Population-wide weight loss and regain in relation to diabetes burden and cardiovascular mortality in Cuba 1980-2010: repeated cross sectional surveys and ecological comparison of secular trends

Manuel Franco, Usama Bilal, Pedro Orduñez, Mikhail Benet, Alain Morejón, Benjamín Caballero, Joan F Kennelly, Richard S Cooper

BMJ 2013;346:f1515 (Published 09 April 2013)

http://www.bmj.com/content/346/bmj.f1515

===============

경제봉쇄로 쿠바인 더 건강해져?

주영재 기자 jyj@kyunghyang.com

경향신문 입력 : 2013-04-10 13:53:29ㅣ수정 : 2013-04-10 13:53:29
http://news.khan.co.kr/kh_news/khan_art_view.html?artid=201304101353291&code=970100

쿠바인들이 1990년대 초반 미국의 경제봉쇄와 러시아 지원의 중단으로 석유와 식량 부족에 시달리며 힘든 시기를 겪으며 오히려 심장 질환과 당뇨의 발병률이 낮아졌다는 연구 결과가 나왔다.

쿠바인들은 1991~1995년까지 고난의 시기 동안 당나귀에 의존해 짐을 날랐고, 정부는 석유를 소비하는 차량 대신 중국에서 150만대의 자전거를 수입해야 했다.

가디언에 따르면 미국, 스페인, 쿠바의 대학 연구자들은 이 기간 식사량이 줄고, 자전거를 타거나 걷는 시간이 늘고, 육체 노동이 증가한 것이 건강에 어떤 영향을 미쳤는지를 확인하려고 했다.

쿠바는 무상 의료가 상당한 수준으로 진척된 국가로 “맨발의 의사”들이 광범위한 기초 진료를 행하고 있으며 국민 건강 상태에 대한 자료도 잘 구축되어 있다.

연구자들은 1980~2010년까지 쿠바인들의 몸무게와 심장질환, 뇌졸중, 당뇨로 인한 사망률의 변화를 관찰한 결과를 영국 메디컬저널에 발표했다.

스페인 마드리드의 알카라 대학의 마누엘 프랑코 교수가 이끈 연구진은 쿠바인의 몸무게가 경제봉쇄로 위기에 몰린 1991~1995년 동안 평균 5.5㎏ 감소했음을 알게됐다. 이는 건강에 직접적인 영향을 줘 당뇨로 인한 사망자를 절반까지 줄였으며 심근경색으로 인한 사망률은 3분의 1로 줄었다.

연구진은 “이런 추세는 소비에트 붕괴와 미국의 경제봉쇄로 쿠바 경제가 식량과 대중교통을 확보할 수 있는 능력이 줄어든 것과 관련이 있었다”며 “심각한 식량 및 에너지 부족은 열량 섭취를 줄이면서 동시에 (대중교통 대신 걷거나 자전거를 타면서) 열량 소비를 증가시켰다”고 말했다.

쿠바 경제 위기가 1996년 이후 끝나고 회복기에 들어서자 몸무게는 다시 증가하기 시작했고 신체활동 수준도 미미하지만 감소했다. 쿠바는 2000년부터 안정적인 성장을 지속했으며 2002년에 이르러서는 음식과 음료 소비량이 증가해 위기 이전 수준을 넘었다. 그 결과 2011년 쿠바 인구의 비만률은 1995년에 비해 거의 세배로 증가했다. 당뇨도 1995년부터 증가해 2002년부터 2010년까지 당뇨사망률은 위기 이전 수준의 증가세로 돌아갔다.

월터 윌렛 하버드 공공의료대학의 영양학과장은 이 연구가 “비만과 과체중 감소가 주는 커다란 이점을 보여주는 강력한 증거”라고 평가했다.

논문 저자들은 이같은 결과가 체중 감소가 실질적인 이득을 가져올 수 있다는 것을 보여준다고 주장하고 있다. 프랑코 교수는 “교통 정책이 근본적인 것으로 교통 수단으로 걷기와 자전거 타기를 장려할 필요성이 있다”고 밝혔다.

또한 육체 활동을 증진시키고 건강에 좋지 않은 음료와 음식을 어린이에게 공격적으로 홍보하는 것을 규제하거나 불량 식품에 더 많은 세금을 부과하는 것도 하나의 전략이라고 과학자들은 조언했다.

그럼에도 그는 쿠바의 경제 위기가 현재 경제위기를 겪는 유럽에 건강과 관련한 어떤 유사한 이득을 주지는 않을 것이라고 내다봤다. 인종과 사회적 환경이 유사한 쿠바와 달리 유럽은 훨씬 이질적이기 때문이다.

연구자들은 또한 과학 논문에 어울리지 않게 위기를 초래한 정치에 비난을, 쿠바인들의 대응 방식에 찬사를 보냈다.

이들은 논문에서 “우리는 고난의 기간 동안 극도로 어려운 사회 경제적 도전에 직면한 쿠바 국민들이 용기와 위엄을 잃지 않고 대응한 것에 존경과 찬사를 보낸다”며 “이 비극은 국제 정치에 의한 ‘인재’이며 다시는 어느 나라에서도 되풀이 되어선 안된다”고 썼다.

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Research

Population-wide weight loss and regain in relation to diabetes burden and cardiovascular mortality in Cuba 1980-2010: repeated cross sectional surveys and ecological comparison of secular trends

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1515 (Published 9 April 2013)

Cite this as: BMJ 2013;346:f1515
http://www.bmj.com/content/346/bmj.f1515

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1. Manuel Franco, associate professor1, adjunct associate professor2, visiting researcher3,
   
2. Usama Bilal, research assistant1, visiting researcher3,
   
3. Pedro Orduñez, regional adviser4, professor5,
   
4. Mikhail Benet, professor5,
   
5. Alain Morejón, assistant professor5,
   
6. Benjamín Caballero, professor6,
   
7. Joan F Kennelly, research assistant professor7,
   
8. Richard S Cooper, professor and chair8

Author Affiliations

1. 
   
   ¹Social and Cardiovascular Epidemiology Research Group, School of Medicine, University of Alcalá, Alcalá de Henares, Madrid, Spain
   
   
2. 
   
   ²Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
   
   
3. 
   
   ³Department of Epidemiology, Atherothrombosis and Cardiovascular Imaging, Centro Nacional de Investigaciones Cardiovasculares Madrid, Spain
   
   
4. 
   
   ⁴Project for Chronic Disease Prevention and Control, Pan American Health Organization, Washington, DC, USA
   
   
5. 
   
   ⁵Centro de Estudios sobre Enfermedades Crónicas, Universidad de Ciencias Médicas, Cienfuegos, Cuba
   
   
6. 
   
   ⁶Center for Human Nutrition, Department of International Health, Johns Hopkins Bloomberg School of Public Health, USA
   
   
7. 
   
   ⁷Division of Community Health Sciences, University of Illinois at Chicago School of Public Health, Chicago, IL, USA
   
   
8. 
   
   ⁸Department of Public Health Sciences, Loyola University Stritch School of Medicine, Maywood, IL, USA

1. Correspondence to: M Franco mfranco@uah.es

• Accepted 11 February 2013

Abstract

Objective To evaluate the associations between population-wide loss and gain in weight with diabetes prevalence, incidence, and mortality, as well as cardiovascular and cancer mortality trends, in Cuba over a 30 year interval.

Design Repeated cross sectional surveys and ecological comparison of secular trends.

Setting Cuba and the province of Cienfuegos, from 1980 to 2010.

Participants Measurements in Cienfuegos included a representative sample of 1657, 1351, 1667, and 1492 adults in 1991, 1995, 2001, and 2010, respectively. National surveys included a representative sample of 14 304, 22 851, and 8031 participants in 1995, 2001, and 2010, respectively.

Main outcome measures Changes in smoking, daily energy intake, physical activity, and body weight were tracked from 1980 to 2010 using national and regional surveys. Data for diabetes prevalence and incidence were obtained from national population based registries. Mortality trends were modelled using national vital statistics.

Results Rapid declines in diabetes and heart disease accompanied an average population-wide loss of 5.5 kg in weight, driven by an economic crisis in the mid-1990s. A rebound in population weight followed in 1995 (33.5% prevalence of overweight and obesity) and exceeded pre-crisis levels by 2010 (52.9% prevalence). The population-wide increase in weight was immediately followed by a 116% increase in diabetes prevalence and 140% increase in diabetes incidence. Six years into the weight rebound phase, diabetes mortality increased by 49% (from 9.3 deaths per 10 000 people in 2002 to 13.9 deaths per 10 000 people in 2010). A deceleration in the rate of decline in mortality from coronary heart disease was also observed.

Conclusions In relation to the Cuban experience in 1980-2010, there is an association at the population level between weight reduction and death from diabetes and cardiovascular disease; the opposite effect on the diabetes and cardiovascular burden was seen on population-wide weight gain.

Introduction

It was recognised early in the course of the global epidemic of type 2 diabetes that variation in the prevalence of the disease among populations could be explained largely by relative weight.1 This observation is supported by survey research from virtually every country in the World Health Organization database.2 Despite predictions on the effect of the obesity and diabetes epidemics on life expectancy,3 it is unclear to what extent they can alter the downward trend of cardiovascular diseases prevalence observed in many countries.4 Furthermore, lack of adequate data for public health precludes the empirical assessment of comparable trends across the developing world. Most cohort studies have suggested a “U” shaped association between body mass index and mortality, with the lowest point in the index range of 24 to 29.5 6 Therefore, key unknown factors are the net health impact of a given downward shift in the distribution of body mass index in a population, and the time lag between changes in body mass index and in the prevalence of non-communicable disease.7

Video abstract

Marked and rapid reductions in mortality from diabetes and coronary heart disease were observed in Cuba after the profound economic crisis of the early 1990s.8 These trends were associated with the declining capacity of the Cuban economy to assure food and mass transportation in the aftermath of the dissolution of the former Soviet Union and the tightening of the US embargo. Severe shortages of food and gas resulted in a widespread decline in dietary energy intake and increase in energy expenditure (mainly through walking and cycling as alternatives to mechanised transportation).

The largest effect of this economic crisis occurred over a period of about five years (1991-95, the so called “special period”), resulting in an average weight loss of 4-5 kg across the adult population.8 This economic crisis was not a full disruption of previous routines of daily life, but was actually characterised by its slow process of economic decline. During these years, the whole population continued to meet responsibilities in relation to work, school, and other social aspects, and the Ministry of Public Health maintained its regular surveillance system activities.9 10

Since then, the Cuban economy has shown a modest but constant recovery, especially after the year 2000.11 12 In fact, surveys have shown that the prevalence of obesity has now exceeded pre-crisis levels.13 The table⇓ shows basic sociodemographic and economic information on Cuba before, during, and after the economic crisis.

