20276 Federal Register / Vol. 60, No. 79 / Tuesday, April 25, 1995 / Notices

in the organization, financing, and

delivery of health care services.

The Council is composed of public

members appointed by the Secretary.

These members are: Robert A. Berenson,

M.D.; F. Marion Bishop, Ph.D.; Linda

Burnes Bolton, Dr. P.H.; John W.

Danaher, M.D.; Helen Darling, M.A.;

Nancy J. Kaufman, M.S.; William S.

Kiser, M.D.; Robert M. Krughoff; Risa J.

Lavizzo-Mourey, M.D.; W. David Leak,

M.D.; Harold S. Luft, Ph.D.; Barbara J.

McNeil, M.D.; Walter J. McNerney,

M.H.A.; Edward B. Perrin, Ph.D.; Louis

F. Rossiter, Ph.D.; Albert L. Siu, M.D.;

and Ellen B. White, M.B.A.

There also are Federal ex officio

members. These members are:

Administrator, Substance Abuse and

Mental Health Services Administration;

Director, National Institutes of Health;

Director, Centers for Disease Control

and Prevention; Administrator, Health

Care Financing Administration;

Commissioner, Food and Drug

Administration; Assistant Secretary of

Defense (Health Affairs); and Chief

Medical Director, Department of

Veterans Affairs.

II. Agenda

On Tuesday, May 16, 1995, the open

portion of the meeting will begin at

12:30 p.m. with the call to order by the

Council Chairman. The Administrator,

AHCPR, will update the status of

current Agency issues and program

initiatives. The meeting will adjourn at

5:30 p.m.

On Wednesday, May 17, 1995, the

open portion of the Council meeting

will resume at 8:30 a.m. with a

discussion of the AHCPR grant

application review process. The open

meeting will adjourn at 10:15 a.m. The

Council will begin the closed portion of

the meeting to discuss the AHCPR grant

portfolio from 10:15 a.m. to 12:00 p.m.

The meeting will then adjourn at 12:00

p.m.

Agenda items are subject to change as

priorities dictate.

Dated: April 19, 1995.

Clifton R. Gaus,

Administrator.

[FR Doc. 95–10121 Filed 4–24–95; 8:45 am]

BILLING CODE 4160–90–M

National Institutes of Health

National Cancer Institute: Opportunity

for a Cooperative Research and

Development Agreement (CRADA) for

the Scientific and Commercial

Development of Monoclonal

Antibodies for the Therapy and/or

Diagnosis of Cancer

AGENCY: National Institutes of Health,

PHS, DHHS.

ACTION: Advertisement.

SUMMARY: The Laboratory of Tumor

Immunology and Biology (LTIB),

National Cancer Institute is seeking

pharmaceutical or biotechnology

collaborator(s) which can effectively

pursue the scientific and commercial

development of a panel of monoclonal

antibodies generated against tumor

associated antigens for use in the

therapy and/or diagnosis of a range of

human cancers. The primary focus of

these collaborations will be the

development and commercialization of

a panel of monoclonal antibodies

consisting of two major groups: (A)

Monoclonal antibodies directed against

the pancarcinoma antigen, TAG–72.

TAG–72 is expressed on a range of

human carcinomas including colorectal,

gastric, pancreatic, ovarian,

endometrial, breast, non-small cell lung,

and prostate. Monoclonal antibody

CC49 is the prototype monoclonal

antibody of this group. Humanized and

other genetically engineered variants of

monoclonal antibody CC49 have already

been developed. (B) Monoclonal

antibodies directed against human

carcinoembryonic antigen, which is

expressed on the following carcinomas:

colorectal, pancreatic, gastric, non-small

cell lung, and breast carcinoma. The

prototype for this group of monoclonal

antibodies is COL–1. (C) Additionally, it

may likely be a further goal of these

collaborations to develop novel

recombinant forms of these monoclonal

antibodies.

It is anticipated that because of the

magnitude, diversity, and expense of

these proposed research projects the

collaboration(s) may take the form of

multiple CRADAs. The collaboration(s)

will involve all aspects of diagnostic

and/or therapeutic development from

basic scientific inquiry to late stage

clinical trials which selected sponsor(s)

will be required to partially support.

The selected sponsor(s) will collaborate

in the development of one or more of

the following diagnostic or therapeutic

forms of these monoclonal antibodies:

(1) Radiolabeled monoclonal antibodies

(diagnostic (oncologic imaging) and/or

therapeutics); (2) Drug and/or toxin

conjugated monoclonal antibodies; (3)

Pro-drug conjugated monoclonal

antibodies; (4) Unconjugated

monoclonal antibodies (including

bifunctional forms).

