Brad Spellberg Speaks. Antibiotics and the FDA - Present and Future

(Brad and I have been corresponding.  He gave me permission to post this email in hopes of engendering a transparent, public discussion of the issues.   Responses can be placed in comments below or you can send me an email and I will post them.) 


Let’s review the guidances available now, shall we?

Otitis, sinusitis, bronchitis all available—none feasible, these pathways are all closed (requiring superiority).
CABP—guidance available now for 2 years, but guidance irrelevant, debate ongoing including extraordinarily irrational thoughts being frequently mentioned…I agree that this pathway is currently non-viable, and I suspect when the next version comes out I will have to pre-medicate before reading it or risk a stroke.  I believe it will be infeasible and clinically irrelevant when it comes out, given the same people mucking with it as with the skin guidance.

HABP/VABP—guidance available, we’ve discussed. I believe mortality is feasible, but no prior antibiotics is not.  Furthermore, even if “feasible”, I doubt any companies will be willing to enroll several thousand patients at $70,000 per patient in a phase III HABP/VABP protocol for a not very big market in return.  I suspect virtually no non-inferiorirty studies of HABP/VABP will ever be done again, until eventually this is revised.

Skin.  What can I say, I’m not convinced this is viable, and if it is viable, it is certainly clinically irrelevant, and I for one will not prescribe an antibiotic that is approved based on this uninterpretable trial design.  Plus, skin represents the disease for which there is the least medical need.  So, ironically, if skin is viable, it will force even more approval into skin, and away from the other areas of much greater need.

For the future, I believe we have a good sense of what cUTI will look like based on the preliminary “guidance” in the appendix of the Non-Inferiority Trial Guidance.  FDA is actively working on cUTI, and indications are that it will likely be similar to what’s in that appendix.  I’m guessing a margin of 7-10% (10% at MOST, quite possibly smaller).  Probably feasible, but much larger studies than before and quite expensive to do.  Furthermore, the real sticking point is not likely to be the margin or endpoint, but rather FDA’s desire to not allow even a single dose of pre-study antibotics.  My clinical trial group at Harbor-UCLA has agreed to operate phase II cUTI studies from a couple of sponsors at our site.  They haven’t started yet but we’ve been prepping.  We have realized that we cannot capture patients in the ER.  BY then, it will be too late.  A substantial proportion of patients with pyelo or obstructive cUTI are given antibiotics in the triage area before they ever get into the ER.  Furthermore, once in the ER, time to antibiotic is very short.  To have any hope of completing informed consent and all pre-study screening procedures, it will not be possible to capture patients after they’ve already arrived in ER.  This places a tremendous premium on extensive man-power to immediately capture patients on arrival at triage.  So, the studies will be expensive.  Furthermore, the studies will likely require a number of testing procedures that are likely to take an hour or more (such as knowing the creatinine before enrollment). It is likely that many such patients will get treated with antibiotics because they will be febrile and sick and ER docs will not want to wait several hours between first notification of study personnel that a potential patient is there and first giving antibiotics.  I anticipate losing at least 80% of eligible patients to this issue.  I don’t know if large scale studies are feasible or not.  No one does because they’ve never been done.

cIAI, no one knows what will happen here because no HESDE has ever been published.  There is 1 study I’m aware of comparing outcomes in modern IAI patients receiving active vs. inactive antibiotic therapy showing a large point estimate of clinical cure difference.  However, before anyone can comment on feasibility here, the first thing that needs to be done is a systematic literature review for more such data.  I suspect very little else will be found.

So, Dave, that’s where I believe we are.  Mostly infeasible, impossible studies, with a sprinkling of possibly feasible and irrelevant studies and feasible but very hard to do and expensive studies.

Oh boy, the future looks…

Antibiotics - FDA 1, Americans 0

I know that you will all be surprised to hear that I have not had a response from Kathleen Sibelius, nor from the FDA for that matter.  I did hear from the FNIH group however.  They were upset that I seemed to dismiss their effort before the results were out in the form of docket submissions.  Although I remain skeptical, I await further developments and I am truly not dismissive of their efforts – just skeptical and more than a little frustrated.  I also recently received a copy of the IDSA submission to the FDA docket on the Draft Guidance on HABP-VABP kindly provided by the IDSA. (The submission does not yet appear on the regulations.gov website so I cannot yet provide a link for you).  I am afraid that I once again lashed out in frustration for which I must apologize to IDSA.  That said, I am disappointed in their watered-down response to the FDA on the proposed endpoint of 28 day all cause mortality.  Here’s what the IDSA says.

