Drug discovery for parasitic diseases: powered by technology, enabled by pharmacology, informed by clinical science.

While prevention is a bedrock of public health, innovative therapeutics are needed to complement the armamentarium of interventions required to achieve disease control and elimination targets for neglected diseases. Extraordinary advances in drug discovery technologies have occurred over the past decades, along with accumulation of scientific knowledge and experience in pharmacological and clinical sciences that are transforming many aspects of drug R&D across disciplines. We reflect on how these advances have propelled drug discovery for parasitic infections, focusing on malaria, kinetoplastid diseases, and cryptosporidiosis. We also discuss challenges and research priorities to accelerate discovery and development of urgently needed novel antiparasitic drugs.

Use-case scenarios for an anti-Cryptosporidium therapeutic.

Cryptosporidium is a widely distributed enteric parasite that has an increasingly appreciated pathogenic role, particularly in pediatric diarrhea. While cryptosporidiosis has likely affected humanity for millennia, its recent "emergence" is largely the result of discoveries made through major epidemiologic studies in the past decade. There is no vaccine, and the only approved medicine, nitazoxanide, has been shown to have efficacy limitations in several patient groups known to be at elevated risk of disease. In order to help frontline health workers, policymakers, and other stakeholders translate our current understanding of cryptosporidiosis into actionable guidance to address the disease, we sought to assess salient issues relating to clinical management of cryptosporidiosis drawing from a review of the literature and our own field-based practice. This exercise is meant to help inform health system strategies for improving access to current treatments, to highlight recent achievements and outstanding knowledge and clinical practice gaps, and to help guide research activities for new anti-Cryptosporidium therapies.

Phone-based monitoring to evaluate health policy and program implementation in Kenya.

Monitoring and evaluating policies and programs in low- and middle-income countries are often difficult because of the lack of routine data. High mobile phone ownership in these countries presents an opportunity for efficient data collection through telephone interviews. This study examined the feasibility of collecting data on medicines through telephone interviews in Kenya. Data on the availability and prices of medicines at 137 health facilities and 639 patients were collected in September 2016 via in-person interviews. Between December 2016 and December 2017, monthly telephone interviews were conducted with health facilities and patients. An unannounced in-person interview was conducted with respondents to validate the telephone interview within 24 h. A bottom-up itemization costing approach was used to estimate the costs of telephone and in-person data collection. In-depth interviews were conducted with data collectors and respondents to explore their perceptions on both modes of data collection. The level of agreement between data on medicines availability collected through phone and in-person interviews was strong at the health facility level [kappa = 0.90; confidence interval (CI) 0.88-0.92] and moderate at the household level (kappa = 0.50, CI 0.39-0.60). Price data from telephone and in-person interviews showed strong intra-class correlation at health facilities [intra-class correlation coefficient (ICC) = 0.96] and moderate intra-class correlation at households (ICC = 0.47). The cost per phone interview at health facilities and households were $19.73 and $16.86, respectively, compared to $186.20 for a baseline in-person interview. Participants considered telephone interviews to be more convenient. In countries with high cell phone penetration, telephone data collection should be considered in monitoring and evaluating public health programs especially at health facilities. Additional strategies may be needed to optimize this mode of data collection at the household level. Variations in cell phone ownership, telecommunication network and data collection costs across different settings may limit the generalizability of the findings from this study.

Availability and prices of medicines for non-communicable diseases at health facilities and retail drug outlets in Kenya: a cross-sectional survey in eight counties.

OBJECTIVES: The objective of this study was to determine the availability and prices of medicines for non-communicable diseases (NCDs) in health facilities and private for-profit drug outlets in Kenya. DESIGN: Cross-sectional study. METHODS: All public and non-profit health facilities in eight counties (Embu, Kakamega, Kwale, Makueni, Narok, Nyeri, Samburu and West Pokot) that purchased medicines from the Mission for Essential Drugs and Supplies, a major wholesaler, were surveyed in September 2016. For each health facility, one nearby private for-profit drug outlet was also surveyed. Data on availability and price were analysed for 24 NCD and 8 acute medicine formulations. Availability was analysed separately for medicines in the national Essential Medicines List (EML) and those in the Standard Treatment Guidelines (STGs). Median price ratios were estimated using the International Medical Products Price Guide as a reference. RESULTS: 59 public and 78 non-profit facilities and 135 drug outlets were surveyed. Availability of NCD medicines was highest in private for-profit drug outlets (61.7% and 29.3% for medicines on the EML and STGs, respectively). Availability of STG medicines increased with increasing level of care of facilities: 16.1% at dispensaries to 31.7% at secondary referral facilities. The mean proportion of availability for NCD medicines listed in the STGs (0.25) was significantly lower than for acute medicines (0.61), p<0.0001. The proportion of public facilities giving medicines for free (0.47) was significantly higher than the proportion of private non-profit facilities giving medicines for free (0.09) (p<0.0001). The mean price ratio of NCD medicines was significantly higher than for acute medicines in non-profit facilities (4.1 vs 2.0, respectively; p=0.0076), and in private for-profit drug outlets (3.5 vs 1.7; p=0.0013). CONCLUSION: Patients with NCDs in Kenya appear to have limited access to medicines. Increasing access should be a focus of efforts to achieve universal health coverage.

