Fred Binka

Randomised controlled trials for Ebola: practical and ethical issues

2 months ago, when the numbers known to have died from Ebola in west Africa could still be counted in hundreds, WHO made an important statement about investigational drugs and vaccines. This crisis is so acute, WHO declared, that it is ethical to offer interventions with potential benefits but unknown efficacy and side-effects, though every effort should be made to evaluate benefits and risks and share all data generated. n nThe need for drugs and vaccines was urgent then. With cases now rising exponentially and health systems overwhelmed, it is even greater today. Vaccine safety trials are underway in the USA and the UK, and poised to roll out to Africa soon. But treatments for those with infection are required too. Besides playing a direct part in containing the epidemic, interventions that could improve outcomes for the sick would help to rebuild the confidence of affected communities in health services, a critical step if Ebola is to be overcome. n nA fast-track initiative for evaluating investigational drugs was launched in September, 2014.1 But although the question of whether unproven treatments should be offered at all is now settled, the question of how they should be deployed and tested is not. Still at issue is whether such treatments should be made available only in the context of randomised controlled trials (RCTs) in which patients receive either a new intervention and conventional care, or conventional care alone or with a placebo. n nAdvocates of this RCT approach2 state that as this experimental design will create the most robust evidence for the future, and is what regulators are used to, it is the only approach that should be considered. We disagree. n nWhile we concur that RCTs provide robust evidence, and support their use where this is ethical and practical, we do not believe that either consideration is likely to be satisfied in the context of this epidemic. The priority must be to generate data about effectiveness and safety as swiftly as possible, so that the most useful new treatments can be identified for rapid deployment. Alternative trial designs have the potential to do this more quickly, and with greatest social and ethical acceptability. n nThe first objection to RCTs in which investigational drugs plus conventional care are compared purely with conventional care is ethical. Such randomisation is ethical when there is equipoise—when there is genuine uncertainty about whether an untested treatment has benefits or risks that exceed those of conventional care. Equipoise is a useful principle, but it can break down when conventional care offers little benefit and mortality is extremely high. This is precisely the problem with Ebola: current conventional care does not much affect clinical outcomes and mortality is as high as 70%. When conventional care means such a high probability of death, it is problematic to insist on randomising patients to it when the intervention arm holds out at least the possibility of benefit. Ethical arguments are not the same for all levels of risk. n nNo-one insisted that western medical workers offered zMapp and other investigational products were randomised to receive the drug or conventional care plus a placebo. None of us would consent to be randomised in such circumstances. In cancers with a poor prognosis for which there are no good treatments, evidence from studies without a control group can be accepted as sufficient for deployment, and even for licensing by regulators, with fuller analysis following later. There is no need for rules to be bent or corners to be cut: the necessary procedures already exist, and are used. n nThe second objection is practical. Even if randomisation were ethically acceptable, it might not be deliverable in the context of health-care systems, and indeed wider social order, that are breaking down as in Liberia, Guinea, and Sierra Leone. Populations who are terrified by the progress of the epidemic, and who lack trust in health-care and aid workers, and in public authorities in the aftermath of civil wars, cannot be expected to offer informed consent to such randomised trials. It is also unclear that any capacity exists to impose controlled conditions during a raging epidemic. Insisting on RCTs could even worsen the epidemic, by undermining trust in the Ebola treatment centres that are central to containing it. n nRandomisation is not, moreover, the only way to gather reliable information about the safety and effectiveness of potential Ebola therapies. Indeed, other methods might be more appropriate for achieving the key objective, which is to identify drug regimens that improve outcomes over existing methods of care, quickly, so that WHO can recommend their use and lives can be saved. n nOne viable approach would be to try different treatments in parallel and at different sites, following observational studies that document mortality under standard care. This approach could effectively triage treatments into those with great benefits that should be rolled out immediately, those with no effect that should be discarded quickly, and those with promise needing follow-up in randomised trials. These trials can be designed adaptively, meaning that patient enrolment can be altered as efficacy data emerge, minimising the numbers of individuals who get ineffective treatments and increasing the numbers getting those that show benefits. This is not different from phase 2 studies as currently conducted and accepted by regulatory authorities for other diseases. It will also enable quick follow-up trials of combinations of antivirals and new treatments that have already shown evidence of activity. A different type of RCT might also become an option once more than one drug has shown efficacy—even efficacy in animal models. Then, patients could ethically be randomised to one investigational drug or another. No-one would get only standard care. n nWe accept that RCTs can generate strong evidence in ordinary circumstances; not, however, in the midst of the worst Ebola epidemic in history. The urgent need is to establish whether new investigational drugs offer survival benefits, and thus which, if any, should be recommended by WHO to save lives. We have innovative but proven trial designs for doing exactly that. We should be using them, rather than doggedly insisting on gold standards that were developed for different settings and purposes.

Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial

BACKGROUNDnThe World Health Organization recommends vitamin A supplementation (VAS) at vaccination contacts after 6 mo of age to reduce mortality. However, it is unknown whether the effect of VAS is independent of vaccinations. One of the original VAS trials from Ghana had collected vaccination information.nnnOBJECTIVEnWe reanalyzed the data to explore the hypothesis that VAS reduces mortality in children who had bacille Calmette-Guérin or measles vaccine as their most recent vaccine but increased mortality when diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccine. On the basis of previous studies, we expected the effects to be strongest in girls.nnnDESIGNnAt enrollment, children aged 6-90 mo were randomly assigned to receive VAS or placebo every 4 mo for 2 y. Vaccination status was assessed at enrollment and after 1 and 2 y by reviewing the childrens health cards. Lack of a health card was presumed to mean that the child had not been vaccinated.nnnRESULTSnVAS had a beneficial effect only in children with no record of vaccination at enrollment (n = 5066); the mortality rate ratio (MRR) was 0.64 (95% CI: 0.47, 0.88) compared with 0.95 (95% CI: 0.72, 1.26) in children with one or more vaccinations (n = 6656). Among vaccinated children, the effect of VAS differed between boys (MRR: 0.74; 95% CI: 0.51, 1.08) and girls (MRR: 1.18; 95% CI: 0.84, 1.67) (P = 0.046 for interaction). VAS had a negative effect in measles-vaccinated girls who were missing one or more doses of DTP at enrollment, a group who often received DTP during follow-up (MRR: 2.60; 95% CI: 1.41, 4.80).nnnCONCLUSIONSnThe effect of VAS differed by vaccination status. This is potentially problematic because VAS is provided at vaccination contacts.

Impact and Effectiveness of Monovalent Rotavirus Vaccine Against Severe Rotavirus Diarrhea in Ghana.

BACKGROUNDnGhana was among the first African nations to introduce monovalent rotavirus vaccine (RV1) into its childhood immunization schedule in April 2012. We aimed to assess the impact of vaccine introduction on rotavirus and acute gastroenteritis (AGE) hospitalizations and to estimate vaccine effectiveness (VE).nnnMETHODSnUsing data from 2 teaching hospitals, monthly AGE and rotavirus admissions by age were examined 40 months before and 31 months after RV1 introduction using interrupted time-series analyses. From January 2013, we enrolled children <2 years of age who were eligible for RV1 from a total of 7 sentinel sites across the country. To estimate VE, we fit unconditional logistic regression models to calculate odds ratios of vaccination by rotavirus case-patient status, controlling for potential confounders.nnnRESULTSnVaccine coverage ranged from 95% to 100% for dose 1 and 93% to 100% for dose 2. In the first 3 years after vaccine introduction, the percentage of hospital admissions positive for rotavirus fell from 48% in the prevaccine period to 28% (49% adjusted rate reduction; 95% confidence interval [CI], 32%-63%) postvaccination among <5-year-olds. With high vaccine coverage, it was not possible to arrive at robust VE estimates; any-dose VE against rotavirus hospitalization was estimated at 60% (95% CI, -2% to 84%;P= .056).nnnCONCLUSIONSnResults from the first 3 years following RV1 introduction suggest substantial reductions of pediatric diarrheal disease as a result of vaccination. Our VE estimate is consistent with the observed rotavirus decrease and with efficacy estimates from elsewhere in sub-Saharan Africa.

