3rd DIA Cell and Gene Therapy Products
Symposium in Japan- Development and Practical Use of Cell and Gene
Therapy Products in Japan -December 13-14, 2018
KFC Hall | Ryogoku, Tokyo

Environmental assessments and shedding studies
for gene therapy products in the US and Japan
Kanazawa Institute of Technology
Teruhide Yamaguchi

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2• Environmental assessment of genetherapy products in USA
Comparison of EA and Biodiversity
Assessment

3

Environmental Assessment for Gene Therapy Products andVirus-shedding Study

Virus Vector<Health Care
Professional>

Viral Shedding
excretion?

secretion ・ Emissions(Urea, faeces, sputum）

???

???

???

Administration<Family><Environment>

4

Environmental assessment and guideline for viral
shedding in USA






USA does not ratify the Cartagena Protocol on Biosafety
According to US federal law, the sponsor should submit theenvironmental assessment about gene therapy product.
The National Environmental Policy Act of 1969 (NEPA); Revisionof Policies and Procedures (Final Rule) 1997
federal law 21CFR25Determining the Need for and Content of Environmental
Assessments for Gene Therapies, Vectored Vaccines, andRelated Recombinant Viral or Microbial Products (GTVV)（Guidance for Industry, FDA CBER, March 2015）
Design and analysis of shedding studies for virus or bacteriabased gene therapy and oncolytic products（Guidance for Industry, FDA CBER, 2015)

FDA Guideline for the Environmental Assessment:
IND Approval The sponsor should submit the following data in IND（21CFR25.15(a)）
 Environmental assessment

 Claim for categorical exclusion
 In the case of no categorical exclusion：
Extraordinary circumstances indicate that the specific proposed agency
action may significantly affect the quality of the environmentExtraordinary circumstances: Specific or unknown risk on human, Risk
on Endangered Species of Wild Fauna and Flora (CITES) In most cases, IND for a clinical study using a GTVV will notsignificantly affect the quality of the environment because, in brief,these clinical trials are closely monitored and are limited to a
designated study group.

FDA Review of Environmental Assessment for IND ofGMO products
 Key Issues of Environmental Assessment for Human Gene Therapy
Investigational New Drug Applications (INDs).


Collection of viral shedding data to evaluate the environmental assessment

Measures to mitigate the potential risk for securing the safety of theinvestigational study

 Environment Reviewer is responsible for evaluation of the environmental risk

 Emergency of replication competent virus is concern risk for replication
incompetent virus vector including recombinant viral vaccine
 Recommend to collect the viral shedding data about 10 patients➡If the viral shedding risk is low, collecting the viral shedding data may beskipped. (Shedding data will be required for EA for marketing authorisationapplication)
 If the data or monitoring protocol is not enough, FDA submit the clinical holdto the sponsor (especial to replication competent virus vector)

FDA Environmental Assessment of Human Drugand Biologics Applications（BLA) BLA of gene therapy products：the sponsor should submit EA

categorical exclusion（Substances that Occur Naturally in the Environment）
are; contain functional protein-coding sequences from one or morespecies within a single genus to “occur naturally in theenvironment” for purposes of 21 CFR 25.31(c).
 differ from a wild-type substance only in attenuating point
mutations or deletions to be substances that “occur naturally inthe environment” for purposes of 21 CFR 25.31(c) have been killed or inactivated by undergoing a specificmanufacturing step designed to eliminate their ability to replicate
to be substances that “occur naturally in the environment”
 consist of genetically-modified human

FDA Environmental Assessment of Human Drugand Biologics Applications：（BLA) BLA of gene therapy products：the sponsor should submit EA

 Identification of Substances Subject to the Proposed Action“Identification of Substances Subject to Proposed Action”; “Identifying andAssessing Potential Environmental Effects”; “Mitigation Measures”; and“Alternatives to the Proposed Action.”

Identification of Substances Subject to the Proposed Action
To identify known and potential variants of the GTVVs released into theenvironment.



