Diabetes: The Paradox of Progress
John C. Lechleiter, Ph.D.
Chairman, President and Chief Executive Officer — Eli Lilly and Company
November 3, 2010
Cleveland Clinic Medical Innovation Summit
Thank you, Jim. I appreciate the opportunity to speak at this forum.
I want to thank all of you who may have been up late last night watching election returns for being here so early today. And for those of you who attended the preceding session this morning, let me begin with a clarification: I’m not an MD but rather a PhD – a chemist – and I’m not going to be performing surgery. What I hope to dissect is a paradox … the paradox of progress against diabetes.
And the basic paradox is this: The treatment of diabetes exemplifies … as brilliantly as any area of medicine … the power of medical innovation to arrest disease and save lives. And yet we face a growing epidemic of diabetes and obesity that indeed represents a “metabolic crisis.”
This paradox of progress in diabetes is really part of a broader paradox of medical innovation … more on that a bit later.
Be assured, as I discuss the paradox of progress, my emphasis today will definitely be on progress –and most importantly, how we can continue to achieve progress against diabetes and other diseases. And I’ll leave some time as well for a conversation on these critical issues.
Not that long ago, a diabetes diagnosis was often a death sentence. Although diabetes had been recognized centuries ago by the ancient Greeks, there was still no effective treatment by the 20th Century. But that all changed in the 1920s with the discovery of insulin by two scientists from the University of Toronto … and, I’m proud to say, with Lilly’s technical assistance in mass producing the first insulin for patients around the world. As you know, in those days, insulin snatched thousands of young patients from the jaws of death. So much so that, today, there are a good number of people with type 1 diabetes on insulin treatment who have lived fairly normal lives for 75 years and more.
Yet, despite this enormous breakthrough, millions of people continue to suffer and die from diabetes and related conditions, such as renal and cardiovascular disease, and depression. Diabetes is a factor in 4 million deaths a year worldwide – including more than 15 percent of all deaths in North America – robbing patients of an average of eight years of life.
The International Diabetes Federation estimates that the number of people around the world with diabetes will grow by more than 50 percent – from 285 million today to a staggering 439 million – by 2030.
And here’s a “red alert” for the entire medical and public health community. According to a report issued in the last few weeks by the Centers for Disease Control and Prevention, in the United States, if current trends continue, by 2050 one in every three Americans will have type 2 diabetes … up from one in ten today.
As we all know, this is a health and an economic time bomb. Among adults, diabetes is the leading cause of new cases of blindness, kidney failure, and non-traumatic amputations, as well as a leading contributor to heart disease and stroke. Even today, caring for people with diabetes eats up 11 percent of total global health care costs – or nearly $400 billion every year.
So, just as the discovery of insulin demonstrates the transformative power of medical advances, the growing devastation of diabetes drives home the need for continued innovation. Breakthroughs against diabetes are just as urgently needed today as they were a century ago … an imperative clearly reflected in the focus of this year’s Medical Innovation Summit … and the paradox we face today: For all our progress in treating diabetes, our ultimate goal seems as far away as ever.
The answer to the paradox is simple: a new wave of invention … simple, but not easy … a wave of invention, not a single medical miracle. Diabetes, obesity, and metabolic syndrome are complex conditions, and meeting the diverse needs of individual patients will require that we pursue many paths of research. Fortunately, exciting work going on right now in biopharmaceutical labs demonstrates the tremendous potential of medical innovation. The panel that follows will take a closer look at “the revolution in diabetes treatment.” Let me touch on just a few exciting developments:
First, we have vast new knowledge about the genetics that underlie susceptibility to diabetes. What we’re learning confirms the complexity of this disease, as no single gene or cluster appears to determine risk of diabetes. So researchers are looking for clues as to how the broad range of genes implicated in diabetes might work in combination.
Another area of growing interest is the entero-endocrine system. Drawing in part on what we’ve learned from patients who’ve undergone bariatric surgery, scientists are investigating the potential therapeutic application of hormones produced in the GI system.
Other avenues of research are improving insulin delivery with novel injection and infusion technology, and improved glucose monitoring and data integration. These advances are creating the distinct possibility of a “closed-loop system” – essentially an artificial pancreas that continuously monitors the body’s glucose levels and delivers insulin as needed.
Researchers are also making progress on so-called “glucose-plus” therapies for patients with diabetes that not only better control glucose levels but also address other related metabolic and hemodynamic abnormalities and co-morbidities – chief among them obesity and cardiovascular disease.
