Conflict of Interest in Drug

Research

Dr. Mansij Biswas

SYR, Dept. of Pharmacology & Therapeutics,

Seth GS Medical College & KEM Hospital.

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Definition

“Circumstances that create a risk that professional

judgments or actions regarding a primary interest can

be unduly influenced by a secondary interest”

“It is a risk, a condition… not necessarily a behavior

or the existence of a biased judgment or action”

20/09/14Richard Smith, Editor, BMJ

• “Conflicts of interests are situations in which financial

or other personal considerations may compromise, or

have the appearance of compromising, an

investigator’s judgment in conducting or reporting a

research.”

(AAMC, 1990)

• “A conflict of interest in research exists when the

individual has interests in the outcome of the research

that may lead to a personal advantage and that might

therefore, in actuality or apparently compromise the

integrity of the research.”

(NAS, Integrity in Scientific Research)

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Significant financial interests:

Anything of monetary value, including but not limited

to, salary or other payment of services (e.g., consulting

fees, honoraria); equity interests (stocks, stock options

or other ownership interests); and intellectual property

rights (e.g., patents, copyrights and royalties from such

rights) when aggregated for the investigator and the

his/her spouse and dependent children, are greater than,

or equal to, $10,000 in value and 5% ownership

interest in any single entity

20/09/14PHS and NSF enacted regulations

‘Financial’ conflicts may be the easiest to

identify but they may not be the most influential

• Other sources of conflict are political, academic,

intellectual, religious, social and personal or

professional relationships; these may be just as

potent as financial conflicts are!!

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Levels of COI

Conflict of Interest by Researchers (PI or CoI)

The REB should assess the likelihood that the

researcher’s judgment may be influenced, or appear to be influenced, by private or personal interests, and

assess the seriousness of any harm that is likely to result

from such influence or from the mere appearance of

undue influence

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• Conflicts of Interest by REB Members

It is of the highest importance that members of the

REB avoid real or apparent conflicts of interest

For example:

• when their own research projects are under review by

their REB

or

• when they have been in direct academic collaboration

with the researcher whose proposal is under review

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• Institutional Conflicts of Interest

• When the parent organization has a strong interest in

seeing a project approved before all ethical questions

are resolved.

• When REB is not acting independently from the

parent organization.

• The institution disrespects the autonomy of the REB

and fails to ensure that it has appropriate financial

and administrative independence to fulfill its primary

duties.

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What comprises COI?

• Stock ownership

• Paid employment or board membership

• Patent (pending or actual)

• Research grants (from whatever source)

• Travel grants and honoraria for speaking or participation at meetings

• Gifts or membership of lobbying organizations

• Relationship with the IEC/IRB, or with possible reviewers of the paper

• Relationship with organizations and funding bodies or Membership of a government advisory board

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• 33% of guideline authors have financial interests in the

drug(s)

• 50% guidelines had no COI documentation

• 34% of guidelines stated no COIs

• 50% had at least one author receiving research support

• 43% had at least one author who had been a paid speaker

for the company

20/09/14Nature; Vol 437 | Issue no. 7062 | 20 October 2005

Some data…

COIs may result in:

• Loss of objectivity

• Reordering of priorities towards research

• Degradation of the nature of science as an open and

collegial enterprise

• Exploitation of trainees

• Transfer of time and interest to commercial ventures

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• Protection of human subjects may be compromised

• Integrity of research may be at risk

• The public may lose trust in research findings

• The investigator/faculty member may lose the respect

of the academic community

• Violation of scientific norms may result

• May violate terms of research grants, contracts and

federal regulations

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• University may lose public support and funding for academic research

• Research results may be excessively delayed or not published

• Students may be negatively impacted, which may lead to inability to pursue their research interests

• University resources may be improperly used

• Increased government regulations may result

• Scandals or negative media attention may occur

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Conflicts Can Occur at all Levels of Research:-

• In awarding a grant

• In ethical reviews

• In recruitment of participants

• During the actual study conduct

• In analysis of data

• In presentation/publication of data

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Three Guiding Principles:

The investigator must:

conduct research activities objectively

operate with transparency

be accountable to all stakeholders, especially

when relationships with industry exist

20/09/14FASEB COI Toolkit 2007

All investigators conducting a research (industry funded or

not) have a professional obligation to the integrity of their

studies:

• Intellectual honesty in proposing and conducting the

research

• Report research results to public and scientific

community

• Lack of influence by other competing secondary

interests, primarily money

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How to maintain objectivity?

