Funding Biomarker Research Through The Sbir Program

The discussion above applies to just about any project for which funding through the SBIR program might be sought. The following discussion relates, more specifically, to funding of biomarker development work. Developing a biomarker is, in many respects, similar to developing a therapeutic product. Both involve a focus on a particular disease or condition. While the therapeutic agent is, obviously, a tangible material that needs to be developed and tested in the laboratory, validated in a clinical study, and then manufactured to specifications, and so on, developing a biomarker has similar issues. Included are (1) demonstrating the possible relationship between a disease state and an expression of the putative marker; (2) establishing that the putative bio-marker can be identified and quantified in tissue, plasma, or urine; (3) developing reagents that can be used reliably and conveniently to assess the marker at the appropriate site; and (4) conducting preliminary and definitive clinical investigations to demonstrate the feasibility of the marker and the utility of the reagents developed. The critical question to ask is this: At what stage in the process of developing a biomarker could one expect to obtain funding through the SBIR program? Another way to phrase the question: What specific question(s) should be put forward in the grant application?

At the theoretical end of the spectrum, one might hypothesize that a particular moiety would be a good biomarker (diagnostic or prognostic) for a particular condition, and then craft an application around demonstrating that such was the case. This might be a candidate for SBIR funding since it is logical to assume that if the moiety could be shown to have biomarker potential, "the commercial ramifications would be obvious." However, reviewers of a grant with such a focus might determine this to be too basic in nature. Slightly less theoretical would be a study to demonstrate that a moiety which was already presumed to be associated with a disease state could be identified reliably (and quantified) in tissue, plasma, or urine. Phrasing the question in this way moves the project one step closer to commercialization. The problem with this approach would be, of course, that one would have to know at the start that factor X was, indeed, a biomarker candidate. Moving even closer to the commercialization end of the spectrum, one could argue that the moiety in question was a good candidate and that there was solid evidence that it could be measured in some relevant biological sample. The issue for the grant would be developing reagents and assay procedures necessary for doing this reliably. Clearly, such a project would not seem too theoretical for the SBIR program. On the other hand, some might consider this to be "product development" and not innovative. Finally, one could propose clinical studies to confirm that demonstrating the presence of a particular moiety in a biologically relevant specimen would have significant predictive value. Such a study would not be thought of as product development, but the "product" aspect (i.e., the commercial potential) would easily be understood. Additionally, such an application would lend itself to SBIR support in that a preliminary assessment could be made in the phase I portion of the grant and a more definitive study during phase II. The downside of such an approach is that by the time that the project was funded through the SBIR grant, millions of dollars would already have been invested in it. Funding at this stage is not what most companies are looking for in an SBIR grant. Furthermore, even a phase II award would provide far less money than required for most clinical studies. Most companies that had gotten to this stage would be less interested in spending the time and effort needed for the amount of money that would be obtained if successful.

Regardless of the stage at which one approaches a government agency for SBIR funding, it is critical to remember that this a research proposal, not a contract proposal. The two are fundamentally different. The successful grant proposal must have an overall goal (i.e., a work plan tied to a testable hypothesis). Achieving the overall goal must be highly desirable, but not assured. The phase I portion of the SBIR grant is designed, a priori, to provide evidence that a novel idea has merit. If the feasibility has already been demonstrated, there is no "testable" hypothesis. Without this, there is no grant. Often, what comes to the SBIR grant reviewers is a "classical" contract proposal. There is a proposed plan of work. The plan will be followed "t o the letter" regardless of findings. There is no testable hypothesis. The problem with such a proposal (from the standpoint of the SBIR program) is that, by definition, it is not innovative. The critique of such an application will undoubtedly contain comments such as "this is development rather than research" and "this should be funded through company resources." The end result is: no money.

The antithetical issue can be just as problematic. To reiterate, although the reviewers of an SBIR grant will want to see innovative research, the project will not be funded if it consists entirely of research, regardless of how innovative. The successful SBIR application must straddle a fine line between basic research and development. The successful application must not only present an interesting hypothesis and a detailed plan, but a road map of how verifying the hypothesis will translate directly into tangible benefit.

