David's New Book

Thursday, January 18, 2018

Antibiotic Price Perversion

I am hoping that readers with access to antibiotic usage data will be able to help here.

One of the legs upon which antimicrobial stewardship rests is to assure that the most efficacious and safe antibiotics are used in the appropriate dosage for the appropriate length of time in the context of any given infection. Based on numerous discussions with infectious diseases physicians, microbiologists and companies over the last 30 years, I believe that this approach to the use of antibiotics is undermined by the pricing within the antibiotics marketplace. 

One can only (with some exceptions) use antibiotics that are available within one’s institution or organization – that is – those that are on formulary. Formulary committees vary somewhat in how they make decisions as to which drugs to make available to physicians and patients, but most take into account clinical data, pharmacoeconomic data, microbiology and price.  They then try and make a value decision. Two factors work against new antibiotics. Generics like colistin are cheap. Most clinical data comes from non-inferiority trials. Pharmacoeconomics and microbiology may act to counter negative factors, but then there is the overall pharmacy budget.  In institutions, regions, and nations where the budget is tight, generics will be favored. Was linezolid favored by antimicrobial stewards for the treatment of MRSA pneumonia – even after it was shown to be superior to vancomycin? I don’t think so. (As I noted in a previous blog, there may have been a number of reasons for this).

One particular comment from a European expert sticks in my mind. We were discussing the issue of value-based pricing for antibiotics.  I was speculating on what the price for a new drug specific for Acinetobacter, for example, would have to be to provide a return on investment for its sponsor.  The discussion was based on a 2013 meeting held by Pew Charitable Trusts. When I mentioned prices ranging from $10,00 to $30,000 per course of therapy, this expert recoiled in disgust saying that in their country they would just continue to use colistin. This was in spite of the fact that at the Pew meeting, insurers had expressed a willingness to cover such costs depending on the data supporting the safety and efficacy of the antibiotic in question. I was shocked – but also na├»ve. This opinion was frequently stated by experts and pharmacists during market studies prior to the launch of Avycaz.

Recently, two antibiotics were shown to be superior to colistin both in terms of safety and efficacy – ceftazidime-avibactam and plazomicin. Of those, only Avycaz is currently marketed (plazo awaits regulatory approval).  A recent prospective observational study of caz-avi demonstrated a 9% mortality in the caz-avi group vs 32% in the colistin group – a 23% reduction in mortality when caz-avi was used as compared to colistin. Most infections treated were pneumonia or bloodstream infections. Renal failure was significantly more common the the colistin group and overall, there was a 64% chance that caz-avi treatment would lead to a better outcome compared to colistin.  A third new antibiotic, Vabomere (meropenem-vaborbactam),  has shown superiority to “best available therapy” (that often included colistin or polymyxin) in the treatment of infections caused by carbapenem-resistant pathogens.    It is now being marketed by Melinta.  

Given that cetazidime-avibactam has now been available globally for a period of time, and given good clinical practice and good stewardship, it should be replacing colistin/polymyxin in terms of prescription volume.  But sales data for 2016 do not yet bear this out.  Apparently, the cost of Avycaz in North America at around $8000 per course of therapy remains prohibitive. Vabomere is priced at about $5000-$10,000 or so per course of therapy as far as I can tell.  I have been unable to examine prescription volumes for these drugs to further substantiate my fear.  But I strongly suspect that the price perversion of the marketplace is leading to continuing use of inferior antibiotics when new but much more expensive antibiotics would be a better choice for patients.

I hope that one of you out there can help research this topic by examining prescription volumes (or by other methods) . . .

I think that all physicians and patients would agree that inferior therapy should not be used for potentially life-threatening infections. The question is – which price are we willing to pay – the price in dollars or the price in lives?

Friday, January 5, 2018

2017 in Review

Once again – Happy New Year to everyone!  2017 was an eventful year and I want to review briefly a few of the highlights (and low lights) for me.

