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Conflicts of Interest in Research

Conflicts of Interest in Research






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    Conflicts of Interest in Research Conflicts of Interest in Research Presentation Transcript

    • Financial Conflict of Interest in Academic Research Leonard A. Zwelling, M.D., M.B.A. Vice President for Research Administration The University of Texas M. D. Anderson Cancer Center
    • Conflict of Interest - Example
      • Professor learns of novel prevention strategy
      • Conducts single arm study on 20 subjects
      • Potentially lethal disease prevented in all 20
      • Professor wishes to charge fee for others to use strategy
    • Conflict of Interest - Example
      • 1799
      • Benjamin Waterhouse
      • Harvard Medical School
      • Preventable disease - Smallpox
      • Read Jenner’s work
      • From Martin and Kasper
      • NEJM 343: 1646, 2000
    • First, A Key Definition
    • Fiduciary Of or relating to a confidence or trust. Power to be used to the benefit of another, based on specialized knowledge or expertise.
    • Conflict of Interest “ A set of conditions in which professional judgment concerning a primary interest (such as a patient’s welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as financial gain).” Quoted in Bekelman et al, JAMA 289:454, 2003 From Thompsen, D, NEJM 329:573, 1993
    • Science in the Private Interest (Has the lure of profits corrupted Biomedical Research?) By Sheldon Krimsky 2003
    • 3 Stages of Conflict of Interest (after Andrew Stark in “Conflict of Interest in Public Life” as quoted in Krimsky, p. 126
      • Antecedent Acts - factors conditioning the state of mind (gifts, equity, consultancies) LEADS TO
      • States of Mind – sentiments, proclivities or affinities affected (favoritism, bias) LEADS TO
      • Outcome behavior (decisions, behaviors)
      • Rules aimed at stage 3 would only find someone guilty if behavior could be linked to antecedent acts and states of mind.
      • Thus, stage 1 is the target of policies, regulations, or laws.
    • Why Now?
    • Environmental Factors in the Debate
      • Decreasing revenues to academic medical centers
      • - Managed care
      • - Payor mix
      • - Decreased Medicare reimbursement
      • - Uninsured
      • Bayh-Dole Act of 1980
      • - The rise of technology transfer
      • Everybody’s got a company
      • Demand for science that benefits man (and woman) rather than mankind
      • Greed - personal, institutional
    • Some Parts of the Problem
      • 1999 - $17.8B in NIH funding - mostly basic research
      • 1999 - Top 10 pharmaceutical companies - $22.7B - mostly clinical research
      • Half advisers to FDA have financial interests in companies whose interests rest on FDA decisions
    • The True Cost of New Drugs
      • Amount usually quoted - $800M
      • Activities included under R & D are unknown
      • 2000 – industry claims $26B on R & D and 98 new drugs = $265M each (after tax cost $175M; R & D tax deductible at 34% corporate tax rate)
      • Actual cost probably closer to $100M per drug
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • AZT – An Example
      • What Burroughs Wellcome did not do:
      • Test whether AZT could suppress the AIDS virus in human cells
      • Determine the effective concentration of AZT in humans
      • Administer AZT to a human with AIDS
      • Perform immunological or virological studies to determine the drug’s effectiveness
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
      • “ The longest, most difficult part of R & D is the front end - the research part – where basic discoveries are made that identify how and where a disease or condition can be successfully attacked by a new pharmacological agent. Big drug companies usually contribute very little to that effort.”
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • 2002 – Expenses and Profits
      • Top 10 U.S. drug companies – sales = $217B
      • R & D cost = $31B
      • Profit margin = $36B
      • Marketing and administration = $67B
      • 675 lobbyists in Washington - $91M
      • Would lower prices really affect R & D expenses or marketing?
