Morals, Money, and Medical Citizenship Nancy Olivieri, MD, FRCPC, Professor, Pediatrics, Medicine and Public Health Sciences, University of Toronto, Canada

Morals, Money, and

Medical Citizenship

Nancy Olivieri, MD, FRCPC,Professor, Pediatrics, Medicine and Public

Health Sciences,

University of Toronto, Canada

“Riveting…a horror story on the involvement of corporations in university research”

Thompson J, Baird P, Downie J. The Olivieri Report: The complete text of the report of the independent committee of inquiry commissioned by the Canadian Association of University Teachers.

Toronto: James Lorimer & Co. Publishers, 2001.

Thompson J, Baird P, Downie J. The Olivieri Report

“[The Olivieri case] raised issues of research ethics and academic freedom so important to the public interest that it has attracted national and international attention”

“Unless the lessons are learned and changes made, there will be repetitions”

The outline of this story• Identification of potential risks in a clinical

trial of children• The backlash: administrative, legal,

regulatory, scientific, professional, personal• A nasty, destructive, no-one-wins story• “Non- scientific” Issues arising:

• Conflicts of interest• Medical citizenship and loyalty• Academic “mobbing”• The costs of “doing the right thing”

What the story is really about

• An erosion of scientific integrity• Obfuscation of medical evidence• A failure to protect patients• Repeatedly triumphant conflicts-of-interests• A lost war on undeserved privilege• No bending of arc toward justice• Personal devastation, and professional ruin

Constraints on discussion

Apotex v Olivieri, December 2008caut.ca

search “Olivieri”

Where I was 1996

• Clinician and researcher at HSC (1986- )• Research funded through MRC• Completing 2nd term (1986-1996) as Career

Scientist, Ontario MOH• Director, Clinical/Research Hemoglobin program• Involved in international thalassemia work• May 1996

• Elected to ASCI• Obtained MRC Scientist Award (1996-2001)• Promoted to Professor, Pediatrics & Medicine

Three trials of an iron chelator

• Long-term open-label trial 1989-

• PI Olivieri [Koren “pharmacokinetic studies”)

• RCT, deferiprone vs deferoxamine 1993-• PI Olivieri [Koren “pharmacokinetic studies”)

• European “toxicity” trial• Scientific Chairs Olivieri & Brittenham (CWRU)

First potential risk identified in 1st (long-term) Toronto trial

• Potential lack of sustained efficacy: evidence from increasing/static [iron] in liver biopsies

• “Apotex disputed the risk, and the need to inform patients” Thompson et al, 2001

• “Ax issued warnings of legal consequences to Dr. Olivieri should she inform patients or anyone else of the risk” Thompson et al, 2001

• HSC REB Chair decreed revised consent forms• May 20, 1996: revised forms sent to company• May 24, 1996: termination of both trials:

Immediate outcomes

• Premature termination of trials • “All legal remedies” in writing and letters• Overnight removal of drug from pharmacy• Successful recruitment of “experts”, “expert

panels”, and “key” experts to “dispute” findings• Discreditation begins : ‘The picture painted …

was of a scientist of almost breathtaking incompetence’

• Successful engagement of patient organizations

Continuing drug administration

• Abrupt termination left some patients unwilling to return to standard treatment

• “Apotex refused to re-instate the trials” » Thompson et al, 2001

• EDR : drug provided to informed patients• Such patients were no longer in a trial*• Dean decreed “very substantial research

funding to Dr. Koren [continued]”» Thompson et al, 2001

How could clinical trials be terminated?

• “…no contractual basis for legal warnings” [legal distinction not appreciated]

• “Each of the two contracts specified … the right to terminate the corresponding trial at any time”

• MRC: – no prohibition of confidentiality – Any industrial sponsor could unilaterally terminate a (MRC co-

sponsored) trial– No (MRC) requirement to ensure patients not adversely affected

The [Olivieri/Koren/Apotex] “contract”

• The University claimed widely (including in 12-point statement for Naimark) that Dr. Olivieri the author of her own misfortune by signing “the contract”

• University did not discuss Koren signature/ REB study approval/obtain legal opinion

• University’s Logic[?]: once the contract signed, it should have been honoured

Was this contract enforceable under common law?

