Does the FDA have the authority to trump the Declaration of Helsinki?

An editorial by Dr. Michael Goodyear, of Dalhousie University (Canada), and a board member of The Alliance for Human Research Protection, provides an insightful explication of the moral significance of FDA’s new rule lifting the requirement from clinical trials performed outside the US to conform to the Declaration of Helsinki when  used to support applications for registration of products in the US.

The Declaration is the primary source and arbiter of research ethics worldwide. It guides legislation and the ethical conduct and oversight of research, particularly in developing countries, which are the site of an increasing share of clinical research.

The move to accept the International Conference on Harmonization Good Clinical Practice (GCP) standards which are nothing more than procedural regulatory frameworks of the US, Japan, and Europe, is a backdoor tactic for reducing safeguards against exploitation of disadvantaged populations in underdeveloped countries.

By withdrawing the Helsinki standards, FDA officials and industry are attempting to circumvent the Helsinki restrictions against use of placebos “where proven interventions” have been established.

This restriction ensures that all human subjects are guaranteed current best therapeutic treatments against which the new experimental treatment would be tested.  Industry much prefers to test new products against placebo–except in psychiatry where the placebo often as not proves as beneficial as the new drug,  without the drug’s hazardous side effects. [In the case of Eli Lilly’s trial the placebo performed better than either its experimental antipsychotic (mGIu2/3) and its most profitable drug, Zyprexa) See: http://www.ahrp.org/cms/content/view/573/9/

High ranking FDA officials had waged a fierce but ultimately losing battle on behalf of industry to eliminate the restrictions on placebo when the Declaration underwent its 5th revision (2000) by the World Medical Association.

However, as Dr. Goodyear points out, although not explicitly part of international or national law, the legal status of the Declaration of Helsinki and the Nuremberg Code are recognized. For example, both international codes were cited by several US courts: TD v NYS Office of Mental Health (1995); Grimes / Higgins v Kennedy Krieger, Court of Appeals of Maryland (2001) ; and in the recent US Court of Appeals, which ruled that the Declaration (and other conventions) constituted a sufficient customary norm to be considered binding in the Pfizer trovafloxacin case in January 2009. The court reversed a dismissal by a lower court of a lawsuit by families of children who had died or were injured in a Nigerian meningitis trial.

The ethical principles articulated in the Declaration of Helsinki and the WMA’s International Code of Ethics are morally binding on physicians:

“It is the duty of the physician to promote and safeguard the health of patients, including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty.” [Principle 3]

“It is the duty of physicians who participate in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects.” [Principle 11]

The physician’s moral obligation under the Declaration of Helsinki overrides local laws or regulations that may be governed by efficiency-based utilitarian standards. At a time of globalization, amidst growing concern about the political, social, and fiscal contexts in which biomedical research occurs, with its potential for power differentials and conflict of interest, the need for an international humanitarian standard of research ethics which (at least) holds physicians responsible for protecting the human subject, is even greater.

posted by Vera Sharav

BMJ Published 21 April 2009, 338:b1559
Editorial
Does the FDA have the authority to trump the Declaration of Helsinki?
A new rule seems to be more about imperialism than harmonisation

The Food and Drug Administration (FDA) of the United States has ruled that clinical trials performed outside the US no longer have to conform to the Declaration of Helsinki if used to support applications for registration of products in the US.1 Instead, the International Conference on Harmonisation Good Clinical Practice (GCP) has been designated as the new regulatory standard. This suggestion met considerable opposition from scientists, ethicists, and consumer groups before and during the consultations.[1] [2] [3] The FDA’s justifications included the arguments that it was merely harmonising its regulations with a global standard, and that legal instruments, such as the US Code of Federal Regulations, cannot embed external documents subject to change beyond the agency’s control (dynamic referencing).[1] [4]

This justification failed to explain why GCP was any different in this respect, or why the declaration and the GCP were considered mutually exclusive. [2] Although such dynamic referencing can create legal problems, [5] [6] because legislatures cannot unreservedly commit to indefinite amendments, the declaration can, and should, be considered a minimum standard that reflects core ethical principles, operationalised through instruments such as the GCP and national regulatory policy. Static referencing of specific versions has not created substantial problems to date, and no reason is given about why this should be a problem now. The concerns remain unresolved, [7] but the question of what impact the change will make needs to be answered at both the instrumental (direct) level and the symbolic (indirect) level.

At first sight, the potential impact seems relatively small. Only a subset of clinical trials performed outside the US are affected, and supporters (mainly from industry) see the differences between the two documents as relatively minor. The real impact cannot be accurately ascertained at present, but it may be much greater than claimed because the US is the world’s largest drug and medical device market. [7] In addition, increasing globalisation and movement of clinical trials “off shore” mean that a large proportion of such trials will be used in applications for marketing in the US.[8] [9]

Some of the differences between the documents, such as those relating to the use of placebo controls in trials, are important and may have motivated the FDA to make this change. The fourth revision of the Declaration of Helsinki (1996) created difficulties for the FDA by restricting the use of placebos where proved interventions had become established. This had major implications for research in resource poor nations, where placebos were being used in such situations.[5] Despite heated debate,[10] the World Medical Association (WMA) has stood firm on the principle of not withholding effective interventions in its most recent (sixth) revision of 2008.[11] The FDA’s decision therefore seems to reinforce its defence of placebo controlled trials.

Whatever the instrumental impact, in light of this history it is the symbolic aspects of the decision that should concern us most.[2] [8] The withdrawal of an unproblematic reference has far more significance than simply omitting it. We have grave misgivings about the future of international ethical norms, at least in the US. Despite assurances by the FDA, GCP is not an ethical code, but a procedural regulatory manual based on the regulatory frameworks of the US, Japan, and Europe. Thus, it is a description of existing procedures, not an aspirational document.

