Big PhRMA + FDA = Antibiotics?

I recently read an article noting that Abbot is splitting into two separate companies.  I have been saying that the large pharma model is dead for a long time now. In the case of Abbott, one company will retain the name Abbot and be a company focused on medical devices, generics, diagnostics and nutritionals. The second company, name unknown, will focus on Abbott’s $18B ethical pharmaceutical business.  Of course, like other pharma companies, Abbott’s business is threatened by generic intrusion.  Their largest product, Humira, is threatened by biosimilars.  On the other hand an $18B company is easier to grow than a $32B company. This move is similar to that of Pfizer and Bayer (back in 2006). I remain hopeful that all these large behemoths will shrink, split, divide or whatever it takes to reduce their overall bottom line to the point where antibiotics again become an attractive business.

In this regard, I note a new report from the Tufts Center for the Study of Drug Development that anti-infectives (excluding antivirals) once again have among the fastest times to approval and lowest risk of development compared to other drug classes.  This is a change from their last report from around 2003. I am surprised given the recent rate of late stage antibiotic failures at FDA and the poor approval rates for antibiotics over the last few years at FDA.  One caveat is that the latest report still only goes through 2009.

If the FDA can turn around their current unrealistically demanding approach to antibiotics, and if companies can succeed in shrinking enough, antibiotics could be in for a big comeback!

Speaking about the FDA, two key anti-infectives advisory committee meetings are coming up this week. Stay tuned.

Related articles

• Let's split (economist.com)

Antibiotic Pipeline - Cautious Optimism

I am NOT reporting from the meeting of the Infectious Diseases Society of America (I have to justify every meeting expense these days).  But I did note an article in Medscape reporting on a discussion of the antibiotic pipeline by Helen Boucher and Jim Hughes of IDSA.  I devine that Dr. Boucher gave a talk similar to the one she presented at the Pew Charitable Trust/IDSA/PhRMA conference in September that I reviewed in a previous blog. She noted that, in contrast to a report in 2009, there are now nine compounds in late stage (phase II or later) development for Gram-negative infections.  She apparently stated that only one was in phase III development, but with the recent announcement by Astra-Zeneca and Forest on their bycyclo-octane B-lactamase inhibitor, avibactam (formerly NXL-104), there are now actually two in phase III. Dr. Boucher  correctly notes that none of the compounds are a panacea against all resistant strains.

Nevertheless, given the pace of discovery and development of new compounds, I think it is like that IDSA will achieve the goal of their 10x20 initiative where they targeted 10 new antibiotics approved by 2020.  When they announced this initiative in December 2009, I was skeptical (dismissive).  I thought it was a great PR move.  I now think that it could become reality.  But, I remain unsure that we will obtain FDA approvals for these new antibiotics in the key indication of hospital-acquired pneumonia, our area of greatest medical need.  For our progress or lack of thereof, see my previous blog. In her IDSA talk, as in the previous presentation for Pew/IDSA/PhRMA, Helen notes the uncertainty around FDA requirements for approval as a key hurdle to the availability of new antibiotics in critical indications for Americans.  This also remains a major disincentive for companies to either stay engaged in the area or to move back in or to start up. 

Back in 2009, at the time of the announcement of the 10x20 initiative, I had not considered the market dynamics that might end up saving us all.  That all changed when I was able to see 2010 antibiotic sales data as tabulated by IMS Health (see my slides from a talk earlier this year by following this link).  As I have noted repeatedly since then, while the US is still a large single-country antibiotic market, we are being overtaken by the emerging economies where the medical need is great and where there is a growing middle class who can afford to pay for new antibiotics of high quality (not “home grown”). I am not the only person to have taken note.  The Bayer deal with Trius is just one example of the fact that PhRMA companies now see emerging economies as an antibiotic opportunity.  

It is interesting, and perhaps inaccurate, that the Medscape coverage of the IDSA conference did not mention the GAIN (Generating Antibiotic Incentives Now) act.  The GAIN act originated in the House and has now been introduced to the Senate. As discussed in a very nice talk at the Pew/IDSA/PhRMA conference in September, Brad Spellberg showed how the additional years of exclusivity are heavily discounted in normal accounting practice and how this provides little if any financial incentive to companies unless they are bringing forward a compound with limited patent life.  (In that case, one wonders what they are doing . . .).  A report by the Office of Health Economics also debunks the idea that the exclusivity proposed by GAIN offers a financial incentive. I am personally not convinced that we need a financial incentive at this point.  I am convinced that a clear regulatory path in the US would be the most important incentive we could offer. It looks like the FDA is trying to get there – but why it is taking so long and why it is so painful, I cannot fathom . . . 

