Beruflich Dokumente
Kultur Dokumente
Summer 2013
Tao Wu
Annagrazia Altavilla
Hongjie Man
Recommended Citation
Anne-Marie Duguet, Tao Wu, Annagrazia Altavilla & Hongjie Man, Ethics in Research with Vulnerable Populations and Emerging
Countries: The Golden Rice Case, 38 N.C. J. Int'l L. & Com. Reg. 979 (2012).
Available at: http://scholarship.law.unc.edu/ncilj/vol38/iss4/2
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Ethics in Research with Vulnerable Populations and Emerging Countries:
The Golden Rice Case
Cover Page Footnote
International Law; Commercial Law; Law
This article is available in North Carolina Journal of International Law and Commercial Regulation: http://scholarship.law.unc.edu/
ncilj/vol38/iss4/2
Ethics in Research with Vulnerable Populations and
Emerging Countries: The Golden Rice Case*
Anne-Marie Duguetf
Tao Wuff
AnnagraziaAltavillafff
f
Dean M Harrisf ff
1. Introduction ........................... ..... 980
II. Background: Research in Emerging Countries ................. 981
III. Worldwide Ethical Principles for Research with Human
Subjects: The Declaration of Helsinki, CIOMS
Guidelines, and the Declaration by UNESCO...................983
IV. Laws and Guidelines of Specific Countries and Regions.. 988
A. U.S. Laws and Procedures on Informed Consent for
Research Conducted in Other Countries ..... .... 988
B. European Guidelines and Regulations ...... ...... 990
This paper is a collaborative work of the PHC Cai Yuanpei program 2012 Project no
28007UF, co-sponsored by the French and Chinese embassies and enabled through the
cooperation between the UMR/INSERM Unit 1027 France and the Law School of
Shandong University China.
t M.D., Ph.D., Senior Lecturer UMR/INSERM 1027 Facult6 de Mdecine 37 Allies
Jules Guesde 31073 Toulouse Cedex France aduguet@club-internet.fr.
tt M.D., Ph.D. in Public Health, Associated Researcher in the Cai Yuanpei and Xu
Guangqi Projects 2012.
itt Associate Senior Lecturer, Espace Ethique M6diterranden (UMR 7268) Aix-
Marseille University. E-Mail annagrazia.altavilla@univ-amu.fr.
tft Ph.D. in Law, Assistant Professor in the Law School, Shandong University. Jinan,
250100, China.
tff t Clinical Associate Professor in the Department of Health Policy and Management,
Gillings School of Global Public Health, University of North Carolina at Chapel Hill;
Adjunct Professor in the Health Economics and Management Institute (HEMI) in the
Guanghua School of Management at Peking University.
980 N.C. J. INT'L L. & COM. REG. Vol. X-XXVIII
I. Introduction
The "Golden Rice case" was an experiment designed to study
the effects of genetically engineered rice on children and was
conducted in a primary school in China, with researchers from
Tufts University of Boston.' In the aftermath of the study,
disputes arose as to the adequacy of the approval process for the
research, the sufficiency of the consent given by parents of study
participants, the amount of Golden Rice ingested by participants,
and the role of the Chinese researchers in the study.2 Due in large
part to these disputes, the case serves as an excellent example of
the ethical issues associated with research conducted in emerging
countries by developed countries, as well as the necessity of
protecting vulnerable study populations.'
18 45 C.F.R. 46: Frequently Asked Questions, U.S. DEP'T HEALTH & HUM.
SERVICES, 2-3 (2011), http://www.hhs.gov/ohrp/policy/45cfr46faqmar2Oll.pdf
(tracing "[tihe history of contemporary human subjects protections" and impliedly
placing the Declaration of Helsinki second in it). "The purpose of the WMA is to serve
humanity by endeavoring to achieve the highest international standards in Medical
Education, Medical Science, Medical Art and Medical Ethics, and Health Care for all
people in the world." About the WMA, I WORLD MED. ASS'N 1,
http://www.wma.net/en/60about/index.html.pdf~print-media-type&footer-
right-[page]/[toPage] (last visited Apr. 17, 2013). The Declaration of Helsinki has been
revised eight times, with a last revision in Seoul in 2008. See DECLARATION OF
HELSINKI, supra note 3, at I (providing this information).
19 External Policies, supra note 13, at 15 (discussing and implying this
significance); CIOMS GUIDELINES, supranote 3, at 15.
20 DECLARATION OF HELSINKI, supra note 3, 2.
21 Id.
22 Id. art. 3, 6.
23 CIOMS GUIDELINES, supra note 3.
24 See generally id. (listing guidelines that pay particular attention to vulnerable
people and developing countries).
