David's New Book

Tuesday, November 24, 2015

Pfizer, Allergan and Antibiotics

With the report this week of the discovery of plasmid mediated resistance to colistin, my thoughts turn to the Allergan/Astra-Zeneca pipeline of antibiotics for highly resistant Gram-negative pathogens. Colistin is our absolute last line against these superbugs.  It’s a toxic drug that no one likes to use, that most physicians don’t even know how to use correctly, and that is now threatened with new, emerging resistance emanating from China. Allergan and AstraZeneca are now marketing ceftazidime-avibactam in the US (soon to be approved in Europe I hope) and are developing aztreonam-avibactam (at tectonic speed).  These antibiotics are active against many (but not all) of the Gram-negative superbugs for which colistin therapy is now used most often. We need these drugs to reach patients – and quickly. And that’s where my concerns about the Allergan half of the equation come in.

Pfizer has proposed an acquisition of Allergan to create shareholder value.  This will be accomplished, in large part, via savings in corporate taxes since the new company will be headquartered in Ireland – where Allergan is currently located. The Newco will then avoid a large portion of US taxes.  The New York Times article also notes that Pfizer may be planning a split into various bits and pieces where innovative drugs will remain in one company while those facing imminent or current generic competition will be part of another company.

So – you all remember Pfizer.  The company was one of the few to market penicillin just after World War II.  It was also the company that walked away from antibiotics back in 2011 believing antibiotics to be subject to regulatory uncertainty at the time and having no confidence that antibiotics would provide a reasonable return on their research investment. AstraZeneca, Allergan’s partner for the development and marketing of ceftazidime-avibactam and aztreonam-avibactam, has also jettisoned their antibiotic research group to form Entasis.  They maintain an antibiotic development group that is now a separate business unit within AZ.

Allergan’s antibiotic group has no discovery research, but does provide clinical development and microbiology support for their pipeline. Will Pfizer-Allergan keep Allergan’s antibiotic group?  Will they even keep their product pipeline?  Or will this all somehow be re-split or even just jettisoned somehow after the merger?

My sources within Allergan are very convinced that Allergan is committed to the antibiotics space – but will it remain committed under Pfizer?

Given the threats of emerging resistance to the last line antibiotics – the carbapenems – and now the new and potentially devastating threat against colistin, the only backstop for many carbapenem-resistant superbugs – it would be perfectly reasonable for the US government to insist that Allergan’s antibiotic pipeline be kept intact and on time (or even accelerated) for the US market post-merger. Will the US administration take an aggressive stance here?  Stay tuned.

Monday, November 16, 2015

Paris - Timeout

I was just getting ready to write my next blog on Saturday morning when I saw the news on the attacks in Paris. We lived and worked in Paris for three years.  The last time, in 2007-8 when I was working with Novexel, a biotech in a Paris suburb, we rented an apartment in the 11th arrondisement where some of the attacks occurred. The apartment was on the 6th floor (7th for Americans) and looked out over the roofs of the city towards the Eiffel Tower. From our window on Avenue Parmentier, we looked out at the Voltaire metro station and the Mairie (town hall) for the 11th.  The Bataclan, where gunmen and suicide bombers killed at least 89 innocents, is just a few blocks down near rue Voltaire.

As we watched French television news (thanks to the internet), we were taken back to other attacks that are engraved deeply in our emotional history.  In 1995, as I was returning from work near Blvd St. Michel on my bicycle, I passed the scene outside the metro station just after one of the bombs from that August had exploded.  A bistro had been turned into a triage center. There were already several white-draped bodies on the ground. We resolved to stop taking public transportation – but, in reality, it was impossible to function in Paris on foot and bicycle. While the bomb attacks continued sporadically into September, we went about our daily lives like everyone else.  And, like everyone else, we became defiant and worried at the same time. Terrorists are called terrorists for this reason. In the grand scheme of things, they don’t destroy countries; they destroy lives, and for those of us remaining, a certain peace of mind.

We were in France on September 11, 2001. Friends were staying with us and had arisen very early that morning to take a train from Avignon, in the south of France, to Paris to catch their plane back to Phillie. That afternoon, our refrigerator repairman asked if we had heard that there had been some sort of accident involving a plane in New York. We had no television, but we did have an internet connection. We looked and were horrified. Not long after that, we got a call from our friends’ babysitter asking if they had left.  We asked when they were expected and she told us that they were due several hours ago.  She said that she had been able to get no information on their whereabouts.

We found out later that their flight, like many others, had been diverted to Gander, Newfoundland. They were welcomed by the citizens of Gander and taken to a religious camp outside of town where they spent the next six days without their luggage but with their carry-on items.  In their case this was a case of Burgundy wine. They still go back to Gander from time to time to reunite with their Newfoundland friends and others who had been diverted there the day of the attacks.

We returned to the US on the 16th – the first day that flights were allowed to go from Paris to Newark.  After we boarded, the captain came by to every passenger to personally ask if we were OK. On arriving, we flew over the smoking remnants of the towers.  On our drive home, we passed by the parking lot for one of the New Jersey PATH trains that takes commuters to New York every day.  There were scattered cars left by those who would never return home. Our home in the New Jersey suburbs was unchanged – but our lives would never be the same.

Watching French television over the weekend, all of these memories flooded back. We got on email and telephone to check with friends in France. So far, so good – everyone is OK including those living near the Bataclan and the caf├ęs where the attacks took place. Many will know someone, or will know someone who knows someone, who was killed or injured Friday night. No one will ever forget.

While I continue to be passionate in my belief that we need new antibiotics – I was just unable to go there this week.

Friday, November 6, 2015

The Wild West!

Will it get wilder?

I don’t usually read Nicholas Kristoff’s columns in the New York Times – but yesterday he caught my eye. In a poignant story, he recounts the death of a 15-year-old child with emotional problems.  His death was apparently caused by an adverse drug effect from an antidepressant. Kristoff talks about the 7-fold rise in use of antipsychotic drugs among children in the last decade and questions how much of this is based on science and how much on marketing.

At the heart of Kristoff’s story, though, is the debate about allowing pharmaceutical companies to market their drugs for off-label uses. There have been a number of articles on this since a federal judge in Manhattan ruled that the FDA could not block Amarin from promoting its drug for non-approved uses based on our right to free speech.

Why this is a debate escapes me.  The most basic tenant underlying the existence of the FDA is the ability to restrict companies from marketing anything for anything as was occurring in the 19th century.  (Of course, this still occurs for supplements – and how far has that gotten us)? Untold numbers of companies have been fined and occasionally people have gone to jail over violation of this basic power of the FDA to make companies adhere to what they have proven scientifically and what has been shown to have (we hope) an acceptable risk for a reasonable benefit.

The judge’s ruling in the Amarin case seems to have been that as long as the statements used by the company are “truthful” they should be allowed under free speech.  But what does that mean?  What is truthful? If an antibiotic representative told a physician that his/her product, approved for the treatment of epilepsy, had also been shown to be good for patients with arthritis based on a single case report – that would be truthful. Should that be allowed? What if it had been studied in several hundred patients with arthritis in an uncontrolled manner, but had never been approved by the FDA – the statement would still be truthful – but should that be allowed? Finally – what if the drug had been studied in a controlled way, and the study had been submitted to and rejected by the FDA as insufficient?  Should the representative be allowed to quote the results of the study claiming benefit?

Bureau of Chemistry 19th C.
I can tell you that negotiation over the label both here in the US and around the world, is among the most contentious that exists between governments and companies.  It even surpasses pricing discussion in importance for the industry. Why? Because you are not allowed to market what is not included in the label. And to the industry, marketing and promotion is where it’s at.  You need to have something in your label that your competitor does not have.  You have to have that lever – less frequent dosing, better activity shown in the clinic, better spectrum of activity – something that demonstrates that patients and physicians need your product in a way that cannot be satisfied with something else or something less expensive.

At the same time, companies are already allowed to provide physicians with scientific literature on request. In fact, there is an entire FDA guidance on this topic. The FDA recognizes that physicians are allowed, based on their own clinical judgment, to use drugs for purposes not contemplated in the drug label.  The agency therefore provides to the industry criteria under which dissemination of such information is permitted – but in a restricted way.  Articles provided must be from the peer-reviewed literature.  Contradicting articles, if they exist must also be provided.  A list of references on the topic must be provided.  This is all so that the health care provider can judge among all the data, which might be the best choice for his/her patients. What is wrong with this approach?

  If the power to restrict how drugs are marketed is taken away from the FDA – our Wild West of drug pricing and the free-for-all market we allow now will become even wilder.  We will be able to sell anything for anything.  Please – lets not go there.  We already have enough of that from the supplements!

Friday, October 30, 2015

FDA and Pathogen Specific Antibiotics

As I promised in my blog on FDA, Roche and Polyphor, I met by telephone with the FDA today (Ed Cox, Sumathi Nambiar).   I began by reminding them of my experience at IDSA at the origin of the last blog.  Specifically, many people both from academia and from industry were complaining that there was no existing pathway for approval of a pathogen specific drug at FDA currently.  Various folks said that the FDA was insisting on some “inferential” (read statistically significant) data to support an approval for a new antibiotic.  But we all know that for rare pathogens like Pseudomonas aeruginosa and Acinetobacter baumanni, there are not enough patient numbers to fulfill this requirement.

For example, lets say that you have a new antibiotic active only against Acinetobacter and no other bacteria. To show that your drug provides an advantage of currently available therapy, you target patients likely to have infections caused by resistant Acinetobacter.  Such infections might be pneumonia, urinary tract or skin infections. As such, you will probably have to treat at least 300 patients to end up with about 30 resistant Acineotbacter infections in your trial.  Such a trial will take at least 18-24 months (the longest reasonable time to spend on a enrolling a trial). And, lets say that standard therapy of patients with pneumonia, urinary tract infection and skin infections provides a clinical response in about 50% of such patients. You hope that your drug will bring the response rate up to 70-80% for a 20-30% improvement over standard therapy. We didn’t even get into the idea of stratifying patients by site of infection – but I’m not sure it would be necessary. To power the study to achieve statistical significance would require studying 100-250 patients with the desired infections – clearly not feasible in a two-year period – to say nothing of the expense involved.

It is clear to me, and to FDA, that these trials will be externally controlled.  Historical controls like retrospective but contemporaneous chart reviews or prospective observational studies where inclusion and exclusion criteria are similar to those used to enroll patients in the treatment trial would be acceptable.  Another approach would be to use pharmacometric data (I think) if robust data were available. The FDA agreed that external controls are OK.  This is not the problem for them.

In general, the FDA understands that they do not have a clear pathway at the moment for such drugs. They have always preferred to have enough data such that statistical significance at P less than 0.05 in a two-sided test was possible. They understand that for these pathogens, this will not be possible in any reasonable time frame.  What they need is a way to approve such drugs given their current regulatory constraints.

I mentioned orphan drugs where I thought that there would be examples where non-significant data would be used for approvals.  Ed corrected me.  He had just studied many such approvals and found that the P values were highly significant for most of these drugs.  The diseases tend to be chronic.  Enrollment seems not to be a problem.  And the effect size is very large making the trial size requirement fairly small.

I suggested that for a pathogen specific antibiotic they accept studies not powered at the 0.05 level, but rather that they accept more statistical trends (P of less than 0.1 for example). This could only occur in the presence of a very substantial PK/PD package including a strong dose-justification rationale. In the case of such an approval, the label would specify use is approved only for those patients with few or no alternatives. There would be a post-approval commitment for the sponsor to continue gathering data to try and provide a more substantial inferential argument.  In the case that this was not achieved, that is, with greater numbers of patients the new therapy could not be shown to be statistically superior to standard of care, both the FDA and the sponsor would have to rethink. This solution is fallible since standard of care might change in the interim making continuing study difficult or even impossible. Both the FDA and the sponsor would have to be willing to accept this risk.

Ed reminded me that I had proposed something very similar back in 2005-6 during a project I carried out with the Manhattan Institute.  I had totally forgotten about this proposal, but it was very similar to what I have proposed above.

Ed asked if I thought that rapid diagnostics would provide a way forward here.  I said – not tomorrow.  For this to be helpful, the diagnostic would have to be “point of care” and CLIA-waived.  I don’t think we are anywhere near something like that for Gram-negative infections today.

I am sure that there are other ways to approach this problem as well.  Ed told me that the FDA has been working hard on this internally, and in fact had spent virtually the entire day today on the subject.  He also told me that he has presented this as a problem to the President’s Advisory Council on Combating Antibiotic Resistance and asked for their help here.

I hope for all our sakes that we find a way forward – and soon.  Pathogen specific drugs are coming and they will be good for the microbiome , good for patients and good for us as a society. Apparently the ball is in the court of the President’s Council for now . . . .

Thursday, October 22, 2015

The Antimicrobial Resistance Congress - Meeting Notes

On Monday and Tuesday, I chaired the World Antimicrobial Resistance Congress – a meeting organized by Terrapinn. The meeting was small,  with about 120 attendees, and the topics covered everything from various aspects of antibacterial discovery to policy and regulatory initiatives. I would like to take this opportunity just to share a few highlights from the meeting.

There were several key presentations from various funding agencies including BARDA, NIH, IMI and the Wellcome Trust.  With the exception of the Trust, it was abundantly clear to everyone that without additional funding, the efforts of these agencies to go beyond their current funding levels or even to maintain them will be threatened.   The funding from these agencies goes to everything from early discovery all the way through phase III clinical development and has been very important for academia and both small and large pharma in the pursuit of new antibiotics.  Any diminution or even an inability to expand these efforts would be a terrible tragedy. 

Several non-antibiotic approaches were discussed including antibodies, peptides and virulence.  Some are being examined for prevention while others are thought of as adjunctive therapy.  All of these approaches will mean superiority trials. How to set control levels of response within these trials then became a topic of conversation.  More later.

Diagnostics, both rapid and not, were discussed by FDA. On the more usual antimicrobial susceptibility testing devices, it is clear that the delays in availability of these devices after antibiotic launch is not being well addressed by FDA.  Until this occurs, the delays will continue to impede acceptance of new antibiotics by end users – not a good state of affairs with continuing increases in resistant infections.This will require some sort of preliminary breakpoint from FDA that would allow device manufacturers to begin their process prior to approval. Everyone will have to work at risk.  Will this ever occur???

Stava Epstein gave a wonderful and elegant talk on the iCHIP. There was nothing really new in his talk, but it was exciting to hear him speak about this wonderful new technology that may revolutionize the way we look for new drugs.

Dr. Sumathi Nambiar provided a discussion on the QDIP designation and on market authorization for products to treat resistant infections.  In the latter portion of her talk, she admitted that the FDA remains somewhat lost on how to proceed in pathogen specific trials. She noted that the FDA prefers a hybrid approach with non-inferiority trials plus some additional data on activity against resistant infections.

Later, Dr. Nambiar was roped (my fault) into a panel discussion where the topic of an orphan drug designation for such unmet needs antibiotics was raised. As I discussed in a previous blog, the orphan drugs group is still back in the 1990s of antibiotic development.  They only think in terms of broad clinical indications like urinary tract infection, pneumonia, etc. In this thinking, the affected populations are much too large to be considered for orphan drug status (200,000 individuals or less in the US). But a pathogen specific indication where the drug is indicated only for those with few or no alternatives (4500-7500 per year in the US for carbapenem-resistant Enterobacteriaceae for example) has not been considered even though this is addressed by the unmet needs guidance both in the EU and in the US. As a result of this discussion, Dr Nambiar agreed to raise this issue with her FDA colleagues.  We await, once again, further developments.

Finally, the economics of the antibiotic markets was broached by Kevin Outterson and Barrett Thornhill.  The proposals for so-called de-linking, where there would be an attempt by governments to provide a guaranteed return on investment for companies pursuing antibiotics for resistant pathogens seem to be in limbo in the US since we have no congress.  In Europe there is hope that such an approach will bear fruit – but whether that will occur soon or with the usual tectonic EU speed is hard to predict. The precise method of implementation of such payments also remains nebulous.  These discussions reminded everyone that, at the end of the day, to progress, we need money.  And, especially in the US congress, that remains a dirty word.