Data Sharing Between Academia and Industry: Drug Companies have a Conscience Too

1. Data Sharing Between Academia and Industry: Drug Companies have a Conscience Too Wes Van Voorhis Professor of Medicine Adjunct Professor of Pathobiology and Microbiology wesley@u.washington.edu

2. Overview of LectureCould be retitled: The Good, the Bad, and the Ugly • Intro to Issues in Industry Interactions • Case Histories • My own case: Help pharma to do the right thing • Ben Hall Ph.D. UW: Value of patents and in discernment of industry agreements • Bruce Psaty, M.D. Ph.D., UW: Be wary of industry, they may try to slay the messenger • Betty Dong, PhD, UCSF: Nightmare at publication time • Lessons learned from the cases

3. Introduction to Issues in Industry Interactions • Industry and Academics: • Generally different values • Ethical principle that academics should participate in patents and industry? • One view: We owe it to the people who pay for our research, i.e. the US public that funds most of our research • Industry transforms intellectual property into goods and services used by the US public • Need to convert our ideas to products • If you publish without patent protection, may have destroyed the ability to convert the idea into a usable product

4. Introduction to Issues in Industry Interactions • Who owns federally-funded research (intellectual property) performed at UW • The researcher • The U.S. Government • The WA State Government • The University of Washington • Washington Research Foundation

5. Introduction to Issues in Industry Interactions • Who owns federally-funded research (intellectual property) performed at UW • The University of Washington

6. Introduction to Issues in Industry Interactions • Bayh-Dole Act of 1980 • Prior to 1980, U.S. Government owned intellectual property (IP) from Federally-sponsored research • US Govt had little incentive to patent inventions • IP generally went into public domain w/out patent • Problematic: w/out patent protection, Industry will not invest in development of an idea • <5% of patents were licensed to companies for commercial applications

7. Introduction to Issues in Industry Interactions • Bayh-Dole Act of 1980 • After 1980, IP became property of universities where work was performed • Inventors share a portion of return • Universities have to report IP to Federal Govt. • In theory, U.S. Govt. maintains right to patent anything Univ. refuse to patent • Huge explosion in patent applications from federally-sponsored research • Offices of Technology Transfer (OTT) generally charged with examining IP, licensing out technology, agreements with industry, materials-transfer agreements, confidentiality agreements • Became a profit center for some universities

8. Wes Van Voorhis MD, PhDCase history: Help Pharma to “do the right thing” • Interested in drug development for the Developing World • Malaria • Trypanosomes • African Sleeping Sickness • American Trypanosomiasis (Chagas’ Disease) Crump: TDR/WHO National Geographic Manning UCI

9. Difficulties in Creating New Drugs for Infectious Diseases in the Developing World • Incentive for Pharma small • Pharma looking for $100 million/year or better for new drugs developed • Market in developing countries is limited • Annual health expenditure per capita often <$5 USD / year • Travelers’ & military market is limited

10. Difficulties in Creating New Drugs for Infectious Diseases in the Developing World • Most of drug-development expertise in Pharma (private sector) • Solutions: • Pharma • Special research units • Devote effort to Devel. Country Diseases • e.g. GSK (Tres Cantos), Novartis (Singapore) • Public-Private Partnerships • Funding through MMV, DNDi, iOWH

11. Medicines for Malaria Venture • MMV: Nonprofit Foundation (about 60% Gates Foundation Funding) • Mission: discover, develop and deliver new affordable antimalarial drugs through effective public-private partnerships

12. Projects in the GSK/MMV mini-portfolio Projects under contract negotiation Medicines for Malaria Venture Portfolio 4th Q 2006 Exploratory Discovery Preclinical Development Regulatory Lead Lead Identification Optimization Phase I Phase II Phase III PSAC antagonists Novel Liver Stage Antimalarials OZ Next Generation OZ + PQP RBx11160 + Piperaquine Tablet, Pediatric and Intravenous RBx11160 Chlorproguanil -dapsone (Lapdap™) - artesunate (CDA) Pf enoyl-ACP reductase (Fab I) Immucillins New dicationic molecules Enantioselective 8-aminoquinoline NPC1161 Pediatric Coartem™ Cameroonian Medicinal Plants TDR22093 Series 4(1H)-pyridones Back ups Isoquine (an improved aminoquinoline) Dihydroartemisinin-piperaquine DHA + PQP Falcipain (cysteine protease) 4(1H)-pyridone GW308678 Pyronaridine – Artesunate PYRAMAX™ Novartis Institute for Tropical Diseases Collaboration Broad Institute of MIT/Harvard – Genzyme Collaboration Novel Macrolides 17 Projects 6 New Projects to be added 3 mini-portfolios Dihydrofolate reductase (DHFR) Natural Products Whole-Cell HTS Natural Products as New Prototypes Dihydroorotate dehydrogenase inhibitors R. Rabinovich, B&M Gates FDN

