BMC Public Health Border malaria in China: knowledge and use of personal protection by minority populations and implications for malaria control: a questionnaire-based survey

Sarah J Moore
Public Health Entomology
Ifakara Health Institute
IfakaraTanzania

School of Biological and Biomedical Sciences
Durham University
DurhamUK

Xia Min
Simao Institute of Parasitic Disease Control
SimaoPR China

Nigel Hill firstname.lastname@example.com
Caroline Jones firstname.lastname@example.com
Zhang Zaixing
Simao Institute of Parasitic Disease Control
SimaoPR China

Mary M Cameron

School of Hygiene and Tropical Medicine
Address: 1 DCVBULondon, LondonUK

BMC Public Health Border malaria in China: knowledge and use of personal protection by minority populations and implications for malaria control: a questionnaire-based survey
10.1186/1471-2458-8-344BioMed Central Page 1 of 8 (page number not for citation purposes) Research article
Background: Malaria control in remote, forested areas of the Mekong region relies on personal protection from mosquito bites. Uptake of these methods may be limited by knowledge of the link between mosquitoes and malaria as well as social and economic aspects. Understanding barriers to uptake will inform malaria control programmes on targets for improvement of delivery.Methods:A total 748 key respondents: health providers and village heads, from 187 villages and 25 different ethnic groups, were interviewed using structured questionnaires. Differences in use of personal protection, and knowledge of malaria between groups were analysed using chi-square; and binary logistic regression used for multivariate analysis.Results: Malaria knowledge was poor with 19.4% of women and 37.5% of men linking mosquitoes with malaria, although 95.6% knew one or more methods of mosquito control. Virtually all respondents used personal protection at some time during the year; and understanding of malaria transmission was strongly associated with bednet use. Those working in forest agriculture were significantly more likely to know that mosquitoes transmit malaria but this did not translate into a significantly greater likelihood of using bednets. Furthermore, use of personal protection while woing outdoors was rare, and less than 3% of respondents knew about the insecticide impregnation of bednets. The use of bednets, synthetic repellents and mosquito coils varied between ethnic groups, but was significantly more frequent among those with higher income, more years of education and permanent housing. The reported use of repellents and coils was also more common among women despite their low knowledge of malaria transmission, and low likelihood of having heard information on malaria within the last year.Conclusion:The use of personal protection must be increased, particularly among outdoor workers that have higher malaria risk. However, personal protection is widely used and widely accepted to prevent nuisance biting mosquitoes, with the major barrier to use being affordability. Therefore, social marketing campaigns aimed at women and those that work outdoors that provide highly subsidised products, especially insecticide impregnation kits for bednets and hammock nets are most likely to succeed in lowering malaria morbidity among non Han-Chinese groups in rural China.

Background

Despite the very significant regional decline in reported malaria cases and deaths due to Malaria in the Greater Mekong sub-region during the 1990s, the disease remains an important public health problem in six countries of the Region [1]. In the six endemic Asian countries, Cambodia, China (Yunnan Province), the Lao People's Democratic Republic, Malaysia, the Philippines and Vietnam, most malaria cases occur in remote forested and hilly areas where mosquito vectors are abundant and health services are frequently inadequate. It is estimated that 36% of the population of the Greater Mekong Sub region reside in these areas without adequate vector control [2]. Malaria prevalence is highest among ethnic minorities, migrants and forest workers, with the most vulnerable members of the population being pregnant women, the very poor and the malnourished [3].

The current study investigates knowledge of malaria prevention and use of personal protection measure among 25, ethnic minority populations in Yunnan Province in Southwest China. Most Chinese are Han-Chinese, but the populations interviewed during this study are recognised as ethnic nationalities by the state: having culture, language and lifestyle unique to their groups [4]. As the groups are autonomous, one group may reside in several countries. They frequently cross international borders to visit family, for cross border marriages, and to conduct trade [4], where they often contract malaria while travelling and import it to their villages [5]. Yunnan Province is one of the two remaining areas of China with high annual transmission of both P. vivax and P. falciparum; the other being Hainan Island. In 2004, the annual reported malaria incidence was 3.09/10,000 [6], although the estimated number of actual cases is at least 18 times greater [7]. Malaria is a particularly severe social and health problem along the border with Myanmar, where mobile workers move back and forth across the border and malaria control is weak. One-third of malaria cases in China came from Yunnan province in 2005, and about a quarter of these were actually infected in Myanmar during trips to visit relatives and conduct business [8].

The mobile populations within the border areas are often vulnerable and of low economic status. However, control of disease and effective treatment is problematic since it is difficult to locate, diagnose and treat infected people in these populations [9]. Annual GDP per capita of the rural population in the border region is one of the lowest in China at <US$100 [10]. Over half of per capita health expenditure is provided by out-of-pocket contributions [11]. Furthermore, 39% of people in rural-poor areas do not seek health care because of economic difficulties [12], and it is estimated that each bout of malaria severely reduces loss of earnings; with a 1.45% loss of annual income per episode experienced [13]. Thus, the prevention of malaria morbidity among minority and mobile populations is a priority for malaria control programmes in this region.

Malaria control is complicated by the fact that the local malaria vector mosquitoes: Anopheles. dirus A, An. minimus A and An. minimus C [14], exhibit behaviours that limit their control through traditional methods such as indoor residual spraying (IRS). These vectors breed in scattered forest sites [15], are exophilic and exophagic [16]; and their tendency to feed in the early evening reduces the impact of bednets [16,17]. Targeted personal protection may have an important role in preventing malaria that is transmitted by exophilic and exophagic vectors that bite early in the evening when people are still outdoors [18,19].