Registration timelines of antiretroviral medicines in Ghana and Kenya.

: This study examines registration timelines of antiretroviral medicines (ARVs) in Ghana and Kenya, to assess whether prior reviews by the US Food and Drug Administration Tentative Approval or WHO prequalification (WHO/PQP) affect in-country approval timelines. Data were collected from online and national databases. Median in-country review period in Ghana was 9 months compared with 25 months in Kenya. ARVs with Tentative Approval and WHO/PQP status did not benefit from shorter in-country review periods.

Effect of Novartis Access on availability and price of non-communicable disease medicines in Kenya: a cluster-randomised controlled trial.

BACKGROUND: Novartis Access is a Novartis programme that offers a portfolio of non-communicable disease medicines at a wholesale price of US$1 per treatment per month in low-income and middle-income countries. We evaluated the effect of Novartis Access in Kenya, the first country to receive the programme. METHODS: We did a cluster-randomised controlled trial in eight counties in Kenya. Counties (clusters) were randomly assigned to the intervention or the control group with a covariate-constrained randomisation procedure that maximised balance on a set of demographic and health variables. In intervention counties, public and non-profit health facilities were allowed to purchase Novartis Access medicines from the Mission for Essential Drugs and Supplies (MEDS). Data were collected from all facilities served by MEDS and a sample of households in study counties. Households were eligible if they had at least one adult patient who had been diagnosed and prescribed medicines for one of the non-communicable diseases targeted by the programme: hypertension, heart failure, dyslipidaemia, type 2 diabetes, asthma, or breast cancer. Primary outcomes were availability and price of portfolio medicines at health facilities, irrespective of brand; and availability of medicines at patient households. Impacts were estimated with intention-to-treat analysis. This trial is registered with ClinicalTrials.gov (NCT02773095). FINDINGS: On March 8, 2016, we randomly assigned eight clusters to intervention (four clusters; 74 health facilities; 342 patients) or control (four clusters; 63 health facilities; 297 patients). 69 intervention and 58 control health facilities, and 306 intervention and 265 control patients were evaluated after a 15 month intervention period (last visit February 28, 2018). Novartis Access significantly increased the availability of amlodipine (adjusted odds ratio [aOR] 2·84, 95% CI 1·10 to 7·37; p=0·031) and metformin (aOR 4·78, 95% CI 1·44 to 15·86; p=0·011) at health facilities, but did not affect the availability of portfolio medicines overall (adjusted ß [aß] 0·05, 95% CI -0·01 to 0·10; p=0·096) or their price (aß 0·48, 95% CI -1·12 to 0·72; p=0·500). The programme did not affect medicine availability at patient households (aOR 0·83, 95% CI 0·44 to 1·57; p=0·569). INTERPRETATION: Novartis Access had little effect in its first year in Kenya. Access programmes operate within complex health systems and reducing the wholesale price of medicines might not always or immediately translate to improved patient access. The evidence generated by this study will inform Novartis's efforts to improve their programme going forward. The study also contributes to the public evidence base on strategies for improving access to medicines globally. FUNDING: Sandoz International (a subsidiary of Novartis International).

Perceptions of Kenyan adults on access to medicines for non-communicable diseases: A qualitative study.

