Costello, Leslie C. PhD
Clinical and experimental biomedical research is an important key to advancing society's health and welfare. Such research is highly dependent on funding from public and private granting agencies. The National Institutes of Health (NIH) is the agency that provides the majority of funding for biomedical research, and its policies for evaluating and funding research generally set the standards for other granting agencies. The success of these high standards is evidenced by the extraordinary scientific research, discoveries, and advances that have occurred since the establishment in 1946 of the NIH Research Grants Division and its scientific review process for research grant applications.
A concern has recently arisen, however, that the current review process for funding biomedical R01 research no longer meets those historically high standards. This concern was reflected in the 2008 directive from Dr. Elias Zerhouni, then director of the NIH, which established a process and committee to develop recommendations, guidelines, and policies for enhancing peer review at the NIH.1,2 The stated and admirable intent was to “fund the best science by the best scientists, with the least amount of administrative burden” and to maintain the objective of the NIH Center for Scientific Review (CSR): “to see that NIH grant applications receive fair, independent, expert, and timely reviews—free from inappropriate influences—so NIH can fund the most promising research.”3
Although I admire these goals, I take issue with emerging NIH policies, which, I submit, are antithetical and counterproductive to their achievement. In addition, the policies introduce discriminatory considerations while ignoring, misunderstanding, or simply not recognizing important factors that contribute to the decline in standards. This article is a subjective perspective based on my experience of nearly 50 years, during which I received about 30 research grants, served on grant review committees for the NIH and other agencies, and presented grantsmanship lectures and workshops at numerous medical institutions. Over this time, equal to about three-quarters of the NIH's existence as a major extramural research grant agency, many significant changes have occurred in the R01 grant review process and its policies.
Emerging NIH Policies Are Counterproductive and Discriminatory
What criteria and conditions should reviewers consider when evaluating R01 grant proposals in order to fund the best science by the best scientists? Although unanimity is unlikely in response to such a question, I believe that proposals should be judged on the merits of the science, the quality and capability of the investigator, the existence of appropriate conditions and availability of essential resources, and the study's potential for new understanding, significant advancement, and/or resolution of a critical biomedical issue. Improving peer review and ensuring that applications receive “fair, independent, expert, and timely reviews—free from inappropriate influences” are means to determining whether a proposal meets those standards. Policies, guidelines, and considerations that modify these standards will likely contradict and impede the NIH's stated goals.
And yet, such modifications are being imposed. The mission of funding the most promising research is no longer the most important objective being applied to the review of R01 grant proposals. A new goal has evolved to ensure funding parity between new investigators and established investigators. The recent and forthcoming requirements, guidelines, and policies developed by the NIH to achieve this parity both contradict the objective of funding the best science by the best scientists and introduce biased and discriminatory considerations into the review process.
R01 Research Grants Are Being Used as New Investigator Development Funds
Recent NIH policies have transformed the R01 grant mechanism from a source dedicated to funding the best science to a development program for young investigators. The funding of young investigators is a response to the concern that, without a generational continuum of young scientists, discoveries and advances in medicine and health may be in jeopardy. Much of this concern is predicated on trends that indicate that, over the past decade or two, the age of recipients of new R01 grants has increased while the number of first-time R01 grants has decreased.4,5 The NIH notes,
There is concern that applications from New Investigators frequently do not fare as well … as those from established investigators. This concern is supported by reduced success rates in the number of New Investigators receiving new grants that started in FY 2003.
To address this concern, the NIH recently introduced its R01 policy,5,6 which states,
The NIH strongly encourages New Investigators, particularly ESIs [early stage investigators], to apply for R01 grants when seeking first-time NIH funding … For FY 2009, Applications from New Investigators will be clustered during initial peer review to the extent possible … Under this new policy, the NIH intends to support New Investigators at success rates comparable to those for established investigators submitting new applications.
The NIH further states that the policy has
resulted in New Investigators having success rates comparable to established investigators who submitted new (Type 1) applications.
