Can the NIH Rescue Antibiotics from the FDA?

The NIH just announced the formation of their National Center for Advancing Translational Studies (NCATS).  It will swallow many of the projects now located in the National Center for Research Resources (NCRR).  The NCRR funded specific projects supporting translation research in universities and small companies. These projects included everything from high throughput screening of various disease target enzymes, receptors and cells to GLP safety studies to GMP manufacturing. It looks like the new center will be more project and therapeutic area based than the NCRR was. The New York Times ran an article on January 22 suggesting that the center was going to function like a drug company.  Francis Collins, Director of the NIH states in the NIH press release that that is not true. Nevertheless, the NCATS is definitely about drug discovery and, at least early, development.

Assuming that NCATS will take on antibiotic discovery and development projects this can be nothing but good news.  Even though academia does not have the expertise to discover and develop drugs, if they work at obtaining that expertise, this could ultimately work in the sense that they might be able to discover new drugs and get them into phase II development.

In one interview, Dr. Collins noted that the NIH would be working closely with the FDA.  I hope he was talking about the anti-infectives division.   If true, and if he can fulfill his promise of exploring and implementing, with the FDA, new and modern trial designs which are FEASIBLE, NCATS could be a road forward to a new era of antibiotic discovery and development both in academia and in industry (or at least biotech). 

So, one suggestion for Dr. Collins and the NIH is to get some people at NCATS trained in industry – hopefully in antibiotic discovery and early non-clinical and clinical development. A second suggestion is to start discussions with the FDA early since if the NIH is going to be stuck developing new antibiotics according to the current set of guidances issued by the FDA, they may as well stop before they start.   At the end of the day, for the NIH or for industry or for biotech, we must remove the FDA roadblock.

Related articles

• NIH Reorganization Draws Scrutiny From Congress (news.sciencemag.org)
• The NIH Gets Into The Drug Development Business (blogs.forbes.com)

The FDA and Antibiotics - the Road to Global Irrelevancy

I am scheduled to present to the International Conference on Drug Development in February. My title is The global threat of infectious diseases and the challenges to develop new drug therapies. But, as you might expect, I will be spending my time speaking about the FDA and antibiotic development.  I think my plan is appropriate since I think that the one most easily reversible cause of the antibiotic pipeline tailspin we find ourselves in is to have the FDA reverse course.  Many of you might think that if that is the most easily reversible cause of our current disaster, then all is lost.  I don’t agree simply because, from a public health perspective, there is no choice.  Further, I can’t contemplate a future as I age, and as many of my friends and loved ones age, where we won’t have the antibiotic therapies we need when we need them.

I have been examining the pharmaceutical marketplace as a starting point.  What I find, compared to what was true back when I was at Wyeth 10 years ago now, is that the US is becoming much less relevant as a pharmaceutical market in global terms.   The US share of the global market for pharmaceuticals has apparently fallen below 40% (figure below).  This is astounding to me since all the years when I was at Wyeth, the US accounted for over 50% of the world pharmaceutical dollar market and about 60% of profits given the higher prices found here.  

If you look at market growth, the US contributes an ever-decreasing share of growth as illustrated by the figure below.

What does this mean for antibiotics?  Well, if the US market share keeps dropping and our growth rate keeps falling, it would make sense to simply market elsewhere in the world and forget trying to comply with impossible FDA standards for approval.  Another strategy would be to launch in the US based on feasible trial designs – right now that would be for skin infections, and then profit from off label use in the US.  At the same time, one could get approved in the rest of the world for all the indications the FDA has now made untenable in the US.   I think this strategy makes the most sense for biotechs that want to or need to go the way of Cubist.  Small companies can wield a hospital sales force in countries outside the US and still make reasonable revenues and profits for their size.  Since many of the new products are now coming from biotech, this could be a viable plan for getting new antibiotics out there – just not for the US, unfortunately.

What this might mean for the US is no access for patients to needed new antibiotics, or access only in an off-label setting.  No one wants this kind of outcome – not the FDA, not physicians and not patients.  To avoid having the US market for antibiotics become completely irrelevant, the FDA has to do something differently.  A great starting point would be feasible ways of registering new antibiotics in the US.

Otitis - The Data are Published - Antibiotics Work!!!

