[Federal Register Volume 69, Number 173 (Wednesday, September 8, 2004)]
[Notices]
[Pages 54292-54293]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-20290]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Opportunities for Cooperative Research and Development Agreements 
(CRADAs) To Undertake Research and Development of Compounds From 
Specific Categories for the Treatment of Drug Dependence

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The National Institute on Drug Abuse (NIDA), a component of 
the National Institutes of Health, is seeking proposals from potential 
collaborators for one or more Cooperative Research and Development 
Agreements (CRADAs) to test, by scientific means meeting U.S. Food and 
Drug Administration (FDA) standards, the hypothesis that compounds 
representative of the following classes (numbered 1-8 below) may be 
useful in the treatment of drug dependence:
    1. CRF-1 antagonists.
    2. Cannabinoid-1 antagonists.
    3. MGluR5 antagonists.
    4. AMPA antagonists.
    5. Selective, high affinity dopamine D3 agonists and antagonists.
    6. Selective, high affinity dopamine D1 full or partial agonists.
    7. Kappa opioid antagonists.
    8. Compounds from classes not named in 1-7 above, but for which 
compelling rationales are provided by potential collaborators.

DATES: NIDA will consider all proposals received within 60 days of the 
date of the publication of this notice. This notice is active until 
November 8, 2004.

ADDRESSES: Questions and expressions of interest concerning this notice 
may be addressed to Dr. Frank Vocci (301-443-2711; e-mail: 
[email protected]) or Mr. Lee Cummings (301-443-1143; e-mail: [email protected]) 
or at the following address: Division of Pharmacotherapies and Medical 
Consequences of Drug Abuse, National Institute on Drug Abuse, 6001 
Executive Boulevard, MSC 955, Room 4123, Bethesda, Maryland 20892-9551.

SUPPLEMENTARY INFORMATION:

Rationale for CRF-1 Antagonists

    Evidence suggests that withdrawal syndromes associated with chronic 
use of drugs of abuse results in elevations of CRF levels. Stress has 
been shown to modify the intake of drugs of abuse in preclinical 
studies of drug self-administration. The effects of stress can increase 
drug intake and can be mimicked by CRF administration. CRF antagonists 
have a robust inhibitory effect on stress-induced increases in drug 
taking behavior.

Rationale for Cannabinoid-1 Antagonists

    Cannabinoid-1 antagonists (CB-1) block the cell surface receptors 
activated by marijuana, but have been reported to be involved in 
effects of other abused substances. A CB-1 receptor antagonist has been 
shown to reduce nicotine self-administration and nicotine-induced 
dopamine release in the nucleus accumbens, reduce heroin self-
administration in rats, and reduce amphetamine self-administration in 
rats. Further, CB-1 antagonists may also prevent relapse to cocaine or 
heroin by blocking rats' responses to both cocaine and heroin priming, 
and to cues associated with cocaine. Finally, mice lacking the CB-1 
receptor do not show stress-induced increases in alcohol consumption, 
suggesting that the receptor may also contribute to stress-induced 
drinking. Taken together, results suggest a role for the cannabinoid 
system in abuse of several classes of drugs.

Rationale for mGluR5 Antagonists

    Drugs of abuse increase glutamatergic neurotransmission in the 
nucleus accumbens, and metabotropic glutamate receptors located there 
may modulate release of glutamate and dopamine. Since gene knockout 
studies reported in 2001 showed that mice lacking the mGluR5 receptor 
show decreased locomotor stimulant effects of cocaine and fail to 
develop cocaine self-administration behavior, a number of studies have 
examined the effects of mGluR5 antagonist on behaviors related to drug 
abuse. Interestingly, mGluR5 antagonists have been reported to decrease 
cocaine and nicotine self-administration in rodents, decrease 
amphetamine-stimulated locomotor activity, and to attenuate relapse to 
alcohol, suggesting a role in abuse of more than one drug.

Rationale for AMPA Antagonists

    AMPA antagonists may be useful in the treatment of cocaine 
addiction because AMPA antagonists have been shown to affect three 
cocaine-induced processes thought to be important in the development of 
cocaine addiction for: (1) Prevention of locomotor sensitization, (2) 
Blockade of cocaine-cue induced drug seeking behavior, and (3) blocking 
cocaine-primed reinstatement in an animal model of cocaine self-
administration.

Rationale for D3 Partial Agonists and Antagonists

    Dopamine D3 receptors are localized in areas of the brain that are 
involved in drug abuse, and have been reported to be up-regulated in 
the brains of cocaine overdose fatalities. The potency of compounds 
that activate D3 receptors is related to their ability to decrease 
cocaine self-administration in rats, suggesting the involvement of 
these receptor types in cocaine drug-taking. Dopamine D3 partial 
agonists have been shown to block the behaviorally activating effects 
of cues that have been paired with cocaine in rats, suggesting 
potential usefulness in blocking relapse following contact with 
environmental cues associated with drug use. Dopamine D3 antagonists 
have recently been reported to block nicotine-primed nicotine seeking 
behavior in rats as well as cocaine-primed cocaine seeking in rats, 
suggesting a potential role in preventing relapse. Further, a D3 
antagonist has been reported to block both the acquisition and 
expression of heroin conditioned place preference in rats, suggesting, 
overall, that both dopamine D3 partial agonists and D3 antagonists may 
be useful treatments for more than one drug of abuse.

