COMMENTARY

Is Peanut Oral Immunotherapy Too Risky?

Brian P. Vickery, MD

Disclosures

November 26, 2019

Avoiding peanut is not easy, and the consequences of accidents can be severe.

For many years, allergists had nothing to offer the population affected by peanut allergy beyond the elimination diet and rescue medications for when accidents inevitably occur. Even when allergen avoidance diets are successful, the never-ending vigilance, alterations in daily living, and worry associated with maintaining that success consumes caregivers and is profoundly debilitating.

Oral immunotherapy (OIT) has been investigated in increasingly rigorous academic and industry-sponsored studies as an approach to address this critical, unmet need. In parallel, a relatively small number of allergists in the United States have been offering an unregulated form of OIT outside of the clinical trial environment, a controversial office-based practice that many patients and caregivers feel strongly has helped improve their lives. It was in this environment of uncertainty about the standard of care that a recent meta-analysis evaluated the evidence base to assess the safety and efficacy of peanut OIT.

A Rigorous Meta-analysis

Chu and colleagues used high-quality methodologies in accordance with GRADE, PRISMA, and Cochrane guidelines to perform a rigorous meta-analysis of selected outcomes from 12 randomized controlled trials of peanut OIT. The primary findings were that, on the basis of moderate- to high-certainty evidence, OIT increased risk for serious adverse events, protocol-defined anaphylaxis, adverse event-related withdrawal, and epinephrine use compared with placebo or avoidance.

Of note, trials that did not confirm peanut allergy diagnosis at study entry had reduced risks for both anaphylaxis and adverse event-driven withdrawals. One randomized controlled trial by Blumchen and colleagues was included in the meta-analysis but was omitted from the calculation of anaphylaxis risk because no anaphylaxis was observed in this study with either OIT or placebo; importantly, this trial used the smallest target maintenance dose and the slowest dosing schedule.

There was clear evidence of OIT's efficacy, with a risk ratio of 12.42 (95% CI, 6.82-22.61) of achieving the primary endpoint measured with the double-blind, placebo-controlled food challenge (DBPCFC), the current gold standard for measuring efficacy in OIT studies. A DBPCFC is a provocation test that uses increasing doses of allergen given under supervision every 20-30 minutes as tolerated to measure the threshold dose of peanut that elicits a reaction after treatment—and in some studies, compared with baseline.

The authors calculated a 26% decrease in the probability of passing the DBPCFC for every additional gram of protein used in the test. In other words, the more provocative the test, the more likely the participant was to react, suggesting that the observed desensitization effect was partial.

Unfortunately, only four studies reported on quality of life, and the observed improvements did not exceed the minimally important difference.

So what are the implications of the analysis?

The authors made several main conclusions. The first was that although clinical benefit (ie, passing a DBPCFC after treatment) is highly likely to occur with OIT, this benefit is outweighed by an increased risk for allergic reactions, including anaphylaxis, which is incompatible with patient goals of treatment.

The second was that the absence of data showing clear improvements in quality of life reinforces this incompatibility. Finally, the authors concluded that the DBPCFC is a flawed surrogate endpoint and rejected the established regulatory precedent designating it as the primary efficacy outcome. They called for future trials to evaluate the value of food allergy treatments by studying the degree to which new treatments enhance patient-reported outcomes and reduce the risk for real-world accidental exposures (effectiveness) rather than using DBPCFCs (efficacy).

But these conclusions left unaddressed several other important considerations.

Some Missing Pieces

In the discussion, the authors did not reflect on the clinical experience of thousands of real-world patients pursuing OIT treatment, nor the published evidence showing improved quality of life during and after treatment in some academic and community-based research settings. Although not directly addressed by their meta-analysis, these realities provide additional context that appears to challenge the authors' proposition that the benefits of OIT are net negative from the patient's perspective.

Given the heterogeneity of trial designs, and outcomes, and patients with peanut allergy, it was surprising to see no mention of the obvious research imperatives: (1) to optimize the therapeutic regimens themselves, especially given Blumchen and colleagues' very reassuring findings, and (2) to select the right patients for treatment. Most OIT participants across studies have a predictable and manageable mild to moderate symptom burden and do not experience serious adverse events or anaphylaxis, but rather enjoy the reassurance of a daily maintenance dose that well exceeds the trace exposures that previously consumed them with fear.

Finally, although the assessment of real-world effectiveness (for example, preventing hospital admission after accidental exposure) is a critically important population-level research question, it is too costly and too impractical to implement as a trial endpoint. Such an approach would probably slow the rate of therapeutic innovation in food allergy—a negative, unintended consequence for patients. The US Food and Drug Administration's Allergenic Products Advisory Committee upheld the primacy of the DBPCFC as a primary efficacy endpoint in food allergy trials in 2016.

Chu and colleagues raise important questions in their rigorous and well-conducted analysis, questions that undeniably need to be addressed with future research. There are substantial gaps in our understanding of food allergy phenotypes, the best way to identify patients for treatment, and the best regimens to use. We also need to develop patient-centered outcome measures and engage patients in the design of studies to ensure that new treatments meet the needs that they—not we—define.

Ultimately, however, no treatment for any condition is right for every patient. The good practice of medicine requires engaging patients and caregivers in a transparent and open discussion of the risks and benefits of that treatment, and helping those families decide whether treatment, and which treatment, is best for them. OIT is no different.

Brian P. Vickery, MD, is a pediatric allergist-immunologist. He has published more than 50 papers in leading medical journals and contributed to the development of national food allergy treatment guidelines.

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