The news Monday from the Centers for Disease Control and Prevention (CDC) on the incidence of resistant infections is disturbing but not surprising. CDC estimates that over two million Americans every year are affected by drug-resistant infections and of those, 23,000 die annually. The report notes that these figures are conservative and are likely an underestimate of the burden of resistant infections. While these numbers reflect domestic rates, antibiotic resistance is a global issue as well.

To further compound the issue, today’s antibiotic pipeline is nearly dry and has been for some time, with only a handful of large pharmaceutical companies and smaller biotech firms still engaged in antibiotic development. The threat of a so-called ‘post-antibiotic era’ – a time when there are no longer any effective antibiotic treatments – could become a reality without a concerted and comprehensive effort to combat this global threat. The evolution of drug resistance is an inherent risk of antibiotic use. The CDC report cited the development of new antibiotics and diagnostic tools, as well as programs and policies to support appropriate use of antibiotics, as being among the core strategies to combat resistance.

Clinical effectiveness and the relatively low cost of antibiotics have had the unintended consequence of contributing to overuse, accelerating the development of antibiotic resistance to all major classes of antibiotics. While there are some diagnostic tools available to support targeted treatment, it is often more time- and cost-effective for a physician to prescribe a relatively inexpensive, broad-spectrum antibiotic than to conduct a diagnostic test (if one exists at all). Antibiotic overuse can also be driven by patients who see antibiotics as safe and often low-cost cure-alls. Recognizing that these past patterns of overuse are dangerous, the clinical community is working diligently to curb inappropriate use and promote public health through stewardship and education programs. However, given the weakness of the current antibiotic development environment, it may be too little-too late; rates of resistance continue to rise globally while the number of effective therapies to treat many pathogens is dwindling. According to the CDC, resistance can be ”slowed but not stopped” – there will always be a need for novel antibiotics that can combat the evolution of these pathogens.

The current system for manufacturer return on investment for antibiotics, which are typically reimbursed at very low levels, is oriented towards volume sales. As a result, stewardship and educational programs geared toward limiting use of novel antibiotics create an ‘antibiotic development paradox.’ How can we incentivize investment in developing new effective antibiotics and also have successful programs that limit the use of these antibiotics in an effort to prevent or delay the development of resistance? Unless this fundamental conflict in the current business model is addressed, pharmaceutical firms are unlikely to expand development efforts.

How do we turn the tide?

There are several proposals that address aspects of the antibiotic development paradox with the goal of reinvigorating the antibiotic drug development ecosystem in a way that maximizes our ability to stay ahead of resistance. While none of these proposals alone will solve this problem, each could support the long-term goal of reinvigorating antibiotic discovery, development, and treatment.

Creating incentives for drug development

Antibiotic drug development has been a losing prospect for drug developers and has driven many of them to exit the antibiotic innovation space in the last few decades in favor of other therapeutic areas that have much larger markets and are easier areas to study. In order to make antibiotic development more attractive, various mechanisms have been proposed to stimulate or better reward successful clinical development. Incentives that can lower the financial risks associated with development include grants, tax credits, public-private partnerships, and intellectual property protections. Post-approval, prizes, advanced market commitments, and value-based pricing could all potentially provide additional incentives to invest in this research. Some potential incentives were discussed at the Incentives for Change: Addressing the Challenges in Antibacterial Drug Development workshop convened by Brookings in February 2013.

Balancing benefit and risk for severely-ill patients

Other incentives are related to the drug approval process. Novel mechanisms for expedited development and approval can speed time to market while still meeting traditional evidentiary requirements for safety and efficacy. In the last several years, a number of proposals – including from the Infectious Diseases Society of America and the President’s Council of Advisors on Science and Technology – have sought to reduce development time and cost and increase regulatory clarity through a more targeted clinical trial process directed at the highest-risk patients. A narrower study population would allow the U.S. Food and Drug Administration to make a more targeted assessment of the product’s safety, efficacy, and benefit-risk profile that could accelerate innovation for patients with serious drug-resistant infections. The need to steward these antibiotics, which was noted as a core action in the CDC report, would be especially important to both prevent the growth of resistance and to reduce the risk of adverse effects in less seriously-ill populations. Additional information on the proposed limited-use pathway and appropriate use is available on the Brookings website.

De-link reimbursement from return on investment

In order to attract investment for new antibiotic research, we must develop a business model that can support ongoing and expanding development without compromising the effectiveness of new therapies. Recognizing the need to “de-link” return on investment from the volume of antibiotics sold, efforts to move away from the volume-based reimbursement system could become an attractive path forward. Promising models, which were discussed at the Brookings workshop in February, included several guaranteed payment schemes supported by public funding. Taken to an extreme, such a system could even allow new antibiotics to be reserved indefinitely until needed, removing the developer’s incentive to sell any drugs in the years following approval. While such a program would likely be expensive (with sufficient returns estimated on the order of $1.75-2.5 billion over five years), government intervention is needed to fix this public health crisis and dangerous market failure. Its societal value in curtailing resistance and providing critical drugs would outweigh the cost to taxpayers.

The antibiotic development paradox will require a multi-pronged strategy that includes incentives to support front-end drug discovery and development, and new reimbursement policies that de-link unit volume sales from return on investment. However, this is by no means a quick fix. Even if this approach is successful, it will take decades for manufacturers to rebuild lost antibiotic development infrastructure and expertise, and to successfully develop and market new treatments. For the few drugs currently in development, even with expedited development and review pathways, they are still years from reaching the market.

       

While antibiotics are necessary and crucial for treating bacterial infections, their misuse over time has contributed to a rather alarming rate of antibiotic resistance, including the development of multidrug-resistance bacteria or “super bugs.” Misuse manifests throughout all corners of public and private life; from the doctor’s office when prescribed to treat viruses; to industrial agriculture, where they are used in abundance to prevent disease in livestock. New data from the World Health Organization (WHO) and U.S. Centers for Disease Control and Prevention (CDC) confirm that rising overuse of antibiotics has already become a major public health threat worldwide.

As drug resistance increases, we will see a number of dangerous and far-reaching consequences. First, common infections like STDs, pneumonia, and “staph” infections will become increasingly difficult to treat, and in extreme cases these infections may require hospitalization or treatment with expensive and toxic second-line therapies. In fact, recent estimates suggest that every year more than 23,000 people die due to drug-resistant infections in the U.S., and many more suffer from complications caused by resistant pathogens. Further, infections will be harder to control. Health care providers are increasingly encountering highly resistant infections not only in hospitals – where such infections can easily spread between vulnerable patients – but also in outpatient care settings.

Fundamental Approaches to Slowing Resistance

Incentivize appropriate use of antibiotics. Many patients and providers underestimate the risks of using antibiotics when they are not warranted, in part because these drugs often have rapid beneficial effects for those who truly need them.  In many parts of the world the perception that antibiotics carry few risks has been bolstered by their low costs and availability without a prescription or contact with a trained health care provider. Education efforts, stewardship programs, and the development of new clinical guidelines have shown some success in limiting antibiotic use, but these fixes are limited in scope and generally not perceived as cost-effective or sustainable. Broader efforts to incentivize appropriate use, coupled with economic incentives, may be more effective in changing the culture of antibiotic use. These options might include physician or hospital report cards that help impact patient provider selection, or bonuses based on standardized performance measures that can be used to report on success of promoting appropriate use.  While these might create additional costs, they would likely help control rates of drug resistant infections and outweigh the costs of treating them.

Reinvigorate the drug development pipeline with novel antibiotics. There has not been a new class of antibiotics discovered in almost three decades, and companies have largely left the infectious disease space for more stable and lucrative product lines, such as cancer and chronic disease. Antibiotics have historically been inexpensive and are typically used only for short periods of time, creating limited opportunities for return on investment. In addition, unlike cancer or heart disease treatments, antibiotics lose effectiveness over time, making them unattractive for investment. Once they are on the market, the push to limit use of certain antibiotics to the most severe infections can further constrict an already weak market.

Late last year, H.R. 3742, the Antibiotic Development to Advance Patient Treatment (ADAPT) Act of 2013, was introduced and referred to the House Energy and Commerce Subcommittee on Health. If enacted, the ADAPT Act would create a streamlined development pathway to expedite the approval of antibiotics that treat limited patient populations with serious unmet medical needs. This could potentially reduce costs and development time for companies, thereby encouraging investment in this space. Regulators have indicated that they would also welcome the opportunity to evaluate benefits and risk for a more selective patient subpopulation if they could be confident the product would be used appropriately. The bill has received a great deal of support and would help address a critical public health need.

Advance new economic incentives to remedy market failure. Innovative changes to pharmaceutical regulation, research and development (R&D), and reimbursement are necessary to alleviate the market failure for antibacterial drugs. A major challenge, particularly within a fee-for-service or volume-based reimbursement system, is providing economic incentives that promote investment in drug development without encouraging overuse.  A number of public and private stakeholders, including the Engelberg Center for Health Care Reform and Chatham House’s Centre on Global Health Security Working Group on Antimicrobial Resistance, are exploring alternative reimbursement mechanisms that  “de-link” revenue from the volume of antibiotics sold. Such a mechanism, combined with further measures to stimulate innovation, could create a stable incentive structure to support R&D.

Improve tracking and monitoring of resistance in the outpatient setting. There is increasing concern about much less rigorous surveillance capabilities in the outpatient setting, where drug-resistant infections are also on the rise. Policymakers should consider new incentives for providers and insurers to encourage a coordinated approach for tracking inpatient and outpatient resistance data. The ADAPT Act, mentioned above, also seeks to enhance monitoring of antibiotic utilization and resistance patterns. Health insurance companies can leverage resistance-related data linked to health care claims, while providers can capture lab results in electronic health records. Ultimately, this data could be linked to health and economic outcomes at the state, federal, and international levels, and provide a more comprehensive population-based understanding of the impact and spread of resistance. Current examples include the Food and Drug Administration’s (FDA) Sentinel Initiative and the Patient-Centered Outcomes Research Institute’s PCORnet initiative. 

Antibiotic resistance is an urgent and persistent threat. As such, patients and providers will continue to require new antibiotics as older drugs are forced into retirement by resistant pathogens. Stewardship efforts will remain critical in the absence of game-changing therapies that parry resistance mechanisms. Lastly, a coordinated surveillance approach that involves diverse stakeholder groups is needed to understand the health and economic consequences of drug resistance, and to inform antibiotic development and stewardship efforts.

       

Antimicrobial resistance is one of the most significant threats to public health globally. It will worsen in the coming decades without concerted efforts to spur the development of new antibiotics, while ensuring the appropriate use of existing antibiotics. Antimicrobial therapy is essential for treating and preventing bacterial infections, some of which can be life-threatening and acquired as a result of
critical medical interventions, including surgery, chemotherapy and dialysis. However, the international rise in antimicrobial resistance has weakened our antibiotic armamentarium and multi-resistant bacteria now cause over 150,000 deaths annually in hospitals around the world (WHO, 2013). Unfortunately, the evolution of drug-resistant pathogens is unavoidable due to random genetic changes in the pathogens that can render antibiotics ineffective. While antibiotic therapy can succeed in killing susceptible pathogens, it also inadvertently selects for organisms that are resistant. Because each exposure to antibiotics contributes to this process, efforts to restrict antibiotic usage only slow the development of resistance. Ultimately, innovative antimicrobial drugs with diverse mechanisms of action will be needed to treat emerging resistant pathogens.

Combating resistance

Inappropriate use of antibiotics contributes significantly to the acceleration of resistance. Needlessly exposing patients to antibiotics (for example, for viral or mild infections likely to resolve on their own), the use of overly broad-spectrum antibiotics and suboptimal doses of appropriate therapy hasten the evolution of resistant pathogens. While affordable, rapid and accurate point-of-care diagnostics are essential for determining appropriate therapy for many bacterial diseases, routine clinical use will be limited if the tests are too expensive or not accessible during routine clinical encounters. In the absence of a clear diagnostic result, many health care providers prescribe empiric broadspectrum therapy without knowing exactly what they are treating. Although inappropriate use is widespread in many parts of the world, where antibiotics are available without a prescription or oversight by a health care provider or stewardship team, overuse abounds even where antibiotic prescribing is more tightly regulated.

Studies conducted in the USA indicate that around 258 million courses of antibiotics are dispensed annually for outpatient use (Hicks, 2013) and up to 75 per cent of ambulatory antibiotic prescriptions are for the treatment of common respiratory infections, which may or may not be bacterial in origin (McCaig,1995). Recent evidence suggests that over half of these prescriptions are not medically indicated. For example, 60 per cent of US adults with a sore throat receive an antibiotic prescription after visiting a primary care practice or emergency department, despite the fact that only ten per cent require treatment with antibiotics. This is particularly troubling given the availability of rapid tests that can detect Group A Streptococcus, the bacteria responsible for the ten per cent of cases that require antibiotic treatment.

The overuse of antibiotics has been driven largely by their low cost and clinical effectiveness, which has led many patients to view them as cure-alls with few risks. This perception is reinforced by the fact that antibiotics are curative in nature and used for short durations. However, the clinical effectiveness of these drugs decreases over time, as resistance naturally increases, and this process is accelerated with inappropriate use. Moreover, there are numerous consequences associated with the use of antibiotics, including over 140,000 emergency department visits yearly in the USA for adverse incidents (mostly allergic reactions; CDC, 2013a). In addition, antibiotics can eliminate protective bacteria in the gut,
leaving patients vulnerable to infection with Clostridium difficile, which causes diarrhoeal illness that results in 14,000 deaths every year in the USA (CDC, 2013b). It is estimated that antimicrobial resistance costs the US health care system over US$20 billion annually in excess care and an additional $35 billion in lost productivity (Roberts et al., 2009).

The inappropriate use of antimicrobial drugs is particularly concerning because highly resistant pathogens can easily cross national borders and rapidly spread around the globe. In recent years, strains of highly drug-resistant tuberculosis, carbapenem-resistant Enterobacteriaceae and other resistant pathogens have spread outside their countries of origin within several years of their detection. Because resistant bacteria are unlikely to stay isolated, stewardship efforts must be improved globally and international attention is needed to improve surveillance of emerging pathogens and resistance patterns.

A major challenge for clinicians and regulators will be to find stewardship interventions that can be scaled-up and involve multiple stakeholders, including providers, drug manufacturers, health care purchasers (insurers), governments and patients themselves. Such interventions should include practical and costeffective educational programmes targeted towards providers and patients that shift expectations for antibiotic prescriptions to a mutual understanding of the benefits and risks of these drugs.

Educational programmes alone, however, will not be sufficient to lower prescribing rates to recommended levels. Pushing down the inappropriate use of antibiotics also warrants stronger mechanisms that leverage the critical relationships between the stakeholders. For example, health care purchasers can play an important role by using financial disincentives to align prescribing habits with clinical guidelines that are developed by infectious disease specialists in the private and public sectors. This type of approach has the potential to be effective because it includes multiple stakeholders that share responsibility for the appropriate use of antibiotics and, ultimately, patient care.

Key obstacles to antibiotic development

The continual natural selection for resistant pathogens despite efforts to limit antibiotic use underscores the need for new antibiotics with novel mechanisms of action. To date, antimicrobial drug innovation and development have not kept pace with resistance. The number of approved new molecular entities (NME) to treat systemic infections has been steadily declining for decades (see Figure 1). Some infections are not susceptible to any antibiotic and in some cases the only effective drugs may cause serious side effects, or be contra-indicated due to a patient’s allergies or comorbidities (e.g. renal failure). There is significant unmet medical need for therapies that treat serious and life-threatening bacterial diseases caused by resistant pathogens, as well as some less serious infections where there are few treatment alternatives available (e.g. gonorrhoea).

Antibiotic development for these areas of unmet medical need has been sidelined by a number of scientific, regulatory and economic obstacles. While the costs and complexity of any clinical trial necessary for approval by drug regulators can be substantial, in part due to the large study samples needed to demonstrate safety and efficacy, the infectious disease space faces a number of unique clinical challenges. Patients with serious drug-resistant infections may be in need of urgent antibiotic therapy, which can preclude efficient consent and timely trial enrolment procedures; prior therapy can also confound treatment effects if the patient is later enrolled in a trial for an experimental drug. In addition, many patients with these pathogens are likely to have a history of longterm exposure to the health care setting and may have significant comorbidities that render them less likely to meet inclusion criteria for clinical trials.

Emerging infections for which there are few or no treatment options also tend to be relatively rare. This makes it difficult to conduct adequate and well-controlled trials, which typically enrol large numbers of patients. However, clinical drug development can take many years and waiting until such infections are more common is not feasible. Another issue is that it may also not be possible to conclusively identify the pathogen and its susceptibility at the point of enrolment due to the lack of rapid diagnostic technologies. Ultimately, uncertainty about the aetiology of an infection may necessitate trials with larger numbers of patients in order to achieve sufficient statistical power, further compounding the challenge of enrolling seriously ill infectious disease patients in the first place.

The need to conduct large trials involving acutely ill patients that are difficult to identify can make antibiotic development prohibitively expensive for drug developers, especially given that antibiotics are relatively inexpensive and offer limited opportunities to generate returns. Unlike treatments for chronic diseases, antibiotic therapy tends to last no longer than a few weeks, and these drugs lose efficacy over time as resistance develops, leading to diminishing returns. The decline in antimicrobial drug innovation is largely due to these economic obstacles, which have led developers to seek more durable and profitable markets (e.g. cancer or chronic disease) in recent decades. There are only a handful of companies currently in the market and the development pipeline is very thin. Changes to research infrastructure, drug reimbursement and regulation are all potentially needed to revitalise antibiotic innovation.

