Antibiotics and Avandia

I have been following with interest the potential scandal over the handling of controversial data on GSK’s Avandia by GSK.  It appears, based solely on various new reports that GSK deliberately tried to cover up negative data concerning the safety of this oral drug for the treatment of diabetes.  Of course, until we have full disclosure we won’t know if this is a scandal or not. But the discussion prodded me to think about the pharmaceutical industry and its ambivalence towards antibiotics.

To many, the pharmaceutical industry is a parasite that does little other than contribute to the rising cost of health care.  The industry may be the source of life-saving drugs for cancer or important symptom-relieving drugs for painful conditions such as rheumatoid arthritis, but the costs of therapy remain unreasonably high.  The public frequently views pharma as greedy beyond belief.  The Avandia scandal does nothing do alleviate these concerns regardless of the ultimate outcome at the FDA.  GSK’s settlement of lawsuits for billions of dollars doesn’t help either.

But GSK is one of the few remaining large pharmaceutical companies actively involved in antibiotics research.  It also diligently pursues opportunities for new antibiotics outside GSK, thus providing opportunities for academia and for biotech in the antibiotics area.   While I presume that GSK is involved in antibiotics because they still believe that the market is a viable one, even if their only or main motivation is humanitarian, I won’t complain.  Some companies, like J&J (who has since abandoned most antibiotics research), have openly stated that their motivation for remaining in the area was humanitarian and societal concerns.  Nothing wrong with that!   But these companies get little credit for their efforts in public opinion.

The Infectious Diseases Society of America has proposed the 10 x 20 initiative – that is – deliver 10 new antibiotics active against resistant bacteria by 2020.  This can probably only be achieved through the auspices of the pharmaceutical industry.  Although this is a great public relations campaign, it is, of course, completely unrealistic.  The initiative is also only undermined by the Avandia scandal. The problem for antibiotic research posed by scandals such as the one around Avandia is that it simply reinforces the already negative opinion of the pharmaceutical industry in the eyes of the public.  That, in turn, makes it harder for politicians to back measures designed to provide incentives for the industry to remain or to get re-involved in antibiotics research and development.  Most of the measures being considered will involve increased monies going, directly or indirectly, from taxpayers to an industry already disliked and distrusted by the public.

The sad thing is that the Avandia scandal may not be a scandal at all.  It is possible that the e-mail messages released by the press have bee taken out of context and that there was never an intention by GSK to cover up anything of any scientific value or validity.  We may get a better idea of what went on in GSK during the next few days and months as the FDA and others examine the case more closely. But the truth is almost irrelevant as far as the damage to GSK’s image and the deepening public distrust of the pharmaceutical industry is concerned. 

As the industry struggles to provide more and more personal care options for serious diseases such as cancer, the more the industry will be resented by the public.  It seems like Alice in Wonderland to me.  The industry provides drugs that work for small populations of seriously ill patients but must charge a high price to provide a sufficient return on investment to their shareholders.  If the industry can show that these prices are justified based on the value provided to society and for healthcare overall, then why should we complain?  There is, in any case, no way the industry can provide drugs designed for very small populations without charging a high price.  They would simply lose money.  So, while I can understand resentment at the high prices being charged, I also think a little injection of reality into public thinking wouldn’t hurt.

I say all this because one future direction for antibiotics is to provide curative treatment for seriously ill patients with particular resistant infections.  This would be another example of a small population where high prices for therapy would be required.  But with the industry shooting itself in its public opinion foot, all I see is the abyss for new antibiotics.

Antibiotics vs. Pricing

I just read a very interesting report entitled, “An Economic Assessment of the Relationship between Price Regulation and Incentives to Innovate in the Pharmaceutical Industry” published by the European School of Management and Technology (ESMT) and sponsored by Novartis (https://www.esmt.org/fm/479/WP-109-03.pdf).  A careful look at the data might suggest that much of the data used by the ESMT came from Novartis itself.   Much also came from the Tufts Center and from other publicly available documents.  The bottom line comes as no surprise to anyone involved in pharmaceutical R&D over the last couple of decades.  The less people are willing to pay for new drugs, the fewer new drugs we will have.  It’s actually quite simple. 

The ESMT report gets much more granular.  They look at various pricing strategies and their effects on pharmaceutical innovation. 

• ·      External Price Benchmarking, according to which the price of a drug in a country is pinned to the price of the same drug in a basket of other countries;
• ·       Internal Reference Pricing, according to which the price of a drug in a country is pinned to the price of similar, potentially already off-patent, drugs in the same country;
• ·      schemes based on a pharmaco-economic assessment, according to which the price of a drug depends on its cost-effectiveness.