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • What’s So New About New Drugs
      • 2002 – 17 of 78 approved were actually new molecular entities (NME)
      • 1998 – 2002 - 415 approved; 133 NME
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • Whose R & D Really Supports the IND
      • 1998 - Only 15% of articles cited in patent applications were from industry; 54% from academic centers; 13% from government
      • 1995 - 16 of 17 key papers supporting commercialization of 5 top selling drugs from outside industry (Zantac, Zovirax, Capoten, Vasotec, and Prozac)
      • 1965 – 1992 - 21 most effective drugs – 15 supported by public research
      • 1992 – 1997 - 45 of 50 best selling drugs supported by government funding
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • Central Argument of Krimsky’s “Science in the Private Interest”
      • Public policies and legal decisions have created new incentives for universities, their faculty, and publicly supported nonprofit research institutes to commercialize scientific and medical research and to develop partnerships with for-profit companies.
      • The new academic-industry and non-profit-for profit liaisons have led to changes in the ethical norms of scientific and medical researchers.
      • Secrecy has replaced openness.
      • Privatization of knowledge has replaced communitarian values.
    • Central Argument of Krimsky’s “Science in the Private Interest” cont.
      • Commodification of discovery has replaced the idea that university-generated knowledge is a free good.
      • The rapid growth of entrepreneurship in universities has resulted in an unprecedented rise in conflicts of interest (COI).
      • COI among scientists has been linked to research bias…the loss of disinterestedness
      • Fewer opportunities will exist in academia for public interest science – a loss to society.
    • “ Scientists who 10 years ago would have snubbed their academic noses at industrial money now eagerly seek it out…The present concentration of industrial interest in academic science is generating no small measure of concern about whether the academy is selling its soul.” Science, 1982 From Krimsky, p. 79
    • Science or Money - Why Choose? “ I’m not comfortable with scientists owning substantial equity in small firms that are sponsoring their clinical research. I think it creates a conflict of interest, and the conflict is particularly difficult to justify in cases where patients’ welfare may be affected.” Dr. David Blumenthal, Director Institute for Health Policy Massachusetts General Hospital “ I don’t know how many millions I’ve made. The motivation was not primarily money.” Dr. William Haseltine, Chief Executive Human Gerome Sciences
    • Are We Truly Managing Conflict or Kidding Ourselves? “ I had two young daughters and not a lot of money, a retirement in my future and I had sense enough to know what I had discovered was important.” Dr. H. Kirk Hammond, Founder Collateral Therapeutics NYT, 2/20/00
    • “ It’s theoretical money; I can’t do anything with it because I’m an insider. The university would love me to sell all of it. They think that makes me less contaminated in some way. I think that’s nonsense.” Dr. H. Kirk Hammond, Cardiologist University of California, San Diego NYT, 2/20/00
    • “ The erosion of the public’s faith in the reliability of scientific findings may, in fact, be one of the greatest harms resulting from the strengthening of ties between industry and academia.” Peter J. Harrington J. of College and University Law 27:775, 2001
    • “ University science becomes entangled with entrepreneurship; knowledge is pursued for its monetary value; and expertise with a point of view can be purchased.” Sheldon Krimsky “ Science in the Private Interest” p.1
    • Entrepreneur - “ a person who organizes and manages any enterprise, especially a business, usually with considerable initiative and risk” -Random House Dictionary “ Even in cases where taxpayers have funded years of research, scientists can turn a discovery built on such research into a profitable drug. Many people, whose taxes funded the research and who are in dire need of the drug, now cannot afford it.” “ The irony cannot be avoided. Capitalism is supposed to operate on the principle that private risk yields private loss or private wealth. Philanthropy turns private wealth into social resources. But the idea that public risk should be turned into private wealth is a perversion of the capitalistic ethic.” From Krimsky, p. 181 Is This Really Entrepreneurship?