Yunnan is part of the Mekong Roll Back Malaria (RBM) initiative that highlighted the need to evaluate innovative treatments to protect those at risk. RBM began in 1999, and the vector control component focuses on improving information about, access to, and use of insecticide treated bednets because bednets have been used for many years in Yunnan without insecticide [20]. The initiative aims to develop better systems for collecting relevant information to make appropriate decisions on vector control and personal protection, so that the limited resources are targeted at those most in need [21]. Therefore, the aim of the current study is to investigate the existing use of, motivation for using and perceptions of personal protection among rural ethnic-minority populations; in order to identify key areas where uptake of personal protection can be maximised through dissemination of knowledge or improvement of provision.

Methods

Study Design

A survey was performed between May and August 2003, in those counties with highest malaria incidence. For each of the twenty five minority populations, approximately ten villages were visited. However, for some groups it was not possible to visit all ten villages due to road conditions and analysis was weighted accordingly. The villages were chosen at random from a list, and interviews were conducted with four key people in each of the 187 villages visited, with 748 interviews conducted in total. The respondents selected were the head of the village and individuals suggested by village heads because they were herbalists or healers. These were selected as respondents because they are most likely to have information on health issues in the region, and because they give information about diseases to their communities, it is important to know what knowledge and practices they have. The survey was designed to rapidly gather information from a large cross section of the population and so those people who are most likely to disseminate information within a community were selected. The survey was designed to measure associations between socioeconomic factors, knowledge and practice. The survey was conducted during the rains because both mosquito numbers and malaria incidence is highest at this time [22], thus the subject matter would be fresh in peoples' minds.

Data collection

Data on the household environment, knowledge and perceptions of personal protection and risk factors for malaria was collected using a structured interview with data entered into questionnaires. This method was favoured over focus groups for health research in this region because replies to questions may sometimes be biased to include what the respondent perceives is a socially desirable response [23]. Reference numbers were used to ensure participant confidentiality.

Structured observations should only be undertaken following exploratory research such as a pilot survey [24], but his was beyond the scope of the study due to time and money constraints. Therefore, the expertise of individuals who had performed this kind of survey previously in the area was resourced. Interviews were conducted by anthropologists from Simao Institute of Parasitic Disease Control who have worked extensively among minority populations in this region and that speak several local dialects. Participants were asked about methods they used to prevent mosquito bites, and their knowledge of malaria. Knowledge of malaria was measured by asking questions about mosquito breeding sites, how malaria is transmitted and preventative measures. Answers were noted using checkboxes but questions were posed in an open fashion to prevent bias of answers. The questionnaire was translated into Mandarin Chinese, and then the questions were translated on the day into local dialect using a translator when necessary, although most respondents spoke Mandarin. The questionnaires were coded using Arabic numbers and all data were entered into a data base using coding to ensure blind data entry. Any sections where informants supplied additional information were backtranslated into English and entered separately. Data were entered using Epi Info 2002 and analysis was performed using SPSS 13.0. Pairs of variables were analysed using chi square to test for significant relationships, followed by stepwise multivariate binary logistic regression of significant variables adjusted for altitude (above and below 1500 m), ethnic group and village.

Ethical Considerations

Ethical clearance for the study has been provided by Yunnan Research Ethical Committee and the LSHTM Research Ethics Committee. Prior to the study, each potential inter-viewee had a full explanation regarding the reason for the study, procedure and time required to perform the interview, and was given the opportunity to opt out. Identification numbers were used to protect the participants' identities and make data analysis simpler.

Results

The majority of the respondents were male (62.7%), working in agriculture (73.5%), with an annual household income greater than 1200Y (86.9%). Most families comprised 3-5 individuals, who had been living in the area for more than 10 years (93.1%), and the most common housing type was the traditional open two storey housing found in Yunnan, which is constructed of wood and allows mosquitoes ready access (listed as "permanent open" in Table 1). The majority of villages were surrounded by crops (76%), rice fields (87%) and forest (63.8%); therefore they are in close proximity to mosquito breeding sites. Educational level was low: 30% of respondents had received no schooling, with 38% receiving primary education and 27% attending secondary education. There was significant gender disparity in education: 47% of females receiving no education versus 22% of males (Fishers exact test P < 0.0001). Educational level was significantly higher in the youngest age group, with more young people having received both primary and secondary education than those in older age groups (Fishers exact test P < 0.0001) ( Table 1).

Only 31% of respondents knew that mosquitoes transmit malaria, and knowledge was significantly lower among women (O.R. 0.443, 95% C.I.: 0.279-0.703, P = 0.001), who were also less likely to have heard information on malaria within the last 12 months (O.R. 0.352, 95% C.I.: 0.176-0.706, P = 0.003) ( Table 1). There was also a strong association between recalling hearing information on malaria and knowing that mosquitoes transmit malaria (O.R. 7.414, 95% C.I.: 4.669-11.442, P < 0.0001).