Opportunities to streamline innovative antibiotic development

In the USA, several proposals have been made to expedite the development and regulatory review of antibiotics while ensuring that safety and efficacy requirements are met. In 2012, the US President’s Council of Advisors on Science and Technology recommended that the US Food and Drug Administration (FDA) create a ‘special medical use’ (SMU) designation for the review of drugs for subpopulations of patients with unmet medical need. Drug sponsors would be required to demonstrate that clinical trials in a larger patient population would need much more time to complete or not be feasible. A drug approved under the SMU designation could be studied in subgroups of patients that are critically ill, as opposed to the broader population, under the condition that the drug’s indication would be limited to the narrow study population. The SMU designation was discussed at an expert workshop convened by the Brookings Institution in August 2013. Many participants at the meeting agreed that there is a pressing need to develop novel antibiotics and that such a limited-use pathway could support the appropriate use of newly approved drugs.

The Infectious Diseases Society of America developed a related drug development pathway called the Limited Population Antibacterial Drug (LPAD) approval mechanism. The LPAD approach calls for smaller, faster and less costly clinical trials to study antibiotics that treat resistant bacteria that cause serious infections. Both the SMU and LPAD approaches would allow drug developers to demonstrate product safety and efficacy in smaller patient subpopulations and provide regulatory clarity about acceptable benefit–risk profiles for antibiotics that treat serious bacterial diseases. The US House of Representatives is currently considering a bill¹ that incorporates these concepts.

A recent proposal from the drug manufacturer industry for streamlined antibiotic development is to establish a tiered regulatory framework to assess narrow-spectrum antibiotics (e.g. active versus a specific bacterial genus and species or a group of related bacteria) that target resistant pathogens that pose the greatest threat to public health (Rex, 2013: pp. 269–275). This is termed a ‘pathogen-focused’ approach because the level of clinical evidence required for approval would be correlated with the threat level and feasibility of studying a specific pathogen or group of pathogens. The pathogen-focused approach was also highlighted at a recent workshop at the Brookings Institution (Brookings Institution, 2014). Some experts felt that the approach is promising but emphasised that each pathogen and experimental drug is unique and that it could be challenging to place them in a particular tier of a regulatory framework. Given that pathogen-focused drugs would likely be marketed internationally, it will be important for drug sponsors to have regular interactions and multiple levels of discussion with regulators to find areas of agreement that would facilitate the approval of these drugs.

Antibiotics with very narrow indications could potentially support stewardship as well by limiting use to the most seriously ill patients. Safe use of these drugs would likely depend on diagnostics, significant provider education, labelling about the benefits and risks of the product, and the scope of clinical evidence behind its approval. Because these antibiotics would be used in a very limited manner, changes would potentially need to be made to how they are priced and reimbursed to ensure that companies are still able to generate returns on their investment. That said, a more focused drug development programme with regulatory clarity could greatly increase their odds of success and, combined with appropriate pricing and safe use provisions, could succeed in incentivising antimicrobial drug development for emerging infections.

Endnote
1 H.R. 3742 – Antibiotic Development to Advance Patient Treatment (ADAPT) Act of 2013.

References
Barnett, M. L. and Linder, J. A., 2014. ‘Antibiotic prescribing to adults with sore throat in the United States, 1997–2010’. JAMA Internal Medicine, 174(1), pp. 138–140.

Brookings Institution, 2013. Special Medical Use: Limited Use for Drugs Developed in an Expedited Manner to Meet an UnmetMedical Need. Brookings Institution. Available at: www.brookings.edu/events/2013/08/01-special-medical-use

Brookings Institution, 2014. Modernizing Antibacterial Drug Development and Promoting Stewardship. Available at: www.brookings.edu/events/2014/02/07-modernizing-antibacterialdrug-development [Accessed 11 March 2014].

CDC, 2013a. Antibiotic resistance threats in the United States,2013 [PDF] CDC. Available at: www.cdc.gov/drugresistance/threatreport-2013/pdf/ar-threats-2013-508.pdf#page=25 [Accessed 16 January 2014].

CDC, 2013b. Clostridium difficile. Antibiotic resistance threats in the United States, 2013 [PDF] CDC. Available at: www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf#page=50 [Accessed 16 January 2014].

Hicks, L. A. et al., 2013. ‘US Outpatient Antibiotic Prescribing, 2010’. New England Journal of Medicine, 368(15), pp. 1461–1463.
Infectious Disease Society of America, 2012.

Limited Population Antibacterial Drug (LPAD) Approval Mechanism. Available at: www.idsociety.org/uploadedFiles/IDSA/News_and_Publications/IDSA_News_Releases/2012/LPAD%20one%20pager.pdf [Accessed 5 March 2014].

Infectious Disease Society of America, 2012. Limited Population Antibacterial Drug (LPAD) Approval Mechanism [PDF] Infectious
Disease Society of America. Available at: www.idsociety.org/uploadedFiles/IDSA/News_and_Publications/IDSA_News_Releases/2012/LPAD%20one%20pager.pdf  [Accessed 18 January 2013].

Kumarasamy, K. K., Toleman, M. A., Walsh, T. R. et al.,2010. ‘Emergence of a new antibiotic resistance mechanism in India,
Pakistan, and the UK: A molecular, biological, and epidemiological study’. Lancet Infectious Diseases, 10(9), pp. 597–602.

McCaig, L. F. and Hughes, J. M., 1995. ‘Trends in antimicrobial drug prescribing among office-based physicians in the United
States’. Journal of the American Medical Association, 273(3), pp. 214–219.

President’s Council of Advisors on Science and Technology, 2012. Report to the President on Propelling Innovation in Drug
Discovery, Development and Evaluation. Available at:www.whitehouse.gov/sites/default/files/microsites/ostp/pcast-fdafinal.pdf    [Accessed 5 March 2014].

Rex, J. H. et al., 2013. ‘A comprehensive regulatory framework to address the unmet need for new antibacterial treatments’. Lancet Infectious Diseases, 13(3), pp. 269–275.

Roberts, R. R., Hota, B., Ahmad, I. et al., 2009. ‘Hospital and societal costs of antimicrobial – Resistant infections in a Chicago
teaching hospital: Implications for antibiotic stewardship’. Clinical Infectious Diseases, 49(8), pp. 1175–1184.

WHO (World Health Organization), 2010. Fact Sheet: Rational Use of Medicines [webpage] WHO. Available at:
www.who.int/mediacentre/factsheets/fs338/en [Accessed 28 February 2014].

WHO (World Health Organization), 2013. Antimicrobial Drug Resistance [PDF] WHO. Available at: http://apps.who.int/gb/ebwha/pdf_files/EB134/B134_37-en.pdf [Accessed 6 March 2014].

WHO (World Health Organization), 2013. Notified MDR-TB cases (number per 100,000 population), 2005–12. WHO. Available at:
https://extranet.who.int/sree/Reports?op=vs&path=/WHO_HQ_Reports/G2/PROD/EXT/MDRTB_Indicators_map [Accessed 28 February 2014].

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• Antibiotics Stewardship and Innovation

       

After years of warnings from the public health community about the growing threat of antibiotic resistance, yesterday the White House announced a national strategy to combat the growing problem of antibiotic resistance within the U.S. and abroad. The administration’s commitment represents an important step forward, as antibiotic-resistant infections are responsible for 23,000 deaths annually, and cost over $50 billion in excess health spending and lost productivity.  The administration’s National Strategy on Combating Antibiotic-Resistant Bacteria includes incentives for developing new drugs, more rigorous stewardship of existing drugs, and better surveillance of antibiotic use and the pathogens that are resistant to them.  President Obama also issued an Executive Order that establishes an interagency Task Force and a non-governmental Presidential Advisory Council that will focus on broad-based strategies for slowing the emergence and spread of resistant infections. 

While antibiotics are crucial for treating bacterial infections, their misuse over time has contributed to a rather alarming rate of antibiotic resistance, including the development of multidrug-resistance bacteria or “super bugs.” Misuse manifests throughout all corners of public and private life; from the doctor’s office when prescribed to treat viruses; to industrial agriculture, where they are used in abundance to promote growth in livestock. New data from the World Health Organization (WHO) and U.S. Centers for Disease Control and Prevention (CDC) confirm that rising overuse of antibiotics has already become a major public health threat worldwide.

The administration’s announcement included a report from the President’s Council of Advisors on Science and Technology (PCAST) titled “Combatting Antibiotic Resistance,” which includes recommendations developed by a range of experts to help control antibiotic resistance. In addition, they outline a $20 million prize to reward the development of a new rapid, point-of-care diagnostic test. Such tests help health care providers choose the right antibiotics for their patients and streamline drug development by making it easier to identify and treat patients in clinical trials.  

The Need for Financial Incentives and Better Reimbursement

A highlight of the PCAST report is its recommendations on economic incentives to bring drug manufacturers back into the antibiotics market. Innovative changes to pharmaceutical regulation and research and development (R&D) will be welcomed by many in the health care community, but financial incentives and better reimbursement are necessary to alleviate the market failure for antibacterial drugs. A major challenge, particularly within a fee-for-service or volume-based reimbursement system is providing economic incentives that promote investment in drug development without encouraging overuse.

A number of public and private stakeholders, including the Engelberg Center for Health Care Reform and Chatham House’s Centre on Global Health Security Working Group on Antimicrobial Resistance, are exploring alternative reimbursement mechanisms that “de-link” revenue from the volume of antibiotics sold. Such a mechanism, combined with further measures to stimulate innovation, could create a stable incentive structure to support R&D. Further, legislative proposals under consideration by Congress to reinvigorate the antibiotic pipeline, including the Antibiotic Development to Advance Patient Treatment (ADAPT) Act of 2013, could complement the White House’s efforts and help turn the tide on antibiotic resistance. Spurring the development of new antibiotics is critical because resistance will continue to develop even if health care providers and health systems can find ways to prevent the misuse of these drugs.

       

While antibiotics are necessary and crucial for treating bacterial infections, their misuse over time has contributed to a rather alarming rate of antibiotic resistance, including the development of multidrug-resistance bacteria or “super bugs.” Misuse manifests throughout all corners of public and private life; from the doctor’s office when prescribed to treat viruses; to industrial agriculture, where they are used in abundance to prevent disease in livestock. New data from the World Health Organization (WHO) and U.S. Centers for Disease Control and Prevention (CDC) confirm that rising overuse of antibiotics has already become a major public health threat worldwide.

As drug resistance increases, we will see a number of dangerous and far-reaching consequences. First, common infections like STDs, pneumonia, and “staph” infections will become increasingly difficult to treat, and in extreme cases these infections may require hospitalization or treatment with expensive and toxic second-line therapies. In fact, recent estimates suggest that every year more than 23,000 people die due to drug-resistant infections in the U.S., and many more suffer from complications caused by resistant pathogens. Further, infections will be harder to control. Health care providers are increasingly encountering highly resistant infections not only in hospitals – where such infections can easily spread between vulnerable patients – but also in outpatient care settings.

Fundamental Approaches to Slowing Resistance

Incentivize appropriate use of antibiotics. Many patients and providers underestimate the risks of using antibiotics when they are not warranted, in part because these drugs often have rapid beneficial effects for those who truly need them.  In many parts of the world the perception that antibiotics carry few risks has been bolstered by their low costs and availability without a prescription or contact with a trained health care provider. Education efforts, stewardship programs, and the development of new clinical guidelines have shown some success in limiting antibiotic use, but these fixes are limited in scope and generally not perceived as cost-effective or sustainable. Broader efforts to incentivize appropriate use, coupled with economic incentives, may be more effective in changing the culture of antibiotic use. These options might include physician or hospital report cards that help impact patient provider selection, or bonuses based on standardized performance measures that can be used to report on success of promoting appropriate use.  While these might create additional costs, they would likely help control rates of drug resistant infections and outweigh the costs of treating them.

Reinvigorate the drug development pipeline with novel antibiotics. There has not been a new class of antibiotics discovered in almost three decades, and companies have largely left the infectious disease space for more stable and lucrative product lines, such as cancer and chronic disease. Antibiotics have historically been inexpensive and are typically used only for short periods of time, creating limited opportunities for return on investment. In addition, unlike cancer or heart disease treatments, antibiotics lose effectiveness over time, making them unattractive for investment. Once they are on the market, the push to limit use of certain antibiotics to the most severe infections can further constrict an already weak market.

Late last year, H.R. 3742, the Antibiotic Development to Advance Patient Treatment (ADAPT) Act of 2013, was introduced and referred to the House Energy and Commerce Subcommittee on Health. If enacted, the ADAPT Act would create a streamlined development pathway to expedite the approval of antibiotics that treat limited patient populations with serious unmet medical needs. This could potentially reduce costs and development time for companies, thereby encouraging investment in this space. Regulators have indicated that they would also welcome the opportunity to evaluate benefits and risk for a more selective patient subpopulation if they could be confident the product would be used appropriately. The bill has received a great deal of support and would help address a critical public health need (I cover this topic in more detail with my colleagues Kevin Outterson, John Powers, and Mark McClellan in a recent Health Affairs paper).

Advance new economic incentives to remedy market failure. Innovative changes to pharmaceutical regulation, research and development (R&D), and reimbursement are necessary to alleviate the market failure for antibacterial drugs. A major challenge, particularly within a fee-for-service or volume-based reimbursement system, is providing economic incentives that promote investment in drug development without encouraging overuse.  A number of public and private stakeholders, including the Engelberg Center for Health Care Reform and Chatham House’s Centre on Global Health Security Working Group on Antimicrobial Resistance, are exploring alternative reimbursement mechanisms that  “de-link” revenue from the volume of antibiotics sold. Such a mechanism, combined with further measures to stimulate innovation, could create a stable incentive structure to support R&D.

Improve tracking and monitoring of resistance in the outpatient setting. There is increasing concern about much less rigorous surveillance capabilities in the outpatient setting, where drug-resistant infections are also on the rise. Policymakers should consider new incentives for providers and insurers to encourage a coordinated approach for tracking inpatient and outpatient resistance data. The ADAPT Act, mentioned above, also seeks to enhance monitoring of antibiotic utilization and resistance patterns. Health insurance companies can leverage resistance-related data linked to health care claims, while providers can capture lab results in electronic health records. Ultimately, this data could be linked to health and economic outcomes at the state, federal, and international levels, and provide a more comprehensive population-based understanding of the impact and spread of resistance. Current examples include the Food and Drug Administration’s (FDA) Sentinel Initiative and the Patient-Centered Outcomes Research Institute’s PCORnet initiative. 

Antibiotic resistance is an urgent and persistent threat. As such, patients and providers will continue to require new antibiotics as older drugs are forced into retirement by resistant pathogens. Stewardship efforts will remain critical in the absence of game-changing therapies that parry resistance mechanisms. Lastly, a coordinated surveillance approach that involves diverse stakeholder groups is needed to understand the health and economic consequences of drug resistance, and to inform antibiotic development and stewardship efforts.

Editor's note: This blog was originally posted in May 2014 on Brookings UpFront.

       

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Editors’ Note: It is time to establish a regional reconstruction strategy for the Middle East, argues Sultan Barakat, that involves collective vision, broad participation, smart security, equality, and other key elements.This post originally appeared in Huffington Post.

The World Bank is hosting its annual Fragility Forum this week with the aim of making progress on the post-2015 Sustainable Development Goals. This week has also seen a fragile ceasefire in Syria, potentially landmark elections in Iran, and a violent clash between Jordanian security and so-called Islamic State members. Together these developments have prompted me to reassess what needs to be done to resolve the issues of conflict and fragility in the Middle East.

For the Middle East, the starting point should be to move away from any process that reinforces the image of the West devising solutions and proposing "new" visions to the region. Such approaches are reminiscent of the Sykes-Picot agreement or the neoconservatives' "grand strategy" of the early 2000s and do not appreciate that the Middle East has changed fundamentally since 2011. The region, at all levels, now expects to be treated with dignity and to be the driving force behind its own development.

It is high time to pull together to establish a "Regional Reconstruction Strategy" that can address all sorts of violence, not just Islamist-related conflict. The region needs an ever-evolving strategy that maintains a holistic, problem-solving outlook while drawing on various forms of intervention (e.g. community driven development, inter-regional development projects, targeted counterinsurgency operations, stabilization, statebuilding, etc.) without being straightjacketed by any one toolkit or template. Novel approaches rooted in genuine regional leadership, broad participation, youth engagement, and the utilization of technology will increasingly need to be applied. The pillars of such a strategy should be a collective regional vision, effective local participation, smart security, reconciliation and justice, equity, reconstruction and development, and capacity.

Collective Vision: With the aspirations of the Arab Spring unrealized and many countries descending into sectarianism, what is needed now is a collective vision that goes beyond national borders. This would include pooling the region's resources, specifically all the ingredients for large-scale development, such as human resources, an educated population, capital, mobility, and nature. We could then look to the day when region-wide development is synergistic and not predatory or a zero-sum game. What Morocco has achieved with solar energy is a shining example—a visionary investment has addressed regional developmental and environmental challenges, stimulated employment, and raised confidence that hi-tech and innovative sectors can thrive in the Middle East. Such a broad vision is crucial if the region is to leapfrog into the twenty-first century and not remain in a vicious cycle of conflict and failed development.

