[Pharm-policy] NIH on: FINANCIAL CONFLICT OF INTEREST IN CLINICAL RESEARCH

[James Love]

Thanks to MP for passing on this article, which appears to be from an NIH intranet link
http://catalyst.cit.nih.gov/catalyst/2000/00.09.01/

 
T H E   N I H    C A T A L Y S T           S E P T E M B E R  -  O C T O B E R   2000
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WHERE TO DRAW THE BOTTOM LINE:

FINANCIAL CONFLICT OF INTEREST IN CLINICAL RESEARCH

text and photos
by Fran Pollner
Steering the Course: (left to right) FDA Commissioner Jane Henney;
Ruth Kirschstein, NIH principal deputy director; and Stuart
Nightingale, an HHS senior medical advisor and chair of the
conference planning committee, set the stage for a two-day
exploration of how best to disarm the threat of what Kirschstein
termed a "collision" of financial interests and investigator
objectivity.

One year after the death of 18-year-old Jesse Gelsinger in a
University of Pennsylvania gene therapy trial, the research
community and its federal overseers continue to grapple with
strategies to ensure the scientific integrity of clinical trials,
the safety of patients enrolled in them, and the objectivity of
investigators conducting them.

These essential components of clinical research-scientific
integrity, patient safety, and investigator objectivity-may be
compromised when researchers or institutions conducting a trial, or
members of the review board that approves it, are financially
invested in the product under study or its sponsor, participants
agreed at an overflow conference here on "Human Subject Protection
and Financial Conflict of Interest."

The conference was convened by HHS and its agencies (FDA, NIH, and
CDC) to tackle the issue of real and perceived investigator bias in
a research environment increasingly invested in "breakthrough"
results and the drive for efficient technology transfer, as mandated
in the Bayh-Dole Act.

The blurring lines between study sponsor and investigator and the
ethical problems this creates-brought into sharp relief by the
circumstances of the Penn trial but not unique to it-were the main
subject of the conference. The spotlight was cast on the potential
threats to study integrity wrought by the growing involvement of
clinical investigators and research institutions in the companies
sponsoring trials they are supervising.
No Two Ways About It


Where do you draw the line on conflicts of interest?

"Would it pass the '60 Minutes' test? If not, don't allow it."-Abbey
Meyers, National Organization for Rare Disorders.

The central questions posed to conference participants revolved
around where to draw the line between acceptable and unacceptable
financial interests among the parties involved in a clinical trial
and whether, when, and how much to disclose to study patients.

The answers were diverse. Many speakers believed that most financial
conflicts of interest could be "managed" to eliminate the
possibility of harm to either research subjects or research results.
Others contended that nothing short of elimination of the financial
conflict itself would do.

(Based on the conference proceedings and written responses to six
questions posed in the July 3 Federal Register notice announcing the
conference, HHS will produce new guidelines for the medical research
community. The deadline for responses is September 30. See "Have
Your Say," below.)

Setting the Stage

"Objectivity," NIH Principal Deputy Director Ruth Kirschstein said,
"lies at the heart of science and must not be compromised by
financial gain-or fame or the pursuit of insights," she added,
noting that it is not only money that can color an investigator's
judgment, but that only money was the issue at hand this time
around. She asked the assembled to "share your best practices" in
the realms of disclosure of financial interest and distinguishing
financial interests that do and do not compromise objectivity.

FDA Commissioner Jane Henney noted that under current FDA
procedures, disclosure of an investigator's financial interest in
the product under study-or certification that there are no such
interests-is required at the time of FDA review of the completed
study, not at the time of application to pursue the study. But she
asked whether disclosure of financial interests alone would be
enough to protect patient safety. The death of Jesse Gelsinger, she
observed, had "raised the question of whether financial interest had
clouded clinical judgment. . . . the multiple hats of the
physician/clinical investigator/sponsor [create] real and perceived
conflicts of interest and must be addressed."

Zero Tolerance
Not eye to eye: James Benson (left) and Marcia Angell

The way to address conflicts of interest, according to Marcia
Angell, a lecturer in social medicine at Harvard and former editor
of the New England Journal of Medicine, is to prohibit them. She
defined a financial conflict of interest as any financial
association that could cause an investigator to prefer one outcome
over another and dismissed the notion that disclosure of financial
conflicts of interest in patient consent forms would in any way
protect patients. "That simply passes the buck to the patient. It's
just 'caveat emptor.'"

