The Perfect Storm Intensifies

The perfect storm hitting the antibiotics R&D has intensified.  According to a recent report by Reuters, the return on investment has fallen by a startling 30% at the world’s 12 largest pharmaceutical companies. The cost of developing a drug through to market has risen from $800 million several years ago to $1.05 billion today.  This rise is mostly due to the increased number of failures – especially late stage failures.  The increase in late stage failures is related in large part to the high regulatory hurdles being encountered across the various therapeutic areas where the industry works. To address this, companies have pared their phase III portfolios from an average of 23 to 18 compounds – a 28% decrease. At the same time, the commercial value of products entering late stage development has increased. Thus, the portfolio prioritization process has narrowed late stage products to those with higher commercial values in most companies. Additional responses from the industry include an insistence on increasing returns on investment.  This is likely to generate additional merger and acquisition activity and further pressure on the portfolio optimization process.  It is likely that this optimization process will place further pressure on antibiotic R&D.

At the same time, a recent report from the European CDC noting a 56% increase in reports of carbapenem resistant Klebsiella pneumoniae between 2005 and 2010.

Resistance to third-generation cephalosporins continues to increase to very high levels throughout the European Community.

The European Union has responded to the crisis of antibiotic resistance with a fairly watered down action plan to member nations. Of the 12 action items in this plan, one is dedicated to the discovery and development of new antimicrobials – shown below.  It calls for the establishment of a public-private partnership under the auspices of the Innovative Medicines Initiative to direct and coordinate academic, non-profit and industry partnerships for this purpose.  But, in the realm of antibiotics, these efforts, so far, have failed to bear fruit with most recent late stage products coming from either large pharmaceutical companies or biotech. Having participated in two framework grants on the industry side, I can only hope that the process for Framework 7 and its successors will be more palatable than that for Frameworks 5 and 6.  As almost a footnote, the action plan calls for implementing procedures for fast-tracking antibiotics against resistant pathogens.  But, as the plan essentially says, these procedural pathways already exist.  The question is how to implement them. The action plan, appropriately in the case of Europe, leaves this to the regulators.  But some more explicit directions would have been helpful.  For example, there should have been a directive to establish feasible pathways for superiority trials leading to early conditional approval. A directive to maintain feasible non-inferiority trial pathways would have also been a welcome addition. While I believe the European regulators already understand this, a clear mandate from the EU would still have been helpful to those of us who want to pursue innovative trial designs for antibiotic development and for the regulators themselves as they try and implement such designs in guidance to sponsors.

While the Perfect Storm intensifies, both the US and EU still fail to address the key issues.  Feasible regulatory pathways forward are the first giant step forward. I can only hope that the EMA will succeed in maintaining feasible procedures and promulgating the new,  innovative and feasible guidance that I know they seek for the development of new antibiotics.

Antibiotics and Innovation at the FDA

In October of this year, the FDA released a report entitled, “Driving Biomedical Innovation: Initiatives to Improve Products for Patients.” There are a number of interesting aspects of this report.  The first is that the word antibiotic is only mentioned once – in a paragraph talking about clinical trails for targeted therapies. But the study of antibiotics in clinical trials has at best only rare and controversial attempts to do just that.  One was the use of emergency use programs to approve the use of linezolid (Zyvox) and quinupristin-dalfopristin (Synercid) for the treatment if serious infections caused by vancomycin-resistant Enterococcus feacium. One major advantage of these emergency use programs is that patients enrolled were documented to have or were very strongly suspected of having a resistan enterococcal infection at the time of enrollment. But given the non-comparative nature of the trials and the bias introduced by the emergency use approach, the FDA has indicated that they would never approve another antibiotic in this way again.  But if not, then how?

The following excerpt is taken directly from the FDA report:

The early discovery of a potential

breakthrough therapy raises ethical and

trial design issues. It is important to gain

confidence that the effects seen in the early

trials are real, and to understand the safety

risks of the new drug. On the other hand,

from an ethical standpoint, it is important to

make sure that people with serious diseases

are getting the best possible therapy. In these

situations, the clinical trials for the drug’s

development must be compressed and the

evidence about its effects gathered in the most

efficient manner possible; however, there is

not a good understanding in the biomedical

community about how to accomplish this.

Additionally, there are questions surrounding

the use of an expedited drug pathway, such as:

• Can FDA, drug developers, and

investigators agree on a threshold to

determine when a treatment poses

“exceptional promise” and should thus

be treated in an expedited fashion?

• Can seamless drug development programs

be created to utilize natural history

data or adaptive trial design concepts to

compress drug development time?

• What are the ethical issues involved in

identifying a promising intervention?