The most worrisome issue that we still face is that of pull incentives for antibiotic R&D. DRIVE-AB has published a summary (this is a link to my blog on this topic) of their recommendations, but their final report originally planned for November is still not available.  Among other options, they highlighted the hybrid model where a market entry award would partially “de-link” revenues from sales volume.  In this model, a company would receive a sum of money on a contractual basis over the first several years after market entry.  At the same time, sales would be allowed to occur and revenues could increase over time. Another model discussed by several experts (see the same blog) was the patent exclusivity voucher approach.  I favor both of these.  The bad news is that NO ONE is making clear progress bringing one of these to reality.   There are more and more papers, reviews and yes, blogs, on the topic but as far as I can tell, there is no concrete action like legislation either here in the US or I Europe that is likely to actually become law in 2018.  But we can always hope.  We should also ACT and keep up pressure on our representatives in government to make this happen.  As I’ve said many times, this is the last frontier!
Linked to the failure to fix the broken antibiotics market, in my view, is the sale of the Medicines Company antibiotics assets to Melinta occurring just after the approval of MedCo's anti-KPC drug Vabormere.  Melinta’s delafloxacin was also just approved in 2017. It remains to be seen what will happen to the outstanding antibiotic research group that was housed within the Medicines Company and that discovered the B-lactamase inhibitor that is part of Vabormere, vaborbactam. I strongly believe that if there had been a market entry reward for which Vabormer would have qualified, the Medicines Company would not have been so quick to jettison their antibiotics assets and their researchers (see my blog on this).

There were a number of developments on the regulatory front in 2017.  I did not blog on all of them – but John Rex is keeping careful track of all these developments. I believe that we will see a guidance in 2018 on the development of antibiotics specific for pathogens like Acinetobacter baumanii and Pseudomonas aeruginosa. John covered the FDA workshop on animal models for pathogen specific antibiotics in March of 2017 for this blog.

The European Medicines Agency is moving from London to Amsterdam.  I am not sure what, if any impact this will have on the way Europe views antibiotic R&D. I worry about this move since I think that the EMA in London has been a shining light for all of us even in the face of the darkness that surrounded the FDA for a number of years. I also worry somewhat about the efforts at harmonization currently gong on between FDA, EMA and other regulatory agencies.  On the one hand, this could be a very good thing and will simplify trial designs for antibiotics.  On the other hand, I am hoping that we can forgo some of the early endpoints that the FDA uses for antibiotic trials in pneumonia and skin infections.  I still favor cure at test of cure as required by EMA as an endpoint here.

The numbers of antibiotic approvals has risen in the last five years.  Whether this will be a sustainable trend or not and whether the drugs in development will truly address the new WHO priority pathogens or not remains to be seen.

A potentially important highlight for 2017 was the paper by Richter et al on how antibiotics enter Gram-negative bacteria and avoid efflux. This was the topic of the blog in May. Richter and coworkers showed that a primary amine was good, rigid was better than flexible and flat was better than globular. Whether these rules will turn out to be universally applicable is not clear – but to me, this was a major milestone.  At the same time, a proposal that I helped formulate to establish a Manhattan Project to attack this very problem, we called it OMEGA, never succeeded in getting the necessary funding to get it off the ground.

In 2017 I saw how physicians face difficult decisions on how to treat highly resistant Gram negative infections every day on hospital wards. The case described in the blog I linked was one where ceftazidime-avibactam was a key component of the therapy that was required for this complicated polymicrobic infection. I am gratified that avibactam plays this role and I only hope that other B-lactamase inhibitor combinations that can be useful, such as aztreonam-avibactam, eventually see the light of day in the marketplace.

I hope that 2017 will mark the beginning of the end for colistin and polymyxin. At least two antibiotics have now been shown to be superior to these drugs that are highly toxic and not very efficacious.  I worry that antibiotic pricing will continue to apply pressure on hospitals and physicians to use these inferior therapies and I will have more to say about that in an upcoming blog.  Stay tuned.

In the meantime, I wish all of you a healthy and happy year to come and I fervently hope that some form of market entry reward becomes a reality in 2018!

Thursday, December 28, 2017

Flu Vaccine - Buyer Beware!

 OK.  This is a little removed from antibiotics.  But I'm still an infectious diseases physician and this situation makes me angry!

