Please note: an updated edition of this guide is now available.
* What's this document for?
If you're a scientist doing research that's directly related to human health, you need to know your way around the National Institutes of Health (NIH). Every young biomedical scientist seeks NIH grants; indeed, the first R01 is a milestone in every biomedical research career.
Unlike most other guides, this one isn't static. In the coming months and years we, the writers and editors of Next Wave, will incorporate changes in NIH procedures, new funding opportunities, and so on, and will keep it evolving as we learn more and get better advice from new sources. We'll keep refining it to reflect input from you and others.
So bookmark this page. Use it as your starting point whenever you start to prepare a new NIH research project grant, and then check back when you have a draft in hand. This guide will be useful throughout the process of preparing and submitting a grant application.
NIH is the most important source of research funds for biomedical research, but don't forget that there are many other sources. Next Wave's sister site GrantsNet is the most complete, best-maintained database of biomedical grants available anywhere. And it's free!
* Can general guidelines help particular applications?
In other words: Are guides like this a waste of time? Is there really anything helpful we can say? We've given this a lot of thought, and we're pretty sure the answer is yes. There are several reasons we think we can help. First of all, according to the experts, otherwise competent and qualified applicants often fail in their quest for NIH funding for one (or more) of a few common reasons. We can help you to avoid those few pitfalls in preparing your application, greatly improving your chances of success. Many researchers know their science inside and out but don't take the time to learn about the intricacies of the proposal-reviewing process, so they end up making mistakes. Indeed, intricacies aside, many applicants lack even a basic notion of what proposal writing is all about, what a grant proposal ought to accomplish. The more time you get to spend on your science, the better, but succeeding in research requires more than just ingenuity and a deep knowledge of your field. We aim to make the process of learning about those other concern--like writing grant proposals--as short and painless as possible. If you're reading this, that's half the battle.
The second reason we think we can help you is that reviewers evaluate and compare applications based on a few common principles. Most reviewers have an outsider's perspective, and they are charged with comparing applications from disparate subfields. They know a lot of science and a lot about your field, but they're almost always working in a field that is closely related to--but not precisely the same as--yours. They are charged with evaluating your application relative to the "state of the science" and not directly to other applications, but it's impossible do this without generalizing, without comparing. In order to compare applications, they must evaluate them based on a few common principles. If you know what those principles are, you're a leg up on the competition, many of whom haven't taken the time to learn about those principles. If we can help you understand how a typical reviewer goes about the process of generalizing and comparising, we'll improve your odds of winning a prize.
Just remember--your goal in writing is to instruct the reviewer on how to review your application.
* There are many different kinds of NIH research support.
The NIH provides many different kinds of intramural and extramural support, each specified by a three-character "activity code." The major kinds of support include research contracts (N-series) cooperative agreements (U-series), interagency agreements (Y-series), research projects and centers (P-series), research project grants (R-series), fellowships (F-series), training grants (T-series), and career development awards (K-series). There are many other kinds; a comprehensive list can be found in the NIH document Activity Codes, Organization Codes, and Definitions Used in Extramural Programs
* This guide is mainly for R01s.
Early-career academic scientists are most likely to be interested in research project grants, fellowships, and career development awards. The latter two categories will be covered elsewhere; this article focuses only on R-series research grants.
A confusing bit of nomenclature: R-series grants (research project grants) aren't the only RPGs in town. Even though RPG stands for research project grant, the NIH considers the U-series (cooperative agreements) and P-series (projects and centers) to be RPGs as well.
* There are many different types of R-series grants.
Here's a list of the most important types of R-series research grants:
R01 Research Project--grant for a project performed by one or more named investigator(s) in an area of specific interest and competence
R03 Small Grant--time-limited and nonrenewable grant in a targeted area
R13 Conference Grant
R15 Academic Research Enhancement Award (AREA)--for small-scale projects at institutions that don't get much NIH funding
R21 Exploratory or Developmental Grant--Small, time-limited grant to explore new ideas in targeted areas
R33 Exploratory/Developmental Grant, Phase II--the next level for an R21 project
R35 Outstanding Investigator Grant--type of grant that isn't applied for.
This is just a sampling; there are many more. If you're a real wonk, you can find a list of all activity codes and technical definitions on the NIH Web site (Acrobat Reader required):
* New investigator grants are now R01s.
