Congress has been responsive to calls for incentivizing antibiotic development. Legislators from both parties are comfortable with voting to relax regulatory barriers, increase tax credits, and extend patent protection in the service of stimulating new drug development.
The GAIN Act of 2012 extends patent exclusivity of qualified new antibiotics for five years, and creates a fast-track/high-priority review process to speed approvals. Additional provisions create a limited-population approval category, in which the bar for clinical testing is lowered for drugs with very small target populations. This approach was formalized as part of the 2016 Cures Act legislation.
How has this worked? Here are new approvals of antimicrobials in the 21st century:
Source: CenterWatch
Hard to say that there has been a huge effect.
Given that a complete R&D cycle for new drugs is on the order of 10–12 years, the effects of the GAIN act to date would only be on drugs that are fairly advanced in their development. The spike in 2014 was probably a clearing-out of submissions for already-completed trials.
The Pew Foundation has a nice list of antibiotics that are in clinical testing. As of Dec 2017, there are
- 15 new antibiotics in Phase I
- 13 in Phase II
- 10 in Phase III
Given the usual attrition rates in clinical trials, we can expect 2–3 of the Phase I, 3 of the Phase II, and 6 of the Phase III drugs to be cleared by the FDA. In other words, we’ll have 2–3 new antibiotics approved each year over the next 5–10 years. That looks like an improvement over the pre-GAIN rate, but it is hardly a gusher of new antibiotics coming out of the pipeline.
Additional legislative sweeteners have been proposed. The Reinvigorating Antibiotic and Diagnostic Innovation Act would increase R&D tax credits for antibiotic research, but seems to have gone nowhere in the current Congress.
But the real issue isn’t regulatory approval. That makes a difference only at the margins. Antibiotics, as a class, are money-losers. Big pharma has mostly pulled out of antibiotic R&D for this reason. If you look at that Pew list of new antibiotics in development, nearly all the trial sponsors are niche pharma and biotech firms. Their business plan is to take on all of the risk and cost of antibiotic R&D, and if they get approval, license or sell their drug to a big pharma company.
Dificid is a great example. It is a narrow-spectrum antibiotic that targets C. difficile and spares other gut microbiota. It has been shown to reduce the risk of relapse from C diff infections as compared to standard antibiotics. This is just the sort of drug that the incentives are targeted at. It was first developed by Optimer Pharmaceuticals (a startup), then acquired by Cubist (a small-mid size pharma) which was then (post-approval) acquired by Merck.
Dificid was approved in 2011. It commands a premium price for an antibiotic – about $3500, vs $1500 for vancomycin or $10 for metronidazole, the current first-line treatments for C diff infections.
Sales for Dificid appear to be around $70M/yr. That may sound like a lot, but it’s couch cushion money at Merck (total sales ~$40B/yr). To a first approximation, the risks and costs of developing Dificid were the same as for Keytruda, a targeted therapy for solid tumors. Keytruda sales are $1.4B per year, 20 times that of Dificid.
Same risk, 20X reward. No amount of regulatory streamlining is going to meaningfully change that equation.
Free-market approaches to drug development do not always serve society well. Drugs that have high societal value but low returns on investment would be better funded under a socialized model. There is no reason – other than lack of funds – that the NIH could not discover and develop new antibiotics. If we really want new antibiotics, we will have to fund them directly, not tinker around with regulations.