Proposal Writing for Clinical Trials

							 Clinical Trials

     Jame Abraham, M.D
Associate Professor of Medicine
 Chief, Section of Hematology-
           Oncology
R word of academic medicine was

      Research
R word of academic medicine is

          RVU
  Clinical Trials; Definition
The NIH defines a clinical trial as a
prospective biomedical or behavioral
research study of human subjects that is
designed to answer specific
questions about biomedical or behavioral
interventions (drugs, treatments,
devices, or new ways of
using known drugs, treatments, or devices).
                Web site; www.Grants.nih.gov/grants/funding/phs398
“A treatise of the scurvy”   James Lind 1753
1990 -   5000 pharmacists and physicians
         conducted clinical trials of a new drug

2000-    More than 60,000 medical
         professionals are principal investigators
  Types of clinical Trials
• Phase I/II/III clinical Trial
• Behavioral medicine study
• Study of a new procedure
• Trial of new devices
   Phase I Clinical Trial
• Phase I clinical trials test a new
  biomedical intervention in a small
  group of people (e.g., 20-80) for the
  first time to evaluate safety (e.g., to
  determine a safe dosage range and to
  identify side effects).

                        NIH definition
• Phase I Trial and Pharmacokinetic Study of
  BMS-247550, an Epothilone B Analog,
  Administered Intravenously on a Daily
  Schedule for Five Days

  Jame Abraham, Manish Agrawal, Susan Bakke, Ann Rutt,
  Maureen Edgerly, Frank M. Balis, Brigitte Widemann,
  Louis Davis, Bharat Damle, Daryl Sonnichsen, David
  Lebwohl, Susan Bates, Herb Kotz, and Tito Fojo

  National Cancer Institute, Bethesda, MD

  JCO May 1 2003: 1866-1873.
     Phase II Clinical Trial

• Phase II clinical trials study the
  biomedical or behavioral
  intervention in a larger group of
  people (several hundred) to
  determine efficacy and to further
  evaluate its safety.
• Phase II Clinical Trial of Ixabepilone
  (BMS-247550), an Epothilone B Analog,
  in Metastatic and Locally Advanced
  Breast Cancer

• Jennifer A. Low, Suparna B. Wedam, James J.
  Lee, Arlene W. Berman, Adam Brufsky, Sherry X.
  Yang, Marianne S. Poruchynsky, Seth M.
  Steinberg, Nitin Mannan, Tito Fojo, Sandra M.
  Swain

• National Cancer Institute
• JCO Apr 20 2005: 2726-2734.
             Phase III trials
• Phase III studies investigate the efficacy of
  the biomedical or behavioral intervention in
  large groups of human subjects (from
  several hundred to several thousand) by
  comparing the intervention to other standard
  or experimental interventions as well as to
  monitor adverse effects, and to collect
  information that will allow the intervention
  to be used safely.
• Ixabepilone Plus Capecitabine for Metastatic
  Breast Cancer Progressing After Anthracycline
  and Taxane Treatment

• Eva S. Thomas, Henry L. Gomez, Rubi K. Li,
  Hyun-Cheol Chung, Luis E. Fein, Valorie F.
  Chan, Jacek Jassem, Xavier B. Pivot, Judith V.
  Klimovsky, Fernando Hurtado de Mendoza,
  Binghe Xu, Mario Campone, Guillermo L. Lerzo,
  Ronald A. Peck, Pralay Mukhopadhyay, Linda T.
  Vahdat, Henri H. Roché

• JCO Nov 20 2007: 5210-5217.
International study with 752 Patients


            Phase III study


 Ixabepilone with
                        Capecitabine
   Capecitabine
• From the M.D. Anderson, Houston, TX;
  Instituto Nacional de Enfermedades
  Neoplasicas; Lima, Peru; Veterans
  Memorial Medical Center, Quezon City,
  Philippines; Yonsei Cancer Center, Seoul,
  Republic of Korea; Centro de Oncologia
  Rosario, Sante Fe; Hospital de Oncologia
  „Maria Curie,‟ Buenos Aires, Argentina;
  Medical University of Gdansk, Gdansk,
  Poland; C.H.U.Institut Claudius Regaud,
  Toulouse, France; Rajive Gandhi Instiute,
  New Delhi, India, Cancer Hospital –
  Chinese Academy of Medical Sciences,
  Beijing, China; and Weill Medical College
  of Cornell University, New York, NY
Oncology Drug Approval Process

     Oncology Drug Advisory Committee




      Industry             Food Drug
Bristol Myers Squibb      Administration
FDA Approval for Ixabepilone
Brand name: Ixempra™
On October 16, 2007, the U.S. Food
and Drug Administration (FDA)
approved ixabepilone
for injection
(Ixempra™, made by Bristol-Myers Squibb)
Drug discovery can cost up to 800
  million to a billion dollars !