IDSA concurs (see our position paper) that, based on currently available data, all-cause mortality is the most appropriate endpoint for a NI HABP/VABP trial. This position is based on the well established effect size of active antibacterial therapy vs. inactive (i.e., “discordant”) therapy for HABP/VABP using a mortality endpoint. Unfortunately, despite active investigation of available datasets and literature, there are very few data currently in the public domain which establish an antibacterial effect size for any non-mortality, clinical endpoint. However, mortality is an insensitive endpoint (i.e., less likely to detect true differences in antibacterial efficacy than clinical endpoints), and clinical response is the preferred endpoint clinically. Therefore, IDSA urges industry and academe to conduct new studies, and reevaluate existing datasets, to establish antibacterial effect size for clinically meaningful endpoints. Upon completion of such analyses in the future, IDSA urges FDA to move rapidly to enable NI studies of HABP/VABP to use clinical primary endpoints.

In my view, the last thing we need is to await more studies before we rescind the use of the mortality endpoint.  As noted in a previous blog, the current construction of the trials and called for in the FDA guidance is completely infeasible and should be immediately changed to the more feasible clinical endpoint until such time as some other endpoint is shown to allow for feasible trials.   In the meantime, one of our most critical needs for new antibiotics, nosocomial pneumonia, will go without any new development for the foreseeable future at least in the US.  Is this what the IDSA wants?  Is this what any of us, including the FDA wants?

Why is it so hard to construct trial designs that can be done on planet earth?  Why do we feel the need to change an approach that has served us well for the last 20 years?  Have we approved ineffective antibiotics?

Europe recently completed its Scientific Advisory Group meeting on antibiotic development.  If they go the way of the FDA, we are truly lost.  But here I remain optimistic. As long as the US market share for antibiotics continues its inexorable decline and other markets continue to emerge, and as long as there is a way forward to register new antibiotics in these markets via Europe or other regulatory agencies, there is hope – just not for Americans.

An Open Letter to Kathleen Sibelius, Secretary HHS

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Dear Madame Secretary Sibelius,

I am writing to you today in desperation.  I am convinced that unless the United States follows a path other than its current one, we will face an onslaught of Superbugs with no new antibiotics to fight the battle and protect our citizens.  I address my concerns to you in particular because the FDA, working under your aegis, is leading us to an untenable situation and they are not changing course.

I feel like I have tried everything.  I have written letters to prestigious medical journals, I speak with the FDA Office of Anti-infectives and Opthalmology on a regular basis, I published a book on the antibiotic problem last year, I write a blog and I speak at various forums.  I was a participant in the whitepaper published in 2004 by the Infectious Diseases Society of America entitled Bad Bugs, No Drugs where we warned of the public health threat and suggested a variety of pragmatic approaches to avoid the worst.  And I have not been alone in this effort.  Yet all this work has been to no avail.

The FDA has listed its accomplishments in antibiotic development in testimony by Dr. Janet Woodcock to Congress last year.  They note that they have now published a series of guidance documents clearly laying out a pathway for industry to develop needed antibiotics.  Unfortunately, most of those guidances call for a pathway that is quite simply infeasible or irrelevant to the clinicians treating the infections in question.  For example, the most recent guidance relates to registering drugs for the treatment of pneumonia acquired in hospitals.  This is a very serious infection and there is a desperate need for new antibiotics to treat these infections since many of the bacteria responsible are antibiotic-resistant. But the guidance specifies the size of clinical trials required for registration and this trial size is not achievable in today’s world- or at least not without spending hundreds of millions of dollars and running the trials for 5 years or longer. For an antibiotic that will never earn the return that a drug like Lipitor will, these trials just do not make sense.  This seems incredible to me since I know how much time and effort is required for the agency to publish these guidance documents.  Why would they promulgate infeasible or irrelevant requirements?  The charitable answer is that the FDA is so far removed from both clinical practice and from the industry it regulates that it no longer understands what is feasible and what is not.

