1.2 The Declaration of Helsinki (1964)

1.2 The Declaration of Helsinki (1964)

Development and Purpose of the World Medical Association (WMA)

While the Nuremberg Code provided a powerful foundation for human rights in research, it was written by jurists prosecuting war crimes, not by clinical researchers navigating the complexities of patient care. Recognizing the need for a document tailored to the medical profession, the World Medical Association (WMA)—an international organization of physicians founded in 1947—developed and adopted the Declaration of Helsinki in June 1964 in Helsinki, Finland.

The Declaration of Helsinki serves as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. Unlike the Nuremberg Code, which focused primarily on healthy volunteers in non-therapeutic experiments, Helsinki was designed to guide physicians conducting clinical trials where research is combined with medical care. It has undergone multiple revisions (1975, 1983, 1989, 1996, 2000, 2008, and 2013) to address emerging ethical issues, such as placebo-controlled trials and post-trial access.

Protocols and Independent Ethics Committees

One of the most significant contributions of the Declaration of Helsinki (introduced in the landmark 1975 revision) was the formalization of independent review.

The Research Protocol

Helsinki establishes that the design and performance of every research procedure involving human subjects must be clearly formulated in a research protocol. This protocol must contain a statement of the ethical considerations involved and indicate how the principles of the Declaration have been addressed. The protocol must also include:

• Information regarding funding, sponsors, institutional affiliations, and potential conflicts of interest.
• Incentives for subjects and provisions for treating and/or compensating subjects harmed as a consequence of participation.
• A clear description of post-trial provisions.

The Independent Committee

Before a study can begin, the protocol must be submitted for consideration, comment, guidance, and approval to a formally appointed, independent research ethics committee (referred to as an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) in modern regulations). This committee must:

• Be independent of the investigator, the sponsor, and any other undue influence.
• Take into consideration the laws and regulations of the country in which the research is to be performed, as well as international norms, but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in the Declaration.
• Have the right to monitor ongoing trials. The investigator must provide monitoring information to the committee, especially regarding any serious adverse events.

The Ethical Use of Placebo Controls

The conditions under which a placebo may be ethically used have been one of the most heavily debated aspects of the Declaration of Helsinki. The WMA maintains a strict stance to protect patients from receiving sub-optimal care simply for the sake of scientific convenience.

According to Paragraph 33 of the 2013 revision, the benefits, risks, burdens, and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances where a placebo (or no treatment) may be used:

1. No Proven Intervention: When no proven intervention exists, the use of placebo or no intervention is acceptable.
2. Compelling Methodological Reasons: Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention, and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to any additional risks of serious or irreversible harm.

On the CCRP exam, candidates must know that if an effective standard of care exists for a condition, using a placebo is generally unethical under Helsinki, unless there is zero risk of serious or permanent harm to the subject (e.g., testing a new drug for a mild headache where withholding active treatment causes temporary discomfort but no lasting damage).

Post-Trial Provisions and Access

Another landmark principle of the Declaration of Helsinki is the requirement for post-trial provisions (Paragraph 34). In advance of a clinical trial, sponsors, researchers, and host country governments must make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.

This requirement ensures that vulnerable populations in developing nations or underinsured subjects are not utilized as "research subjects" to prove a drug's efficacy, only to have the drug priced out of their reach once the trial concludes.

Revisions and the FDA Regulatory Break

For many years, the U.S. Food and Drug Administration (FDA) incorporated the Declaration of Helsinki by reference in its regulations governing clinical trials conducted outside the United States that were intended to support applications for drug approval (under 21 CFR 312.120). Specifically, the FDA referenced the 1989 version of the Declaration.

However, as the WMA updated the Declaration in 2000 and 2008, the revisions to the placebo guidelines and post-trial access requirements conflicted with the FDA's regulatory approach. The FDA argued that the strict placebo restrictions would hinder the scientific validation of new drugs and that post-trial access mandates were outside its regulatory purview.

The 2008 Regulatory Shift

Effective October 27, 2008, the FDA amended 21 CFR 312.120:

• The FDA removed all direct references to the Declaration of Helsinki.
• Instead, the FDA required that foreign clinical trials not conducted under an Investigational New Drug (IND) application must be conducted in accordance with Good Clinical Practice (GCP) as defined in ICH E6, which includes review by an independent ethics committee and obtaining informed consent.