By Carla Garnett

Photos by Ernie Branson

On the Front Page...

When the advisory committee to the director (ACD) last met in June 2003, NIH director Dr. Elias Zerhouni described for them his ambitious Roadmap for Medical Research initiative, which embodies the concept of team science. At the most recent ACD meeting on Jan. 12, he expressed great satisfaction that the fall 2003 public rollout of his three-pronged research strategy had been widely reported and enthusiastically received.

Continued...

In reassuring ACD members that despite recent criticism of some grants and some consultancy arrangements, NIH must not shrink from its duty to provide health research for the benefit of all, Zerhouni also reemphasized a large part of the Roadmap strategy — NIH's need to establish and maintain strong collaborations with both public and private sector scientists.

"The public will not be served," he remarked in his state-of-the-NIH report to the ACD, "if we completely eliminate the ability of government scientists to interact with the private sector — either non-profit or for-profit — in appropriate ways."

Roadmap Hits the Road Running

Describing the media response to the Roadmap public unveiling, Zerhouni said, "I'm told that this was one of the largest press conferences at NIH. Most important, though, was that the stories were accurate and well-reported. In that sense we have done what we needed to do, what you asked us to do in June, which was communicate extensively with multiple constituencies."

There are 28 initiatives in the Roadmap; several have been launched already and all will be launched in the coming months, with the help and guidance of NIDCR deputy director Dr. Dushanka Kleinman, who was introduced as assistant director for Roadmap coordination, a post she assumed on a temporary detail to the Office of the Director.

NIH director Zerhouni (r) and deputy director Kington meet with the ACD.

New ACD member Dr. R. Sanders Williams, a cardiologist and dean of Duke University's medical school, applauded the Roadmap for "making room for mavericks, but providing a structure" for trends in biology.

In a discussion launched by ACD member and former U.S. Sen. Connie Mack on balancing investigator-initiated research and targeted research, Zerhouni explained that 57 percent of NIH-supported research can be classified as so-called investigator-initiated or basic science, 33 percent is research targeted toward a specific disorder, and 10 percent represents research training.

"You can't dictate what will be done and how," stressed Zerhouni. "[However] we can identify grand challenges and let scientists self-assemble research teams."

ACD member Phillip Williams, retired vice chair of the Times Mirror Co., said that communicating to non-scientists about the benefits of basic research versus targeted research will be essential in garnering public support of the NIH research agenda.

People will want to know why you seem to be studying something without a purpose, he commented. "You must communicate the tension [between the two] as you have here."

Issues in the News

In his fourth ACD session as director, Zerhouni took the opportunity to discuss two issues that have gained a lot of attention in the past 6 months, both inside and outside NIH.

In no uncertain terms, Zerhouni said, NIH stands behind its peer-review system, which determines which research grants the agency funds. A model for others in the international research community, NIH's system of evaluating which research proposals are worthy of funding is sufficiently rigorous —second to none — he pointed out, and its decisions should not be second-guessed. Justification for several NIH-funded grants on such topics as sexual behavior was questioned by some members of Congress, who requested that NIH look into the specific grants and report back.

"We have reviewed this field," said Zerhouni, who explained that each grant cited was examined for public health relevance and each was determined to be quality research whose results would benefit the public. "There is absolutely no evidence whatsoever that these grants are not in the interest of the public. Our peer review system is working. It is actually one of the most comprehensive processes that can assure one that we are performing and funding good science...We found that in every case, when you looked at the details and when you looked at the public health relevance, that there was no question that these grants should have been funded, and should continue to be funded."

Zerhouni also provided details about his response to Congress regarding possible conflicts of interest that were suggested by a December series of Los Angeles Times articles. The stories raised questions about several NIH intramural scientists who receive compensation from outside organizations for consulting on research, and the propriety and public disclosure of such agreements. A thorough review of all outside consulting arrangements by NIH scientists was ordered by the director and is under way. Zerhouni also pointed out that — contrary to suggestions by the media reports — all of the arrangements had been disclosed, reviewed and approved under existing ethics rules.

