Imagine waking up in the morning, your throat hurts a little, your nose is running, and you've got a light fever. You take the day off, and go see your doctor. A few hours and a throat culture later you're told that you have strep throat - a bacterial infection caused by the streptococcal bacteria, usually treated with a regimen of penicillin or amoxicillin. However, your doctor tells you that there's not much he can do for you - even if he were to prescribe the antibiotic it would do little to help you because the bacteria has become resistant to most antibiotics.

Though this may sound like something out of a third-world country, this may be the direction that the U.S. is heading in without swift and decisive regulatory reform.

Antibiotic resistance is an ever growing problem, with more deaths from methicillin-resistant Staphylococcus aureus (an antibiotic-resistant staph bacterium also known as MRSA) than from AIDS according to the Centers for Disease Control and Prevention (CDC). Yet, at the same time, antibiotic development is progressing at a snail's pace. The expected returns from antibiotic drugs (the Net-Present Value or NPV) are a paltry $100 million for pharmaceutical companies, compared with over $1 billion for musculo-skeletal drugs or $300 million for oncology drugs (the latter of which has a much faster approval pathway) according to a 2009 report by the London School of Economics; it should be no surprise then that fewer antibiotics are being developed less often. (To be fair, the relatively low NPV of antibiotics is also illustrative of the fundamental difference between antibiotic regimens and chronic-disease regimens - the former is a short-term therapy, while the latter is long-term. Still, the regulatory barriers imposed by the FDA are significant.)

Development hasn't halted, however. The Belgian biotech group, Galapagos, just announced that they have identified an antibiotic drug candidate - that has shown promise in treating MRSA infections, with hopes of beginning clinical trials by 2014. Without regulatory reform at the FDA, however, it is likely that Galapagos, as other drugmakers, will conduct trials and seek approval outside of the U.S.

And the regulatory burden of outdated clinical trial requirements is where much of the difficulty in developing new antibiotics lies. For instance, the FDA's non-inferiority requirements (the margin by which a new drug may be worse than a comparator to qualify for approval) are much more rigid than those required by the EMA (the EU's medicines regulator), which allows for more discretion by the investigator. Other regulatory inefficiencies include requirements for no antibiotic use 30 days before the trial (because patients are usually given antibiotics when being admitted into hospitals, this is a very difficult requirement to meet) and overly burdensome clinical endpoints. Indeed, even the FDA itself has recognized the need for reform to address antibiotic resistance, though progress has been rather slow. (For more on FDA's reform attempts, see Paul Howard's previous post.)

Reform should focus on establishing a predictable development pathway for antibiotics.  In particular, it should allow more broadly the use of pharmacometric data (David Shlaes at The Perfect Storm explores how the EMA has acknowledged "big data's" importance) to establish patient samples, give more discretion to investigators in establishing non-inferiority margins, and be more lenient with clinical endpoints than the current 24-48 hour overall success requirement. Moreover, faster approval of antibiotic drugs will increase the NPV of such drug candidates, making them more attractive investment opportunities.