FDA HAP/VAP Discussion March 30

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As I noted in my last blog, I did have a conversation with the FDA on March 30 regarding their draft guidance on trial design in HAP/VAP.  For my meeting, I constructed a series of talking points.  The FDA team asked me to submit the document to the docket which I did.  Because the submission has not yet appeared on regulations.gov, I reproduce it below. I tried to summarize key issues identified almost uniformly in the docket submissions and to provide solutions going forward.

•  NI Margin – as this becomes more relaxed – lots of good reasons to do this – everything else gets easier.
• Please provide numbers required for studies where mortality is lower than 20%.  (they provided an estimate which was, as expcted, staggering).
• APACHEII now underestimates mortality and scores higher than 15 will be required to assure mortality greater than 20%.
• Proscription against antibiotics – most commonly cited problem for infeasibility and probably unnecessary.  Also will exclude those patients you most want to include.
•  Mortality as an endpoint is insensitive and irrelevant to clinicians treating the disease.
• VAP is a disappearing disease – probably related to better care plus significant recent underreporting in the US under pressure from CMMS reimbursement guidelines.  Therefore, special consideration should be given to the fact that there is a small and shrinking population available for study even though the medical need in this population is greatest.  SEE J&J DOCKET SUBMISSION.
•   Inclusion of HCAP per Cubist?

SOLUTIONS

• 1.     Admit that diagnosis is difficult and a perfect rationale for the NI margin in this disease does not exist nor does a perfect AND feasible trial design and go on from there. Allow the use of endpoints - mortality, OR clinical outcome OR clinical outcome plus survival at 28 days as a composite.
• 2.     Allow the use of PK/PD measures to justify a margin for clinical benefit as determined by extrapolations to no therapy and/or comparing inappropriate to appropriate therapy.
• 3.     Increase the margins to something more reasonable – 15%.  Forget the odds ratio method constraint.
• 4.     Allow the use of up to 24 hours of an antibiotic at the time of enrollment.
• 5.      Discard the proscription against any antibiotic within the previous month.
• 6.     Consider the inclusion of HCAP patients where HAP/VAP pathogen is documented.

The FDA seemed receptive.  I think they were a little surprised by the extent of the response.  They wondered why the issue of feasibility was not discussed at the advisory committee almost two years ago.  I reminded them that it was, by Steve Barriere.  It is clear that on the one hand, they are driven to provide guidance by the IDSA, by industry and by congressional mandate.  But it is also clear that they are so removed from the industry they regulate and from medical practice that they do not understand what is feasible and what is not in today’s world of medicine and clinical trials. I would add that they seem to understand that not developing new antibiotics for Americans is a bad thing.  When I told them that for HAP/VAP I was advising my clients to go to Europe first, they cringed.  They said, tell them to talk to us.  We’re much more flexible in person than we are in our guidance – or words to that effect. In checking with friends involved in such discussions, it seems clear that this is not the case.  I think maybe the top management believes this is true, but on the ground at the team level, the guidance is the guidance.  That has always been my experience in any case.

On the one hand, I believe that the FDA agrees that issuing guidance with infeasible trial design requirements is at best counterproductive.  I think they feel like they made a mistake at least with HAP/VAP if not also with CABP.  Even though our discussion did not touch on the origins of their motivation for proposing specific design considerations, I think that the FDA may feel trapped between industry, IDSA and others on one side, and groups like Public Citizen and Tom Fleming along with the Grassley – Markey crowd on the other.

I fault industry for not being clear and vocal enough during numerous workshops and AIDAC meetings to make clear to the FDA what would and would not be feasible.  Industry has been too timid in their approach to the FDA in this regard. This is especially true when you consider the agency’s naïveté around considerations of feasibility.

Finally, I think it is time for industry to start to provide a new approach to trial design for consideration by the FDA. More on this in the future. 

Pfizer Update etc.

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OK.  I’m back and swamped.  But during my absence, several pieces of information have filtered in regarding Pfizer.  First, Bernstein Research reported that Pfizer was planning to reduce its overall revenue base from $67B to $35-40B by spinning off or selling much of its non-pharmaceutical portfolio including its animal health business.  The strategy seems to be a logical one to increase growth as a percentage of revenues.  The idea is that the pharmaceutical business core of Pfizer is the one that brings in most of its revenues.  Therefore, from a lower base of $35-40B, it is theoretically more likely that they would be able to grow the business by 5-10% annually. Of course, this still will require existing product sales to grow enormously plus the introduction of new blockbuster products to offset the loss of Lipitor. But at least the hurdle will be less daunting.