Almost all of the households perceived mosquitoes as a nuisance (97.1%) and women were more aware of this than men (O.R. 6.104, 95% C.I.: 1.185-31.436, P = 0.031), but only 21.9% of respondents mentioned that mosquitoes are a problem because they transmit malaria. Those who lived close to rice fields were also more likely to perceive mosquitoes as a nuisance (O.R. = 5.085, 95% C.I.: 2.111-12.246, P = 0.001), but were less likely to perceive mosquitoes as a problem because they cause malaria (O.R. 0.480, 95% C.I.: 0.302-0.762, P = 0.002). Those who understood that malaria was transmitted by mosquitoes were more likely to use bednets (OR 1.572, 95% C.I.: 1.117-2.212, P = 0.005), but not repellents or mosquito coils. Use of all three methods of personal protection were strongly related to receiving primary and secondary edu- The number and percentage of respondents in each socioeconomic category was stratified by gender and age of respondent, housing quality, annual household income, occupation of the head of the household, educational level of respondent, occupation of the head of household and the village altitude (> or < 1500 m). The likelihood of those respondents in each category correctly identifying night-biting mosquitoes as the cause of malaria 1 ; having heard information on malaria in the last year 2 ; and answering yes to the question do you use bednets 3 , coils 4 , and repellents 5 to protect yourself against mosquitoes were calculated with binary logistic regression.

cation, and even more strongly predictive of use was higher income (Table 1).

Although knowledge that mosquitoes transmit malaria was low, knowledge of mosquito control methods was high. When asked (without prompting), "What methods do you know that can be used to prevent mosquito nuisance?" 80% of respondents mentioned bednets, 75.5% mentioned indoor residual spraying (IRS) and 65% mentioned repellents as methods for controlling mosquitoes. However, when this question was rephrased later in the questionnaire as "how can you protect yourself against malaria" 43% replied that they didn't know, 12.5% answered IRS, 8.6% mentioned bednets and 19% mentioned drugs such as chloroquine.

Although most people used personal protection, this was largely confined to use inside of houses, and use of personal protection outdoors besides wearing long clothing was rare (Figure 1). Importantly, those working in occupations where they are likely to encounter mosquitoes used insect repellents less frequently than those in agriculture i.e. foresters (OR 0.210, 95% C.I.: 0.038-1.150, P = 0.001) and plantation workers (OR 0.68, 95% C.I.: 0.019-23.960, P = 0.001) ( Table 1). This result was surprising, since foresters had the best knowledge of malaria transmission: 61.3% identified mosquitoes as the cause of malaria compared to 37.9% who were employed in 'other' indoor occupations including medicine and business (Table 1), and more than twice as many people engaged in forestry or plantation agriculture had heard information on malaria when compared to other occupations (Pearson Chi Square P = 0.017). Importantly, those working in forestry and plantation agriculture were four times more likely to use bednets, although the association was not significant (Table 1).

Bednet use varied greatly between different groups, ranging from 3.6% among the Zang to 100% among the Shui; with a mean of 66.5% of respondents using bednets at home; and 97.4% of users said that they used the nets because they were effective rather than cheap. Of those who used nets, 62.7% used them to protect themselves from mosquitoes with low numbers using them for privacy (1.8%), to stop dust (7.6%) and for warmth (4.8%). The same trend was observed among repellent and coil users with 95.8% and 96.2%, respectively, of those respondents that used repellents or coils, perceiving them as effective. Almost all of the bednets used were unimpregnated because only 0.9% of households heads interviewed used a treated net, and only 3.1% knew about the insecticide treatment of bednets.

Discussion and conclusion

Key informants were chosen for this survey because they are the information givers on health issues in remote areas, and traditional healers were selected as they may also treat those with malaria. It is of particular importance to identify the knowledge of malaria held by these groups as they disseminate knowledge to others in the community. However, it is appreciated that the survey may not be extrapolated to the whole autonomous population of Yunnan, because the interviewees are not representative of the population as a whole, with males and older people receiving over representation.

The two most important predictors of use of personal protection were income and education. Overall more educated people used personal protection more frequently and also had better knowledge of malaria. A similar trend was found by a survey conducted in Laos which showed that education was predictive of knowledge of transmission and use of bednets [25]. As there was no statistical relationship between education and income, it would appear that some health education is received whilst at school because those with more years of education were more likely to state mosquitoes as a cause of malaria. Disseminating malaria knowledge through schools is one of the areas of focus of the Mekong RBM project [20], and appears to be an effective strategy to improving community knowledge of malaria transmission. Additionally, those of higher educational status were more likely to have heard something about malaria in the last year. This indicates that there may also be language or literacy barriers resulting in low knowledge of malaria. Such barriers to knowledge may be overcome by the use of spoken messages about malaria prevention such as community plays and workshops [26].

Knowledge of malaria transmission was low overall, but women knew significantly less about the link between mosquitoes and malaria. However, this did not reduce their use of personal protection, a phenomenon that was also identified in a survey in Thailand [27]. The perception that mosquitoes are a nuisance may explain why women were more likely to use bednets, coils and repellents even though they had lower understanding of malaria transmission.

