Maryn McKenna

Journalist and Author

Incentives for making new antibiotics: What would it take?

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Let’s play a thought experiment. Imagine that you’re a major pharmaceutical company, a public company, with shareholders that you answer to, and market analysts looking over your shoulder to see whether this quarter’s earnings are up to projections. Imagine that you want to make a new drug. Let’s make it an antibiotic, because — as we talk about here all the time (and SUPERBUG explores in detail) — new antibiotics that can leapfrog over existing drug resistance are very needed. Thus, you imagine, a new antibiotic ought to sell well, even though any individual course of that antibiotic will only be a few weeks by mouth, or maybe a few months by IV if the patient is very sick. You know there’s a big market out there.

But: Imagine — as is generally accepted to be true — that it will take about 10 years, and about $1 billion dollars, to get that novel antibiotic through the development pipeline and into the marketplace. And then imagine that — as has been shown for a number of drugs, most recently the new antibiotic daptomycin — bacteria begin developing resistance to your drug within a year of its deployment in patients. And after that, imagine — as has been cited in a number of papers — that once local resistance to your antibiotic appears in approximately 20% of isolates, physicians will cease prescribing your antibiotic, for fear their patient will be one of that 20%.

So, to recap: 10 years, $1 billion; short course; short market life; rapid obsolescence.

Would you make that investment? Or would you, if you were a pharma company, opt instead to make insulin, which Type 1 diabetics will take every day for the rest of their lives? Or statins, which at this point we’re practically ready to put in the water supply? Or a cancer drug that costs $10,000 per dose? Or Viagra, or Cialis?

If you’re a company that is responsible to its shareholders, or listening to its analysts — or even capable of doing basic math — the answer’s obvious: Antibiotics lose. Which goes a long way to explaining why so many companies have backed off from making antibiotics, and why many of the few antibiotics in the pipeline are “me too” formulations, rather than new compounds with truly new mechanisms of action.

How to respond to this impasse has been an active debate for a while, largely focused on proposals to give market incentives, changes in tax credits, or patent extensions to pharma companies to persuade them to stay in or re-enter the marketplace. The Infectious Diseases Society of America, the specialty society for infectious-disease physicians (many of whom are also academic researchers), has been addressing this through its campaign “10x 20”, which has a goal of getting 10 new compounds into if not through the pipeline by the year 2020.

But, as a new article in the British Medical Journal points out, good incentivizing demands complexity — not just in developing both “push” and “pull” mechanisms (say, tax incentives to fund research v. prizes and wildcard patent extensions), but also in making sure that the incentives can be taken advantage of by companies of all sizes, not just the international mega-pharmas:

The characteristics of an ideal incentive mechanism and the desire for an equitable approach that engages developers of all sizes would suggest that neither push, pull, nor lego-regulatory mechanisms would be optimal to spur the desired investment in antibiotics …. Rather, elements of each should be combined. The exact shape of the ideal package is, however, as yet unclear. (Morel et al.)

 And an accompanying editorial emphasizes that new antibiotics are not the only things needed; new diagnostic tests, for instance, need funding as well:

Catchy as 10×20 sounds, the public sector strategy for funding such research and development must prioritise among different health technologies, such as diagnostics and vaccines, to combat antibiotic resistance. For example, three million children die each year from acute respiratory bacterial infections in developing countries, but penicillin sensitive pneumococcal strains have declined to a half, even a quarter, in some countries. A diagnostic test for bacterial pneumonia would save an estimated 405 000 lives a year, by targeting treatment and avoiding overprescription of antibiotics. New vaccines may also reduce reliance on drugs as the use of pneumococcal vaccine has suggested. (So et al.)

This is a hard discussion. I confess, as a longtime reporter, I flinch reflexively at the thought of handing more money to the pharmacos. At the same time, the state of the market demonstrates that the current model is not working. And though I would much prefer we focus on the ecological model of preserving antibiotics as a resource — dialing back on overuse and encouraging rigorous stewardship — it’s clear that we’ll always need new drugs for the most serious, most resistant infections.

So some sort of incentivizing seems necessary. And the multi-layered approach recommended in the BMJ, with appropriate attention paid to incentivizing the development of tests and vaccines as well, seems worth heeding.