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Basic sociodemographic and economic information on Cuba at various stages of economic crisis¹²

To advance the prevention of non-communicable diseases, population-wide data remain crucial. Comparing disease rates over time, in relation to changes in risk factor levels in the population, indicates the extent to which disease can be prevented and what the most important risk factors are at the population level.14 The population preventive approach articulated by Geoffrey Rose in his seminal paper,15 is of importance when preventing and controlling non-communicable diseases, particularly cardiovascular diseases. The current study exemplifies a unique situation where population-wide body weight changed considerably, as a result of the combined and sustained effect of reduced energy intake and elevated physical activity. This scenario allowed us to assess its effect on diabetes and cardiovascular disease.16

Our objective was to examine the effect of population-wide changes in body weight—over a full cycle of weight loss and regain—on diabetes incidence, prevalence, and mortality in Cuba, from 1980 to 2010. We also assessed the effects of this weight change cycle on rates of death from cardiovascular disease, cancer, all causes.

Methods

To study the population-wide changes in body weight over time, we used four cross sectional surveys in the city of Cienfuegos, on the southern coast of Cuba. These surveys are part of the Project of Cienfuegos, an initiative designed to study the risk factors for non-communicable diseases in Cuba.

To obtain all available data from government and published sources on mortality, physical activity, energy intake, and smoking in Cuba between 1980 and 2011, we did a systematic search. We used the following databases: Medline, Spanish Bibliographic Index in Health Sciences (IBECS), and the Scientific Library Online (BVS-SciELO Cuba), which includes most Cuban journals. Web appendix 1 details the 12 references included.

Height, weight or overweight, and obesity

The four cross sectional surveys measured height and weight, on the basis of stratified probability samples from the urban population aged 15-74 years. The surveys included 1657, 1351, 1667, and 1492 adults for the years 1991, 1995, 2001, and 2011, respectively. The age distribution of the population in Cienfuegos is similar to the general Cuban population (web appendix 2). We used the following categories for body mass index: underweight (<18.5), normal weight (18.5-<25), overweight (25-<30), and obesity (≥30). All participants in the four surveys signed the informed consent. The ethics committee of the University of Medical Sciences, Cienfuegos, approved protocols.

Physical activity

Measures of self reported physical activity were available from representative samples of the population in Havana in 1987, 1988, and 1994 and from the national surveys on risk factors and chronic diseases (conducted nationally in 1995, 2001, and 2010, respectively). In these surveys, participants were designated as physically active if they engaged in regular physical activity, defined as 30 minutes of moderate or intense activity on at least five days per week.

Energy intake

The Food and Agriculture Organization of the United Nations provides disappearance data on energy intake per capita, by dividing total calories available for human consumption by the total population consuming the food supply during the reference period.

Smoking

National use of cigarettes per capita was calculated as the total number of cigarettes sold per year divided by the population aged 15 years and over. The prevalence of smoking was obtained from the national surveys on risk factors and chronic diseases conducted in 1995, 2001, and 2010, and other national studies previously conducted. We defined smoking as self reported current use of cigarettes or cigars (or both).17

Diabetes prevalence and incidence

In the Cuban national health system, the primary care doctor-nurse team is responsible for collecting health data for all residents in the neighbourhood of their catchment area (about 1500 individuals per team). One of the team activities organised by the health system is continuous assessment and risk evaluation (CARE, or Dispensarización in Spanish).18 19 All households are visited at least once a year for a comprehensive health evaluation of the family, while patients with chronic diseases receive a visit at least once every three to six months. These health examinations covered 61.2% (n=595 1088) of the population in 1979,20 75.9% (n=7 918 647) in 1989,20 and 98.2% (n=11 038 820) in 2009.21 We obtained data for diabetes prevalence and incidence from the CARE registries, spanning the time period of 1980-2009.20 21 These registries allow the monitoring of chronic disease trends, such as diabetes incidence or prevalence.

Mortality

We obtained annual, age adjusted rates of mortality per 100 000 people from the Cuban Ministry of Public Health. ICD-10 (international classification of diseases, 10th revision) codes were used for death from type 2 diabetes (E10-E14), coronary heart disease (I20-I25), stroke (I60-I69), cancer (C00-C97), and all causes for the period of 1980-2010. We used data from 1980 to examine possible trends unrelated to the economic crisis during the special period in 1991-95. The 1981 Cuban population census was used for age adjustment. Vital records in Cuba are essentially complete. Postmortem examinations in some hospitals include up to 85% of people coded as dying from cardiovascular disease, which provided considerable confidence in an accurate designation of the cause of death.22

Statistical analysis

To illustrate the distributions of body mass index in the four surveys from Cienfuegos (in 1991, 1995, 2001, and 2011), we used Stata SE version 12.1 to generate density plots through the Gaussian kernel function. To analyse changes in prevalence and mortality, joinpoint regression analysis was conducted using software developed by the Surveillance Research Program of the United States National Cancer Institute.23 This regression model allows identification of significant changes in linear trend slopes. The estimated annual change (%) was then computed for each mortality trend by fitting a regression line to the natural logarithm of the rates within each period or phase.

We did not use this procedure to analyse diabetes incidence, owing to missing data from the years during the crisis. Because incidence estimates are inherently unstable, we enhanced visual presentation by constructing moving averages for each year with available data, using the incidence data from the previous, current, and following year.

Results

Risk factor trends

From its lowest point in the mid-1990s, average daily intake of energy per capita increased monotonically, reaching pre-crisis levels in 2002 and levelling off in 2005 (fig 1⇓). On the other hand, physical activity had a slight downward trend after the mid-1990s, remaining stable from 2001, with more than half of the population being physically active. Although 80% of the population was classified as active in surveys conducted during the special period in 1991-95, this proportion fell steadily in the last decade, and is currently at 55% (fig 1). These population-wide changes in energy intake and physical activity were accompanied by large changes in body weight over this entire interval (figs 2⇓ and 3⇓).

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Fig 1 Physical activity, dietary energy intake, and smoking in Cuba, 1980-2010. Red shaded area=period of economic crisis; blue shaded area=period of economic recovery. Physical activity data recorded in 1987, 1988, and 1994 obtained from Havana surveys; data recorded in 1995, 2001, and 2010 come from national surveys. *1 kcal=0.00418 MJ

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Fig 2 Distributions of body mass index as recorded by national surveys conducted in Cienfuegos in 1991, 1995, 2001, and 2010

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Fig 3 Prevalence of obesity and diabetes, incidence, and mortality in Cuba, 1980-2010. Red shaded area=period of economic crisis; blue shaded area=period of economic recovery. Diabetes prevalence increased by 2.93% per year from 1980 to 1997, and 6.27% per year from 1997 to 2010. Diabetes mortality increased by 5.85% per year from 1980 to 1989, but fell by 0.68% per year from 1989 to 1996 and 13.95% per year from 1996 to 2002, before increasing by 3.31% per year from 2002 to 2010

Smoking prevalence (fig 1) slowly decreased during the 1980s and 1990s (42% in 1984, 37% in 1995), before declining more rapidly in the 2000s (32% in 2001, 24% in 2010). The number of cigarettes consumed per capita decreased during and shortly after the crisis. In 1990, 1934 cigarettes per capita were consumed (fig 1). This number changed to 1572, 1196, and 1449 cigarettes per capita in 1993, 1997, and 1999, respectively. Cigarette consumption has since remained stable.

Figure 2 depicts the distribution of body mass index from the Cienfuegos surveys of 1991, 1995, 2001, and 2010 with kernel density plots of each year’s measurements. During the special period of 1991-95, there was a weight loss of 5.5 kg across the entire range of body mass index (that is, not only among obese people), with a mean reduction in body mass index of 1.5 units. After a period of economic recovery and stability, an increase in body mass index of 2.6 units was observed from 1995 to 2010; weight regain also occurred across the entire population, irrespective of body mass index. These distribution shifts in body mass index were consistent across surveys. The proportion of the population in the normal weight category decreased from 56.4% at the end of the special period in 1995 to 42.1% in 2010. At the same time, proportions in the overweight and obesity categories increased by 19.4%, from 33.5% in 1995 to 52.9% in 2010 (web appendix 3).

Diabetes trends

Diabetes prevalence and incidence

Joinpoint regression analyses showed two different phases of diabetes prevalence (fig 3). The first phase had a slow and stable increase from 1980 (1.5 per 100 people) to 1997 (1.9 per 100 people), a total increase of 26.6% (2.9% per year). In the second phase, diabetes prevalence increased from 1.9 per 100 people in 1997 to 4.1 per 100 people in 2009 and 2010, a total increase of 115.8% (6.3% per year).

Incidence of diabetes fluctuated widely (fig 3). For the decade before the crisis, incidence was stable, between 1980 (1.5 per 1000 people) and 1989 (1.8 per 1000 people). The only data point in the middle of the economic crisis showed a decrease in diabetes incidence, falling to 1.2 per 1000 people in 1992. For the years immediately after the crisis, incidence was lower than pre-crisis levels (1 per 1000 people in 1996 and 1997 v 1.4 per 1000 people in 1999). Sharp increases were observed from 2000 onwards, peaking in 2002 (2.2 per 1000 people) and 2009 (2.4 per 1000 people). Thus, overall diabetes incidence decreased by 53% from its peak in the pre-crisis years (1986) to its lowest point after the crisis (1996 and 1997). Subsequently, incidence rose by 140% from 1996 to 2009.

Diabetes mortality

Joinpoint regression analysis of diabetes mortality showed four different phases (fig 3). The first phase, from 1980 to 1989 (pre-crisis years), was characterised by an increase of 60% (5.9% per year). The second phase from 1990 to 1996 overlapped with the special period in 1991-95, during which diabetes mortality stabilised (0.7% decrease per year). However, from 1996 to 2002, we recorded a decrease in diabetes mortality of 50% (13.95% per year). Finally, from 2002 onwards, mortality rose by 49% (3.31% per year; from 9.3 deaths per 10 000 people in 2002 to 13.9 deaths per 10 000 people in 2010), returning to pre-crisis rates.

Mortality trends

Coronary disease mortality

Mortality from coronary heart disease evolved in three phases (fig 4⇓). From 1980 to 1996, mortality fell consistently (reduction of 8.8%, 0.5% per year). After the crisis in 1996-2002, mortality decreased sharply by 34.4% (6.5% per year). After 2002, the rate of decline slowed to 7.4% (1.4% per year), similar to pre-crisis rates.

