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					           National Institute on Drug Abuse – Medications Development Program

      Transitioning from Basic Research to the
 Development of Drug Addiction Pharmacotherapies:
     Opportunities for Collaboration with NIDA



                          David J. McCann, Ph.D.
             Chief, Medications Discovery & Toxicology Branch
  Division of Pharmacotherapies & Medical Consequences of Drug Abuse
                              NIDA/NIH/DHHS




AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

      Transitioning from Basic Research to the
 Development of Drug Addiction Pharmacotherapies:
     Opportunities for Collaboration with NIDA



                The NIDA Medications Development Program

                          Medications Discovery Resources

                Preclinical Medications Development Resources

                  Clinical Trials Capabilities/Contact Information



AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

                       Mission of the NIDA
                Medications Development Program




                                           

       To facilitate the translation of basic research findings into
        pharmacotherapies for the treatment of drug addiction

AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

                       Mission of the NIDA
                Medications Development Program

                          National program on biological and
   March, 1990            pharmacological approaches to heroin and
                          cocaine addiction treatment

     NIDA                  Establish a close working relationship with the
  Medications              pharmaceutical industry
  Development
                           Conduct studies to gain approval of new
    Division
                           medications for addiction treatment
  Established
                           Work with FDA to assure that efficacy of
 Congressional             compounds is expeditiously evaluated and
   Mandate                 approved

AAPS-NIDA Symposium – September 10, 2004
            National Institute on Drug Abuse – Medications Development Program

              NIDA Division of Pharmacotherapies
            & Medical Consequences of Drug Abuse
                                                Frank Vocci
                                                 Director


                                              Richard Hawks
                                              Deputy Director



                                Jag Khalsa                      Jim Glass
                                    Chief                          Chief

                                 Medical                        Informatics
                               Consequences                        Unit
                                  Branch




      Nora Chiang       David McCann           Robert Walsh           Ahmed Elkashef     Jamie Biswas
         Chief              Chief                  Chief                      Chief          Chief

      Chemistry &        Medications             Regulatory           Clinical/Medical    Medications
     Pharmaceutics       Discovery &              Affairs                  Branch          Research
        Branch           Toxicology               Branch                                 Grants Branch
                           Branch

AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

                          NIDA Collaborations in
                      Drug Discovery & Development

            Input from Industry, Academia, or Govt.



                       Preclinical
                                                        Phase 2
                        Profiling Preclinical Phase 1              Phase 3     NDA
          Screening                                     Activity
                         & Lead     Safety     Safety              Efficacy   Approval
                                                         Dose
                      Optimization




                                   Licensing



AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

                Most Noteworthy Accomplishments



   Three NDA approvals:
             Levo-Alpha Acetyl Methadol (LAAM; Orlamm®)
             Buprenorphine SL tabs (Subutex®)
             Buprenorphine/Naloxone SL tabs (Suboxone®)

   Use of NIDA contracts to generate full toxicology package
   for a NME (potential cocaine addiction treatment) within
   13 months to support IND filing by industry partner.


AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

      Transitioning from Basic Research to the
 Development of Drug Addiction Pharmacotherapies:
     Opportunities for Collaboration with NIDA



           NIDA and the NIDA Medications Development Program

                        Medications Discovery Resources

                Preclinical Medications Development Resources

                  Clinical Trials Capabilities/Contact Information



AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

                 Medications Discovery Resources



        Established Programs:
                  Cocaine Treatment Discovery Program
                  Opiate Treatment Discovery Program
                  Methamphetamine Treatment Discovery Program


         Adding flexibility to address smoking cessation and the
         treatment of marijuana addiction on a limited basis




AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

       Sites Contracted for CTDP Screening & Profiling
       NovaScreen
        - High-throughput library screening
       SRI
        - Biogenic amine receptor activity testing
       Portland VA Medical Center
        - Biogenic amine transporter binding and uptake assays
        - Biogenic amine release assays
       University of North Texas Health Science Center at Fort Worth
        - Locomotor activity testing (cmpd alone & cocaine antagonism)
        - Cocaine discrimination (rats)
       McLean Hospital
        - Cocaine discrimination (monkeys)
        - Cocaine self-administration (rats & monkeys)
       Virginia Commonwealth University
        - Cocaine relapse models (rats)
AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program


                 Old Pharmaceutical Industry Model:




                      Discovery             Development


                 New Pharmaceutical Industry Model:


                      Discovery             Development

AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program


                 Old Pharmaceutical Industry Model:



                                                  Expensive Failures



                              $            $      $      $          $
            Target            Hit          Lead   SAC      Proj.    IND
                   HTS         In vitro In vivo       Preclinical
                                                      Safety/PK
                               Pharmacology
AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program


                 New Pharmaceutical Industry Model:
                                                                   Earlier
                                                In Vitro          Failures &
                                               Tox & PK-          Improved
                                                Related             SACs
                                                Testing

