Last year, the CGD Drug Resistance Working Group released a report with actionable recommendations for decision-makers to consider as they work to reduce the effects of drug resistance.  The Center for Disease Dynamics, Economics & Policy (CDDEP) recently introduced the CDDEP Drug Resistance Map which reflects the first recommendation from the working group – to improve surveillance by collecting and sharing resistance information.  The map consolidates information from over 150 zip codes across the United States and uses color-coded, animated maps to illustrate the spread of drug resistance across the country (demonstrating that chances are drug resistance has come to a neighborhood near you).

Source: http://www.cddep.org/resistancemap

This tool provides a good platform for displaying drug resistance in the United States.  Still, similar coordinated surveillance needs to take root in developing countries where drug resistance poses an even greater risk due to the high price of second line drugs (14 times higher for ARVs and 175 times higher for anti-tuberculosis drugs) and a largely unregulated market for prescription drugs.  When combined with poor laboratory and clinical infrastructure, these circumstances lead to increasingly high levels of drug resistance and yield a deadly outlook for those affected (see table below).

Despite the dangers of misuse, as much as 40 percent of global spending by some major health donors is spent on the procurement of drugs and supplies. Without adequate surveillance of drug resistance, the efforts of global health funders to provide needed medications may actually be undermining their attempts to reduce disease burden.

The CDDEP Drug Resistance Map demonstrates a great tool that can be expanded to encompass drug resistance rates in the developing world and provide the surveillance needed to protect donor funding and, more importantly, the lives of thousands. And once in place, the data can be leveraged to achieve CGD’s Drug Resistance Working Group’s remaining three recommendations:

• Secure the drug supply chain and to ensure quality products and practices;
• Strengthen national drug regulatory authorities; and
• Catalyze research and innovation to speed the development of resistance-fighting technologies.

Moreover, these kinds of surveillance tools need to be embraced by local, regional, and international communities and used to inform higher standards for national and international policies and health regulations.  After all, drug resistance doesn’t respect borders – what’s resistant halfway across the world today could be in your neighborhood tomorrow.

We are looking forward to hearing what other great ideas and research will emerge on this topic following the CCDEP’s Global Forum on Bacterial Infections this October.

We have received very positive feedback since publishing the report in June. However, we are acutely aware that talk is cheap. Simply writing what needs to be done (much to the chagrin of my co-authors and myself!) is far easier than actually doing it. Since the report was published, we have been working with a range of organizations to advance the ideas and see them implemented.

A critical place to begin a common response to drug resistance –our report puts this first among four major recommendations – is to collect and share drug resistance information across disease networks. The working group report recommended that the many organizations that gather information about drug resistance should join forces to identify gaps in public health and clinical knowledge about where and when drugs aren’t working, and produce a biannual global drug resistance report to inform donors and public health agencies.  I’m pleased to share that a “network of drug resistance surveillance networks” seems to be within reach.

We are working with others to form a coalition of drug resistance surveillance networks and private companies that have stated their intention to share information, methods and tools for detecting and documenting drug resistance. This would mean antimicrobial resistance people would talk to malaria resistance people (for a change) and hopefully, create a rapid diagnostic test to differentiate between malaria and pneumonia, for instance before dispensing the wrong drug and waiting to see if the fever worsens. It could mean that regions with strong TB surveillance but weak information about Strep pneumonia drug resistance might find ways to build on existing infrastructure to improve health outcomes.

The working group proposed that such a network eventually produce a biannual report of global drug resistance across diseases so that policymakers, public health agencies, and clinicians understand what they are up against, identify the gaps in knowledge, and begin to turn the tide on drug resistance. The first step of bringing together the disease-specific surveillance networks is being planned. Let’s hope the interest and momentum continue to build.

Addendum: While we’re speaking about improving diagnosis … the long-awaited announcement of a new fast-acting and reliable Tuberculosis (TB) diagnostic test last month sent ripples of anticipation through the TB community. As reported in the New England Journal of Medicine, the new molecular test can reduce the time to diagnose TB from 10 days to less than two hours. This test is a huge advance from the standard sputum smear test that has been used for many decades to identify TB. Not only can it diagnose drug-sensitive TB, the Xpert test can bypass the slow process of culturing a sputum sample for drug sensitivity and determine whether a case is Rifampin drug-resistant. And the test works with 97% accuracy to detect confirmed TB cases.

