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_at_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

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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

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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

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Introduction to Issues in Industry Interactions

• Who owns federally-funded research (intellectual
  property) performed at UW
• The University of Washington

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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
• lt5 of patents were licensed to companies for
  commercial applications

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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

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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
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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 lt5
  USD / year
• Travelers military market is limited

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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

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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

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

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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

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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

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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

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Engaging Pharma Lessons Learned

• Talk to scientists, not lawyers
• Realize the value of Pharmas compounds
• Concede Phamas 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 wont 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)

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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

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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
  Halls 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 doesnt sign

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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

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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

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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

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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

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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

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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 asscd 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
• Psatys office flooded by calls from upset
  patients and doctors

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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 Psatys integrity
• Most often dont disclose their ties to companies
• Companies making Ca channel blockers try to block
  publication of paper with Psatys results
• Go as far as to protest to the Dean of UW

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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

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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
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Betty Dong, Pharm.D.

• Up to the time of Dr. Dongs 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 patients dose to a therapeutic level,
  following TSH and clinical outcome
• Boots (later Knoll) pharmaceutical company
  dominated the 600 million/yr market of
  levothyroxine

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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

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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 problemsdemanded disclosure
  of conflict of interest, present, past, future

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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

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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

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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

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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

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Betty Dong, Pharm.D.

• Publication of Dr. Dongs 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 et al.
• Other preparations of levothyroxine are
  therapeutically inequivalent
• Favors Boots marketshare
• Published in new journal, Am. J. Therapeutics
• Dr. Mayor Associate Editor

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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

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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

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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

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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

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Summary of Concepts

• Academics should participate in patenting and
  technology transfer to industry
• Work with OTT to secure patents
• Otherwise goods and services wont be created
• The University owns the Intellectual Property
  (IP)
• Disclose IP early to UW, dont 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 industrys 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

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Acknowledgements

• 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
  2771238
• Richard Deyo, Bruce Psaty, Gregory Simon, Edward
  Wagner, and Gilbert Omenn. 1997 The messenger
  under attack Intimidation of researchers by
  special interests groups NEJM 3361176