USDA Inspection report 01/24/2017 No non compliant items identified. Pass

USDA VS inspection 11/09/2017 Pass , inspection report 93-R-0434 PASS

IBC Approval 10/02/2019 1999-471 Approved 3 year

IACUC inspection Jan-16-2019 to Jan-16-2022 UC Irvine Pass

ISSUING AGENCY	DOCUMENT TYPE	REFERENCE	DATE APPROVED	EXPIRATION DATE
CDC 12/21/2017	Import Permit Policy Statement: Date and Conditions of the Import Permit (Section 71.54(d) of these regulations provides that the CDC permit is valid only for: (1) the time period and/or term indicated on the permit, and (2) only for so long as the permit conditions continue to be met.) "The requested vectors are not capable of transferring an infectious biological agent to a human if it is uninfected; therefore, an import permit is not required. "	10252017-10037	6/11/14	N/A
UCI-IACUC	Expression of Exogenous Genes in Mosquitoes	Protocol No. 1998-1411-9	3/10/16	3/9/19
Centers for Disease Control & Prevention (CDC)	Permit to Import Infectious Biological Agents, Infectious Substances, and Vectors	PHS PERMIT NO. 2016-06-052	6/13/16	6/13/17
UCI- Institutional Biosafety Committee	Expression of Exogenous Genes in Mosquitoes	IBC Protocol Number: 1999-471	10/4/16	10/3/19
USDA-APHIS	ROUTINE INSPECTION - No non-compliant items identified during the inspection.		1/24/17
UCI Radiation Safety Committee	RADIATION USE AUTHORIZATION	RUA#: R 8906	3/17/17	3/31/20
PATH	Material Transfer Agreement - frozen aliquots proprietary	Protocol No. 1998-1411-9	5/2/17	9/30/20
NIAID	Collaboration Agreement HNIH Carolina Barillas-Mury proprietary	Protocol No. 1998-1411-9	5/2/17
USDA-APHIS (DARPA)	US Veterinary Permit for Importation and Transportation of Controlled Materials and Organisms and Vectors	Permit No. 135681	8/12/17	8/12/18
USDA-APHIS	Application 17299032 for University of California, Irvine for Aedes (mosquito eggs) - Aedes aegypti Higgs (Submitted 26 Oct 2017)	Ref. No. 17299032	8/12/17	12/8/18
USDA	Interstate Movement of Anopheles gambiae	PERMIT NO. 17-233-101m	9/7/17	9/7/18
UCI and PENN STATE	Non-disclosure Agreement (Processes, designs, sequences, data and findings related to CRISPR/Cas9 and its uses for genome editing and gene regulation)	NDA	9/25/17
California Department of Public Health	Authorizing UCI the continued usage and importation of the new Aedes aegypti strain for vector control	Signed: Vicki Kramer, Chief of Vector-Borne Disease Section	10/13/17
USDA inspection IACUC	Pre inspection prior to permit	18-004-106m	11/7/17	at will
UCSD MTA TIGS	Material Transfer agreement for Anopheles gambiae and stephensi	MTA00009219	1/30/18
USDA-APHIS 01/17/2018m interstate only, notified CDPH if movement within state (intrastate)	DARPA Akbari Aedes aegypti eggs Vector 986G-pBac-Aedes-Ubiq (AAEL006511)-dCas9-VPR-p10-UTR-Opie2-dsRed Vector 986H-pBac-Aedes-AAEL011410 (AaKLC2)-dCas9-VPR-p10-UTR-Opie2-eGFP Vector 1002-pBac-3xp3-eGFP-UTR-AAEL010097-RGR-dmeFlightN-UVW-iSce1CutSite-XYZ-optimized-tdTomato_Attb-Modified Vector 1003-pBac-3xp3-tdTomato-AEEL010097-Cas9-HR5Ie1-XYZ-Sce1-Sce1-UVW-eGFP-UTR_attB-Modified	18-004-106m	2/2/18	2/1/19
USDA John Hopkins University	Anopheles stephensi 44c LINE	18-012-101m	2/22/18	2/22/19
USDA to UC Davis	Permit to Import Infectious Biological Agents, Infectious Substances, and Vectors	136098	2/28/18
UCSD MTA DARPA	Material Transfer agreement for Aedes aegypti	MTA 94443	4/6/18
John Hopkins University (Fidel Zavala MD)	Trap P berghei CSP P vivax CS repeat	MTA	4/17/18	4/18/19
Leids University (Shahid Kahn)	Pf CelTOS (NF54), Pv CelTOS, Pf CSP (NF54-full), PvCSP variant 210 full, Pv CSP variant 247 full, Pf TRAP NF54, Pv TRAP, Pf CSP/TRAP NF4, Pv CSP/TRAP, Pv CSP/TRAP/CelTOS	MTA	5/2/18