13. Piggy-backing To Select Drug Targets • Drug development is difficult starting from scratch • Look for promising drug targets where a lot of development has already been performed • See if the existing “drugs” show promise against malaria, thus piggy-back onto existing efforts • Mike Gelb, Fred Buckner, Christophe Verlinde, Erkang Fan http://www.ed.arizona.edu/ward/Design-Plane/piggyback.jpg

14. Engaging Pharma: Difficulties • Asking Pharma for their most valuable resource, their compounds • Impede future use of compounds for more lucrative markets • Endanger patents for compounds by disclosure of compounds in research results • Reveal the range of their compound holdings for competitor advantage

15. Engaging Pharma: Difficulties • Academic researchers using Pharma drugs/compounds • Might find a liability/toxicity not described for a compound • Results may be artifact, no Pharma control • Could hold up launch of drug • Millions $$ at stake

16. Engaging Pharma: Difficulties • Concern that identification of a drug for a developing world use will: • Make drug company look bad for charging a lot for the drug • Make the drug company look bad for having a two-tiered pricing scheme: expensive for US, cheap for Dev. World • Cheap drugs from abroad might “contaminate” the US market • Might engender “generic” off-shore production before patent has expired

17. Piggy-backing Antiparasitic Drug Targets at UW: Two Examples • Protein Farnesyltransferase • Target for oncology, in Phase III trials • Effective leads from Bristol Myers Squibb (BMS), others donated by Schering-Plough, Merck, & others • Inhibitors cure rodent malaria • Optimizing Pharmacokinetics • Glycogen Synthase Kinase • Target for mania, Alzheimers, diabetes • Leads from Serono Inc., negotiating with Glaxo Smith Klein (GSK) • Inhibitors kill malaria and trypanosomes • Testing in animal models

18. Engaging Pharma: Lessons Learned • Talk to scientists, not lawyers • Realize the value of Pharma’s compounds • Concede Phama’s due rights to fruits of research • Read agreements carefully • Pass all agreements through the Office of Technology Transfer • Do not sign anything that will impede your (eventual) right to publish (OTT won’t let you) • They cannot own the IP from your lab results but can get non-exclusive rights to use of results (OTT watches for this)

19. Ben Hall Ph.D.Case Study:The Value of Patents and in Discernment of Industry Agreements • Professor of Biology and Genome Sciences • Patents for yeast production of protein and HepBsAg for immunization • Discovered and characterized 18S and 28S rRNAs at Harvard for PhD • Interested in yeast transcription and translation in 1980s • Prevailing view at time by many academics: Patents are very time consuming and produce nothing for the academic researcher or the public

20. Ben Hall Ph.D. • Studying alcohol dehydrogenase (ADH1) promoter of yeast for protein expression • Collaborate with Genentech early 1981 • First obtained a written agreement with Genentech to not use ADH1 promoter for other genes without Hall’s consent • Alpha-interferon: great production by ADH1 • Genentech sent consulting agreement • Any subsequent inventions in the Hall lab would become property of Genetech • Hall has lawyer review: doesn’t sign

21. Ben Hall Ph.D. • HepBsAg: Key to immunization against hepatitis B • Huge effort in early 1980 to produce recombinant HepBsAg in E. coli fails • E. coli becomes sick and chews up protein

22. Ben Hall Ph.D. • Suitably tailored ADH1 promoter and yeast strain: Key to highly competitive race for rHepBsAg • Hall & UCSF collaborators • First production of rHepBsAg • Filed for patent in 1981: not granted until 1988 • Dated and signed lab records critical • Had Genetech been able to use ADH1 constructs, they would have been first • Letter that they could not use ADH1 constructs to express other genes was the key to stopping them

23. Ben Hall Ph.D. • Revenue stream from patents substantially funds • Office of Tech Transfer • Royalty Research Fund • Dr. Hall has never written a grant since 1994 • Patent revenues fund lab expenses • Scientific freedom

24. Ben Hall Ph.D.Lessons learned • Enter industry consultations with written agreements about scope of work • Get a good lawyer to review documents • Think twice about consultancy agreements • Work with Office of Technology Transfer to secure patent protection for your work

