Guideline on Clinical Investigation of Immunosuppressants for solid Organ Transplantation

The aim of this guideline is to provide guidance on the clinical development of compounds for the prevention and treatment of allograft rejection in solid organ transplantation.

The immune system is vital for the human body and immunosuppression in organ transplantation should be as selective as possible, to minimise the risk of over-immunosuppression which can cause increased risks of infections and malignancies. Many problems exist in currently approved regimens: Treatments are often very complex, e.g. quadruple immunosuppression, and vary over time for each patient. This complexity also increases the risk for low patient compliance. Therapeutic margins can be very narrow and there are considerable risks of over- as well as of under immunosuppression. The pharmacokinetic interaction potential is high and causes problems (decreased efficacy, increased toxicity) as transplant patients are often on multiple other drugs. Many widely used immunosuppressive protocols in transplants performed in low numbers,  i.e., lung, bowel and islet transplantation, are not approved for that indication.

Different treatment settings and modalities, such as type of organ transplantation (renal, liver, heart, lung, etc.) type of therapy (induction, initial, maintenance, tolerance induction), type of allograft rejection (hyperacute, acute, subacute, ‘chronic’ and/or (steroid) resistant) and type of pathophysiology (cellular or humoral type of rejection) are distinguished. Many different immunosuppressive drugs and a number of different combinations are currently available and new agents are under development. Other treatment concepts that are explored include steroid withdrawal or total avoidance of steroids, drug minimisation and induction of tolerance.

This document considers these circumstances and provides guidance for proper development of new immunosuppressant for solid organ transplantation. Potential claims provided reflect principal aims of management of transplanted allograft with immunosuppressant. Baseline subject characteristics and selection criteria of subjects considers immunological and global transplantation risk assessment; both of donor/transplant and recipient. Primary efficacy criteria are provided in general terms and are seen as constructed by composed and/or co-primary endpoints only. Guidance on pharmacokinetic and pharmacodynamic investigations reflects mainly specific pathophysiology during peri-transplantation period, co-therapies and monitoring strategies. Exploratory trials should reflect concepts of immunosuppression for investigated agent or process and base strong rationale for confirmative investigations. Guidance on confirmatory trials is provided mainly for  major transplantation areas, such as renal, liver, heart, lung and pancreas transplantation. Specific areas with limited experience gathered
up till now, such as development of minor transplantation areas as well as choice of non-approved comparators are recommended to be guided by European regulatory advice procedures. Special issues in paediatric, elderly population and in case of certain infections during peri-transplantation period are advised to be investigated by tailored trials. Clinical safety investigation should reflect certain essential
characteristics of immunosuppression in solid organ transplantation, such as life-long lasting treatment in a population with extensive co-morbidity. Specific factors to be considered include proper time for assessment of infectogenic and cancerogenic potential, risk of premature death due to primary disease and overlapping safety signals.

This document should be conceived as general guidance and should be read in conjunction with other EU and ICH guidelines that apply to the subject (see Section 3 ‘Legal basis’). Due to the dynamics of the field, frequent revisions and amendments are foreseen.
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This document provides guidance for proper development of new immunosuppressant for solid organ transplantation. Potential claims provided reflect principal aims of management of transplanted allograft with immunosuppressant. Baseline subject characteristics and selection criteria of subjects considers immunological and global transplantation risk assessment; both of donor/transplant and recipient.

The 15-page Guideline on clinical investigation of immunosuppressants for solid organ transplantation can be downloaded here: Guideline on clinical investigation of immunosuppressants for solid organ transplantation