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The Risk Assessment of Pharmaceuticals in the Environment: EU and US Regulatory Approach

Published online by Cambridge University Press:  22 June 2018

Shona WALTER  and
Katerina MITKIDIS
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Abstract

The potential exposure to organisms and humans of pharmaceutical waste presents society with a wicked problem. The health benefits of pharmaceuticals are obvious, but the public awakening to the risks posed by pharmaceutical residues in the environment is in its early stages. Regulators in the US and the EU require an environmental risk assessment of a medicinal product before it can enter the market. This article compares the US and EU approach to assessing these risks, with the purpose of providing a different perspective on how to approach this delicate balancing act of risk and benefit and to reveal the different values underpinning the risk assessment.

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Articles
Information
European Journal of Risk Regulation , Volume 9 , Issue 3: Symposium on Effective Law and Regulation , September 2018 , pp. 527 - 547
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© Cambridge University Press 

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Footnotes

*

Corresponding author. Research assistant, Department of Law, Aarhus University, e-mail: [email protected]. This article is one of the outcomes of a project entitled “Pharmaceuticals in the Environment: Legal Solutions Informed by Behavioural Science”, funded by the Aarhus Universitets Forskningsfond. The authors would like to extend special thanks to Professor Ellen Margrethe Basse and Dr Elodie le Gal for their invaluable comments on the draft version of this paper.

**

Associate professor, Department of Law, Aarhus University, e-mail: [email protected].

References

1 This article focuses solely upon pharmaceuticals for human use, as pharmaceuticals for veterinary use undergo a different risk-benefit analysis, under a different set of regulations.

2 World Health Organisation, “WHO Technical Report Series” (2011) No 961, Annex 10 (Procedure for prequalification of pharmaceutical products) pp 374–375: “active pharmaceutical ingredient (API): A substance used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings”.

3 Besse, J-P et al, “Anticancer drugs in surface waters: What can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs?” (2012) 39(1) Environment International 73–86 CrossRefGoogle ScholarPubMed.

4 Jobling, S et al, “Widespread sexual disruption in wild fish” (1998) 32 Envir Sci Technol 2498 CrossRefGoogle Scholar; Larsson, DG et al, “Ethinyloestradiol – an undesired fish contraceptive?” (1999) 45 Aquat Toxicol 91 CrossRefGoogle Scholar.

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7 Schoenfuss, HL et al, “Complex mixtures, complex responses – Assessing pharmaceutical mixtures using field and laboratory approaches” (2016) 35(4) Environmental Toxicology and Chemistry 953 CrossRefGoogle ScholarPubMed, <toxics.usgs.gov/highlights/2015-11-13-pharmacuticals_and_minnows.html> accessed 29 May 2018. This study is part of a larger scientific investigation investigating the health risks to humans and wildlife from low level exposure to toxic substances.

8 Eg F Hoffmann-La Roche Ltd, “Roche Position on Pharmaceuticals in the Environment”, first adopted and published 17 August 2011, reviewed in April 2017, p 1 <www.roche.com/dam/jcr:05ea28bc-d654-47cb-a6ae-9d46de15b29b/en/15_Position_Pharmaceuticals-in-the-Environment_reviewed_4_2017.pdf> accessed 29 May 2018. See also European Federation of Pharmaceutical Industries and Associations (EFPIA), “Pharmaceuticals in the Environment (PIE)” <www.efpia.eu/about-medicines/development-of-medicines/regulations-safety-supply/pharmaceuticals-in-the-environment-pie/> accessed 29 May 2018.

9 BIO Intelligence Service, “Study on the environmental risks of medicinal products” Final Report prepared for Executive Agency for Health and Consumers (2013) p 25 (BIOIS Report). The authors of this report favour the inclusions of environmental risk assessment results into the final risk-benefit analysis. The Swedish government also supported this approach in their official response to the EU Commission’s call for submission on the strategic approach to pharmaceuticals in the environment: Government Offices of Sweden, “Swedish response on roadmap regarding strategic approach to pharmaceuticals in the environment” Memorandum 26 May 2017. The European pharmaceutical industry favours the implementation of soft law instruments rather than additional regulations and changes in policy: EFPIA et al, “Eco-Pharmaco-Stewardship (EPS) A Holistic Environmental Risk Management Program” p 5 <www.efpia.eu/media/25628/eps-a-holistic-environmental-risk-management-program.pdf> accessed 29 May 2018.

