FDA and Community-Acquired Pneumonia - GETTING THERE.

As I noted earlier this week, The FDA has just announced two days of advisory committee meetings on clinical trial design in pneumonia. November third will cover community-acquired pneumonia and November fourth will cover hospital-acquired and ventilator associated pneumonia.  The briefing materials for CABP and HABP/VABP are now available.  I have now had a chance to review the materials for CABP. The FDA is to be commended for listening to feedback and for responding. 

One key area, the proscription against use of any prior antibiotics, is left open for discussion at the AIDAC.  The FDA’s position is that, based on data from the daptomycin trials, patients receiving prior antibiotics do better than those who do not both at early and later endpoints. The FDA’s suggested solution is to try and find ways to speed the enrollment of patients such that they do not get a dose of antibiotic prior to enrollment. Are they going to ask the people who can actually deal with the logistical issues of this approach in the setting or clinical trials?

I have focused on NI margins and the analysis populations proposed by the FDA since these affect the numbers of patients to be enrolled.  I view this as a critical area for concerns around feasibility.

Here are the FDA’s proposals –

The table below is provided in an appendix.

Option 3 would allow for a single trial assuming there are other clinical data such as a successful trial in skin infections.  In this case, for a single trial, 828 patients would be required in ITT in an 80% power trial with a 15% NI margin.  This would provide the 223 microbiologically documented patients required. This would actually be feasible!

Even the two non-inferiority trials where the mITT population would be pooled with a total of around 1300 patients would be at least approaching feasibility.

The FDA asks for advice on trial design for oral drugs when an IV formulation is not available.  Why not use the same approach? 

           

Trials at 90% power with lower enrollment requirements would require an  increase in margins or an increase in diagnosis rate or both.  In my view, if you discount the FDA treatment effect discounting (see blog on discounting) there is plenty of room in the treatment effect for pneumonia to allow for a more generous NI margin.

I will post a blog on the HABP/VABP briefing material as soon as I can get my arms around it . . .

FDA and Pneumonia - Here We Go Again!

The FDA has just announced two days of advisory committee meetings on clinical trial design in pneumonia. November third will cover community-acquired pneumonia and November fourth will cover hospital-acquired and ventilator-associated pneumonia. 

For CABP, I think this will be at least the third advisory committee meeting in the last several years and the second since the release of guidance in 2008 requiring infeasible trial designs.  The agenda has not been set as far as I know.  But the FNIH has submitted comments to the FDA docket focusing on the early endpoints the FDA would like to use for these trials.  But the issue of trial infeasibility has not, to my knowledge, been addressed by FNIH officially.  The design infeasibility centers around the use of the microbiologically documented population as the analysis population which increases trial numbers by 3-4 fold, making the trials infeasible based on that alone.  The other issue, especially in the US, is that with the early endpoints, the FDA is very worried about the effects of even a single dose of antibiotics before enrollment in the trial – so this has been prohibited.  But when the emergency room is required to dose antibiotics within 6 hours of presentation for pneumonia as is the case in the US, this constraint rules out enrolling all but a tiny number of Americans in the trials. Even outside the US, the prohibition against any prior antibiotics adds significant additional difficulties to enrolling a trial. The other problem is that, at least as currently stated, for an oral only antibiotic, the NI margin is set a 10% making the patient numbers required astronomical.  Some companies have hastily put together an IV program to avoid the trials size requirements for oral only drugs - but even for IV oral drugs, where the NI margin is 15%,  the size will be daunting. 

The factors leading to infeasibility of the design required for hospital-acquired and ventilator-associated pneumonia are legion and have been well documented in previous blogs.

Will the FDA ask the advisory committee questions around trial feasibility?  Will they ask the committee to choose between what they would like to have in a perfect world and what is possible, or will we be once again left with a demand for a scientifically “perfect” trial design which can never be carried out?  In my view, these questions are the most important ones and the ones that, in the past, have been almost entirely ignored by the FDA and its advisory committee.

So, you will not be surprised to learn that I have requested time to speak to the advisory committee.  My comments will, once again as in the past, be focused on these critical issues of trial feasibility. 

From the Pew Charitable Trusts - 2

This is the second (longer than usual) installment from the meeting at Pew Charitable Trust, September 22, 2011. 

In this installment, I review discussions by the Infectious Diseases Society (Dave Gilbert and Helen Boucher), from John Rex of Astra-Zeneca and from Ed Cox of the FDA and others like Mark Goldberger (ex-FDA and currently at Abbot).

