VOLUME 33 : NUMBER 5 : October 2010
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Readers are invited to write in with their questions about decisions of the Pharmaceutical Benefits Advisory Committee (PBAC). Australian Prescriber publishes selected questions from readers, together with answers from the PBAC. Questions may address issues such as regulatory decisions, pharmaceutical benefits listings and withdrawals.
This exclusive arrangement helps Australian Prescriber readers understand how the contents of the Pharmaceutical Benefits Scheme (PBS, see www.pbs.gov.au) are determined.
Letters and responses are reviewed by the Editorial Executive Committee and may be edited before publication. It may not be possible to reply to all individual questions.
While reviewing an article on bacteria with resistance to multiple antibiotics (Aust Prescr 2010;33:68–71), the Editorial Executive Committee found an anomaly in the availability of rifampicin on the Pharmaceutical Benefits Scheme (PBS). The restrictions for rifampicin do not include the treatment of methicillin-resistant Staphylococcus aureus (MRSA). For infections which can be managed with oral antibiotics, rifampicin is often given with fusidic acid. The PBS restrictions for fusidic acid require it to be used with another antibiotic in the treatment of proven serious staphylococcal infections. The other antibiotic is likely to be rifampicin, but this cannot be prescribed as a pharmaceutical benefit.
The purpose of using two antibiotics is to try to prevent further resistance. The Editorial Executive Committee therefore asked for the advice of the Pharmaceutical Benefits Advisory Committee on how to resolve the apparent anomaly in the PBS restrictions.
The PBAC has to consider the terms of marketing approval of a product. This approval is granted by the Therapeutic Goods Administration (TGA) and specifies the conditions in which the drug has shown acceptable safety and efficacy. The PBAC is not in a position to recommend that a drug be listed outside the terms of marketing approval specified by the TGA.
Currently, rifampicin is approved by the TGA for the treatment of tuberculosis, leprosy, prophylaxis of meningococcal disease and prophylaxis of household contacts of patients with Haemophilus influenzae type B. Under the National Health Act 1953 there is no provision for the subsidised supply of an item listed as a restricted benefit for use in a condition which lies outside the terms of the restriction specified in the Schedule of Pharmaceutical Benefits. The current PBS listing for rifampicin reflects the TGA registration and so rifampicin cannot be prescribed for MRSA under the PBS.
The PBAC is concerned that rifampicin is not available as a pharmaceutical benefit for treating MRSA and has previously asked the drug's sponsor to seek marketing approval for this indication. However, neither the PBAC nor the government can compel a manufacturer to apply for registration of a drug for a particular indication.
The Editorial Executive Committee sought responses from the manufacturers of rifampicin in Australia.
Dr Alex Condoleon, Medical Director Australia & New Zealand, Sanofi-aventis, comments:
The availability of rifampicin as a pharmaceutical benefit in combination with fusidic acid for methicillin-resistant Staphylococcus aureus (MRSA) would require supporting evidence to achieve registration with the TGA and subsequently reimbursement through the PBS. Sanofi-aventis has therefore searched the literature about this combination, to determine the feasability of increasing access to this regimen for patients.
The Therapeutic Guidelines: Antibiotic1 lists the combination of rifampicin and fusidic acid as a treatment option for recurrent staphylococcal skin infections (including MRSA-positive infections), and MRSA osteomyelitis involving the bone or joint prostheses, in both adult and paediatric patients. Similarly, the Australian Medicines Handbook2 lists combination treatment of MRSA infection as an indication under both the monographs for rifampicin and fusidic acid.
Contrary to the Australian guidelines, the combination is not included in DrugDex Evaluations,3 the American Hospital Formulary Service (AHFS) Drug lnformation,4 the Centers for Disease Control and Prevention (CDC),5 the World Health Organization (WHO),6 and the European Centre for Disease Prevention and Control.7
Published clinical studies and reviews
A search of the medical literature retrieved a small number of studies evaluating the combination for the management of MRSA infections and a large number of review articles on the management of MRSA infections. This search is subject to the limitations inherent in these databases and cannot be considered exhaustive.
Studies in adults
Two small (n=<12) Australian trials89 studied the combination of rifampicin and fusidic acid for the treatment of MRSA infections in orthopaedic patients and patients with cystic fibrosis respectively. Both studies found this combination to be effective at eradicating MRSA infection.
Studies in children
None of the small number of studies10–13 of MRSA infections evaluated the combination of rifampicin and fusidic acid.
None of six paediatric review articles18–23 specifically listed the combination of rifampicin and fusidic acid as a recommended treatment option. However, five of these reviews18–22 listed rifampicin as a treatment option, stating that it must be used in combination with other antibiotics.
Upon current assessment of available data there appear to be inconsistencies in treatment guidelines and only a small number of studies evaluating the combination of rifampicin and fusidic acid for the treatment of MRSA infections. Sanofi-aventis therefore does not believe that the evidence base exists to satisfy regulatory requirements to support this additional indication. However, we are open to reassessing options should further evidence emerge, or be brought to our attention, that could support a formal regulatory submission.
Dr Greg Pearce, Director, Medical Affairs, Alphapharm, comments:
Most parties with an interest in making older medicines more freely available, at an affordable cost, for unapproved indications agree that this is an important issue. Unfortunately, no-one has been able to devise a satisfactory process for registering the indication and listing the product on the PBS. At a minimum, this process needs to balance evidence requirements, commercial considerations and regulatory scrutiny to a point where the documentation expectations are consistent with the commercial objectives of a potential supplier.
This impasse remains, despite meetings between the Royal Australasian College of Physicians, the TGA and industry representatives, a consultancy commissioned by the Department of Health and Ageing on behalf of the Paediatric Medicines Advisory Group, and direct representation by Alphapharm to the TGA.
Alphapharm is sympathetic to addressing this gap in our ability to deliver quality use of medicines but cannot move forward under the current regulatory and reimbursement framework. Recent PBS reforms have shifted the sponsor's fulcrum even further away for supporting these requests.
The company would support any further discussions aimed at developing innovative approaches to improve access to treatment. These would need to match the costs and evidence requirements for registration against the needs of a manufacturer to achieve a financial return which at least covers the resource and financial costs associated with applying for approval of a new indication.