Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine (2022) / Chapter Skim
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6 Bringing New Products to Market and Ensuring Their Reach
6 Bringing New Products to Market and Ensuring Their Reach
Pages 223-300
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. The market for new medical products needed to combat antimicrobial resistance includes novel antimicrobials.
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. As long as the prevalence of gram-negative infections not susceptible to available treatments is substantially lower than the prevalence of infections susceptible to them, the market incentive alone is not likely to motivate new drug development (provided the prices are constrained)
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After the drug is approved, there are regulatory requirements such as pharmacokinetic studies in children and special adult populations (e.g., overweight or obese patients) , routine pharmacovigilance and postmarket surveillance, susceptibility testing for diagnostic devices (discussed in the next section)
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Plazomicin is a striking example of the gap between need and availability for new antimicrobials. This example prompted the ReACT network to call for changes to the design and conduct of clinical trials, allowing for greater participation in low and middle-income countries and a global registration to ensure the drugs would be available in the parts of the world where they are most needed.
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They aim to reduce the costs of research and development to any one entity by spreading these costs across a range of interested parties (Renwick et Outcome-based pull incentives Lego-regulatory pull Early-stage push incentives Late-stage push incentives Basic Preclinical Clinical Market Commercial science development development authorization ization FIGURE 6-1 Push and pull incentives operate at different stages of antimicrobial development. SOURCE: Renwick, M., and E
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DiMasi (2016) FIGURE 6-2 Research and development cost, both direct and cost of capital, by clinical trial phases.
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. Figure 6-4 shows how the NIH's National Institute of Allergy and Infectious Diseases (NIAID)
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The strong, adaptable research base described in Figure 6-4 is an investment in the response to future threats. Preclinical and Early Clinical Development There are also many push incentives providing direct funding for preclinical research and early clinical trials, sometimes called the midstage of antimicrobial development (Årdal et al., 2018)
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. The Joint Programming Initiative on Antimicrobial Resistance provides similar research funding in Europe (JPIAMR, n.d.)
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GARDP works with public- and private-sector partners to develop new antibacterial medicines. Their focus is on treatment for the WHO priority pathogens list, late-stage clinical trials, and access to these medicines in low- and middle-income countries.
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CARB-X (2020) works mainly in preclinical development and early clinical trials for WHO and CDC priority pathogens.3 With $500 million of funding for its first 5 years, CARB-X is the world's largest early development investor in new antimicrobials and related products (Alm and Gallant, 2020)
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. At this point, however, most products would no longer be part of the CARB-X portfolio, but possibly handed off to BARDA for phase 2 and 3 clinical trials (Singer et al., 2020)
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. The DHS material threat list did not, however, overlap with the CDC list of antimicrobial resistance threats (Billington, 2015; Eichberg, 2015)
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Diagnostic IL-6 Sepsis Sepsis, COVID-19 Preclinical P1 CARB-X Portfolio Multiple Multiple Multiple FIGURE 6-7 BARDA's antimicrobial portfolio, fall 2021. Figure legend: Figure 6-7 NOTE: ABSSSI = acute bacterial skin and skin structure infections; BL = beta-lac tam; BL/BLI = beta-lactam/beta-lactamase inhibitor; CABP = community-acquired bacterial pneumonia; CDI = Clostridioides difficile infection; cIAI = complicated intra-abdominal infection; CRAB = carbapenem-resistant Acinetobacter bauman nii; CRE = carbapenem-resistant Enterobacterales; cUTI = complicated urinary tract infection; DFUI = diabetic foot ulcer infections; ESBL = extended spectrum beta-lactamase; GCI = gonococcal infection; HABP/VABP = hospital-associated bacterial pneumonia/ventilator-associated bacterial pneumonia; MDR = multidrug resistant; MDR G– = multidrug-resistant gram-negative bacteria; rCDI = recur rent Clostridioides difficile infection; rUTI = recurrent urinary tract infection; SAB = Staphylococcus aureus bacteremia; uUTI = uncomplicated urinary tract infection.
