Drug Criteria & Outcomes: Antibiotic Agents: A drought in discovery
Drug Criteria & Outcomes
Antibiotic Agents: A drought in discovery
Resistance is rising amid decline in research and development
By Derek D. Gatlin, PharmD candidate Samford (AL) University, McWhorter School of Pharmacy
In the past decade, there has been a marked decline in research aimed at developing novel antibiotic agents, but a noticeable increase has occurred in the resistance of bacteria to current agents.
Though the pharmaceutical industry owes much of its early prosperity and growth to the discovery and marketing of antibiotics, major manufacturers are reducing, and in some cases, halting their efforts and funding in the fields of antibacterial research and development.1 However, one shouldn't be so quick to point a finger solely at "big Pharma" seemingly little urgency, on behalf of the research community, the Food and Drug Administration (FDA), political leaders, and general public, is being placed on the matter. Many of these groups assume the view that there is no compelling drive to address antibiotic-resistant bacteria with new agents.2
In the U.S., methicillin-resistant Staphylococcus aureus accounts for the majority of hospital-acquired S. aureus infections. Although two drugs (linezolid and tigecycline) have emerged lately to battle resistant gram-positive organisms, sparse attention is being given to multi-drug resistant gram-negative bacteria such as Pseudomonas, Stenotrophomonas, and Acinetobacter. The previously mentioned bacteria accompanied by extended spectrum beta-lactamase producing E. coli and Klebsiella, vancomycin-resistant Enterococcus faecium, and Aspergillus species comprise the Infectious Disease Society of America (IDSA) "hit list" of multi-drug resistant organisms that pose a threat to public health.3 In 2004, the U.S. Congress appropriated $890 million for "Project Bioshield" to encourage the private sector pharmaceutical manufactures to develop vaccines, drugs, and other bio-terror countermeasures. More action has been proposed by IDSA, in the form of "Bioshield II", to spark development of drugs to protect the public against naturally occurring "super bugs". Americans are more likely to be infected by a naturally occurring organism than they are to be threatened with a bio-terrorism agent.4 Complacency towards antibiotic development may transform ever-increasing organism resistance from the annoying hum of a mosquito in the ear, into the thundering gallop of the pale steed of the Apocalypse, on which is riding Pestilence.2
Antibacterial market has lost buoyancy
Lurking in the depths of any highly discussed issue, inevitably, is money. Antibiotic usage continues to escalate, but the market size remains stagnant. The pharmaceutical industry is continually being burdened with increasing costs for each drug brought to market. It is estimated that around $100 to 800 million are spent researching, developing and marketing a new product; this figure excludes the liability to which private producers are exposed. Several aspects of antibiotics segregate them from other drug products in terms of return on investments. These divisions may explain, in part, why the antibacterial market is far less lucrative.
- Antibiotics work very efficiently. In fact, they work so well that their duration of use is much shorter than many other drugs, thus they have a smaller market than drugs used to treat chronic conditions.
- As resistance to the antibiotic is expressed, the agent becomes no longer viable in therapy. Thus long-term market potential is stifled.
- Infectious disease experts judiciously govern the use of new antibiotics in efforts to preserve effectiveness of such agents for those who need them most; quite a sensible approach from a public health standpoint. But, restrictions on use dampen incentives for companies to develop and market new entities.
- To be economically attractive, an antibiotic should have a wide spectrum of action. Along with this, are an additional "burden of proof" and a more rigorous set of criteria for FDA approval. The "patent clock" begins ticking as soon as the drug reaches the development stage, and each day the drug is not on the market is money lost.5,6
Legislative recommendations proposed by the IDSA include offering tax credits for research and manufacturing expenses, directing the FDA in clarifying and streamlining clinical trial phases, and awarding vouchers for FDA fast-track review to the companies that develop a product directed at a "hit list" organism.1,3,5,7
An ethical dilemma
In a time when bacterial resistance to antibacterial drugs is widely considered to be a critical issue affecting public health, only 13 new antibiotics (only two of which are truly novel) have been FDA approved since 1998.3 Due to market pressure by generic companies, longer approval processes, and the enormous cost of bringing drugs to market, "big Pharma" is making few attempts to improve this statistic. Our society is faced with certain ethical dilemmas: Do we value the ability of private companies to develop and administer antibiotics to benefit their interests more highly than we value the benefit that the public would realize from their development and judicious use? Should market forces, public interest, or a hybrid of the two govern production and use of antibacterials? And, who should pay?6
With that stated, progress is being made on behalf of public health officials, clinicians, and the pharmaceutical industry. If these groups can compromise and cooperate on the above-mentioned issues, a positive projection may be made toward anti-infective development over the next 10 years.
References
- Projan SJ, Shlaes DM. Antibacterial drug discovery: is it all downhill from here? Clin Microbiol Infect. 2004; 10 (Suppl 4):18-22.
- Projan SJ. Why is big Pharma getting out of antibacterial drug discovery? Curr Opin Microbiol. 2003;6:427-430.
- ISDA Website. Available at: http://www.idsociety.org/Content/ContentGroups/IDSA_News.
- Nelson R. Antibiotic development pipeline runs dry. Lancet.2003;362:1726-1727.
- Reed SD, Laxminarayan R, Black DJ, Sullivan SD. Economic issues and antibiotic resistance in the community. Ann Pharmacother. 2002;36:148-154.
- Aiello AE, King NB, Foxman B. Ethical conflicts in Public Health Research and Practice: Antimicrobial resistance and the ethics of drug development. Am J Public Health. 2006;96:1910-1914.
- Talbot GH, Bradley J, Edwards JE, Gilbert D, Scheld M, Bartlett JG. Bad bugs need drugs: An update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Disease.2006;42:657-668.
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