Thursday, August 25, 2011

Dysfunctional Large Pharma

In the July 28 edition of Fortune magazine online there is a fascinating report by Peter Elkind and Jennifer Reingold with Doris Burke on Jeff Kindler’s rise to power at Pfizer and his subsequent fall from grace.  The reporters spent four months interviewing over 100 people including current and past Pfizer employees as well as colleagues of Kindler from his previous jobs at McDonalds where he rose from General Counsel to President of Partnered Brands. Kindler joined Pfizer at the beginning of its end as the pharmaceutical giant with Lipitor. When Kindler’s predecessor, Hank McKinnell took over as CEO in 2001, Pfizer’s stock price (corrected for splits) was $31. McKinnel was a businessman who took the reins from Bill Steere.  Bill Steere got his degree in biology and worked his way up through the Pfizer sales organization.  Under Steere, Pfizer acquired and marketed Lipitor and marketed azithromycin (Zithromax). Pfizer stock went from $2.00 to over $30.00. Under McKinnel, Pfizer brought in Zyvox through its acquisition of Pharmacia-Upjohn. The Pfizer stock went from $31 to $49 to $20.  Today, six years after Kindler took over, the stock sits at $18.

It is interesting to me that the successful CEO (Steere) was trained in science and worked in sales.  The two successors, neither of whom could be described as having advanced Pfizer from a business perspective, were a businessman and a lawyer – neither with any science background.  While this is not necessarily a detriment, I always worry about that in the key leadership position of a science driven business like pharmaceuticals.  My pharmaceutical CEO idol is Roy Vagelos the ex-CEO and chairman of Merck – a trained physician scientist.

The Fortune article goes into great detail exploring the political machinations behind the replacement of Steere by McKinnel and then McKinnel by Kindler.  Steere is characterized as the Wizard of Oz pulling strings behind the curtain to manipulate the characters involved and get the result he wanted.  These sorts of politics seem rampant in large corporations where the powerful frequently have large egos that overmatch their abilities.

One counter-example is Iain Buchanan.  Iain is still one of the best CEOs with whom I have had the pleasure of working.  He led a small biotech, Novexel.  Iain learned the science enough to make key strategic decisions and, more importantly, he understood his limits and listened to the advice of the experts he brought in for that very purpose.  Listening is frequently not a characteristic of heads of large corporations and was certainly not among the descriptions of Jeff Kindler in the Fortune article. I am sure there are also people like Iain in key positions in less dysfunctional large corporations.

Of course, we can’t blame the CEOs for the failings of an entire industry.  The large pharma model just seems to be outmoded.  Blockbuster drugs are now coming too infrequently to support the bottom lines of any of these behemoths.  Most of these giants are making their numbers by slicing divisions, including large segments of R&D, and even by selling off large parts of their business.  Pfizer, for example, now plans to sell off a number of non-pharma businesses like animal health and consumer health to bring down their bottom line and concentrate on ethical pharmaceuticals.  Whether this will be enough remains to be seen.  But clearly, shrinking is, from my viewpoint, the only positive way forward for these large companies.  If they shrink enough, maybe antibiotics will be an attractive business for them again.  Getting small might also help avoid the kinds of political shenanigans and manipulative behavior that apparently went on at Pfizer and was reported in such detail by Fortune.

Looking at all this from where I sit, in order for us to think small about antibiotics, we still need to solve the phase III problem.  Outside of mid-size companies (Cubist, Shire) with the cash on hand to support phase III trials, the smaller, private companies are still stuck having to partner with a larger company or with going to the public markets to fund these trials. A number of new and valuable antibiotics are being discovered and developed at such small companies. I don’t think we should count on large pharma to pull us out of this hole.

Pictured below are Jeff Kindler, Hank McKinnell and Bill Steere.

Thursday, August 18, 2011

FDA Guidance for Antibiotic Development - A Cautionary Note

As I understand it, the FDA will soon be releasing a series of new Draft Guidance documents for the development of antibiotics.  The subjects that have been under consideration include quite a number as noted below.

Community-acquired bacterial pneumonia – hopefully a modification of the previous draft that will now provide for feasible designs.

Hospital-acquired and ventilator associated bacterial pneumonia – again hopefully a modification of the previous draft that will now provide for feasible designs.