10 When referring to these EU and US procedures together, the term “regulatory procedures” is used. The term “medicine” is used to cover both the US legal term “drug” and the EU legal term “medicinal product”. The term E(R)A is used to refer to the both the EU “Environmental Risk Assessment” procedure and the US “Environmental Assessment” procedure.

11 Eg Carson, R, Silent Spring (Houghton Mifflin 1962)Google Scholar; Lokke, S, “The Precautionary Principle and Chemicals Regulation” (2006) 5 Environment Science Pollution Resources 342 CrossRefGoogle Scholar; Taylor, D et al, “Human pharmaceutical products in the environment – The ‘problem’ in perspective” (2014) 115 Chemosphere 95 CrossRefGoogle Scholar.

12 Taylor et al, supra, note 11.

13 Louis, GE et al, “Representing inequities in the distribution of socio-economic benefits and environmental risk” (2002) 79 Environmental Monitoring and Assessment 102 CrossRefGoogle ScholarPubMed.

14 Taylor, D, “There is a Conflict at the Heart of EU Water Pollution Policy” (2015) 3 EJRR 430 Google Scholar.

15 This article examines the EU level of regulation within the EU context and the federal level of regulation within the US context. Differences at national and state level respectively are not addressed.

16 In 2016, the global sale of pharmaceutical drugs was estimated at USD$ 967 billion. The US was responsible for USD$ 446 billion and the EU for USD$ 201 billion <www.statista.com/statistics/272181/world-pharmaceutical-sales-by-region/> accessed 29 May 2018.

17 Sanderson, H et al, “Ranking and prioritization of environmental risks of pharmaceuticals in surface water” (2004) 39 Regulatory Toxicology and Pharmacology 159 CrossRefGoogle Scholar. Between 10–70% of orally administered medicines’ active ingredients are metabolised by the body; the rest are excreted and end up in the wastewater treatment system, BIOIS Report, supra, note 9, p 19.

18 “US–EC Measures Concerning Meat and Meat Products (Hormones)” WT/DS26/R/USA, 18 August 1997; Report of the Appellate Body, “EC Measures Concerning Meat and Meat Products (Hormones)” WT/DS48/AB/R, 16 January 1998. This decision is discussed in Part II, section 3 below.

19 See <www.ich.org/about/mission.html> accessed 29 May 2019.

20 Supra, note 10.

21 European Commission, “Strategic approach to pharmaceuticals in the environment”, DG ENV, Ares(2017)2210630, p 28 April 2017.

22 In the EU context, Directive 2001/83/EC. In the US context, the United States Code, Title 21 Food and Drugs, Chapter 9 Federal Food, Drug and Cosmetic Act, subchapter 5, section 355(1)(a) (21 USC §355(1)(a)).

23 The EU has financed several research projects focused on improving the ERA of pharmaceuticals, see eg Environmental Risk Assessment of Pharmaceuticals (ERA Pharm): the aim of the project was to advance existing knowledge and methods for evaluating potential risks posed by human and veterinary medicines to the environment, <www.erapharm.org/> accessed 29 May 2018. EMCO: a project which aimed to reduce environmental risk, posed by emerging contaminants, through advanced treatment of municipal and industrial wastes, <cordis.europa.eu/project/rcn/74202_en.html> accessed 29 May 2018.

24 WHO, “Pharmaceuticals in Drinking-water” (2011) WHO/HSE/WSH/11.05, p 28 “Analysis of the results indicated that appreciable adverse health impacts to humans are very unlikely from exposure to the trace concentrations of pharmaceuticals that could potentially be found in drinking-water”.

25 F Hoffmann-La Roche Ltd, supra, note 8, p 1.

26 European Medicines Agency, “Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use”, EMEA/CHMP/SWP/4447/00 corr 2 (2006), p 3 (EMA Guidelines).

