Here's some more BG reading on ABSSSI I pulled from that monster report on the development of Antibacterial drugs released by the Dept of HHS... good stuff, if a long read (shhh don't tell the boss) I tried to pull most relevant parts -- market size, costs, mortality/morbidity See actual revenue data on Cubicin uptake following Market Launch (2003-2012), as well as expected market share for a new antibacterial drug Bottom-line, Brilacidin as 1-dose (fingers crossed) then cost-savings alone (plus fewer side effects, less chance of resistance) ought to convince many docs to switch to Brilacidin, hospitals to push protocols emphasizing B over other drugs I posted this yesterday (worth posting again), but this research out of ASU (antimicrobial peptides) also backs up Brilacidin MOA https://asunews.asu.edu/20141217-antibiotic-research-asu (note: Tables don't come across, might want to go to original article) Analytical Framework for Examining the Value of Antibacterial Products http://aspe.hhs.gov/sp/reports/2014/antibacterials/rpt_antibacterials.cfm#_Toc382832100
ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTION (ABSSSI) A.2.1 Background Acute bacterial skin and skin structure infections (ABSSSIs) are a subgroup of skin and soft tissue infections (SSTIs), which are commonly occurring microbial infections of the epidermis, dermis and subcutaneous tissues For the purpose of clinical trial design, ABSSSIs are defined by FDA guidance to include such conditions as cellulitis/erysipelas, wound infections, burn infections, cutaneous abscesses, and impetigo. Infections of animal or human bites, necrotizing fasciitis, diabetic foot infections, decubitus ulcer infections, myonecrosis, ecthyma gangrenosum, and catheter-site infections are specifically excluded because they generally require different medical management than ABSSSI. SSTIs can have diverse etiologies, and identification of the causative agent is often difficult; however, the majority of SSTIs are caused by Staphylococcus aureus and streptococci. The economic burden associated with SSTIs is substantial and growing. Total hospital admissions for SSTIs increased by 29 percent between 2000 and 2004 and the number of visits (and visit rate) to ambulatory care facilities increased from 8.6 million (32.1 visits per 1000 population) to 14.2 million visits (48.1 per 1000) between 1997 and 2005. These increases have been attributed largely to increasing resistance to antibacterial drug agents among the microorganisms that most commonly cause these infections especially methicillin-resistant Staphylococcus aureus (MRSA) According to a recent study, the total economic burden of S. aureus infection was estimated to be $14.5 billion for all inpatient stays in 2003 A.2.2 Current Treatment While uncomplicated SSTIs may be treated in the outpatient setting with oral dicloxacillin–flucloxacillin or cephalexin (or, alternatively, penicillin, amoxicillin/clavulanic acid, macrolides, tetracyclines, or clindamycin), more serious SSTIs often require parenteral administration of antimicrobial agents, such as ceftriaxone, clindamycin, penicillins, and cefazolin In cases of complicated SSTIs caused by MRSA, intravenous administration of vancomycin, linezolid, daptomycin, telavancin, or clindamycin is recommended. Outpatient treatment of MRSA infections may involve oral clindamycin, trimethoprim-sulfamethoxazole, doxycycline, minocycline, linezolid, or cephalexin. 