Declaration of Helsinki
The Declaration of Helsinki is a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association (WMA). It is widely regarded as the cornerstone document of human research ethics. (WMA 2000, Bošnjak 2001, Tyebkhan 2003)
It is not a legally binding instrument in international law, but instead draws its authority from the degree to which it has been codified in, or influenced, national or regional legislation and regulations (Human and Fluss 2001). Its role was described by a Brazilian forum in 2000 in these words "Even though the Declaration of Helsinki is the responsibility of the World Medical Association, the document should be considered the property of all humanity" (Human and Fluss 2001).
The Declaration was originally adopted in June 1964 in Helsinki, Finland, and has since undergone six revisions (the most recent at the General Assembly in October 2008) and two clarifications, growing considerably in length from 11 to 32 paragraphs (35 paragraphs in 2008 version). The Declaration is an important document in the history of research ethics as the first significant effort of the medical community to regulate research itself, and forms the basis of most subsequent documents.
Prior to the 1947 Nuremberg Code there was no generally accepted code of conduct governing the ethical aspects of human research, although some countries, notably Germany and Russia, had national policies [3a]. The Declaration developed the ten principles first stated in the Nuremberg Code, and tied them to the Declaration of Geneva (1948), a statement of physician's ethical duties. The Declaration more specifically addressed clinical research, reflecting changes in medical practice from the term 'Human Experimentation' used in the Nuremberg Code. A notable change from the Nuremberg Code was a relaxation of the conditions of consent, which was 'absolutely essential' under Nuremberg. Now doctors were asked to obtain consent 'if at all possible' and research was allowed without consent where a proxy consent, such as a legal guardian, was available (Article II.1).
First revision (1975)
The 1975 revision was almost twice the length of the original, and introduced the concept of oversight by an 'independent committee' (Article I.2) which became a system of Institutional Review Boards (IRB) in the US, and research ethics committees or ethical review boards in other countries (Riis 1977). In the United States regulations governing IRBs came into effect in 1981 and are now encapsulated in the Common Rule. Informed consent was developed further, made more prescriptive and partly moved from 'Medical Research Combined with Professional Care' into the first section (Basic Principles), with the burden of proof for not requiring consent being placed on the investigator to justify to the committee. 'Legal guardian' was replaced with 'responsible relative'. The duty to the individual was given primacy over that to society (Article I.5), and concepts of publication ethics were introduced (Article I.8). Any experimental manoeuvre was to be compared to the best available care as a comparator (Article II.2), and access to such care was assured (Article I.3). The document was also made gender neutral and
Second to Fourth revisions (1975-2000)
Subsequent revisions between 1975 and 2000 were relatively minor, so the 1975 version was effectively that which governed research over a quarter of a century of relative stability.
Second and Third Revisions (1983, 1989)
The second revision (1983) included seeking the consent of minors where possible. The third revision (1989) dealt further with the function and structure of the independent committee. However from 1982 onwards, the Declaration was not alone as a universal guide since CIOMS and the World Health Organization (WHO) had also developed their International Ethical Guidelines for Biomedical Research Involving Human Subjects.
Fourth revision (1996)
The AIDS Clinical Trials Group (ACTG) Study 076 of Zidovudine in maternal-infant transmission of HIV had been published in 1994 (Connor et al. 1994). This was a placebo controlled trial which showed a reduction of nearly 70% in the risk of transmission, and Zidovudine became a de facto standard of care. The subsequent initiation of further placebo controlled trials in developing countries and funded by the United States Center for Disease Control or National Institutes of Health raised considerable concern when it was learned that US patients in trials had essentially unrestricted access to the drug, but not in developing countries. Justification was provided by a 1994 WHO group in Geneva which concluded "Placebo-controlled trials offer the best option for a rapid and scientifically valid assessment of alternative antiretroviral drug regimens to prevent transmission of HIV". These trials appeared to be in direct conflict with recently published guidelines (Levine 1993) for international research by CIOMS, which stated "The ethical standards applied should be no less exacting than they would be in the case of research carried out in country", referring to the sponsoring or initiating country. In fact a schism between ethical universalism and ethical pluralism was already apparent before the 1993 revision of the CIOMS guidelines (Levine 1993).
In retrospect, this was one of the most significant revisions because it added the phrase "This does not exclude the use of inert placebo in studies of where no proven diagnostic or therapeutic method exists" to Article II.3. This led to the US Food and Drug Administration (FDA) ignoring this and all subsequent revisions.   The European Union similarly only cites the 1996 version in the EU Clinical Trials Directive published in 2001.