In terms of antibiotics, it seems that Pfizer wants to milk its cash cow franchise of piperacillin-tazobactam (Zosyn), linezolid (Zyvox), and tigecycline (Tygacil) as long as possible.  But the Zosyn patent has run out and generics are already creeping into the marketplace around the world.  Zyvox becomes generic in 2015 and it looks like Tygacil will start to go around 2015-2016.  Pfizer is probably currently spending something like 25% of product revenues to sell these antibiotics including the cost of the sales force and other marketing outlays.  According to the latest numbers from Pfizer, the 2010 sales from these three products totaled about $2.5B (4% of revenues) and falling. By the time Pfizer completes its spinoff/sale of non-pharma units, these revenues will have fallen further to say $2B.  This will represent just 5% of their projected total revenues at the point in time where they have completed their spinoff process.  This point in time will probably occur just when both Zyvox and Tygacil are getting ready to jump over the cliff.

Pfizer says that they are moving their antibiotic discovery to China.  I have finally been able to confirm that they do actually have an address in Shanghai and that they are hiring scientists.  But what does this mean exactly?  China does not have a tradition of antibiotic discovery.  They do not have the same sophistication of approach.  This new unit will require years to establish themselves.  They will require sophisticated and careful supervision in order to actually accomplish anything.  Is Pfizer planning to provide for this?  I see no evidence of that.  I can only suspect that this is more about getting a tax break in China or some other business oriented edge in Asia than about actually discovering and marketing new antibiotics.  To me, this move is essentially an abandonment of antibiotic discovery and development. 

Since Pfizer has essentially decided to get out of the antibiotic discovery business, they will rapidly lose their internal expertise to evaluate external products.  Therefore they will not be able to bring in products from outside the company or they will exercise poor judgment in their choices. Therefore, I suggest, plead, beg them to be smart and include their antibiotics franchise or even a portion of the franchise in their spinoff plans.  I would love to help make this happen.  I am sure that appropriate investors could be identified and that an acceptable royalty plan could be negotiated.

Two other quick updates –

I will be speaking to the FDA on the 30^th regarding their HAP/VAP Draft guideline.  For those of you who have sent me comments already – many thanks.  If anyone does want to send me additional comments that I can use to help the FDA improve their guideline, please send them on.

Along with my co-author, Matt Cooper, I will have a perspective appear in Nature in April – more later.

Related articles

• UPDATE 1-Pfizer reviewing possible divestitures, exec says (reuters.com)
• Pfizer antibacterial research moving to China (fiercebiotech.com)

Absence

I'm sorry to disappoint all of you out in antibiotic land - but I'll be on vacation (the "V" word as Bob Levy used to say at Wyeth) for about a week.  The next post will be towards March 25.

Have a great week.  I'll be thinking of you . ..

When it comes to antibiotics, the Pharmaceutical Industry is a wimp!

I guess it will not surprise anyone to hear that, when it comes to directly challenging the FDA, pharmaceutical companies, large and small, are wimps.  I have spoken to a number of companies over the last two weeks and no one is willing to be clear and honest with the agency.  They will tell me that the trials called for in recent FDA guidance are infeasible or at best on the edge.  But they will not be clear with the agency.  You can find all the submissions to the docket at regulations.gov.  

Astra-Zeneca states “trials of this size may not be feasible in a reasonable time frame.”  They further suggest that the trials required by the guidance (in this case in VABP) “could hinder the pursuit of further research in this area of high medical need.” 

The Pfizer submission, from a company that just abandoned the entire area of antibiotics, is a complete wimp-out.  GSK talks about how the design is challenging and risky.

PhRMA was more open in their response to the FDA.

  

PhRMA goes on further to note that the FDA’s double discounting of the treatment effect to establish the NI margin is overly conservative and not scientifically based.  But instead of simply saying that the approach is not acceptable, they ask the agency to clarify its rationale for the discounting.  Is this diplomacy or what exactly?

Perhaps the best and most compelling submission comes from Johnson & Johnson. J&J has also essentially abandoned antibiotic discovery research but they continue to try and develop and market doripenem.  They describe their ongoing attempt to carry out a study for doripenem.