25. Bruce Psaty, M.D., Ph.D.Case Study: Be wary of industry, they may try to slay the messenger • Professor of Medicine, Epidemiology and Health Services, UW • Investigator, Center for Health Studies, Group Health Cooperative of Puget Sound • Renowned for his work on drug safety • UW Public Service Award 2005 • Responsible for recognizing problems with Ca++ Channel Blockers for high blood pressure and increased heart disease vs. older (cheaper) medicines

26. Bruce Psaty, M.D., Ph.D. • Am. Heart Asscn. Meeting, 1995 • Dr. Psaty presents study examining association between: • Incidence of heart attacks (myocardial infarction, MI) • Types of high blood pressure medications • Ca Channel Blockers use were assc’d with 60% increased risk of MI compared with less expensive generic drugs such as diuretics or beta blockers • A news release was prepared by AHA • Front page coverage • Psaty’s office flooded by calls from upset patients and doctors

27. Bruce Psaty, M.D., Ph.D. • Aftermath of press coverage • Psaty gets requests from several pharmaceutical companies for documents, tables, manuscripts • Freedom of Information Act cited by one company • Huge request of all documents of Psaty and collaborators • University forced to negotiate a response, after several months of work, the company withdraws the request • Academic Consultants to companies making Ca++ channel blockers issue: • Blistering critiques • Emphasize dubious harms of cheaper generics • Publicly question Psaty’s integrity • Most often don’t disclose their ties to companies • Companies making Ca channel blockers try to block publication of paper with Psaty’s results • Go as far as to protest to the Dean of UW

28. Bruce Psaty, M.D., Ph.D.Lessons Learned • Be wary of industry, they may try to slay the messenger • Psaty was scrupulous in eschewing support from industry • He felt then would stand up to public scrutiny during the accusations of industry and academic consultants • Industry-sponsored research • May be tainted by not asking the right questions • Need to stand up to industry for research integrity and freedom • Less-believed by the public than public-sponsored research

29. Betty Dong, Pharm.D.Case Study: Nightmare at publication time • Professor of Clinical Pharmacy, UCSF • Respected researcher in endocrinology, cardiovascular, and HIV pharmacology • Contracted by Boots (later, Knoll) Pharmaceuticals to study bioequivalence of Synthroid vs. other preparations synthetic thyroid hormone UCSF faculty website

30. Betty Dong, Pharm.D. • Up to the time of Dr. Dong’s study(1987-1990), Synthroid (levothyroxine, Boots) was felt to have superior bioavailability (amount of effective drug from a pill) • Thus, dissimilar bioequivalence to other cheaper/generic sources of levothyroxine preparations • Physicians tended to continue to prescribe Synthroid, introduced in 1958, rather than switch to cheaper generics • Switching would supposedly require re-titration of the patient’s dose to a therapeutic level, following TSH and clinical outcome • Boots (later Knoll) pharmaceutical company dominated the $600 million/yr market of levothyroxine

31. Betty Dong, Pharm.D. • Dr. Dong conducted a randomized cross-over trial (patients took one for a while, then another, etc) of 4 preparations of synthetic thyroid • Measured effective blood levels of thyroid hormones and thyroid stimulating hormone • Boots visited UCSF site 3x/yr to convince work was being done right, no signs of any major problems • Study found no differences in any measurement for 4 preparations studied including Synthroid of Boots/Knoll, it was clear all 4 were bioequivalent

32. Betty Dong, Pharm.D. • Over the next 4 years Boots campaigned to discredit the study • Dr. Dong sent Boots numerous drafts of a manuscript • Boots refused publication cited numerous deficiencies including • Failure to carry out procedures not in the protocol • Deficiencies in patient selection criteria • Assay reliability • Statistical analysis • Unspecified ethical problems:demanded disclosure of conflict of interest, present, past, & future

33. Betty Dong, Pharm.D. • Over the next 4 years Boots campaigned to discredit the study • Boots sent letters of complaint to UCSF officials • Two UCSF investigations failed to find any wrong doing by the investigator • Conclusion was that the study was rigorously conducted as per the protocol with only very minor deviations as are acceptable and expected in a clinical trial • UCSF characterizes Boots handling of Dr. Dong as “harassment” and “deceptive and self-serving” • UCSF: suppression of the manuscript was an unprecedented infringement on academic freedom • Dong et al. decided they would publish