               Phase III




             Phase II

            Phase I
4,500 dollars for one infusion of
           Ixempra!!




Ixabepilone: A Novel Microtubule Stabilizing agent:
                              Expert Reviews in Oncology ( in press)
                              Gerald Higa and Jame Abraham
           Phase IV trial

• Phase IV studies are conducted after
  the intervention has been marketed.
  These studies are designed to monitor
  effectiveness of the approved
  intervention in the general population
  and to collect information about any
  adverse effects associated with
  widespread use
Cardiovascular Events Associated with
Rofecoxib in a Colorectal Adenoma
Chemoprevention Trial

Robert S. Bresalier, M.D., Robert S. Sandler, M.D., Hui
Quan, Ph.D., James A. Bolognese, M.Stat., Bettina
Oxenius, M.D., Kevin Horgan, M.D., Christopher Lines,
Ph.D., Robert Riddell, M.D., Dion Morton, M.D., Angel
Lanas, M.D., Marvin A. Konstam, M.D., John A. Baron,
M.D., for the Adenomatous Polyp Prevention on Vioxx
(APPROVe) Trial Investigators
                                    Volume 352:1092-1102
                                    March 17, 2005 Number 11
Why Clinical Trials?
• Conventional-Dose             • SCIENTIFIC
  Chemotherapy                    MISCONDUCT:
  Compared with High-
  Dose Chemotherapy plus          Cancer
  Autologous                      Researcher
  Hematopoietic Stem-Cell         Sacked for Alleged
  Transplantation for
  Metastatic Breast               Fraud
  Cancer
                                 Michael Hagmann
                                 Science 17 March 2000:
  Edward A. Stadtmauer, M.D.,    Vol. 287. no. 5460, pp. 1901 - 1902
  Anne O'Neill, M.S.,
  NEJM, Volume 342:1069-
  1076 April 13, 2000 Number
  15
Investigator Initiated
   Clinical Trials
    Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
   Review Board
• Execution of the clinical Research
Claude Bernard (1813-1878)




    The first requirement…in practicing experimental
    medicine, is to be an observing physician and to
    start from pure and simple observations of patients
    made as completely as possible.

   “An Introduction to the Study of Experimental Medicine” 1865.
           He is considered as the "Father of Physiology”.
“Can chemotherapy affect
     my memory?”
     Adjuvant Breast Cancer Therapy
            and Cognition
                                               Cognitive
                                              Impairment   Odds
Treatment Arm                       n            (%)       Ratio   P-Value

CMF*                               39            28         —        —

Controls                           34            12         6.4     .013


      Unaffected by anxiety, depression, fatigue, and time
       since treatment


                                         5-fluorouracil.
*CMF = cyclophosphamide + methotrexate + 5-fluorouracil.
Schagen SB, et al. Cancer. 1999;85:640-650.
Epo receptors
in the CNS
Erythropoietin inhibits apoptosis
Cognitive impairment is a problem in patients
receiving Chemotherapy

Erythropoietin may be an effective treatment!!




Excellent question!!
Valid pre-clinical Model
      Selling points?
• Is it a novel idea?
• What is the relevance of the
  study?
• Is it a high priority study?
 Objectives of the study
In patients receiving adjuvant chemotherapy for breast cancer


      1. To study the Patho-physiology of
      cognitive dysfunction Using 15O Water
      PET Scan

      2. Evaluate the effectiveness of the
      erythropoietin using 15O Water PET
      scan
    Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
   Review Board
• Execution of the clinical Research
         Protocol development
•   Collaboration
•   Design the study
•   Statistician
•   Writing the proposal
Naresh Gupta, M.D
Nuclear Medicine

