeopardise the fairness of the trial.   

Regulations and ethical considerations in oncology trials

In oncology, regulatory frameworks mandate blinding and do not allow it as an elective choice.

• ICH-GCP: Demands that blinding techniques be justified.
• FDA: Demands that unblinding events be transparently documented.
• For cancer endpoints, EMA: Favours blinded independent imaging review.
• Ethics committees: Limit the use of placebos when there are previously proven treatments that work.  

However, authorities are also aware of the intricacy of oncology. Sponsors must present a compelling argument and ensure strong data integrity for regulators to accept rare cancer open-label single-arm studies

Conclusion for blinded & unblinded clinical study in oncology

In conclusion, blinding is rarely simple in a clinical study in oncology. Compared to nearly every other area, it is more challenging due to visible tumour responses, unique side effects, and the pressing safety requirements of novel medicines. Effective blinding, however, protects your data, increases regulatory confidence, and enhances your company’s reputation in the marketplace.

Sponsors must figure out how to create a plan that benefits their trial, therapy, and patients, not only whether to blind. Because in cancer, the effectiveness of your blinding strategy could be the deciding factor in whether your medication is successful.

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