Petra Brhlikova

No evidence that patient choice in the NHS saves lives

The Health and Social Care Bill 2011 has been framed to abolish direct parliamentary control and public accountability for the National Health Service (NHS) in England. In the face of enormous public opposition to the Bill, the UK Government stood down the legislative process between April and June, 2011. Prime Minister David Cameron used the temporary pause to advance the case for the Bill and argued “Put simply: competition is one way we can make things work better for patients. This isn’t ideological theory. A study published by the London School of Economics found hospitals in areas with more choice had lower death rates.” The study to which Cameron referred was a working paper by Zack Cooper and colleagues. However, contrary to Cooper and colleagues’ claims, their study did not show a causal inverse relation between patient choice and death rates. A statistical association is not the same as causation. As set out by Bradford Hill in his seminal paper, certain factors must be considered when determining whether a statistical association is likely to be causal: ”experiment” or study design, plausibility of intervention and outcomes, strength, consistency, specifi city, coherence, temporality, and quality of data. Cooper and colleagues’ study does not meet scientifi c standards. In the absence of evidence proving that competition improves health, Cooper and colleagues’ work should not be cited as scientifi c evidence in support of choice, competition, or the current market-oriented Health and Social Care Bill 2011. A revised version of the study, published in The Economic Journal, clarifi ed points of detail, but Cooper large comparative studies, one reporting data from two academic institutions and one from a multicentre community-based cohort, both noted—after many adjustments for case-mix and disease risk—substantially improved outcomes after surgery compared with radiation. The community-based analysis also recorded, as did Warde and colleagues, better out comes after either surgery or radiation than after androgen deprivation monotherapy. In both studies, diff erences between treatments were small for men with low-risk disease, and increased progressively as risk rose. Warde and colleagues have provided the strongest evidence to date that androgen deprivation therapy alone for men with high-risk prostate cancer is not adequate. These patients require an aggressive, multimodal approach incorporating prostate-directed local therapy. However, the crucial question—whether the optimum initial strategy should include radiation combined with androgen deprivation therapy, or surgery followed by selective radiation on the basis of pathological fi ndings and early biochemical outcomes— is still open. The defi nitive answer will only come through trials of men with high-risk disease randomly assigned to receive surgery or radiation as an initial treatment.

Rethinking WHO guidance: review of evidence for misoprostol use in the prevention of postpartum haemorrhage

This article describes and critically appraises clinical trials assessing misoprostol effectiveness in preventing primary postpartum haemorrhage (PPH) in home and community settings in low- and middle-income countries. Of 172 identified studies of misoprostol use in labour only six fulfilled the inclusion criteria. All trials used 600μg misoprostol in the intervention arm; three assessed misoprostol alongside components of active management of the third-stage labour (AMTSL), two used expectant management of labour and one allowed birth attendants to choose management practice. The three AMTSL studies showed no significant differences in PPH incidence or referral to higher centres and only one study showed significant decrease in severe PPH using misoprostol. One expectant management study and the choice of management by birth attendants study found significant decreases in PPH incidence with misoprostol. All studies showed significantly increased risk of shivering with misoprostol. Studies were biased by use of alternative uterotonics in the control arm, confounding management practices, and subjective assessment and, with one exception, exclusion of high-risk women. PPH incidence fell in both the control and intervention groups in both the landmark papers that informed the World Health Organization (WHO) decision to admit misoprostol to the Essential Medicines List. This suggests factors other than misoprostol use are crucial. Current evidence does not support misoprostol use in home and community settings in low- and middle-income countries for PPH prevention. WHO should rethink its recent decision to include misoprostol on the Essential Medicines List.