34. Betty Dong, Pharm.D. • Study by Dong et al. submitted to JAMA 4/1994 • Reviewed by 5 reviewers, revised, accepted 11/1994, publication scheduled 1/25/95 • Dr. Dong withdraws Ms 1/13/95 • Cites: “impending legal action” • Discloses 5/88 protocol/contract has a clause: “Data obtained by the investigator while carrying out this study is …considered confidential and is not to be published or otherwise released without written consent…”

35. Betty Dong, Pharm.D. • Why did Dr. Dong sign restriction on publication? • She considered it “routine” for contracts • Before 1993, UCSF had no mandatory review of contracts • Why did she go so far with publication? • First lawyer at UCSF felt academic freedom trumped clause in contract and Boots would probably not take legal action if Dong published

36. Betty Dong, Pharm.D. • Why did Dr. Dong withdraw the publication? • Dr. Dong: threatened with lawsuit twice if sales of Synthroid dropped • Boots/Knoll denies this • First lawyer left UCSF, new lawyer felt Boots would take legal action • Boots considered for purchase; loss of revenue from blockbuster Synthroid would decrease value of company (Company bought by BASF for 1.4 billion in 3/96: Div. of Knoll Pharma) • Dr. Dong might not get legal protection from UCSF because of contract she signed

37. Betty Dong, Pharm.D. • Publication of Dr. Dong’s data by Boots • Dr. Gilbert Mayor, employee of Boots, publishes Dong et al. data in 1995 • No acknowledgement of primary researchers • Reanalyzes the data of Dong et al. using different (flawed) algorithms • Finds opposite result of Dong etal. • Other preparations of levothyroxine are “therapeutically inequivalent” • Favors Boots’ marketshare • Published in new journal, Am. J. Therapeutics • Dr. Mayor: Associate Editor

38. Betty Dong, Pharm.D. • Came to attention of public 4/25/96 • Wall Street Journal Article by Ralph King • “Bitter Pill: How a drug company paid for a university study then undermined it” • Boots/Knoll position summarized by President of Knoll, Carter Eckert, “I stopped a flawed study that would have put millions of patients at risk”

39. Betty Dong, Pharm.D. • FDA involvement • FDA warns Boots 1994 • Cited misleading information on labeling and product info • Boots’ studies: insufficient data that other levothyroxine preparations are different (lack bioequivalence w/Synthroid) • After publication of Wall Street Journal article, 11/96, FDA concluded that Knoll had violated the Federal Food, Drug, and Cosmetic Act • Misbranded Synthroid based on lack of bioequivalence of other preparations • Noted Knoll was in possession of data from Dong et al. which came to the opposite conclusion

40. Betty Dong, Pharm.D. • Knoll relents 11/96 • Negotiates with UCSF, allows publication of Dong et al. paper in JAMA • Comes out in 4/97 • Unchanged from original accepted paper from 1/95 • Knoll publishes in same JAMA • letter of apology • letter objecting to the papers conclusions

41. Betty Dong, Pharm.D. Lessons learned • Read and understand all that you sign • Have agreements reviewed by Office of Technology Transfer (OTT) • Be wary of studies that: “can only come out in favor of companies product” • If they do not, the company may vigorously fight to suppress the findings

42. Summary of Concepts • Academics should participate in patenting and technology transfer to industry • Work with OTT to secure patents • Otherwise goods and services won’t be created • The University owns the Intellectual Property (IP) • Disclose IP early to UW, don’t delay publication • Consult OTT for direction for IP issues • Talk to industry scientists, not lawyers

43. Summary of Concepts • Read agreements carefully • Pass all agreements through OTT • Do not sign anything that will impede your (eventual) right to publish • Realize the value of industry materials • Concede industry’s due rights to fruits of research • Industry cannot own the IP from your lab results but can get non-exclusive rights

44. Summary of Concepts • Be wary of industry, they may try to slay the messenger • Carefully consider consultancy agreements • May create apparent conflict of interest later

45. John DesRosier PhD Ben Hall PhD Lee Huntsman PhD Eric Larson MD Bruce Psaty MD, PhD Ari Santander, UW OTT Rob Gillespie Debra Jarvis Rennie Drummond, 1997 “Thyroid Storm” JAMA 277:1238 Richard Deyo, Bruce Psaty, Gregory Simon, Edward Wagner, and Gilbert Omenn. 1997 “The messenger under attack – Intimidation of researchers by special interests groups” NEJM 336:1176 Acknowledgements