michael schwarzschild, md phd · 2011/10/17 · professional life. the challenge for academic...

Responsible Conduct of Research (RCR) Series

Disclosure

Michael Schwarzschild reports having no financial conflict of interests or commercial relationship relevant to this presentation.

DisclosureDisclosure

Michael Schwarzschild reports having no financial conflict of Michael Schwarzschild reports having no financial conflict of interests or commercial relationship relevant to this presentatiinterests or commercial relationship relevant to this presentation. on.

Michael Schwarzschild, MD PhDMichael Schwarzschild, MD PhDNeurology Department, MGHNeurology Department, MGH

October 13, 2011October 13, 2011

Why Should We Care About Conflict of Interests?

Researchers have a tradition of free inquiry and free exchange of ideas, "united in the shared purpose to create knowledge, to critique existing knowledge, and to disseminate knowledge."11 Trust, the core ethical value in this issue, is essential in the scientific pursuit of the truth. A relationship based on trust

is necessary with colleagues, the government, the study sponsors, and, of course, the public. Objectivity is fundamental to this trust.

Conflicts of interest are intrinsic to the researcher's enterprise. And that is why conflicts of interest are so serious. Not only can a conflict lead to injury or harm to particular study participants but, on a

larger scale, a conflict of interest can damage an entire research enterprise by reducing the trust and confidence that people generally have in research.

Columbia University RCR Program @ http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/foundation/index.html#1Columbia University RCR Program @ http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/foundation/index.html#1

Trust …CoI, if not declared or well managed, can undermine that trust –with colleagues, grantors and most importantly the public.

http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/foundation/index.html#sup1ref

Jessie Gelsinger

• 1999 ‐ Eighteen year old subject enrolled in a University of Pennsylvania trial designed to test gene therapy for genetic liver disorder.

• The subject was enrolled despite his ammonia level exceeding cutoff for entry eligibility.

http://www.nih.gov/catalyst/2000/00.01.01/page1.html / (adapted from) Fred Hamilton ’05 UCMC http://www.nih.gov/catalyst/2000/00.01.01/page1.html / (adapted from) Fred Hamilton ’05 UCMC

http://www.nih.gov/catalyst/2000/00.01.01/page1.html /

http://www.nih.gov/catalyst/2000/00.01.01/page1.html /

Jessie Gelsinger

• Following administration of large dose of genetically‐engineered viruses, Gelsinger experienced multisystem organ failure and died in September, 1999. Federal investigation following the incident revealed that monkeys given similar injections by Penn researchers before Gelsinger enrolled had experienced similar reactions, not reported to FDA, and not mentioned on consent form.

Fred Hamilton ’05 UCMC Fred Hamilton ’05 UCMC

Jessie Gelsinger

• NIH sent a circular reminding gene therapy investigators that all adverse events must be reported; as a result, 652 new adverse event reports were received from 80 institutions, including reports of seven prior deaths.


Jessie Gelsinger

• Principle Investigator Dr. James Wilson and the University of Pennsylvania each held stock in Genovo, the study sponsor; Genovo was founded by Wilson and provided 20% of the funding for Wilson’s lab.

Fred Hamilton ’05 UCMC Fred Hamilton ’05 UCMC Jenks S. J Natl Cancer Inst 2000;92:98-100

Jessie Gelsinger

• In 1995 (five years before Gelsinger’s death) a University Conflict of Interest Committee had considered the Penn‐Genovo‐Wilson relationship and raised questions concerning conflict management procedures and liability coverage.


Jessie Gelsinger

• Alan Milstein filed a conventional malpractice claim

• Defendants included the investigator, University, and IRB members.

• Settled (estimated) for $ 5 million to $ 10 million.


Jessie Gelsinger

“…Gelsinger's father, and many others, viewed Jesse's death as a sort of sentinel case exposing the hazards of merging academia and the private sector. Genovo, which held licensing rights to the study intervention, provided US $4 million to the institute pursuing the study. The parent institution held a 5% equity interest in Genovo, and lead investigator James Wilson's stake was 30% — double the university's normal limit for clinical researchers.”

Kimmelman J. (2008) Nature Reviews Genetics 9, 239-244.

[Financial conflict of interest] has been a discussion for many years. However, when Jesse Gelsinger died last fall during a gene therapy clinical trial, questions were raised about the financial interests of investigators, and whether these interests clouded judgment or influenced decisions that were made.

It has never been more important to insure that adequate controls are in place to guard against improper behavior or bias, conscious or not, caused by conflicting loyalties on the part of clinical researchers.

