This guidance document is for comment purposes only.
Submit one set of either electronic or written comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.
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For questions on the content of this guidance, contact OCOD at the phone numbers or email address listed above.
U.S. Department of Health and Human Services
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
The Center for Biologics Evaluation and Research (CBER)/Office of Cellular, Tissue, and Gene Therapies (OCTGT) is issuing this guidance to provide sponsors of virus or bacteria-based gene therapy products (VBGT products)and oncolytic viruses or bacteria (oncolytic products)with recommendations on how to conduct shedding studies during preclinical and clinical development. For purposes of this guidance, the term “shedding” means release of oncolytic or VBGT products from the patient through one or all of the following ways: excreta (feces); secreta (urine, saliva, nasopharyngeal fluids etc.); or through the skin (pustules, sores, wounds). Shedding is distinct from biodistribution because the latter describes how a product is spread within the patient’s body from the site of administration while the former describes how it is excreted or released from the patient’s body. Shedding raises the possibility of transmission of product-based viruses and bacteria from treated to untreated individuals. When finalized, this guidance will represent FDA’s current thinking on how and when shedding data should be collected for VBGT products and oncolytic products during preclinical and clinical development and how shedding data can be used to assess the potential for transmission to untreated individuals.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required.
The products covered by this guidance are oncolytic and VBGT products that OCTGT reviews. The focus of this guidance is shedding studies, including both how and when shedding data should be collected and how shedding data can be used to assess the potential for transmission to untreated individuals.
This guidance does not cover plasmids, peptides, and genetically modified mammalian cells that OCTGT also reviews because, unlike virus or bacteria-based products, plasmids, peptides, and genetically modified mammalian cells are neither infectious nor transmissible. This guidance also does not address collection or submission of adverse event information, including those adverse events that could be attributed to shedding. Please see the regulations at Title 21 of the Code of Federal Regulations (CFR) Part 312, specifically 21 CFR 312.32 and 21 CFR Part 600, specifically 21 CFR 600.80, for information on the collection and submission to FDA of adverse event information.
Finally, while assessment of shedding can be utilized to understand the potential risk to the environment, the scope of this document does not include shedding as it may relate to potential environmental concerns with respect to a specific oncolytic or VBGT product. For more information on this topic, you may wish to consult the draft guidance entitled, “Guidance for Industry: Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines and Related Recombinant Viral or Microbial Products” dated June 2014. When finalized, this guidance will represent FDA’s current thinking on this topic.
Oncolytic and VBGT products are derived from infectious viruses or bacteria. In general, these product-based viruses and bacteria are not as infectious or as virulent as the parent strain of virus or bacterium because of, in part, the derivation methods and/or modifications made during product development that lead to attenuation. Hence, it is likely that these products are shed to a lesser extent than during natural infection by the parent strain. Nonetheless, the possibility that infectious product-based viruses and bacteria may be shed by a patient treated with an oncolytic or VBGT product raises safety concerns related to the risk of transmission to untreated individuals. To understand this risk, shedding studies that are conducted in the target patient population(s) may be appropriate before licensure.
Typically, clinical shedding studies are not stand-alone studies but are integrated into the design of a safety or efficacy trial. Because there are many product-specific factors and patient-specific factors, as described throughout this guidance, that can influence the design of a shedding study, sponsors should consult with OCTGT in the early stages of product development for specific recommendations as to their product.
Shedding studies of oncolytic or VBGT products are conducted to provide information about the likelihood of transmission to untreated individuals and about measures to prevent such transmission. Shedding data collected during clinical development should provide a clear and comprehensive understanding of the shedding profile of oncolytic or VBGT products in the target patient population(s). Note that it may be appropriate to describe this data in the package insert for an approved Biologics License Application (BLA).
Shedding of each oncolytic or VBGT product should be studied during clinical development because the shedding profile is not always predictable from historical or preclinical data. For these products, sponsors should consider product-specific variables and patient-specific factors (as described below and throughout this guidance) that could affect shedding. For example, the biological characteristics and route of administration (entry) of oncolytic or VBGT products can be different from that of the parent strain of viruses and bacteria. Specifically, these products may be:
Also, oncolytic or VBGT products may be derived from human-specific strains and therefore, animal models may not adequately predict shedding in humans. In addition to product-associated variables that are described above, patient-specific factors, such as differences in the immune status at the time of treatment, can contribute to the potential for product shedding (for more details refer to section VII.B.).
The main considerations in the design of shedding studies are: the choice of clinical samples that are collected from subjects in a trial (feces, urine, nasal swabs etc.); the periodicity of sample collection and duration of the monitoring period; and the assay methodology selected to test for the presence of the shed oncolytic or VBGT product in the clinical sample (Ref. 1).