3.2.13 Total Market Size As noted in Section 1.3, we obtained data on drug expenditures from IMS Health through FDA’s third party agreement. Based on antibacterial drugs approved for the treatment of each of the six indications, IMS Health provided data on total sales of these drugs across all indications by formulation (oral or IV) for the years 2007 to 2011. Using these data, we estimate market size based on 2011 sales in three different ways: § Estimate 1: Total sales of antibacterial drugs that are in the formulation of interest (i.e., oral or IV) labeled to treat the indication. § Estimate 2: Total sales of all antibacterial drugs in Estimate 1, plus other formulations of the antibacterial drugs in Estimate 1, plus any other antibacterial drugs (in any formulation) approved to treat the indication. § Estimate 3: Total sales of all antibacterial drugs in Estimate 2 plus any antibacterial drugs that compete with antibacterial drugs in Estimate 2 for treating other indications (i.e., if a drug included in Estimate 2 is also used to treat another indication, all other drugs used to treat that other indication are added to the total sales calculation for this final estimate). Due to the extent of overlap among drugs used to treat these indications, Estimate 3 is the same across all indications considered ($9.23 billion). The three estimates are intended to reflect differing visions of drug manufacturers as they consider potential market size. The smallest estimate is for the drug and formulation specifically under development, which represents the most conservative or narrowly defined market vision. The medium estimate represents the larger potential market for treating the same indications, but also reflects the possibility that the NME can be formulated for oral administration as well. The largest estimate represents all potential antibacterial drugs with which the NME might compete if it can also be approved to treat other indications. Table 10 presents the total market size estimates for each indication under consideration. The lists of drugs used for each type of estimate are included in Appendix A. Table 10: Estimates of Total Market Size, by Indication (in $ Million) Estimate ABOM ABSSSI CABP CIAI CUTI HABP/VABP 1 $2,720 $3,070 $2,290 $2,530 $5,760 $1,780 2 $2,950 $6,590 $7,970 $4,660 $6,540 $3,470 3 $9,230 $9,230 $9,230 $9,230 $9,230 $9,230 Source: (IMS Health, 2012) For the model, we assume that the total market size for each indication has a uniform distribution with Estimate 1 and Estimate 3 constituting the lower and upper bounds, respectively. Additionally, Estimate 2 serves as our point estimate in the model. 3.2.15 Market Uptake for a New Antibacterial Drug over Time Table 11 presents sales data on Cubicin (daptomycin,) an antibacterial drug launched in the U.S. in 2003. Cubicin is indicated for the treatment of complicated skin and skin structure infections (cSSSI) and Staphylococcus aureus bloodstream infections, including cases caused by methicillin-resistant Staphylococcus aureus (MRSA). As can be observed from the figure, it takes an antibacterial drug much longer to achieve peak year sales compared to other drugs. According to Shlaes (2010), healthcare providers have little incentive to use the antibacterial drug unless it addresses an immediate antibacterial drug resistance problem. Physicians will restrain their use of the new drug to avoid rapid emergence of resistance to the new agent thereby slowing down market uptake. In the model, assuming no real change in antibacterial drug reimbursement, we use the rate of uptake reported in Table 11 as the typical rate for a novel antibacterial drug. Assuming that the novel drug would be able to capture between 27 percent and 12 percent of the total market (see previous Section 3.2.14 for a discussion on the basis for these numbers) when it reaches its peak year sales. Table 12 presents the market size estimates from launch year to peak year sales years which is reached approximately 10 years after product launch. Table 11: Annual Total Net Revenues for CUBICIN from Launch (2003) to 2012 Year Total Net Revenues Year-to-Year % Change 2003 $3.7 0% 2004 $68.1 1741% 2005 $120.6 77% 2006 $194.7 61% 2007 $294.6 51% 2008 $433.6 47% 2009 $562.1 30% 2010 $636.4 13% 2011 $754.0 18% 2012 [a] $915.0 21% Source: Cubist, 2013 [a] The figure is the midpoint of the reported range of $900 to $930 million.