Global Burden of Disease estimates of depression – how reliable is the epidemiological evidence?:

Summary Objectives To re-assess the quality of the epidemiological studies used to estimate the global burden of depression 2000, as published in the GBDep study. Design Primary and secondary data sources used in the global burden of depression estimate were identified and assigned to country of origin. Each source was assessed with respect to completeness and representativeness for national/regional estimates and against the inclusion criteria used by the scientific team estimating GBDep. Setting Not applicable. Participants Not applicable. Main outcome measures Not applicable. Results First, National estimates: The 28 scientific sources cited in the GBDep study related to 40 of the 191 WHO member countries. The EURO region had studies relating to 15 of 52 countries whereas AFRO region had studies for only three of 46 countries. Only six of the 40 countries had data drawn from a nationally representative population: the three AFRO country studies were based on a single village or town and, likewise, SEARO region had no nationally representative data; second, GBDep criteria: GBDep inclusion criteria required study sample size of more than 1000 people; 19 (45%) of the 42 studies did not meet this criterion. Sixteen (44%) of 36 studies did not meet the requirement that studies show a clear sample frame and method. GBD estimates rely on estimates of incidence; only two of the 42 country studies provided incidence data (Canada and Norway), the remaining 34 studies were prevalence studies. Duration of depression is based on three studies conducted in the USA and Holland. Conclusions Most studies exhibit significant shortcomings and limitations with respect to study design and analysis and compliance with GBDep inclusion criteria. Poor quality data limit the interpretation and validity of global burden of depression estimates. The uncritical application of these estimates to international healthcare policy-making could divert scarce resources from other public healthcare priorities.

Do cervical cancer data justify HPV vaccination in India? Epidemiological data sources and comprehensiveness.

The Indian government suspended research in April 2010 on the feasibility and safety of human papillomavirus (HPV) vaccine in two Indian states (Andhra Pradesh and Gujarat) amid public concerns about its safety. This paper describes cervical cancer and cancer surveillance in India and reviews the epidemiological claims made by the Programme for Appropriate Technology in Health (PATH) in support of the vaccine in these two states. National cancer data published by the Indian National Cancer Registry Programme of state registry returns and the International Agency for Research on Cancer cover around seven percent of the population with underrepresentation of rural, northern, eastern and north-eastern areas. There is no cancer registry in the state of Andhra Pradesh and PATH does not cite data from the Gujarat cancer registries. Age-adjusted cervical cancer mortality and incidence rates vary widely across and within states. National trends in age standardized cervical cancer incidence fell from 42.3 to 22.3 per 100,000 between 1982/1983 and 2004/2005 respectively. Incidence studies report low incidence and mortality rates in Gujarat and Andhra Pradesh. Although HPV prevalence is higher in cancer patients (93.3%) than healthy patients (7.0%) and HPV types 16 and 18 are most prevalent in cancer patients, population prevelance data are poor and studies highly variable in their findings. Current data on HPV type and cervical cancer incidence do not support PATHs claim that India has a large burden of cervical cancer or its decision to roll out the vaccine programme. In the absence of comprehensive cancer surveillance, World Health Organization criteria with respect to monitoring effectiveness of the vaccine and knowledge of disease trends cannot be fulfilled.

Classification Problems and the Dividing Line between Government and the Market: An Examination of NHS Foundation Trust Classification in the UK

In this paper we argue that national accounting categories provide an inadequate basis for evaluating differences between public and private sector services. This is because accounting categories rely on economic concepts such as market price but do not take account of substantive public policy goals such as universality. The argument has important consequences for the structures and systems of delivery especially where nonprofit providers and social enterprise models are substituted for public bodies formerly integrated into the governments delivery system. Using an example taken from the UKs National Health Service, we show that the mechanisms for ensuring universality through redistribution are not sufficiently taken into account for classification purposes.