If you've never had an NIH grant before, you'll probably want a new investigator grant. In the past, early-career grants had separate designations--R23 and R29--but now they, too, are R01s. Just remember to indicate (by checking "yes" on item 3 of form PHS-398) that you qualify for consideration as an early-career scientist. The only qualification is that you must not have previously received a regular NIH grant. Applicants who qualify for early-career status are evaluated using criteria that are young-scientist friendly. The bar isn't so much lowered as moved horizontally--the criteria are still stringent, they're just more appropriate for researchers who haven't had time to amass publications and a reputation. More emphasis is put on potential--and less on actual accomplishments--than for established researchers. Remember to take this difference into account when writing your proposal! More on this later...
* Application Dates
There are three cycles for R01s--three deadlines each year for the receipt of new R01 applications: February 1, June 1, and October 1. These deadlines also apply to most other awards young scientists are likely to apply for, including research career awards, research center awards, and research program awards--note, however, that competing continuations, supplemental grants, and revised applications are due exactly 1 month later (March 1, July 1, and November 1). Note, also, that the schedule for all AIDS-related grants--including R01s--is different: Applications for new AIDS-related work are due on May 1, September 1, and January 2. Schedules for other types of grants are available here.
NIH takes its submission deadlines seriously; get your application to NIH by the specified date. If your application arrives late, it will be accepted only if it is postmarked one week or more before the deadline or if there were extenuating circumstances, such as a flood or international terrorism. If your circumstances are extenuating, you need to include a letter with your application explaining why your application is late. Your application may or may not be accepted. You cannot apply in advance for an extension, so if your request is denied you're out of luck.
If the deadline falls on a weekend or a holiday, it is automatically extended to the next business day.
* Application Forms
Researchers apply for R01 awards on form PHS- 398, which is available (along with instructions) here. Download the instructions and not the form, because Section 7 of the instructions contains editable PDF forms. The instructions are exhaustive (112 pages!) and relatively clear; there isn't that much to say about completing the forms that isn't said reasonably well in the instructions. You'll need a recent version of Adobe Acrobat Reader to read and edit them. You can get Acrobat Reader here.
The same form, PHS 398, is used to apply for research career development awards and AREAs (R15s).
Note that these new, downloadable forms are a bit different from the older forms, and the new forms will be required come January. Until then, Luddites can continue to use the old forms.
* Electronic submission
NIH has an active pilot program, the NIH electronic research administration (ERA) initiative, in which it will soon encourages applicants to submit certain types of applications--renewals and training grant applications--online. But for now applications are still made the old-fashioned way: by mail (or more precisely, by FedEx; see this photo of the loading bay on the day the applications are received).
And this isn't going to change soon: It will be a while before electronic submission of NIH grant applications becomes mandatory. See this GrantsNet/Next Wave feature, Federal Corner, for more information on the Federal Commons project. We'll keep you posted when there are new developments.
As mentioned in the previous section, NIH is taking a small step toward electronic submission with the introduction of editable PDF forms. These new forms are much more convenient than the old ones, because you can fill them out before you print them--no typewriter needed. But you'll need to send in hard copies by snail mail for a while longer. These new forms--which, in addition to being editable, are also a little bit different--will be required beginning in January 2002.
* R01 Types
This isn't crucial information, but knowledge of the main types is useful for understanding some of NIH's online statistics.
Type l -- A shiny new R01 application
Type 2 -- A competing continuation (that is, renewal) application
Type 3 -- An application for additional (supplemental) support
Type 4 -- An application for additional support beyond that previously recommended
Type 7 -- A change of grantee institution
Type 9 -- A change of NIH awarding institute or division (a competing continuation in a new institute)
If your grant application isn't funded in the first around and you revise and resubmit, your resubmitted application will still be Type 1, but it will be classified as "amended."
* Who qualifies?
If you are a biomedical scientist with a faculty position, you technically qualify to apply for an NIH research grant. You don't need to be a U.S. citizen or even to work in the U.S. All you need is the support of a qualified institution, the proper educational credentials, and a completed application.
Just because you qualify doesn't mean that you are competitive. In order to receive an award, you have to have a strong record of accomplishment (or, for new investigators, demonstrated strong "research potential"). You have to prove to the reviewers that you can get the work done.
This last point not only means you have to prove your general competence as a scientist; it also means you have to have a research plan that the reviewers are persuaded you can execute. Furthermore, it helps a great deal to have a long-term appointment and a reasonable workload, because that provides evidence of institutional commitment: The NIH doesn't want to see you lose your job or move on to another institution, leaving an NIH-funded research project unfinished. Although the NIH is interested in career development, it isn't a public works program for research scientists. The NIH is very serious about getting the work done--which means that it also helps to have experience running a lab and managing money, although these criteria are loosened for new investigators.