27 E Touraud, “KNAPPE Report” (2008) p 1, available at <cordis.europa.eu/docs/publications/1245/124584761-6_en.pdf> accessed 14 June 2018.

28 For example, antimicrobial resistance (AMR) has been directly related to the chronic presence of low levels of antibiotics in the environment: K Kummerer, “Antibiotics in the aquatic environment – a review – part II” (2009) 75(4) Chemosphere 417. In the US, every year at least two million people are infected by bacteria resistant to antibiotics, which leads to 23,000 deaths because of these infections <www.cdc.gov/drugresistance/index.html> accessed 29 May 2018.

29 Concerning the effects upon aquatic species from long-term chronic exposure to endocrine disrupting substances see S Jobling et al, “Ethinyl oestradiol in the aquatic environment” ch 13 in European Environment Agency, Late lessons from early warnings, EEA Report No 1/2013; concerning the effects of AMR see Kummerer, supra, note 28.

30 In the US, Pharmaceuticals and Personal Care Products are not regulated in surface and drinking water, meaning that we have no reliable data about the level of their presence: National Environmental Services Center at West Virginia University, Pipeline (Winter 2007) 18(1), p 1.

31 WHO, supra, note 24, p 6.

32 For more detailed discussion on the same, see Part III, section 3 below.

33 By comparison, Regulation (EC) 1907/2006 of the European Parliament and of the Council of 18th December 2006 concerning the Registration, Authorisation and Restriction of Chemicals [2006] OJ L 396, p 1 (REACH Regulation) considers multiple sources of exposure from a substance or similar substances.

34 SCHER, SCCS, SCENIHR, “Opinion on the Toxicity and Assessment of Chemical Mixtures”, European Union (2012) p 30 Google Scholar.

35 WHO, supra, note 24, p 29. See also Touraud, supra, note 27, p 1. Some possible effects include endocrine disruption, disruption of microbial ecosystems, growth inhibition, cytotoxicity, mutagenicity and teratogenicity: Silva, E et al, “Something from ‘nothing’ – Eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects” (2002) 36/8(1) Environ Sci Technology 751 Google Scholar.

36 This article does not discuss the possible use of the precautionary principle for managing the risks of PiE.

37 Jobling et al, supra, note 29, p 279.

38 Directive 2001/83/EC, Art 8(3)(ca) “Evaluation of the potential environmental risks posed by the medicinal product. This impact shall be assessed and, on a case-by-case basis, specific arrangements to limit it shall be envisaged”.

39 However, Art 8(3)(ca) of Directive 2001/83/EC was not the first implementation of environmental concerns into the European pharmaceutical law. The first such inclusion of environmental protection can be found in Art 4(6) of Council Directive 65/65/EEC on the approximation of provisions laid down by Law, Regulation or Administrative Action relating to proprietary medicinal products [1965] OJ L 22, 369, introduced in 1994 “If applicable, reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of any potential risks presented by the medicinal product for the environment”. See also Spindler, P et al, “Environmental Assessment for Human Medicines in the European Union” (2007) 41 Drug Information Journal 149 Google Scholar.

40 Consolidated Version of the Treaty on the Functioning of the European Union (2016) OJ C 202, Art 11, “Environmental protection requirements must be integrated into the definition and implementation of the Union policies and activities, in particular with a view to promoting sustainable development”.

41 42 USC §4321 et sqq (1969).

42 US Department of Health and Human Services et al, “Guidance for Industry Environmental Assessment of Human Drug and Biologics Applications”, July 1998 (US Guidance for industry) p 1.

43 The USC, also known as the Code of the Laws of the United States of America, is the codification and compilation of the federal statutes of the United States. They are the Acts of Congress, which are then signed by the President.

44 21 USC § 355.

45 21 CFR 25.15; 21 CFR 25.20(l). The Code of Federal Regulations is a codification of the rules and regulations published by the federal government and executive departments and agencies of the US.

46 21 CFR 25.15; 21 CFR 25.20.

47 21 CFR 314.101(d)(4), 601.2(a) and (c), and 25.15(a). The categorical exclusions are discussed later on in the paper.

48 21 CFR 25.15(a).