Several authors have recommended that malaria control for the region should target personal at men of working age, who have greater occupational exposure to mosquitoes [28][29][30]. Although it is likely that working men do bear a high malaria burden in the Mekong Region, there is evidence from some areas suggesting that mosquito exposure is similar among men and women, although the timing and location of their exposure might be different [31,32]. Women engage in many agricultural tasks alongside men -they provide 46.6% of agricultural labour in Yunnan, and also participate in forestry [33]. Since women are responsible for maintaining the household as well as performing agricultural tasks they tend to get up earlier than men, which also exposes them to early morning vector biting [34]. Some of the bias towards malaria burden in men may be due to underreporting in passive surveillance [35]. Women are less likely to seek health care due to a lack of recognition of women's health problems and barriers to mobility [34]; and are at high risk of malaria morbidity when pregnant [36][37][38]. Therefore targeting of personal protection information at both men and women may be more appropriate in this scenario. Although women generally have lower status than men in Yunnan, they are responsible for making household purchases [39,40]. This survey shows that they are most open to using personal protection methods. Improving women's knowledge and exposure to personal protection is important as they may be able to encourage use by other members of the family through their purchases. Again, the lower educational status of women suggests that verbal campaigns rather than written literature may be the best way to spread messages about malaria prevention and treatment.

It is interesting that those most exposed to mosquitoes i.e. those engaged in plantation agriculture and forestry only protect themselves from bites with long clothing whilst working, even though they had better knowledge of malaria transmission than those engaged in other occupations. However, they did use bednets more frequently (and they did not receive a higher income than other groups) which illustrates the importance of health education programmes in translating knowledge into practice. This lack of personal protection use away from home is common in Southeast Asia [30,34], and this phenomenon has been targeted as part of the RBM initiative, with NGOs investigating the potential for Social Marketing of hammock nets and deet (di-ethyl toulamide) based repellents for migratory populations [35]. Additionally, the mandatory use of personal protection in the field by plantation workers or those working for commercial logging companies in Southeast Asia could be negotiated as has occurred in Bolivia [41].

Health policy for the region targets increased coverage of long-lasting insecticidal nets [21], and the research clearly demonstrates a lack of knowledge about insecticide treatment of bednets among the surveyed population. Personal protection use among the participants of the survey Differences in the use of personal protection when at home, or outdoors in the forest or field where malaria risk is higher

At home

In forest In field is high despite low understanding of malaria transmission or control. This has been shown by several other surveys conducted among ethnic minority groups in Laos, Thailand and Myanmar [42][43][44][45]. There was a statistically significant relationship between mentioning that mosquitoes cause malaria and use of bednets, as was also seen in a similar survey conducted in Hainan Province [46]. However, the use of other methods of personal protection was motivated only by nuisance biting. The lack of relation between knowledge and practise, where nuisance is the greatest motivator for using personal protection, is widely recorded in the literature and has lead some researchers to advocate the use of protection measures independent of people's knowledge, stressing the importance of low price of interventions to facilitate purchase [47]. In fact, cost may be the most important hindrance to uptake of personal protection in this region as the strongest statistical association between factors was seen between income and personal protection use.

Health policy for the region targets increased coverage of long-lasting insecticidal nets [21], and the research clearly demonstrates a lack of knowledge about insecticide treatment of bednets among the surveyed population. The survey has shown that the use of insecticide impregnated nets among autonomous groups in Yunnan needs to increase alongside outdoor use of personal protection, especially among high risk groups such as forest workers. In an area like Yunnan where language and literacy can be a barrier, health education based on verbal communication such as village meetings and radio broadcasts for both men and women that coincide with bednet distribution may be required. However, personal protection is widely used and widely accepted, with the major barrier to use being affordability. Therefore social marketing campaigns with highly subsidised products are most likely to succeed.

Figure 1
1Differences in the use of personal protection when at home, or outdoors in the forest or field where malaria risk is higher. The figure represents the percentage of respondents that use personal protection when at home or outdoors. Bars denote the mean and 95% c.i. percentage of responses (n= 748). The respondents were asked "Do you try to protect yourself from mosquito bites? If you do, how do you protect yourself when you are at home? How do you try to protect yourself when you enter the forest? How do you protect yourself when you are working in the fields? Respondents could make multiple responses.

Table 1 :
1Binary logistic regression to identify key determinants of malaria knowledge and personal protection useVariable
n (%) 1
Know
mosquito
transmits
malaria 2

Odds
ratio

Recently
heard
info on
malaria 3

Odds
ratio

Uses
bednets 4

Odds
ratio

Uses
coils 5

Odds
ratio

Uses
repellents 6

Odds
ratio

Gender
p = 0.001
p = 0.003
p = 0.092
p < 0.001
p < 0.0001
Male
480 (62.7)
180 (37.5)
1
085 (17.7)
1
313 (65.3)
1
234 (48.8)
1
232 (48.3)
1
Female
268 (35.0)
052 (19.4)
0.443
(0.279,
0.703)

017 (06.3)
0.352
(0.176,
0.706)

185 (69.0)
1.457
(0.938,
2.321)

160 (59.7)
2.331
(1.500,
3.624)

172 (64.2)
2.578
(1.664,
3.994)

Age
p = 0.978
p = 0.342
p = 0.711
p = 0.143
p = 0.066
< 30
119 (14.4)
030 (27.3)
1
011 (10.0)
1
078 (70.9)
1
048 (43.6)
1
048 (43.6)
1
30 to 50
378 (49.4)
116 (30.7)
1.025
(0.650,
1.684)

062 (16.4)
0.628
(0.330,
1.195)

260 (68.8)
0.858
(0.546,
0.346)

205 (54.2)
1.332
(0.891,
1.991)

202 (53.4)
1.574
(1.002,
2.471)
> 50
255 (33.3)
084 (32.9)
1.072
(0.529,
2.174)

029 (11.4)
0.830
(0.329,
2.095)

158 (62.0)
0.795
(0.432,
1.464)

138 (54.1)
1.808
(0.952,
3.431)

