[Federal Register Volume 70, Number 97 (Friday, May 20, 2005)]
[Notices]
[Pages 29330-29332]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-10066]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Opportunity for a Cooperative Research and Development Agreement 
(CRADA) for Research and Development of Vigabatrin as a Potential 
Pharmacotherapy for the Treatment of Cocaine and Methamphetamine 
Dependence

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The National Institute on Drug Abuse, a component of the 
National Institutes of Health, Department of Health and Human Services 
(DHHS) seeks an agreement with a pharmaceutical or biotechnology 
company to test the hypotheses that vigabatrin may be a safe and 
effective medication for the treatment of cocaine and methamphetamine 
dependence.
    A body of literature relevant to preclinical studies of vigabatrin 
as a potential treatment agent for various types of substance 
dependence (including cocaine and methamphetamine) and a more limited 
body of literature concerning clinical results exists. As there are 
currently no medications approved by the U. S. Food and Drug 
Administration (FDA) for the treatment of cocaine and/or 
methamphetamine dependence, and cocaine and methamphetamine dependence 
have substantial negative public health impacts, the National Institute 
on Drug Abuse is interested in evaluating the safety and efficacy of 
vigabatrin for the treatment of cocaine and methamphetamine dependence.

[[Page 29331]]

Rationale for Studying Vigabatrin in Stimulant(s) Dependence

    The dependence-producing properties of stimulants have been 
associated with their pharmacological actions on the mesolimbic 
dopamine reward pathways in the central nervous system (CNS). Gamma-
amino butyric acid (GABA) inhibits striatal dopamine release, and 
attenuates cocaine-induced increases in extracellular dopamine in the 
striatum and nucleus accumbens (Molina et. al., 1999). Selective 
increases in GABAergic tone attenuate cocaine-induced dopamine release 
without the apparent side effects typically associated with GABA 
agonists. Therefore, targeting brain GABAergic systems is a potentially 
effective pharmacologic treatment strategy for cocaine and 
methamphetamine dependence (Molina et. al., 1999). Data from proof of 
concept clinical trials of similar GABAergic medications e.g. 
topiramate, baclofen, and tiagabine show efficacy in reducing cocaine 
use or in preventing relapse to use. These data suggest that 
vigabatrin, which possesses more potent GABAergic action, may be more 
efficacious than these medications. Preclinical studies in animal 
models have confirmed that dosing with vigabatrin can block the 
manifestations of consumption of cocaine typically seen in these models 
(Stromberg et. al., 2001), without impairing the usual dopamine 
mechanisms necessary to maintain a stable equilibrium. In rodent 
models, vigabatrin has been shown to reduce self-administration of 
cocaine and alcohol (Stromberg et. al., 2001; Kushner et al., 1999), 
and to block conditioned place preference induced by cocaine (Dewey et. 
al, 1998), nicotine (Dewey et. al., 1999), and heroin (Paul, et. al., 
2001). Further, vigabatrin can reduce the increases in nucleus 
accumbens dopamine induced by cocaine (Schiffer et. al., 2003), as well 
as methamphetamine, heroin, and ethanol (Gerasimov et. al., 1999).
    Vigabatrin (GVG) is an irreversible gamma-amino butyric acid (GABA) 
transaminase inhibitor that produces a two to three fold rise in brain 
GABA concentrations (Guberman et. al., 2000). Following oral 
administration, vigabatrin readily crosses the blood-brain barrier and 
is active within the central nervous system. It has been shown to be 
effective, both as an add-on agent and in monotherapy in resistant and 
newly-diagnosed epilepsy (Guberman et. al., 2000) and as first line 
monotherapy in the treatment of infantile spasms (West syndrome) 
(Hancock et. al., 1999). After oral dosing, vigabatrin is well absorbed 
(bioavailability c. 75%) and widely distributed. The drug is eliminated 
primarily by the renal route and is not significantly bound to plasma 
proteins. The elimination half-life is approximately 5-9 hours in 
healthy subjects and may be prolonged in elderly patients or those with 
impaired renal function (Rey et. al., 1992). The usual adult dose of 
vigabatrin for epilepsy is 1-3 g/day. There is no evidence that plasma 
concentrations of vigabatrin correlate closely with therapeutic effects 
(Brodie et. al., 2003).
    There are anecdotal reports that dosing with vigabatrin prevents 
the ``high'' associated with cocaine intake in humans dependent on 
cocaine and can, therefore, result in decreased cocaine consumption. 
Two open label pilot studies suggest a therapeutic effect in most 
patients recruited in abstaining from cocaine or methamphetamine 
(Brodie et. al., 2005) use (Brodie et. al., 2003; Brodie et. al., 
2005).
    Therefore, it may be predicted that dosing with vigabatrin in a 
cocaine dependent population might prevent the cocaine ``high'' and the 
subsequent ``craving'', and possibly reduce the perceived need for 
repeated use, and often higher, drug doses (Dewey et. al., 1999).
    As an initial step in the clinical development of vigabatrin for 
stimulants dependence, it is important to assess the potential efficacy 
and safety of this compound in cocaine and methamphetamine dependent 
subjects.

