The Need for New Drugs against Tuberculosis
Obstacles, Opportunities, and Next Steps

RICHARD J. O'BRIEN and PAUL P. NUNN

Special Programme for Research and Training in Tropical Disease, World Health Organization, Geneva, Switzerland

	INTRODUCTION

TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

It has been nearly 30 years since the introduction of a novel compound for the treatment of tuberculosis. Despite many calls for the development of new antituberculosis drugs during the past two decades, the pharmaceutical industry has, with few exceptions, indicated little interest in undertaking work in this area. This lack of interest is due in large part to two key perceptions: that currently available drugs are adequate for the control of tuberculosis and that sufficient profit could not be realized to justify the expense of bringing a new tuberculosis drug to market. This article will argue that new drugs are badly needed and that new opportunities for real progress exist. Private-public sector partnerships, a new approach that is being tried, may overcome existing financial impediments and lead to the development of major new drugs in the coming decade.

	THE GLOBAL TUBERCULOSIS PROBLEM

TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

We are entering the new millennium with tuberculosis being an even greater global problem than it was at the beginning of the twentieth century. Tuberculosis continues to kill young and middle-aged adults faster than any other disease apart from acquired immune deficiency syndrome (AIDS). It is estimated that in 1997 there were approximately eight million new tuberculosis cases and nearly two million deaths due to the disease (1).

In sub-Saharan Africa and south Asia where the human immunodeficiency virus (HIV) pandemic has spread rapidly, rates of tuberculosis are soaring, overwhelming fragile tuberculosis control programs. In the Russian Federation and other former USSR countries, the breakdown of health services in all settings has resulted in an upsurge in tuberculosis cases and the emergence of strains of Mycobacterium tuberculosis resistant to most of the available drugs (MDR TB). On the other hand, the disease is at its lowest levels ever in many countries of Western Europe and North America, where calls for the elimination of tuberculosis have recently been issued (2).

	STATUS OF EXISTING TUBERCULOSIS CONTROL EFFORTS

TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

In the 1960s and 1970s, effective control measures led to significant decreases in tuberculosis cases in industrialized countries. However, in many developing countries with gross domestic products less than 1% that of the United States, inadequate control practices emphasized case finding over effective treatment, and cases of tuberculosis rose. Moreover, widespread use of bacillus Calmette-Guérin (BCG) vaccine was not effective in reducing the incidence of infectious pulmonary cases in adults (3). Thus, it was slowly realized that provision of effective tuberculosis control required an adequately functioning health infrastructure that could support well-organized tuberculosis diagnostic and treatment services.

Only during the past 20 years have effective systems of tuberculosis control been developed in low-income countries. These have been encapsulated in the directly observed therapy, short-course (DOTS) strategy, the tuberculosis control policy developed by the World Health Organization (WHO) and its partners (4). The essential components of DOTS are (1) microscopic examination of sputum for acid-fast bacilli (AFB) from patients with suspected tuberculosis, (2) DOT using rifampin-based regimens, (3) a reliable supply of high-quality drugs and diagnostic supplies, (4) reporting of treatment outcome for all patients and monitoring of program performance, and (5) political commitment from responsible governments. This strategy has been shown to be among the most cost-effective global health interventions available today (5).

In 1991, WHO established two global targets for tuberculosis control: curing 85% of newly diagnosed patients and diagnosing 70% of new patients with infectious tuberculosis. With optimal implementation of the DOTS strategy, WHO felt that these targets might be achieved by the year 2000. Over the past decade, the rate of uptake of the DOTS strategy has been remarkable. In 1990, just 10 countries had implemented the strategy; by 1998, 119 had adopted DOTS (6).