25 UNESCO Declaration, supra note 6.
2013 ETHICS INRESEARCH: GOLDENRICE 985
48 Convention for the Protection of Human Rights and Dignity of the Human
Being with Regard to the Application of Biology and Medicine, Apr. 4, 1997, E.T.S. No.
164 [hereinafter "Oviedo Convention"].
49 European Medicines Agency, Reflection Paper on Ethical and GCP Aspects of
ClinicalTrials of Medicinal Productsfor Human Use Conducted Outside of the EU/EEA
and Submitted in Marketing Authorisation Applications to the EU Regulatory
Authorities, 10-12, EMA/121340/2011 (Apr. 16, 2012).
50 Tang et al., supra note 1, at 658 n.3.
2013 ETHICS IN RESEARCH: GOLDEN RICE 989
57 TUFTS MED. CTR., POLICIES AND OPERATIONS MANUAL FOR THE INSTITUTIONAL
REVIEW BOARD OF TUFTS MEDICAL CENTER AND TUFTS UNIVERSITY HEALTH SCIENCES 11
n.5 (2012).
58 See 21 C.F.R. § 312.120 (2012) (setting forth the guidelines for "[f]oreign
clinical studies" that are not performed under the FDA's investigational new drug
("IND") procedure).
59 See id (detailing the requirements when there are "[fjoreign clinical studies not
conducted under an IND"); 21 C.F.R.§ 314.106 (2012) (detailing the requirements when
there is "[fjoreign data").
60 See Jennifer J. Couture, The Changes in Informed Consent in Experimental
Procedures:The Evolution ofA Concept, I J. HEALTH & BIOMEDICAL L. 125, 148 (2004)
("The European Union, under the European Commission, follows the most current
version of the Declaration of Helsinki in regards to all analytical, pharmacological and
clinical standards for testing any experimental treatments."); see, e.g., Investigational
New Drug Safety Reporting Requirements for Human Drug and Biological Products and
Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in
Humans, 75 Fed. Reg. 59935, 59936 (proposed Sept. 29, 2010) to be codified at 21
C.F.R. §§ 312, 320 (mentioning proposed requirements that would "harmonize the
regulations" with both the CIOMS and the European Union).
61 See Oviedo Convention, supra note 48, at 7, 18 (providing the date of signing).
62 Id. arts. 15-18.
2013 ETHICS INRESEARCH: GOLDENRICE 991
72 Id. at 3.
73 Eur. Medicines Agency Working Group on Clinical Trials Conducted Outside
the EU/EEA [EMA], Reflection Paper on Ethical and GCP Aspects ofClinical Trials of
Medicinal Productsfor Human Use Conducted Outside of the EU/EEA and Submitted in
Marketing Authorization Applications to the EU Regulatory Authorities,
EMA/121340/2011 (Apr. 16, 2012) [hereinafter Reflection Paper].
74 See id at 4 ("The scope of this Reflection Paper is to clarify the practical
application of requirements for clinical trials conducted outside of the EU/EEA and
submitted in Marketing Authorization Applications to the EMA .. . or to National
competent Authorities.").
75 Id. at 18 (emphasis added).
76 See id. at 26-28 (describing the proper use of placebo/active comparator in
research studies).
994 N.C. J. INT'L L. & COM. REG. Vol. XXXVIII
77 See id. at 4 ("The final scope of the document is to strengthen the process
(mainly in its earlier phases) to assure, at the time of MAA assessment, that clinical trials
conducted in countries outside EU/EEA have been conducted in accordance with the
principle of Good Clinical Practice (GCP) and equivalent ethical standards as those
applied/requested in the EU.").
78 See Reflection Paper, supra note 73, at 23, 29 (emphasizing the importance of
making compensation available to any subjects injured in the course of treatment and
reinforcing the requirement that applicants disclose whether and how continued
treatment may be available to subjects after the clinical trial).
79 See id. at 36 (describing the regulatory action/action plan for doing so).
80 See id at 18 (instructing EU authorities to "disregard data obtained in a such
unethical manner").
81 See id at 39 (stating that these consequences should be considered where non-
compliance is identified after the Marketing Authorization has been granted).
82 Annagrazia Altavilla, EthicalStandardsfor Clinical Trials Conducted in Third
Countries: The New Strategy of the European Medicine Agency, 18 EUR. J. OF HEALTH
2013 ETHICS IN RESEARCH: GOLDENRICE 995
A. The FactualBackground
The experiment with Golden Rice was presented as a study of
the preventive treatment of vitamin A deficiency in children89 and
the vitamin A value of b-carotene in [Golden Rice] and in spinach with that of pure b-
carotene in oil when consumed by children").