Before beginning my story, let’s review a little bit about influenza vaccines. For a long time we’ve known that older patients and those with certain underlying diseases such as kidney failure, diabetes and others had a lower response to many vaccines than young, healthy subjects. One way to deal with this problem might be to give the vaccine in higher dosage.  This has been done with hepatitis B vaccine in patients with kidney failure as one example – and it does work. Very recently, the same strategy was applied to flu vaccine. A high dose vaccine was developed by Sanofi-Pasteur (Fluzone).  In a clinical trial published in the New England Journal of Medicine, researchers demonstrated that the high dose vaccine was 22-45%more effective at preventing flu than regular vaccine in patients 65 years of age or older. Another study examined all respiratory illness occurring during flu season among older vaccine recipients. This study demonstrated a 13% advantage for the high dose vaccine. There are two other new flu vaccines that may also work better in older patients but the data to support that conclusion for those vaccines is much less strong than the data behind Fluzone (see below). So there is at least one flu vaccine available that works better than other vaccines.

This story starts two years ago at an assisted living facility here in Connecticut where my mother was living at the time. During the winter my mother was telling us about several friends who had contracted “pneumonia” and ended up hospitalized. Some never came back.  I asked the administration at the facility which flu vaccine was offered to the residents the previous fall and discovered to my surprise that they did not offer the high dose vaccine to their elderly residents.  The average age there was probably around 80. I then sent them information on the high dose flu vaccine and asked that they offer it to their residents the next year (last year) – and they did. This past spring my mother moved to another assisted living facility in Connecticut. Thinking ahead, I sent them information from the CDC website on the high dose vaccine and asked them both in writing and in person to make it available for their residents this past fall.  In spite of my request, they decided not to offer the high dose vaccine even though I think the average age of their residents is probably close to 75.

That led me to search for pharmacies that would offer the high dose vaccine.  I called three CVS pharmacies in our area. One had the vaccine early on but had already run out by the beginning of November. A second had never ordered the high dose vaccine.  The third had it available. My personal physician also offered high dose vaccine for all his patients age 65 years and older and that’s where we finally went to get our vaccinations. Further inquiries showed that the high dose vaccine was 2-3 times more expensive than the regular vaccines.  But the vaccine is reimbursed by Medicare at a higher rate as well.  My physician’s office staff confirmed that they did not lose money nor make less money giving the high dose compared to regular flu vaccine. But the higher procurement cost may have deterred some providers from ordering the high dose vaccine.

In discussing this situation with friends and with other residents at my mother’s facility, I was surprised to find that no one knew that there was a high dose vaccine and no one knew that there might be an advantage in taking the high dose vaccine compared to any other vaccine. I also called the Connecticut Department of Health and learned that they and no specific policy on which vaccine long term care facilities in the state should offer.  They said that they just go by what the CDC recommends.

 And that brings me to the CDC and Advisory Committee for Immunization Practices (APIC). APIC provides recommendations as to which vaccine should be given to which population in what dosage, when and how often. In many cases, these recommendations serve as guidance for insurers for reimbursement policies especially for childhood vaccinations. In considering flu vaccines, the APIC has decided NOT to make a specific “preference” for the high dose flu vaccine for subjects 65 years of age or older.  As such, state health departments and providers have no incentive to offer this vaccine.  Since procurement costs for the vaccine are higher, they may be reluctant to order the vaccine even though it may be better for their patients and their reimbursement will make up the difference in cost.

I spoke with Dr. Lisa A. Grohskopf who is the CDC’s liaison with the APIC. She explained that there are 13 different influenza vaccines available this season of which two are licensed for use in persons aged 65 years of age and older. They are Fluzone, a high dose killed vaccine, and Flublock, a recombinant flu vaccine also using a higher dose of antigen. Data from various clinical trials are shown in table 3 from this CDC webpage. The best data including a study carried over two seasons and enrolling about 32,000 subjects are those for Fluzone*. The improved efficacy ranges from 22-45% improvement as compared to standard dose vaccines depending on which population you are looking at. The APIC will not provide a specific “preference” for this vaccine because (1) there might be differences across different flu seasons (only two were studied); (2) it was not compared to other high dose or newer adjuvanted vaccines; and (3) it is not clear that the manufacturer would have been able to provide it to a larger popultion.  (I did not speak to Sanofi-Pasteur about this). But to me – this reasoning is specious since there was a large randomized trial showing consistent improvements in efficacy across several different analysis populations in two different flu seasons for Fluzone.  If the objection is that it should have been compared to other high dose or adjuvanted vaccines – that seems unreasonable.  Those other manufacturers should be encouraged to come up with the same kind of data that Sanofi-Pasteur provided in order to get a preference for use in older individuals.

