# Presentation: 045165

## Financial Conflicts of Interest in Research:What do the data show?

- Lindsay Hampson
- Department of Clinical Bioethics
- National Institutes of Health

## Outline

- Background
- Interest in Conflicts of Interest
- Definition
- What is a Conflict of Interest?
- Data
- Conflicts of Interest and Research
- Protections

## Does Money Talk?

- Would you interpret data differently in a lecture if a drug company were paying you $5,000 to give the lecture?

## Interest in Conflict of Interest

- Why is there all the interest in researchers’ conflicts of interest?
- Recent deaths have raised the question of whether researchers were more concerned about financial matters than patient safety
- Gelsinger case at University of Pennsylvania
- Fred Hutchinson Cancer Center

## Interest in Conflict of Interest

- Bayh-Dole act of 1980:  Encouraged universities and medical schools to commercialize their research conducted with government funds

**Notes:**
-Bayh-Dole act gives universities the exclusive licensing/patent control over intellectual property achieved through government-funded research
-250 to 4,800 is almost a 2,000% increase
-46% to 92% is a 100% increase (or doubled)

## Interest in Conflict of Interest

-  Phase I-III Trials:
- -Pharmaceuticals	$20 billion
- -NIH		$  8 billion

- Industry has dramatically increased its funding of clinical research compared to the government

- 32%

- 62%

**Notes:**
Between 1980 and 2000, industry support of biomedical research increased from 32% to 62% while the federal government’s share fell

## DISCLAIMER

-    The views expressed in this presentation do not represent the views of the NIH, DHHS, or any other government agency or official.

## Slide 8

## What is a Conflict of Interest?

- Professionals have a primary interest—the goal of their profession
- For researchers:
- Producing generalizable knowledge
- Ensuring the safety of research subjects
- Disseminating research results

**Notes:**
Professions have multiple primary interest—there is not just one goal but several

## What is a Conflict of Interest?

- Professionals also have secondary interests beyond their professional goals
- Publishing
- Spending time with his/her family
- Obtaining a good income
- Political activism or volunteerism
- Obtaining future research funding
- Pursuing other interests such as religion, traveling, social activities, etc.

**Notes:**
Secondary interests can be non-financial

## What is a Conflict of Interest?

- It is important to note that secondary interests on their own are not _**bad**_ or _**unethical**__** **_
- Usually these secondary interests are good and often praiseworthy
- Time devoted to one’s family
- Lobbying for a political belief
- Volunteering for a local charity

## What is a Conflict of Interest?

- What makes secondary interests problematic is their ability to unduly influence decisions about an individual’s primary interest
- The key ethical issue is the relationship between a primary and a secondary interest

## What is a Conflict of Interest?

- A conflict of interest occurs when a secondary interest _distorts_ or _has the potential to distort_ a judgment related to a primary interest
- A professional’s judgment does not necessarily have to be biased in order for that researcher to have a conflict of interest — even the appearance of a conflict of interest is ethically worrisome

## How Does This Affect YOU?

- Do not necessarily realize that your judgment is biased or that a conflict is occurring
- It happens to everyone
- Having a conflict of interest does not make you a bad person

## Researcher Conflicts of Interest

- For researchers, concern that some secondary interest might threaten:
- Valid research design
- Data integrity
- Researchers’ interpretation of data
- Dissemination of results
- Patient safety

## Financial Conflicts of Interest

*Why all the emphasis on *_*financial*_* conflicts of interest?*
- Money is...
- Multi-purposed
- Universally recognized as a good
- A key motivating factor
- Relatively easy to regulate

## Frequency of Financial Interests

*How frequently do researchers have financial interest in their own research?*
- Not much data
- Often, must rely on self-reporting

## Frequency of Financial Interests

- It seems that financial relationships between industry and researcher are relatively common:

| Author | Date | Study Type | Ties with industry sponsors |
| --- | --- | --- | --- |
| Bekelman et al.
(JAMA) | 2003 | Review
(10 studies) | Approximately 1/3 of researchers |
| Boyd & Bero
(JAMA) | 2000 | 1993 self-reported data | 7.6% of UCSF faculty investigators |