Remarks of FDA Commissioner Jane Henney, M.D ."Human Subject Protection and Financial Conflict of Interest“ (August 15, 2000)

NIH Conference on Human Subject Protectionand Financial Conflicts of Interest (August, 2000)


Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics

Reconciling Conflicts in Research -- not just COI

Conflicts of InterestsConflicts of Interests

Conflicts of CommitmentsConflicts of

Commitments Conflicts of ConscienceConflicts of Conscience

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics




Commitments Conflicts of Ethics

Conflicts of Ethics

Investigator Conflicts of Interstest

2: Conflicts of Interest at the Individual Level2.1 Academic Conflicts of Interest or Intellectual Bias2.2 Other Types of Conflicts of Interest2.3 Clinical Research2.4 The Bayh-Dole Act (1980)2.5 Professional Societies and Associations2.6 Managing Conflicts of Interest at the Individual

Level


http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/foundation/index.html#2

http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/foundation/index.html#2_1







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When do Interests (>1) Conflict?

• A conflict of interests (COI) can arise when a person is faced with a decision that might be influenced by two competing interests.

• Although the term “conflict of interest” is often used, there is only a conflict by virtue of the existence of more than one interest—hence the plural form.

• We may digress to the singular form, which most people use anyhow.

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NOTE: A conflict of interests is NOT a statement of wrongdoing.

A conflict of interests exists when a secondary interest conflicts with a primary interest

POSSIBLE CONFLICT

Primary Interest“Do what is right”

Secondary Interest“Personal Financial Gain”

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Secondary interests conflict with primary interests in a number of circumstances

• Primary interest: Train students by having them work on projects• Secondary interest: Use graduate students as free labor on startup

• Primary interest: Spend time working on class lectures• Secondary interest: Spend time marketing patent for licensing

• Primary interest: Order best equipment for lab• Secondary interest: Order equipment from a company that adds

research funding and pays for travel to meetings

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics





Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics




Conflicts of Ethics

FCOIFCOI otherCOI

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• Receives research support from, or evaluates products or procedures of a business in which he or she or a family member has an ownership interest (stock/options/deferred compensation)

• Receives payments (consulting fees/honoraria/other) from an outside entity

• Uses institution’s resources for an outside entity, provides current or future rights to an entity for institution’s IP

A Potential for COI Exists if an Individual…

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• Accepts compensation for serving on an advisory or governing board

• Can influence institution’s business decisions with an entity he or she has an ownership interest in

• Agrees to limits on publication, peer-review of research

• Agrees to favorable research results

• Conducts research with an invention (any IP) involving possible future royalties or other cash flows

• Supervises a member of his or her immediate family

A Potential for COI Exists if an Individual…

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Non-Financial Conflicts of Interest may also interfere with researchers’ decision-making

• Career Advancement

• Personal Advancement

• Favoritism – Family and Other

• Scientific Bias

• Glory – PR

Not easily identifiable or manageable

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SSafety of URURate EElevation in PDPD

SURESURE--PDPDA randomized, doubleA randomized, double--blind, placeboblind, placebo--controlled, dosecontrolled, dose--

ranging trial of oral inosine to assessranging trial of oral inosine to assesssafety and ability to elevate CSF urate in early PDsafety and ability to elevate CSF urate in early PD

MGH, HSPH and the Univ RochesterMGH, HSPH and the Univ Rochester

Michael J. Fox Foundation for ParkinsonMichael J. Fox Foundation for Parkinson’’s Resarchs Resarch

Rules rightly target FCOI, but note other COI

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics

Conflicts of Ethics




Conflicts of Ethics

FCOIFCOI otherCOI

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• A situation in which financial or other considerations have the potential to compromise or bias professional judgment and objectivity.

• At least 2 interests are conflicted (e.g. objectivity vs. $$$).

• Involves the use of authority for financial or other gain.

• May involve both individuals and institutions.

• Planning, conduct, reporting of research.

• Not a statement of wrongdoing.

Conflict of Interests Defined

COI ≠ Wrongdoing

• “Conflicts of interest are ubiquitous and inevitable in academic life, indeed, in all professional life. The challenge for academic medicine is not to eradicate them, which is fanciful and would be inimical to public policy goals, but to recognize and managethem sensibly and effectively.”

• David Korn JAMA 284, 2234-2236, 2000

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• Individual– Investigators– Students– Research technicians, data analysts– IRB members– Anyone involved in technology transfer– Anyone involved in procurement, education, healthcare

• Institutional– Financial & IP holdings of the institution– Allocation of resources for research– Executives and board members

Either individual or institutional interests may create potential conflicts

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…Perception is Reality

When addressing real or perceived conflicts of interests…

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• Human Subject Protection

• Research Integrity

• Individual Integrity

• Public Trust in Institution

• Research Participation

• Public Trust in Research

• Progress in Biomedical Research

• Funding and Reimbursement

Conflicts of Interests introduce a number of added risks to any research endeavor

A world-renowned Harvard child psychiatrist whose work has helped fuel an explosion in the use of powerful antipsychotic medicines in children earned at least $1.6 million in consulting fees from drug makers from 2000 to 2007 but for years did not report much of this income to university officials, according to information given Congressional investigators.

