ATTAINing Europe

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Europe comes through again!  EMA and CHMP have recommended approval of Theravance-Astellas’ telavancin for use in nosocomial pneumonia based on the same data package rejected by the FDA.  This should be encouraging to all who are developing new antibiotics and for patients and physicians who so desperately need them.  Of course, I’m not so sure that telavancin will answer these needs, but its approval by Europe is nevertheless a very positive sign. This situation is similar to that for doripenem by J&J where it was rejected for the same indication by FDA but accepted by Europe.  These FDA rejections are based on the new draft guidance for clinical trial design promulgated by FDA whereby the infeasible and insensitive endpoint of all cause mortality at 28 days in the microbiologically documented population in the absence of any prior antibiotics and with a non-inferiority margin of between 5.6 and 10% is required.  Europe has clearly (1) stuck with their policy of having their scientific advice be binding such that once trials are completed, if the agreed-upon endpoints are achieved, the product will be approved and (2) rejected the FDA’s guidance on nosocomial pneumonia at least so far.

The ATTAIN data have been published and presented.  I reviewed their data in a previous blog.  The trials showed that telavancin was non-inferior to vancomycin for the endpoint of cure in the all-treated population where cure rates were 58.9 and 59.5% for telavancin and its comparator, vancomycin, respectively.  Of the 1503 such patients across the two trials, 480 were microbiologically evaluable (had only Gram positive pathogens isolated at baseline).  (Parenthetically, if you add those who had gram negatives – this total becomes 629 or 42% having had a pathogen of any sort at baseline). Telavancin remained non-inferior overall in the microbiologically evaluable population. More than half the patients had received an antibiotic prior to enrollment and all were considered to have been failures at the time of enrollment. 

It is of great interest that Europe would find that the potential benefits of a new therapy for these severe infections would outweigh the risks of telavancin.  Telavancin is associated with nephrotoxicity at a higher rate than vancomycin and there is a fetal risk.  In addition, recent data from the Zephyr trials indicate that linezolid, for similar endpoints, might be superior to vancomycin in nosocomial pneumonia.  Therefore, one could question the comparator choice for the ATTAIN trials (even given that the trial was designed long before Zephyr data became available). I conclude from these ruminations that Europe, unlike the US, apparently believes that having alternatives can only be good for patients.  Europe also will now leave specific marketing negotiations to member countries who will take all of these factors into consideration when thinking about price and conditions for reimbursement for telavancin. This seems to be another difference between Europe and the US. Europe sees the regulatory approval as one thing and national marketing and reimbursement decisions as something else entirely.

Even though one might be critical of the ATTAIN trial data, there can be no doubt that the data showed that telavancin is non-inferior to vancomycin at the pre-chosen per protocol primary endpoint.  They also showed some toxicity risk of telavancin compared to vancomycin, but in this very sick population, it seems wise to leave a borderline risk-benefit decision to the clinicians and their patients who can decide on a case-by-case basis. In my view, Europe made the right decision.  The marketplace, national authorities, clinicians and their patients, will now sort things out as to whether telavancin is a useful addition to the antibiotic armamentarium for nosocomial pneumonia or not. In this regard, the FDA, in my view, and once again, made the wrong decision.

Related articles

• Astellas Receives Positive Opinion From CHMP For European Approval Of VIBATIV™ For Nosocomial Pneumonia Caused By MRSA (medicalnewstoday.com)

Antibiotic Trial Design and FDA - a Discussion

The current predicament of antibiotics within FDA can be traced back to the scandal around Ketek.  See my earlier blog on this. The FDA has been backpedaling on antibiotics ever since. Clearly the FDA is caught between congressional critics out for votes and the infectious disease community clamoring for new antibiotics to treat resistant infections.  Most of FDA’s recent guidances for carrying out trials for antibiotics have required infeasible trial designs – catering to congressional pressure demanding a more strict approach to the non-inferiority trials we must use for antibiotics. Of course the fact that requiring infeasible designs leads to an empty antibiotic pipeline is apparently not considered by congress or the FDA. The one exception among recent guidances has been for skin infections where the required design is feasible. 

Starting last week and going through the weekend, I was privileged to be able to participate in a stimulating and reasoned email discussion on the FDA and antibiotic development.  Participants will remain anonymous, but included captains of industry; participants in the Foundation for the National Institutes of Health discussions on trial design issues with the FDA, the Infectious Diseases Society of America (IDSA) and industry; active members of IDSA; academics including experts in PK/PD and pharmacometrics; and finally, most humbly and not anonymously, myself. Keeping the discussants anonymous allows me to summarize the discussion in my own way without having to have the drafts reviewed by multiple people who don’t always agree with each other or with me.  I thought that could be a never-ending process.

The discussion was initiated by several emails noting recently presented results of phase II trials where the FDA’s new early endpoints of halting lesion progression for acute bacterial skin and skin structure infections (ABSSSI) were being compared with more traditional late endpoints of clinical cure. It is clear that there is not always a one-to-one correlation between success at the early endpoint and clinical cure – no surprise to anyone. The participants launched into a discussion on whether the early endpoints were or were not clinically relevant and whether they would predict the more traditional and clearly relevant endpoint of clinical cure in a reliable enough way.  Of course, this discussion could also be relevant to the early endpoints now being demanded for pneumonia trials as well – hence the importance of the exchange.  We then began to try to look into the future . . .

