Declaration of Helsinki

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The Declaration of Helsinki (DoH) is a cornerstone document outlining ethical principles for conducting medical research with human subjects. Originally adopted in Helsinki, Finland in June 1964, it has undergone several revisions, the most recent being the 2013 version. The Declaration of Helsinki is produced by the World Medical Association (WMA), an international body representing physicians since its founding in 1947.

The full title of the statement is "WMA Declaration of Helskini: Ethical Principles for Medical Research Involving Human Subjects." While the Declaration's preamble notes it is "addressed primarily to physicians," the WMA encourages its wider use by all those involved in medical research involving human subjects.

As a product of a nongovernmental organization, rather than a governmental or intergovernmental body, the Declaration of Helsinki is not legally binding. However, it is influential, impacting official policies of organizations and governmental regulations. It is a source for Institutional Review Boards (IRBs) in reviewing and approving medical research, researchers in conducting research, and funders in deciding whether or not to support research, and it has been incorporated into national legislation. The Declaration is one of most widely recognized and respected statements on ethical principles for researchers engaged in human subject research, although some of its stated principles, notably a paragraph dealing with use of placebos, have engendered controversy.

The history of research with human subjects has been fraught with horror stories, where human subjects have been mistreated as objects of study rather than individuals with inherent human rights and dignity. Indeed, the roots of the Declaration of Helsinki can be found in the Nuremberg Code, which was drafted to deal the the atrocities of Nazi human experimentation. Several of the principles of the Declaration of Helsinki can be traced to the Nuremberg Code. The Declaration of Helsinki represents a major step forward in correcting abuses in the realm of medical research.

Summary of Declaration of Helsinki

The following is an overview of the Declaration of Helsinki. In keeping with the convention of scholarly publications and the Declaration itself ("The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with consideration of all other relevant paragraphs"), the numbered points in the Declaration will be referred to as paragraphs. However, it should be noted that some of the numbered points actually include multiple paragraphs under that particular number ("paragraph").

The current Declaration of Helsinki (2013 revision) includes 37 numbered points (paragraphs), presented in somewhat over two thousand words (2,240 including the preamble, numbering, and section subheads). The Declaration includes sections on the following topics:

  • Preamble
  • General Principles
  • Risks, Burdens, and Benefits
  • Vulnerable Groups and Individuals
  • Scientific Requirements and Research Protocols
  • Research Ethics Committees
  • Privacy and Confidentiality
  • Informed Consent
  • Use of Placebo
  • Post-Trial Provisions
  • Research Registration and Publication and Dissemination of Results
  • Unproven Interventions in Clinical Practice

These sections will be summarized below. For the full statement, please see the document presented by the World Medical Association (WMA 2018), as listed in the references.

Preamble

The Preamble's two paragraphs outline the purpose of the Declaration and the intended audience. This is reproduced in its entirety here:

  1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with consideration of all other relevant paragraphs.
  2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA encourages others who are involved in medical research involving human subjects to adopt these principles.

General Principles

This section includes 13 paragraphs that address the following issues:

  • Centrality of the patient/human subject's best interests (well-being, rights, etc.) (Paragraphs 3, 4, 7, 8, 9, 10)
  • Purpose of involving human subjects in research (5,6,8)
  • Minimizing harm to the environment (11)
  • Researcher competency (12)
  • Underrepresented groups (13)
  • Involving a physician's patient in that physician's research (14)
  • Compensation and treatment for subjects who are harmed (15)

The following are some excerpts from this section, with the respective paragraphs noted:

  • 4. It is the duty of the physician to promote and safeguard the health, well-being, and rights of patients, including those involved in medical research...
  • 5. Medical progress is based on research that ultimately must include studies involving human subjects.
  • 8. While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.
  • 9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects...
  • 12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and scientific education, training and qualifications...
  • 15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured.

Risks, Burdens and Benefits

This section includes three paragraphs (16, 17, 18) that deal with risk/benefit analysis. The following are some excerpts from this section:

  • Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects.
  • All medical research involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them and to other individuals or groups affected by the condition under investigation.
  • Physicians may not be involved in a research study involving human subjects unless they are confident that the risks have been adequately assessed and can be satisfactorily managed.

Vulnerable Groups and Individuals

This section includes two paragraphs (19,20) dealing with those individuals and groups that "are particularly vulnerable" and "should receive specifically considered protection."

Scientific Requirements and Research Protocols

The two paragraphs (21,22) in this section deal with the importance that the research be justified in a research protocol, be based on a knowledge of the subject matter, be adequate in terms of laboratory facilities, and, when appropriate, be based on animal experimentation. The paragraph on the protocol, 22, is detailed (point 22 actually is composed of three paragraphs) and specifies some of the essential ethical considerations to include in the protocol.