                              $            $        $         $          $
            Target            Hit          Lead       SAC       Proj.    IND
                   HTS         In vitro In vivo            Preclinical
                                                           Safety/PK
                               Pharmacology
AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

       Sites Contracted for Predictive Tox & PK Testing
  UCSF
   - CaCo-2 cell assay (20 mg)                   Absorption
  BioReliance
   - Spot Ames test (20 mg)                      Mutagenicity
  Chan Test
   - hERG channel assay (50 mg)                  QT-prolongation
  Quintiles
   - APD assay in Purkinjie fibers (75 mg)       QT-prolongation
  FDA Center for Testing and Research
   - Computational toxicology (0 mg)             Mutagenicity
                                                 Carcinogenicity
                                                 Teratogenicity
  NovaScreen
   - Broad in vitro receptor profiling (50 mg)   Side effects
   - Cytochrome P450 assays (20 mg)              Drug or food interactions
AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program
              NIDA Policy on Data Rights and
      Confidentiality for Medications Discovery Studies.


  Resulting data are the property of the compound submitter.


  Contracted test sites are blinded to the identity of compounds under
  study
       - helping to ensure confidentiality
         - preventing bias from influencing results.


  NIDA contractors are legally prohibited from releasing any
  contract-generated data without NIDA approval.



AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

      Transitioning from Basic Research to the
 Development of Drug Addiction Pharmacotherapies:
     Opportunities for Collaboration with NIDA



           NIDA and the NIDA Medications Development Program

                          Medications Discovery Resources

              Preclinical Medications Development Resources

                  Clinical Trials Capabilities/Contact Information



AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

    Preclinical Medications Development Resources



    Standard GLP Safety Studies                   GMP Synthesis

    Drug Interaction/Safety Studies               Dosage Formulation

    Bioanalytical Assay Development               Stability Testing

    Pharmacokinetics




AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

     Preclinical Interaction Studies to Establish Safety of
       Medication in the Presence of Drugs of Abuse


   For all NMEs under development as cocaine or methamphetamine
   addiction therapies, the FDA requires special preclinical drug
   interaction studies to establish medication safety in the presence of
   drugs of abuse.

   These studies must be completed prior to initiating Phase Ib
   medication/cocaine or medication/methamphetamine interaction
   studies.




AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

         NIDA Battery of Preclinical Interaction Studies
               for Cocaine Addiction Therapies
                                                          Dogs or
                                              Rats        Monkeys

              Morphine:                    Lethality          -
                                           Tail-Flick

              Ethanol:                     Lethality          -
                                           Rotorod

              Cocaine:                     Lethality    Cardiovascular




AAPS-NIDA Symposium – September 10, 2004
             National Institute on Drug Abuse – Medications Development Program
                Typical Design of Rat Studies:
       Test Article/Morphine Interaction as an Example
                     TEST            MORPHINE                    STUDY SCHEDULE
     GROUP          ARTICLE            DOSE         Tail-Flick     Clinical Signs   Euthanasia
   (N=10 each)     DOSE (P.O.)      (mg/kg, S.C.)    Day 1          & Lethality       Day 4
                                                                     Days 1-3
        1                0                  0          yes              yes         # Remaining
        2                0                  1          yes              yes         # Remaining
        3                0                  2          yes              yes         # Remaining
        4                0                 400         no               yes         # Remaining
        5               Low                 0          yes              yes         # Remaining
        6               Low                 1          yes              yes         # Remaining
        7               Low                 2          yes              yes         # Remaining
        8               Low                400         no               yes         # Remaining
        9              High                 0          yes              yes         # Remaining
        10             High                 1          yes              yes         # Remaining
        11             High                 2          yes              yes         # Remaining
        12             High                400         no               yes         # Remaining

AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program
             Dog or monkey cardiovascular studies are
             conducted using a DSI-Telemetry System.




AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program
                       Typical Study Design for
               Test Article/Cocaine Interaction in Dogs
          Test Article Administration         Cocaine Challenge
          (0, low dose, high dose, P.O.)     (0, 0.56, 3.0 mg/kg, I.V.)
                                             

             23 hours       60 minutes     24 hours       Washout at
             Cardiovascular Cardiovascular Cardiovascular least 5 days
             monitoring     monitoring     monitoring

             Unless data dictate otherwise, interactions are evaluated based
             on the first five minutes after cocaine/vehicle injection.