The FDA has opted for these early endpoints because they tie back to measurements made during the pre-antibiotic era when sulfonamides were being compared to placebo or placebo-like treatments (UV light being an example of the latter for skin infections). In these 80-year-old studies, the treatment difference between sulfonamides and UV light in skin infections was greatest early in the course of therapy.  Therefore, the FDA has a way of tying modern therapy back to a treatment effect demonstrated 80 years ago.  Critics of this approach note that the patients are not the same, the pathogens are not the same, the disease is not the same and the treatments are not the same anymore – so why should we tie ourselves to an 80-year-old trial design that was not really placebo controlled anyway?

Critics also charge that the early endpoint is clinically irrelevant. The only relevant endpoint is cure of the infection that is measured at 7-14 days when the patient should have returned to his/her baseline status.  Pragmatics are so relieved that they have a trial design from the FDA that is actually feasible, that they are happy to carry out trials and obtain approvals based on the early endpoints while making clinical cure a secondary endpoint.  Of course, most clinicians would agree that this approach is bass-ackwards. The early response is secondary while cure is primary.  It is clear that the early response is already included in the consideration of cure anyway since a patient not responding to treatment in the first few days of therapy will be considered a therapeutic failure anyway and the astute clinician will start looking for the cause of failure. But the converse – early success – may not always predict cure. Time to response is valuable to the clinician, but not pivotal information.

One way around the entire disagreement is to use more modern approaches such as pharmacometrics to define effect size both early and late.  In this way, one could use the treatment effect size to justify a non-inferiority margin for an endpoint at time of cure.  One could also justify a composite endpoint combining early and late response or one could even define margins for two endpoints, early and late (although that would take some non-traditional statistical approach I expect).  Unfortunately, at least so far, the FDA has been deaf to such arguments.

These arguments are equally applicable to trials for community-acquired bacterial pneumonia where, in the current guidance, the analysis population must be the bacteriologically documented one, the endpoints are again early resolution or improvement in signs and symptoms (but not cure), no prior antibiotics are allowed, and the margins are 15% for parenteral therapy and 10% for oral therapy.  This means that an oral only drug will never be developed for pneumonia since that trial requires 5000 patients and is simply infeasible. Even a parenteral drug will require a diagnosis rate of at least 50% which would be a world record and nothing short of miraculous for a modern trial in order for that trial to be within the realm of possibility.  But, as soon as we start talking about using pharmacometrics to define a treatment effect for cure, we can at least get to a relevant endpoint with a reasonable non-inferiority margin.  Again – the FDA is hard of hearing.

Beyond defining a treatment effect for cure in modern times, we need to look at modern statistical approaches to trial design – more later.

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. 

Avibactam at ECCMID

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I hope all of you are wondering what on earth avibactam is.  It is the generic name for Novexel’s (was Sanofi-Aventis’, now Astra-Zeneca and Forest’s) non-beta-lactam broad spectrum beta-lactamase inhibitor previously designated NXL-104.  At the ongoing ECCMID meetings in Milan, Astra-Zenca presented two abstracts describing the results of two phase II trials with ceftazidime combined in a 4:1 ratio with avibactam.  Avibactam is a potent inhibitor of both class A and C beta-lactamases including ESBLs.  Of great interest, it works well against the class A carbapenemase, KPC as well.

Once again, I get a chance to brag about compounds that I consider at least partly mine.  I spent the years from 2006-2009 working hard for Novexel and NXL-104 (among other compounds) while consulting for them and serving on their Board.  I always thought, and stated from my initial evaluation of their portfolio, that NXL-104 was their star.  The data from phase II is consistent with this belief.  Once again I get to say how proud I am of everyone who worked at Novexel and their relentless and aggressive pursuit of developing NXL-104 and in their early identification of partners (first Forest and later Astra Zeneca) for this novel and promising compound.

Poster 1532 by Lucasti et. al.,  presented the data on a prospective randomized double blind trial of ceftazidime-avibactam plus metronidazole vs. imipenem for the treatment of complicated intra-abdominal infections (cIAI).  Of the 101 and 102 patients randomized to the two groups resp., 68 and 76 were microbiologically evaluable. The mean APACHE II score was <10.  E.coli was by far the most common pathogen occurring with 52 and 53 isolates in the ceftaz-avi and imipenem groups.  In the ceftaz-avi group, of 26 infections involving ceftaz resistant (MIC 8 mg/L or more) but ceftaz-avi susceptible Gram negatives, 25 were cured.  Almost half of the Gram negative enterics isolated in this study appear to have been resistant to ceftazidime.  To me this is an astounding figure. Given the global nature of the study, a breakdown of resistant isolates geographically would be more than interesting. Overall, 91 of patents treated with cetaz-avi and 93% of those treated with imipenem were cured at test of cure.  There were no outstanding safety issues for either treatment arm.

