RESEARCH INTEGRITY SERIES

THE SCIENTIST AS A RESPONSIBLE MEMBER OF SOCIETY

Henry Brem, M.D.Harvey Cushing Professor

Neurosurgery, Oncology, Ophthalmology and Biomedical Engineering

Director, Department of NeurosurgeryJohns Hopkins University

Baltimore, MD

February 14, 2013

From: Diana Ennis <dennis1@jhmi.edu>Date: July 14, 2011 10:41:58 PM GMT+03:00To: Henry Brem <hbrem@jhmi.edu>Cc: Sheila Garrity <sgarrity@jhmi.edu>Subject: Sent on behalf of Dr. Chi DangDr. Brem,The following note is being forwarded to you on behalf of Dr. Chi Dang.Thank you,Diana  Dear Henry: As announced in my e-mail sent in June, the School of Medicine is initiating a Responsible Conduct of Research (RCR) Training Program to ensure compliance with NIH and NSF guidelines.  All SOM faculty and post-doctoral fellows involved in research (excluding house staff) are required to complete training in RCR.  The Division of Research Integrity in the Office of Policy Coordination will administer the program.The RCR Program will include: 1) an online RCR course; 2) a Research Integrity lecture series, and 3) an annual department/division meeting on a relevant RCR topic.

I am writing to ask you to deliver one of the Dean’s Research Integrity lectures on the following topic: Research Integrity, The Scientist as a Responsible Member of Society. We have secured space from 3:30 to 5:00 on the following dates for this lecture: January 4, 9, 10, 11, 12, 17, 18, 19, 23, 24, 25, and 26, 2012.   As an institutional leader, you exemplify leadership in research integrity and your message will be well received by the community.  Ms. Sheila Garrity, Director of the Division of Research Integrity, will be following up on this request. If you have questions, please contact her at 516-4973 or sgarrity@jhmi.edu.  I appreciate your help. Best regards,Chi V. Dang, M.D., Ph.D.Vice Dean for Research

DISCLOSURE

Under a license agreement, JHU receives royalty income on taxol-releasing cardiac stents from Angiotech.  Dr. Brem is entitled to a share of the royalties received by the University.

ACADEMIC MEDICINE

• FUNDAMENTAL GOAL IS TO IMPROVE HEALTH CARE WITH A HIGH IMPACT

• VIRTUALLY IMPOSSIBLE TO DO SO BY STAYING WITHIN SILOS

BRAIN TUMORS

• In 1984 – many systemic treatments had been tried with no benefit.

• The FDA had not approved any new therapy in over 20 years.

BRAIN TUMORS

• E.R. VIDEO• SHOWING STANDARD APPROACH TO

‘FATAL DISEASE’

Segment 1

McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery. St Louis, MO: Mosby-Wolfe; 1994: chap 26.

0

2

4

6

8

10

12

Surgery Only Surgery + Radiotherapy

Surgery + Radiotherapy +Chemotherapy

9.25

4

10

Med

ian

Surv

ival

(Mon

ths)

Glioblastoma: Treatment Outcome

Drug Development Process

6 ½ 1 ½ 2 3 ½ 1 ½

Preclinical/Animal Testing

Clinical Testing

FDA

Phase I

Phase IIIPhase II

In Vivo and In Vitro testing are performed to evaluate efficacy, toxicity

and safety

Evaluates the safety

of the drug in a small number of patients

Effectiveness of the drug is evaluated and

a precise dose

established

Full scale, multi-center trial to compare the effectiveness of the new drug to other

standard treatments

Average Duration in Years

Reviews data and

determines if drug will be released

Problem: Clinical effectiveness of new cancer therapies

Hypothesis: Better delivery of agents to target sites would improve outcome

Solution: Targeted controlled delivery (polymers)

Langer described use of polyanhydrides:

Polifeprosan

Commercial finding: this polymer was useless for clothing because it dissolved when it rained

PRECLINICAL STUDIES

• Safety-Implantation in cornea and brain-Rats, rabbits, and monkeys

• Drug Distribution-Autoradiography: rats, rabbits, monkeys

• Efficacy-Rodent models

[CANCER RESEARCH 53, 329-333, January 15, 1993]

Interstitial Chemotherapy of the 9L Gliosarcoma: Controlled Release Polymers for Drug Delivery in the Brain

Rafael J. Tamargo, John S. Miseros, Jonathan I. Epstein, Michael B. Yang, Mark Chasin, and Henry Brem

Department of Neurological Surgery [R. J. T., J. S. M., M. B. Y., H.B.], Oncology [H.B.], and Pathology [J. I. E.], The Johns Hopkins University School of Medicine, Brain Tumor Research Center, Baltimore, Maryland 21205, and Nova Pharmaceutical Corporation, Baltimore, Maryland 21224 [M. C.]