Angell decried "dancing on the margins of the issue . . . to
accommodate something that shouldn't exist in the first place" and
pointed to Harvard's "impenetrable pages" as an example of
"mind-boggling guidelines" that miss the essential point:
"Investigators with grant support from industry must have no other
financial ties to that company, just like a judge on the bench
deciding the merits of a case."

"In my two decades [at the NEJM]," Angell said, "it has been my
impression that bias in study design and interpretation of data are
far more likely in investigators with industry ties."

Moreover, she advised that:

 Grants from industry to institutions should come with no strings
attached, as they used to.

 Technology transfer does not require consultancy fees.

 Institutions and their senior officials should limit their
investment portfolio to "rubies and racehorses."

"This might seem radical," she added, "but it's only because our
society is so drenched in market ideology that opposition seems
quixotic."

"It's a lot more complex than that," countered James Benson, an
officer of the Advanced Medical Technology Association (formerly the
Health Industry Manufacturers Association). Up to two-thirds of
"breakthrough" devices, he said, originate from an engineer who
creates a small start-up company and has no other way of financing
research but through offering scientists equity.

Speakers for the Association of American Universities and the
Association of American Medical Colleges cautioned against
overregulation and equating conflict of interest with scientific
misconduct. The latter could be prevented with appropriate
institutional safeguards.

Industry Influence

Traditional sources of financial support for medical schools have
been drying up, and industry has been stepping in. According to a
survey undertaken by the Massachusetts General Hospital Institute
for Health Policy, director David Blumenthal said, about 25 percent
of medical school facilities have research support from industry and
about 8 percent have equity in companies related to their research.
Sid Wolfe

Sid Wolfe, long-time director of the Washington-based Health
Research Group, a patient advocacy organization, warned of the
burgeoning "for-profit human experimentation industry" with its
"business model of recruiting research subjects for their paying
clients, the pharmaceutical companies." These corporations, he said,
have no teaching or care responsibilities and they "recruit from
private practices, offering monetary incentives to private
physicians with no clinical research experience who persuade their
vulnerable patients to sign up." They should be abolished, Wolfe
said, as should finders' fees to physicians (typically in the range
of $1,000 to $5,000 per patient).
Thomas Bodenheimer

Further cause for alarm over industry control of clinical studies
was provided by Thomas Bodenheimer, clinical professor of family and
community medicine at the UCSF School of Medicine and a
correspondent for the NEJM. He presented data showing that published
findings are nearly always favorable to the study drug when the
study was funded by the drug maker and that study drugs are given
more favorable write-ups when the author has financial ties to the
sponsor.

He presented documented cases of faulty trial design (competing
drugs given in ineffective doses or by inappropriate routes; study
population substantially different from intended patient
population), skewed data analysis (results reported only from those
sites in a multicenter trial at which the study drug did well),
suppression of publication altogether in the face of unfavorable
findings, "conclusions" in abstract or summary that are not
supported by the data, and the use of hired "ghosts" to write
reports under an investigator's name.

Remedies, he said, include separating sponsors from all aspects of
study design, data analysis, and publishing. More funding of
clinical investigators should come from NIH than from industry, he
urged, and industry should funnel its budgeted clinical trial money
through NIH and then walk away, leaving NIH to sponsor the trial.

Some Policies and Practices

>From a professional society: Savio Woo, president of the American
Society of Gene Therapy, announced that his organization had adopted
the policy that its members either refrain from participation in a
study sponsored by a company in which they have a financial interest
or, alternatively, give up that interest.

At research institutions:

 At Boston Children's Hospital, said Susan Kornetsky, director of
clinical research compliance, disclosure of financial interests
accompanies research protocols submitted to the IRB, which decides
whether and how much to inform research subjects (an IRB member with
a conflict must leave the room during the final discussion and
vote); all faculty must comply with Harvard policy, which places a
ceiling on the amount of allowable financial gain; a trial may not
be supervised or conducted by the inventor of the study product;
recruitment fees and completion bonuses are prohibited; if the
hospital has an equity interest, that must be disclosed in the
informed consent document; and issues of budget, publishing rights,
and data ownership must be agreed upon before protocol approval.

