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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.

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Presentation on theme: "RESEARCH INTEGRITY SERIES THE SCIENTIST AS A RESPONSIBLE MEMBER OF SOCIETY Henry Brem, M.D. Harvey Cushing Professor Neurosurgery, Oncology, Ophthalmology."— Presentation transcript:

1 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

2 From: Diana Ennis Date: July 14, :41:58 PM GMT+03:00 To: Henry Brem Cc: Sheila Garrity Subject: Sent on behalf of Dr. Chi 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 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.

3 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, 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 or I appreciate your help. Best regards, Chi V. Dang, M.D., Ph.D. Vice Dean for Research

4 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.

5 ACADEMIC MEDICINE FUNDAMENTAL GOAL IS TO IMPROVE HEALTH CARE WITH A HIGH IMPACT VIRTUALLY IMPOSSIBLE TO DO SO BY STAYING WITHIN SILOS

6 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.

7 BRAIN TUMORS E.R. VIDEO SHOWING STANDARD APPROACH TO ‘FATAL DISEASE’ Segment 1

8 McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery. St Louis, MO: Mosby-Wolfe; 1994: chap Surgery OnlySurgery + Radiotherapy Surgery + Radiotherapy + Chemotherapy Median Survival (Months) Glioblastoma: Treatment Outcome

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11 Drug Development Process 6 ½1 ½23 ½1 ½ Preclinical/Animal Testing Clinical Testing FDA Phase I Phase III Phase 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

12 Problem: Clinical effectiveness of new cancer therapies Hypothesis: Better delivery of agents to target sites would improve outcome Solution: Targeted controlled delivery (polymers)

13 Langer described use of polyanhydrides: Polifeprosan

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

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17 PRECLINICAL STUDIES Safety -Implantation in cornea and brain -Rats, rabbits, and monkeys Drug Distribution -Autoradiography: rats, rabbits, monkeys Efficacy -Rodent models

18 [CANCER RESEARCH 53, , 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 [M. C.]

19 Rat Rabbit Dog Monkey Human ~3mm diameter 1.45cm/disc x 8 = 11.6cm diameter

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23 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)

24 GLIADEL DEVELOPMENT 1985 – 2013 Nova Scios Nova Guilford Rhone Poulenc Rhorer Aventis Guilford MGI PHARMA Eisai Co, LTD Arbor Pharmaceuticals

25 GLIADEL DEVELOPMENT 1984 – 2013 JOHNS HOPKINS MIT And many colleagues collaborating world wide

26 BRAIN TUMORS E.R. VIDEO Aggressive surgery with Gliadel in tertiary center improves survival Segment 2 Segment 3

27 Brain Tumor Therapy CLINICAL TRIAL DESIGN Phase I Phase II-III

28 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: , 1995

29 Brain Tumor Therapy FDA approval of Gliadel ® September 24, 1996

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31 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

32 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

33 September, 2004 European approval is given for initial therapy CMS creates new DRG for patients treated with Gliadel

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36 MORE EFFECTIVE AGENTS DELIVERED TO THE BRAIN VIA POLYMERS

37 Agents in Pre-Clinical Development at the Hunterian Laboratory ChemotherapyMechanism of ActionReference Adriamycin (Doxorubicin) Intercalates DNAAnti Can Res 2005 BCNUAlkylating agent J Control Rel 2007 Camptothecin Topoisomerase inhClin Can Res 2006 Carboplatin Alkylating agent Childs Nerv Syst 2009 Cyclophosphamide Alkylating agentJNS1995 Docetaxel Mitotic InhibitorJNO 2006 EpirubicinIntercalates DNA JNO 2010 Methotrexate Inhibits DNA synthesisCan Res 1994 Mitoxantrone Type II Topoisomerase InhJNS 2002 OncoGel (Taxol)Mitotic Inhibitor JNS 2009 Paclitaxel Mitotic Inhibitor JNO 2006 Temozolomide Alkylating agent Neurosurgery 2010 Angiogenesis inhibitors BevacizumabVEGF InhibitorAANS 2010 Endostatin Angiogenesis inhibitor Neurosurgery 2005 mFc-endostatinAngiogenesis inhibitor In preparation Minocycline Angiogenesis inhibitor JNO 2003 RapamycinmTOR inhibitorIn review Squalamine Angiogenesis inhibitor Can Res 1998 Immunotherapy TGF-alpha-PE38Antineoplastic AgentCan Res 1994 IL-2 T cell stimulatorJNO 2005 IL-4B and T cell Stimulator Neurosurg Focus 2000 IL-12T cell stimulator Anticancer Drugs 2008 GM-CSFStimulates stem cellsJ Immunother 1996 Molecular Targets A AKT InhibitorMol Cancer Ther 2009 L-Buthionine Sulfoximine Alkylating inactivatorNeurosurgery 2001 Clostridium perfringens enterotoxinInduces cytolysisCancer Res 2007 Fas ligandInduces apoptosis NeuroOncol, 2010 Lactacystin Induces apoptosis NeuroOncol 2006 O6-Benzylguanine Inhibits AGT DNA repairCan Res 2000 Riluzole Glu tamate Receptor Ant SFN 2004 AmphibinaseAntineoplastic RNAse Pharm Res 2009 Updated 6/2010

38 Agents in Pre-Clinical Development at the Hunterian Laboratory ChemotherapyMechanism of ActionReference Adriamycin (Doxorubicin) Intercalates DNAAnti Can Res 2005 BCNUAlkylating agent J Control Rel 2007 Camptothecin Topoisomerase inhClin Can Res 2006 Carboplatin Alkylating agent Childs Nerv Syst 2009 Cyclophosphamide Alkylating agentJNS1995 Docetaxel Mitotic InhibitorJNO 2006 EpirubicinIntercalates DNA JNO 2010 Methotrexate Inhibits DNA synthesisCan Res 1994 Mitoxantrone Type II Topoisomerase InhJNS 2002 OncoGel (Taxol)Mitotic Inhibitor JNS 2009 Paclitaxel Mitotic Inhibitor JNO 2006 Temozolomide Alkylating agent Neurosurgery 2010 Angiogenesis inhibitors BevacizumabVEGF InhibitorAANS 2010 Endostatin Angiogenesis inhibitor Neurosurgery 2005 mFc-endostatinAngiogenesis inhibitor In preparation Minocycline Angiogenesis inhibitor JNO 2003 Rapamycin(Sirolmus)mTOR inhibitorIn review Squalamine Angiogenesis inhibitor Can Res 1998 Immunotherapy TGF-alpha-PE38Antineoplastic AgentCan Res 1994 IL-2 T cell stimulatorJNO 2005 IL-4B and T cell StimulatorNeurosurg Focus 2000 IL-12T cell stimulator Anticancer Drugs 2008 GM-CSFStimulates stem cellsJ Immunother 1996 Molecular Targets A AKT InhibitorMol Cancer Ther 2009 L-Buthionine Sulfoximine Alkylating inactivatorNeurosurgery 2001 Clostridium perfringens enterotoxinInduces cytolysisCancer Res 2007 Fas ligandInduces apoptosis NeuroOncol, 2010 Lactacystin Induces apoptosis NeuroOncol 2006 O6-Benzylguanine Inhibits AGT DNA repairCan Res 2000 Riluzole Glu tamate Receptor Ant SFN 2004 AmphibinaseAntineoplastic RNAse Pharm Res 2009 Updated 6/2010

39 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!

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

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