RatRabbit

DogMonkey

Human

~3mm diameter

1.45cm/disc x 8 = 11.6cm diameter

This approach will not work because:• Polymers cannot be synthesized (1981)

• Polymers will react with encapsulated drugs (1983)

• These polymers are fragile (1985)

• The polymer drug system would be toxic (1987)

• Drugs would not diffuse far enough (1989)

• Models do not reflect clinical reality (1991)

• BCNU is a very poor drug (1993)

• FDA approval would be impossible for a polymer system (1995)

• How will it be paid for? (1997)

• Which patients will maximally benefit? (1999)

• Would the FDA broaden the indications? (2003)

• Precludes phase I studies (2005)

• Need better targeted drugs! (2007….)

• Need more sophisticated delivery approaches (eg Microchips and nano-

technology) (2013)

GLIADEL DEVELOPMENT 1985 – 2013

• Nova• Scios Nova• Guilford• Rhone Poulenc Rhorer• Aventis• Guilford• MGI PHARMA• Eisai Co, LTD• Arbor Pharmaceuticals

GLIADEL DEVELOPMENT1984 – 2013

• JOHNS HOPKINS• MIT

And many colleagues collaborating world wide

BRAIN TUMORS

• E.R. VIDEO• Aggressive surgery with Gliadel in tertiary

center improves survival

Segment 2

Segment 3

Brain Tumor Therapy

CLINICAL TRIAL DESIGNPhase I

Phase II-III

THE LANCET

Placebo-controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of

Chemotherapy for Recurrent Gliomas

Henry Brem, Steven Piantadosi, Peter C Burger, Michael Walker, Robert Selker, Nicholas A Vick, Keith Black, Michael Sisti, Steven Brem, Gerard Mohr, Paul Muller, Richard

Morawetz, S Clifford Schold, for the Polymer-Brain Tumor Treatment Group

Lancet 345:1008-12, 1995

Brain Tumor Therapy

FDA approval of Gliadel®

September 24, 1996

CHALLENGES• DESPITE SCIENTIFIC WORK, CLINICAL TRIALS AND

REGULATORY APPROVAL:

• GLIADEL WAS NOT BEING USED BECAUSE MEDICARE WOULD NOT PAY FOR IT!

SOLUTION: PETITION MEDICARE, THEN PATIENT ADVOCATE GROUPS TO CONGRESS, AND FINALLY TO DIRECTOR OF CMS

• CMS creates new DRG for patients treated with Gliadel

Medicare created a new DRG to ensure that beneficiaries continue to have access to Gliadel

The final rule states:

“We recognize that the implantation of chemotherapeutically active wafers for local therapy of malignant brain tumors represents a significant medical technology that currently offers clinical benefits to patients.…”*

* Federal Register / Vol. 69, No. 154 / Wednesday, August 11, 2004, page 48958.

