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keys2level7 6 posts  |  Last Activity: Dec 6, 2014 10:50 AM Member since: Apr 22, 2014
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  • Reply to

    President Obama tackles drug resistance

    by keys2level7 Sep 27, 2014 11:48 PM
    keys2level7 keys2level7 Dec 6, 2014 10:50 AM Flag

    Show me a politician whose credibility is NOT suspect.

  • Reply to

    President Obama tackles drug resistance

    by keys2level7 Sep 27, 2014 11:48 PM
    keys2level7 keys2level7 Nov 29, 2014 9:58 PM Flag

    These extracts from the 2012 GAIN legislation cover the FDA's new mandate:

    [ ... the FDA should be encouraged to implement more broadly effective processes for the expedited development and review of innovative new medicines intended to address unmet medical needs for serious or life-threatening diseases or conditions, including those for rare diseases or conditions, using a broad range of surrogate or clinical endpoints and modern scientific tools earlier in the drug development cycle when appropriate. ]

    [ The Secretary may approve an application for approval of a product for a serious or life-threatening disease or condition, including a fast track product, under section 505(c) or section 351(a) of the Public Health Service Act upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. ]

    Arikayce is representative of the "innovative new medicines intended to address unmet medical needs for serious or life-threatening diseases or conditions" the legislators were asking the FDA to fast-track.

    The data from the studies in Pseudomonas infection and NTM infection are collectively "reasonably likely to predict ... clinical benefit" in any amikacin-susceptible pulmonary infection.

    Why so little FDA interest in a therapy "reasonably likely" to -

    1. address an unmet medical need in NTM infection, for which there are currently no FDA-approved antibiotics

    2. kill almost all of the pathogens specifically targeted by the GAIN legislation

    3. reduce amikacin resistance

    4. reduce clostridium difficile infection

    5. reduce liver and kidney toxicity?

  • Reply to

    President Obama tackles drug resistance

    by keys2level7 Sep 27, 2014 11:48 PM
    keys2level7 keys2level7 Nov 15, 2014 12:58 PM Flag

    An estimated 12,000,000 people Worldwide have TB - 630,000 of whom have multi-drug-resistant TB.

    Aminoglycosides such as amikacin are highly effective against TB, but are only used these days in MDR-TB because of the risk of kidney damage and loss of hearing.

    Yet they remain a top-ranked antibiotic for MDR-TB despite the risk to the patient.

    Doubtless for the foreseeable future the far higher cost of Arikayce compared with aminoglycoside injections will be prohibitive in the vast majority of cases. But even a very small percentage of 12,000,000 can be a big number.

    How long could it realistically take for the World Health Organisation and the Worldwide medical community to realise that Arikayce is better suited to the treatment of TB than any single antibiotic currently used?

    Even if the new federal task force doesn't adopt / fast-track inhaled delivery of antibiotics for pulmonary infections - Europe, not the US, is the gateway to the rest of the World.

    Most antibiotics currently used in TB are being used off-label. The CDC has even issued guidelines for the off-label use of bedaquiline.

    It seems a price of $31,000 for a six-month course of tablets isn't considered an automatic barrier to off-label use.

  • Reply to

    President Obama tackles drug resistance

    by keys2level7 Sep 27, 2014 11:48 PM
    keys2level7 keys2level7 Oct 25, 2014 8:20 AM Flag

    The EMA has acknowledged that it views Arikayce as a superior version of intravenous amikacin -

    [ The sponsor presented early clinical data showing better lung penetration and lower incidence of side effects as compared to the existing intravenous formulation. The Committee considered that this can translate into a clinically relevant advantage for patients affected by nontuberculous mycobacterial lung disease, as there are well-known and documented side-effects of the existing intravenous formulation that limit its use. ]

    The FDA has previously accepted Phase II culture conversion data, when approving JNJ's bedaquiline for MDR-TB subject to a Phase IV study.

