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
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).
Clinical Trials; Definition
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
Phase I/II/III clinical Trial
Behavioral medicine study
Study of a new procedure
Trial of new devices

Types of clinical Trials
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 I I 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 I I I 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. Roch

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
Food Drug
Administration
Industry
Bristol Myers Squibb
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
Ixabepilone: A Novel Microtubule Stabilizing agent:
Expert Reviews in Oncology ( in press)
Gerald Higa and Jame Abraham
4,500 dollars for one infusion of
Ixempra!!
Phase IV trial
Phase I V 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
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.,
SCIENTIFIC
MISCONDUCT:
Cancer
Researcher
Sacked for Alleged
Fraud

Michael Hagmann
Science 17 March 2000:
Vol. 287. no. 5460, pp. 1901 - 1902

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
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.

Claude Bernard (1813-1878)
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
Adjuvant Breast Cancer Therapy
and Cognition
and Cognition
Unaffected by anxiety, depression, fatigue, and time
since treatment

.013

6.4
28
12
39
34
CMF*
Controls
P-Value
Odds
Ratio
Cognitive
Impairment
(%) n Treatment Arm
Schagen SB, et al. Cancer. 1999;85:640-650.
*CMF = *CMF = cyclophosphamide cyclophosphamide + + methotrexate methotrexate + 5 + 5- -fluorouracil fluorouracil. .
Epo receptors
in the CNS
Erythropoietin inhibits apoptosis
Excellent question!!
Valid pre-clinical Model
Cognitive impairment is a problem in patients
receiving Chemotherapy

Erythropoietin may be an effective treatment!!
Selling points?
Is it a novel idea?
What is the relevance of the
study?
Is it a high priority study?

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

2. Evaluate the effectiveness of the
erythropoietin using
15
O Water PET
scan

Objectives of the study
In patients receiving adjuvant chemotherapy for breast cancer
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 Oshaughnessy M.D
Texas Oncology


z = -5 z = 26 z = 21 z = 23
z = 47 z = 52 z = 40 z = 52
Anterior peaks
Posterior peaks
Solvent exposed
Control subjects
t = 4.04 5 6 7
Study development
Collaboration
Design the study
Statistician
Writing the proposal

24 patients
12 patients
12 patients
PET scan
NPT
AC X 4 cycles
AC X 4 cycles
Placebo
Procrit
PET scan
NPT
Schema of the study
Randomized
Prospective
Double blinded
Placebo controlled
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
http://www.hsc.wvu.edu/mbrcc/ctru/
Clinical Trials Research Unit
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
0
10
20
30
40
50
60
70
80
90
100
Digit Symbol
Patients
Controls
0.64
0.66
0.68
0.7
0.72
0.74
0.76
0.78
0.8
Genu Splenium
Patients
Controls
Abraham et al. Clinical Breast Cancer, Feb 2008
Cognitive impairment in rats
receiving chemotherapy
CON AC AC/N
l
a
t
e
n
c
y

[
s
]
0
20
40
60
80
100
120
140
160
180
before shock
after shock
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

Cathy Patriarca
Gerry Hobbs- Statistician

Marc Haut
Greg Konat
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

Campbell E. N Engl J Med 2007;357:1796-1797
Frequency of Various Types of Physician-Industry Relationships

Conflict of Interest or Conflict of Priorities?

Elizabeth G. Nabel, M.D.

N
e
x
t



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!!