SLA	Pfs14M etal	MTA/SLA	5/2/18
USDA (UCIMI)interstate only, notified CDPH if movement within state (intrastate)	pCO-6-pSL_attB_AgvasCas9DsRed_3xP3CFP (VASA) and (Nanos) interstate transport for injection at UMD X1 gambiae	18-100-103m	5/7/18	5/4/19
Leidos.com (Gabriel Gutierrez)	PFCelTos (Hybridoma sequence for 3C3 clone)	MTA	5/14/18
UCI/UCSD USDA Interstate to UMD	80.9 Helper line to UMD for injection from UCI (vasa cas9)	18-141-101m	6/13/18	6/13/19
UCI Outgoing to UCSD TIGS Ethan Bier	Material Transfer agreement for Anopheles stephensi (research lines) 80.9 docking site submitted 06/12/2018	MTA	6/27/18	6/27/18
USDA UCI Outgoing to UMD	Stephensi docking site 80.9	18-163-113-m	6/29/18	7/1/19
USDA Outgoing and incoming UMD UCI	Stephensi lines UMD PENDING helper line	18-165-104m	7/23/18	7/23/19
UCSD DARPA Akbari Out and In UMD for injection	Aedes Aegypti 1002B and 1003B	181-191-103m	7/25/18	7/31/19
Letter from STP	Acceptance of year 1 proposal to UC Davis, sample collection	N/REFa 1191p.n.6/GMS/18	9/14/18	9/13/19
UMD to and from UCI USDA	X1 and Good direction + pC0-19 and pC0-28 gambiae	18-260-101	9/28/18	9/28/19
UMD to UCI Interstae USDA	Good Direction gambiae pC0-6	180-256-103	10/2/18	pending
UC Irvine /TIGS India (Items deemed commercially availble and no MTA required)	Plasmid GS62894-2 pET-26b(+)-311_AA Plasmid GS62894-3 pET-26b(+)-317_AA Plasmid GD26894-1 pET-26b(+)-m2A10-_AA	MTA	N/A	N/A
Department of Health & Human Services (DHHS)	Approval to import infectious biological agents, infectious substances or vectors
UC Davis BUA #311	IBC BUA approval Analysis of host pathogen interactions in Drosophila and Mosquito and CRISPR based drives	311	11/26/18	2/12/21
USDA UC Davis	Permit to Import Infectious Biological Agents, Infectious Substances, and Vectors	136098/app #18053016	11/24/18
IBC	UCI BUA	1999-471	6/11/18	3/19/19
UCSD Beir UCI MTA	80.9 Helper line and 80.9 docking site	MTA	1/11/19	N/A
IACUC UCI AUP-18-189	3 year renewal IACUC Exongenous genes of mosquitoes	18-189	1/16/22	1/16/22
LOI (letter of Intent)	Union of Comoros Ministry of Health Solidarity Social Protections and Gender Promotion (vector control Comoro Islands)		1/28/19
USDA permit outgoing JHU	AgCd1(lines) gambiae GATES	19-061-101m	4/8/19	4/8/20
USDA import permit	Ag Vasa helper line Institut de Biologie Moléculaire et Cellulaire, France	19-093-104m	4/19/19	4/19/20
IRB Exemtion UCSD	IRB exemption for survey questionnaires UCIMI A17-0209-002	1436188-1	5/22/19
JH to UCI USDA	A gambiae Permit not required	19207007	7/26/19
JH to UCI CDPH	Permission granted to ship A gambiae eggs	email	7/26/19
UC Davis USDA permit to import	Dead mosquitoes in silica or 70% ETOH/Live unifected mosquitoe larvae Anopheles gambiae	136098	2/13/19	2/13/20
UC Davis CDC	Permit to import Biological Agents and vectors	20181210-099aA	11/1/19	1/11/20
Leidos request to move 3C3 UCSD/TIGS	3C3 mAb request to trasfer to UCSD/TIGS		9/9/19	pending
LUMC
UC Davis CDC	Permit to import Biological Agents and vectorsAlive or dead mosquito eggs, larvae, and adults (Anopheles stephensi, Anopheles gambiae, Anopheles funestus, Anopheles coluzzi, Anopheles darlingi, Aedes aegypti, Aedes albopictus, Anopheles sundiacus).	20190502-2768A	9/3/19	9/3/20
MTA UCI to UCSD DARPA	MTA multi line	MCA S00920	4/27/17	FE
UCI to UCSD and JHU	44c Anopheles stephensi 44c	19-263-102m	9/22/19	pending
UCI to UCSD and JHU	kh recoded	19-274-103m	10/1/19	pending
UCI to NIH	IB2 insertion locus	19-290-101m	10/17/19	pending
UCI to NIH	3C3 effector locus	19-290-102m	10/24/19	10/23/20