The last statement is ludicrous. Of course the new policy achieved parity for the new investigators, just as it had dictated. But this occurred at the expense of a decline in the quality of R01s that were funded. In fact, the situation is exacerbated further by the recent National Cancer Institute (NCI) announcement:
NCI has a strong commitment to first-time R01 awardees. Applicants eligible as new R01 investigators will be paid using an extended payline of the 20.0 percentile. Other applications up to the 15.0 percentile will be paid.7
Suffice to say that I strongly agree that a system for developing a continual pool of outstanding young scientists is critical, as it has been in the past and will be in the future. Several NIH vehicles have existed for more than two decades that develop new investigators and ESIs without competing with established investigators. Unfortunately, for the most part, these programs have not increased the success rate of young investigators in obtaining R01 grant awards. For example, the 1997 Report of the NIH Working Group on New Investigators4 concluded that the R23, R29, R03, or K-type development awards have had little or no impact in enhancing the success rate of young investigators. The NIH has reported5 that “recent analyses indicate that a smaller proportion of individuals with initial R21 or R03 grant support subsequently apply for and obtain R01-equivalent funding.” This problem must be addressed, but not by compromising the quality of research receiving R01 funding. Using the R01 research grant mechanism as a development fund diverts precious resources from achieving the original goal of funding the best science by the best scientists.
In earlier times, neither a myriad of development programs nor special considerations existed for young investigators. Previous generations (including mine) had to compete for R01 funding with established investigators, under the same conditions and guidelines and without the interjection of preferential treatment. The NIH made awards to investigators who demonstrated a capability of conducting the research, regardless of their stage of development. There was no shortage of outstanding investigators who evolved from that competition.
Should we conclude from the NIH's new policy that today's ESIs, even after receiving up to 10 years of support from various developmental/training grant programs, are incapable of competing on the basis of scientific quality or that they lack the strong dedication and sacrifices required for a lifelong career in biomedical research? What are, in fact, the reasons behind their lack of success? Before imposing an unfounded and unlikely “solution” to the detriment of excellence in biomedical research, the NIH should identify these causes. This is a complex issue that involves changing demographics, long-term salary and security considerations, changing university policies and commitments, and other factors beyond the scope of this article. However, one major contributing factor that is inseparable from this issue and is potentially resolvable is the failure of the contemporary biomedical graduate and postgraduate training programs to produce broad-thinking and creative scientists, as I will discuss later.
Discrimination Is Being Introduced Into the Review Process
Equally and perhaps more objectionable, in my view, is that the policy introduces, promotes, and justifies bias and discrimination in the review process and in the reviewers. The policy discriminates against senior investigators and long-time funded researchers, so that being a successful and experienced scientist now becomes a detriment in the evaluation of current and future grant proposals submitted by senior investigators. This violates CSR's own requirement that NIH grant applications receive fair reviews free from inappropriate influences. What more inappropriate influence could there be than prejudice? The NIH policy exacerbates and justifies any existing covert prejudicial tendencies and attitudes of reviewers, and it inculcates prejudicial considerations in all reviewers. Comments criticizing longevity of funding have already found their way into the review process and, what's more, have been considered to be appropriate. Does this policy not introduce a form of “age discrimination” into the R01 research grant review process? The report, Enhancing Peer Review at NIH,2 states that it is guided by the principle to “do no harm” with regard to the goal to fund the best science by the best scientists. The NIH should reconsider the implementation of its ill-advised and discriminatory policies that result in the funding of lesser-quality grants at the expense of funding the best science by the best scientists.
Lest I be accused of being critical for self-interests, my concern is in the interest of maintaining the highest level of and support for the best science by the best scientists. I will soon be gone from the competition for future funding, but as a 50-year beneficiary of the outstanding and extremely successful research grant program and process of the NIH, I am obliged to defend and support the integrity of that system.
Broad-Thinking, Creative Scientists Are Disappearing
The NIH report, Enhancing Peer Review at NIH,2 presents four priorities, the first of which, “Priority 1—Engage the best reviewers,” asserts that “the excellence of peer review is directly correlated with the ability to recruit and retain the most accomplished, broad-thinking, and creative scientists to serve on NIH study sections.” I would argue that the same characteristics are essential to funding the best science by the best scientists. The current generation of biomedical researchers, however, is not being trained, as were their predecessors, to be broad-thinking and creative scientists. Most contemporary biomedical graduate and postgraduate training programs forego the historical and philosophical background of science and the scientific method, which are important elements for cultivating and expanding the inquiring mind of a developing scientist. Also missing is the fundamental understanding of cell physiology and biochemistry, organ systems physiology, pathophysiology, and other critical areas, which are essential to the integration and translation of one's specialty interest to the holistic biological system. Instead, these programs are designed to produce a generation of researchers and “supertechnologists” (not scientists) who excessively—often solely—focus on molecular biology and molecular technology. I discussed this more fully in a perspective published in Academic Medicine in 2009.8
This has had a major impact on the situation I am addressing in this perspective. These narrowly trained young investigators are often competing against accomplished, broad-thinking, creative scientists; no wonder their success rates have fallen. The NIH, however, has failed to understand or even identify this major contributing factor. Continued failure to address this educational and training deficiency could soon deplete the pool of broad-thinking, creative biomedical scientists. In that case, the parity the NIH now desires will be achieved, not through preferential treatment but from a permanent decline in excellence in science, much to the detriment of the medical/scientific and public communities.
