Rapid Diagnostics

In previous posts I wrote about the three principal barriers to new antibiotic development: economics, biology and regulatory approval.

I'll add another. A really great diagnostic would be of immense help in executing clinical trials. Enrollment in trials is often a problem. Patients may be initially treated with an antibiotic other than the test or control antibiotic. The infecting bug may not be the one indicated for the new antibiotic. Or it may be equally susceptible to both the control and test antibiotic. All of these issues increase the cost and decrease the power of a clinical study.

A rapid diagnostic that identified the infecting bacteria and determined antibiotic resistance and susceptibility would go a long way to resolving these issues. Right now, standard methods require 2-3 days to return results, too late to be of use in trial enrollment.

What would a great bacterial infectious disease diagnostic device look like? As always, the ideal device would be perfectly accurate, give instant results with no specimen workup, and cost nothing. That's the fantasy anyway.

Having tried, succeeded (in getting regulatory clearance) and failed (in the marketplace) in developing such a device, I have a few thoughts about the challenges involved.

First, as always in our system, is economics. No one is going to develop a diagnostic device solely for the purpose of enabling clinical studies. There has to be a viable market for the device in routine clinical use. This requirement turns out to be a surprisingly severe constraint.

There are lots of visits to doctors offices and ERs for infectious disease complaints. But the vast majority of these are for non-lethal indications: urinary tract infections, wounds, sinusitis, otitis, bronchitis. At MicroPhage we looked long and hard at the case for developing a urinary tract infection (UTI) test. There are many millions of prescriptions written for these every year, and the rate of resistance of the principal pathogen (E. coli) to frontline antibiotics is high, 10-30%.

Sounds like a great business opportunity, right? Big market, high rates of resistance, lots of ineffective scrips being written. But what is the consequence of getting the antibiotic wrong? The patient will experience a couple additional days of discomfort, then call her doctor and get a different prescription. That's it.

How much would she (or her insurer) be willing to pay for a test to avoid this inconvenience? How long would she be willing to wait in the doctors office while a tech ran the test? After all, antibiotics are cheap and her time is valuable. The principal harm done is to further weaken the effectiveness of frontline antibiotics such as ciprofloxacin. That is a cost that is diffused throughout society, and no one is willing to pay to prevent it.

The story is much the same with wounds and most other infectious disease indications. There just really aren't that many indications where rapid identification and susceptibility results are critical to the patient's well-being. Hospital-acquired/ventilator-associated pneumonia is one. But that market is tiny and getting samples is hard.

Bacteremia is another critical indication. There are about 5 million positive blood cultures in the US per year (several per patient on average). About 100,000 patients will die. There is good evidence that getting the right antibiotics to the patient reduces length of stay and mortality for S. aureus bacteremia. But only about a million of those positive blood cultures are Gram-positive cocci in clusters, and are thus potential S. aureus bacteremias.

Venture capitalists simply don't get excited (greedy would be the less kind term) about market sizes less than a billion dollars. Even if you could charge $100 for your MRSA/MSSA test, and owned the entire market, you would fall well short of arousing the interest of serious money for developing a new technology.

And rest assured, few microbiology labs will spend anything like $100 per test. PCR MRSA tests, like Cepheid GeneXpert and BD GeneOhm, cost $25-75 on top of a capital outlay of $25-150K. They have been adopted by only a few percent of hospital micro labs. The MicroPhage MRSA/MSSA test was $50 and was adopted by about a dozen labs in the year that it was on the market. The attitude at Northwestern University Hospital, one of our clinical trial sites, was typical: "It's a nice test. I would buy it if it was $5."

That's unfortunate. Several very nice studies (Brown, Goff, Schweizer) show that getting the right antibiotics to S. aureus bacteremia patients in a timely fashion decreases mortality and length of stay in both the ICU and the hospital. Cutting just 1 or 2 days stay in the ICU pays for an awful lot of testing, even at $50 or $100 a pop.

So why are hospitals so unwilling to spend this money? After all, most bacteremias are hospital acquired, and so those extra costs (and deaths) are supposed to be the hospitals' responsibility. Even under the most conservative assumptions, rapid testing should be a great investment for hospitals.

The problem is that the costs are all borne by the micro lab, whose budget pays for the test and the staff to run it. The savings accrue to the hospital as a whole - no one gets to take credit for them, and thus no one is incentivized to champion rapid testing. Furthermore, the hospital has a strong incentive to game the system. If they attribute the extra care to causes other than the infection acquired in the hospital, then they can get fully reimbursed by insurers. Gaming ICD codes is much easier than implementing a new testing and reporting scheme. Everybody wins - if we define "everybody" as the hospital and micro lab. The patients and insurers not so much.

The bottom line here is that the market for rapid ID/AST is not great - markets are small and hospitals are reluctant customers at best. So long as antibiotics and antibiotic stewardship are not highly valorized there is little incentive to invest in the new technology needed to facilitate antibiotic clinical trial execution. There are also significant technical barriers, particularly with respect to prospects for a rapid AST, and I will discuss these in a future post.

 

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