Finally: Even though non-U.S. applicants qualify (even foreign institutions can win NIH research grants), reviewers are asked to consider whether similar work is being done in the U.S. If similar work is being done in the U.S., your chances as a foreign investigator aren't as good. This is an extra hurdle that non-U.S. scientists must clear.
For non-U.S. researchers, especially if you're living in "developing" parts of the world, the best strategy is probalby to find an NIH-funded--or fundable--U.S. partner. Several programs exist to facilitate international collaborations, including the CIPRA and FIRCA programs.
* When should I start writing?
Yesterday. Better still, last year.
In all seriousness, it's never too soon to start writing your first R01 application. If you can find the time, start developing ideas as soon as you're comfortably settled in to your postdoc position. That's right, I said postdoc. True, it's unlikely that you'll actually be able to submit your application while you're still a postdoc. That would require university sponsorship, and most universities won't sponsor a postdoc for independent funding, and even if they did NIH wouldn't fund it. Nevertheless, there are many advantages to starting a grant proposal while you're still a postdoc.
For one thing, you get an early start thinking independently and developing your own ideas: if this were MY lab, here's what I'd do differently. For another, a well-developed, well-conceived R01 proposal in-hand makes you look good to prospective employers. Submit it as supplemental material.
But the best reason for writing an R01 while still a postdoc is that you can submit it as soon as you accept the offer of a permanent job. If you get your first R01 application in that early, you'll have time to be rejected, revise, resubmit, get accepted, do the work, and win a competitive renewal--all before you stand for tenure.
* The Center for Scientific Review
NIH's grant-reviewing organization--the Center for Scientific Review (CSR)--is one of 24 NIH institutes. It's the first stop for any grant application; indeed, your grant application will be reviewed for scientific merit entirely within the CSR, regardless of which institute ultimately funds (or decides not to fund) your research project. So you need to understand how the CSR is organized.
You need to understand this, because your cover letter will advise the CSR on which study section to send your application to. Spend some time on this decision. Your request won't automatically be honored, but if it makes sense it will.
Note that the above roster index includes links to study-section membership rosters. (Some study sections don't have links to membership rosters directly, but you can see which members were present at the most recent meeting by clicking on the most recent "meeting roster" link.) Once you've narrowed your search for the ideal study section down to a couple or a few study sections, look at the membership rosters. See names you recognize? If you don't, look up their publications and see if they're doing work that is similar to yours--or, more generally, if they're likely to appreciate the value of the work you're proposing. If you don't recognize any of the names, and their papers seem to be written in Martian, try another study section.
Studying the membership roster will also help you decide how to pitch your project--how technical to be and how general: If your preferred study section is populated by people who are likely to know your science very well, you may want to discuss your work at a higher level of technical detail. Imagine that you are having a one-on-one conversation with them. What would you say? How would you present your work to that audience? But even if your study section includes experts in your field, don't forget to emphasize the big picture. You want to show that you know how to do your work, and you have to show that it's worth doing.
If your study section consists of people whose work is quite different from yours, you'll need to write for a more general, less expert audience. You may want to put less emphasis on technical details and more on the big picture--but keep in mind that you may not get the study section you want, and there are often last-minute membership substitutions, so you're playing the odds here. You want to cover your bets, to make sure that your application is strong even if you get a different study section than you request. You have to find the right balance between breadth and specificity, and you need to use each where it's appropriate.
It's one of the oldest bits of writing advice around, a cliché: Know your audience. The CSR is your audience; you aren't writing for some abstract group, you're writing for this core group. When you're writing an NIH grant proposal, you can actually get to know your audience pretty well. That's a huge advantage.
One other thing you need to consider when preparing NIH applications: You can submit an application in response to a specific program announcement (PA) or request for applications (RFA)...or you can choose not to. It's exciting to see that the NIH is seeking to fund research like yours, so you might be tempted to run out and apply under a particular RFA. But that might not improve your odds. Not every RFA is well funded, and some get lots of applications. So you'll have to decide whether your odds will be better within an RFA, or whether your application is likely to fare better among the general pool of applications. For a complete list of all RFAs and PAs, see the NIH Guide
* NIH Organization
Your proposal will be reviewed by a study section, but it will be funded by an institute. An institute committee will make the ultimate funding decision, based on the scores your application got from the study-section reviewers, on the institute's scientific priorities. This is the second tier of NIH's lauded two-tier system. Just as you can (and should) recommend a study section, you can (and should) also recommend an institute in your cover letter to fund your application. This list of institutes has links to the home pages of the various centers and institutes that make up the NIH.