    • Even the New England Journal of Medicine Broke Its Own Rules WSJ, 5/18/00 WSJ, 2/24/00
    • New England Journal of Medicine New Policy - June 13, 2002
      • No author of a review article or editorial can have any significant financial interest ($10,000) in a company (or its competitor) that makes a product discussed in the article
      • Disclosure for all original and special articles (in place since 1996)
    • Dr. Marcia Angell Speaks “ Is Academic Medicine for Sale?” (NEJM - May 18,2000) Financial ties of articles’ author so great, they cannot be summarized in print. (placed on NEJM web site)
    • What Are the Financial Ties?
      • Research support - grant/contracts
      • Consultants
      • Advisory Boards
      • Speakers Bureaus
      • Royalties, licenses
      • Ghostwriting
      • Promotion at sponsored symposia
      • Gifts, trips
      • Equity, options
      • From Angel, M.
      • NEJM - 5/18/2000
    • “ Is Academic Medicine for Sale?”
      • Difficult to find editorialists without financial ties to companies where products are the subject of the editorial
      • Faculty are demanding loosening of conflict of interest policies so that members may make more money
      • Institutions, as well as faculty, are also financially tied to sponsors of research within the institution
      • Trainees are given gifts and meals by corporate sponsors
      • Two reasons given: technology transfer (Bayh-Dole Act), and money (decreased Medicare reimbursement from 1997 BBA and effects of managed care)
      • Problems with these “excuses”:
        • - In clinical research technology transfer has already occurred
        • - Equity, consultantships and world-wide trips for faculty help neither patient nor really assist scientific discovery
        • - How can research not be biased? Results and the choice of projects can be influenced
        • - Commitments to companies detract from commitment to academic institutions
      Is Academic Medicine for Sale? (cont.)
    • Industry Sponsors Can Legally Suppress the Publication of Research Supported by Them The literature is dominated by research reports of positive studies. Is this why? NYT NYT
    • A Problem List - The Conflicts Inherent in the Industry - Academic Partnership Surveys of the medical literature indicate that positive reports are more likely when the research is industry sponsored Bodenheimer, NEJM; May 18, 2000
    • What Industry Sponsors do to Influence Study Outcomes
      • Opt not to do a post-approval study the results of which could negatively impact drug sales
      • Study designs may favor the sponsor’s product - use of younger population than is targeted by the drug; dose of competitor’s comparison drug is too low
      • Use of surrogate end-points that may not correlate with meaningful clinical results
      (from Bodenheimer, NEJM; May 18, 2000)
      • Sponsor controls data - participants do not get to examine all results
      • Sponsors may control publication including order of authorship and whether results get published at all
      • Publications are “ghost-written” by company authors
      What Industry Sponsors do to Influence Study Outcomes (cont.)
    • Help From the Federal Government? Not Really
    • Federal Rules - Granting Agencies
      • Public Health Service - 1995
      • Must have conflict of interest policy
      • Disclosure of “significant financial interest”* to “appropriately designated university official (*Anything of monetary value usually >$10,000 or >5% ownership)
      • Disclosures reviewed by official
      • Establish “enforcement mechanisms and provide sanctions where appropriate”
      • Conflict of interest exists when designated official reasonably determines significant financial interest could directly and significantly affect the design, conduct or reporting of PHS-funded research
      • No mandated disclosure to human subjects
      • Nothing is strictly prohibited
      • National Science Foundation - Like PHS
      • Department of Defense
      • Ethics training program
      • Establish hotline
      • Must disclose:
      • Compensation tied to favorable outcome
      • Compensation tied to product sales
      • Equity interests where value unascertainable through referring to public prices
      • Equity interest in public company >$50,000
      • Proprietary interests in tested product - patent, trademark, copyright, license
      • Net payments from sponsor of >$25,000
      • Occurs after data collected
      Federal Rules - FDA
      • “ Doubt faculty member can devote time and energy to the university and a company”
      • Conflict in norms governing dissemination of knowledge. Two separate research programs; results of one widely disseminated, the results of other kept secret.