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The Novo Nordisk Foundation's REPAIR Impact Fund, for example, has a $165 million budget to invest in about 20 different therapies for antimicrobial resistance (Novo Nordisk Foundation, 2018)
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France and Germany have instituted a number of legal and regulatory pull incentives that allow for more flexible pricing and accelerate the regulatory review process for antimicrobial drugs. Both programs work through attention to list price and sales incentives, though the French one puts more emphasis on rewarding added therapeutic value (Gotham et
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.5 Formal outcome evaluations for these programs are not yet available, but it is reasonable to expect that they have increased company revenues from sales of their qualified antimicrobial drugs in those markets. The United States also uses several legal and regulatory pull incentives, Box 6-4 describes some of the more common ones employed as of midyear 2021.
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• Limited Population Pathway for Antibacterial and Antifungal Drugs enacted in 2016 as part of the 21st Century Cures Act allows for a more streamlined clinical development (i.e., smaller, shorter, or fewer clinical trials) for those drugs "intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs." • Revisions to the Centers for Medicare & Medicaid Services' (CMS's)
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To start, eligibility as a qualified infectious disease product, a determination on which many of the proposed incentives hinge, appear to be overly broad (Darrow and Kesselheim, 2020)
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Act Working? , Open Forum Infectious Diseases, 2020, Vol 7, Issue 1, by permission of Oxford University Press.
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. Moreover, during the same period, FDA approved a total of 20 new antimicrobial drugs, 17 of which had activity against the so-called ESKAPE pathogens, pathogens designated as urgent threats by the CDC or the WHO.9 Of these 17 new antimicrobials, 12 qualified as infectious disease products, thereby 9 ESKAPE pathogens include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneu moniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (CDC, 2019a)
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. Further, most of the recently approved drugs appear to offer little to no added clinical value over existing treatments (Schulz et al., 2019; WHO, 2019b)
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Market entry rewards that fully or partially delink product revenues from quantity sold are one promising strategy. Such additional incentives could improve the expected net present value of antimicrobial drug projects compared to other therapeutic areas and entice large pharmaceutical companies to reenter the antimicrobial market, goals that existing mechanisms have not yet achieved (Daniel et al., 2018; PACCARB, 2019; WHO, 2019b)
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Hospital administrations can move slowly, but it may be rash to conclude that they will not move at all to adjust to a new incentive. The Amount of Market Entry Reward The Infectious Diseases Society of America (IDSA)
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Full or Partial Delinking of Sales and Revenues One of the main questions in offering a market entry reward for novel antimicrobials is the delinking of the drug's revenues from sales. Originally proposed as a way to encourage development of medicines for neglected diseases, delinking essentially pays the development costs of a new drug up front, rather than gradually through sales (Aagaard et al., 2021)
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. Despite good consensus that rewarding added clinical value is the best use of a market entry reward, this is something that is difficult to discern.
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. Superiority in clinical trials is a clear indicator of added clinical value, but such trials are not often feasible for antimicrobial medicines.
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Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: The case for post-marketing, adaptive randomised controlled trials, e-444-e451, Copyright (2019) , with permission from Elsevier.
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The varied experiences with legal and regulatory pull incentives described here point to a need for deliberation and piloting of possible market entry reward programs, as both Sweden and the United Kingdom are currently doing (Gotham et al., 2021)
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While the threat of antimicrobial resistance is real and more antimicrobial drugs are needed in our arsenal, it is important to ensure the best possible design and execution of reward payments to minimize the risk to taxpayers. Before funding any market entry reward, the government needs to be clear that it is rewarding a truly novel and useful antimicrobial.
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Purchased drugs would also be available to Medicare, Medicaid, and Veterans Health Administration beneficiaries in the United States; the revisions also allow for smaller contracts with new developers and a requirement that the list of high-priority microbes for which medicines are needed be updated every other year.17 The PASTEUR Act aims to reward drugs that improve clinical outcomes in drug-resistant infections. It contains similar provisions for the establishment of an interagency Committee on Critical Need Antimicrobials to identify products that meet a real clinical need.18 This group is an essential feature not just of the PASTEUR Act, but of any public effort to reward novel antimicrobials.
