New Antibiotic Development: Barriers and Opportunities in 2012
Brad Spellberg, M.D.
Assistant Professor of Medicine
David Geffen School of Medicine at UCLA
Harbor-UCLA Medical Center
In 2012, antibiotic development continues to stagnate. Two systemic antibacterial agents have been approved for use in humans by the U.S. FDA from 2008 through the current year. Compare that to sixteen that were approved from 1983-1987. In particular, we have had no new classes of antibiotics to treat Gram-negative bacilli (GNB) for more than 40 years – amazingly, the fluoroquinolones were the last new class of antibiotics to treat GNB. Meanwhile, antibiotic resistance continues to spread like wildfire, particularly among the GNB. The U.S. and global healthcare systems are encountering on a regular basis extensively drug-resistant (XDR) organisms resistant to all antibiotics except for colistin, a highly toxic agent of questionable efficacy whose use was abandoned in the 1960s when safer and more effective therapies became available.
Even worse, we are seeing pan drug-resistant (PDR) organisms, resistant to all available antibiotics, including colistin. Examples of XDR and PDR bacteria that plague the US and global healthcare systems include carbapenem-resistant bacteria, such as KPC Klebsiella and Acinetobacter. Both of these organisms are increasingly XDR, and are causing increasing infections in the US and worldwide. These infections cause high death rates despite available therapy. They will continue to kill a high percentage of infected patients until new prevention and treatment methods become available.
Twelve years ago, Nobel Laureate Dr. Joshua Lederberg wrote that “The future of humanity and microbes will likely evolve…as episodes of our wits versus their genes.” In the 12 years since Dr. Lederberg wrote those prescient words, we have witnessed a continued expansion of antibiotic resistant pathogens due to their genes. Amazingly, we seem to have stopped trying to use our wits to keep up. So, why is this?
There are three principal causes of the antibiotic market failure. The first is scientific: the low-hanging fruit have been plucked. Drug screens for new antibiotics tend to re-discover the same lead compounds over and over again. There have been more than 100 antibacterial agents developed for use in humans in the U.S. since sulfonamides. Each new generation that has come to us has raised the bar for what is necessary to discover and develop the next generation. Thus, discovery and development of antibiotics has become scientifically more complex, more expensive, and more time consuming over time. The second cause is economic: antibiotics represent a poor return on investment relative to other classes of drugs. The third cause is regulatory: the pathways to antibiotic approval through the U.S. FDA have become confusing, generally infeasible, and questionably relevant to patients and providers over the past decade.
A key concept in dealing with these three causes is to understand that they interact, much like a Venn Diagram, and that they cannot be considered in isolation. For example, the scientific and regulatory challenges markedly increase the cost and timeline of development, which greatly exacerbates the economic disadvantages of antibiotics. Conversely, if antibiotics were billion-dollar-per-year blockbuster drugs, companies would be willing to tolerate high barriers scientifically and from a regulatory perspective. Since antibiotics tend to sell much less than a billion dollars per year, there is instead low tolerance for scientific and regulatory barriers.
There are multiple economic barriers to antibiotic development. The most obvious is that antibiotics are short course therapies, and companies know that they will make much more money selling a drug you have to take very day for the rest of your life. Also, there are many types of infections, and approval for one type gets a company only one slice of the overall market pie. When anti-hypertensive drugs are approved, they are not approved to treat hypertension of the lung, or hypertension of the kidney. They are approved to treat hypertension. When antifungals are approved, they are approved to treat “invasive aspergillosis,” or “invasive candidiasis.”
Not so for antibacterials, which the FDA continues to approve based on disease state one at a time (pneumonia, urinary tract infection, etc.) rather than based on the organisms the antibiotic is designed to kill. Thus, companies spend $100 million for a phase III program and as a result capture as an indication only one slice of the pie. There is also imbalanced drug pricing in society. We will pay $50,000 for a course of cancer chemotherapy that prolongs life by 3 months, but we don’t want to pay more than $100 for a course of antibiotics that cures the target infection. This pricing difference is neither rational nor data-driven; there is no cost-efficacy analysis that supports cancer drug pricing. Rather, drug pricing in the U.S. is based on public perception and fear. People are terrified of cancer, but not of infections. After all, we’ve had penicillin since 1942. So, we need to educate the public and payors about the true value of antibiotics.