While a number of factors contribute to our current lack of antibiotics in the pipeline, the FDA stance is the factor most readily reversed.  The FDA roadblock can only serve to further dissuade companies from working in the area. There has been a continual loss of large pharmaceutical companies working in antibiotics. Pfizer is the latest departure. Since large companies are the main resource for small companies to fund expensive late-stage clinical trials, the loss of large companies leads to an investment climate for small companies working on antibiotics that is going from bad to worse.

One of the solutions proposed to the problem has been to provide incentives to both industry and government to discover and develop new antibiotics.  But this will be throwing good money after bad if there is no way the new antibiotic can be approved in the US. We might just end up supplementing research that will ultimately benefit other countries but not our own.

The FDA stands alone in the world.  With few exceptions, no other countries are following the FDA’s lead here.  Notably, the FDA’s sister regulatory agency in Europe has declared that developing antibiotics active against resistant pathogens is their highest priority.  The FDA has made no such commitment – quite the opposite it seems.

I am at a loss to explain the FDA’s lurch into Neverland as far as antibiotics are concerned.  I can only assume that it is partly a response to political pressure to further distance themselves from industry and to increase their standards for both efficacy and safety.  But I consider that a lack of new antibiotics is also a serious safety issue – a fact that the FDA and their congressional critics appear to be ignoring.

In a recent speech entitled, “The FDA and Antibiotics - The Road to Global Irrelevance”, I suggested that we hit the reset button.  The FDA needs to start over.  Because I believe they are no longer competent to find their way, I ask you, Madame Secretary, to organize a task force reporting to you that will help them recover their bearings. Please let me know if I can be of any help.

Sincerely,

David Shlaes MD PhD

Anti-infectives Consulting, LLC

Anybody Home?

I just returned from the International Conference on Drug Development held in Austin, Texas.  All the big FDA brass were there including Janet Woodcock, Bob Temple, Bob O’Neill and others.  Ed Cox was on the schedule, but he hurt his back (I hope you’re feeling better, Ed) so his deputy, John Farley came instead.  Poor John had to endure my tirades.  At least he reads my blog so he knew what to expect. NO ONE from FDA top management stayed around to hear the antibiotics section of the meeting.  They abandoned John to the wolves (myself and Barry Eisenstein of Cubist).  Bob Temple had already departed.  I heard that Janet Woocock was in her room working.  Now, it’s true that the antibiotics section occurred as the last set of meetings for the three-day conference.  Nevertheless, I think the FDA attendance tells us something about the priority they give both to antibiotics and to those of us who disagree with their current approach to antibiotics. I wanted to cry!

John Farley mentioned that the only comments to the docket on the recent guidance on nosocomial pneumonia came from me!  Where are all of you????

My talk was entitled, The FDA and Antibiotics – the Road to Global Irrelevance. The argument I tried to make was that the US share of the world pharmaceutical market and of the world antibiotic market in particular is shrinking.  The growth of the US market is shriveling compared to other world markets.  (I received a download of IMS data from my good friends at Astra-Zeneca to whom I am very grateful).  You can find all my slides at my website or just follow this link.  The US now accounts for only about 25% of the world antibiotic market compared to 35-40% 5 years ago and up to 50% a decade or more ago.  While the US is still a large market, it has recently been surpassed by the Asia-Pacific countries.  Those markets are expected to continue to grow at a rapid pace while US growth is expected to be relatively flat.  So, for small companies who can make it through the expensive Phase III trials, I argued that it would make sense for them to register their products in Europe and use the EU approval to drive approvals in Asia-Pacific and other emerging markets as well as Europe. I’m not sure this will work at the current time for large pharma – but it may well be a viable approach in 5 or 10 years.  Then again, with our current situation, I don’t expect to have any big pharma companies still pursuing antibiotic R&D after 5 or 10 more years. 

I also argued that there would be three conclusions to the current FDA pathway.  1.  Companies will abandon the field entirely or the US entirely.  2.  Companies will register their antibiotics in the US where trials are feasible (ABSSSI), for other indications in the rest of the world and count on some US off label use for increased returns.  3. The current FDA anti-infectives group will eventually go away since they won't have any work.  4.  All of the above.  In any case, off label use of approved antibiotics will increase in the US since physicians understand where and how they will work better than the FDA in most cases.  None of these outcomes are desirable by anyone.

