More Ambiguous Financial Arrangements at the NIH

We have posted frequently, most recently here and here, about conflicts of interest affecting top US National Institutes of Health (NIH) scientists and leaders.

The Los Angeles Times again has published another investigative report (in two articles, here and here) on relationships between officials at the NIH and pharmaceutical and bio-technology companies. The articles focused on Dr Thomas J Walsh, Head, Immunocompromised Host Section, Pediatric Oncology Branch, Center for Cancer Research and the National Cancer Institute (NCI).

The articles raise two questions:

• Were Walsh's spoken or written comments about anti-fungal drugs influenced by his relationships with several pharmaceutical companies, particularly when Walsh was speaking to US Food and Drug Agency (FDA) advisory panels as an NIH scientist?
• Were clinical studies of these drugs, with which Walsh was involved in a variety of ways, designed so that they were likely to favor particular drugs?

Since the issues raised by the second question are very complex, I can't hope to try to answer it without spending a lot of time reading reports of all the trials, and relevant background information. So I will set it aside for now.

The issues raised by the first question are perhaps clearer. I will summarize what the articles said about Dr Walsh's relationships with several companies.

Merck & Co

By 1999, Walsh was collaborating with Merck & Co., on its new antifungal drug, Cancidas.

Merck persuaded the FDA to conduct a fast-track review of Cancidas for a more narrow use: treating aspergillus in patients who had either not tolerated or failed to improve while taking another antifungal drug.

On Jan. 10, 2001, representatives of Merck — assisted by Walsh — presented the company's case for approval of the drug to the FDA advisory committee in Bethesda.

Walsh, in his statement to The Times, said: 'I did not appear as a consultant to Merck.'

But that is how Merck identified him to the FDA committee, both orally and in a slide.

Tamara Goodrow, a Merck regulatory affairs official, said: 'Merck has brought several consultants to the meeting today so that they are available to facilitate the advisory committee's discussion and deliberations.' Goodrow then named the consultants, including 'Dr. Thomas Walsh.'
Another Merck official said Walsh served as the head of a company committee of three researchers who assessed how patients with aspergillus infections had responded to treatment with Cancidas in the smaller company study.

A videotape of the meeting shows, Merck's senior director of clinical research, Dr. Carole A. Sable, gestured to the audience and said: 'Perhaps Dr. Walsh, who is actually the head of our expert panel, would like to make a comment.'

Walsh strode to the podium, took the microphone and assured the FDA committee that Merck's case-by-case information for the 69 patients was reliable.

An editorial by Walsh, published in December 2002 by the New England Journal of Medicine, referred to an antifungal drug made by Merck & Co. — but did not mention his receipt of fee income from the company. The journal's conflict-of-interest policy requires authors to acknowledge such income.

After inquiries from The Times, the journal asked Walsh to submit a revised disclosure statement. A spokeswoman for the journal, Karen Pedersen, said Walsh had 'failed to disclose' the income from Merck when he submitted the editorial. On March 16, the journal published a correction, saying the editorial 'should have included the fact that Dr. Walsh received an honorarium from Merck.'

Walsh told The Times that his lack of disclosure was inadvertent.

A Merck spokesman said recently that Walsh was paid a total of $3,000 in fees, in 1999 and 2001, not related to his involvement with the company's drug. Walsh said in his statement to The Times that Merck had not paid him for any appearance before the FDA.

U.S. conflict of interest law generally prohibits a federal employee from representing anyone before a government agency, regardless of whether outside compensation is paid.

Fujisawa USA Inc

The first major study that Walsh helped lead compared one of the new, modified drugs, AmBisome, with conventional amphotericin.

The study was paid for by the developer of the new drug, Fujisawa USA Inc., and by a grant from the NIH. Walsh had conferred about the study design with Fujisawa and with a national network of other physicians who would carry out the project.

On July 16, 1997, Walsh anchored Fujisawa's presentation of AmBisome to the FDA advisory committee, which met in Silver Spring, Md. The FDA's agenda listed Walsh as part of the 'Fujisawa USA Presentation.'
Fujisawa's vice president for regulatory affairs, Jerry Johnson, told the FDA committee: 'Our presentation will conclude with Dr. Walsh presenting the key results from the U.S. study.'

Walsh narrated a series of slides and told the committee that AmBisome 'was more effective in preventing proven invasive fungal infections and fungal-infection-related deaths' than conventional amphotericin.

In his recent statement to The Times, Walsh said: 'I have never appeared at any FDA meeting as a consultant to Fujisawa.' Referring broadly to industry, Walsh also said: 'While a company might consult with me, i.e., in the generic sense of seeking my insights or knowledge, these are not consultancies in the official, governmental sense, but rather collaborations.'