150 (58.8)
2.022
(1.002,
2.471)

Income
p = 0.656
p = 0.127
p = 0.004
p < 0.0001
p < 0.0001
< 600 Y
013 (01.7)
002 (15.4)
1
003 (23.1)
1
003 (23.1)
1
001 (07.7)
1
001 (07.7)
1
600-1200 Y
056 (07.3)
010 (17.9)
1.313
(0.619,
2.785)

003 (05.4)
2.864
(0.953,
8.613)

024 (42.9)
1.774
(0.911,
03.454)

010 (17.9)
04.257
(1.838,
009.857)

015 (26.8)
02.849
(1.347,
006.024)
Over 1200 Y
665 (86.9)
216 (32.5)
1.858
(0.415,
8.320)

094 (14.1)
0.374
(0.065,
2.138)

461 (69.3)
8.012
(1.784,
35.977)

380 (57.1)
21.584
(2.373,
196.316)

385 (57.9)
27.993
(3.212,
243.985)

Housing
p = 0.629
p = 0.015
p = 0.386
p = 0.0001
p = 0.012
Temporary
059 (07.7)
009 (15.3)
1
009 (15.3)
1
033 (55.9)
1
013 (22.0)
1
019 (32.2)
1
Semi-perm
057 (07.5)
015 (26.3)
1.347
(0.645,
2.813)

010 (17.5)
1.049
(0.364,
03.020)

029 (50.9)
0.818
(0.393,
1.702)

014 (24.6)
1.586
(0.789,
03.186)

015 (26.3)
1.654
(0.891,
03.069)
Perm Open
539 (70.5)
166 (30.8)
1.617
(0.611,
4.279)

058 (10.8)
2.852
(1.360,
05.983)

383 (71.1)
1.418
(0.511,
3.934)

305 (56.6)
4.847
(1.769,
13.283)

308 (57.1)
4.955
(1.765,
13.916)
Perm Closed
088 (11.5)
040 (45.5)
2.240
(0.575,
8.742)

024 (27.3)
2.476
(0.607,
10.094)

050 (56.8)
1.215
(0.481,
3.070)

058 (65.9)
5.895
(2.002,
17.361)

057 (64.8)
3.222
(1.14,
09.075)

Education
p = 0.001
p = 0.002
p = 0.01
p < 0.0001
p = 0.004
None
232 (30.3)
043 (18.5)
1
015 (06.5)
1
139 (59.9)
1
096 (41.4)
1
114 (49.1)
1
Primary
291 (38.0)
088 (30.2)
1.548
(0.944,
2.536)

040 (13.7)
2.020
(1.122,
3.637)

194 (66.7)
2.063
(1.218,
3.493)

149 (51.2)
2.171
(1.311,
3.594)

057 (54.0)
1.241
(0.751,
2.049)
Secondary
209 (27.3)
091 (43.5)
2.980
(1.666,
5.332)

045 (21.5)
3.412
(1.677,
6.942)

160 (76.6)
2.496
(1.352,
4.610)

142 (67.9)
4.216
(2.445,
7.268)

128 (61.2)
2.465
(1.437,
4.229)

Occupation
p = 0.001
Not
calculated

p = 0.168
p = 0.1
p = 0.001

Agriculture
562 (73.5)
157 (28.9)
1
071 (13.1)
369 (68.0)
1
284 (51.1)
1
300 (54.0)
1
Forestry
031 (04.0)
019 (61.3)
2.194
(0.373,12.9
09)

008 (25.8)
017 (63.0)
2.196
(0.255,
018.925)

011 (40.7)
0.374
(0.041,
3.441)

006 (19.4)
0.210
(0.038,
01.150)
Plantation
027 (03.5)
005 (18.5)
0.131
(0.030,
00.567)

008 (29.6)
023 (74.2)
4.009
(0.101,
158.693)

009 (29.0)
0.348
(0.040,
3.056)

005 (18.5)
0.680
(0.019,
23.960)
Labourer
014 (01.8)
003 (25.0)
0.722
(0.210,
02.475)

000 (00.0)
009 (75.0)
4.051
(0.694,
023.657)

004 (28.6)
0.152
(0.023,
1.015)

005 (35.7)
0.295
(0.054,
01.621)
Other
096 (12.5)
044 (37.9)
0.645
(0.173,
02.407)

013 (11.0)
066 (56.9)
2.206
(0.362,
013.452)

075 (74.3)
0.113
(0.017,
0.767)

077 (76.2)
1.746
(0.230,
13.242)

Altitude
P < 0.0001
p < 0.0001
P < 0.0001
p = 0.183
p < 0.0001
< 1200 m
314 (42.0)
134 (42.7)
1
060 (19.3)
1
238 (75.8)
1
172 (54.8)
1
143 (45.5)
1
> 1200 m
424 (58.0)
098 (22.6)
0.392
(0.285,
0.538)

042 (09.7)
0.449
(0.294,
0.687)

260 (59.9)
0.447
(0.346,
0.658)

222 (51.2)
0.865
(0.646,
1.157)

261 (60.1)
1.804
(1.345,
2.420)