The promise of this new TB diagnostic is great for several reasons. First, simple public health. Almost 40% of estimated TB cases remained undetected (2008 figures), and therefore untreated. Only about one in ten cases of drug-resistant TB is estimated to be detected, and a small fraction of those are treated properly. These figures are tragic and illustrate once again that TB has been neglected. A new technology is way overdue to detect TB. Second, this test can be used by less skilled lab workers than the standard methods of culturing currently employed. The result can be faster results from a more extensive group of facilities. Finally, I am optimistic about the potential for molecular tests – such as Xpert – to revolutionize laboratory work by de-specializing the resources and procedures needed for disease diagnosis and drug susceptibility testing. Cross-disease labs should become the norm, replacing specialized labs. All these advances are envisioned in the Working Group’s recommendation #1: improve the ability to detect and monitor resistance. New technology and human willingness to work together, combined, will make this a reality.

For more on CGD’s drug resistance work, please sign up for or visit our monthly e-newsletter.

We all know that drugs can get “worn out” from overuse. In rich countries, some of us remember when penicillin used to reliably treat many diseases, but now many disease agents are resistant to it. How, why and when do drugs stop working? CGD’s new report, The Race Against Drug Resistance, drives home the limited lifespan of all drugs and urges global action to contain this growing threat. A graphic in the report’s Annex depicts the lifespan of many different drugs in several important classes arrayed on a historical timeline. Among antibiotics, penicillin started failing after about ten years of use.

Source: Annex B of “The Race Against Drug Resistance”.  For larger image click here.

Antiretrovirals, at the bottom right of this figure, are not immune to drug resistance.  In fact, because the AIDS retrovirus, HIV, replicates literally billions of times each day inside the body of a single patient, the chances of a resistant strain of HIV appearing are higher than they would be for a microbe that replicates more slowly.  Note in the figure that several antiretrovirals have had extremely short lifespans.

Increased access to any given drug also means an increase in the risk that the drug will be worn out –because the more exposure a pathogen has to a drug, the more chances that pathogen has of “discovering” how to evade it.  This tradeoff between how long a drug lasts and how many people it reaches each year can be displayed as a tradeoff frontier like the left-most panel here:

Of course, as the CGD working group’s report explains in fascinating detail, this tradeoff is not immune to policy. The report details a range of policy options available to individual countries, pharmaceutical manufacturers, and the broader public health community. Collective, global action can shift the tradeoff frontier to the northeast – so that we can have more years of drug efficacy for any given level of access.

The PLoS article provides useful insights into some of the parameters affecting the speed with which antiretrovirals will become worn out and scarily suggests that much ART resistance may remain hidden for some time, meaning that measured resistance may be underestimated. But, because the article assumes universal access to ARVs, it sheds no light on the tradeoff between access and the duration of drug efficacy. Because universal free access to ART is unlikely in the most severely affected countries, the question then arises whether some of the policies recommended in the new working group report can help minimize the development and spread of drug-resistant HIV variants in situations where free public access is less than universal.

As laid out in logical sequence on pages 24 – 30, the unfettered operation of existing market-driven supply and consumption of drugs like ARVs actually hastens drug obsolescence. Unfortunately, if left to their own devices, physicians and patients may insufficiently encourage adherence to ARV regimes, a practice that speeds the development of drug resistance within an individual patient and can lead to the spread of that resistant strain to others. In a 2004 study of the benefits and costs of ART in India, my coauthors and I recognized this issue by defining “structured” ART as having the following seven features:

• Standardized, competency-based training of physicians in antiretroviral therapy management.
• Prescription of a standard triple-drug regimen.
• Support from a multidisciplinary team that includes a counselor and a nutritionist.
• Regular clinical and lab-based monitoring of the patient’s treatment status.
• Counseling to prevent transmission.
• Prophylaxis for opportunistic illnesses when indicated.
• Diagnosis and treatment of opportunistic illnesses.