* Don't let competitors be your reviewers.
If your arch-competitors are doing the same sort of work you're doing, make sure they don't end up reviewing your proposal. Include in your cover letter a request that particular competitors not be named as reviewers.
* What NIH Tells Reviewers
There are loads of resources out there to help you write successful NIH proposals. We encourage you to read and compare all of them--if you have the time. We'll provide a list of some of the best resources momentarily. But the goal of the CDC Toolkit is to save you time by bringing together all the best advice.
Here's the most important document you can read--required reading. It's short. Read it now.
These are the instructions given to reviewers of R01s. It's a carefully written document that doesn't require much explication. Study it, and tape it to the wall above your desk. This document specifies the criteria that reviewers must use in evaluating research grant applications. These are, consequently, the criteria you must use in writing your application. Note, in particular, the five criteria listed: significance, approach, innovation, investigator, and environment. Your goal in writing an application is to convince reviewers that your project is important, your approach makes sense, your approach is innovative, you (and your collaborators) are qualified to do the work, and your institution provides an environment that is conducive to getting the work done (that is, that it doesn't make unreasonable demands on your time and that it provides the infrastructure you need to succeed).
Just how important are these criteria? How closely are these instructions followed? Pretty closely, we suspect: After all, these aren't merely suggestions; they form an outline. They dictate the form that R01 reviews are to take--one paragraph for each criterion listed--so they're pretty hard for reviewers to ignore.
* The most important advice you'll receive
Write a draft of the application and then write your own evaluation, using the reviewer's guidelines, one paragraph for each of the five criteria. Be honest. How does your proposed research compare--specifically, in each area--to work in your field that you respect and admire...to the "state of the science?" Does your application make the best possible case for the significance, approach, degree of innovation, qualifications (or potential) of the investigator, and the strength of your institutions support? Does the work you hope to do, in an honest, objective evaluation, measure up to the work that the best (NIH-funded) scientists in your field are doing? If the work you propose falls short, is the problem with the science or with the presentation?
If the problem is with the presentation, it's easy to brush up the prose. Get some help (more on this momentarily...). If the problem is with the substance, you need to solve it. Think of a different approach, another way of doing things. Either way, you can't expect to win your first R01 until you fix those problems.
Once you feel that your application meets the standard for each of those five criteria, send it on to a mentor or one or more close colleagues. It's a good idea to send it to two different colleagues, one who is an expert in your field (an insider) and one who is from a related field who can provide the outsider's perspective. Circulating your proposal widely carries a small risk that someone will steal your ideas. But it has the considerable advantages that: 1. it will make your proposal stronger, and 2. it can help to build a consensus within your network of colleagues that the work you propose must be done, and that you are the best person for the job. That sort of thing has a way of filtering back to potential reviewers. Give your colleagues the NIH reviewer guidelines and ask them to review your proposal. Don't take their suggestions and opinions as gospel: evaluate their comments critically, but don't be defensive. If you think they have merit, address them. Fix the problems.
* A funding proposal is an argument.
Never forget that your proposal is a work of persuasion and not a collection of disparate facts. It isn't merely a description of the work you want to do; you are making an argument that it is work that needs to be done and that you are the right person to do it. Make your argument convincingly.
* The Big Picture
A related point: You need to include enough technical detail to be convincing, but your main objective should be to present the big picture. Focus on the significance of your research and what's novel about your approach.
Criterion number three, innovation, is a recent addition. It was added to the list as a result of concerns that NIH reviewing was too conservative and--hence--favored complacent senior scientists over more daring younger ones. This means that innovation is currently a point of emphasis...but to what extent will depend on the particular reviewer. So emphasizing innovation carries risks. Innovation is valued if you can convince the reviewers that your approach will work. But more innovative approaches may be seen by some reviewers as dicey; you may have a harder time convincing some that your approach is viable.
If your approach is particuarly innovative, you may want to apply to a program that is designed to fund high-risk research, like an R21 exploratory/developmental research grant. But read the instructions carefully to make sure you qualify. The work must really be new.