One case example they use is Germany.  A better one, at least for antibiotics, might have been Australia.  These counties exemplify situations where, for advances in side effect profiles and ease of drug administration, where the molecule in question is not a totally new or novel class, governments won’t pay – or at least not very much.  In both cases there are examples where new drugs have simply not been marketed.  But if such policies were to spread to other world markets, this would clearly have a major impact on drug discovery and development within industry.

The fact that such pricing strategies are already having an effect can be seen by simply looking at the kinds of drugs in development in large pharmaceutical companies. A perusal of Clintrials.gov or the PhRMA website showed that there are 5-8 times more trials being carried out for cancer than for antibiotics. In the ESMT analysis, under almost all pricing scenarios, antibiotics are placed in the lowest priority among projects at various stages of development compared to all other therapeutic areas in a large pharmaceutical company.  Of course, this is patently ridiculous given what we know about the medical need for new antibiotics.  But it reflects today’s perceptions of pricing in a world where health care costs are government budget busters.

My conclusion is that in a world where drug-pricing strategies are designed to keep drug prices low even when drugs offer clear answers to important medical needs, antibiotics end up at the bottom of the priority list within the pharmaceutical company.  The company tends to focus on drugs where governments cannot argue too much over price – like cancer and Alzheimer’s disease. Antibiotics are not helped by the fact that they are miracle drugs and cure disease.  In fact, because there are cheap antibiotics that still work for many infections, antibiotics are hurt by their own success in most drug pricing scenarios. Even when they meet the medical need and innovation tests to justify a high price, the patient population to be treated becomes so small (Pseudomonas aeruginosa resistant to all other antibiotics) that the market is hardly worth thinking about. 

Reality check – Zyvox and Cubicin are high-priced antibiotics in most countries where they are sold. Cubicin was approved relatively recently.  Therefore, not too long ago, Cubist was able to defend its position during the drug pricing negotiations with most countries.  What this means is that the perception within industry does not necessarily reflect realities on the ground.  I think it also means that the pricing policies of many countries are not very transparent and what they say is not always exactly what happens.

My conclusions.

1.              Pressure on drug prices will, by necessity, mean fewer new drugs.  Period.
2.  Antibiotics, for many reasons, will still struggle to be prioritized within large pharmaceutical companies.
3.    Pharmaceutical companies need to improve their studies to demonstrate the societal and economic value of the antibiotics they bring forward to the marketplace.
4.    Governments need to be much more transparent regarding their pricing policies and their expectations for data justifying higher prices. 
5.     Governments also need to keep the problem of antibiotic resistant infections in mind in developing their pricing strategies for antibiotics in particular.

The day will come (unfortunately), as I noted in another recent blog, where antibiotics active against those resistant Pseudomonas will fetch 10s of thousands of dollars per course of therapy just like oncology drugs.

Europe?

Its been two years since the FDA has been struggling to provide guidance for sponsors trying to study pneumonia and skin and soft tissue infections.  In the meantime, the antibiotic approval drought at the FDA continues unabated as resistance fails to take a vacation.  So what’s going on in Europe?  Good question. 

The European regulatory authority, the EMEA, has stated categorically that the development of new antibiotics is its highest priority. This stands in stark contrast to the attitude at the FDA where standards based on 80 year old placebo controlled trials seem much more important than developing new antibiotics. I recently learned that the EMEA has not been following events at the FDA too carefully.  They are comfortable with their current position on pneumonia and skin infections as far as I can tell. As it stands now, Europe has no plans to provide guidance to sponsors on specific infections – they never have.  Europe has always been more flexible than the FDA but at the same time, less predictable and more variable in terms of both regulatory requirements for approval and ultimately for pricing within the individual markets of Europe. They have also been more difficult to deal with in that to discuss a topic with Europe, you must request Scientific Advice.  This meeting requires a set of advisors and takes several months to organize.  It has been much easier and more straightforward to communicate with the FDA.  Europe, on the other hand, has traditionally kept its word once advice is given whereas the FDA has been unabashed about changing its mind in the midst or even at the end of expensive Ph. III trials.

I have encouraged clients to approach individual European country agencies (e.g. MHRA in the UK or AFFSAPS in France) rather than Europe (EMEA).   Meetings are easier to arrange – but of course, the advice you receive may be different than what one might hear from the EMEA representing Europe.

Another problem in Europe is that even if you succeed in obtaining regulatory approval for your drug, you still have to negotiate the conditions of marketing and pricing with individual countries.  This adds to the delay in marketing in Europe and increases the uncertainty for companies.