             Endpoints:
             Systolic, Diastolic, and Mean Arterial Pressures
             Heart Rate and Rate Pressure Product
             RR, PR, QT, QTc, ST, QRS Intervals
             ST Segment Amplitude and T-Wave Morphology


AAPS-NIDA Symposium – September 10, 2004
                      National Institute on Drug Abuse – Medications Development Program

                                           Cocaine Effects on Mean Arterial Pressure in Dogs

                                 100

                                                           High Cocaine Dose (3 mg/kg)
          Change in MAP (mmHg)



                                 80
                                                                       Low Cocaine Dose (0.56 mg/kg)
                                 60


                                 40


                                 20


                                   0


                                 -20
                                       0             5            10           15         20           25          30

                                                         Time After Cocaine Infusion (minutes)

                                       0 mg/kg
                                           0 mg/kg            mg/kg
                                                         0.560.56 mg/kg        mg/kg
                                                                           1.01.0 mg/kg   1.7 mg/kg
                                                                                           3.0 mg/kg        3.0 mg/kg
                                                                                                            1.7 mg/kg



AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program
        NIDA Policy on Protocols, Data Rights, and
     Confidentiality for Preclinical Development Studies.


     Compound submitters have input into protocol development
     (e.g., related to appropriate test article dosing) and studies are
     not initiated without submitter approval.

     Resulting data are the property of the compound submitter.

     NIDA contractors are legally prohibited from releasing any
     contract-generated data without NIDA approval.




AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

      Transitioning from Basic Research to the
 Development of Drug Addiction Pharmacotherapies:
     Opportunities for Collaboration with NIDA



           NIDA and the NIDA Medications Development Program

                          Medications Discovery Resources

                Preclinical Medications Development Resources

               Clinical Trials Capabilities/Contact Information



AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

               Clinical Trials Capabilities -
       Cocaine and Methamphetamine Addiction Tx
       • Phase I: 6 contracted sites, including a NIDA-dedicated unit at
         USUHS.
          – Ia: med alone
          – Ib: med/cocaine or med/meth safety interaction study

       • Phase II: 6 contracted sites for cocaine, 5 contracted sites for
         methamphetamine.
            – IIa: 60 – 80 patients
            – IIb: 180 patients (1 or 2 sites)

       • Phase III: Veterans Administration Cooperative Study
         Program (VACSP); unlimited number of VA and non-VA sites;
         hundreds to thousands of patients (multi-site).


AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

               Clinical Trials Capabilities -
       Cocaine and Methamphetamine Addiction Tx
                               Powell Chemical Dependency CTR (Des Moines)

                     Comprehensive Medical Health Services, Inc. (Kansas City)

                                                              University of
                                                               Cincinnati
      Friends                                                                         McLean Hospital
      Research                                                                      Boston University
      Institute
      (Costa Mesa)                                                               New York University
                                                                              USUHS
      UCLA
      Coordinating
      Center
                                                                          Medical University of
             South Bay                                                         South Carolina
             Treatment Center
             (San Diego)


  John Burns School of
  Medicine (Honolulu)           University of Texas San Antonio

                                                                                      VACSP
                                                                                      Nationwide
AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program


                      Focus of the NIDA
             Medications Development Program
            (historical shift in contract resources)



                                                                        ?
    1991          LAAM                     Buprenorphine Products   2003
                               Opiate Addiction
                               Cocaine Addiction
                               Methamphetamine Addiction
                               Nicotine/Tobacco Addiction & MJ Addiction
AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

            The NIH Working Group on
  Pharmacological Approaches to Nicotine Addiction

  • Trans-NIH initiative was started by Drs. Leshner (former Director,
    NIDA) and Klausner (former Director, NCI) in 2001.
  • Stimulated by public health concerns: It is estimated that 1 billion
    people will die from smoking-related illnesses this century.
  • NIDA, NCI and NIAAA have held a series of meetings to assess
    challenges and develop strategies related to the development of new
    medications for smoking cessation.
  • The U.S. Veterans Heath Administration, Department of Veterans
    Affairs (VA) was engaged in the process.
  • There is strong support for a trans-funded program, melding NCI
    clinical trial approaches that have proved successful for cancer
    treatments with those of NIDA that recognize special challenges
    posed by treatments for addiction.

AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

        Strategy for Smoking Cessation Medications

  • Utilize an existing NIDA/VA Inter-Agency Agreement to
    manage the trials

  • Get funding for sites from NCI, NIAAA, VA Central Office and
    pharmaceutical companies

  • NMEs for smoking cessation may proceed to Phase II studies
    without special Phase Ib nicotine interaction studies, as long
    as smokers are included in Phase I studies

  • Utilize the VA IAG system to conduct Phase II/III studies for
    investigational medications obtained from pharmaceutical
    companies
AAPS-NIDA Symposium – September 10, 2004
           National Institute on Drug Abuse – Medications Development Program

                                           Contacts



     Medications Discovery -                 Dr. Jane Acri, 301-443-8489

     Preclinical Safety -                    Dr. David McCann, 301-443-2999

     Chemistry/Pharmaceutics -               Dr. Nora Chiang, 301-443-8099

     Clinical Trials -                       Dr. Ahmed Elkashef, 301-443-5055

     Division Director -                     Dr. Frank Vocci, 301-443-2711



AAPS-NIDA Symposium – September 10, 2004

				
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