David's New Book

Wednesday, July 20, 2016

FDA Workshop on Pathogen-Specific Antibiotics - Part 2

To continue our discussion of the FDA Workshop on the development of pathogen-specific antibiotics, I’ll start briefly with a discussion of statistical issues and approaches that concluded day 1 of the meeting.  Honestly, since it was a fairly authoritative and intense set of presentations that left me n the dust, I have little to say other than to refer you to the slides. What was clear is that there are a number of Bayesian methods that would allow for a more comprehensive analysis of trials where the numbers are small.  Enough said.

The second day of the workshop was the meat of the meeting and was set-up by our discussion on the first day.  John Rex and colleagues invented a fictional drug they called X-1 that was active only against Pseudomonas aeruginosa.  They then set about trying to design a non-inferiority trial to compare the new drug to a comparator agent – in this case, meropenem.  Why, I asked myself, did he start with a non-inferiority design. In trying to read John’s mind, I thought the following. (1) NI trials are the most reliable way to antibiotic approval and have been used for the approval of new agents (like ceftazidime-avibactam). (2) The exercise would expose in a very quantitative way the costs and risks of such a program. (3) The discussion would stimulate thinking about new approaches to the NI design or to thinking about other designs.  You can find all the details about X-1 in the slide packages provided for the meeting.

John started with a few assumptions and limitations.  The most important was that the trial could not exceed 1000 patients for cost and time reasons. Given the numbers of potentially enrollable patients with these infections, mostly HAP/VAP and IAI, under the usual circumstances of such a trial, you cannot meet the 1000 patient limitation. The proportion of Pseudomonas infections among enrolled patients is just too small. So, to meet this goal required several manipulations.  First, a wide NI margin of 30% is required for HAP/VAP and 25% for IAI.  He was able to justify this in that for HAP/VAP he used the FDA endpoint of 28 day all cause mortality in the microbiologically documented population and for IAI he used cure in the microbiologically documented population as endpoints based on the FDA’s own guidance documents.  The development of agents for patients with unmet needs specifically states that wider NI margins could be considered and the margins chosen lie within the crude M1 calculations provided by the FDA. The design involved the use of X-1 + ertapenem (erta is not active vs. Pseudomonas) vs. meropenem.  Investigators were allowed to add amikacin to each arm for up to 4 days initially (a potential confounder). Even with these wide NI margins, to reduce the trial size, John had to invent a rapid, bedside test for the diagnosis of Pseudomonas in respiratory secretions or abdominal culture swabs to increase the chances of culture-positivity. This led to a total of almost 1900 screened patients in the two indications and 915 enrolled. Then came the results.  Based on John’s impeccable math, 175 patients with Pseudomonas across the two indications were treated divided in a 2:1 randomization schedule. You can see that the numbers are going to be small.  The table shows numbers achieving the endpoint over the total treated for each treatment group and each indication. These fit within the prescribed margins. But what if one or two patients are moved or removed on various sides of this table?  It can all rapidly fall apart.  What if there is no diagnostic test or if the test used fails to predict culture positivity?  The numbers then become really small. In all cases, the conclusions based on the trial, whether positive or negative, are very fragile.

 I was convinced from the beginning, and even more so after all of John’s marvelous mathematical scenarios and contortions, that such a trial would be too risky, too expensive and would expose too many patients to an unknown drug that might well still be unknown at the end of the study.  I made the statement that no one would run such a trial.  Jeff Lowtit from the Medicines Company then promptly jumped up and said that he would run such a trial! Nevertheless, it was clear to all in the room what the costs and risks of such a trial would be and what the prospects for funding and for return on investment in such a scenario would be.  It was not a pretty picture. One caveat – could a Bayesian approach substantially de-risk the NI venture?

I suggested that we should abandon the NI trial design concept for such a drug altogether and go towards a superiority design approach as I have argued consistently in the past.  Even here, there are major problems. (1) External controls are probably required as well as some sort of within-trial validation set to show that control levels of response are real. (2) Even with such controls, the trial might not be inferential at the P=.05 level – although possibly it would be for P=.1 or .2.  The trial would probably have to include amikacin for several days in both arms thus failing to avoid this potential confounder.  This puts the trial at higher risk and the addition of amikacin would have to be factored in to the external controls one would use. As I have discussed, such control levels of response could be established pre-trial – so the calculations could be more informed.

