Letter of Intent (GAP-JAPAN)

LETTER OF INTENT
between

RIKEN Yokohama Institute Center for Genomic Medicine (CGM)
and the
NIH Pharmacogenetics Research Network (PGRN)
and the
National Institute of General Medical Sciences (NIGMS),
National Cancer Institute (NCI), and
National Heart, Lung, and Blood Institute (NHLBI)

on the establishment of a
Global Alliance for Pharmacogenomics with Japan (GAP-JAPAN)

I. Parties/Definitions

The Center for Genomic Medicine (CGM) is a component of the RIKEN Yokohama Institute, Japan, and was established to develop high-throughput services for single nucleotide polymorphism (SNP) analysis, and to detect human genes and the variation involved in common diseases and medication responses.

The NIH Pharmacogenetics Research Network (PGRN) is a consortium of research groups, funded as individual cooperative agreements by the NIH. The PGRN conducts studies of variation in human genes relevant to pharmacokinetics (drug disposition) and pharmacodynamics (drug action), and the relationship of the variation to drug responses. PGRN investigators have appointments at institutions across the U.S. and Canada.

The National Institute of General Medical Sciences (NIGMS) is a component of the National Institutes of Health (NIH), Bethesda, MD, and was established to fund research programs at academic and medical institutions. NIGMS is the lead institute responsible for funding and managing the PGRN. Other institutes of the NIH, including the National Cancer Institute (NCI) and the National Heart Lung and Blood Institute (NHLBI), have contributed substantially to creating the sample collections proposed for the research projects.

A Global Alliance for Pharmacogenomics (GAP) is an innovative, strategic alliance between the PGRN and other participating parties, designed to facilitate collaborative research studies that lead to new discoveries of genetic variants that are associated with therapeutic and adverse responses to drugs. GAPs will be designated by name; this will be the GAP-JAPAN.

II. Purpose

The CGM and NIH-PGRN intend to establish a Global Alliance for Pharmacogenomics between U.S. and Japanese scientists who conduct research in the fields of genetics, pharmacology, medicine, and pharmacogenetics/pharmacogenomics (GAP-JAPAN). This partnership plans to bring together scientists at the institutions to establish a series of collaborative studies between the CGM laboratories and the PGRN groups. Under the leadership of the NIGMS, NIH, the parties intend to enter into specific agreements to accomplish their common scientific goals of finding relationships between genetic variants and the therapeutic effects and adverse reactions to medicines. All parties desire to contribute their understanding to the establishment of “personalized medicine.”

This Letter of Intent (LOI) is written to describe plans for the formation, operation, and termination of this alliance. While these organizations have common goals and missions, nothing in the LOI is intended to be binding under international or under the domestic law of the participants. It describes the intent to interact in an innovative and productive alliance. The benefits to the founding parties likely may be discoveries of polymorphisms associated with drug responses, which may be presented in the form of publications, data deposits, and public talks. These discoveries may be developed into marketable applications for “personalized medicine," which may ultimately have direct benefits for the health care of global populations.

III. Objectives/Leadership of the GAP-JAPAN:

The objectives of the GAP-JAPAN are to achieve the following:

(a) Facilitate research discoveries of genetic/genomic factors that contribute to efficacy, non-response, or adverse reactions to therapeutic drugs;

(b) Facilitate the translation of research discoveries into clinical drug therapy (“personalized medicine”);

The parties intend for the GAP-JAPAN to be led by a Steering Committee consisting of the Director of the CGM (Dr. Yusuke Nakamura); the Director of NIGMS (Dr. Jeremy Berg, or his designate); and the PGRN Co-Chairs for the GAP-JAPAN (Drs. Mark Ratain and Kathleen Giacomini).

The Steering Committee intends to meet semi-annually to address issues of common interest to the participants, such as the following:

Monitoring the progress of current collaborative studies
Proposing new areas for collaboration
Issuing calls and procedures for collaborative studies
Scheduling new, ongoing, and completed studies
Providing a forum for resolving disputes that may arise in the conduct of studies
Approving plans for joint authorship and publications
Planning for presentation at meetings and other public venues
Addressing intellectual property issues
Issuing press releases and communicate with the public
Considering other groups for membership in the GAP-JAPAN

IV. Responsibilities for Materials Transfer, Data Handling, Data Deposition, and Intellectual Property:

PGRN groups intend to provide the CGM with de-identified biological samples. The parties anticipate that samples will derive from various sources including private and academic collections, and may include samples from NIH-supported clinical trials. It is understood that (a) materials and any accompanying data will be transferred only in accordance with applicable international and domestic law and NIH Policies; (b) any genetic analyses of samples will proceed only as permitted by applicable consents; and (c) the lead investigators for each of the collaborations will be responsible for ensuring that the required permissions to use the samples are in place before any transfer of samples or accompanying data to CGM occurs. This letter does not contemplate the transfer or exchange between the parties of any personally identifiable information regarding any research participants.