49 BIOIS Report, supra, note 9, p 146.

50 Caneva, L et al, “Critical review on the environmental risk assessment of medicinal products for human use in the centralised procedure” (2014) 68 Regulatory Toxicology Pharmacology 312 CrossRefGoogle ScholarPubMed.

51 ibid, p 313.

52 ibid, p 315.

53 BIOIS Report, supra, note 9, p 130. See also Caneva, supra, note 50, p 315.

54 Directive 2001/83/EC, Art 8(3)(ca).

55 Directive 2001/83/EC, Art 1(28d).

56 AESGP, EFPIA & EGA, “Eco-Pharmaco-Stewardship (EPS) A Holistic Environmental Risk Management Program” p 5 <www.efpia.eu/media/25628/eps-a-holistic-environmental-risk-management-program.pdf> accessed 14 June 2018.

57 Touraud, supra, note 27, p 4.

58 Gross, M et al, “Environmental Risk Assessment of Human Pharmaceuticals: Regulatory Developments” (2016) 12(1) Journal of Integrated Environmental Assessment and Management 7–8 (retracted)Google Scholar.

59 Agerstrand, M et al, “Improving Environmental Risk Assessment of Human Pharmaceuticals” (2015) 49 Environmental Science and Technology 5341 CrossRefGoogle ScholarPubMed.

60 ibid.

61 Case T-13/99 Pfizer Animal Health SA v Council of the European Union [2002] ECR II-3305. The Pfizer decision concerned the risks of AMR due to the non therapeutic use of antibiotics in the feed of animals for human consumption and is widely known for its discussion of the precautionary principle.

62 Pfizer, supra, note 61, paras. 150–151.

63 The Directive refers to Art 95 of the Treaty establishing the European Community, now Art 114 of the Treaty on the Functioning of the European Union (TFEU).

64 Directive 2001/83/EC, Preamble, para. 2 “The essential aim of any rules governing the production, distribution and use of medicinal products must be to safeguard public health”.

65 Commission, “Safe, Innovative and Accessible Medicines: a Renewed Vision for the Pharmaceutical Sector”, COM 666 final, p 3. “Since 1965, Community action in the field has always had the dual objective of safeguarding public health by providing Europe with safe and effective medicines, while at the same time creating a business environment that stimulates research, boosts valuable innovation and supports the competitiveness of the industry”.

66 Natural Defence Council, INC, et al v United States Food and Drug Administration, et al, US Dist Court Southern District NY 42 ELR 20117, decided 1 June 2012.

67 ibid, p 15.

68 ibid. See also 21 USC § 360b(b)(1)(A).

69 ibid.

70 ibid, p 18.

71 Massachusetts v EPA, 549 US 535; Natural Defence Council, Inc, et al v United States Food and Drug Administration, et al, 42 ELR 20117, p 16.

72 CFR Part 25.40(a).

73 CFR Part 25.40(e).

74 CFR 25.52(b).

75 Directive 2010/84/EU amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use [2010] OJ L 348.

76 Directive 2001/83/EC, Annex 1, sec 1.6.

77 CFR title 21, part 25.15(a).

78 CFR title 21, part 25.15(b).

79 CFR title 21, part 25.15(b).

80 ICH, “Testing for Carcinogenicity of Pharmaceuticals S1B” dated 16 July 1997.

81 ICH, “Guidance on Genotoxicity testing and Data Interpretation for Pharmaceuticals intended for Human use S2(R1)” dated 9 November 2011.

82 ICH, “Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent Toxicity Testing) S4” dated 2 September 1998.

83 ICH, “Detection of Toxicity to Reproduction for Medical Products & Toxicity to Male Fertility S5(R2)” dated 24 June 1993.

84 ICH “Immunotoxicity Studies for Human Pharmaceuticals” dated 15 September 2005.

85 Under US law CFR title 21, part 25.15(c) uses the term “not significantly affecting the human environment”. Under EU law, the EMA Guidelines state that if the predicted environmental concentration (PEC) of the medicine is below a certain level, it is not considered a risk to the environment: EMA Guidelines, supra, note 26, p 5.