And other advances could allow us to move from management of type 2 diabetes to true disease modification – slowing or halting the progression of the disease and forestalling the eventual need for insulin. One of most exciting areas of research involves mechanisms which could augment differentiation of pancreatic beta cells from precursor cells.
For our part, Lilly is engaged in a broad diabetes and metabolic disease research strategy that follows the science in pursuit of unmet needs. Our goal is to offer a full range of treatment options for diverse patients in the many different stages of this disease. Our research encompasses both large and small molecules. Some examples from our diabetes pipeline are:
- insulins, including the next generation of basal insulin analogs;
- incretin mimetic peptides such as Bydureon – in concert with Amylin – which is in regulatory review in the U.S. and Europe, and GLP-1Fc, currently in Phase 3;
- small molecules that improve beta cell function through the activation of glucokinase; and
- and other novel treatments … as well as new and better delivery devices … and potential diagnostic tools.
A key area of focus for Lilly is the heterogeneity of patients with diabetes around the world … particularly in emerging economies where the disease has reached epidemic proportions … and the need to tailor treatment to the distinct physiological path of diabetes in these populations.
Just yesterday, we announced that Lilly will establish a center for basic diabetes research in China. A recent article in The New England Journal of Medicine estimated that 92 million people in China – almost 10 percent of the adult population – have diabetes. And that number is expected to increase in the coming decade … due in large part to lack of exercise, dietary changes, and longer life expectancy.
Our new research center will initially employ approximately 100 scientists and support staff, the majority of whom will be hired from within China. Scientists at the center will seek to tailored their efforts to the particular needs and physiology of patients in China.
At the outset, I promised to focus on progress, and I hope this brief scan of research helps illustrate the exciting progress toward a new generation of breakthrough medicines to fight diabetes. Nor should we overlook the progress that has already been made.
We’ve already developed new forms of insulin that help patients with diabetes better control their blood sugar, delivery devices that make injections simpler and more discrete, and oral medication that can delay the need for insulin for years. Some new classes of drugs give people with diabetes greater sensitivity to what insulin their body produces, while others enable the insulin-producing beta cells to work better.
But this leads to yet another aspect of our paradox: While treatments for diabetes are more sophisticated and convenient than ever before, more patients than ever before struggle to achieve critical goals in managing their condition.
A study published in 2008, based on data in the U.S. National Health and Nutrition Examination Survey from 1999 to 2004, found that more than 85 percent of Americans with diabetes are not able to maintain good control of their blood glucose, cholesterol, and blood pressure. Medco – the largest pharmacy benefit manager in the U.S. – estimates that nearly 60 percent of patients with type 2 diabetes stop taking their prescribed therapies within a year.
Folks, this is another red alert for all of us here – especially in light of the dire consequences for patients! It’s clear that effectively managing diabetes requires more than medicine. People with diabetes need education and steady support. Primary care physicians are the first line of defense against this epidemic, but face-to-face interactions in the doctor’s office are just the start. We must ensure the availability of health care resources to improve patients’ daily ability to live with diabetes – including, for example, adequate treatment of depression, a common co-morbidity of diabetes often associated with poor adherence.
Indeed, such support is essential if we’re to manage exploding health care costs. Medco has calculated the costs of treating people with diabetes, as a function of how well they adhered to their prescribed course of medicine. A 2005 study of Medco’s prescription claims database found that total medical costs for those in the least compliant group were nearly $9,000 a year. Costs in the most compliant group were about $4,600 – just about half. What’s interesting is that as people kept taking their medicine, their costs for prescription drugs increased (as you would expect) … but this increase drove overall costs way down.
While the consequences of diabetes can be significantly lessened if patients can take full advantage of what's already available, the simple fact is that there is still no cure. As scientists carry on the search for that cure, we must continue to develop medicines that offer new and better options for patients – and we must be equally innovative in the ways we support patients and doctors in the effective, long-term management of this devastating disease.
Having said this, while the potential of research has never been greater, and the need for breakthroughs more urgent, there are today serious barriers to innovation itself. So I’d like to turn now to the issue of what we must do to ensure that progress against diabetes can continue.
The first barrier is the high cost of discovering and developing new treatments in an environment where payers face tremendous budget pressures … and aging and affluent populations drive ever-increasing demands on the health care system.
The fact is that health care is, in many ways, a victim of its own success. In the U.S., life spans have increased by 10 years – just in my lifetime, and I’m not that old! And the rates of increase throughout most of the world are truly unprecedented in human history.