However, DOTS coverage in most of the 22 countries that contain 80% of the world's burden of tuberculosis has been slow to expand. In 1998, only 21% of the world's estimated infectious tuberculosis patients were treated in DOTS programs, and only Peru, Vietnam, and a number of small island nations met the WHO targets for case finding and treatment (7). The reasons for this are many, but of paramount importance is the reluctance by governments in affected countries and donor agencies to address fully the tuberculosis problem. It is admittedly unrealistic to expect that the governments of the world's poorest countries will be able to make the required commitment to improved tuberculosis control without external assistance. The G8 leaders' recent commitment to a "massive effort" to reduce by 50% the global burden of tuberculosis morbity and mortality by 2010 is a step in the right direction (8).

	LIMITATIONS OF THE DOTS STRATEGY

TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

Unfortunately, as DOTS coverage has expanded, it has become apparent that the performance of existing tools for tuberculosis diagnosis and treatment limits more efficient implementation of the strategy. AFB microscopy detects only those patients with advanced pulmonary tuberculosis. The technique is arduous and time-consuming and requires continued training and supervision of microscopists to maintain effective performance.

The current tuberculosis treatment regimens, although highly effective, are far from ideal. Using the optimal combination of available drugs, the duration of treatment required for curing patients cannot be reduced below 6 mo. In most low-income countries, an 8-mo regimen is used. When given under suboptimal program conditions, these regimens are associated with high rates of patient nonadherence with the consequence of increased mortality and creation of chronic, infectious drug-resistant cases (9). Furthermore, all four of the most effective oral drugsisoniazid, rifampin, ethambutol, and pyrazinamidemust be taken together during the first 2 mo of treatment. Although rates of serious adverse reactions are low, many patients experience unpleasant side-effects when taking 10 or more tablets and capsules altogether at one time. The remaining drugs are either much more expensive, more toxic, and/or less effective.

It is recommended that treatment be directly observed by a health-care provider, especially during the first 2 mo and whenever rifampin is being used. The infrastructure required is cumbersome, labor intensive, and expensive. Because the margin of error for the development of drug resistance is small, treatment nonadherence commonly leads to the development of drug-resistant disease. Development of drug resistance is far more likely when supervised treatment is not given, when recommended regimens are not used, and when drugs with poor bioavailability are used. All of these factors are frequently present in countries in which DOTS has not been established.

	THE NEED FOR NEW TUBERCULOSIS DRUGS

TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

There are three reasons usually given for needing new tuberculosis drugs: (1) to improve current treatment by shortening the total duration of treatment and/or by providing for more widely spaced intermittent treatment, (2) to improve the treatment of MDR TB, and (3) to provide for more effective treatment of latent tuberculosis infection (LTBI) in programs that are able to implement this practice.

Of greatest impact would be new drugs to improve current treatment by providing for regimens that facilitate patient and provider compliance. Shorter regimens and those that require less supervision can accomplish this. Most of the benefit from treatment comes during the first 2 mo, the "intensive" or "bactericidal" phase when four drugs are given together, the bacterial burden is greatly reduced, and patients become noninfectious (10). The "continuation" or "sterilizing" phase of 4 to 6 mo is required to eliminate persisting bacilli and minimize the risk of relapse. A potent sterilizing drug that shortens treatment to 2 mo or less would be of great benefit. Drugs that facilitate compliance by providing for less intensive supervision are also of great interest. Obviously, a compound that would reduce both the total length of treatment and the frequency of drug administration would provide the greatest improvement.

The need for drugs to improve the treatment of patients with drug-resistant tuberculosis has received a great deal of attention, as global rates of MDR TB are rising in countries such as the Russian Federation where MDR TB has spread in Russian prisons and to the general population (11). Patients with MDR TB must be treated with a combination of "second-line" drugs, which are not only significantly more expensive but also much more toxic and less effective than the drugs used in standard therapy (12). To address this problem, WHO and others have advocated the strategy of "DOTS-Plus," a combination of effective control practices and the provision of "second-line" antituberculosis drugs in a systematic way (13). However, it remains to be seen whether this strategy will be effective in stemming the rise of MDR TB. As compelling as the argument may be that new drugs are needed for MDR TB, new drugs alone will not solve the problem. Introducing new drugs into a poorly run program only accelerates the development of resistance to the new compounds.