86 CFR title 21, part 25.15(c).

87 EMA Guidelines, supra, note 26, p 4. Any medicine which has a PEC below a certain value is not considered a risk.

88 See CFR title 21, part 25.15 General Procedures.

89 CFR title 21, part 25.21(b) specifically mentions the Endangered Species Act of 1973, the Convention on the International Trade in Endangered Species of Wild Flora and Fauna (signed at Washington, DC, on 3 March 1973, entered into force 1 July 1975) and any endangered wild flora or fauna entitled to protection under federal law.

90 CFR title 21, part 25.21(b).

91 CFR title 21, part 25.40(c) encourages applicants to consult “FDA EA guidance documents, which provide additional advice on how to comply with FDA regulations.” CFR title 21, part 25.21. See also US Guidance for Industry, supra, note 42, pp 6–7.

92 CITES covers species located all over the world: <checklist.cites.org/#/en> accessed 29 May 2018. The Endangered Species Act of 1973 protects 631 species located outside of the US, see <ecos.fws.gov/ecp0/reports/ad-hoc-species-report-input> accessed 14 June 2018.

93 SumOfUS, “Bad Medicine – How the pharmaceutical industry is contributing to the global rise of antibiotic-resistant superbugs” June 2015 <www.sumofus.org> accessed 29 May 2018, p 7.

94 ibid, p 26. This report recommends that legislators in the EU and US should revise the Good Manufacturing Practices (GMP) to include environmental criteria, such as water quality standards and good waste management, p 35. Companies wishing to import antibiotics to the US and EU are required to comply with the GMP guidelines, see Directive 2001/83/EC, Art 46b(1) and 21 USC §381(a) and §360j(f).

95 The EMA Guidelines explicitly state that “Directive 2001/83/EC, as amended, relates to those risks to the environment arising from the use, storage and disposal of medicinal products and not to risks arising from the synthesis or manufacture of medicinal products”: EMA Guidelines, supra, note 26, p 3.

96 Directive 2010/75/EU of the European Parliament and of the Council of 24 November 2010 on industrial emissions (formally known as the integrated pollution prevention and control) [2010] OJ L 334.

97 National legislation from Sweden, Germany and the Netherlands also does not include emission limit values for APIs: see BIOIS report, supra, note 9, p 152.

98 For example, any species listed in Annex II of the Habitats Directive or Annex I of the Birds Directive. Directive 92/43/EEC on the Conservation of Natural Habitats and of Wild Fauna and Flora (Habitats Directive) [1992] OJ L206/7, Directive 79/409/EEC on the Conservation of Wild Birds (Birds Directive) [1979] OJ L103/1.

99 Habitats Directive, Art. 3. See also European Commission, Natura 2000, <ec.europa.eu/environment/nature/natura2000/index_en.htm> accessed 29 May 2018.

100 CFR title 21 part 25.31

“Human drugs and biologics.

The classes of actions listed in this section are categorically excluded and, therefore, ordinarily do not require the preparation of an EA or an EIS:

(a) …if the action does not increase the use of the active moiety.

(b) …the estimated concentration of the substance at the point of entry into the aquatic environment will be below 1 part per billion.

(c) … for substances that occur naturally in the environment when the action does not alter significantly the concentration or distribution of the substance, its metabolites, or degradation products in the environment”.

101 US Guidance for Industry, supra, note 42, p 1.

102 Gross, supra, note 58, p 6.

103 21 CFR part 25.21(b) Extraordinary circumstances.

“As required under 40 CFR 1508.4, FDA will require at least an EA for any specific action that ordinarily would be excluded if extraordinary circumstances indicate that the specific proposed action may significantly affect the quality of the human environment (see 40 CFR 1508.27 for examples of significant impacts). Examples of such extraordinary circumstances include:

(a) …the potential for serious harm to the environment; and

(b) Actions that adversely affect a species or the critical habitat of a species determined under the Endangered Species Act or the Convention on International Trade in Endangered Species of Wild Flora and Fauna to be endangered or threatened or wild flora or fauna that are entitled to special protection under some other Federal law”.