Fifth revision (2000)
Following the fourth revision in 1996 pressure began to build almost immediately for a more fundamental approach to revising the declaration (Levine 1999). In 1997 Lurie and Wolfe published their seminal paper on HIV trials, raising awareness of a number of central issues. These included the claims that the continuing trials in developing countries were unethical, and pointing out a fundamental discrepancy in decisions to change the study design in Thailand but not Africa. The issue of the use of placebo in turn raised questions about the standard of care in developing counties and whether, as Marcia Angell wrote "Human subjects in any part of the world should be protected by an irreducible set of ethical standards" (1988). The American Medical Association put forward a proposed revision in November that year,   and a proposed revision (17.C/Rev1/99) was circulated the following year,   causing considerable debate and resulting in a number of symposia and conferences. Recommendations included limiting the document to basic guiding principles.   Many editorials and commentaries were published reflecting a variety of views including concerns that the Declaration was being weakened by a shift towards efficiency-based and utilitarian standards (Stockhausen 2000, Loff and Black 2000, Zion, Gillam and Loff 2000, Brennan 1999, Rothman, Michaels and Baum 2000), and an entire issue of the Bulletin of Medical Ethics was devoted to the debate. Others saw it as an example of Angell's 'Ethical Imperialism', an imposition of US needs on the developing world,  and resisted any but the most minor changes, or even a partitioned document with firm principles and commentaries, as used by CIOMS. Brennan summarises this by stating "The principles exemplified by the current Declaration of Helsinki represent a delicate compromise that we should modify only after careful deliberation". Nevertheless, what had started as a controversy around a specific series of trials and their designs in Sub-Saharan Africa, now had potential implications for all research.
Even though most meetings around the proposed revisions failed to achieve consensus, and many argued that the declaration should remain unchanged or only minimally altered, after extensive consultation the Workgroup  eventually came up with a text that was endorsed by WMA's Council and passed by the General Assembly on October 7, 2000,  and which proved to be the most far reaching and contentious revision to date. The justification for this was partly to take account of expanded scope of biomedical research since 1975 (Riis 2000). This involved a restructuring of the document, including renumbering and re-ordering of all the articles, the changes in which are outlined in this Table. The Introduction establishes the rights of subjects and describes the inherent tension between the need for research to improve the common good, and the rights of the individual. The Basic Principles establish a guide for judging to what extent proposed research meets the expected ethical standards. The distinction between therapeutic and non-therapeutic research introduced in the original document, criticised by Levine (1999, 2000) was removed to emphasise the more general application of ethical principles, but the application of the principles to healthy volunteers is spelt out in Articles 18-9, and they are referred to in Article 8 ('those who will not benefit personally from the research') as being especially vulnerable. The scope of ethical review was increased to include human tissue and data (Article 1), the necessity to challenge accepted care was added (Article 6), as well as establishing the primacy of the ethical requirements over laws and regulations (Article 9).
Amongst the many changes was an increased emphasis on the need to benefit the communities in which research is undertaken, and to draw attention to the ethical problems of experimenting on those who would not benefit from the research, such as developing countries in which innovative medications would not be available. Article 19 first introduces the concept of social justice, and extends the scope from individuals to the community as a whole by stating that 'research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research'. This new role for the Declaration has been both denounced  and praised,  and even considered for a clarification footnote (Carlson 2004). Article 27 expanded the concept of publication ethics, adding the necessity to disclose conflict of interest (echoed in Articles 13 and 22), and to include publication bias amongst ethically problematic behaviour.
The most controversial revisions  (Articles 29, 30) were placed in this new category. These predictably were those that like the fourth revision were related to the ongoing debate in international health research. The discussions (Christie 2000) indicate that there was felt a need to send a strong signal that exploitation of poor populations as a means to an end, by research from which they would not benefit, was unacceptable. In this sense the Declaration endorsed ethical universalism.