Senator Charles E. Grassley pushed three experts in child psychiatry at Harvard to expose their income from consulting fees. Some of their research is financed by government grants.

Like Dr. Biederman, Dr. Wilens belatedly reported earning at least $1.6 million from 2000 to 2007, and another Harvard colleague, Dr. Thomas Spencer, reported earning at least $1 million after beingpressed by Mr. Grassley’s investigators. But even these amended disclosures may understate the researchers’ outside income because some entries contradict payment information from drug makers, Mr. Grassley found.

Researchers Fail to Reveal Full Drug PayNew York TimesJune 8, 2008

UAMB Slide setUAMB Slide set

A prominent psychiatrist at Emory University is the latest researcher to come under fire in Congress for violating federal and university rules against financial conflicts of interest.

The New York Times reports that Charles B. Nemeroff, chairman of the psychiatry department at Emory and former editor in chief of thejournal Neuropsychopharmacology, earned more than $2.8-million for consulting with drug companies from 2000 to 2007 and hid much of that income from his university. The figures were disclosed in documents provided to Congressional investigators working forSen. Charles E. Grassley, a Republican of Iowa, as part of his continuing inquiry into scientists’ financial conflicts of interest.

Emory U. Psychiatrist Failed to Report Income From Drug Makers

Chronicle of Higher EducationOctober 4, 2008

UAMB Slide setUAMB Slide set

Wakefield et al. 1998 Lancet. 351:637‐41.

Retraction in Lancet. 2010 Feb 6;375(9713):445.

Partial retraction inMurch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Valentine A, Davies SE, Walker‐Smith JA. Lancet. 2004 Mar 6;363(9411):750.

CNN Wire Staff (2011) CNN.com http://www.cnn.com/2011/HEALTH/01/06/autism.vaccines/index.html CNN Wire Staff (2011) CNN.com http://www.cnn.com/2011/HEALTH/01/06/autism.vaccines/index.html

“…Most of his co‐authors withdrew their names from the study in 2004 after learning he had had been paid by a law firm that intended to sue vaccine manufacturers ‐‐ a serious conflict of interest he failed to disclose.

After years of controversy, the Lancet, the prestigious journal that originally published the research, retracted Wakefield's paper last February….”

http://www.ncbi.nlm.nih.gov/pubmed/20137807




The GoutThe Gout by James Gillray (1799)by James Gillray (1799)

Better to disclose earlier rather than later…

37 37

Evolving Rules for Reporting/Managing FCOI

Annual/interim Disclosure at MGH (vs HMS)

38 38

Evolving Rules for Reporting/Managing FCOI

Annual/interim Disclosure at MGH (vs HMS)

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FCOI Regulations Framework

Compliance with RegulationsCompliance with RegulationsReporting to NIHReporting to NIH

Institutional PolicyInstitutional PolicyImplementationImplementationEvaluation of SFIEvaluation of SFIIdentification of FCOIIdentification of FCOIManagementManagement

InstitutionInstitution

Disclosure of SFIDisclosure of SFICompliance with Institutional PolicyCompliance with Institutional Policy

InvestigatorInvestigator

OversightOversight

NIHNIH

PHS regulation 42 CFR Part 50, Subpart F and 45 CFR Part 94PHS regulation 42 CFR Part 50, Subpart F and 45 CFR Part 94

FCOI Regulations ‐ Final Rule• Revising the regulations on Responsibility of Applicants for Promoting

Objectivity in Research for which Public Health Service Funding is Sought and Responsible Prospective Contractors

• Federal Register published August 25, 2011– http://www.gpo.gov/fdsys/pkg/FR‐2011‐08‐25/pdf/2011‐21633.pdf

(this link points to a non‐HHS website which may not be accessible to all visitors)

• Implementation no later than 365 days after publication of the final rule in the Federal Register, i.e., August 24, 2012. In the interim:– Institutions comply with 1995 regulations

– Institutions revise policies, establish procedures for compliance, and train Investigators

– NIH provides training materials for extramural community and NIHstaff, expands FCOI reports database

• Basic framework remains the same

http://www.gpo.gov/fdsys/pkg/FR-2011-08-25/pdf/2011-21633.pdf

Major Areas Addressed in the Revised Regulations

• Definition of Significant Financial Interest (SFI)

• Extent of Investigator Disclosure

• Information Reported to PHS Awarding Component (e.g., NIH)

• Information made accessible to the public

• Investigator Training

Major Changes to the Regulations

• Significant Financial Interest (SFI)– Minimum threshold of $5,000 generally applies to payments and

equity interests– Includes any equity interest in non‐publicly traded entities– Exclusions include income from seminars, lectures, or teaching, and

service on advisory or review panels for government agencies, Institutions of higher education, academic teaching hospitals, medical centers, or research institutes affiliated with an Institution of higher education.