Both Dave Gilbert and Helen Boucher emphasized the growing medical need for new therapies to deal with resistant Gram-negative infections.  Both provided data, either from recent surveys of physicians, from the literature or from personal experience to demonstrate the relentless increase in the frequency of infections for which either the only antibiotics left for treatment were either carbapenems or polymyxins or nothing.  CDC data derived from their National Health Surveillance Network from 2009-10 showed that bloodstream infections caused by Enterobacteriaceae resistant to everything except carbapenems and polymyxins ranged from 4-16% and those resistant to ALL antibiotics were an astounding 2-12%.  Among Acinetobacter bacteremias, the numbers were an incredible 68 and 63%.  All these numbers are up from 2008 data.  The personal stories behind these numbers are nothing less than poignant.  The folks at Pew Charitable Trusts shared a film of the parents talking about the death of their son, a young military victim of one of these infections.

To answer this increasing medical need, the IDSA has documented a paltry 10 new antibiotics in the late stage pipeline and they have noted that none address those organisms resistant to all antibiotics (I presume they mean those carrying a metallo-beta-lactamase like NDM-1).   The approvals of new antibiotics continue their inexorable decline in spite of a rising number of drugs entering early development.

National, government-funded efforts to meet the scientific challenges associated with studying antibiotics for these severe infections are severely underfunded and will not even start until the last half of 2013.  According to IDSA this is too little too late!

Finally, regulatory challenges were reviewed.  IDSA notes that NO new drugs are currently being studied for hospital-acquired pneumonia where we expect that up to 20% of patients will die.  This is partly because of the general difficulty and expense of doing the trials, the high risk of studying drugs in such severely ill patients and finally, because there is no viable regulatory path forward for studying this disease in the US since the FDA trial design requirements are simply infeasible. The IDSA notes that even studies in community-acquired pneumonia have been made highly risky in the US given current guidance.  They suggest that the constant debate and revisions of guidance at the FDA create uncertainty in industry that only further discourages industry from continuing or entering or re-entering the antibiotics field.  

Ed Cox responded to these critiques by noting that the FDA is committed to providing feasible trial designs in their guidance.  But, in concrete terms, he only offered recent FNIH deliberations on the scientific justification and validation of new endpoints in trials of both skin infections and pneumonia.  He did not resolve areas of pneumonia trials that actually result in trial infeasibility such as making the analysis population in CABP trials the microbiologically documented population.  This requirement increases the trial population by 3-4 fold over what is normally the case rendering the design infeasible. The aspects of the hospital-acquired pneumonia guidance that make these trials infeasible are many and have been covered in previous blogs.

John Rex pointed out the incredible paradox of the discovery and then development-regulatory processes.  These processes take a good deal of time.  We need to anticipate resistance problems 10-15 years before they occur.  If this timeline could be shortened we could actually respond to resistance more quickly.  A great example was the outbreak of vancomycin-resistant enterococcal infection that started in 1989.  Our first drugs for treatment of these infections were approved 10 years later – and that was quick!

John noted the following –

•21 CFR 314.126 (US Code of Federal Regulations)

–“Reports of adequate and well-controlled [clinical]¹ investigations provide the primary basis for determining whether there is ‘substantial evidence’ to support the claims of effectiveness for new drugs.”

•Important implications

–Preclinical data are usually insufficient alone²

–Adequate & well-controlled clinical data are required

–Confirmation via more than 1 trial is desired: investigations

–FDA has flexibility:³ Other confirmatory evidence may be acceptable at FDA’s discretion in support of an adequate and well-controlled trial

This has been stated by others, including Mark Goldberger when he occupied Ed Cox’s position (essentially) at the FDA over a decade ago now.  In fact, at the Pew meeting Mark reiterated that the FDA has the statutory flexibility to find new paradigms for antibiotic development for severe and life threatening infections. John Rex raised the idea of progressive approval or conditional approval based on a more limited data set.  This is similar to arguments made by the Manhattan Institute back in 2005-6 to the Office of the Commissioner of the FDA.  This would be feasible – if only we could agree on a way forward.  One way would be organism-specific approaches backed by sound scientific preclinical and clinical data (PK in appropriate sites like ELF and appropriate populations like ICU patients, and preclinical and clinical PK/PD or pharmacometrics).  These might then be combined with more limited trials in more standard clinical indications such as intraabdominal or other infections. The conditional approval would then be validated by ongoing studies and safety registries. These paradigms already exist for a number of other therapeutic areas within FDA. The FDA has the flexibility to make this happen. 