90 See Vitamin A Equivalence of Plant Cartenoids in Children,
CLINICALTRIALS.GOV (Feb. 17, 2009), http://www.clinicaltrials.gov/ct2/show/
NCT00680212?term=NCT00680212&rank=I [hereinafter Vitamin A Equivalence]
(noting that the official title of the study is "Phase 2 Study of VITAMIN A
EQUIVALENCE OF PLANT CARTENOIDS IN CHILDREN").
91 See China Sacks Officials Involved in GM Rice Test, XINHUA (Dec. 6, 2012),
http://www.china.org.cn/china/Off the Wire/2012-12/06/content_27337035.htm
(describing the Golden Rice research project).
92 See Wang Qingyun, Better Supervision of Research Urged, CHINA DAILY-HONG
KONG EDITION, Dec. 13, 2012. (specifying that the Ethics Committee approved the
project).
93 See Wang Qingyun and Shan Juan, CDC to Probe Whether GM Study Used
Schoolchildren,CHINA DAILY-HONG KONG EDITION, Sept. 12, 2012 ("Zhejiang Academy
of Medical Sciences, said it cooperated with Tufts University in 2004."). Guangwen
Tang was responsible for the whole project, whereas Wang Yin and Shian Yin were
responsible for the study in China. See Jane Qui, China Sacks Officials over Golden
Rice Controversy, NATURE (Dec. 10, 2012), http://www.nature.com/news/china-sacks-
officials-over-golden-rice-controversy-I. 11998 (identifying Wang Yin as the head of
science and technology at Zhejiang Academy of Medical Sciences and Yin Shi'an as the
principal investigator of the Chinese Center for Disease Control and Prevention).
94 See Qui, supra note 93 (noting that the study was approved at Zhejiang
Academy of Medical Sciences and conducted in Hunan Province).
95 See id.
96 See id (providing that Chinese Centers for Disease Control and Prevention staff
2013 ETHICS IN RESEARCH: GOLDEN RICE 997
Sciences.105
Shortly after publication, Greenpeace China criticized the
authors for performing experiments on the effect of transgenic rice
on children aged six to eight years old.' 0 6 As a result, Chinese
agricultural officials asked the Academy of Medical Sciences of
Zhejiang Province to investigate these events.' 07 Some Chinese
collaborators distanced themselves from the work.' Hu and
Wang stated that they did not know why their names appeared on
the paper.' 09 The Chinese Centers for Disease Control and
Prevention suspended one of these authors for "inconsistencies" in
his story."o Ultimately, the authorities of Hunan Province offered
financial compensation to the participants in the amount of
Y80,000 for the twenty-five children who received the Golden
Rice and Y10,000 per person for the others."'
105Id.at 658.
106Press Release, Greenpeace International, Greenpeace Alarmed at US-Backed
GE Food Trial on Chinese Children (Aug. 29, 2012), available at
http://www.gmwatch.org/latest-listing/51-2012/14157.
107 See Mara Hvistendhal & Martin Enserink, Charges Fly, Confusion Reigns Over
Golden Rice Study in Chinese Children, 1337 SCI. 1281, 1281 (2012) (explaining the
sequence of events leading from the Greenpeace press release to the Zhejiang Academy
of Medical Sciences' decision to stop the Tang study).
108 See id. (providing quotes found in Chinese state-run media from purported co-
authors Chinese Hu Yuming and Wang Yin claiming to be "completely baffled" and
"unaware" of the Tang article).
109 Id.
110 Id.
11I Qiu Quanlin, Parents of Students in GM Rice Test Win Payout, CHINA DAILY
(Dec. 8, 2012), http://www.chinadaily.com.cn/china/2012-12/08/content_15996929.htm
[hereinafter Quanlin] (stating that the families of the 25 children received what was the
equivalent of $12,800).
2013 ETHICS INRESEARCH: GOLDENRICE 999
B. Risks andBenefits
The parents were frightened by the use of genetically modified
organisms and the possible risks.125 Moreover, as discussed above,
119 See Tom Bartlett, The Golden Rice Controversy, CHRONICLE OF HIGHER EDUC.
(Sept. 11, 2012), http://chronicle.com/blogs/percolator/the-golden-rice-
controversy/30836 ("One oddity is that last week government officials in China told
reporters that the study did not involve genetically modified rice and that it was not done
in association with American researchers-even though just a glance at the paper's
abstract indicates otherwise.").
120 Tang et al., supra note 1, at 659.
121 Id
122 Id.
123 Id. In addition to any factual or scientific changes that may have occurred in the
interim, there is also the significant possibility that the protocol for approval changed
during that time.
124 See supra note 120 and accompanying text.
125 See Quanlin, supra note IlI ("The development of genetically modified rice
enjoys strong government support in China, but the public remains sceptical [sic] about
its safety.").
2013 ETHICS INRESEARCH: GOLDEN RICE 1001
126 See supra notes 102-103 and accompanying text (noting that it is unclear in
what amounts and at what times the children ingested Golden Rice).