Complicated urinary tract infection (cUTI).

Complicated intraabdominal infection (cIAI).

The utilization of superiority trial designs for antibiotics.

Rumor has it that the FDA will be releasing a number of these new guidance documents over the next six months or so starting in September.  I am writing this blog as a cautionary note.

Since the list of commercially interesting indications for antibiotics in the US has now shrunk to skin infections, intraabdominal infections, urinary tract infections and perhaps infection in neutropenic patients, the above list includes some blockbuster topics. The potential indications for much needed drugs to fight Gram negative bacterial infections are all in the above list.  Hospital-acquired and ventilator associated pneumonia frequently involve Gram negative pathogens, but the development of antibiotics for this indication is no longer feasible in the US (thanks to the FDA). cUTI and cIAI trial designs based on guidance dating back to the 1990s remain feasible for now.  A number of companies, including Cubist, Forest, Astrazeneca and others are targeting these indications for their new Gram negative antibiotics.   If the Draft Guidance documents for cUTI and cIAI require infeasible designs – that will quite simply be the end of antibiotics for Gram negative infections in the US. No more no less. So, before releasing any new Draft Guidance in these indications the FDA needs to get the proposed designs vetted for feasibility by people who actually know what they are doing in this regard.  Given performance on recent guidance documents, we can assume that this does not include the FDA folks.

Who can advise the FDA on feasibility? FNIH? FNIH includes all stakeholders and as such will provide comments written by committee – always challenging and may not be the best representation of  key issues.  Industry?  Clearly those in industry can tell the FDA about feasibility, but they are “biased.” Consultants? We never agree.  In this area, to a certain extent, I sympathize with FDA.  What is required is an FDA insider who can actually make these judgements and parse the advice received by FDA.  Even a key consultant would help – but the FDA seems not to have such a consultant specifically tasked to evaluate trial design feasibility. This key individual or group seems to be entirely missing from the anti-infectives group at FDA. I wonder if that situation can be repaired  . . . .

Wednesday, August 10, 2011

Points of View on Antibiotic Development: FDA and Infectious Diseases Clinicians



In the current issue of Clinical Investigation, four interviews focused on the development of antibiotics are featured.  From left to right - Brad Spellberg, the Rib-X CEO, Mark Leuchtenberg, Rib-X CMO Scott Hopkins and Joseh Kuti, are interviewed along with Sumathi Nambiar of the FDA. 

Dr. Nambiar states that, “ The non-inferiority margin should be prespecified, based on historical evidence of treatment effect for the active comparator and be reliable and reproducible.”  Drs. Spellberg (especially) and Kuti note that the endpoints found in today’s guidance documents are anything but that. In discussing the guidance for skin infection trials, Brad notes, “Given that sulfon­amides were clearly greatly less effective than modern antibiotics and yet had a >95% success rate with this end point, how can this end point possibly distinguish less effective drugs from more effective drugs? This end point has no assay sensitivity according to the very data used to justify the end point. It is ironic that the statis­tical concern that non-inferiority studies could lead to approval of inferior therapies has led to selection of a new end point for future studies which, according to the very historical data used to justify it, can’t distinguish inferior from superior therapy. Finally, recent experience suggests that the cessation of lesion spread end point has much lower success rates (e.g., 70%) in modern studies than in the Snodgrass and Anderson data. This is another example of lack of constancy.”

Dr. Nambiar also notes that the trials should be feasible.  While that is the case for trials in skin infections (even though that guidance document might have lots of other problems), it is certainly not so for any respiratory infections.  The FDA has stated this before – that trial designs required by guidance must be feasible.  So where are the feasible designs?  Dr. Nambiar’s response when challenged on this point by the interviewer was to say that trials must be scientifically rigorous.  Good – who could disagree with that?  But if you can’t actually conduct the trial – what’s the point?

In discussing endpoints, luckily, Dr. Nambiar recognizes that a physicians assessment is valuable, even beyond specific data on how a patient feels, functions or survives. In conclusion, Dr. Nambiar discusses the fact that the new, scientifically rigorous approach by the FDA, along with guidance being provided by the Foundation for NIH, is important in thisw time of difficult challenges for antimicrobial chemotherapy.  But both Drs. Spellberg and Kuti question the scientific rigor of the FDA’s approach as exemplified in recent Draft Guidance documents on several fronts.   It seems that from the clinicians’ point of view, the FDA has developed a “pseudoscience” (my interpretation) around non-inferiority.  In my own view,  this restrictive view of non-inferiority design is impeding development of new antibiotics and is chasing companies out of the field.

Of interest, the Rib-X interview was very focused on the data gathering they are doing to be able to do in order to argue their case before the FDA.  They also addressed issues of running global trials when the FDA and EMA do not agree on endpoints.  There were no questions for R-b-X inviting them to challenge the FDA on trial feasibility.  I suspect that Rib-X, like most companies, did not want to get into that discussion – certainly not publicly.  But as I suggested in my last blog – I hope they will get into that discussion vocally when they do meet with the FDA privately.

The bottom line for me from these very interesting interviews is that infectious diseases clinicians and the FDA live on different planets or in different dimensions – I’m not sure which.  Scientific rigor for the FDA is not at all that for the clinicians.  Feasibility of trial design is another point of clear disagreement. So here we are – back where we started in 2006-8. How will we find a way forward?

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Thursday, August 4, 2011

Sign the Pledge!

Having watched the debate over the debt limit along with the struggles of Republican candidates, I have come to the conclusion that some of them have the right (no pun intended) idea. We need antibiotics developers to sign a pledge.  They must pledge to just say “no” to quote the words of Nancy Reagan.   They must also pledge to explain this response to the FDA in frank, simple and straightforward terms. 

What am I talking about?   As it stands, the FDA has made it infeasible to develop antibiotics for approval in the US for essentially all respiratory tract indications.  Mild infections such as otitis, bronchitis and sinusitis now require placebo controlled trials for approval.  The conduct of such trials in moderate to severe bacterial exacerbations of COPD would be considered unethical by most investigators.  The FDA also has so far ignored data published last year showing a very important antibiotic effect in otitis media whereby any equipoise that might have previously existed no longer does. They also require an infeasible design both for community-acquired and for hospital acquired pneumonia.  Thus, all key respiratory infection indications have been wiped off the map of the US antibiotics market. 

The problem is that I don’t think that the FDA yet understands that these designs are both unnecessary and infeasible.  They continue to suffer the delusion that one can actually carry out such trials. This delusion is apparently reinforced by two factors.  (1) The FDA continues to receive a number of INDs for new antibiotics.  This makes them think that there is no problem in the introduction of new antibiotics to market in spite of the dearth of approvals in the last decade. (2) When companies do come to them at the end of phase II, I believe from a few contacts at such meetings that the FDA is not being told in clear terms that the trial designs required are infeasible and that sponsors will not engage in carrying out such trials. I don’t even know if FDA understands their role in the recent Novartis-Paratek debacle for example.

Sponsors, especially large pharmaceutical companies, don’t want to alientate “the agency” since they work in many therapeutic areas.  Regulatory departments of these large companies are usually extremely conservative and, understandably, don’t like to challenge regulatory agencies.  But for antibiotics, especially at FDA, there is no other way.

My recommendation is shock therapy.  This must be administered by the pharmaceutical industry since the FDA is not listening to words.  Sponsors, at the time of discussions around both phase II designs and at the end of phase II meetings where phase III trial designs are discussed, must be clear and forthright with the agency stating what their limits are in terms of trial designs and what, for them, is commercially feasible and what is not. Even though the FDA does not care about the business aspect of pharmaceuticals, I think they do care about the public health implications of having no new antibiotics approved in key indications.  They also care (I think) about the imminent prospect for off label use where physicians recognize the value of therapy in an indication that the FDA could not approve (doripenem and hospital-acquired pneumonia leaps to mind).

So I ask all sponsors to sign the pledge!  Be frank (politely) and forthcoming with the agency about your limits in trial designs both during discussions around phase II (where the agency is less concerned) and around phase III. The only way for shock therapy to succeed, unfortunately, is if sponsors start walking away in large numbers from the US marketplace while clearly explaining their position to the FDA. 

I already hear the hoof beats – but does the FDA hear the departing stampede yet?