to regulate itself, and it built upon the previously developed Nuremberg Code of 1947. Major revisions were made in 1975, 2000, and most recently in 2013. The first revision was the Tokyo (1975) revision, the second was the Venice (1983), the third was the Hong Kong (1989), and the fourth was the Somerset West, South Africa, (1996) revision.
The first 700-word Declaration of Helsinki developed and corroborated the 10 principles that were first stated in the Nuremberg Code with the Declaration of Geneva, which was more geared toward the ethical duties of physicians.
The first major revision in 1975 doubled the length of the original document, ensuring that concern for the subject (the patient volunteer) must always come before the interests of science and of society. This revision also included the introduction of the requirement of an independent oversight committee for the clinical research project. This concept was adapted in the United States as the Institutional Review Board (IRB), and in other countries with similar equivalent ethics review committees.
Calls for the Edinburgh (2000) revision of the Helsinki Report
Having been developed out of controversy, the fifth revision in 2000, known as the Edinburgh (2000) revision, also resulted, and to some extent remains, in considerable controversy. This revision required monitoring of clinical scientific research to ensure and reinforce ethical standards, and was in part spurred by a seminal paper published by Peter Lurie and Sidney M. Wolfe in 1997, which called for the discontinuation of human immunodeficiency virus (HIV) trials in developing countries, citing discriminations in change of study design between Thailand and Africa. Importantly, the proclamation of the Tokyo (1975) version remained in paragraph 5 of the Introduction in the Edinburgh (2000) version, stating that “In medical research on human subjects, considerations related to the well-being of the human subject should take preference over the interests of science and society.” Much of the controversy, however, arose around the area of the ethical requirements of placebo-controlled trials, described below.
Major changes in the 2000 revision
It is of note that a major change in the 2000 version was in the organization of the original four versions, which were grouped under three headings: I. Basis Principles, II. Clinical Research Combined With Professional Care, and III. Non-Therapeutic Clinical Research. The separate headings distinguished between clinical research that was purely scientific without therapeutic value or that was of therapeutic value to the subject, but was removed in the Edinburgh (2000) revision. Instead, the utility of healthy volunteers replaces Non-therapeutic Clinical Research. In paragraph 16, the participation of healthy volunteers as research subjects is described as being permissible, and in paragraph 18, they are described as an important group for prior weighing of the risks and burdens against the importance of research. While the revision is supported on the one hand as having a much more logical organization and sequence of reasoning, it is criticized as being of concern in that there is no section that distinctly discusses research involving no benefit to the participants, except perhaps that such groups are often paid for their participation in research.
Perhaps the most controversial parts of the fifth revision of the Declaration of Helsinki are paragraphs 29 and 30, which fall under the heading Additional Principles for Medical Research Combined With Medical Care. These are described separately below. Some of the other successes and sources of debate are described here and begin with the Introduction. Today, discussions still arise, perhaps purposely, on the dilemma described in the Introduction of the Edinburgh (2000) version of the declaration, which argues on both sides—for the challenge of current medical practices and against the use of people as a means to an end. The Introduction ends with no real conclusion, and therefore perhaps this unwritten subtlety calls for the continued debate contained in the words of the 1975 version that recommendations “should be kept under review in the future” removed in this 2000 revision.
The beginning of paragraph 1 repeated the words of older versions, but added a second sentence stating, “Medical research involving human subjects includes research on identifiable human material or identifiable data.” This sentence brings about the question of research involving anonymous human research, for example, that which utilizes de-identified clinical samples. This concern was discussed by Povl Riis in his paper Perspectives on the Fifth Revised Declaration of Helsinki. In this same paper, Riis raises discussion on paragraph 6. Again, in paragraph 6, it is the second sentence that was added, which is the subject. Here, the ethical onus is placed on physicians to challenge their practices through research for greater efficacy, efficiency, accessibility, and quality, but it does not elaborate on the definitions of these criteria. In this way, the challenge to delicately balance the obligations of protecting and respecting patient subjects and volunteers, with scientific innovation and medical progress through research, is brought up again.
Paragraph 9 has not raised a great deal of debate, but it is important in that it sets up a minimal standard that all physicians worldwide should follow, specifically, distinguishing that “No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.” This is emphasized in the WMA 2003 statement, which included that “In some cases the law mandates unethical conduct. The fact that a physician has complied with the law does not necessarily mean that the physician has acted ethically. When the law is in conflict with medical ethics, physicians should work to change the law. In circumstances of such conflict, ethical responsibilities supersede legal obligations.”
Controversies of Paragraphs 29 of the Edinburg (2000) revision: Are patient subjects worse off in the clinical trial than they were before? The Somerset West, South Africa (1996), revision was the first in which the use of placebo in clinical trials was described. The wording of this 1996 version—“The potential benefits, hazards and discomfort of a new method should be weighed against the best current diagnostic and therapeutic methods”—was changed in the 2000 version to state that “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.” The 2000 version completely removed the 1996 statement that “In any medical study, every patient—including those of a control group, if any—must be assured of the best proven diagnostic and therapeutic method.”
The first controversy brings into question the definition of the “best current” therapeutic methods. Indeed, “best current” could mean either in existence globally, best used in practice globally, or best available within the local community. Then there is the question of even the word “best”—does this refer to the most effective, the least toxic, a weighing of the two, or simply the most widely used and therefore best studied and understood? With personalized medicine on the horizon, arguments today may additionally question, “best” for whom—the general population of patients with the condition under study, or for the individual patient?
Additionally, an ensuing outcry of protest following the release of the Edinburgh (2000) version was that this paragraph appears to disallow the use of placebo as a control where there is a proven treatment, which led to the WMA issuing a clarification on paragraph 29. The clarification described the use of a placebo as acceptable where there is a scientifically compelling reason, or where the subject is at no increased risk of serious or irreversible harm, for example, when the condition under study is a minor one. However, the clarification itself continues to fall under question, for example, in the use of the connector “or.” It is argued, for example, by R. Macklin in her 2003 paper “Future Challenges for the Declaration of Helsinki” that the connector used should be “and” since the statement, as it is written, suggests that a scientifically compelling reason may supersede or justify an increased risk of serious or irreversible harm to the subject.
Nonetheless, counterarguments exist, for example, that paragraph 5 covers