At that time in India, when free public provision of ART had just begun, most AIDS patients in the country sought ART in the private sector and the limited evidence available suggested that most of it – and indeed most ART available at that time in the public sector – was “unstructured.”

One solution to this problem is regulation of the private sector in an attempt to assure that private sector ART is “structured.” Another approach, adopted by the AMFm initiative (see Box 4.6 on page 44 of the report) is to subsidize the price of a drug-efficacy extending technology in order to crowd out the free market’s drug-corroding influence. My coauthors and I incorporated assumptions of the magnitude of this crowding-out effect in order to arrive at advantageous estimates of the cost-effectiveness of the AMFm initiative for malaria and of ART in India.

Through a subsidy—either of a more durable drug (as in the case of the AMFm) or of an adherence maximizing form of treatment (“structured” ART as we recommended in India )—the tradeoff between access and drug durability will become less acute, as in the second panel of the figure above, thus benefiting both current and future patients and reducing the potential future fiscal burden of more expensive newer medications.

Working with Health Subcommittee Chair Frank Pallone, the committee staff has organized three hearings on AMR, the second of which was held last week before a full hearing room. (I wrote about the first hearing here.) So far, the hearings have focused exclusively on antimicrobial resistance (commonly referred to as AMR), and the most visible ways that AMR is manifested in the U.S., including MRSA (Methicillin-resistant Staphylococcus aureus) and Acinetobacter baumannii (sometimes called “Iraqibacter” because soldiers increasingly are sent home with resistant infections of this bug.) While this political attention is encouraging, it must extend to drug resistance across all infectious diseases and move beyond a U.S. focus.

Most of the committee members at last week’s hearing seemed genuinely concerned about the two issues on the agenda: the poor pipeline for new antibiotics, and overuse and misuse of currently available antibiotics. A stream of public and private sector witnesses did not shy from using words such as “crisis” to describe the drug pipeline. During her testimony, Janet Woodcock, who is responsible for new drug approvals at the FDA, said, “The pipeline is diminished when the need could not be greater.”

It is not yet clear what kind of bill the subcommittee might try to get through Congress, or even if it will try, before the end of the current session. Congressional Quarterly recently reported on Pallone’s plans. “It’s clear that action is needed,” Pallone said after the hearing. But “the problem is we need to know what to act on.” Pallone offered no timetable for when a decision would be made, or any guarantees that legislation would be moved this year.

In the spirit of support for the efforts of the subcommittee, I offer some thoughts about what to include in new legislation. Some of these steps don’t require any new money– which should be a plus in the current environment!

Encourage USG agencies to address drug resistance globally. Antimicrobial resistance is clearly a global issue, with huge increases in drug use occurring in emerging and developing countries–including many of the same drugs relied on in the U.S. and Europe. A stronger awareness of drug resistance is needed in developing parts of the world to reduce the inappropriate use of medicines that speeds resistance.  Through existing programs at CDC and NIH, the U.S. is a world leader in disease detection and infectious disease research. We need to build on what we’re doing with greater emphasis on drug resistance surveillance–not just disease surveillance, basic science research into resistance mechanisms, and incentives for resistance-specific technology–not just new drugs.

USAID is also a global leader in building capacity in developing countries for monitoring and improving drug quality and appropriate use of medicines, but its important role in supporting global work through WHO and other partners has been hobbled by inadequate funding. USAID’s line item funding for antimicrobial resistance was zeroed out in recent years.  It needs and deserves a shot in the arm with the green medicine.

Beyond enhancing existing programs, Congress could incorporate language into the Strategies to Address Antimicrobial Resistance Act (STAAR) Act introduced by Congressman Matheson and others, or into new legislation, recognizing the global nature of drug resistance and the need for greater coordination to fight it. Congress should also appropriate funding to the EU-US Task Force on Antimicrobial Resistance and give it some useful tasks, such as producing a credible picture of drug resistance worldwide. It may seem like a small thing, but a step toward global awareness has already been achieved with a common Antimicrobial Awareness Day in the U.S. and EU on November 18 for the first time this year (actually, in the U.S. it’s an entire week.) Next goal: make it global.