References

Brodie JD, Figueroa E, Dewey SL (2003). Treating cocaine addiction: 
From preclinical to clinical experience with gamma-vinyl GABA. 
Synapse 50: 261-265.
Brodie JD, Figueroa E, Lasha EM, Dewey SL (2005). Safety and 
efficacy of gamma-vinyl GABA (GVG) for the treatment of 
methamphetamine and cocaine addiction. Synapse 55(2): 122-125.
Dewey SL, Brodie JD, Gerasimov M, Horan B, Gardner EL, Ashby CR 
(1999). A pharmacological strategy for the treatment of nicotine 
addiction. Synapse 31: 76-86.
Dewey SL, Morgan SE, Ashby CR, Horan B, Gardner EL, Brodie JD 
(1998). A novel strategy for the treatment of cocaine addiction. 
Synapse 30: 119-129.
Gerasimov MR, Ashby CR, Gardner EL, Mills MJ, Brodie JD, Dewey SL 
(1999). Gamma-Vinyl GABA inhibits methamphetamine, heroin, or 
ethanol-induced increases in nucleus accumbens dopamine. Synapse 34: 
11-19.
Gillis MC (2005). CPS: Compendium of Pharmaceutical and Specialties 
(CPS). 37th Edition, Canadian Pharmaceutical Association, Ottawa, 
pp: 1513-1515.
Guberman A, Bruni J & The Canadian Vigabatrin Study Group (2000). 
Long-term open multicentre, add-on trial of vigabatrin in adult 
resistant partial epilepsy. Seizure 9:112-118.
Hancock E, Osborne JP (1999). Vigabatrin in the treatment of 
infantile spasms in tuberous sclerosis. J Child Neurol 14:71-74.
Kushner SA, Dewey SL, Kornetsky C (1999). The irreversible gamma-
amino butyric acid (GABA) transaminase inhibitor gamma vinyl-GABA 
blocks cocaine self-administration in rats. J.Pharmacol ExpTher 
290(2): 797-802.
Molina PE, Ahmed N, Ajmal M, Dewey S, Volkow N, Fowler J, Abumrad N 
(1999). Co-administration of Gamma-Vinyl GABA and Cocaine: 
Preclinical Assessment of Safety. Life Sciences 11:1175-1182.
Rey E, Pons G, Olive G (1992). Vigabatrin. Clinical 
pharmacokinetics. Clin Pharmacokinet 23:267-278.
Schiffer WK, Martsteller D, Dewey SL (2003). Sub-chronic low dose 
gamma vinyl GABA (vigabatrin) inhibits cocaine-induced increases in 
nucleus accumbens dopamine. Psychopharmacology 168: 339-343.
Stromberg MF, Mackler SA, Volpicelli JR, O'Brien CP, Dewey SL 
(2001). The effect of gamma-vinyl-GABA on the consumption of 
concurrently available oral cocaine and ethanol in the rat. 
Pharmacol Biochem Behav 68:291-299.

DATES: NIDA will consider all proposals received within 45 days of the 
date of publication of this notice. This notice is active until July 5, 
2005.

