Xenotransplantation

“sponsors have important responsibilities in terms of documenting information relating to the xenotransplantation product and procedure, for recipient monitoring and follow-up, and for collection and storage of archival tissue samples from animal source and recipient. Assessment of proposed clinical trials involving xenotransplantation requires GTAC to assess data on source animal and xenotransplantation product characterisation, preclinical data, patient selection, medical procedures to be undertaken, plans for post-transplant patient monitoring, and the qualifications and experience of professionals involved in patient care, the animal facility and animal-testing laboratories.”

With regards to deriving xenografts from source animals, the
guidelines recommend the use of closed herds with documented health screening programs, and avoidance of using source animals that are raised under free-ranging conditions or those obtained from slaughterhouses or abattoirs. Production of source animals should occur in an adequately designed facility and there should be a defined protocol for the operation of the facility to minimise the animals’ exposure to infectious agents.

With regards to pre-clinical evidence to support the initiation of clinical trials, the GTAC guidelines assert that pre-clinical studies should be conducted usually in a minimum of two animal models (including one non-human primate model). These studies should focus on activity (the intended alteration to the human pathophysiologic state) and toxicity (unintended effects to the host system), and should use the xenotransplantation product that will be tested in the proposed clinical trial. The guidelines also stipulate the pre-clinical data that should be available and parameters that should be considered depending on whether it is a xenotransplantation product intended to synthesise and provide bioactive molecules such as cytokines or hormones (as would be the case in insulin-producing porcine islet cells); heterogeneous xenotransplantation products containing varying proportions of constituent cell types; or xenotransplantation product/device combination products (as in the case of encapsulated porcine islets).

With regards to patient selection in first-in-human clinical trials, the GTAC guidelines recommend that trial subjects should be limited to patients with a serious or life-threatening disease for which adequately safe and effective alternative therapies are not available, except when very high assurance of safety can be demonstrated; patients who have the potential for a clinically significant improvement with increased quality of life following the procedure; and patients with the ability to comply with public health measures, including long-term monitoring. Regarding post-procedural monitoring of patients, the guidelines recommend a four-pronged approach that incorporates not only diagnostic testing but also ongoing recipient screening programs for clinically inapparent infections and seroconversions:

1) Diagnostic testing - for both acute and chronic infections when a recipient appears ill
2) Passive screening program - in which appropriate clinical samples are obtained periodically and archived for possible future testing
3) Active screening program – to screen prospectively for evidence of infection in the absence of symptoms.
In particular, if a xenotransplantation product known to harbour an infectious agent is used, active screening for that infectious agent should be implemented (e.g. assess all recipients of xenotransplantation products involving the use of porcine products for evidence of infection by PERV)
4) Provide a plan for post-mortem detection of infectious agents and archiving of autopsy samples

The screening program should extend for the life of the patient, although frequency of follow-up may decrease with the length of time post
procedure.

The GTAC guidelines also stipulate the importance of uniformity in data management to ensure that each xenograft recipient’s medical record contains relevant xenotransplantation-related information including procedures adopted, a description of the xenotransplantation product, and any xenotransplantation product-related adverse events.
Where a serious adverse event occurs, the sponsor of the trial is obligated to report it to Medsafe within 72 hours of being informed of the adverse events. Simultaneously to recording information on recipients, animal facilities should also record animal health events such as any breaks in the environmental barriers of the secured animal facility, disease outbreaks and any sudden, unexplained or unexpected animal deaths. The animal facility should report animal health events to the sponsor who should include this information in its tracking system for recipients and in reports to the Ministry of
Health.