Article 29 restates the use of placebo where 'no proven' intervention exists. Surprisingly, although the wording was virtually unchanged, this created far more protest in this revision. The implication being that placebos are not permitted where proven interventions are available. The placebo question was already an active debate prior to the fourth revision but had intensified, while at the same time the placebo question was still causing controversy in the international setting. This revision implies that in choosing a study design, developed-world standards of care should apply to any research conducted on human subjects, including those in developing countries. The wording of the fourth and fifth revisions reflect the position taken by Rothman and Michel (1994), and Freedman et al. (1996), known as 'active-control orthodoxy'. The opposing view, as expressed by Levine (1999) and by Temple and Ellenberg (2000) is referred to as 'placebo orthodoxy', insisting that placebo controls are more scientifically efficient and are justifiable where the risk of harm is low. This viewpoint argues that where no standards of care exist, as for instance in developing countries, then placebo-controlled trials are appropriate. The utilitarian argument (Elander and Hermerén 1995) held that the disadvantage to a few (such as denial of potentially beneficial interventions) was justifiable for the advantage of many future patients. These arguments are intimately tied to the concept of distributive justice, the equitable distribution of the burdens of research (Brennan 1999, Benatar 2001). As with much of the Declaration, there is room for interpretation of words. 'Best current' has been variously held to refer to either global or local contexts (Nuffield Council on Bioethics 2005).
Article 30 introduced another new concept, that after the conclusion of the study patients 'should be assured of access to the best proven' intervention arising from the study, a justice issue. Arguments around this have dealt with whether subjects derive benefit from the trial and are no worse off at the end than the status quo prior to the trial, or of not participating, versus the harm of being denied access to that which they have contributed to. There are also operational issues that are unclear.
Given the lack of consensus on many issues prior to the fifth revision it is no surprise that the debates continued unabated (Macklin 2001, Williams 2004). The debate over these and related issues also revealed differences in perspectives between developed and developing countries (Loff 2000, Schuklenk 2001; CMAJ 2003). Zion and colleagues (Zion 2000, Loff and Black 2000, Loff 2000) have attempted to frame the debate more carefully, exploring the broader social and ethical issues and the lived realities of potential subjects lives as well as acknowledging the limitations of absolute universality in a diverse world, particularly those framed in a context that might be considered elitist and structured by gender and geographic identity. As Macklin (2001) points out, both sides may be right, since justice "is not an unambiguous concept".
Clarifications of Articles 29, 30 (2002-2004)
Eventually Notes of Clarification (footnotes) to articles 29 and 30 were added in 2002 and 2004 respectively, predominantly under pressure from the US (CMAJ 2003, Blackmer 2005). The 2002 clarification to Article 29 was in response to many concerns about WMA's apparent position on placebos. As WMA states in the note, there appeared to be 'diverse interpretations and possibly confusion'. It then outlined circumstances in which a placebo might be 'ethically acceptable', namely 'compelling… methodological reasons', or 'minor conditions' where the 'risk of serious or irreversible harm' was considered low. Effectively this shifted the WMA position to what has been considered a 'middle ground' (Emmanuel 2001, Huston 2001). Given the previous lack of consensus, this merely shifted the ground of debate,  which now extended to the use of the 'or' connector. For this reason the footnote indicates that the wording must be interpreted in the light of all the other principles of the Declaration.
Article 30 was debated further at the 2003 meeting, with another proposed clarification (CMAJ 2003) but did not result in any convergence of thought, and so decisions were postponed for another year (De Roy 2004, WMA 2003), but again a commitment was made to protecting the vulnerable. A new working group examined article 30, and recommended not amending it in January 2004.  Later that year the American Medical Association proposed a further note of clarification that was incorporated (Blackmer 2005). In this clarification the issue of post trial care now became something to consider, not an absolute assurance.
Despite these changes, as Macklin predicted, consensus was no closer and the Declaration was considered by some to be out of touch with contemporary thinking (Lie 2004), and even the question of the future of the Declaration became a matter for conjecture (Wolinsky 2006)
Sixth revision (2008)
The sixth revision cycle commenced in May 2007. This consisted of a call for submissions, completed in August 2007. The terms of reference included only a limited revision compared to 2000. In November 2007 a draft revision  was issued for consultation till February 2008, and led to a workshop in Helsinki in March.  Those comments were then incorporated into a second draft in May.   Further workshops were held in Cairo and São Paulo and the comments collated in August 2008. A final text was then developed by the Working Group for consideration by the Ethics Committee and finally the General Assembly, which approved it on October 18. Public debate was relatively slight compared to previous cycles, and in general supportive.  Input was received from a wide number of sources, some of which have been published, such as Feminist Approaches to Bioethics.  Others include CIOMS and the US Government. 
The Declaration is morally binding on physicians, and that obligation overrides any national or local laws or regulations, if the Declaration provides for a higher standard of protection of humans than the latter. Investigators still have to abide by local legislation but will be held to the higher standard.