In Kenya, noncommunicable diseases (NCDs) account for 27% of all deaths. Adult Kenyans have an 18% chance of dying prematurely from cancers, diabetes, cardiovascular diseases or chronic respiratory diseases. A Novartis Access Initiative is making medicines available to treat cardiovascular diseases, diabetes, chronic respiratory diseases, and breast cancer in 30 countries, including Kenya. Little is known about patients' perceptions of access to medicines for NCDs in Kenya. The study objective was to understand patients' perceptions of access to medicines; as well as barriers and facilitators at the household, community, and healthcare system level. A baseline qualitative study was conducted in eight of 47 counties as part of an evaluation of the Novartis Access Initiative in Kenya. The 84 patients interviewed through a household survey had been diagnosed and treated for an NCD. Although medicines at government facilities were free or cheaper than those sold in private pharmacies, the availability of medicines presented a constant challenge. Patients often resorted to private pharmacies, where NCD medicines cost more than at public facilities. Participants with an NCD took their health seriously and strove to get the medicines, even under difficult circumstances. Buying NCD medicines put a strain on the household budget, especially for the lower-income participants. Some actions to overcome affordability barriers included: borrowing money, selling assets, seeking help from relatives, taking on extra work, buying partial dosages, leaving without the medicines, or resorting to non-medical alternatives. In conclusion, access to NCD medicines is a major challenge for most adults in Kenya. As a result, they engage in complex interactions between public, private facilities and pharmacies to overcome the barriers. The government should ensure well-stocked public sector pharmacies and subsidize prices of medicines for lower-income patients. Integration of industry-led access to medicine programs may help governments to obtain low cost supplies.

Influence of newborn health messages on care-seeking practices and community health behaviors among participants in the Zambia Chlorhexidine Application Trial.

BACKGROUND: Identifying and understanding traditional perceptions that influence newborn care practices and care-seeking behavior are crucial to developing sustainable interventions to improve neonatal health. The Zambia Chlorhexidine Application Trial (ZamCAT), a large-scale cluster randomized trial, assessed the impact of 4% chlorhexidine on neonatal mortality and omphalitis in Southern Province, Zambia. The main purpose of this post-ZamCAT qualitative study was to understand the impact of newborn care health messages on care-seeking behavior for neonates and the acceptability, knowledge, and attitudes towards chlorhexidine cord care among community members and health workers in Southern Province. METHODS & FINDINGS: Five focus group discussions and twenty-six in-depth interviews were conducted with mothers and health workers from ten health centers (5 rural and 5 peri-urban/urban). Community perceptions and local realities were identified as fundamental to care-seeking decisions and influenced individual participation in particular health-seeking behaviors. ZamCAT field monitors (data collectors) disseminated health messages at the time of recruitment at the health center and during subsequent home visits. Mothers noted that ZamCAT field monitors were effective in providing lessons and education on newborn care practices and participating mothers were able to share these messages with others in their communities. Although the study found no effect of chlorhexidine cord washes on neonatal mortality, community members had positive views towards chlorhexidine as they perceived that it reduced umbilical cord infections and was a beneficial alternative to traditional cord applications. CONCLUSION: The acceptability of health initiatives, such as chlorhexidine cord application, in community settings, is dependent on community education, understanding, and engagement. Community-based approaches, such as using community-based cadres of health workers to strengthen referrals, are an acceptable and potentially effective strategy to improve care-seeking behaviors and practices.

Comparison of medicines management strategies in insurance schemes in middle-income countries: four case studies.

BACKGROUND: Many middle-income countries are scaling up health insurance schemes to provide financial protection and access to affordable medicines to poor and uninsured populations. Although there is a wealth of evidence on how high income countries with mature insurance schemes manage cost-effective use of medicines, there is limited evidence on the strategies used in middle-income countries. This paper compares the medicines management strategies that four insurance schemes in middle-income countries use to improve access and cost-effective use of medicines among beneficiaries. METHODS: We compare key strategies promoting cost-effective medicines use in the New Rural Cooperative Medical Scheme (NCMS) in China, National Health Insurance Scheme in Ghana, Jamkesmas in Indonesia and Seguro Popular in Mexico. Through the peer-reviewed and grey literature as of late 2013, we identified strategies that met our inclusion criteria as well as any evidence showing if, and/or how, these strategies affected medicines management. Stakeholders involved and affected by medicines coverage policies in these insurance schemes were asked to provide relevant documents describing the medicines related aspects of these insurance programs. We also asked them specifically to identify publications discussing the unintended consequences of the strategies implemented. RESULTS: Use of formularies, bulk procurement, standard treatment guidelines and separation of prescribing and dispensing were present in all four schemes. Also, increased transparency through publication of tender agreements and procurement prices was introduced in all four. Common strategies shared by three out of four schemes were medicine price negotiation or rebates, generic reference pricing, fixed salaries for prescribers, accredited preferred provider network, disease management programs, and monitoring of medicines purchases. Cost-sharing and payment for performance was rarely used. There was a lack of performance monitoring strategies in all schemes. CONCLUSIONS: Most of the strategies used in the insurance schemes focus on containing expenditure growth, including budget caps on pharmaceutical expenditures (Mexico) and ceiling prices on medicines (all four countries). There were few strategies targeting quality improvement as healthcare providers are mostly paid through fixed salaries, irrespective of the quality of their prescribing or the health outcomes actually achieved. Monitoring healthcare system performance has received little attention.