Profile: The Dodowa HDSS

The Dodowa Health and Demographic Surveillance System (DHDSS) operates in the south-eastern part of Ghana. It was established in 2005 after an initial attempt in 2003 by the Dodowa Health Research Centre (DHRC) to have an accurate population base for piloting a community health insurance scheme. As at 2010, the DHDSS had registered 111 976 residents in 22 767 households. The district is fairly rural, with scattered settlements. Information on pregnancies, births, deaths, migration and marriages using household registration books administered by trained fieldworkers is obtained biannually. Education, immunization status and household socioeconomic measures are obtained annually and verbal autopsies (VA) are conducted on all deaths. Community key informants (CKI) complement the work of field staff by notifying the field office of events that occur after a fieldworker has left a community. The centre has very close working relationships with the district health directorate and the local government authority. The DHDSS subscribes to the INDEPTH data-sharing policy and in addition, contractual arrangements are made with various institutions on specific data-sharing issues.

Risk factors for buruli ulcer in ghana-a case control study in the suhum-kraboa-coaltar and akuapem South districts of the eastern region

Background Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans. Its exact mode of transmission is not known. Previous studies have identified demographic, socio-economic, health and hygiene as well as environment related risk factors. We investigated whether the same factors pertain in Suhum-Kraboa-Coaltar (SKC) and Akuapem South (AS) Districts in Ghana which previously were not endemic for BU. Methods We conducted a case control study. A case of BU was defined as any person aged 2 years or more who resided in study area (SKC or AS District) diagnosed according to the WHO clinical case definition for BU and matched with age- (+/−5 years), gender-, and community controls. A structured questionnaire on host, demographic, environmental, and behavioural factors was administered to participants. Results A total of 113 cases and 113 community controls were interviewed. Multivariate conditional logistic regression analysis identified presence of wetland in the neighborhood (ORu200a=u200a3.9, 95% CIu200a=u200a1.9–8.2), insect bites in water/mud (ORu200a=u200a5.7, 95% CIu200a=u200a2.5–13.1), use of adhesive when injured (ORu200a=u200a2.7, 95% CIu200a=u200a1.1–6.8), and washing in the Densu river (ORu200a=u200a2.3, 95% CIu200a=u200a1.1–4.96) as risk factors associated with BU. Rubbing an injured area with alcohol (ORu200a=u200a0.21, 95% CIu200a=u200a0.008–0.57) and wearing long sleeves for farming (ORu200a=u200a0.29, 95% CIu200a=u200a0.14–0.62) showed protection against BU. Conclusion This study identified the presence of wetland, insect bites in water, use of adhesive when injured, and washing in the river as risk factors for BU; and covering limbs during farming as well as use of alcohol after insect bites as protective factors against BU in Ghana. Until paths of transmission are unraveled, control strategies in BU endemic areas should focus on these known risk factors.

A time series analysis of weather variability and all-cause mortality in the Kasena-Nankana Districts of Northern Ghana, 1995-2010

