Friday, April 9, 2010

Novel Drugs Need Novel Regs

 This week as I was catching up on journals, I was struck by the number of potential novel approaches to anti-infectives being considered in academia. Many of these ideas target the microbe’s ability to invade the human body.  Some target functions that weaken the microbe’s ability to deal with a threatening environment such as the presence of life-threatening antibiotics.  These compounds or proteins would not actually work like an antibiotic in that they would not kill the microorganism in a test tube. Such a product, when combined with an antibiotic, might make the antibiotic more powerful and might reduce the likelihood of resistance.  Some experts think that our traditional antibiotics work so well because they not only inhibit one essential life function of the bacteria, but they also target a second or even third essential function or they hit additional non-essential functions that might otherwise help the microbe survive in humans.  In fact, I see ideas to target non-essential functions of microbes all the time at grant review sessions, in print, and in start-up companies that are trying to exploit these ideas to make new products.  But there is always one large stumbling block that stops me in my tracks.  How can we actually develop such products? 

The problem is that antibiotics work very well.  In most indications, cure rates are somewhere between 75 and 95%.  Go try and do that in treating arthritis!  Many of the novel ideas being generated in academia would probably only be viable as part of combination therapy.  It seems unlikely that something that inhibits one portion of the bacterial invasion mechanism, since the bacteria uses multiple such tools, would clear, all by itself, an infection once it has taken hold.  On the other hand, in very serious infections, which are frequently not studied in clinical trials leading to approval of antibiotics, such an addition to an antibiotic might provide an additional edge.  The question is, how can we demonstrate this in clinical trials?

This conundrum has led me to be very negative about these novel ideas.  I feel torn since they are frequently based on good science. But I see no way to bring these novel nascent products forward in today’s regulatory environment.  This leads me to my question.  Are the novel ideas not worth pursuing or do we need a new regulatory paradigm that allows us to pursue them?

What would a new regulatory paradigm look like?  I can think of several approaches that we might explore.  Dr. Janet Woodcock at the FDA has been pushing us to identify biomarkers that correlate with infection and with resolution of infection such that these could be used to support our clinical trial data.  This is now done all the time for HIV/IDS where the number of viruses present in the blood is used to predict clinical success.  Of course, at the end of the day, the drug has to show ultimate clinical success – but marketing can be conditionally approved based on viral load data.  There are, as yet, no such markers for bacterial infection.  It turns out that bacterial load data is not so predictive either of success or failure for a variety of reasons. But obviously this is something we should be pursuing vigorously. 

Another approach, for example, would be to study the combination of drug X plus an appropriate antibiotic in a very small number of patients with very serious disease comparing it to the antibiotic alone or to standard of care.  The problem is that, even in such patients, you might not be able conduct a superiority trial since this might require large numbers of hard to find patients. A non-inferiority trial could not be large enough to provide reliable statistical power.  Thus, we would end up having to accept a smaller, less statistically conclusive clinical trial with supportive in vitro, animal model and pharmacokinetic/pharmacodynamic data.  The regulators might then grant conditional approval while these more difficult but definitive trials are carried out.  This would allow a company to earn money on the new product selling in a limited patient population while pursuing their additional data.

I think that a new approach such as this, or others that I have not considered, would be worth discussing.  There are many very smart people out there who have been thinking along these lines for a while.  Lets get them together with the regulators and start thinking about a new way forward.  Only by providing a feasible path forward for the development of these novel compounds that do not, by themselves, actually kill bacteria in a test tube, can we expect to have any to help deal with our most serious and antibiotic-resistant infections.  In the meantime, I guess I’ll continue to be skeptical about their chances of success.

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