Rationale for D1 Agonists

    There is evidence that dopamine D1 receptors are down-regulated in 
rats and monkeys following exposure to cocaine using in vitro measures. 
In addition, D1 agonists have been shown to lack priming effects in 
rats trained to self-administer cocaine, and are able to block the 
effects of a priming dose of cocaine in this model. Other cocaine-self 
administration models indicate that D1 agonists can reduce the self-
administration of both low and high

[[Page 54293]]

doses of cocaine. In a cocaine self-administration reinstatement model 
in monkeys that may model relapse following a period of abstinence in 
humans, a D1 agonist can reduce the effect of a priming dose of cocaine 
that might lead to relapse. In humans, a D1 agonist blunted the 
subjective effects of cocaine, and reduced craving for cocaine and 
other drugs.

Rationale for Kappa-Opioid Antagonists

    Kappa-opioid antagonists block receptors for the endogenous opioid 
ligand dynorphin, which is up-regulated by chronic opioid use and has 
been linked to dysphoric states that can lead to opioid relapse. There 
is also evidence that kappa antagonists have anti-stress effects, which 
may make them useful in the prevention of relapse to drugs of abuse 
like cocaine.

Rationale for Compounds Not Named Above To Be Considered

    The possibility exists that compounds that have mechanisms of 
action other than those described in items 1-7 above may be potentially 
useful in the treatment of drug dependence. NIDA will consider 
candidate compounds from other classes if, and only if, scientific 
evidence exists to support a compelling rationale for testing and/or 
development.

Potential for Collaborative Development

    NIDA does not currently own or have adequate access to compounds 
representing the referenced classes. To this end, NIDA is seeking to 
enter into a CRADA collaboration with entities that may qualify as 
CRADA collaborators. These would include, but not be limited to 
pharmaceutical companies, academic research institutions with company 
affiliations, and other commercial entities with adequate capacity to 
participate in the evaluation and development of candidate compounds 
from the classes listed for the treatment (reduction in use in drug 
dependent persons and prevention of relapse in formerly drug dependent 
individuals). NIDA will consider proposals from all qualified entities 
and will, subject to negotiation of the details of a mutually agreed 
upon research plan and CRADA, provide the CRADA collaborator access to 
services and data generated from its comprehensive preclinical and 
clinical trials facilities. CRADA Collaborators will be able to utilize 
data derived from the CRADA to pursue regulatory filings in the U.S. 
and abroad. Compounds of the representative classes at all stages of 
development will be considered. NIDA's Medications Development Program 
possesses the capacity to perform pharmacological and toxicological 
testing, pharmacokinetics, dosage form development, regulatory 
management, and clinical testing from Phase I through Phase III testing 
and is willing to apply these capacities in the assessment of specified 
compounds as may be warranted.
    Following classical drug development schema, decisions to proceed 
to each subsequent preclinical or clinical study will be based on data 
derived from previous or ongoing studies. Assuming adequate safety can 
be demonstrated, it is NIDA's intention to provide clinical trials 
services sufficient to permit, subject to FDA approval, research and 
development up to and including Phase II hypothesis testing. Assuming 
demonstration of safety and efficacy at the conclusion of Phase II 
trials and subject to negotiation, NIDA will, in some cases, also 
consider collaborations to undertake Phase III trials sufficient to 
permit collaborator to seek a U.S. New Drug Approval (NDA).
    No funding may be provided to a collaborator under a CRADA: all 
assistance is provided ``in-kind''. Therefore the collaborator will 
bear the financial and organizational costs of meeting its obligations 
under collaborator's portion of any research plan that may be 
negotiated. Benefits of collaborating with NIDA beyond access to NIDA's 
clinical and preclinical resources include the option to an exclusive 
license to any subject inventions made by NIDA scientists during the 
course of the collaboration, and exclusivity with respect to submitting 
data from the collaboration for regulatory filings.

Selection Factors and Considerations

    Selection factors and considerations of importance of NIDA include:
    1. It is mandatory that collaborators possess commercialization 
rights to the compound sufficient to permit research and commercial 
development for the intended field of use, i.e., treatment of drug 
dependence. In the event the collaborator does not own the compound or 
composition, collaborator must provide appropriate documentation of a 
license permitting research and commercialization for the field of use 
sufficient to permit the CRADA to proceed.
    2. NIDA will consider the amount of research and development 
documentation and experience already in the collaborator's possession. 
NIDA will sign appropriate confidential disclosure agreements in order 
to review confidential and unpublished data. While NIDA will review all 
proposals concerning candidate compounds representative of the listed 
classes, it will give a higher priority to proposals that can document 
a more advanced level of development with the proposed compound(s).
    3. NIDA will consider the amount and type of research and 
development resources the collaborator proposes to undertake as part of 
a proposed CRADA.
    4. NIDA will consider the background, experience, and expertise in 
medications development of the proposed collaborator.

    Dated: August 27, 2004.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 04-20290 Filed 9-7-04; 8:45 am]
BILLING CODE 4140-01-P