Thursday, December 28, 2017
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
The National Academies of Science, Engineering and Medicine recently released a reportOverall 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.
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
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.
Sunday, November 19, 2017
Last week I was honored to give the Philip Lerner Memorial Lecture at Case Western Reserve University School of Medicine, my alma mater. I talked about the economics of antibiotics and the broken antibiotic market. Surprised? But I want to talk to you today about another aspect of my visit. I went to their infectious diseases case conference where fellows training in infectious diseases and attending infectious diseases physicians discuss difficult cases as a way of educating themselves and to find solutions for patients.
One case was a patient with a particularly serious lung infection caused by a carbapenem-resistant Enterobacter cloacae and a carbapenem-resistant Stenotrophomonas maltophilia. Aspergilus fumigatus was also identified as part of the mix. By the time the case conference was meeting, the patient had already passed away from his underlying disease and this polymicrobic lung infection. But the physicians present discussed his treatment to show how they were able to piece together a therapy that at least offered some hope for the patient and his family.
The Enterobacter was shown not to produce a carbapenemase. It was in fact, probably a strain with reduced expression of porins combined with a high level of expression of its chromosomal B-lactamase. It was susceptible to sulfamethoxazole-trimethoprim (Bactrim) and to ceftazidime-avibactam. The results for colisitin were not even mentioned. The Stenotrophomonas was typical and was susceptible to sulfamethoxazole-trimethoprim and to aztreonam. This result is because the carbapenem resistance in this isolate was caused by the normal, chromosomally encoded metallo-carbapenemase, L1. Aztreonam is resistant to hydrolysis by L1. The patient was treated with a combination of ceftazidime-avibactam, aztreonam and voriconazle (for the Aspergillus), but the family rapidly withdrew therapy agreeing with their physicians that further therapy would be futile given the disease underlying this terrible infection.
Even though this patient could not be saved, his physicians were able to construct a potentially life-saving therapy for him. Without ceftazidime-avibactam, it is unlikely that other therapies would have even been effective. Sulfamethoxazole-trimethoprim has no real track record in the treatment of serious lung infections with Gram-negative pathogens like those infecting this patient. The other alternative would have been colistin or polymyxin, which, as we know, is both toxic and not very efficacious.
Of course, the combination of aztreonam plus ceftazidime-avibactam, like so many antibiotic combinations we put together for desperately ill patients, is a construct for which there is no good data. We don’t really know if the dosage chosen based on current FDA labels for the individual components of this combination are optimized. But aztreonam-avibactam is in the late stage pipeline and would have been adequate based on careful PK/PD modeling of the dose being studied. A PK study in seriously ill hospitalized adults has been completed and an efficacy trial in such patients is about to start recruiting (finally!!). Lets get a move on, Pfizer!
The physicians at the case conference asked me a difficult question. Why, they asked, was ceftazidime chosen as the partner for avibactam and not aztreonam. In fact, we struggled with this question back at Novexel because we knew that both drugs would have been good partners on a scientific basis. We hesitated about aztreonam mainly because it simply was not used clinically outside the realm of clinical trials. Its main advantage over ceftazidime, as demonstrated by our patient, is that it resists hydrolysis by the metallo-B-lactamases such as L1. At Novexel we thought that these infections were still rare in most areas of the world and we didn’t know whether they would increase in frequency or not. So we divised a strategy to develop both ceftazidime-avibactam and, shortly thereafter, aztreonam-avibactam. In fact, one of the constant arguments against pursuing aztreonam-avibactam was that physicians would simply use the very combination utilized for our patient. We thought that we needed a strong dosage rationale that would optimize therapy compared to the dosing physicians might randomly choose in administering this combination for which there is precious little data. Our strategy was ultimately taken over by AstraZeneca (now at Pfizer) and Forest (now Allergan) and the rest is history.
Without ceftazidime-avibactam, and hopefully in the not too distant future, aztreonam-avibactam, and other therapies to come, patients and physicians will be left with few options for patients like this one. There are probably thousands of patients around the globe with infections like this one where, unlike our case, patients have a real chance at full recovery from their infection – given that we have effective antibiotics with which to treat them. Our hope lies in the continuing availability of new antibiotics (and maybe other antibacterial therapies). That hope is not going to be realized given today’s paltry pipeline.