Most experts considering the subject agree that the antibiotic development pipeline is not sufficient by a long shot. The days when there was always a new antibiotic just around the corner to treat the latest superbug are long gone.
Still, fixing the antibiotic pipeline is not rocket science. The main difficulty lies in finding molecules that enter the bacterial cell, stay there and inhibit growth of the bug without being toxic to us. What prevents us from overcoming this difficulty is that the number of people working on the problem has shrunk to historically low levels.
Continuing consolidation (mergers and acquisitions) among large pharmaceutical companies, and the outright abandonment of antibiotic research by these companies has severely impacted our ability to come up with new ideas, new approaches and new molecules. And the lack of experience and training of academics in the science of drug discovery undermines current efforts in the public sector.
We can’t make scientific discovery any easier, but there are three areas over which we have some control.
First and foremost, we need regulatory reform. One of the reasons industry has abandoned the area is increasing regulatory stringency, which translates into larger clinical trials and greater development expense – and the accompanying regulatory uncertainty for antibiotics. This has mainly been a problem at the US Food and Drug Administration (FDA). While the FDA has recently started to undertake such reform, its precise requirements for antibiotic development are not yet known, making it harder for companies to commit to expensive trials.
One area where the United States has been leading is in the idea of using data in one indication (such as abdominal infection) to support data in another (such as urinary tract infection). In such cases, companies could run one trial in each indication and get approval for both. While this is helpful, the trial required for each indication still has to be feasible and affordable, which is currently not the case for many antibiotic trials.
Regulators are working on the use of small, streamlined trials to get antibiotics targeting specific resistant bacteria to the market quickly to help those patients in need of these life-saving drugs. Since this is a relatively small number of patients compared to the general population, and since the dossiers supporting these products will, in one way or another, have to show superiority over existing drugs (such as activity against superbugs), we can anticipate paying a high price for them.
Two approaches can address the economic factors that have led industry to leave antibiotic research and development. The kind of push incentive that has been provided by government agencies such as the Biomedical Advanced Research and Development Authority (BARDA) in the United States has been enormously important for providing confidence that industry can develop antibiotics without sinking unrealistic amounts of money into late-stage trials.
Glaxo Smith-Kline, for instance, was awarded up to $97 million for the development of an exploratory new antibiotic. Such push incentives have a quick and positive impact on the net present value of products by reducing initial expense outlays.
The other economic factor we can control is drug pricing. This is a contentious issue that’s not often openly discussed in Australia. We’re happy to pay tens of thousands of dollars for cancer drugs but we expect to pay only a few dollars for antibiotics that can be incredibly effective in curing disease, but that are only taken for a few weeks.
Currently, Australia is not willing to pay for drugs that don’t show a “clear advantage” over older, cheaper drugs. But what does “clear advantage” mean? Sometimes it might be an expanded spectrum of activity; for example carbapenems are able to kill more types of bacteria than cephalosporins. Sometimes it might mean an oral form of a drug taken in pill form that might otherwise be lacking. But in Australia’s pricing system, the comparison is always to the price of the cheaper drug within the same class.
Australia is almost unique in the world in this regard, and doesn’t take into account the potential long-term health benefits of newer drugs compared to older ones. Such benefits include fewer side effects, faster cure times, better compliance with the dosing schedule or other improvements that might not be obvious in clinical trial data. Taking a pill once a day, for instance, is easier to remember than taking one three times a day.
One area we don’t need to fix is the market itself. There’s been discussion of pull incentives where governments provide a guaranteed market for antibiotics active against key drug-resistant superbugs. Given the evolving dominance of emerging economies in the global antibiotic market and the high incidence of superbugs in many of these countries, we think that the market will provide enough incentive itself.
Finally, we need to train our academic researchers in the science of drug discovery. We suggest using government funds to provide such training within industry in exchange programs. Academics should be allowed, even encouraged, to spend time with partner pharmaceutical companies and “learn by doing.”
So here’s our five-point plan for new antibiotics:
streamlined clinical trials for antibiotics against resistant superbugs;
better antibiotic pricing policies;
marketing in emerging economies and;
training for academic researchers.
This will all take political will and funding, but it will get us where we need to be – one step ahead of the superbugs.
This is the sixth article in Superbugs vs Antibiotics, a series examining the rise of antibiotic-resistant superbugs. Click on the links below to read the other instalments.
Part nine: New antibiotics: what’s in the pipeline?