Editorials
Pharmacology
Volume 199 - Issue 2

How can we improve access to new (and old) antibiotics in Australia?

Authors:  Allen C Cheng and Roger L Nation

Med J Aust 2013; 199 (2): 81-82. || doi: 10.5694/mja13.10657
Published online: 22 July 2013
With very few new antibiotics in the pipeline, promoting their development is important, as is balancing priorities when treating patients
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It is hoped that new registration mechanisms and economic incentives will encourage much-needed drug development

That there is a problem with antibiotic resistance is no surprise to clinicians who deal with antibiotic-resistant organisms in day-to-day practice. Scenarios increasingly being faced include health care-associated infections (particularly those acquired overseas) where few therapeutic options are available, bacteraemia following transrectal prostate biopsy, simple urinary tract infections for which no oral antibiotics are effective, and drug-resistant gonorrhoea, tuberculosis and typhoid fever. The inexorable rise in antibiotic resistance coincides with a dwindling pipeline of novel antimicrobial agents under development.1,2 A recent review identified only two new antibiotics registered in the United States since 2009 (of which only one is currently available in Australia) and only seven antibiotics active against gram-negative bacteria in clinical development.3 Only four multinational pharmaceutical companies were engaged in the development of antibacterials; barriers to development and registration of new antibiotics were noted (including the need for large efficacy and safety trials), as was low profitability relative to other drugs.

The Infectious Diseases Society of America (IDSA) has proposed measures to encourage the development of 10 new antibiotics by 2020,4 including a new mechanism for registering new antimicrobials, termed the limited population antibacterial drug approval pathway.5 The features of this regulatory pathway include designation of eligible drugs on application to the US Food and Drug Administration; establishment of efficacy using small clinical trials in specific populations; limitation of marketing approval to specific populations, with regulation of marketing materials; and surveillance and monitoring of drug utilisation during the postmarketing period. IDSA has also proposed a number of economic incentives to promote antibiotic development, and harmonisation of European and American guidance.3

In Australia, access to unregistered pharmaceuticals is possible through the Special Access Scheme, and this has been used extensively for intravenous artesunate (for malaria), fosfomycin and chloramphenicol (for bacterial infections) and even relatively commonly used drugs where there has been an interruption to supply of the approved formulation (eg, ethambutol for tuberculosis). Although hospitals and distributors often stockpile commonly used unregistered antimicrobials to expedite access, this system, which requires faxing each patient’s details to the Therapeutic Goods Administration (TGA), can introduce delays of a few days or even weeks.

Two existing policies are designed to facilitate registration of drugs for uncommon indications. First, “orphan drugs”, defined by low incidence of the disease treated and lack of supply for another indication, are exempted from application fees when submitted to the TGA for approval.6 Second, the “rule of rescue” is used when there is a small number of patients with severe illness, no other drug is available, and there is evidence that the proposed treatment is efficacious. Although these criteria are used when drugs are considered for Pharmaceutical Benefits Scheme subsidies (less relevant to drugs that are primarily used in hospitals), they also apply to assessments of balance between safety and efficacy when drugs are considered for registration.7

The approval of new drugs on the basis of limited data is not without risk. An example is bedaquiline, a novel antibiotic active against multidrug-resistant tuberculosis that was recently approved in the US.8 This antibiotic appears efficacious on the basis of animal data and small clinical trials showing improved outcomes based on surrogate microbiological end points. However, the clinical studies were small (sample sizes of 47 and 161 patients), and there was a much higher mortality rate among patients receiving bedaquiline compared to those receiving placebo, and the causes of death were not well defined. Thus, the benefits of timely availability of treatment for patients with drug-resistant tuberculosis are traded off against uncertainty in terms of safety and efficacy, which will only be defined with further experience and research.

Older generic drugs, such as fosfomycin, may also be useful in the treatment of patients with infections caused by drug-resistant organisms. Locally funded research on older drugs has been shown to be a worthwhile investment. For example, colistin, an important last-line treatment for infections caused by multidrug-resistant gram-negative bacteria, was abandoned in the 1960s because of renal toxicity. A new formulation was registered in Australia in 2010 (as an orphan drug product), facilitated by studies led by Australian researchers.9 If supporting clinical data are limited, the conditions of antibiotic registration should include restriction of use to relevant specialist groups, a commitment to provide results of ongoing studies, and careful monitoring of postmarketing efficacy and safety.

Australia is relatively protected from resistant bacteria by geography, robust regulatory policies governing antibiotic use, and the longstanding use of national guidelines.10 There is still work to be done in prevention, but there is also a need to have treatment available for people infected with resistant organisms. The Australian market alone is insufficient to encourage the development of new drugs, but has a valuable role in supporting research. Barriers to the availability and registration of antibiotics needed for otherwise untreatable infections should be minimised while protecting the public against new drugs that may be of limited efficacy or unsafe. In the meantime, it is essential that currently available antibiotics are used judiciously, with dosing regimens optimised to reduce resistance and maximise patient benefits.

Authors

  • Allen C Cheng FRACP, MPH, PhD1,2
  • Roger L Nation PhC, MS, PhD3
  • 1. Infectious Disease Epidemiology Unit, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC.
  • 2. Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, VIC.
  • 3. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC.

Correspondence: allen.cheng@monash.edu

Competing interests

Allen Cheng is a member of the TGA’ s Advisory Committee on Prescription Medicines. The views outlined here do not necessarily reflect the views of the Committee or the TGA.

References

Provenance: Commissioned; externally peer reviewed.

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