## Frequency of Financial Interests

- In a survey of published randomized controlled trials, of authors that disclosed a financial interest...
- 30% Employment
- 22% Consultancies and Honorarium
- 18% Grants
- 7% Educational/Speaker’s Bureau
- 7% Stock ownership
- 5% Advisory Board
- 1% Patents/Licenses

- Gross et al. JAMA 2003

## Financial Conflicts of Interest and Research Design

*Do financial interests compromise research design?*
- Data indicate that industry-sponsored research is no worse methodologically than clinical research sponsored by non-profit organizations
- In fact, industry-sponsored research studies may even be more methodologically rigorous

## Assessing Methodological Quality

- Instruments for assessing methodological quality of drug studies
- Cho and Bero (JAMA 1994)
- Oxman and Guyatt (J Clin Epidemiol 1991)
- Jadad et al. (Controlled Clinical Trials 1996)
- 5-point scale
- For each question, yes = 1, no = 0; add/subtract extra point if method is *appropriate* or *inappropriate*
- Look at the article and answer these questions
- Was the study described as randomized?
- Was the study described as double blind?
- Was there a description of withdrawals and dropouts?

## Financial Conflicts of Interest and Research Design

- Liebeskind et al. 1999 (Stroke)
- Used a 100-point scale to assess methodological quality
- Randomization, outcome, inclusion/exclusion criteria, description of intervention, statistical analysis
- 	Industry			73.1
- 	Non-industry		53.4 		p<0.0001
- Industry-sponsored research was more likely to be double blind and to report adverse events

**Notes:**
blinding

## Financial Conflicts of Interest and Data

*Do financial interests compromise data collection?*
- Data suggest that industry funded clinical research leads to “positive results” more frequently than non-industry funded research

**Notes:**
Ie, results more favorable to the industry drug

## Financial Conflicts of Interest and Data

- Of 11 meta-analyses, 9 reported that industry sponsored trials were significantly more likely to yield pro-industry results
- Odds ratio of having industry sponsorship and pro-industry conclusion:OR=3.60 (2.63-4.91)

- Bekelman et al. JAMA 2003

## Conflicts of Interest and Data

- These data do not necessarily demonstrate bias or compromised studies
- Is this a “pipeline” issue?
- Industry commits resources only to clinical research that is likely to yield positive results
- Industry terminates large randomized studies early that are likely to have side effects and less likely to be successful or to generate huge profits

## Financial Conflicts of Interest and Researcher Interpretation

*Do financial interests bias researchers’ interpretation of data?*
- Data suggest that having financial ties with industry does distort the judgment of researchers
- Not necessarily fabrication of data, but could influence interpretation of data

## Financial Conflicts of Interest and Researcher Interpretation

- Stelfox et al. study: reviewed all studies on the safety of Ca channel blockers in hypertension published in 1995-96
- 70 articles
- 	- 5 original research papers
- 	- 32 reviews
- 	- 33 letters to the editor

## Financial Interests and Researcher Interpretation

|  | Support of Ca Blockers | Neutral | Critical of Ca Blockers | P Value |
| --- | --- | --- | --- | --- |
| Financial Interest in Ca Channel Blockers | 
96% | 
60% | 
37% | 
<0.001 |
| Financial Interest in Any Manufacturer | 100% | 67% | 43% | <0.001 |
| Honorarium | 75% | 40% | 17% | <0.001 |
| Research Funding | 87% | 40% | 20% | <0.001 |
| Employment or Consultation | 25% | 33% | 17% | 0.45 |

## Financial Conflicts of Interest and Researcher Interpretation

- Complex SituationMoney TalksMoney Affects JudgmentsNot Uniformly or Consistently

## Financial Conflicts of Interest and Dissemination

*Do financial interests influence dissemination of research results?*
- Industry-funded clinical research that produces positive results are more likely to be published compared to government-funded clinical research

## Conflicts of Interest and Dissemination

- Analysis of 42 placebo-controlled trials of SSRI (selective serotonin reuptake inhibitors) drugs submitted to Swedish drug regulators
- Results:
- Experimental drug more effective than placebo: 19/21 published (90.5%)
- Experimental drug not more effective than placebo: 6/21 published (28.6%)

## Conflicts of Interest and Dissemination

- Meta-analysis of data from randomized trials that evaluated a 5 SSRI’s against placebo in the treatment of depression in children
- Articles reviewed were published in a peer-reviewed journal or unpublished (and reviewed by the Committee on Safety of Medicines)