How should the needs of all patients with

the disease be balanced against the need

for better therapy for an individual?

• Can surrogate outcome measures that

could be used for accelerated approval

be rapidly identified?

• Can we arrive at a consensus view of

the goal of monitoring commitments

companies will make once a product is

on the market after such a development

program, such as scientific expectations

and timelines?

These are all great questions.  I can’t wait to hear the answers!

In other sections of the report, the FDA discusses their intent to better communicate with small business. While I am excited about this initiative since the FDA indicates that it wants to improve their understanding of the challenges faced by small businesses, I wonder whether the FDA will actually be able to provide feasible pathways forward for small businesses developing antibiotics.  As it stands now, for example, there is almost no way a small biotech can take on the expense of a registrational trial for antibiotics.  Only truly innovative trial designs will change this.  But given the departure of large pharmaceutical companies and their deep pockets from the antibiotic R&D area, and given the current dismal situation for private funding, we desperately need these biotech to be able to proceed on their own.  A feasible and less expensive pathway for FDA approval would go a long way to bring new therapies, including new antibiotics, to the patients that so desperately need them. 

So – if the FDA is serious about their small business initiative and if antibiotic development is included within this rubric – I hereby volunteer my services. Of course, the problem is that they might not like what they hear.

No matter how one feels about the FDA, their report on initiatives in biomedical innovation is an important one. I think it does indicate a sincere desire to move forward.  But, as always, the devil is in the details.  

Pfizer Abandons Antibiotics R&D in China!

You read it here first!  I first reported Pfizer’s exit from antibiotics R&D back in February of this year. In that report, I noted that they claimed they were moving their antibiotic discovery effort to China  I also expressed doubts that they would ever be able to do that.  I have a source that tells me that they have now announced (at least internally) that they are cancelling their plans (such as they were) to establish antibiotic discovery in China. They still claim that they will continue to pursue what antibiotics they have in development.  I seriously doubt they will be successful there either. My doubts around Pfizer’s confused efforts in the antibiotic arena are based on the following –

• 1.     In firing everyone in their US-based discovery group, they lost all their internal scientific expertise.
• 2.     Antibiotics expertise, including everything from basic science to clinical microbiology to animal model expertise, is required throughout the development process and throughout the period of marketing.  With the loss of this internal expertise, Pfizer is lost.
• 3.     To come to intelligent decision on in-licensing antibiotics, you still need the expertise that Pfizer no longer has.
• 4.     To establish a new group in China, Pfizer needed to hire a scientific leader.  They approached me for recommendations for people to lead the group.  I pointed out that NO ONE in the antibiotic area who knows anything about Pfizer’s history of firing their most valued people would ever trust Pfizer enough to want to work for them. I also noted that they had an opportunity to offer that job to the very talented people they fired earlier this year – an opportunity they ignored.  Who would work for a company like that?

So, I get to say “I told you so” on their failure in China, but I also predict that they will never be able to successfully develop whatever assets they want to move forward since they have lost virtually all their internal expertise.  When Wyeth moved out of antibiotic R&D, they at least had the sense to retain a small core of scientists to support the ongoing development and later marketing of tigecycline.  Pfizer appears not to even have that much foresight – or they just don’t care.

It is all very interesting because I occasionally hear from clients that Pfizer business folks want to talk to them about whatever antibiotic the client may have in various stages of development. But I always warn them that they should take these approaches with a large grain of salt since I doubt, for the reasons noted above, whether Pfizer can even intelligently evaluate an antibiotic in-licensing opportunity.  So far, I have been correct in this assessment.

Of course, this is an incredibly sad state of affairs.  When the world’s largest pharmaceutical company is so incompetent that they bungle their exit from a deprioritized area to this extent, it brings into question the entire management of the company.  I also lament Pfizer’s exit from antibiotics R&D since it is just one less large pharmaceutical company in the fight against resistant infections and it is an additional large number of unemployed microbiologists with industry experience looking for work. Finally, I fear that there will be more competition in the consulting business! 

The FDA AIDAC on Pneumonia Nov 3-4.

I usually try and limit my blogs to 800 words or less.  That’s just not happening today – sorry.  I attended the recent FDA Anti-infectives Drug Advisory Committee (fondly known as AIDAC) meetings on community-acquired (CABP) and hospital-acquired or ventilator-associated pneumonia (CABP). The FDA briefing materials, can be found by following these links - (CABP), (HABP/VABP). It is clear from the briefing materials and the meeting itself that the FDA wants to make their trial design requirements feasible.  For CABP they are getting there.  For oral antibiotics for CABP - who knows? For HABP/VABP we have a long way to go. 

CABP

To remind yourself of the FDA-proposed trial designs, see the previous blog. 

