Who’s Trying to Fix the Pipeline Problem?
The problem is clear: There aren’t enough new antibiotics. The question is why aren’t more pharmaceutical companies filling the gap – and what’s being done to try to reverse this trend?
Most experts point to three big reasons for the decline in pharmaceutical companies developing antibiotics.
The first is science. Antibiotic researchers say it’s gotten harder to find new drugs. Most early antibiotics were discovered by identifying naturally occurring antibiotic properties in soil samples, but these research efforts aren’t happening at the same pace anymore.
What’s more, Gram-negative bacteria are inherently harder to find new drugs for because their double cell wall makes it more difficult to get enough antibiotics to penetrate and ultimately kill the bacteria.
“It is just challenging biologically to find chemicals that you and I can tolerate in large concentrations without side effect,” says John Rex, clinical research director of antibiotic development at AstraZeneca, one of the few large companies in the field.
Economics have also played a major role in the shift away from antibiotic research. Antibiotics aren’t easy drugs to make money off of. Unlike diabetes or blood pressure medication, where patients usually need to take the drug for life, antibiotics are short-course therapies, less likely to create a dependable market. There have been some exceptions, such as Pfizer’s Zithromax, which netted over $1 billion annually. But generally, drugs for chronic disease offer a higher return on investment than antibiotics.
The relatively low market price for antibiotics is another financial roadblock for drug companies. “We’re not comfortable as a society paying more than say $100, $200 for an antibiotic course, because we’ve been sort of spoiled by the penicillin experience,” explains Brad Spellberg, an infectious disease specialist at Harbor-UCLA Medical Center. “We’re willing to shell out tens of thousands of dollars for cancer chemotherapy but we’re not willing to do that for antibiotics.”
The third key hurdle for antibiotic development is the regulatory environment. The Food and Drug Administration requires three stages of clinical trials to test the safety and efficacy of new drugs, and the third stage requires testing a candidate drug on large numbers of people. The clinical trials can be expensive and, industry officials argue, challenging to conduct for diseases that can kill people within of contracting them. They say that a new model may be necessary for testing antibiotics in clinical trials if they are to bring new antibiotics to market, perhaps clinical trials with fewer people in them.
The result is that only a handful of big pharmaceutical companies are involved in antibiotic research and development. Some smaller companies and biotechs are also doing research, but many don’t have the financial ability to take a potential drug through expensive clinical trials.
Yet there are some efforts to help jumpstart further antibiotic research and development.
Among those was a law passed by Congress last year called the GAIN Act. The bill gives companies that develop new antibiotics an additional five years of patent protection. One company already taking advantage of these incentives is Cubist, a smaller drug company that has focused on antibiotic research. It has a Phase III drug candidate targeting some Gram negatives, which will receive this extended patent protection if it makes it through the last stage of clinical trials.
The federal government is also trying to put more attention and money toward antibiotic development research. In May, The Biomedical Advanced Research and Development Authority (BARDA), a unit of the Department of Health and Human Services involved in biodefense, awarded GlaxoSmithKline, one of the few large pharmaceutical companies still doing antibiotic research, a $200 million contract to develop new antibiotics.
An FDA committee is also reviewing potential regulatory changes to attract more companies into this research area, such as changes to clinical trials or ways to include additional kinds of data. And the National Institutes of Health continues to invest in basic research on antibiotics.
But groups like the Infectious Disease Society of America (IDSA) say more is still needed to reverse the trend before it’s too late. They have proposed a plan called Limited Population Antibacterial Drug Approval Mechanism to allow potential drugs to be put in use for very sick patients with scaled-down clinical trials. They say it’s similar to a program used for rare diseases and argue that the benefits for patients who might otherwise die outweigh the safety risks.
Meanwhile, there are seven potential drug candidates to address gram negatives in ongoing clinical trials, according to a study published this year by the IDSA. The downside is that none of them would treat all of the resistant Gram-negatives. This poses a treatment challenge for doctors because it can be several days before testing tells them exactly what kind of bacteria is causing an infection. And if doctors prescribe an ineffective antibiotic during this waiting period, they are giving the bacteria a chance to become even more resistant.
For now, the new drugs can’t come fast enough. “The lack of a robust research and development pipeline is a huge problem for patients today and for the future,” says Helen Boucher, an infectious disease specialist Tufts Medical Center and co-author of the IDSA study. “That’s the alarm we’ve been trying to sound.”