Center for Health & Pharmaceutical Law & Policy Submits Comments on Conflicts of Interest in Research to the National Institutes of Health

On August 19, 2010, on behalf of Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy, Seton Hall Law Professors Kathleen Boozang and Carl Coleman, along with Research Fellow Kate Greenwood, submitted comments on the National Institutes of Health’s proposed revisions to its regulations governing conflicts of interest in federally-funded research.  While the Center’s November 2009 White Paper Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight endorsed limits on conflicts of interest beyond those that the NIH has proposed, the revised regulations are a step in the right direction and in its comments the Center commends the NIH for its decisive action on this issue.


Briefly, the Center:

• Supports the NIH’s proposal that that researchers disclose to their institutions any significant financial interest that “reasonably appears to be related to the Investigator’s institutional responsibilities,” with “institutional responsibilities” defined to include “activities such as research, research consultation, teaching, professional practice, institutional committee memberships, and service on panels such as Institutional Review Boards or Data and Safety Monitoring Boards.” This comports with the Center’s recommendation in the White Paper that investigators not be charged with determining for themselves whether one or more of their financial interests could be affected by a specific research project.

• Supports the NIH’s decision to significantly lower the monetary threshold at which a researcher’s financial interest becomes “significant” to $5,000, but argues that a lower threshold would be better. Collection of data about all of a researcher’s relationships with industry, even those that fall below the proposed $5,000 threshold, would facilitate better conflict of interest assessment and management and make possible research into the effects of conflicts on research integrity and human subject welfare.

• Supports the NIH’s decision not to exclude income from non-profit entities for lectures and similar engagements from the definition of significant financial interest and its conclusion that any equity interest in a non-publicly traded entity is significant, as are any and all intellectual property rights, but encourages the agency to revisit its decision to shield from disclosure (1) equity interests held by investigators in commercial or for-profit institutions and (2) royalties and other remuneration other than salary paid to an investigator by an institution that appoints or employs him or her.

• Notes that the draft revised regulations do not address the White Paper’s criticisms that the conflict of interest regulations place no “substantive limits on the kinds of conflicts that may exist” and fail to put forth “a required minimum response for conflicts that pose the greatest risks to participants and the integrity of the research” and encourages the NIH to consider again the benefits of setting forth required minimum responses to those conflicts that are the most problematic.

• Supports the NIH’s decision to require that grantees provide “sufficient information to enable the [agency] to understand the nature and extent of the financial conflict, and to assess the appropriateness of the Institution’s management plan.”

• Supports the requirement in the draft revised regulations that any significant financial interest that (1) is still held by a principal investigator or senior/key person, (2) is related to PHS-funded research, and (3) is a financial conflict of interest must be disclosed to the public via the world wide web.

• Supports the draft revised regulations’ requirement that investigators complete training on “the Institution’s policy on financial conflicts of interest, the Investigator’s responsibilities regarding disclosure of significant financial interests, and of these regulations” before the commencement of research and then at least once every two years. As recommended in the Center’s White Paper, it would be beneficial for the training to include as well a discussion of the nature of conflicts of interest and their potential for harm.

• Recommends that the agency adopt its own suggestion that institutions be required to “maintain up-to-date, written, enforced policies” on institutional conflicts of interest, as they are for investigator conflicts, and that these policies be made publicly available via the world wide web. The nudge this requirement would provide is necessary because institutions have been slow to develop and adopt policies on institutional conflicts.

• Recommends that the section of the regulations devoted to remedies be revised to include a non-exclusive list of potential enforcement actions such as temporary withholding of cash payments pending correction of the deficiency, suspension or termination of the contract or grant in whole or in part, monetary assessments and penalties, and suspension or debarment from eligibility for future contracts or grants.

The Center’s comments in their entirety are available here.

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy. The Center is a think tank that fosters dialogue, scholarship, and policy solutions to critical issues in health and pharmaceutical law. As part of its mission, it convenes policymakers, consumer advocates, the medical profession, industry, and government in the search for concrete solutions to the ethical, legal, and social questions presented in the health and pharmaceutical arenas. The Center also runs a compliance training program covering the state and federal laws governing the development and marketing of drugs and medical devices.