Table 12: Expected Market Share Estimates over Time for a New Antibacterial Drug Year Market Share Product Launch Success Probability [a] Expected Market Share Lower Bound Upper Bound 1 (Launch) 0.05% 0.11% 60% 0.07% 2 0.87% 1.91% 1.29% 3 1.57% 3.47% 2.33% 4 2.57% 5.68% 3.81% 5 3.92% 8.64% 5.81% 6 5.79% 12.77% 8.58% 7 7.52% 16.59% 11.15% 8 8.52% 18.80% 12.63% 9 10.10% 22.30% 14.98% 10 12.27% 27.08% 18.19% [a] See Section 3.2.12 for further discussion on the basis for this parameter The expected market share is computed as: (Lower Bound % × [1 – 60%]) + (Upper Bound % × 60%) 3.6.3 Percentage Increase in Disease Duration for Patients Not Responding to Existing Commonly Used Antibacterial Drugs There are no publicly available estimates of how long each of the different types of illnesses last in patients who do not respond to existing commonly used antibacterial drugs. Thus, for analysis purposes, we assume that those patients who do not respond to existing drugs have an average duration of illness 50 percent longer than those who do respond. For sensitivity analysis purposes, we further assume that the parameter follows a uniform distribution with a lower bound of 25 percent and an upper bound of 100 percent. In the analysis, we further assume that 1) all those not responding to existing commonly used antibacterial drugs respond to the new drug and 2) their duration of illness is reduced to the average of those responding to existing drugs.[13] Combining these assumptions, we then calculate that a new antibacterial will reduce the total social burden of illness by about 9 percent. This estimate is highly uncertain, as we do not know the actual improvement in patient response to a hypothetical new antibacterial drug. It should also be noted that this does not imply that the new antibacterial drug will avert 9 percent of deaths attributable to the different types of indications studied here. Given data limitations, our analysis cannot distinguish between avoided mortality and morbidity cases due to the new antibacterial drug. We only are able to compute overall reductions in the total social burden of illness due to these new drugs in monetary terms. Table 16: Reported Estimates of Antimicrobial Resistance Source % of Patients Resistant to Commonly Used Antibacterial Drugs Evans, et al., 2007 [a] 23.0% Roberts, et al., 2009 13.5% ECDC/EMEA Joint Technical Report, 2009 [c] Methicillin-resistant S. aureus (MRSA) 25.0% Vancomycin-resistant Enterococcus faecium 8.0% Penicillin-resistant S. pneumonia 4.0% Third-generation cephalosporin-resistant E. coli 9.0% Third-generation cephalosporin-resistant K. pneumoniae 20.0% Carbapenem-resistant P. aeruginosa 19.0% Expert 1 Inpatient 30.0% Outpatient 10.0% - 15.0% Expert 2 20.0% - 25.0% [a] Based on a sample of 604 surgical admissions treated for at least one Gram-negative rod (GNR) infection Based on a sample of 1,391 patients in a Chicago area hospital [c] Based on European Antimicrobial Resistance Surveillance System (EARSS) for EU Member States, Iceland and Norway for each year during the period 2002–2007 3.6.5.2 ABSSSI Total Number of Cases that do not Result in Death The total number of cases per year was obtained from the literature on skin and skin structure infections. Using data from the Healthcare Cost and Utilization Project National Inpatient Sample (HCUP NIS) for the 5-year period from 2000 to 2004, Edelsberg, et al. (2009) estimated the total number of hospital admissions for SSTIs to be 869,777 in 2004. The authors also provided estimates broken down by type of skin infection, allowing us to exclude chronic ulcers and infections, gangrene, necrotizing fasciitis, decubitus ulcer infections, diabetic foot infections, and certain healthcare-associated infections (as specified in the FDA guidance for ABSSSIs) and arrive at an estimated 678,956 hospital admissions for ABSSSIs, or approximately 231.9 per 100,000 population. Applied to the 2011 U.S. population, this rate is equivalent to an estimated 726,321 inpatient ABSSSI cases for the year 2011.