The fundamental principle is respect for the individual (Article 8), their right to self determination and the right to make informed decisions (Articles 20, 21 and 22) regarding participation in research, both initially and during the course of the research. The investigator's duty is solely to the patient (Articles 2, 3 and 10) or volunteer (Articles 16, 18), and while there is always a need for research (Article 6), the subject's welfare must always take precedence over the interests of science and society (Article 5), and ethical considerations must always take precedence over laws and regulations (Article 9).
The recognition of the increased vulnerability of individuals and groups calls for special vigilance (Article 8). It is recognised that when the research participant is incompetent, physically or mentally incapable of giving consent, or is a minor (Articles 23, 24), then allowance should be considered for surrogate consent by an individual acting in the subject's best interest. In which case their assent should still be obtained if at all possible (Article 25).
Research should be based on a thorough knowledge of the scientific background (Article 11), a careful assessment of risks and benefits (Articles 16, 17), have a reasonable likelihood of benefit to the population studied (Article 19) and be conducted by suitably trained investigators (Article 15) using approved protocols, subject to independent ethical review and oversight by a properly convened committee (Article 13). The protocol should address the ethical issues and indicate that it is in compliance with the Declaration (Article 14). Studies should be discontinued if the available information indicates that the original considerations are no longer satisfied (Article 17). Information regarding the study should be publicly available (Article 16). Ethical publications extend to publication of the results and consideration of any potential conflict of interest (Article 27). Experimental investigations should always be compared against the best methods, but under certain circumstances a placebo or no treatment group may be utilised (Article 29). The interests of the subject after the study is completed should be part of the overall ethical assessment, including assuring their access to the best proven care (Article 30). Wherever possible unproven methods should be tested in the context of research where there is reasonable belief of possible benefit (Article 32).
Additional guidelines or regulations
Investigators often find themselves in the position of having to follow several different codes or guidelines, and are therefore required to understand the differences between them. One of these is Good Clinical Practice (GCP), an international guide, while each country may also have local regulations such as the Common Rule in the US, in addition to the requirements of the FDA and Office for Human Research Protections (OHRP) in that country. There are a number of available tools which compare these.  Other countries have guides with similar roles, such as the Tri-Council Policy Statement in Canada. Additional international guidelines include those of the CIOMS, Nuffield Council and UNESCO.
The controversies and national divisions over the text have continued. The US FDA rejected the 2000 and subsequent revisions, only recognizing the third (1989) revision (Wolinsky 2006), and in 2006 announced it would eliminate all reference to the Declaration. After consultation, which included expressions of concern,  a final rule was issued on April 28, 2008 replacing the Declaration of Helsinki with Good Clinical Practice effective October 2008.  This has raised a number of concerns regarding the apparent weakening of protections for research subjects outside the United States.          The NIH training in human subject research participant protection no longer refers to the Declaration of Helsinki. The European Commission refers to the fourth (1996) revision.
While the Declaration has been a central document guiding research practice, its future has been called into question. Challenges include the apparent conflict between guides, such as the CIOMS and Nuffield Council documents. Another is whether it should concentrate on basic principles as opposed to being more prescriptive, and hence controversial. It has continually grown and faced more frequent revisions (Carlson 2004). The recent controversies undermine the authority of the document, as does the apparent desertion by major bodies, and any rewording must embrace deeply and widely held values, since continual shifts in the text do not imply authority. the actual claims to authority particularly on a global level, by the insertion of the word "international" in article 10 has been challenged. 
Carlson raises the question as to whether the document's utility should be more formally evaluated, rather than just relying on tradition.
Timeline (WMA meetings)
- 1964: Original version. 18th Meeting, Helsinki
- 1975: First revision. 29th Meeting, Tokyo
- 1983: Second revision. 35th Meeting, Venice
- 1989: Third revision. 41st Meeting, Hong Kong
- 1996: Fourth revision. 48th Meeting, Somerset West (SA)
- 2000: Fifth revision. 52nd Meeting, Edinburgh
- 2002: First clarification, Washington
- 2004: Second clarification, Tokyo
- 2008: Sixth revision, 59th Meeting, Seoul
- ^ Declaration of Helsinki - Current (2008) version
- ^ "Recommendations from the Meeting on Prevention of Mother-to-Infant Transmission of HIV by Use of Antiretrovirals". World Health Organization. June 23, 1994. http://name.umdl.umich.edu/5571095.0283.004.
