Monday, May 17, 2004

Ethical Questions at NIH

A while ago, I posted several articles on the safety and effectiveness of antidepressant medication.  On of the posts provoked an e-mail from Alex, the author of the Pseudoscience in Psych  blog.  Although he is an outspoken critic of certain aspects of psychopharmacology, he is well-informed and well-meaning.  part of his message to me was:

I'll believe that antidepressants work better than placebos when I see
large-scale, rigorously designed, independently conducted (i.e., not
financed by Big Pharma) studies where an active placebo is used and where
the double-blind conditions are tested and not simply taken for granted.

I have gotten distracted by other things, but I always meant to write up an explanation of why his objections are so important, and what is being done about them.  To this end, I started to look into the Star*D (Sequenced Treatment Alternatives to Relieve Depression) research program.  Star*D is a large, multicenter research program that is funded by NIH.  A synopsis is located on the University of Michigan Health System Depression Center page (here, scroll down).  For more information, go to PubMed and search for "Star-D".  SInce the program is funded by NIH, I thought that it might answer at least one of Alex's concerns. 

Unfortunately, there are complications.  I decided to look into the state of things at NIH.  This   article is about the complications at NIH.  I conclude with some comments of my own. 

The US National Institutes of Health (home, about) is one of the largest research organizations in the world.  Their budget in  FY 2003 was $27,066,782,000 in Congressional appropriations.  Their mission statement is as follows:

NIH is the steward of medical and behavioral research for the Nation. Its mission is science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability. The goals of the agency are as follows: 1) foster fundamental creative discoveries, innovative research strategies, and their applications as a basis to advance significantly the Nation's capacity to protect and improve health; 2) develop, maintain, and renew scientific human and physical resources that will assure the Nation's capability to prevent disease; 3) expand the knowledge base in medical and associated sciences in order to enhance the Nation's economic well-being and ensure a continued high return on the public investment in research; and 4) exemplify and promote the highest level of scientific integrity, public accountability, and social responsibility in the conduct of science.

Sounds good, doesn't it, especially the part where they talk about how they exemplify and promote the highest level of scientific integrity, public accountability, and social responsibility in the conduct of science

On December 7, 2003, (which, ironically, is the anniversary of Pearl Harbor Day) an article was published in the LA Times (free registration required): 

Stealth Merger: Drug Companies and Government Medical Research
Some of the National Institutes of Health's top scientists are also collecting paychecks and stock options from biomedical firms. Increasingly, such deals are kept secret.

By David Willman, Times Staff Writer

BETHESDA, Md. — "Subject No. 4" died at 1:44 a.m. on June 14, 1999, in the immense federal research clinic of the National Institutes of Health. 

The cause of death was clear: a complication from an experimental treatment for kidney inflammation using a drug made by a German company, Schering AG.

Among the first to be notified was Dr. Stephen I. Katz, the senior NIH official whose institute conducted the study.

Unbeknown to the participants, Katz also was a paid consultant to Schering AG.

Katz and his institute staff could have responded to the death by stopping the study immediately. They also could have moved swiftly to warn doctors outside the NIH who were prescribing the drug for similar disorders. Either step might have threatened the market potential for Schering AG's drug. They did neither.

Questioned later, Katz said that his consulting arrangement with Schering AG did not influence his institute's decisions. His work with the company was approved by NIH leaders.

Such dual roles — federal research leader and drug company consultant — are increasingly common at the NIH, an agency once known for independent scientific inquiry on behalf of a single client: the public.

Two decades ago, the NIH was so distinct from industry that Margaret Heckler, secretary of Health and Human Services in the Reagan administration, could describe it as "an island of objective and pristine research, untainted by the influences of commercialization."

Today, with its senior scientists collecting paychecks and stock options from biomedical companies, the NIH is no longer an island.

The article was the product of five years of investigational reporting.  It followed the time-honored media principle of "If it bleeds, it leads."  Unfortunately, the credibility of the article was tarnished by the sensationalism, as explained in the Slate article here.  Still, the main point of the article, that the NIH no longer can claim the moral high ground, caused a significant turmoil at NIH and in Congress. 

NIH commissioned a Blue Ribbon Panel to investigate, and to make recommendations.  The political fallout was considerable, as echoed in the Detroit News:

Probe sought into NIH officials' outside work
By David Willman / Los Angeles Times
Saturday, January 17, 2004

WASHINGTON -- Three leading House Democrats on Friday asked the General Accounting Office to investigate consulting fees and stock options paid by drug companies to employees at the National Institutes of Health.

Citing details from a Los Angeles Times article published last month, the House members called for an “investigation into potential conflicts of interest” at the federal government's center for medical research on humans.[...]

The request made Friday by Democratic Reps. Henry A. Waxman of California, John D. Dingell of Michigan and Sherrod Brown of Ohio follows the announcement of an inquiry being led by the Republican chairman of the House oversight and investigations subcommittee, Rep. James C. Greenwood of Pennsylvania. The Appropriations subcommittee on labor, health and human services and education, chaired by Sen. Arlen Specter, R-Pa., also plans to question NIH officials at a hearing on Thursday.

A spokesman for NIH, John Burklow, said the agency's director, Dr. Elias A. Zerhouni, was cooperating and “working closely with the committees.” Burklow added, “He takes these, and NIH takes these, concerns very seriously. Extremely seriously.”

Additional follow-up articles are here: 1  2  3  4.  The director of NIH, Elias A. Zerhouni, M.D.,  was interviewed in an editorial published in the New England Journal of Medicine, here.  A subscription is required to see the text at NEJM, but someone posted a full copy here.  As except follows:

In an interview in early January, Zerhouni said: "What is being portrayed in the press is not the reality, but that doesn't mean that we couldn't do a better job of managing the conflict issues." The controversy "still leaves the question of perception of inappropriate conflict-of-interest management and whether or not we pass the smell test in terms of perception. It is important for me to address that."

The NIH Blue Ribbon Panel released a draft report (689 KB PDF download, here) on May 5, 2004.  They agreed that there is a problem, although they took pains to report the problems in a way that minimized the potential impact:

In its deliberations the Panel found an extremely complex set of rules governing conflicts of interest at NIH. These rules are widely misunderstood by some of the very people to whom they are intended to apply, thereby creating uncertainty as to allowable behavior and adversely affecting morale. [...]

The Panel found that relatively few NIH employees engage in consulting agreements with biotechnology or pharmaceutical companies -- an activity that currently involves approximately 120 of NIH's 17,526 employees. Yet the high level of reasonable concern expressed by Congress and the media about the potential for conflicts of interest when consulting with industry -- itself a small fraction of the outside activities engaged in by NIH scientists -- has had a decidedly negative impact on the morale of a large number of NIH intramural scientists.

They went on to make 18 specific recommendations.  I won't go over them in detail, but to summarize, most of the recommendations serve to increase transparency and accountability.  There is a recommendation that income from outside activities by limited to 50% of the employee's base pay, and that no more than 25% should come from any one source.  They also recommend that the cap on base pay be increased.  The latter recommendation was made because The Panel is concerned that the present ceiling is limiting the agency's ability to recruit and retain the nation's best scientists as the leaders of NIH.

The publication of the draft report has not quelled the criticism.  Among the four follow-up articles cited above, the most recent is this one:

NIH Conflict Findings Left Out
Ethics panel's final report did not detail all permissive practices, agency documents show.
By David Willman, Times Staff Writer
May 12, 2004

WASHINGTON — A blue-ribbon panel that examined conflict of interest at the National Institutes of Health found permissive practices that were not detailed in its final report last week, internal agency documents show.

The documents also show that top aides to NIH Director Elias A. Zerhouni were allowed to review and comment privately on the panel's draft findings.

Congressional investigators have expressed interest in the circumstances surrounding compilation of the report, issued Thursday. The next day, the chairman of the House Oversight and Investigations subcommittee, Rep. James C. Greenwood (R-Pa), wrote to Zerhouni, seeking "all records relating to the minutes and records of closed sessions of the Blue Ribbon Panel, as well as all drafts of the report." [...]

Again, Mr. Willman strikes an adversarial tone in is article, immediately keying in on what was left out  of the report, rather than reporting on what is in  the report. 