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Fig 4 Obesity prevalence and coronary heart disease, cancer and stroke mortality in Cuba (1980-2010). Red shaded area=period of economic crisis; blue shaded area=period of economic recovery; CHD=coronary heart disease. CHD mortality decreased by 0.50% per year from 1980 to 1996, 6.48% per year from 1996 to 2002, and 1.42% per year from 2002 to 2010. Cancer mortality decreased by 0.12% per year from 1980 to 1996, but increased by 0.47% per year from 1996 to 2010. Stroke mortality fell by 0.39% per year from 1980 to 2000, 5.03% per year from 2000 to 2004, and 0.01% per year from 2004 to 2010

Stroke mortality

Mortality from stroke mirrored the pattern of mortality from coronary heart disease, with a modest decrease of 6.9% lasting from 1980 to 2000 (0.4% per year) and a sharp fall between 2000 and 2004 of 13.6% (5.3% per year). From 2004 to 2010, mortality fell by 1.3% (0.01% per year, similar to pre-crisis rates).

Cancer mortality

Cancer mortality followed a distinctly different pattern to that observed in coronary heart disease, stroke, and diabetes, with two distinct phases (fig 4). From 1980 to 1996, a slight decrease of 2.4% in cancer mortality was observed (0.1% per year), which reverted to a slight increase of 5.4% in 1996-2010 (0.5% per year).

All cause mortality

Mortality from all causes, as expected, was highly influenced by trends in coronary heart disease and stroke, showing three different phases (data not shown). A prolonged decrease in mortality of 1.7% from 1980 to 1996 (0.1% per year) was followed a sharp decline of 10.5% from 1996 to 2002 (2.9% per year). From 2002 to 2010, there has been a modest decrease of 2% (0.7% per year).

Discussion

During the deepest period of the economic crisis in Cuba, lasting from 1991 to 1995, food was scarce and access to gas was greatly reduced, virtually eliminating motorised transport and causing the industrial and agricultural sectors to shift to manual intensive labour. This combination of food shortages and unavoidable increases in physical activity put the entire population in a negative energy balance, resulting in a population-wide weight loss of 4-5 kg.8 The decline in food availability was associated with a neuropathy outbreak in the adult population in 1993.24 25 The Cuban economy started recovering in 1996 with a sustained growth phase from 2000 onwards. Since 1996, physical activity has slightly declined. By 2002, energy intake had increased above pre-crisis levels.

As a result of the above trends, by 2011, the Cuban population has regained enough weight to almost triple the obesity rates of 1995. This U shaped, population-wide pattern in body weight is historically unique because of several factors: the initial weight loss occurred in a population that had been well nourished previously, lasted for five years, and affected people at all initial levels of body mass index.

Diabetes trends could have been substantially influenced by these population-wide changes in body weight. Diabetes prevalence surged from 1997 onwards, as weight started to rebound. Diabetes incidence decreased during the crisis, reaching its lowest point in 1996. The largest economic recovery saw diabetes incidence peaking in 2004 and 2009.

Five years after the start of the economic crisis in 1996, an abrupt downward trend was observed in mortality from diabetes, coronary heart disease, stroke, and all causes. This period lasted an additional six years, during which energy intake status gradually recovered and physical activity levels were progressively reduced; in 2002, mortality rates returned to the pre-crisis pattern. A particularly dramatic shift in diabetes mortality was observed: from 2002 to 2010, the annual increase in diabetes mortality was similar to that before the crisis. Moreover, declining rates of coronary heart disease and stroke slowed to annual decreasing rates similar to those before the crisis.

Comparison with other studies

The effect of high risk, preventive approaches on diabetes or cardiovascular mortality has been extensively studied and has reported conflicting and non-conclusive results. For example, the Look AHEAD clinical trial,26 aimed at reducing cardiovascular risk associated with diabetes through weight reduction and exercise, has been prematurely terminated for lack of an effect on cardiovascular mortality. Other high risk approaches, such as the prevention and control of diabetes through massive screenings, has recently shown no improvements in diabetes, cardiovascular, or all cause mortality.27 Overall, it seems that high risk preventive approaches have either not produced a beneficial effect on cardiovascular mortality or diabetes control and mortality, or have been unsuccessful in reducing risk to a sufficient degree to warrant a conclusion.

The complementary pathway to disease prevention, the population approach, has received scant attention in the literature. To our knowledge, the effect of population-wide weight regain on diabetes and cardiovascular mortality has not been previously studied. Research on population-wide interventions has so far only studied modelling studies28 or small scale interventions.14

Research on weight cycling, described in obese individuals undergoing repeated attempts at weight loss followed by weight regain, has reported conflicting results: either an increase29 30 31 32 or no association with general mortality.33 Specifically, no association between weight cycling and diabetes incidence has been recorded.34 35 Since individual weight cycling usually refers to multiple weight changes over an extended period, those results might have limited relevance for the population experience of a single cycle of weight gain, loss, and regain that we report here.

As shown in our results, smoking levels were affected by the crisis. The number of cigarettes smoked per capita in Cuba decreased in the crisis years, only to slightly recover afterwards and remain stable thereafter. Smoking prevalence has continuously decreased during the past 15 years in Cuba. The role of tobacco in the development and control of diabetes has been recently studied; both active and passive smoking are associated with increased incidence.36 This association is dose dependent37; therefore, the decrease in smoking in Cuba during the crisis may have contributed to the decline in diabetes incidence in those years. The effects of decreasing smoking rates should drive down the rates of diabetes incidence and mortality in the long term. In this case, the observed decline in smoking rates during and after the crisis should cause a decrease in diabetes mortality in the last decade of our study. The increase in diabetes mortality from year 2002 seems to rule out smoking as a major confounding factor in the observed trends, although it could be masking the true size of the effect of changes in dietary and physical activity on diabetes mortality. This consideration is analogous for coronary heart disease and stroke, which should fall as smoking prevalence declines.

Strengths and limitations of study

Our study presents the first observation of a population-wide event of this magnitude and its subsequent effects on public health. Population-wide shifts in other risk factors, such as cholesterol and blood pressure, have been described in large scale prevention interventions, for example, the North Karelia and FINRISK studies.38 In the Cuban experience, the changes in population-wide body weight were adaptive responses to dietary energy availability and energy expenditure; therefore, it is not possible to separate these two effects on mortality patterns.

Other unique effects of this experience should also be considered. Problems with food production in Cuba led to the creation and expansion of urban agriculture, allowing citizens to buy fresh produce directly from farmers. Large public health campaigns in schools and communities are currently in place using community gardening as an effort to improve nutrition education and diet quality.39 During the crisis, the Cuban government acquired and distributed more than one million bicycles, which contributed to the population-wide increase in physical activity.39 These unique features of the Cuban experience make it to that degree non-comparable with other examples of economic crises. For example, previous research on the health consequences of the Great Depression in the US showed that banking suspensions (as a proxy for large scale economic decline) was not followed by a decrease in mortality.40

As noted previously, controversy persists over the net benefit of generalised weight loss in modern populations.41 As articulated by Geoffrey Rose,15 a key element of a prevention strategy for diseases in populations with near universal exposure to the causal risk factor is a downward shift in the overall mean. The data presented here confirm this theory. The Cuban experience shows that within a relatively short period, modest weight loss in the whole population can have a profound effect on the overall burden of diabetes. In Cuba, weight loss also had a major effect on trends in cardiovascular diseases and all cause mortality. Although obesity is an important risk factor for cancer,42 only modest changes in cancer mortality were observed.

Our study has some important limitations. We had no data on diabetes incidence for most crisis years, and rates in the subsequent years showed wide fluctuations. Data for diabetes mortality were available for the whole study period, but might not have adequately represented the health burden of diabetes. Death certificates are subject to misclassification bias, although the parallel trends in cardiovascular and all cause mortality rule out substantial shifts away from diabetes to major illnesses that occurred at the same time—the most common of which would have been vascular in cause. The cyclic pattern of the observed trends makes a bias less likely, owing to widespread changes in coding of death certificates. Estimating dietary intake from food disappearance data has known limitations, but data from available dietary surveys for the years before, during, and after the special period were consistent with food disappearance data from the Food and Agriculture Organization.8

Conclusions and policy implications

We found that a population-wide loss of 4-5 kg in weight in a relatively healthy population was accompanied by diabetes mortality falling by half and mortality from coronary heart disease falling by a third. Furthermore, a rebound in body weight was associated with an increased diabetes incidence and mortality, and a deceleration of the decline in mortality from coronary heart disease. So far, no country or regional population has successfully reduced the distribution of body mass index or reduced the prevalence of obesity through public health campaigns or targeted treatment programmes.16 The latest reports in the US have documented a plateau in the epidemic curve of obesity in adults,43 children, and adolescents,44 but the public health effects of these changes have not yet been reported. It is therefore not possible to compare the Cuba findings with other populations. Therefore, the generalisability of our findings is uncertain. Nonetheless, these data are a notable illustration of the potential health benefits of reversing the global obesity epidemic.

What is already known on this topic

• 
  

  The health effects of population-wide changes in body weight on a well nourished population with a functioning universal health system is unknown

  
  
• 
  

  Large reductions in diabetes and cardiovascular mortality were noted after the population-wide weight loss in Cuba, during the economic crisis of the early 1990s

What this study adds

• 
  

  Body weight regain in the Cuban population was associated with an increase in diabetes prevalence, incidence, and mortality, as well as a deceleration in the previously declining rates of cardiovascular death

  
  
• 
  

  Small losses in body weight and prevention of body weight gain across the population could be a critical strategy in the prevention of non-communicable diseases

Notes

Cite this as: BMJ 2013;346:f1515

Footnotes

• 
  

  We would like to acknowledge our great respect and admiration for the Cuban people who faced extremely difficult social and economic challenges during the special period—and by making common cause against this tragedy held up with courage and dignity. This tragedy was “man made” by international politics and should never happen again to any population.

  
  
• 
  

  Contributors: MF and RC contributed to the original design. PO, MB, and AM organised and conducted data collection. UB conducted the statistical analyses. MF, UB, and RC carried on the systematic literature research. MF, UB, PO, BC, JFK, and RC were active in the interpretation of results. The manuscript was drafted by MF, UB, JFK, and RC, and reviewed by all authors. All authors have approved the final report. All authors had full access to the data in the study and take responsibility for its integrity and the accuracy of the data analysis. MF is the guarantor for this study.

  
  
• 
  

  Funding: No funding sources had any role in the decision to submit this manuscript or in its writing.

  
  
• 
  

  Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

  
  
• 
  

  Ethical approval: The ethics committee of the University of Medical Sciences, Cienfuegos, approved protocols.

  
  
• 
  

  Data sharing: No additional data available.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.