- Whittington et al.  Lancet 2004

**Notes:**
= FDA in US

## Conflicts of Interest and Dissemination

- Results:
- When published data alone were considered, it appeared that there was a favorable risk-benefit profile for 5/5 drugs studied
- Addition of unpublished data indicated that the risks outweigh the benefits for 4/5 drugs studied
- Unknown if unpublished articles were not published due to publication bias against negative studies at major journals or the result of industry withholding negative data

## Financial Conflicts of Interest and Dissemination

- Multiple high profile attempts by industry to prevent publication of negative data:
- The Olivieri case
- Boot Pharmaceuticals-USCF synthroid case

## Financial Conflicts of Interest and Patient Safety

*Do financial interests compromise patient safety and well-being?*
- No data
- No data on overall safety of clinical research

## Financial Conflicts of Interest and Patient Safety

- In a bone marrow transplant protocol at Fred Hutchinson Cancer Research Center, 80/82 enrolled research subjects with metastatic breast cancer and leukemia died
- Study investigators had $294 million of holdings in Genetic Systems, a drug company sponsoring part of the research

**Notes:**
Bone marrow transplant for patients with metastatic breast cancer, leukemia, and other diseases

## Conflicts of Interest and Patient Safety

- This does not necessarily indicate that a conflict of interest impacted researchers’ judgment or patient safety
- Need to be sure we do not draw unsubstantiated conclusions from the data
- Raises questions and concerns, but deaths are not necessarily due to the presence of conflicts of interest

## Why Do We Need Protections?

- Protections aim to reduce:
- _Likelihood of harm_: Limit the possibility of a harm occurring in the first place
- _Magnitude of harm_:Lessen the negative consequences of the harm

## Protections for Financial Conflicts of Interest

- Disclosure
- To institution/IRB/COI committee
- To patients
- In journals
- Management
- Data safety and monitoring boards (DSMBs)
- Independent consent monitors
- Prohibitions
- Against types/amounts of financial interests
- By removing researchers from study

## Problems with Protections

- No consistent standards for disclosure:
- 2001 GAO study of 5 major research institutions
- UCLA, UNC, UW, Washington University, Yale
- Rules regarding disclosure and prohibitions of financial interests varied widely
- Limits of financial interests varied from $10,000 to $100,000

## Problems with Protections

- Disclosed information is not well recorded and not readily available to the IRBs
- Researchers are not aware or well-informed of disclosure policies
- At UCSF and Stanford, 58% of researchers could not accurately describe the COI policy of their institution

## Patient Worries aboutFinancial Conflicts of Interest

- More and more people are talking about wanting to disclose financial interests of researchers to research participants
- 2003 Boyd, Cho, Bero: 1⁄4 of investigators felt that public disclosure was the best way to mitigate the ethical risks of COIs
- In a 1995 study of post-marketing research: 75% of doctors and 86% of patients believed that their patients should be informed if their doctor was paid a fee for enrolling them in the study

## Patient Worries aboutFinancial Conflicts of Interest

- Disclosure, especially to research subjects, lets them know about a problem without tools to solve the problem (other than not participating in the research)
- Places responsibility on subjects rather than on researchers and institutions, putting the onus on the least powerful group
- No data that patients
- Understand disclosure of financial interests
- Understand how it might affect judgments
- Will change their actions regarding participation in research

## Patient Worries aboutFinancial Conflicts of Interest

- At the NIH, currently conducting 2 studies interviewing research participants about their understanding and views about financial interests
- How worried are they?
- How would certain financial ties affect their participation in research studies (why)?
- What do they want to know about financial ties?
- Always know about financial ties
- Know if only over a certain monetary limit
- Never know about financial ties
- Know about safeguards in place to protect subjects
- If they could set limits, what would they allow?

## Conclusions

- Researcher financial interests are common: 25% to 33% of researchers
- Financial interests
- Do appear to influence **researcher interpretation** and **data dissemination**
- Do _not_ appear to influence **research design**
- ? Influence **data collection **?
- ? Influence **patient safety** ?

## Conclusions

- Protections, but not without problems
- Disclosure
- Management
- Prohibitions
- Swift endorsement of disclosure to research subjects before this option has been fully thought out or shown to be of any benefit