Suboptimal Reporting of Adverse Events in Pivotal Cancer CTs

Kristin Jenkins

October 07, 2016

COPENHAGEN — During the past 15 years, most pivotal trials of new drugs that were approved by the US Food and Drug Administration (FDA) for treatment of solid malignancies in adults had suboptimal reporting of adverse events (AEs), according to researchers.

A review of 81 treatment trials for advanced colorectal, lung, and breast cancer, as well as melanoma, found that that 91% got a poor score on reporting recurrent and late toxicities and AE duration, said Paolo Bossi, MD, from the Istituto Nazionale dei Tumori in Milan, Italy. He will report on the findings in a poster presentation here at the 2016 European Society for Medical Oncology (ESMO) Congress.

"Suboptimal reporting of AEs in trials leading to approval of targeted therapies and immunotherapy was shown," said Dr Bossi. "Toxicities of [these] targeted agents and immunotherapy are obviously different from the toxicities we are used to observing and treating due to chemotherapy, and there are some aspects of the toxicities of these newer agents that we are not so well informed about."

The trials of new drugs, which received FDA approval between 2000 and 2015, were retrieved from the FDA website. Published study reports were scored by using the 25-point Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Most of the trials looked at the efficacy and toxicity of new drugs, either as single agents (51%) or with chemotherapy (32%). More than 45,000 patients were enrolled in the trials.

One third of trials did not report AE-related dose reductions, the review showed. The time of occurrence of AEs was poorly described in 86% of trials, and 75% reported only AEs occurring above a fixed threshold. In more than 50% of the clinical study reports, descriptions of toxicities leading to withdrawal of therapy and follow-up were limited, Dr Bossi said.

"Better description of AEs, particularly in the case of new drugs, should be a priority in ongoing trials as well as in postmarketing safety analyses," Dr Bossi said. Careful measurement and reporting of the effect of treatment dose and the duration of AEs are crucial to everyday clinical practice, he pointed out.

Even though toxicities can be mild or moderate in severity, for instance, they also can last longer and recur, affecting patients' quality of life. "New drugs are approved by regulatory agencies on the basis of the safety and efficacy results deriving from pivotal trials, but the impact on broader use is often misunderstood," Dr Bossi said.

In commenting on the study, Nathan Cherny, MD, from the Shaare Zedek Medical Center in Jerusalem, Israel, noted that when toxicity is reported by clinicians rather than patients, it "consistently leads to underreporting of adverse events and the severity of those events."

Findings from this study "lend further support to the proposal to radically re-evaluate the collection and reporting of adverse event data to give weighting to patient-reported data," he said.

The full data set submitted to licensing authorities for drug approval and registration may not be represented in published reports of studies, he added.

The reporting of AE duration — also known as the "third axis" along with severity and frequency — has improved with the introduction of new instruments that allow both physicians and patients to more easily and accurately measure and assess treatment toxicity. Baseline, weekly, and post-treatment toxic effects can be assessed by physicians using the National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE), and patients can use the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE).

Other researchers have also raised concerns about AE reporting, as previously reported by Medscape Medical News. The current way of reporting adverse events gives information only on high-grade events, as defined by the CTCAE, that occur during clinical trials, argued a group of researchers who proposed adding a ToxT (Toxicity over Time approach) measure to take into account the time dimension.

Others have also argued for adding the patient's voice because adverse events experienced by patients undergoing anticancer therapy are too often undocumented by physicians. The PRO-CTCAE, which is "being proposed and disseminated" by the NCI in the United States, is a good begining, these researchers said.

The authors have disclosed no outside funding source or relevant financial relationships.

European Society for Medical Oncology (ESMO) Congress. Abstract 320P. To be presented October 10, 2016.

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