Newsletter Vol. 30 No. 1


Fewer Drugs, More Superbugs: Strategies to Reverse the Problem

Jennie Choe, M.S.
Staff Reporter
Alliance for the Prudent Use of Antibiotics

 




Resistance to antibiotics among the world’s most dangerous pathogens is a serious public health threat, but hardly a new phenomenon. Alexander Fleming himself warned as early as 1945 that penicillin and similar antibiotics would eventually make themselves obsolete through natural selection and the very nature of bacteria [1]. Today, ever-increasing types of resistant bacteria and fewer new antibiotics being developed against them portend a post-antibiotic era on the horizon rather than a regression to the pre-antibiotic era [2]. A post-antibiotic era would again be plagued by common, potentially fatal medical conditions, but have far less hope of finding effective treatments.

Societal consequences of drug resistance
What would medical treatment look like in a post-antibiotic era? Many types of surgery would become impossible, including organ transplants. So would cancer chemotherapy and care for both premature infants and the critically ill. 2 million patients in the U.S. develop drug-resistant healthcare-associated infections every year, of which 99,000 will die [3]. Direct expenses alone cost the healthcare system anywhere from $21 billion to $34 billion. Additional medical expenses, restrictions on international travel, and decreased tourism, trade, and commerce could incur far greater economic losses to society.

Infectious disease and drug resistance is never just one country’s problem. Drug-resistant pathogens like XDR-TB, hypervirulent C. difficile, and multidrug-resistant S. pneumoniae and N. gonorrhoeae incur huge costs not only to human life but also to the global economy and international security. Resistant infections in the U.S. required more than 8 million additional days spent in the hospital compared to non-resistant infections. The same loss of labor (and with higher mortality rates, the loss of working-age citizens) in developing countries such as those in the sub-Saharan region can cost up to 20% GDP [4]. The resulting difficulty in developing resources and creating products for export, and the decreased demand for imports from their trading partners, makes the crisis bleed over from developing countries into industrial ones. Developed countries end up shouldering much of that burden through both federal funding and private aid from philanthropic organizations, to prevent other countries’ losses from becoming their own. Moreover, the Bipartisan WMD Terrorism Research Center warns that a terrorist attack using a drug-resistant pathogen could cause a “potentially uncontrollable” number of casualties and “catastrophic consequences” to the international economy.

The dwindling antibiotic development pipeline
It’s not that all hope is lost just yet. Drugs still exist to treat infections like XDR-TB that are resistant to most drugs – but they are expensive and have serious side effects that can drastically affect quality of life. In the meantime, an alarming number of major pharmaceutical companies are shifting their efforts away from the antibiotic market. Between 1983 and 1987, the FDA approved 16 new antibiotic drugs for use in humans. Between 2003 and 2007, it approved six, and since 2009, only two. More than 20 pharmaceutical companies had large antibiotic R&D programs in 1990, but today only AstraZeneca and GlaxoSmithKline remain [5].

Why are so many companies losing interest in developing antibiotics just when the demand projected for resistant infections seems highest? Simply put, an antibiotic will not bring enough return on investment on the current market to make it worthwhile to invest the time and effort required to develop one. They are less likely to be approved by the FDA, with a roughly 1 in 72 approval rate compared to 1 in 15 for other types of drugs. Also, there is less to be gained. Antibiotics are priced low, used for short durations, and responsible physicians hold newer antibiotics in reserve and encourage patients to use them sparingly to ward off the development of antibiotic resistance.

The current state of the market leaves pharmaceutical manufacturers with two options, both undesirable from a public health point of view: they can stop wasting their time and money, or they can encourage patients and practitioners to use more antibiotics. The latter strategy is largely responsible for opposing any effort made towards the responsible stewardship of antibiotics. All pharmaceutical manufacturers are in a race to sell as many units of a drug as they can before their 20-year patent period runs out. After lengthy and expensive clinical trials ($50-100 million for phase III trials alone) are finally concluded, they have even less time before competitors get approval for similar drugs or resistance arises to similar drugs already on the market.

