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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 Neurosurgery
Johns Hopkins University
Baltimore, MD
February 14, 2013
From: Diana Ennis <[email protected]>
Date: July 14, 2011 10:41:58 PM GMT+03:00
To: Henry Brem <[email protected]>
Cc: Sheila Garrity <[email protected]>
Subject: Sent on behalf of Dr. Chi Dang
Dr. 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 [email protected].
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 taxolreleasing 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
Glioblastoma: Treatment Outcome
Median Survival (Months)
12
10
10
9.25
8
6
4
4
2
0
Surgery Only
Surgery +
Radiotherapy
Surgery +
Radiotherapy +
Chemotherapy
McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery.
St Louis, MO: Mosby-Wolfe; 1994: chap 26.
Drug Development Process
Preclinical/Animal Testing
Clinical Testing
In Vivo and In Vitro testing are
performed to evaluate efficacy, toxicity
and safety
Phase I
Evaluates
the safety
of the drug
in a small
number of
patients
6½
1½
Phase II
Phase III
Effectiveness
of the drug is
evaluated and
a precise
dose
established
2
Average Duration in Years
Full scale, multi-center
trial to compare the
effectiveness of the
new drug to other
standard treatments
3½
FDA
Reviews
data and
determines
if drug will
be released
1½
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.]
1.45cm/disc x 8 = 11.6cm diameter
~3mm
diameter
Human
Monkey
Dog
Rat
Rabbit
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 nanotechnology) (2013)
GLIADEL DEVELOPMENT
1985 – 2013
•
•
•
•
•
•
•
•
•
Nova
Scios Nova
Guilford
Rhone Poulenc Rhorer
Aventis
Guilford
MGI PHARMA
Eisai Co, LTD
Arbor Pharmaceuticals
GLIADEL DEVELOPMENT
1984 – 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 DESIGN
Phase 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
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Chemotherapy
Adriamycin (Doxorubicin)
BCNU
Camptothecin
Carboplatin
Cyclophosphamide
Docetaxel
Epirubicin
Methotrexate
Mitoxantrone
OncoGel (Taxol)
Paclitaxel
Temozolomide
Angiogenesis inhibitors
Bevacizumab
Endostatin
mFc-endostatin
Minocycline
Rapamycin
Squalamine
Immunotherapy
TGF-alpha-PE38
IL-2
IL-4
IL-12
GM-CSF
Molecular Targets
A-443654
L-Buthionine Sulfoximine
Clostridium perfringens enterotoxin
Fas ligand
Lactacystin
O6-Benzylguanine
Riluzole
Amphibinase
Mechanism of Action
Intercalates DNA
Alkylating agent
Topoisomerase inh
Alkylating agent
Alkylating agent
Mitotic Inhibitor
Intercalates DNA
Inhibits DNA synthesis
Type II Topoisomerase Inh
Mitotic Inhibitor
Mitotic Inhibitor
Alkylating agent
Reference
Anti Can Res 2005
J Control Rel 2007
Clin Can Res 2006
Childs Nerv Syst 2009
JNS1995
JNO 2006
JNO 2010
Can Res 1994
JNS 2002
JNS 2009
JNO 2006
Neurosurgery 2010
VEGF Inhibitor
Angiogenesis inhibitor
Angiogenesis inhibitor
Angiogenesis inhibitor
mTOR inhibitor
Angiogenesis inhibitor
AANS 2010
Neurosurgery 2005
In preparation
JNO 2003
In review
Can Res 1998
Antineoplastic Agent
T cell stimulator
B and T cell Stimulator
T cell stimulator
Stimulates stem cells
Can Res 1994
JNO 2005
Neurosurg Focus 2000
Anticancer Drugs 2008
J Immunother 1996
AKT Inhibitor
Alkylating inactivator
Induces cytolysis
Induces apoptosis
Induces apoptosis
Inhibits AGT DNA repair
Glu tamate Receptor Ant
Antineoplastic RNAse
Mol Cancer Ther 2009
Neurosurgery 2001
Cancer Res 2007
NeuroOncol, 2010
NeuroOncol 2006
Can Res 2000
SFN 2004
Pharm Res 2009
Updated 6/2010
Agents in Pre-Clinical Development at the Hunterian Laboratory
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Chemotherapy
Adriamycin (Doxorubicin)
BCNU
Camptothecin
Carboplatin
Cyclophosphamide
Docetaxel
Epirubicin
Methotrexate
Mitoxantrone
OncoGel (Taxol)
Paclitaxel
Temozolomide
Angiogenesis inhibitors
Bevacizumab
Endostatin
mFc-endostatin
Minocycline
Rapamycin(Sirolmus)
Squalamine
Immunotherapy
TGF-alpha-PE38
IL-2
IL-4
IL-12
GM-CSF
Molecular Targets
A-443654
L-Buthionine Sulfoximine
Clostridium perfringens enterotoxin
Fas ligand
Lactacystin
O6-Benzylguanine
Riluzole
Amphibinase
Mechanism of Action
Intercalates DNA
Alkylating agent
Topoisomerase inh
Alkylating agent
Alkylating agent
Mitotic Inhibitor
Intercalates DNA
Inhibits DNA synthesis
Type II Topoisomerase Inh
Mitotic Inhibitor
Mitotic Inhibitor
Alkylating agent
Reference
Anti Can Res 2005
J Control Rel 2007
Clin Can Res 2006
Childs Nerv Syst 2009
JNS1995
JNO 2006
JNO 2010
Can Res 1994
JNS 2002
JNS 2009
JNO 2006
Neurosurgery 2010
VEGF Inhibitor
Angiogenesis inhibitor
Angiogenesis inhibitor
Angiogenesis inhibitor
mTOR inhibitor
Angiogenesis inhibitor
AANS 2010
Neurosurgery 2005
In preparation
JNO 2003
In review
Can Res 1998
Antineoplastic Agent
T cell stimulator
B and T cell Stimulator
T cell stimulator
Stimulates stem cells
Can Res 1994
JNO 2005
Neurosurg Focus 2000
Anticancer Drugs 2008
J Immunother 1996
AKT Inhibitor
Alkylating inactivator
Induces cytolysis
Induces apoptosis
Induces apoptosis
Inhibits AGT DNA repair
Glu tamate Receptor Ant
Antineoplastic RNAse
Mol Cancer Ther 2009
Neurosurgery 2001
Cancer Res 2007
NeuroOncol, 2010
NeuroOncol 2006
Can Res 2000
SFN 2004
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!!