Research Ethics Committees

This section includes only one paragraph, 23, which deals with the consideration and approval of the research by a research ethics committee before the study commences. It details some of the nature of this committee and its "right to monitor ongoing studies." Essentially, this paragraph, which is rather extensive (this point 23 is actually composed of two paragraphs), deals with the importance and nature of an Institutional Review Board (IRB).

Privacy and Confidentiality

This section (paragraph 24) deals with the ethics of protecting the privacy of the research subjects and the "confidentiality of their personal information."

Informed Consent

The section on Informed Consent is composed of eight separate numbered points (paragraphs 25 to 32). The importance of informed consent can be recognized in that it is the most extensive section of the Declaration of Helsinki, involving 658 words, or over one-quarter of the statement. (The section on General Principles is composed of more numbered points, 13, but 475 words).

The eight paragraphs ("paragraph" 26 actually runs over 3 paragraphs) deals with such issues as the voluntary consent of the research subjects, adequately informing the research subject regarding the research, issues of undue pressure to participate, and those subjects incapable of giving informed consent. Also included is informed consent in terms of "collection, storage and/or reuse" of "identifiable human material or data."

The following are some excerpts from this section:

  • 25. Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary...
  • 26. .. each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest... anticipated benefits and potential risks...The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal...
  • 28. For a potential research subject who is incapable of giving informed consent, the physician must seek informed consent from the legally authorized representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless ...[three conditions named, including] ... and the research entails only minimal risk and minimal burden.

Use of Placebo

The sole paragraph (33) in this section deals with ethical considerations relative to using a placebo in medical research. The statement regarding placebos is among the more controversial in the Declaration, as will be addressed in the history section below.

Post-Trial Provisions

This paragraph (34) deals with making provisions, prior to a clinical trial, for "post-trial access for all participants who still need an intervention identified as beneficial in the trial."

Research Registration and Publication and Dissemination of Results

The two paragraphs (34, 35) in this section deal with (a) the requirement to register every human subject research study in a publicly accessible database and (b) ethical obligations relative to publishing and disseminating research results.

Unproven Interventions in Clinical Practice

The final paragraph (37) provides guidelines for using an unproven intervention in the treatment of an individual patient, provided proven interventions do not exist or existing interventions have been ineffective. This deals with the cases where "in the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering." The document concludes with this statement: "This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available."

History

The Declaration of Helsinki was developed by the World Medical Association. The first version was adopted in June 1964 by the 18th World Medical Assembly held in Helsinki, Finland, and was a relatively short document of about 700 words and 11 points (14 separate paragraphs, since one of the numbered points had three paragraphs—3a,3b,3c—and one had two—4a,4b). It was amended seven times since (1975, 1983, 1989, 1996, 2000, 2008, and 2013). The current version was adopted at the General Assembly in October 2013 and had tripled in size (about 2,200 words) since the initial version. Below is a description of the World Medical Association and a brief outline of the history of the Declaration.

World Medical Association

The World Medical Association (WMA) is an international non-governmental organization whose membership consists of physicians and associations representing physicians. As of August 2021, it has 115 Constituent Members (largely national associations of physicians and medical students) and about 1,500 Associate Members (individual physicians) and represented about ten million physicians overall. It was founded in 1947, when it held it First General Assembly in Paris with physicians from 27 different countries (WMA 2021a).

The mission of the WMA is to establish international standards in areas of medical ethics, education, science, health care, and so forth. In addition to the Declaration of Helsinki, the WMA has produced the Declaration of Geneva (modern version of the Hippocratic Oath) and the International Code of Medical Ethics (duties of physicians in general and to patients). It has produced statements on the rights of patients, torture of prisoners, use and abuse of drugs, care of the sick and wounded in armed conflict, family planning, and pollution (WMA 2021a).

Development of initial declaration

On October 27, 1962, the British Medical Journal announced a draft code of ethics for human experimentation. This was revised and the new version, titled Declaration of Helsinki (with the subtitle Recommendations Guiding Doctors in Clinical Research), was adopted in June 1964 at the 18th WMA General Assembly in Helsinki, Finland, being approved by three-quarters majority vote.

One of the foundational documents for the development of the original Declaration of Helsinki (DoH) was the Nuremberg Code. This Code arose from the portion of the Nuremberg Trials dealing with the atrocities of Nazi human experimentation (the "Doctors' Trial") and was released as part of the judges' decision in April 1947. As noted by Carlson et al. (2004), "The original DoH is seen as having its roots in the Nuremberg Code." Carslon et al. go on to note that researchers had identified 10 markers of ethical research within the Nuremberg Code that appear in the original DoH, with only 2 Nuremberg Code markers being abandoned. One of two that was abandoned was the requirement of the Nuremberg Code that "the voluntary consent of the human subject is absolutely essential," with the DoH allowing consent to be given by a legal guardian when the subject lacks the capacity to give consent. The other marker that was abandoned was the Nuremberg Code statement: "During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him impossible." The original DoH does have the statement: "The investigator or the investigating team should discontinue the research if in his or their judgement it may, if continued, be harmful to the individual."