Leverage U.S. donor funds to improve drug quality and resistance monitoring. Congress could also get tough in its role as a global health donor. Through Pepfar, the President’s Malaria Initiative, and contributions to the Global Fund to Fight HIV/AIDS, TB, and Malaria, the U.S. is purchasing drugs by the semi-trailer to distribute in poor countries. Congress should require that all drugs procured with U.S. taxpayer funds be monitored for quality throughout the entire supply chain, not just at the point of manufacture, thereby reducing opportunities for resistance to emerge. Drug producers that demonstrate greater responsibility for the quality of their products should be recognized and rewarded.  This is among the recommendations made in a new report from CGD to be released on Tuesday at the National Press Club.

My final thought for Congressmen Waxman, Pallone and their colleagues on Capitol Hill: don’t wait for new drugs to solve the antimicrobial resistance problem. Prioritize the steps that can prolong the usefulness of drugs we already have, and reduce drug use where it’s not needed.

Fifteen members joined the subcommittee’s chairman, Frank Pallone (D-N.J.), and ranking member, John Shimkus (R-Ill.), including Rep. Henry Waxman (D-Calif.), chairman of the full committee, Rep. John Dingell (D-Mich.), Waxman’s predecessor as chairman, and two major supporters of legislation designed to tackle problems caused by drug resistance, Reps. Jim Matheson (D-Utah) and Jan Schakowsky (D-Ill.).

This is the kind of serious, high-level attention we need to meet the challenge of drug resistance, a growing crisis that is undermining the global health community’s efforts to treat malaria, HIV, tuberculosis, and a range of other diseases in both developing countries and wealthier nations.

Reminding us that local often trumps global, nearly every member in attendance mentioned the large – and growing – number of hospital-acquired infections that are resistant to at least one common antibiotic, and many expressed concern over methicillin-resistant Staphylococcus aureus (MRSA), citing infections or deaths in their home states. Most of the legislators’ questions dealt with the use of antibiotics in feed animals and agriculture, one key aspect of drug resistance that would benefit from substantial further research. The use of antibiotics in animals has received much of the attention paid to drug resistance because it represents a deep struggle between agriculture and health interests. But, as the panel’s witnesses indicated, there are other issues that are far less controversial and politically charged.

Dr. Fauci testified that any strategy to address drug resistance must include proper surveillance of its spread as well as infection control, the rational use of antibiotics, and sufficient biomedical research. Dr. Frieden told the subcommittee that increasing resistance leads to greater death rates and higher health-care costs, and said we must improve and monitor the use of existing antibiotics while developing new drugs.

Without action, he said, we may enter a post-antibiotic world.

That’s a frightening prospect, but one that we have the ability to avoid. Next month, CGD’s expert Drug Resistance Working Group will release a report, more than two years in the making, on the steps necessary to meet this global challenge. In line with Dr. Fauci and Frieden’s statements, the Working Group strongly emphasizes the importance of improved surveillance to understand where and how resistance is spreading. Collectively, the Group’s recommendations urge coordinated international action across all infectious diseases.

It’s good to see that Congress seems ready to be part of that effort.

There’s a lot of attention being paid to the counterfeit drug trade at the moment. Former President of France, Jacques Chirac, recently chaired a meeting with West African leaders to discuss how to crack down on counterfeiting. Meanwhile, the Wellcome Trust and the American Pharmaceutical Group held an Opinion Formers’ conference on counterfeit medicines (presentations here); the International Federation of Pharmaceutical Manufacturers and Associations produced a brief on the issue; and Roger Bate has continued to draw attention to counterfeits and other drug quality issues in developing countries, including through his book Making a Killing. And this is all on top of the WHO-hosted IMPACT initiative on counterfeits, which started in 2006.

This attention is fully justified. Counterfeit drugs kill – and they do it while shaking people’s confidence in governments’ ability to protect the health of their citizens. The Pharmaceutical Security Institute, an industry supported non-profit, identified 1,834 incidents of known counterfeiting in 2008. While some counterfeits are close copies of the original drug, most are not, and many contain no active ingredients at all. The result for the patient is prolonged illness and even death, with the risks particularly high for children suffering an acute febrile illness, such as malaria.

