If this is your first or second visit to the Blog, then I should tell you that I am a former employee of FDA interested in discussing issues regarding FDA, good clinical practice (GCP), and good laboratory practice (GLP). I have posts on several issues in the past two weeks that I hope you will look through. Who knows, one or two may be of interest to you. In this post I offer my opinions on FDA’s decision to break with the ethical standards found in the Declaration of Helsinki last year. I welcome your comments on this or any other post.
Few, if any, documents carry more prestige than than the Declaration of Helsinki. First issued in 1964 by the World Medical Association it is a direct result of the atrocities committed in World War II by Nazi Germany by physicians carrying out “research” on concentration camp inmates, frequently in “studies” designed to kill the participants. It is a document that is the direct result of a critical need to establish ethicall research standards for biomedical research. It was a scientific extension of the Nuremburg Code, published in 1949, which came about as a result of the war crimes tribunals that took place in Nuremburg directly after the war.
The Declaration of Helsinki also predates the Belmont Report by 15 years, a document on research ethics that was released by the United States in 1979, that set the bases for our modern IRB regulations. The Declaration has been updated throughout the years and was referenced in the FDA investigational new drug application (IND) regulations (§ 312.120 ) until last year. At that time FDA issued a Final Rule that replaced the Declaration with “good clinical practice” or GCP as a standard for accepting research not conducted under an IND. One primary reason is a difference in policy regarding the use of placebos in clinical trials.
The Declaration of Helsinki, the Nuremburg Code, and the Belmont Report are all attached as links on the right under important documents, along with ICH E6, the original GCP document. The Final Rule for § 312.120 is attached as a PDF file at the bottom of this post.
Now, with a new administration setting international policy, is it possible that FDA will listen to criticism about severing ties with the Declaration? Is it possible that in a globalized economy and a globalized industry that FDA will try to bring itself into harmonized research ethics standards? It is an interesting question and one that the new commissioner, whomever gets the job, will need to deal with sooner or later. Who President Obama selects will give us a better idea of whether its sooner rather than later.
Last fall I participated in publishing an article (also attached to this post) discussing the Final Rule. Now I would like to pose three questions that I believe need to be reviewed in depth as we decide if FDA should embrace or reject the Declaration of Helsinki.
First, the Final Rule issued by FDA states: “The final rule replaces the requirement that these studies be conducted in accordance with the ethical principles stated in the Declaration of Helsinki (Declaration) issued by the World Medical Association (WMA), specifically the 1989 version (1989 Declaration), with a requirement that the studies be conducted in accordance with good clinical practice (GCP), including review and approval by an independence committee.”
For most of us the document that is the primary reference for GCP is a well established, internationally recognized document: E6: Good Clinical Practice: Consolidated Guidance (E6) published by the International Conference on Harmonization (ICH). There are only two small problems: although FDA recognizes E6 as a standard for GCP and in fact participated in the ICH discussions that produced E6 and even published E6 as official FDA guidance in the Federal Register, it doesn’t recognize E6 as the standard for GCP in the Final Rule, only that “the standard of GCP we propose § 312.120 was consistent with that in ICH E6 and was sufficiently flexible to accommodate differences in how countries regulate the conduct of clinical research and obtain informed consent, while helping to ensure adequate and comparable human subject protection.”
One problem is that the introduction in E6 specifically mentions the Declaration: “Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.” Now this is something that FDA has noticed as well. In fact they cite this reference in responding to one comment to the Final Rule. FDA points out that GCP is more than an operational guideline, it is an ethical standard as well. (my emphasis)
However, FDA conveniently fails to mention to this particular response that FDA is not adopting E6 as the standard for GCP. (my emphasis) So that is my second issue with the Final Rule for § 312.120. GCP is an internationally recognized standard that FDA participated in creating. However, FDA rejects the use of this internationally recognized definition of GCP in favor of one that conveniently leaves out the Declaration. It also doesn’t mention where anyone uses this new definition of GCP. The Final Rule specifically states that E6 is:
“Specific incorporation of ICH E6 into § 312.120 would constrain our ability to accept data from non-IND foreign clinical studies from countries that use other comparable GCP standards. Finally, ICH E6 contains a level of detail and specificity that is not appropriate or regulations. We believe that the GCP standard in § 312.120 is appropriate because it provides sufficient flexibility to accommodate differences in how countries regulate the conduct of clinical research, while still ensuring adequate and comparable human subject protection. Therefore, we do not require that sponsors or applicants follow ICH E6”
In their new definition, shared by no one else that they cite, FDA has now defined GCP a little differently: “Under CFR §312.120(a)(1)(i), Good Clinical Practice (GCP) is defined as ‘a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected.’” FDA continues to say that GCP includes review and approval (or provision of a favorable opinion) by an independent ethics committee (IEC) prior to study initiation and continuing review of an ongoing study by an IEC. This CFR part further states the freely given informed consent of the trial subject as mandatory requirement in GCP.
It should be pointed out that the definition of an IEC is also found in E6. However, FDA’s Final Rule for § 312.120 doesn’t. The result is very interesting, on the one hand FDA counterposes the Declaration with GCP. On the other hand FDA states that GCP in E6 is based on the Declaration. Then FDA rejects its own analysis and does not allow E6, with its foundations in the Declaration, to be used as the internationally recognized standard for Good Clinical Practice. I would put forward that GCP and the Declaration are complementary to one another and both necessary for sound, ethical research.
Finally, I think we need to consider if FDA and the U.S. should conduct itself as part of an international community with internationally accepted standards. And that includes the issue of placebo controls, one of the primary reasons for the FDA severing connections with the Declaration. I’m really not qualified to discuss study design and if placebo controls are necessary. However, I do think we need international regulatory and inspection standards. I’m not at all sure that the Final Rule for § 312.120 helps in that effort.