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At this time, the drug sponsor could also receive a milestone payment, which may be necessary to keep the company in business. This split approach to market entry rewards also controls the risk to the taxpayer, as the pay
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. If so, one alternative to public spending in the form of market entry rewards is to invest the same amount of money (or less)
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. The push and pull incentives described earlier in this chapter are evidence of the considerable sums of money the United States and other high-income countries are willing to spend to fight antimicrobial resistance.
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Given the vastly higher burden of antimicrobial resistance in these parts of the world and problems with access to safe, affordable medicines, it would seem that almost any product, at least any novel antimicrobial, rapid point-of-care diagnostic, or preventive product would be disproportionately beneficial in low- and middle-income country markets, markets these products do not currently reach. For this reason, the ReACT network, an international group dedicated to mitigating antimicrobial resistance, has proposed that any product developer that takes government money for product development should enter a patent pool facilitating global procurement (Aagaard et al., 2021)
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Vet erinary antimicrobial susceptibility testing is done with broth micro dilution; disk diffusion is less common (Bowden and Burbick, 2020)
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. Most clinical laboratories in the United States today use only automated methods for susceptibility testing (Humphries et al., 2018b,c)
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. After any changes to automated susceptibility tests, either the addition of new drugs or updating of breakpoints, the testing device and software all need to be updated (Humphries et al., 2018c)
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. FDA's 2016 draft guidance publication, Coordinated Development of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices, encouraged collaboration between drug and device companies in relatively early stages of drug development (FDA, 2019a)
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262 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE TABLE 6-2 Antimicrobial Susceptibility Testing Challenges Addressed by the 21st Century Cures Act and Remaining Needs Addressed by 21st Challenge Century Cures Act? Test devices cleared after 2007 can only test Yes antimicrobials against organisms for which there are clinical indications listed in drug label Current breakpoints are not available on all test Partially devices used by clinical laboratories Lack of test devices for new drugs No
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M., and J Hindler, Twenty-first Century Cures Act and Antimicrobial Susceptibility Testing: Clinical Implications in the Era of Multidrug Resistance, Clinical Infectious Diseases, 2018, Vol.
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Ideally, automated susceptibility testing devices would include new antimicrobials immediately upon market entry and revised breakpoints
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. A similar fast track approval option is necessary for automated susceptibility testing devices.
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.23 Recommendation 6-3: Congress should make automated sus ceptibility test manufacturers eligible for tax incentives to bring new automated susceptibility tests to market. Tax incentives and streamlining regulatory processes could do much to reduce the lag time in bringing automated susceptibility tests to market, but there are some drugs for which there will simply never be sufficient demand to warrant inclusion in an automated susceptibility panel.
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While clearance of automated susceptibility test panels would remove a major hurdle, it is still likely that the testing for new antimicrobials will not be a priority if the drug is not commonly used or not on the hospital formulary. The CDC Antibiotic Resistance Laboratory Network (ARLN)
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should expand the capacity of the Antibi otic Resistance Laboratory Network by offering expedited, expanded susceptibility testing of all broad-spectrum antibiot ics via certain CLIA-certified laboratories.24 The CDC should also promote this service to clinical laboratories. It is not reasonable to expect hospital clinical microbiology laboratories to be able to test microbe–drug combinations they see only once or twice a year.
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Most of the CLIA-certified laboratories best placed to offer expanded susceptibility testing will be at tertiary care, teaching hospitals. Major medical centers often have an infrastructure in place to do broad-spectrum antimicrobial susceptibility testing.
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. There is a need for a variety of new and innovative products to combat antimicrobial resistance.
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separated; outbreak tracing Community- Near-patient, rapid To diagnose cause • Rapid <1h • Multiplex NAAT based tests for a variety acquired response (eg, in larger of infection and • Ability to detect pathogen of pathogens and resistance determinants pneumonia outpatient clinic or recommend effective and distinguish pathogen requiring minimal user skill and hands-on laboratory adjacent and proportionate from colonisers time (already available but with minimal data to accident and antimicrobial therapy, • Ability to detect drug regarding performance and clinical utility) emergency)
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SOURCE: Reprinted from The Lancet Infectious Diseases, Vol.
