Pharma's Wet Toes

In a recent business news article for the Wall Street Journal, Hester Plumridge noted that some large pharmaceutical companies are once again testing the antibiotic waters. Of course, she would have known all about this had she been reading this blog (Sanofi, Roche).  I would like to add some granularity to her article.  The first large pharmaceutical company to announce they were abandoning antibiotics research was, in fact, Roche in 1999.  Roche was followed in rapid succession by Bristol Myers Squibb, Lilly, and Wyeth.  Abbott and Bayer followed in 2003 and 2006.  Sanofi spun out their antibiotics assets into Novexel in 2004 (Novexel and its products were acquired by Astra-Zeneca and Forest in 2009). J&J and Pfizer pulled out in 2011 or so.  Novartis never formally pulled out of antibiotics research and maintains a research effort in their Emeryville site in California.  But they are a schizophrenic company with a strong and enthusiastic research group and very unenthusiastic commercial and development organizations.  So I count Novartis as de facto out.  This left us with Astra-Zeneca, GSK and Merck.  Even there, Merck’s program is small and is based on a single product (MK-7655 – B-lactamase inhibitor in phase II). 

 

But the trend is now going in the opposite direction.  Sanofi rapidly changed its mind and re-entered antibiotic R&D recently.  They just don’t know where they’re going yet.  They had hired Rodger Novak from Nabriva in Vienna in 2011 to run their antibacterial effort, but he left after less than two years in place.  Roche has completed two deals in the antibiotics space – one for drug discovery and one with Polyphor for its phase II ready anti-Pseudomonas drug. Whether they know exactly where they are gong yet or not is yet to be determined.  But it is not surprising that companies trying to re-enter the antibiotics arena would have problems.  Since these companies lost most or all of their expertise years ago, they will need time to build this back up and re-establish themselves.  How much time required depends on their corporate will and resources.  In this regard, those companies that got out most recently like Pfizer and J&J might expect to have the least difficulty getting back in.  In the case of J&J I believe this might be true since I know that a number of their old antibiotics R&D folks are still in place but working elsewhere in the company.  Pfizer has pretty much dismantled their team and has left so much ill will behind them, that I predict that their climb back to antibiotics, if they so decide, will be a steep one.

The resurgence of interest in antibiotics has clear origins.  There has been a complete turn around at the US FDA in terms of antibiotic development.  They are no longer hostile – in fact – I think it has become just the opposite.  They still need a few tweaks (big ones on hospital acquired pneumonia), but you can get things done at the FDA again. The EMA in Europe has been the stalwart regulatory agency throughout and remains so. The other main contributing factor is the increasing medical need caused by resistance and the possibility that this will drive higher prices in the marketplace. The convergence of rapid and efficient regulatory pathways to the market and higher prices combine to suggest that companies may once again be able to make a return on their investment in this area.

On a more pessimistic note, we are all still awaiting further developments at Astra-Zeneca who, under pressure from generic intrusions, announced that they would slow their investment in antibiotics research.  Apparently, although they believe that the regulatory piece is in place (just talk to John Rex), they are not sure that the pricing piece is ready for prime time yet (just talk to their CEO).  But if they were to back out entirely, it would be catastrophic for antibiotics R&D given their pipeline and their expertise in the area.

FTC takes over for FDA

 Or maybe this should be titled, “The FTC goes where the FDA cannot.”  This month the Federal Trade Commission announced penalties and refunds levied against several companies selling diet aids for false advertising.  They claimed that there was insufficient scientific proof that these products, including Sensa, L’Occitane skin cream and HCG Diet Direct actually benefited consumers in terms of weight loss. The implication is that in order to advertise health benefits for “supplements” or any other commodity, the sponsor would have to demonstrate “scientific proof” of efficacy.  The question is, what constitutes scientific proof?  Does it have to be randomized double blind trials as the FDA requires.  The answer may be a resounding “yes!”

If all of this is true, then how come these products are not regulated by the FDA who actually have the expertise to evaluate whether or not they have achieved proof of efficacy or not?  Well, because these products are not considered drugs and therefore, according to congress and the laws of the land, do not fall under the aegis of the FDA even if they claim drug like properties or effects from such products.   Personally, I think any product making a health claim should fall under the FDA for approval to market based on such claims. Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, the sponsor is responsible for ensuring that the product is safe prior to marketing.  Apparently, there is no requirement that the product actually provide any benefit whatsoever. The FDA can only intervene if there is reason to believe that the product is unsafe after it has been placed on the market. Does anyone (besides supplement manufacturers) believe that this makes any sense at all?  It is clear that the majority of the time being spent by the FDA office of investigation is focused on bogus and unsafe supplements with undeclared additives, unlabeled ingredients and other problems all putting the health of Americans at risk.