CGM investigators intend to describe which platform(s) will be used for genome-wide association studies for the PGRN projects. All data are expected to be returned by the CGM to the PGRN groups for analysis as soon as possible. The parties plan to describe in what time frame and how results will be delivered. The lead investigators for each of the collaborations should specify who will be able to see the genotyping results and who will see phenotyping files, data records, etc.

It is anticipated that the Steering Committee will seek to approve projects that accelerate discoveries of genetic/genomic factors that contribute to efficacy, non-response, or adverse reactions to therapeutic drugs and clinical translation of that knowledge. It is expected that papers will be jointly written and published as collaborations. The NIH intends to require that the results from these collaborations be deposited into dbGAP, according to the NIH Policies for genome wide association studies (GWAS). dbGAP provides an assurance that investigators agree to, stating that they will not re-identify research participants.

The parties intend for development of intellectual property (IP) to proceed at both the PGRN’s institutions and the RIKEN-CGM, consistent with applicable international and domestic laws and institutional and funding agency policies. No promises about IP rights are implied by this document; however, it is expected that the Steering Committee will want to approve projects with IP plans that do not slow or impede data-sharing or future research activities.

It is expected that each project will proceed pursuant to a detailed memorandum of understanding consistent with this LOI, generated and approved between the specific study sites within the PGRN and the CGM, and any other involved sites, and the funding institutes of the NIH, which will be copied to the RIKEN-CGM, NIH-PGRN, and NIGMS. The research groups anticipate that the genotyping for the initial set of studies will be completed by March 2009.

V. Duration, Amendment, and Termination

It is understood that this agreement shall enter force upon signatures and shall remain in force until amended, extended, or terminated by mutual written agreement of the participants. It is anticipated that amendments to this LOI will be in writing and agreed to by the participants. This LOI may be terminated by any party upon 30 days advanced written notice. It is understood that after termination, resources (e.g., DNA samples) and data (e.g., raw and finished reads) will be returned to the respective parties.

Jeremy Berg, Ph.D.
Date
Director, National Institute of General Medical Sciences

Yusuke Nakamura, M.D., Ph.D.
Date
Director, Center for Genomic Medicine

John E. Niederhuber, M.D.
Date
Director, National Cancer Institute

Elizabeth G. Nabel, M.D.
Date
Director, National Heart, Lung, and Blood Institute

Scott T. Weiss, M.D., M.S.
Date
Chair, Pharmacogenetics Research Network

APPENDIX A

At its inception, the GAP-JAPAN intends to have five joint collaborative studies. Approval of future projects for collaborative studies should involve the GAP-JAPAN Steering Committee.

Current studies:

Pancreatic cancer trial with gemcitabine and bevacizumab (Drs. F. Innocenti, N. Cox, K. Owzar, H. Kindler, K. Giacomini, H. McLeod, M. Ratain, with Dr. Y. Nakamura); approximate number of samples = 374 initially
Aromatase inhibitors (Drs. J. Ingle, R. Weinshilboum, D. Flockhart, V. Stearns, with Dr. T. Mushiroda); approximate number of samples = 1000 initially
Drug-induced long QT syndrome (Drs. D. Roden, M. Province, M. Ritchie and A.L. George, with Dr. T. Tanaka); approximate number of samples = 1000 initially
Anti-cancer drugs for breast cancer (Drs. D. Kroetz, E. Jorgenson, K. Owzar, J. Witte, L. Shulman, H. McLeod, M. Ratain, with Dr. H. Zembutsu); approximate number of samples = 1940 initially
International Warfarin Consortium (Drs. J. Johnson, D. Roden, M. Caldwell for the International Warfarin Pharmacogenetics Consortium, IWPC, with Dr. T. Mushiroda); approximate number of samples = 1000 initially

The GAP-JAPAN gratefully acknowledges the contributions of the following groups, whose vision was necessary to make these studies possible. This LOI and individual acknowledgements of all participating parties in assembling the sample sets will appear on a public website at NIH.

NCI Clinical Trials Cooperative Groups

Fondation Leducq Alliance Against Sudden Cardiac Death