As acknowledged in NIH Priority 1, the quality of reviewers is the most important element in the entire peer review process. Narrow training also degrades the quality of the pool of reviewers. The new generation of reviewers judge grant proposals through the myopic lenses of their specialties. The appreciation and capability essential to evaluating scientific ideas require a more holistic understanding of the physiological and pathophysiological implications. Important ideas and proposals that lie outside the current focus on molecular biology are unlikely to get a credible and knowledgeable review and, it follows, will have little possibility of receiving funding.
In 1978, after having been a recipient of several grants, I received my first invitation to serve on an NIH grant review committee. My very first impression was of the broad and extensive knowledge and scientific expertise of the committee members. Despite 20 years of prior experience, including being a chairman of a department of physiology, serving on that committee and listening to the thoughtful scientific dialogue broadened my scientific knowledge and insight. In the past two decades, in contrast, I have been impressed with the narrowing of the reviewers' knowledge base, which has resulted in scientifically inaccurate and incorrect statements interjected into the evaluation of a grant. NIH CSR often deals with this problem by inviting an ad hoc reviewer knowledgeable in the area of a grant proposal to complement the regular study section members. These “outside the mainstream” proposals also elicit the assignment of regular members of the study section to review the grant, even though they lack appropriate knowledge of the subject matter. These become “pretenders” of representing the essential background as well as a genuine positive interest in the subject matter, both of which are essential to providing a scientifically credible, fair review. So, such adjustments to deal with outside-the-mainstream proposals do not solve the problem. When even one reviewer of the two or more assigned reviewers raises doubt or issues (scientifically unfounded or founded), the grant proposal will most likely be doomed. The NIH was right that “the excellence of peer review is directly correlated with the ability to recruit and retain the most accomplished, broad-thinking, and creative scientists to serve on NIH study sections.” We must once again train and produce such scientists!
The replacement of the pool of broad-thinking scientists by the contemporary generation of narrowly trained researchers has an impact in another important way. The latter now strongly influences the NIH's (and other funding agencies') policy decisions regarding which areas of research to emphasize and where to direct funding. This has resulted in molecular biology and molecular technology dominating the available resources at the expense of other important areas of biomedical research. Indeed, this dominance is self-perpetuating, as researchers are swept into this mainstream and directed away from other important areas because of the lack of funding opportunity in the out-of-the-mainstream areas. Notably, Dr. Zerhouni9 acknowledged this concern when he said, “What new areas of science do we need to focus on that have a lot of promise to them, but may need NIH encouragement? Systems biology is one… . Solving the puzzle of complex diseases … will require a holistic understanding of the interplay between factors such as genetics, diet, [and] infectious agents.”
I find the situation that the NIH has created ironic and hypocritical. On the one hand, the NIH identifies the critical value of broad-thinking, creative scientists to study sections and the review process, a description that obviously applies to senior scientists with deep experience and many funded research grants on their résumés. On the other hand, these accomplished scientists are penalized in the grant review process for those very capabilities and experience. Is this not a striking contradiction?
In addition, the imposed “retiring” of successful senior investigators has the negative effect of closing down their research programs and their associated graduate and postgraduate training programs. So, we lose the most experienced, knowledgeable, thoughtful, and excellent mentors for the development of the succeeding generation of outstanding, broad-thinking and creative scientists. This is the loss of a critical and unrecoverable resource that cannot be replicated by younger investigators until or unless they evolve to the level of outstanding scientists.
It is noteworthy that all of the attention has been directed toward young investigators, with no concern for the issues facing senior investigators. If one compares success rates for the period 1983–1995, one finds that those of senior investigators (age >55) have been consistently lower than those of young investigators (age <37).10 This is the same period from which much of the justifiable data have been presented regarding concerns for young investigators. I was not able to find any more recent comparable information. Nevertheless, it is most likely that the new policy will further deplete this pool of senior investigators. Is this not an important issue to address?
Summary: New Peer Review Policies Are Incompatible With the NIH Goal to Fund the Best Science by the Best Scientists
I have described some (there are other) conditions that impede the NIH's objective and—in my view—responsibility to ensure that R01 grants “fund the best science by the best scientists.” Special considerations, quotas, and preferential and discriminatory criteria, all of which are incompatible with that objective, should be eliminated from the R01 review process.