Another issue that is pertinent to biomarker development (as well as to the development of a therapeutic) is the nature of the problem for which the biomarker or therapeutic is being developed. Conditions that are primarily cosmetic or of a trivial medical nature, as opposed to serious medical conditions, will not elicit much enthusiasm, regardless of how novel the research is.

Even if the technology ultimately developed has the potential to be economically viable, interest will be low. In a like manner, interest will be low if other diagnostic or prognostic markers are already available for the condition under study. Of course, demonstrating that the new biomarker is clearly superior to existing diagnostic or prognostic markers in some way would mitigate this criticism. This is especially true if existing markers are a part of a foreign-owned technology.

Disease biomarkers are, by definition, moieties whose detection and/or quantification has predictive value in relation to the disease. In most cases, moieties with significant predictive value have such value because they are related in some way to disease pathophysiology. Thus, it is a good strategy, if possible, to combine mechanistic studies with the more technology-driven aspects of the research program. It would not be a good idea to focus entirely, or even primarily, on the mechanistic studies, as the reviewers would question the tangible benefits of the work. Nonetheless, mechanistic studies in the appropriate context always help in that they raise the overall interest level of the reviewers and provide a measure of credibility to the investigators. It goes almost without saying, of course, that weak mechanistic studies are worse than none at all. Only the investigative team can know how their proposal is likely to be helped or hindered by whatever mechanistic studies they can incorporate into their application.

There are a number of additional issues that should be considered before trying to fund a biomarker study through the SBIR program. As indicated above, the feasibility portion (phase I) of the grant may be limited to $100,000 or less. Any study that involves obtaining and processing clinical specimens quickly becomes very expensive. It is important to understand what can be accomplished with the level of funding expected and whether this will satisfy the reviewers at phase II that feasibility has been demonstrated. One can argue all he wants that what was accomplished was limited by the funding available. This reasoning won 't, however, be persuasive to reviewers of the phase II application. The only thing they will want to be convinced of is that feasibility has been demonstrated. Given this reality, much of what is accomplished during phase I in many studies is supported only partially by the phase I application. Cost sharing with retained company earnings is common. This is not necessarily good or bad; the point is to be prepared to partially fund the work independent of the SBIR grant.

Another consideration is the timing. Corporate investigations, particularly at the initiation of projects, are fast-paced compared to the workings of any federal grant program. The SBIR program was designed to have a short lag between application and funding, but it is still a slow process. There are typically three deadlines spaced throughout the year. Should a company intend to meet the deadline for a phase I submission in April, much of February and March will be consumed with putting together a high-quality application. That assumes, therefore, that the idea for the project has already been generated and thought through (at least in a preliminary way). Whatever preliminary data are to be included will also have to have already been generated. If the grant submitted for the April deadline is approved for funding without revision, the earliest time that funding would be available is the latter part of the year. Today, very few grants are funded on the first cycle. What this means is that even a high-quality application for an interesting and supportable project will probably need to be resubmitted at least once. The grant submission and review cycles are constructed so that a revised application cannot be submitted for the deadline immediately following the cycle in which it was originally submitted. The earliest that a revised application could be resubmitted for one initially put forward in April would, therefore, be December. Assuming that the applicant responded (successfully) to all of the initial criticisms and was approved for funding, June would be about the earliest that one could expect the money to arrive. Thus, a gap of one and a half years between conception of the grant and funding is not unreasonable. Often, the criticisms are such that two or more deadlines pass between the initial application and the revised submission. Often, a second resubmission is required.

When funding for the phase I application is attained, the period of support is normally up to one year. This is the period in which the studies needed to demonstrate feasibility are conducted. Often, they may not be completed within the one year of support. In that case, there is no reason why additional experiments, as necessary, cannot be carried out with company funds. It is simply a question of time and money. If the idea has merit, this is often what occurs. At whatever time it is deemed that sufficient evidence for feasibility is in hand, the phase II application is written. Again, assume one or two months for putting the application together to meet one of the three annual deadlines. Again, assume one or even two rewrites before it is approved, bringing the gap between the end of phase I and the restart of phase II at between one and a half to two and a half years. The point is that a small company should not intend to support its R&D effort on funding through the SBIR program alone. Rather, it is better to think of the program as a way to supplement ongoing research activities with new initiatives, and as a way to provide additional resources for essentially untried and inherently risky endeavors.

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