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

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ALLIANCE FOR HUMAN RESEARCH PROTECTION Promoting Openness, Full Disclosure, and Accountability http://www.ahrp.org  FYIThe FDA is sliding rapidly down the slippery slope, abandoning widelyaccepted, international ethical research standards articulated in theinternationally accepted Declaration of Helsinki--to facilitate commercialmedical experiments.An editorial by Dr. Michael Goodyear, of Dalhousie University (Canada), anda board member of The Alliance for Human Research Protection, provides aninsightful explication of the moral significance of FDA's new rule liftingthe requirement from clinical trials performed outside the US to conform tothe Declaration of Helsinki when  used to support applications forregistration of products in the US.  The Declaration is the primary sourceand arbiter of research ethics worldwide. It guides legislation and theethical conduct and oversight of research, particularly in developingcountries, which are the site of an increasing share of clinical research. The move to accept the International Conference on Harmonization GoodClinical Practice (GCP) standards which are nothing more than proceduralregulatory frameworks of the US, Japan, and Europe, is a backdoor tactic forreducing safeguards against exploitation of disadvantaged populations inunderdeveloped countries. By withdrawing the Helsinki standards, FDA officials and industry areattempting to circumvent the Helsinki restrictions against use of placebos"where proven interventions" have been established. This restriction ensuresthat all human subjects are guaranteed current best therapeutic treatmentsagainst which the new experimental treatment would be tested.  Industry muchprefers to test new products against placebo--except in psychiatry where theplacebo often as not proves as beneficial as the new drug,  without thedrug's hazardous side effects. [in the case of Eli Lilly's trial the placeboperformed better than either its experimental antipsychotic (mGIu2/3) andits 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 battleon behalf of industry to eliminate the restrictions on placebo when theDeclaration underwent its 5th revision (2000) by the World MedicalAssociation. However, as Dr. Goodyear points out, although the Declaration of Helsinkiand the Nuremberg Code are not explicitly part of international or nationallaw, their legal status is recognized. For example, both were cited byseveral US courts: TD v NYS Office of Mental Health (1995); Grimes / Higginsv Kennedy Krieger, Court of Appeals of Maryland (2001)http://www.courts.state.md.us/opinions/coa/2001/128a00.pdf ; and in therecent US Court of Appeals, which ruled that the Declaration (and otherconventions) constituted a sufficient customary norm to be consideredbinding in the Pfizer trovafloxacin case in January 2009. The court reverseda dismissal by a lower court of a lawsuit by families of children who haddied or were injured in a Nigerian meningitis trial. The ethical principles articulated in the Declaration of Helsinki and theWMA’s International Code of Ethics are morally binding on physicians: "It is the duty of the physician to promote and safeguard the health ofpatients, including those who are involved in medical research. Thephysician's knowledge and conscience are dedicated to the fulfillment ofthis duty." [Principle 3] "It is the duty of physicians who participate inmedical research to protect the life, health, dignity, integrity, right toself-determination, privacy, and confidentiality of personal information ofresearch subjects." [Principle 11]The physician's moral obligation under the Declaration of Helsinki overrideslocal laws or regulations that may be governed by efficiency-basedutilitarian standards. At a time of globalization, amidst growing concernabout the political, social, and fiscal contexts in which biomedicalresearch occurs, with its potential for power differentials and conflict ofinterest, the need for an international humanitarian standard of researchethics which (at least) holds physicians responsible for protecting thehuman subject, is even greater Contact: Vera Hassner Sharavveracare212-595-8974http://www.bmj.com/cgi/content/short/338/apr21_1/b1559?rss=1BMJ (British Medical Journal)April 21, 2009, 338:b1559 EditorialDoes the FDA have the authority to trump the Declaration of Helsinki?A new rule seems to be more about imperialism than harmonisation By Michael Goodyear, Trudo Lemmens, Godfrey TangwaThe Food and Drug Administration (FDA) of the United States has ruled thatclinical trials performed outside the US no longer have to conform to theDeclaration of Helsinki if used to support applications for registration ofproducts in the US.1 Instead, the International Conference on HarmonisationGood Clinical Practice (GCP) has been designated as the new regulatorystandard. 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 merelyharmonising its regulations with a global standard, and that legalinstruments, such as the US Code of Federal Regulations, cannot embedexternal documents subject to change beyond the agency’s control (dynamicreferencing).[1] [4] This justification failed to explain why GCP was any different in thisrespect, or why the declaration and the GCP were considered mutuallyexclusive. [2] Although such dynamic referencing can create legal problems,[5] [6] because legislatures cannot unreservedly commit to indefiniteamendments, the declaration can, and should, be considered a minimumstandard that reflects core ethical principles, operationalised throughinstruments such as the GCP and national regulatory policy. Staticreferencing of specific versions has not created substantial problems todate, and no reason is given about why this should be a problem now. Theconcerns remain unresolved, [7] but the question of what impact the changewill make needs to be answered at both the instrumental (direct) level andthe symbolic (indirect) level. At first sight, the potential impact seems relatively small. Only a subsetof clinical trials performed outside the US are affected, and supporters(mainly from industry) see the differences between the two documents asrelatively minor. The real impact cannot be accurately ascertained atpresent, but it may be much greater than claimed because the US is theworld’s largest drug and medical device market. [7] In addition, increasingglobalisation and movement of clinical trials "off shore" mean that a largeproportion of such trials will be used in applications for marketing in theUS.