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AcknowledgementsThe authors thank all the study participants for their time in answering the questionnaire. The study was funded by The Gates Malaria Partnership. The authors would like to thank Jane Bruce for statistical advice and the field team of Simao Institute of Parasitic Disease Control for data collection. Many thanks to Wakagari Deressa and Susanta Gosh generously reviewed the manuscript and whose comments greatly improved it.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsSJM designed the questionnaire, inputted and analysed data and wrote the manuscript. XM led the field collection team, assisted with questionnaire design and inputted data. NH conceived the study, assisted with study design, obtained ethic approval, liaised between institutes and revised the manuscript and obtained ethics approval. CJ assisted on design of questionnaire and revision of manuscript. ZZ designed the questionnaire and revised the manuscript. MCC designed the study and questionnaires and edited manuscript.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/8/344/pre pub
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Does the FDA have regulatory authority over adult autologous stem cell therapies? 21 CFR 1271 and the emperor's new clothes

Michael Freeman
Mitchell Fuerst
Does the FDA have regulatory authority over adult autologous stem cell therapies? 21 CFR 1271 and the emperor's new clothes
C O M M E N T A R Y Open Access
FDA has recently asserted that many autologous cell therapies once considered the practice of medicine are in fact drugs. These changes began with the creation of new sections of 21 CFR 1271 and a subsequent one word change where the FDA, without public commentary, altered a single word in its regulatory language regarding cell and tissue based therapies that asserted the authority to classify autologous tissue as drugs. The bright line between medical care and drug production can be delineated in many ways, but a simple metric that defines the dichotomy is the consent status of the patient. In healthcare, a patient can either be consented individually for a medical procedure or exposed to an unconsented risk where regulatory assurances are already in place. These new FDA policies apply rules meant to keep drugs safe in a drug factory (unconsented mass production risks) to individually consented surgical procedures. We argue that there is little societal benefit to these changes and that they are already stifling medical innovation.

Background

A recent editorial entitled, The King is Dead, Long Live the King: Entering A New Era of Stem Cell Research and Clinical Development by Ichim piqued our interest [1]. The piece described how the recent failure by Geron to commercialize embryonic stem cells for treatment of spinal cord injury might have signaled the decline of the commercial pursuit of such cells, and a change of market focus from embryonic to adult stem cells. We would argue that the primary reason that the cell therapy industry now finds itself in the midst of a financial funding crisis is in fact, due to unrestrained over-regulation by the FDA, rather than any lack of viability of the technologies. This over-regulation threatens to smother innovation in a nascent clinical movement that is already successfully translating promising therapies involving adult stem cells from the lab to the clinic. Although the FDA has never had the authority to govern and restrict the practice of medicine, this is precisely what they are now doing with regard to clinical uses of autologous stem cells. Until recently, this regulatory expansion has gone largely unnoticed, attracting little attention, with a few notable exceptions. To carry Ichim's regal metaphor a bit further, not only is the king dead, but the emperor has no clothes, and nobody's telling him he's naked.

Discussion

Since it was first enacted in 1938, the U.S. Food, Drug, and Cosmetic Act (FDCA) has regulated medical drugs and devices based on basic public health concepts that recognize the differences between the practice of medicine and the mass production of drugs [2]. The regulation of mass manufactured and widely distributed medical products led to a revolution in healthcare that greatly increased public safety and unquestionably saved lives due to the reduction of unsafe products. The FDA regulation of transplant tissues through the Public Health Service Act has also advanced the public health through reduced disease transmission. This all changed in 2006, when the FDA, without public commentary, altered a single word in its regulatory language regarding cell and tissue based therapies that moved their focus from protecting the public from communicable disease transmission to asserting authority over virtually all therapies using autologous cells and tissue [3]. In effect, the Agency now claims regulatory authority over a broad category of medical procedures. Fifteen years ago a similar proposal brought forth an industry-wide tsunami of objections and complaints; today, there is nary a whimper [4].

The bright line between medical care and drug production can be delineated in many ways, but a simple metric that defines the dichotomy is the consent status of the patient. In healthcare, a patient can either be consented individually for a medical procedure or exposed to an unconsented risk where regulatory assurances are already in place. For example, an Individual Consented Risk (ICR) is defined as a medical procedure or therapy for which a patient is formally consented in order to ensure a thorough understanding of the risks and possible benefits of the care. An example of ICR is a cardiac surgery for which the health risk may be extreme and the benefits difficult to quantify. In this situation the onus is on the patient to make an informed decision, after full disclosure of the best estimate of risk of the procedure by the physician, whether to undergo the procedure. In contrast with ICR, Mass Production Risk (MPR) is not associated with formal patient consent, as there is a general assumption on the part of the prescribing physician as well as the patient that the risk associated with the use of medicine that has passed through regulatory oversight is acceptably low. In the U. S. the FDA is the entity that provides public assurance that certain minimal standards (i.e. purity, potency, efficacy, and safety) have been met before a drug can be legally introduced to the market. Cellular medicine is a rapidly growing trend in healthcare that finds itself at the confusing crossroads of the regulatory concepts associated with ICR and MPR. An example of a widespread practice of cellular medicine is the use of autologous platelet rich plasma (PRP) to promote healing [5][6][7]. A less practiced but promising evolution of PRP involves the use of adult autologous stem cells (A-ASCs) for promotion of healing of injured tissue [8]. From a common sense perspective, it should be obvious that both of these autologous therapies are associated with ICR rather MPR, in that there is no mass production or distribution involved, the risk of procedure to the individual patient can only be estimated by the clinician who is providing the therapy, and it is up to the patient to weigh and ultimately accept the risk and provide consent for undergoing the procedure. This sort of common sense is absent in the FDA's adoption of 21 CFR 1271 in 2006, the rule that made a patient's own cells subject to the same regulation as mass produced drugs. This movement away from common sense began in the 1990's when the FDA first signaled an interest in regulating the use of autologous cells [4,[9][10][11]. The administrative records of the hearings from this time show that many large and highly credible organizations spoke out in opposition to this proposed intrusion into the practice of medicine. The list of organizations that objected to the FDA's proposed rule change included the American Red Cross, the American Society for Clinical Oncology, and the Society for Assisted Reproductive Techniques, among others. Many of the groups noted that the FDA was only granted authority by the U.S. Congress to regulate allogeneic tissue transplants in order to control communicable disease transmission, and that the Agency had no authority to regulate human cells of any type like mass produced prescription drugs. The most vocal opponent to these proposed regulations was the ASCO, who stated:

• "ASCO objects in the strongest terms to FDA's proposed regulation of stem cell transplants. This misguided proposal is unnecessary... and exceeds FDA's legal authority.

• "...stem cell transplants are medical procedures. Their use is the practice of medicine, not the manufacturing of a drug as FDA asserts.

• "A striking aspect of FDA's proposal to regulate stem cell procedures is the virtual absence of any justification for the initiative".

• "The FDA should not regulate stem cell procedures undertaken within an institution... or in any other setting where the cells are procured from a donor for a preselected recipient under the direction of physicians caring for these patients.... The proposed approach is a threat to good medicine and should not be adopted."

Despite these industry concerns, by 2005 the Agency had completed publically announced changes to its regulations that classified "more than minimally manipulated" allogeneic cells the same as prescription drugs. This regulatory change at least made some sense, since allogeneic cells could be grown in large bioreactors and distributed to the public like a mass produced drug product. The FDA did not stop at allogeneic cell therapy in their bid to control all cellular therapy; in 2006, the FDA "clarified" 1271, asserting that the rule applied to all human tissue and cells, which meant that it now applied to autologous cells and tissue as well. This was accomplished with the alteration of a single word: "into another human" was changed to "into a human." a For the first time, by nothing more than semantic sleight of hand, the agency bequeathed itself authority over a broad group of medical procedures and their attendant ICR risks. Recent decisions by agency show that it isn't yet done with expanding its regulatory authority into the practice of medicine.

Since 2006 the FDA has made several public statements regarding their intent to regulate the autologous use of human cells and tissue, with an ever-widening number of therapies being caught in their regulatory dragnet. As an example, in 2008, the FDA sent a notice to Regenerative Sciences, a medical practice that utilized expanded bone marrow derived mesenchymal stem cells for autologous orthopedic use [12]. Despite the medical procedures involving only ICR, the FDA asserted that their drug mass production rules applied to the practices at the clinic. In fact, the Agency's actions directed at Regenerative Sciences appear to only be the FDA's foot in the door of medical practice regulation, as long as the practice involves use of autologous tissue or cells.

As an example, the Agency has recently made a worrisome assertion about the processing of adipose tissue, a medical practice that has been around for more than 100 years [13]. The Agency's Tissue Reference Group (TRG) has issued a statement in which they claim that any isolation of the stem cell rich fraction of fatty tissue for orthopedic use (the stromal vascular fraction or SVF) by a physician for his or her own use in patients equates to the manufacture of a drug, even if that tissue is processed at the bedside [14]. In addition, the same TRG has also recently issued the same edict for the use of bedside processed SVF for breast reconstruction, claiming this procedure is also a drug [15]. While the same FDA arguments are used in this letter, more worrisome is that the agency claims that adipose stem cells taken from adipose tissue and used to reconstruct adipose breast tissue may be non-homologous. Since the agency's own definition of homologous is, "[cells that] perform the same basic function or functions", it's unknown what logic drove this decision [16]. These assertions will immediately restrict the medical practices of hundreds of U.S. physicians who use SVF to assist in healing, as no clinical practices can meet the stringent regulations that are applied to drug manufacturing. In addition, these decisions will only hamper medical innovation without measurably improving public safety.

To illustrate how poorly thought out the language in 1271 is, consider a recent publication in which it was reported that the magnetic field fluctuations of a routine MRI changes the biologic characteristics of stem cells [17]. These authors demonstrated that the magnetic fields induced by diagnostic MRI can alter fundamental biologic characteristics of stem cells such as gene expression and bone forming ability. Thus if, as is common surgical practice, an orthopedic surgeon creates a dilute autologous stem cell mix using a bone marrow aspirate, places the mixture into a patient's spine to promote fusion, and then orders an MRI post-procedure, the stem cells will become more than minimally manipulated. Whatever the FDA intended when they slipped new and greatly expansive language into 21 CFR 1271 in 2006, it is doubtful that they intended to shut down or restrict many commonly practiced and effective medical therapies that have nothing to do the mass manufacture and interstate of transport of drugs. It is even more doubtful that the U.S. Congress ever intended to the FDA to have such broad power over the practice of medicine.