Key to an inclusive and non-adversarial vision will be both accepting and embracing Islam as a majority religion while building on human security as an area of common ground. For this to happen some real changes are required in places such as Iran and Saudi Arabia—which would enable both to exercise their regional leadership in coalescing a constructive collective vision rather than perpetuating sectarian hostility.

Broad Participation: It is important that the regional vision recognizes that development requires an active civil society, a free media, and rooting action and ideas at the local level and with popular participation. The process of engaging in a region-wide consultation where contributions are coming from schools, villages, city halls, political parties, unions, and many other civic forums can help the region start dreaming about what it wants to look like in the 50 years to come.

Smart Security: Instead of a collective vision for development we have one for defense, formed with the excuse of the Islamic State group. All appreciate that a minimum level of security is important for implementing reconstruction, but a lack of security cannot be a pretext to do nothing. Experience has shown that delaying reconstruction efforts pushes people down the slope of conflict and violence and leads to dependence on humanitarian assistance. The region needs to find ways of better understanding the granular texture of security at local and regional levels so that strategies can be developed in which localized insecurity does not hold back development in other areas. This could support "spot reconstruction" efforts that create exemplars of what a degree of stability combined with reconstruction intervention can achieve in the midst of larger instability.

Reconciliation and Justice: No long-term investment in reconstruction can be protected without genuine reconciliation across the region. Twenty years ago the main fault line was Israel-Palestine. Today, there are many additional fault lines that need to be addressed, including Muslim-Christian tensions, tensions between displaced and host communities, and tensions between Sunni and Shiite communities. The most fundamental way to initiate reconciliation is to make sure that the rule of law applies to all and that everyone has access to justice regardless of the mechanism. On this a lot can be built on local and traditional systems for achieving justice and reconciliation.

Equity: A common mistake with reconstruction is that it proceeds without sufficient regulation and monitoring to ensure that benefits are equitably distributed. This region has repeatedly seen how easily reconstruction "lords" (most of whom were previously warlords) can emerge to line their pockets at the expense of the general public, thus perpetuating that country's crisis. World Bank arguments for the private sector to take the lead in reconstruction in Afghanistan and elsewhere have done nothing but strengthen this model. Assad's efforts to liberalize Syria's economy prior to 2011 led to the further enrichment of a corrupt elite, contributing to what we see today. Going forward, reconstruction efforts must take into consideration the poorest and least capable—so that nobody is left out.

Reconstruction and Development: There is an urgent need to find new ways of inducing development through international engagement with the region. The current instability has shifted spending toward security and away from the basics of development. As a result, some of the most important development indicators—freedom of expression, women's participation, poverty, quality of education—have taken a step back. All this is happening when the region is facing financial challenges due to severely reduced oil prices. This may prove to be an opportunity as some countries needed a good wake-up call to the pernicious effects of a model of capital development in which billions of dollars are invested in the West, generating jobs and stabilizing economies thousands of miles away at the expense of the region. If the West wants to help the region it should seek to focus minds within the Arab world on the value of investment in addressing regional problems in a mutually beneficial way. Ultimately a more stable region will lead to more prosperous neighbors both in the East and the West.

Building Capacity: To do this we must invest enormous amounts in fostering sustainable capacity at regional, national, and local levels. It is essential to invest in education at all levels, in particular going beyond primary education to support the young men and women that will become leaders with the conviction and capabilities to rebuild the region. In a rush to capture development, we have focused on the hard sciences, engineering, business studies, and computer science while ignoring our own culture, languages, and history. We must correct this imbalance, and it is time we develop our ideas in our own language and not rely on translation.

For all this to happen, fragility must be addressed within a coherent regional vision, not individual national plans. It would be constructive if the international community and donors would try to view the region as a whole—as one canvas in which to facilitate cross-border mobility of population, capital, ideas, and labor—and encourage regional responsibility with different countries leading in their areas of competency. International partners can support this with new and innovative forms of funding that utilize collateral guarantees from the region, not just individual countries. If we can embrace a truly regional approach, there may be a day when we elevate human dignity and human development above petty politics and sectarianism.

      

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As Africa's oldest independent country, Ethiopia has a history that is unique in the continent. The country has faced its share of conflict, including a protracted civil war from 1974 through 1991. A land-locked location in Eastern Africa, the country has also been witness to climate catastrophes, — including the drought that killed a half a million people in the 1980s and the threat of a new drought today. Despite being one of Africa's poorest countries, Ethiopia has experienced significant economic growth since the end of the civil war, and a majority of its population is literate. In addition, Ethiopia is a crucial U.S. security partner, particularly when it comes to counterterrorism, in a region plagued by threats.

On April 25, the Africa Security Initiative at Brookings hosted a discussion examining the security situation in Ethiopia, in broader political, economic, and regional context. Panelists included Abye Assefa of St. Lawrence University and Terrence Lyons of George Mason University. Michael O’Hanlon, co-director of the Center for 21st Century Security and Intelligence, moderated.

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• The security situation in Ethiopia and how it relates to the broader region

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• The security situation in Ethiopia and how it relates to the broader region

      

We are kicking off the new Millions Learning video series with a spotlight on Teach For All, one of the 14 case studies examined in the Millions Learning report. Teach For All is an international network of local, independent partner country organizations dedicated to improving educational opportunities for children and youth around the globe. From China to Bulgaria to Peru to Ghana, each partner organization recruits and trains recent top-performing graduates and professionals to teach in their country’s underserved communities for two years, with the ultimate goal of developing a cadre of education leaders, both inside and outside of the classroom.

In this video, Wendy Kopp, CEO and co-founder of Teach For All, discusses Teach For All’s unique approach to building a pipeline of future “learning leaders and champions” and the role that a supportive policy environment plays in enabling this process. Kopp then explains how Teach For All grew from the original Teach For America and Teach First in the United Kingdom to an international network of 40 partner countries, sharing her own lessons learned along the way.

To learn more about Millions Learning, please visit our interactive report, Millions Learning: Scaling up quality education in developing countries, and/or visit our webpage.

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• Getting millions to learn: Interview with Wendy Kopp of Teach For All

       

Extreme poverty around the world has decreased from around 2 billion people in 1990 living under $2 per day to 700 million today. Further, nine out of 10 children are now enrolled in primary schools, an increase over the last 15 years. Progress in both areas since 2000 has been part of the United Nations Millennium Development Goals, which set targets for reducing extreme poverty in eight areas, and which were the guiding principles for global development from 2000 to 2015. Today, the global community, through the UN, has adopted 17 Sustainable Development Goals to continue these poverty reduction efforts. 

In this new episode of Intersections podcast, host Adrianna Pita engages Brookings scholars Laurence Chandy and Rebecca Winthrop in a discussion of how digital technologies can be harnessed to bring poverty reduction and education to the most marginalized populations.

Listen:

Chandy, a fellow in the Global Economy and Development program at Brookings, says that the trends in getting people digitally connected "are progressing at such speed that they’re starting to reach some of the poorest people in the world. Digital technology is changing what it means to be poor because it’s bringing poor people out of the margins.”

Winthrop, a senior fellow and director of the Center for Universal Education at Brookings, says that "I think [education] access is crucial. And I do think that’s almost the first wave because without it we could work on all the ed tech—fabulous apps, great language translated content—but if you do not have the access it’s not going to reach the most marginalized."

Listen to this episode above; subscribe on iTunes; and find more episodes on our website.

Chandy was a guest on the Brookings Cafeteria Podcast in 2013; Winthrop has been a guest on the Cafeteria a few times to discuss global education topics, including: access plus education; investing in girls' education; and getting millions learning in the developing world.

       

While the South African labor market faces many large challenges, some more subtle trends might also be developing that undermine the country’s growth. Yes, the current level of unemployment stands at 24 percent. True, school dropout rates remain high: Only 50 percent of students will make it to the last year of high school, which means that the number of skilled workers in the country remains low. In addition, income inequality in South Africa is an overwhelming obstacle—with the country having one of the highest Gini coefficients (a statistical tool commonly used to measure inequality) in the world—and has been slowing its fight against poverty.

In their recent paper, Demographic, employment, and wage trends in South Africa, Haroon Bhorat, Karmen Naidoo, Morné Oosthuizen, and Kavisha Pillay examine important, perhaps precarious, trends in South African employment, such as the combination of South Africa’s weak educational system and labor demand biased toward skilled workers and the significant rise in temporary employment over full-time positions. However, the authors argue that perhaps the most interesting is the spike in public sector employment and the subsequent development of a new segment of the labor market, what they call a “new elite”: the unionized public sector employee.

The shift to services and the public sector

Like so many of sub-Saharan African countries, South Africa’s labor makeup (as well as contributions to GDP) has swiftly been shifting towards the services sector, especially since 2001. Table 1 clearly shows the dramatic shift in labor towards community, social, and personal (CSP) services and financial services: These two areas accounted for 73 percent of the shift in employment between 2001 and 2012 (Column 3). 

Employment Shares            Share of Change (ΔEi/ΔE) (a)
	2001	2012	(2001-2012)
Primary	0.15	0.07	-0.28
Agriculture	0.1	0.04	-0.2
Mining	0.05	0.02	-0.08
Secondary	0.2	0.21	0.21
Manufacturing	0.14	0.12	0.04
Utilities	0.008	0.008	0.004
Construction	0.05	0.07	0.16
Tertiary	0.63	0.71	1.08
Trade	0.21	0.21	0.2
Transport	0.04	0.6	0.11
Financial	0.09	0.13	0.31
CSPS	0.17	0.22	0.42
Private households	0.09	0.08	0.04
Total	1	1	1

Note: 1. CSPS stands for community, social, and personal services, which is predominantly made up of public sector employment.⁾

2.^(a) The ratio of the percentage change in the share of employment to the overall change in employment over the period (share of change in employment). This measure shows, within each broad sector, where the sources of employment growth are. For example, employment in the tertiary sector is 1.08 times (or 108 percent of) the level of employment in 2001, which is the sum of the changes for all the industries within this sub-sector. CSPS then is the greatest contributor to employment growth in the tertiary sector.

Source: Bhorat et al. (2014) using PALMS dataset (2012).

Importantly, the authors emphasize, the CSP sector, which accounted for 42 percent of this shift, is mostly made up of public sector jobs—hinting that expansion of the public sector has contributed to this trend. The share of public sector employment rose to 17.5 percent by the end of 2014 from 14.2 percent in 2004. In addition, they note that the largest expansion of the public sector came in 2009, just after the global financial crisis, showing that the public sector was more capable of absorbing” excess unskilled and medium-skilled labor at times of economic and labor market distress.”

Another important trend the authors point to within the shift to the public sector between 2008 and 2014 is that a great number of jobs in which employment grew quickly involve unskilled workers (such as sweepers, farmhands and laborers, helpers and cleaners, construction and maintenance laborers, and garbage collectors) and medium-skilled workers (such as police and traffic officers, institution and home-based care workers, prison guards, cooks, and childcare workers) (Figure 1). For a deeper analysis of South African labor market’s skill needs, see the full paper.

Figure 1: Share of change in public sector jobs by detailed occupation (2008 Q1-2014 Q4)

Notes: These occupations are the largest 42 public sector occupations, making up 80 percent of total employment in the public sector in 2014, and 97 percent of the change in the number of public sector jobs over the 2008-14 period.

Source: StatsSA QLFS 2008Q1; StatsSA QLFS 2014Q4; own calculations.

From these trends, the authors infer that the South African government’s Expanded Public Works Program (EPWP)—which “creates jobs through government-funded infrastructure projects, through its non-profit organization and community work program, as well as through its public environment and culture programs”—has played a major part in the expansion of the public sector.

Interestingly, though, the authors also find that overall the public sector has a bigger proportion of high-skilled employees than the private sector), though, between 2008 and 2013 the public sector barely saw a change in its proportion of high-skilled workers. Rather, it experienced its largest growth in the medium- and low-skilled jobs, as noted in Figure 1. They note that this phenomenon suggests that “the state [is] able to absorb excess unskilled and medium-skilled labor at times of economic and labor market distress.” The private sector’s proportion of high-skilled workers, on the other hand, grew by 25 percent. There is then, they say, a “mismatch” between the supply and demand of South Africa’s labor market when it comes to high-skilled workers.

After exploring this trend, the authors also delve into the demographic differences between public and private sector workers. For example, they find that the average public sector worker is older (41 versus 38) and likely to have a higher educational level on average. There are more women in the public sector—52 percent compared to 44 percent. There are also more Africans—77 percent in the public sector (up from 72 percent in 2008) and 66 percent in the private sector (unchanged). The authors argue that these two statistics demonstrate that public sector has “transformed” its labor force at a faster pace since both are groups that historically have been marginalized in the South African labor market.

The impact of unions in the South African labor market

The public sector in South Africa also has a higher unionization rate: 69.2 percent compared to the private sector’s 24.4 percent rate in 2013). As public sector employment has grown, the authors say, so has its proportion of workers in unions. Unions in South Africa are influential, as the authors note, “Powerful labor unions are often associated with creating a wage premium for their members, given their ability to mobilize industrial action and negotiate in favor of their members during times of wage negotiations.”

Indeed, this seems to be the case. Past studies have found that bargaining power—as part of a bargaining council or a union—presents a wage premium.  The authors have similar results: The average public sector worker makes 11,668 rand ($1,209) per month compared to an average private sector employee (7,822 rand per month). Most importantly, though, when the authors disaggregate based on participation in a union, they actually find that, among non-unionized workers, the private sector employee actually receives a higher wage than the public sector worker, by about 952 rand per month. This finding, they say, suggests that the public sector premium might be tied to public sector union membership.

The authors admit a caveat: Public sector union workers tend to be white, older, and better educated than their non-unionized public sector counterparts. In fact, non-union public sector workers are 80 percent African and 10 percent colored[1] (two groups more likely to be under the EPWP). In addition, non-union occupations are usually less skilled (elementary occupations, service and sales occupations, and technical and associate professional occupations). However, they emphasize, “Ultimately though, the wage distributions above suggest that, at least in terms of earnings, a dual labor market may indeed be prevalent in the South African labor market.”  (For the authors’ full quantitative analysis, including an examination of how this trend interacts with state-owned enterprises and temporary workers, see the full paper.)

Thus, they argue, a “new labor elite” is forming.

Note: The African Lions project is a collaboration among United Nations University-World Institute for Development Economics Research (UNU-WIDER), the University of Cape Town’s Development Policy Research Unit (DPRU), and the Brookings Africa Growth Initiative, that provides an analytical basis for policy recommendations and value-added guidance to domestic policymakers in the fast-growing economies of Africa, as well as for the broader global community interested in the development of the region. The six papers, covering Mozambique, Kenya, Ghana, South Africa, Ethiopia, and Nigeria, explore the key constraints facing African economies as they attempt to maintain a long-run economic growth and development trajectory.

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[1] In this paper, “African” is used to refer to people classified by the apartheid state as “native,” “Bantu,” or “black.” “Colored” refers mainly to people in the Western Cape province, and is an ethnic label for people of mixed ethnic origin who possess ancestry from Europe, Asia, and various Khoisan and Bantu tribes of Southern Africa.

       

In 2015 the international community agreed on a set of ambitious sustainable development goals (SDGs) for the global society, to be achieved by 2030. One of the lessons that the implementation of the Millennium Development Goals (MDG s) has highlighted is the importance of a systematic approach to identify and sequence development interventions—policies, programs, and projects—to achieve such goals at a meaningful scale. The Chinese approach to development, which consists of identifying a problem and long-term goal, testing alternative solutions, and then implementing those that are promising in a sustained manner, learning and adapting as one proceeds—Deng Xiaoping’s “crossing the river by feeling the stones”—is an approach that holds promise for successful achievement of the SDGs.

Having observed the Chinese way, then World Bank Group President James Wolfensohn in 2004, together with the Chinese government, convened a major international conference in Shanghai on scaling up successful development interventions, and in 2005 the World Bank Group (WBG ) published the results of the conference, including an assessment of the Chinese approach. (Moreno-Dodson 2005). Some ten years later, the WBG once again is addressing the question of how to support scaling up of successful development interventions, at a time when the challenge and opportunity of scaling up have become a widely recognized issue for many development institutions and experts.

Since traditional private and public service providers frequently do not reach the poorest people in developing countries, social enterprises can play an important role in providing key services to those at the “base of the pyramid.”

In parallel with the recognition that scaling up matters, the development community is now also focusing on social enterprises (SEs), a new set of actors falling between the traditionally recognized public and private sectors. We adopt here the World Bank’s definition of “social enterprises” as a social-mission-led organization that provides sustainable services to Base of the Pyramid (BoP) populations. This is broadly in line with other existing definitions for the sector and reflects the World Bank’s primary interest in social enterprises as a mechanism for supporting service delivery for the poor. Although social enterprises can adopt various organizational forms—business, nongovernmental organizations (NGOs), and community-based organizations are all forms commonly adopted by social enterprises—they differ from private providers principally by combining three features: operating with a social purpose, adhering to business principles, and aiming for financial sustainability. Since traditional private and public service providers frequently do not reach the poorest people in developing countries, social enterprises can play an important role in providing key services to those at the “base of the pyramid.” (Figure 1)

Figure 1. Role of SE sector in public service provision

Social enterprises often start at the initiative of a visionary entrepreneur who sees a significant social need, whether in education, health, sanitation, or microfinance, and who responds by developing an innovative way to address the perceived need, usually by setting up an NGO, or a for-profit enterprise. Social enterprises and their innovations generally start small. When successful, they face an important challenge: how to expand their operations and innovations to meet the social need at a larger scale. 