The end result of APIC’s dithering is that no one understands that there is a better vaccine available for older individuals and therefore, that those who need it don’t get it. 

*I did not count the study shown in the table from 2009-10 where the virus circulating was not present in the vaccine and therefore no conclusions about the relative efficacy of the vaccine could be drawn.

Friday, December 15, 2017

Drug Pricing in America

The National Academies of Science, Engineering and Medicine recently released a report on drug pricing.  They also touch on drug shortages. They conclude with Overall sales of biopharmaceuticals globally is over $900 million.  The US accounts for 46% of these revenues.  The next most important region is Europe that accounts for only 21%. Americans spend 30-70% more on drugs on a per capita than other developed countries. 

In one of the most ironic observations for me, the report notes that the median monthly cost of cancer drugs at the time of FDA approval increased from approximately $1,500 in 1965 to $150,000 in 2016, stated in constant 2014 dollars…. The complexity of these issues is noted in one study that found that the average price of an episode of treatment using anti-cancer drugs is $65,900 and results in an average survival benefit of 0.46 years (not quality-adjusted). At the same time, the antibiotics market, for drugs that actually save lives, has withered.

Why is this true, what should we do about it and what are the potential consequences of our decisions? The National Academies report delves into this subject in detail and with gust. They provide a number of key recommendations falling under eight general categories.  But – there is little new here and there is nothing we haven’t known for years.  When I was working at Wyeth in the 1990s, the US accounted for 55% of global pharmaceutical sales and profits far outstripping the contributions of other regions.  The reason was and remains the drug pricing structure in the US.  We remain one of the few nations in the world that has no national negotiation for drug pricing. Every time this topic would come up back then (and even now), the industry would cry that any change that reduced their ability to charge higher prices would have an effect on innovation.  And that might be true.  The industry supports its research and development with its profits – usually plowing 10-20% of profits back into research. In this sense, many would argue that the US is subsidizing pharmaceutical research for the rest of the world. If the US were to become like other countries with a more rational approach to negotiation for drug pricing, these revenues would fall. Therefore, research dollars would also likely decline. Why, you might ask, would other countries not pick up the slack? Are you kidding? That seems unlikely to me. But national negotiations for drug pricing is one of the top recommendations by the Academies.

Another key recommendation is to speed generic entry where drug prices can fall as much as 80% or more. At the same time, the loss of competition among generic manufacturers through mergers and other agreements has led to dramatic increases in generic drug prices over time. An overwhelmed FDA has been slow to approve generics – another area that could use improvement – as in more resources.

Drug shortages is a complex problem with multiple causes none of which seem to be the major cause. I refer you to the report for more details here.

The key recommendations from the Academies are listed below.

Recommendation A: Accelerate the market entry and use of safe and effective generics as well as biosimilars, and foster competition to ensure the continued affordability and availability of these products.

Recommendation B: Consolidate and apply governmental purchasing power, strengthen formulary design, and improve drug valuation methods.

Recommendation C: Assure greater transparency of financial flows and profit margins in the biopharmaceutical supply chain.

Recommendation D: Promote the adoption of industry codes of conduct, and discourage direct-to-consumer advertising of prescription drugs as well as direct financial incentives for patients. (I have always hated direct-to-consumer advertising).

Recommendation E: Modify insurance benefits designs to mitigate prescription drug cost burdens for patients.

Recommendation F: Eliminate misapplication of funds and inefficiencies in federal discount programs that are intended to aid vulnerable populations.

Recommendation G: Ensure that financial incentives for the prevention and treatment of rare diseases are not extended to widely sold drugs.

Recommendation H: Increase available information and implement reimbursement incentives to more closely align prescribing practices of clinicians with treatment value.