Our concerns regarding the feasibility of conducting studies that adhere to the recommendations in this guidance are based on our recent experience conducting several studies in HABP/VABP patients and more specifically the challenges we are encountering with recruitment into an ongoing Phase 3 study in patients with VABP (DORI-NOS-3008). Study DORI-NOS-3008 is a double blind, randomized, multi-center comparator controlled Phase 3 safety and efficacy study that implements many of the principles proposed in this draft guidance document. Eligible patients must be hospitalized for at least 5 days, on mechanical ventilation for ≥48 hours, have a chest radiograph consistent with pneumonia, have a fever/hypothermia or WBC count indicative of systemic infection, have a CPIS ≥6, an APACHE II Score >8 and <35, and a bronchoalveolar lavage (BAL) or mini-BAL performed at baseline from which at least one bacterial pathogen must be isolated from culture at ≥104 CFU/mL. Patients are excluded if they receive >24 hours of prior antibiotic therapy (before the first dose of study drug) for the current episode of VAP. The use of adjunctive aminoglycoside therapy is only permitted at initiation of study drug therapy as empiric adjunctive therapy for infections suspected to be caused by a carbapenem-resistant gram-negative pathogen. The adjunctive aminoglycoside must be discontinued by 72 hours unless a pathogen is isolated from the baseline lower respiratory tract (LRT) specimen that is resistant to the comparator, and presumably the investigational agent also. The first patient was enrolled into this study April 1, 2008 and as of February 15, 2011 only 272 patients have been enrolled (approximately 100 pts/year). A total of 128 sites have been initiated and had study drug shipped. However 89 sites have been closed due to lack of enrollment. Of the 39 sites that remain open, only 22 sites recruited 1 or more subjects in 2010. Given the enrollment challenges, the feasibility of completing this study and providing data in a relevant timeframe is currently under evaluation. In addition, given the very sick and complex patient population, the limited number of patients with VABP, the small numbers of patients enrolled per site, and the complexity of study design, there are very high costs per patient enrolled into these trials (much higher than costs we are aware of in other indications). Therefore, the feasibility of recovering the costs for conducting this and future HABP/VABP studies is low, and potentially warrants re-assessment of the feasibility of initiating development programs for new antibacterial agents.

But lets be clear.  There is NO WAY any of these companies or any other will be able to carry out the trials called for in this guidance.  Why can’t someone from industry say just that?  The agency needs to hear it from someone other than Brad Spellberg and me.

Antibiotics and FDA - Industry must take the lead.

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After my conversation with Brad Spellberg as noted in the previous blog, I have come to the conclusion that the ways forward for dealing with the crisis at FDA are limited.  The guidance documents we are discussing are clearly delineated by Brad in the last blog.

The FDA clearly believes that they are on the right path and that, through the process occurring with the Foundation for NIH Consortium on Biomarkers, they will achieve consensus.  They clearly dismiss my own opinions, and apparently those of several members of the Infectious Diseases Society of America (IDSA) Task Force on Antimicrobial Availability as being misguided or just plain wrong.  This mindset blinds the FDA to the critiques contained in the various industry responses to guidance document dockets.  They seem to believe that the gaps are bridgeable within the context of the released guidance.

One approach for us all is to simply await the results of all the deliberations and hope that we eventually end up with feasible and clinically relevant designs for carrying out pivotal trials of antibiotics.  If such designs are not forthcoming, and if sponsors are either unable to negotiate feasible designs with the FDA or, in a worst scenario, negotiate a design but fail to  to carry out the trial in spite of great expense, where will we be? 

How long is that wait?  Will industry wait?  Will biotech in particular even be able to wait? I think the wait is approximately at least another year – perhaps two or three years.  In that time, I predict that at least one more company currently active in antibiotic R & D will drop out.  I predict that the climate for funding for biotechs and their ability to bring products forward through partnering with larger companies will continue to diminish.

Therefore, the way forward is not to wait.  Industry must be honest and clear with the FDA.  In addition to including in their response to FDA guidance critiques and suggestions on how to change the guidance, they must state that they cannot and will not undertake the trials currently called for in the guidance document in question.  Only this message will draw a clear line in the sand for the agency. 

I understand the reluctance of industry, especially large and mid-sized pharmaceutical companies to take such a stance.  They may be currently trying to negotiate trial designs with the agency either in anti-infectives or in other therapeutic areas and they may be concerned about negative repercussions. Their departments of regulatory affairs are not used to such direct confrontations with the agency (in general).  Nevertheless, for companies still truly committed to the discovery and development of antibiotics, I think that waiting is not an option and that there is little left to lose. 

One way for industry to take this on if they do not feel that they can act individually as a company is to use their trade group, PhRMA to both lobby congress and the administration, and to deal with the FDA. 

So, other than continuing to try and keep this issue up front both for those of you who read this blog and for the world at large, I am running out of things that I myself can do.  I have the impression that IDSA finds itself in a similar position. Industry must help.