    The FDA even saw fit to overlook (but for a Black Box warning) an unexplained higher mortality rate in the bedaquiline arm - 9 of 79 patients vs 2 of 81 on placebo, with this rationale -

    [ Nonetheless, treatment for resistant TB is complex, costly, toxic and prolonged, requiring at least 5 second-line drugs for up to 2 years. Second-line drugs include injectable drugs (amikacin, kanamycin, capreomycin) and oral fluoroquinolones (FQs) and other second line drugs; the optimal use of which has not been well studied in randomized controlled trials, and whose safety when used in concert with various doses and regimens is not sufficiently described. ]

    If the FDA is so concerned about the unquantified risk posed by co-administration of multiple drugs - including intravenous amikacin - in resistant Tuberculosis, surely it must have been obvious that a therapy which has now delivered amikacin safely and effectively to -

    Pseudomonas infection

    Mycobacterium Avium Complex infection and

    Mycobacterium Abscessus infection

    - is likely to improve a "toxic and prolonged" antibiotic regimen for Mycobacterium Tuberculosis infection by eliminating the "documented side-effects" of kidney damage and loss of hearing?

    The financial health of the FDA's special friends may not be so much of a priority for President Obama.

  • Reply to

    President Obama tackles drug resistance

    by keys2level7 Sep 27, 2014 11:48 PM
    keys2level7 keys2level7 Oct 11, 2014 11:39 AM Flag

    Interesting to compare the FDA-approved uses of intravenous amikacin ...

    [ Amikacin Sulfate Injection, USP is indicated in the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria, including Pseudomonas species, Escherichia coli, species of indole-positive and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter (Mima-Herellea) species. ]

    ... with potential "serious threats to public health" targeted by the GAIN legislation President Obama signed into law in July 2012 -

    [ In this section, the term 'qualifying pathogen' means a pathogen ... that has the potential to pose a serious threat to public health, such as--

    ... (A) resistant gram positive pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, and vancomycin-resistant enterococcus;

    ... (B) multi-drug resistant gram negative bacteria, including Acinetobacter, Klebsiella, Pseudomonas, and E. coli species;

    ... (C) multi-drug resistant tuberculosis; and

    ... (D) Clostridium difficile. ]

    Arikayce converted 29 of 52 patients chronically infected with multi-drug resistant NTM (usually treated for a minimum of eighteen months) to 'sputum culture negative' during a six-month study - 15 of whom tested negative after just one month of therapy.

    Gram-negative bacteria pose less of a problem than mycobacteria (TB and NTM) being unable to survive within the macrophages. The FDA also had the data from the successful EMA Phase III study of Pseudomonas infection in Cystic Fibrosis, and additional data suggesting Arikayce is far safer than intravenous amikacin.

    But it seems the FDA was in no real hurry to establish the efficacy of Arikayce against those "public health threat" pathogens.

    The new task force, on the other hand, may view inhaled liposome delivery as a key strategy.

    The resulting decrease in Clostridium difficile infection alone would be a major bonus.

  • Executive Order -


    National Strategy -


    [ Over the next six months, an interagency task force co-chaired by the Secretaries of Health and Human Services, Agriculture, and Defense will develop a National Action Plan for Combating Antibiotic-Resistant Bacteria that will detail the specific steps that agencies are taking, or will take, both individually and in coordination to implement this National Strategy.

    The task force will also address recommendations made in a recent report by the President's Council of Advisors on Science and Technology on Combating Antibiotic Resistance.

    The National Action Plan will establish clear milestones and metrics for success.

    These activities will be coordinated by the White House National Security Council and Office of Science and Technology Policy.

    Because this initiative will require a sustained effort, the task force will regularly report to the President on progress made in implementing the National Strategy and Action Plan, and toward achieving the National Targets described in Table 3.

    It is expected that departments and agencies would also take steps to combat antibiotic resistance that are not explicitly included in either the National Strategy or Action Plan; ]

    From the PCAST recommendations -

    [ FDA should use existing mechanisms to facilitate approval of drugs based on demonstration of safety and efficacy in specific patients infected with antibiotic-resistant bacteria ... ]

    The FDA could have conditionally approved Arikayce, subject to a Phase IV study, for the treatment of all pulmonary infections presently treated with intravenous amikacin - including infection by an 'Urgent Threat Level' pathogen, CRE Klebsiella.

    Instead it chose to add a minimum of three years to the timeline of the inhaled liposome delivery program by requesting two additional studies restricted to NTM infection.


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