In this day and age, few truly broad spectrum antibiotics are in development, although this does not hold true for narrow-spectrums.\u00a0 Just think of all the MRSA drugs (quinolones, FabI inhibitors), the pseudomonas drugs (NCEs and monoclonals) or some narrow spectrum drugs that will need to be tested in MDR pathogen infections.<\/p>\n
Almost gone are the days of indication-based antibiotic development, although FDA Guidances still make you believe the indication-driven approach is the main one leading to approval.\u00a0 Instead, pathogen-driven development is now the norm, and it creates some very difficult problems:<\/p>\n
There are no easy answers, and it takes much thought and planning to address these problems\u00a0and to find workable solutions.\u00a0 Worse, every drug seems to require its own fairly unique testing scenario\u00a0which has\u00a0to be discussed and agreed-to by Regulators.\u00a0 Despite the great\u00a0need for new drugs, showing their efficacy in patients with highly resistant populations is not straight-forward.<\/p>\n
EXAMPLE<\/span><\/strong> Are we to evaluate a new anti-pseudomonal in combination with an aminoglycoside?\u00a0 This would fly in the face of the often-made argument that (1) concomitant antibiotics with overlapping activity invalidate a case for efficacy determination; (2) even short courses of non-study antibiotics can profoundly affect the outcome; and (3) such therapy would lead to regression towards the mean and slant outcomes towards non-inferiority, resulting in a Type II error.<\/span><\/p>\n<\/div>\n One often hears from KOLs that finding patients with a specific MDR profile is doable.\u00a0 Take CRE as an example: these organisms are no longer uncommon in India, Greece, Italy, Spain and some other locales where antibiotic stewardship is successfully avoided. According to the literature, these pathogens are popping up everywhere, including the US [1]<\/a>.\u00a0 Only problem: there are not enough cases yet in the USA to even consider a traditional randomized trial of a new antibiotic against SoC[2]<\/a>.\u00a0 If you do, you do it at your own risk.<\/p>\n Remember what happened to Advanced Life Sciences (ALS).\u00a0 They tried to conduct a study showing that cethromycin (Restanza\u00ae) has clinical activity against erythromycin-R respiratory pathogens.\u00a0 The FDA had asked for \u201ca superiority trial design comparing Restanza to a marketed macrolide antibiotic\u201d in not one but two trials [3]<\/a>. \u00a0\u00a0Did KOLs convince ALS that such a trial was feasible?\u00a0 Well, the new Phase 3 study did not make it very far because ALS ran out of money in the futile attempt to pull off \u2018mission impossible\u2019.\u00a0 Only a few months after the proud announcement that \u2018agreement with FDA on a Phase 3 study design\u2019 had been reached in the form of a Special Protocol Assessment (SPA), they threw in the towel [4]<\/a>.<\/p>\n Some may still remember the difficulties Ortho \/ J&J had in the 90s trying to enroll patients with penicillin-resistant (PCN-R) S. pneumoniae.\u00a0 The goal was to show that ofloxacin had good activity against these strains; based on MICs, this would seem a foregone conclusion. However, it took many years to collect such cases despite the fact that PCN-R S. pneumoniae was all over the news.\u00a0 Turns out that most PCN-R strains were found in pediatric populations, not in adults.\u00a0 And because we cannot expose children to fluoroquinolones, this study did not go anywhere fast.<\/p>\n Now Achaogen has set out to lift a similarly heavy load: \u00a0they embarked on a Phase 3 study comparing plazomicin to colistin in CRE-infected patients [5]<\/a>.\u00a0 Their lofty goal (360 patients) is certainly ambitious, to the point of appearing unrealistic.\u00a0 But hey, who is to say they won\u2019t succeed where others failed?\u00a0 Nonetheless, I smell the good but self-serving advice of KOLs and the purist demands of regulators emanating from this endeavor.<\/p>\n Follow Artie\u2019s Law [6]<\/a> that says: Avoid bad advice but certainly don\u2019t follow \u2018Mission Impossible\u2019 advice.<\/p>\n Also, don\u2019t forget Lasagna\u2019s Law [7]<\/a> which states that the \u201cincidence of patient availability sharply decreases when a study begins and returns to its original level as soon as a study is completed\u201c.<\/p>\n And then there is also Muench\u2019s Third law \u2026<\/p>\n References:<\/strong><\/p>\n [1]<\/a> Gupta\u00a0 CID 53: 60, 2011 In this day and age, few truly broad spectrum antibiotics are in development, although this does not hold true for narrow-spectrums.\u00a0 Just think of all the MRSA drugs (quinolones, FabI inhibitors), the pseudomonas drugs (NCEs and monoclonals) or some narrow spectrum drugs that will need to be tested in MDR Continue reading Artie\u2019s Law: Avoid Bad Advice and Don\u2019t Follow \u2018Mission Impossible\u2019 Advice<\/span>
\nA new drug with specific activity against P. aeruginosa is much needed, hence the attractiveness of LpxC inhibitors and POL7080.\u00a0 But how to prove efficacy when therapy for P. aeruginosa is typically initiated as a combination regimen?\u00a0 Admittedly, the benefit of combination over monotherapy has never been proven beyond doubt but it is established clinical practice and supported by practice guidelines.<\/span><\/p>\n
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\n[2]<\/a> Temkin\u00a0 Ann N Y Acad Sci. 2014; 1323: 22
\n[3]<\/a> http:\/\/www.ukmi.nhs.uk\/applications\/ndo\/record_view_open.asp?newDrugID=4445
\n[4]<\/a> http:\/\/www.fiercebiotech.com\/story\/cash-shortage-puts-advanced-life-sciences-ice\/2011-05-06
\n[5]<\/a> https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01970371?term=Achaogen&rank=1
\n[6]<\/a> Don\u2019t look it up, I made it up
\n[7]<\/a> http:\/\/www.appliedclinicaltrialsonline.com\/improving-clinical-trial-enrollment-forecasts-using-sorm<\/p>\n","protected":false},"excerpt":{"rendered":"