Decoding Health Care

Part 25: Biomedical research

The United States is the undisputed global leader in biomedical research and Americans are rightly proud of US accomplishments in medicine. But as with many things in health care, most people really don’t understand how research “gets done”. I won’t claim to be an absolute authority in this area, but I know just enough to be dangerous (or at the minimum, critical). The last time I applied for an NIH grant was 40 years ago but amazingly from an operational perspective not that much has changed. And the success (or lack thereof) of biomedical research is largely related to how the system is set up.

The United States government is the largest source of research funding in the world. The National Institutes of Health (NIH) funds the greatest number of basic biomedical research projects, with the Department of Defense and the VA also funding a substantial number. Historically, the federal government has been responsible for over half of all basic research funding (it is now at about 40%), but over the last 20 years, the private business sector has increased its level of funding such that it is now a close number two. Universities are the third big funders of basic biomedical research.

The NIH is comprised of 27 agencies and institutes, the largest being the National Cancer Institute. The budget of the NIH was $48 billion last year with over 80% funding grants awarded by a competitive process. The funding of the NIH is dependent on an annual Congressional appropriation. As a consequence, the funding is subject to the political climate in Congress. Prior to 2000, the funding grew robustly every year, but since 2000 funding has not grown much at all. Since the funding of basic research is a long-term investment, many have condemned this “underfunding” as being short-sighted. But let’s be clear, research funding is about 3% of GDP (with basic science making up about 25% of all research funding), so it is still a lot of money.

Obtaining research funding from the NIH is a competitive process, and it is very competitive. The NIH funds about 50,000 grants a year, with the average grant award about $600,000. Only about 20% of all grant applications are funded overall, but this varies by agency; only about 12% of NCI grants are funded. But these numbers are a little deceiving because there are investigators with many grants. In fact, if you look at the top 1% of investigators (based on amount of grant dollars), 80% have more than one grant. So the grant money is not evenly distributed. This also obscures the fact that a lot of the grant awardees work “under” or in close affiliation with the big labs, so that although they are classified as independent principal investigators, that is sometimes a stretch.

The success rate for first-time applications is a little lower than 20%. A fair number of these get funded over time but it’s certainly not the majority. Which means that either there are a lot of bad ideas, or a lot of good ideas just don’t get funded. A recent study suggested that the absolutely highest scored grants (top 1%) actually produce the best (i.e. most often cited) science, but that there is a fairly abrupt fall-off in how well the grant review process evaluates all others (Researchers: Peer Review System for Awarding NIH Grants Is Flawed | Johns Hopkins | Bloomberg School of Public Health). So why is this true?

It makes sense to discuss the evaluation process for research grants. The grant submission process is arduous. The applications are long. And they usually require a fair amount of “preliminary data”, which means that a lot of the work the grant is supposed to fund has already been done. The grants are then reviewed by expert panels (peer review) that read and discuss the merits of the proposal. The process is NOT anonymous, and I assure you that reputation matters. This is not necessarily a bad thing. Investigators with a track record (or applications from investigators affiliated with those who have a track record) tend to be viewed favorably. A score is assigned and after all the grants have been reviewed, a funding line is determined (based on the budget available). If you are above the line, you win and if you are below the line you lose. The decision is binary.

There are a couple of important factors to consider in this competitive process. The first is that the areas of research that get funded are often subject areas that have particular appeal. For example, for many years HIV research was the #1 subject area. Cancer is always a major area. Other diseases, no matter the global societal burden, just don’t make the list. Malaria for example. This shifting of priorities can doom you if you are on the cusp of funding.

The second factor is that funding is usually just for a couple of years. The average duration of an NIH grant is 3-5 years. This means that most investigators spend a lot of time chasing research funding to allow them to keep working. This also means that a lot of grants are submitted with the same (or only slightly different) research proposals, and this funding may well overlap. And these “same” grants may be sent to different funding sources: the NIH, the Department of Defense, non-profits, etc. With a limited pool of money, it’s hard to fault funded investigators from using a tried-and-true formula to keep the lights on. But of course, since money is limited that means somebody loses.