 "There is no evidence that financial interests, which have become
part of the research landscape, are inherently harmful," said Julie
Gottlieb, executive director of the Office of Policy Coordination at
Johns Hopkins University School of Medicine in Baltimore, "but they
require disclosure and review, and their management is
labor-intensive." Hopkins has a separate Conflict of Interest
Committee, made up of senior faculty and administrators, that meets
regularly and is advisory to the IRB. Hopkins policy requires
reporting of all financial interests, however small and whatever the
nature of the research-basic or clinical-and public disclosure in
the patient consent form. Investigators with a financial interest
may not be the principal investigator, obtain informed consent, or
analyze data. Divestiture of financial interests and bottom-line
rejection of the protocol are also possibilities.
Greg Koski

Summing Up

Greg Koski, the first director of the newly revamped HHS Office for
Human Research Protections, summed up what he saw as areas of
consensus:

 Conflict of interest in clinical research is real and is a threat
to clinical research.

 Conflict of interest has intensified over the last two decades and
has gotten "out of control" in the last five years.

 Those conflicts of interest that cannot be eliminated completely
must be "managed," and institutional review boards cannot do it
alone. There need to be uniform guidelines throughout government-or,
if compliance is lagging, then rules.

 
Have Your Say

Though the conference on "Human Subject Protection and Financial
Conflict of Interest" unexpectedly drew nearly 800 registrants,
several speakers observed that the meeting was short on clinical
investigators and patients. Federal officials expressed the hope
that some of that gap would be filled by written responses to six
questions posed in the July 3 Federal Register to jump-start the
conference. For a conference overview, with links to the questions
and other materials, visit

<http://aspe.hhs.gov/sp/coi>.

Responses may be sent to

<coi@osaspe.dhhs.gov>

or to Stuart Nightingale, Office of the Assistant Secretary for
Planning and Evaluation, Hubert H. Humphrey Building, Room 447D, 200
Independence Ave., S.W., Washington, D.C. 20201.

The deadline is September 30.

 
The Wheels of Change

Much of the public examination of the conduct and federal oversight
of the University of Pennsylvania gene therapy trial, as well as of
clinical trials in general, has taken place on the NIH campus. Last
December, newspapers across the country carried the details of how
the Penn study was conducted, the pitfalls of adenovirus gene
vectors, and the controversies over clinical trial adverse event
reporting and the curtailed authority of the NIH Recombinant DNA
Advisory Committee (RAC)-the substance of a heavily attended
three-day meeting here of the RAC (see The NIH Catalyst,
January-February 2000).

Subsequent meetings of the RAC and the Advisory Committee to the NIH
Director (ACD) examined the boundaries of NIH and RAC oversight of
clinical gene transfer research. An ACD working group convened last
year by then-NIH director Harold Varmus issued a preliminary report
in July suggesting changes in protocol submission and review
procedures that would ensure RAC input into novel gene therapy
protocols before they are presented to authorizing bodies such as
the Food and Drug Administration. Although investigators would not
be required to comply with any RAC requests, such as more
preclinical work or protocol changes, they would be required to
respond publicly. The overall effect of the ACD working group
proposals would be, first, to ensure that no patient is enrolled in
a gene transfer study that the RAC has not reviewed and, second, to
make it more likely that RAC advice is followed. A majority of the
working group, as well as the RAC itself, also opted to modify RAC
requirements for the reporting of serious adverse events that occur
in gene therapy trials to be more in line with those of the FDA,
which requires immediate notification only of those serious adverse
events that are both unexpected and related to the experimental
therapy. A minority of the working group, however, urged that all
serious adverse events be reported as they occur, and that a central
body of experts, with both FDA and RAC presence, be established to
receive and interpret these reports. NIH Principal Deputy Director
Ruth Kirschstein will act on the final ACD report.

Meanwhile, the NIH Intramural Research Program has crafted interim
guidelines regarding reporting adverse events for intramural
investigators involved in any and all clinical research. The details
of these guidelines are under discussion, but the current
requirement is expedited reporting to the IRB of all serious adverse
events except those anticipated in the IRB-approved research
protocol.