- ^ Council for International Organizations of Medical Sciences (1993). "Guideline 11: Selection of pregnant or nursing (breastfeeding) women as research subjects". International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: World Health Organisation. ISBN 92-9036-056-9. http://www.codex.uu.se/texts/international.html#pregnant.
- ^ Angell M (October 1988). "Ethical imperialism? Ethics in international collaborative clinical research". The New England Journal of Medicine 319 (16): 1081–3. doi:10.1056/NEJM198810203191608. PMID 3173435.
- ^ Barry M (October 1988). "Ethical considerations of human investigation in developing countries: the AIDS dilemma". The New England Journal of Medicine 319 (16): 1083–6. doi:10.1056/NEJM198810203191609. PMID 3173436.
- ^ Center for Drug Evaluation and Research. Guidance for industry: acceptance of foreign clinical studies. March, 2001
- ^ a b Temple R. Impact of the Declaration of Helsinki on medical research from a regulatory perspective. Address to the Scientific Session, World Medical Association General Assembly, September 2003.
- ^ General Assembly WMA Hamburg, Germany 1997
- ^ "Americans want to water down Helsinki Declaration". Bulletin of medical ethics 136: 3–4. 1998. PMID 11657531.
- ^ World Medical Association. Proposed revision of the Declaration of Helsinki Document 17.C/Rev1/99
- ^ World Medical, Association (1999). "Proposed revision of the Declaration of Helsinki". Bulletin of medical ethics 147: 18–22. PMID 11657218.
- ^ Nicholson, RH; Crawley, FP (1999). "Revising the Declaration of Helsinki: a fresh start". Bulletin of medical ethics 151: 13–7. PMID 11657985.
- ^ WMA Medical Ethics Committee. Updating the WMA Declaration of Helsinki. Wld Med J 1999 45: 11-13
- ^ Deutsch E, Taupitz J. Göttingen Report. Freedom and control of biomedical research- the planned revision of the Declaration of Helsinki. Wld Med J 1999 45: 40-41
- ^ Nicholson, RH (2000). "If it ain't broke, don't fix it". The Hastings Center report 30 (1): 6. PMID 11645209.
- ^ Nancy Dickey, Kati Myllymäki, Judith Kazimirsky
- ^ Christie B (October 2000). "Doctors revise Declaration of Helsinki". BMJ 321 (7266): 913. doi:10.1136/bmj.321.7266.913. PMC 1118720. PMID 11030663. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1118720.
- ^ a b c Macklin R. Future challenges for the Declaration of Helsinki: Maintaining credibility in the face of ethical controversies. Address to Scientific Session, World Medical Association General Assembly, September 2003, Helsinki
- ^ Workgroup report on the revision of paragraph 30 of the Declaration of Helsinki 5 January 2004
- ^ WMA Ethics Unit Invitation of Submissions
- ^ Schmidt, Harald; Schulz-Baldes, Annette (November 28, 2007). "The 2007 Draft Declaration of Helsinki - Plus ça Change...?". Bioethics Forum. Hastings Center. http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=666.
- ^ Draft revision Nov 2007
- ^ Second draft revision May 2008
- ^ Williams J. The Declaration of Helsinki and public health. Bulletin of the World Health Organisation 86(8) 2008
- ^ APPI endorses proposed updates to Declaration of Helsinki APPI 22 July 2008
- ^ Eckenwiler, Lisa; Feinholz, Dafna; Ells, Carolyn; Schonfeld, Toby (Spring 2008). "The Declaration of Helsinki through a feminist lens". International Journal of Feminist Approaches to Bioethics 1 (1): 161–77. doi:10.2979/FAB.2008.1.1.161.
- ^ Goodyear MD, Eckenwiler LA, Ells C (2008). "Fresh thinking about the Declaration of Helsinki". BMJ 337: a2128. doi:10.1136/bmj.a2128. PMID 18930967.
- ^ Comparison of Common Rule, Declaration of Helsinki and GCP
- ^ Lurie P, Greco DB (2005). "US exceptionalism comes to research ethics". Lancet 365 (9465): 1117–9. doi:10.1016/S0140-6736(05)71856-0. PMID 15794954.
- ^ DHHS FDA 21 CFR part 312 Human Subject Protection: Foreign clinical studies not conducted under an investigational new drug application. Final Rule April 28 2008, effective October 27 2008
- ^ Obasogie O. Goozner on the FDA and the Declaration of Helsinki. Biopolitical Times. Center for Genetics and Society May 15th 2008
- ^ FDA abandons Declaration of Helsinki for international clinical trials. Social Medicine Portal June 1st 2008
- ^ Rennie S. The FDA ditches the Declaration of Helsinki. Global Bioethics Blog May 6 2008.