So, with this in mind, how will Europe (EMEA/CHMP) deal with the recent FDA stance (or lack thereof) on pivotal trials in antibiotics?  Judging by past behavior, Europe will stick to its plan of not providing specific guidance for specific indications, but will be open to trials where the endpoints are as the FDA has specified.  Since, in the case of SSSI, there is a clear correlation between success at the early timepoint and success at the customary later timepoint, The EMEA will probably be happy with either.  The EMEA also understands that there are limits to what sponsors can do to run pivotal trials on a global scale – so they are unlikely to make sponsors use an endpoint in Europe that markedly differs from that required in the US. 

I would guess that the same arguments would hold when the FDA finally issues guidance on CABP.  The major issue there will be around trial feasibility.  In the case of CABP, my guess is that the EMEA remains happy with the old endpoints and that if the trials required by the FDA are infeasible, the EMEA will stick with its current approach.  This would theoretically allow registration of antibiotics for treatment of pneumonia in Europe that would not be acceptable to the FDA. 

Apparently, the CHMP will address at least some of this in a meeting this Fall.  Maybe, by then, we will have some idea of where the FDA will be going for trials in pneumonia.

Skin No. 4 - The World Turns

Sometime in early March, the FDA let it be known through the Infectious Diseases Society and others that they no longer knew how to set a non-inferiority margin for designing trials in serious infections of skin and skin structures (ABSSSI).  Since then, there have been a number of conversations with the agency including my own that I described in a previous blog (http://antibiotics-theperfectstorm.blogspot.com/2010/04/skin-infections-follow-up.html).  The last chapter involved a gathering on May 5 to explore whether there was a need for the NIH to carry out actual developmental work (clinical trials) to help establish the validity of endpoints in the study of complicated skin infections as described in the blog for May 23 (http://antibiotics-theperfectstorm.blogspot.com/2010/05/skin-no-3-fnih.html). 

Yesterday, Trius announced that they had come to an agreement with the FDA on endpoints for their proposed Ph. III trial in skin infections (http://www.triusrx.com/trius-therapeutics-news-100616.php).  They said, “The double-blind pivotal study will compare the efficacy and safety of once-daily oral administration of 200 milligrams of torezolid phosphate over six days of treatment to twice-daily oral administration of 600 milligrams of linezolid (Zyvox) for 10 days of treatment. The primary efficacy endpoint will be the cessation of spread of infected lesions and absence of fever at 48 to 72 hours following initiation of treatment. Secondary endpoints will include, among other things, sustained clinical response at the end of therapy visit, and the investigator’s assessment of clinical response at all visits and clinical success at the post treatment evaluation visit. Provided non-inferiority is met, an assessment of superiority of torezolid phosphate to linezolid with respect to the primary efficacy endpoint will also be made.”  I clarified that the NI margin will not apply to fever, but that patients will have to be afebrile at the 48-72 hour timepoint for the treatment to be considered a success.  Trius and the FDA agreed to a 10% NI margin. Lots of other questions remain regarding the proposed Trius trials such as how the trials will be blinded for example.  Nevertheless,  this is the first indication that the FDA has indeed applied what I believe will be the criteria for their new guidelines for the study of skin infections. 

The NI margin of 10% seems strict given the large treatment effect seen at the 48-72 hour end point. Even with some discounting - this seems excessive for the treatment effect of at least 20-40% compared to not placebo but to UV light which itself is efficacious. 

 This does not clarify what will happen to Paratek who were in the midst of their trials for PTK-0796 or to Forest who have completed their Phase III trials for ceftaroline under the old guidelines for skin infections.  Paratek apparently halted enrollment (see http://www.clintrials.gov) while awaiting new guidance from the agency. 

For companies embarking on programs in skin infections, there seems to be a feasible path forward.  This is nothing but good news for everyone involved in the discovery and development of new antibiotics. Formal guidelines from the FDA are expected sometime this summer. 

The Move from University to Industry was Murder!

When I left Case Western Reserve University to assume a position at Wyeth, it was two years after the Wyeth take-over of American Cyanamid (Lederle).  The anti-infectives group consisted of both an anti-bacterial and an anti-viral effort.  The group of about 35 people, which I was to direct, had still not really been assimilated into Wyeth.  Two weeks before I was due to start my new job, on a Sunday evening, I received a telephone call from the Associate Director for Viral Research, Dr. B.  I had not met him during my visit just a few days earlier when I was introduced to a number of the people who would be working for me.  Dr. B was clearly in a panic and was talking so fast (with an Irish accent), that I could barely understand him. I was told during my interview process that Wyeth management was considering jettisoning the entire anti-viral effort in order to focus on their anti-bacterial effort.  I had explained that if they were going to take that step, they would have to do so before my arrival.  The other choice for them was to await my arrival, let me review the program myself and make a decision on whether to continue the anti-viral effort or not.  All the employees were aware of the ax hanging over them.