Nosocomial Pneumonia - Not there yet.

In reading the briefing material for the November 4^th FDA advisory committee meeting on nosocomial pneumonia, I have mixed feelings.  On the positive side, they do offer a feasible way forward for trials at least in terms of trial numbers. They are considering allowing enrollment of patients who have received prior antibiotics.  Both of these steps represent major progress from the original draft guideline and, again, the FDA should be commended for their efforts to make these trials feasible once again.  But neither of these steps will be sufficient to solve our current problem.  We are nowhere near where we were before the convulsion at FDA led us to our current predicament. We need, as we had prior to the new draft guideline, a clinically relevant and feasible design. 

First, somehow we have gotten down to a 10% NI margin when the treatment effect for mortality (before the usual and overly conservative FDA discounting) is a huge 42%.  And that 42% is already a conservative estimate because it comes not from controls who received no therapy but from those who received inappropriate therapy – not the same thing at all.  So why the FDA insists on discounting the treatment effect for nosocomial pneumonia, I don’t know. With a treatment effect of 42%, it is easy to justify trials with an NI margin of 20%.  At an NI margin of 10%, a single trial is feasible.  If two trials are required, the numbers remain impossible. At a 20% NI margin, the trial numbers are drastically reduced and, in my view, treatment effect is preserved.

The other issue the FDA continues to grapple with is the endpoint.  They are unable to justify a clinical endpoint by looking at studies of appropriate vs. inappropriate therapy. All these studies look at mortality.  But all these studies are of an observational nature – none come from the unique and artificial context of the clinical trial. Therefore, their relevance is highly questionable. But the FDA is wrong.  Pharmacometric studies justifying a treatment effect for clinical outcome DO exist and are compelling – see below.

All other problems stem from this.  The mortality endpoint requires a high enough mortality rate, 20% according to the FDA, that one could expect to see differences between treatment arms if they existed.  As the mortality rate goes down from 20%, the trial size increases dramatically.  But studying patients this sick increases the risk for the antibiotic under study in such trials.  Antibiotics that work very well might be subject to variations in enrollment such that slightly sicker patients are included in the test arm.  In that case a (falsely) higher mortality might be seen for the new antibiotic.  There is also a safety risk in that there are many opportunities for false safety signals for an antibiotic being studied in such populations.

In looking at clinical trials over the years, the mortality rates are almost always very close between comparators. One explanation is that the antibiotics studied are all comparable.  Another is that mortality is an insensitive endpoint that is determined by the severity of the patient’s underlying diseases and antibiotics, for those with severe underlying disease, do not always prolong survival to 28 days. Both of these are likely to be true. 

  

In terms of a clinical endpoint, the pharmacometric approach offers a very nice way to determine treatment effect in the clinic and to establish, therefore, a justified NI margin.  Why the FDA will not consider this approach at the same time that Europe is doing so baffles me.  As shown in the figure below (from a recent Paul Ambrose blog), one can extrapolate the exposure MIC relationship seen in clinical failures to zeros and estimate the effect of no treatment.  Subtracting the effect among those with adequate exposure-MIC relationships provides the desired treatment effect. Recent articles on tigecycline, in the situation of HAP/VAP in particular, are very informative in this regard. At the European regulatory authority workshop on anti-infectives, Ambrose showed data from the tigecycline experience demonstrating a 40-60% treatment effect based on these methods.

Antibiotics target bacteria.  They cure infection but not heart or lung disease.  The endpoints used must reflect this basic scientific fact.  Because the FDA can’t figure out how to do this at this moment in time, the earth must stop spinning on its axis and we must use an unrelated and insensitive endpoint that they can justify based on data obtained outside the trial situation.  Of course why they can’t figure this out when lots of others can also baffles me.

My suggestion is that the FDA does one or more of the following –

·      Declare a moratorium on implementation of their draft guidance requiring a mortality endpoint. 

·      Consider the use of pharmacometrics to support a calculation of treatment effect and therefore NI margins in the design of trials with clinical endpoints as Europe is doing.

·      We should go back to the previous guidance using clinical endpoints while we gather data to justify the use of such endpoints in these trials.  

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.