The Chasm Between the Bench and Bedside
by Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
6 December 2008
On November 1, 2008, Newsweek Magazine’s Sharon Begley pointed out in an article entitled Where Are the Cures? that “Scientists call the gulf between a biomedical discovery and new treatment ‘the valley of death.’ The article reiterated a common misperception of scientists and their role in therapy development.
It has been years since Hans Keirstead worked his biological magic, injecting stem cells into rats with severed spinal cords and thus making them walk almost normally. But the real miracle—since other experiments, too, have cured paralysis in lab animals—is that Geron Corp. plans to test the technique in people next year. Between Keirstead’s experiment and Geron’s trial lie these obstacles: Keirstead, a professor at the University of California, Irvine, had to invent instruments to squirt the stem cells into spinal cords (“what do we academics know about developing medical devices?” he asked me), find someone to try the technique in monkeys (“I know two researchers who handle monkeys; you have to get in line”), ramp up production of the stem cells (“it meant going from pipettes to this massive hydraulic setup”) and … well, more industrial-strength biology that he wasn’t trained in, that the government rarely funds and that brings exactly zero glory to a university scientist. “We hacked through the jungle and paved the road,” Keirstead said. “But how many others are willing to do that?”
A Chasm Between the Bench and Bedside
Scientists are neither trained nor equipped to take therapies from laboratory to clinical trial. They do experiments on rats and other small animals in their laboratories to establish proof of concept. Most scientists don’t know how to scale therapies from rats to humans. They don’t know how to get therapy ready for human use. Few have participated in or organized clinical trials. Very few know how to raise the funding necessary for clinical trials.
In the days of Jonas Salk, it was possible for a single scientist to usher a therapy from laboratory to clinic without involving a company. These days are now over. Therapy development has become big business. Pharmaceutical companies are therapy development machines. They have regulatory, preclinical, and clinical departments. What they cannot do in-house, they farm out to consultants and contract to professional organizations that will do the job in accordance to regulatory standards and on schedule.
Many clinicians are too busy to participate in, much less organize clinical trials. Most have not been trained to run clinical trials. Despite the advent of “evidence-based” medicine, most therapies (particularly surgery) that clinicians use have never been tested in double-blind randomized placebo-controlled trials while new therapies are subject to rigorous standards of multicenter phase 3 clinical trials. Who will bridge the chasm?
In theory, the pharmaceutical industry is the bridge between the bench and bedside. However, the industry estimates that it now takes over a billion dollars and ten years to move a therapy from discovery to market. The funds must come from the investors, government, or foundations. If funds are insufficient, it takes forever to develop therapies and many bite the dust along the way. This problem is not unique to spinal cord injury or so-called “orphan disease” that affects less than 200,000 people. It affects development of all therapies.
The Solution is Not Medical Tourism
Pessimism seems to have gripped the clinical and patient communities. In spinal cord injury, for example, after decades of telling patients that they will never walk, many clinicians do not believe that any therapy will restore function, particularly in people who have been injured for many years. Understandably, patients, having been told by their doctors that no therapies are or will be available, are going overseas in droves to spend their life savings for unproven experimental therapies.
Medical tourism only aggravates the problem by diverting people and resources to therapies that are unlikely to help and may well cause harm. Few of these clinics have done any serious research on the conditions that they are claiming to be able to cure. They often take some undocumented therapy, claim that it is 100% safe and 80% effective, advertise the therapy to patients with incurable conditions, and charge them what the market will bear. At present, that market price is US$20,000-$30,000.
Clinics that sell experimental therapies have a serious conflict of interest. They depend on the funds for their existence and therefore cannot be relied upon to provide objective opinions concerning the therapies. Most will not submit their therapies to rigorous clinical trials and few collect or publish data concerning the risk and benefit of the therapies. Worse, many offer false hope to lure people to pay the cost of therapies that are unikely to work.
In the end, the choice is of course up to the individual. But, the harm is not to just to the individuals but to development of therapies. In order for a therapy to be accepted and available to other people and covered by insurance, well-run and rigorous clinical trials are necessary. Once a therapy is shown to be safe and effective, it will then become available to all who need it. Most countries cannot afford to waste time and resources on therapies that are unsafe or ineffective.
The Economics of Therapy Development
Competition for funds to develop therapies is fierce at every level. At the National Institute of Health (NIH), less than 10% of grant applications are being funded. Clinical trial grants must compete with basic science. Some diseases, such as cancer and AIDS, get much more funding than others. Within companies, the fight for resources is just as intense. Probably less than 5% of initiatives get off the ground. In the marketplace, probably less than 1% of biotech companies succeed in getting a therapy to market.
