Drug development regulations and guidance from the EMEA has been published in draft for comment on Clinical Evaluation of Antifungals, as a replacement for points to consider on the clinical evaluation of new agents for invasive fungal infections which came into force in November 2003. it is intended to address the clinical developm,ent of anti-fungal agents for the treatment and prophylaxis of invasive fungal disease . The Guidance includes:

• Non-clinical data on anti-fungal activity that should be generated prior to and during the clinical development programme.
• Clinical study design recommendations for studies that evaluation anti-fungal agents for the treatment of invasive fungal disease
• Drug development guidance for; drug combinations, salvage therapy, studies in neutropenic patients and the assessment of prophylaxis
• Bio-marker guidance for patient selection
• paediatric development plans (a regulatory requirment discussed extensively on this site)
• Clinical Safety Assessment
• SPC sections 4.1 and 5.1 layout and content

Background

Clinical and drug development of anti-fungal agents for the treatment and prophylaxis of invasive fungal disease (IFD) requires special attention because IFD occurs in a heterogeneous group of patients most of whom have evidence of debilitation and/or immunosuppression. IFD may occur with or without detection of fungi in the blood cultures, and in some cases it is detected in the blood but source of infection can’t be found.

Factors such as infection site and fungal pathogen, complexity of the underlying illness, variable degree and duration of immunosuppression and its mode of management and incidence of concomitant infections with bacteria and viruses may affect the mycological response to therapy and the overall clinical outcome.

Changes in the clinical practice has prompted these updated guidelines:

• Increased availability of anti-fungal agents
• Prophylaxis use has increased
• Emergence of rapid diagnostic tests
• Revised definitions of IFD published by the Invasive Fugal Infections Co-operative Group (IFIG) of the European Organization for Research and Treatment of Cancer, and the Mycosis Study Group of the National Institute of Allergy and Infections Disease (NIAID)
• Anti-fungal susceptibility testing standardisation published by The European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Drug Development Guidance Scope

The guideline is primarily concerned with the content of clinical development programmes to assess the safety and efficacy of anti-fungal agents administered by oral or parenteral routes for the treatment and prophylaxis of IFD. The guidance includes:

• Consideration of the non-clinical data on anti-fungal activity that should be generated prior to and during the clinical development programme
• Criteria for enrolment and criteria for assessing the certainty of diagnosis
• The assessment of clinical efficacy including the design of studies that evaluate antifungal agents for treatment or prophylaxis of IFD.
• The assessment of clinical safety.
• Reflection of the mycological and clinical data in the SPC.

Clinical Evaluation

Assessment of antifungal activity is required:

• Spectrum of in-vitro antifungal activity.
• Mode of action
• Mechanism(s) of resistance
• Cross-resistance within and between anti-fungal drug classes.
• Synergy or antagonism with antifungal agents of different classes
• Efficacy in animal models
• Pharmacokinetic/pharmacodynamic (PK/PD) relationship.

Assessment of Efficacy:

• All fungi that are isolated and considered to be causative of IFD should be forwarded to one or more designated reference laboratories for confirmation of identity and susceptibility testing
• Clinical and mycological outcomes should be analysed in the light of in-vitro susceptibility and patient pharmacokinetic data to further assess the PK/PD relationship
• It is recommended that at least some of the in-vitro data should be generated using susceptibility testing methodologies published by EUCAST since this will facilitate the setting of EUCAST-recommended breakpoints.
• Any available EUCAST-recommended susceptibility testing breakpoints for common Candida species and Cryptococcus species should be included in the SPC
• Susceptibility and resistance should be further assessed in the post-approval period

Patient Selection Criteria

• Sponsors may choose to enrol patients who already have proven or probable IFD
• studies may enrol patients who are considered likely to have the type of IFD under investigation.
• Patient Selection Criteria:
  • Clinical history, signs and symptoms
  • Imaging studies
  • Microscopic findings in suitable specimens
  • Rapid antigen or nucleic acid detection tests.
  • Culture results from suitable specimens
  • Histological findings
  • The presence (degree and prior duration) or absence of neutropenia at baseline.
  • Prior IFD within a defined timeframe and/or during a previous period of neutropenia
  • Specific pre-disposing factors for IFD (e.g. HIV infection, type of immunosuppressive therapy).

Treatment Regimens

Monotherapy – The selection of proposed regimen(s) to be studied in confirmatory studies of clinical efficacy should be based on all the available non-clinical data, human pharmacokinetic data and exploration of the PK/PD relationship. Whenever possible the active comparative therapy should be restricted to a single regimen. The protocol should pre-define a minimum duration of therapy for patient evaluability and a maximum duration beyond which patients who have not met the response criteria should be considered to have failed therapy.

Combination Therapy

The choice of antifungal agents to be co-administered should take into account the in-vitro activity of the combination against target genera/species. if possible, the selection of combination regimens to treat specific types of IFD should also be supported by a demonstration of benefit for co-administration over each agent given alone in an animal model. Consideration should also be given to the potential for significant drug-drug pharmacokinetic or pharmacodynamic interactions to occur, which may preclude co-administration or may indicate a need for dose adjustment of one or both agents.

The guidance goes on to give plenty of details of the study designs. Outcomes testing and specific patient groups, its a detailed guidance that needs careful consideration for anybody working in the area.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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