The problem – if that’s what you call it – is that all of us who are living longer … thanks, in large part, to advances in medical technology… are demanding more and more of the health care innovations that have become available to us.
This is the second paradox I promised to address this morning: the paradox of medical innovation. By extending life and expanding the range of available treatments, medical innovation creates unprecedented demands on health care that threaten the further pursuit of innovation itself.
The stakes, and the challenges, of drug development are higher than ever – but so is the potential of the science and technology available today. It is up to companies like Lilly, first and foremost, to create greater value for patients and payers. We must be able to demonstrate clear superiority over existing treatments, and clear benefits for an identifiable group of patients, with a balance of benefits and risks aligned with society’s expectations.
We flat out must find new approaches that reduce the cost and time of drug development and deliver more value to patients. Now, if the answer to the paradox of diabetes is “invention,” the answer to the paradox of medical innovation is “reinventing invention.” Let me offer just a few examples:
The first is greater collaboration in precompetitive stages of research.
Academic and government research has historically maintained a symbiotic relationship with the private sector, often supplying the raw material … such as insights on disease processes and leads on promising molecules … which industry has helped advance toward commercialization.
And now we are seeing significant collaboration across the industry itself … rethinking what information must be proprietary and what information is more valuable when it’s shared. Several industry consortia have been formed to undertake common efforts such as developing disease progression models or validating biomarkers.
To take just one example, so-called outcome studies looking at cardiovascular disease endpoints typically require around five years of follow-up and 9 to 10 thousand patients, and the time and cost required represent a huge hurdle for new diabetes medicines. The industry has a common interest in finding new biomarkers that track with long-term outcomes … for example, new imaging techniques that might make it possible to track in six months the cardiovascular effects of a new diabetes medicine that can be expected to result in a change in hard endpoints over five years.
A second innovation in research is in the design of clinical trials – the most costly and time-consuming part of pharmaceutical R&D. As you know, a large-scale Phase 3 trial can involve tens of thousands of patients, take several years to complete, and cost hundreds of millions of dollars. In the traditional model, each trial is designed basically to answer one question, yes or no. It’s a slow, disjointed process.
At Lilly, we’re working to apply new analytical methods that allow us to learn and adjust as we go. We’re developing adaptive trial designs that allow us, for example, to identify optimal doses or target tumor types more quickly, with smaller trials, and thus at lower cost.
We’re also developing “seamless” approaches. One example is the study of our GLP-1Fc investigational treatment for diabetes. The study combines into a single trial objectives typically addressed in separate Phase 2 and Phase 3 studies. Specifically, dose finding, which is usually conducted during Phase 2, is embedded in a large Phase 3 study of safety and efficacy, eliminating the time gap between trials.
We’re also applying advanced analytics to transform pharmaceutical R&D more broadly … using tools such as data mining, Bayesian statistics, and more advanced modeling and simulation techniques.
A third example of “reinventing invention” – and perhaps the most important – is tailoring.
We increasingly have the ability to identify the subgroups of patients who are most likely to benefit from a medicine – as well as those who might be at higher risk of side-effects – using phenotypic characteristics, such as age or weight; established biomarkers, such as HbA1C levels; and increasingly genetic markers, as well.
At Lilly, we’re applying tailoring strategies throughout our pipeline, and we have biomarkers associated with virtually every molecule in clinical development. Using biomarkers, we can identify groups of patients for whom a molecule offers a better benefit/risk profile. It’s also increasingly within our grasp to target R&D efforts on a subset of patients who have not been helped by earlier treatments. And, as I noted earlier, we recognize the importance of tailoring diabetes treatments to the diverse physiologies of populations around the world.
A tailored therapy provides greater value to patients, physicians, and payers … a higher degree of confidence that it will work effectively with a minimum of harmful side-effects.
Yet all of these new approaches … all of the potential of current medical advances … are at risk without an environment that supports medical innovation. To sustain progress against diabetes, public policies – including benefit/risk assessments, reimbursement decisions, and prescribing guidelines – must enable and foster true medical innovation.
Again, we’re a victim of our own success. The public has come to take for granted continual improvement in medical care and expects progress to be essentially free of risks.
In particular, while the increasing ability to gather and interpret post-marketing data on new medicines is undoubtedly a good thing, it exposes regulators using current methods of benefit/risk assessment … which are rooted primarily in clinical judgment … to having decisions second-guessed on the basis of safety issues that might emerge only after approval, when medicines are used by larger numbers of patients. The simple fact is that a potential medicine that’s not approved will not expose regulators to any risk whatsoever.
