News & views ethical standards for clinical trials conducted in third countries: The new strategy of the European medicines agency

European Journal of Health Law

Volumn 18, Issue 1, 2011, Pages 65-75

  Altavilla, Annagrazia ^a,b  

^a AIX MARSEILLE UNIVERSITY   (France)

^b Bar of Taranto ^*  (Italy)

Author keywords

clinical research; ethical trials; Europe; European Medicines Agency (EMA); third countries

Indexed keywords

ARTICLE; CLINICAL TRIAL (TOPIC); DEVELOPING COUNTRY; ETHICS; EUROPE; GOVERNMENT; HUMAN; HUMAN EXPERIMENT; STANDARD;

CLINICAL TRIALS AS TOPIC; DEVELOPING COUNTRIES; EUROPE; GOVERNMENT AGENCIES; HUMAN EXPERIMENTATION; HUMANS;

EID: 79952151975     PISSN: 09290273     EISSN: 15718093     Source Type: Journal    
DOI: 10.1163/157180911X546129     Document Type: Review

References (45)

1. The information presented in this report relates mainly to new applications (347) and line extensions (63), but also includes some variations (42) where new clinical trial information was provided. Care needs have to be taken into account when interpreting these data. In particular, it should be considered that only those trials identified by the applicant as pivotal at the time of the MAA are included. Supportive trials are not included, which means Phase I, most Phase II and some Phase III trials. Finally, many products so the clinical trials on those products do not appear in these data. European Medicines Agency, Clinical trials submitted in marketing authorisation applications to the EMA: Overview of patient recruitment and the geographical location of investigator site, Doc. Ref. EMA/INS/GCP/154352/2010, 5 of November 2010. Retrieved November 15th, 2010 http://www.ema.europa.eu/docs/en-GB/ document-library/Other/2009/12/WC500016819.pdf.
2. It should be noted that those countries with more than 100 pivotal clinical trials included in MAAs to the EMA, during the whole period are: USA and Canada (North America), Germany, France, Italy, UK, Spain, Belgium, Poland and the Netherlands (EU/EEA/EFTA), Australia and Russia (ROW).
3. The average number of patients for sites is higher in Africa (25) and in Central/South America (21).
4. The average number of patients per site in the new European countries is higher (19) than in the others.
5. The data collection period (2005-2008) is very short and the major trends are undoubtedly taking place over a longer term. The widespread information on increases in clinical trials in Asia has probably not yet been reflected in the MAAs or is related to trials that will not all be included in MAAs. Maybe a bias in the data is because the pharmaceutical companies may prefer to conduct (part of) their pivotal trials in the key EU and North American markets.
6. F. Hirsch and E. Hirsch (eds.), Éthique de la recherche et des soins dans les pays en développement, Paris, Espace Éthique, Vuibert, 2005, 179 pp.;
7. Nuffield Council on Bioethics, The ethics of research related to healthcare in developing countries, 2002, 190 p. Retrieved 31 July 2010, online at: http://www.nuffieldbioethics.org/fileLibrary/pdf/errhdc-fullreport001.pdf;
8. H. T. Shapiro and E. M. Meslin, "Ethical Issues in the Design and Conduct of Clinical Trials in Developing Countries", NEJM, 345, (2001), 139-142. (Pubitemid 32634575)
9. G. Koski and S. L. Nightingale, "Research Involving Human Subjects in Developing Countries", NEJM, 345(2001), 136-138; (Pubitemid 32634574)
10. H. Varmus, D. Satcher, "Ethical Complexities of Conducting Research in Developing Countries", NEJM, 337(1997), 1003-1005. (Pubitemid 27425960)
11. C. Rowland, "Clinical trials seen shifting overseas", Int. J. Health Serv., 34(2004), 555-556.
12. SOMO, 2008, Briefing paper: examples of unethical trials, Centre for Research on Multinational Corporations, December 2006, Updated February 2008, 16pp. online at: http://somo.nl/html/paginas/pdf/Examples-of-unethical-trials- nov-2006-NL.pdf.
13. S. Yusuf, "Randomized clinical trials: slow death by a thousand unnecessary policies?", CMAJ, 171(2004), 889-892.
14. S. Rai, "Drug companies cut costs with foreign clinical trials", New York Times. 24 February 2005, C4.
15. WHO, 2006, Making the most of existing health workers (chapter 4), Working together for health: the World Health Report. Geneva: World Health Organization, retrieved 30 December 2009 online at: http://www.who.int/whr/2006/ chapter4/en/index.html.
16. W. Bailey, C. Cruickshank and N. Sharma, "Make your move: taking clinical trials to the best location", retrieved 30 December 2009, online at: http://www.atkearney.com/main. taf?p=5, 1, 1, 116, 3, 1/)
17. In one study only 56% of the 670 researchers surveyed in developing countries reported that their research had been reviewed by a local institutional review board or Health Ministry.
18. AA. Hyder, S. A. Wali, A.N. Khan, N. B. Teoh, N. E. Kass and L. Dawson, "Ethical review of research: a perspective from developing country researchers", J Med Ethics, 30(2004), 68-72. (Pubitemid 38262812)
19. In another study it was underlined that 90% of published clinical trials conducted in China in 2004 did not report ethical review of the protocol and only 18% adequately discussed informed consent.
20. D. Zhang, P. Yin, N. Freemantle, R. Jordan, N. Zhong and K. K. Cheng, "An assessment of the quality of randomized controlled trials conducted in China", Trials, 9(2008), 22.
21. M. Angell, "Investigators' Responsibilities for Human Subjects in Developing Countries", NEJM, 342(2000), 967-969. (Pubitemid 30177058)
22. A study of 42 genetic variants associated with pharmacologic response in drug studies showed that more than two thirds had significant differences in frequency between persons of African ancestry and those of European ancestry.
