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Conflicts of Interest in International Human Drug Research and the Insufficiency of International Protections

Published online by Cambridge University Press:  06 January 2021

Robert Gatter
Robert Gatter*
Affiliation:
Penn State University, Dickinson School of Law
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Extract

The world relies largely on private firms for the development of new medicine, and the system is efficient. Driven by the incentive to profit from sales of new pharmaceuticals, drug companies risk millions of dollars and years of work to shepherd basic scientific discoveries through laboratory and human testing in the hope of developing a marketable drug. For example, it is estimated that in 2002 alone, pharmaceutical companies invested $45 billion the development of new medicine worldwide.

While the profit incentive generates such enormous private investment in human drug development, it also encourages firms to pose inappropriate risks to the safety of human subjects when speeding a new drug to the market. The risks posed by financial conflicts of interest associated with human subjects research on new pharmaceutical products are notable examples, both in the U.S. and internationally.

Type
Article
Information
American Journal of Law & Medicine , Volume 32 , Issue 2-3 , June 2006 , pp. 351 - 364
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2006

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References

I thank the editors and authors participating in this symposium for their invaluable comments on this essay.

1 See International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), Position Statement, at http://www.ifpma.org/Issues/issues_research.aspx (claiming that the drug development investments of capital by private pharmaceutical firms are the most significant contribution to health research worldwide and that most of the world's existing medicines were discovered or developed through private investment).

2 In particular, the incentive is to make monopoly profits at least for the first 5 to 10 years a new drug is on the market based on the varying levels of patent protection afforded by national governments worldwide. See IFPMA, A Review of Existing Data Exclusivity Legislation in Selected Countries (4th ed. 2005) (cataloging and summarizing patent protection law country by country), available at http://www.ifpma.org/News/Publications.aspx.

3 See IFPMA Position Statement, supra note 1.

4 For commentary addressing conflicts of interest in human subjects research in the U.S., see Gatter, Robert, Walking the Talk of Trust in Human Subjects Research: The Challenge of Regulating Financial Conflicts of Interest, 52 EMORY L. J. 327 (2003)Google ScholarPubMed; Goldner, Jesse A., Dealing with Conflicts of Interest in Biomedical Research: IRB Oversight as the Next Best Solution to the Abolitionist Approach, 28 J. L. MED. & ETHICS 379 (2000)Google ScholarPubMed; Saver, Richard S., Medical Research Oversight from the Corporate Governance Perspective: Comparing Institutional Review Boards and Corporate Boards, 46 WILLIAM & MARY L. REV. 619, 621-633 (2004)Google ScholarPubMed.

5 For commentary addressing conflicts of interest in human subjects research internationally, see Robert Gatter, Financial Conflicts of Interest in Human Subjects Research: Domestic and International Issues, in ANNALS OF BIOETHICS (Sandra H. Johnson, ed.) (forthcoming) (manuscript available upon request).

6 Id. at 334-344.

7 Id.

8 Id. at 346-348.

9 Id. at 344-348.

10 See Janet Rehnquist, Office of the Inspector General, U.S. Department of Health and Human Services, The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects, available at http://oig.hhs.gov/oei/reports/oei-01-00-00190.pdf (Sept. 2001). See also Gatter, supra note 5, (manuscript at 7-8).

11 Id. at 8.

12 Id. at 7-8.

13 Id. at 8 (“As manufacturers in the major drug-producing economies outsource clinical trials to foreign countries, they also export financial COIs and the risks those COIs pose to human subject safety”).

14 See Joe Stephens, The Body Hunters: Exporting Human Experiments (pt. 1), WASH. POST, Dec. 17, 2000, at A1; Mary Pat Flaherty et al., The Body Hunters: Overwhelming the Watchdogs (pt. 2), WASH. POST, Dec. 18, 2000, at A1.

15 Flaherty et al., supra note 14, at A1.

16 See Stephens, supra note 14; Flaherty, supra note 14.

17 See Rehnquist, supra note 10, at 12-13, 15.

18 For international guidelines, see Council for International Organizations of Medical Sciences (2002) [hereinafter CIOMS], INTERNATIONAL ETHICAL GUIDELINES FOR BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS (2002), http://www.cioms.ch/frame_guidelines_nov_2002.htm; WHO, GUIDELINES FOR GOOD CLINICAL PRACTICE (GCP) FOR TRIALS ON PHARMACEUTICAL PRODUCTS (1995); International Conference on Harmonisation, GUIDELINES FOR GOOD CLINICAL PRACTICE (1996), http://www.ich.org/LOB/media482.pdf. For domestic laws, see, e.g., 45 C.F.R. pt. 46 (U.S. regulations); Directive on Clinical Trials (2001/20/EC) of the European Parliament and the Council of the European Union (2001), available at http://eudract.emea.eu.int/docs/Dir2001-20_en.pdf. According to an international survey of laws related to human subjects research recently published by the U.S. Office for Human Research Protections in the Department of Health and Human Services, Japan has adopted the ICH's Good Clinical Practice Guidelines as law. See OHRP, International Compilation of Human Subjects Research Protections (2d ed. Oct. 1, 2005), available at http://www.hhs.gov/ohrp/international/HSPCompilation.pdf.

19 See World Medical Association, Declaration of Helsinki, reprinted in, CIOMS, INTERNATIONAL ETHICAL GUIDELINES FOR BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 89 (2002) (App. 2), http://www.wma.net/e/policy/b3.htm.

20 The Helsinki Declaration was itself an effort to describe in more detail the general statements in the Nuremberg Code of 1947 and the Universal Declaration of Human Rights of 1948 that humans shall not be subject to medical experimentation without their consent. See CIOMS, INTERNATIONAL ETHICAL GUIDELINES FOR BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 15 (2002).