Development partner organizations—donors, for short—have recognized the contribution that social enterprises can make to find and implement innovative ways to meet the social service needs of people at the base of the pyramid, and they have started to explore how they can support social enterprises in responding to these needs at a meaningful scale. 

The purpose of this paper is to present a menu of approaches for addressing the challenge of scaling up social enterprise innovations, based on a review of the literature on scaling up and on social enterprises. The paper does not aim to offer specific recommendations for entrepreneurs or blueprints and guidelines for the development agencies. The range of settings, problems, and solutions is too wide to permit that. Rather, the paper provides an overview of ways to think about and approach the scaling up of social enterprise innovations. Where possible, the paper also refers to specific tools that can be helpful in implementing the proposed approaches. 

Note that we talk about scaling up social enterprise innovations, not about social enterprises. This is because it is the innovations and how they are scaled up that matter. An innovation may be scaled up by the social enterprise where it originated, by handoff to a public agency for implementation at a larger scale, or by other private enterprises, small or large. 

This paper is structured in three parts: Part I presents a general approach to scaling up development interventions. This helps establish basic definitions and concepts. Part II considers approaches for the scaling up of social enterprise innovations. Part III provides a summary of the main conclusions and lessons from experience. A postscript draws out implications for external aid donors. Examples from actual practice are used to exemplify the approaches and are summarized in Annex boxes.

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Let’s take a moment for a thought experiment. I do this days after more Palestinian attacks on Israelis, including the horrific murder of a mother of six children; soon after Israel announced the expropriation of another 370 acres of land near Jericho; and after Majed Faraj, the Palestinian security chief, announced that Palestinian security forces had intercepted 200 potential terrorist attacks against Israel. The thought experiment focuses on whether the “Plan B” for the Israel-Palestine dispute should be Israel’s annexation of the territories it occupied in 1967 and the extension of full citizenship rights to the Palestinians in those areas.

To be sure, I still count myself among the dying breed of those who believe fervently in the two-state solution—two states living side by side in peace and security, each enjoying sovereignty and political independence in part of the land that both claim as their exclusive national homes. This is still the best, by far, of all possible outcomes of the dispute. This is not to say that the two-state solution is without faults. Thus far, the two sides have not been able to agree on critical details, and there is no guarantee that achieving two states would assure peaceful relations. But the two-state solution, based on partition of the land, appears to offer the best chance for long term peace. I would dump all Plan B’s and C’s in a heartbeat if leadership emerged in Israel and Palestine—and in the United States—that proved willing to move toward a two-state outcome. 

I still count myself among the dying breed of those who believe fervently in the two-state solution.

But hoping for better, stronger, more farsighted leadership is not a substitute for policy. The fact is that both Israel and the Palestine Liberation Organization (PLO) are further today from bringing forth such leaders than at any time before. Even if Benjamin Netanyahu yields the prime minister’s office to another contender, no one in Israel is proposing the kind of far-reaching accommodation toward which Ehud Olmert was heading in 2008. None of Mahmoud Abbas’s likely successors has even articulated a reasonable peace plan. And none of the candidates for U.S. president is likely to be as committed to the search for peace as Barack Obama has been, and even his commitment has fallen far short of what is needed to move the recalcitrant parties toward peace. The sad reality is that politics—not policy, per se—is what blocks progress toward a two-state solution.

The sad reality is that politics—not policy, per se—is what blocks progress toward a two-state solution.

Regional solution?

In the absence of progress toward two states, are there better alternatives than throwing in the towel and looking at annexation as Plan B? The search for alternative Plan B’s is a fool’s errand. Some of those ideas are creative, but none of them will be accepted by both sides. For example, one Plan B variant du jour rests on the premise of a “regional solution”—that is, having Israel and the Arab world reach a comprehensive peace agreement that includes a resolution of the Palestinian issue. Sounds good, except it makes no sense. 

First, Israel has not accepted the Arab Peace Initiative (API) of 2002, the closest the Arab world has come to accepting Israel within the borders of the 1949 armistice line and agreeing to normalize relations with Israel once peace has been achieved. But no Israeli government has liked its terms, especially the paragraph on Palestinian refugees, the notion of a Palestinian capital in Jerusalem, and the API’s insistence on full Israeli withdrawal. Thus, the question to those who propose a regional solution today is whether there is a coalition in Israel ready to use the API as the basis for negotiating a comprehensive peace. I think not.

Second, the Arab world is in no position to deliver on what the API promises. The Arabs have never followed up the API by engaging Israel. And the premise of the API has been that the Arabs will recognize Israel and agree to normalize only after peace is concluded with the Palestinians (and the Syrians and Lebanese)– not a very attractive incentive for Israelis to enter a risky peace process.

[T]he Arab world of 2002, however dysfunctional, was far more stable than the Arab world of 2016.

And third, the Arab world of 2002, however dysfunctional, was far more stable than the Arab world of 2016. The opponents of the two-state solution in Israel point to this when describing the security dangers that Israel would face were it to concede anything now to the Palestinians. Even if a comprehensive solution were to rest on the shoulders of Egypt and Jordan, Israel’s peace treaty partners, would Israeli skeptics truly be assuaged that these countries could assure Israel’s security in the face of continued instability (Egypt) or the impact of refugees and economic distress (Jordan)? Indeed, the idea of a regional or comprehensive solution based on Arab stability today is chimerical. 

Status quo?

The alternatives to the regional idea are equally unrealistic. The idea of confederation rests on the agreement of Jordan (and potentially Egypt) to join a political entity with the Palestinians. However, neither state has indicated any interest in doing so. 

“Maintaining the status quo” is a non-starter, because status quos are never static—as the events of recent years prove, they tend to get worse. How many Intifadas or stabbings will it take for the people of Israel to believe their own security chiefs, who recognize that these actions are born of frustration over the occupation and related grievances? Why should Israelis believe that the majority of Palestinians are interested in peace when Hamas—opposed to Israel’s very existence—still rules Gaza and commands significant popular support, and while the Palestinian Authority is crumbling and hardly represents anyone anymore? And how long will it take Palestinian supporters of armed and violent resistance to recognize that their abortive efforts to destroy Israel and indiscriminate attacks on Israeli civilians are repugnant: targeting civilians is a morally unacceptable tactic for any resistance movement. 

Thus, the idea of “conflict management” or even “conflict mitigation”—staple products of those who support maintaining the status quo until somehow things change—is pernicious, for it rests on an assumption that the rest of us simply don’t understand the conflict.

[T]he idea of a regional or comprehensive solution based on Arab stability today is chimerical.

A futile search for alternatives

And so it is for all other Plan B’s. Several years ago, my Princeton graduate students embarked on an effort to find a viable alternative to the two-state solution; and they told me at the outset that they intended to prove that such an alternative existed. In the end, they failed and returned to the idea that the only viable solution was to partition the land into two states. Others, too, have tried to find alternatives, and some retain the hope that their policy proposal might win the day. I wish them well—for I really do believe in peace, whether it’s via two states or otherwise. But I have no confidence they will succeed.

[T]he idea of “conflict management” or even “conflict mitigation”—staple products of those who support maintaining the status quo until somehow things change—is pernicious, for it rests on an assumption that the rest of us simply don’t understand the conflict.

And so we are back to the thought experiment. This would take as a starting point what Israeli Minister Uri Ariel told my students several years ago: we (Israel) have won, and the land of Israel is ours. Under this scenario, Israel would:

• Formally annex the territories it occupied in 1967, basing its legal argument on its belief that these are “disputed” rather than “occupied” territories. 
• In connection with this act of annexation, Israel would offer full citizenship rights to all the Palestinians living in the territories. While Israel would probably want to include only the West Bank in this arrangement, excluding Gaza would make it impossible to secure any support internationally, in that Gaza is as much a part of Resolution 242 as is the West Bank.
• Those Palestinians who accept citizenship would then enjoy equal rights with all other Israelis; those Palestinians who reject citizenship would be offered permanent residency, a status that would include certain rights and privileges but not full citizenship rights (for example, voting in national elections). 
• Israel would then approach the United Nations Security Council to argue that these measures constituted an act of self-determination, and that the outcome represented an end of the conflict in accordance with Resolution 242. I am not a lawyer and I assume that many—including Palestinians and Arabs—would dispute this Israeli argument. But the process would change the status quo fundamentally and offer a real alternative to the two-state solution.

Could this work, and is it a real Plan B for the conflict? This is but a thought experiment. I suppose most Israelis will hate this idea for it exposes the most significant weakness of the Israeli right wing and the settlements movement, namely that it undercuts fundamentally the idea of a permanent Jewish majority state. Similarly, most Palestinians will also hate this idea because it forecloses the possibility of a real act of self-determination culminating in an independent state and forces Palestinians to confront the emptiness of the slogans that their leaders have employed over the years in the context of the Arab-Israeli dispute. 

The thought experiment is thus not very sound. Perhaps, then, it will scare everyone enough for leaders to get serious about peace.

      

Indian and Israeli relations are getting even friendlier: Indian Foreign Minister Sushma Swaraj visited Israel in January, and the trip is widely thought to precede higher level visits, including by Prime Minister Narendra Modi (he’d be the first Indian head of government to visit Israel). Israeli President Reuven Rivlin and Prime Minister Benjamin Netanyahu have both also indicated that they plan to travel to India “soon.”

The foreign minister’s visit was part of the ongoing Indian effort not just to broaden and deepen India’s relationship with Israel, but also to make it more public. But the trip—not just to Israel, but to what the Indian government now routinely calls the state of Palestine—also highlighted the Modi government’s attempt to de-hyphenate India’s relations with the Israelis and Palestinians. 

What is the state of India’s relationship with Israel, the Modi government’s approach toward it, and this de-hyphenated approach? 

A blossoming friendship

Since India normalized relations with Israel in 1992, the partnership has developed steadily. The countries have a close defense, homeland security, and intelligence relationship—one that the two governments do not talk much about publicly. Shared concerns about terrorism have proven to be a key driver; so have commercial interests (including Israel’s quest for additional markets and India’s desire to diversify its defense suppliers, get access to better technology, and co-develop and co-produce equipment). India has become Israeli defense companies’ largest customer. Israel, in turn, has shot up on India’s list of suppliers. 

In the early 1990s, Israel—like the United States—did not really figure on India’s list of defense suppliers. However, between 2005 and 2014, it accounted for 7 percent (in dollar terms) of military equipment deliveries—the third highest after Russia and the United States. As Indian President Pranab Mukherjee recently noted, Israel has crucially come through for India at times “when India needed them the most” (i.e. during crises or when other sources have not been available, for example, due to sanctions). The president referred to the assistance given during the Kargil crisis in 1999 in particular, but there has also been less publicly-acknowledged help in the past, including during India’s 1965 and 1971 wars with Pakistan. 

Beyond the defense and security relationship, cooperation in the agricultural sector—water management, research and development, sharing of best practices—might have the most on-the-ground impact, including in terms of building constituencies for Israel at the state level in India. Israeli ambassadors have indeed been nurturing this constituency and reaching out to the chief ministers of Indian states for a number of years. (Incidentally, India, for its part, has felt that the closer relationship with Israel has created a constituency for it in the United States.)

Economic ties have also grown: The two countries are negotiating a free trade agreement, and have been trying to encourage greater investments from the other. The success of Indian and Israeli information technology companies has particularly led to interest in collaboration in that sector. 

The governments have also been trying to increase people-to-people interaction through educational exchanges and tourism, with some success. Israeli tourism officials have highlighted the 13 percent increase in arrivals from India over the last year. And tourist arrivals to India from Israel have doubled over the last 15 years, including thousands of Israelis visiting after their compulsory military service. 

Let’s go public

The India-Israel relationship has developed under Indian governments of different stripes. It was normalized by a Congress party-led government and progressed considerably during the United Progressive Alliance coalition government led by the party between 2004 and 2014. However, while some ministers and senior military officials exchanged visits during that decade, there were not that many high-visibility visits—especially from India to Israel, with the foreign minister only visiting once. A planned 2006 trip by then Defense Minister Mukherjee was reportedly cancelled because of Israeli military operations in Gaza and then the Lebanon war. The last Israeli prime minister to visit India was Ariel Sharon in 2003, and no defense minister had ever visited despite those ties. 

The Israeli ambassador has talked about the relationship being “held under the carpet.” More bluntly, in private, Israeli officials and commentators have said that India has treated Israel like a “mistress”—happy to engage intimately in private, but hesitant to acknowledge the relationship in public. The explanations for this have ranged from Indian domestic political sensitivities to its relations with the Arab countries.

[I]n private, Israeli officials and commentators have said that India has treated Israel like a “mistress”—happy to engage intimately in private, but hesitant to acknowledge the relationship in public.

When the Bharatiya Janata Party (BJP)-led government took office in May 2014 with Modi at its helm, there was a belief that the partnership with Israel would be a priority and more visible. Relations under the BJP-led coalition government between 1998 and 2004 had been more conspicuous. When in opposition, BJP leaders had visited Israel, and also been supportive of that country in election manifestos and speeches. 

As chief minister of the state of Gujarat, Modi himself had expressed admiration for Israel’s achievements, including “how it has overcome various adversities to make the desert bloom.” Traveling there in 2006 with the central agricultural minister, he also helped facilitate trips for politicians, business leaders, and farmers from his state to Israel. His government welcomed Israeli investment and technological assistance in the agricultural, dairy, and irrigation sectors. And, at a time when Modi was not welcome in many Western capitals, Israelis reciprocated: Businesses and government engaged with him, with Israeli ambassadors and consul generals from Mumbai meeting with him long before European and American officials did so. Thus, Modi’s elevation to prime minister was welcomed in Israel, as was the appointment as foreign minister of Swaraj, a former head of the India-Israel Parliamentary Friendship Group.

However, the Modi government’s response to the Gaza crisis in summer 2014 left many perplexed and some of its supporters disappointed. The Indian government initially sought to avoid a debate on the crisis in the Indian parliament, on the grounds that it did not want “discourteous references” to a friend (Israel). After opposition complaints, there was a debate but the government nixed a resolution. In its official statements, the Modi government consistently expressed concern about the violence in general—and, in particular, both the loss of civilian life in Gaza and the provocations against Israel—and called for both sides to exercise restraint and deescalate. Yet, it then voted in support of the U.N. Human Rights Council (UNHRC) resolution that condemned Israel, a move that left observers—including many in the BJP base—wondering why the government didn’t instead abstain. 

Since then, however, the Modi government has moved toward the expected approach. The first sign of this was Modi’s decision to meet with Netanyahu on the sidelines of the opening of the U.N. General Assembly in 2014—despite reported hesitation on the part of some in the foreign ministry. Since then, there have been a number of high-level visits and interactions (and Twitter exchanges), including a few “firsts.” This past October, Pranab Mukherjee, for example, became the first Indian president to travel to Israel, where he declared the state of the relationship to be “excellent.” 

The Israeli ambassador to India has observed the “high visibility” the relationship now enjoys. Also noticed more widely was India abstaining in a July 2015 UNHRC vote on a report criticizing Israeli actions in the 2014 Gaza crisis. Indian diplomats explained the vote as due to the mention of the International Criminal Court (ICC) in the resolution, but observers pointed out that India has voted for other resolutions mentioning the ICC. Israeli commentators saw the abstention as “quite dramatic;” the Israeli ambassador expressed gratitude. Palestinian officials, on the other hand, expressed “shock” and criticized the vote as a “departure.” 

In the defense space, cooperation is only growing: The Indian government moved forward on (delayed) deals to purchase Spike anti-tank missiles and Barak missiles for its navy; it recently tested the jointly-developed Barak 8 missile system, along with Israel Aerospace Industries; and an Indian private sector company has reportedly formed a joint venture with an Israeli company to produce small arms. Cooperation is also continuing in the agricultural sector, with 30 centers of excellence either established or planned across 10 Indian states. More broadly, the two governments are seeking to facilitate greater economic ties, as well as science and technology collaboration. 

There have been questions about why Modi hasn’t visited Israel yet, despite the more visible bonhomie. But, in many ways, it made sense to have the Indian president take the first leadership-level visit during this government. Mukherjee’s position as head of state, as well as the fact that he was a life-long Congress party member and minister, helped convey to both Indian and Israeli audiences that this is not a one-party approach. This point was reinforced by the accompanying delegation of MPs representing different political parties and parts of the country. For similar reasons, it would not be surprising if there was a Rivlin visit to India before a Netanyahu one. 

De-hyphenation? 

The deepening—and more open—relationship with Israel, however, hasn’t been accompanied by a U-turn on the Indian government’s policy toward Palestine. What the Modi government seems to be doing is trying to de-hyphenate its ties with Israel and Palestine. Previous governments have also tried to keep the relationships on parallel tracks—but the current one has sought to make both relationships more direct and visible, less linked to the other, while also making it clear that neither will enjoy a veto on India’s relations with the other. 

The deepening—and more open—relationship with Israel, however, hasn’t been accompanied by a U-turn on the Indian government’s policy toward Palestine.

