```
[Federal Register Volume 62, Number 232 (Wednesday, December 3, 1997)]
[Notices]
[Pages 63954-63955]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-31638]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Cancer Institute; Opportunity for a Cooperative Research 
and Development Agreement (CRADA) for the Scientific and Commercial 
Development of Transgenic Mice That Express Human Cytochrome P450 Genes

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Department of Health and Human Services (DHHS) seeks an 
agreement with a pharmaceutical or biotechnology company to effectively 
pursue the development and characterization of transgenic mice that 
express human cytochrome P450 genes CYP2D6 and CYP3A4. The National 
Cancer Institute has data suggesting that these animals may be useful 
in drug development, carcinogen bioassays for risk assessment, and the 
determination of genetic regulatory mechanisms.

ADDRESSES: Proposals and questions about this opportunity may be 
addressed to Robert Dell'Orco, Ph.D., Technology Development and 
Commercialization Branch, National Cancer Institute, Executive Plaza 
South, Suite 450, 6120 Executive Blvd., Rockville, MD 20852, tel: 301-
496-0477, fax: 301-402-2117.

DATES: In view of the important priority of developing new drugs for 
the treatment of cancer and methods for determining carcinogenic risk, 
interested parties should notify this office in writing not later that 
January 2, 1998. Respondents will then be provided an additional 30 
days for filing of formal proposals.

SUPPLEMENTARY INFORMATION: ``Cooperative Research and Development 
Agreement'' or ``CRADA'' means the anticipated joint agreement to be 
entered into by NCI pursuant to the Federal Technology Transfer Act of 
1986 and Executive Order 12591 of April 10, 1987 as amended by the 
National Technology Transfer Advancement Act of 1995 to collaborate on 
the specific research project described below.
    The National Cancer Institute seeks an agreement with a 
pharmaceutical or biotechnology company for joint development and 
evaluation of transgenic mice that express human cytochrome P450 genes 
CYP2D6 and CYP3A4 in a tissue specific manner that reflects the 
expression in humans. These two human P450 enzymes are involved in the 
metabolism of over 75% of the drugs that are now on the market; 
however, these two enzymes are poorly conserved between rodents and 
humans. This poor conservation precludes the use of unmodified rodent 
model systems for the analysis of new drugs with respect to their 
metabolism by these two enzymes. The development of a human P450 
transgenic mouse system will allow for the determination of human 
metabolism and toxicity of new drugs, the prediction of drug 
interactions, and the definition of pharmacokinetic parameters in an 
intact animal system. Additionally, such a system would avoid the 
utilization of human liver tissue samples which forms the basis of the 
current methods used in the pharmaceutical industry. The animal model 
would also form the basis of carcinogen bioassays for human risk 
assessment and allow for the analysis of P450 gene regulation. In the 
proposed studies, the animals will be used to determine the tissue 
specific degradation of drugs. Drugs known through in vitro metabolism 
studies to be metabolized by CPY2D6 and CYP3A4 will be administered to 
the transgenic mice, and their pharmacokinetics will be studied.
    The Laboratory of Metabolism has many years of experience in 
cloning and characterizing human P450 genes. More recently, the 
laboratory has developed a series of knockout and transgenic mice to 
study various aspects of the role of cytochrome P450 enzymes in 
carcinogenesis and drug metabolism; and the development of transgenic 
mice with the human CYP2D6 and CYP3A4 enzymes is a continuation of the 
laboratory's commitment to this research area. The Laboratory of 
Metabolism is interested in establishing a CRADA with a company to 
assist in the continuing development of transgeic animals containing 
human cytochrome P450 enzymes to study known drug substrates and 
proprietary drug candidates. The Government will

[[Page 63955]]

provide all available expertise and information to date giving the 
company full access to existing data and data developed pursuant to the 
CRADA.
    The successful company will provide the necessary scientific, 
financial and organizational support to characterize and test the 
animals.
    Background information is available from the above-referenced 
address. Patent applications and pertinent information not yet publicly 
described can be obtained under a Confidential Disclosure Agreement.
    The CRADA aims include the rapid publication of research results 
and the timely exploitation of commercial opportunities. The CRADA 
partner will enjoy rights of first negotiation for licensing Government 
rights to any inventions arising within the scope of the agreement. The 
license option and commercialization of inventions shall not conflict 
with NIH Guidelines for the availability of transgenic/knockout animals 
(http://www1.od.nih.gov/wals/transgen.html).
    The expected duration of the CRADA will be 2 years.
    The role of the Laboratory of Metabolism in this CRADA will be as 
follows:
    1. Isolate and characterize genomic clones of human CYP2D6 and 
CYP3A4.
    2. Generate mice by standard injections of oocyte pronuclei and 
screen founders.
    3. Characterize tissue specificity of expression.
    4. Jointly publish research results.
    The role of the Collaborator will be:
    1. Characterize in vitro metabolism using hepatic microsomal 
fractions.
    2. Evaluate in vivo pharmacokinetics with probe substrates and 
proprietary compounds.
    3. Analyze the role of CYP2D6 and CYP3A4 on bioavailability and 
efficacy of test compounds.
    4. Jointly publish research results.
    Selection criteria for choosing the CRADA partner will include but 
not be limited to:
    1. Ability to collaborate with NCI on further research and 
development of this technology. Demonstration of experience and 
expertise in this or related areas of technology and the ability to 
provide intellectual contribution to the ongoing research and 
development. Ability to accomplish objectives according to an 
appropriate timetable to be outlined in the Collaborator's proposal.
    2. Willingness to comply with NIH IRP Guidelines for the 
Availability of Transgenic/Knockout Animals (http://www1.od.nih.gov/wals/transgen.html). The proposal should specifically address the 
methods by which the animals will be made available.
    3. Demonstration of the resources (facilities, personnel and 
expertise) necessary to perform research, development and 
commercialization of this technology.
    4. Commitment of reasonable effort and resources on research, 
development and commercialization of this technology.
    5. Expertise in the commercial development, production, marketing 
and sales of products related to this area of technology.
    6. The level of financial support the Collaborator will supply for 
CRADA-related Government activities.
    7. A willingness to cooperate with the National Cancer Institute in 
the publication of research results.
    8. An agreement to be bound by the DHHS rules involving human 
subjects, patent rights and ethical treatment of animals.
    9. A willingness to accept the legal provisions and language of the 
NIH model CRADA with modifications to address selection criteria #2 and 
other minor modifications.
    10. Provisions for distribution of patent rights to any inventions. 
Generally, the rights of ownership are retained by the organization 
which is the employer of the inventor, with (1) an irrevocable, 
nonexclusive, royalty-free license to the Government (when a company 
employee is the sole inventor) or (2) an option to negotiate an 
exclusive or nonexclusive license to the company on terms that are 
appropriate (when the Government employee is the sole inventor).

    Dated: November 21, 1997.
Kathleen Sybert,
Acting Director, Technology Development and Commercialization Branch, 
National Cancer Institute, NIH.
[FR Doc. 97-31638 Filed 12-2-97; 8:45 am]
BILLING CODE 4140-01-M
```