The urgent need described by the NIH to recruit the “most accomplished, broad-thinking and creative scientists” as reviewers is closely tied to the determination and capability of biomedical graduate and postdoctoral training programs to develop such scientists, rather than “narrowly trained researchers and supertechnologists.” The NIH's discriminatory policy against the funding of senior investigators further diminishes the pool of accomplished scientists, eliminating their important influence in the development of aspiring investigators. These issues must be resolved to create the future generations of outstanding biomedical scientists that the NIH concedes are essential to maintaining excellence and ensuring further advances in biomedical research.
It seems evident from this presentation that the NIH is conflicted, with two opposing goals. One goal, as emphasized by Dr. Zerhouni, is to create conditions that continue the NIH's traditional commitment of using R01s to fund the best science by the best scientists. The other goal is the recent commitment to achieve parity of R01 funding between new and senior investigators, regardless of the consequences this has on the quality of the science that is funded. Both goals cannot coexist; the latter goal imposes discriminatory considerations. The NIH should clearly define the purpose of the R01 grant mechanism.
To add a constructive input to my critical analysis, I offer the following suggestion for consideration. Maintain the R01 mechanism to fund the best science by the best scientists as competition open to all investigators (including ESIs), without any special or preferential considerations. Each grant proposal will be judged on the merits of the science, the potential impact of the proposal, the capability of the investigator/team of investigators to conduct the study, and the existence of facilities and resources in support of the study. Considerations of applicants' age, stage, and history should be of no consequence or consideration unless they are intimately involved as a direct factor in the grant proposal, as is the case for a renewal grant application.
For the development of ESIs, I propose that the NIH end the “pigeonholing” of the various development grant programs and combine all of the young investigator development programs into one generic R01-type development program. Allow the applicants to make the case for their grant proposal. Provide substantial funding of direct costs up to $175,000 per year for up to three years. Allow up to two funded cycles (i.e., a funded new grant and a competitive renewal grant). To the extent possible, apply all of the requirements and operational conditions that exist for R01s. The review of these applications should be conducted apart from the review of R01s. For unsuccessful grant proposals, permit unlimited resubmissions. Rewriting a grant proposal, especially with the benefit of comments and suggestions by experienced reviewers, is a tremendous learning experience. If it takes two, three, or more submissions to achieve success, is this not a suitable outcome? If resubmissions do not have a favorable outcome, does this not send an important message? In either event, this is an important experience in grantsmanship for the aspiring young investigator. This approach will provide the young principal investigator with a more realistic development process and with a funding level that is more personally, as well as scientifically, attractive. If, pursuant to such an experience, the young investigator cannot successfully compete against the senior investigators for R01 grants, find out why!
The process of peer review, in my view, is still potentially the best mechanism for R01 grant evaluation and funding of biomedical research. However, the process must be cleansed of inappropriate influences and prejudice. It will succeed only with the existence and involvement (as described by the NIH) of accomplished, broad-thinking, and creative scientists to serve on study sections. In the absence of such conditions, it is difficult to retain the strong advocacy and confidence in the study section peer review process that I had held for more than 40 years.
In this perspective, I have presented views based on nearly 50 years of experience in submitting grant proposals and in serving as a reviewer on grant review committees. I believe these views speak to changing conditions that much of today's biomedical research community has not experienced. I anticipate strong opposing viewpoints. You, the reader, must assimilate this information and judge for yourself the legitimacy, or lack thereof, of the issues and views I have presented here.
Note added in proof. During the period of the editing of this manuscript, a highly relevant report11 from the Government Accountability Office appeared, which provides data regarding R01 grant awards to new investigators. The data (summarized in Figure 1) reveal the increase in 2007 in the awards outside the pay line that were made to new investigators. This fully accounts for the increase in all of the awards outside the pay line. This coincides with the initiation of the special considerations for R01 funding for new investigators.12 In 2007, nearly 10% of the total R01 awards were new investigator awards outside the pay line. So, one can now ascertain the “quantitative” impact of this new NIH policy. It is reasonable to conclude that 532 grants were awarded to new investigators for proposals of lesser scientific quality, displacing the funding of some of the best science by the best senior scientists. This does not include any of the special considerations given to new investigators' proposals that resulted in awards within the pay line. Now that the new requirements are being fully implemented in the grant review process, one can expect this trend to increase. The combination of the overt and covert upgrading for new investigators' grant proposals and the downgrading for senior investigators' grant proposals will magnify this most unfortunate outcome. The medical, scientific, and public communities deserve better.