* Advice for New Investigators
Reviewers of new investigator R01s are given special instructions. You'll find them in the document Review of New Investigator R01s.
The NIH charges reviewers with evaluating new investigator applications differently than applications from established researchers. The instructions are fairly specific: "All applicants," writes the NIH, "should be evaluated in a manner appropriate for the present stage in their careers." In particular, new investigator awards are evaluated more for feasibility; actual preliminary data are weighed less heavily. New investigators are expected to be less accomplished--fewer publications are expected--but they are charged with demonstrating their "training and research potential." This means that you probably should include more biographical information. New investigators have to sell themselves as well as the science. Established researchers can sit on their laurels, but most new investigators don't have enough laurels yet to sit on. Besides, laurels are pointy.
* Hire a writing consultant.
If you're a lousy writer, use your start-up funds to hire a writing consultant. Look for someone who is generally familiar with your field, someone who has experience assisting successful proposal writers. You might need to be creative to find someone you trust. Try a trade journal: Writers for biomedical research publications (professional magazines, not scientific journals) often know quite a bit about biomedical science...and they can write, too. Contact two or three, and talk to them about your needs and the nature of the collaborative process you envision. Then, trust your instincts and make a choice. Be prepared to pay for talent--you get what you pay for!
Oh, and don't forget about your own institution's support staff, and your buddies in the English department.
* Other Resources
Here's a guide--with links--to some of the best NIH-grant-writing resources available (besides this one). Some are quite general, some are from particular institutes within NIH, and some are for the particular application form--phs 398--that's used for R01s:
- NIH Grantwriting Tip Sheet, from NIH's Office of Extramural research
- All About Grants, from the National Institute of Allergy and Infectious Diseases (NIAID)
- National Institute for General Medical Sciences Tips
- three from the National Cancer Institute
- from The Scientist
Note, also, that NIH goes around the country giving grant writing seminars--see http://nextwave.sciencemag.org/cgi/content/full/2001/04/02/2 for details.
Next Wave Resources:
- Vid on writing an application
- How Not to Kill a Grant Application, in five parts:
-- Part 1: Murder Most Foul
-- Part 2: Abstract Killers
-- Part 3: So What?
-- Part 4: Lost at Sea
-- Part 5: The Facts of the Case
-- Part 6: Developing Your Research Plan
Want to skip the book and wait for the film to come out? Too late: There's even a movie about writing NIH grants: Getting Funded: It Takes More Than Just a Good Idea, a two-tape set available in VHS format, by Liane Reif-Lehrer. Call 1-800-341-9757 to order.
GrantSlam is software that has been well reviewed and is updated regularly. Some say it makes the process of writing an NIH proposal more manageable.
* Sending In Your Application
Get a return receipt to establish a paper trail...or drive it to Maryland yourself (some people do). Send it to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive MSC 7710
Bethesda, MD 20892-7710
If you use express or courier service, you should use a different zip code--20817--and you'll need a telephone number: 301-435-0715.
Be sure to send in a complete application. Submission of supplemental material (e.g., papers accepted for publication after the review date) is at the discretion of the scientific review administrator (SRA).
Eventually you'll all be submitting your applications electronically, via Federal Commons (part of the ERA initiative).
* If you schmooze, you lose.
I once saw a presentation by a senior, very successful researcher--one with an impressive record of funding and accomplishment, one you might have heard of--called "Getting your first NIH grant." His talk was heavy on schmoozing. He emphasized the importance of personal contact. Contact your SRA, he suggested, before you even apply. Send that person a short list of objectives and ask for feedback. Is your work something he or she would be interested in funding? Then, the speaker argued, stay in contact throughout the process. Shepherd your application through.
Is this good advice?
The NIH is eager to mentor young scientists, and most NIH officers are eager to help. If they didn't like the role of mentor and facilitator, they wouldn't be working as NIH officers. So you should definitely interact. Don't hesitate to call if you have a legitimate reason (see below for what qualifies as a legitimate reason).
But--schmooze? Be careful. The key is not to be--or seem--cynical. Another worry is that you could be perceived as too dependent and lacking in original ideas.
One of the worst things that can happen to a young researcher is to be labeled as cynical. Young researchers aren't supposed to be cynical; cynical is for old, established researchers. Young researchers are supposed to be bright-eyed, bushy-tailed, earnest, and serious.
I'll make two points that I think will convince you that caution is warranted when it comes to schmoozing.