Thursday, November 30, 2017

Linezolid - A Case Study

In thinking about pricing of antibiotics as it relates to revenues, I wanted to go back and think about linezolid as a case example. Linezolid was approved in 1999, at the very height of the global pandemic of MRSA (methicillin-resistant S. aureus) infection and during endemic levels of VRE (vancomycin-resistant enterococcus) infection especially in the US.  At the time, the only recognized effective therapy for serious MRSA infection was vancomycin.  Vancomycin has always been thought to be inferior to B-lactams for the treatment of staphylococcal infections based on scanty data.  But I was certainly convinced. Vancomycin also had its problems with safety – especially nephrotoxicity- mainly when used with other potentially nephrotoxic agents such as furosemide or aminoglycosides. Linezolid was associated with anemia and thrombocytopenia – but this was related to therapy that went beyond the usual 7-10 days for most infections. Vancomycin could only be used intravenously for MRSA infections, while linezolid was available both in intravenous and oral formulations.  This allowed earlier discharge from hospital for many patients. Based on this major advantage, and based on the availability of generic vancomycin at the time, linezolid was sold as the highest priced antibiotic in history at around $1800 for a course of therapy. And, its peak year sales reached somewhere between $1.5 and 2 billion in spite of it being reserved because of its high price.  One analysis I did showed that in North America, oral linezolid was an important driver of revenues while IV linezolid was the main driver in Europe. I was at first surprised that the oral form was not more important in Europe, but I realized later that in those days, rapid hospital discharge was not such an important issue for the Europeans as it was in the US.

One of the great debates of the day was bactericidal vs bacteriostatic therapy.  Vancomycin kills bacteria, albeit slowly compared to B-lactam antibiotics.  Linezolid inhibits bacterial growth without killing them. The worry always was that linezolid would be an inferior therapy of very serious infections like nosocomial pneumonia because of this difference. But linezolid was better at penetrating into respiratory secretions than vancomycin and in clinical trials was always easily shown to be non-inferior to vancomycin.

To address this potential shortcoming head-on, Pfizer undertook a randomized, controlled, double blind trial of linezolid vs. vancomycin in MRSA pneumonia.  The trial (Zephyr) included all comers including those who had acquired their infections outside the hospital (HCAP) who accounted for about 15% of the patients in this trial. By way of background, it is important to understand that about 30% of all staphylococcal infections in US hospitals at the time of the trial were caused by MRSA. A study in emergency rooms showed that up to 70% of staph infections were caused by MRSA.  This is probably the most dominant form of multiple antibiotic resistance ever seen before or since. In spite of the extent of spread of MRSA, the trial was slow to enroll taking over 5 years to enroll 1184 patients from 156 centers globally. Patients were required to have a positive culture for MRSA. The endpoint was clinical cure or improvement at End of Study (7-30 days after end of therapy).  Mortality at 60 days was also an endpoint, but I view that as irrelevant since at that point, most mortality is probably related to underlying disease and not the pneumonia.  Therefore this would always tend to be similar across groups assuming that the distribution of underlying disease was similar as was the case for this trial. Clinical cure was defined as resolution of clinical signs and symptoms of pneumonia, compared with baseline; improvement or lack of progression in chest imaging; and no requirement for additional antibacterial treatment. The trial was designed as a non-inferiority trial (NI margin 10%) with a possibility for nested superiority. Of the 1184 patients enrolled, only 348 were evaluable at the end of the study.

The results of the study showed that 57% of linezolid treated patients had a positive clinical response compared to 47% of vancomycin-treated patients. This is a statistically significant and a clinically relevant difference (p=0.04). Similar differences were observed when looking at microbial eradication or presumed eradication where linezolid was also superior. Kidney toxicity was twice as common in the vancomycin group but anemia and thromobocytopenia were equal between the treatment groups.

When this study was published in 2012, I thought that this would be followed by greater use of linezolid.  Wrong.  Why? Well, several economic analyses based on the results of the trial were carried out and came to varied conclusions.  The main driver for an economic advantage for linezolid was the kidney toxicity associated with vancomycin in the trial. But for some analyses (in Europe), this was not enough to overcome the increased drug costs of linezolid. Early discharge from the hospital in these studies did not seem to be all that important.  The one analysis where a clear economic advantage was shown was done in the US where shorter length of stay coupled with lower nephrotoxicity supported an advantage for linezolid.  

The other issue might have been the statistical “fragility” of the data.  Just a few patients either way would have swayed the data and superiority for linezolid would have been lost.

The other lesson, if there is one here, is that the trial was extremely expensive and took over five years in over 150 centers. And this occurred in the face of high resistance rates. Carrying out trials targeting resistant pathogens with lower rates of resistance is going to be harder and we hope unnecessary.