Every therapy must be championed by one or more people who obtain the support of key opinion leaders, compete for internal and external funds, and lead the product development and clinical trial teams. These teams may have hundreds of people. Many companies spend a large portion of their budget on public relations to convince internal and external investors to support the project. Each therapy must pass through many gauntlets in the quest for funds.
Product development decision-making is risk-averse. A therapy must supported by good basic science before peer review panels at NIH will approve a clinical trial grant. It must be well-patented before any company will invest. Once underway, each therapy must achieve multiple milestones or else the entire project may be “canned”. Many companies have “canning” committees, whose only purpose is to stop development of risky projects. Many therapy development projects run out of steams or funds before reaching clinical trial stage.
Many companies consequently invest a lion’s share of their research funds on “me-too” products or product cycle development that pose the little risk of failure. “Me-too” products are drugs that do the same thing and the clinical trials just have to show therapeutic equivalence. Product cycle development usually produce different versions, such as capsules or time-release, of the same drug, to extend the life of the product. But these activities just split the market and do not generate new business.
Pessimism and Optimism
A mantra in the pharmaceutical industry is that the market size must be sufficient to justify the investment. Because therapies now cost a billion dollars and over ten years to move from discovery to market, most companies have been reluctant to invest in therapies for so-called “orphan diseases”, conditions that affect less than 200,000 people in the United States. For this reason, the U.S. Food and Drug Administration (FDA) gives an additional 7 years of market exclusivity for orphan disease therapies,
Spinal cord injury is not only a small market condition but is regarded by many doctors to be one of the most challenging unsolved problems in medicine. Many in the spinal cord injury community have given up and have gone overseas to fly-by-night clinics to try unproven therapies. In the face of economic, clinical, and community pessimism, how does one convince our government, companies, and foundations to invest in developing therapies for spinal cord injury?
Christopher Reeve once pointed out that he could accept it if scientists told him that we don’t know enough about growing the spinal cord and it will take a long time. Instead, most scientists told him that the spinal cord can regenerate. The major obstacles to cure is money and politics. Relatively little money is required and a large majority of Americans favor the research. We spend more before breakfast in one day of an unpopular war in Iraq than a whole year of spinal cord injury research. Christopher set about reversing the money and politics. Unfortunately, he died before he completed his task. It is now up to us.
Three developments in recent years give me hope that curative therapies for spinal cord injury will happen and faster than most of us think. First, much recent evidence suggest that spinal cord injury therapies are profitable and worthwhile. Several therapeutics companies are investing in therapies for spinal cord injury. Second, we have a pipeline full of promising therapies that work in animals. We just need clinical trials to test these therapies. Third, spinal cord injury clinical trials are much efficient than for other conditions. We have well-standardized and validated clinical outcome measures. I will discuss each of these sequentially.
Therapies for Small-Market Conditions Can Be Profitable
The therapeutics industry is under much pressure to reduce costs and increase the efficiency of therapy development. “Me-too” drugs and product cycle development can only generate so much revenue. A company that succeeds in developing a new class of products for a new condition can make many billions. One successful product can boost a company from a struggling biotech company to a fortune 500 company. A few major products can make a big difference, even for large companies such as Pfizer.
Much evidence suggest that investors now believe that profits can be made from small-market conditions. For example, multiple sclerosis (MS) affects only about 380,000 people in the U.S. Biogen and Teva are making billions from several drugs they have developed for this condition. One spinal cord injury company, Acorda Therapeutics, has made it through its initial public offering and has achieved market capitalization of about $600 million in the past year.
These examples are attracting the attention of major pharmaceutical companies. They appreciate the argument that spinal cord injury may serve as a bridge to other conditions. For example, a therapy that protects, repairs, regenerates, or remyelinates the spinal cord may well be applicable to other more prevalent conditions such as traumatic brain injury and stroke, multiple sclerosis, peripheral nerve or neurodegenerative diseases. More important, Just spinal cord injury alone can provide sufficient return.
What is the price of a therapy that restore function in spinal cord injury? As people found out, the limit is much higher than people thought. Would people and insurance companies be willing to pay $20,000 for a therapy that restores bowel and bladder function? Insurance companies will because that is how much they would pay for surgery or life-long care of complications. Even if only 100,000 people received a $20,000 therapy, the revenues could potentially add up $2 billion.
Pipeline of Therapies that Work in Animal Models
The standard joke in the spinal cord injury community is that the rats have it better than humans because there are therapies that allow them walk. We should be glad that there are many therapies that make rats walk. Things that work in a rat may not work in human. That is why is good that many therapies work because the chances that one or more may be effective in humans is greater. The vast majority of scientists believe that the spinal cord can regenerate if several obstacles to regeneration can be overcome.
