Conflicts of Interest in Research

Delia Y. Wolf, MD, JD, MSCI

Assistant Dean, Regulatory Affairs & Research ComplianceDirector, Human Research AdministrationHarvard School of Public Health

Email: dywolf@hsph.harvard.edu

September 27, 2013

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Topics to be Covered

Research misconduct

Conflicts of interest

What is COI

Regulatory requirements

Institutional policies

Cases

What is a Conflict of Interest

Many definitions, only some consensus One possible working definition: an

individual or institution has a primary interest or duty (e.g., scientific integrity and objectivity, protection of subjects) that may be affected or undermined by a competing interest (e.g., financial reward, professional advancement, etc.)

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Types of Potential Conflicts

Individual financial, examples Equity interests: ownership of stock and stock options in a

company sponsoring research Royalty: when an investigator is conducting a research

project for a company that is developing the technology, of which the investigator is also the inventor

Consulting fees, over-scale honoraria and gifts, or other monetary compensation from companies whose products are affected by investigators’ research results

Recruitment bonus or milestone payments from sponsoring company to investigators in order to “accelerate” research process

Finder’s fees

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Significant Financial Interest Significant Financial Interest does not include:

Salary, royalties or other remuneration from the investigator’s institution;

An equity interest which when aggregated for the investigator and his/her spouse and dependent children (a) does not exceed $5,000 in value and (b) represents no more than five percent (5%) ownership in any single entity;

Salary, royalties or other payments that when aggregated investigator and his/her spouse and dependent children over twelve months is not reasonably expected to exceed $5,000;

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Significant Financial Interest Significant Financial Interest does not include:

Income from lectures, seminars, or teaching engagements sponsored by public or nonprofit entities; a federal, state, or local government agency, an Institution of higher education, an academic teaching hospital, a medical center, or a research institute that is affiliated with an Institution of higher education.

Income form service on advisory committees or review panels for public or nonprofit entities; or

Any ownership interests in the institution, if the institution is an applicant under the Small Business Innovation Research (SBIR) Program.

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Types of Potential Conflicts

Individual non-financial, examples Academic promotion and peer recognition Securing job or grant support Publishing results of research (often promotion

depends on the number of publications) Scientific Advisory Board membership Withholding research data or other research

information from other researchers in order to gain a competitive advantage

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Types of Potential Conflicts

Institutional, examples Intellectual property rights that may impact

oversight of research (license deals, royalty/milestone payments, etc.)

“Gifts” to institution Equipment/building Secure research funding Institutions reputation

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Conflicts of Commitment Competing demands on researchers’ time

Working on one or more funded projects Teaching and advising students Attending professional meetings and giving lectures Serving as a peer reviewer

Allocation of time Time and effort reporting – seek advice if unsure

whether a particular commitment of time is allowed under an institution's or funding agency’s policy

Use of resource Equipment purchased with public funds cannot be used

for private research

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Examples of potential COI

An academic researcher in a NIH study section reviews a grant application from a competitor in the same field

A clinical investigator receives $3,000 in patient care costs for each patient she recruits into a clinical trial

A university’s IRB reviews a research proposal sponsored by a compay that has recently given $10 million to the university

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Examples of potential COI (cont.)

A university holds stock in a chemical plant but also hires employees to monitor its emissions.

A university president owns stock in a company that sponsors research on campus and has made large gifts to the campus

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Impact of Financial Interests

Existing evidence suggests an impact on science doe to financial relationships: Industry-sponsored studies that are published

are more likely to reach pro-industry conclusions (Bekelman et al., 2003)

Gifts change physicians’ prescribing behaviors (to the benefit of the gift-giver)

In one survey, 15.5% of 3,247 scientists surveyed reported that they had changed the design, methodology or results of a study in response to pressure from a funding source (Martinson et al., 2005)

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How COI is identified/judged