Open Doors, Disclose Facts

"The philosophy we used [to answer the allegations] fairly immediately was to be completely transparent and completely proactive," Zerhouni said, noting that his first concern was to refute implications by the articles that patient safety may have been compromised by the relationships. "I'm pleased to tell you," he stressed, "that we have gone through the reviews — all the reviews for NIH aren't completely done at this point — but for the cases that were mentioned, there is absolutely no indication whatsoever that a patient was harmed because of this relationship. I want the committee to understand that our actions were to, as completely as possible, shed light on the facts alleged, so that we can at least be sure that the reality of conflict was not there."

Dr. Michael Gottesman (l), NIH deputy director for intramural research, and ACD member Dr. Cecil Pickett, president of Schering-Plough Research Institute, listen to reports at the recent ACD session.

Beyond patient safety, Zerhouni said his next major concern was the research itself, to determine that no "tainting of the decision-making process" occurred during the consultancies. "In each case we found the appropriate recusals," he explained. "We found no evidence that what was alleged in the [original] article relates to reality."

Still, the director acknowledged the public perception left by such media reports cannot be allowed to impugn NIH's reputation, or impede its mission.

"When you look at the reality, we find very little," Zerhouni said. "However, the fact that the article triggered such a reaction tells you that we have an appearance problem, and not only an appearance problem, but we have a limit problem. Do we have the ability to have our scientists consult without limits — limits on time, on dollars, on kinds of relationships? I think that's a valid question."

To address such questions and others involving conflict of interest and human subject research, he has called for an independent committee to look at NIH policies.

"Our mission is too important to have it undermined by the sense that there was no independent review of the process," Zerhouni said. "The situation is not as bad as it was portrayed, but [it] could be improved so that the appearance of conflict is eliminated. We all feel very strongly that collaborations between public and private scientists are important and essential to translating basic science into tangible products, methods and...that there is a way to assure the public of the lack of conflict.

"We are subject to conflicting tensions," he continued. "On the one hand the public expects us to create tangible benefits. Those tangible benefits cannot be created in a vacuum. They have to be created in connection and in conjunction with the non-governmental sector, because of the high level of complexity related to research. That connection needs to be reinforced and appropriately managed. The principles in my mind are full transparency — there's nothing in a relationship that should not be done in full light of day, full disclosure, appropriate review and proactive monitoring."

On the Administrative Front

In addition to Williams, another new ACD member attending his first meeting of the group was Dr. Raghavendra Vijayanagar, a cardiovascular surgeon from Florida.

Two newly appointed institute directors were introduced — Dr. Story Landis, who took the reins of NINDS last August, and Dr. Jeremy Berg, who claimed NIGMS's top job in November.

Further lauding the agency's "continued success in recruiting outstanding individuals," Zerhouni also announced recent appointees Dr. Norka Ruiz Bravo, NIH deputy director for extramural research, and Richard Turman, NIH associate director for budget. Zerhouni mentioned that NHGRI director Dr. Francis Collins is leading the search committee to replace Dr. Claude Lenfant, who retired as NHLBI director last summer.

Reiterating his commitment to pursue diversity in all aspects of NIH operations — not only in research and research training, but also in the workforce — Zerhouni also acknowledged a rare honor for a federal agency, an award for best diversity practices that he accepted on behalf of NIH a few months ago. NIH was the only government organization among 2003's 10 recipients, and is only the second federal group so honored.

"I think it is important to continue to pay attention to the need for diversity," Zerhouni said. "There is no greater need for diversity than in health and health research. We are providing research to a diverse population and we need a workforce that reflects that diversity. We are not there yet. There is a lot more to do, but I think the intent and the momentum are there."

Other issues addressed at the meeting include the NIH budget: Zerhouni reported that at the time, NIH continued to operate under a fourth Continuing Resolution, using fiscal year 2003 funding levels. Congress was expected to complete the 2004 budget process before the end of January, he said.

In NIH deputy director Dr. Raynard Kington's report, he gave updates on several administrative fronts, including the NIH steering committee, which employs a 9-member panel of institute and center directors to streamline agency decisionmaking; the administrative reorganization advisory committee (ARAC), whose summer 2003 report was accepted by HHS Secretary Thompson as a blueprint for NIH; and the reactivation of 5-year reviews for IC directors. The review process has been expanded to include Office of the Director components such as the Office of AIDS Research and the Office of Disease Prevention.

Commenting on the strong potential for flat NIH budgets over the next few years, Zerhouni concluded that "scientific opportunity has never been better" and that NIH will be looking to capitalize on "synergy, efficiency and prioritization."