It is not the procedural nuances that are at stake, but rather the moral reasoning that forms the basis of a culture of ethically responsible research. [5] [11] [12] The declaration, along with other international ethical guides, [5] remains a signpost for the collaborative development of international ethical principles and practice, the influence of which far exceeds national laws and regulations, and which was extended further in the 2008 revision. The declaration is the primary source and arbiter of research ethics worldwide. It guides legislation and the ethical conduct and oversight of research, particularly in developing countries, which are the site of an increasing share of clinical research.

This symbolic move away from the declaration contrasts with its growing recognition elsewhere. Although not explicitly part of international or national law, the legal status of codes of ethical principles is recognised. The US Court of Appeals ruled that the declaration (and other conventions) constituted a sufficient customary norm to be considered binding in the Pfizer trovafloxacin case in January 2009.13 The court reversed a dismissal by a lower court of a lawsuit by families of children who had died or were injured in a Nigerian meningitis trial. The children had received this experimental antibiotic, and the court ruled that the declaration established a universal norm prohibiting non-consensual experimentation. At a time of growing concern about the politics and increased globalisation of biomedical research, a more international view of research ethics is needed, rather than primacy of national policies that fall short of accepted principles. [9]

The FDA is at best acting as if its standards are distinct from globally accepted norms by pressuring the declaration to agree to its demands. At worst, it is creating an impression that it is more interested in facilitating research than respecting the rights of people who are the subjects of research. This has been variously depicted as entrenching different standards for different parts of the world (ethical pluralism), [5] [8] establishing the US’s right to unique policies (exceptionalism), [2] and one country imposing standards on others (moral imperialism). [8] We must hope that the new administration in Washington will review the FDA’s ill advised actions. [7]

The declaration and the WMA’s International Code of Ethics contain the crucial statement that a doctor or investigator’s conscience and ethical duty of care must transcend national laws. To be compliant with national laws that respect basic human rights and ethical norms is necessary, but is not in itself a sufficient standard

How then can we best protect ethical principles in research? Historically, individual conscience, training, and ethical culture were considered sufficient. These have repeatedly fallen short of expectations, however, given the political, social, and fiscal contexts in which research occurs, with its potential for power differentials and conflict of interest. If organisations such as the FDA are unable or unwilling to foster an international culture of ethical research, it must fall to others, such as professional associations, to ensure that ethical reasoning is as central to research as it is to care,[10] and that ethical oversight has sufficient powers and resources to be effective. Although transgressions of ethical codes sometimes invite administrative and criminal sanctions, all professional associations have a responsibility to scrutinise the ethical competence, capacity, and practice of their members’ research. Ultimately, ethically responsible research remains a collective responsibility. [5]

Cite this as: BMJ 2009;338:b1559

Michael D E Goodyear, assistant professor of medicine1, Trudo Lemmens, associate professor of medicine and law2, Dominique Sprumont, professor of health law and deputy director3, Godfrey Tangwa, professor of philosophy4

1 Dalhousie University, Halifax, Nova Scotia, Canada B3H 2Y9, 2 University of Toronto, Toronto, Ontario, Canada M5S 2C5, 3 Institute of Health Law, University of Neuchâtel, 2000 Neuchâtel, Switzerland, 4 University of Yaoundé 1, PO Box 13597, Yaoundé, Cameroon

mgoodyear@dal.ca

Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References
1. DHHS Food and Drug Administration. 21 CFR part 312. Human subject protection; foreign clinical studies not conducted under an investigational new drug application. 2. Final rule 28 April 2008, effective, October 27 2008. , www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=0900006480537f08.
3. Lurie P, Greco DB. US exceptionalism comes to research ethics. Lancet 2005;365:1117-9.[CrossRef][ISI][Medline]
4. Trials on trial: the Food and Drug Administration should rethink its rejection of the Declaration of Helsinki [editorial]. Nature 2008;453:427-8.[Medline]
5. Normile D. Ethics. Clinical trials guidelines at odds with US policy. Science 2008;322:516.[Abstract/Free Full Text]
6. Goodyear MD, Krleza-Jeric K, Lemmens T. The Declaration of Helsinki. BMJ 2007;335:624-5.[Free Full Text]
7. Sprumont D, Girardin S, Lemmens T. The Declaration of Helsinki and the law: an international and comparative analysis. In: Frewer A, Schmidt U, eds. History and theory of human experimentation: the Declaration of Helsinki and modern medical ethics. Stuttgart: Franz Steiner Verlag, 2007:223-52.
8. Kimmelman J, Weijer C, Meslin EM. Helsinki discords: FDA, ethics, and international drug trials. Lancet 2009;373:13-4.[CrossRef][ISI][Medline]
9. Garrafa V, Lorenzo C. Moral imperialism and multi-centric clinical trials in peripheral countries. Cad Saude Publica 2008;24:2219-26.[ISI][Medline]
10. Glickman SW, McHutchison JG, Peterson ED, Cairns CB, Harrington RA, Califf RM, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med 2009;360:816-23.[Free Full Text]
12. Lemmens T, Sprumont D, Nys H, Singh J, Glass KC. CIOMS’ placebo rule and the promotion of negligent medical practice. Eur J Health Law 2004;11:153-74.[CrossRef][Medline]
13. World Medical Association. Declaration of Helsinki. 2008. www.wma.net/e/policy/pdf/17c.pdf.
14. Goodyear MD, Eckenwiler LA, Ells C. Fresh thinking about the Declaration of Helsinki. BMJ 2008;337:a2128.[Free Full Text]
15. Abdullahi v Pfizer. US Court of Appeals 2d Cir. 2009 US App LEXIS 1768, 30 Jan 2009.