      • Risk of putting students and associates in ambiguous situations
      A. Bartlett Giamatti, President, Yale University (Science, 1982)
    • Conflict of Interest in Clinical Research A Unique Subset
    • “ Gifts, hospitality, or subsidies offered to physicians by the pharmaceutical industry ought not to be accepted if acceptance might influence or appear to others to influence the objectivity of clinical judgment. The useful criterion in determining acceptable activities and relationships is: Would you be willing to have these arrangements generally known?” From American College of Physicians Ann. Int. Med. 112: 624, 1990 as quoted by Hutchison and Halperin in Int. J. Rad Oncol. Biol. Phys. 54: 989, 2002
      • Discourage all gifts
      • - consider opinion of patients, public, media, colleagues
      • - consider gift’s purpose
      • Disclose all financial relationships
      • - ownership of patient care entity unwise
      • - speeches and writing in own words only
      • - make sure “post-marketing” studies are studies, not just marketing
      • Make sure CME is not marketing
      • Medical societies receiving industry support must be independent
      Annals of Internal Medicine, March 5, 2002 2 Part Paper on Physician - Industry Relations
      • The difference between practice and research - informed consent is not a professional treatment recommendation
      • “ The result of conflict of interest and bad research is that public confidence and trust in the entire research enterprise vanishes.”
      • Abolitionist position - eliminate conflicts
      • Absent political will to abolish, must manage
      Important Conflict of Interest Points From Goldner - J. Law, Medicine and Ethics 28:379, 2000
      • Inadequate disclosure of risk
      • Exaggeration of benefits
      • Enrolling ineligible subjects
      • Failure to report AEs
      • Data manipulation
      • Failure to suspend or terminate a trial
      • From Barnes and Florenico
      • J. Law, Medicine, and Ethics, 30:390, 2002
      How Conflict of Interest Could Influence Oversight of Human Subjects Research
      • 36% of IRB members had relationship with industry (research funding, compensation, speaker, royalties, equity, board)
      • 15% (78) reviewed protocols sponsored by a company with which they had a relationship or was a competitor of the company
      • The relationship was disclosed sometimes (58% of the 78 always did)
      • Campbell et al; NEJM 355:2321, 2006
      Conflicts of Interest and Institutional Review Boards
      • 64% of doctors (N=394) found it acceptable to be paid a fee to enter patients on a post-marketing study
      • 56% of patients (N=200Z) did
      • 75% of doctors, but 86% of patients thought patients should be informed if doctor received fee
      • Most doctors (67%) and patients (69%) thought doctors would be influenced by the fee
      • La Puma et al., BMJ 310:1660,1995
      Conflicts of Interest Post Marketing Research
      • 20,205 patients with coronary artery disease, breast cancer, or depression got e-mail
      • 6,363 screened; 5,478 completed survey
      • Majority thought knowing about COI important and should be disclosed
      • Some would not participate if COI present
      • Breast cancer patients more willing to participate
      • Kim et al., J. Med. Ethics 30:73,2004
      Potential Participants’ Views on COI in Clinical Research
      • >90% of patients unconcerned
      • Most would enroll despite COI
      • >80% thought payments ethical
      • 40% wanted disclosure of COI
      • Hampson et al., NEJM 355:2330,2006
      Conflicts of Interest in Cancer Clinical Trials
    • The Death of Jesse Gelsinger The ‘Near Death” of Gene Therapy How one death started an avalanche of investigating, finger-pointing and ill will WSJ, 2/1/00 NYT, 1/21/00 WSJ, 1/24/00
    • The NIH Failed to Adequately Oversee Gene Therapy Trials
      • Of 691 serious adverse events experienced by patients only 39 had appropriately been reported
      • 652 were submitted following Mr. Gelsinger’s death
      The New York Times, 2/2/00 The Wall Street Journal
    • Gelsinger Case - Conflict of Interest Issues
      • Genetic deficiency, but well controlled on drugs and diet
      • Liver function not adequate for protocol
      • FDA had not received AEs - monkey or human
      • Toxicities not in consent document
      • Director of Institute for Human Gene Therapy owned stock in sponsor
      • Director and Dean had patents