The Declaration of Helsinki also addressed "clinical research" rather than employing the "human experimentation" phrase used in the Nuremberg Code.

Revisions

Since its adoption in 1964, the Declaration of Helsinki has undergone seven revisions:

  • 1975 (October) at the 29th WMA General Assembly in Tokyo, Japan
  • 1983 (October) at the 35th WMA General Assembly in Venice, Italy
  • 1989 (September) at the 41st WMA General Assembly in Hong Kong
  • 1996 (October) at the 48th WMA General Assembly in Somerset West, Republic of South Africa
  • 2000 (October) at the 52nd WMA General Assembly in Edinburgh, Scotland
  • 2008 (October) at the 59th WMA General Assembly in Seoul, Republic of Korea
  • 2013 (October) at the 64th WMA General Assembly in Fortaleza, Brazil

The first revision in Tokyo (1975) involved substantial revisions from the original DoH, including the addition that independent committees review research protocols. There was also a significant elaboration of the requirements for informed consent. There was an almost doubling of the size of the document, as "almost nothing was removed from the 1964 version and much was added" (Carlson et al. 2004).

The second revision in Venice (1983) involved on a slight alteration of the text. Carlson et al. (2004) note: "it could be argued that the very minor changes of 1983 hardly warrant the term revision. Among changes were the substitution of the word "physician" for "doctor."

The third revision in Hong Kong (1989) was likewise minor. Carlson et al. (2004) note: "This revision requires a fairly careful reading to see where any difference at all occurs." The only changes were an elaboration of the statements on experimental protocols being transmitted to a independent committee for review, adding 29 words to the length of the document.

The fourth revision in Somerset West (1996) also involved slight changes to the text, but with significant later repercussions. Carlson et al. (2004) note: "As in 1983 and 1989, the actual changes to the text were minimal." They go on to say "However, the nature of the small textural changes provided a seed out of which grew a much larger debate." Essentially, there was an addition to the section dealing with combining medical research with clinical care. This addition introduced discussion of the use of placebos in studies. Carlson et al. (2004) note: "it is the first time the DoH makes reference to any specific type of research methodology, i.e., the placebo-controlled trial." It was this addition that eventually led the US Food and Drug Administration (FDA) to decide to eliminate reference to the Declaration of Helsinki.

The fifth revision in Edinburgh (2000) was a substantial change. Carlson et al. (2004) note that in this revision "only three of the 32 paragraphs are completely unchanged, while eight are completely new." There also was a complete restructuring of the document in terms of subheads and presentation of the paragraphs. Carlson et al. (2004) noted three particularly controversial new paragraphs: 19, 29, and 30.

  • 19. Medical 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.
  • 29. 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.
  • 30. At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.

Carlson et al. (2004) note that, as with the fourth revision, paragraph 29 deals with use of placebos. However, they note with respect to the wording changes in paragraph 29 that "little has changed in the overall ethical guidance with respect to placebo use. Therefore, what is surprising is that the outcry following the 2000 revision far exceeded the response to the 1996 revision." It was after the publication of the 2000 revision that the US Food and Drug Administration decided to "rewrite its regulations to eliminate any reference to the Declaration of Helsinki (DoH)," with the FDA reacting to paragraphs 29 and 30 (Wolinski 2006). Wolinski (2006) noted "critics were especially alarmed by paragraph 29, portraying it as an attach on the use of placebos, which would make it more difficult to assess the safety and efficacy of drug candidates."

Carlson et al. (2004) note the controversies engendered by paragraphs 19 and 30 related to issues of whether or not addressing social justice is an appropriate role of the DoH (19) and debate about the burden placed on researchers in terms of what happens to subjects once the trial is over.

The sixth revision in Seoul (2008) was another minor revision.

The seventh and most recent revision in Fortaleza (2013) had some noteworthy additions. As Millum et al. (2013) note: "For the first time, the declaration requires compensation and treatment for research-related injuries (paragraph 15), an explicit recognition that research participants should not bear the costs of research gone wrong." They also note an emphasis on dissemination of research results, including those with negative results.

The issue with placebos continues with the most recent revision. Skierka and Michels (2018), in discussing this current version, note that "its paragraph on the use of placebo controls in clinical trials divides the research community into active-control and placebo orthodox proponents, both continuously demanding revision of the Declaration of Helsinki in favour of their position."

Importance

Overall, the Declaration of Helsinki remains a very influential document. Millum et al. (2013) note "The declaration is consulted by ethics review committees, funders, researchers, and research participants; has been incorporated into national legislation; and is routinely invoked to ascertain the ethical appropriateness of clinical trials."

Skierka and Michels (2018) further note: "Since 1964, when the Declaration of Helsinki was adopted by the World Medical Association, it represents one of the most respected set of ethical principles to guide medical researchers protecting patients enrolling in biomedical experimentation." However, they further observe that the Declaration "has always been a document of constant change and controversy."

See also

References

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