When compassionate phage therapy case reports are described in published works, patients are often described as being treated with phages “under the umbrella” of the Declaration of Helsinki (sometimes called the Helsinki Declaration). (For an example/more context, check out last week’s Capsid & Tail article on how the Queen Astrid Military Hospital in Brussels does phage therapy). This week, we’re going over where the Declaration of Helsinki came from, why it’s so commonly referenced, and how it applies to phage therapy.
What is the Declaration of Helsinki?
The Helsinki Declaration is a set of ethical principles for medical research involving human subjects. It is meant to protect patients. It was written by the World Medical Association (WMA), an association of physicians, and the first version was adopted in 1964 (55 years ago). It has been described as the most widely recognized source of ethical guidance for biomedical research.
Perhaps surprisingly, it is a relatively short document that is clearly laid out in bullet points, and which only takes about 10 minutes to read. (Some have stated that its brevity likely contributed to its widespread use).
Who is it for?
The Declaration of Helsinki is addressed primarily to physicians. However, it encourages others involved in medical research to adopt its principles.
What are some of the main points?
The Declaration is meant to protect individual patients while still allowing clinical trials to be done on human subjects, since this benefits society. It addresses subjects such as informed consent, placebo controls, conditions that should lead to a trial being done or discontinued, minimum training of researchers, reporting the results of a trial, the conditions under which an unproven therapy can be used as a medical intervention, and more.
Is it legally-binding?
No. The Declaration is not a legal framework, and is not legally binding. Each country may have its own laws regarding human experimentation, but these are separate from the Declaration. However, the most recent version of the Declaration states that “no national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration”. In other words, it calls for protection of patients even in regions where laws have lower barriers for what constitutes ethical medical research. In other words, it seems to be written as being above the law, while at the same time, it is not legally enforceable. Still, for some reason, the Declaration of Helsinki seems to occupy a position of authority in many parts of the world.
Where did it come from?
The original Declaration of Helsinki was developed from the Nuremberg Code, which was produced in 1947 in response to the highly unethical human research that was done in Germany during World War II. Both were meant to protect against the kinds of human experimentation performed during the war.
How has it evolved over the years?
The Declaration has been revised seven times since the original version in 1964, with the most recent version being adopted in 2013. Because of this, the document has been considered a ‘living document’ (a fact that has sparked criticism, due to the paradox that a list of fundamental ethical principles would also be subject to frequent change).
Controversy and criticisms
Some of the recent modifications have led to serious debate among medical and research professionals, and have led to some groups (such as the US FDA) refusing to adopt certain versions, or to the creation of new international documents to be used in place of the Declaration. Specifically, much of the controversy relates to the Declaration’s dealing with placebo controls (e.g. under what conditions are placebos ethical?) and post-trial access to medical interventions, especially in developing countries.
More generally, critics have claimed that the Declaration is internally inconsistent, vague, that it lacks sufficient discussion of exceptions, is overreaching in its self-proclaimed authority, and more. Some have sounded warnings that the continued controversy surrounding its contents could lead to it gradually losing credibility.
How does the Declaration of Helsinki apply to phage therapy?
In most articles where the Declaration is mentioned, it is in the context of demonstrating to readers that compassionate use of phage therapy was done ethically. Often, a simple statement like “the patient was treated in accordance with the Declaration of Helsinki” is included in the report. Article 37, “Unproven Interventions in Clinical Practice”, is typically the part of the Declaration referenced in phage therapy reports. Of note, this is not an aspect of the Declaration that is generally considered controversial.
Full text of Article 37: Unproven Interventions in Clinical Practice
“In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorised representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. 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.”
Not all aspects of Article 37 are consistently followed
Interestingly, although Article 37 of the Declaration is commonly referenced in phage publications, and the first half of the paragraph appears to be diligently followed, the second half of the paragraph, “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”, is not always heeded. Phages used in compassionate use cases are relatively rarely made the subject of safety and efficacy trials, and phage therapy case reports are frequently unpublished (for more discussion on compassionate phage therapy, see this Capsid & Tail article by guest writer Shawna McCallin). Does this practice proceed without consequence? Is this because of the lack of enforceability of the Declaration? Are there examples of groups who have been penalized for treating patients with phages without complying with this part of the directive? (If any readers have answers to these questions, we’d love to know!)
The Declaration of Helsinki is a set of ethical principles surrounding medical research that is meant to guide the international medical community. Originating from the Nuremberg Code, it is one of the most renowned documents of its kind. However, the Declaration is not a legal framework, and is not legally enforceable.
The Declaration has sparked much criticism and debate among physicians and medical researchers over the years, and many have questioned why it continues to be held in such high esteem. Although it is meant to be an “international” set of guidelines, different physicians and researchers in different countries heed its principles to different degrees, and some countries have replaced the Declaration with other guidelines.
To this day, in many countries where phage therapy is not approved, physicians provide phages to patients in open accordance with the Declaration. However, certain parts of the Declaration are not always heeded when it comes to phage therapy, such as making data publicly available and following up on experimental treatments with safety and efficacy testing. It is unclear what the consequences may be for such selective adherence. However, this apparent inconsistency between the Declaration and general practice should serve as a reminder for physicians, researchers and drug developers involved in compassionate phage therapy under the Declaration to make an effort to prioritize phage therapy case reporting. As well, perhaps we should discuss as a phage community how best to undertake safety and efficacy followup on phages used in compassionate phage therapy.
An interesting analysis of how the Declaration of Helsinki began and was modified from 1964-2000.
The JAMA website has a clearly laid out guide to the Declaration of Helsinki, the Declaration of Geneva, and the Nuremberg Code, and has links to the original versions of each.
For articles on the controversy of the Declaration of Helsinki, see:
For examples of phage therapy in accordance with the Declaration of Helsinki, see:
To read about how a legal framework could lead to phage therapy being done without relying on the Declaration of Helsinki’s stipulations, see our Capsid & Tail article on Belgium’s magistral phage framework.