      • University received money for rights and had equity
      • Law suit settled
      • From Goldner in J. Law, Medicine and Ethics
      • 28: 379, 2000
    • Conflict of Interest After FDA Review Wall Street Journal 9/23/02
    • Drug Companies and the FDA
      • 1992 - Prescription Drug User Fee Act
      • To expedite drug approval, not safety review
      • $576,000 per NDA
      • 13 drugs withdrawn from market
      • 92% of FDA hearing meetings had at least one member with a financial conflict of interest; 55% of meetings with more than half advisors in conflict
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • Conflict of Interest Among Authors of Clinical Guidelines New York Times 2/6/02
    • Conflict of Interest - CME Wall Street Journal - 1/14/03
      • Industry funds 60% of CME, $729M in 2001
      • Accreditation Council for CME proposal:
      • - organizing committees disclose conflicts
      • - could be cause for disqualification to serve
      • - speakers disclose prior to meeting
      • - speakers from company bureaus disqualified
      • from making interpretations/recommendations
      • - no educational materials during sales calls
      • - companies with educational subsidiaries cannot
      • give courses in areas in which they have
      • products
    • Marketing Disguised as Education
      • Professional meetings
      • The Patient Channel - with drug ads
      • Sponsoring patient advocacy groups
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • Conflict of Interest - Industry Gifts Houston Chronicle 11/03/02
      • $19.1B for marketing
      • $10.5B for free drug samples
      • Sales force = 81,532; up from 34,847 in 1993
      • “ Patients get better because they believe in us. They believe in our honesty because they believe we have their best interests at heart.”
      • “ And so anything that harms that perception, whether it’s real or just perception, is ultimately harmful to the therapeutic process.”
      • Dr. Jeffrey Starke
      • Chief of Pediatrics
      • Ben Taub General Hospital
    • The Cost of Marketing
      • 2001 - $11B in “free samples”
      • 88,000 sales reps
      • 35% of revenues spent on marketing
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • Institutional Conflict of Interest
      • Why control:
      • Inappropriate decision-making by institutional decision-makers or IRB members
      • Institutional conflict of interest can be transferred to others in institution
      • Cause preferential treatment or resource allocation
      • “ While entrepreneurship in academia has accelerated scientific innovation, on occasion it has also marred academia’s reputation as independent truth-seeker, reduced public trust in the research enterprise, and resulted in a burgeoning literature on conflicts of interest.”
      • From John et el. JAMA 289: 741, 2003
    • The University of Florida Case Institutional Conflict of Interest
      • Researcher patented drug delivery system
      • Licensing company gave $1M to University of Florida
      • Inventor named Vice President of start-up
      • Other faculty hired and given stock
      • Different faculty found invention was toxic
      • This information blocked by faculty-owners
      • Once data public, faculty member got negative review; small salary increase
      • No one would investigate
    • Collaborating With Industry - Choices for the Academic Medical Center (AMC) (Mars et al, NEJM 347: 1371, 2002) 1. Should commercial ties be encouraged? 2. Should industry ties be managed within the AMC? -Free standing institutes? -Alliances / foundations? 3. Should faculty be identified with companies? -Part-time appointment? Leave of absence? -Must separate academic from company roles 4. Should restrictions on clinical research and basic research be treated differently? -Definitions needed 5. Should devices be treated as a special case? -Should be like drugs -Exceptions need supervision and independent assessment of outcomes 6. How is the proper balance between commercially sponsored research and government or foundation research to be achieved? -Judge all research by same criteria 7. How should institutional conflicts of interest be managed? -Manage by separate entity
    • A Hospital’s Worst Nightmare Conflict of Interest in Patient Care New York Times – August 12, 2003 Dr. Moon Dr. Realyvasquez
    • Issues
      • Redding Medical Center – Redding, CA
      • Internist suspected leading physicians were recommending and doing unnecessary surgery.