At that point manufacturers sometimes tout an antibiotic as a treatment for conditions even when it has not yet been clinically proven to be effective against them, contributing to misuse and driving up resistance to that entire class of antibiotics. It is also unfeasible to prevent misuse by taxing antibiotics or placing tighter FDA regulations on prescriptions. Unilaterally discouraging the use of antibiotics will disincentivize manufacturers from developing new drugs that are desperately needed against the growing number of cases of resistant infections.

What is being done?
Through PDUFA V
The Infectious Diseases Society of America (IDSA), in collaboration with many medical societies and public health organizations, has been instrumental in urging diverse stakeholders to collaborate in the quest for urgently needed drugs. The Alliance for the Prudent Use of Antibiotics is proud to support initiatives like 10x’20 and IDSA’s newly proposed Limited Population Antibiotic Drugs (LPAD) approval mechanism [6]. Originally called the Special Population Limited Medical Use (SPLMU) mechanism and proposed for inclusion into the GAIN Act, LPAD was presented to the House Energy and Commerce Committee on March 8 and is now under consideration as part of the reauthorization legislation for PDUFA V.

LPAD is an alternative FDA regulatory pathway intended to speed the approval process for drugs that may be the only treatment (or one of few treatments) for patients who have serious resistant infections. If the FDA grants LPAD designation to a drug manufacturer, they will be permitted to conduct fast, cheap clinical trials on a small population. The resulting drug with its LPAD logo will only be sold to the small, specific population for whom the benefits of treatment have been proven to outweigh the risks.

While the risks associated with a drug tested through LPAD might be greater than drugs approved for the general population, this population can tolerate more uncertainty about risk in exchange for the option of treatment where before there was none. Not only will LPAD make it cheaper to develop much needed drugs, but it is also hoped that the small demand for such drugs will drive up prices sufficiently for pharmaceutical companies to start investing in their development. Patients will also be more likely to use expensive drugs carefully and abide by measures such as confirmatory follow-up tests, which will slow the development of resistance.

Fourteen pharmaceutical companies have signed onto a letter of support for inclusion of the LPAD pathway into the PDUFA reauthorization bill. All 14 agree that a major flaw in the current FDA approval pathway is that companies are encouraged to develop antibiotics that are as broad-spectrum as possible and can be used in the largest population possible. This is the worst strategy possible for furthering antibiotics stewardship and combating the development of resistance. The letter has prompted positive reactions from members of the House Energy and Commerce Committee and the Senate Health, Education, Labor, and Pensions Committee. APUA and 22 other nonprofit patient, physician, and stakeholder organizations have signed on to a separate letter in support of LPAD inclusion.

Potential market strategies
Other potential solutions have been put forth but not yet officially proposed before Congress. Kevin Outterson (editor-in-chief of the Journal of Law, Medicine & Ethics) and Aaron Kesselheim (assistant professor of pharmacoeconomics at Harvard Medical School) have long advocated the seemingly simple but radical strategy of making antibiotics more expensive [7]. They pinpoint drug pricing as the reason that pharmaceutical companies are losing interest in development. Antibiotics are currently priced as though they are plentiful and easy to make, when the opposite is true.

Outterson and Kesselheim attest that drugs should be priced in accordance with the “true value” of antibiotics to society. Manufacturers should also be given incentives to use careful marketing and awareness of infection control to slow the development of resistance – namely, by being reimbursed more when fewer units of their antibiotic have been prescribed. This could be accomplished if the CDC set public health goals for how much of any type of antibiotic should be on the market at any given time in order to meet established conservation and resistance targets. Manufacturers would be allowed to retain marketing exclusivity for as long as their sales data met the target. Under this system, it would be in pharmaceutical companies’ best interests to develop diagnostic tests that accurately determine the need for antibiotic use, and other surveillance or infection control products.

