Should Expected Clinical Outcomes of the Disease under Study, which are study endpoints, be reported as AEs/SAEs?

Generally not. The new IND safety reporting regulation and associated guidance state that study endpoints that are Serious Adverse Events (SAEs) (i.e., the study is evaluating whether the Investigational Medicinal Products reduces the rate of the SAE) do not require immediate reporting to the sponsor unless there is evidence suggesting a causal relationship between the drug and the event. For example, a death ordinarily would not require immediate reporting to the sponsor as an SAE under a trial designed to compare all-cause mortality in subjects receiving either drug treatment or a placebo. On the other hand, in the same trial with an all-cause mortality endpoint, if the death occurred as a result of an anaphylactic reaction that coincided with initial exposure to the drug, or as a result of fatal hepatic necrosis, the death must be immediately reported to the sponsor as a SAE

Study endpoint information should be collected, tracked, and monitored, usually by a data monitoring committee, during the course of the study. The sponsor must report study endpoints to the FDA according to the protocol and not as IND safety reports, except in unusual cases as described above.

Some protocols instruct investigators to record and report all untoward events that occur during a study as AEs/SAEs, which could include common symptoms of the disease under study and/or other expected clinical outcomes that are not study endpoints. This approach enables frequency comparisons of all events between treatment groups, but can make event recording in the CRF burdensome, result in more expedited reports from investigators to sponsor, and fill safety databases with many untoward events that most likely have no relationship to study treatment and that could obscure signal identification.

In practice, some companies take the conservative approach and report the underlying disease symptoms / outcomes as the adverse events or serious adverse events. To report all  underlying disease symptoms / outcomes as adverse events is overkill and the symptom worsening could just be the lack of efficacy for the study drug. It may be reasonable not to report the underlying disease symptoms / outcomes as adverse events, but if the underlying disease symptoms / outcomes result in the consequences that meet the criteria for serious adverse event (see the SAE criteria in ICH E2D or EMA document ICH topic E2 A), the underlying disease symptoms / outcomes should be reported as AE and SAE. This seems to be the approach that a lot of pharmaceutical companies are taking.

In a clinical trial with tiotropoim in COPD patients, Boehringer-Ingelheim reported the most commonly serious adverse events as the following:

“COPD exacerbations were the most commonly reported serious adverse events. The incidence of COPD exacerbations reported as SAEs was lower in the Tiotropium group compared to placebo group (4.2% vs. 6.7% of patients, respectively).”

COPD exacerbation is underlying disease symptom and efficacy measure of the COPD, but if COPD exacerbation requires the hospitalization (also meet the severe exacerbation definition), the COPD exacerbation would need to be reported as SAE even though the mild / moderate COPD exacerbation may not be reported as adverse event.

For a clinical trial with thrombolytic agents such as tPA, any bleeding event should be reported as AE. However, in trials in Hemophilia patients, the bleeding event is the manifestation for the underlying disease (hemophilia A). The bleed event should not be reported as AE unless it meet the SAE criteria in which case, the bleeding event should be reported as SAE.  Bleeding would also be included in the efficacy assessment.  It would be appropriate to specify in the study protocol what should be and what should not be reported. The following language would be adequate in Hemophilia trials.

“Spontaneous and trauma-related bleeding episodes are expected as usual events in subjects with severe Hemophilia A. Thus, bleeding episodes need not be reported as adverse events unless severe enough to be classified as a serious adverse events. “

 In the summary of approval document for ADVATE, the bleeding event (Hematoma)  is reported as serious and drug related adverse event.

The worst situation is that the rule for reporting is not explicitly specified in the study protocol and different investigational sites take different approaches (at investigator’s discretion) in reporting the AE/SAE for underline disease symptoms / outcomes. In this situation, data are inconsistent across different sites.