The final impetus to the development of new tuberculosis drugs is for improved treatment of persons with LTBI. It is estimated that among the approximately 2 billion persons throughout the world with LTBI, between 100 and 200 million will develop active disease during their lifetimes. In North America and several other low-incidence countries, isoniazid has been used for the treatment of LTBI in persons at greatest risk of disease progression. Isoniazid has also been shown to be effective in persons with tuberculosis and HIV coinfection and has recently been recommended by WHO for such persons (14). However, there are significant limitations to this intervention, and new drugs to improve LTBI treatment have been deemed essential to the elimination of tuberculosis in low-incidence countries such as the United States (2). The recent report from the Institute of Medicine, "Ending Neglect: The Elimination of Tuberculosis in the United States," gives high priority to the development of new drugs for LTBI treatment (15).

	OPPORTUNITIES AND BOTTLENECKS IN TUBERCULOSIS DRUG DISCOVERY AND DEVELOPMENT

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Of the approximately 1,200 new drugs approved for marketing during the past 20 yr, fewer than 1% have been for infectious diseases found predominantly in developing countries (16). For tuberculosis, known activity within the pharmaceutical industry is small compared to the size of the problem.

A number of reasons have been suggested for lack of commercial interest in new tuberculosis drugs (17). In addition to the perceived lack of need and profit opportunity, other reasons include the difficulties of identifying potentially active new compounds and of clinical development of promising new compounds.

The complex pathobiology of M. tuberculosis, which permits organisms to persist in a dormant stage for years, renders treatment difficult. Current lack of understanding about the mechanisms of mycobacterial metabolism in the vegetative state and the site of infection also poses impediments to the identification of new compounds with potent sterilizing activity. Agents with potent activity against latent bacilli may not be detected in the current drug screens performed to identify promising compounds for clinical testing.

A potentially invaluable source of information that might permit both the identification of new drug targets and novel methods to shorten treatment may come from the recent cloning of the genome of M. tuberculosis (18). Optimal methods of applying the information coming from DNA sequencing to new drug development are being developed. In addition, the development of combinatorial chemistry and robotic screening promises the introduction of an era of rational tuberculosis drug discovery (19).

Clinical development of tuberculosis drugs is not simple. Efficacy trials are long and complex, with intricacies known to very few investigators. Because few products have been newly registered for the treatment of tuberculosis in the past three decades, current regulatory requirements are not well defined or standardized, and previous guidelines are outdated. Regulatory authorities generally require that for approval, a new drug must be at least as safe and effective as the standard treatment. For tuberculosis, this means that new agents will be incorporated into a multidrug regimen which will be compared with the standard 6-mo short-course regimen. The commonly accepted primary end point for an efficacy trial is the rate of relapse during a 2-yr period of observation following treatment. There is great interest in and a clear need for surrogate markers of efficacy, and recent studies using molecular methods show promise (20).

Despite these obstacles, there has been recent progress on longer acting rifamycins that may provide for more widely spaced intermittent treatment and thus a reduction in the number of directly observed doses. The most promising work has been on rifapentine (Aventis Pharmaceuticals, Parsippany, NJ), which was approved for the treatment of tuberculosis in the United States in 1998 (21). A related compound, rifabutin (Pharmacia Corporation, Peapack, NJ), has been recommended for HIV-infected tuberculosis patients who cannot receive rifampin because of interactions with antiretroviral agents (22).

Significant advance in tuberculosis treatment has also come from the development of the broad-spectrum fluoroquinolone antibiotics. A number of reports of patients with tuberculosis treated with these drugs have suggested their utility (23), and, consequently, these agents are now among the preferred "second-line" drugs for MDR TB. Newer compounds in this class, such as moxifloxacin (Bayer Corporation, West Haven, CT) and gatifloxacin (Bristol Meyers Squib Company, New York, NY), appear to be much more active against M. tuberculosis than any of the currently available agents (24, 25), and might also be useful in the treatment of drug-susceptible tuberculosis.