- ^ Shah S. FDA Puts Medical Test Subjects in Danger. The Nation May 19, 2008
- ^ "Trials on trial: The Food and Drug Administration should rethink its rejection of the Declaration of Helsinki". Nature 453 (7194): 427–8. May 2008. doi:10.1038/453427b. PMID 18497763.
- ^ FDA scraps Helsinki Declaration on protecting human subjects. Integrity in Science May 5 2008
- ^ Camporesi, Silvia (2009). "The FDA decision to shelve the Helsinki Declaration: Ethical considerations". Ecancermedicalscience 3. doi:10.3332/eCMS.2008.LTR76.
- ^ Kimmelman J, Weijer C, Meslin EM (January 2009). "Helsinki discords: FDA, ethics, and international drug trials". Lancet 373 (9657): 13–4. doi:10.1016/S0140-6736(08)61936-4. PMID 19121708.
- ^ Goodyear MD, Lemmens T, Sprumont D, Tangwa G (2009). "Does the FDA have the authority to trump the Declaration of Helsinki?". BMJ 338: b1559. doi:10.1136/bmj.b1559. PMID 19383751.
- ^ Rid, Annette; Schmidt, Harald (Spring 2010). "The 2008 Declaration of Helsinki — First among Equals in Research Ethics?". The Journal of Law, Medicine & Ethics 38 (1): 143–8. doi:10.1111/j.1748-720X.2010.00474.x. PMID 20446992.
- Riis P (July 1977). "Letter from...Denmark. Planning of scientific-ethical committees". British Medical Journal 2 (6080): 173–4. doi:10.1136/bmj.2.6080.173. PMC 1631019. PMID 871832. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1631019.
- Levine RJ (August 1993). "New international ethical guidelines for research involving human subjects". Annals of Internal Medicine 119 (4): 339–41. PMID 8328746. http://www.annals.org/cgi/pmidlookup?view=long&pmid=8328746.
- Connor EM, Sperling RS, Gelber R, et al. (November 1994). "Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group". The New England Journal of Medicine 331 (18): 1173–80. doi:10.1056/NEJM199411033311801. PMID 7935654.
- Rothman KJ, Michels KB (August 1994). "The continuing unethical use of placebo controls". The New England Journal of Medicine 331 (6): 394–8. doi:10.1056/NEJM199408113310611. PMID 8028622.
- Elander G, Hermerén G (June 1995). "Placebo effect and randomized clinical trials". Theoretical Medicine 16 (2): 171–82. doi:10.1007/BF00998543. PMID 7570396.
- Freedman B, Weijer C, Glass KC (1996). "Placebo orthodoxy in clinical research. I: Empirical and methodological myths". The Journal of Law, Medicine & Ethics 24 (3): 243–51. doi:10.1111/j.1748-720X.1996.tb01859.x. PMID 9069851.
- Lurie P, Wolfe SM (September 1997). "Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries". The New England Journal of Medicine 337 (12): 853–6. doi:10.1056/NEJM199709183371212. PMID 9295246.
- Studdert DM, Brennan TA (November 1998). "Clinical trials in developing countries: scientific and ethical issues". The Medical Journal of Australia 169 (10): 545–8. PMID 9861913. http://www.mja.com.au/public/issues/nov16/studdert/studdert.html.
- McNeill PM (November 1998). "Should research ethics change at the border?". The Medical Journal of Australia 169 (10): 509–10. PMID 9861904. http://www.mja.com.au/public/issues/nov16/mcneill/mcneill.html.
- Levine RJ (August 1999). "The need to revise the Declaration of Helsinki". The New England Journal of Medicine 341 (7): 531–4. doi:10.1056/NEJM199908123410713. PMID 10441613.
- Brennan TA (August 1999). "Proposed revisions to the Declaration of Helsinki--will they weaken the ethical principles underlying human research?". The New England Journal of Medicine 341 (7): 527–31. doi:10.1056/NEJM199908123410712. PMID 10441612.
- Lurie P, Wolfe SM (July 1999). "Proposed revisions to the Declaration of Helsinki. Paving the way for globalization in research". The Western Journal of Medicine 171 (1): 6. PMC 1305720. PMID 10483334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1305720.