Another resistant bug rising: Acinetobacter

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From the excellent and forward-thinking research team at Extending the Cure comes a dismaying report: over 7 years, a more than 3-fold increase in resistance in the Gram-negative bacterium Acinetobacter baumanii to its drug of last resort, imipenem.

Because MRSA is a Gram-positive, we don’t talk much here about the Gram-negatives — the two categories of bacteria have different cell-wall structures and thus are treated using different categories of drugs. (That structural difference causes them to react in different ways to a stain invented by a scientist named Gram in the 19th century.) But the resistance situation with Gram-negatives is at least as dire as with MRSA, possible more so, because there are fewer new drugs for Gram-negatives in the pharmacology pipeline (as discussed in a New Yorker article by Dr. Jerome Groopman last year.)

And Acinetobacter is one nasty bug, as science journalist Steve Silberman ably documented in Wired in 2007 when he traced the spread of the organism through the military medical-evacuation chain from Iraq, demonstrating that the vast increase in resistant Acinetobacter among US forces was due to our own poor infection control.

The Extending the Cure paper (which will be published in February in Infection Control and Hospital Epidemiology) puts hard numbers to the Acinetobacter problem. Drawing on data from the private Surveillance Network, which gathers real-time electronic results from 300 US hospitals, they find:

  • full resistance to imipenem rose from 4.5% of isolates in 1999 to 18.2% in 2006 — a 300% increase
  • intermediate resistance rose from 1.3% of isolates to 9.4 — a 623% increase
  • susceptible isolates declined from 94.1% to 72.4% — a 23% decrease.

The authors write:
Our results demonstrate substantial national and regional increases in carbapenem resistance among clinical isolates of Acinetobacter species over the period 1999–2006. Increasing carbapenem resistance among Acinetobacter species is particularly troubling, because it is very often associated with multidrug resistance and because it is occurring in the context of increases in the incidence of Acinetobacter infection.

There’s a further point to be made that is not explicit in the paper that I can see (though it is often made by Extending the Cure researchers). Acinetobacter needs attention, just as MRSA does — but if we focus just on the individual organisms, we are not going far enough. Antibiotic resistance is a system problem: It is an issue of infection control, of drug development, of agricultural organization, of federal priorities. It needs sustained attention and comprehensive, thoughtful, wide-ranging response. Now would not be too soon.

Guest Q&A: Dr. Brad Spellberg and RISING PLAGUE

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I’m thrilled today to present another guest blogger: Dr. Brad Spellberg, associate professor of medicine at the David Geffen School of Medicine at UCLA and author of the new book Rising Plague: The Global Threat from Deadly Bacteria and Our Dwindling Arsenal to Fight Them (Prometheus Books). This new book is important reading for anyone concerned, as all of us are here, about the narrowing pipeline for new antibiotics against MRSA and other resistant pathogens. That pipeline problem is something Dr. Spellberg knows well: He is not only a practicing infectious-disease physician, but also a member of the Antimicrobial Availability Task Force of the Infectious Diseases Society of America, the specialty society that produced the “Bad Bugs” reports that I’ve posted on before.

Below, Dr. Spellberg thoughtfully answers some questions about the difficulties of treating resistant infections and of developing drugs to control them.

From your point of view as a practicing ID physician, why is it so difficult to prevent resistant infections?

It’s difficult to prevent all infections period. Not more difficult to prevent infections caused by resistant organisms than any other organisms. However, also difficult to prevent the spread of resistance among bacteria that are causing infections.

So, why is it difficult? People have this crazy belief that hospital acquired infections are the result of sloppy medicine. Not so. They are the result of very sick people with tremendously sophisticated levels of intensive medical care being delivered in a concentrated environment (i.e., a hospital). Crowd a bunch of sick people together with plastic catheters, mechanical ventilators, and nasty bacteria, and such infections are inevitable. What we are learning is that we have to go above and beyond normal to stop these infections from happening. Research is needed on how best to do this. It’s not as simple as people think.

You can’t stop the spread of the resistance itself. It is inevitable.