21 See CIOMS, supra note 18, (Discussing three notable guideline publications by international organizations since the publication of CIOMS 1993 Guidelines).

22 WHO, Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products, in THE USE OF ESSENTIAL DRUGS 97-137 (Technical Report Series No. 850)(1995)(Annex 3) (WHO's guidelines were originally published as an appendix to this technical report).

23 See International Conference on Harmonisation, GUIDELINES FOR GOOD CLINICAL PRACTICE (1996), http://www.ich.org/LOB/media/MEDIA482.pdf.

24 See CIOMS, supra note 18.

25 This examination is based upon the current version of the Helsinki Declaration. The conflicts of interest provisions of the declaration appear to have been added in 2000 (Edinburgh, Scotland) because they do not appear in the 1996 version.

26 Declaration of Helsinki, supra note 19, at 91, para. 13.

27 Id. (“The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.”)

28 Id.

29 See id. at 92 para. 22.

30 Id. at 93-94 para. 27.

31 See CIOMS, supra note 24, at 29-30 (commentary to guideline 2).

32 See id. at 27 (commentary to guideline 2).

33 Id.

34 In the guideline's introductory statement of general ethical principles, it notes that researchers and sponsors should not “take advantage of the relative inability of low-resource countries or vulnerable populations to protect their own interests, by conducting research inexpensively and avoiding complex regulatory systems of industrialized countries … .” Id. at 18.

35 CIOMS, supra note 24, at 31 (guideline 3).

36 See id. (commentary to guideline 6).

37 See id. at 24 (commentary to guideline 2).

38 See id. at Appendix 1.

39 See id. at 80-81 (guidelines 20 and its commentary).

40 Id. at 81 (commentary to guideline 20).

41 See id. at 39 (guideline 5).

42 Id.

43 See WHO, supra note 22, at 115 (sec. 2.11).

44 Id. at 103.

45 Id.

46 See generally WHO, supra note 22.

47 See Id. at 110-112 (sec. 3.3), 136-137 (Appendix 2) for informed consent disclosures.

48 See generally WHO, supra note 22.

49 See Kelleher, Finnuala, The Pharmaceutical Industry's Responsibility for Protecting Human Subjects of Clinical Trials in Developing Nations, 38 COLUM. J.L. & SOC. PROBS. 67, 78Google Scholar. See generally Kubiak, Cinead R., Conflicting Interests & Conflicting Laws: Re-Aligning The Purpose And Practice Of Research Ethics Committees, 30 BROOKLYN J. INT'L L. 759, 784-786 (2005)Google Scholar.

50 See Kubiak supra note 49, at 808 (quoting “Unfortunately, since the [ICH] GCP mirrors U.S. human-subject research regulations, it also carries the same flaws … The ICH GCP requires documentation of financial arrangements among investigators, institutions and sponsors. Yet, these documents are only required to be maintained by the sponsor and research institution. As with the 1989 Declaration and U.S. regulations, the ICH GCP does not require that RECs are provided COI disclosure statements”).

51 See ICH, supra note 23, at sections 4.9.6 and 5.9.

52 The guidelines provide that the protocol should address “financing and insurance” if not addressed in a separate agreement, see ICH, supra note 23, at sec. 6.14, but it is unclear whether this very vague language is meant to encompass conflicts of interest. Additionally, given that there is no statement that a separate agreement concerning finances should be made part of a protocol submitted to an ethics committee, the request for information on “financing and insurance” may in effect be optional because the information could always be put in a separate agreement that does not appear to be subject to review.

53 See Saver, supra note 4, at 621-626 (referring to several highly publicized incidents of conflicts of interest related to human subjects research from 1999 through 2001).

54 See Gatter, supra note 5, at 329-330.

55 See id.

56 See The World Medical Association's organization definition of the Declaration of Helsinki on their website, http://www.wma.net/e/ethicsunit/helsinki.htm.

57 See CIOMS, International Ethical Guidelines for Biomedical Research Involving Human Subjects, Guidelines 8, 14, 15 and their commentary (1993), http://www.fhi.org/training/sp/RETC/cioms.htm.

58 See ICH Implementation Grid, http://www.ich.org/cache/compo/276-254-1.html. In the U.S., the Food and Drug Administration adopted the ICH GCPs as an industry guidance in 1997. See Good Clinical Practice: Consolidated Guideline, 62 Fed. Reg. 25692 (May 9, 1997). And in 2004, proposed making those conditions into mandatory standards. See Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application, 69 Fed. Reg. 32467 (June 10, 2004).

59 See Council of Ministers of the EU, Directive on Clinical Trials, Directive 2001/20/EC, L 121 OFFICIAL JOURNAL OF THE EUROPEAN COMMUNITIES 34 (May 1, 2001), available at http://europa.eu.int/eur-lex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf.

60 See id. at Art. 6, ¶ 3(j).

61 Id.

62 ICH Implementation Grid, supra note 58.

63 See ICH Home Page, http://www.ich.org/cache/compo/276-254-1.html.

64 WHO, supra note 22, at 100.

65 Id.

66 Id.

67 This may be as a result of its affiliation with WHO and WHO's interest in promoting international commerce in pharmaceuticals.

68 See generally CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects, supra note 18.

69 See Gatter, supra note 4.

70 Molzon, Justina, The International Conference on Harmonization Common Technical Document – Global Submission Format?, 60 FOOD & DRUG L.J. 447, 448 (2005)Google ScholarPubMed.

71 See 42 CFR §§ 50.603-605 (2006); 21 CFR §§ 54.2, 54.4-54.5 (2006).

72 See 21 C.F.R. § 312.120 (2006).