1. These folks see a lot of grant applications. Your phone call will likely not be the first they've received that day (unless you call before they've had their first cup of coffee--a very bad idea). These folks can smell a schmooze a mile a way, even through coffee fumes; they can tell if you're wasting their time. So don't call unless you have a good reason.
2. The PHS 398 application includes explicit instructions for "interacting" with program officials. Nowhere do these guidelines say, "Don't contact the NIH for any other reason"--indeed, the tone of the comments is solicitous; NIH encourages your interactions--but the fact that guidelines exist means that they should be followed. Here's what they say, in brief:
First, you are encouraged to gather any additional information that might be available for the particular grant program you're applying for. You can probably find it on the Web, but it's reasonable to contact a human being to make sure you have everything you need. Indeed, it's accepted, so you probably should.
Second, you are encouraged to contact "relevant Institute or Center staff for advice in preparing an application and for information regarding programmatic areas of interest." Phone numbers to call are listed in the PHS 398 instructions. Once again, do this. If you don't, you'll be at a disadvantage. It's a bit like visiting your professor's office when you had a question about the homework in college and grad school: You get to hear from the horse's mouth what he or she is driving at.
Third, you are encouraged to let them know if your initial CSR assignment seems erroneous. Once again, the PHS 398 instructions tell you whom to call.
Fourth, once you've received your "summary statement," you are encouraged to contact "the appropriate Institute program official (noted on the Summary Statement) for an interpretation of the reviews and the disposition of the application."
Consider these your prime windows of opportunity to interact with NIH program officials. If you really need to call about something else, at another point in the process, do. But except in special circumstances, limit your contact with the NIH to these times, and contact only appropriate personnel. Don't call just to chat or to ask about something that can easily be found on the Web. It's disrespectful.
These are general suggestions; special circumstances may lead to different advice. If, for example, you already have a warm, personal relationship with an NIH program officer, then your instincts are worth far more than these instructions--which are, after all, intended to be the best advice for the most people. If they don't apply to you, you're likely to know it. Follow those instincts.
Your postdoc advisor and senior colleagues with an established record of NIH funding and research accomplishment can probably get away with schmoozing. Some NIH folks might even be honored to receive a phone call from a venerable scientist. Just remember that what works for the goose very possibly might not work for the gander (or vice versa). Unless you're venerable, play it safe. And speaking of geese and ganders: Gender and race inevitably color these kinds of interactions. For better or for worse, social dynamics are often different depending on the gender of the participants.
Indeed, much depends on particular, individual personalities. If you doubt your ability to pull off an effective schmooze, trust your instincts. If you are confident and your motives are pure, then call. But don't be cynical.
* What if your proposal isn't funded?
Well, most of them aren't. But many people react to this in exactly the wrong way. If your grant isn't funded, take advantage of that fourth window of communication opportunity: Once you've received your "summary statement," contact the "appropriate institute or program official for an interpretation of the reviews and the disposition of the application." Take careful notes. Get as much insight as you can into the reviewers' responses to your application. This isn't at all for cynical reasons; well, maybe just a little. You want to have the best information you can get for revising your application (yes, it's a forgone conclusion that you'll resubmit). But it doesn't hurt to be perceived as serious and determined.
Then get to work rewriting the application. After all, the funding rate for "first amendments" is higher than the funding rate for new proposals. The funding rate for second amendments is higher still. In a sense, having your proposal rejected gets you that much closer to getting a grant--if you handle rejection and use it to your advantage.
No matter how tempting it might be, don't dismiss the criticisms of your reviewers. Address them; take them seriously. True, the occasional reviewer will be clueless, but that really doesn't matter. Once your application has been reviewed, it has a paper trail that you have to deal with, like it or not. Even if the comments are dumb, address them. If a reviewer doubts that your approach will work, come up with an alternative approach that definitely will. If a reviewer doesn't think your research is important enough to merit funding, then change the focus to bring it more into alignment with NIH's particular, stated goals. Even if your score doesn't improve all that much the next time around, you are more likely to be funded as an exception if the goals of your research are precisely aligned with the objectives of the NIH.
* What is streamlining, or, what if your proposal isn't scored??
NIH has a process called "streamlining" that is designed to reduce the workload of reviewers. About half of the proposals are dismissed after a preliminary reading, without being scored. But not being scored is not the kiss of death. You could be near the cutoff, after all, and with funding rates hovering near 30%, your score doesn't have to improve that much in order for your proposal to be funded. Many applications that are initially streamlined are eventually funded. It isn't a lost cause.