To guide the design of shedding studies, the following should be considered:
A. Biological Characteristics
B. Route of Administration
In addition to the tropism of the oncolytic or VBGT product, the route of product administration should be considered in the selection of sample types to collect in a shedding study. For example, to assess shedding in patients administered an oncolytic virus by the intradermal route, we recommend the collection of skin swabs at the site of injection in addition to the other samples routinely assessed for shedding, such as urine, feces and saliva. Similarly, we recommend the collection of nasopharyngeal washes when an oncolytic virus is administered by inhalation or via the intranasal route.
Shedding data that are collected in animals following administration of the oncolytic or VBGT product can help estimate the likelihood and potential shedding profile in humans, particularly when there is concern about transmission to untreated individuals. The decision to assess shedding in preclinical studies is based on the biological characteristics, derivation, and genetic make-up of the oncolytic or VBGT product. For example, preclinical shedding data may be requested for an oncolytic or a replication competent VBGT product, if:
The use of the animal species/model(s) is an important factor that can affect the biological relevancy of the shedding profile generated in the animal. Considerations include the permissiveness or susceptibility of the animal to infection from the oncolytic or VBGT product under investigation, and any preexisting immunity the animal has to the product.
Collection of shedding data is an endpoint that can be included in preclinical studies designed to collect other data, such as safety and biodistribution. The decision to include an assessment of the shedding profile of an oncolytic or VBGT product in an animal study will depend on various product-specific factors, as described above and in sections I. and V. of this document. We recommend that sponsors initiate communication with the Pharmacology/Toxicology staff in OCTGT early in their product development program to discuss the need for generating a shedding profile for their oncolytic or VBGT product in animals, and the planned methodology to collect this shedding data.
Shedding data collected in clinical studies provides a shedding profile of a product in the target patient population and is used to estimate the potential of transmission to untreated individuals. Depending on the shedding profile, it may be appropriate to include the information on shedding in the Investigator Brochure and in the Informed Consent for Investigational New Drug studies. Depending on the shedding profile, it also may be appropriate to include shedding data in the package insert for licensed products to inform patients and physicians if shedding could occur with the use of an oncolytic or VBGT product, the potential for transmission of the product to untreated individuals, and of the measures to take to prevent such transmission.
A. When to Collect Shedding Data in Clinical Studies?
B. Study Design
The plan to collect shedding data in clinical studies can be based on prior clinical experience with the same or similar product, but when there is no such experience, as in the case of first-in-human oncolytic or VBGT products, the shedding profile generated in animals can be informative (see section VI. of this guidance). We recommend that sponsors prospectively design and incorporate the sampling plan in the clinical study to collect shedding data.
There are three critical choices in the design of a sampling plan:
However, there are many aspects that can influence these choices, as described earlier in section V. and further elaborated below.
An analytical assay that measures shedding is designed to detect product in the clinical sample, either by detection of nucleic acids or for the presence of infectious viral particles or dividing bacteria. Based on the design and output (nature of the assay readout), shedding assays can vary greatly in their performance and suitability. Hence, the choice of a shedding assay can greatly affect the quality of the data collected, and is important in the generation of meaningful shedding data, i.e., data that provides a complete shedding profile for a product and can be used to estimate the potential of transmission to untreated individuals.
We recommend that sponsors consider the following in the selection of the analytical assay to measure shedding:
Similarly, if shedding of conditionally replicating oncolytic or VBGT products is noted by qPCR assay at a level significantly above the LOD, we recommend that sponsors further characterize the shed material to confirm infectivity or growth because such products could be shed in their infectious form even if replication is confined, mostly, to tumors or to a particular tissue-type.
Sponsors may justify limiting the shedding analysis of a replication competent or conditionally replicating product to qPCR assay, if:
The effect of sample type and composition on assay performance should be well understood. Clinical samples such as feces and urine are rich in complex organic matter that can adversely affect the performance of an assay and lead to an underestimation of shedding. Also, samples such as feces, saliva and nasal swab are rich not only in host proteins and nucleic acids but also in the body’s natural flora and in circulating strains of viruses and bacteria from the environment. Thus, the assay conditions should be optimized to selectively analyze for the product under investigation. For that, the specificity of the reagents used in the assay should be assessed and the quality of the reagents should be controlled. Certified and contaminant-free reagents should be used in the analysis of clinical samples in a shedding assay.