The discussion was extensive and took the entire day.  There were notable presentations from Tom File, IDSA (John Bartlett) and PhRMA (Barry Eisenstein).  

Dr. Sumati Nambiar began the day with a nice review of 4 years of FDA discussions and guidance documents in this area including comments to the docket. Basically, by reviewing the preantibiotic era literature and through work with FNIH, the FDA was able to convince itself that an NI margin based on early clinical outcome (symptoms only) could be justified since the treatment effect comparing sulfonamides to placebo was so dramatic. The FNIH process defined an early endpoint of symptom improvement at study day 4 (72 hours of therapy) as a one point improvement in at least two symptoms of cough, dyspnea, pleuritic chest pain, sputum production AND no worsening of other symptoms.  An absence of elevated body temperature and improvement in important measures of physiological stability would be important but not part of the primary endpoint.  Likewise, the need for a later assessment to assure long-term response was recognized but only included as an “important” secondary endpoint.

The FDA, based mainly on daptomycin data as published by Pertel et al, and partly based on a potential masking of ceftaroline superiority to ceftriaxone in the FOCUS studies, believes that prior antibiotics, even a single dose of a short acting drug, might confound a non-inferiority trial and drive the results towards the null - hence the importance of the question on prior antibiotic use.

Presentations by John Bartlett, Tom File and PhRMA made the strong argument that trials would be difficult to enroll in general, but impossible to enroll in the US if all prior antibiotic use was precluded.  In Forest’s FOCUS 1 and 2 trials only 2% of all patients came from the US.  I presented the recent experience of a phase II study of an IV-oral antibiotic for CABP where most US centers refused to participate because of the exclusion of all prior antibiotic use.  Even overseas this was a problem.  The study was carried out in the US, Canada, Hungary and Poland.  Of 860 patients screened, only 32 were enrolled.  220 failed to enroll because of prior antibiotic use.  The rest of the screening failures were a mixture of causes with the most common being that the patients were not felt to have pneumonia after evaluation or refused consent.

The discussion of FDA’s question 1 centered around whether the symptom assessment at the early endpoint was sufficiently objective. Many physicians wanted to include signs such as temperature, pulse and respiratory rate as part of the assessment as noted in FDA’s option 2. The usual objection from Tom Fleming was that these are biomarkers.  But surprisingly, a few clinicians noted that they thought the pulse and respiratory rates recorded on hospital wards were highly unreliable and that getting temperature measurements more than 2-3 times per day would require an act of God.  Conclusion – physiological signs are not necessary but could be used at the sponsor’s option.  From my point of view this is good since option 2 is infeasible just based on trial size alone. Option 1 would require 1376 subjects if powered at 80% for the overall program and therefore 90% for each trial.  This is quite feasible.

As noted in the FDA’s options, the NI margin for clinical outcome was proposed as 10% but they allowed pooling of the microbiologically documented population for two trials in options 1 and 2 and proposed a margin of 15% for that analysis.  Both would have to be met to achieve approval.  In the single trial option (FDA’s option 3), they proposed several margins where the primary analysis population is the microbiologically documented one.  An 80% powered trial at a 10% NI margin would require 1862 patients – probably infeasible.  A 12.5-15% NI margin would require 1192 and 828 respectively at 80% power.  These are feasible.  The committee suggested a 10% margin for the single trial.

A further discussion of the margins led to questioning of the entire rationale for the early endpoint.  This exists because the FDA could find historical data to justify a treatment effect.  I noted that one could easily do ths is the context of previous prospective, controlled clinical trials using a pharmacometric approach as noted in previous blogs. The thought is to use pharmacometrics to define an NI margin for the more clinically relevant test of cure endpoint that has been used traditionally and is still used in Europe as an endpoint. The topic was taken up by John Rex and others and became even more important during the discussion of HABP/VABP on Nov. 4. The pharmcometric method has been shown to be robust and applicable across many indications and many antibiotic classes.  I remain baffled as to why the FDA continually refuses to look at this option.

The most contentious discussion of the day occurred over whether prior antibiotics would be allowed or not. The basic tension was between whether one wanted to have any US patients enrolled in a trial or not.  John Bartlett even raised the ethics of conducting a trial overseas where, if we know that delaying antibiotics in seriously ill CABP patients increases mortality, than those patients should not be subjected to that risk either by the time consuming enrollment procedures.  Thus, he argues that they too should be allowed a single dose of a short acting antibiotic and that it might not be ethical to disallow that for overseas patients.  I found this a powerful argument – and apparently so did at least some committee members.  About half the committee agreed that a single dose of a short acting antibiotic would be acceptable.  They requested that the FDA provide a list of acceptable antibiotics.  They did not address the use of concomitant therapy for Legionella like the clarithromycin that was allowed in one of the ceftaroline trials since that is required by guidance in North America. 

