IVGT Business Meeting

ILSI Health and Environmental 1156 15th Street, NW 1.202.659.3306 office Sciences Institute Second Floor 1.202.659.3617 fax Washington, DC 20005 www.hesiglobal.org USA

Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing

Thursday, April 26, 2012 10:30AM – 12:00PM (Eastern Time)

Action Report

Participants Marilyn Aardema BioReliance Corp Chinami Aruga Mitsubishi Tanabe Pharma Corporation Jan van Benthem RIVM Julie Clements Covance Labs Laura Custer Bristol-Myers Squibb Firouz Darroudi Leiden University Medical Center Kerry Dearfield USDA/FSIS/OPHS Stephen Dertinger Litron Laboratories George Douglas Health Canada Rosie Elespuru US FDA Mick Fellows AstraZeneca Bhaskar Gollapudi The Dow Chemical Co. Tsuneo Hashizume Takeda Pharmaceutical Company Limited Robert Heflich US FDA/NCTR Lya Hernandez RIVM Masamitsu Honma National Institute of Health Sciences David Jacobson-Kram US FDA Peter Kasper BfArM James Kim HESI David Kirkland Kirkland Consulting Tim Lawlor BioReliance Matt LeBaron The Dow Chemical Co. Anthony Lynch GSK James MacGregor Toxicology Consulting Services Manju Manjanatha FDA/NCTR Mike O'Donovan AstraZeneca R&D Stefan Pfuhler Procter & Gamble Lynn Pottenger* The Dow Chemical Company Leslie Recio Integrated Laboratory Systems

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Maik Schuler Pfizer Global Research and Development Robert Smith Covance Laboratories Leon Stankowski BioReliance Willi Suter Novartis AG Veronique Thybaud Sanofi research and development Freddy Van Goethem Janssen R&D James Whitwell Covance Laboratories Ltd Kristine Witt NIEHS/NTP Li You US FDA Errol Zeiger Errol Zeiger Consulting * by teleconference

Summary of the Meeting

IVGT Business Meeting - 4-26-12.pptx Slide Set for Discussion: (to open in regular mode, right-click, go to “Presentation Object”  “Open”)

I. Committee Business Meeting

Jim Kim welcomed the IVGT Project Committee and took a roll call. The purpose of this meeting was to provide an overview of all of the committee’s activities.

a. Budget

Jim Kim noted that the 2012 budget is tight for this year. There will probably not be funding available to support the Quantitative Database this year. The budget is tight because of large expenditures for the Cell Comparison project (2011-2012) and the New Approaches workshop in 2012.

b. Membership and steering committee membership

Jim reviewed the Steering Committee roster. The purpose of the Steering Committee is to ensure that the IVGT Workgroup leaders are informed about all of the committee’s activities. It is also designed to ensure representation from both public and private sectors, different geographical areas (North America, Europe and Japan), and different industry sectors (e.g., pharmaceuticals, chemicals, consumer products). The Steering Committee is not a governance body, but serves as an advisory group to IVGT leadership and management.

In late 2011, ILS-Inc. joined HESI and the IVGT. Other potential sponsors include Unilever (Paul Carmichael). Jim noted that Bayer Healthcare is at risk of dropping out of IVGT because their representative, Lou Mylecraine, has retired. Jim contacted Neil Carmichael (also a HESI Board

member) to identify another Bayer IVGT representative. However, Neil Carmichael was unable to identify anyone.

Other companies that could be approached for membership include Merck, Syngenta, Abbott (John Nicolette), Roche, and DuPont. Merck is a past member, and had withdrawn over budget issues. Jim spoke with a Syngenta researcher during the New Approaches workshop about IVGT membership. Roche has been approached in the past, and also has not joined because of budget issues. Jim reminded the Committee that as the objectives and mission of IVGT become broader, interested parties may include other biotechnology companies and CROs. Members are encouraged to reach out to potential sponsoring companies.

c. Other meetings scheduled in 2012/2013 i. JSOT ii. EMS / EEMS iii. SOT

Lynn Pottenger noted that she and George Johnson were included as speakers on a workshop proposal for 2013 SOT that will focus on dose-response (non-linear extrapolation) and mode-of- action.

The IWGT is planning on holding a workshop in 2013 in conjunction with the ICEM. Two of the IVGT activities – Pig-a and Quant will carry forward as Workgroups in IWGT.

Manju Manjanatha noted that IVGT agreed to sponsor a session at EMS 2012 on Risk Assessment ($2500 for Silver Sponsorship). Bhaskar Gollapudi is a speaker.

A proposal was submitted for the 2013 IUTOX meeting to be held in Seoul, South Korea, that will focus on quantitative dose-response analyses of genetox data. Jim Kim has submitted a letter requesting HESI funding if this proposal is accepted, so that the IVGT Committee would not be the primary sponsor.

II. Updates from Workgroups a. Quantitative Workgroup i. Health Canada collaboration ii. on-going action items iii. objectives of the April meeting iv. anticipated deliverables v. tentative milestones

Véronique Thybaud provided an overview of the Quantitative Workgroup. Paul White summarized the Health Canada collaboration.

The Health Canada Chemical Management Plan (CMP) funded the relational database. Paul White received a new grant to support his research. Built into his grant is funding of $50K towards data

analysis ($25K/year for 2 years). This is in addition to the pro bono work that has been contributed by George Johnson, Lya Hernandez, and Lynn Pottenger.

A concept paper on dose-response analyses for genetox data was led by Bhaskar Gollapudi and recently resubmitted with revisions (in response to reviewers’ comments).

Steve Dertinger reported that the HESI “perspectives” paper (Schuler et al., 2011) in the EMM Pig-a Special Issue has been getting a lot of downloads.