Why is it not happening?  For that – we have no answer. But we better come up with SOMETHING soon.  If not, the vision I shared with you in my last blog, and that I stated at the Pew meeting, will surely come to pass.

Antibiotics in 2020 - A Vision - Reporting from the Pew Charitable Trust

Image via Wikipedia

This is the first installment from a fascinating meeting at Pew Charitable Trust, September 22, 2011. 

• ·      Revenues from Antibiotic sales in Asia-Pacific (not Japan), Russia, Brazil and South America will exceed those in the US by at least 200%. We might even meet the IDSA goal of 10 by 20 – just not in the US.
• o   The medical need for therapies for multi-resistant Gram negative infections are as great or greater than the need existing in the US.
• o   There is a growing middle class who will be able to afford these new therapies.
• ·      Driven by these sales revenues, there will be six large pharmaceutical companies actively pursuing antibiotic R&D by 2020 compared to just 2-3 today.
• ·      This growth is made possible by a flexible and balanced regulatory environment in Europe where approval for antibiotics in key indications such as respiratory infections remains feasible. These approvals then drive approvals in the rest of the world outside the US.
• ·      This bright future leaves the US in perpetual antibiotic darkness.  While the Chinese, Koreans, Russians and South Americans have access to approved new antibiotics active against resistant infections, Americans do not.
• ·      In the US there remains no feasible regulatory path for key infectious diseases indications where there is a high medical need such as hospital-acquired pneumonia. 
• ·      If the new antibiotics are approved in the US for an indication where the trials are feasible, Americans would only have access to therapy for pneumonia via off-label use. 
• o   The off-label use, however, would be paid for by Medicare and other payors in the US based on medical need.
• ·      The lack of a significant market in the US in 2020 has led to an innovation drain.  Much of the antibiotic R&D has moved to Asia where the revenues are and where a growing entrepreneurial class has taken hold.
• o   Antibiotic research in biotech and academia is flourishing with ample opportunities for partnering with large pharma and even for accessing the public markets.  But these companies do not flourish in the US – but rather in Europe and especially in Asia.
• ·      At the beginning of the decade (that is, today), BARDA showed that they could support even phase III trials providing a very important incentive for the industry to continue or even restart antibiotic R&D. But that effort fizzled before 2020 since no novel therapies could be approved by the FDA even though the same drugs were approved in Europe.
• ·      But this vision might just be a nightmare.  We could wake up to a different future.  The first step must be that the FDA must provide a feasible regulatory path for antibiotics in key indications such that new products can be approved here in the US.  No amount of monetary incentive can overcome this regulatory roadblock.
• ·      If we do not act now, the US will be left on the sidelines.  Antibiotic R&D in the US and in fact the US antibiotic market altogether will be irrelevant compared to the rest of the world.  And Americans will pay a high price for our lack of foresight today.

Related articles

• Visualizing Antibiotic Resistance With a New Online Tool (blogs.wsj.com)

Hope from ICAAC 2011

Image via Wikipedia

Hello out there in blog-land.  I am writing from the 51^st ICAAC here in Chicago.  David Livermore gave an opening address where he reviewed antibiotic resistance in Gram-negative bacteria – focusing on common Enterobacteriaceae like E. coli, a frequent cause of urinary tract and other infections. David pointed out the rapid emergence not only of resistance to our latest cephalosporin antibiotics, but also to our last line antibiotics for these bacteria, the carbapenems. He ended his talk by noting the regulatory hurdles (FDA) that are stifling development of new antibiotics and by also stating that the pipeline of new antibiotics to address the resistance problem is woefully inadequate.  The only compound David recognized as possibly addressing the emerging resistance was the boron-containing GSK-052 that has a strong Gram-negative profile and which is in phase II development. While I agree with David’s view of the threat of resistance emerging in Gram-negative pathogens on a global basis, I take slight issue with him on the promise of the late stage antibiotic pipeline to address this threat. 

I will be giving a talk myself tomorrow afternoon focusing on new Beta-lactam-beta-lactamase inhibitor combinations in the late stage pipeline for Gram-negative infections. I will cover CXA-201, a combination of the anti-pseudomonal cephalosporin, CXA-101, with the older beta-lactamase inhibitor, tazobactam. This antibiotic is very active against resistant strains of Pseudomonas aeruginosa that can cause very serious infections in our hospitals – especially pneumonia .  These infections are associated with a high mortality.  There are more and more of these infections caused by strains resistant to all or almost all currently available antibiotics.  CXA-201, being developed by Cubist, is active against many of these strains.  Phase II trials in urinary tract infection and in intra-abdominal infections have already been completed with promising results.  Phase III trials in urinary tract infection have been initiated.