September, 2004

• European approval is given for initial therapy

• CMS creates new DRG for patients treated with Gliadel

MORE EFFECTIVE AGENTS DELIVERED TO THE BRAIN VIA POLYMERS

Agents in Pre-Clinical Development at the Hunterian Laboratory• Chemotherapy Mechanism of Action Reference• Adriamycin (Doxorubicin) Intercalates DNA Anti Can Res 2005• BCNU Alkylating agent J Control Rel 2007• Camptothecin Topoisomerase inh Clin Can Res 2006• Carboplatin Alkylating agent Childs Nerv Syst 2009• Cyclophosphamide Alkylating agent JNS1995 • Docetaxel Mitotic Inhibitor JNO 2006• Epirubicin Intercalates DNA JNO 2010• Methotrexate Inhibits DNA synthesis Can Res 1994• Mitoxantrone Type II Topoisomerase Inh JNS 2002• OncoGel (Taxol) Mitotic Inhibitor JNS 2009• Paclitaxel Mitotic Inhibitor JNO 2006• Temozolomide Alkylating agent Neurosurgery 2010• Angiogenesis inhibitors• Bevacizumab VEGF Inhibitor AANS 2010• Endostatin Angiogenesis inhibitor Neurosurgery 2005 • mFc-endostatin Angiogenesis inhibitor In preparation• Minocycline Angiogenesis inhibitor JNO 2003• Rapamycin mTOR inhibitor In review• Squalamine Angiogenesis inhibitor Can Res 1998• Immunotherapy• TGF-alpha-PE38 Antineoplastic Agent Can Res 1994• IL-2 T cell stimulator JNO 2005 • IL-4 B and T cell Stimulator Neurosurg Focus 2000• IL-12 T cell stimulator Anticancer Drugs 2008• GM-CSF Stimulates stem cells J Immunother 1996• Molecular Targets• A-443654 AKT Inhibitor Mol Cancer Ther 2009• L-Buthionine Sulfoximine Alkylating inactivator Neurosurgery 2001• Clostridium perfringens enterotoxin Induces cytolysis Cancer Res 2007• Fas ligand Induces apoptosis NeuroOncol, 2010• Lactacystin Induces apoptosis NeuroOncol 2006 • O6-Benzylguanine Inhibits AGT DNA repair Can Res 2000• Riluzole Glu tamate Receptor Ant SFN 2004• Amphibinase Antineoplastic RNAse Pharm Res 2009

Updated 6/2010

Agents in Pre-Clinical Development at the Hunterian Laboratory• Chemotherapy Mechanism of Action Reference• Adriamycin (Doxorubicin) Intercalates DNA Anti Can Res 2005• BCNU Alkylating agent J Control Rel 2007• Camptothecin Topoisomerase inh Clin Can Res 2006• Carboplatin Alkylating agent Childs Nerv Syst 2009• Cyclophosphamide Alkylating agent JNS1995 • Docetaxel Mitotic Inhibitor JNO 2006• Epirubicin Intercalates DNA JNO 2010• Methotrexate Inhibits DNA synthesis Can Res 1994• Mitoxantrone Type II Topoisomerase Inh JNS 2002• OncoGel (Taxol) Mitotic Inhibitor JNS 2009• Paclitaxel Mitotic Inhibitor JNO 2006• Temozolomide Alkylating agent Neurosurgery 2010• Angiogenesis inhibitors• Bevacizumab VEGF Inhibitor AANS 2010• Endostatin Angiogenesis inhibitor Neurosurgery 2005 • mFc-endostatin Angiogenesis inhibitor In preparation• Minocycline Angiogenesis inhibitor JNO 2003• Rapamycin(Sirolmus) mTOR inhibitor In review• Squalamine Angiogenesis inhibitor Can Res 1998• Immunotherapy• TGF-alpha-PE38 Antineoplastic Agent Can Res 1994• IL-2 T cell stimulator JNO 2005 • IL-4 B and T cell Stimulator Neurosurg Focus 2000• IL-12 T cell stimulator Anticancer Drugs 2008• GM-CSF Stimulates stem cells J Immunother 1996• Molecular Targets• A-443654 AKT Inhibitor Mol Cancer Ther 2009• L-Buthionine Sulfoximine Alkylating inactivator Neurosurgery 2001• Clostridium perfringens enterotoxin Induces cytolysis Cancer Res 2007• Fas ligand Induces apoptosis NeuroOncol, 2010• Lactacystin Induces apoptosis NeuroOncol 2006 • O6-Benzylguanine Inhibits AGT DNA repair Can Res 2000• Riluzole Glu tamate Receptor Ant SFN 2004• Amphibinase Antineoplastic RNAse Pharm Res 2009

Updated 6/2010

Brain Tumor Therapy

• These improvements are only the beginning and there is much more now in the “pipeline”

• However, none of this would have been possible if not for reaching across borders between specialties, academic centers, industry, NIH, FDA, Patient Advocate Groups, Congress and CMS as well as international regulatory agencies!

Changing Times

Exciting new challenges, and extraordinary opportunities, and responsibilities for scientists and clinicians to significantly improve health care!!