Europe?

Its been two years since the FDA has been struggling to provide guidance for sponsors trying to study pneumonia and skin and soft tissue infections.  In the meantime, the antibiotic approval drought at the FDA continues unabated as resistance fails to take a vacation.  So what’s going on in Europe?  Good question. 

The European regulatory authority, the EMEA, has stated categorically that the development of new antibiotics is its highest priority. This stands in stark contrast to the attitude at the FDA where standards based on 80 year old placebo controlled trials seem much more important than developing new antibiotics. I recently learned that the EMEA has not been following events at the FDA too carefully.  They are comfortable with their current position on pneumonia and skin infections as far as I can tell. As it stands now, Europe has no plans to provide guidance to sponsors on specific infections – they never have.  Europe has always been more flexible than the FDA but at the same time, less predictable and more variable in terms of both regulatory requirements for approval and ultimately for pricing within the individual markets of Europe. They have also been more difficult to deal with in that to discuss a topic with Europe, you must request Scientific Advice.  This meeting requires a set of advisors and takes several months to organize.  It has been much easier and more straightforward to communicate with the FDA.  Europe, on the other hand, has traditionally kept its word once advice is given whereas the FDA has been unabashed about changing its mind in the midst or even at the end of expensive Ph. III trials.

I have encouraged clients to approach individual European country agencies (e.g. MHRA in the UK or AFFSAPS in France) rather than Europe (EMEA).   Meetings are easier to arrange – but of course, the advice you receive may be different than what one might hear from the EMEA representing Europe.

Another problem in Europe is that even if you succeed in obtaining regulatory approval for your drug, you still have to negotiate the conditions of marketing and pricing with individual countries.  This adds to the delay in marketing in Europe and increases the uncertainty for companies.

So, with this in mind, how will Europe (EMEA/CHMP) deal with the recent FDA stance (or lack thereof) on pivotal trials in antibiotics?  Judging by past behavior, Europe will stick to its plan of not providing specific guidance for specific indications, but will be open to trials where the endpoints are as the FDA has specified.  Since, in the case of SSSI, there is a clear correlation between success at the early timepoint and success at the customary later timepoint, The EMEA will probably be happy with either.  The EMEA also understands that there are limits to what sponsors can do to run pivotal trials on a global scale – so they are unlikely to make sponsors use an endpoint in Europe that markedly differs from that required in the US. 

I would guess that the same arguments would hold when the FDA finally issues guidance on CABP.  The major issue there will be around trial feasibility.  In the case of CABP, my guess is that the EMEA remains happy with the old endpoints and that if the trials required by the FDA are infeasible, the EMEA will stick with its current approach.  This would theoretically allow registration of antibiotics for treatment of pneumonia in Europe that would not be acceptable to the FDA. 

Apparently, the CHMP will address at least some of this in a meeting this Fall.  Maybe, by then, we will have some idea of where the FDA will be going for trials in pneumonia.

Skin No. 4 - The World Turns

Sometime in early March, the FDA let it be known through the Infectious Diseases Society and others that they no longer knew how to set a non-inferiority margin for designing trials in serious infections of skin and skin structures (ABSSSI).  Since then, there have been a number of conversations with the agency including my own that I described in a previous blog (http://antibiotics-theperfectstorm.blogspot.com/2010/04/skin-infections-follow-up.html).  The last chapter involved a gathering on May 5 to explore whether there was a need for the NIH to carry out actual developmental work (clinical trials) to help establish the validity of endpoints in the study of complicated skin infections as described in the blog for May 23 (http://antibiotics-theperfectstorm.blogspot.com/2010/05/skin-no-3-fnih.html). 

Yesterday, Trius announced that they had come to an agreement with the FDA on endpoints for their proposed Ph. III trial in skin infections (http://www.triusrx.com/trius-therapeutics-news-100616.php).  They said, “The double-blind pivotal study will compare the efficacy and safety of once-daily oral administration of 200 milligrams of torezolid phosphate over six days of treatment to twice-daily oral administration of 600 milligrams of linezolid (Zyvox) for 10 days of treatment. The primary efficacy endpoint will be the cessation of spread of infected lesions and absence of fever at 48 to 72 hours following initiation of treatment. Secondary endpoints will include, among other things, sustained clinical response at the end of therapy visit, and the investigator’s assessment of clinical response at all visits and clinical success at the post treatment evaluation visit. Provided non-inferiority is met, an assessment of superiority of torezolid phosphate to linezolid with respect to the primary efficacy endpoint will also be made.”  I clarified that the NI margin will not apply to fever, but that patients will have to be afebrile at the 48-72 hour timepoint for the treatment to be considered a success.  Trius and the FDA agreed to a 10% NI margin. Lots of other questions remain regarding the proposed Trius trials such as how the trials will be blinded for example.  Nevertheless,  this is the first indication that the FDA has indeed applied what I believe will be the criteria for their new guidelines for the study of skin infections. 

