EMEA Publishes ICH Considerations on the General Principles to Address Virus and Vector shedding
a copy is available here.
Introduction
Drug Regulators Publish ICH consideration on Virus and Vector Shredding Virus / vector shedding should not be confused with biodistribution, e.g., spread within the patient’s body from the site of administration.1 Virus / vector2 includes gene therapy vectors3 and oncolytic viruses.
Assessment of shedding can be utilized to understand the potential risk associated with transmission to third parties and the potential risk to the environment. The scope of this document excludes shedding as it relates to environmental concerns because it is regulated differently in various regions.
The focus of this document is to provide recommendations for designing non-clinical and clinical shedding studies when appropriate. In particular, emphasis will be on the analytical assays used for detection, and considerations for the sampling profiles and schedules in both non-clinical and clinical studies. The interpretation of non-clinical data and its use in designing clinical studies is also within the scope of this paper, as well as the interpretation of clinical data in assessing the need for virus / vector transmission studies.
Biological Properties of the Virus / Vector
Information on the known properties of the wild-type strain from which the virus / vector under consideration was derived is essential in guiding the design of shedding studies.
In practice, most viral / vector products currently under investigation are replication incompetent or conditionally replicative. It is likely that virus / vector shedding in these cases would be of a much shorter duration, and, depending on the route of administration, would display a different shedding profile as compared to shedding following infection with the wild-type counterpart.
Other property of the replication-competent virus / vector that should be considered when designing shedding studies would be whether infection is expected to be short- or long-term.
Analytical Assay Considerations
Having suitably qualified analytic assays in place for shedding studies is very important. Assays should be specific, sensitive and reproducible. Quantitative assays are preferred as these will aid in quantifying the probability of transmission. Assessment of interference from the biological sample matrix is important and it might be appropriate to dilute the sample prior to analysis to avoid extensive interference.
Polymerase chain reaction (PCR) and infectivity are the two assays typically used for the detection of shed virus / vector. Use of a quantitative PCR (qPCR)-based assay to detect viral / vector genetic material is recommended.
To accurately assess the potential for transmission of shed material, the use of an infectivity assay is considered important as this will allow for an accurate assessment of the nature of the shed material (e.g., intact virus / vector vs. fragments of virus / vector).
Non-Clinical Considerations
Non-clinical shedding studies help guide the design of clinical shedding studies. The aim of a nonclinical shedding study is to determine the secretion / excretion profile of the virus / vector.
Animal Species
One of the difficulties of investigating virus / vector products in non-clinical studies is the relevance of the animal species as a large number of virus / vector products under clinical evaluation are derived from parental strains which do not readily infect and rarely replicate in non-human species.
Dose and Route
Wherever possible the dose and route of administration used in non-clinical shedding studies should reflect those intended for use in the clinical setting.
Sampling Frequency and Study Duration
Known biological properties of the wild-type strain can be used to guide the frequency of sampling after virus / vector administration. In general, one might need to take samples more frequently in the first days following administration in order to detect a transient shedding profile.
Sample Collection
The characteristics of the virus / vector, the route of administration, and animal species should be taken into consideration in determining the samples to be collected. Examples of collected samples most commonly include urine and faeces, but could include other sample types such as buccal swabs, nasal swabs, saliva, and bronchial lavage. It is worth considering the samples that should be taken and the volumes that should be collected in order to perform quantitative, suitably qualified analytical assays. For certain secreta or excreta, such as urine, it can be difficult to collect sufficient sample material. Pooling of samples from several animals at the same time point receiving the same dose might be an option so that sufficient sample size or volume can be obtained.
Interpretation of Non-Clinical Data and Transmission Studies
It is important to keep in mind that data from non-clinical shedding studies are useful in guiding the design of clinical shedding studies, particularly as to sample types, sampling frequency, and duration.
Clinical Consideration
The considerations raised above for non-clinical studies are relevant to the design of virus / vector shedding studies in a clinical setting (i.e., route of administration, duration of shedding observed, sample types to be taken and frequency). The known biological properties of the parental virus / vector, the replication competence of the product, dose, route of administration, and patient population will be key factors to consider in the design of clinical shedding studies.
Interpretation of Clinical Shedding Data
There are a number of factors to take into account when assessing the clinical shedding data and the potential risk associated with transmission from shed virus / vector. An important factor to consider is to identify and characterize what is being shed. Specifically, if the assay used does not distinguish intact from degraded or non-infectious virus / vector, then the data might not be informative as to the potential risk associated with transmission.
Determining how virus / vector is shed is an important factor when assessing the potential risk associated with transmission. One should also consider how much is being shed and the duration of shedding.
Third Party Transmission
In some cases, when shedding is observed, the potential for transmission to third parties might need to be investigated. These investigations would involve evaluation of persons that come into close contact with virus / vector recipients (e.g., family members, healthcare workers) for evidence of transmission. The immunological status of the third party should be considered. A high proportion of the population might already have pre-existing immunity to the virus / vector; in this case, clearance should be effective in those individuals. However, the immune status of the third party contacts could be compromised, e.g., in the elderly or very young, and so clearance mechanisms might be inefficient. Thus the consequences of infection might be more significant in these individuals.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