Conflicts usually judged in retrospect Hard to “prove” causative effect

(conflict bias) Often only an issue in the wake of an

adverse event and compounds the problem for investigators and/or institutions

Public perception/media focus

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Regulatory Requirements

FDA Regulations (21 CFR Parts 54; 312.53; 812.43) Investigators must disclose certain financial

interests to sponsors; sponsors then disclose to FDA

FDA may take action if it determines that the financial interests of an investigator raise a serious question about data integrity

PHS Regulations 42 CFR Parts 50 and 94 (1995) Revised final rule public August 2011

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University-wide Policy

Harvard University policy on individual financial conflicts of interest policy can be found at: http://vpr.harvard.edu/content/conflicts-interest

Approved by the President and Fellows of Harvard College on May 26, 2010

Applies to holders of faculty and teaching appointments at the Schools

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Responses to COI Concerns

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Common themes in existing responses: DISCLOSURE

Information gathering IDENTIFICATION

Defining what constitutes a COI MANAGEMENT

Disclosure component (transparency) Reducing impact of conflicted investigator

Managing Financial COI

Disclosure to the IRB Protocol-specific $1 threshold at Harvard Catalyst institutions

Following management plan such as: Disclosure to potential research participants Refrain from recruitment activities Refrain from interpretation of data Appoint another investigator to be the

principal investigator (PI)

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Limitations of disclosure to subjects: Can subjects make meaningful use of that

information? Evidence that some patients view their

doctors’ financial interests positively: Demonstrates knowledge and that they are on

cutting edge If physicians are more vested they will work

harder

Managing Financial COI (cont.)

COI in International Research

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Globalization of research/clinical trials Increased outsourcing of research by

industry This has resulted in the outsourcing of COIs as

well (Gatter, R.) Drug company payments to health

professionals in resource-poor countries can double or triple their annual incomes (Washington Post, Dec. 2000)

COI in International Research (cont.)

Reliance on industry funding Many countries want to be viewed positively

to industry as a good place to site trials Trials bring funding for research as well as

access to investigational therapies and, for resource-poor countries, often additional capacity-building for the institution and/or nation that goes beyond the research study (e.g., access to standard of care therapy for all patients, funds to improve facilities, etc.)

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COI in International Research (cont.)

Government involvement In many countries, regional and/or national

approval of research is required

Governments may have incentives either to

ensure research happens (reflects positively

on country, financing is dependent on it) or

block it (if anticipated results may damage

country’s reputation)

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CASE STUDY

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A U.S.-based pharmaceutical company is conducting a drug trial in a resource-poor country; the protocol involves studying the safety and effectiveness of a new drug for hypertension.

In addition to the research budget, the local investigators are being paid through consulting agreements to advise the company on research and political strategy and to liaison with local officials (the amounts, while modest by US standards, are 3 times what the investigators make in annual salary at their institutions).

The consulting agreements give the company the rights to control access to data and approval any publications.

The local institution’s Ethics Committee is comprised primarily of hospital management and prominent community members.

In addition to the institutional EC, the protocol must be reviewed by a regional Ethics Committee, the Chair of which holds a prominent position in the local government.

CASE STUDY

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Local government officials have repeatedly expressed a desire to improve their reputation as a “research-friendly” locale.

The local health system, including the site, desperately needs investment in infrastructure.

The standard of care for hypertension in the US is currently prohibitively expensive for the site’s patient population.

The company has offered to invest a significant amount of resources in improving the site, building local health clinics, as well as providing infrastructure and resources for the EC.

The company has also offered to ensure that all patients at the site (whether on protocol or not) receive the standard of care for hypertension during the course of the trial and for 3 years following; additionally, if benefits are shown, the company has offered to make the new drug available to all patients at the site for the same time-frame.

CASE STUDY: Q & A

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What conflicts do you see with this arrangement?

Whose responsibility is it to question the validity of the regional EC approval?

How should the reviewing ECs balance just reward to the site for participating against the potential to create conflicts?

What management techniques might work in this context?