Interference from clinical sample matrix can lead to a false negative result or an underestimation of the amount of shedding. For example, clinical samples like urine, saliva, and feces are rich in proteases, nucleases, ions and salts that can affect the amplification process in a polymerase chain reaction (PCR); specifically, nucleases in saliva/feces can degrade template DNA, bile salts in feces or urea in urine can affect the activity of thermostable DNA polymerases in the PCR mixture. When PCR inhibition is suspected due to interference from components in a clinical sample, the clinical sample can be diluted to a limited extent to reduce the interfering component. Since dilution of the clinical sample also leads to template dilution, the sensitivity of PCR assay should be assessed in each assay run. For that, each diluted sample should be tested in parallel with one that is spiked with a reference standard or positive internal control prior to dilution. If interference cannot be decreased by limited sample dilution, alternative or additional extraction procedures should be considered to remove the interfering component(s) in the clinical sample.
An underestimate of the level of shedding may also result due to degradation of viral or bacterial nucleic acids in enzyme-rich clinical samples such as feces and saliva during storage, handling/shipping and nucleic acid extraction. To account for such effects, we recommend that mock/donor sample types be spiked, soon after collection, with the reference standard or internal positive control and the percent recovery of the reference standard or internal positive control should be determined on a one-time basis. Sample collection, storage, shipping, extraction and analysis should be performed with the same methodology as that planned for the clinical (test) samples.
In order to assess the potential of transmission to untreated individuals due to shedding, the analysis of shedding data for oncolytic or VBGT products should address the following:
A. The Nature of the Shed Material
When clinical samples are scored positive for product in a shedding assay, the subsequent analysis of these samples should provide answers to the following questions:
Ideally, the shedding assay should be able to discern complete genomes from degraded genome fragments, or infectious from noninfectious product-based viruses, or dividing from non-dividing product-based bacteria in the samples. We refer you to section VIII. for details on shedding assays and for our recommendations. If qPCR is the only assay you have relied on in your shedding analysis of replication competent products, or the shedding assay screens for small genome fragments of the product, then we will assume that the shed material in the positively scored samples is infectious.
B. The Extent of Shedding
In the analysis of shedding data, the extent of shedding noted for each sample type as a factor of time, dose (amount of product administered) and regimen (number of doses) should be reported for all the patients monitored in the study. Raw data in the shedding report should be accompanied by a corresponding analysis that is comprehensive and describes the following:
Note that your analysis of shedding data should be accompanied by a summary of the shedding profile of the product in patients treated for a specific indication. While it is common practice in clinical development of oncolytic and VBGT products to study a product for different indications in multiple trials, the shedding pattern may be distinct in each study population. We recommend against pooling shedding data from multiple trials in which the same product is studied for different indications because results from a shedding study in a given indication may not be generalizable to other indications.
Finally, we recommend that the shedding data be submitted in a format as described in the next section.
In order to address the potential for transmission to untreated individuals due to shedding of oncolytic or VBGT products from the patient, the following should be provided to us for review as the information is obtained during product development, and a full report should be provided in the BLA:
See section VIII. for a discussion of analytical assay types and conditions, section VII.B. for a discussion of clinical sample collection, section IX. for analysis of shedding data, and section XI. for details on assessing the potential for transmission to untreated individuals due to shedding.
Our current understanding is that in most cases, the potential for transmission to untreated individuals is extremely low when oncolytic or VBGT products are shed because of the derivation methods and/or modifications that are designed to attenuate the product when compared to the parent strain of virus or bacterium. Nevertheless, you should discuss the potential for transmission based on the analysis of the shedding data collected in the clinical studies and taking into consideration the factors described below.
A. What Information in the Shedding Data Can be Used to Assess Potential for Transmission to Untreated Individuals?
B. Monitoring Untreated Individuals for Transmission
Because transmission to untreated individuals is an extremely low probability event, monitoring such individuals for transmission is usually not required during the clinical development of a product. However, if we believe there is a potential for transmission, additional data will be needed to assess that possibility; in which case, we recommend that you consult with OCTGT in connection with developing a monitoring plan.
1. Gene therapy products are all products that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in vivo or transferred to cells ex vivo before administration to the recipient. See section III of FDA’s guidance document entitled “Guidance for Industry: Gene Therapy Clinical Trials - Observing Subjects for Delayed Adverse Events” dated November, 2006.
2. Oncolytic products refer to replication competent viruses or dividing bacteria that are used as therapeutic agents to mediate lysis of tumor cells. Some oncolytic products carry foreign genes (immune modifying genes, genes that enhance oncolysis etc.), and mediate part of their anti-tumor effect by transcription and/or translation of these foreign genes in the host. Hence, oncolytic products that carry foreign genes can also be classified as gene therapy products.
4. For general information about preclinical assessment of these products see FDA’s guidance entitled “Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products” dated November 2013, at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/