USFDA Guidance for Industry:

Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products

Background

Under 21 CFR 25.40 of the Code of Federal Regulations, most pharmaceutical and biotechnology companies are required to submit an Environmental Assessment (EA) when submitting a new drug for  approval.

The assessments are meant to show how a drug might affect the environment. Many drugs enter the environment as sewage after being excreted by patients.

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.

The need for environmental assessments is taken seriously by FDA. A company's failure to submit an EA can result in a submission being rejected by FDA. For more information read FDA's 1998 guidance, Environmental Assessment of Human Drug and Biologics Applications .

But FDA's 1998 guidance was written at a time when the term "drug" was largely synonymous with "chemical"—not "biotechnology." Nearly 20 years later, FDA has asked itself whether its environmental guidelines ought to apply to biotechnology products like gene therapies, vectored vaccines and related recombinant viral or microbial products (GTVVs) as well.

Guidance Development

In June 2014, FDA released a draft guidance document, Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products.

The guidance document explained that since most GTVV's are not naturally found in the environment—FDA's standard for exclusion—they will generally be subject to FDA's environmental testing regulations.

Even biotechnology products which are highly similar to naturally occurring species will need to undergo an environmental assessment, FDA said in the guidance. "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.

One concern highlighted by FDA is the potential for variants of the approved product to make their way into the environment. For example, while some biotechnology products are engineered to make them unable to replicate, defects in the manufacturing process may allow some products to do so.

What Does FDA Want to Know?

The guidance also contained extensive details regarding what information should be included in a company's EA submission to FDA, including a lengthy list of questions sponsors are supposed to answer:

• 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?

Final Guidance, No Changes

On 23 March 2015, FDA announced the release of the final iteration of its GTVV environmental assessment guidance (as attached).

In an accompanying Federal Register notice, FDA said that while there were "a few comments on the draft guidance," the final guidance contains "no changes … except for one correction to a technical error regarding influenza taxonomy."

This guidance also supplements the guidance entitled “Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications” dated July 1998, (July 27, 1998, 63 FR 40127) (1998 Guidance) and supersedes the recommendations for GTVVs in section IV.B.1 “Assessing Toxicity to Environmental Organisms” in the 1998 Guidance.

The guidance is immediately in effect.