- Prior to fifth revision
- Levine, RJ (2000). "Some recent developments in the international guidelines on the ethics of research involving human subjects". Annals of the New York Academy of Sciences 918: 170–8. doi:10.1111/j.1749-6632.2000.tb05486.x. PMID 11131702.
- Temple, R; Ellenberg, SS (2000). "Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues". Annals of internal medicine 133 (6): 455–63. PMID 10975964.
- Loff, Bebe; Zion, Deborah; Gillam, Lynn (2000). "The Declaration of Helsinki, CIOMS and the ethics of research on vulnerable populations". Nature Medicine 6 (6): 615–7. doi:10.1038/76174. PMID 10835665.
- Loff, B; Black, J (2000). "The Declaration of Helsinki and research in vulnerable populations". The Medical journal of Australia 172 (6): 292–5. PMID 10860097.
- Stockhausen, K (2000). "The Declaration of Helsinki: revising ethical research guidelines for the 21st century". The Medical journal of Australia 172 (6): 252–3. PMID 10860086.
- Loff, B (2000). "Violence in research". The Lancet 355 (9217): 1806. doi:10.1016/S0140-6736(00)02310-2.
- Rothman, KJ (2000). "Declaration of Helsinki should be strengthened". BMJ (Clinical research ed.) 321 (7258): 442–5. doi:10.1136/bmj.321.7258.442. PMC 1127802. PMID 10938059. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1127802.
- Following fifth revision
- Vastag B. Helsinki Discord? A Controversial Declaration. JAMA 2000 Dec 20 284:2983-2985 (password required)
- Riis P. Perspectives on the fifth revision of the Declaration of Helsinki. JAMA 2000 Dec 20 284(23): 3045-6
- Human D, Fluss S. The World Medical Association's Declaration of Helsinki: Historical and contemporary perspectives. 5th draft. WMA 2001
- Bošnjak S. The Declaration of Helsinki - the cornerstone of research ethics. Arch Oncol 2001 9(3): 179-84
- Schuklenk U. Helsinki Declaration revisions. Indian Journal of Medical Ethics. Jan-Mar 2001 9(1)
- Singer P, Benatar S. Beyond Helsinki: a vision for global health ethics. BMJ 2001 March 31 322:747-748
- Benatar SR. Distributive justice and clinical trials in the third world. Theoretical Medicine and Bioethics 2001 22: 169-76
- Macklin R. After Helsinki: Unresolved issues in international research. Kennedy Inst Ethics J 2001 11(1): 17-36 (password required)
- Emanuel, Ezekiel J.; Miller, Franklin G. (2001). "The Ethics of Placebo-Controlled Trials — A Middle Ground". New England Journal of Medicine 345 (12): 915–9. doi:10.1056/NEJM200109203451211. PMID 11565527.
- Huston, Patricia; Peterson, Robert (2001). "Withholding Proven Treatment in Clinical Research". New England Journal of Medicine 345 (12): 912–4. doi:10.1056/NEJM200109203451210. PMID 11565526.
- Lilford RJ, Djulbegovic B (February 2001). "Declaration of Helsinki should be strengthened : Equipoise is essential principle of human experimentation". BMJ 322 (7281): 299–300. doi:10.1136/bmj.322.7281.299/a (inactive 2010-09-02). PMC 1119536. PMID 11157551. http://bmj.com/cgi/pmidlookup?view=long&pmid=11157551.
- Lewis, JA; Jonsson, B; Kreutz, G; Sampaio, C; Van Zwieten-Boot, B (2002). "Placebo-controlled trials and the Declaration of Helsinki". Lancet 359 (9314): 1337–40. doi:10.1016/S0140-6736(02)08277-6. PMID 11965296.
- "Dismantling the Helsinki Declaration". CMAJ 169 (10): 997, 999. 2003. PMC 236218. PMID 14609962. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=236218.
- Frankish, H (2003). "WMA postpones decision to amend Declaration of Helsinki. Working group will consider controversy over sponsors' duties to provide treatment at study end". Lancet 362 (9388): 963. doi:10.1016/S0140-6736(03)14398-X. PMID 14513842.
- MacKlin, Ruth (2003). "Bioethics, Vulnerability, and Protection". Bioethics 17 (5–6): 472–86. doi:10.1111/1467-8519.00362. PMID 14959716.
- Tyebkhan, G (2003). "Declaration of Helsinki: the ethical cornerstone of human clinical research". Indian journal of dermatology, venereology and leprology 69 (3): 245–7. PMID 17642902.