The Modi government doesn’t demure from referring to the “state of Palestine” rather than “the Palestinian Authority.” It held the first-ever Foreign Office consultations with the Palestinians last spring, and the Indian foreign ministry made it a point to release separate press releases for the president’s and the foreign minister’s trips to Israel and Palestine. The Indian president became the first foreign head of state to stay overnight in Ramallah. Modi met with Mahmoud Abbas, whom the Indian government refers to as the “president of the state of Palestine, on the sidelines of both the U.N. General Assembly meeting in New York and the climate change summit in Paris in 2015. The Indian foreign minister met with Abbas in 2014 in New York, and again in Ramallah on her visit. During their trips, both she and the Indian president also went to the mausoleum of Yasser Arafat (who the BJP in the past called “the illustrious leader of the Palestinian people”).

The government has reiterated India’s traditional position on a two-state solution, indicating its belief in an independent Palestinian state with East Jerusalem as its capital. It voted in favor of the resolution on raising the Palestinian flag at the United Nations, and has continued to sign on to BRICS declarations “oppos[ing] the continuous Israeli settlement activities in the Occupied Territories.” In Ramallah, Sushma Swaraj emphasized that India’s support for Palestinians remained “undiluted.” 

The continuity on this front is not just driven by historic and domestic political factors, but also by India’s broader balancing act in the region. Even as India’s relations with Israel have deepened, it has maintained—and even enhanced—its relations with Iran and the Gulf Cooperation Council (GCC) countries. Modi has welcomed the emir of Qatar, visited the UAE, and met with Iran’s Hassan Rouhani. The first-ever Arab-India Cooperation Forum ministerial meeting also took place in January. It would not be surprising if the Indian prime minister visited Saudi Arabia this year or there were high-level visits exchanged between Delhi and Tehran. The government has emphasized its “strategic intent and commitment to simultaneously enhance relations with the Arab world as well as Israel, without allowing it to become a zero sum game.” And, overall, the Israelis, Palestinians, and GCC countries have not pushed for Delhi to make a choice. 

The de-hyphenated approach, in turn, potentially gives Indian policymakers more space to take India’s relationship with Israel further. But, as was evident during the Indian president’s visit to the region, it hasn’t been problem-free and it has not been feasible to keep the two relationships entirely insulated. An upsurge in violence reportedly caused Israel to nix a proposal for Mukherjee to visit the Al-Aqsa mosque in Jerusalem. There was also some heartburn about the Israeli delay in clearing 30 Indians' computers destined for an India-Palestine Centre for Excellence in Information and Communication Technology at Al-Quds University in Ramallah, as well as its refusal to allow communications equipment to be transferred. In the Israeli press, there was criticism of the president’s lack of mention of Palestinian violence. The Indian president and the foreign ministry also found themselves having to explain the president’s remark in Israel that “religion cannot be the basis of a state.”

There have been other differences between India and Israel as well, notably on Iran (something officials have tended not to discuss publicly). There might be other difficulties in the future, stemming, for example, from: negative public and media reaction in India if there’s another Israel-Palestine crisis; the stalled free trade agreement negotiations; potential Israeli defense sales to China; renewed questions about defense acquisitions from Israel; or the behavior of Israeli tourists in India. But the relationship is likely to continue to move forward, and increase in visibility, including with visits by Rivlin, Netanyahu, and Modi—potentially before the 25th anniversary of the two countries establishing full diplomatic relations on January 29, 2017.

      

While Israeli and Palestinian interests are best served by a negotiated two-state state solution, the peace plan that Sam Bahour proposed in his February post disregards Israel's demographic and security concerns and is tantamount to a Palestinian veto on a negotiated solution. His insistence on the right of return for Palestinian refugees and rejection of security limitations on Palestinian sovereignty in effect asks Israel to become a binational state while creating a militarized Palestinian state alongside it. Bahour rejects the notion of unilateral action, but his case only reinforces my belief that Israel may need to act independently to protect its interests.

The logic behind the Clinton parameters and President Obama’s peace plan was that in return for the creation of a Palestinian state, Palestinian refugees would relinquish their claim to Israel; the hope was that this would allow for the "two states for two peoples" to exist side-by-side. Yet Bahour rejects compromise on the refugee issue as the forfeiture of “basic components of statehood and basic principles of Israeli-Palestinian peace that are enshrined in international law.” Any peace agreement that both establishes a Palestinian state and recognizes the rights of millions of Palestinians to enter Israel would hasten the end of Israel's Jewish identity.

Israel's interest in the creation of a Palestinian state is also built upon the assumption that a sound agreement would improve its security rather than threaten it. To this end, Israel has called for a demilitarized Palestinian state, and this has been echoed by the United States, France, the Czech Republic, the European Union, and Australia’s Labor Party. Even Mahmoud Abbas accepted the premise of demilitarization, saying, “We don’t need planes or missiles. All we need is a strong police force.” Nevertheless, Bahour’s piece declares any limitations on the sovereignty of Palestine unacceptable. For Israel, a peace deal that grants one’s adversaries access to more deadly weaponry would be absurd.

Bahour argues that my strategies for reaching a two-state solution are doomed because they do not meet the "mutual interests" of the parties to the conflict, but his plan does not offer incentives for Israel to make peace.

Bahour argues that my strategies for reaching a two-state solution are doomed because they do not meet the "mutual interests" of the parties to the conflict, but his plan does not offer incentives for Israel to make peace. His proposal not only fails to improve Israel's situation in any tangible sense, but further endangers it. Rejectionist Palestinian positions like Bahour's (and Abbas's recent dismissal of Biden's initiative) would veto the two-state solution as a means to move towards a single binational state. That is precisely why Israel may need to act independently to keep a two-state solution viable.

      

Event Information

The Brookings Doha Center (BDC) hosted a panel discussion on April 19, 2016, about the ongoing reconstruction of the Gaza Strip. The panelists included Omar Shaban, director of Pal-Think, a research institution based in Gaza; and Naglaa Elhag, head of rehabilitation and international development at the Qatar Red Crescent Society (QRCS). Sultan Barakat, the BDC’s director of research, moderated the event, which was attended by members of Qatar’s diplomatic, academic, and media community.

Barakat opened by noting the slow progress of reconstruction in Gaza. Almost two years since the cessation of hostilities between Hamas and Israel, the rebuilding process has stalled for a number of reasons. First, the distribution of aid money pledged by donor countries during the October 2014 Cairo Conference has slowed. According to the World Bank, as of March 31, 2016, donor countries had dispersed only 40 percent of the pledged money. At the current rate, the fulfillment of all pledges will not occur until 2019, two years after the target date. Second, construction materials only enter Gaza from one border crossing. As a result of the sluggish rebuilding process, only 9 percent of totally damaged houses and 45 percent of partially damaged houses in Gaza have been repaired, leaving over 14,800 families internally displaced. Additionally, job opportunities promised by various construction projects have failed to materialize, leading to increased feelings of desperation and frustration among Gaza’s population.

Shaban expanded on these developments, expressing the notion that the people in Gaza feel neglected. Due to the high levels of frustration, he feels that a new round of hostilities between militants and Israel could happen at any moment. He explained further by highlighting the volatility of the area and mentioning how previous conflicts were easily ignited by an array of incidents: a kidnapping, a cross-border raid, an assassination, continuous rocket fire. Since frustration among Gazans continues to mount, arguably to its highest level, renewed conflict seems almost certain. Consequently, Shaban argued, fear of another round of conflict between Hamas and Israel has instilled a sentiment of donor fatigue. Donors do not want to see their support go to waste in another round of destruction, turning the delivery of assistance into an exercise of futility.

Shaban attributed this attitude among some donors to the lack of a political solution to the crisis in Gaza. Hamas, the de-facto governing authority in Gaza, does not work for the people, nor does the Palestinian Authority (PA), based in Ramallah. Neither body provides economic opportunities for Gazans, as those employed by either the PA or Hamas often do not receive their salaries. Reconciliation talks between both groups failed to establish a unity government. Egypt, Israel, and the United States would feel more comfortable negotiating with a unity government, presumably dominated by the PA, not Hamas, which each of the aforementioned countries designate as a terrorist organization. If the PA does reach an agreement with Hamas, Egypt has implied that it would open its border with Gaza at Rafah, as long as the PA stations a security presence at the crossing. This could enhance the slow trickle of construction materials into Gaza, allow for the increased export of commercial goods, and also enable Gazans to leave and return at a higher rate than currently permitted. According to Shaban, opening another access point for Gaza to the outside world would temporarily ease the burden faced by Gaza’s citizens, but the current crisis requires a solution to ameliorate the economic and political situation in the long term.

Elhag opened her remarks by reviewing the difficulties of implementing aid projects in Gaza. While working in Gaza for the QRCS, she noticed little progress from international agencies, as they do not address the main problems, typically taking short cuts, which she highlighted by stating, “We don’t treat the wounds, we cover it with a bandage.” To elaborate on this point she mentioned that lack of access in and out of Gaza and the Israeli naval blockade as two factors hindering reconstruction. Due to these restrictions, aid workers have difficulty entering Gaza. Elhag surmised that the lack of accountability on the part of international agencies and the Israelis and the fear of aid projects being destroyed again because of the political situation both contribute to the stalled reconstruction, producing grim realities in Gaza.

Furthermore, Elhag explained that a resolution to the Gaza crisis does not rest on the distribution of money. She believes that only solutions from both sides of the conflict will end the suffering in Gaza. To exemplify the frustrations felt by donors, Elhag noted that since 2008, QRCS invested $100 million in housing units and other aid projects in Gaza, but some of these projects were destroyed during the 2014 war. QRCS observed this and shifted their focus to securing food sources and enhancing the education and health sectors in Gaza.

At the conclusion of Elhag’s observations, Barakat asked the panel where the money donated for reconstruction goes and how the Gaza reconstruction mechanism (GRM) works. Shaban described how the money actually gets funneled through the PA’s ministry of finance in Ramallah, before it reaches Gaza. Hamas officials or members of Gaza’s civil society do not oversee any aspect of aid distribution. So from the start, the distribution of funds lacks transparency, as the PA gives the money to the U.N. office in Gaza, which administers the GRM. From there, the United Nations composes a list of people in Gaza that require construction materials. The Israeli administrative body in the ministry of defense, the Coordination of Government Activities in the Territories (Cogat), must approve the names on the list. Construction materials can then be distributed through the GRM. Shaban concluded his explanation of the GRM by noting the many levels of bureaucracy involved have created a slow distribution process for a populace in desperate need.

From the regional perspective, some Arab states’ past political differences with Hamas has stymied political progress in Gaza, but the panel agreed that some of these relationships, especially with Saudi Arabia, are on the mend. The work of regional actors like Egypt, Qatar, Saudi Arabia, and Turkey could help push a reconciliation deal between Fatah and Hamas. Shaban proposed allowing some Hamas members to take part in any future coalition government, as some of their relationships in Sinai could help Egypt secure the troubled region. Cooperation on security matters between Egypt and Hamas could inspire enough confidence in the Egyptians for them to open the Rafah crossing.

Ending the discussion, Barakat clarified the proposals of the panel by reiterating the need for donors to fulfill aid pledges. The GRM needs reform, especially through the inclusion of Gaza’s civil society in the reconstruction process. Finally, reconciliation between Fatah and Hamas, as well as Egypt and Hamas, would help foster security cooperation at the borders.

Video

• Reviving the stalled reconstruction of Gaza

Transcript

• Event Transcript (.pdf)

Event Materials

• gaza transcript

       

Two years after Hamas and Israel agreed to a cessation of hostilities, reconstruction in Gaza has been painfully slow. This was the focus of a panel discussion at the Brookings Doha Center on April 19. As Senior Fellow and Director of Research Sultan Barakat explained, rebuilding has stalled in part because the distribution of aid money pledged by donor countries during the October 2014 Cairo Conference has slowed; according to the World Bank, donor countries had dispersed only 40 percent of the pledged money as of the end of March. At this rate, the pledged funds will not be dispersed until 2019, two years after the target date.

Moreover, construction materials only enter Gaza through one border crossing and must be cleared by layers of bureaucracy. As Omar Shaban—director of Pal-Think, a research institution in Gaza—explained, money for Gaza reconstruction is funneled through the PA’s ministry of finance in Ramallah, which transfers it to the U.N. office in Gaza. The United Nations composes a list of people in Gaza that require construction materials, and the Coordination of Government Activities in the Territories (Cogat)—an Israeli administrative body in the ministry of defense—must approve the names on the list. The U.N. then distributes construction materials. Shaban emphasized that the bureaucratic nature of this process has slowed reconstruction considerably, adding that the process isn’t transparent enough, since neither Hamas officials nor members of Gaza’s civil society oversee any aspect of aid distribution.

As a result of the sluggish rebuilding process, Barakat said, only 9 percent of totally damaged houses and 45 percent of partially damaged houses in Gaza have been repaired, leaving over 14,800 families internally displaced. Meanwhile, promised job opportunities in construction projects have failed to materialize, exacerbating feelings of desperation and frustration among Gaza’s population.

[T]he process isn’t transparent enough [said Shaban], since neither Hamas officials nor members of Gaza’s civil society oversee any aspect of aid distribution.

Shaban agreed that people in Gaza feel neglected. With high levels of frustration, he expressed fear that a new round of hostilities between militants and Israel could begin at any time. Previous conflicts were easily ignited—by a kidnapping, a cross-border raid, an assassination, or continuous rocket fire. Shaban argued that the volatility of the situation may be heightening fatigue among donors, who do not want to see their support go to waste in another round of destruction.

Naglaa Elhag, head of rehabilitation and international development at the Qatar Red Crescent Society (QRCS), discussed the difficulties of implementing aid projects in Gaza. She argued that international agencies do not always address the main problems and typically take shortcuts, saying of her own organization and others: “We don’t treat the wounds, we cover it with a bandage.” She highlighted various factors slowing reconstruction, including the lack of accountability on the part of international agencies, fears of renewed conflict, and the Palestinian political stalemate. Since 2008, according to Elhag, QRCS invested $100 million in housing units and other aid projects in Gaza, but some were destroyed during the 2014 war. As a result, QRCS shifted its focus away from physical reconstruction and towards food security, education, and health. 

A related problem is the Palestinian political stalemate. According to Shaban, neither Hamas (the de-facto governing authority in Gaza) nor the Palestinian Authority (PA, based in Ramallah) provides economic opportunities for Gazans, and those nominally on Palestinian government payrolls often do not receive their salaries. Reconciliation talks have failed to establish a unity government, making Egypt, Israel, and the United States reticent to negotiate. Egypt has indicated that if the PA does reach an agreement with Hamas, it would open its border with Gaza at Rafah (presuming the PA has a security presence there). This could increase the flow of construction materials into Gaza, allow for the increased export of commercial goods, and enable Gazans to come and go more frequently. But while opening another crossing for Gaza would temporarily ease the burden faced by the people there, Shaban stressed that a long-term political and economic solution is needed. Elhag, too, emphasized that a resolution to the Gaza crisis isn’t about the distribution of money—rather, she believes a joint Israeli-Palestinian solution is needed to end the suffering in Gaza. 

In the past, tensions between some Arab states and Hamas have also hampered progress in Gaza, but the panelists agreed that some of these relationships—especially with Saudi Arabia—are on the mend. Regional actors like Egypt, Qatar, Saudi Arabia, and Turkey could help push a reconciliation deal between Fatah and Hamas, which would help improve the situation in Gaza. And as Barakat stressed in conclusion, there is an urgent need for donors to fulfill aid pledges and for the Gaza reconstruction mechanism to become more inclusive, so that Gazans themselves can more fully participate in rebuilding their neighborhoods. 

       

As the two-year anniversary of the last round of conflict in Gaza approaches, the inhumane conditions to which 1.8 million Palestinians are being subjected threaten to reach boiling point by the summer months, when the lack of access to water and electricity - available for a maximum of eight hours a day - combined with the oppressive heat and the lack of a reconstruction progress, could exacerbate frustrations, culminating in a new cycle of violence.

Despite the relative calm since the August 26, 2014 ceasefire between Israel and Hamas, there have been more than 20 serious incidents that involved incursions, air raids, and missile exchanges with 23 Palestinians killed in the Gaza Strip since December 2015.

As antagonistic verbal exchanges between Hamas and Israel continued over the past few months, scenes of rising violence in the West Bank and Jerusalem - seemingly outside the control of Hamas and the Palestinian Authority (PA) - started to further fuel people's frustration, thus adding to the volatility of the situation.

Reconstruction of Gaza

The Israeli/Palestinian question has become notorious for the international community's inaction.

Nevertheless, the reconstruction of Gaza is one area where action is not only possible but is also badly needed from both strategic and humanitarian perspectives.

The estimates for how much construction has been completed vary depending on the source, and range from about 17 percent (3,000) of the approximately 18,000 homes destroyed or severely damaged in July/August 2014 according to the UN Office for the Coordination of Humanitarian Affairs; to 9 percent by the World Bank, or to "nothing" by the average Gazan.

Regardless of the exact figure, the fact remains that more than 75,000 people remain displaced across Gaza as a direct result of the July/August 2014 war, a problem made worse by insufficient funding.

There are many factors to explain the slow progress. Chief among them is the continued Israeli blockade; the underlying cause of all the wars in Gaza since Israel’s unilateral withdrawal in 2005.