Sponsors will be selected based upon

their ability to collaborate with NCI for

the development of any of these

therapeutic or diagnostic forms in

accordance with the corporate role and

selection criteria outlined below. It is

emphasized that selection of a

collaborator will not be dependent upon

an entity’s ability to perform the largest

portion of the research project. Rather,

a collaborator will be selected based

upon the scientific merit and

intellectual contributions brought to

each individual project(s). Potential

collaborators are, therefore, urged to

submit proposals which focus on

particular area(s) of expertise in a wellorganized and precise manner which

clearly outlines a development and

commercialization plan. Finally, it is

also possible that logical extensions of

these research protocols may be

considered as potential collaborative

projects. Accordingly, proposals must

address the requested criteria and

protocols, but in addition, may include

any additional unique development

projects relating to the core technology.

The term of the CRADA(s) is

anticipated to be three (3) to five (5)

years.

ADDRESSES: Inquiries and proposals

regarding this opportunity should be

addressed to either Michael Christini or

Mark Noel (Tel #301–496–0477, Fax

#301–402–2117), Office of Technology

Development, National Cancer Institute,

Building 31, Room 4A49, NIH, 9000

Rockville Pike, Bethesda, MD 20892.

DATES: Proposals must be received at the

above address by 5 p.m. June 26, 1995.

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

October 10, 1987 to collaborate on the

specific research project described

below. Under the present proposal, the

Government is seeking collaborator(s),

which in accordance with the

requirements of the regulations

governing the transfer of technology in

which the Government has taken an

active role in developing (37 CFR

404.8), can further develop this

technology to a commercially available

status to best meet the needs of the

public.

This technology has been the focal

point of much research and
Federal Register / Vol. 60, No. 79 / Tuesday, April 25, 1995 / Notices 20277

development within the LTIB for many

years. During that time, there has been

continual advances in the field of

antibody development within LTIB via

extensive intramural research, corporate

sponsored CRADA projects, and

independent corporate development

under licensing arrangements.

When the excellent tumor targeting

characteristics of anti-TAG–72

monoclonal antibody B72.3 in the clinic

were observed, the LTIB developed a

series of second generation, higher

affinity monoclonal antibodies for TAG–

72. This ‘‘CC’’ series, of which

monoclonal antibody CC49 is the

prototype, has been extensively

characterized both preclinically and

clinically. Radiolabeled CC49 shows

much better tumor targeting in the clinic

than B72.3. CC49 reacts with the

majority of the following carcinomas:

Colorectal, gastric, pancreatic, nonsmall cell lung, ovarian, endometrial,

breast and prostate.

The LTIB has also developed a series

of anti-carcinoembryonic antigen

monoclonal antibodies (COL series).

The prototype (COL–1) reacts to the vast

majority of gastrointestinal and

pancreatic cancers, and also to 50% of

breast cancers and 70% of non-small

cell lung cancers. A Phase 1 trial has

just been completed with radiolabeled

COL–1.

The LTIB has shown successful tumor

targeting in cancer patients with

radiolabeled forms of both monoclonal

antibodies which are the primary focus

of these collaborations: CC49 and COL–

1. Phase I therapy trials for both

monoclonal antibodies have been

completed. Additionally, radiolabeled

forms of CC49 are currently in Phase II

clinical trials for colorectal, breast,

ovarian, and prostatic cancer as a

murine monoclonal antibody.

As a corollary, the progression of the

technology can be illustrated in two

specific examples of ongoing research

collaborations which will not be a part

of the present CRADA:

(A) The LTIB, NCI initially developed

a monoclonal antibody designated

B72.3, which reacts to the pancacinoma

antigen termed TAG–72. This

breakthrough technology provided the

basis for the first and still only

monoclonal antibody approved by the

FDA for any in vivo use in cancer.

Under a separate licensing agreement,

Cytogen Corporation conjugated B72.3

with 111 In and developed Onco Scint

CR/OV for oncologic imaging to be

used in conjunction with CT scan.

OncoScint CR/OV has been approved

for use in both colorectal cancer and

ovarian cancer.

(B) Under a separate CRADA

agreement, a Phase III multicenter trial

is also in progress employing 125 Ilabeled murine CC49 with an

intraoperative hand held probe as a

method of radioimmunoguided surgery.

Additional Background Information

• The LTIB has shown via

immunohistochemistry that anti-TAG–

72 and anti-carcinoembryonic antigen

monoclonal antibodies complement

each other extremely well in

overcoming antigen heterogeneity.

Serum assays for carcinoembryonic

antigen and TAG–72 (CA72–4) are also

complementary in that non-coordinate

expression is observed.

• Previous collaborative studies on

the use of the CC49 and COL–1

monoclonal antibodies as drug

conjugates demonstrated anti-tumor

effects in animal models.