Should there be concern that the FDA will continue to expand their attempts to regulate the practice of medicine? The FDA has recently demonstrated that the answer to this question is an emphatic YES. The aforementioned action against Regenerative Sciences spawned a series of suits and countersuits that are still in litigation. As part of this process, the Court hearing the cases recently issued an "Order to Show Cause" to the FDA. The order stated that, since Congress had only authorized the FDA to classify a substance that affected the body through "chemical action" as a drug, the Agency needed to clarify its position as to why a patient's own stem cells could be considered a drug [18]. The Agency's response to the order was dismaying; they responded with: "When living cells interact with their environment to mediate repair of and/or regenerate damaged tissue, they do so by chemical action." Since all living cells produce chemicals to interact with their environment, the Agency has made it clear that they believe that they have the authority to classify any living organism as a drug! Is it reasonable for the FDA to assert that there is any benefit to imposing MPR regulations on medical procedures involving ICR? Medical therapeutic innovation comes to the public via two pathways; the slower big pharma drug pathway, and the substantially faster physician practice/discovery pathway. The pharma pathway has the advantage of producing high quality data from randomized controlled trials in support of a new therapy, but the disadvantages of inflexibility and glacially slow laboratory to clinical translation. In comparison, the physician practice pathway has the disadvantage of reliance on lower quality data (beginning, in all cases, with anecdotal experience), but the advantages of flexibility and a shorter time from discovery to clinical implementation. Physicians typically publish smaller studies that are reactive to problems encountered in daily clinical practice, and result from the rapid adoption of new therapies that appear to be effective in a semi-or uncontrolled setting. The pharma pathway has the potential to produce societal benefit in the form of increasingly effective and safer prescription drugs, but it is a far from foolproof system associated with a laundry list of unsafe drugs that were initially hailed as medical marvels (Vioxx, fen/phen, propoxyphene, Avandia, Baycol, inter alia) but later found to have unacceptable rates of serious, sometimes fatal complications. The physician pathway has also produced major medical advancements and benefits to public health such as modern in-vitro fertilization and almost all modern surgical procedures. To be sure, there have been major missteps along the way as well (bloodletting and most lobotomies, hysterectomies, and radical colectomies, to name just a few), but the medical profession and the bodies that provide education, licensure, regulation, and peer review tend to rapidly self-correct for harmful practices. The imposition of regulations meant to minimize MPR on the pharma pathway makes sense, as this pathway results in products meant for mass distribution. In contrast, the attempt to shoehorn medical practices into an MPR regulation model, as the FDA has done with autologous stem cell therapies, will produce no benefit to society, and harm public health by depriving society of the benefits of physician-initiated medical innovation.

Ultimately, the FDA's assertion that certain clinical or laboratory processes transform autologous cells into drugs is not based in a scientific risk analysis, and goes far beyond the Agency's mandate to protect the public from the risks associated with the mass production of drugs or devices. It certainly begs the question of how far the "medical procedure vs. drug" line may get redefined in the future. Are there compounded drugs that will be assigned MPR status? What about fertility culture procedures, such as a 5-day blastocyst transfer? If the therapeutic culture of a human being from two gametes isn't "more than minimal manipulation" of those cells then it's hard to imagine what is. Will surgical procedures have to someday comply with drug manufacturing guidelines?

All of these regulatory decisions have significant economic consequences for society. For example, medical care and drugs have different requirements for safety. An apt example that demonstrates the societal cost associated with imposing MPR regulations on ICR is applying drug factory Good Manufacturing Practices (GMP) to a hospital surgical procedure. GMP regulations are strict guidelines that ensure a minimum level of safety when millions of doses of a drug are manufactured, but are not used in a hospital setting. For example, if GMP regulations were applied to a hospital setting they would require that a hospital operating room (O.R) have a separate quality assurance program as does a major pharmaceutical factory. All surgical supplies would need to be separately validated to confirm the already FDA regulated manufacturer's claims. For example, sterile medical gases already regulated by the state would have to be again tested by the hospital. In addition, every surface in the operating room would have to be swabbed for microbial, viral, and fungal contamination on a regular basis and the FDA regulated cleaning solution claims separately validated in expensive testing performed by the hospital staff. In addition, each patient's wound would also have to be swabbed and sent for microbial, viral, and fungal contaminants before completion of the surgery. Operating room air handling would also have to be upgraded to GMP standards, costing hundreds of thousands of dollars per O.R. In addition, while surgeons are used to making adjustments in technique to fit the patient, each change in process would require a separate Standard Operating Procedure change control process. As a result, surgeons would be unable to alter the procedure to fit the patient. In addition, every step in the surgery would have time limits that would be strictly monitored and recorded and when any step exceeded timed parameters the surgeon would be written up by a quality assurance manager as having exceeded "processing parameters". While all of these changes may make good sense to protect the nation's drug supply from contamination, they make little sense when applied to an operating room and would also financially hobble an already expensive medical care system.

Conclusion

The FDA has a long and important history of safeguarding the health of the U.S., but always in the context of its mandate to regulate medical products that carry with them risks associated with mass production. For the most part, the Agency usually gets it right; however in altering that single word of 21 CFR 1271, the FDA has overstepped its mandate, and through over expansive regulation is threatening to cripple medical innovation. Their most recent interpretation of 21 CFR 1271 indicates that the FDA is in need of a course correction. It's time that someone has the courage to tell the Emperor about the problems with his new wardrobe.

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Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution. Cite this article as: Freeman and Fuerst: Does the FDA have regulatory authority over adult autologous stem cell therapies? 21 CFR 1271 and the emperor's new clothes. 1060Submit your manuscript at www.biomedcentral.com/submitCite this article as: Freeman and Fuerst: Does the FDA have regulatory authority over adult autologous stem cell therapies? 21 CFR 1271 and the emperor's new clothes. Journal of Translational Medicine 2012 10:60. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit