A recent article in Newsweek discussed “how the road from promising scientific breakthrough to real-world remedy has become all but a dead end,” with FDA approval for a newly discovered molecule, targeting a newly discovered disease mechanism at a dismal 0.6 percent.
This unfortunate path has concerned many and frustration is growing “with how few seemingly promising discoveries in basic biomedical science lead to something that helps patients, especially in what is supposed to be a golden age of genetics, neuroscience, and biomedical research in general.” For example, from 1996 to 1999, the U.S. Food and Drug Administration (FDA) approved 157 new drugs, compared to 74 from 2006 to 2009. More shocking was that “none were cures or even meaningfully effective treatments for Alzheimer’s disease, lung or pancreatic cancer, Parkinson’s disease, Huntington’s disease, or a host of other afflictions that destroy lives.”
Even work that has shown significant promise, such as Hynda Kleinman and her colleagues at the National Institutes of Health (NIH)—who discovered in 2004 that a molecule known as A5G27, a peptide that blocked the metastasis of melanoma to the lungs and other organs in lab animals—was shelved because there was not a lot of support for work in cancer there at the time.
Accordingly, while the budget for NIH has grown considerably from 1998 to 2003 (doubled to $27 billion, and is now $31 billion), patients and taxpayers view this kind of “return on investment approximately as satisfying as the AIG bailout.” Mainly because patients and taxpayers “want to see treatments for diseases their money has bought,” not the discoveries about cells, genes or synapses that have been made. In other words, although “basic research is healthy in America … patients aren’t benefiting,” according to John Adler, a Stanford University professor who invented the CyberKnife, a robotic device that treats cancer with precise, high doses of radiation. Adler noted that while “our understanding of diseases is greater than ever,” academics are incorrectly thinking “we had three papers in Science or Nature, so that must have been NIH money well spent,” while patients are left asking how do those papers help them.
This leads “more and more policymakers and patients to ask where the cures are?” Unfortunately, “the answer is that potential cures, or at least treatments, are stuck in the chasm between a scientific discovery and the doctor’s office: what’s been called the valley of death.”
The problem that creates this chasm is that “in academia and the NIH, the system of honors, grants, and tenure rewards basic discoveries (a gene for Parkinson’s or a molecule that halts metastasis!), not the grunt work that turns such breakthroughs into drugs.” Although NIH grants and taxpayer money is going towards fundamental discoveries, the problem is that “they have no prospect of producing something that helps human diseases,” says cancer biologist Raymond Hohl of the University of Iowa.
Another problem slowing scientific discovery is the obstacles in the patent system, such as those experienced by Robert Sackstein, a bone-marrow-transplant surgeon in the 1980s. His decade-long research with his colleagues found a molecule they named HCELL, and in 2008 “announced in a paper in Nature Medicine that by injecting HCELL into human bone-forming stem cells tagged with HCELL into mice, they had found a long-sought cure for osteoporosis, as well as other diseases that might be treatable with stem cells.”
This significant breakthrough however, was rejected by the U.S. patent office “because Sackstein had described HCELL in a scientific paper. This technicality led to “ten years of appeals and hundreds of thousands of dollars in attorney fees,” that only hurt patients and prevented the timely conveyance of valuable scientific data. Despite the HCELL patent being granted in Europe and Japan, no multinational drug company will develop HCELL without patent protection in the U.S. as well.
In another case of problems with the patent system, vascular surgeon Jeffrey Isenberg, now at the University of Pittsburgh Medical Center, and colleagues were studying how the gas nitric oxide promotes blood flow. Their discovery led to what “might be a potent drug for saving heart-attack victims; restoring blood flow in patients with severe diabetes, in which impaired blood flow leads to gangrene; and treating hypertension.” As a result, a biotech startup in the Midwest began the process for a university or NIH technology licensing office to develop the professors’ discoveries. This process also included licensing and upfront fees, plus a promised share of royalties should the molecule become a commercial drug.
The biotech startups efforts were met with difficulty when “attempts to negotiate the rights to develop this discovery were Kafkaesque,” with “NIH’s licensing office demanding payments that the startup could not make.” As Eric Gulve, president of BioGenerator, a nonprofit in St. Louis that advises and provides seed money for biotech startups noted, NIH “has no skin in the game, so they have no inducement to work with a company” to get a discovery from the lab to patients, and “there isn’t a sense of urgency.”
For NIH, a “push to get something licensed to move a discovery toward commercialization is just another piece of paper to them.” But “without the license, the startup struggles to stay alive,” and as a result, patients suffer without having such treatments available. Although Mark Rohrbaugh, the director of NIH’s technology-transfer office, notes that it licensed 215 discoveries last year,” this number is down from the 2004–2008 average of 273 a year, with a high of 313 in 2005.