Introduction : Climate and weather variability can have significant health consequences of increased morbidity and mortality. However, today the impact of climate and weather variability, and consequentially, of climate change on population health in sub-Saharan Africa is not well understood. In this study, we assessed the association of daily temperature and precipitation with daily mortality by age and sex groups in Northern Ghana. Methods : We analysed daily mortality and weather data from 1995 to 2010. We adopted a time-series Poisson regression approach to examine the short-term association of daily mean temperature and daily mean precipitation with daily mortality. We included time factors and daily lagged weather predictors and considered autocorrelation. Results : For all populations, a statistically significant association of mean daily temperature with mortality at lag days 0–1 was observed below and above the 25th (27.48°C) and 75th (30.68°C) percentiles (0.19%; 95% confidence interval CI: 0.05%, 0.21%) and (1.14%; 95% CI: 0.12%, 1.54%), respectively. We also observed a statistically significant association of mean daily temperature above 75th percentile at lag days 2–6 and lag days 7–13 (0.32%; 95% CI: 0.16%, 0.25%) and 0.31% [95% CI: 0.14%, 0.26%]), respectively. A 10 mm increase in precipitation was associated with a 1.71% (95% CI: 0.10%, 3.34.9%) increase in mortality for all ages and sex groups at lag days 2–6. Similar results were also observed at lag days 2–6 and 14–27 for males, 2.92% (95% CI: 0.80%, 5.09%) and 2.35% (95% CI: 0.28%, 4.45%). Conclusion : Short-term weather variability is strongly associated with mortality in Northern Ghana. The associations appear to differ among different age and sex groups. The elderly and young children were found to be more susceptible to short-term temperature-related mortality. The association of precipitation with mortality is more pronounced at the short-term for all age and sex groups and in the medium short-term among males. Reducing exposure to extreme temperature, particularly among the elderly and young children, should reduce the number of daily deaths attributable to weather-related mortality.INTRODUCTIONnClimate and weather variability can have significant health consequences of increased morbidity and mortality. However, today the impact of climate and weather variability, and consequentially, of climate change on population health in sub-Saharan Africa is not well understood. In this study, we assessed the association of daily temperature and precipitation with daily mortality by age and sex groups in Northern Ghana.nnnMETHODSnWe analysed daily mortality and weather data from 1995 to 2010. We adopted a time-series Poisson regression approach to examine the short-term association of daily mean temperature and daily mean precipitation with daily mortality. We included time factors and daily lagged weather predictors and considered autocorrelation.nnnRESULTSnFor all populations, a statistically significant association of mean daily temperature with mortality at lag days 0-1 was observed below and above the 25th (27.48°C) and 75th (30.68°C) percentiles (0.19%; 95% confidence interval CI: 0.05%, 0.21%) and (1.14%; 95% CI: 0.12%, 1.54%), respectively. We also observed a statistically significant association of mean daily temperature above 75th percentile at lag days 2-6 and lag days 7-13 (0.32%; 95% CI: 0.16%, 0.25%) and 0.31% [95% CI: 0.14%, 0.26%]), respectively. A 10 mm increase in precipitation was associated with a 1.71% (95% CI: 0.10%, 3.34.9%) increase in mortality for all ages and sex groups at lag days 2-6. Similar results were also observed at lag days 2-6 and 14-27 for males, 2.92% (95% CI: 0.80%, 5.09%) and 2.35% (95% CI: 0.28%, 4.45%).nnnCONCLUSIONnShort-term weather variability is strongly associated with mortality in Northern Ghana. The associations appear to differ among different age and sex groups. The elderly and young children were found to be more susceptible to short-term temperature-related mortality. The association of precipitation with mortality is more pronounced at the short-term for all age and sex groups and in the medium short-term among males. Reducing exposure to extreme temperature, particularly among the elderly and young children, should reduce the number of daily deaths attributable to weather-related mortality.

The 2030 sustainable development goal for health

Must balance bold aspiration with technical feasibility

Factors associated with DELAY in diagnosis among tuberculosis patients in Hohoe Municipality, Ghana

BackgroundAny delay in diagnosis and consequently treatment of TB patients not only increases the infectivity of the disease in the community, but may also lead to more advance disease state, which may result in more complications and expose patients to higher risk of death. The aim of this study was to assess delays in diagnosing new TB patients and the factors associated with these delays in Hohoe Municipality of Ghana.MethodsA cross sectional study was carried out among 73 new TB Patients, 15xa0years or older, registered between 1st June, 2013 and 31st May, 2014 in Hohoe Municipality. Questionnaires were administered to patients to evaluate factors related to delay by patients in seeking care, delays at healthcare facilities, and total diagnostic delay. Logistic regression was used to determine the factors associated with patient delay (>30xa0days), healthcare services delay (>15xa0days), and total delay (>45xa0days).ResultsThe median total delay was 104xa0days (inter-quartile range (IQR):17–191). The median patient delay was 59xa0days (IQR: 5–123), and the median healthcare services delay was 45xa0days (IQR: 38–128). Not medically insured (AORu2009=u20096.12; 95xa0% CI: 1.26–29.88; Pu2009<u20090.025) and perceived stigma (AORu2009=u20095.30; 95xa0% CI: 1.33–21.18; Pu2009<u20090.018) were risk factors associated with prolonged patient delay. Multiple healthcare contact following signs and symptoms (AORu2009=u200910.26; 95xa0%CI: 2.95–35.72; Pu2009<u20090.0001) was the only risk factor associated with prolonged healthcare services delay.ConclusionThere is a considerable delay in TB case detection mainly due to patients delay in seeking healthcare. The factors associated with patients’ delay include lack of medical insurance, perceived stigma, and making multiple healthcare encounters. Health system strengthening towards decentralizing TB diagnosis and management, raising public awareness about the disease, training of healthcare providers, and collaborating with non-formal healthcare providers may reduce long delays in the management of TB.

Multimorbidity of chronic diseases among adult patients presenting to an inner-city clinic in Ghana

BackgroundVery little is known about multimorbidity and chronic diseases in low and middle income countries, particularly Sub-Saharan Africa, and more information is needed to guide the process of adapting the health systems in these countries to respond adequately to the increasing burden of chronic diseases. We conducted a hospital-based survey in an urban setting in Ghana to determine the prevalence of multimorbidity and its associated risk factors among adult patients presenting to an inner city clinic.MethodsBetween May and June 2012, we interviewed adult patients (aged 18xa0years and above) attending a routine outpatient clinic at an inner-city hospital in Accra using a structured questionnaire. We supplemented the information obtained from the interviews with information obtained from respondents’ health records. We used logistic regression analyses to explore the risk factors for multimorbidity.ResultsWe interviewed 1,527 patients and retrieved matching medical records for 1,399 (91.6%). The median age of participants was 52.1xa0years (37–64xa0years). While the prevalence of multimorbidity was 38.8%, around half (48.6%) of the patients with multimorbidity were aged between 18–59xa0years old. The most common combination of conditions was hypertension and diabetes mellitus (36.6%), hypertension and musculoskeletal conditions (19.9%), and hypertension and other cardiovascular conditions (11.4%). Compared with patients aged 18–39xa0years, those aged 40–49xa0years (OR 4.68, 95% CI: 2.98–7.34), 50–59xa0years (OR 12.48, 95% CI: 8.23–18.92) and 60xa0years or older (OR 15.80, 95% CI: 10.66–23.42) were increasingly likely to present with multimorbidity. While men were less likely to present with multimorbidity, (OR 0.71, 95% CI: 0.45–0.94, pu2009=u20090.015), having a family history of any chronic disease was predictive of multimorbidity (OR 1.43, 95% CI: 1.03–1.68, pu2009=u20090.027).ConclusionsMultimorbidity is a significant problem in this population. By identifying the risk factors for multimorbidity, the results of the present study provide further evidence for informing future policies aimed at improving clinical case management, health education and medical training in Ghana.

Does the design and implementation of proven innovations for delivering basic primary health care services in rural communities fit the urban setting: the case of Ghana’s Community-based Health Planning and Services (CHPS)

BackgroundRapid urban population growth is of global concern as it is accompanied with several new health challenges. The urban poor who reside in informal settlements are more vulnerable to these health challenges. Lack of formal government public health facilities for the provision of health care is also a common phenomenon among communities inhabited by the urban poor. To help ameliorate this situation, an innovative urban primary health system was introduced in urban Ghana, based on the milestones model developed with the rural Community-Based Health Planning and Services (CHPS) system. This paper provides an overview of innovative experiences adapted while addressing these urban health issues, including the process of deriving constructive lessons needed to inform discourse on the design and implementation of the sustainable Community-Based Health Planning and Services (CHPS) model as a response to urban health challenges in Southern Ghana.MethodsThis research was conducted during the six-month pilot of the urban CHPS programme in two selected areas acting as the intervention and control arms of the design. Daily routine data were collected based on milestones initially delineated for the rural CHPS model in the control communities whilst in the intervention communities, some modifications were made to the rural milestones.ResultsThe findings from the implementation activities revealed that many of the best practices derived from the rural CHPS experiment could not be transplanted to poor urban settlements due to the unique organizational structures and epidemiological characteristics found in the urban context. For example, constructing Community Health Compounds and residential facilities within zones, a central component to the rural CHPS strategy, proved inappropriate for the urban sector. Night and weekend home visit schedules were initiated to better accommodate urban residents and increase coverage. The breadth of the disease burden of the urban residents also requires a broader expertise and training of the CHOs.ConclusionsAccess to improved urban health services remains a challenge. However, current policy guidelines for the implementation of a primary health model based on rural experiences and experimental design requires careful review and modifications to meet the needs of the urban settings.