Egypt's refusal to open the Rafah border crossing without the presence of the PA, along with the Palestinians' inability to activate a unity government, makes the situation even worse.

However, one controversial factor that has received little attention is the UN's Gaza Reconstruction Mechanism (GRM).

The GRM is a complicated system of surveillance intended to: "a. Enable the GoP to lead the reconstruction effort; b. Enable the Gazan private sector; c. Assure donors that their investments in construction work in Gaza will be implemented without delay; d. Address Israeli security concerns related to the use of construction and other 'dual use' material" (UN, October 2014).

By attempting to be both the humanitarian and the jailer at the same time, the UN has fast become the recognizable face of the blockade.

Moral legitimacy

Two years into the reconstruction process, it is now clear that the GRM not only poses difficulties for the people of Gaza seeking to rebuild their homes - as it forces them to wait for a long time before they receive any construction materials - but also, more importantly, erodes the moral legitimacy of the role of the United Nations in Gaza.

For more than 70 years, the UN in Gaza has been associated largely with the work of the United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA).

While the Palestinian people have come to accept that the UN cannot resolve their problems, they still expect that it should at least attempt to take an impartial position, and on occasions adhere to its own values by acting as a witness and speaking up against the atrocities that Palestinians face.

With the GRM, the role of the UN changed. The humanitarian imperative that the UN clings to as it delivers aid in the occupied Palestinian territory is no longer neutral.

In fact, in order to facilitate the flow of construction material under the GRM, the UN is increasingly seen as favoring the status quo and siding with the one with power - Israel.

Arguably, among the four main objectives behind the establishment of the GRM, the one related to Israel's security interest seems to take precedence all the time.

Under the current arrangements, a person seeking construction materials must first go to the GRM administrator to be placed on a list. Once their name reaches the top of the list, the Israeli Coordinator of Government Activities in the Territories (COGAT) must approve of the request before the distribution of any materials. The process between COGAT and the GRM can take weeks.

The sight of UN personnel in armored vehicles accompanying sacks of cement (to ensure delivery and use as proposed) incenses the population of Gaza, as they view this practice as the UN placing a higher value on the protection of construction commodities than on human life.

Complex politics of occupation

The inability of the GRM to engage the local population has alleviated tensions over the past two years. During the conception of the GRM, the civil society of Gaza did not participate in the formation of policies governing the distribution of reconstruction materials.

Only the United Nations, the Israeli government, and the PA devised the plan to rebuild Gaza. Due to their pre-determined position to deny Hamas any opportunity of engagement, the process effectively resulted in excluding citizens and civil society organizations, which was a big mistake.

Nickolay Mladenov and other senior UN officials understand well that the GRM has fallen victim to the complex politics of occupation and resistance.

It is being used every day to punish or "incentivize" Hamas and/or to frustrate any possibility of reaching an understanding between Gaza and the West Bank.

It has also provided a fig leaf to the Egyptian President Abdel Fattah el-Sisi which allowed him to close his borders while pursuing a doomed-to-fail securitization agenda in Sinai.

Its lack of effectiveness has also provided many donors with the excuse to not honor their pledges, thus compounding the suffering.

In short, the situation in Gaza requires immediate action. Regardless of whose fault it is that the GRM has not been able to alleviate the suffering of the people of Gaza, it seems appropriate for the United Nations to admit to the failure of the mechanism and even to withdraw its services.

In fact, a walkout by the UN from administering the crossing and use of construction material is not only the right thing to do morally, but might also force constructive action from Israel, EU governments, the Gulf states, and the US as well as Hamas and the PA.

Given the security concerns in Iraq, Syria, Egypt, and elsewhere, the international community would not stand by and allow for a complete meltdown in Gaza.

The alternative is to continue to deny the reality of the mechanism and to watch the grievances of Palestinians in Gaza reaching an unresolvable level that explodes into another violent round of conflict, worse than the last.

This piece was originally published on Al Jazeera English.

       

Are Turkey and Israel on the verge of signing a normalization agreement, after a six-year hiatus? Comments in recent days by senior officials in both countries suggest so. A senior Israeli official, quoted in the Times of Israel, stated that “95% of the agreement is completed,” while Turkish Foreign Minister Mevlüt Çavuşoğlu said the parties are “one or two meetings away” from an agreement.

Media outlets in both countries have revealed that a meeting between senior Turkish and Israeli officials is expected to be held in Turkey on June 26—and that shortly after, an agreement is likely to be signed and go into effect. 

For two of America’s closest allies in the Middle East to bury the hatchet, reinstate ambassadors, and resume senior-level dialogue would surely be a boost for U.S strategic interests in the region. It would contribute to greater cohesion in dealing with the Syrian crisis, for example, and in the fight against the Islamic State. 

A quick recap

Let’s first recall how the crisis between the two former strategic allies developed, when in the aftermath of the Mavi Marmara incident (May 31, 2010)—resulting in the deaths of 9 Turks—Turkey recalled its ambassador in Tel Aviv and suspended nearly all defense and strategic ties with Israel. Israel also called back its ambassador in Ankara. At the time, Turkey set three conditions for resuming dialogue with Israel: a formal apology, compensation for the families of the victims, and a removal of Israel’s Gaza naval blockade. Relations came to a practical standstill, except in the economic sphere: trade between the two countries exceeded $5 billion in 2014, an unprecedented level. 

Israel formally apologized to Turkey in 2013 and in 2014 committed to paying compensation to the families of the victims. But the Gaza naval blockade has not been lifted. Turkey further demands greater access and presence in Gaza. For its part, Israel demands that Turkey not allow Hamas operative Salah al-Arouri, who resides in Istanbul, to coordinate terrorist operations against Israeli targets in the West Bank. Israel also wants Ankara to pressure Hamas to return the remains of two Israeli soldiers killed in the 2014 war in Gaza. 

Since the flotilla incident, Turkey was not always convinced that repairing relations with Israel actually served its interests. As the Arab Spring unfolded, Turkey hoped to assume a leadership role in the Arab and Muslim worlds—having good relations with Israel did not serve that purpose. And as Turkey went through periods of some unrest in the political arena (whether during the Gezi Park protests in 2013 or the hotly contested local and national elections), many in the ruling AKP party saw restoring relations with Israel as a potential liability in domestic politics. Israel, for its part, was mostly in a reactive mode: sometimes it tried to initiate contacts with Turkey, and sometimes it denounced Turkish anti-Israeli or anti-Semitic rhetoric.

The times they are a-changing

Now, however, new developments have prompted Turkey to seek a rapprochement with Israel. One key factor is the crisis in the Turkish-Russian relationship—in the aftermath of the suspension of the Turkish Stream natural gas pipeline project, Israeli natural gas is viewed as a possible substitute in the medium term for some of Turkey’s natural gas imports from Russia. And as the impact of the war in Syria on Turkey (including the refugee crisis and terrorist attacks) has made clear to Turkey that it must enhance its intelligence capabilities, and Israel can help. Israel, meanwhile, is searching for an export destination for its natural gas (Israeli Energy Minister Steinitz stated recently that “Turkey is a huge market for gas…they need our gas and we need this market”). Israeli leaders also know that resuming a political and military dialogue with Turkey may contribute to a more comprehensive view of the challenges Israel faces in the region. 

Five years after Israel’s formal request to open a representation office at NATO’s Brussels headquarters, Israeli Prime Minister Benjamin Netanyahu announced last month that NATO has approved the Israeli request. Turkey had opposed it, blocking progress, since NATO decisions are adopted by consensus. In a move seen signaling a thawing of relations, Turkey recently removed its objection to Israel’s request, paving the way to NATO’s decision. Israel continues to be a partner in NATO’s Mediterranean Dialogue along with Egypt, Algeria, Tunisia, Jordan, Mauritania and Morocco. 

At a time when Turkish President Recep Tayyip Erdoğan is attempting to strengthen his country’s regional strategic position and enhance its economic opportunities, a rapprochement with Israel makes sense. Bilateral negotiations are in the final stretch, as they have reached a compromise on the complex issue of Gaza and Hamas (Turkey will reportedly not demand the full lifting of Israel’s naval blockade on Gaza, settling for greater access and presence in Gaza. Israel will acquiesce to continued Hamas political activities in Turkey and will not demand the removal of Hamas operative al-Arouri from Turkey, but will get Turkish assurances that al-Arouri’s involvement in terror will cease.)

Fixing the troubled Turkish-Israeli relationship has been a mighty task for senior negotiators on both sides over the last few years, and although an agreement seems around the corner, the experience of recent years suggests that there can be last minute surprises. Israel’s Prime Minister had to jump over several hurdles, holding off pressure from Russia and Egypt not to seek rapprochement with Turkey, and ensuring support of the deal with Turkey from his newly appointed Defense Minister Avigdor Liberman, a known opponent of a deal. On the Turkish side, it seems that President Erdoğan wants a rapprochement with Israel, and feels that he needs it. This is tied directly to the Turkish domestic arena: Erdoğan has recently completed his consolidation of power, ousting Prime Minister Ahmet Davutoğlu and paving the way to the election of his trusted confidant, Binali Yıldırım, as prime minister. In addition, his new allies—the military-judicial establishment—are in favor of mending ties with Israel. One caveat is that Erdoğan’s top priority is establishing a presidential system, and so if he feels at any point that reaching an agreement with Israel will somehow undermine those efforts, he may opt for maintaining the status quo. 

       

Last month’s decision by the Palestinian Authority to schedule municipal elections in early October hardly registered in the West Bank and Gaza Strip, much less here in Washington. In light of Hamas’ recent decision to take part in the process, however, those elections have suddenly taken on new meaning. While the election of some 414 village, town, and city councils across the West Bank and Gaza Strip will not change the face of the Palestinian leadership or alter the diplomatic impasse with Israel, local elections have the potential to unlock the current paralysis within Palestinian politics.

Although Palestinian law calls for local elections to take place every four years, they have only been held twice since the creation of the Palestinian Authority (PA) in 1993, only one of which could be deemed genuinely competitive. The first and only local elections to take place in both the West Bank and Gaza Strip were held in 2004-05, in which Hamas—in its first foray into electoral politics—made major gains. Local elections were again held in 2012, although this time Hamas boycotted the process, preventing the vote from taking place in Gaza and allowing Fatah to declare a sweeping, if somewhat hollow, victory. 

Hamas’ decision to take part in this year’s local elections was therefore something of a surprise. Indeed, Hamas initially expressed dismay at the announcement, accusing the leadership in Ramallah of acting without consulting the other parties. Moreover, should the elections proceed as planned on October 8, they would be the first competitive electoral contest in the occupied territories since Hamas defeated Mahmoud Abbas’s ruling Fatah faction in the 2006 legislative election. Those elections triggered an international boycott of the PA which eventually led to the split between Fatah and Hamas and the current political paralysis.

If nothing else, Hamas’ entry into the elections averts another needless internal crisis in Palestinian politics. A boycott by Hamas would likely have further entrenched the political and geographic division between the Fatah-dominated West Bank and Hamas-ruled Gaza Strip, while dealing yet another blow to the beleaguered National Consensus Government, which despite being accepted by both factions in April 2014 has yet to physically return to Gaza. Movement on the reconciliation track could also help push the long-stalled reconstruction of Gaza, which has yet to recover from the devastating war of 2014.

Hamas has little to lose from participating in an election that is unlikely to significantly alter the political landscape one way or the other...[and Fatah] has little to gain from “winning” another electoral process that is largely uncontested.

What explains Hamas’ apparent change of heart? For one, Hamas may believe it has an advantage over Fatah, which continues to suffer from widespread perceptions of corruption and incompetence—a perception reinforced by the collapse of the peace process as well as the unprecedented unpopularity of President Abbas. Hamas may also view the upcoming vote as a way to gauge its current standing and future prospects in anticipation of long-awaited legislative and presidential elections. Either way, Hamas has little to lose from participating in an election that is unlikely to significantly alter the political landscape one way or the other. 

Hamas’ decision to participate in the elections is welcome news for Palestinian voters eager to see the return of competitive elections and a revival of political life after years of stagnation. It even helps Fatah, which has little to gain from “winning” another electoral process that is largely uncontested. More important, as the party that lost both parliamentary elections and a civil war in 2006-07 and that remains the chief proponent of a failed process, Fatah desperately needs a political victory of some kind as well as a basis on which to stake its claim to legitimacy and continued grip on power.

That said, it is important not to overstate the significance of local elections, which in the end will do nothing to address the deeper problems facing Palestinians in the occupied territories, whether from Israel’s continued occupation and its ever-expanding settlement enterprise or the ongoing political dysfunction within their own ranks. On the other hand, the prospect of the first competitive Palestinian elections in a decade represents a small but significant ripple in the otherwise stagnant waters of Palestinian politics.

       

       

While antibiotics are necessary and crucial for treating bacterial infections, their misuse over time has contributed to a rather alarming rate of antibiotic resistance, including the development of multidrug-resistance bacteria or “super bugs.” Misuse manifests throughout all corners of public and private life; from the doctor’s office when prescribed to treat viruses; to industrial agriculture, where they are used in abundance to prevent disease in livestock. New data from the World Health Organization (WHO) and U.S. Centers for Disease Control and Prevention (CDC) confirm that rising overuse of antibiotics has already become a major public health threat worldwide.

As drug resistance increases, we will see a number of dangerous and far-reaching consequences. First, common infections like STDs, pneumonia, and “staph” infections will become increasingly difficult to treat, and in extreme cases these infections may require hospitalization or treatment with expensive and toxic second-line therapies. In fact, recent estimates suggest that every year more than 23,000 people die due to drug-resistant infections in the U.S., and many more suffer from complications caused by resistant pathogens. Further, infections will be harder to control. Health care providers are increasingly encountering highly resistant infections not only in hospitals – where such infections can easily spread between vulnerable patients – but also in outpatient care settings.

Fundamental Approaches to Slowing Resistance

Incentivize appropriate use of antibiotics. Many patients and providers underestimate the risks of using antibiotics when they are not warranted, in part because these drugs often have rapid beneficial effects for those who truly need them.  In many parts of the world the perception that antibiotics carry few risks has been bolstered by their low costs and availability without a prescription or contact with a trained health care provider. Education efforts, stewardship programs, and the development of new clinical guidelines have shown some success in limiting antibiotic use, but these fixes are limited in scope and generally not perceived as cost-effective or sustainable. Broader efforts to incentivize appropriate use, coupled with economic incentives, may be more effective in changing the culture of antibiotic use. These options might include physician or hospital report cards that help impact patient provider selection, or bonuses based on standardized performance measures that can be used to report on success of promoting appropriate use.  While these might create additional costs, they would likely help control rates of drug resistant infections and outweigh the costs of treating them.

Reinvigorate the drug development pipeline with novel antibiotics. There has not been a new class of antibiotics discovered in almost three decades, and companies have largely left the infectious disease space for more stable and lucrative product lines, such as cancer and chronic disease. Antibiotics have historically been inexpensive and are typically used only for short periods of time, creating limited opportunities for return on investment. In addition, unlike cancer or heart disease treatments, antibiotics lose effectiveness over time, making them unattractive for investment. Once they are on the market, the push to limit use of certain antibiotics to the most severe infections can further constrict an already weak market.

Late last year, H.R. 3742, the Antibiotic Development to Advance Patient Treatment (ADAPT) Act of 2013, was introduced and referred to the House Energy and Commerce Subcommittee on Health. If enacted, the ADAPT Act would create a streamlined development pathway to expedite the approval of antibiotics that treat limited patient populations with serious unmet medical needs. This could potentially reduce costs and development time for companies, thereby encouraging investment in this space. Regulators have indicated that they would also welcome the opportunity to evaluate benefits and risk for a more selective patient subpopulation if they could be confident the product would be used appropriately. The bill has received a great deal of support and would help address a critical public health need (I cover this topic in more detail with my colleagues Kevin Outterson, John Powers, and Mark McClellan in a recent Health Affairs paper).

Advance new economic incentives to remedy market failure. Innovative changes to pharmaceutical regulation, research and development (R&D), and reimbursement are necessary to alleviate the market failure for antibacterial drugs. A major challenge, particularly within a fee-for-service or volume-based reimbursement system, is providing economic incentives that promote investment in drug development without encouraging overuse.  A number of public and private stakeholders, including the Engelberg Center for Health Care Reform and Chatham House’s Centre on Global Health Security Working Group on Antimicrobial Resistance, are exploring alternative reimbursement mechanisms that  “de-link” revenue from the volume of antibiotics sold. Such a mechanism, combined with further measures to stimulate innovation, could create a stable incentive structure to support R&D.

Improve tracking and monitoring of resistance in the outpatient setting. There is increasing concern about much less rigorous surveillance capabilities in the outpatient setting, where drug-resistant infections are also on the rise. Policymakers should consider new incentives for providers and insurers to encourage a coordinated approach for tracking inpatient and outpatient resistance data. The ADAPT Act, mentioned above, also seeks to enhance monitoring of antibiotic utilization and resistance patterns. Health insurance companies can leverage resistance-related data linked to health care claims, while providers can capture lab results in electronic health records. Ultimately, this data could be linked to health and economic outcomes at the state, federal, and international levels, and provide a more comprehensive population-based understanding of the impact and spread of resistance. Current examples include the Food and Drug Administration’s (FDA) Sentinel Initiative and the Patient-Centered Outcomes Research Institute’s PCORnet initiative. 