Finally, I suggested a new path forward.  Push the reset button.  Start over.  Scrap all the recent guidance documents.  Convene a task force or committee (I can’t believe I’m saying this.  I hate committees and task forces!)  to provide totally new trial designs not to the FDA but to the Secretary of HHS.  This committee cannot include any of the current players.  The FNIH group would be out.  It would have to include industry.

With the FDA continually releasing guidance requiring infeasible trials, the US will be irrelevant for registering antibiotics in any case.  I am extremely disappointed that the FDA top management didn’t bother to attend that section of the meeting.  The message is quite clear.  We are on our own.  Without congress, the administration, or some influential lobbying group of consumers, we are doomed in the US.  

The EMEA had its Scientific Advisory Group on Anti-infectives this week.  I don’t know what happened.  I know the FDA was there by phone briefly . . .I can only hope that they continue to ignore the recent FDA guidances.

Maybe I’ll be a little less depressed next week . . .

Pfizer Abandons Antibiotic Research!

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While traveling this week I received a surprising and frightening email from a colleague at Pfizer.  He said that Pfizer had just announced that they were moving their antibacterial research and development from Groton, CT in the US to China. They move cardiovascular research to Massachusetts, but antibiotics go to China.  Their facility in Sandwich, UK, the origin of Viagra and, if I’m not mistaken, Diflucan, will be closed. This was announced as part of an almost 25% cut in research and development overall within Pfizer.  I was able to confirm all of this through various stories in the press.

Pfizer is facing a $15 billion dollar cliff with the patent expiry of Lipitor, their blockbuster statin drug.  Global sales were down to $11 billion in 2010 but were expected to be as low as $4 billion in 2012. They have little from the Pfizer legacy to replace this gaping hole in their revenue, although they do have a number of products from the Wyeth legacy that should help.  Nevertheless, to keep growing a $66 billion dollar behemoth – cost cutting is the rule of the day.  All of these companies are gong to be much smaller in the next decade and some will no longer exist.

Pfizer has been saying publicly for several years that antibiotics was not one of their so-called areas of focus.  So while I am disappointed and depressed by the news from Pfizer, I’m not surprised.  According to Chemical and Engineering News,  

Pfizer will focus research on several core areas: neuroscience, cardiovascular health, metabolic and endocrine diseases, inflammation and immunology, oncology, and vaccines. The company is creating specialized units in pain and sensory disorders, biosimilars, and Asia R&D.

The firm is exiting research in allergy and respiratory medicine, located in Sandwich; internal medicine, which includes some research in lung, kidney, and urinary diseases, also located in Sandwich; oligonucleotides and tissue repair, in Cambridge, Mass.; and antibacterials, in Groton. The company is also abandoning regenerative medicine research in Cambridge, Mass., but will fold similar R&D conducted in Cambridge, U.K., into a new pain and sensory disorder research unit.

The claim that they are only moving their antibiotics R&D to China is an interesting one.  While it might be true, it is hard to imagine how that will succeed given the difficulty we are all having in discovering new antibiotics under the best of circumstances.  China, still, is not the best of circumstances. It does, however, position them well for intrusions into the pharmemerging markets as noted in a previous blog.

Of course, IF there were a feasible way to develop antibiotics in the US, we could all get righteously indignant and say that the profit motive is preventing us from having new antibiotics.  Giving big PhRMA the benefit of the doubt, I think the truth is that the impossibility of developing antibiotics in the US as a result of the FDA’s current stance is playing at least some role in recent decisions by companies like Pfizer and J&J. 

It is important to understand that once a company abandons antibacterial research, they lose their internal expertise in the area.  This makes it difficult if not impossible for the company to evaluate opportunities in this space from external (i.e. biotech) sources. Therefore, it further erodes opportunities for biotech.  This then leads to a ripple effect where no one can work on antibiotics because of a lack of partners with big pockets to support the late stage research required to get the products registered.

I have been warning everyone that this would come.  I think we can expect more of the same.  When will we act?

Related articles

• Pfizer to Cut Research, Shut Plants in Savings Effort (businessweek.com)
• Cambridge, MA a rare winner in Pfizer R&D gambit (fiercebiotech.com)