The first obstacle is the injury site itself, which is often inhospitable to axonal growth. Astrocytes in the spinal cord may wall off the injury site, if it considers it to be “outside” of the cord. The injury site may be surrounded by extracellular chondroitin-6-sulfate-proteoglycan (CSPG) that normally deflects axonal growth. These problems can be overcome to some extent by transplanting cells that bridge the injury site. The bacterial enzyme chondroitinase breaks down CSPG.
The second obstacle is the lack of sustained growth factor support. During the first hours and days after injury, the injury response and inflammation causes cells to release growth factors. However, regeneration is slow and may take months or even years after injury. A sustained soure of growth factors is needed to stimulate long-distance regeneration. The recent discovery that lithium and other glycogen synthetase kinase (GSK) inhibitors stimulates neurotrophic factor production by umbilical cord blood mononuclear cells is of considerable interest.
The third obstacle is the presence of axonal growth inhibitors. The most prominent and best studied of these inhibitors in myelin-based Nogo which can be covered by antibodies. Alternatively, it is possible to use soluble Nogo receptor protein itself which binds to all the proteins that activate the Nogo receptor. Finally, the intracellular messenger for the Nogo receptor is rho which is phosphorylated by rho kinase. Inhibitors of rho and rho kinase stimulate regeneration, leading to a new class of therapies called “rhok and rho” inhibitors.
Efficient Clinical Trials for Spinal Cord injury
Unlike other conditions such as stroke and traumatic brain injury, spinal cord injury outcomes are predictable and well-defined. For example, less than 5% of people who have so-called “complete” spinal cord injury will recover walking spontaneously. Any therapy that restores walking in even 20% of such patients can be detected with small populations of patients. Thus, while a trial for stroke may require a thousand or more patients, a trial for spinal cord injury may show significant results with only 100 patients.
Several outcome measures in spinal cord injury are well-defined and have been extensively validated. For example, the American Spinal Injury Association (ASIA) classification, motor and sensory scores have been successfully used in the National Acute Spinal Cord Injury Studies (NASCIS), the first double-blind randomized placebo-controlled clinical trials to show an effective therapy for acute spinal cord injury. Other examples include the Walking Index of Spinal Cord Injury (WISCI) and the spinal cord independence measure (SCIM).
Neuroprotective, reparative, regenerative, and remyelinative therapies can be tested in spinal cord injury. The first should be tested in acute spinal injury. The second would be appropriate in subacute injury. The third and fourth can be tested in chronic spinal cord injury, where there is no dearth of patients willing to volunteer for clinical trials. Thus, spinal cord injury is an excellent model injury in which to develop and test therapies.
Finally, rehabilitation of spinal cord injury is more advanced and standardized than for other types of neurological disorders. Recent studies, for example, have shown that intensive locomotor exercise facilitates recovery of walking in spinal-injured patients with incomplete spinal cord injury. In many ways, that is what therapies are supposed to do, i.e. make the injury more “incomplete”. Well-established locomotor training and other rehabilitation protocols are available.
Trials, Trials, and Trials
We should be optimistic about the likelihood of safe and effective therapies that restore function in spinal cord injury. Progress in the past 8 years has been slow and limited but this is astonishingly not due to the difficulty of the problem or ignorance about the therapeutic mechanisms needed tor restore function. Rather, the problem appears to due to lack of investment by government and companies in clinical trials. If I had to choose a problem to have, I would choose this one because it is easy to solve.
Christopher Reeve once said he could accept it if the reason why we don’t have a cure for spinal cord injury is because the science is too difficult or the spinal cord simply cannot regenerate. However, he simply cannot tolerate it when the problem is not science or the inability of the spinal cord to regenerate but lack of funding and politics. Worse of all, the amount of funding required to cure spinal cord injury is not so great. We probably spend more in one day of the Iraq war.
The “chasm” between the bench and bedside is not unique to spinal cord injury. The pharmaceutical industry estimates that it takes an average of more than ten years and over a billion dollars to take a therapy from discovery to market. All fields, from cancer to AIDS, have this problem. The solution to this problem is to have develop many therapies in parallel. Each clinical trial has a finite probability of success. More clinical trials add up to a greater probably of success. Unlike casino, if anyone wins, everybody wins.
In summary, the field of spinal cord injury is poised for the first successful clinical trials showing therapies that restore function in chronic spinal cord injury. We have many promising therapies that restore function in animals and are likely to be safe and effective in humans. Some evidence suggest that combination therapies will be more effective than individual therapies. Well-standardized, sensitive, reliable, and extensively validated outcome measures are now available for spinal cord injury clinical trials. The solution is clear. We need to do clinical trials.