Recommended Reading, “Regulating Conflicts of Interest in Research: The Paper Tiger Needs Real Teeth”

Jesse Goldner’s Regulating Conflicts of Interest in Research:  The Paper Tiger Needs Real Teeth, 53 St. Louis U. L.J. 1211 (2009), is a must-read for anyone who has anything to do with oversight of researchers’ conflicts of interest.  The article reflects an insider’s understanding of academic physicians’ perspectives on this still-contentious topic, provides a terrific survey of the literature, and proposes regulatory fixes by the feds that HHS will hopefully seriously consider.  The article’s timing is perfect, given that HHS is receiving comments until August 19, 2010 on proposed changes to its conflict of interest regulations.  See http://grants.nih.gov/grants/policy/coi/. Even in the short time since the publication of Goldner’s article, HHS OIG has issued yet another report on conflicts of interest management, entitled “How Grantees Manage Financial Conflicts of Interest in Research Funded by the National Institutes of Health,” (Nov. 2009), available at http://oig.hhs.gov/oei/reports/oei-03-07-00700.pdf.  Based upon an in-depth audit of 41 grantee institutions that reported conflicts in FY 2006, the OIG found that equity interests represent the most pervasive form of financial conflict of interest. The most popular tool employed by entities managing conflicts is disclosure to publications or at academic presentations; entities only rarely required the reduction or elimination of conflicts.  As important, and unsurprising based upon AAMC surveys, is the unreliability of the conflict reporting mechanisms used by most academic institutions.

The OIG report emphasizes the need for increased oversight of conflicts of interest.  Academic medical centers have had plenty of time and forewarning to address the issue but, as demonstrated by a vignette described by Goldner about his own efforts to accomplish this through the IRB which he chaired, faculty resistance is significant.  Consequently, Goldner is exactly right in calling upon HHS to issue aggressive regulations that accomplish the necessary reforms.  He would require the establishment of conflict of interest committees at every research institution, comprised primarily of independent members, to which faculty would report all financial relationships that create conflicts of interest. Resolution of such conflicts would be a condition precedent to proceeding with proposed research, and violations would result in significant penalties, including debarment from research.

As shall be discussed in a forthcoming Seton Hall White Paper entitled The Limits of Disclosure as a Response to Conflicts of Interest in Clinical Research, I do not have confidence in benefits accruing from requiring disclosure of conflicts to research participants in consent forms, although research participants do have a right to know of such conflicts.  This is a minor quibble.  Goldner’s article is a great contribution to the literature. 

Financial Remuneration of Clinical Study Investigators

In November 2009, the Center for Health & Pharmaceutical Law & Policy, in its White Paper, Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight, explored payments to investigators — and other potential motivators — to conduct research.  A study in this month’s IRB: Ethics & Human Research explores the impact payments may have on researchers to conduct and complete studies.  In Motivated by Money? The Impact of Financial Incentive for the Research Team on Study Recruitment, Sharon Unger and her colleagues examine the effect financial remuneration has on researchers in a neonatal intensive care unit (NICU).

Taking advantage of a “fortuitous set of circumstances” in which two separate clinical trials with nearly identical inclusion criteria were conducted simultaneously in an NICU in Canada, the authors looked at two issues: 1) whether financial remuneration impacted the rate at which the research team approached parents about research participation, and 2) whether financial remuneration impacted the rate at which parents provided consent to participate.

In the first study (Study A), a placebo-controlled trial involving a medication that was the standard of care for treatment of newborns nearing extubation to prevent apnea of prematurity, members of the research team were financially compensated for their time if they were successful in obtaining parental consent (parents were unaware of this arrangement).  In the second study (Study B), which involved two different forms of noninvasive respiratory support following extubation, there was no financial compensation of the research team.  Both studies had the same recruiting team.  Study A was federally funded, multicentered and high-profile, while Study B was a single-center, unfunded trial.

The payments in Study A were per capita, which, while creating a direct incentive to recruit individual enrollees, is usually not problematic as long as the payment is not excessive.  The Center recommends “that the benchmark for compensation for physician services for research should be comparable payment for time and services for treatment. This will compensate physicians fairly for their time and services, and will assure that there are no hidden bonuses or incentives for physicians to recruit patients into research or to refer them to research rather than treatment.”  As noted in the study, finder’s fees are increasingly considered “ethically problematic;” the Center recommends a wholesale bar on finder’s fees because they can create conflicts of interest that can incentivize investigators to recruit and retain individuals who do not meet the study’s inclusion and exclusion criteria.

As the authors noted, and as acknowledged in the Center’s White Paper, potential enrollees are increasingly vulnerable as increasing numbers of individuals seek to participate in research either as a primary means of access to treatment or as a form of income.  The results of this study indicate a much higher likelihood of approach when there was a prospect of financial remuneration.  These results are concerning, and were anticipated by the Center’s White Paper, which noted the potential for poor compliance with inclusion and exclusion criteria and pressure to enter or remain in a clinical trial.

However, surprisingly, the authors found that, despite the much higher likelihood of approach for Study A than Study B, parents were much more likely to actually agree to enroll their newborn in Study B — for which there was no financial remuneration of the research team.  The authors explored various explanations for this result, including that the research team was overly cautious about giving the appearance that their approach for consent was motivated by financial compensation, or that parents chose to withhold consent  due to the research team’s  increased pressure.