Two entirely novel classes of compounds also are of great interest as tuberculosis drugs. Oxazolidinones (Pharmacia Corporation), which have been developed as broad-spectrum antimicrobials, appear to have substantial antimycobacterial activity (26). With the recent approval of the lead compound in this series, linezolid, for the treatment of specific acute bacterial infections, it is hoped that there will be corporate interest in studying other compounds in this class for tuberculosis.

The other class is the nitroimidazopyrans, drugs related to nitroimidazoles that have been studied in the past as possible tuberculosis drugs. The most promising compound in this series, PA-824 (Chiron Corporation, Emeryville, CA), has a novel mechanism of action against M. tuberculosis and bactericidal activity comparable with that of isoniazid (27). Moreover, the drug also appears to be active against nonreplicating organisms, suggesting that it might be a potent sterilizing agent capable of shortening tuberculosis treatment significantly.

	FINANCIAL DISINCENTIVES FOR TUBERCULOSIS DRUG DISCOVERY AND DEVELOPMENT

TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

Most pharmaceutical companies do not pursue tuberculosis research because of the high investment required to bring a product to market and the lack of likely commercial return (14). To stimulate the interest of industry in new tuberculosis drug development, the public sector itself must initiate the dialogue needed to address the following financial impediments:

1. Drug development is costly: It is estimated that the average cost of developing a drug, from laboratory to market, is $300 to $500 million. The environment is highly competitive, with companies trying to recoup investment and profit quickly. Due to high costs of development, companies measure the price of investment and the associated opportunity costs. Relative to other therapeutic areas, tuberculosis research requires long-term scientific commitment and offers uncertain and limited financial reward.

2. Market size is insufficient: The industry estimates that the tuberculosis market is less than $150 million, although defining "market size" is difficult. Targets vary for companies, but many want to generate a minimum $200 million per annum. Tuberculosis is considered to be declining in the industrialized world, so companies see little commercial potential. Because 95% of new tuberculosis cases occur in the developing world, industry believes that few patients with tuberculosis could pay the high prices required for profit. Additional concern stems from insecurity about patent protection for new compounds in an era of calls for compulsory licensing of new products for use in low-income countries.

3. Pricing pressures are strong: The total cost for a standard treatment regimen currently is as little as $11, which, when combined with the numbers of patients to be treated, is too low to generate interest. To justify higher prices, companies have to develop a product superior to those used in the current regimens. With antituberculosis drugs, a multitiered pricing scheme is considered inevitable, which opens up the risk of parallel importing.

Work is now needed to define more precisely the costs of developing new tuberculosis drugs, taking into account the assistance provided by the public sector, for example, in conducting clinical efficacy trials that provide the data required for registration. Parallel to this, the "real" market for tuberculosis drugs must be better defined and include those millions of patients in low-income countries that fuel the global tuberculosis epidemic. This exercise should also include cost-effectiveness analyses that consider possible reductions in program costs to provide for trade-offs for higher drug costs when program efficiency is enhanced by new drugs and regimens.

A detailed plan that addresses the technical aspects of tuberculosis drug development must also be developed so that the private sector can better understand the process. Agreement must also be built among regulatory agencies on the requirements for registration of new tuberculosis drugs. The U.S. Food and Drug Administration has provided through its recent approval of rifapentine an example that could serve as the basis for further discussion on this critically important topic.