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==================

Economic Hard Times in Cuba Reduces Rates Of Heart Disease And Diabetes

Medical News Today Article Date: 10 Apr 2013 – 11:00 PDT
http://www.medicalnewstoday.com/articles/258930.php

During the 1990s in Cuba, food was sparse and gasoline was nearly unavailable because of the US embargo and loss of Russian support; one of the positive consequences of that situation was a reduction in rates of diabetes and heart disease.

The “special period” (as it became known) was between 1991 and 1995 and consisted of people using donkeys to move loads, as well as the government importing 1.5 million bicycles from China for modes of transportation. The current study, published in BMJ, aimed to determine whether eating less, cycling, walking, and manual labor contributed to the health of the nation as a whole. In other words, might a change in whole nation’s dietary intake plus increased physical activity caused by transportation policies impact on the incidence of type 2 diabetes and cardiovascular disease?

The shortage of food and fuel in Cuba produced a reduction in dietary energy intake and a large increase in physical activity. These changes produced a population-wide weight loss of 4-5kg (8-11 lbs.) Significant decreases in death rates from coronary heart disease and diabetes were seen shortly after.

A team of investigators from Cuba, Spain, and the U.S. analyzed..:

• ..link between diabetes prevalence and population-wide body changes
  
• ..incidence and death rates from type 2 diabetes and cardiovascular disease
  
• ..cancer and all-causes

Cuba is a nation with a long history of public health and cardiovascular research, which provided the data needed from primary chronic disease registries, cardiovascular studies, and national health surveys. The Cuban population has seen economic and social changes directly associated with physical activity and food intake from 1980 to 2010.

The data used for the analysis included participants between the ages of 15 and 74 years and information on:

• height
  
• weight
  
• energy intake
  
• smoking
  
• physical activity

Dramatic Drop in Rates Seen Just From This Instance

Changes in physical activity and energy intake went hand-in-hand with changes in body weight. For example, between 1991 and 1995 there was a 5kg reduction on average, while between 1195 and 2010 a weight rebound was seen of 9kg.

The incidence of smoking fell during the 1980s and 1990s and decreased even more quickly in the 2000s.

The prevalence of diabetes continued to rise from 1997 as the population started to gain weight. It then decreased during the weight loss period, followed by another increase until it peaked in the weight regain years.

A sudden downward cycle in deaths from diabetes was seen five years after the beginning of the weight loss period, in 1996. This went on for about six years during which energy consumption status slowly recovered and physical activity levels decreased. In 2002, death rates went back to pre-crisis figures and a significant increase in diabetes deaths was seen.

Stroke and coronary heart disease death rates slowly dropped from 1980 to 1996 with a bigger decrease occurring after the weight-loss phase. During the weight regain phase, these declines stopped.

The investigators concluded that the “Cuban experienced in 1980-2010″ showed that within a short period, noteworthy weight loss in the whole population can greatly affect the overall burden of deaths from diabetes and cardiovascular disease.

They point out that findings show that a 5kg population-wide weight loss “would reduce diabetes mortality by half and CHD mortality by a third”, however, these findings are an unusual circumstance from this one experience. On the other hand, they do provide a “notable illustration of the potential health benefits of reversing the global obesity epidemic”.

Previous research has shown that there is a link between diabetes and heart disease. Diabetics are more likely to develop hardened arteries than non-diabetics.

A separate study demonstrated the association between sitting for long periods and developing heart disease and diabetes. Even for people who are physically active, sitting for long periods could raise the risk for both conditions.

Written by Kelly Fitzgerald

.

Apology from the BMJ for erroneous flu vaccine profits allegation

출처 : The Pharma Letter Article | 6 July 2010
http://www.thepharmaletter.com/file/96423/apology-from-the-bmj-for-erroneous-flu-vaccine-profits-allegation.html

The British Medical Journal has published a correction and apology for the use of incorrect figures in its expose on whether advisors to the World Health Organization had a conflict of interest in so far as they had financial ties to drugmakers (The Pharma Letter June 7).

Fiona Godlee, editor-in-chief of the BMJ, conceded that she was quoting from the Council of Europe report which itself was quoting a JP Morgan report that estimated total sales (not profit as she stated) for pandemic vaccine and adjuvant, and was $6.9 billion. The industry’s audited accounts for 2009 give sales figures for pandemic vaccine in 2009 in the region of $2.5 billion, according to a posting on the European Federation of Pharmaceutical Industries and Associations (EFPIA) web site.

The JP Morgan figures quoted in a TPL (June 10 issue) story on the issue said that producers of pandemic vaccines had so far “netted” an estimated $7-$10 billion from government orders, so not implying this was profit.

Apparently, Ms Godlee took the numbers not directly from the JP Morgan report, but from the Council of Europe report, which had in turn quoted “incorrectly” from the JP Morgan report, declaring that industry sales figures were profits.

The EFPIA posting says that is worth noting a quote from the author of the Council of Europe report – Member of the European Parliament Paul Flynn (UK, SOC) – on his blog referring to the press conference he gave with the BMJ: “We have never met before but we cooed in harmony and just avoided saying it was the Pharmas that did it.”  This “tells us a great deal about Mr Flynn’s attitude towards the pharmaceutical industry,” the EFPIA commented.

An industry insider told TPL in a personal capacity: “I don’t want to be too critical of BMJ, but [Ms Godlee’s] closeness to Paul Flynn, a severe critic of the industry (and her decision not to check the facts from the primary source) does not reinforce an impression of objectivity on the industry.

The international response to the influenza pandemic: WHO responds to the critics

Pandemic (H1N1) 2009 briefing note 21

출처 : WHO 10 JUNE 2010
http://www.who.int/csr/disease/swineflu/notes/briefing_20100610/en/index.html

Background

10 JUNE 2010 | GENEVA — On Friday 4 June 2010, the BMJ, formerly British Medical Journal, and the Parliamentary Assembly of the Council of Europe (PACE) simultaneously released reports critical of the World Health Organization’s handling of the H1N1 pandemic. WHO takes the issues and concerns that were raised seriously and wishes to set the record straight on several points.

Is this a genuine pandemic?

The outbreaks of infection with the new H1N1 virus, which have been confirmed in virtually every country and territory in the world, differ from seasonal influenza in distinct ways. These differences meet the criteria for an influenza pandemic.

1. The first human infections with the new H1N1 virus were confirmed in April 2009. Analysis of laboratory samples showed that the new virus had never before circulated in humans. This is a virus of animal origin with a unique mix of genes from swine, bird, and human influenza viruses. The genetic composition of this virus is distinctly different from that of the older H1N1 virus that has been causing seasonal epidemics since 1977.

2. As the virus spread, it demonstrated epidemiological patterns not seen during seasonal epidemics of influenza. Widespread, high levels of infection with the new virus occurred during the summer in the northern hemisphere in multiple countries, followed by even higher levels during the fall and winter months. In countries with a temperate climate, seasonal epidemics typically taper off in the spring and end before summer.

3. The pattern of illness and death caused by the H1N1 virus differed in striking ways from that seen during seasonal influenza. During seasonal epidemics, more than 90% of deaths occur in the frail elderly. The H1N1 virus affected a younger age group in all categories: those most frequently infected, those requiring hospitalization, those requiring intensive care, and those dying from their infection.

A frequent cause of death was viral pneumonia, caused directly by the virus and difficult to treat. During seasonal epidemics, most cases of pneumonia are caused by secondary bacterial infections, which usually respond well to antibiotics. While many of those who died had underlying medical conditions associated with a higher risk, many others who died were previously in good health.

4. The new H1N1 virus rapidly crowded out other circulating influenza viruses and appears to have displaced the older H1N1 virus. This phenomenon is distinctly seen during pandemics.

5. Early studies showed that antibodies to H1N1 seasonal influenza did not protect people from infection with the new virus. This finding provided critical evidence that the virus was new to the human immune system. Later studies in some countries determined that around one third of people older than 65 years had some immunity to the virus. Younger people, however, had no such protective immunity.

Did WHO remove severity from the definition of a pandemic?

WHO regards severity as an important feature of pandemics and a critical factor when deciding on which actions to take. However, WHO has not required a set level of severity as part of its criteria for declaring a pandemic. Experience shows that all pandemics cause excess deaths, that severity can change over time, and that severity can vary according to location and population.

WHO has published three definitions of an influenza pandemic in the context of phases of pandemic alert. These definitions were contained in broader guidelines for pandemic preparedness issued in 1999, 2005 and 2009. Research on influenza pandemics and pandemic viruses increased considerably following the first human cases of infection with the H5N1 avian influenza virus in 1997. Definitions changed over time in line with this evolving knowledge and the need to increase the precision and practical applicability of phase definitions.

The 2009 guidelines, including definitions of a pandemic and the phases leading to its declaration, were finalized in February 2009. The new H1N1 virus was neither on the horizon at that time nor mentioned in the document.

The media make frequent reference to a 2003 document, available on the WHO web site, stating that an influenza pandemic results in “enormous numbers of deaths and illness”. At the time, this was considered a likely scenario should the highly lethal H5N1 avian influenza virus develop an ability to spread readily among humans, but it was never a formal definition.

Did WHO exaggerate the threat?

When WHO Director-General Dr Margaret Chan announced the start of the pandemic, on 11 June 2009, she expressed the view that the pandemic would be of moderate severity. She further noted the relatively small number of deaths worldwide, and clearly stated that “we do not expect to see a sudden and dramatic jump in the number of severe or fatal infections.”

In every assessment of the pandemic, WHO consistently reminded the public that the overwhelming majority of patients experienced mild symptoms and made a rapid and full recovery, even without medical treatment.

WHO also noted, early on, that influenza viruses are unstable and can undergo rapid and significant mutations, making it difficult to predict whether the moderate impact would be sustained. This uncertainty, which persuaded WHO and many national health authorities to err on the side of caution, was further enforced by the behaviour of past pandemics, which varied in their severity during first and second waves of international spread.

Were any WHO pandemic decisions made to increase industry profits?

No. Allegations that WHO declared a pandemic to boost the profits of the pharmaceutical industry arise from WHO’s use of expert advisers and the way declarations of interest from these experts are handled. No evidence of any specific instance of wrongdoing has emerged from recent enquiries.

What safeguards are in place to guard against conflicts of interest?

Potential conflicts of interest are inherent in any relationship between a normative and health development agency, like WHO, and profit-driven industry. Advice from top experts is sought by industry as well as by agencies like WHO that need to issue guidance based on the best expertise. Many experts who advise WHO have ties with industry, and these ties can range from funding to conduct research, to paid consultancies, to participation in conferences sponsored by industry.