• “A physician is under a legal duty to disclose material or significant risks; failure may well amount to the tort of negligence”

• “Any term in a contract that prohibits disclosure that would amount to the commission of a tort is, to the extent that it does so, illegal and void”

» DA Soberman, Professor of Law Emeritus, Queen’s University

Was this contract enforceable under common law?

• “The patient must be given the opportunity to decide whether to continue with treatment. The researcher does not have to establish the complete accuracy of her concern -- a risk is a risk, not a certainty -- but only that it was not an unreasonable concern”

» DA Soberman, Professor of Law Emeritus, Queen’s University

A second risk identified in 1st trial

• Risk of progressive hepatic fibrosis • Associated potential safety implications• Followed by more legal warnings• Led to return of all patients to standard Rx• Only effective support was CMPA* “…not

always effective” Thompson et al, 2001

Two risks

• First risk, 1996: increase in hepatic iron concentration -> possible inadequate sustained effectiveness

• Second risk, 1997: accelerated progression

of hepatic fibrosis -> possible liver damage

Ongoing threats to disclosure

• Malta 1997 meeting ; new opportunity for disclosure

• “[An attempt] through legal warnings to suppress information” Thompson et al, 2001

• Our data taken and “re-interpreted” without knowledge

• Led to first substantive aggressive action by University: “Freidland committee”

A first “investigation”: The “Friedland Committee”

• “Friedland Committee” evaluated complaint about data published without knowledge, attribution, or citation

• Friedland: – “….no misconduct or serious scientific error was

committed …” – “Dr. Olivieri used poor judgment in bringing these

very serious charges…”

“Some of the findings of the Friedland Committee are difficult to understand.”

Thompson et al, 2001

“The [F] Committee reached the conclusion that ‘the authors committed no serious scientific error’ without … appropriate investigation”


• “HSC and the University did not provide effective support to Dr. Olivieri during the first two and a half years of the controversy”

• “After the controversy became public, the University claimed that it had provided support, but this was not true.”


Subsequent actions by administration

The Response of the Academic Institutions: Sick Kids and The University of Toronto

• June 1996: Dean of Medicine:“It’s OK for company to stop the studies; it is paying. Don’t you think this will just blow over?”

• July 1996: Chairman of Pediatrics:“Not a matter in which the Hospital wishes to involve itself … this is a scientific controversy.”

• 1996 and 1997: Written legal threats copied to all

The academic institutions“did not provide effective support”

• Research– Accusations of sloppiness, incompetence, research

misconduct– HSC Executive: public circulation of allegations made

by company against the quality of work– Pressure to provide clinical data to company– Harassment, marginalization of students and fellows:

evicted; emails, pagers, phones cut– Delays in approval of research proposals– Removal of research space– Closure of lab

The institutions“did not provide effective support”

• Clinical – Clinic co-worker “replaced” by Chief’s “friend”– Private “interviews” with nurses, students and fellows– Patient encouraged to sue [HSC eventually pays]– “Citizenship” graded as “0.5”: annual bonuses refused – Successive “removals” from Directorship: ‘96, ‘98, ‘99– Erosion of resources for SCD patients– Attempt to move office away to vacant, Q-fever-infected

wing -- > Evacuation to lower floor -> Evacuation to TGH

The academic institutions“did not provide effective support”

• Personal– Whisper campaign: medical errors, stealing money

from grants, misconduct, promiscuity– Shunned at work by “friends” & co-workers– Private emails published front page, Nat /Post– Documents about Olivieri circulated by HSC

lawyer to OHA “by mistake”– Twelve Clinical Chiefs “vote” to ‘remove’ Olivieri

after SCD program cuts made public

Repeated appeals

• Approached:• Eaton Professor of Medicine Philipson• Director, Research HSC, Buchwald• Dean of Medicine, Aberman• University Vice-President (Research), Munroe-

Blum • Provost, Sedra• CAUT• UTFA

Donation discussions

Donation discussions

• “[This] controversy was linked to a much larger university-industry project”

• “Since the early 1990s, the University … had been engaged in discussions for a multimillion-dollar donation toward a new research centre”


Donation discussions• In 1998 “agreement in principle reached

on … the largest donation University had ever received”, to be “matched to provide ≈$92 million”

• “After the controversy in media, donation discussions suspended, until matters ….resolved”


A “public” inquiry gone wrong

• HSC had no effective grievance procedure for staff (as of 2001, still no procedure in place)

• CEO rejects inquiry: “over my dead body”• CEO appoints Dr. Arnold Naimark• “[As president of U of M] Naimark had

successfully lobbied Apotex for … just under $1 million … and was on the CIBC Board chaired by a member of the Hospital’s Board.”


A “public” inquiry gone wrong

• Public outrage expressed, but• “Instead of recusing himself, Naimark

accepted … in final 10 days joined by two academics” [Lowy and Knoppers]

• Naimark paid $150K for 10 weeks work

Assisting Naimark:Chairman of Peds Hugh O’Brodovich (“HOB”)

• HOB “put forward incorrect allegations and testimony, to Naimark” …“used information from and with Dr. Koren” …“was seriously neglectful in not checking validity of testimony”


Assisting Naimark: REB chair Dr Aideen Moore

• Dr Moore [REB Chair appointed shortly after trials terminated] “put forward incorrect testimony … [although] correct information was available to her….[Moore’s] information cited by

Koren to bolster referrals to MAC and CPSO”


Assisting Naimark:Dr Gideon Koren

• Koren, one of “primary submitters …” • “forwarded allegations and testimony which he

knew to be incorrect … cited ‘information’ he knew was mistaken”

• “Koren’s false allegations and testimony were believed” Thompson et al, 2001

• Led to referral to Medical Advisory Committee• Used to defend drug in legal proceedings

Naimarked: The Shadow of an “Independent” Inquiry

• Olivieri entirely blameworthy, Hospital entirely innocent• Empowerment of mobbers• Imposition of “gag orders”• Imposition of punitive financial and academic actions• Another firing (#3)• Libel in international press• False accusations provided in Naimark led to

• Allegations of research misconduct: to University’s highest investigative Committee

• Allegations of medical misconduct: to licensing authority (CPSO)

What Naimark et al “found”

• After risks identified in data from liver biopsy, biopsy alleged to be unnecessary, risky, and obtained only for research purposes (“after similar criticisms of procedure by company” Thompson et al, 2001)

• “Concerns” that Dr. O had not notified REB, patients*

• Arising from Koren /HOB/ Moore/* / testimony• All false• Olivieri referred to MAC then CPSO

Proceeding from Naimark

• Allegations & testimony {“concerns”} made in secret • After spirited legal defense hired (and paid for) by

Olivieri, most of the false testimony disclosed• HSC abruptly announced [press conference] referral

to CPSO - two weeks after compelled to acknowledge Koren’s misconduct

• For 18 months, HSC posted unfounded Olivieri accusations on a university-hospital web site

• Dean Naylor referred Koren’s accusations of research misconduct v Olivieri to Univ committee

“The key organizational strategy is to transform

[resistance] from an issue of policy and principle, into one of

private disobedience and psychological disturbance”

CF Alford. Whistleblowers: Broken lives and organizational power. 2001 Cornell University Press

“This ain't the shop for justice.”Dickens

In the midst of Naimark,a series of anonymous letters….

• Seven months of harassing hate mail received by media and MDs at HSC

• A public inquiry for hate letters stalled “by lying”

• Finally author identified … by DNA on a licked stamp!

More familiar responses• HSC Chairman Aird: “unwanted letters” • U of T & HSC President & CEO: “mitigating

factors” “research accomplishments;” “recent MRC Scientist Award”; “outpouring of sympathy”

• Acquitted by CPSO• On appeal to CPSO citizens’ panel, ruled guilty• Suspended for five months: two without pay

Response to Koren hate mail

• “Humphrey” hate mail investigation characterized by lying, blaming “secretaries”, institutional defensiveness

• Humphrey claimed x 7 months to be “stalled”; but “declined to accept” DNA evidence

• Humphrey recommended “mediation” with Koren as his targets bore responsibility for a “web of conflict in which Koren had become enmeshed”

“No dismissal for hate mail author” Nat Med June 2000

“I came to realize that, by comparison with reality, my story was as tame as a holiday postcard.”

John Le Carre

{Final CPSO decision on Koren issued by board of citizens on appeal}

• “It defies belief that an individual of professed integrity could author such vicious [childish, vindictive, and dishonest] diatribes”

• “…only when confronted with irrefutable scientific evidence of guilt, did Koren admit as perpetrator”

• “Though claimed ‘extreme remorse’ …we are constrained to point out that Dr. Koren’s statement was silent on this issue”

Doctors for Research Integrity: April 22, 2002 :“HATE MAIL DOCTOR ESCAPES PENALTY FOR

LATEST RESEARCH MISCONDUCT”

• Koren revealed guilty of research misconduct in studies published w/o knowledge of colleagues

• Announced penalty:

• withdrawal of offending article (*) • made to “apologize”• no discipline

• Koren's proven misconduct “confided” by Dean Naylor to Faculty Council

Koren rehab program

• Awarded prizes by CDN Pharma societies, all widely trumpeted in CMAJ

• Awarded The Richard Ivey Foundation Chair at University of Western Ontario

• The “Local Hero of the Week”, Star• The “hero of Shuchman’s book”

Yet more donation discussions…

• In 1999, company asked President Prichard to lobby Government against proposed changes to patent regulations that were adverse to company’s revenues

• Prichard wrote to PM Chretien, claiming that the proposed patent regulations “could jeopardize” funding of U of T’s building

End* of donation discussions

• President P apologizes: “inappropriately” • Lobbying against regulations unsuccessful• 1999: company withdraws from agreement

‘donation-on-principle’ • Smaller donation

“Some were led to speculate that the University’s failure to recognise and support Olivieri’s academic freedom might not have

been unconnected to its eagerness to secure financial support for the university’s proposed

molecular medicine building project.”

A Schafer. Biomedical conflicts of interest: a defence of the sequestration thesis: learning from the cases of Nancy Olivieri and David Healy

J Med Ethics 2004;30:8-24. doi: 10.1136/jme.2003.005702

Naimark’s last stand

• October 26, 2001: The Olivieri Report

• December 18, 2001: Naimark/Lowy/Knoppers

release new, false public accusations in their:

“commentary on Report of the CAUT Committee”

• December 19, 2001: CPSO’s complete acquittal:

“[O]judgement not only reasonable: commendable”

• January 2002: HSC “decides” not to appeal acquittal;

Dean “decides” to drop “charges” of “misconduct”

“Five years after Apotex terminated the Toronto trials

and issued its first legal warnings …

the controversy continues, widened and intensified”


• Olivieri et al lodge grievances, multiple lawsuits, against University and Hospital

• HSC initiates action to quash summonses for documents in grievance. They lose.

• November 2002: Mediated settlement with Hospital and University

• L: Nader

Pushback after acquittals:

Legal threats, claims and counterclaims arising from the controversy

• (Threats) company vs Dr Olivieri, 1996-1999 • Gideon Koren vs Dr Brenda Gallie• The Hospital for Sick Children vs Olivieri • The Hospital for Sick Children vs Olivieri • Deans Aberman, Naylor vs Arthur Schafer, D4R• Olivieri vs Ax• Ax vs Olivieri = countersuits• Ax vs CBS (60 minutes) – dropped• Olivieri et al vs The Hospital for Sick Children• Olivieri v Aird @ The Hospital for Sick Children• Olivieri et al vs University of Toronto• Olivieri v WmCarter, Borden Ladner [HSC lawyer]• Olivieri v National Post • Olivieri v CBC• Olivieri v Stuart MacLeod (Koren mentor)• Olivieri v Random House Canada, Shuchman• Ax v Olivieri (2008)

• Olivieri vs The Commission of the European Communities, European Agency for the Evaluation of Medicinal Products and Apotex Europe

Where I am now

• 1996-2013: international research (Sri Lanka, Bangladesh, India)

• 2001-2012: Research outside of Asia [NIH]• 2001: Sabbatical, MA Medical Ethics and Law• 2003: Executive Director, Hemoglobal® • 2006: Settlement with HSC; now at TGH• 2009: UNI440 “Health and Pharmaceuticals”

2009-2013“Corporate UHN thinks you’re trouble”

• Painful professional existence• Groundswell of support at UHN retired• TGH Admin refuse clinical care, impede

research program, suggest resignation• Hematologist “donates” $1M, hires MD• Aggressive campaign against staff

Academic marginalization

“Pretty soon, you realize it’s not just the things you know you’re not getting that you’re not getting, you’re also not getting the things you don’t know you’re not getting”

» Healy D, in: review of The Drug Trial Monash Bioethics Review 2005; (24) 4

Who helped? Who didn’t?

• “Gang of Four”• One ethicist• UTFA• CAUT• Some colleagues,

citizens, patients

• Most “friends”, “colleagues”, “public intellectuals” and patients

• CMAJ• CBC• Anonymous sources

What I still hear

• “This is such a complicated story.”• “You did the right thing, the wrong way.”• “I did a lot behind the scenes.”• “I’m so glad everything turned out OK.”• “At least you appeared on 60 minutes.”

“We blew it, big.”

An unidentified administrator at the Hospital for Sick Children, 2005

The last years (2001-2013)

• Settlements• 2002: Olivieri et al, University & Hospital• 2004: Olivieri, CBC• 2004: Olivieri, company• 2006: Olivieri, Hospital for Sick Children• 2012: Olivieri Random

House/Shuchman

If you have God, the facts, the law, and the press on

your side, you have a 50:50 chance of defeating the

bureaucracy

Dr. David Kern: “When Medical Science meets an Amoral Administration”

• Founder and Director, Occupational Med, Brown

• Observed interstitial lung disease in workers at nearby industrial plant

• Published relationship between occupational exposure and disease

• Threatened with legal action by company

• Dismissed by Brown U

Dr. Aubrey Blumsohn, University of Sheffield“We are losing the battle over what it means to be an academic,

and the raison d’etre of a university.”

• P & G repeatedly refused to provide raw data to academic “collaborators” to verify “ghost written” publications

• Data provided (3 years later, following press exposure) showed “fair” analysis would not have yielded findings desired by the sponsor

• Intriguing attempts made to prevent problem from being raised or discussed (See: http://scientific-misconduct.blogspot.com)

Citizenship

• Noun: a legally recognized subject or national of a state or commonwealth …an inhabitant of a particular town or city

Medical Citizenship?

• Collegiality?• Leadership?• Professsionalism?• Resistance?

“Citizenship”

“A tough occupation, which obliges the citizen to make his own informed opinion and stand by it”

Martha Gellhorn

Medical Citizenship = Resistance?

• One who raises concerns in the face of unethical, unsafe practices in medicine

• One who is [truly] “loyal to the profession of medicine, and just and generous to its members”

“I represented the real organization. They said I was disloyal, but they’re the real traitors. They forgot who

we were working for.” Quoted in Alford 2001

Problem is, nobody likes a whistleblower

“They invite snide remarks about their competency and their twisted motives. One man or woman against the medical establishment … is a minnow waiting to be crushed, shamed, and thrashed out of the medical profession.

“We don't protect whistleblowers; we persecute them”

Kamran Abbasi. A way forward for whistleblowing. J R Soc Med. 2011; 104: 275

Whistleblowing in medicine

• Romanticized• Rarely supported• Most who attempt, become targets of

career-ending retaliation

Workplace Mobbing

• Leymann (1980s): “impassioned, collective

campaign to exclude, punish, and humiliate a

target” observed in “ostensibly rational”

workplaces

• Universities among most highly represented

• Shunning, gossip, ridicule, bureaucratic hassles,

withholding of deserved rewards

• Loaded, stigmatizing term

• Well recognized; illegal in Europe [Quebec 2004]

• Ken Westhues http

://arts.uwaterloo.ca/~kwesthue/mobbing.htm

http://arts.uwaterloo.ca/~kwesthue/mobbing.htm



An erosion of citizenship in medicine?

Is academic medicine for sale?M Angell, NEJM 2000;342:1516

No. The current owner is very happy with it.TJ Ruane, NEJM 2000;343:510

The Funding of Medical Research

Moses et al JAMA 2005; 294: 1333-42

“A person is in a conflict-of-interest situation if she is in a relationship with another in which she has a moral obligation to exercise her judgment in that other’s service

…and, at the same time, has an interest tending to interfere with the proper exercise of judgment in that relationship.”

A Schafer

Medical researchers today find themselves in a conflict-of-interest

Conclusions of industry-sponsored randomized trials favour industry drugs

“The privatization of profits and the socialization of losses”

Ralph Nader

• Research in publicly-funded institutions (=expertise, infrastructure) “partnered” by private industry (=profits)

• ‘Currency’ = publication • A premium on ‘new’, ‘positive’ results

What Medical Schools Accept in Clinical Trial Agreements with Industry

Asked whether the industry sponsor may:

Yes(%)

No(%)

Unsure

(%)

Decide whether results should not be published? 1 93 6

Make revisions to manuscript written by investigator? 6 89 6

Prohibit sharing raw data after trial over? 41 34 24

Write up results but investigator can “review and

make suggestions”?50 40 11

Own data? 80 16 5

Alter study design after agreement executed? 62 27 11

Mello et al. NEJM 2005;352:2202-10

Why should doctors act as citizens?

• The social /personal relationships once encountered eroded in one generation

• Shared backgrounds, interests, experiences are rare

• Manager CEOs are the new chiefs• Apprentice-trainee relationships

{“I trained with…”} have disappeared• There is no common country

Why should doctors act as citizens?

• Medicine is no longer “a calling”• No sanctions for ‘making it’ with industry;

rather, academic and personal rewards• Endowed chairs are named for industrial

giants, not admired physicians• Doctors compete for: academic kudos;

salaries; protected time; recognition• Clinical/research tensions and hierarchy

complicate collegiality

Reform?

Reform of academic research

• The research agenda is dictated by a corporate imperative

• Research results follow industry funding across all studies

• The “evidence base” of medicine has been distorted

Reform• Return to public funding (“The sequestration

package”, Schafer, 2004): tax corporations for profit from university research

• Establish individual and institutional policies to prevent entanglement with industry

• Scrutinize clinical trial agreements• Establish a public data base (Rxisk.org)• Improve internal complaint procedures• Provide financial support for litigation• Honor policies to preserve academic freedom,

freedom of speech and publication

CMA Policy Medical Professionalismhttp://policybase.cma.ca/dbtw-wpd/Policypdf/PD06-02.pdf

“The profession needs to meet [these] challenge[s] by demonstrating its ability to uphold its values and its commitment to doing so. Supporting strong and transparent self-regulatory systems will be a key component of this endeavour…”

http://policybase.cma.ca/dbtw-wpd/Policypdf/PD06-02.pdf

Can citizenship be promoted?

• “The world is a dangerous place, not because of those who do evil but because of those who look on and do nothing”

Albert Einstein

• “The hottest places in hell are reserved for those who, in times of moral crisis, maintain their neutrality”

Dante Aligheri

“There is no kingdom too small for a doctor to be king of”

John Green, Royal Society of Medicine

What might help

• Systemic solutions: Clinical trials registry; industry-academic contract reform; regulatory reform

• Protection from scientific suicide: standing committee to appoint those w/o CsOI to assess “controversial” data:

– scientists & statisticians from “both sides”– data anonymized– opinions signed – publish dissenting/minority opinions

• Sanctions for research misconduct• Democratize the debate: level the playing field! offer legal

fund for those attacked from within• Increase awareness: Education. Un-purchase ethicists.

Celebration of role models. Education!

Recommended

• Elliott, Carl 2010. White Coat, Black Hat. Adventures on the Dark Side of Medicine. Boston: Beacon Press.

• Healy, David 2012. Pharmageddon. University of California Press

• Abramson, John 2005. Overdosed America: The Broken Promise of American Medicine. New York: Harper.

• Angell, Marcia 2005. The Truth about the Drug Companies: How they Deceive us and what we can do about it. Random House Press

Recommended

• CF Alford, 2001. Whistleblowers: Broken lives and organizational power. Cornell University Press

• Westheus Ken 1999. Eliminating Professors: A Guide to the Dismissal Process.

• T Devine 1997. The Whistleblower’s Survival Guide: Courage without Martyrdom. Government Accountability Project: Washington

Recommended• Schafer, A. Biomedical conflicts of interest: a

defence of the sequestration thesis-learning from the cases of Nancy Olivieri and David Healy. J Med Ethics 2004; 30:8-24

• Blumsohn A. While Rome burns: collusion with pharmaceutical scientific fraud and the prognosis for dispassionate academic discourse. CAFAS 2006

• Young, T. 2009. Death By Prescription: A father takes on his daughter's killer. Key Porter Books