23. D. B. Goldstein, S. K. Tate and S. M. Sisodiya, "Pharmacogenetics goes genomic", Nat Rev Genet, 4, (2003), 937-947. (Pubitemid 37474641)
24. [Erratum, Nat Rev Genet 2004;5:76.].
25. WMA, Declaration of Helsinki 2008, art.17;
26. WHO-International Ethical Guidelines for Biomedical Research Involving Human Subjects-CIOMS, Ethical Guidelines n. 10.
27. S. W. Glickman, J. G. Mchutchison, E. D. Peterson, C. B. Cairns, R. A. Harringhton, R. M. Califf and K. A. Schulman, "Ethical and scientific implications of the globalization of clinical research", The New England Journal of Medicine, 360(8) (2009), 816-823.
28. In the 'Community' or 'centralised' procedure, the CHMP is responsible for conducting the initial assessment of medicinal products for which a Community-wide marketing authorisation is sought. The CHMP is also responsible for several post-authorisation and maintenance activities, including the assessment of any modifications or extensions ('variations') to the existing marketing authorisation. In the 'mutual-recognition' and 'decentralised' procedures, the CHMP arbitrates in cases where there is a disagreement between Member States concerning the marketing authorisation of a particular medicinal product ('arbitration procedure'). The CHMP also acts in referral cases, initiated when there are concerns relating to the protection of public health or where other Community interests are at stake ('Community referral procedure').
29. Since the implementation of the GCP inspection policy in 2006, there is an increase of GCP inspections in Third counties. The countries with highest number of sites inspected are USA (21.9%) followed by Canada (5.7%), India (3.9%), Russia (3.5%) and China (1.8%). Germany and Czech Republic were the countries in the EU with most inspection of trial sites.
30. See the above mentioned EMA report.
31. J. S. Hawkins, E. J. Emanuel, Exploitation and developing countries. The ethics of clinical research, Princeton, NJ: Princeton University Press, 2008, 327 pp.
32. DIRECTIVE 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. (Consolidate version: 30 December 2008.
33. REGULATION (EC) N. 726/2004 of the European Parliament and of The Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.
34. This statement is applicable for all new applications (including extension applications), and other relevant post-authorisation regulatory procedures (e.g. variations) for which clinical trial reports are submitted.
35. This phase plays a pivotal role in the Marketing Authorisation process of drugs.
36. See the case of Abilify (aripiprazole), a drug for schizophrenia approved by the EMEA 2004. In the case of Abilify, the trials that were pivotal in the EPAR can be considered unethical because of the use of placebos, which involve serious risks for schizophrenia patients, while effective alternative treatments already exist.
37. See also the case of Olmetec (olmesartan medoxomil), a drug for hypertension approved for the EU by the German drug authorities in March 2003. I. Schipper and F. Weyzig, "Ethics for Drug Testing in Low and Middle Income Countries, Considerations for European Market Authorisation", SOMO, (2008), 77 p.
38. The European Public Assessment Report (EPAR) reflects the scientific conclusion reached by the Committee for Medicinal Products for Human use (CHMP) at the end of the centralised evaluation process. The legal basis for its creation and availability is contained in Article 13(3) of Regulation (EC) No 726/2004. It is made available by the EMA for information to the public, after deletion of commercially confidential information.
39. The EPAR provides a summary of the grounds for the CHMP opinion in favour of granting a marketing authorisation for a specific medicinal product. It results from the Committee's review of the documentation submitted by the applicant, and from subsequent discussions held during CHMP meetings. The EPAR is updated throughout the authorisation period as changes to the original terms and conditions of the authorisation (i.e. variations, pharmacovigilance issues, specific obligations) are made. EPARs also contain a summary written in a manner that is understandable to the public. The summary, list of authorised presentations and the product information (SPC, labelling and package leaflet) for all authorised presentations are provided in all EU languages. The scientific discussion, procedural steps before authorisation and steps taken after authorisation are available in English only.
40. European Group on Ethics in Sciences and New Technologies, 2003, Opinion n. 17: Ethical aspects of clinical research in developing countries, 4 February 2003, 16pp. Online at: http://ec.europa.eu/european-group-ethics/docs/avis17-en. pdf.
41. European Medicines Agency, 2008, Action plan: Acceptance of clinical trials conducted in third countries for evaluation in Marketing Authorisation Applications, EMA, December 2008, online at: http://www.ema.europa.eu/ Inspections/docs/22806708en.pdf.
42. The document focuses mainly on the following EMA activities: Scientific Advice in the drug development phase, Paediatric Investigation Plan (PIP) evaluation, Orphan Drug designation, Marketing Authorisation procedures.
43. In this document the term "Third Country" means any country that is not a Member State of the European Union or European Economic Area.
44. See: "Reflection paper on ethical and GCP aspects of clinical trials conducted in third countries for evaluation in Marketing Authorisation Applications for medicines for human use, submitted to the EMA", online at: http://www.ema.europa.eu/docs/en-GB/document-library/Regulatory-and-procedural- guideline/2010/06/WC500091530.pdf.
45. Z. Zong, "Should post-trial provision of beneficial experimental interventions be mandatory in developing countries?", J Med Ethics. 34(3), (2008), 188-192.