Biological Materials Permits

	Importation	Facility Inspection	Other	Comments
CDC	Need permit for importing from outside USA	Maybe / courtesy		https://www.cdc.gov/od/eaipp/importapplication/agents.htm http://www.cdc.gov/od/eaipp/importApplication/
California Department of Public Health	Need to provide written request & receive written approval	None required		Law: California Health and Safety Code Section 116120 http://www.leginfo.ca.gov/cgi-bin/displaycode?section=hsc&group=116001-117000&file=116120 Contact: Vicki Kramer, Vector-Borne Disease Section, 1616 Capitol Avenue MS 7307, P.O. Box 997413, Sacramento, CA 95899-7413
USDA/APHIS	Permit as a importation aid	Required for receiving transgenic mosquitoes from across state lines		https://www.aphis.usda.gov/aphis/ourfocus/biotechnology https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/permits-notifications-petitions/SA_Permits (look for transgenic insect tab) Their primary focus is on animal / crop pathogens, but lack of a permit may stop shipments at customs.
USDA	For transgenic species	Yes		https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/permits-notifications-petitions/SA_Permits (same site as above for export permit for some transgenic organisms.

USDA permits

MIT cheat sheet for permitting biological materials

Permits and Field work

Duke Permits and Procedures for Field work

Guidelines for Shipping/Receiving Biological Materials

Unv Minn Guidelines

Permit to Import or Transport Etiologic Hosts or Vectors of Human Disease

Required for importation, interstate and intrastate transport of human pathogens. Expedites the package through customs.

Contact:

Centers for Disease Control and Prevention at 404-718-2093.

Materials such as blood, bodily fluid, animals, etc that come from areas of endemic infection should be permitted.

Takes 2 weeks to process, expires after movement of material occurs,

Examples of materials for permit: blood, serum or plasma from different countries unless verified to be virus free, dengue,

https://www.aphis.usda.gov/aphis/resources/permits

Apply for ePermit access and authenticate. You may need to authenticate in person.

Fill out online questionnaire according to permit type and submit,. You can check status https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/sa_permits_notifications_and_petitions/sa_check_status

sample of status check

FDA and EPA would be for live mosquitoes. The constructs should go through IBC and EHS locally, IATA...etc.