Identifying and Assessing Potential Environmental Effects

Is the vector virulent, pathogenic, what is known regarding the genetic stabilityand prevalence of gene exchange in natural populations of the strain orvector?

the product have traits that may give it a selective advantage over naturalorganisms?

Assessing the magnitude of potential environmental effects

What is known about the effectiveness of monitoring and mitigation plans?

FDA Environmental Assessment for GMO products
 The release of vector DNA into the environment is detectable by PCR at theinjection site and/or in excreta Replication competent impurity may cause an active infection in the patient orstudy participant capable of disseminating to others. ⇒ These variants mayarise during manufacture or after product administration because of mutations,or recombination events.
 A super-coiled plasmid may still retain the ability to transfer genetic material(such as antibiotic resistance genes) to other bacteria even after limited
degradation.

Levy et al: Quantitation of supercoiled circular content in plasmid DNA solution using
fluorescence based method. NAR 28, e57, 2000

Environmental assessment of gene therapy
products in USA
Comparison of EA and Biodiversity
Assessment© 2018 DIA, Inc. All rights reserved.

11

Environmental Risk of Replication Competent Virus andViral Vector
 Recombinant Oncolytic Virus Vector
 Wild and Attenuated Oncolytic Virus Attenuated Viral Vaccine expressing recombinant Antigen(Ebola, MERS antigen etc.)
 Imlygic, recombinant oncolytic HSV-1 virus has a risk on immunecompromised patients, new-born children, pregnant women.

 The sponsor was required to mitigate the risk on transmission ofImlygic to intimate 3rd party and HCP.
 To prevent the 3rd party transmission, the sponsor provides themedication-guide and the education program to patients
Sponsor is required to mitigate the risk for transmission of vectors to3rd parties in clinical use of gene therapy products (ICHConsideration, viral shedding).
Sponsor should consider the risk of viral vector on various humanpopulation.

Comparison of GMO Regulation about Gene
Therapy Products between EU, USA and Japan
Cartagena
ProtocolEnvironment
Assessment GL
Focus

Japan

USA

EU

Adopt

No

Adopt

None

Adopt

Adopt

Gene Therapy Products include
Plasmid
At Approval for Market
Authorization (MA)(except for replication competentvirus or etc）

Gene Therapy Products include
Plasmid

Viral Shedding GL

ICH ConsiderationSubmit with Approval for MA

Submit with Approval for MA

Recombinant Virus

Review Timing

Before Clinical Study

Viral Shedding

ICH Consideration

Shedding Data
When collectshedding data

Phase I

Control Pts

In hospital(isolated room)

Replication Competent Virus:
Phase I
Non-replication : Phase II
In or out hospital

Before Clinical Study by each
Regulatory Agency
At Approval for MA（EMA）

UK：Phase I

In or out hospital*Cartagena law

Japanese Cartagena Law may correspond to EU and USA environmental Assessment.

Environmental Assessment of GMO in EU, USA and Jpn
R&D

Clinical TrialSubmission
for AMA

Ph-III

viral shedding
Data

RMP

Review the viral
shedding data as
EA
Ph-II

Ph-I

CMC

Review of GMO ineach regulatory
agencyIND

Submission
for AMAviral shedding
DataEU
N-clinical

RMP

How to evaluate the EA

Ph-III

Pre IND
meeting

IND

Ph-II

Pre-PreIND
meetingviral shedding
Data

Ph-I

CMC
Consultation

N-Clinical

Submission
for AMAUSA

2nd Class
USE st1 Class
USE

Ph-III

R&D consul.

Sub.CTIND

Ph-I

CMC

N-clinical

Ph-II

Jpn

Market

RMP

Review the viral
shedding data as

Conclusions
Basically EU and USA perform the environmental assessment for genetherapy products during the review of approval for marketing
authorization.
US FDA considers the replication competent virus vectors may havehigh risk to immune-compromised population, and requires the sponsor
to submit the design for viral shedding studies during clinical trail.
In Japan, environmental risk of gene therapy product is pre-reviewed
onset of clinical trials according to national biodiversity law which havebeen adopted as part of GMO risk assessment .

Thank you !
Any question?

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