Research Misconduct Public Health Service Policies on Research

Misconduct, 42 CFR 50 & 93 Office of Research Integrity:

http://ori.dhhs.gov Be familiar with your institutional policy

The institution may make findings of research misconduct or other breaches of research integrity under internal policies and standards adopted by the institution even if no misconduct or other breaches of integrity are found under the HHS regulation

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Definitions

Research Misconduct means fabrication, falsification, or plagiarism, in proposing, performing, or reviewing research, or in reporting research results. It does not include honest error or differences of opinion

Fabrication is making up data or results and recording or reporting them

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Definitions (cont.)

Falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record

Plagiarism is the appropriation of another person's ideas, processes, results, or words without giving appropriate credit

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Definitions (cont.)

Plagiarism: ORI considers plagiarism to include both the theft or misappropriation of intellectual property and the substantial unattributed textual copying of another's work. It does not include authorship or credit disputes. unauthorized use of ideas or unique

methods obtained by a privileged communication, such as a grant or manuscript review

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Definitions (cont.)

Allegation means any disclosure, whether by written or oral statement, or any other communication, to an institutional, Department of Justice (DOJ), or a DHHS official who receives the allegation while acting in their official capacity, that a covered institution or member thereof has engaged in research misconduct

Definitions (cont.)

Whistleblower is an individual, who makes an allegation or demonstrates an intent to make an allegation (or what is perceived to be an allegation) while a member of the institution at which the alleged research misconduct occurred

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Definitions (cont.)

Good faith allegation means an allegation of scientific misconduct made with a belief in the truth of the allegation which a reasonable person in the whistleblower's position could hold based upon the facts. An allegation is not in good faith if made with reckless disregard for or willful ignorance of facts that would disprove the allegation

Definitions (cont.) Retaliation means any adverse action or

credible threat of an adverse action taken by a covered institution, or member thereof, in response to a whistleblower's good faith allegation of scientific misconduct

Preponderance of the evidence means proof by information that, compared with that opposing it, leads to the conclusion that the fact at issues is more probably true than not

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Finding of Research Misconduct

There must be significant departure from accepted practices of the relevant research community

The misconduct must have been committed intentionally, knowingly, or recklessly

The allegation must be proven by preponderance of the evidence

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Who has the burden of proving The institution or HHS has the burden of

proving research misconduct The respondent must prove by a

preponderance of the evidence that honest error or difference of opinion occurred

The finder of fact must give due consideration to admissible, credible evidence of honest error or difference of opinion presented by respondent

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PHS Responding to Allegations

receipt of an allegation preliminary assessment of the allegation conduct of the inquiry and investigation institutional decision ORI oversight review PHS decision option to request a hearing imposition of PHS administrative actions

when research misconduct is found

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Complainant

The complainant (whistleblower) is an essential element in the effort to protect the integrity of research determine what information should be

included in the allegation, to whom the allegation should be reported, what protections are provided for the

complainant, and what role the complainant will play in

the ensuing proceedings

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Complainant (cont.)

Research misconduct allegations should be made to the institutional official named to receive such allegations in the institutional policy for responding to research misconduct allegations. Allegations may also be made to ORI

HSPH – all allegations of research misconduct shall be brought to the attention of the Dean of the School of Public Health

Complainant (cont.)

Institution is required to: Provide confidentiality to all respondents,

complainants, and research subjects identifiable from research records or evidence

Take all reasonable and practical steps to protect the positions and reputations of good faith complainants, witnesses and committee members and protect them from retaliation by respondents and other institutional members

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Respondent When accused of research misconduct, a

respondent should review the PHS Policies on Research Misconduct - 42

C.F.R. 93, review the institution’s policies on responding to

research misconduct gather documentation and identify witnesses consider whether an advisor, expert, or counsel is

needed avoid actions which are or could be perceived as,

retaliatory against the whistleblower, and maintain the confidentiality of the proceedings

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Respondent (cont.) In responding to an allegation, an institution

must provide notification of receipt of an allegation confidential treatment to the maximum extent possible an opportunity to comment on allegations and findings a copy of the inquiry report for comment notification whether an investigation will be initiated a prompt, fair, objective, thorough and competent

investigation a copy of the investigation report for comment access to the evidence on which the report is based a diligent effort, as appropriate, to restore the

reputation of the respondent if the allegation is not confirmed

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Allegations Allegations are made to the institution

where the research misconduct has occurred

A whistleblower may also make an allegation of research misconduct to ORI or a PHS funding agency

