RESEARCH INTEGRITY SERIES

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 <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 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.

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, 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

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. 12 10 10 9.25 8 Median Survival (Months) 6 4 4 2 0 Surgery Only Surgery + Radiotherapy Surgery + Radiotherapy +Chemotherapy Glioblastoma: Treatment Outcome McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery. St Louis, MO: Mosby-Wolfe; 1994: chap 26.

11. 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 Phase II Phase III Effectiveness of the drug is evaluated and a precise dose established FDA Full scale, multi-center trial to compare the effectiveness of the new drug to other standard treatments Reviews data and determines if drug will be released 6 ½ 1 ½ 2 3 ½ 1 ½ Average Duration in Years

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

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, 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.]

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

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 DEVELOPMENT1984 – 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 345:1008-12, 1995

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

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 48958.

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

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 DNA Anti Can Res 2005 BCNU Alkylating agent J Control Rel 2007 CamptothecinTopoisomeraseinhClin Can Res 2006 CarboplatinAlkylating agent Childs NervSyst 2009 CyclophosphamideAlkylating agent JNS1995 Docetaxel Mitotic Inhibitor JNO 2006 Epirubicin Intercalates DNA JNO 2010 Methotrexate Inhibits DNA synthesis Can Res 1994 Mitoxantrone Type II TopoisomeraseInh JNS 2002 OncoGel (Taxol) Mitotic Inhibitor JNS 2009 Paclitaxel Mitotic Inhibitor JNO 2006 TemozolomideAlkylating 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 RapamycinmTOR 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-ButhionineSulfoximineAlkylatinginactivator Neurosurgery 2001 Clostridium perfringensenterotoxin Induces cytolysis Cancer Res 2007 Fasligand Induces apoptosis NeuroOncol, 2010 Lactacystin Induces apoptosis NeuroOncol 2006 O6-Benzylguanine Inhibits AGT DNA repair Can Res 2000 RiluzoleGlutamate Receptor Ant SFN 2004 AmphibinaseAntineoplasticRNAsePharm Res 2009 Updated 6/2010

38. Agents in Pre-Clinical Development at the Hunterian Laboratory ChemotherapyMechanism of ActionReference Adriamycin (Doxorubicin) Intercalates DNA Anti Can Res 2005 BCNU Alkylating agent J Control Rel 2007 CamptothecinTopoisomeraseinhClin Can Res 2006 CarboplatinAlkylating agent Childs NervSyst 2009 CyclophosphamideAlkylating agent JNS1995 Docetaxel Mitotic Inhibitor JNO 2006 Epirubicin Intercalates DNA JNO 2010 Methotrexate Inhibits DNA synthesis Can Res 1994 Mitoxantrone Type II TopoisomeraseInh JNS 2002 OncoGel (Taxol) Mitotic Inhibitor JNS 2009 Paclitaxel Mitotic Inhibitor JNO 2006 TemozolomideAlkylating 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-ButhionineSulfoximineAlkylatinginactivator Neurosurgery 2001 Clostridium perfringensenterotoxin Induces cytolysis Cancer Res 2007 Fasligand Induces apoptosis NeuroOncol, 2010 Lactacystin Induces apoptosis NeuroOncol 2006 O6-Benzylguanine Inhibits AGT DNA repair Can Res 2000 RiluzoleGlutamate Receptor Ant SFN 2004 AmphibinaseAntineoplasticRNAsePharm 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!!