Dr. B said something about murder – which got my full attention. 

“Say that again.”

“My boss, the Director of Antiviral Research, was murdered last night.  His wife and a cousin were discovered trying to ditch body parts in the Passaic River in the middle of the night.”

Of course, what I didn’t know was that the Director was like a father figure to his employees – they worshipped him.  I met the Director just a few days prior when I was at Wyeth for my pre-employment physical exam.  Dr. B was distraught to say the least.  Behind his immediate loss of a well-loved supervisor was his worry, and that of everyone else, about the potential loss of jobs and a way of life at Wyeth (American-Cyanamid (Lederle).  What could I do, anyway?  I was 600 miles away in Cleveland getting ready to move. I didn’t really know any of the employees nor did I know anything about their programs (at least in any detail).  (I leave you to reflect on this method of recruitment). 

“Please give everyone my sincere condolences.  Tell them not to worry about their job situation.  Nothing is going to change for now.  Everyone should spend some time dealing with his or her loss.  We’ll get to the programs after that.  Will you be able to take over leadership of the group at least until I get there?”  All this said before I had formally started working.

I called my soon to be new boss – Dr. J – and explained the situation that was brewing.  He had already been informed of the murder. He offered to get involved personally, but since the employees identified him with the threat of the ax, I counseled that he let me deal with the situation from Cleveland for the next couple of weeks.  He could always intervene if needed.  Dr. J agreed.  Dr. B and I had daily telephone conversations for the two weeks until my arrival in Pearl River, New York.

As it turned out, I thought that two of the programs in anti-virals were promising – one on CMV where the compounds turned out to be unstable and toxic, and the other for RSV where we made it all the way to Phase II before we discovered that the lead compound caused birth defects in animals and that program was terminated.  The anti-viral group survived and almost doubled in size during my tenure at Wyeth.  We even established an active collaboration with ViroPharma for the discovery and development of drugs targeting Hepatitis C virus.  After my departure, the entire anti-infectives group was laid off when Wyeth abandoned this field of research altogether.

I will never forget my experience of those first few weeks and months transitioning to industry from academia with the cloud of a brutal murder and the threat of mass firings hanging over both my new employees and me.  I’m sure they will never forget it either.  

Consolidation - the end of the big pharma model?

http://www.wikinvest.com/stock/Pfizer_(PFE)/Data/Market_Capitalization/2000

Explore more PFE Data at Wikinvest

Since the year 2000, what has Pfizer done?  Back in 2000, when I was at Wyeth, we were in the midst of merger talks with Warner-Lambert.  Warner-Lambert had acquired Parke-Davis in the 1970s and Parke-Davis had an antibiotics research group – so I was interested to say the least.  Then, just as things were about to draw to a close, Wyeth management was pushed aside by Pfizer, who apparently came in with a bigger pocketbook, and Pfizer became the acquirer, not Wyeth.  With Warner-Lambert, Pfizer also got Agouron, a hot new antiviral research group on the west coast that had several promising compounds in development.

In 2002, Pfizer acquired Pharmacia.  Pharmacia previously had acquired Upjohn, another antibiotics company, and Monsanto-Searle which had the very promising anti-inflammatory drug, Celebrex, in its late stage pipeline. This was a another case where Pfizer beat out Wyeth in the merger discussions to become the “winner.”  Celebrex did not turn out to be the barn burner it was predicted to be. And,  of course, in the ultimate “insult,” Pfizer acquired Wyeth last year.  How much did all these acquisitions cost?  $68 Billion for Wyeth alone.  

What has all this consolidation done for Pfizer?  Well, it allows them to obtain additional products and revenues while shedding jobs at the same time.  How many jobs have been lost from Pfizer and its acquisitions since 2000?  I don’t know.  100,000?  When I think about this in terms of antibiotics, we have now lost Upjohn and Parke-Davis antibiotics research partly as a result of Pfizer’s consolidation.  Wyeth had already cut their antibiotics research group prior to the Pfizer take-over.