Allegations (cont.) An allegation should contain the following

information: Name of respondent(s) Name of whistleblower(s) Names of witnesses Description of misconduct When misconduct occurred Where misconduct occurred Supporting documentation Grant number or title Funding source

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Preliminary Assessment

Falsification: substituting one subject's record for that of

another subject; altering the dates and results from subjects'

eligibility visits; altering the dates on patient screening logs

and/or submitting the same log with altered dates on multiple occasions;

failing to update the patients' status and representing data from prior contacts as being current;

Preliminary Assessment (cont.)

Falsification (cont.) altering the results of particular tests on

blood samples to show that the test accurately predicted a disease or relapse;

backdating follow-up interviews to fit the time window determined by the study protocol; and

falsifying the times that blood samples were drawn from human subjects

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Preliminary Assessment (cont.)

Fabrication: creating records of interviews of subjects

that were never performed making up progress notes for patient visits

that never took place and inserting them into the medical record to support published and unpublished research reports

preparing records for calls and follow-up contacts to subjects who had already died

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Inquiries Following the preliminary assessment, if the

institutional official determines that the allegation provides sufficient information to allow specific follow-up, he/she should immediately initiate the inquiry process

The purpose of the inquiry is to make a preliminary evaluation of the available evidence and testimony of the respondent, whistleblower, and key witnesses to determine whether there is sufficient evidence of possible research misconduct to warrant an investigation

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Investigation

The purpose of the investigation is to explore in detail the allegations, to examine the evidence in depth, and to determine specifically whether misconduct has been committed, by whom, and to what extent

The findings of the investigation need to be set forth in an investigation report that is submitted to ORI for oversight review

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Institutional Decisions The institution’s deciding official usually makes

the final determination whether to accept the investigation report, its findings, and the recommended institutional actions

The deciding official's determination, together with the investigation committee's report, constitutes the final investigation report for purposes of ORI review

When a final decision on the case has been reached, the institution needs to notify both the respondent and the whistleblower in writing

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ORI Oversight Review

During its review, ORI staff examine the institution’s report and conclusions to determine whether the institutional findings are defensible, well supported by the evidence, and acceptable as a final resolution of the allegations

When ORI completes an oversight review of an institutional inquiry or investigation, it usually prepares an ORI oversight report that describes the institutional process and the rationale it developed for determining whether the allegation was substantiated

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PHS Decision and Hearing The Assistant Secretary for Health (ASH) makes

the final PHS/HHS decision on the imposition of administrative actions after reviewing the recommendations made by ORI

ORI sends the respondent a copy of the final ORI report and a notification letter that describes the proposed administrative actions to be taken against the respondent

If a hearing is not requested by the respondent within 30 days from receipt of the notification, the research misconduct finding and administrative actions become final

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Administrative Actions The administrative actions PHS may take against

respondents include, but are not limited to: debarment from eligibility to receive Federal funds for grants

and contracts prohibition from service on PHS advisory committees, peer

review committees, or as consultants certification of information sources by respondent that is

forwarded by institution certification of data by institution imposition of supervision on the respondent by the institution submission of a correction of a published article by

respondent submission of a retraction of a published articles by

respondent

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The Poehlman Case Eric Poehlman, PhD, was an internationally

recognized, tenured professor at the UVM In October 2000, Walter Denino, a junior

member of Poehlman’s laboratory became convinced that he had altered data from a study on aging volunteers from the Burlington area

The case developed into one of the most significant cases of scientific misconduct in the history of the DHHS ORI, launching a DOJ civil and criminal fraud investigation and eventually, to a guilty plea and felony conviction

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The Poehlman Case (cont.)

Poehlman admitted to 54 findings of scientific misconduct made by the UVM and ORI

Was sentenced on June 28, 2006 to a year in prison

Permanently barred from obtaining federal research grants

Agreed to retract or correct ten of his publications