As of January 2017 the FDA defines GMO Mosquitoes as;

1. Examples of New Animal Drugs a. Products intended to reduce the virus/pathogen load within a mosquito, including reduction in virus/pathogen replication and spread within the mosquito and/or reduction in virus/pathogen transmissibility from mosquitoes to humans. b. Products intended to prevent mosquito-borne disease in humans or animals. (FDA)

It recommends approvals from both agencies (FDA and EPA) to assure due diligence.

https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM533600.pdf

2. Example of Pesticide Products a. Products intended to reduce the population of mosquitoes (for example, by killing them at some point in their life cycle, or by interfering with their reproduction or development)5 . (EPA)

https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/epas-regulation-biotechnology-use-pest-management#applying

UCI IRB does not have specific guidance for GMO mosquitoes, however it would expect documentation of community consent prior to any release.

SITE Regulatory plan

Based upon WHO Guidance for vector approvals, NASEM, FNIH and UCI MI project plan

1) Determine final site. Finalize decision on partner institution and local PI, who should represent the project in stakeholder engagement with the PNLP of Comoros and STP, (Programme National de Lutte contre le Paludisme)

Contact to see if there is interest and capacity to begin
Compile contact listing
Send out introduction emails, letters etc.
Arrange meeting
Draft agreements
Chart responsibilities
Local informational workshop venue
Presentations
Materials
Hire local staff
PI approvals
Finalize contracts

2) Complete TPP

3) Field protocols

4) Laboratory approvals

5) Train staff

UC I Þ SITEÞINTERNATIONAL AND NGO

6) Make contact with Biosafety Clearing House focal point for Comoros, who can help clarify the regulatory pathway for LMOs (Will check with Tony on this). Mlle Assani Moinahalima

Spécialiste en Gestion et Conservation de la Biodiversité

Direction Générale de l'Environnement et des Forêts

Ministère de l'Agriculture, de la Pêche, de l'Environnement, de l'Aménagement du territoire et de l'Urbanisme BP 5414 Moroni Comoros

Phone: +260 334 31 02

Email: assanimoinahalima@yahoo.fr

3. Determine status of national biosafety law, application and review process (There are none in the Comoros, not even for agriculture, they do not restrict GMO)

4. Encourage national authorities to request training and support from AUDA-NEPAD –(Requested that our Community Engagement consultant, Ana Kormos engage on the subject with our partners in the Comoros)

5. Focus initially on requirements for contained use

6. Establish IBC at partner (Local PI) University (STP or Comoros )

7. Determine requirements of Comoros/STP responsible authority (Ministry of Environment?) for certification of contained use facility for gene drive mosquitoes, Adapt crop policy, such as exists in Burkina faso.

a. Comoros has no GM rules or guidance

b. Sao Tome has no capacity to enforce

8. Establish plan and timeline for building containment facility at partner institution. (ACL2 + should be a priority and be complete before training of local postdocs or scientist)

9. Identify trainee candidates and establish timeline for training that correlates with completion of containment facility.

10. Check with the university/PNLP to make sure they understand the technology (especially the persistence issue) and feel comfortable that their insurance adequately covers the field work

11. CISRO will be unable to hold a slot for Risk assessment and we should consider engaging with them soon for a projected time frame for assessment.

• Consider reaching out to Tanzania

12. Obtain copies of previously approved ACL2 + laboratories in Africa

13. Conduct hazard analysis with the research team (including representatives from the field site) and any external experts desired by the project. The project may choose to stop there.