Blogosphere commentary is limited, which surprises me.  Robert M. Centor, MD, on Medrants, stated:

Medical researchers (not unlike most humans) like the ability to make extra money. Being a paid consultant has the veneer of appropriateness and respectability. The researchers easily delude themselves that as scientists they are immune from influence. Unfortunately, this naivety allows them to unknowingly make mistakes.

They justify their actions as necessary to support their overall research. They truly mean well. However, much like Dr. Faustus they are selling their souls. This is the dirty secret of much medical research.

We need a new ethical standard. We need to understand why we engage in this dance. We need to stop.

One of the comments on his post led to this, by Carey Cuprisin (a University of Michigan Law student) at Glorfindel of Gondolin:

Unfortunately, I think we'll have to make them stop. The siren song of $$ is, again, proving resistant to wholly voluntary "ethical standards."

On McConchie on Bioethics, Daniel McConchie wrote:

Major changes urged at NIH to avoid conflict-of-interest charges
[...] While many view the ability of NIH employees to privately consult as essential for an effective medical research complex, the unlimited policy has created a situation where government employees can profit from their policy decisions that either help or hurt specific pharmaceutical or biotech companies. The risk of abuse is very real as those charged with promoting useful medical research could try to benefit companies who could, in turn, benefit the employee who made it happen. Congress has now gotten into the mix by urging NIH to adjust its policies.

Our cutting-edge medical research establishment is a cornerstone of the best available healthcare in the world. Everything must be done to ensure that the research has every tool it needs while balancing that need with enough oversight that ensures the system isn't manipulated. I'm happy that we allow talented researchers to make more than our government positions can pay as it helps the NIH keep some of the best people in important and necessary government roles. Let's just make sure the taxpayer doesn't suffer from a system that could allow personal greed, rather than societal need, run the show.

Medpundit, written by the pseudonymous Sydney Smith, has a post  that deals with the topic in general, without addressing the NIH issue directly:

Tales from Cloud Cuckoo Land: Shannon Brownlee has a lengthy piece in the Washington Monthly about the corporate corruption of scientific research. Even the editors of major medical journals know there's a problem:

As Dr. Drummond Rennie, deputy editor of The Journal of the American Medical Association (JAMA), puts it, 'This is all about bypassing science. Medicine is becoming a sort of Cloud Cuckoo Land, where doctors don't know what papers they can trust in the journals, and the public doesn't know what to believe.'

Looking at all the sources, it appears that the only people defending the NIH are the people who work there, and perhaps some of the members of the Blue Ribbon Panel.  Personally, I think that the issue is not quite as horrific as the LA Times writer, David WIllman, makes it out to be.  And I think that the Slate commentator, Jack Shafer, has a good point when he says:

Willman undercuts his considerable accomplishment with an opening (and a conclusion) that is as sensational as anything you'd read in an "if it bleeds, it leads" tabloid.

Even so, NIH is getting a well-deserved housecleaning courtesy of the US Congress, and it appears that the initial efforts have fallen short of most people's expectations.  The key problem they face is that if they completely cut off ties with industry, that could stifle biomedical development.  People who otherwise could be helped, will stay sick and possibly die, if biomedical development is stifled.  But too much industry influence could lead to the loss of the only source of objectivity we have in the biomedical research arena.  I agree with the NIH director, Dr. Zerhouni, when he states that "Transparency — full light on any relationship — is one of the best protections against any real or perceived conflict of interest," as quoted in the NEJM editorial.  Medical journals need to accelerate the trend of reporting potential conflicts of interest by the authors. 

One idea that came to me as I was preparing this is that perhaps the federal government could establish a central registry, in which all researchers are required to submit information when they accept industry funding from any source.  This goes against my usual ideal that the less information the government has about individuals, the better.  And the less paperwork we have to do, the better.  I think, though, that the potential for misuse of the information in a central registry is minimal, and the benefits of the paperwork would outweigh the hassle.  There would be three benefits: 1) greater trust in biomedical research, 2) greater accountability for industry, and 3) researchers would be forced to take stock of the influences that affect them. 

One of the criticisms on Medrants  was this: The researchers easily delude themselves that as scientists they are immune from influence. Unfortunately, this naivety allows them to unknowingly make mistakes.  Having a central registry of financial influences would address this, by making the researchers keep track of their financial gains from industry sources. 

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