104 However, these two examples do not limit the meaning of the term “extraordinary circumstance”.

105 CFR part 25.21(a); US Guidance for Industry, supra, note 42, pp 6–7.

106 CFR part 25.21(b). This includes species or habitat protected under the Endangered Species Act, or the Convention on International Trade in Endangered Species of Wild Fauna and Flora, or protected under some other Federal Law; see US Guidance for Industry, supra, note 42, pp 6–7.

107 Directive 2001/83/EC, Art 10(2)(b) “‘generic medicinal product’ shall mean a medicinal product which has the same qualitative and quantitative composition in active substance and the same pharmaceutical form as the reference medicinal product”.

108 Also known as Type II variations, this is a change which may have an effect on the safety, efficacy or quality of the medicine concerned.

109 EMA Guidelines, supra, note 26, p 3. In this situation, the MA holder can reuse environmental information submitted in the original application.

110 European Medicines Agency, “Questions and answers on ‘Guidelines on the environmental risk assessment of medicinal products for human use’” EMA/CHMP/44609/2-10, p 4.

111 BIOIS Report, supra, note 9, p 117.

112 ibid, p 118.

113 See <www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/05/WC500205987.pdf> accessed 29 May 2018, 2. The interpretation of the guidelines has not been clear on this point and the EMA is due to issue a revised set of Guidelines clarifying this issue and others in 2018.

114 BIOIS Report, supra, note 9, p 117.

115 ibid, p 118.

116 Directive 2001/83/EC, Art 24(1) “Without prejudice to paras. 4 and 5, a marketing authorisation shall be valid for five years”.

117 Directive 2001/83/EC, Art 24(2) “The marketing authorisation may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the competent authority of the authorising Member State”.

118 Directive 2001/83/EC Annex I, 1.6. Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms [2001] OJ L106/1.

119 S Jasanoff, “Citizens at Risk: Cultures of Modernity in the US & EU” (2002) 11(3) Science as Culture 369.

120 On 1 October 2001 the US, supported by Canada, launched two official protests before the SPS Committee, in protest to the requirements contained in Directive 2001/18/EC. In particular, they disagreed with the requirements with regard to the labelling and traceability of GM produce and the approval process; Hornsby, DJ, Risk Regulation, Science, and Interests in Transatlantic Trade Conflicts (Palgrave Macmillan 2014) pp 142 and 158CrossRefGoogle Scholar.

121 Eg mad cow disease, dioxin contamination and hormone fed beef: ibid, p 143.

122 ibid, p 143.

123 ibid, p 142.

124 CFR part 25.40(e).

125 Directive 2001/83/EC, Art 8(3)(ca).

126 Directive 2001/83/EC, Art 8(3)(g).

127 Directive 2001/83/EC, Art 8(3)(j).

128 The EMA has interpreted this as situations when “the possibility of environmental risks cannot be excluded,” see EMA Guidelines, supra, note 26, p 9.

129 Directive 2001/83/EC, Art 54(j).

130 21 USC § 355(r)(2)(F).

131 21 USC § 355(n)(3)(B). The regulation mentions expertise in the fields of “clinical and administrative medicine, pharmacy, pharmacology, pharmacoeconomics, biological and physical sciences”.

132 21 USC § 355(n)(3)(A). For example, in the development, manufacture and use of medicines.

133 21 USC § 355(n)(3)(C).

134 21 USC § 355(n)(3).

135 Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency [2004] OJ L 136, Art 55. CHMP evaluates the MA application, with the support of the PRAC, which provides input related to risk management, and the Committee for Advanced Therapies (CAT) on advanced therapy medicines. NB different rules will apply within each Member State for products registered under the decentralised, mutual recognition and national procedures.

136 EMA, “Pharmacovigilance Risk Assessment Committee Rules of Procedure” EMA/PRAC/567515/2012 Rev.1, Art 1(1).

137 ibid, Art 1(2).

138 BIOIS Report, supra, note 9, p 196.

139 Jasanoff, supra, note 119, p 373.

140 For example, in the EU during the 1970s it was discovered that DES (dethylstilboestrol) was illegally used in veal production in France, which caused hormonal irregularities in adolescents. Consumers reacted by calling for a boycott of veal: WTO Panel Decisions EC v US, para. 2.22. Jasanoff, supra, note 119, p 368. The US has taken a more cautious approach to stem cell research and cloning than the EU, as seen by President Bush’s decision to limit funding for stem cell research in 2001 and the House of Representative’s ban in 2001 on all forms of cloning, Jasanoff, supra, note 119, pp 364–365.