[14] FOOTNOTE [14] The total number of ABSSSI cases—including patients who are treated in the outpatient setting only—is, however, far greater. Hersh, et al. (2008) examined visits by patients with SSTIs to physician offices, hospital outpatient departments, and emergency departments using NAMCS and NHAMCS and found that the overall rate of visits for SSTIs was 48.1 visits per 1000 population in 2005, totaling 14.2 million visits. As patients with skin infections are likely to visit these healthcare settings multiple times over the course of their SSTI episode, it is necessary to divide the total number of visits by the average number of visits per episode to arrive at the number of episodes per year. According to Marton, et al. (2008), who analyzed skin and skin structure infections caused by Staphylococcus aureus using managed care claims data for the years 2002-2005, the mean number of physician visits per episode was 6.3. Thus, 14.2 million outpatient visits divided by 6.3 visits per episode equals roughly 2.3 million episodes per year in 2005, or 778.1 per 100,000 population. Thus, the estimates presented herein constitute a lower bound. We calculated the total number of patients hospitalized with ABSSSIs that do not die in a given year by subtracting those who die in that year from the total number of ABSSSI patients. This number can then be subtracted from the estimated total number of hospital admissions for ABSSSI in 2011, 726,321 (explained above), to get 724,397 surviving ABSSSI hospital patients. QALYs Lost per Case To calculate lost QALYs for patients who have an ABSSSI but recover, we first searched the Tufts database and found a QALY weight of 0.642 for cellulitis, abscess, and wound infection, three major types of ABSSSI (though this QALY weight was for hospital patients infected with MRSA and therefore might represent cases on the more serious end of the severity spectrum) (Lee, et al., 2010). As with ABOM, we then adjusted the QALY weight by period of illness. The average length of inpatient stay for patients hospitalized for an SSTI is 6.1 days (Menzin, et al., 2010). However, many skin infection patients are treated in both inpatient and outpatient settings, and length of hospital stay does not capture additional days spent sick or recovering outside the hospital. The mean number of days of episode duration is 24.4 days, which includes time spent in both inpatient and outpatient treatment settings (Marton, et al., 2008). Using 24.4 days as the illness period, we calculated the lost QALYs per patient to be 0.02393 as:
Total QALYs Lost due to Morbidity Given that lost QALYs per ABSSSI case is 0.02393 and the total number of ABSSSI cases that do not result in death in the US is around 724,397, we computed the total annual QALYs lost due to ABSSSI morbidity to be 17,336 in the US. Morbidity Cost To calculate VSLY-based illness costs (for patients who do not die), we first calculated an average VSLY weighted by ABSSSI incidence by age group (available from Edelsberg, et al., 2009). This weighted average VSLY is roughly $365,500, which is then multiplied by the average lost QALYs per patient (0.02393) to arrive at $8,749 per patient. The total morbidity cost due to ABSSSI is then $6.3 billion (= $8,749 × 724,397) per annum. 3.6.6.2 ABSSSI Total Number of Cases that Result in Death We estimated the number of deaths attributable to ABSSSI to be 1,868 in 2008, or 0.61 per 100,000 population. Applying this rate to 2011 population estimates yields a total of 1,923 deaths attributed to ABSSSI in 2011. QALYs Lost To calculate lost QALYs for patients who die from skin infections, we used the Compressed Mortality File. Using the mortality rate and age breakdowns for 2008 from the Compressed Mortality File, we estimated the total number of deaths by age group for the year 2011. Life expectancies by age were available from the National Vital Statistics Report (NVSR). To illustrate the calculation, there were an estimated 497 deaths caused by an ABSSSI among Americans aged 75-84 in 2011. The life expectancy for an 80-year-old is 8.8 years; thus, each person who died from an ABSSSI at that age was assumed to have lost 8.8 years of life. After matching the Compressed Mortality File age cohorts to an appropriate age in the NVSR data (usually the age in the middle of the cohort), we calculated total QALYs lost by the 75-84 age cohort as 4,374 (8.8 × 483). Summing lost QALYs across all ages yielded a total of 26,167 QALYs lost due to ABSSSI deaths in 2011. Mortality Cost To calculate VSL-based mortality costs, we multiplied the number of deaths in each age group by the VSL for those age groups. For ABSSSI, this resulted in $10.8 billion in mortality costs. The average per-patient VSL, weighted by the number of deaths by age, is $5.62 million.
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