Marc Haut, Ph.D
Behavioural Medicine

Hiroto Kuwabara, M.D, PhD
Johns Hopkins

Joyce O’shaughnessy M.D
Texas Oncology
   Solvent exposed
                            Anterior peaks
                                                   Control subjects




z = -5        z = 26                             z = 21         z = 23


                           Posterior peaks




z = 47         z = 52                            z = 40         z = 52


                        t = 4.04   5   6     7
          Study development
•   Collaboration
•   Design the study
•   Statistician
•   Writing the proposal
                 Procrit      Double blinded
  Randomized

                12 patients    AC X 4 cycles



               Prospective                      PET scan
24 patients                                       NPT


                12 patients    AC X 4 cycles

 PET scan
   NPT                         Placebo controlled
                  Placebo

                                   Schema of the study
       Study development
• Collaboration
• Design the study
• Statistician
• Writing the proposal
       Study development
• Collaboration
• Design the study
• Statistician
• Writing the proposal
    Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
   Review Board
• Execution of the clinical Research
           Grant sources
http://grants1.nih.gov/grants/index.cfm

http://cdmrp.army.mil/
           Grant writing


• Scientific part

• Budget
  Ms. Elsa Nadler
Office of the sponsored program (OSP)
    Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
   Review Board
• Execution of the clinical Research
Clinical Protocol
1. Protocol
2. Consent
3. Budget
Clinical Trials Research Unit

   http://www.hsc.wvu.edu/mbrcc/ctru/
Scientific Protocol Review Committee

 (Protocol Review and Monitoring
       Committee – PRMC)
     Institutional Review Board


                   Patient safety




Improving Protection for Research Subjects
Robert Steinbrook, M.D. Volume 346:1425-1430 May 2, 2002
New England Journal of Medicine
Johns Hopkins Admits Fault in Fatal Experiment


''Regardless of the fact that we are
unlikely ever to know precisely how or
why this happened, Hopkins takes full responsibility
for what did happen,''

Dr. Edward B. Miller, the dean and chief executive
of Johns Hopkins Medicine

                           July 17 2001
    Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
   Review Board
• Execution of the clinical Research
Erythropoietin, the FDA, and
          Oncology

    Robert Steinbrook, M.D.
    Volume 356:2448-2451 June 14, 2007
                         100

                         90

                         80

                         70


                         60

                         50                                     Patients
                                                                Controls
                         40

                         30


                         20

                         10


                          0
                                      Digit Symbol



                   0.8


                  0.78


                  0.76


                  0.74


                  0.72                                                     Patients
                                                                           Controls

                   0.7


                  0.68


                  0.66


                  0.64
                               Genu                  Splenium




Abraham et al. Clinical Breast Cancer, Feb 2008
Cognitive impairment in rats
  receiving chemotherapy
               180

               160                        before shock
                                          after shock
               140

               120
 latency [s]




               100

                80

                60

                40

                20

                 0
                      CON            AC                  AC/N



               Konat et. al Metabolic Brain Disease, Accepted for Publication
Research Team
Principal Investigator
Co-Investigators
Research Nurse
Statistician
Pharmacist
Data Manager
Accountant
Collaborators
Clinical Trials Unit
Shannon Filburn
Rebecca Keller
Leah Darr

Angela Price
Christen Tringes
                            Marc Haut
Cathy Patriarca             Greg Konat
Gerry Hobbs- Statistician   William Petros
                            Aasim Sehbai
                            Maria Moran
                            Cliff Martin
      Execution of Clinical Trial
•   Patient recruitment
•   Follow the protocol
•   Be scientific and objective
•   Maintain a highly ethical approach
Research   RVU
              Conflict of Interest
•   DOD Funding- 325,000 dollar
•   Ortho Biotech- 425,000 dollars
•   AstraZeneca – 110,000 dollars (not active)
•   Co-operative Groups
    – NSABP
    – ECOG
• Other Pharma
    – Pfizer
    – Eli Lilly
 Frequency of Various Types of Physician-Industry Relationships




Campbell E. N Engl J Med 2007;357:1796-1797
                                                   N
                                                   e



Conflict of Interest — or Conflict of Priorities?
                                                   x
                                                   t




             Elizabeth G. Nabel, M.D.



          Volume 355:2365-2367 November 30, 2006
    Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
   Review Board
• Execution of the clinical Research
But why think, why not try the experiment?
                          John Hunter, 1775
Thank you!!