But the public health risks go beyond such immediate suffering. Drugs that contain a little – but not enough – active ingredient, or that include only one active ingredient where a combination is needed for effective therapy, present ideal conditions for microbes to mutate in response to the drug. The drug resistance that results creates a huge additional cost, threatening the usefulness of quality-assured products for all prospective patients.

Drug manufacturers share responsibility with regulatory authorities for providing safe, quality-assured drugs and for tracking their continued effectiveness. Pharmaceutical companies should be more actively engaged in efforts to ensure that the drugs that reach patients are what they say they are. While there are examples of industry investing in this area – as GSK did through the Alexander Project when they had investments in antibiotics to protect – more is needed.

The CGD Drug Resistance Working Group’s draft report recommends development of industry-wide standards for pharmaceutical companies and distributors to encourage them to pay attention to quality issues that affect drug resistance beyond the manufacturing stage, as they package, store, and distribute their products. Such standards might also cover post-marketing surveillance activities, and the information provided to healthcare providers and patients, for example through promotional materials or package inserts.

Another part of the answer is to strengthen national drug regulatory agencies so they are better equipped to stem the circulation of substandard and counterfeit products on their markets. The CGD draft report recommends using regional regulatory networks to facilitate the sharing of data on substandard and counterfeit products as well as other information relevant to drug resistance.

For now, the attention of politicians, national drug regulators, global health agencies, and pharmaceutical companies is focused on tackling counterfeiting. But as they meet, they must keep drug resistance and other public health impacts uppermost in their minds. Counterfeiting is a crime. But its victims go beyond the companies whose intellectual property has been stolen and the procurement agencies whose resources are being wasted. The victims are sick patients everywhere, now and in the future – and substandard products of every type, not just counterfeits, present a risk. Sadly, every day we wait to address this problem, the number of victims grows.

The Center’s name may be long and a bit wonky, but the purpose is simple: conduct analysis to improve prediction and prevention of disease outbreak and spread – here in the U.S. and globally. That sounds a lot like the CDC, doesn’t it? But RFF’s prowess in the economics of infectious disease, and a strong focus on drug resistance and how to control it, fill at least two major gaps in infectious disease knowledge. Its work in these areas will complement the CDC, WHO, and other agencies who fulfill basic surveillance and public health roles, but can’t give us much (if any) insight into the economic consequences of pandemic flu and other health disasters, nor can they use this insight to promote needed policy reform in the U.S. and globally. We recently called for global leadership to address drug resistance. The Center will provide important evidence for the need to heed that call.

We applaud the foresight of the Center’s funders, and congratulate its researchers.

The value of the voucher is found in the expedited, 6 month review time for the new product, instead of FDA’s standard 10 month review period (which has been known to actually last over a year in many instances). For a potential blockbuster product, this quicker-to-market advantage has been estimated by experts to be worth anywhere from $50 million to $500 million¹². But these figures are nothing but speculation. For the first time, we will be able to track the voucher to see how Novartis chooses to use it and possibly extrapolate its value. Will Novartis sell it to a rival? Will they save countless lives by bringing one of their promising oncology candidates to market faster? A better question is: Will it truly result in an accelerated FDA review? Only time will tell, but we’ll be watching carefully.

†For more information on Priority Review Vouchers, see www.prvinfo.org, run by our colleagues at BIO Ventures for Global Health.

¹ http://prvinfo.org/about/value
² http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2009/04/fda-approves-coartem-with-priority-review-voucher-voucher-market-is-untested-and-unclear.html

It’s a good thing, too, as China has the second highest number of resistant-TB cases in the world. That’s the expensive kind of TB; the kind that is almost impossible to cure and equally as difficult to afford. The bill for China to treat its roughly 100,000 cases of resistant TB with 2nd line drugs would approach $350 million. Yes, that’s $3500 per case – more than Switzerland spends on health per capita! Compare that to $2 million to treat the same number of people with the standard TB regime and you could understand how quickly a drug-resistant strain of an infectious disease can overwhelm even a capable health care system such as China’s.