Now imagine the situation where infections are even less frequent such as would be the case for Acinetobacter infections.

Paul Ambrose kept coming back to the same theme – and not without justification.  If the trials are not inferential, wouldn’t a strong pharmacometric argument be a strong rationale for approval?  In the case of the externally controlled superiority trial, 30 patients enrolled, receiving the new therapy (X-1 in our hypothetical case), where PK is performed, could provide evidence of response-exposure relationships and these could be placed in the context of the preclinical and phase 1 target attainment data available prior to the start of the “pivotal” trial. I agree with Paul – but would the regulatory authorities consider the more robust PK data substantial evidence in combination with everything else to allow approval? I’m not sure – but I think maybe the FDA is not sure either.

The EMA responded by again pointing out their tools including conditional approval with regular re-review of ongoing data for key products like X-1. Although this tool does not exist for the FDA per se, the FDA could approve a drug, require post-market studies and convene additional advisory committees or take other action based on emerging post-market data.

While the workshop was unable to establish a clear pathway forward for pathogen-specific antibiotics, it was clear that the usual pathways were going to be challenging to say the least.  It was also clear that post-approval data collection was going to be an essential piece of any approval for a pathogen-specific product for a Gram negative pathogen. And all of these considerations are now, thanks to the FDA, in the public domain.

Tuesday, July 19, 2016

FDA Workshop on Pathogen-Specific Antibiotic Development - Part 1

For the last two days, July 18-19, I was pleased to be able to attend a fascinating FDA Workshop on the development of antibiotics for use in a subset of patients with unmet needs. I am writing this blog while waiting for my very delayed flight from DC back home.

Unmet needs patients include, mostly, those with infections due to highly resistant pathogens where options for therapy are limited and/or where antibiotics for more usually resistant pathogens are not available in an oral formulation necessitating intravenous therapy. The subset of products specifically considered during this workshop is that targeting specific pathogens – e.g. an antibiotic active only against a single species of bacteria such as Pseudomonas aeruginosa or Acinetobacter baumanii. You can find all the slides used and other information here. I have blogged in the past regarding the FDA in particular and this thorny clinical development problem (1, 2, 3).

My impression in general is that, even if the FDA does not yet know what is the best approach to the development of pathogen-specific antibiotics, they wanted a public discussion of the issue to highlight both the need for these agents to be developed and the consequential need for a feasible pathway for their development.  They also wanted to be able to point to a public discussion of the extreme difficulty of designing and carrying out a standard trial with inferential statistics in this setting.  This public understanding would then make it just a little more comfortable for them to venture into heretofore unexplored territory in antibiotic development.

The meeting started with the usual general statements both from FDA and from EMA, the European regulatory agency. These were helpful and only emphasized the additional tools available in Europe for the approval of such agents compared to the US.  But, at least on day 1 of the meeting, the most important presentations, I thought, were the real life experiences of two companies attempting such trials. There were questions on the rationale for designing and carrying out the trials - I will review this below.

Example 1 – the CARE trial by Achaogen – presented by Ian Friedland. Achaogen is developing a new aminoglycoside antibiotic with activity against resistant pathogens called Plazomicin. Their original plan was to carry out a randomized superiority trial in infections caused by highly resistant pathogens –a noble but ultimately doomed endeavor. The original design called for the study of bloodstream infection and nosocomial pneumonia caused by carbapenem-resistant Gram negative pathogens. The endpoint was all cause mortality at day 28 (because the FDA requires this for non-inferiority nosocomial pneumonia trials?). The plan called for a 1:1 randomization between plazomicin + meropenem or tigecycline vs. colistin + meropenem or tigecycline calling for the enrollment of 360 evaluable patients (assumed 80% evaluability). Note the use of combination therapy – thought to be essential in these desperately ill patients with complicated infections. The trial initially screened 694 patients to enroll 14. Screening failures were caused by the lack of a carbapenem-resistant pathogen or the presence of more than 72 hours of previous antibiotic therapy (excluded by protocol) in these very sick patients in intensive care units (no surprise to most of us here).  The company quickly decided to carry out a standard, non-inferiority trial in urinary tract infection and altered their CARE trial design to be more accommodating to enrollment. Having started the original trial in early 2014, they project an enrollment of 100 patients by the end of this year – still far from their original goal of 360 patients. Enrollment appears to be speeding up slightly after their study amendments – but not enough to make this trial feasible as a stand-alone pivotal study for registration under today’s FDA standards. At this point the company plans to use the data in this smaller number of patients to support an application for approval based on the urinary tract infection trial data.