Social networks and health policy: The case of misoprostol and the WHO model essential medicine list

The WHO Essential Medicines List (EML) was established to help countries prioritise medicines according to their health care needs. Selection for the List is based on rigorous scrutiny of public health relevance, evidence on efficacy and safety, and comparative cost effectiveness. The WHO ideal is that a medicine and its efficacy are based on science, but in reality a medicine has a social life and the acceptance of a pharmaceutical intervention involves the interaction of a wide array of governmental and civil society organisations, and industry. Misoprostol is a medicine widely used for both abortion and prevention of postpartum haemorrhage in low income countries. Although the evidence for the latter is highly contested it was nevertheless added to the WHO EML in 2011. We use social network analysis to examine the social, political and economic field surrounding the WHO EML applications and health policy. We describe a chronology of the drugs use and of the applications to the WHO EML and carry out a social network analysis of the organisations and individuals involved in the applications, research and dissemination. The research identified a network of 238 organisations and individuals involved in the promotion of misoprostol for postpartum haemorrhage and present at the time of the WHO EML applications. There is a strong interdependency between the funding bodies, civil society organisations, researchers and clinician organisations. The research was part of an EU FP7 funded project on Accessing Medicines in Africa and South Asia (2010-2013).

Commentary: Evidence versus influence in the WHO procedure for approving essential medicines: misoprostol for maternal health

In 2002, the World Health Organization changed its procedures for revising the model list of essential medicines as part of a shift to a more transparent and evidence based approach.1 Barbui and Purgato’s analysis highlights how poor quality applications unaccompanied by a systematic review of evidence may lead to the WHO expert committee prioritising reviews of medicines with limited value. Another problem is that the influence of civil society organisations in the application and review process can apparently trump evidence. A case in point is misoprostol, a synthetic analogue of naturally occurring prostaglandin E1 that was, after six attempts, added to the essential medicine list in 2011 for the prevention of postpartum haemorrhage when oxytocin is not available or cannot be safely used. However, an application to include the drug for the treatment of postpartum haemorrhage was rejected at the same time because it “could divert the attention from or reduce attempts to implement oxytocin availability, a superior treatment.” The drug of choice for preventing and treating postpartum haemorrhage is oxytocin, followed by ergometrine, both of which are heat sensitive and require parenteral administration. Because misoprostol is stable at room temperature and can be administered orally, sublingually, rectally, and vaginally it has been presented as an ideal alternative in low resource settings, where most maternal deaths from haemorrhage occur. However, the evidence in support of using misoprostol is weak despite the large number of trials. Over 10 years, four successive versions of a …

Aid conditionalities, international Good Manufacturing Practice standards and local production rights: a case study of local production in Nepal

BackgroundLocal pharmaceutical production has been endorsed by the WHO as a means of addressing health priorities of developing countries. However, local producers of essential medicines must comply with international pharmaceutical standards in order to be eligible to compete in donor tenders. These standards determine production rights for on-patent and off-patent medicines, and guide international procurement of medicines. We reviewed the literature on the impact of Good Manufacturing Practice (GMP) on local production; a gap analysis from the literature review indicated a need for further research. Over sixty interviews were conducted with people involved in the Nepali pharmaceutical production and distribution chain from 2006 to 2009 on the GMP areas of relevance: regulatory capacity, staffing, funding and training, resourcing of GMP, inspectors’ interpretation of the rules and compliance.ResultsAlthough Nepal producers have increased their overall share of the domestic market, only the public manufacturer, Royal Drugs, focuses on medicines for public health programmes; private producers engage mainly in brand competition for private markets, not essential medicines. Nepali regulators and producers state that implementation of GMP standards is hindered by low regulatory capacity, insufficient training of staff in the industry, financial constraints and lack of investment for upgrading capital. The transition period to mandatory compliance with WHO GMP rules is lengthy. Less than half of private producers had WHO GMP in 2013. Producers are not directly affected by international harmonisation of standards as they do not export medicines and the Nepali regulator does not enforce the WHO standards strictly. Without an international GMP certificate they cannot tender for donor dependent health programmes.ConclusionsIn Nepal, local private manufacturers focus mainly on brand competition for private consumption not essential medicines, the government preferentially procures essential medicines from the only public producer while donor funded programmes rely on international manufacturers compliant with international GMP standards. We also found evidence of private hospitals bypassing national medicines approvals process.Policies in support of local pharmaceutical production in developing countries as a source of essential medicines need to examine carefully how GMP regulations impact on regulators, local industry and production of essential medicines in practice.