Has the strategy worked?  Not if you look at market capitalization as shown in the chart above.  Since 2000, when Pfizer’s market cap was $264.2 Billion, it had shriveled to $119.6 Billion as of the end of 2009.  What about needed new medicines?  Have there been any additions to the Pfizer medicine chest as a result of all this?  If so – they haven’t been enough to stop an inexorable slide in investor value for the company.

The depressing part of the story is that Pfizer is not alone in its hunger for consolidation to salve its sorry pipeline.  Most of the large pharmaceutical companies have been pursuing a similar path with similar losses in both research, especially antibiotics research, jobs and market valuation.   To me, these data provide compelling evidence that the large pharma model is dying if not already dead.  We need a new way forward that I believe will involve much smaller and more nimble companies.

Skin No. 3 - the FNIH

Sometime in early March, the FDA let it be known through the Infectious Diseases Society and others that they no longer knew how to set a non-inferiority margin for designing trials in serious infections of skin and skin structures (ABSSSI).  Since then, there have been a number of conversations with the agency including my own that I described in a previous blog (http://antibiotics-theperfectstorm.blogspot.com/2010/04/skin-infections-follow-up.html).  The latest of these took place under the aegis of the Foundation for the NIH.  The reason for this gathering on May 5 was to explore whether there was a need for the NIH to carry out actual developmental work (clinical trials) to help establish the validity of endpoints in the study of complicated skin infections.  I was not invited to the meeting.  But – luckily – I have friends who were invited who provided me with the slides they presented. George Talbot, who organized the meeting, has sent an executive summary that he says is a public document. 

At the meeting, Ed Cox divided the possible process to select endpoints in the study of skin infections into three “Tiers.”  1) Current endpoints are acceptable and no modifications or studies are needed.  2) Development work is still needed but can be “piggybacked” onto ongoing or proposed trials.  3) Development work is required which must be carried out de novo, outside of current trial designs.   It would be within the last category that the NIH might be called into action.

Presentations by John Quinn of Pfizer and Philippe Prockocimer of Trius on trials of linezolid and TR-701 respectively, demonstrated that halting of spread of the lesion occurs in modern trials in a way similar to what was observed in the sulfonamide trials of the 1930s.  The same was actually true of fever, but in modern trials only 10-20% of patients were febrile.  As a biomarker, the lesion of ABSSSI is clearly on the disease pathway since it reflects bacterial multiplication, release of inflammatory factors, etc. and an antibacterial agent’s inhibitory effect on bacterial growth will lead to stabilization and then regression of the lesion. The working group at the meeting reached a consensus that this was both a feasible and desirable endpoint.  It is readily observable, it correlates with ultimate clinical outcome, and it allows for the enrollment of a diverse patient population. They rejected requiring fever for entry into trials since this would not be representative of the population to be treated in the real world and since it would render the trials much less feasible. The working group also recognized the need to ascertain some more sustained response at a later time point.

The FNIH working group will follow up these meetings to discuss a number of remaining questions.  Originally, they were also supposed to have discussed community-acquired pneumonia as well, but they focused on skin during the May 5 meeting.  Follow-up meetings could address pneumonia as well as some remaining questions on skin infections.

This is all interesting, but I wonder if it can possibly have any effect at all on the draft guidance on trial design in skin infections that the agency has said was to appear imminently (around July).  I believe, however, that the FNIH discussion is in line with what the agency will propose in their guidance in any case.  The remaining questions for me, that were not listed in proposed agendas for future FNIH meetings, are; 1) What will the non-inferiority margin be given that the treatment effect of antibiotics on halting the spread of lesion measured at 48-72 hours is well over 30% when compared to UV light treatment which, itself, is more effective than placebo? 2) Will prior antibiotics be proscribed given the potential effect on an early response? (I suspect we can already assume that prior antibiotics will not be allowed). 3) If only cellulitis is studied, in the context of wound infections, ulcers, abscesses, etc., will the label require cellulitis or erysipelas?  How restrictive will the language be and will the FDA force physicians into situations where off-label use is the rule or is very common?  Given a reasonable NI margin, I believe that the trial design as contemplated will be feasible and clinically relevant (thank goodness).  But until the draft guidance appears, we remain in a sort of limbo. 

I understand that the FDA is providing guidance to those companies caught by this reconsideration of design in skin trials, but I have no insight into what this guidance could be.  Forest seems especially vulnerable since they have already completed their pivotal trials and submitted their NDA to the agency. 

As far as I can tell, there has been no substantial progress in the pneumonia discussions.  I do not know where the agency is now in their thinking. I understand from at least one company that the FDA has been very helpful in the design of their trials in pneumonia. As always, for both skin and pneumonia, we await further developments.