Example 2 – TANGO trials of meropenem plus a new beta-lactamase inhibitor, vaborbactam, from the Medicines Company presented by Mike Dudley. TANGO I was a standard, non-inferiority trial in urinary tract infection and the top line data has already been presented. They actually showed superiority (just) over their comparator, piperacillin-tazobactam.  Would meropenem have done the same without vaborbactam? One must ask . . . 

The company also is carrying out a TANGO 2 trial of meropnem-vaborbactam vs. best available therapy in urinary tract infection, intra-abdominal infection, nosocomial pneumonia and bacteremia suspected to be caused by carbapenem- resistant Gram negative pathogens. The trial is a comparative superiority trial with a 2:1 randomization. To support the control data for their trial, they carried out a retrospective study to gather data on the efficacy of best available therapy in regions where they would carry out the prospective clinical trial. The results of this retrospective study were surprising in that the patients were very sick and the mortality rates were high with a surprising 18% 28 day all cause mortality rate in patients with urinary tract infection. They also discovered an astounding 69 different best available therapy regimes in the different centers studied and they noted that combination therapy seemed not to improve outcome over monotherapy. They amended their trial protocol based on the findings of their retrospective study. They note that this trial will probably not yield inferential data.

Paul Ambrose raised the following question. If we can’t do inferential studies in these so-called pathogen specific indications, why don’t we just rely on PK/PD data to show that therapy is feasible and likely to be efficacious? While scientifically, one can’t argue with this position, the retort from companies is that physicians want to see actual clinical data in the patient population they will treat.  But does non-inferential data count? Can we not, rather, educate physicians to understand the importance of scientific basis of the PK/PD argument?

Day 2 was even more interesting.  Hold on to your hats!

Sunday, July 3, 2016

Brexit Antibiotics

The question of the meaning of the Brexit for the future of antibiotics has been haunting me since the surprising result of the referendum last week. I have more questions than answers. With this historic and world-shaking divorce between England (UK?) and the European Union comes uncertainty with regard to the future of efforts to provide for a sustainable supply of antibiotics to address the superbugs of today and tomorrow.

The UK is the epicentre, in many ways, of our current efforts in this regard.  David Cameron, who just announced that he would step down in October, appointed Jim O’Neill, the ex-Goldman-Sachs economist, to lead the Antimicrobial Resistance Review (I call it the O’Neill Commission). What an incredibly brave and wonderful move that was! Without the imprimatur of Cameron, where will we be? The entire effort within in the UK has been driven by George Osborne, the Chancellor of the Exchequer.  It seems unlikely that he will be around.

The O’Neill Commission itself may be winding down. While I hope that its effects will continue to be felt for years to come. I worry.  In the absence of key figures from the Commission and in the absence of an ongoing government imprimatur, I’m not sure what the future of the body of work that they produced will be. Will the reports lie fallow until some public health crisis occurs?  Are we back to waiting for disaster to strike instead of anticipating it?

Dame Sally Davies is the Chief Medical Officer for the UK and has been an essential and outspoken leader in the struggle to deal with the problem of antibiotic resistance on many fronts.  Will she remain in place to continue her efforts given that there will likely be a new government for the UK in the next few months.

The Wellcome Trust has also assumed a leadership role in the struggle against antibiotic resistance. While it is an independent, private, charitable organization, the Trust has worked closely with the UK government on issues around antibiotics and resistance. There is no doubt that the efforts of the Trust would be less effective and less far-reaching in the absence of British government support.