It is fair to say that the system is really set up to provide support for established investigators, or at the minimum to support “conventional” research ideas. It is certainly not set up to support truly innovative ideas. There just isn’t enough money to fund speculation. I thought about this as the Nobel committee awarded the Nobel prize in Medicine last year and this year.

The Nobel prize in Medicine in 2023 was awarded to Drew Weissman and Katalin Kariko for their work identifying the potential for mRNA to be used as a therapeutic. This led to the development of the mRNA Covid vaccine and has opened the door for potentially game changing cancer therapeutics. But Dr. Kariko’s journey was not without bumps (Why UPenn demoted Katalin Kariko for research that won her the Nobel Prize | World News - Business Standard). When she was at U Penn she could not get research funding, and U Penn basically pushed her out the door. She subsequently went to industry (BioNTech) and the rest is history.

Why didn’t she get funded? It is impossible to know. Maybe she didn’t know how to write a good grant (and there is DEFINITELY an art to writing a grant in a manner that increases the likelihood of getting funded). Maybe her preliminary data was poor. Or maybe her idea was just too out of the mainstream.

History repeated itself in 2024. The Nobel prize in Medicine was awarded to Gary Ruvkun and Victor Ambros for their discovery of microRNA. Micro RNA are small fragments of non-translated RNA that regulate gene expression. Previously transcription factors were felt to be the primary regulator of gene expression, but now over 1000 microRNA species have been identified in humans. Drs. Ruvkun and Ambros started at MIT and then joined the Harvard faculty where they did their seminal work. But Dr. Ambros was denied tenure (essentially fired) and went on to Dartmouth and then U Mass. Why was he denied tenure? Nobody knows for certain (The Nobel Laureate Harvard Didn’t Want | News | The Harvard Crimson). But he was certainly unconventional compared to other Harvard faculty members (details about how he was unconventional and why tenure was denied multiple times are unclear). I have no reason to think he wasn’t funded. But the system isn’t really set up to reward “unconventional” scientists.

The obvious question that these two stories raise is: does the system select against investigators who are unconventional? The answer is certainly yes. But the more important question is: how much has that hurt us?

There are clearly other mechanisms to obtain research funding. As I mentioned, industry is a major source of research funding. But it would be naïve to assume that the research funded by industry does not have at least some relationship to a particular commercial impact. A lot of the research funded by industry is clinical research, that is research that directly examines impact on patients. The NIH does fund clinical research, but not in the same way as it funds basic science research. Nobody submits a grant application for a clinical project.

For many years, the NCI funded clinical research through the Cancer Cooperative Groups. These groups were consortiums of academic medical centers (with some affiliated community practices) that conducted large multi-site clinical trials. For example, most of the critical trials comparing chemotherapy regimens in lung cancer and breast cancer were done by these cooperative groups. But these trials (often randomized clinical trials) tended to be very large, take many years to complete, and were very expensive. The Cooperative Group paradigm has largely disappeared, being replaced by pharmaceutical company funded phase 2 trials. Although these trials in no way give us the same quality of evidence, they can be done a lot faster and they pass muster with the FDA.

So we are left with a system that very much supports the status quo, or more precisely a “certain type” of research. And this system has largely handed over clinical research to industry which has had unintended consequences (with respect to profound influences on drug development, FDA approval processes, and drug pricing). What we don’t have is a system that rewards out of the box thinking.

The bottom line is that there just isn’t enough government money to go around. And it is extraordinarily naïve to think that the level of government funding is going to increase. Given the lack of political interest in increasing NIH funding over the last several years it is much more likely that government support will decrease.

So what should we do? I have four suggestions.

First, a much greater percent of funding should be set aside for new investigators. Although there is some funding earmarked for career development of young investigators, by increasing the funding level of this cohort I think we might see some bright new faces on the research scene.

Second, the grant review process should be anonymous. It is just too easy in today’s world for a grant to be funded based on reputation. It’s not that track record is irrelevant. But the process of “peer review” can be distorted by reviewer prejudices. Parenthetically, this is also true of the medical literature, which also is dependent on peer review. And recently major issues regarding fraud in medical research have come to light that have at their core well established well regarded investigators having their names “attached” to papers to increase the likelihood of publication in a prestigious journal (Dana-Farber Cancer Institute Seeks to Retract Flawed Studies - The New York Times).