A slide summarizing presentations by George Johnson and Véronique Thybaud was presented.

b. Improving Existing Assays Workgroup i. on-going action items ii. objectives of the April meeting iii. anticipated deliverables iv. tentative milestones

David Kirkland reviewed the Cell Comparison project. Paul Fowler (Covance) was in charge but moved to Unilever. James Whitwell has taken over. The project has had issues – it is impossible to do MN in L5178Y in presence of cyto b. The protocol had to be changed, and is now done in the absence of cyto b. The data is interesting – surprising. David Kirkland asked the Committee to consider 3 questions during presentations this afternoon during the Improving Existing Assays Workgroup meeting: 1) do we think project has been satisfactorily completed, 2) other work because of questions? 3) do we think data are suitable for publication/presentation?

Elisabeth Lorge reviewed the Cell Repository project. The purpose of the Cell Repository project is to deposit cells that are well characterized, where we feel comfortable that we can rely on genotoxicity results.

Paul White reviewed the Metabolism project.

c. New Approaches Workgroup i. Leadership ii. Practical Aspects

Véronique Thybaud provided an overview of the New Approaches Workgroup. The Workgroup first prepared a proposal for a SOT Contemporary Concepts in Toxicology (CCT) Workshop. The proposal was withdrawn last fall because of difficulty in workshop sponsorship and organization. SOT provides $25,000 in funding to support CCT workshops, however, the SOT earns back this sponsorship through high registration fees.

The Committee briefly discussed future IVGT projects in the context of the New Approaches Workshop. The IVGT will discuss this in greater detail on Friday morning, April 27. Page 4 of 6 ILSI Health and Environmental Sciences Institute

Errol Zeiger thought the New Approaches workshop was informative; Errol thought the workshop went outside of the genetox box and appreciated the extended time for discussion. Lynn Pottenger also voiced her pleasure with the workshop presentations. Laura Custer was particularly impressed with Peter Dedon’s talk and requested slides and references. Jim Kim noted that all the workshop presentations will be made available.

Laura Custer commented that there was a theme for regulatory use during discussions, but that some of the presentations were so out-of-the-box that they cannot really be considered ready to go through validation. It would be important to establish new routes for technologies not ready for regulatory use in near future but could provide valuable information for risk assessment. It was also noted that technologies do not always have to have an OECD guideline, but it helps to have it – particularly for tools are useful.

Bhaskar Gollapudi and Rosie Elespuru valued the workshop forum, and encouraged the committee to continue holding these events.

III. Transition to Technical Committee (2012) a. Leadership b. Mission and Objectives

Jim Kim explained that the IVGT was established as an Emerging Issues Subcommittee in 2006, and was chartered as a Project Committee in 2008. Since last year, IVGT has had discussions about transitioning to a Technical Committee – allowing it to be a longer standing committee with broader objectives. Program Strategy and Stewardship Committee (PSSC) reviews would be held every 3 years for Technical Committees as opposed to every 2 years for Project Committees.

David Kirkland commented that as an Emerging Issues Subcommittee, the future was unknown. It is a testament to the IVGT activities that it can transition to becoming a Technical Committee.

Jim also explained that because of recent issues regarding conflict-of-interest, the HESI Board of Trustees revised the bylaws requiring HESI Committees to have public and private co-leaders. This is to ensure that HESI’s commitment to tripartite membership not only applies to committee rosters but to the leadership. Bhaskar Gollapudi has indicated that he would like to step down as Co-chair. In the last year, Stefan Pfuhler and Jan van Benthem have been nominated to co-lead the IVGT. They have agreed and received their organizations’ approval for this role. Véronique Thybaud is planning on staying as a co-leader for one additional year.

Jim explained that one of the issues the Committee has to address is term limits for the leadership roles. There are no specific bylaws that address this. Some HESI committees rotate through leadership roles every 2 years, with staggered and overlapping terms. Since PSSC reviews are done every 3 years for Technical Committees, IVGT could also consider a change in leadership every 3 years. Some HESI committees do not rotate leadership. This can be discussed in the future.

 Action: The IVGT Committee held a vote to elect Stefan Pfuhler and Jan van Benthem as co- leaders of the IVGT, where Véronique Thybaud will also maintain a co-leader role for one more year. Jim MacGregor provided a motion to support this; David Kirkland and Errol Zeiger seconded the motion; the IVGT Committee was all in favor of this leadership plan, effective immediately. There were not comments or abstentions.

As a Technical Committee, the mission and objectives for the IVGT will be broader than they are currently. The Committee briefly discussed potential areas of expansion.

Jan van Benthem commented that germ cell mutagenesis is becoming a larger issue in Europe. There is also the concerns on genotoxicity of nanomaterials.

Other topic areas include genetox of biologics (e.g., oligos, antibodies – particularly since there are no universal regulatory guidelines), gene therapy, stem cell therapy.

Bhaskar Gollapudi suggested that similar to the previous ACSA project at HESI, the IVGT could start with a clean sheet and design a testing strategy. Kerry Dearfield supported this idea since with new assays, testing design strategies also need to be re-thought. However, we need to be clear on the questions we want to address and how they might be answered. If newer assays are used, we need to understand the limiting factors (e.g. no stamp of OECD approval).

It was also suggested that we could survey HESI member companies for topics of interest. This might also attract new companies to join IVGT. Jim will ask Nancy Doerrer if there were any genetox proposals submitted for the Emerging Issues process.

Another suggested topic was NextGen Sequencing technologies.

Laura Custer suggested that once a list of potential new IVGT projects are defined, members can rank order topics in consideration of where they would be willing to commit their time.

IV. Adjournment

Hearing no additional discussion, the meeting was adjourned at 12:00PM.

______James Kim, Ph.D., DABT Senior Scientific Program Manager, HESI