      • When he alerted administration, the CEO told him to “mind his own business”.
      • Tenet Healthcare, hospital’s owner, agreed to pay government $54M, but admitted no wrongdoing.
    • How This Could Happen
      • Business model based on increased Medicare billing
      • Tenet increased retail rate upon which Medicare “outlier” rates are based
      • Dr. Moon’s jobs:
      • - Chief of Cardiology
      • - Hospital Director
      • - Head of Cardiology Care Committee (peer review of quality - rarely met)
      • - Not boarded in internal medicine or cardiology
      • He billed for 876 cardiac catheterizations in year ending 6/30/02 (4 times more than any colleagues in Northern California)
      • Billed more than $4M in that year
      • Nurses were dictating his charts
      • Large marketing campaign based on cardiology care
      • Multiple examples of unnecessary surgery
      • Federal agents raided the hospital
    • Bottom Line
      • Health care is a commodity
      • Science available to one hospital is available to all
      • Hospital companies cannot sustain double digit growth
      • “ The hospital industry is, by its very nature, a mature industry. It is not a high-margin business. It can’t be a growth industry like some internet company. That is just unreasonable.”
      • Uwe Reinhardt
      • Princeton University
      • Separate the producers of knowledge and those with a financial interest in the knowledge
      • Separate clinical investigators from those with a financial interest in the drug being tested
      • Separate those assessing the safety and efficacy of products from those with a financial interest in the product
      • - The courts don’t run the prisons
      • Physicians shouldn’t earn income for each pill swallowed or each subject registered on a clinical trial
      • Members of Congress do not sit on boards of corporations
      • University scientists should not be corporate CEOs of for- profit companies
      Krimsky’s 3 Principles for Re-establishing the University’s Traditional Role
    • Dr. Angell’s Suggestions
      • Shift emphasis from “me too” - all new drugs must be compared with current, available ones. Minimize placebo-control trials.
      • Strengthen the FDA – no users’ fees. Increase public support including safety monitoring. Eliminate conflicts of interest on FDA panels.
      • New institution to oversee drug testing - within NIH
      • Curb monopoly marketing rights – patents don’t start until drug comes to market. No 6 month extension for pediatric trials. Close loopholes that extend exclusivity.
      • Get drug companies out of medical education
      • Open the industry’s books
      • Reasonable and uniform pricing
      • From Marcia Angell, M.D. “The Truth About the Drug Companies”
    • Health Industry Practices That Create Conflicts of Interest: A Policy Proposal for Academic Medical Centers
      • Brennan et al , JAMA 295:429, 2006
      • Prohibit all gifts
      • Prohibit all free drug samples. Substitute with voucher system for low-income patients.
      • Physicians on formulary committees may receive no gifts, grants, contracts, or stock from a drug company.
      • No direct or indirect CME support from drug companies
      • No direct travel grants from drug companies
      • No faculty on drug company speakers’ bureaus
      • All funds from drug companies must be for specific work and accompanied by a contract. “No strings” gifts are prohibited to individuals. Any such grants or contracts should be posted on an internet site.
      • No “ghostwritten” articles allowed
    • “ Because gifts of even minimal value carry influence and because disclosure is an inadequate safeguard, the guidance presently provided by the medical profession, the pharmaceutical industry, and the federal government fails to protect the best interests of patients and the integrity of physician decision making.” Brennan et al ., JAMA 295:429, 2006
    • “ Without these policies and procedures, the academic institutions where most clinical research is based and their faculty members who perform the research are in grave danger of losing the support and respect of the public. Without this support and respect, trust in new medical discoveries and their applications will not be forthcoming. Without trust, medical research is doomed.” Catherine D. DeAngelis, M.D. Editor, JAMA in JAMA 284: 2237, 2000