Third, some coordination among various funding entities could reduce the amount of overlap that clearly exists in today’s research world. This was recently discussed in the New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMsb2412007). Again, funding of duplicate projects reduces funding available for new ideas.

Finally, and perhaps most importantly, the United States taxpayers ought to get a return on their investment and as of now they do not. What do I mean? If basic research results in a block buster drug, plenty of people get rewarded. The biopharmaceutical company that did the late stage development work gets rewarded. Usually so does the investigator, because as soon as a research finding looks like it has commercial potential the investigator (as well as the academic institution where the work has been done) file patents. This protects their interests, and they can  sell these patents to biopharmaceutical companies or even start their own companies. This is commonplace in the academic world, but the United States is never a patent holder. This is ridiculously unfair to every American who pays taxes.

The government has recently tried to use a process called “march-in rights” to get some financial benefit from products discovered using government funded research that turn out to be commercial successes. The Bayh-Dole act, passed in1980, made it possible for academic institutions to patent discoveries (that arose from federally funded research) that had commercial potential. But this act also allowed the federal government to cancel these exclusive patents if the resultant commercialization wasn’t available to the American public on “reasonable terms”.

The ability of the government to take this action is called “march-in rights” (https://www.milbank.org/quarterly/articles/do-march-in-rights-ensure-access-to-medical-products-arising-from-federally-funded-research-a-qualitative-study/). How does this work? The government would void all patents held by private entities and then in turn license the discovery to another commercial entity that would commercialize the discovery in a fashion agreeable to the government. The reasoning was as follows: it seemed absurd that commercial entities and investors were reaping billions in profits on drugs discovered as a result of federally funded research projects while at the same time the United States was paying many times more for these drugs compared with prices in Europe or other countries.

During the Biden administration, the government tried to take this approach with enzalutamide (Using Bayh-Dole Act March-In Rights to Lower US Drug Prices | Health Policy | JAMA Health Forum | JAMA Network). Enzalutamide is a very important treatment for advanced prostate cancer; it works by blocking the androgen receptor. It is also quite expensive, and since prostate cancer is a disease of Medicare aged men, that price acutely impacted the federal government.  The government argued that the price created a barrier to access. The pharmaceutical firms went nuts.

It has been argued that this isn’t a legitimate interpretation, and that drug pricing was never the intent of the law. Plus there are all kinds of barriers to making this work (Much Ado About Nothing: Why 'March-In' Rights Won’t Lower Drug Prices | Health Affairs). The patents need to be exclusively held by the investigator/institution; in many cases, during the process of a drug’s development, many patents are added (often by industry) making the march-in strategy not applicable. Plus, the FDA is restricted in how quickly it can approve a drug due to the Hatch Waxman Act and the Biologic Product Innovation and Competition Act. These laws, which paved the way for generic/biosimilars to come to market, did so in exchange for prolonged exclusivity of the reference drug (adding years to when a generic can actually be FDA approved even after a patent expires).  At this point, using march-in has gone nowhere. And if it does move forward, we can expect a ton of lawyers to be involved.

Nonetheless, it seems that making the government party to all patents that arise out of federally funded research is a darn good idea. And a perfectly fair one. And we could use that money to help underwrite an expanded research enterprise, particularly funding for new investigators. Just add a requirement that all patents arising out of federally funded biomedical research include the opportunity for HHS to join the patent.

I am certain that there is a law somewhere that precludes such a practical solution to our challenges in research funding, particularly for really innovative work. But I am certain there are other ways for the government (and by extension, us) to benefit from its investment in basic science research. As long as Congress is involved we are going to face yearly battles around NIH funding.

A young person must be really committed (or independently wealthy) to pursue a career in basic science research. You can say the same thing about a young person who chooses a career in medicine. And then there are those who choose BOTH a career in medicine and a career in basic science research. In our next post we will discuss medical education, how it has evolved and the careers new medical school graduates are pursuing.