“Hazard analysis is the first step in risk assessment. A hazard analysis is a systematic exercise to think collectively about everything that could potentially go wrong with the system, no matter how unlikely. The hazard analysis will include consideration of the possible steps that would have to occur for each of these hazards to occur (the pathway to harm). Early hazard analysis is a benefit to the project. The utility is that it helps the project identify data or information that may be needed to predict the probability that any of the steps in the pathway to harm might occur. Prediction of the probability that a hazard will occur, and the consequence if it does, is part of risk assessment. If risk assessment determines that a particular hazard has a high level of probability, or a high level of uncertainty, this may cause the project to have to stop and go back to collect missing data, which could result in serious delays.”

14. Risk assessment will be conducted by national regulatory authority(ies) in any case, but this is unlikely to conform to the NASEM recommendation for probabilistic ecological risk assessment of gene drive organisms. An external risk assessment that is made public by the project can help with transparency issues later on and provide information that may be useful to national authorities in their own risk assessment. (Review Mark Benedick Pathway to Development)

15. Local Approvals and requirements

Permits

Scientific Review

Contracts

Visas

Approvals

16. Initiate WHO l approvals

Assesses Quality, Safety, and Efficacy of manufacturing facilities (Continuous)

WHO Prequalification Team Vector control products MVP/EMP/RHT/PQT World Health Organization 20, Avenue Appia 1211 Geneva 27 Switzerland

Single point of entry (PQT-VC) Electronic submission and one hard copy.
Service Code
Service
PQ100 Request for Determination of Pathway
PQ200 Protocol Review
PQ300 New Vector Control Product PQ301 New Equivalent Vector Control Product
PQ400 Active Ingredient: New Manufacturing Site PQ401 New Active Ingredient Hazard Assessment via JMPR
PQ40 New Active Ingredient Hazzard Assessment via JMPR
PQ500 Post PQ Change: Major PQ501 Post PQ Change: Minor
PQ501 Post PQ changes Minor/Major

New interventions Pathway

1) Cover letter requesting Service PQ100

2) Dossier, letters forms, studies, data, (living document using GLP)

Cover letter
Application form
Table of Contents
Letter(s) of authorization
Letter(s) of access
Declaration of Labelling

3) Request for Determination of Pathway Form ◦ Handout

4) Draft Label (if available)

5) Additional supporting documentation

6) Submit to the PQT-VC Case Managers via pqvectorcontrol@who.int

7) http://www.who.int/pq-vector-control/resources/presubmission/en/

8) Meeting requests, Submit to the PQT-VC Case Managers via pqvectorcontrol@who.int

Dossier requirements

Example of cover letter

University of California Approvals
Site Ministry Approvals
1. Community Consent
2. International and NGO approvals

Example of Letter of Authorization

Example of Letter of Access

Example of labeling

Appendix 1 Guiding Principles

Engagement with colleagues, partners, all stakeholders

• Practice openness and transparency

• Collaborate, engage, and listen through proactive/constructive 2-way communication

• Demonstrate integrity (judgement/confidentiality/tact/consistency)

• Be respectful and demonstrate respect

Process and Decision Making

• Action oriented, i.e., value-added processes which focus on end user access to products

• Evidence-based

• Adhere to established roles and responsibilities

• Transparent

• Timely

• Well documented policies and decisions

• Continuous evaluation and process improvement

Broader Impact

• Embrace innovation and creativity

• Apply a global perspective to meet varying geographic and disease needs

• Monitor and evaluate current approaches to meet changing global needs, i.e., remain relevant

Summaries:

1) Summary of Quality Dossier

Physical/Chemical Data
Declaration of Product Formulation
Description of Manufacturing Process
Declaration of Manufacturing Sites
Confidential Appendices

2) Summary of Safety Dossier

*Acute toxicology (6-pack) - Acute Inhalation - Acute Oral - Acute Dermal - Primary Eye Irritation - Primary Skin Irritation - Dermal Sensitization
Product Risk Assessment (Occupational and Residential Exposure)
AI Specific Hazard Assessment (or summary of publically available information)

3) Summary of Efficacy Dossier

Lab studies
Field studies
Supporting Documentation

*TPP

You can email your approved documents to: UCI-Malaria-Initiative@uci.edu

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