– Excludes income from investment vehicles, such as mutual funds and retirement accounts, as long as the Investigator does not directly control the investment decisions made in these vehicles.

• Investigator Disclosure– All SFIs related to Investigators’ institutional responsibilities– Institutions responsible for determining whether SFIs relate to PHS‐

funded research and are financial conflicts of interest (FCOI)

Major Changes to the Regulations (cont’d)• Reporting to PHS Awarding Component (NIH)

– Previous requirements, (grant/contract number, name of PD/PI, name of Investigator with FCOI) plus:

• Name of the entity with which the Investigator has a FCOI• Value of the financial interest• Nature of FCOI, e.g., equity, consulting fees, honoraria• A description of how the financial interest relates to PHS‐funded research and

the basis for the Institution’s determination that the financial interest conflicts with such research

• Key elements of the Institution’s management plan• Public Accessibility

– The Institution’s FCOI policy must be made available via a publicly accessible Web site. If the Institution does not have any current presence on a publicly accessible Web site, the Institution shall make its written policy available to any requestor within five business days of a request.

– Before spending funds for PHS‐supported research, an Institution shall ensure public accessibility of information on certain SFIs that the Institution has determined are related to the PHS‐funded research and are FCOI, via a publicly accessible Web site or by a written response to any requestor.

• Investigator Training– FCOI training required for Investigators before engaging in PHS‐funded

research, every four years thereafter, and immediately under designated circumstances.

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Evolving Rules for Reporting/Managing FCOIManaging FCOI

Managing Conflicts of Interest at the Individual Level... In handling individual investigator conflicts of interest, disclosure and oversight of the research by an independent board seem to be the most common management strategies. Specific steps might include: •The investigator's financial interests with the sponsor of the trial could be fully disclosed to any human research volunteers. •The investigator's financial relations to the sponsor should be included in all written and oral presentations, publications, and abstracts.

Depending on the seriousness of the conflict, other management strategies could include: •Modifying the research plan, including changing the site(s) of the trial. •Monitoring of research by independent reviewers. This could include special oversight and approval of any consulting agreement language when faculty consult with companies in which they also hold equity interests. In a clinical study, oversight could include participant recruitment and enrollment, the informed-consent process, analysis of the study data, and the subsequent reporting to the sponsor. •Divestiture of significant financial interests. •Severance of relationships that create actual or potential conflicts. •Disqualification of the researcher from part or all of the research project


Investigator Conflicts of InterestCase Study #1

The ResearcherABC Pharmaceuticals has agreed to sponsor Dr. C's proposed human subjects' research project to be conducted at the Medical Center. The study involves research on using antiemetics to reduce the side effects caused by chemotherapy. In 2008, ABC Pharmaceuticals gave Dr. C $8,000 in honoraria for speaking about their products and he expects to receive approximately the same amount in 2009.

Dr. C also participates in the Scientific Advisory Board (SAB) of Combat Chemo, Inc. who recently started exploring new methods of minimizing the side effects of chemotherapy to become a more formidable competitor in the pharmaceutical market. Dr. C expects to receive $25K-30K in 2009 for his service on the SAB, but has not received any compensation to date.

Langone Medical Center CIMU @ http://cimu.med.nyu.edu/education/coi‐case‐studies‐and‐examples#Langone Medical Center CIMU @ http://cimu.med.nyu.edu/education/coi‐case‐studies‐and‐examples#


The Researcher

Is this a conflict?

Which policy applies to this conflict?

Can this conflict be managed? If so, how?

Langone Medical Center CIMU @ http://cimu.med.nyu.edu/education/coi‐case‐studies‐and‐examples#Langone Medical Center CIMU @ http://cimu.med.nyu.edu/education/coi‐case‐studies‐and‐examples#

http://cimu.med.nyu.edu/education/coi-case-studies-and-examples




The Case of the Entrepreneurial Anthropologist

Columbia University RCR Program @ http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/case/case02_anthro.htmlColumbia University RCR Program @ http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/case/case02_anthro.html


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michael schwarzschild, md phd · 2011/10/17 · professional life. the challenge for academic...

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