Kevin Outterson

Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis

BACKGROUND The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. METHODS We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. FINDINGS We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacteriums total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. INTERPRETATION Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori. FUNDING World Health Organization.

International cooperation to improve access to and sustain effectiveness of antimicrobials

Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action.

Repairing the Broken Market for Antibiotic Innovation

Multidrug-resistant bacterial diseases pose serious and growing threats to human health. While innovation is important to all areas of health research, it is uniquely important in antibiotics. Resistance destroys the fruit of prior research, making it necessary to constantly innovate to avoid falling back into a pre-antibiotic era. But investment is declining in antibiotics, driven by competition from older antibiotics, the cost and uncertainty of the development process, and limited reimbursement incentives. Good public health practices curb inappropriate antibiotic use, making return on investment challenging in payment systems based on sales volume. We assess the impact of recent initiatives to improve antibiotic innovation, reflecting experience with all sixty-seven new molecular entity antibiotics approved by the Food and Drug Administration since 1980. Our analysis incorporates data and insights derived from several multistakeholder initiatives under way involving governments and the private sector on both sides of the Atlantic. We propose three specific reforms that could revitalize innovations that protect public health, while promoting long-term sustainability: increased incentives for antibiotic research and development, surveillance, and stewardship; greater targeting of incentives to high-priority public health needs, including reimbursement that is delinked from volume of drug use; and enhanced global collaboration, including a global treaty.

An international legal framework to address antimicrobial resistance

Antimicrobial resistance is a growing threat to global health. Currently it accounts for approximately 700,000 deaths annually, but is predicted to cause as many as 10,000,000 deaths by 2050 if nothing is done to address it. To effectively deal with this problem three areas must be addressed simultaneously: access, conservation, and innovation. However, solving issues of access, conservation and innovation at the same time requires new coordination and financing mechanisms, some of which must be organized globally. This bulletin outlines the possible role that a binding international legal framework can play in the fight against antimicrobial resistance.

Regulating Compounding Pharmacies after NECC

FDA rules are often forged in crisis. Compounding pharmacies are at the center of a controversy after an outbreak of fungal meningitis that was traced to methylprednisolone acetate from the New England Compounding Center. Congress is already discussing new regulations.

Antibiotic reimbursement in a model delinked from sales: a benchmark-based worldwide approach

Despite the life-saving ability of antibiotics and their importance as a key enabler of all of modern health care, their effectiveness is now threatened by a rising tide of resistance. Unfortunately, the antibiotic pipeline does not match health needs because of challenges in discovery and development, as well as the poor economics of antibiotics. Discovery and development are being addressed by a range of public-private partnerships; however, correcting the poor economics of antibiotics will need an overhaul of the present business model on a worldwide scale. Discussions are now converging on delinking reward from antibiotic sales through prizes, milestone payments, or insurance-like models in which innovation is rewarded with a fixed series of payments of a predictable size. Rewarding all drugs with the same payments could create perverse incentives to produce drugs that provide the least possible innovation. Thus, we propose a payment model using a graded array of benchmarked rewards designed to encourage the development of antibiotics with the greatest societal value, together with appropriate worldwide access to antibiotics to maximise human health.

Approval and Withdrawal of New Antibiotics and Other Antiinfectives in the U.S., 1980-2009

Numerous reports have noted decreasing numbers of antibiotic approvals. To determine the context for this decline, we examined all new molecule entities (NMEs) and new biologic licenses (NBLs) approved by the FDA from 1980-2009, and compared approval rates of the 61 approved antibiotics to trends in other drug classes. We also tracked withdrawals of approved drugs and found more withdrawals for antibiotics than other drug classes. After adjusting for drugs subsequently withdrawn, the record for antibiotic innovation is less dire than previously reported. We also report problems with the quality of the approved antibiotics studied. Future policies providing incentives for new antibiotic development should not be based on simple numerical targets and key provisions should ensure appropriate quality as well as quantity of antibiotic drug innovation.

Should Access to Medicines and TRIPS Flexibilities Be Limited to Specific Diseases

From the perspective of public health, limiting access programs and TRIPS flexibilities to particular diseases would be quite dangerous and unnecessary. Dangerous because the diseases of the worlds rich and poor countries are converging, including non-communicative diseases such as heart disease, stroke, diabetes, cancer and depression. Radically cheaper medicines for these conditions could significantly improve health in LMICs. Limitation is also unnecessary because proven tools can be deployed to preserve high-income markets while LMICs pursue equitable flexibilities.To date, the important global legal texts retain broad application to all relevant diseases, but the some parties continue to propose disease-specific limitations, most recently in the World Health Organizations Intergovernmental Working Group on Public Health, Innovation and Intellectual Property (the WHO IGWG). The WHO IGWGs task is to distill the WHO CIPIH Report into a global strategy and plan of action. This article hopes to influence the final text of the IGWG Global Strategy, finding that disease-specific limitations on access programs and TRIPS flexibilities are inappropriate in markets for medicines, but disease-specific programs are important in markets for neglected disease innovation.

Market-Based Licensing for HPV Vaccines in Developing Countries

Human papillomavirus (HPV) vaccines hold great promise for preventing cervical cancer, but 93 percent of mortality worldwide occurs in low- and middle-income countries, where high vaccine costs can restrict dissemination. Current models for promoting international access to health care innovations include differential pricing, advance market commitments, and voluntary and compulsory licensing. Some of these mechanisms have been effective, but much room for improvement remains. We discuss the usefulness of a new type of license that uses market forces to lower prices through generic competition in low- and middle-income countries while ensuring that pharmaceutical companies are appropriately reimbursed for their research and development.

Patent Buy-Outs for Global Disease Innovations for Low- and Middle-Income Countries

Drug prices are uniquely susceptible to radical price reductions through generic competition. Patented pharmaceuticals may be priced at more than 30 times the marginal cost of production; the excess is the patent rent collected by the drug company while the patent and exclusive marketing periods remain. Patent rents are significant. AIDS drugs which sell for US