Clinical Trials

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Clinical Trials

• Jame Abraham, M.D
• Associate Professor of Medicine
• Chief, Section of Hematology-Oncology

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R word of academic medicine was
Research
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R word of academic medicine is
RVU
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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
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A treatise of the scurvy James Lind 1753
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1990 - 5000 pharmacists and physicians
conducted clinical trials of a new
drug 2000- More than 60,000 medical
professionals are principal investigators
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Types of clinical Trials

• Phase I/II/III clinical Trial
• Behavioral medicine study
• Study of a new procedure
• Trial of new devices

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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
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• 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.

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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.

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• 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.

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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.

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• 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.

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International study with 752 Patients
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• 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

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Oncology Drug Approval Process
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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)
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Drug discovery can cost up to 800 million to a
billion dollars !
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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
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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

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• 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 3521092-1102 March 17, 2005 Number 11
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Why Clinical Trials?
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• SCIENTIFIC MISCONDUCTCancer Researcher Sacked
  for Alleged Fraud
• Michael Hagmann
• Science 17 March 2000Vol. 287. no. 5460, pp.
  1901 - 1902

• Conventional-Dose Chemotherapy Compared with
  High-Dose Chemotherapy plus Autologous
  Hematopoietic Stem-Cell Transplantation for
  Metastatic Breast Cancer
• Edward A. Stadtmauer, M.D., Anne O'Neill, M.S.,

NEJM, Volume 3421069-1076 April 13, 2000 Number
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Investigator Initiated Clinical Trials
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Investigator initiated studies

• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
• Review Board
• Execution of the clinical Research

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Claude Bernard (1813-1878)
The first requirementin 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.
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Can chemotherapy affect my memory?
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Epo receptors in the CNS
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Erythropoietin inhibits apoptosis
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Cognitive impairment is a problem in patients
receiving Chemotherapy Erythropoietin may be an
effective treatment!!
Excellent question!! Valid pre-clinical Model
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Selling points?

• Is it a novel idea?
• What is the relevance of the study?
• Is it a high priority study?

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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

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Investigator initiated studies

• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
• Review Board
• Execution of the clinical Research

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Protocol development

• Collaboration
• Design the study
• Statistician
• Writing the proposal

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Naresh Gupta, M.D Nuclear Medicine Marc Haut,
Ph.D Behavioural Medicine Hiroto Kuwabara, M.D,
PhD Johns Hopkins Joyce Oshaughnessy M.D Texas
Oncology
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Anterior peaks
Solvent exposed
Control subjects
z -5 z 26
z 21
z 23
Posterior peaks
z 47 z 52
z 40
z 52
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Study development

• Collaboration
• Design the study
• Statistician
• Writing the proposal

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Procrit
Double blinded
Randomized
12 patients
AC X 4 cycles
Prospective
PET scan NPT
24 patients
12 patients
AC X 4 cycles
PET scan NPT
Placebo controlled
Placebo
Schema of the study
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Study development

• Collaboration
• Design the study
• Statistician
• Writing the proposal

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Study development

• Collaboration
• Design the study
• Statistician
• Writing the proposal

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Investigator initiated studies

• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
• Review Board
• Execution of the clinical Research

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Grant sources

• http//grants1.nih.gov/grants/index.cfm
• http//cdmrp.army.mil/

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Grant writing

• Scientific part
• Budget
• Ms. Elsa Nadler

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Office of the sponsored program (OSP)
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Investigator initiated studies

• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
• Review Board
• Execution of the clinical Research

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Clinical Protocol

• Protocol
• Consent
• Budget

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Clinical Trials Research Unit
http//www.hsc.wvu.edu/mbrcc/ctru/
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Scientific Protocol Review Committee (Protocol
Review and Monitoring Committee PRMC)
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Institutional Review Board
Patient safety
Improving Protection for Research SubjectsRobert
Steinbrook, M.D. Volume 3461425-1430 May 2, 2002
New England Journal of Medicine
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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
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Investigator initiated studies

• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
• Review Board
• Execution of the clinical Research

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• Erythropoietin, the FDA, and Oncology
• Robert Steinbrook, M.D.
• Volume 3562448-2451 June 14, 2007

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Abraham et al. Clinical Breast Cancer, Feb 2008
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Cognitive impairment in rats receiving
chemotherapy
Konat et. al Metabolic Brain Disease, Accepted
for Publication
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Research Team Principal Investigator Co-Investiga
tors Research Nurse Statistician Pharmacist Data
Manager Accountant Collaborators
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Clinical Trials Unit Shannon Filburn Rebecca
Keller Leah Darr Angela Price Christen Tringes
Cathy Patriarca Gerry Hobbs- Statistician
Marc Haut Greg Konat William Petros Aasim
Sehbai Maria Moran Cliff Martin
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Execution of Clinical Trial

• Patient recruitment
• Follow the protocol
• Be scientific and objective
• Maintain a highly ethical approach

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Research
RVU
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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

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Frequency of Various Types of Physician-Industry
Relationships
Campbell E. N Engl J Med 20073571796-1797
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Conflict of Interest or Conflict of
Priorities? Elizabeth G. Nabel, M.D.
Volume 3552365-2367 November 30, 2006
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Investigator initiated studies

• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
• Review Board
• Execution of the clinical Research

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But why think, why not try the
experiment? John Hunter, 1775
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Thank you!!