Funding for the incentives we have been discussing must come from various national authorities. Will the UK still participate in this effort? Some have argued that the G7 or G20  or even the UN will step up to the plate and provide funding in some international effort.  I remain sceptical of that concept.  However the funding is to be provided, though, the leadership of the UK to make it happen will be sorely missed. I fear that any organized, international effort may now be doomed and efforts to convince various national authorities to provide their own funding will also suffer in the absence of clear UK leadership.

Then there is the question of the European Medicines Agency and England’s own regulatory agency the MHRA. The EMA offices are currently located in London.  They would probably now want to move to the continent.  But what would happen to the central regulatory filing procedures that are now in place?  Would the UK or England drop out or continue as before? The MHRA has been a leader in regulatory reform in Europe for antibiotic development. Will this continue or will the EMA now be struggling to find new and less experienced leadership for this all-important effort?

As I said, I have more questions than answers.  But I am much less optimistic today than I was just a few weeks ago.

Thursday, June 16, 2016

Antibiotic Incentives - What's Missing?

In a word – training. I’m beginning to feel like a broken record.  I’ve been talking to various funding agencies about this need for 12 years now (1, 2, 3).  Either no one is home, or they think they have already addressed the problem, or they don’t believe there is a problem to address. 

Between mergers, acquisitions and frank abandonment of antibiotic research and development, there are precious few companies involved in the area anymore. While there has been an increase in funding for antibiotic discovery research in academia over the last decade, most academic researchers are poorly prepared to conduct this sort of research. At the same time, the committees that review grant proposals in the area are frequently made up, mostly, of the same academic researchers who are often unprepared to either judge or carry out the proposed research. Happily, at least during the years I was involved in reviewing proposals for the National Institutes of Health in the US, there were a few researchers from industry present who could help the committee understand the advantages and, more often, failings, of the proposals before us.  But we are a shrinking commodity. Many of us are older and retired. Many have moved on to areas of research outside of antibiotics  (you have to make a living after all).

Antibiotic discovery and development is a highly specialized endeavour.  It requires an understanding of a huge variety of topics and skills including clinical microbiology, epidemiology, biophysics, biochemistry, structural biology, pharmacology, pharmacokinetics, pharmacodynamics, animal testing, toxicology, chemical manufacturing, medical need, clinical infectious diseases and much more. While one does not have to have expertise in all these areas, you do have to have enough of an understanding to converse with the experts and to make judgements about how and whether to take compounds forward to the next step or not. This sort of breadth of knowledge and experience is found everyday within companies pursuing antibiotic discovery and development.  It is only rarely found in academia.

Where will our next generation of antibiotic hunters come from? I believe that they cannot come solely from academia as things stand today.  What I have been proposing for all these years is a training program of 3-12 months to take place within industry where all these skill sets can be found. For some reason (conflict of interest?), academia and therefore funding agencies seem unwilling to go forward with this sort of effort. Recently, a highly placed official from the NIH quipped that I should just fund these training programs out of my own pocket!  I just don't understand the reluctance here.

Who should be trained?  First – established researchers who are now or want to in the future conduct antibiotic discovery and development research. Next we should concentrate on post-doctoral training to give our new researchers the skills they need.  Finally, once we have trained mentors in place, we should focus on PhD candidates who want to make a career out of antibiotic research.

Who should fund this research?  We should!  Government should align with various companies still active in antibiotic research who have the appropriate skill sets to provide this training for academics. Private organizations such as Wellcome Trust and perhaps the Pew Charitable Trust could also take this on.

If we fail to act on this key area of need, we can offer all the incentives we want, but there will be no one left to take up the task of actually delivering the antibiotics we need.

Friday, June 3, 2016

Antibiotics - the Virtuous Cycle

I just returned from two days of DRIVE AB meetings in Amsterdam.  I am so excited that I couldn’t wait to get something in writing for the blog.

