Belmont Club

Bugs vs Man or Man vs Man?

A form of tuberculosis that cannot be treated has been identified in India. According to Nature “physicians in India have identified a form of incurable tuberculosis there, raising further concerns over increasing drug resistance to the disease.”

“The cases are a story of mismanagement,” says Migliori. “Resistance is man-made, caused by exposure to the wrong treatment, the wrong regimen, the wrong treatment duration.” …

The fact that no new first-line TB drugs have been developed for half a century has probably contributed to the emergence of strains that are unresponsive to treatment, says Mitnick. “If you keep using the same drugs for that long, resistance is inevitable.”

Tuberculosis trails behind only HIV as the world’s leading cause of death from infectious disease. But in spite of its impact on human health and economic growth, it has not ranked among the pharmaceutical industry’s priorities.

The disease has so far afflicted only the poorest people in India’s slums, according to the Daily Mail, and only a dozen of them. But the idea of an infectious disease totally resistant existing drugs is a a worrying idea. Part of the problem, according to the New Scientist, is that the regulators have made it prohibitively difficult and expensive to develop new antibiotics.

The FDA keeps on changing the criteria needed to get new antibiotics approved. In particular, it is making it harder to get some kinds of antibiotics approved on a “non-inferiority basis” (see below). Some of the changes are “arbitrary and unfounded”, according to George Talbot, a biopharma consultant and member of the Antimicrobial Availability Task Force set up by the Infectious Diseases Society of America.

Normally, a drug’s efficacy is established by showing it works better than a placebo. But it is unethical to give patients placebos when they might be killed by superbugs. Instead, companies have been allowed to do so-called non-inferiority trials where the new antibiotic is compared with an existing one, and if it works roughly as well it can get approval. Now the FDA is pushing companies to show new antibiotics are superior to existing ones …

[but] an antibiotic that does not perform better than another according to one narrow set of criteria established by regulators might still turn out to be very useful in some other way. For instance, resistance can sometimes be overcome by combining antibiotics with other drugs, but only some combinations work. So the more approved antibiotics there are, the better our chances of finding ways of dealing with new superbugs.

At least part of the problem is rooted in efforts to curb antibiotic resistance by overprescription.  Paul Rubin of Emory University calls this an attempt to solve the problem by regulating demand. He goes on to make the argument that it is more cost effective to solve the problem of antibiotic resistance by encouraging the development of new drugs rather than by curtailing the use of existing ones.

Both the Food and Drug Administration and the Centers for Disease Control are very concerned about this issue. Both agencies advocate reducing the use of antibiotics in order to slow down or prevent this selection pressure for resistant bacteria. That is, the agencies advocate reduction in demand in order to slow the resistance process …

The current demand-side policy has the unfortunate side effect of reducing the value to a pharmaceutical company of investing in the creation of new antibiotics. As usage is reduced to eliminate resistance, sales are also reduced, and antibiotics become relatively less profitable.

The problem, as ever has become political.  Steve Dickman at Biotech Watch says it has all the appearance of Geek Tragedy:

The broad outlines of the antibiotics tragedy-in-the-making are familiar: overuse and misuse of antibiotics has combined with a slowdown in new drug research to create what Shlaes aptly calls a “perfect storm:” more powerful and versatile bugs are morphing into existence daily, it seems, but the drugs to combat them have ceased to reach the market, felled by irrational regulators and markets not huge enough for Big Pharma. Consequently, we overuse those antibiotics that are still effective, which elicits resistance and then leads to disaster: the spread of multiply resistant superbugs and no way to stop them. Just two new classes of antibiotics have reached the market in forty-two years, writes Shlaes: linezolid (Zyvox, Pfizer), belonging to the oxazolidinone class, and daptomycin (Cubicin, Cubist), a cyclic lipopeptide. Meantime, the “perfect” bug, equipped with resistance to every known antibiotic, creeps ever closer.

Maryn McKenna of Wired described in 2011 how a new antibiotic called Fidaxoimin was having trouble proving to the FDA that it possessed the degree of superiority to existing therapies which would justify its approval. The combination, she wrote, of higher development costs and increasing regulation meant the day could come when routine procedures can no longer be performed.