ADDRESSES: Proposals and questions about this opportunity may be 
addressed to Frank Vocci, Ph.D., Division of Pharmacotherapy and 
Medical Consequences of Drug Abuse, National Institute on Drug Abuse, 
6001 Executive Blvd., MSC 9551, Bethesda, Maryland 20892-9551. For 
overnight mail service, 6001 Executive Blvd., Room 4123, Rockville, 
Maryland 20852. Tel: (301) 443-2711, Fax: (301) 443-2599.

SUPPLEMENTARY INFORMATION: NIDA will consider proposals from all 
qualified entities and will, subject to negotiation of the details of a 
mutually agreed upon Research Plan, provide the CRADA Collaborator 
access to its comprehensive preclinical and clinical trials resources 
with the understanding that the CRADA Collaborator will be able to 
utilize data derived from the CRADA to pursue regulatory filings in the 
U.S. and abroad. NIDA's Medications Development Program possesses the 
capacity to perform chemical synthesis, dosage form development, 
pharmacokinetics, pharmacodynamics, toxicology, regulatory management, 
and clinical testing (Phase I through Phase III) meeting FDA 
requirements for Good Manufacturing, Good Laboratory Procedures, and 
Good Clinical Practices standards. NIDA may apply these capacities in 
the assessment of vigabatrin, as may be warranted based

[[Page 29332]]

on NIDA's evaluation of the information, capacities, and plans provided 
by potential Collaborator(s).
    NIDA follows stepwise development processes and procedures common 
to the medications development paradigm, i.e., a candidate compound 
must successfully complete each necessary pre-requisite step prior to 
being advanced for further testing and development. It is NIDA's 
intention to provide, assuming pre-requisite preclinical and clinical 
safety, preclinical and clinical trials services sufficient to permit 
the completion of Phase II hypothesis testing trials for cocaine and 
methamphetamine dependence indications. Assuming demonstration and 
review of safety and efficacy at the conclusion of Phase II trials and 
subject to negotiation, NIDA will consider undertaking Phase III trials 
sufficient to permit Collaborator to seek a U.S. New Drug Application 
(NDA).
    Please note that a CRADA is not a funding mechanism. No NIH 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 share of obligations 
under any Research Plan that may be negotiated in connection with the 
CRADA.
    ``Cooperative Research and Development Agreement'' or ``CRADA'' 
means the anticipated joint agreement to be entered into by NIDA 
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 National Institute on Drug Abuse seeks an agreement with a 
pharmaceutical or biotechnology company for joint research, 
development, evaluation, and potential commercialization of vigabatrin 
for the treatment of cocaine and methamphetamine dependence.
    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 under the agreement and will advance 
funds payable upon signing the CRADA to help defray Government expenses 
for patenting such inventions and other CRADA-related costs.
    The expected duration of the CRADA will be 3 to 5 years.
    Selection criteria for choosing the CRADA partner will include but 
not be limited to:
    1. Ability to collaborate with NIDA on further research and 
development of this technology in Phase I and Phase II clinical 
studies. All such studies will occur in the United States and under FDA 
IND rules. 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. At an absolute minimum, 
Collaborator must be able to provide vigabatrin and placebo sufficient 
to complete all clinical and preclinical studies required in the 
Research Plan.
    2. Demonstration of the resources (facilities, personnel and 
expertise) necessary to perform research, development and 
commercialization of this technology.
    3. Commitment of reasonable effort and resources on research, 
development and commercialization of this technology.
    4. Expertise in the commercial development, production, marketing 
and sales of products related to this area of technology .
    5. The level of financial support, if any, the Collaborator will 
supply for CRADA-related Government activities.
    6. A willingness to cooperate with the National Institute on Drug 
Abuse in the publication of research results.
    7. An agreement to be bound by the DHHS rules involving human 
subjects, patent rights and ethical treatment of animals.
    8. A willingness to accept the legal provisions and language of the 
CRADA with only minor modifications (if any).
    9. Provisions for equitable distribution of patent rights to any 
inventions made during the course of the subject CRADA research. 
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 a Government employee is an inventor).

    Dated: May 11, 2005.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 05-10066 Filed 5-19-05; 8:45 am]
BILLING CODE 4140-01-P