Clinical Trials Jame Abraham, M.D Associate Professor of Medicine Chief, Section of Hematology-...

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 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

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 ofIxempra!!

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 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 HagmannScience 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 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.

Claude Bernard (1813-1878)

“An Introduction to the Study of Experimental Medicine” 1865. He is considered as the "Father of Physiology”.

“Can chemotherapy affectmy memory?”

Adjuvant Breast Cancer Therapy Adjuvant Breast Cancer Therapy and Cognitionand Cognition

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

—

.013

—

6.4

28

12

39

34

CMF*

Controls

P-ValueOdds Ratio

Cognitive Impairment

(%)nTreatment Arm

Schagen SB, et al. Cancer. 1999;85:640-650.

*CMF = *CMF = cyclophosphamide cyclophosphamide + + methotrexate methotrexate + 5+ 5--fluorouracilfluorouracil..

Epo receptorsin 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 15O Water PET Scan

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

Objectives of the study

In patients receiving adjuvant chemotherapy for breast cancer




• Writing a grant


Review Board


Protocol development

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

Naresh Gupta, M.DNuclear Medicine

Marc Haut, Ph.DBehavioural Medicine

Hiroto Kuwabara, M.D, PhDJohns Hopkins

Joyce O’shaughnessy M.DTexas 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


24 patients

12 patients

12 patients

PET scanNPT

AC X 4 cycles

AC X 4 cycles

Placebo

Procrit

PET scanNPT

Schema of the study

Randomized

Prospective

Double blinded

Placebo controlled

Study development





• Writing a grant


Review Board


Grant sources

http://grants1.nih.gov/grants/index.cfm

http://cdmrp.army.mil/

http://grants1.nih.gov/grants/index.cfm

Grant writing

• Scientific part

• Budget Ms. Elsa Nadler

Office of the sponsored program (OSP)




• Writing a grant


Review Board


Clinical Protocol

1. Protocol2. 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 SubjectsRobert 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

http://query.nytimes.com/search/article-page.html?res=9501E2DE1E3BF934A25754C0A9679C8B63




• Writing a grant


Review Board


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

Konat et. al Metabolic Brain Disease, Accepted for Publication

Research Team

Principal InvestigatorCo-Investigators

Research NurseStatisticianPharmacistData ManagerAccountant Collaborators

Clinical Trials UnitShannon Filburn Rebecca KellerLeah Darr

Angela PriceChristen Tringes

Cathy PatriarcaGerry Hobbs- Statistician

Marc HautGreg KonatWilliam PetrosAasim SehbaiMaria 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.

Nex

t

Volume 355:2365-2367 November 30, 2006




• Writing a grant


Review Board


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

Thank you!!

Clinical Trials Jame Abraham, M.D Associate Professor of Medicine Chief, Section of Hematology-...

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