You say in Rising Plague that physician misuse and overuse of antibiotics is not the cause of antibiotic resistance. What do you consider the primary driver?

This is by far the biggest misperception among the public. Let’s start from first principles. Who invented antibiotics? Who invented antibiotic resistance? When were both invented?

Humans did NOT invent antibiotics. Bacteria did…about 2 billion years ago. And they invented antibiotic resistance at the same time. So, bacteria have been creating and defeating antibiotics for 20 million times longer than humans have even known that antibiotics exist (about 78 years, as the original sulfa compound was developed in late 1931 by Gerhard Domagk). Over the past 2 billion years, bacteria warring among themselves have learned to target virtually every targetable biochemical pathway with antibiotics, and have learned to create defense mechanisms to defeat virtually all such antibiotics. They are already resistant to drugs we haven’t even developed yet. It is bacteria that cause antibiotic resistance, not humans.

What humans do, is we apply natural selection when we use antibiotics. We kill off susceptible bacteria, leaving behind already resistant bacteria to replicate and spread their resistance genes.

This may seem like a subtle distinction: We don’t create antibiotic resistance, we just increase its rate of spread. But, from the perspective of effective response planning, this is a critical distinction. If inappropriate antibiotic use caused antibiotic resistance, all we would have to do to defeat resistance is never prescribe drugs inappropriately. Unfortunately, that won’t work. All antibiotic prescription, even appropriate antibiotic prescription, increases selective pressure, which increases the rate of spread of resistance.

Eliminating inappropriate antibiotic use, and always using antibiotics appropriately is indeed critical, because it will slow the spread of resistance, buying us time to develop new antibiotics. But if 100% of our efforts are focused on antibiotic conservation, all we will achieve is a slowing of the inevitable exhaustion of the antibiotic resource. What is needed is to marry antibiotic conservation with antibiotic restoration. That is, we need new drugs to be developed. Just conserving what we have is not enough.

Why are “antibiotic stewardship” policies not a sufficient remedy for controlling resistance?

See above. Stewardship leads to conservation. That is half the battle, but by itself it will only lead to a slowing of the inevitable exhaustion of the resource.

Furthermore, the initial calls for stewardship were made by people like Max Finland in the late 1940s and early 1950s. This is not a new call. It’s more than a half century old. It just doesn’t work very well. An analogy is the temptation to say that we don’t need condoms to stop the spread of STDs, we just need abstinence. It is true that abstinence will stop the spread of STDs. But, an abstinence-only policy just doesn’t work. You’ve got to have the condoms too. Well, stewardship, by itself, just hasn’t worked after more than 60 years of calls for it. It is too hard to change behavior, and the pressures on physicians not to be wrong about their patients’ illnesses is too great.

What do you consider the chief impediments to developing newer/better antibiotics?

The two major impediments are: 1) economic, and 2) regulatory.

The primary economic impediment is that antibiotics have a lower rate of return on investment than other classes of drugs. You make a lot more money back on your R&D investment if the drug is taken every day for the rest of the patient’s life (e.g. cholesterol, hypertension, dementia, arthritis) than if it is taken for 7 days and then the patient stops because he/she is cured.

The regulatory problem is a startling degree of confusion at the FDA regarding what types of clinical trials should be conducted ot lead to approval of new antibiotics. There has been a total rethinking of antibiotic clinical trials at the FDA over the past 5 years. Right now, companies don’t know what trials they are supposed to do to get drugs done, and increasingly the standards are calling for infeasible study designs that simply can’t be conducted. This revisionist thinking is being driven by statisticians who know nothing about clinical medicine or patient care. They are asking for things to be done that can’t be done to human beings. The balance of clinical and statistical concerns is totally out of whack, and must be restored if this problem is to be solved.

What types of policies are needed to kick-start development of new antibiotics?

Simple. Solutions follow the problems above.

For the economic problem, we need Congress to pass legislation that creates special economic incentives for companies to re-enter the antibiotic R&D market. The return on investment calculation must be changed. Antibiotics are a unique, critical public health need. Congress should recognize this. Examples of programs that would work include increase in funding to scientists (e.g. via NIH) who study bacterial resistance and antibiotic development. Increased small business grants to help translate basic science discoveries to lead compound antibiotics. Tax credits, guaranteed markets, patent extensions, and prizes to serve as pull strategies to help companies improve the return on investment for antibiotics.