Exciting news!  Back in November, I posted a blog describing the results of the University of Pittsburgh placebo-controlled trial of antibiotic therapy of well-documented otitis media in children 6 months to two years of age.  Those results were taken from clintrials.gov where the authors had posted their data. The latest issue of the New England Journal of Medicine carries two articles, one from the Pittsburgh group and the other from Finland describing placebo-controlled trials of antibiotics for otitis. Both show clearly that, when properly diagnosed, antibiotics work well in the treatment of otitis and that placebo does not. Of course, this is something that most parents knew anyway – but here it is in black and white.

In the Pittsburgh study of 291 young children, when looking just at resolution of symptoms, although antibiotics were better than placebo, the differences were small.  The authors used a well-validated symptom score to follow progress. Here, antibiotic treatment was clearly superior.  At the day 10-12 visit, only 23% of antibiotic treated patients had a symptom score >8 compared to 61% of placebo treated patients for a treatment effect of 38%. The effect was greatest among those children with the highest symptom score at baseline. When looking at failure, defined as persistence of signs of infection on exam, the differences were also striking. The greatest difference occurred at day 10-12 where the failure rate among placebo-treated patients was 51% compared to 16% among antibiotic treated patients – a 35% treatment effect.  One placebo treated child suffered mastoiditis.

In the Finnish study of children aged 6-35 months, quoting directly from the article,

The primary outcome was the time to treatment

failure, which was a composite outcome consisting

of six independent components: no improvement

in overall condition by the first scheduled

visit (day 3) (i.e., unless parents thought that their

child’s overall condition was improving, the case

was categorized as treatment failure), a worsening

of the child’s overall condition at any time, no

improvement in otoscopic signs by the end-of treatment

visit on day 8 (see videos 4 through 8),

perforation of the tympanic membrane at any

time, severe infection (e.g., mastoiditis or pneumonia)

necessitating systemic open-label antimicrobial

treatment at any time, and any other reason

for stopping the study drug (e.g., an adverse

event or nonadherence to the study drug) at any time.

Overall, treatment failure occurred in an astounding 45% of patients receiving placebo compared to 19% of those receiving antibiotics – a 26% treatment effect. Five placebo patients and only one antibiotic treated patient suffered perforation of the eardrum.  Antibiotics reduced the need for rescue therapy by over 80%. Antibiotic-treated children had shorter absences from school and their parents had shorter absences from work.

In an accompanying editorial, Dr. Jerome Klein posed and answered the question,

Is acute otitis media a treatable disease? The investigators in

Pittsburgh and Turku have provided the best data

yet to answer the question, and the answer is yes;

more young children with a certain diagnosis of

acute otitis media recover more quickly when

they are treated with an appropriate antimicrobial agent.

I hope these studies put to rest the unreasonable requirement both in the US and in Europe for placebo controlled trials of antibiotics for marketing approval.  The studies published in the New England Journal should be the last such placebo controlled trials of well-documented otitis that we should perform.

Related articles

• Antibiotics Can Ease Kids' Ear Infections (nlm.nih.gov)
• Early Antibiotics Help Ear Infections in Young Children (webmd.com)

New at the FDA

Image via Wikipedia

Today I have some updates from the FDA to share with those of you out in antibiotic land and anyone else who might be interested.

Open FDA – a New Website.

The FDA recently announced the establishment of a new website called, FDA Basics for Industry.  The website is actually very useful, especially for those just dipping their feet into the waters of drug, biologic, device etc. discovery and development.  There are links to basic, explanatory documents to guide the visitor to the appropriate FDA agency for their project, to show them where and how to find appropriate guidance documents and, perhaps most importantly, how to ask questions and identify appropriate contacts within the agency.  The website is part of the overall transparency initiative taking place at the agency.

Of course, as far as antibiotics are concerned, transparency has not been the issue.  The problem has been the release of guidance documents requiring infeasible trial designs for product-registration.  The FDA has been transparent about what they want – it’s just that what they want cannot be done on planet Earth.  In one case, where at least the design was feasible, for skin infections, the Infectious Diseases Society has complained that the endpoints required by the agency are clinically irrelevant.

Speaking at the Reuters Health Summit in New York last week, Dr. Hamburg, the Commissioner of the FDA, announced the establishment of the website.  She also discussed her intention to speed review processes and to examine and perhaps reform the “troubled” device unit at the agency, according to Reuters.

Guidance for the Development of Combination Products.

Last year, a revised ICH guidance for non-clinical studies to support human trials was released. In section XVII, the topic of development of fixed combination products is addressed.  This guidance should be very useful for all who are developing such products – and I’m specifically talking to all those of you who are developing B-lactam-B-lactamase inhibitor combinations!  The key portions of the guidance are shown below –

Where there are two late stage products for which there is not adequate clinical experience with co-administration, but there are no causes for significant toxicological concern based on the available data, nonclinical combination studies generally are not recommended to support small-scale, relatively short-duration clinical studies (e.g., phase 2 studies of up to 3 months’ duration). Nonclinical combination studies, however, are recommended before large-scale or long-term combination trials, as well as for marketing.