• The LTIB has recently developed

CDR grafted (humanized) forms of

monoclonal antibody CC49, and other

novel genetically engineered

immunoglobulin forms for CC49 could

be the subject of any CRADA. Similar

constructs of anti-carcinoembryonic

antigen monoclonal antibodies could

also be the subject of any CRADA.

• Recent clinical trials have

supported the preclinical observations

that recombinant interferon will

selectively upregulate both TAG–72 and

carcinoembryonic antigen expression on

the surface of tumor cells. This finding

should enhance both diagnostic and

therapeutic uses of these classes of

monoclonal antibodies, and these

studies could be included as CRADA

activities.

• The NIH has exclusively licensed

the rights for monoclonal antibody CC49

for use with the radioimmunoguided

surgery intraoperative probe as part of a

separate collaboration.

• A comprehensive list of

publications relating to this technology,

intellectual property and background

licensing information, and general

CRADA information will be provided

upon initial contact with NCI.

Party Contributions

The role of the National Cancer

Institute includes the following:

(1) Develop novel recombinant forms

of monoclonal antibodies.

(2) Initial characterization of

hybridoma cell lines producing

monoclonal antibodies.

(3) Conduct preclinical testing (tumor

targeting and therapy) of these

monoclonal antibodies both in vivo and

in vitro as unlabeled immunoglobulin

forms and/or as antibody conjugates.

(4) Conduct preclinical studies on the

use of biologic response modifiers to

upregulate tumor targeting and therapy.

(5) Analyze pharmacokinetics and

anti-immunoglobulin responses in some

clinical trials.

The role of the successful corporate

sponsor(s) will include:

(1) Develop high producer clones of

the monoclonal antibodies and

recombinant immunoglobulin

producing cells lines and cultures

supplied by the NCI and optimize

production and purification procedures

for experimental tumor targeting and

therapy studies.

(2) Produce and purify clinical grade

(GMP) monoclonal antibodies for

clinical trials and submit Drug Master

Files in support of the monoclonal

antibody production.

(3) Conduct toxicity studies as

required by the FDA.

(4) Develop methodologies for the

conjugation of monoclonal antibodies

with (A) Radionuclides, (B) Drugs and/

or toxins, (C) Pro-drugs, (D) Bifunctional

antibodies.

(5) Submit IND application in support

of clinical trials.

(6) Conduct clinical trials using

monoclonal antibody and

immunoglobulin forms.

The role of both the National Cancer

Institute and the successful corporate

sponsor(s) will include:

(1) Optimize purification schemes for

immunoglobulin forms, prior to and

post conjugation.

(2) Collaborate on clinical trial design

including protocols using biologic

response modifiers (e.g., recombinant

interferon).

(3) Collaborate on data analysis in

support of clinical trials.

Selection Criteria

Proposals submitted for consideration

should fully address each of the

following qualifications:

(1) Experience in the GMP

production, purification, quality control

of monoclonal antibodies and regulatory

requirements of monoclonal antibody

clinical trials.

(2) Experience in the conjugation of

monoclonal antibodies with one or more

of the following: (A) Radionuclides, (B)

Drugs and/or toxins, (C) Pro-drugs, (D)

Bifunctional Antibodies and the

analyses of these reagents.

(3) Ability to provide necessary

reagents on a timely basis.

(4) Experience in conducting clinical

trials.

(5) Willingness to cooperate with the

National Cancer Institute in the

collection and evaluation of data.
20278 Federal Register / Vol. 60, No. 79 / Tuesday, April 25, 1995 / Notices

(6) Agreement to be bound by the

DHHS rules involving the use of human

and animal subject, and human tissue.

(7) Ability to obtain background

license to relevant patent rights.

(8) Willingness to agree to Federal

Statutory provisions for the equitable

distribution of patent rights to any

CRADA subject-matter inventions.

Generally, the rights of ownership are

retained by the organization which is

the employer of the inventor, with (A)

an irrevocable, non-exclusive, royaltyfree research license to the Government

(when a company employee is the sole

inventor) or (B) an option for an

exclusive or non-exclusive license to the

company on terms that are appropriate

(when the Government employee is the

sole or joint inventor).

(9) Willingness to cost share in

laboratory studies including the funding

of personnel dedicated to completion of

the CRADA research project.

(10) Submission of an initial response

to the NIH Model CRADA boilerplate

provisions.

Dated: April 13, 1995.

Dr. Thomas Mays,

Director, Office of Technology Development,

National Cancer Institute, National Institutes

of Health.

[FR Doc. 95–10110 Filed 4–24–95; 8:45 am]

BILLING CODE 4140–010–P

National Cancer Institute: Opportunity

for a Clinical Trial Cooperative

Research and Development Agreement

(Clinical Trial ‘‘CRADA’’) for the

Scientific and Commercial

Development of the Signal

Transduction Inhibitor, ‘‘CAI’’, as an

Anticancer Agent

AGENCY: National Institutes of Health,

PHS, DHHS.