The problem lies not in the regulators, but in the system itself, which creates incentives to put off decisions and to err on the side of avoiding risk … even if some patients might willingly accept that risk in return for the potential benefits.
We believe that regulators – and the regulatory process – must bring forward a systematic approach that documents the basis for any such decision … the data used, the rationale, and the values that regulators applied in reaching the decision. Fortunately, the FDA recognizes this need, as well, and just last month the agency issued a Report on the Status of Regulatory Science, calling for systematic tools for benefit/risk assessment.
Such an approach would allow regulators to demonstrate why a decision was reasonable even when viewed in the light of subsequent data. Just as important, I believe that such an approach would result in regulatory decisions that are predictable, balanced, and timely.
We have an opportunity to implement such a framework here in the U.S. in the reauthorization of PDUFA – the Prescription Drug User Fee Act. The law comes up for reauthorization in 2012, but our industry and others are already in discussions with the FDA. I’m hopeful that through this process we can achieve a real victory for innovation … and for patients.
And there are important issues beyond the regulatory process, as well. Diabetes is a complicated, personal disease, and new medicines – even in an existing class – can improve the health of patients for whom available therapies are ineffective or hard to use. If prescribing or reimbursement rules force population-based standardization that neglects individual patient needs, then these potential new medicines will never reach many of the patients who stand to benefit from them.
It’s important to maintain the ability for doctors and patients to make informed choices from all available alternatives, and to let the market determine the value of new medicines – measured ultimately by how they work for individual patients.
More broadly, we need to promote an environment where innovation can thrive. The current outlook is not good:
A recent study ranked the U.S. sixth among the top 40 industrialized nations in innovative competitiveness, but 40th out of 40 in “the rate of change in innovation capacity” over the past decade. The ranking measured what countries are doing – in higher education, investment in R&D, corporate tax rates, and more – to become more innovative in the future. The U.S. ranked dead last.
As I’ve made clear, I firmly believe that, the burden of sustaining innovation remains on enterprising businesses like Lilly. At the same time, the one thing that the biomedical industry has a right to ask of public policy is to help preserve the environment in which innovation is possible.
The fact is, the pursuit of innovation in any field is a difficult, high-risk venture. If innovation is to take root and grow, it requires a combination of elements I have described as an “ecosystem.”
The first element is an atmosphere in which innovation can thrive, a society that understands and appreciates scientific inquiry, and free markets where innovators can expect to be rewarded for the value they create. Today you'll hear some people say that we have all the innovation we need — or that, in this difficult economic climate, we just can't afford any more of it! Our discussion today puts the lie to that nonsense.
The second element of the ecosystem — nutrients — comes in the form of monetary investments. For investors to take the high risks associated with medical innovation, they must have a fair chance at earning a return when they succeed. That requires the ability to offer innovative products at market prices; solid protection of intellectual property; fair, rigorous, and transparent regulation; and a tax structure that provides companies the ability and incentives to invest in the first place.
The final and most important elements of the ecosystem are the seeds of innovation, which equate to talented people and their ideas. Human talent is our most precious resource, but one that remains woefully underdeveloped in this country. This is a huge issue in itself, but let me just mention two essential tasks:
- First, we've got to get dead serious about broad improvement in science and math instruction in our grade schools and high schools.
- Second, we need immigration laws that allow and encourage top scientists from other countries to choose to work and to remain in the United States, including a sensible increase in visas for highly skilled immigrants and a shorter, simpler green-card application process.
Today, I’ve talked about the paradox that, for all our progress in treating diabetes, our ultimate goal seems as far away as ever. The only answer to the paradox of progress against diabetes is innovation … invention … and reinventing invention. With new medicines – along with education and support – that improve individual patient outcomes, we can reduce the toll of diabetes even as we seek a cure.
All of us here today are engaged in that important work as physicians, scientists, and investors. We must achieve continued innovation in diabetes treatment. We must aggressively pursue the fight, to alleviate the suffering brought about by the long-term consequences of this devastating disease. And, to sustain this progress against diabetes, we must all support public policies that enable and reward medical innovation.
We’ve already come a long way in the fight, and I’m convinced that future medical innovations will lead to more victories over diabetes. Through the commitment of everyone here in this room today, and relentless efforts in medical research and treatment around the world, continued progress against diabetes will lead not to a paradox, but to a cure.