The authors do acknowledge other potential factors — beyond financial remuneration –  that could have affected the study’s results.  For example, parents’ hesitancy to enroll their newborn in a placebo-controlled drug trial could explain the discrepancy between enrollment in the studies.  Likewise, the authors consider that parents may not have been able to differentiate between the two modes of support being investigated in Study B.  In addition, the recruiting team, when presented with the results of the study, did not recall feeling influenced by the financial arrangement of Study A, but did “recall being highly motivated to ensure the success of Study A as it was part of a high-profile, multicentered trial.”

The authors concluded by noting concerns that “there may be a point at which the amount of the financial remuneration or the manner in which it is assigned could negatively impact the ethical conduct of the researcher,” but cautions that these concerns should be balanced with the value of conducting research in patients’ best interests.  This balancing act is considerably important.  As the Center notes,

Research is critical to the advancement of medical treatment and health. It must be structured to produce high quality data that facilitates the assessment of safety and efficacy in the population for whom the treatment will be used. The good of the enterprise requires that the clinical trial system sufficiently balance the costs and benefits to physicians and prospec­tive trial participants to ensure the continued sufficient supply of researchers and subjects. The system must also be imbued with actual and perceived integrity — so that it produces scientifi­cally reliable results, participants are safe, and people trust the system sufficiently to be willing to participate.

Further Calls for Increased Oversight on Medical Research & Physician Conflitcs of Interest

The Center for Health & Pharmaceutical Law & Policy has continued to focus on the implications of research funding in patients’ decisions to participate in clinical research, as well as the effects such funding can have on researcher behavior and research results.  In January 2009, the Center recommended that all financial relationships between industry and physicians be publicly disclosed by industry.  And just this month, the Center released its most recent White Paper, “Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight.”

Similarly, in a November 17 letter to Francis Collins, 100 researchers, academics, and public policy analysts asked the NIH to “fund studies on medical ethics, conflicts of interest in medicine and research, and prescribing behavior” in order to determine the effects of industry-academic relationships on human health.  The letter implores the director of NIH to focus on “the research gap on the effect of conflicts of interest and commercial influence on medical decisionmaking” and to establish a mechanism for funding relevant research.

One of the primary concerns in the researchers’ letter is an issue also identified in a November OIG report, “How Grantees Manage Financial Conflicts of Interest in Research Funded by the National Institutes of Health,” which found that a majority of academic researchers’ conflicts of interest are unreported.   The report flags the potential for extensive conflicts between faculty members and their government-financed research.  In response, the US Senate Finance Committee recently sent letters to several universities requesting such information.  Just yesterday, Northwestern University’s Feinberg School of Medicine, reacting to national concern about physicians’ and researchers’ financial conflicts of interest, began posting external professional and industry relationships for approximately 2000 faculty members — including service on boards of directors, consulting and related activities, ownership or investment interests, royalties and inventor shares, and additional activities such as lectures and participation in scientific advisory boards and professional societies.

Further research is obviously necessary to determine how financial relationships influence — as the authors of the letter to NIH call it — “the beliefs and behaviors of researchers and clinicians, and the effects of industry-academic relationships on the generation and dissemination of medical knowledge.”  In the meantime, increased oversight of physician-industry relationships by the federal government to evaluate and oversee investigator or institutional conflicts of interest, both for research within and without academic medical centers, is necessary.

Reform Rodeo

1. Kaiser Health News rounds up today’s editorials on health reform.

2. The New York Times reports that the CBO’s latest report finds that the Senate’s health bill will not increase premiums for the majority of Americans.

3. David Leonhardt describes how the Senate’s bill may offer more cost-cutting options than it is typically given credit.

4. John Iglehart offers his perspective on the the process that has allowed the Senate’s health reform bill to proceed to floor debate.

5. The Hastings Center has a thorough piece on the controversy surrounding the U.S. Preventitive Services Task Force’s decision to alter the recommended guidelines for mammography.

6. In case you missed it: Associate Dean Kathleen Boozang in The Health Care Blog regarding the Center for Health & Pharmaceutical Law & Policy’s latest White Paper: “Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight.”

7. In case you missed it again: Professor John V. Jacobi in the New Jersey Law Journal on “Genetic Discrimination and the Future of Health Insurance.” (First posted here on HRW).

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy Issues White Paper Calling for Major Reforms in the Financing and Oversight of Clinical Research

Seton Hall University School of Law’s Center for Health & Pharmaceutical Law & Policy has called for major substantive reforms in the financing and oversight of clinical research. In a White Paper entitled “Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight,” the Center proposes legal and policy changes to address conflicts of interest in the relationships between industry and doctors that can create unwarranted risks to trial participants and to the scientific integrity of research.

