Tuesday, May 10, 2011

Antibiotics - Yet Another FDA Victim Bites the Dust

The end of Advanced Life Sciences has arrived.  Advanced Life Sciences was formed in 1999.  In 2005, they acquired cethromycin, a ketolide antibiotic, from Abbot Labs that had already undergone extensive Phase II testing.   Ketolides are antibiotics with a structure like the infamous Ketek – the GREAT SCANDAL of FDA’s approach to antibiotics and the most proximate cause of all our current problems at FDA. Ketolides are also active against many antibiotic-resistant pathogens that cause pneumonia. Advanced Life Sciences rapidly submitted a phase III plan to the FDA and began their pivotal trials.  In 2008, they submitted their NDA, which was accepted by the FDA later that same year. An advisory committee meeting was held in 2009.  In the meantime, the FDA held a workshop on clinical trial design in community acquired pneumonia in 2008 and released new guidance for this indication in early 2009 – all between the time Advanced Life Sciences negotiated their trial design protocol with FDA and even after they had submitted their NDA.  This did not stop the FDA from reanalyzing Advanced Life Science’s data based on the new guidelines.

Lets just talk about these new guidelines for a minute.  The guidelines preclude the development of an oral drug for pneumonia.  First, they require that PORT II-III patients be studied – where most PORT III patients will be admitted to hospital and, in many countries, will require intravenous therapy. Second, they do not allow the use of prior antibiotics – certainly an impossible situation for US patient enrollment.  Third, the analysis population is the microbiologically documented population and the non-inferiority margin is 10%.  A quick calculation shows that two such trials would require about 5000 patients – five times the number that Advanced Life Sciences enrolled. 

Only a great deal of good luck could have allowed them to achieve such a margin with that number of patients.  Nevertheless, in the FDA’s analysis, they certainly came close.  But at the advisory committee meeting – it was no cigar.  The FDA excluded all patients who had received prior antibiotics, all those with atypical pathogens (oh yes, the new guidance does not allow you to include these patients either), and all those with PORT scores of I (almost half the patients). Even though, under these terrible circumstances, one trial actually achieved the 10% margin, the other did not.  This was an approach even more draconian than the one that Cerexa/Forest recently survived – but they had an intravenous drug and studied more severely ill patients. The committee voted 11 to 3 that Advanced Life Sciences had not demonstrated efficacy for cethromycin. 

The company went on to acquire grant funding to study cethromycin in various biothreat indications.  They also negotiated what I thought was a very risky and possibly infeasible superiority trial to study cethromycin in pneumonia caused by macrolide-resistant, cethromycin susceptible pathogens. Apparently, many funding sources agreed with me since the company was not able to raise money to fund the additional trials they had agreed with FDA nor to keep the lights on.

This is the tragic story of antibiotics and the FDA today. The door is closed to antibiotics that can only be given orally for the treatment of pneumonia.  And because the agency can change its mind even after previously agreed upon trials are successfully completed and filed, all companies face the risk that they will end up like Advanced Life Sciences unless they have a back-up plan for the FDA.  Here is mine.  Europe.  Forget the FDA.  If you are a small company and you plan to market your product alone – or better -with a small company partner – go to Europe. No one is home here in the US. 

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