'Landscape Is Completely Different' ACD Contemplates Future of Intramural Clinical Research Alot can change in half a century, and in a thoughtful discussion about the revitalization of NIH's intramural clinical research program, advisory committee to the director (ACD) members and guests at their Jan. 12 meeting heard innovative suggestions for returning the program to its past glory. Looking forward to the opening later this year of the Clinical Research Center, NIH director Dr. Elias Zerhouni had enlisted a blue-ribbon panel to study the status quo and seek ways to meet the demands of a 21st century clinical environment that has changed dramatically since the Clinical Center first opened in 1953. "What can and should NIH do in the realm of clinical research?" he asked. "If you compare clinical research in 2003 with 1953, you will see that the landscape is completely different in our country." Zerhouni welcomes advice of a blue-ribbon panel he appointed to consider intramural clinical research. Noting that in the early fifties, "there were very few, if any, centers that could conduct interventional clinical trials, or train a large cadre of talented physician-scientists," Zerhouni said there were not many alternatives to the NIH Clinical Center back then. "Today, you have dozens of outstanding programs in academic health centers, and the specific role of a national center such as the Clinical Center became not only an issue of managing the program internally, but also an issue of strategy and priority. We believe that in the next few years, the role of the Clinical Center may actually increase in importance compared to 5 to 10 years or so ago. Academic health centers are facing very difficult fiscal times. Margins of clinical activity have pretty much collapsed; the margins have come down from 5 or 6 percent to 1 or 2 percent. It's very hard to invest boldly as a trustee or chancellor or dean of an academic health center into high-risk clinical research that requires any kind of margin of excellence. So perhaps there is a role for the Clinical Center in that context." Chaired by Dr. Edward Benz, president of Dana-Farber Cancer Institute, and cochaired by Nobel laureate Dr. Joseph Goldstein, professor and chair of the department of molecular genetics at the University of Texas Southwestern Medical Center, the 15-member blue-ribbon panel brought together top-notch investigators from a range of specialties and research disciplines both within and outside NIH. On a fast-tracked assignment, they met three times in 2003 and were briefed extensively by a number of intramural NIH'ers and outside experts. "The charge to the panel was to give some thought and recommendations to how the NIH intramural clinical research program (ICRP) could revitalize the national mission in clinical research, take advantage of the unique resources and deal with the unique disadvantages that come from an intramural program on this campus," said Benz, presenting the panel's final report. Specifically, he said, Zerhouni asked the group to consider where the ICRP can produce paradigm-shifting research, whether its current portfolio is appropriate, how accomplishments can be made by reassigning existing resources and how success can be evaluated. First among six recommendations is that a "single high-level oversight committee" be created to handle all responsibilities related to NIH's ICRP. The committee replaces all current oversight boards and would report to the NIH director. It would govern, plan strategy, set priorities and develop budget, in addition to making recommendations about transdisciplinary clinical initiatives and resource allocation. A new external advisory committee to the NIH director would monitor the overall quality and vitality of the ICRP. The panel also recommended that a new deputy director for clinical research position be created on par with the deputy director for intramural research post. "While no one would claim that the entire [nation's clinical research] enterprise is where it should be," Benz said, "the idea that the Bethesda campus is a unique place or the only place that the very most talented people are going to pass through in the course of their training and career development is not true anymore. The NIH intramural program needs to develop a unique position in what is now a very fertile field for clinical research." In finding a "niche that is distinct and complements what goes on in the extramural community," the ICRP should emphasize study of rare diseases, stressing pathophysiology and novel therapeutics, he said. Other recommendations by the panel require the ICRP to develop new training and career pathways in patient-oriented research, and reduce regulatory barriers to clinical research. Benz said clinical research should be as respected and valued as laboratory research. Currently 17 institutes use the Clinical Center for some part of their intramural clinical research portfolio, according to CC director Dr. John Gallin, who briefed the panel and who served — along with Dr. Michael Gottesman, NIH deputy director for intramural research, and NIDDK director Dr. Allen Spiegel — as an ex-officio participant. Zerhouni thanked Benz and the panel for their recommendations, noting the challenge presented in reconciling this group's ideas with those offered last year in an Institute of Medicine report. He indicated that the intramural clinical research issues would be further deliberated at an upcoming Office of the Director staff retreat.