	THE WAY AHEAD: PUBLIC-PRIVATE PARTNERSHIPS FOR THE DISCOVERY AND DEVELOPMENT OF TUBERCULOSIS DRUGS

TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

The remarkable history of the development of drugs for tuberculosisfrom the initial studies of streptomycin in the late 1940s to rifampin in the 1970shas been one of public-private sector collaboration. Groups such as the British Medical Research Council and the U.S. Public Health Service closely collaborated with pharmaceutical companies to produce the clinical trial data required for drug registration and to define the optimal use of the drugs in treatment regimens. Unfortunately, as tuberculosis cases declined in industrialized countries, interest in the development of tuberculosis drugs also lessened, and the public infrastructure to support tuberculosis clinical trials was greatly eroded.

However, during the past decade as concern about the global tuberculosis problem increased, the capacity to undertake large-scale clinical tuberculosis trials in the public sector has been restored. The United States Centers for Disease Control and Prevention (CDC) has established the TB Trials Consortium, with trial sites in the United States and Canada conducting high-quality studies of new drugs and regimens (28). The U.S. National Institutes of Health (NIH) supports the Tuberculosis Research Unit, which is able to conduct clinical trials largely outside the United States. In addition, public sector institutions in countries such as Brazil, India, and South Africa have substantial and well-developed expertise in the conduct of tuberculosis drug trials, as well as easier access to patients.

The public sector has also begun to invest in drug discovery and has developed the capacity to assist pharmaceutical companies in these activities. The NIH through its Tuberculosis Antimicrobial Acquisition and Coordinating Facility has a tuberculosis drug discovery activity that provides for in vitro screening and animal testing of compounds, as well as other assistance to sponsors for candidate antibiotics (29). The Special Programme for Research and Training in Tropical Disease (TDR) at WHO has recently added tuberculosis to the list of diseases under study and hopes to partner with industry in the full range of activities required to develop new compounds for tuberculosis treatment (30).

What is now most needed to exploit these new resources is an active dialogue among interested private sector companies, those groups in the public sector that are working in a variety of areas related to tuberculosis drug development, and funding agencies that have become interested in supporting these activities. This dialogue should lead to the development of a coalition of these groups working together with the common purpose of developing and profitably marketing new compounds that significantly improve the treatment of tuberculosis, making DOTS implementation easier and reducing the global tuberculosis burden substantially. Optimally, these partnerships should involve both north-south and south-south collaboration.

Formation of one such coalition began at a meeting on new drugs for tuberculosis held in Cape Town, South Africa, in February 2000, organized by the Rockefeller Foundation and cosponsored by Stop TB and its global partners, including WHO, TDR, CDC, and the World Bank, the NIH, the Wellcome Trust, the Bill and Melinda Gates Foundation, and the U.K. Department for International Development. Participants at this meeting, including a large group of representatives from companies in the private sector, pledged to work together to develop a Global Alliance for TB Drug Development (31). Just eight months after the Cape Town meeting, the alliance was formally launched by the director-general of the WHO in Bangkok, Thailand (32). If successful, this partnership will provide leadership, raise funds, advocate, and coordinate efforts in various sectors and settings to improve health equity by developing and making available to poor people in poor countries more effective, simple, and affordable tuberculosis treatment before the end of this decade.

In conclusion, although significant obstacles remain, the prospects for the development of new and effective drugs against tuberculosis are much greater than at any time in several decades. If we dedicate ourselves and our institutions to this effort, we can look forward to the prospect of global elimination of this ancient scourge within this century.

	Footnotes

Correspondence and requests for reprints should be addressed to Dr. Richard J. O'Brien, Division of TB Elimination, Mailstop E-10, Centers for Disease Control and Prevention, Atlanta, GA 30333.

(Received in original form July 25, 2000 and in revised form November 14, 2000).

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TOP INTRODUCTION THE GLOBAL TUBERCULOSIS PROBLEM STATUS OF EXISTING TUBERCULOSIS... LIMITATIONS OF THE DOTS... THE NEED FOR NEW... OPPORTUNITIES AND BOTTLENECKS... FINANCIAL DISINCENTIVES FOR... THE WAY AHEAD: PUBLIC-PRIVATE... REFERENCES

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