Antibiotic resistance is an urgent and persistent threat. As such, patients and providers will continue to require new antibiotics as older drugs are forced into retirement by resistant pathogens. Stewardship efforts will remain critical in the absence of game-changing therapies that parry resistance mechanisms. Lastly, a coordinated surveillance approach that involves diverse stakeholder groups is needed to understand the health and economic consequences of drug resistance, and to inform antibiotic development and stewardship efforts.

Editor's note: This blog was originally posted in May 2014 on Brookings UpFront.

      

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As policy agendas for 2015 come into sharper focus, much of the national conversation is aimed at tackling challenges in biomedical innovation. The first two months of the year alone have seen landmark proposals from Congress and the Obama Administration, including the House’s 21^st Century Cures initiative, a bipartisan Senate working group focused on medical progress, President Obama’s Precision Medicine Initiative and a number of additional priorities being advanced by federal agencies and other stakeholders.

On March 13, the Engelberg Center for Health Care Reform hosted the State of Biomedical Innovation Conference to provide an overview of emerging policy efforts and priorities related to improving the biomedical innovation process. Senior leaders from government, academia, industry, and patient advocacy shared their thoughts on the challenges facing medical product development and promising approaches to overcome them. The discussion also examined the data and analyses that provide the basis for new policies and track their ultimate success.

 Join the conversation by following @BrookingsMed or #biomed

Video

• State of biomedical innovation conference: Panel 1
• State of biomedical innovation conference: Panel 2

Audio

• State of biomedical innovation conference

Transcript

• Uncorrected Transcript (.pdf)

Event Materials

• 20150313_biomed_transcript
• 313 MASTER DECK2

      

Breakthrough therapy designation (BTD) is the newest of four expedited programs developed by the U.S Food and Drug Administration (FDA) to accelerate the development and review of novel therapies that target serious conditions. The public response to the program has been largely positive, and dozens of drugs have successfully received the designation. However, the FDA denies many more requests than it grants. In fact, as of March 2015, less than one in three of the BTD requests submitted have been granted. By contrast, roughly 75 percent of the requests for fast track designation (another of the Agency’s expedited programs) were granted between 1998 and 2007. This discrepancy suggests ongoing uncertainty over what exactly constitutes a “breakthrough” according to the FDA’s criteria.

On April 24, the Center for Health Policy at Brookings will host an event, Breakthrough Therapy Designation: Exploring the Qualifying Criteria, that will discuss qualifying criteria for the BTD program using real and hypothetical case studies to explore how FDA weighs the evidence submitted. Below is a primer that describes the definition, value, and impact of BTD.

What is BTD?

BTD was established in 2012 under the Food and Drug Administration Safety and Innovation Act, and is intended to expedite the development and review of drugs that show signs of extraordinary benefit at early stages of the clinical development process. However, BTD is not an automatic approval. The drug still has to undergo clinical testing and review by the FDA. Rather, BTD is designed to facilitate and shorten the clinical development process, which can otherwise take many years to complete.

What criteria does FDA use to evaluate potential breakthroughs?

In order to qualify for the designation, a therapy must be intended to treat a serious or life-threatening illness, and there must be preliminary clinical evidence that it represents a substantial improvement over existing therapies on at least one clinically significant outcome (such as death or permanent impairment).

In considering a request for BTD, FDA relies on three primary considerations:

1) the quantity and quality of the clinical evidence being submitted;

2) the available therapies that the drug is being compared to; and

3) the magnitude of treatment effect shown on the outcome being studied.

In practice, however, it can be difficult to define a single threshold that a therapy must meet. The decision depends on the specific context for that drug.  In some cases, for example, the targeted disease has few or no treatments available, while in others there may be several effective alternative treatments to which the new therapy can be compared. The request may also be made at different stages of the clinical development process, which means that the amount and type of data available to FDA can vary. In some cases, early evidence of benefit may disappear when the drug is tested in larger populations, which is why FDA reserves the right to rescinded the designation if subsequent data shows that the therapy no longer meets the criteria.

How many therapies have received the designation?

As of March 2015, FDA had received a total of 293 requests for BTD. Of these, 82 received the designation, and 23 have since been approved for marketing. Ten of these approvals were new indications for already approved drugs, rather than novel therapies that had never before received FDA approval.

What are the benefits of BTD?

For drug manufacturers, it is about the intensity and frequency of their interactions with FDA. Once the designation is granted, the FDA takes an “all hands-on-deck” approach to providing the manufacturer with ongoing guidance and feedback throughout the clinical development process. Products that receive BTD are also able to submit portions of their marketing application on a rolling basis (rather than all at once at the end of clinical trials) and BTD can also be used in combination with other expedited programs in order to further reduce the product’s time to market.

For patients, the potential benefits are straightforward: earlier access to therapies that may significantly improve or extend their lives.

How does BTD relate to the other three expedited programs?

The other three expedited review and development programs—fast track designation, priority review, and accelerated approval—are also geared at facilitating the development and approval of drugs for serious conditions. These other programs have been in place for over 15 years, and have played a significant role in accelerating patient access to new therapeutics (Table 1). In 2014 alone, 66 percent of the 41 drugs approved by FDA's Center for Drug Evaluation and Research used at least one of these four pathways, and 46 percent received at least two of the designations in combination.

Table 1: Overview of FDA’s Expedited Review Programs

 Adapted from FDA's Guidance for Industry: Expedited Programs for Serious Conditions - Drugs and Biologics

      

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Established by the Food and Drug Administration Safety and Innovation Act of 2012, breakthrough therapy designation (BTD) is one of several programs developed by the U.S. Food and Drug Administration (FDA) to speed up the development and review of drugs and biologics that address unmet medical needs. In order to qualify for this designation, the treatment must address a serious or life-threatening illness. In addition, the manufacturer (i.e., sponsor) must provide early clinical evidence that the treatment is a substantial improvement over currently available therapies. The FDA is working to further clarify how it applies the qualifying criteria to breakthrough designation applications.

On April 24, under a cooperative agreement with FDA, the Center for Health Policy convened a public meeting to discuss the qualifying criteria for this special designation. Using examples from oncology, neurology, psychiatry, and hematology, the workshop highlighted considerations for the BTD application process, the evaluation process, and factors for acceptance or rejection. The discussion also focused on key strategies for ensuring that the qualifying criteria are understood across a broad range of stakeholder groups.

Video

• Breakthrough therapy designation: Two and a half years in
• Applying the breakthrough therapy criteria: Oncology
• Applying the breakthrough therapy criteria: Neurology
• Applying the breakthrough therapy criteria: Anti-infective/psychiatry/hematology
• Summary and discussion of lessons learned

Event Materials

• Breakthrough Therapy Designation_final
• Breakthrough therapy slide deck

      

Many proposals to accelerate and improve medical product innovation and regulation focus on reforming the product development and regulatory review processes that occur before drugs and devices get to market. While important, such proposals alone do not fully recognize the broader opportunities that exist to learn more about the safety and effectiveness of drugs and devices after approval. As drugs and devices begin to be used in larger and more diverse populations and in more personalized clinical combinations, evidence from real-world use during routine patient care is increasingly important for accelerating innovation and improving regulation.

First, further evidence development from medical product use in large populations can allow providers to better target and treat individuals, precisely matching the right drug or device to the right patients. As genomic sequencing and other diagnostic technologies continue to improve, postmarket evidence development is critical to assessing the full range of genomic subtypes, comorbidities, patient characteristics and preferences, and other factors that may significantly affect the safety and effectiveness of drugs and devices. This information is often not available or population sizes are inadequate to characterize such subgroup differences in premarket randomized controlled trials.

Second, improved processes for generating postmarket data on medical products are necessary for fully realizing the intended effect of premarket reforms that expedite regulatory approval. The absence of a reliable postmarket system to follow up on potential safety or effectiveness issues means that potential signals or concerns must instead be addressed through additional premarket studies or through one-off postmarket evaluations that are more costly, slower, and likely to be less definitive than would be possible through a better-established infrastructure. As a result, the absence of better systems for generating postmarket evidence creates a barrier to more extensive use of premarket reforms to promote innovation.

These issues can be addressed through initiatives that combine targeted premarket reforms with postmarket steps to enhance innovation and improve evidence on safety and effectiveness throughout the life cycle of a drug or device. The ability to routinely capture clinically relevant electronic health data within our health care ecosystem is improving, increasingly allowing electronic health records, payer claims data, patient-reported data, and other relevant data to be leveraged for further research and innovation in care. Recent legislative proposals released by the House of Representatives’ 21st Century Cures effort acknowledge and seek to build on this progress in order to improve medical product research, development, and use. The initial Cures discussion draft included provisions for better, more systematic reporting of and access to clinical trials data; for increased access to Medicare claims data for research; and for FDA to promulgate guidance on the sources, analysis, and potential use of so-called Real World Evidence. These are potentially useful proposals that could contribute valuable data and methods to advancing the development of better treatments.

What remains a gap in the Cures proposals, however, is a more systematic approach to improving the availability of postmarket evidence. Such a systematic approach is possible now. Biomedical researchers and health care plans and providers are doing more to collect and analyze clinical and outcomes data. Multiple independent efforts – including the U.S. Food and Drug Administration’s Sentinel Initiative for active postmarket drug safety surveillance, the Patient-Centered Outcomes Research Institute’s PCORnet for clinical effectiveness studies, the Medical Device Epidemiology Network (MDEpiNet) for developing better methods and medical device registries for medical device surveillance and a number of dedicated, product-specific outcomes registries – have demonstrated the potential for large-scale, systematic postmarket data collection. Building on these efforts could provide unprecedented evidence on how medical products perform in the real-world and on the course of underlying diseases that they are designed to treat, while still protecting patient privacy and confidentiality.

These and other postmarket data systems now hold the potential to contribute to public-private collaboration for improved population-based evidence on medical products on a wider scale. Action in the Cures initiative to unlock this potential will enable the legislation to achieve its intended effect of promoting quicker, more efficient development of effective, personalized treatments and cures.

What follows is a set of both short- and long-term proposals that would bolster the current systems for postmarket evidence development, create new mechanisms for generating postmarket data, and enable individual initiatives on evidence development to work together as part of a broad push toward a truly learning health care system.

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The breakthrough therapy designation (BTD) program was initiated by the U.S. Food and Drug Administration (FDA) in 2012 to expedite the development of treatments for serious or life-threatening illness that demonstrate “substantial improvement” over existing therapies. The program has since become a widely supported mechanism for accelerating patient access to new drugs. As of March 2015, FDA has received a total of 293 requests for BTD. However, it has granted just  82 (28%), which indicates an ongoing lack of clarity over what exactly meets the criteria for the designation.

On April 24, the Center for Health Policy at Brookings convened a public meeting to explore the designation’s qualifying criteria and how FDA applies those criteria across therapeutic areas. Panelists used real-world and hypothetical case studies to frame the discussion, and highlighted major considerations for the application process, the FDA’s evaluation of the evidence, and the key factors for acceptance or rejection. The discussion also identified strategies to ensure that qualifying criteria are well understood. Here are the five big takeaways:

1.  The BTD program is viewed positively by drug companies, researchers, advocates, and others 

Across the board, participants expressed enthusiasm for the BTD program. Industry representatives noted that their experience had been extremely positive, and that the increased cooperation with and guidance from FDA were very helpful in streamlining their development programs. Receiving the designation can also raise a drug company’s profile, which can facilitate additional investment as well as clinical trial patient recruitment; this is particularly important for smaller companies with limited resources.

Patient and disease advocates were likewise supportive, and expressed hope that the early lessons learned from successful breakthrough therapy approvals (which have been mostly concentrated in the oncology and antiviral fields) could be translated to other disease areas with less success. However, while BTD is an important tool in expediting the development of new drugs, it is just one piece of broader scientific and regulatory policy landscape. Accelerating the pace of discovery and development of truly innovative new drugs will depend on a range of other factors, such as developing and validating new biomarkers that can be used to measure treatment effects at an earlier stage, as well as establishing networks that can streamline the clinical trial process. It will also be important to develop effective new approaches to collecting, analyzing, and communicating information about these treatments once they are on the market, as this information can potentially be used by FDA, providers, and patients to  further improve prescription drug policy and medical decision-making.

2.  BTD requests far outnumber those that actually meet the qualifying criteria

Since the program began, less than 30 percent of requests have received BTD designation. A substantial majority were denied at least in part due to either a lack of data or problems with the quality of the data, or some combination of the two. For example, some sponsors requested the designation before they had any clinical data, or submitted the request using clinical data that was incomplete or based on flawed study designs. Many requests also failed to meet the Agency’s bar for “substantial improvement” over existing therapies.

One reason for the high denial rate may be a lack of a clear regulatory or statutory bar that could be used as a definitive guide for sponsors to know what is needed to qualify for the designation. BTD denials are also confidential, which means that sponsors effectively have nothing to lose by submitting a request. Going forward, manufacturers may need to exercise more discretion in deciding to request the designation, as the process can be resource- and time-intensive for both sides.

3.  There is no single threshold for determining what defines a breakthrough therapy

About 53 percent of the 109 total BTD denials were due at least in part to the fact that the drug did not represent a substantial improvement over existing therapies. During the day’s discussion, FDA and sponsors both noted that this is likely because the criteria for BTD are inherently subjective. In practice, this means there is no clear threshold for determining when a new therapy represents a “substantial improvement” over existing therapies. Designation decisions are complex and highly dependent on the context, including the disease or condition being targeted, the availability of other treatments, the patient population, the outcomes being studied, and the overall reliability of the data submitted. Given the multiple factors at play, it can be difficult in some cases to determine when a new product is potentially “transformational” as opposed to “better,” especially for conditions that are poorly understood or have few or no existing treatments. In making its determinations, FDA considers the totality of the evidence submitted, rather than focusing on specific evidentiary requirements.

4.  Early communication with FDA is strongly recommended for BTD applicants

Roughly 72 percent of the BTD denials related at least in part to trial design or analysis problems, which led several people to suggest that sponsors engage with FDA prior to submitting their request. Though there are several formal mechanisms for interacting with the agency, informal consultations with the relevant review division could help sponsors to get a better  and much earlier sense of what kind of data FDA might need. This early communication could both strengthen viable BTD requests and reduce the number of frivolous requests.

5.  FDA may need more resources for implementing the BTD program

Drugs that receive breakthrough designation are subject to much more intensive FDA guidance and review. However, when the program was established in 2012, Congress did not allocate funding to cover its costs. There have been ongoing concerns that the program is exacting a significant toll on FDA’s already limited resources, and potentially affecting the timeline for other drug application reviews. These concerns were reiterated during the day’s discussion, and some suggested that Congress consider attaching a user fee to the BTD program when the Prescription Drug User Fee Act comes up for reauthorization in 2017.

      

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The Risk Evaluation and Mitigation Strategies (REMS) program has become an important tool of the U.S. Food and Drug Administration (FDA) in ensuring that the benefits of a given medical product outweigh the associated risks, and has enabled FDA to approve a number of products that might not otherwise have been made available for patient use. Since the implementation of the REMS program, however, concerns have been raised regarding its impact on patient access to products and the associated burden on providers and health care systems. In an effort to address these concerns—and as part of its commitments under the Prescription Drug User Fee Act reauthorization of 2012—FDA has undertaken efforts to standardize and improve the effectiveness of REMS, and to better integrate REMS programs into the health system. As part of this broader initiative, the Agency is currently assessing the feasibility of integrating accredited continuing education (CE) programs and activities into REMS programs that have been developed for a single drug.

Under a cooperative agreement with the FDA, the Center for Health Policy held an expert workshop on May 18, titled “Incorporating Continuing Education into Single-Drug REMS: Exploring the Challenges and Opportunities”. This workshop provided an opportunity for pharmaceutical manufacturers, regulators, CE providers, accreditors, and other stakeholders to explore the ways that CE can be a valuable addition to the REMS toolkit, discuss potential barriers to the development and implementation of REMS-related CE for single products, and identify strategies for addressing those barriers.

Event Materials

• Bio sheet
• REMS CE Meeting Agenda
• REMS_CE_Meeting_Discussion_Guide_Final
• REMS CE Meeting Summary

      

For the last several years, the US government has been negotiating a free-trade agreement known as the Trans-Pacific Partnership (TPP) with 11 other countries across the Asia-Pacific and Latin American regions, which could have major impact on the pharmaceutical market.  When finalized it will be the largest free-trade agreement in history, impacting up to one-third of world trade and roughly 40 percent of the global gross domestic product. The deal has attracted a fair share of criticism from a wide range of groups, including concerns over proposed regulations for biologic drugs in participating countries. Specifically, critics are concerned about the length of data exclusivity granted to the companies that hold the patents on these drugs. Below is a primer on biologics and how they are being addressed in the TPP.

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What are biologics and biosimilars?

Biologic drugs include any therapy derived from a biological source; a group which includes vaccines, anti-toxins, proteins, and monoclonal antibodies. Because they are typically much larger and more structurally complex than traditional ‘small-molecule’ drugs, they are also more difficult—and much more costly—to develop and manufacture. Biologics are also among the most expensive drugs on the market, costing an average of 22 times more than nonbiologic drugs. Avastin, a cancer drug, can cost more than $50,000 a year, while the rheumatoid arthritis drug Remicade can cost up to $2,500 per injection.