[8] [9] Some of the differences between the documents, such as those relating to theuse of placebo controls in trials, are important and may have motivated theFDA to make this change. The fourth revision of the Declaration of Helsinki(1996) created difficulties for the FDA by restricting the use of placeboswhere proved interventions had become established. This had majorimplications for research in resource poor nations, where placebos werebeing used in such situations.[5] Despite heated debate,[10] the WorldMedical Association (WMA) has stood firm on the principle of not withholdingeffective interventions in its most recent (sixth) revision of 2008.[11] TheFDA’s decision therefore seems to reinforce its defence of placebocontrolled trials. Whatever the instrumental impact, in light of this history it is thesymbolic aspects of the decision that should concern us most.[2] [8] Thewithdrawal of an unproblematic reference has far more significance thansimply omitting it. We have grave misgivings about the future ofinternational ethical norms, at least in the US. Despite assurances by theFDA, GCP is not an ethical code, but a procedural regulatory manual based onthe regulatory frameworks of the US, Japan, and Europe. Thus, it is adescription of existing procedures, not an aspirational document. It is not the procedural nuances that are at stake, but rather the moralreasoning that forms the basis of a culture of ethically responsibleresearch. [5] [11] [12] The declaration, along with other internationalethical guides, [5] remains a signpost for the collaborative development ofinternational ethical principles and practice, the influence of which farexceeds national laws and regulations, and which was extended further in the2008 revision. The declaration is the primary source and arbiter of researchethics worldwide. It guides legislation and the ethical conduct andoversight of research, particularly in developing countries, which are thesite of an increasing share of clinical research. This symbolic move away from the declaration contrasts with its growingrecognition elsewhere. Although not explicitly part of international ornational 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 thePfizer trovafloxacin case in January 2009.13 The court reversed a dismissalby a lower court of a lawsuit by families of children who had died or wereinjured in a Nigerian meningitis trial. The children had received thisexperimental antibiotic, and the court ruled that the declarationestablished a universal norm prohibiting non-consensual experimentation. Ata time of growing concern about the politics and increased globalisation ofbiomedical research, a more international view of research ethics is needed,rather than primacy of national policies that fall short of acceptedprinciples. [9] The FDA is at best acting as if its standards are distinct from globallyaccepted norms by pressuring the declaration to agree to its demands. Atworst, it is creating an impression that it is more interested infacilitating research than respecting the rights of people who are thesubjects of research. This has been variously depicted as entrenchingdifferent 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] Wemust hope that the new administration in Washington will review the FDA’sill advised actions. [7] The declaration and the WMA’s International Code of Ethics contain thecrucial statement that a doctor or investigator’s conscience and ethicalduty of care must transcend national laws. To be compliant with nationallaws that respect basic human rights and ethical norms is necessary, but isnot in itself a sufficient standard How then can we best protect ethical principles in research? Historically,individual conscience, training, and ethical culture were consideredsufficient. 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. Iforganisations such as the FDA are unable or unwilling to foster aninternational culture of ethical research, it must fall to others, such asprofessional associations, to ensure that ethical reasoning is as central toresearch as it is to care,[10] and that ethical oversight has sufficientpowers and resources to be effective. Although transgressions of ethicalcodes sometimes invite administrative and criminal sanctions, allprofessional associations have a responsibility to scrutinise the ethicalcompetence, 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 ofhealth law and deputy director3, Godfrey Tangwa, professor of philosophy4 1 Dalhousie University, Halifax, Nova Scotia, Canada B3H 2Y9, 2 Universityof Toronto, Toronto, Ontario, Canada M5S 2C5, 3 Institute of Health Law,University of Neuchâtel, 2000 Neuchâtel, Switzerland, 4 University ofYaoundé 1, PO Box 13597, Yaoundé, Cameroon mgoodyear Competing interests: None declared. Provenance and peer review: Commissioned; not externally peer reviewed. References1. DHHS Food and Drug Administration. 21 CFR part 312. Human subjectprotection; foreign clinical studies not conducted under an investigationalnew drug application. 2. Final rule 28 April 2008, effective, October 272008. ,www.regulations.gov/fdmspublic/component/main?main=DocumentDetail & o=0900006480537f08. 3. Lurie P, Greco DB. US exceptionalism comes to research ethics. Lancet2005;365:1117-9.[CrossRef][iSI][Medline] 4. Trials on trial: the Food and Drug Administration should rethink itsrejection of the Declaration of Helsinki [editorial]. Nature2008;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. BMJ2007;335:624-5.[Free Full Text] 7. Sprumont D, Girardin S, Lemmens T. The Declaration of Helsinki and thelaw: an international and comparative analysis. In: Frewer A, Schmidt U,eds. History and theory of human experimentation: the Declaration ofHelsinki and modern medical ethics. Stuttgart: Franz Steiner Verlag,2007:223-52. 8. Kimmelman J, Weijer C, Meslin EM. Helsinki discords: FDA, ethics, andinternational drug trials. Lancet 2009;373:13-4.[CrossRef][iSI][Medline] 9. Garrafa V, Lorenzo C. Moral imperialism and multi-centric clinical trialsin 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 globalizationof 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 andthe promotion of negligent medical practice. Eur J Health Law2004;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 Declarationof 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. FAIR USE NOTICE: This may contain copyrighted (© ) material the use of whichhas not always been specifically authorized by the copyright owner. Suchmaterial is made available for educational purposes, to advanceunderstanding of human rights, democracy, scientific, moral, ethical, andsocial justice issues, etc. It is believed that this constitutes a 'fairuse' of any such copyrighted material as provided for in Title 17 U.S.C.section 107 of the US Copyright Law. This material is distributed withoutprofit.  =====In accordance with Title 17 U.S.C. Section 107, this material is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.