Two weeks ago, the O’Neill Commission (officially the Antimicrobial Resistance Review) released its final report.  If you haven’t read it – do it now! The report makes a number of very specific, key recommendations all of which make common sense.  They all fall under two general rubrics -
1.     Reduce the demand for antibiotics.
2.     Increase the supply of new antimicrobials active against resistant microorganisms.
These two are clearly conflicting – the paradox of the antibiotic market in a nutshell.  A new antibiotic hits the market and physicians don’t want to use it for fear of selecting for resistance too quickly. But this is what we must somehow achieve.

DRIVE AB is an effort to combat antibiotic resistance funded by the European Commission, the Innovative Medicines Initiative and EFPIA, the European version of PHRMA in the US.  DRIVE AB is founded on three principles – Access, Sustainability and Innovation. You can immediately see the similarity between the DRIVE AB goals and the O’Neill Commission report.  I look at DRIVE AB as the group that will provide more specific recommendations to various national and supranational authorities on how to implement the recommendations of the O’Neill Commission.

To me, the most exciting aspect of the DRIVE AB effort revolves around providing post-market incentives to pull companies into antibiotic R&D –a key recommendation of the O’Neill Commission.  Some have termed this de-linking with the idea that these incentive payments should alleviate the marketing pressure on the company to increase sales volumes and therefore to provoke a more rapid emergence of resistance. A significant upfront payment would address this need and resolve the paradox.  

Again – according to the O’Neill Commission - The reward would be given only based on societal priorities shaped by key medical needs. The CDC list of key resistance threats is a good starting point for these priorities. Payments should be free from political risk. The size of the reward should be linked to the value of the product to society (or to a given country). The payment would come soon after regulatory approval, but need not come all at once. Control for manufacturing, distribution, post-market research all should remain in the hands of the developer.

The DRIVE AB group discussed several models for such post-market rewards of which I would like to highlight just two. The first is called an insurance type reward. (See Rex & Outterson) John Rex’s favourite way to explain this is to compare the payment required to our need for fire extinguishers and for firemen. We buy the extinguishers and place them strategically in our homes and businesses and we pay the salaries of our firemen and firewomen even though, happily, most of us never actually have a fire. Paying for an antibiotic that we don’t actually need today, but that we might desperately need tomorrow is similar – its insurance. In the example we discussed, a collar and cap model is used for insurance payments. A government of payer provides a developer with an annual payment up to some specific volume of courses of therapy. If this volume is exceeded (the collar), the payer must provide additional payments on a per course basis.  This volume though, is capped.  If the cap volume is exceeded, the payer would pay some discounted price for additional courses of therapy. From my understanding, some variation of this is likely to occur in a couple of EU countries as soon as this fall for antibiotics recently approved in Europe.

The other model we discussed is the market entry model. In this model, the developer is paid one or more payments upfront. As in the insurance license model, the developer has a number of obligations by contract including those relating to good stewardship.

The model I personally prefer is similar to the insurance license model but where the upfront payment is on the order of say $1B given over the first 3-4 years post-approval. But where the developer is still allowed to sell units at some capped price.  This price would be enough to encourage good stewardship at the level of the user and the company would still have to abide by their good stewardship contract with the payer. I envision that the cap would increase after the first 3-4 years such that by the end of the exclusivity period, all sales would be based on whatever price the developer was charging.  This provides several advantages.  It keeps the developer’s skin in the game – its motivating.  It provides for a potential upside beyond the initial payment – also very motivating. And it would encourage generic manufacturers to enter the market after the period of exclusivity has expired.  The key would be to make sure that principles of stewardship and responsible end user education are maintained while actual selling the product.

The reality is that for any innovative product education will be required.  That would probably occur via some sort of medical liaison group from the developer, but would not involve “sales” representatives.

Our discussion made clear that no one model would work for any one product for all regions and no one model would fit all products for any region.  We need a choice of different post-market incentives such that various regions can choose the one that best suits their needs.

One exciting result of these incentives is the virtuous cycle. Large pharmaceutical companies like Pfizer and J&J might be motivated enough to get back into antibiotic R&D. This means that there would be more private capital to invest in academic and biotech R&D – completing a virtuous cycle leading to an even more robust antibiotic pipeline for the future.

As John Rex noted several times during the meeting – such a meeting could not have occurred even one or two years ago.  Yet here we are – at the beginning of what could be a new world.