141 US–EC Measures Concerning Meat and Meat Products, supra, note 18; Report of the Appellate Body, EC Measures Concerning Meat and Meat Products (Hormones), supra, note 18, para. 2.26.

142 The EU Commission did not consider growth hormones a health risk, whereas the Council and the Parliament did consider them to be such a risk: Hornsby, supra, note 120, p 138.

143 ibid, p 139.

144 ibid, p 138.

145 US–EC Measures Concerning Meat and Meat Products (Hormones), supra, note 18. See eg para. 8.140 “The United States argues that the European Communities has never performed an appropriate assessment of these alleged risks and has, in any event, not relied on, nor put forward, any assessment of these risks that could serve as a basis for the EC ban”.

146 ibid, paras. 8.165 and 5.28. The measures should be based upon in particular Arts 2, 5.2, 5.3, 5.4, 5.5 and 5.6 of the SPS Agreement.

147 ibid, para. 5.18. They argue this is an established principle under Art XX(b) of the GATT Agreement.

148 ibid, para. 5.19.

149 For a resumé of the academic debate concerning the reasons for this trans-Atlantic divide, see Hornsby, supra, note 120, pp 4–6.

150 Directive 2001/83/EC, Art 10; 21 USC § 355. While the data protection period lasts for eight years and the market exclusivity period for another two years within the EU, the data protection period within the US lasts for five years only. This is justified by the possibility to prolong patent protection for pharmaceuticals for five years.

151 CFR part 25.50(b); Directive (EU) 2016/943 on the protection of undisclosed know-how and business information (trade secrets) against their unlawful acquisition, use and disclosure, [2016] OJ L 157.

152 CFR part 25.51(a); see also US Guidance for Industry, supra, note 42, pp 26–27.

153 CFR part 25.51(a).

154 CFR part 25.52(b)(2).

155 Küster, A et al, “Pharmaceuticals in the environment: scientific evidence of risks and its regulation” (2014) 369 Philosophical Transactions of the Royal Society B: Biological Sciences (1656) p 6 CrossRefGoogle ScholarPubMed.

156 Regulation No 726/2004, Art 13(3).

157 Agerstrand et al, supra, note 59, p 5339.

158 BIOIS Report, supra, note 9, pp 180–183; Agerstrand et el, supra, note 59, p 5337; Caneva et al, supra note 50, pp 312–316.

159 A pilot open-access database of ecotoxicity data for pharmaceutical substances has been established in Sweden <www.mistrapharma.se/wikipharma-13497291> accessed 29 May 2018.

160 EMA, “Concept paper on the revision of the ‘Guideline on the environmental risk assessment of medicinal products for human use EMEA/CHMP/SWP/4447/00 corr 2’” (2016) EMA/CHMP/SWP/65429/2016, <www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/05/WC500205987.pdf> accessed 29 May 2018.

161 Case T-235/15, Pari Pharma v EMA; Case T-718/15, PTC Therapeutics International v EMA; Case T-729/15, MSD Animal Health Innovation and Intervet international v EMA.

162 EMA, “General Court confirms EMA approach to transparency, Three rulings clarify the scope of commercial confidentiality with regard to authorised medicines”, 6 February 2018, EMA/73690/2018.

163 Directive 2003/4/EC on public access to environmental information, [2003] OJ L 41, Art 7(2)(g).

164 EMA policy on access to documents (related to pharmaceuticals for human and veterinary use), Policy/0043, effective on 1 December 2010, Doc Ref EMA/110196/2006 “(A)ny information which is not in the public domain or publicly available and where disclosure may undermine the economic interest or competitive position of the owner of the information”. NB the policy has been revised and opened for public consultation in February 2017 (EMA/729522/2016).

165 Directive 2003/4/EC, Art 4(2)(d).

166 See relevant discussion on the case in Part II, section 1 above.