By David Jensen PhD, RAC

I am not one to usually nit-pick (and having survived a month of those lousy louses with my daughters, I know what that means) but I was recently reminded that not all of my regulatory colleagues know (or remember) that the US FDA does not require “compliance with the Declaration of Helsinki.” It was at a training I recently attended in which the materials included brief reports of clinical trails; e.g. abstract, methods, tables of data. At the end of every study abstract was the phrase “This study was performed in compliance with the Declaration of Helsinki.” I was surprised to read this because the US FDA has not required such a statement of sponsors and investigators for some time; indeed the US has not been a signatory to the Declaration of Helsinki since before 2000. 

The Declaration of Helsinki is a set of ethical principles regarding human experimentation that was developed for the medical community by the World Medical Association. It is not a legally binding document (here in the US or anywhere else) but instead draws its authority through its influence of national or regional legislation and regulations (e.g., ICH E6 Good Clinical Practice guidance). The original Declaration of Helsinki (1964) has been revised several times over the years.  Prior to 2008, the FDA had used the Declaration of Helsinki as a baseline for what would constitute the “ethical principles acceptable to the world community” which formed part of its criteria for accepting non-IND foreign clinical study data.

In April 2008, the FDA changed its stance on the criteria for accepting non-IND foreign clinical study data. It issued a final rule that replaced its requirement in 21 CFR 312 that non-IND foreign clinical studies be conducted in accordance with the ethical principles stated in the Declaration of Helsinki with new language stating that these studies needed to be conducted in accordance with good clinical practice (GCP), including review and approval by an independent ethics committee (IEC). The stated reason for this change was the United States’ objection to paragraphs 29 and 30 of the 2000 version of Declaration of Helsinki (text and commentary below) which the FDA deemed inconsistent with U.S. law and policy because it imposed a standard for the design of clinical trials that was different from the standard of “adequate and well controlled investigations” required by the FD&C Act. Notes of Clarification to articles 29 and 30 were added in 2002 and 2004 respectively. The 2002 clarification to Article 29 outlined circumstances in which a placebo might be “ethically acceptable”, for example for “compelling… methodological reasons” or “minor conditions” where the risk of harm was considered low. The footnote indicates that the wording must be interpreted in the light of all the other principles of the Declaration. In January 2004 a World Medical Association working group examined article 30 and recommended that it not be amended. Later that year the American Medical Association proposed a note of clarification that was incorporated with the issue of post trial care now something to consider, not an absolute assurance.

Finally, in April of this year, the World Medical Association released for comment proposed changes to the Declaration of Helsinki’s language. The changes to the placebo language (now paragraph 33) and continued access to “…the best proven prophylactic, diagnostic and therapeutic methods identified by the study” (now paragraph 34) seem unlikely to stem the debate about these issues. You can find a table comparing the text of the 2008 Declaration of Helsinki’s to the newly proposed text here (PDF).

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Declaration of Helsinki (2000) Paragraph 29 states: “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.” This paragraph appears to rule out the use of placebo-controlled trials in all but a few instances. Placebo-controlled trials are a cornerstone of FDAs interpretation of “adequate and well controlled investigations” and are a common clinical trial design in the United States. 

Paragraph 30 states: “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.” FDA stated that it invoked issues of health care policy (i.e., continuing access to medical products) that were not directly related to FDA’s mission of ensuring that medical products are safe and effective.

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