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More infectious diseases today are vaccine-preventable than in any other time in history. Vaccines that prevent human infections caused by bacteria, particularly those bacteria that are resistance prone, such as pneumococci, Haemophilus influenzae, cholera, and typhoid fever, may also prevent the emergence of resistance (Kaufhold et al., 2019; Lewnard et al., 2020; Lipsitch and Siber, 2016; Moore et al., 2015; Okeke, 2009)
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. Another promising alternative tool to directly fight antimicrobial resistance is the use of oligonucleotides for silencing resistance genes or other approaches still in research stages (Czaplewski et al., 2016)
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Agricultural vaccines Reducing the use of antimicrobials in animal production demands alternatives that can be used to maintain animal health and welfare and sustain the productivity of animal agriculture. Vaccines have been successfully used for the prevention and control of infectious diseases and represent promising alternatives for antibiotics (Hoelzer et al., 2018)
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When TABLE 6-4 Regulation of Directly Fed Micro-Organisms (Probiotics) by FDA Claim or Intended Use Legal Status Regulated as Regulated by Cure, mitigate, treat, or New animal drug Drug FDA prevent disease Affect the structure and New animal drug Drug FDA function of the body Without any therapeutic Food Food State or structure/function claim government (micro-organisms listed in AAFCO official publication)
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. Despite extensive research on the benefits of probiotics in animal agriculture, there are relatively few commercially available probiotic and prebiotic products consistently used in clinical practice or animal husbandry (FAO, 2016; Hasan and Banerjee, 2020)
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Research to develop highthroughput screening for probiotics could allow for investigation of the mechanisms of action in the target environmental conditions, facilitating discovery of effective probiotics. The same tools are already being used in antimicrobial development and animal breeding.
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There is some indication that political will for action against antimicrobial resistance has reached a tipping point. A recent statement from finance ministers and central bank governors of the G7 countries pledged to "work together with our health colleagues … including with industry, to explore proposals for strengthening market incentives for antibiotic drug development" (USDT, 2021)
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The partnership would have working groups on diagnostics, alternatives to antibiotics, and prevention, with a goal of supporting a diversified and balanced portfolio of tools to reduce antimicrobial resistance using a One Health approach. Public–private partnerships are well suited to medical product development, as Figure 6-12 illustrates.
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, for example, is a 5-year old coalition of private-sector partners working on solutions to prevent and mitigate antimicrobial resistance. This coalition includes generic and innovator pharmaceutical companies as well as diagnostics companies and small biotechnology firms (AMR Industry Alliance, 2019)
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Continuing and building on such collaborative relationships would be an important role for the partnership envisioned in this recommendation. There is also a need to balance investments in antimicrobial resistance across new medicines, diagnostics, and preventive products.
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Committee on the Long Term Health and Economic Effects of Antimicrobial Resistance in the United States, Webinar. January 5, 2021.
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2020. Antimicrobial susceptibility testing: Currently used methods and devices and the near future in clinical practice.
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H Rex, and Infectious Diseases Society of America.
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Public Workshop -- Coordinated De velopment of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices, Sep tember 29, 2016, Silver Spring, MD. https://www.fda.gov/media/100293/download (accessed July 13, 2021)
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Lancet Infectious Diseases 16(2)
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act working? Open Forum Infectious Diseases 7(1)
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2019a. Coordinated development of antimicrobial drugs and antimicrobial susceptibility test devices: Guidance for industry and food and drug administration staff.
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Lancet Infectious Diseases 20(1)
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2018a. Twenty-first century cures act and antimicrobial susceptibility testing: Clinical implications in the era of multidrug resistance.
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Clinical Infectious Diseases 66(7)
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2021b. The relationship between antimicrobial susceptibility testing devices and antibiotic markets.
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The Lancet Infectious Diseases 15(3)
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Clinical Infectious Diseases. Epub ahead of print.
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Clinical Infectious Diseases 65(1)
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Clinical Infectious Diseases 45(Suppl 1)
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Clinical Infectious Diseases 59(8)
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2018. Antimicrobial resistance tackling the gap in R&D resources with pull incentives.
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The Lancet Infectious Diseases 14(11)
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