Poster 1533 by Vazquez et. al., presented data on a randomized, investigator-blinded trial of ceftaz-avi in a 4:1 ratio compared to imipenem in the treatment of complicated urinary tract infections (cUTI).  In this case, the “urinary” dose of ceftazidime had to be used – 500 mg q 8 hours.  Therefore, the dose of cetaz-avi was 500/125 mg q 8 hours.   It was striking to me that the numbers enrolled in this trial were smaller and that the number of microbiologically evaluable patients were quite small – 27/49 and 35/54 patients completing therapy respectively.  One can only imagine how difficult it must have been to complete such a trial with drugs that could only be administered intravenously.  The microbiological response rates were 70.4 and 71.4% in both groups.  The microbiological response of patients with ceftaz resistant Gram negatives treated with ceftaz-avi was >80% - no different than imipenem therapy in this trial.  Again – no particular safety issues were identified.

These data suggest that ceftazidime-avibactam should be pursued further in pivotal phase III trials.  Avibactam is being developed by Forest in combination with ceftaroline as well.  These Phase II data should provide them with a very positive signal as well.


There is so much potential for this compound and for others like it to address the Gram negative bacterial resistance problems that challenge us today and will do so for years to come. It just seems like forever to me for us to get this drug through trials and to the patients that need it.  I am getting impatient!  One can only hope that a feasible way forward for phase III will be forthcoming both in the US and in Europe.  

Antibiotics at FDA vs. EU - Compare and Contrast

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I just ran across something so striking, I had to share it with you.  The European Medicines Agency (EMA) just released a report on their Workshop on Antibacterials held in February. Clearly, the EMA is considering issuing guidances specific to anti-infective indications similar to the way FDA has issued such specific guidances.  Hopefully, that is where the similarity with FDA will end.  The agenda for the workshop covered non-inferiority trial designs for skin and skin structure infections and hospital acquired pneumonia.  They also discussed the issue of placebo-controlled vs. active comparator controlled non-inferiority trials for mild infections including acute otitis media in light of recent data.  Superiority trials for agents active against resistant pathogens were discussed.

For hospital-acquired pneumonia, Pr. Chastre essentially made the case for the FDA approach using all cause 28-day mortality as the appropriate endpoint for these trials. But a very reasoned discussion by Dr. Fromtling responded by noting that all cause mortality was not relevant to clinical practice nor is it a sensitive endpoint.  He also notes that the 10% NI margin applied to the microbiologically documented population makes such trials essentially infeasible.  He takes issue with the FDA proscription against any prior antibiotics that would make the study population irrelevant to clinical practice and is an infeasible design criterion in any case.  He makes a number of positive suggestions as to trial designs that would be both relevant and feasible.

Paul Ambrose presented an approach to justifying NI margins using PK/PD data and a Bayesian based pharmacometric method. He presented the application of such data to the tigecycline trial where M1 could be determined with great precision in a modern setting.  Clearly, there are important implications of the use of these methods for modern trial data analysis as well as the statistical design of such trials.  The opportunity for reducing patient numbers could be an attractive feature of such an approach.

John Rex made the case that for skin infections, the analysis at test of cure already takes into account any response or lack thereof at early time points.  Dr. Brad Spellberg has previously noted the clinical irrelevance of the proposed FDA early endpoints.  Dr. Rex also notes that a large treatment effect easily justifies margins of 15% or greater rather than the 10% suggested by FDA.

On the topic of superiority vs. NI studies of otitis, the discussion centered on data recently published on well-designed placebo controlled trials in the US and EU.  It is clear that otitis is an important entry indication into pediatric therapy.  But since the proscription against non-inferiority trials, industry has not studied this indication at all.  Further, the recent trials showing a clear advantage of therapy over placebo in young children with well-documented acute otitis media remove equipoise from consideration for this population.  It is no longer ethical to carry out such trials.  So, either we will develop new antibiotics for this indication in pediatrics or we will not – but a justification for NI trials now exists and one for placebo-controlled trials does not.

 There was a very well considered discussion of superiority trials for agents active against resistant pathogens.  It seemed clear that some way of bridging across multiple indications (where PK is at least somewhat similar) would be required to make such an approach viable.  Mark Goldberger noted that some clinical data combined with strong clinical and pre-clinical PK/PD and microbiological data could be used to support at least a conditional approval. This would depend on having approval for at least one standard anti-infective indication in a serious infection. It is likely that such approaches to new therapies for MDR pathogens will have to be evaluated on a case-by-case basis.

Overall, the tone and tenor of the discussion as portrayed in the report was considered and rational.  No one seemed to be screaming that clinical signs are biomarkers and therefore invalid as parts of endpoints in clinical trials. The EMA seems to appreciate antibiotics and they take seriously their responsibility to make sure that we have a pipeline of these valuable therapeutic agents – especially during a time when new resistance mechanisms or old mechanisms in new virulent strains seem to be popping up at every turn. The EU understands the importance of feasible trial designs in maintaining such a pipeline. This report stands in stark contrast to the Anti-infectives Drug Advisory Committee meetings of the FDA. I leave it to you to compare and contrast.