Kathleen Boozang, a dean who oversees the Law School’s Center, explains that “Some of the ways that drug and device trial sponsors pay the physicians who lead clinical trials can tempt them to recruit individuals for clinical trials who would be better off receiving conventional therapy. This is of particular concern if physicians encourage their own patients to enroll in trials that these same physicians are overseeing.”

Over 60% of testing of experimental drugs and medical devices now occurs in physicians’ private offices; unlike years past, industry funds a much higher percent of clinical trials than government, frequently paying researchers significantly more than government does.  For some physician practices, conducting clinical trials represents a significant portion of their income.

According to Carl Coleman, a Seton Hall Law professor who collaborated on the White Paper, “A different kind of problem arises if people are enrolled in trials who don’t meet the criteria for who should participate - these individuals’ health can be put at risk, and their participation can skew the results of the trial, which is bad for everyone.”

Federal regulations in this area have not kept up with the rapid changes in how research occurs, and even those regulations that exist are poorly enforced, according to recent government studies.  Understanding that the collaboration among industry, government, and medicine in the pursuit of clinical research is critical to driving scientific progress, particularly as industry increasingly replaces the government as the primary source of research funding, the Center’s recommendations include:

1) Establishing a norm of financial neutrality between treatment and research. Ensuring that physicians receive comparable compensation for treatment and research will help ensure that their decisions to conduct research, as well as to recommend that a particular individual participate in a clinical trial, are grounded in reasons unrelated to their personal financial interests. This will be best accomplished, in the first instance through regulations that ban certain kinds of research compensation, and provide examples of acceptable payment methodologies that industry can follow. Reform by prosecution signals what practices government dislikes, but does not provide a clear vision of ideal approaches to managing conflicts of interest related to the conduct of research.

2) Establishing federal guidelines as to the principles or methodology by which to determine fair market value of physician time spent in clinical work. Federal regulations should be promulgated that establish a benchmark formula for determining fair market value of physicians’ time, effort and expenses for clinical research. Such regulations would promote the goal of financial neutrality between treatment and research. Physicians cannot be underpaid for research either - compensation for clinical trial work should therefore include reimbursement for any additional expenses that are unique to the research environment.

3) Banning payments with equity interests; disqualification of investigators who hold direct interests in the outcome of the research. Federal regulations should prohibit compensation for research in the form of an equity interest in the sponsor of a clinical trial. The law should preclude researchers who have investments that give them a direct interest in the outcome of the research from leading clinical trials.  Where absolutely necessary, such individuals might appropriately serve as consultants.

4) Banning payments of finder’s fees and bonuses for recruitment and retention of trial subjects. Certain forms of compensation create conflicts of interest that can incentivize investigators to enroll individuals in a clinical trial who are too healthy or too sick to participate, or to deemphasize information that might discourage individuals from consenting to trial enrollment. Federal law should ban such compensation methods, including finder’s fees and bonuses for meeting recruitment and retention goals.

5) Reforming federal regulations to compel and better guide the evaluation of relationships between industry and would-be physician investigators prior to the commencement of research.   The White Paper includes overlapping but sometimes distinctive recommendations for federal regulation to evaluate and oversee investigator or institutional conflicts of interest, both for research within and without academic medical centers.  Specific to research outside of academic medical centers, federal regulations should spell out clearly the obligation of community-based physicians acting as investigators or institutions acting on their behalf to report information about compensation for research and other financial interests to Institutional Review Boards.

Summarizing the importance of this White Paper, Boozang states, “The pharmaceutical and medical device industries save millions of lives each year with their innovations.  It is imperative that we maintain the integrity of research, and the public’s trust in the process.”

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy. The Center is a think tank that fosters dialogue, scholarship, and policy solutions to critical issues in health and pharmaceutical law. As part of its mission, it convenes policymakers, consumer advocates, the medical profession, industry, and government in the search for concrete solutions to the ethical, legal, and social questions presented in the health and pharmaceutical arenas. The Center also runs a compliance training program covering the state and federal laws governing the development and marketing of drugs and medical devices. The White Paper, “Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight,” may be found here.

Seton Hall University School of Law, New Jersey’s only private law school and a leading law school in the New York metropolitan area, is dedicated to preparing students for the practice of law through excellence in scholarship and teaching, with a strong focus on clinical education. The Law School’s health law program has been ranked as one of the top programs in the country. Founded in 1951, Seton Hall Law School is located in Newark and offers both day and evening degree programs. For more information visit law.shu.edu.