Registration, procurement, distribution, and use of misoprostol in Uganda: an interview-based observational study

Abstract Background Poor access to essential medicines remains a barrier to improvement of health in low-income countries. The maternal mortality rate from post-partum haemorrhage (PPH) in Uganda is one of the highest in the world. Uganda launched a misoprostol rollout programme for prevention of PPH in 2009, before WHO added it to the Essential Medicines List. We assessed the rollout programme in Uganda. Methods We reviewed relevant documents (WHO and Ministry of Health guidelines, registration dossier), interviewed key informants, and assessed procurement data collected from the Accessing Medicines in Africa and South Asia project (2010–13). We interviewed informants from purposively selected districts of Mbarara, Bundibugyo, Kampala, and Apac (one for each Ugandan Ministry of Health performance rank). We interviewed key informants about the introduction, registration, procurement, distribution, availability, and use of misoprostol, treatment guidelines, and human resources. Findings We interviewed 82 participants. Civil society organisations promote misoprostol rollout across Uganda as part of a larger assemblage of groups working on maternal health and had a key role in misoprostol registration with the National Drug Authority and development of clinical guidelines. Evidence-based requirements for registration, guideline development, and addition to the Essential Medicines List of Uganda were scarce. Civil society and national medical stores were procuring and distributing misoprostol to health centres 2 years before its inclusion in clinical guidelines and Ugandas Essential Medicines List, despite the contested evidence for its effectiveness. Promotion and distribution of misoprostol is continued by local affiliates offering incentives to private health-care providers promoting their programmes. Interpretation Civil society organisations accelerated misoprostol rollout in Uganda. Despite its introduction as a second choice treatment, evidence suggests an increasing trend of misoprostol procurement and availability over the medicine of choice—oxytocin. Absence of guidelines and lack of training precludes rational use of misoprostol and has ramifications for maternal care that need urgent evaluation. Funding European Union.

Availability of brands of six essential medicines in 124 pharmacies in Maharashtra

Background The aim of this study is to assess the availability and rational use of six essential medicines in private retail outlets in Maharashtra state. The study focuses on the range of brands for each medicine, and the availability of these brands in the pharmacies. The medicines were chosen because they are included in the World Health Organization’s (WHO) essential medicines list (EML), the Indian national and Maharashtra state medicines list, and are all included in existing Indian public health initiatives and national disease control programmes. Methods Data was gathered on the availability of the medicines and the range and frequency of brands in 124 private retail pharmacies between January and May 2012. As there is currently no centralised database in India of available pharmaceutical brands, we collected data on the range of products of the 6 essential medicines available in the Indian market by consulting three open access Indian pharmaceutical databases, CIMS India, Medindia, and Medguide, and the commercial database, Pharmatrac; we compared this data with the results of the survey. The six essential medicines used in this study are: artemisinin (malaria), lamivudine (HIV/AIDS), rifampicin (tuberculosis control), oxytocin (reproductive health), fluoxetine (mental health) and metformin (diabetes). Results The study found that for each of the selected medicines there were multiple approved products listed in Indian databases, 2186 in total. The Pharmatrac database lists only 1359 brands of the selected medicines; 978 (72%) of these had zero sales in 2011-2012. Our survey found very low availability of the brands: 17% Pharmatrac marketed brands (163/978) and 12% of all Pharmatrac brands (163/1359) were available. Metformin was the only medicine with high availability in the study pharmacies at 91%, Rifampacin was the second highest at 64.5%; the other four medicines were available in less than half the pharmacies. A small number of brands were dominating the market. Conclusion the survey shows that market competition has generated a large number of brands of the six study medicines but this has not translated into sufficient availability of these medicines in the study pharmacies. The data calls for a review of available brands, taking into consideration levels of sale and grounds for approval, and the setting up of a centralised database of registered pharmaceutical products.