For combinations of an early stage entity(ies) with clinical experience with a late stage entity(ies), for which there is no significant toxicological concern, combination toxicity studies are not recommended to support clinical proof-of-concept studies of up to one months’ duration. The clinical study of the combination should not be longer than the clinical experience of the individual entities. Later stage or longer duration clinical studies should be supported by a nonclinical combination toxicity study.

For combinations of two early stage entities, nonclinical combination toxicity studies are recommended to support clinical trials.

Guidance for Industry  Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination has also just been released. Again, for anyone developing such combinations of early stage drugs, this is an important guidance.  In this case, the guidance focuses on two compounds that have not been studied in people to any significant extent.  But there is a good deal of useful information here for anyone considering development of any combination product, including those of you working on B-lactam-B-lactamase inhibitor combinations.

What have we ATTAINed?

Well – the data are finally out – sort of.  Rubinstein and collaborators have published the results of the ATTAIN phase III trials of telavancin for the treatment of hospital-acquired pneumonia.  Telavancin is being developed and marketed by Theravance and their partner Astellas. The study was completed in 2007 and the NDA was submitted to the FDA in April of 2009.

Two independent trials of identical design were undertaken – ATTAIN-1 and -2. The data show that, for the originally defined endpoints of clinical response in the ITT and in the Clinically Evaluable populations, telavancin was non-inferior to vancomycin.  A record 1532 patients were randomized for these two trials from 274 study sites in 38 countries.  Patient recruitment accrued over 18 months between January 2005 and June 2007 for an average enrollment rate of 0.31 randomized, 0.13 clinically evaluable and 0.10 microbiologically evaluable patients per center per month, . Of the ITT population of 1503 (29 never received drug), only 654 were clinically evaluable, 480 of which were in the microbiologically evaluable population (had a Gram positive pathogen at baseline).  Baseline characteristics were similar between the treatment groups – although 57 and 89 telavancin and vancomycin treated patients resp. required pressor support (P=0.03).  The mean APACHE II scores were around 15-16 and about 25% of patients had scores of over 20 demonstrating that this trial took place in a severely ill patient population. More than half of the patients enrolled had received >24 hours of prior antibiotic and were judged to have been antibiotic failures at the time of enrollment.  The data justifying this classification were not provided, though. 

Over 70% of patients with a pathogen isolated at baseline had only Gram-positives present.  Of the Gram positives, almost 90% were Staph. aureus with more than half of these being MRSA.  Against pure S. aureus  infections, telavancin was more effective than vancomycin (84% vs. 74% cured) regardless of whether the strain was MRSA or MSSA.  A vancomycin MIC of >1 mg/L did not affect clinical response to vancomycin therapy. Both drugs performed equally well in mixed infections when Gram-negative therapy was adequate. The overall mortality rate was similar between both groups.  Telavancin was associated with somewhat greater numbers of serious adverse events and discontinuations due to adverse events than was vancomycin, although these differences were not significant.

Key data missing from the publication were mortality (or survival) data at day 28 in the analysis populations – especially in the microbiologically evaluable population.  The latter is now the analysis endpoint in the new FDA guidance on hospital-acquired pneumonia.  I posed these questions to Steve Barriere.  He kindly provided me with slides that were shown at the 2010 JP Morgan Conference. 

These data show that in the ITT and Clinically Evaluable populations, there is no difference in survival rates as estimated by a Kaplan-Meyer survival curve and that the NI margin is very tight. But, what is still missing, and what Steve Barriere tells me has not been made public yet, are the 28-day mortality rates for the microbiologically documented population.  One wonders why not. 

It is hard to understand the difficulties being faced by Theravance and Astellas at the FDA.  I speculated, as have others, that perhaps the two identically designed trials were not viewed as independent by the agency.  But a review of the design and discussions with clinical investigators and the sponsor convince me that they were independent. Maybe the 28-day mortality could not be accurately determined since it was not originally part of the statistical plan for the trial.  But the data provided by Theravance indicate that the mortality data are consistent with the clinical response data. I also wonder why the sponsors have not pursued their case in Europe. I guess all will become clear with time . . .

In the meantime – Happy New Year and welcome back to work!