A new class of beta-lactamase inhibitor, called the bicyclo-diaza-octanes, was discovered at Aventis.  These compounds were spun off into Novexel in 2005 (the lead drug was called NXL-104). In combination with ceftazidime, the drug (now called avibactam) inhibits most organisms resistant to our last line carbapenem antibiotics including Pseudomonas.  The only exception is those emerging but still rare bacteria carrying a metalo-beta-lactamase that is resistant to the new class of inhibitors.  Novexel developed the inhibitor in combination with ceftazidime through phase II trials in intraabdominal infection and in urinary tract infection.  These trials demonstrated that the combination works in the clinic and is able to cure infections caused by ceftazidime-resistant Gram negatives.  Avibactam is now being developed by Astra-Zeneca. Phase III trials are hopefully imminent.

Avibactam + ceftaroline is being developed by Forest/Cerexa.  Ceftaroline is a cephalosporin that is active against MRSA – a rarity.  When combined with avibactam, the drug can inhibit an extremely broad spectrum of Gram negative and Gram-positive pathogens – but is not very active against Pseudomonas. This combination just entered phase II development in urinary tract infection.

Merck is developing its own version of avibactam combined with their carbapenem, imipenem.  It is called MK-7655. Imipenem-MK7655 is active against many imipenem-resistant Gram-negatives and is still in phase I development.

Finally, even though the beta-lactamase inhibitor avibactam inhibits most beta-lactamases causing resistance to cephalosporins and carbapenems, it does not inhibit the metallo-beta-lactamases as I noted above. But, certain beta-lactam drugs, like the monobactams, themselves are not hydrolyzed by the metallo-beta-lactamases.  Therefore, a combination of a monobactam with avibactam should be active against these types of superbug (like NDM-1).  I have mentioned this in a blog after the last ICAAC. In fact, David Livermore’s lab has shown that this prediction is accurate. Currently, no such combination is under development – but what a great idea.

It is true that these antibiotics do not cover all the resistant pathogens that are emerging today.  Note that I have not mentioned Acinetobacter.  But there are new products for them too – like TP-434, a novel tetracycline from Tetraphase that is now in phase II clinical trials and which is also the subject of a presentation tomorrow afternoon.

So my message is one of hope for patients and physicians confronted by these highly resistant pathogens.  There are antibiotics in the late stage pipeline that will address many but not all of our current medical needs in this regard.  If a company would/could develop a monobactam-avibactam combination, we could treat most infections caused by even the most resistant of the superbugs. I am hoping that this will come to pass . . .

BARDA "Pushes" the Envelope

In several previous blogs, I noted how important funding Phase III trials would be to incentivize the industry to work on new antibiotics.  I had criticized BARDA specifically stating that they excluded Phase III funding from eligibility for support.  They then wrote to me indicating that was not true and that they did not exclude phase III support from funding, but they also admitted that, at least up until that point, no applicant had been funded for phase III.  I corrected my blog with a follow-up comment.

Now, the proof is in the pudding.  A recent press release shows that GSK has received a grant of up to $94MM to fund development of a broad spectrum antibacterial compound under a new program aimed at just such a public health need at BARDA.  This funding includes support for phase III trials in intraabdominal infections.  In their press release, BARDA specifically requests additional applications under this program.  You can access the application instructions through this link.  Of course, not everyone has an antibiotic in their back pocket that might qualify for such support – but there are definitely a few out there.

I believe that this is a major breakthrough in our ability to incentivize industry, large and small and academia.  The lack of support for phase III trials has constituted a major roadblock, especially for small companies that are privately funded through venture capital.  The venture investors cannot afford the costs of phase III.  Thus those companies have always been dependent on either large pharma (deep pockets) partners or on the public markets.  The availability of BARDA support for phase III opens up a number of new opportunities for such small companies. Academia would also be able to benefit from such support.

In addition, such funding constitutes an incentive for large pharma (like GSK) where phase III contributes heavily on the negative side of the NPV ledger.  Funding for these trials will clearly improve the NPV calculation for large companies.  Will this be enough for large companies?  I think it will help those companies like GSK, who are already committed to the area.  It will provide a way for them to stay in at a time when the environment otherwise might not be favorable.  But I doubt that, by itself, such funding will be enough to entice those companies that have abandoned antibiotic R&D to re-commit the resources required. For those companies, the pull incentive, such as some sort of guaranteed market post approval would also be required. 