127 See supra note 117 and accompanying text.
128 Tang et al., supra note 1, at 660.
129 See id. at 659 (the entire study was to last for thirty-five days, including a
fourteen day diet period).
130 See Qiu, supra note 93 (noting that it is unclear how much Golden Ric subjects
ingested).
'31 Id.
132 Vitamin A Equivalence,supra note 90.
133 Tang et al., supra note 1, at 659.
134 See Quanlin, supra note Ill ("[Nione of the children, their parents or school
1002 N.C. J. INT'L L. & COM. REG. Vol. XXXVIII
teachers were aware that Golden Rice was involved, according to .. . CCTV, China's
state television channel.").
135 See id. (explaining that the parents were not properly informed and therefore
could not have provided fully informed consent when allowing their children to
participate in this study).
136 See supra Part III (discussing the worldwide ethical principles for human
subject research including the Declaration of Helsinki, CIOMS Guidelines, and the
Declaration by UNESCO).
137 See Art Caplan, Greenpeace Out to Sea on GM Rice Issue, Bioethicist Says,
NBCNEWS.COM (Jan. 11, 2013), http://vitals.nbcnews.com/_news/2012/09/14/13863010-
greenpeace-out-to-sea-on-gm-rice-issue-bioethicist-says?lite ("[Greenpeace] say[s]
Chinese children were given dangerous genetically engineered rice in a study without
any consent from the kids, parents or the approval of the appropriate review bodies.").
138 Id
139 Id
2013 ETHICS IN RESEARCH: GOLDEN RICE 1003
140 Id
'41 Id
142 DEAN M. HARRIS, ETHICS IN HEALTH SERVICES AND POLICY: A GLOBAL
APPROACH 5-6 (2011).
143 Id
144 Id
145 Id
146 Id
147 Id
148 HARRIS, supra note 142, at 5-6.
1004 N.C. J.INT'L L. &COM. REG. Vol. XXXVIII
149 Nor does it end the ethical discussion to say that the study apparently violated
U.S. and Chinese laws. In some situations, an ethical imperative, such as saving lives,
might require doing something contrary to law. This is not to suggest that a violation of
law would have been justified in this particular case. Rather, the point is that merely
demonstrating a violation of law would not terminate all ethical analysis.
150 See Tang et al., supra note 1, at 658 (citing reports by the World Health
Organization and UNICEF).
151 Id. at 662.
152 See Abdullahi v. Pfizer, 562 F.3d 163, 186-87 (2d Cir. 2009) (noting that
"failure to secure consent for human experimentation has the potential to generate
substantial anti-American animus and hostility"); see also HARRIS, supra note 142, at
116-17 (discussing the complex litigation resulting from Pfizer's alleged failure to obtain
informed consent for Nigerian children's participation in a clinical trial).
2013 ETHICS IN RESEARCH: GOLDEN RICE 1005
153 Lynn R. Goldman & Michael J. Klag, CIA Deception Threatens Global Effort to
Eradicate Polio, BALTIMORE SUN (Jan. 7, 2013), http://articles.baltimoresun.com/2013-
01-07/news/bs-ed-polio-20130107_Ipolio-vaccine-fake-vaccination-program-global-
polio-eradication-initiative.
154 Id
155 Clinical Trials of Drug Quality Management Practices State Food and Drug
Administration Order No. 3, STATE FOOD & DRUG ADMINISTRATION,
http://www.sda.gov.cn/WSOI/CL0053/24473.html (last visited Apr. 18, 2013).
156 Id.
1006 N.C. J.INT'L L. &COM. REG. Vol. XXXVIII
191 See London, supra note 3, at 1080 (reaffirming that "reliance on procedural
aspects of consent is wholly insufficient to guarantee ethical standards in research" and
encouraging researchers to adjust consent procedures according to the participants'
cultural views and understanding).
192 See WHO STANDARDS, supra note 186, at 16-17 (encouraging extensive
interaction between researcher and community to promote clear communication); see 45
C.F.R. § 46.116 (2012) ("The information that is given to the subject or the
representative shall be in language understandable to the subject or the representative.").
193 See Man, supra note 166, at 61-62.
194 See id. (discussing the primary school's role in Golden Rice experiment).
'95 Id.
196 Id. As of April 14, 2013, 500 RMB (Chinese Yuan Renminbi) was equivalent
to $80.76. See Currencies, REUTERS, http://uk.reuters.com/business/currencies (last
visited Apr. 17, 2013) (providing up-to-date currency converter and currency table).
197 See Man, supra note 166, at 62-63.
2013 ETHICS INRESEARCH: GOLDENRICE 1013
198 See supra Part III (discussing the laws and guidelines for specific countries and
regions).