WHO has systems in place to protect the Organization from advice biased by commercial interests. WHO requires all expert advisers to declare their professional and financial interests when they participate in advisory groups and consultations. WHO assesses declared interests to determine whether a potential conflict or a potential perception of conflict exists. Where necessary, WHO requests more detailed information and then decides on the appropriate action to be taken.

The publication of summaries of relevant interests following meetings is inconsistent and needs to be made routine. WHO further acknowledges that safeguards surrounding engagement with industry need to be tightened, and is doing so.

What is the function of the Emergency Committee and why have the names of its members not been disclosed?

The International Health Regulations (IHR) contain a set of requirements that are legally binding for WHO and the 194 States Parties of the IHR. The IHR call upon the WHO Director-General to convene an Emergency Committee, drawn from a standing roster of IHR experts, to provide WHO with independent guidance during public health emergencies of international concern, such as an influenza pandemic. The IHR came into force in 2007.

The emergence of the new H1N1 virus prompted the first convening of an Emergency Committee under the IHR. At that time, WHO debated whether or not to publicly disclose the names of members, and faced a dilemma. On one hand, the names of members of other advisory groups are made public after they meet; the identification of persons offering guidance adds transparency to their advice and subsequent WHO decisions. On the other hand, experiences during the SARS outbreak demonstrated the considerable economic and social disruption caused by some public health emergencies, meaning that experts could well be lobbied or pressured for commercial or political reasons, potentially compromising the objectivity of their advice.

After considering these issues, WHO decided to apply its usual practice of disclosing the names of experts after an advisory body has completed its work. The members themselves welcomed this decision as a protective measure, and not as an attempt to veil their deliberations and decisions in secrecy. However, given the duration of the pandemic, the Emergency Committee has held a number of meetings over more than a year, rather than a single meeting like most advisory groups, thus delaying even further the release of the names of its members.

WHO is now fully aware that this decision has fostered suspicion that the Committee might be providing guidance shaped by commercial interests or pressures. Names of members and a summary of relevant declarations of interest will be made public when the Committee advises that the pandemic has ended. Procedures for revealing names of members of future Emergency Committees are under review.

What evidence supports a role for antiviral drugs during an influenza pandemic?

Given widespread population vulnerability to infection, an influenza pandemic presents health authorities with a significant challenge in finding ways to protect populations. From the outset, WHO has recommended a wide range of measures, including hand washing, respiratory hygiene, and not travelling or going to work when ill, and has offered advice on the clinical care of patients and the use of antiviral drugs and vaccines.

At the start of the pandemic, data from the Centers for Disease Control and Prevention (USA) showed that the new virus was sensitive to oseltamivir and zanamivir. Prior to the pandemic, WHO had developed guidelines for the treatment of severe influenza infections caused by the avian H5N1 influenza virus. These two factors allowed WHO to rapidly issue guidelines for use of antivirals in the context of H1N1 pandemic influenza, with emphasis on the treatment and prevention of severe illness.

Over the course of the pandemic, an increasing volume of clinical data has been published in peer-reviewed medical journals. These studies confirm that prompt use of antivirals correlates with improved recovery from illness and fewer deaths. Evidence shows that antivirals have been especially effective for treating patients at increased risk of developing complications from H1N1^[1].

Was a WHO meeting held in 2002 on influenza vaccines and antiviral drugs influenced by industry?

In 2002, WHO convened a consultation with experts to develop a document, WHO guidelines on the use of vaccines and antivirals during influenza pandemics, which was published in 2004. Some critics have alleged that certain experts who participated in the meeting and the drafting of the guidelines had ties with industry interpreted as conflicts of interest. In line with WHO policy, all experts who participated in this meeting were required to submit a declaration of interest form and all such forms were duly reviewed by WHO. However, a summary of relevant interests was not issued together with the publication. WHO regrets this oversight.

Since that time, a number of administrative and legal changes have been implemented to strengthen procedures for addressing potential conflicts of interest that might influence the advice provided to WHO. WHO is committed to tightening these procedures further and ensuring their more consistent application.

^[1] See for example: Siston et al. Pandemic 2009 Influenza A(H1N1) virus illness among pregnant women in the United States. Journal of the American Medical Association, 2010, 303: 1517-1525


===============

WHO 사무총장, `신종플루 음모설’ 부인

| 기사입력 2010-06-08 23:05

(제네바=연합뉴스) 맹찬형 특파원 = 세계보건기구(WHO) 마거릿 찬 사무총장은 8일 신종플루 대유행(pandemic)을 처리하는 과정에서 몇몇 과학자들이 제약회사와 부적절한 유착 관계를 맺었다는 의혹을 강하게 부인했다.

찬 사무총장은 이날 브리티시 메디컬 저널(BMJ)에 보낸 서한을 통해 “어떤 경우에도, 단 한 순간도 내가 의사 결정을 하는 데 있어서 상업적 이해관계를 고려한 적은 없었다”고 말했다.

BMJ는 최근 비영리조사단체인 언론조사국(BIJ)과 공동으로 실시한 조사에서 지난 2004년 WHO의 신종플루 관련 가이드라인 작성에 참여한 과학자 세 명이 대형 제약업체들로부터 이전에 돈을 받은 적이 있었다는 내용의 보고서를 유럽의회를 통해 지난 4일 발표했다.

보고서는 WHO 가이드라인의 저자인 프레드 하이든, 아널드 몬토, 칼 니컬슨 등은 타미플루 제조사인 로슈와 레렌자 제조사인 글락소스미스클라인(GSK)으로부터 다른 사안으로 돈을 지급받은 일이 있으며, 신종플루 대유행을 결정한 WHO의 16인 비상위원회 위원 중에서도 지난해 GSK로부터 돈을 받은 사례가 있다고 폭로했다.

이에 대해 찬 사무총장은 비상위원회에 참여한 전문가들의 이름은 상업적 영향으로부터 보호하기 위해 철저하게 비밀에 부쳐지고 있다고 반박했다.

찬 사무총장은 또 WHO가 신종플루에 대해 과장된 공포를 불러일으켰다는 BMJ 등의 지적에 대해, 자신이 신종플루 대유행을 선언할 때 치사율이 낮다는 점을 분명히 밝혔고 그것이 기록에 남아있다는 점을 강조했다.

하지만 WHO 외부 전문가위원회 위원장인 하비 파인버그 미국 국립의학연구소(IOM) 소장은 지난 7일 BJM의 보고서를 환영한다면서 신종플루 대응 실태를 평가하는 데 있어서 보고서의 내용을 충분히 고려할 것이라고 말했다.

외부 전문가위원회의 최종 검토 보고서는 내년 초에 발간될 예정이며, 제약회사 결탁설 등이 사실로 드러날 경우 큰 파장이 일 전망이다.

mangels@yna.co.kr


====================

WHO ‘신종플루 과잉대응’ 내홍

독립기구 국제보건규정검토위원 2명 사임

오애리기자 aeri@munhwa.com | 문화일보 기사 게재 일자 : 2010-06-23 14:20 http://www.munhwa.com/news/view.html?no=20100623010326320710020

세계보건기구(WHO)가 신종 인플루엔자 A(H1N1·신종 플루) 과잉대응 논란 속에 내홍을 겪고 있다.

22일 AP통신은 신종 플루 대응조치의 타당성을 평가하기 위해 구성된 독립기구인 국제보건규정검토위원회(IHRRC)의 29명 위원 중 2명이 WHO와의 밀접한 관계 때문에 사임했다고 보도했다.

하베이 파인버그 IHRRC 위원장은 이날 발표한 성명을 통해 “그동안 위원으로 활동해온 존 매킨지 박사와 앤서니 에번스 박사가 WHO와의 관계 때문에 IHRRC의 독립성을 훼손할 우려를 피하기 위해 자진사퇴 결정을 내렸다”고 발표했다.

호주 커틴대 교수이자 열대질병 전문가인 매킨지와 국제민간항공기구(ICAO) 의료팀 책임자인 에번스 박사는 지난해 신종 플루가 전세계를 휩쓸었을 당시, WHO의 자문기구인 비상위원회 위원장과 위원으로 각각 활동하면서 가이드라인을 만드는 데 중요한 역할을 했던 인물들이다.

지난 1월 마거릿 챈 WHO 사무총장의 제안에 따라 구성된 IHRRC에 이들이 포함된 것을 두고 전문가들은 “WHO의 대응과정에 대한 객관적 평가가 어려워 면죄부를 줄 가능성이 높다”며 비난해왔다.

최근 영국의 권위있는 의학전문지 브리티시 메디컬 저널(BMJ)은 신종 플루 대처 가이드라인 작성에 관여한 WHO 전문가들 중 일부가 제약사로부터 보수를 받는 등 이해관계에 연루됐던 사실을 폭로해 파장을 일으켰다.

이들이 의약품과 백신의 대량구매를 촉구하는 WHO 권고안에 영향을 주어, 연관된 제약사의 이익을 추가시켰을 가능성이 있다는 것이다. 이에 대해 챈 사무총장은 “WHO 의사결정에 상업적 이해관계가 절대 개입될 수 없다”는 입장을 고수해오고 있다. IHRRC는 내년초쯤 신종 플루에 관한 보고서를 발표할 예정이다.