A spokeswoman for Fujisawa, which now operates as Astellas Pharma US Inc., said the company had paid the NIH for Walsh's efforts dating to the 1990s and the development of its first antifungal drug, AmBisome.

'He's been a consultant of ours since the early days, since the preapproval of AmBisome, through currently,' said the spokeswoman, Maribeth Landwehr, adding that the company had paid for Walsh's 'general consulting' by writing checks to the NIH, not to him. Fujisawa, she said, paid 'at a rate which we believe to be acceptable.'

Vestar Inc., a San Dimas company that developed AmBisome originally and later in partnership with Fujisawa, also worked closely with Walsh. Richard T. Proffitt, a co-inventor of AmBisome who headed research for Vestar, said the company collaborated with Walsh on testing the drug in animals.

Proffitt said Walsh suggested that Vestar could make contributions to a foundation that would make funds available for Walsh's research. Proffitt said that from about 1990 to 1993, Vestar wrote checks, totaling approximately $60,000, to the foundation. Proffitt said he did not recall its name. 'It wasn't like he implied that we had to give money to the foundation,' said Proffitt. 'But he certainly gave me the foundation name.'

Records obtained under the Freedom of Information Act show that some companies supported Walsh's government research by making donations to the Gift Fund of the National Cancer Institute.

For instance, in March 1998, Fujisawa sent Walsh a $40,000 check to the fund along with a letter of explanation, saying the money was intended for his government laboratory and '"clinical research program.' Fujisawa also told Walsh that the money could be used for 'personnel, support services and travel,' plus equipment and supplies.

After reviewing the NIH's overall policy for accepting gifts, the Government Accountability Office last year raised concern. The federal auditors said the NIH's policy 'does not provide sufficient assurance that potential conflicts of interest between NIH and donor organizations will be appropriately considered.'

Pfizer Inc.

Walsh also has consulted with Pfizer, said Mariann Caprino, a spokeswoman for the company. She said Walsh was paid from 2001 to 2005 for participating in private meetings at Pfizer 'to discuss clinical trial designs.'

'We did compensate him for his time,' Caprino said in an interview.

When Pfizer brought its antifungal drug before an FDA advisory committee in October 2001, a company executive identified Walsh as part of its 'sponsor section.' The FDA approved the drug, Vfend, about seven months after the advisory committee meeting.

'He attended the advisory committee in the capacity of an expert in this area,' Caprino said, adding: 'His relationship was fully disclosed by us at that meeting.'

Walsh said that he was not paid by Pfizer to attend the meeting. He did not respond to questions seeking details about his compensation from Pfizer.

Caprino declined to state how much Pfizer had paid Walsh over the years, but said: 'He received a standard per-diem rate. Basically, that compensates him for time out of the office.'

In response to questions from the LA Times,

In written comments for this article, Walsh said his advice to industry did not conflict with his position at the NIH's National Cancer Institute, or affect his scientific judgment.

'I am not and have never been a representative of, or advocate for, any pharmaceutical company,' Walsh said.

Walsh, 54, heads a medical research and treatment unit within the pediatric branch of the National Cancer Institute, where he arrived in 1986. He said that collaborating with companies has been fundamental to his government work.

'My efforts are in service of the public interest in sound, reliable science concerning potentially effective agents for the treatment of life-threatening infections in children and adults with cancer,' Walsh said in a statement to The Times. 'This mission frequently includes collaboration with companies that research and develop new compounds in this area — for example, utilizing my [staff's] expertise to ensure that clinical trials relating to these compounds are designed and implemented in a manner that elicits reliable and useful results.'

He said he has appeared before the FDA only 'as a government scientist providing information and/or evaluation' regarding clinical trials. Referring to studies he helped lead, Walsh said, 'There is no conflict of interest, and the trials were well and appropriately designed.'

This tangled story reminds us of several points.

When people have financial relationships with multiple organizations with differing agendas, it is hard to tell who they are representing at any given time.

People who have such financial relationships often seem honestly unaware of how others may perceive the relationships, and seem to ignore the influence of particular relationships, while acknowledging the influence of others.

My conclusions are:

• There is nothing wrong with government-industry, or academia-industry collaborations.
• However, those physicians, researchers, faculty, and administrators involved in such collaborations should not try to work for two or more parties whose interests are not necessarily the same.
• If the actors in a particular collaboration do have conflicts of interest, the rest of us must be very skeptical about interpreting what they say and understanding what they do

With any luck, since the NIH has restored the rigor of its policies about conflicts of interest, its collaborations with industry should produce less ambiguous results.

It would be nice if other government agencies, and also academic medical institutions, would also develop much more rigorous policies about conflicts of interest. Meanwhile, we need to be very skeptical about assessing their work.