Transcript TDR Drug Target Selection Group

Data Sharing Between
Academia and Industry: Drug
Companies have a
Conscience Too
Wes Van Voorhis
Professor of Medicine
Adjunct Professor of Pathobiology and
Microbiology
[email protected]
Overview of Lecture
Could 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
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
Introduction to Issues in Industry
Interactions
•
Who owns federally-funded research
(intellectual property) performed at UW
a)
b)
c)
d)
e)
The researcher
The U.S. Government
The WA State Government
The University of Washington
Washington Research Foundation
Introduction to Issues in Industry
Interactions
•
Who owns federally-funded research
(intellectual property) performed at UW
d) The University of Washington
Introduction to Issues in Industry
Interactions
• Bayh-Dole Act of 1980
– Prior to 1980, U.S. Government owned
intellectual property (IP) from Federallysponsored 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
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 federallysponsored 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
Wes Van Voorhis MD, PhD
Case history: Help Pharma to “do the right
thing”
• Interested in drug
development for the
Developing World
– Malaria
– Trypanosomes
Crump: TDR/WHO
• African Sleeping
Sickness
• American
Trypanosomiasis
(Chagas’ Disease)
National
Geographic
Manning
UCI
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
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
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
Medicines for Malaria Venture Portfolio 4th Q 2006
Exploratory
PSAC
antagonists
Pf enoyl-ACP
reductase
Discovery
Lead
Identification
Lead
Optimization
Novel
Liver Stage
Antimalarials
OZ
Next
Generation
Immucillins
New
dicationic
molecules
(Fab I)
Cameroonian
Medicinal
Plants
TDR22093
Series
Novartis Institute for Tropical
Diseases Collaboration
Broad Institute of MIT/Harvard –
Genzyme Collaboration
Natural Products
Whole-Cell
HTS
Natural Products
as
New Prototypes
Preclinical
Phase I
Tablet, Pediatric and Intravenous RBx11160
Enantioselective
8-aminoquinoline
NPC1161
Isoquine
(an improved
aminoquinoline)
Falcipain
(cysteine
protease)
4(1H)pyridone
GW308678
Dihydrofolate
reductase
(DHFR)
Dihydroorotate
dehydrogenase
inhibitors
Phase II
OZ + PQP
RBx11160 + Piperaquine
4(1H)pyridones
Back ups
Novel
Macrolides
Development
Regulatory
Phase III
Chlorproguanil dapsone
(Lapdap™) artesunate (CDA)
Pediatric
Coartem™
Dihydroartemisininpiperaquine
DHA + PQP
Pyronaridine –
Artesunate
PYRAMAX™
17 Projects
6 New Projects to be added
3 mini-portfolios
Projects in the GSK/MMV mini-portfolio
Projects under contract negotiation
R. Rabinovich, B&M Gates FDN
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
Betty Dong, Pharm.D.
Case Study: Nightmare at publication time
UCSF faculty website
• 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
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
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
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
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
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…”
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
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
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 et al.
• Other preparations of levothyroxine are
“therapeutically inequivalent”
– Favors Boots’ marketshare
– Published in new journal, Am. J. Therapeutics
• Dr. Mayor: Associate Editor
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”
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
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
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
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
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
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
Acknowledgements
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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