WHO Director-General Margaret Chan recently linked drug resistance to the economic crisis. In a speech in Berlin on March 18, she said,

“Dire consequences can also be contagious. Interruptions in the supply of drugs, especially for diseases like AIDS, TB, and malaria, contribute to preventable deaths in high numbers. Such interruptions also accelerate the development of drug resistance. Drug-resistant forms of disease can quickly spread internationally. We are seeing this, right now, with the rise of multi-drug resistant TB, and the even more alarming rise of extensively-drug resistant TB. This form of the disease is virtually impossible to treat, with fatality rates approaching 100%. Its further international spread could take us back to the treatment era that pre-dates the development of antibiotics. Can the world really afford another risk of this magnitude?”

The approach of the Gates-Chinese Government partnership is a clever one. It avoids the hard choice currently splitting the TB community between a focus on “ordinary” TB and resistant TB by working hard at resistance prevention rather than just expanding 1st line treatment; it includes careful attention to incentives, including improving the payments to community health care workers who monitor patient treatment adherence; and it takes advantage of China’s strength in surveillance and health information management by using e-health to convey patient information that might indicate resistance at an earlier stage than currently happens.

It’s also optimistic. The plan relies on at least three non-existent or unproven technologies: a new 1st line TB drug (not yet developed), a new rapid diagnostic test that is 98 percent accurate (still being tested), and newly available fixed-dose combinations that can replace the medley of pills currently required to treat the disease. And then there’s the dream of a vaccine. The Gates Foundation is betting the bank on these technologies, and one can only hope that it’s a more sound investment than the rest of our banking system.

That’s why the Chinese Government part of this partnership is so important. New technology quickly becomes useless technology if it is introduced into a health system that uses it inappropriately, or not at all. That fate has befallen many drugs designed to treat malaria, TB, and other infections due to resistance emergence. The Chinese Health Ministry is rightly looking for ways to improve how patients and providers use drugs and diagnostics, by making combination drugs cheaper and more easily available, and by monitoring patient adherence among those most likely to have problems. And see Steven Levitt’s description of one new technology that helps monitor TB patient drug adherence in his Freakonomics blog.

In addition to encouraging these and other health systems and behavioral changes, the most important step the Chinese Government and the Gates Foundation can take is to create a greater awareness of how quickly and dramatically drug resistance can undermine investments in new technology and disease eradication. Joining efforts by WHO’s Dr. Chan and others, momentum is building to deal aggressively and comprehensively with drug resistance.

This new Gates-China program for TB treatment will start with a “pilot” phase of 20 million people. After five years, it will be available to 100 million people in China, if successful in the initial phase. Let’s hope that the experimentation and learning this partnership entails will be shared very widely as soon as possible. Five years is a long time for TB patients to wait.

If you are interested in the global problem of drug resistance and what can be done about it, please see the Center for Global Development’s Drug Resistance Working Group and sign up for the monthly newsletter.

The author, Yazeed Kamaldien, seems to find solace in the fact that “these drugs are used only to treat primary TB, however, and not other cases, such as multi-resistant TB.” He appears to completely misunderstand a primary cause of MDR-TB (multi-drug resistant TB) and drug resistance in general. While he is correct to breathe a sigh of relief that this discovery will, hopefully, not cause any MDR-TB cases to become the virtually untreatable XDR-TB (extremely-drug resistant TB), episodes such as this undoubtedly increase the risk of resistance among uncomplicated, primary TB patients. As MDR-TB can cost up to 300 times as much (in time, money and human resources) to treat as primary TB, these errors can put incredible strain on an already weak health system.

Also disturbing is the fact that this episode comes right on the heels of a recall of anti-retrovirals (ARVs), manufactured by Adcock Ingram to treat patients with HIV, after a packaging mix-up last week. At a time when news reports of substandard, counterfeit therapeutics in the developing world are dominated by stories on antimalarials, I hope that these South Africa cases do not signal a new trend.

A recent study conducted in six African countries found that only around 1/3 of the antimalarials purchased in local pharmacies were of a high quality and not in violation of WHO guidelines. My colleague, Rachel Nugent, discusses these findings in a recent blog and asks some probing questions about the cause of the substandard products. Whatever the reason (and there can be many), it is vital to find out, because if poor quality drugs are still making their way to the sick, it will terribly undermine treatment efforts – not only by not curing the patient, but also by proliferating the epidemic of drug resistance.