오애리 선임기자 aeri@munhwa.com

=================

WHO 사무총장, `신종플루 음모설` 없다

출처 :매일경제 2010.06.09 08:59:35 입력 http://news.mk.co.kr/outside/view.php?year=2010&no=296413

세계보건기구(WHO) 마거릿 찬 사무총장은 8일 신종플루 대유행(pandemic)을 처리하는 과정에서 몇몇 과학자들이 제약회사와 부적절한 유착 관계를 맺었다는 의혹을 강하게 부인했다. 찬 사무총장은 이날 브리티시 메디컬 저널(BMJ)에 보낸 서한을 통해 “어떤 경우에도, 단 한 순간도 내가 의사 결정을 하는 데 있어서 상업적 이해관계를 고려한 적은 없었다”고 말했다. BMJ는 최근 비영리조사단체인 언론조사국(BIJ)과 공동으로 실시한 조사에서 지난 2004년 WHO의 신종플루 관련 가이드라인 작성에 참여한 과학자 세 명이 대형 제약업체들로부터 이전에 돈을 받은 적이 있었다는 내용의 보고서를 유럽의회를 통해 지난 4일 발표했다. 보고서는 WHO 가이드라인의 저자인 프레드 하이든, 아널드 몬토, 칼 니컬슨 등은 타미플루 제조사인 로슈와 레렌자 제조사인 글락소스미스클라인(GSK)으로부터 다른 사안으로 돈을 지급받은 일이 있으며, 신종플루 대유행을 결정한 WHO의 16인 비상위원회 위원 중에서도 지난해 GSK로부터 돈을 받은 사례가 있다고 폭로했다. 이에 대해 찬 사무총장은 비상위원회에 참여한 전문가들의 이름은 상업적 영향으로부터 보호하기 위해 철저하게 비밀에 부쳐지고 있다고 반박했다. 찬 사무총장은 또 WHO가 신종플루에 대해 과장된 공포를 불러일으켰다는 BMJ 등의 지적에 대해, 자신이 신종플루 대유행을 선언할 때 치사율이 낮다는 점을 분명히 밝혔고 그것이 기록에 남아있다는 점을 강조했다. [뉴스속보부]

Published 3 June 2010, doi:10.1136/bmj.c2912
Cite this as: BMJ 2010;340:c2912
http://www.bmj.com/cgi/content/full/340/jun03_4/c2912

Feature

Conflicts of Interest

WHO and the pandemic flu “conspiracies”

Key scientists advising the World Health Organization on planning for an influenza pandemic had done paid work for pharmaceutical firms that stood to gain from the guidance they were preparing. These conflicts of interest have never been publicly disclosed by WHO, and WHO has dismissed inquiries into its handling of the A/H1N1 pandemic as “conspiracy theories.” Deborah Cohen and Philip Carter investigate

It was the culmination of 10 years of pandemic preparedness planning for WHO—years of committee meetings with experts flown in from around the world and reams of draft documents offering guidance to governments. But one year on, governments that took advice from WHO are unwinding their vaccine contracts, and billions of dollars’ worth of stockpiled oseltamivir (Tamiflu) and zanamivir (Relenza)—bought from health budgets already under tight constraints—lie unused in warehouses around the world.

A joint investigation by the BMJ and the Bureau of Investigative Journalism has uncovered evidence that raises troubling questions about how WHO managed conflicts of interest among the scientists who advised its pandemic planning, and about the transparency of the science underlying its advice to governments. Was it appropriate for WHO to take advice from experts who had declarable financial and research ties with pharmaceutical companies producing antivirals and influenza vaccines? Why was key WHO guidance authored by an influenza expert who had received payment for other work from Roche, manufacturers of oseltamivir, and GlaxoSmithKline, manufacturers of zanamivir? And why does the composition of the emergency committee from which Chan sought guidance remain a secret known only to those within WHO? We are left wondering whether major public health organisations are able to effectively manage the conflicts of interest that are inherent in medical science.

Already WHO’s handling of the pandemic has led to an unprecedented number of reviews and inquiries by organisations including the Council of Europe, European Parliament, and WHO itself, following allegations of industry influence. Dr Chan has dismissed these as “conspiracies,” and earlier this year, during a speech at the Centers for Disease Control and Prevention in Atlanta, she said: “WHO anticipated close scrutiny of its decisions, but we did not anticipate that we would be accused, by some European politicians, of having declared a fake pandemic on the advice of experts with ties to the pharmaceutical industry and something personal to gain from increased industry profits.”

The inquiry by British MP Paul Flynn for the Council of Europe Parliamentary Assembly—due to be published today—will be critical. It will say that decision making around the A/H1N1 crisis has been lacking in transparency. “Some of the outcomes of the pandemic, as illustrated in this report, have been dramatic: distortion of priorities of public health services all over Europe, waste of huge sums of public money, provocation of unjustified fear amongst Europeans, creation of health risks through vaccines and medications which might not have been sufficiently tested before being authorised in fast-track procedures, are all examples of these outcomes. These results need to be critically examined by public health authorities at all levels with a view to rebuilding public confidence in their decisions.”

The investigation by the BMJ/The Bureau reveals a system struggling to manage the inherent conflict between the pharmaceutical industry, WHO, and the global public health system, which all draw on the same pool of scientific experts. Our investigation has identified key scientists involved in WHO pandemic planning who had declarable interests, some of whom are or have been funded by pharmaceutical firms that stood to gain from the guidance they were drafting. Yet these interests have never been publicly disclosed by WHO and, despite repeated requests from the BMJ/The Bureau, WHO has failed to provide any details about whether such conflicts were declared by the relevant experts and what, if anything, was done about them.

It is this lack of transparency over conflicts of interests—coupled with a documented changing of the definition of a pandemic and unanswered questions over the evidence base for therapeutic interventions¹—that has led to the emergence of these conspiracies.

WHO says: “Potential conflicts of interest are inherent in any relationship between a normative and health development agency, like WHO, and a profit-driven industry. Similar considerations apply when experts advising the Organization have professional links with pharmaceutical companies. Numerous safeguards are in place to manage possible conflicts of interest or their perception.”

Another factor that has fuelled the conspiracy theories is the manner in which risk has been communicated. No one disputes the difficulty of communicating an uncertain situation or the concept of risk in a pandemic situation. But one world expert in risk communication, Gerd Gigerenzer, director of the Centre for Adaptive Behaviour and Cognition at the Max Planck Institute in Germany, told the BMJ/The Bureau: “The problem is not so much that communicating uncertainty is difficult, but that uncertainty was not communicated. There was no scientific basis for the WHO’s estimate of 2 billion for likely H1N1 cases, and we knew little about the benefits and harms of the vaccination. The WHO maintained this 2 billion estimate even after the winter season in Australia and New Zealand showed that only about one to two out of 1000 people were infected. Last but not least, it changed the very definition of a pandemic.”

WHO for years had defined pandemics as outbreaks causing “enormous numbers of deaths and illness” but in early May 2009 it removed this phrase—describing a measure of severity—from the definition.²

The beginnings

The routes to the Council of Europe’s criticisms can be traced back to 1999, a pivotal year in the influenza world. In April that year WHO—spurred on by the 1997 chicken flu outbreak in Hong Kong—began to organise itself for a feared pandemic. It drew up a key document, Influenza Pandemic Plan: The Role of WHO and Guidelines for National and Regional Planning.

WHO’s first influenza pandemic preparedness plan was stark in the scale of the risk the world faced in 1999: “It is impossible to anticipate when a pandemic might occur. Should a true influenza pandemic virus again appear that behaved as in 1918, even taking into account the advances in medicine since then, unparalleled tolls of illness and death would be expected.”

In the small print of that document it states: “R Snacken, J Wood, L R Haaheim, A P Kendal, G J Ligthart, and D Lavanchy prepared this document for the World Health Organization (WHO), in collaboration with the European Scientific Working Group on Influenza (ESWI).” What this document does not disclose is that ESWI is funded entirely by Roche and other influenza drug manufacturers. Nor does it disclose that René Snacken and Daniel Lavanchy were participating in Roche sponsored events the previous year, according to marketing material seen by the BMJ/The Bureau.

Dr Snacken was working for the Belgian ministry of public health when he wrote about studies involving neuraminidase inhibitors for a Roche promotional booklet. And Dr Lavanchy, meanwhile, was a WHO employee when he appeared at a Roche sponsored symposium in 1998. His role at that time was in the WHO Division of Viral Diseases. Dr Lavanchy has declined to comment.

In 1999 other members of the European Scientific Working Group on Influenza included Professor Karl Nicholson of Leicester University, UK, and Professor Abe Osterhaus of Erasmus University in the Netherlands. These two scientists are also identified in Roche marketing material seen by this investigation which was produced between 1998 and 2000. Professor Osterhaus told the BMJ that he had always been transparent about any work he has done with industry. Professor Nicholson similarly has consistently declared his connections with pharmaceutical companies, for example, in papers published in journals such as the BMJ and Lancet.

Both experts were also at that time engaged in a randomised controlled trial on oseltamivir supported by Roche. The trial was subsequently published in the Lancet in 2000.³ It remains one of the main studies supporting oseltamivir’s effectiveness—and one that was subsequently shown to have employed undeclared industry funded ghostwriters.¹

The influence of the European Scientific Working Group on Influenza would continue as the decade wore on and the calls for pandemic planning became more strident. Founded in 1992, this “multidisciplinary group of key opinion leaders in influenza aims to combat the impact of epidemic and pandemic influenza” and claims links to WHO, the Robert Koch Institute, and the European Centre for Disease Prevention and Control, among others.⁴ Despite the group’s claims of scientific independence its 100% industry funding does present a potential conflict of interest. One if its roles is to lobby politicians, as highlighted in a 2009 policy document.⁵

At a pre-pandemic preparation workshop of the European Scientific Working Group on Influenza in January last year, Professor Osterhaus said: “I can tell you that ESWI is working on that idea [that is, convincing politicians] quite intensively. We have contact with MEPs [members of the European Parliament] and with national politicians. But it is they who have to decide at the end of the day, and they will only act at the request of their constituencies. If the latter are not prompted, nothing will happen.”

The group’s policy plan for 2006-10 specifically stated that government representatives needed to “take measures to encourage the pharmaceutical industry to plan its vaccine/antivirals production capacity in advance” and also to “encourage and support research and development of pandemic vaccine” and to “develop a policy for antiviral stockpiling.” It also added that government representatives needed to know that “influenza vaccination and use of antivirals is beneficial and safe.” It said that the group provided “evidence based, palatable information”; and also “networking/exchange with other stakeholders (eg, with industry in order to establish pandemic vaccine and antivirals contracts).” In the meantime, in Roche’s own marketing plan, one goal was to “align Roche with credible third party advocates”. They “leveraged these relationships by enlisting our third-party partners to serve as spokespeople and increase awareness of Tamiflu and its benefits.”⁶

Barbara Mintzes, assistant professor in the Department of Pharmacology and Therapeutics at the University of British Columbia, is currently part of a group working with Health Action International and WHO developing model curricula for medical and pharmaceutical students on drug promotion and interactions with the industry, including conflicts of interest. She thinks that caution is advised when working with medical bodies of this sort.

“It is legitimate for WHO to work with industry at times. But I would have concerns about involvement with a group that looks like it is for independent academics that is actually mainly industry funded,” she told the BMJ/The Bureau, adding: “The Institute of Medicine has raised concerns about the need to have a firewall with medical groups. To me this does not sound like an independent group, as it is mainly funded by manufacturers.”

She also thinks that there is a difference between the conflict of interest in having a clinical trial funded by a company and the conflict of interest in being involved in marketing a drug—for example, on a paid speaker’s bureau or in marketing material. “Some academic medical departments, for example Stanford University, have banned staff from being involved in marketing or being on a paid speakers bureau,” she said.

The presence of leading influenza scientists at promotional events for oseltamivir reflected not just the concern of an impending pandemic, but the excitement over the potential of a new class of drugs—neuraminidase inhibitors—to offer treatment and protection against seasonal influenza.