Why do I, an infectious diseases physician, care about this topic?  Just do a Google search on the term antibacterial supplements and you will see.  There are myriad products out there from garlic to grape seeds to St. John’s Wort that are claimed to provide beneficial effects for infections sometimes when applied topically – but more importantly, when ingested.  The data to support these claims, for the most part, do not come up to any standard of proof recognized by any sophisticated physician or scientist. For bacterial infections in particular, the ingestion of these so called cures could delay appropriate antibiotic therapy and lead to more severe illness and even death. But these claims are being allowed to stand as is on the internet, in newspapers and in health food stores.

It is time for congress either to give the FDA the power to protect us from these patently false claims of effectiveness or for the FTC to come to our rescue and prevent these manufacturers from continuing to bamboozle the American public.  This is a potentially dangerous practice that should be stopped immediately.

What is wrong with us?

FDA and Pneumonia - Better and Better

The FDA just released new Draft Guidance on the development of antibacterial drugs for the treatment of community-acquired bacterial pneumonia. This is an important document and represents a major improvement over the FDA stance as of the last such guidance appearing in 2009.  The current document reflects what the FDA has been saying to sponsors over the last year. But we have come a very long way since those dark days when the FDA was considering requiring sponsors to prove that drugs for this disease ac-

tually improved mortality when the overall mortality rate for the disease (all comers) is something like 0.2%.

The reason the FDA turned to mortality is that they wanted to justify their statistical design for trials – using non-interiority. This assumes that treatment has an effect greater than no treatment.  To find quantitative data for this, one has to search the preantibiotic era literature.  The patients studied in those 80 year old trials were more severely ill than those we study today. The FDA wanted to approximate the mortality rates of yesteryear in modern studies. Therefore, during the FDA discussions back in 2008, there were calls to limit the study of pneumonia to those with more severe disease or at least to disease occurring in patients with a higher risk of mortality. But even if you study patients with PORT risk classes III and IV, the expected mortality will only range from 0.9 to 9.3%.  Going to PORT V would get you a mortality of 27%, but it is not clear that antibiotics work well at all in such patients and sponsors would not be willing to carry out such studies to register a new antibiotic. The studies proposed to look at mortality as an endpoint as discussed by the FDA in 2008 would have required a sample size in the 10s of thousands and is completely impractical. 

In their draft guidance in 2009, the FDA recognized the impracticality of mortality as an endpoint and that is still true today (thank goodness!). To show you how far we have come – positive aspects of the new draft guidance are:

• ·      All common bacterial pathogens can now be included in the trial including Mycoplasma, Legionella and others.
• ·      The FDA now allows for a single trial in CABP with supporting evidence from another trial such as in complicated skin infection (ABSSSI per FDA).
• ·      The safety data base could be as small as 700 patients.
• ·      75% of the population studied should have PORT scores of III or higher.  For oral only antibiotics, the FDA suggests that they might allow some patients with PORT II scores.
• ·      Bacterial detection methods other than culture like urinary pneumococcal antigen and PCR methods are acceptable for establishing a bacterial etiology (!!!).
• ·      Prior antibiotics are now allowed for some patients with the caveat that there be a stratification along these lines.
• ·      The ITT population could be the analysis population – but there are a number of caveats here and sponsors should discuss this point with the agency specifically.  My own interactions (through clients) with the agency indicate that this is feasible in the context of a single trial.
• ·      The NI margin could be 12.5% or even higher!!!!!

What is the downside?  The endpoint.  The endpoint for the FDA is clinical response based on resolution of certain symptoms between days 3-5 of therapy. As is the case with the FDA endpoint for skin infection, the endpoint that patients and clinicians care about is cure at test of cure and that is still what is sought by the European authorities. There are recent data (ceftaroline NDA) suggesting that there is a good correlation between early endpoints and cure at test of cure – so why not go back to the latter as the most relevant and universally accepted endpoint?  Further, we could examine the possibility of using pharmacometric data to establish a link between the early and late endpoints as well.  The FDA has the data that would be required for such an analysis.

Other concerns I have revolve around the single trial and whether the analysis population should be the ITT or population with microbiologically documented infection since that would change the trial numbers considerably.

But all in all, we have come a very long way since those dark days post Ketek. It looks like clinical trials in community acquired pneumonia will now be feasible on both sides of the Atlantic – all we need to do now is to harmonize a little better on endpoints.