For the regulatory problem, Congress needs to stop hammering the FDA into a state of paralysis, where fear permeates every decision to approve a drug. We should be encouraging a balance between statistical concerns and clinical concerns, and we need to restore a sense that the agency is regulating drugs used by physicians for patients, and that trials showing those drugs are safe and effective must be feasible to conduct and relevant to how the drugs will be used in clinical medicine after they are approved.

Antibiotics – the EU pipeline is empty too

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We’ve talked before about the shrinking number of drugs available to treat MRSA and about the challenges of getting new drugs to market. Well, it’s not just a problem in the United States.

A new report from the European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMEA) — that’s the CDC and the FDA of the European Union — analyzes the bench-to-market “pipeline” of new drug development in the EU and finds… not good news. Out of 167 antibacterial agents that are somewhere in the pipeline of development, only 15 look likely to improve treatment of resistant organisms over drugs that already exist — and 10 of those 15 are in early-stage trials and will not come to market anytime soon.

That leaves 5 potential new drugs, for an epidemic of antibiotic resistance that, just in the EU, causes 25,000 deaths and $1.5 billion Euros ($2.27 billion) in extra healthcare spending each year.

(Within that epidemic of resistance, by the way, the single most common organism is MRSA.)

It’s worth understanding how the agencies conducted their analysis. When we look for new drugs to treat resistant organisms, we ideally need several things:

  • a formula or molecule that is new (and not just an improved version of an existing one, because if bacteria have developed resistance against the existing one, they have a head start in developing resistance against the new one)
  • a new mechanism or target on the bacterial cell, and not an improved version of an existing one (ditto)
  • evidence that it works in living organisms, and not just in lab dishes (in vivo, not just in vitro)
  • evidence that it can be given internally, not just topically (necessary for addressing the most serious infections)
  • and some indication that it is making its way through the regulatory approval process in time to achieve some practical good.

Here’s what the EU pipeline looks like:

  • 167 agents in process
  • 90 that have shown effectiveness in vivo
  • 66 that are new substances
  • 27 that have a new target or mechanism
  • 15 that can be administered systemically

If you’re wondering whether you should be depressed, the answer is Yes.

… it is unclear if any of these identified agents will ever reach the market, and if they do, they may be indicated for use in a very limited range of infections.

The agencies call for a concerted government effort to turn this around, and ask for quick action because it takes years to get drugs through the pipeline:

…a European and global strategy to address this serious problem is urgently needed, and measures that spur new antibacterial drug development need to be put in place.

This echoes a call that has already been made in this country by the Infectious Diseases Society of America, which has asked for changes in incentives to drug-makers, and has backed what’s known as the STAAR Act (STrategies to Address Antimicrobial Resistance). With this latest EU report — which comes on the heels of a US-ER agreement to work cooperatively on resistance — the IDSA is asking for an international commitment to bringing forth 10 new drugs in 10 years, what they are calling 10 x ’20.

Media round-up: recommending MRSA stories

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By chance — or is it because interest is really picking up? — a couple of worthwhile stories on MRSA have been published almost simultaneously:

  • For when the science gets wonky: Environmental Health Perspectives has an excellent lay-language explanation of how drug resistance emerges and spreads — with gorgeous graphics!
  • For when yet another drug doesn’t work: Scientific American covers development of new antibiotics, and even more important, development of new ways of creating antibiotics.
  • For yet more depressing news about MRSA in meat: Prevention adds to the discussion of MRSA in the food supply with a “special report” review. Constant readers who have been following along as we’ve drilled into this topic over the past two years won’t find a lot new, except for an intriguing account of an outbreak of MRSA in an Arkansas chicken plant (in which the bug went disappointingly untyped, so we don’t know whether it was a human strain or ST398). The story hits on issues we have talked about here: Surveillance for MRSA in animals is non-existent, practically speaking, and when the bug is found, investigation falls between human and animal health agencies. It’s a longer than usual story for Prevention, and should bring the knotty food-policy questions around MRSA in meat to a new audience.

