tga approval

Hi All

Thinking about the PBS chances, I just found this report on Mannitol on the TGA website.
It seems Bronchitol was lucky to be approved by the TGA earlier this year and they seemed to have asked some questions to an advisory committee. It might explain why the EMEA had issues also.

Full report is here.
http://www.tga.gov.au/pdf/auspar/auspar-bronchitol.pdf

Summary of conclusion is below.

Risk-Benefit Analysis
Delegate Considerations
The applicant should confirm that “rhDNase” means quite specifically dornase alfa and that its use
was consistent by way of dose and administration with the approved Australian product information
or disclose how it was not. The approved product information of dornase alfa suggests a significant
treatment effect for dornase alfa alone.
As hypertonic saline is the widely used hyperosmotic agent, it would therefore have been an
appropriate active comparator in clinical trials. This may have to be pursued.
The pivotal study may marginally satisfy the requirements for the submission of one pivotal study
as stipulated in the TGA-approved EU Guidelines.25 The evidence is certainly not “exceptionally
compelling”; especially in relation to external validity, the study outcome does not establish that
mannitol relieves the symptoms affecting quality of life or most other secondary endpoints nor has
its role against hypertonic saline been explored
Overall, there is modest efficacy data to recommend approval and the Delegate was inclined to
approve this application conditionally upon commitment to further studies. The added value of
mannitol in addition to dornase alfa seems small. Ultimately, the worth of exposing patients with
cystic fibrosis to an agent such as mannitol that is associated with numerous common adverse
effects relates to long term improved morbidity and mortality or at least improved quality of life to
offset the commonly experienced adverse reactions.
The Delegate asked the following questions of the Advisory Committee.
1. Is the dose finding adequate?
2. Are the results for the primary efficacy variable in the Phase III study persuasive, that is, are they
clinically significant? As this is a one-study submission, the relevant guideline would suggest that
both statistical and clinical significance is necessary.
3. Is the pivotal study transferrable to typical outpatient care settings?
25 EMEA, Committee for Proprietary Medicinal Products (CPMP), 31 May 2001. Points to Consider on Application
with 1. Meta-analyses, 2. One Pivotal Study, CPMP/EWP/2330/99.
AusPAR Bronchitol Mannitol Pharmaxis Ltd PM-2009-03748-3-5 Final 29 March 2011 Page 34 of 49
4. Is there any need to conduct further postmarketing studies? If so, what endpoints should be
tested?
5. Given the nature of the device that is proposed for use, is a study in children aged under 7 years
necessary?
The Delegate proposed to approve the submission for the following indication:
Bronchitol is indicated for the treatment of cystic fibrosis (CF) in both paediatric and adult
populations six years and above as either add-on therapy to dornase alfa or in patients intolerant
of), or inadequately responsive to dornase alfa.
As a condition of registration, the sponsor should commit to post-marketing data capture, desirably
via a clincial trial, to demonstrate the long term efficacy and safety of Bronchitol in cystic fibrosis