How to operate with transparency?

• Transparency in academia-industry relationships is

important to advance research and promote trust of

colleagues and the public

• What is Transparency?

- Openness and willingness to accept scrutiny & criticism

• How can you be more transparent?

Full and regular internal reporting

External disclosure

Perception in reality

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How to be accountable?

• Investigators are accountable to all stakeholders

including the public, sponsor, institution, research

team, and human subjects or patients

• What is Accountability?

Obligation to take responsibility for one’s actions, may berequired to explain them to others

• Who are you accountable to?

State or Federal sponsors

All study co-ordinators

Human Subjects in Clinical Trials

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Steps to resolve

• Disclosure / transparency

• Stringent analysis of COI

• Review of contracts between funding agencies and researchers

• Elimination of the conflicting interest (e.g., divestment of

financial interest or removal from project)

• Substitution of non-interested personnel in the project

• Close external monitoring by independent reviewers

• Blinding of study, when possible

• Restrict review of colleague’s work

• Peer review of manuscripts

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Recommendations: Individual-level conflicts

• Adopt conflict of interest policies for individuals

• Make disclosures specific enough to identify and

assess risks of relationships

• Create conflict of interest committee to review

disclosures and determine response to conflicts

• Avoid unnecessary administrative burdens

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Recommendations:Institution-level conflicts

• Create board-level policies and procedures to identify

and respond to conflicts of interest at the institutional

level

• Develop rules for grantees on institutional conflicts of

interest

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Recommendations:Standardize disclosure

• Broad-based consensus process to develop standard categories and formats for disclosure of conflict of interests to institutions

Goals: • Reduce burden on researchers• Improve information to assess relationships

Problem:

Some researchers need to make disclosures to multiple institutions (university, granting agencies, journals, CME courses), each with different requirements and format

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Recommendations:Report company payments

Pharmaceutical, medical device, and

biotechnology companies should publicly report

payments to physicians, researchers, and medical

institutions (e.g. teaching institutions, professional

societies, providers of continuing medical

education etc)

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Recommendations: Clinical research

• Research institutions: adopt policy that investigators

generally may not conduct research with human

subjects if they have a significant conflict of

interesst in the outcome of the research

• Exceptions: investigator essential, conflict managed

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Recommendations: Medical education

• Academic medical centers should:

Prohibit gifts, ghostwriting, speakers bureaus

Limit drug samples, consulting, sales reps

Provide education on conflicts of interest

End or restrict relationships with risk but little

benefit

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Recommendations: Medical practice

• Physicians should:

Not accept gifts, ghostwriting, speakers bureaus

Limit drug samples, sales reps, consulting

• Professional societies and health care providers

should amend policies to support these

recommendations

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The Conflict of Interests Committee

• Determines if a conflict exists, evaluates, manages COI

in research, and ensures that the institution’s COI

policies and regulations are met

• A “real” and a “perceived” COI: both are treated equally

• Encourage investigators to submit a conflict of interests

statement even if there is uncertainty of whether or not a

conflict exists

The COI Committee…contd.

• Significant financial interests are reviewed as per

federal guidelines

• If COI is determined, then it must have an

acceptable management plan. The investigator

submits a proposed management plan depending on

the nature of the conflict. The COI Committee

reviews the plan and accepts or rejects it

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May 2004…

Pfizer agreed to pay $430 million to settle a lawsuit by aformer employee turned whistle-blower, who was joinedin the lawsuit by the U.S. federal government and 11other state governments.

The lawsuit exposes various marketing practices bythe company Warner-Lambert, later bought by Pfizer.