In 1999 two new drugs first came to market: oseltamivir, from Roche; and zanamivir, manufactured by what is now GlaxoSmithKline. The two drugs would battle it out over the coming years, with oseltamivir—aided by its oral administration—trumping its rival in global sales as the decade wore on.

The potential was quickly grasped. Indeed, that year Professor Osterhaus published an article proposing the use of neuraminidase inhibitors in pandemics: “Finally, during a possible future influenza pandemic, in view of their broad reactivity against influenza virus neuraminidase subtypes and the expected lack of sufficient quantities of vaccine, the new antivirals will undoubtedly have an essential role to play in reducing the number of victims.”⁷

However, he also warned that antivirals should not be seen as a replacement for vaccinations. “Close collaboration and consultation between, on the one hand, companies marketing influenza vaccines and, on the other, those marketing antivirals will therefore be absolutely essential. It is important that a clear and uniform message indicating the complementary roles of vaccines and antivirals is delivered.”

That article appeared in the European Scientific Working Group on Influenza’s bulletin of April 1999; Professor Osterhaus signs off with the affiliation of WHO National Influenza Centre Rotterdam, The Netherlands.

Other experts soon followed suit—recommending the role neuraminidase inhibitors could play in any future pandemic—in both the academic literature and in the general media.

Food and Drug Administration

While the excitement over these drugs fuelled scientific symposiums, the US Food and Drug Administration (FDA) was less than convinced. The BMJ/The Bureau has since spoken to people from within the American and European drug regulators, the FDA and the European Medicines Agency (EMEA), who said that both regulators struggled with the paucity of the data presented to them for zanamivir and oseltamivir, respectively, during the licensing process. At the end of last year, the BMJ called for access to raw data for key public health drugs after the Cochrane Collaboration found the effectiveness of the drugs impossible to evaluate.⁸ The group are continuing to negotiate access to what they say they need to fully assess the effectiveness of antivirals.

In the US, the FDA first approved zanamivir in 1999.⁹ Michael Elashoff, a former employee of the FDA, was the statistician working on the zanamivir account. He told the BMJ how the FDA advisory committee initially rejected zanamivir because the drug lacked efficacy.

After Dr Elashoff’s review (he had access to individual patient data and summary study reports) the FDA’s advisory committee voted by 13 to 4 not to approve zanamivir on the grounds that it was no more effective than placebo when the patients were on other drugs such as paracetamol. He said that it didn’t reduce symptoms even by a day.

“When I was reviewing the data, I tried to replicate the analyses in their summary study reports. The issue was not of data quality, but sensitivity analyses showed even less efficacy,” he said. “The safety analysis showed there were safety concerns, but the focus was on if Glaxo had demonstrated efficacy.” Dr Elashoff’s view was that zanamivir was no better than placebo—and it had side effects. And when the FDA medical reviewer made a presentation, her conclusion was that it could either be approved or not approved. It was a fairly borderline drug.

There were influenza experts on the FDA’s advisory committee and much of the discussion hinged on why a drug that looked so promising in earlier studies wasn’t working in the largest trials in the US. One hypothesis was that people in the US were taking other drugs for symptomatic relief that masked any effect of zanamivir. So zanamivir might have no impact on symptoms over and above the baseline medications that people take when they have influenza.

Two other trials—one in Europe and one in Australia— showed a bit more promise. But there was a very low rate of people taking other medications. “So in the context of not being allowed to take anything for symptomatic relief, there might be some effect of Relenza. But in the context of a typical flu, where you have to take other things to manage your symptoms, you wouldn’t notice any effect of Relenza over and above those other things,” Dr Elashoff said. The advisory committee recommended that the drug should not be approved.

Nevertheless, FDA management decided to overturn the committee’s recommendation.

“They would feel better if there was something on the market in case of a pandemic. It wasn’t a scientific decision,” Dr Elashoff said.

While Dr Elashoff was working on the zanamivir review, he was assigned the oseltamivir application. But when the review and the advisory committee decided not to recommend zanamivir, the FDA’s management reassigned the oseltamivir review to someone else. Dr Elashoff believes that the approval of zanamivir paved the way for oseltamivir, which was approved by the FDA later that year.

European Medicines Agency

In Europe the EMEA was similarly troubled by the evidence for oseltamivir. By early 2002 Roche had sought a European Union-wide licence from the EMEA. It was a lengthy process, taking three meetings of the Committee for Medicinal Products for Human Use as well as expert panels, according to one of the two rapporteurs, Pekka Kurki of the Finnish Medicines Agency. Echoing the Cochrane Collaborations’s 2009 findings⁶ Kurki told us: “We discussed the same issues that are still discussed today: does it show clinically significant benefits in treatment and prophylaxis of flu and what was the magnitude of the benefits presented in the RCTs? Our assessment and Cochrane’s in 2009 are very similar with regard to the effect size in RCTs. The data show that the effects of Tamiflu were clear but not very impressive.

“What was unclear and is still unclear is what is the impact of Tamiflu on serious complications. Circulating influenza was very mild when Tamiflu was developed and therefore it is very difficult to say anything about serious complications. The data did not clearly show an effect on serious complications—it was not demonstrated by the RCTs.”

In documents obtained under the freedom of information legislation, two of the experts who provided opinions during the EMEA licensing process have also featured in Roche marketing material: Annike Linde and Rene Snacken. In Dr Snacken’s EMEA presentation dated 18 February 2002, he discussed the need for chemoprophylaxis and called for the use of oseltamivir during a pandemic. He made his presentation as a representative of the Belgian Ministry of Public Health. At the time Dr Snacken was also “liaison officer” for the European Scientific Working Group on Influenza. He also played a key role in the Belgian government during its pandemic planning, and he later became a senior expert at the Preparedness and Response Unit, European Centre for Disease Prevention and Control. We do not know what, if anything, he declared to the EMEA about his relationship with Roche.

Annike Linde has confirmed in an email that she has had connections with Roche over a number of years. She made a presentation to the EMEA on “influenza surveillance” in her capacity as a representative of the Swedish Institute for Infectious Disease. Again, it is not clear what, if anything, she declared to the EMEA concerning her previous relationship with Roche.

Dr Linde, now the Swedish state epidemiologist, has told the BMJ/The Bureau that she received payments from Roche International in respect of various pieces of work she did for the company until 2002. She has subsequently given occasional lectures for Roche Sweden. All money she has received from Roche was given, Dr Linde says, to the Swedish Institute for Infectious Disease Control.

We asked the scientists whether they declared their relationship with Roche at the time to the EMEA. Neither has answered that question entirely satisfactorily. Dr Snacken has not replied to repeated emails posing this question. Dr Linde responded by telling the BMJ/The Bureau: “We contribute with our expertise to the regulatory agencies when asked. When we do so, a declaration of interest, where e.g. participation at advisory meetings at Roche, is given and evaluated by the regulatory agency.” The BMJ/The Bureau requested Linde and Snacken’s declaration of interest statements for the 2002 meeting from the EMEA under the freedom of information act. The EMEA was unable to provide statements for those particular people at that time.

Developing the guidelines

In October 2002 WHO convened a meeting of influenza experts at its Geneva headquarters. Their purpose was to develop WHO’s guidelines for the use of vaccines and antivirals during an influenza pandemic.

Included at this meeting were representatives from Roche and Aventis Pasteur and three experts who had lent their name to oseltamivir’s marketing material (Professors Karl Nicholson, Ab Osterhaus, and Fred Hayden).

Two years later the WHO published a key report from that meeting, WHO Guidelines on the Use of Vaccines and Antivirals during Influenza Pandemics 2004. The specific guidance on antivirals, Considerations for the Use of Antivirals During an Influenza Pandemic, was written by Fred Hayden. Professor Hayden has confirmed to the BMJ/The Bureau in an email that he was being paid by Roche for lectures and consultancy work for the company at the time the guidance was produced and published. He also told us in an email that he had received payments from GlaxoSmithKline for consultancy and lecturing until 2002. According to Prof Hayden: “DOI [declaration of interest] forms were filled out for the 2002 consultation.”

The WHO guidance concluded that: “Based on their pandemic response goals and resources, countries should consider developing plans for ensuring the availability of antivirals. Countries that are considering the use of antivirals as part of their pandemic response will need to stockpile in advance, given that current supplies are very limited.” Many countries around the world would adopt this guidance.

The previous year Professor Hayden was also one of the main authors of a Roche sponsored study that claimed what was to become one of oseltamivir’s main selling points—a claimed 60% reduction in hospitalisations from flu, which the Cochrane Collaboration was later unable to verify.⁸

Our investigation has also identified relevant and declarable interests relating to the two other named authors of annexes to WHO’s 2004 guidelines. Arnold Monto was the author of the annexe dealing with vaccine usage in pandemics. Between 2000 and 2004—and at the time of writing the annexe—Dr Monto has consistently and openly declared honorariums, consultancy fees, and research support from Roche, ^{10 11 12} consultancy fees and research support from GlaxoSmithKline ^{10 12 13 14}; and also research funding from ViroPharma.¹⁵

No conflict of interest statement was included in the annex he wrote for WHO. When asked if he had signed a declaration of interest form for WHO, Dr Monto told the BMJ/The Bureau: “Conflict of Interest forms are requested before participation in any WHO meeting”.

Professor Karl Nicholson is the author of the third annex, Pandemic Influenza. According to declarations made by Professor Nicholson in the BMJ¹⁶and Lancet in 2003,¹⁷ he had received travel sponsorship and honorariums from GlaxoSmithKline and Roche for consultancy work and speaking at international respiratory and infectious diseases symposiums. Before writing the annexe, he had also been paid and declared ad hoc consultancy fees by Wyeth, Chiron, and Berna Biotech.

Even though the previous year these declarations had been openly made in the Lancet and the BMJ, no conflict of interest statement was included in the annex he wrote for WHO. Professor Nicholson told the BMJ/The Bureau that he last had “financial relations” with Roche in 2001. When asked if he had signed a declaration of interest form for WHO, Prof Nicholson replied: “The WHO does require attendees of meetings, such as those held in 2002 and 2004, to complete declarations of interest.”

Leaving aside the question of what declarations experts made to WHO, one simple fact remains: WHO itself did not publicly disclose any of these conflicts of interest when it published the 2004 guidance. It is not known whether information about these conflicts of interest was relayed privately to governments around the world when they were considering the advice contained in the guidelines.

