Equipoise lost in RCTs - dropout at random assignment

data analysis comparative methods
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Inviting comment on this paper and a related proposal we called the Observation-enriched RCT.

Equipoise Lost? Trial Conduct Challenges in an Era of Breakthrough Therapies https://ascopubs.org/doi/10.1200/JCO-24-01200?source=email

Snip: When RCTs are blinded, perceived loss of equipoise may have minimal effect outside of accrual challenges; however, the impact on open-label RCTs can be substantial. Patients with severe and life-threatening diseases like cancer enroll on trials hoping to benefit from a novel investigational agent.

Patient dissatisfaction if assigned the control arm can result in higher rates of dropout at random assignment, instilling bias that can challenge the interpretation of results.2,3 More challenging still, those who drop out may be patients with a better performance status or those with higher socioeconomic status who can afford to seek the investigational drug off of the trial in a country where it has been approved.

Question for this group: Would the hybrid, observation enriched, RCT trial, I proposed with Dr. James Omel mitigate this issue?

Proposing the Observation-enriched Randomized Controlled Trial (ORCT)

When it’s not feasible to do a randomized controlled trial – such as when strong PI or patient preferences or aversions exist for one or the other study arm.

Snip:

Here we are seeking input on the ORCT - as an additional tool to consider when comparing treatments for cancer - such as (but not limited to) when the compared interventions have very different risks, or when both treatment protocols can be used off-study.

The ORCT lets the patient either (1) choose to be randomized or (2) pick the study arm they want to be in. Their arm selection may be based on their expectations, preference or aversion to one of the study arms, or their unique clinical risk factors. Such decisions will most often be guided by the patient’s physician.

Mary, for example, might prefer the study arm that would not put her fertility at risk. John might prefer the treatment arm that appears to have the greater chance to achieve a cure. Tom, having no opinion or expectation about which is better, will choose to let a computer decide.

In particular, we are seeking input from statisticians who are the most qualified to tell us if the ORCT can be a better choice than RCT - and large single-arm studies with historical controls - in select cases, such as when the study arms have very different goals or risk factors making full enrollment infeasible.

The ORCT is a hybrid system - one that we hope can help to reliably answer the study question, mitigate the enrollment problem, and also address the ethical concern of forcing patients to be randomized - particularly for studies that lack clinical equipoise.

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First study the randomized consent design.

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Are those the same as Zelen designs? If so, these probably don’t fit the bill: “A Zelen design requires a waiver of the usual requirement for informed consent prior to random assignment of treatment.” [1] (The concept might however provide a useful comparison with which to illuminate the ORCT, I suppose.)

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371763/
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We touched on the consent process, but much depends of course on the specifics of the interventions compared:

Mary, this is your condition (natural history) …
This is the [usual\ way to treat your condition …
We can do the regular treatment of course.
You have another choice – a clinical trial, comparing the regular way to an experimental
approach (or a second, competing, “standard” approach).

  • This is the background on the competing approaches – the preliminary evidence of
    efficacy, risks, and areas of uncertainty. If you choose to be in the ORCT trial you will have
    three choices, Mary:
     You can decide to let a computer assign you by chance to one or the other
    study arm.
     You can choose the regular treatment
     You can choose the study drug (or the competing regular treatment)
    Let the computer decide if you, like the [me] researchers, have no idea which is better and are willing to leave the decision to chance.
    Doing it this way helps to answer the question more objectively.
    However, choosing to be in the study requires some extra procedures that would not be
    part of regular care.
    Because being in the study requires that you contribute time, pay for travel expense, and
    perhaps lose time off work, and because there is some discomfort for doing these extra
    tests, you will receive a modest compensation (as for jury duty).
    Also Mary, all the expenses are NOT your expense or your insurance company’s. They are
    paid for by the trial itself … not by you.
    Each of these tests will better help us to help patients with your disease that follow after
    you Mary. You will be greatly helping each one of them.
    Note: It must be a modest compensation/reimbursement so to avoid selecting mostly
    patients who have lower income – who may have different risk factors than the general
    population with this condition.
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In summary - points of emphasis.

The Observation-enriched RCT

  • is for select study questions, such as when both approaches are available off study and the risks are very different for the compared interventions.
  • it removes the possibility of bias from dropouts after randomization in RCTs, because patients are given the choice to be randomized or to select the preferred intervention.
  • it ends what patients consider coercion - compelled to leave it to chance when they have a strong treatment preference.
  • it illuminates the level of clinical equipoise for the compared interventions
  • it accepts that individual risk factors play a role in decision-making. (e.g., A stem cell transplant is not equally appropriate for every eligible patient participant.)
  • it still avoids selection bias - but only for participants choosing to be randomized - where there is genuine clinical equipoise.
  • it increases trial expense, but likely improves trial enrollment.
  • it can answer the question on the role of choice in the outcome. Do patients aided by their physicians do better when deciding on the type of treatment - compared to those randomized?
  • it dovetails with a new draft FDA guidance recommending RCT integration with Routine clinical care.

Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice Draft Guidance for Industry

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/integrating-randomized-controlled-trials-drug-and-biological-products-routine-clinical-practice

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Randomize, or do not. There is no ‘try’.
— Yoda

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