The US Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) has released a new draft guidance document meant to clarify when companies need to conduct an Environmental Assessment (EA) for gene therapy and other recombinant products.
Under 21 CFR 25 of the Code of Federal Regulations, most pharmaceutical and biotechnology companies are required to submit EAs as part of their approval package. The assessments are generally meant to show how a drug might affect the environment, such as how drugs—for example hormones—might be excreted by a patient and enter a city's supply of drinking water.
FDA has explained in the past that it's particularly concerned with how drug substances behave once they enter "into the aquatic environment" (i.e. the water supply), whether they can be filtered out by water treatment facilities, and how those drug substances might cause harm to the environment or any wildlife.
Failure to submit an EA can result in a submission being rejected by FDA—an action formally known as a refuse to file determination.
For more information read FDA's 1998 guidance, Environmental Assessment of Human Drug and Biologics Applications.
Guidance: What's "Naturally Occurring"
But FDA's 1998 guidance was written at a time when the term "drug" was largely synonymous with "chemical," and not "biotechnology."
FDA's latest guidance document, Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products, is meant to change that.
The 2014 guidance is largely similar in layout to FDA's 1998 guidance, but instead focused on biotechnology products—gene therapies, vectored vaccines, and related recombinant viral or microbial products (GTVVs)—submitted under a Biologics License Application (BLA) instead of pharmaceuticals submitted under a New Drug Application (NDA).
Like the original guidance, Investigational New Drug (IND) applications, used to initiate clinical testing of a drug, are exempt from EAs.
Also exempt are products which "occur naturally in the environment" and would not be introduced in quantities or concentrations higher than usual. However, if the GTVV has been altered such that the "functional protein-coding sequence" differs from that found in the environment, FDA will require an EA.
"Accordingly, FDA considers most GTVVs to be substances that do not 'occur naturally in the environment' because most GTVVs include functional protein-coding sequences from a different genus. Therefore, applications requesting agency action for GTVVs that are engineered to express one or more proteins from a different genus should include an EA because FDA would not consider the criteria for a claim of categorical exclusion to be met," the regulator explained.
But even then, the type of changes will matter, FDA said. For example, GTVVs that only change the substance by attenuating point mutations, which can be used to reduce virulence or restrict replication, to still be naturally occurring, and thus exempt from EA requirements. In addition, FDA said it "generally" considers genetically=modified human cells to be exempt from EA requirements since they are generally "not viable in the environment."
Killed or inactivated GTVVs are also considered "naturally occurring," FDA said.
The Environmental Assessment
The remainder of the guidance goes into what information should be included in each EA.
FDA recommends that each application have a description of the substance and its metabolites, degradants and byproducts that might find their way into the environment.
The EA should also include experimental data on variants that might be released into the environment, with FDA expressing concern that some GTVVs engineered to be unable to replicate could have a "low level of replication competent product … present as an impurity."
In other cases, natural selection may result in "the development of variants that have a selective advantage," FDA continued.
Those risks, as well as the risks inherent to the product, should be identified and evaluated according to a provided list of questions, regulators said.
Is the strain or vector virulent, pathogenic, or known to be associated with animal, plant or microbial toxicities?
Is there an understanding of the environmental distribution, host range, and tropism?
Are there substrates that may limit growth or reproduction?
Is the strain or vector susceptible to control by antibiotics, antivirals, or biocides?
What is known regarding the genetic stability and prevalence of gene exchange in natural populations of the strain or vector?
What is known about the stability of the strain or vector in the environment and is the strain capable of survival under adverse conditions (spores, dormancy, etc.)?
Does the product have traits that may give it a selective advantage over natural organisms?
Would susceptible species be exposed?
Does the environment provide limited or reduced capacity for growth or reproduction?
Are species or strains closely related to the product present in the environment that may be affected?
Can dispersal be naturally controlled by barriers in the environment?
What is known about the effectiveness of monitoring and mitigation plans?
Does the alteration affect the ability of the product to replicate?
What effects could transgene expression or exposure have outside of the target population?
What is known about the genetic stability of the altered sequence?
FDA is accepting comments on the guidance until 18 September 2014.
Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products (FR)