- Zion, D (2003). "Justice as equitable power relations: beyond the "standard of care" debate and the Declaration of Helsinki". The American journal of bioethics 3 (2): W12. doi:10.1162/152651603322874906. PMID 14635633.
- Lie, R K; Emanuel, E; Grady, C; Wendler, D (2004). "The standard of care debate: the Declaration of Helsinki versus the international consensus opinion". Journal of Medical Ethics 30 (2): 190–3. doi:10.1136/jme.2003.006031. PMC 1733825. PMID 15082816. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1733825.
- Schuklenk, U (2004). "The standard of care debate: against the myth of an "international consensus opinion"". Journal of Medical Ethics 30 (2): 194–7. doi:10.1136/jme.2003.006981. PMC 1733846. PMID 15082817. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1733846.
- Carlson, Robert V.; Boyd, Kenneth M.; Webb, David J. (2004). "The revision of the Declaration of Helsinki: past, present and future". British Journal of Clinical Pharmacology 57 (6): 695–713. doi:10.1111/j.1365-2125.2004.02103.x. PMC 1884510. PMID 15151515. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1884510.
- De Roy PG. Helsinki and the Declaration of Helsinki; Benatar SR. Linking moral progress to medical progress. World Medical Journal 2004 50(1): 9-11, 11-13
- Williams JR. The promise and limits of international bioethics: Lessons from the recent revision of the Declaration of Helsinki. Int J Bioethics 2004 15(1): 31-42
- Blackmer, J.; Haddad, H (2005). "The Declaration of Helsinki: an update on paragraph 30". Canadian Medical Association Journal 173 (9): 1052–3. doi:10.1503/cmaj.045280. PMC 1266330. PMID 16247102. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1266330.
- Williams JR. The Physician's Role in the Protection of Human Research Subjects. Science and Engineering Ethics 2006; 12: 5-12
- Wolinsky, Howard (2006). "The battle of Helsinki: Two troublesome paragraphs in the Declaration of Helsinki are causing a furore over medical research ethics". EMBO reports 7 (7): 670–2. doi:10.1038/sj.embor.7400743. PMC 1500825. PMID 16819460. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1500825.
- Carlson RV, van Ginneken NH, Pettigrew LM, Davies A, Boyd KM, Webb DJ. The three official language versions of the Declaration of Helsinki: what's lost in translation? J Med Ethics 2007; 33: 545-548
- S Frewer A, Schmidt U, eds. History and theory of human experimentation: the Declaration of Helsinki and modern medical ethics. Stuttgart: Franz Steiner Verlag, 2007.
- Goodyear, M. D E; Krleza-Jeric, K.; Lemmens, T. (2007). "The Declaration of Helsinki". BMJ 335 (7621): 624–5. doi:10.1136/bmj.39339.610000.BE. PMC 1995496. PMID 17901471. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1995496.
- Following sixth revision
- WMA News: Revising the Declaration of Helsinki. World Medical Journal 2008; 54(4): 120-25
- Normile, D. (2008). "ETHICS: Clinical Trials Guidelines at Odds With U.S. Policy". Science 322 (5901): 516. doi:10.1126/science.322.5901.516. PMID 18948510.
- WMA Press Release: WMA revises the Declaration of Helsinki. 9 October 2000
- WMA Press Release: WMA to continue discussion on Declaration of Helsinki. 14 September 2003
- International response to Helsinki VI (2000). WMA 2001
Other codes and regulations
- Nuremberg Code
- Declaration of Geneva
- Belmont Report
- Good clinical practice (GCP)
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
- Code of Federal Regulations
- Nuremberg Code
- Declaration of Geneva 1948
- Declaration of Helsinki: 1964 (Original)
- Declaration of Helsinki: 1975 (First revision)
- Declaration of Helsinki: 1983 (Second revision)
- Declaration of Helsinki: 1989 (Third revision)
- Declaration of Helsinki: 1996 (Fourth revision)
- Declaration of Helsinki: 2000 (Fifth revision, with footnotes from 2002, 2004)
- Declaration of Helsinki: 2008 (Sixth revision - Current)
- International ethical guidelines for biomedical research involving human subjects. 2002 CIOMS
- WMA Medical Ethics Manual 2005
- Nuffield Council on Bioethics: The ethics of research related to healthcare in developing countries. 2005
- UNESCO: Universal declaration on bioethics and human rights. 2005
- CFR Title 45 Public Welfare
- CFR Title 45 Part 46 Protection of Human Subjects
- Tri-Council Policy Statement: Ethical conduct for research involving humans (Canada)
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