Table 3.

Summary of an evaluation of the EORTC/MSG clinical trial definitions of response to antifungal therapy in patients with invasive mould disease

	Arguments in support of updating the current definitions	Arguments in support of the current definitions
Treatment success versus failure	Stable disease is considered to be a treatment failure, but this can be a desirable outcome for clinicians and patients (particularly those receiving salvage therapy). Not all deaths may be a result of antifungal treatment failure (particularly in patients with comorbidities receiving salvage therapy; clinicians may be less willing to enrol these patients in clinical trials, which can introduce selection bias).	The current criteria are appropriately designed to differentiate treatment success versus failure based on objective evidence.
Clinical criteria and assessments	Clinical signs and symptoms of IFD are often subjective and non-specific, and rely on clinicians to arbitrate outcomes in current assessments; clear, non-subjective criteria are important to ensure standardized antifungal assessment in clinical trials. Treatment success in patients with clinical responses may not be determined if radiological or mycological data are missing; increasing the weighting of clinical criteria would avoid categorizing these patients as treatment failures. The patient experience is not considered, e.g. through assessment of PROs.	Although resolution of signs and symptoms can be seen as a success in the clinic, this alone (irrespective of radiological/mycological outcomes) may not be enough to ensure unequivocal efficacy of a new agent in clinical trials. Different timepoints should be considered for the main endpoints of efficacy for clinical, mycological and radiological criteria, as not all of them appear or improve simultaneously.
Radiological criteria and assessments	CT scans of lesions alone do not fully account for the effects of patient, treatment or disease characteristics. PET/CT is not included as a method of assessment, despite evidence that it could provide a comprehensive assessment of lesions.	PET/CT is not widely accessible, in both low- and high-income regions. PET/CT has not been sufficiently validated and can be limited by lack of reimbursement for use in IFD.
Mycological criteria and assessments	Documented fungal clearance (required for confirmation of a complete response) is difficult to obtain for many patients, including those with difficult-to-reach foci; the invasive biopsies required are not ideal for unwell patients. New methods of assessment are undervalued; for example, serum galactomannan and PCR could provide clarity of treatment responses when other criteria are conflicting.	Microscopy and culture are near universally available, while access to PCR and galactomannan tests is limited. Current evidence on the use of PCR and galactomannan tests for IFD is limited in select populations, so may not be applicable for large clinical trials. Serial PCR and galactomannan testing may only be useful if patients have a positive test at baseline, which is not universally achieved. High false-positive rates have been reported from galactomannan tests in non-haematology patients, raising concerns regarding its validity as a method of assessment.
Time period of assessment	Divergence among clinical, radiological and mycological criteria can be common during the defined assessment period; e.g. patients with cavitation or persistent mould isolation (radiological or mycological outcomes that indicate treatment failure) may still demonstrate an improvement in signs and symptoms (a clinical outcome that indicates treatment success). The assessment period fails to consider patient and disease characteristics: stable disease may precede a complete or partial response, as response is rarely seen at 6 weeks in some patients (particularly those receiving salvage therapy).	The time period of assessment is clinically relevant: natural immune reconstitution within 6 weeks of antifungal therapy may confound results, whereas underlying comorbidities may lead to worsening conditions over time, as is common in salvage settings.
Regulatory considerations		Regulatory agencies require the type of clear and evidence-based definitions of treatment success versus failure provided in the current response definitions.
Diversity, inclusion and practicality	Definitions were based on the clinical expertise and experience of a group of leading experts in 2008, which have since progressed. Encouraging geographical diversity should not come at the cost of excluding patients with rarer and endemic IFDs (who are unlikely to be largely and evenly represented), as this could lead to issues with recruitment.	The current definitions have been designed to ensure that clinical trials are accessible to a geographical range of centres and countries, and translate to a global patient population, while ensuring recruitment targets are achievable.

PRO, patient-reported outcome.