Given these high costs, there is substantial interest in encouraging the development of biosimilars, a term used to describe follow-on versions of an original biologic. Estimates of the potential cost savings vary substantially, but some have predicted that competition from biosimilars could reduce US spending on biologics by $44 to $66 billion over the next ten years.  In the European Union, biosimilars have been on the market since 2006, and a 2013 analysis found that, for the 14 biosimilars on the market, the average price discount was about 25 percent. By 2020, the overall cost savings are projected to total $16-$43 billion.

After the Affordable Care Act (ACA) was passed in 2010, the US Food and Drug Administration (FDA) developed an accelerated approval pathway for biosimilars, modeled after the pathway used for the approval of small-molecule generics. In order to meet the criteria for biosimilarity, the drug must share the same mechanism of action for the approved condition of use, and there must be no clinically significant differences between the two drugs in terms of purity, safety, or potency. FDA recently approved its first biosimilar, Zarxio, which is a copy of the oncology drug Neupogen.

What issues are being raised over data exclusivity in the US?

Under current FDA regulations, biologic drugs are granted 12 years of data exclusivity following approval. During this period of exclusivity, the FDA may not approve a biosimilar application that relies on the data submitted as part of the original biologic application. This form of temporary monopoly is distinct from patent protection, which is granted well before approval and is not related to clinical data.  Data exclusivity does not prevent another company from generating the data independently, but drug companies are unlikely to go to the considerable (and costly) effort of replicating a full course of clinical trials for a drug that is already on the market. (Though biosimilars may need to undergo some additional clinical testing under current FDA regulations, the amount of data required to support approval would certainly be less than what is required for an original biologic approval.)

The 12-year exclusivity period for biologics was established in the ACA following intense debate, and has continued to attract criticism. (By contrast, the period of data exclusivity is just five years for small-molecule drugs.) Supporters argue that given the greater cost and difficulty of bringing a biologic to market a longer period of exclusivity is necessary to incentivize innovation. Others argue that the resulting restrictions on competition keep drug prices unnecessarily high, inevitably putting a strain on the health system and keeping potentially life-saving drugs out of reach for many patients.

How would the TPP affect data exclusivity?

For the 11 countries besides the U.S. that are involved in the TPP, current data exclusivity protections range from zero (Brunei) to eight years (Japan). Under the Obama Administration’s current proposal, participating countries would increase those periods to match the US standard of 12 years. Curiously, this proposal directly contradicts the administration’s ongoing domestic efforts to lower the period of data exclusivity. Since the ACA passed, the Obama administration has repeatedly proposed reducing it to seven, arguing that this would save Medicare $4.4 billion over the next decade. Some have noted that, once the 12-year period is enshrined in the TPP, it will become significantly more difficult to change it through the US legislative process. Furthermore, imposing US standards on the 11 member countries would inevitably restrict competition at the global level, and many patient advocacy and international humanitarian organizations have argued that doing so would undermine the efforts of US global health initiatives like the Vaccine Alliance and the Global Fund to Fight AIDS, Tuberculosis and Malaria, which rely on price competition to manage program costs.

It is unclear whether the US will be successful in its efforts. There have been reports that the issue of data exclusivity has become a significant point of contention, and the US delegation may seek to compromise on its demands. It may, for example, negotiate exceptions for the poorer countries involved in the negotiation, as the Washington Post notes. However, the details of the negotiations are largely confidential, which makes it challenging to assess the possibilities, their relative advantages, or how the US Trade Representative (which is leading the US negotiations) is balancing the need to ensure adequate incentives for innovation with the need to control drug costs and facilitate patient access to potentially life-saving therapies.

Editor's note: Elizabeth Richardson, a research associate in the Center for Health Policy, contributed to the research and writing of this post. 

       

The Risk Evaluation and Mitigation Strategies (REMS) program has become an important tool of the U.S. Food and Drug Administration (FDA) in ensuring that the benefits of a given medical product outweigh the associated risks, and has enabled FDA to approve a number of products that might not otherwise have been made available for patient use. Since the implementation of the REMS program, however, concerns have been raised regarding its impact on patient access to products and the associated burden on providers and health care systems. In an effort to address these concerns—and as part of its commitments under the Prescription Drug User Fee Act reauthorization of 2012—FDA has undertaken efforts to standardize and improve the effectiveness of REMS, and to better integrate REMS programs into the health system. As part of this broader initiative, the Agency is currently assessing the feasibility of integrating accredited continuing education (CE) programs and activities into REMS programs that have been developed for a single drug.

Under a cooperative agreement with the FDA, the Center for Health Policy held an expert workshop on May 18 titled, “Incorporating Continuing Education into Single-Drug REMS: Exploring the Challenges and Opportunities”. This workshop provided an opportunity for pharmaceutical manufacturers, regulators, CE providers, accreditors, and other stakeholders to explore the ways that CE can be a valuable addition to the REMS toolkit, discuss potential barriers to the development and implementation of REMS-related CE for single products, and identify strategies for addressing those barriers.

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Under the Food and Drug Administration Amendments Act (FDAAA) of 2007, the FDA has the authority to require pharmaceutical manufacturers to develop Risk Evaluation and Mitigation Strategies (REMS) for drugs or biologics that carry serious potential or known risks. Since that time, the REMS program has become an important tool in ensuring that riskier drugs are used safely, and it has allowed FDA to facilitate access to a host of drugs that may not otherwise have been approved. However, concerns have arisen regarding the effects of REMS programs on patient access to products, as well as the undue burden that the requirements place on the health care system. In response to these concerns, FDA has initiated reform efforts aimed at improving the standardization, assessment, and integration of REMS within the health care system. As part of this broader initiative, the agency is pursuing four priority projects, one of which focuses on improving provider-patient benefit-risk counseling for drugs that have a REMS attached.

Under a cooperative agreement with FDA, the Center for Health Policy at Brookings held an expert workshop on July 24 titled, “Risk Evaluation and Mitigation Strategies (REMS): Building a Framework for Effective Patient Counseling on Medication Risks and Benefits”. This workshop was the first in a series of convening activities that will seek input from stakeholders across academia, industry, health systems, and patient advocacy groups, among others. Through these activities, Brookings and FDA will further develop and refine an evidence-based framework of best practices and principles that can be used to inform the development and effective use of REMS tools and processes.

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• REMS_PBRC_Meeting_Agenda
• REMS BR Speaker Bios
• REMS BenefitRisk Meeting Summary
• REMS BenefitRisk communication white paper

       

If current economic growth trends persist, the “great divergence” between Western Europe and East and South Asia in per capita income that commenced 200 years ago will close sometime this century. Key to the closing will be greater accessibility to technology, higher education in East and South Asia, and the relentless diffusion of knowledge including in the biosciences. Advances in the biosciences are poised to contribute in a major way to English economist Thomas Malthus’s four necessities of human life–food, fiber, fuel, and building materials–as well as to human and animal health, biodiversity conservation, and environmental remediation and sustainability.

As my coauthor Leo Furcht and I recently wrote in “Divergence, Convergence, and Innovation: East-West Bioscience in an Anxious Age”, 21st century history will describe the great economic and technological convergence between East and West. It will also further entwine the economic and ecological storylines of the human experience as the vast populations of China and India strive to enter the middle class. Environmentally sustainable economic growth will require putting knowledge of life code, cellular processes, biosynthesis, and biological regeneration to practical use. That prospect is at hand because the biosciences are in the midst of their own convergence–with information technology, nanotechnology, microelectronics, materials, artificial intelligence, robotics, architecture, and design.

From William Hoffman and Leo Furcht, "The Biologist’s Imagination: Innovation in the Biosciences" (Oxford University Press, 2014)

Biomolecules, brainpower, and Malthusian limits

Products arising from molecular biology constitute a growing share of the global economy with each passing year as technologies evolve, production processes improve, and markets expand. In recent years industrial biotechnology has grown faster than the biologic drugs and agricultural biotech sectors in the U.S.

 

U.S. biotech revenue in billions of U.S. dollars.
Source: Robert Carlson, "Nature Biotechnology", In press

Industrial biotechnology employs greener and cleaner technologies to make chemicals, solvents, fuels, and materials such as biocomposites and bioplastics. Growth in this sector can weaken the link between economic growth, environmental pollution, and greenhouse gas emissions. Genomics, synthetic biology and metabolic engineering are poised to accelerate growth in the design and manufacture of industrial enzymes and renewable bio-based products. East and South Asian production and consumption of industrial enzymes are on the rise as the Asian middle class expands.

Bioscience is enabling major cereal crops such as wheat, rice, and corn to adapt to a changing climate. Cereal crop yields need to grow by an estimated 70 percent by mid-century to feed the projected nine billion people expected to then inhabit our planet. The challenge of feeding nine billion people without further deforestation and environmental degradation has resurrected the specter of Malthusian limits to our planet’s ecological carrying capacity. These limits are expressed in food and water shortages, forced migrations, political instability, armed conflict, abatement and cleanup activities, and health care related to pollution and climate change. Even with the powerful tools of food crop bioscience–marker-assisted selection, targeted mutation-selection, genetic modification, and others–maintaining crop production levels at expected higher temperatures and with less water is highly questionable.

Precise genomic editing of cereal grains could equip rice, wheat, and corn with nitrogen fixation capabilities, thus reducing the need for synthetic fertilizers with their environmental and atmospheric costs. East and South Asia, facing major food production challenges, ecological limits, pollution from fertilizer use, and drought from climate change, may take the lead over the West in adopting innovative food crop technologies.

Meanwhile, hundreds of thousands of human beings of many ethnicities have had their genomes decoded over the past decade, with the number expected to increase exponentially as sequencing technologies grow in productivity and decline in price. Genomic information coupled with precise genomic editing and bioregenerative tools give us unprecedented power to shape the course of evolution, including our own.

             

Cost trend of sequencing a human-sized genome and Moore’s Law 2001 – 2015.
Source: Kris A. Wetterstrand, DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program.

The practice of technological innovation in the industrial era – the systematic application of ideas, inventions and technology to markets, trade, and social systems–is now being joined with the code of life, DNA, and the basic unit of life, the cell. Even as the economic gap between East and West narrows, no other convergence has such profound implications for our future and the future health of living systems and ecosystems. That makes the task for policymakers a daunting one.

       

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The biomedical innovation ecosystem continues to evolve and enhance the processes by which treatments are developed and delivered to patients. Given this changing biomedical innovation landscape, it is imperative that all stakeholders work to ensure that development programs, regulatory practices, and the policies that enable them are aligned on and achieving a common set of goals. This will require a thorough reexamination of our understanding of biomedical innovation – and the subsequent ways in which we seek to incentivize it – in order to more effectively bridge research and analysis of the process itself with the science and policy underpinning it.

Traditional research into the efficiency and effectiveness of drug development programs has tended to focus on the ‘inputs’ and process trends in product development, quantifying the innovation as discrete units. At the opposite end of the research spectrum are potential measures that could be categorized as “value” or “outcomes” metrics. Identifying the appropriate measures across this spectrum – from inputs and technological progress through outcomes and value – and how such metrics can be in conversation with each other to improve the innovation process will be the focus of this expert workshop. On October 14, the Center for Health Policy at Brookings, under a cooperative agreement with the U.S. Food and Drug Administration, convened a roundtable discussion that engaged key stakeholders from throughout the innovation ecosystem to explore the factors and characteristics that could improve our understanding of what constitutes modern “innovation” and how best to track its progress.

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• FINAL 1014 BrookingsFDA Agenda
• FINAL 1014 BrookingsFDA Participant List

       

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Strategies for facilitating biomarker development

The emerging field of precision medicine continues to offer hope for improving patient outcomes and accelerating the development of innovative and effective therapies that are tailored to the unique characteristics of each patient. To date, however, progress in the development of precision medicines has been limited due to a lack of reliable biomarkers for many diseases. Biomarkers include any defined characteristic—ranging from blood pressure to gene mutations—that can be used to measure normal biological processes, disease processes, or responses to an exposure or intervention. They can be extremely powerful tools for guiding decision-making in both drug development and clinical practice, but developing enough scientific evidence to support their use requires substantial time and resources, and there are many scientific, regulatory, and logistical challenges that impede progress in this area.

On October 27th, 2015, the Center for Health Policy at The Brookings Institution convened an expert workshop that included leaders from government, industry, academia, and patient advocacy groups to identify and discuss strategies for addressing these challenges. Discussion focused on several key areas: the development of a universal language for biomarker development, strategies for increasing clarity on the various pathways for biomarker development and regulatory acceptance, and approaches to improving collaboration and alignment among the various groups involved in biomarker development, including strategies for increasing data standardization and sharing. The workshop generated numerous policy recommendations for a more cohesive national plan of action to advance precision medicine.  

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• 1027 Brookings biomarkers workshop agenda
• 1027 Biomarkers workshop backgrounderfinal
• 1027 Biomarkers workshop slide deckfinal
• 1027 Biomarkers workshop participant listfinal

       

Summary

Global education plays an important role in contributing to U.S. foreign policy objectives. In a recent speech, Secretary of State Hillary Clinton highlighted education, along with health, agriculture, security, and local governance as the core areas for U.S. international development investment. She emphasized the importance of education, particularly of girls and youth, in improving global stability, speeding economic growth, and helping global health, all of which advance U.S. interests in the world.

But how effective has the U.S. government been in supporting global education? Unfortunately, its many good education activities and programs are not leveraged for maximum impact on the ground, especially in situations of armed conflict and state fragility. Challenges of U.S. foreign assistance—for example, fragmentation across multiple agencies, lack of policy coherence, diminished multilateral engagement—generally affects its work in education. Luckily some of the core strengths of U.S. assistance have an impact as well, specifically the large amount of resources (in total terms, if not relative terms) devoted to education and the vast breadth and depth of American academic, philanthropic and NGO partners engaged in pioneering work on education in the developing world.

This report analyzes the effectiveness of U.S. government education work specifically in relation to conflict-affected and fragile states. Findings across five domains—global reach, resources, technical expertise, policy and multilateral partnerships—show that U.S. education aid falls critically short of what it is capable of achieving. The U.S. government has substantial strengths in this area, especially in global reach, resources, and technical expertise, demonstrating a real comparative advantage in the field of education in situations of conflict and fragility. However, its fragmented policy across agencies and its limited multilateral engagement prevent it from maximizing its strengths, leaving it punching below its weight on this important issue. In this sense, the U.S. government is a classic underachiever, failing to efficiently deploy its many capabilities and potential for maximum impact.

There has never been a better time for looking at the aid-effectiveness of U.S. government education work. The Obama administration is bringing increased focus on the Paris Principles for Aid Effectiveness to its development initiatives. The U.S. Congress is actively engaged with pending legislative action to modernize foreign assistance and improve U.S. support for universal education. Two major reviews of foreign assistance are underway: the Quadrennial Diplomacy and Development Review led by the Department of State and USAID, and the Presidential Study Directive on U.S. Global Development Policy led by the White House.

Questions about foreign assistance reform asked in these two reviews can be applied to the education sector. For example, how can the U.S. government improve its education assistance by using a “whole-of-government” approach, by focusing on comparative advantages and strengths, and by improving coordination and by increasing multilateral engagement?

Careful analysis and answers to these questions can help propel the U.S. from its current position as an underachiever to being a leader in global education, specifically in contexts of conflict and state fragility.

This report makes nine specific recommendations, many of which could be achieved without any substantial increase in funding, that would enable the U.S. government to greatly increase the effectiveness of its education aid to populations living in contexts of conflict and state fragility.

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Overview

Increasing educational attainment is likely to reduce conflict risk, especially in countries like Pakistan that have very low levels of primary and secondary school enrollment. Education quality, relevance and content also have a role to play in mitigating violence. Education reform must therefore be a higher priority for all stakeholders interested in a more peaceful and stable Pakistan. Debate within the country about education reform should not be left only to education policymakers and experts, but ought to figure front and center in national dialogues about how to foster security. The price of ignoring Pakistan’s education challenges is simply too great in a country where half the population is under the age of 17.

There has been much debate concerning the roots of militancy in Pakistan, and multiple factors clearly come into play. One risk factor that has attracted much attention both inside Pakistan and abroad is the dismal state of the national education sector. Despite recent progress, current school attainment and literacy levels remain strikingly low, as does education spending. The Pakistani education sector, like much of the country’s public infrastructure, has been in decline over recent decades. The question of how limited access to quality education may contribute to militancy in Pakistan is more salient now than ever, given the rising national and international security implications of continued violence.

The second half of 2009 witnessed not only the Pakistani government stepping up action against insurgents but also the release of a new Pakistan National Education Policy that aspires to far-reaching and important reforms, including a commitment to increase investment in education—from 2 to 7 percent of gross domestic product. Hundreds of millions of dollars in international education aid have been newly pledged by donor countries. This renewed emphasis on education represents a substantial opportunity to seek to improve security in Pakistan and potentially also globally over the medium to long term. Policymakers both inside and outside Pakistan should give careful consideration to whether and how education investments can promote peace and stability, taking into account what we now know about the state of the education sector and the roots of militancy.

This report takes a fresh look at the connection between schools, including but not limited to Pakistan’s religious seminaries, known as “madrasas,” and the rising militancy across the country. Poor school performance across Pakistan would seem an obvious area of inquiry as a risk factor for conflict. Yet to date, the focus has been almost exclusively on madrasas and their role in the mounting violence. Outside Pakistan, relatively little attention has been given to whether and how the education sector as a whole may be fueling violence, over and above the role of the minority of militant madrasas.

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