The year before WHO issued the 2004 guidance, it published a set of rules on how WHO guidelines should be developed and how any conflicts of interest should be handled. This guidance included recommendations that people who had a conflict of interest should not take part in the discussion or the piece of work affected by that interest or, in certain circumstances, that the person with the conflict should not participate in the relevant discussion or work at all. The WHO rules make provision for the director general’s office to allow declarations of interest to be seen if the objectivity of a meeting has been called into question.¹⁸

The BMJ/The Bureau has asked WHO for the conflict of interest declarations for the Geneva 2002 meeting and those related to the guidance document itself. WHO told us that the query went directly up to Margaret Chan’s office. “WHO never publishes individual DOIs [declaration of interest], except after consultation with the Office of the Director-General. In this case, we put in a request on your behalf but it was not granted. In more recent years, many WHO committees have published summaries of relevant interests with their meeting reports.”

In a BMJ interview (see film on bmj.com), WHO spokesperson Gregory Hartl reiterated the fact that Dr Margaret Chan, “is very committed personally to transparency.” Yet her office has turned down repeated requests for declaration of interest statements and declines to comment on the allegations that authors of the guidelines had declarable interests.

Nevertheless, Prof Hayden told the BMJ/The Bureau: “I strongly support transparency in declarations of interest, in part because this allows those reading documents, particularly ones authored by specific individuals (eg, Annex 5) [the part he wrote], to make their own judgments about the possible relevance of any potential conflicts.”

While experts need to work with industry to develop the best possible drugs for illnesses, questions remain about what level of involvement experts with industry ties should have in the formulation of public health policy decisions and guidelines. Professor Nicholson told the BMJ/The Bureau: “The WHO and decision makers must be informed of ongoing developments and research findings to ensure that they are as up to date as possible. Some of the most relevant expertise and information are held by companies or individuals with conflicts of interest. I understand the view that experts with conflicts of interest should not advise governments or organisations such as the WHO. But to exclude such people from discussions could deprive WHO and decision makers of important new information.”

But not everyone agrees. Barbara Mintzes is unequivocal about what role they should play. “No one should be on a committee developing guidelines if they have links to companies that either produce a product—vaccine or drug—or a medical device or test for a disease. It would be preferable that there are no financial ties when it comes to making big decisions on public health—for example, stockpiling a drug—and that includes if they have a currently funded clinical trial,” she said.

“Ideally, what you want are independent experts who are in the public sector to provide expertise on drugs and vaccines. But they can be hard to find. One solution is consult with the experts who are involved in industry, but not put them on any decision making committee. You need a firewall,” she added.

Indeed, Professor Harvey Fineberg, president of the Institute of Medicine and chairman of the panel reviewing WHO’s management of the pandemic, takes a similarly hard line. His own institution went through a detailed review of how they interact with industry and experts with conflicts of interests last year.¹⁹ “Sometimes publication of conflict of interests is enough—for example with a journal. But if you are giving expert judgment to influence policy, revealing is not enough,” he told the BMJ, referring to the Institute of Medicine’s policy.

WHO also says that it takes conflicts of interests seriously and has the mechanisms in place to deal with them. But what action does it take when a scientist declares a conflict of interest, and when does it judge a scientist to be too conflicted to play a leading role in the formulation of global health policy? Since WHO has not provided us with an answer to this question, we are left to guess.

As it stands, this situation is the worst possible outcome for WHO, according to Professor Chris Del Mar, a Cochrane Review author and expert on WHO’s Strategic Advisory Group of Experts on Immunization group. “If it proves to be the case that authors of WHO guidance which promoted the use of certain drugs were being paid at the same time by the makers of those drugs for other work they were doing for these companies that is reprehensible and should be condemned in the strongest possible terms.”

WHO’s endorsement of oseltamivir was not lost on Roche. In an advert placed by the company for the drug in the main conference programme of the European Scientific Working Group on Influenza’s 2005 conference in Malta, it says: “Antivirals will initially be the principal medical intervention in a pandemic situation and Roche is working as a responsible partner with governments to assist in their pandemic planning.” The source reference for this is the WHO Global Influenza Preparedness Plan.

Throughout the following years, WHO would appear to have been inconsistent in how it treated conflicts of interest. Updated pandemic plans would continue to be prepared by experts who openly had work funded and acted as consultants to manufacturers of vaccines and antivirals. WHO produced its global influenza preparedness plan in 2005, and in 2006 it constituted an interim Influenza Pandemic Task Force. No public declarations of interest have been made and to date no details have been provided by WHO in response to our requests.

WHO’s stance that it does not publish declarations of interest from its experts is far from consistent. It is undermined, for example, by the position WHO adopts in relation to the Strategic Advisory Group of Experts on Immunization, its standing vaccine advisory body. Here, contrary to its approach to pandemic planning advisers, WHO does publish summaries of declarations of interest.

Emergency Committee

These seeming inconsistencies in WHO’s approach to transparency and its handling of conflicts of interest extend into the workings of the Emergency Committee formed last year to advise the director general on the pandemic. The identities of its 16 members are unknown outside WHO. This secret committee has guided WHO pandemic policy since then—including deciding when to judge that the pandemic is over.

WHO says it has to keep the identities secret to protect the scientists from being influenced or targeted by industry. In a phone call to the BMJ/The Bureau in March, WHO spokesperson Gregory Hartl explained: “Our general principle is we want to protect the committee from outside influences.”

The committee advised the WHO director general on phase changes as well as temporary recommendations. According to WHO, When the Emergency Committee met to discuss a possible move to a declaration of a pandemic, the meeting additionally included members who represented Australia, Canada, Chile, Japan, Mexico, Spain, the UK, and the US, eight countries that experienced widespread outbreaks at the time. These national representatives were present to ensure full consideration of the views and possible reservations of the countries expected to bear the initial brunt of economic and social repercussions.

WHO says all members of the Emergency Committee sign a confidentiality agreement, provide a declaration of interests, and agree to give their consultative time freely, without compensation. However, only one member of the committee has been publicly named: Professor John MacKenzie, who chairs it.

This is a troubling stance: it suggests that WHO considers other advisory groups whose members are not anonymous —such as the Strategic Advisory Group of Experts on Immunization—to be potentially subject to outside influences, and it allows no scrutiny of the scientists selected to advise WHO and global governments on a major public health emergency.

Under the International Health Regulations framework, the membership of the Emergency Committee is drawn from a roster of about 160 experts covering a range of public health areas. This framework provides guidelines about how WHO deals with acute public health risks. The BMJ/The Bureau has identified approximately 15 scientists from the International Health Regulations roster with influenza expertise and has emailed them to ask if they were on the Emergency Committee. Under the framework at least some of these scientists are members of the Emergency Committee. Yet because of the confidentiality agreements they have signed, these scientists cannot acknowledge their membership of the committee, putting them in an invidious position.

David Salisbury, chair of WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) committee at the time of the pandemic and a member of the International Health Regulations, says the secrecy has caused problems for his group. “It certainly caused problems for SAGE. Since all of the details of SAGE are in the public domain, there was a perception that it had been SAGE that had given advice about the changing of definitions or the pandemic levels—when we had not done so. SAGE members came in for unfair personal abuse by journalists,” he told the BMJ/The Bureau.

“Given the importance of the advice, the transparency of the source of the advice was important. I believe it is necessary to keep confidential the source of advice if revealing details might put individuals at risk, for example when bioterrorism is being discussed. This does not seem to be the case for pandemic flu,” he added.

The secrecy of the committee is also fuelling conspiracy theories, particularly around the activation of dormant pandemic vaccine contracts. A key question will be whether the pharmaceutical companies, which had invested around $4bn (£2.8bn, 3.3bn) in developing the swine flu vaccine, had supporters inside the emergency committee, who then put pressure on WHO to declare a pandemic. It was the declaring of the pandemic that triggered the contracts.

The BMJ/The Bureau can confirm that Dr Monto, Dr John Wood, and Dr Masato Tashiro are members of the Emergency Committee.

Although Dr Monto did not answer the question directly, his Infectious Disease Society of America biography states that he is a member.²⁰

Last year, according to figures made public in the US by GlaxoSmithKline, Professor Monto received $3000 speakers fees from the company in the period between the second quarter and the last quarter of 2009. As a national official of the Japanese government, Dr Tashiro says that he must “have nothing concerning conflict of interest with private companies”. Dr John Wood works for the UK National Institute for Biological Standards and Control (NIBSC). Dr Wood, like Dr Tashiro, has no personal conflict of interests but he told the BMJ/The Bureau that as part of its statutory role in developing standards for measurement of biological medicines to ensure accurate dosing and carrying out independent control testing to assure their safety and efficacy, the institute must work closely with the pharmaceutical industry. This is made clear on their website.

“The International Federation of Pharmaceutical Manufacturers and Associations has also made publicly available the nature of their close interaction with NIBSC and similar organisations in order to develop influenza vaccines,” he said.²¹

Those who said that they were not on the committee include David Salisbury, Alan Hampson, Albert Osterhaus, Donato Greco, and Howard Njoo. Maria Zambon, from the UK’s Health Protection Agency told the BMJ: “I undertake various advisory roles to WHO. Declaration of interest statements are prepared before undertaking such roles.

“The HPA Centre for Infection, as part of its role in national infectious disease surveillance, provision of specialist and reference microbiology and vaccine efficacy monitoring, works closely with vaccine manufacturers and biotechnology companies.”

International Health Regulations review

WHO’s own review into the operation of the International Health Regulations and WHO’s handling of the pandemic is now being conducted by Harvey Feinberg, president of the US Institute of Medicine, and will report its findings next year. Dr Chan and Professor Feinberg have both made clear the need for a thorough investigation. But questions are already arising about how independent the review will turn out to be. According to the International Health Regulations list in our possession, some 13 of the 29 members of the review panel are members of the International Health Regulations itself and one is the chair of the Emergency Committee. To critics that might suggest a somewhat incestuous approach.

Professor Mintzes does not agree with WHO’s explanation that secrecy was needed to protect against the influence of outside interest on decision making. “I can’t understand why the WHO kept this secret. It should be public in terms of accountability like the expert advisory committees. If the rationale of secret membership is not to be unduly influenced, there are other ways of dealing with this through strong conflict of interest provisions,” she said.

She also believes that the very nature of allowing a trigger point for vaccine contracts opens the system up unnecessarily to exploitation. “It seems a problem that this declaration might trigger contracts to be realised. There should be safeguards in place to make sure those with an interest in vaccine manufacturers can’t exploit the situation. The WHO will have to look long and hard at this in future,” she said.

The number of victims of H1N1 fell far short of even the more conservative predictions by the WHO. It could, of course, have been far worse.. Planning for the worst while hoping for the best remains a sensible approach. But our investigation has revealed damaging issues. If these are not addressed, H1N1 may yet claim its biggest victim—the credibility of the WHO and the trust in the global public health system.

Cite this as: BMJ 2010;340:c2912

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