Through government oversight
As well as the high-profile LPAD pathway and GAIN Act, groups like the IDSA recommend practical short-term strategies such as strengthening antibiotic R&D through tax credits, grants, and more support for public-private collaborative programs like the ones at NIH and BARDA [8]. Building off of the patent exclusivity extension that the GAIN Act would offer to new antibiotics, antibiotics could also be given additional patent extensions if they are the first of a new class or use a novel mechanism of action. Large-scale measures to slow the development of resistance are still as necessary as ever. The IDSA has strongly urged forceful policies like banning the nontherapeutic use of antibiotics in agriculture and food animal production, and the mandatory implementation of antibiotic stewardship programs in all healthcare facilities as a prerequisite for participating in Medicare and Medicaid.

The current crisis in antibiotics could benefit from strategies being applied in other fields. When shortages occur for drugs that are life-supporting, life-sustaining, or treat a debilitating condition, HHS would be required (under the recently proposed Patient Access to Drugs in Shortage Act) to keep an up-to-date list of drug shortages and address them by increasing production quotas or ingredient availability [9]. HHS should similarly monitor a list of priority infections and resistant pathogens that may create an unmet medical need, and act upon antibiotic shortages that are reported. Surveillance of antibiotic resistance should be carried out in real time by a federally funded network of sentinel sites and made available to the public. Also, like the Cancer Human Bio-Bank, NIAID and FDA should establish a centralized repository of human clinical samples to facilitate the development of better diagnostic tools. A repository would quickly identify patients who are eligible for the kind of fast-track clinical trials proposed in LPAD, and serve as controls that diagnostic tools could be tested against.

Conclusions
The U.S. has a responsibility – not only to itself, but also to its allies in the developing world – to lead the search for new drugs against infectious diseases that every day threaten to surpass our ability to treat them. The first step is to incentivize research and innovation at home, but once new drugs have been discovered, they need to be marketed to the developing world at affordable and sustainable prices. Diagnostic and vaccine development are also essential to deal with in current antibiotic crisis. Arguably the most cost-effective medical interventions available today, access to vaccines in the developing world would start to remedy an area of gaping unmet need in which the most virulent, most resistant pathogens are infecting the populations that are least able to afford treatments [10].

It is difficult to imagine an antibiotic-free future. With financial incentives for novel drug development and nationwide regulation of appropriate antibiotic use in human and veterinary medicine, we can prevent that future from becoming a reality. APUA will continue its efforts at the forefront of this global public health crisis. By sharing the opinions of our distinguished expert contributors in each issue of the APUA Clinical Newsletter, we hope to engage healthcare providers, patients, and policymakers in dialogue that will help us find solutions.
 




References
1. S. Levy, The Antibiotic Paradox (Perseus, Cambridge, MA, ed. 2, 2002).
2. Chan, M. (2012, March). Antimicrobial resistance in the European Union and the world. Keynote address at the conference on Combating Antimicrobial Resistance: Time for Action, Copenhagen, Denmark.
3. IDSA, Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis 52, S397-S428 (2011).
4. J. Champagne, Access to essential medicines in developing countries: the role of international intellectual property law & policy in the access crisis. Alb L J Sci & Tech 22, 75-101 (2012).
5. McArdle M. “Resistance is futile.” The Atlantic October 2011. Accessed 24 April 2012 <http://www.theatlantic.com/magazine/archive/2011/10/resistance-is-futile/8647/>.
6. IDSA, Promoting anti-infective development and antimicrobial stewardship through the U.S. Food and Drug Administration Prescription Drug User Fee Act (PDUFA) Reauthorization, House Committee on Energy and Commerce, Subcommittee on Health, March 8, 2012.
7. Kesselheim A & Outterson K. “Superbugs call for super changes in drug-sale rules.” Boston Globe 15 Nov 2010. Accessed 19 April 2012 <http://www.boston.com/bostonglobe/editorial_opinion/oped/articles/2010/11/15/
superbugs_call_for_super_changes_in_drug_sale_rules/
>.
8. SHEA, IDSA, PIDS, Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 33, 322-327 (2012).
9. United States. Cong. Senate. Patient Access to Drugs in Shortage Act. 112th Cong., 2nd sess. Washington: GPO, 2012. Discussion draft.
10. Foege B. “When words fail.” Global Health Magazine Winter 2012. Accessed 18 April 2012 <http://www.globalhealthmagazine.com/top_stories/when_words_fail>.
 




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