Nevertheless, the inclusion of phase III support in BARDA funding is an important step forward.

Related articles

• BARDA backs GSK antibiotic with $94M in R&D support (fiercebiotech.com)

Conundrum

I have been invited to participate in a meeting later in September  where the FDA, congressional staffers, the pharmaceutical industry large and small, clinicians and finally, the press will gather. The purpose of the meeting is to expose for congressional staffers the special nature of antibiotics and the challenges currently faced by society in bringing needed new antibiotics from the research laboratory to patients and clinicians.  I need to explain that I have been invited not as a participant from industry, not as a clinician or scientist, but as a member of the press.  I don’t know if I should be grateful to have been invited at all (I am!) or if I should be insulted.  What do you think?

The draft agenda I have seen suggests that there will first be a discussion of antibiotics and areas of current urgent medical needs for new products.  This will be followed by a discussion of the regulatory challenges for antibiotics followed by a discussion of the economic challenges for companies and academics wanting to bring new products to market. Of course, there is nothing in this meeting that has not been discussed previously ad nauseum. There have been multiple reviews from IDSA and others summarizing the dire threat of rising antibiotic resistance both in our hospitals and our communities.   The clinical needs are clear and are becoming more urgent with time, especially for treatment of Gram-negative infections.

The regulatory situation, especially in the US, has been the subject of countless FDA advisory committee meetings, IDSA-FDA workshops, and has been discussed publicly in a variety of other forums.   There have been many appearances on Capitol Hill by infectious diseases clinicians, the IDSA and industry discussing the medical need, regulatory environment and economics of antibiotic development.  So, while I welcome the opportunity for another shot on goal with Congress, I don’t understand what it is that they don’t get. Are they not listening?  Do they not care?  If it’s the latter, let’s not waste more time. If it’s the former, what makes us think they will listen now – especially in the current political and economic climate?

I recently had a discussion with a colleague on incentives in regard to this upcoming meeting.  I have been contemplating once again the various economic incentives that could be used to encourage industry to get back in the antibiotics game.  But you know what? Effective incentives for industry will never be passed in the current political and economic environment.  Lets face it. But, even though I find that disappointing, I disagree with my colleagues who are prioritizing incentives over regulatory reform.  As I have stated on multiple occasions, without a clear regulatory path for antibiotic development in the US, no amount of money will suffice to attract industry back into the business.

As I see the ongoing evolution of the state of antibiotic research and development within industry, we have probably reached bottom.  The number of large pharmaceutical companies exiting the area will now be balanced by those getting back in to one extent or the other.  I see the imminent departure of Novartis balanced by the arrival of Sanofi-Aventis and the toe-dipping exercise of Bayer with Trius.

We should learn from the companies who are getting back into the business, Sanofi-Aventis and Bayer.  I believe that both, but most certainly Bayer, are targeting Asia.  Why?  There is a clear regulatory path forward and a growing market – especially for antibiotics. The clear regulatory path, so far, is coming from Europe where one can leverage a European approval to win approval in most emerging economy countries. The US has a clear regulatory path for skin infections – period.  The pathway for respiratory infections no longer exists.  The FDA has promised new guidelines for intraabdominal infections and for urinary tract infection. This does nothing but increase fear and uncertainty in industry given what has already happened with respiratory infections.  So the US market is being wiped off the map by our lack of a clear and feasible regulatory path for key antibiotic indications. Companies see this clearly but they also see the rising market opportunities in the merging economies especially in Asia-Pacific (see figure - Antibiotic sales in dollars last 5 years 2006-10).  This leaves us n a situation where needed new antibiotics will be developed and will be available for patients and physicians in China and India but not for Americans here in the US.

So – here’s my suggestion for Congress.  It won’t cost taxpayers a dime.  Ask the FDA in public hearings why we do not have feasible regulatory paths for the development of needed new antibiotics and why India is a more attractive places to develop and sell antibiotics than the US. In my view, at this point in time, this is the only practical starting point in the real world.  Of course my caveat is that Congress doesn’t really know what it’s doing either . . .

Now – my conundrum.  I want to participate in the meeting I mentioned earlier.  But as a member of the press, I probably can’t get up and make statements.  I will actually have to ask questions to make my points.  I’m not sure I know how to do that.  So – any suggestions are much appreciated.