Leading academic researchers were paid to deliverpromotional lectures at educational events and topublish favourable reports on the off-label use of itsepilepsy drug, Neurontonin

20/09/14L. Kowalczyk “Pfizer Drug Strategy Probed: States Question

Marketing Tactics for Neurontin,” Boston Globe, October 18, 2004

The Case of Nancy Oliveiri

• 1996, Olivieri found that Deferiprone in a clinical trial at the

Hospital for Sick Children in Toronto was showing

unexpected potential risks to some patients as hepatic

fibrosis.

• The drug company sponsoring her research (Apotex)

abruptly terminated the trials and issued warnings of legal

action against Olivieri if she inform her patients or publish

her findings, as it would violate the confidentiality

agreement

• However, she published her findings in NEJM in 1998

• She was subsequently dismissed from her position as

Director of the Hospital for Sick Children Program of

Hemoglobinopathies 20/09/14

• After more than 7 years of legal battle, an independent committee

looked into the matter and concluded that neither the university nor

the hospital offered her appropriate support in her conflict with

the drug company.

• Olivieri was reinstated to her position

The other side of the story: publicity seeking??

• Deferiprone- effective orally active iron-chelating agent licensed for

the treatment of patients with thalassaemia major

• Only alternative to Deferoxamine- daily subcutaneous infusions, lack

of compliance, high cost, toxicity, hypersensitivity

• No other clinicians using Deferiprone found evidence for long-term

liver damage and her interpretation of the data was immediately

questioned in letters to NEJM

• 4 of her 5 patients in whom liver fibrosis was suggested also had

hepatitis C and all 5 had iron overload- both causes liver fibrosis

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Vioxx: Merck Vs. FDA• March 2000: A new study found Vioxx patients had double the rate of serious

cardiovascular problems than those on naproxen, an older NSAID.

• November 2000: NEJM published the study, called VIGOR.

• February 2001: An advisory panel recommends that FDA require a label warning of the possible link to cardiovascular problems.

• September 2001: FDA warns Merck to stop misleading doctors about Vioxx'seffect on the cardiovascular system.

• April 2002: FDA tells Merck to add information about CV risk to Vioxx'slabel.

• August 2004: An FDA researcher presents results of a database analysis of 1.4 million patients; it concludes that Vioxx users are more likely to suffer a heart attack or sudden cardiac death than those taking Celebrex or an older NSAID.

• Sept. 23, 2004: Merck agrees on that patients taking Vioxx in a study were twice as likely to suffer a heart attack or stroke as those on placebo.

• Sept. 30, 2004: Merck withdraws Vioxx from the U.S. and more than 80 other countries in which it was marketed.

October 4, 2008

Emory University Psychiatrist Failed to Report Income From Drug Makers. Comes under fire for violating federal and university rules against financial conflicts of interest.

The New York Times reports that Charles B. Nemeroff, chairman of psychiatry department at Emory and former editor in chief of Neuropsychopharmacology, earned more than $2.8-million for consulting with drug companies from 2000 to 2007 and hid that income from university.

October 14, 2008

The National Institutes of Health halted a $9.3-million five-year research project at Emory University, pending an investigation into potential conflicts of interest by the project’s former leader, Dr. Nemeroff.

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Indian scenario Diabetologist Dr. V. Mohan

Letter to PMO to ban Pioglitazone due to increase risk of

bladder cancer

IPA confronts health ministry- alliance of Dr. Mohan’s diabetes

education academy + PHFI + MSD which promote Sitagliptin,

newer & 10 times costlier than Pioglitazone

Mohan bounced back- Gliptins can’t be a replacement of

pioglitazone

MSD responds by saying it has no interest with the letter and the

diabetes traing programme is an independent pure academic

initiative by MSD, PHFI & Dr. Mohan’s academy

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To conclude…

Take home message:-

there is nothing wrong in having a conflict of

interest, but one has to disclose it and proper

actions has to be taken to get rid of it…

“Knowing is not enough; we must apply…Willing is

not enough; we must do.”

— Goethe

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