Even more bad news on new drugs

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Via Forbes.com comes news that the Food and Drug Administration has turned back Targanta Therapeutics‘ application for its new antibiotic oritavancin, which was designed specifically to target drug-resistant staph, and has asked for additional trials. This is a follow-on to a decision by an FDA advisory panel last month that also expressed doubt about the drug.

This comes on the heels of last month‘s withdrawal of dalbavancin and delay in approval of ceftobiprole.

The long, thin pipeline of new drugs for MRSA just got longer and thinner.

More bad news on new drugs

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The Infectious Diseases Society of America (IDSA) has published a new report that fills in the background on last week’s news below, and confirms: The landscape for new drugs against MRSA and other multi-drug resistant organisms is bleak. (The organisms, summarized in the acronym ESKAPE, are: E. faecium, MRSA, Klebsiella, Acinetobacter, Pseudomonas aeruginosa and Enterobacter.)

The report, published in the journal Clinical Infectious Diseases, is both an update of surveys of the new-drug landscape done in 2004 and 2006, and also a call to action that asks for broad federal effort to encourage pharma companies to produce new drugs.

Here are the highlights:

  • Since the last iteration of the survey in 2006, only one new antimicrobial, doripenem — a very broad-spectrum injectable that is most active against the Gram-negative bacterium P. aeruginosa — has been approved.
  • Only three new compounds — ceftobiprole, dalbavancin and Paratek Pharmaceutical’s PTK-0796 — are in their final rounds of trials. (The report was obviously written before the latest news about ceftobiprole and dalbavancin.)
  • Four of seven efforts to achieve a staph vaccine have been terminated.
  • Though the pharma industry, through its lobbying arm PhRMA, claims “388 infectious diseases medicines and vaccines and 83 antibacterial drugs in development“, that number is misleading:

Careful review of these data reveals that most are preclinical and phase 1 compounds. Also included are topical and nonabsorbable antimicrobials, which we do not consider here, and several compounds for which development has been terminated. Finally, … many of the listed drugs are previously approved agents that are being studied for new indications.

Just to make sure no one misses the big picture, the authors emphasize:

…The number of new antibacterials that make it through the complete development process and ultimately receive FDA approval has precipitously decreased over the past 25 years. Indeed, we found a 75% decrease in systemic antibacterials approved by the FDA from 1983 through 2007, with evidence of continued decrease in approvals, even during the most recent 5-year period.

What are the answers? IDSA is candid, as in its earlier reports, that it believes incentives for drug companies are the only way to improve the situation: financial boosts, patent extensions and changes in trial requirements. Two things are critical, the group says:

  • Novel intravenous and oral drugs to treat both hospitalized and community-based patients are needed, as opposed to “me too” drugs that provide minimal improvement over existing therapies.
  • Priority should be given to antimicrobials with the potential to treat serious infections that are resistant to current antibacterial agents.

Bad news on the new-drugs front

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Via the very robust pharma blogosphere, reports that two much-anticipated new antibiotics will be remaining in the pipeline a while longer:

Fierce Biotech says that Pfizer has withdrawn its US and European applications for dalbavancin, a much-awaited new MRSA drug, and will conduct another Phase III trial.

Pharmalot reports (via Reuters) that the Food and Drug Administration has asked for additional trials for ceftobiprole, another much-anticipated new drug for MRSA, coming from Johnson & Johnson. Shearlings Got Plowed has more detail, speculates that a “new game face” is emerging at the FDA, and notes that J&J’s partner in ceftobiprole, Basilea, acknowledged that the FDA raises “issues of data integrity” regarding the current application. J&J’s press release is here.

So it’s back to vancomycin, again, for now.

Contributing to resistance: fake drugs?

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There’s news this morning that Interpol has seized $6.65 million of counterfeit medicines in the culmination of a 5-month undercover investigation that stretched across Cambodia, China, Laos, Myanmar, Singapore, Thailand and Vietnam. The fakes included purported antiretrovirals for HIV, anti-TB drugs, antimalarials (especially artemisinin) — and, chillingly for our purposes here, fake antibiotics for pneumonia and other bacterial illnesses.