ACTION: Notice.

SUMMARY: The Department of Health and

Human Services (DHHS) seeks a

pharmaceutical company which can

effectively pursue the clinical

development of the signal transduction

inhibitor, carboxyamide-amino triazole

(‘‘CAI’’, NSC 609974), for the treatment

and/or prevention of cancer. The

National Cancer Institute has data

suggesting that CAI may have potential

for the treatment and prevention of

cancer. The selected sponsor will be

awarded a CRADA for the codevelopment of this agent with the

National Cancer Institute.

ADDRESSES: Questions about this

opportunity may be addressed to Mark

W. Noel, Office of Technology

Development, NCI, Building 31/Room

4A51, 9000 Rockville Pike, Bethesda,

Maryland 20892, (301) 496–0477,

facsimile (301) 402–2117, from whom

further information including a

summary copy of the preclinical and

clinical data may be obtained.

DATES: In view of the important priority

of developing new agents for the

treatment or prevention of cancer,

interested parties should notify this

office in writing no later than June 25,

1995. Respondents will then be

provided an additional 60 days for the

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

October 10, 1987 to collaborate on the

specific research project described

below. The present opportunity will be

for a Clinical Trial CRADA. The Clinical

Trial CRADA is a modification of the

standard NIH Model Agreement

wherein additional language has been

drafted to enable the Collaborator to

access and utilitize clinical trial data.

The Government is seeking a

pharmaceutical company which, in

accordance with the requirements of the

regulations governing the transfer of

agents in which the Government has

taken an active role in developing (37

CFR 404.8), can further develop CAI

through Federal Food and Drug

Administration approval and to a

commercially available status to meet

the needs of the public and with the

best terms for the Government.

CAI is a novel chemically defined

compound which has shown promising

antitumor activity in several preclinical

trials. The drug is under patent to Merck

& Co., Inc. (U.S. Patent 4,590,201). The

use of CAI in a method of treating

peritoneal carcinomatosis of solid

tumors is claimed in U.S. Patent

5,132,315 assigned to the Dept. of

Health and Human Services. A method

for the detection and quantitation of CAI

levels in blood is claimed in U.S. Patent

5,405,782 which is also assigned to the

Dept. of Health and Human Services. Its

use in the treatment of cancer in

patients with a surgically excised tumor

with a high probability of metastasis

and its use in treatment of cancers

involving the transportation of

individual cells to other tissue from a

metastasizing tumor are claimed in U.S.

Patent 5,045,543 (assigned to Merck &

Co. Inc). The Clinical Trial CRADA will

allow a pharmaceutical company to

provide resources, in collaboration with

the NCI, for the continuing preclinical

and clinical development work for this

agent and its eventual

commercialization. Merck & Co.’s patent

rights will be available for licensing on

terms to be mutually agreed upon by

Merck and the selected Collaborator.

Similarly, the Government will make its

relevant intellectual property rights

available for licensing to the

Collaborator.

Based on the promising data obtained

from the ongoing Phase I clinical trials,

there is a need to obtain greater

quantities of CAI and to continue

clinical development of this agent. The

NCI is interested in establishing a

Clinical Trial CRADA with a

pharmaceutical company to assist in the

continuing development of CAI. The

government will provide all relevant

available expertise and information to

date and will jointly pursue new trials

as required giving the pharmaceutical

company exclusive rights to all

preclinical and clinical data for

regulatory approval and its New Drug

Application (NDA). The successful

pharmaceutical company will provide

the necessary quantities of drug plus the

necessary financial and organizational

support to complete further

development of CAI to establish clinical

efficacy and possible commercial status.

The expected duration of the CRADA

will be three (3) to five (5) years.

The role of the National Cancer

Institute, includes the following:

1. The government has data for the

bulk production of clinical grade CAI.

The successful pharmaceutical company

will be allowed access to this data.

2. The government will provide data

concerning pharmaceutical

manufacturing and controls, including

dosage form development data for the

finished product.

3. The government will allow the

pharmaceutical company to review and

cross-file the NCI’s IND.

4. The government will make the

NCI’s IND proprietary under such

circumstances and make the IND

available (exclusively) to the

pharmaceutical company.

5. The government will continue the

clinical development of this compound

under its clinical trials network in

coordination with the pharmaceutical

company.

6. Relevant Government intellectual

property rights are available for

licensing through the Office of

Technology Transfer, National Institutes

of Health. For further information

contact Jack Spiegel, Office of

Technology Transfer, National Institutes

of Health, Box OTT, Bethesda, MD

20892; (301) 496–7735; facsimile (301)

402–0220.