The NI margin of 10% seems strict given the large treatment effect seen at the 48-72 hour end point. Even with some discounting - this seems excessive for the treatment effect of at least 20-40% compared to not placebo but to UV light which itself is efficacious. 

 This does not clarify what will happen to Paratek who were in the midst of their trials for PTK-0796 or to Forest who have completed their Phase III trials for ceftaroline under the old guidelines for skin infections.  Paratek apparently halted enrollment (see http://www.clintrials.gov) while awaiting new guidance from the agency. 

For companies embarking on programs in skin infections, there seems to be a feasible path forward.  This is nothing but good news for everyone involved in the discovery and development of new antibiotics. Formal guidelines from the FDA are expected sometime this summer. 

The Move from University to Industry was Murder!

When I left Case Western Reserve University to assume a position at Wyeth, it was two years after the Wyeth take-over of American Cyanamid (Lederle).  The anti-infectives group consisted of both an anti-bacterial and an anti-viral effort.  The group of about 35 people, which I was to direct, had still not really been assimilated into Wyeth.  Two weeks before I was due to start my new job, on a Sunday evening, I received a telephone call from the Associate Director for Viral Research, Dr. B.  I had not met him during my visit just a few days earlier when I was introduced to a number of the people who would be working for me.  Dr. B was clearly in a panic and was talking so fast (with an Irish accent), that I could barely understand him. I was told during my interview process that Wyeth management was considering jettisoning the entire anti-viral effort in order to focus on their anti-bacterial effort.  I had explained that if they were going to take that step, they would have to do so before my arrival.  The other choice for them was to await my arrival, let me review the program myself and make a decision on whether to continue the anti-viral effort or not.  All the employees were aware of the ax hanging over them.

Dr. B said something about murder – which got my full attention. 

“Say that again.”

“My boss, the Director of Antiviral Research, was murdered last night.  His wife and a cousin were discovered trying to ditch body parts in the Passaic River in the middle of the night.”

Of course, what I didn’t know was that the Director was like a father figure to his employees – they worshipped him.  I met the Director just a few days prior when I was at Wyeth for my pre-employment physical exam.  Dr. B was distraught to say the least.  Behind his immediate loss of a well-loved supervisor was his worry, and that of everyone else, about the potential loss of jobs and a way of life at Wyeth (American-Cyanamid (Lederle).  What could I do, anyway?  I was 600 miles away in Cleveland getting ready to move. I didn’t really know any of the employees nor did I know anything about their programs (at least in any detail).  (I leave you to reflect on this method of recruitment). 

“Please give everyone my sincere condolences.  Tell them not to worry about their job situation.  Nothing is going to change for now.  Everyone should spend some time dealing with his or her loss.  We’ll get to the programs after that.  Will you be able to take over leadership of the group at least until I get there?”  All this said before I had formally started working.

I called my soon to be new boss – Dr. J – and explained the situation that was brewing.  He had already been informed of the murder. He offered to get involved personally, but since the employees identified him with the threat of the ax, I counseled that he let me deal with the situation from Cleveland for the next couple of weeks.  He could always intervene if needed.  Dr. J agreed.  Dr. B and I had daily telephone conversations for the two weeks until my arrival in Pearl River, New York.

As it turned out, I thought that two of the programs in anti-virals were promising – one on CMV where the compounds turned out to be unstable and toxic, and the other for RSV where we made it all the way to Phase II before we discovered that the lead compound caused birth defects in animals and that program was terminated.  The anti-viral group survived and almost doubled in size during my tenure at Wyeth.  We even established an active collaboration with ViroPharma for the discovery and development of drugs targeting Hepatitis C virus.  After my departure, the entire anti-infectives group was laid off when Wyeth abandoned this field of research altogether.

I will never forget my experience of those first few weeks and months transitioning to industry from academia with the cloud of a brutal murder and the threat of mass firings hanging over both my new employees and me.  I’m sure they will never forget it either.