Bloomberg News says:

Under Operation Storm, which ran from April 15 to Sept. 15, police seized more than 16 million pills…
Asia is the world’s biggest producer of all counterfeit products, the Organization for Economic Cooperation and Development said in a report last year. About 40 percent of 1,047 arrests related to fake drugs worldwide last year were made in Asia, according to the Washington-based Pharmaceutical Security Institute.
Counterfeits account for as much as 30 percent of all drugs in developing nations and less than 1 percent of all medicines in developed nations such as the U.S. (Byline Simeon Bennett.)

Counterfeiting medicines is both a huge business — the World Health Organization estimates that “counterfeit drug sales will reach US$ 75 billion globally in 2010, an increase of more than 90% from 2005” — and an appalling crime that attacks the most vulnerable people at their most vulnerable moments. In a recent issue brief, the WHO recounts a number of instances of counterfeiting that led to deaths in a number of countries.

Why should we care here? Because some counterfeits are not complete fakes; they contain a small amount of the active ingredient of the drug they purport to be. That means that, if someone takes a faked version of an antibiotic, they may not be going untreated. Instead, they may be undertreated, the exact situation that can lead to the emergence of resistance. Just last year, according to the Pharmaceutical Security Institute, known counterfeiting episodes involving anti-infective drugs rose 26%.

Now, NB: Activism against counterfeit drugs is politically complicated; it is supported by the pharma industry (PSI is a coalition of 26 manufacturers) and is tangled up with opposition to online pharmaceutical sales and to decisions by developing-world countries to abrogate Western drug patents. But that turf-defending by the pharma industry does not alter the reality that counterfeit drugs are an enormous international problem that imperil not only people unfortunate enough to take them, but anyone who contracts a resistant strain that those drugs helped foster.

And anyone concerned about MRSA will already know that resistant strains do not stay where they are generated. They have already demonstrated their ability to move rapidly around the world.

Despite stewardship efforts, antibiotic use increasing

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Well, this is bad news.

I hope we can all agree that antibiotic use creates antibiotic resistance. (Proof, if any were needed, that the universe has a captious sense of humor; but then it has had millennia to practice. OK, sorry for the anthropomorphizing.) The more pressure bacteria are placed under, the more resistant mutants emerge and survive. So the challenge in using antibiotics is to use them sufficiently and not too much: enough to quell infection and save lives, but not so much that the benefit of successful treatment is outweighed by the cost of increased resistance.

That’s the theory, anyway. In practice, according to a paper published today in the Archives of Internal Medicine, we’re not living up to the plan.

Amy L. Pakyz, Pharm.D. and colleagues at Virginia Commonwealth University surveyed antibiotic use at 22 academic medical centers — tertiary care teaching hospitals, ones that would be most likely to have high awareness of the dangers of resistance and good antibiotic stewardship programs — between 2002 and 2006. And found: Despite all that awareness, antibiotic use is going up, and the use of broad-spectrum agents and vancomycin, MRSA’s drug of last resort, is going up most of all.

The third significant observation is the marked increase in vancomycin use during the 5-year period such that it became the single most commonly used antibacterial in this sample of hospitals from 2004 to 2006. …
The reasons for the continued increase in vancomycin use are likely multifactorial, including the increasing numbers of hospital-acquired infections caused by MRSA and the emergence of community-associated MRSA, all of which encourage greater empirical use of vancomycin.

With only a few new drugs of comparative effectiveness on the market, and none that are significantly better, this is bad news, the authors underline:

Vancomycin use is a risk factor for emergence of vancomycin-intermediate S aureus and vancomycin-resistant S aureus, although these strains are rare in the United States. Of greater concern may be the emergence of low-level resistance in MRSA to vancomycin, referred to as minimum inhibitory concentration (MIC) “creep,” and this is far more common. Strains of MRSA having vancomycin MICs of 2.0 μg/mL are associated with longer median times to clearance of bacteremia compared with strains having MICs of 1.0 μg/mL or less, as well as frank treatment failures.

The cite is: Pakyz, AL et al. Trends in Antibacterial Use in US Academic Health Centers 2002 to 2006. Arch Intern Med. 2008;168(20):2254-2260.