Fidaxomicin’s existing competition is vancomycin, the 50-year-old broad-spectrum big gun used for MRSA and many other serious bacterial infections. As compared against vancomycin, fidaxomicin was “noninferior,” in industry jargon; its selling point was a lower rate of recurrence of C. diff among patients who received it compared to those getting the older drug …

Fidaxomicin has been in the works for a while — it was given Fast Track status by the Food and Drug Administration back in 2003 — and it has faced some criticism for not being different enough from vanco to justify the price that a new drug can charge. Nevertheless, on the basis of this and other trials, Optimer has completed its New Drug Application, and the FDA’s Anti-Infective Drugs Advisory Committee will review it at a meeting in April.

Things have gotten so bad that representatives of the Infectious diseases Society of America wrote that “the antibiotic pipeline problem may change the practice of medicine as we know it. Advanced interventions currently taken for granted—for example, surgery, cancer treatment, transplantation, and care of premature babies—could become impossible as antibiotic options become fewer.”

The solution, for some companies, is up stakes and move out. “Dr. David Shlaes, formerly an executive at Wyeth and Idenix (and author of Antibiotics: The Perfect Storm), blogged:”

While traveling this week I received a surprising and frightening email from a colleague at Pfizer. He said that Pfizer had just announced that they were moving their antibacterial research and development from Groton, CT in the US to China. They move cardiovascular research to Massachusetts, but antibiotics go to China. Their (2,400-employee) facility in Sandwich, UK, the origin of Viagra and, if I’m not mistaken, Diflucan, will be closed. This was announced as part of an almost 25% cut in research and development overall within Pfizer …

It is important to understand that once a company abandons antibacterial research, they lose their internal expertise in the area. This makes it difficult if not impossible for the company to evaluate opportunities in this space from external (i.e. biotech) sources. Therefore, it further erodes opportunities for biotech. This then leads to a ripple effect where no one can work on antibiotics because of a lack of partners with big pockets to support the late stage research required to get the products registered.

Recognizing that the market as currently won’t develop new antibiotics, the Guardian, in an article by Sarah Bosely, discusses imposing a tax to fund subsidies for anti-biotic development.

Professor Richard James, director of the centre for healthcare associated infections at the University of Nottingham … he points out, antibiotic usefulness is finite. And the cost of drug resistance is not reflected in the price of the drug. “If you consider antibiotic sensitivity as a resource like oil, you want to maintain that by introducing a tax,” he says. It would be worldwide and the proceeds could fund new drug development.

Of all the commodities that are bought and sold on the market, none is more politically sensitive than pharmaceuticals. Government purchases constitute a large part of total pharmaceuticals sales in ‘developed’ countries.

The Largest Single Customer

Dr. David Shlaes, MD who blogs on the subject, recently wrote an open letter to Secretary of HHS Kathleen Sibelius. In it he concluded:

I am at a loss to explain the FDA’s lurch into Neverland as far as antibiotics are concerned. I can only assume that it is partly a response to political pressure to further distance themselves from industry and to increase their standards for both efficacy and safety. But I consider that a lack of new antibiotics is also a serious safety issue – a fact that the FDA and their congressional critics appear to be ignoring.

What Dr. Shlaes neglected to note is that a major infectious crisis caused by the lack of antibiotics has not yet broken out in the First World. So far the only people who have been condemned by a lack of treatment are poor people in the Third World. Given a choice between preparing for a future crisis and succumbing to present-day political pressure, politicians will kick the can down the road every time.

The sad fact is that politicians only temporarily escape their special-interest captors — and then only briefly — usually following some catastrophe. Just as September 11 was necessary before governments took Islamic extremism seriously and a banking crisis may be needed before Big Government realizes it is unaffordable, there may have to be an epidemic in the West before the need for new antibiotics trumps “political pressure”.

Politicians may have only a limited capacity to pro-actively address impending problems and will only act when the danger is not only imminent, but in many cases, actually wreaking having on the populace.

Some people believe that politicians are actually far-seeing. For example, Andrew Sullivan asks in a Newsweek cover article, “Why are Obama’s critics so dumb? … it remains simply a fact that Obama has delivered in a way that the unhinged right and purist left have yet to understand or absorb.”

Leaving aside the policy merits of his assertion, Sullivan seems almost oblivious to the possibility that the President’s efforts to “deliver” may precisely be the problem. He has issued himself a license to pick winners and losers. And the precise problem in the antibiotic crisis is that somewhere along the line the system lost the ability to picking out the medicines which need to be developed based on a future need. To some extent the pharmaceutical deficit mirrors the fiscal deficit. The discount rate has gone awry and governmental foresight has proved a poor substitute. Far from being a far-seeing guardian of the future, government may in fact by the guardian of the present, optimizing its actions for the current election and media cycle.

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