Study protocol for a cluster-randomised controlled trial of an NCD access to medicines initiative: evaluation of Novartis Access in Kenya.

INTRODUCTION: Novartis recently launched Novartis Access, an initiative to provide a basket of reduced price medicines for non-communicable diseases (NCDs) to be sold through the public and private non-profit sectors in programme countries. This study will evaluate the impact of Novartis Access on the availability and price of NCD medicines at health facilities and households in Kenya, the first country to receive the programme. METHODS AND ANALYSIS: This study will be a cluster-randomised controlled trial. 8 counties in Kenya will be randomly assigned to the intervention or control group using a covariate constrained randomisation method to maximise balance on demographic and health characteristics. In intervention counties, public and private non-profit health facilities will be able to order Novartis Access NCD medicines from the Mission for Essential Drugs and Supplies (MEDS). Data will be collected from a random sample of 384 health facilities and 800 households at baseline, midline after 1-year of intervention, and end-line after 2 years. Quarterly surveillance data will also be collected from health facilities and a subsample of households through phone-based interviews. Households will be eligible if at least one resident has been previously diagnosed and prescribed a medicine for an NCD addressed by Novartis Access, including hypertension and diabetes. The primary outcomes will be availability and price of NCD medicines at health facilities, and availability, price, and expenditures on NCD medicines at households. Impacts will be estimated using intention-to-treat analysis. ETHICS AND DISSEMINATION: This protocol was approved by the Institutional Review Boards at Strathmore University and at Boston University. Informed consent will be obtained from all participants at the start of the trial. The findings of the trial will be disseminated through peer-reviewed journals, international conferences, and meetings and events organised with local stakeholders. TRIAL REGISTRATION NUMBER: NCT02773095.

Challenges of medicines management in the public and private sector under Ghana's National Health Insurance Scheme - A qualitative study.

BACKGROUND: Ghana established its National Health Insurance Scheme (NHIS) in 2003 with the goal of ensuring more equitable financing of health care to improve access to health services. This qualitative study examines the challenges and consequences of medicines management policies and practices under the NHIS as perceived by public and private service providers. METHODS: This study was conducted in health facilities in the Eastern, Greater Accra and Volta regions of Ghana between July and August 2014. We interviewed 26 Key Informants (KIs) from a purposively selected sample of public and private sector providers (government and mission hospitals, private hospitals and private standalone pharmacies), pharmaceutical suppliers and NHIS district offices. Data was collected using semi-structured interview guides which covered facility accreditation, reimbursement practices, medicines selection, purchasing and pricing of medicines, and utilization of medicines. Codes for data analysis were developed based on the study questions and also in response to themes that emerged from the transcripts and notes. RESULTS: Most KIs agreed that the introduction of the NHIS has increased access to and utilization of medicines by removing cost barriers for patients; however, some pointed out the increased utilization could also be corollary to moral hazard. Common concerns across all facilities were the delays in receiving NHIS reimbursements, and low reimbursement rates for medicines which result in providers asking patients to pay supplementary fees. KIs reported important differences between private and public sectors including weak separation of prescribing and dispensing and limited use of drugs and therapeutic committees in the private sector, the disproportionate effects of unfavorable reimbursement prices for medicines, and inadequate participation of the private sector providers (especially pharmacies and licensed chemical sellers) in the NHIS. CONCLUSIONS: Health providers generally perceive the NHIS to have had a largely positive impact on access to medicines. However, concerns remain about equity in access to medicines and the differences in quality of pharmaceutical care delivered by private and public providers. Routine monitoring of medicines use during the implementation of health insurance schemes is important to identify and address the potential consequences of medicines policies and practices under the scheme.