HABP/VABP

The FDA proposals for feasible trials are shown below.  Again – see their briefing materials and the previous blog on this topic!

  

There was a clear consensus among all present that this indication is the one with the highest unmet medical need and the one with the least feasible regulatory path forward (except those where placebo trials are required like otitis, sinusitis and bronchitis in my view). The key to understanding the issues here is a full comprehension of the implications of the 28-day all cause mortality endpoint that the FDA requires.  I noted that in their questions, they do not ask the committee if they agree with this endpoint.  Nevertheless, this became a central area of discussion during the day.

A discussion of the statistical considerations in trial design was presented by Dr. Komo of the FDA.  He reviewed a large number of trials in HABP and VABP.  The microbiological evaluability rates for VABP ranged from 72 to 84% for trials of broad-spectrum agents and 56-63% for those studying Gram positive pathogens. For HABP, the range was from 50-63% for broad-spectrum agents and from 45-53% for Gram positive pathogens.

Dr. Komo followed this with a discussion of the determination of M1 and the NI margin.  He reviewed the FDA discounting methods but both he and later Tom Fleming noted that if mortality is the endpoint and the control mortality rate is set at 20%, anything larger than a 10% margin might lead to potentially unacceptable increases in mortality for the treatment arm in any case.  Therefore, using a mortality endpoint, no increase in margin would be permissible anyway purely on clinical grounds.  

Dr. Komo then reviewed the Risk Difference, Relative Risk and Odds Ratio methods of measuring risk of mortality based on NI trial data.  Since I am NOT a statistician, I only have an elementary understanding of these methods.  But, what I clearly understand based on the presentation and the FDA briefing materials is that with the OR method, as the mortality rate goes down – which seems likely given current trends – the sample size required increases asymptotically!  

There were excellent presentations by Don Craven (IDSA), Tom File and Robert Fromtling (of Merck for PhRMA).  Of these, I will focus on the latter. The PhRMA proposal was for a composite endpoint where cure at TOC and alive at 28 days would be required for success.  The suggested analysis would use an odds ratio of 1.714.   If the FDA insists on a mortality endpoint, PhRMA prefers the approach the FDA took for CABP where there would be a margin of 10% for the ITT population and a margin of 15% for the microbiologically evaluable population.  The study would be powered based on a risk difference approach (where the trial size actually decreases with decreasing mortality).  PhRMA also pointed out that in the current assumptions by the FDA, drugs which focus on Pseudomonas would be excluded from the non-inferiority approach since the microbiologic evaluability would only be around 10%.  They even questioned whether S. aureus infections would be feasible to study even under the proposed PhRMA standards. A final point from PhRMA related to the key issue of setting breakpoint – never discussed again while I was present.  They pointed out that if breakpoints were set at the MIC50, this would dissuade virtually all companies from proceeding with anti-infective discovery and development.

During my open public hearing presentation I once again raised the idea of using pharmacometrics to define a treatment effect for a clinical endpoint.  This is a much more critical issue for nosocomial pneumonia than for CABP since the FDA was able to finally get comfortable with a clinical endpoint there. To make trials feasible, we have to get away from mortality as the sole endpoint. John Rex raised this topic during the discussion.  He hammered the point that this discussion was critical to whether or not antibiotics would eve be available to Americans or not and to whether companies would want to begin, restart or continue work in the antibiotic field. While I believe that many on the AIDAC were deaf to the urgency of his appeal, they did finally get the message of using pharmacometrics.  This was discussed by enough committee members that I think even the FDA might have gotten the message.  In my view, this is the only way forward here.

For the committee response  – most agreed that a single trial would be OK and a significant number agreed that the single trial could be of both HABP and VABP patients.  Again – if mortality is the endpoint and the mortality of the control must be 20% to maintain trial size at a reasonable level - this is going to be extremely hard to achieve, plus the microbiologically evaluable rate will decrease.  Nevertheless, this represents an extremely important option for companies. Unfortunately, most on the committee agreed with the use of the odds ratio approach which really punishes sponsors for going under 20% mortality at a time when both the incidence of this disease and its mortality are falling.

Finally, there was a discussion of the use of prior antibiotics.  The consensus seemed to be that there was little or no evidence that such treatment confounded trial interpretation and therefore that 24 hours or possibly even longer use might be tolerated.  There was no real resolution of the issue of concomitant therapy such as aminoglycoside use that was common in previous trails and is frequently required by clinical guidelines.  This will likely remain a thorny issue – but one which, might, once again be susceptible to interrogation using PK/PD methods.