The net effect of these economic barriers has been described in a monograph from the Office of Health Economics (Sharma and Towse, 2011), which found that, at discovery, the net present value of antibiotic to a drug company is MINUS $50 million. That compares to a positive $1 billion for a new musculoskeletal drug. The Generating Antibiotic Incentives Now (GAIN) Act has recently been introduced into both the House and Senate to address this problem. We owe a debt of gratitude for Representative Gingrey (R-GA) for taking on this issue and to his colleagues, both Democrats and Republicans, in both the House and Senate, for making it a priority. GAIN seeks to use a form of prolonged exclusivity, among other mechanisms, to enhance the value of antibiotics to companies. My own personal opinion is that the economic incentives in GAIN are a good starting point for discussion, but not strong enough to rekindle pharmaceutical companies’ interest in discovering new antibiotics.
Recently, the Infectious Diseases Society of America proposed a new regulatory pathway, which is hoped to be included in the GAIN Act. The new pathway is called the Special Populations Limited Medical Use (SPLMU) [since renamed the LPAD pathway]. SPLMU would empower the FDA to approve drugs to treat drug-resistant, life-threatening infections with limited available therapies (and possibly drugs to treat other serious diseases with limited available therapies) based on small, rapid, and relatively inexpensive clinical trials. Since the drugs would have a much smaller safety database prior to approval, the indication would be extremely narrow. The drug would only be approved for patients with the highly resistant target pathogens in the setting of the studied diseases. Thus the SPLMU would seek to limit use to the small population of patients in whom the benefits of a drug outweigh the risks incurred by its smaller safety database. The goal here is to converge new development with unmet medical need and with stewardship to prolong the useful lives of these critically needed new drugs. It is possible that drugs approved by this mechanism would be able to charge a price premium, given the lack of availability of comparative therapies, the serious nature of the infections, and the smaller scope of patient populations eligible for therapy.
The SPLMU would help overcome the very substantial regulatory challenges that are currently obstructing new antibiotic development. Without going into the specifics of why the FDA has changed the rules governing antibacterial clinical trials, the effect has been a stifling of the new antibiotic pipeline. In the last year, two new draft guidance documents have been released by the FDA governing clinical trials for antibacterial agents with Gram-negative activity: trials for hospital-acquired and ventilator-associated bacterial infections (HABP/VABP), and trials for complicated urinary tract infections (cUTI).
Unfortunately, in my opinion, the trials called for in the guidances are not feasible to conduct, at least with respect to enrolling patients in the U.S. Both guidances require patients to be enrolled in trials before even a single dose of prior treatment is administered to the patients. We cannot make our severely infected patients wait the hours it takes to screen, consent, obtain safety laboratories, randomize, and administer study drug without receiving any therapy. There are other features that also make such trials not feasible to conduct. It may be that physicians in other countries, where patients’ rights are less fully developed, can force their patients to wait hours to receive drug, or can simply abbreviate the process of consenting to enroll such patients. But, a serious ethical dilemma is raised in the encouragement by a U.S. federal agency of the practice of what we would consider to be substandard medicine to support clinical trial conduct. Furthermore, if >90% of patients in such studies are enrolled outside the U.S., it is not clear that the data resulting from the trials would inform providers or patients in the U.S. about how and when to use the drugs. I speak from experience. For many months, I attempted to enroll patients in a cUTI clinical trial recently, and we failed to enroll even a single patient despite the fact that cUTI is a common reason patients are seen in our Emergency Department.
Meanwhile, across the pond, the European Medicines Agency (the FDA equivalent in Europe) has recently released a broad guidance on antibacterial trial conduct that specifies: 1) that patients can be enrolled in trials after receipt of a dose of prior antibiotic therapy, making enrollment possible; 2) the possibility of conducting organism-specific rather than disease-specific studies; 3) the possibility of conducting small studies to support approval of antibiotics that treat resistant, critical infections; 4) and clinical response endpoints at test-of-cure. Each of these principles should be incorporated into FDA guidances, but have not been to date.
Over the past year, several companies have publicly stated, and numerous others have stated to me privately, that given how difficult it is to get antibiotics approved by the FDA, they are considering simply abandoning the U.S. antibiotic market. The European regulatory landscape is more facile (although price-fixing keeps revenues low in Europe). Some have suggested that the Chinese antibiotic market will be larger than the U.S. market in 5 to 10 years. Thus, these companies are saying, we may simply develop antibiotics and sell them overseas and not in the U.S. This begs the question: who will be held accountable when the antibiotics that doctors need to save our patients’ lives are available in Beijing and not in Washington DC?
We have to think of antibiotics as a precious, limited resource, like fisheries, forestry, and energy. We have to both conserve and restore the resource. The time has come to admit that the ways we have used, developed, and protected antibiotics over the past 70 years have failed. The time for bickering over half-measures has passed. The time has come for innovative and bold solutions to slow resistance and speed development of new antibiotics.
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