The next step in producing a drug, if a discovery is licensed, is to raise enough money “to test the compound’s toxicity, to figure out how to make it in quantity and with uniform quality, to test the drug in larger lab animals such as dogs, and then to test it in people.” This crucial step, where “turning a discovery into something that can be manufactured and that is safe and effective,” is where “the valley of death has gotten dramatically more fatal over the last few years,” for various reasons.
First, once scientists are able to identify basic discoveries, they “aren’t capable of creating assays [test systems] to do that because it is a time-consuming drudgery that takes an expertise that hasn’t trickled down to the typical academic scientist,” according to Sharon Terry, CEO of the Genetic Alliance, which supports research on rare genetic diseases.
Second, efficacy testing “is not something an academic lab is interested in,” because “incentives driving academic labs are grants for creative, innovative research, and not research on whether a compound kills a rat.” As a result, without toxicity and efficacy tests in lab animals, “no company that actually develops drugs will consider buying the rights to it.”
Third, efficacy testing is not something science careers are structured for because “big labs get established based on a theory or a target or a mechanism, and the last thing they want to do is disprove it and give up what they’re working on.” Consequently, “that is why there are so many targets” because although we want to “move them from a ‘maybe’ to a ‘no,’ it’s bad for careers to rule things out: that kind of study tends not to get published, so doing that doesn’t advance people’s careers.”
Other factors include biotech firms taking more of a role in this testing, but not having adequate resources, and “NIH grants not supporting the kind of research needed to turn a discovery into a drug.” Money, which traditionally came from venture capital is also a problem because “over the last four or five years it has decreased dramatically for early-stage drug discovery.”
What is happening now is that venture capitalists—“essentially the only source of money to move preliminary discoveries forward—are demanding that startups prove themselves far more than in the past.” For example, “Duke” Creighton had the idea of “using magnets to amplify the effects of drugs that dissolve stroke-causing clots.” As a result of this idea, “he founded Pulse Therapeutics to develop the discovery, but eventually ran out of money because “venture-capital firms said ‘show me animal data and we’ll talk.’” Creighton, who needed at least $300,000 to carry out such studies, is still “short of what he needs,” and the amount of money required for “human testing is even more expensive—tens of millions of dollars.
Interestingly some money might be available through a provision in the health-care-reform bill known as the “Cures Acceleration Network.” The network, which Senator Arlen Specter (D-PA) sponsored, “would be located at the NIH and would give grants ($500 million is authorized this year) to biotech companies, academic researchers, and advocacy groups to help promising discoveries cross the valley of death. Seemingly, money is not the only thing that is needed.
“Academia, the NIH, and disease foundations will have to change how they operate” as well. While some changes include private foundations beginning to “manage and direct scientists more closely, requiring them to share data before it is published,” these organizations must maintain a careful balance in collaborating and sharing information so as not to “jeopardize funding, patent protection, and publication.” Moreover, any proposed changes must preserve the vital role that industry support and collaboration play in bringing about such drugs.
One possible solution being implemented currently is that “universities are encouraging the creation of drug-development groups,” so that academics can get funding to turn their discoveries into something. These groups are crucial since there “is still very little funding for steps such as testing a compound’s toxicity in several species of lab animals, synthesizing the molecule, and scaling up that synthesis,” according to Daria Mochly-Rosen of Stanford.
She added that “academia needs an understanding that these steps can be intellectually interesting, too.” So she founded Spark four years ago to “scrutinize discoveries from Stanford scientists that have not been licensed to a company and, with industry input, identify 20 per year that have promise.” This model, using the support of industry, will help bring safe and effective medicines to patients more efficiently by teaching an inventor “the basics of drug development and getting funding support to carry out” the testing and other processes.
Ultimately, the process of bringing a discovery funded by taxpayer dollars into the taxpayers hand is long and hard, but not without promise. By keeping industry support and collaboration throughout the drug development process, key discoveries have been consistently made for decades, and the progress of medicine is evident from such relationships by the prolonged life Americans have today, and the decreasing rates in serious conditions such as heart disease and cancer. Consequently, with 30 million people entering our health care system over the next few years, “the last thing we want to do is slow down science.”
Since NIH does not “sense an urgency” to get drugs and products in the hands of biotech companies and firms willing and ready to bring breakthroughs to patients, what we need is the expertise of industry to carry out the time-consuming work of drug development and the discovery of academia to work together to produce something that actually helps human diseases.
Update:
Francis M. Creighton, PhD
I just wanted to update that the Newsweek article didn’t quite capture reality. Pulse Therapeutics actually closed a $600k round and are about to complete animal clinical work. We have also launched our Series A effort. Also, human testing is much cheaper for 510k technologies. Ultimately, and especially in this economic climate, you want to prove your value for as little dilutive investment as possible, thereby ensuring a relatively high return of investment if you can attract an early buyout.