FDA is revising its policy on accepting trials conducted abroad, replacing language concerning protections for human subjects to require that firms follow Good Clinical Practice standards instead of adhering to the Declaration of Helsinki.

The removal of references to the ethical principles stated in the Declaration is being done to allow the agency to overlook certain ethical principles that it does not endorse, Peter Lurie of Public Citizen suggests.

"I really do see [the two ethical standards] as complementary," Lurie told "The Pink Sheet." "They address some of the same issues, but the Declaration is generally so general that it can't really contradict the GCP."

"And then you have a whole set of issues that the GCP barely address and there you have some, maybe general but still important, statements from the Declaration, and that's what they're trying to avoid," Lurie said.

In an article in The Lancet published in March 2005, Lurie wrote that, "GCP guidelines were not developed transparently and mainly address procedural issues, not overarching ethical ones."

FDA's ¹ final rule, issued April 28, applies to foreign clinical studies not conducted under an Investigational New Drug Application.

The rule, which is intended to ensure the protection of human subjects and the quality and integrity of data obtained from these studies, is very similar to the draft version proposed in 2004 (² Also see "FDA Foreign Trials Proposed Rule Drops Reliance On Helsinki Declaration" - Pink Sheet, 21 June, 2004., p. 19).

As overseas trials have proliferated, sponsors and regulators are becoming acutely aware of the challenges involved in meshing the requirements of various cultures and oversight bodies (³ Also see "Sponsors Often Compromise Ethics For Cost Efficiency With Trial Outsourcing" - Pink Sheet, 3 December, 2007., p. 16).

Decoupling From Helsinki Avoids Confusion

FDA says that it is changing the rule to provide regulatory clarity to help avoid sponsor confusion.

"Although the Declaration states that it is unethical to enroll human subjects in poorly designed or conducted clinical trials, it does not provide guidance on how to ensure proper conduct of trials," FDA says.

"We proposed the GCP provisions to help ensure data quality and integrity by, among other things, specifying that GCP includes providing assurance that data are credible and accurate and requiring the submission of information on study monitoring and conformance with protocols," the rule states.

In addition, FDA is concerned about basing regulations on guidelines that are out of its control. "Although revisions to the Declaration could not supersede U.S. laws and regulations, the changes might be confusing to sponsors," the rule states.

FDA has made sponsors deal with that exact situation for years. Previously, FDA accepted clinical trials to support an IND or marketing application if they adhered to the 1989 version of the Declaration, which is composed by the World Medical Association.

However, the agency did not revise its regulations when the Declaration was updated in 2000.

Inconsistencies On Placebos And Access To Therapy

Among other reasons for overlooking the updated ethical principles, language regarding appropriate trial comparators "is inconsistent with U.S. law and policy because it would impose a standard for the design of clinical trials that is different from the standard of 'adequate and well-controlled investigations,'" the rule states.

The Declaration now states that new products should be tested against the "best current prophylactic, diagnostic and therapeutic methods." FDA is concerned the requirement could curtail the use of placebo-controlled trials (⁴ Also see "Electronic Databases Could Replace Random-Controlled Trials, AHRQ Says" - Pink Sheet, 27 November, 2000., p. 26).

However, the 2000 version of the Declaration "has a footnote there at the behest of the FDA among others, which helps to clarify their concern about placebos being prevented," Lurie pointed out.

"I think there is enough of a loophole for them, but evidently they didn't think so. They want the loophole to be wider, and because the GCP does not address this issue they are more comfortable with it because that is the biggest loophole of all."

Another change made to the Declaration in 2000 also concerned FDA.

Paragraph 30 of the Declaration 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.''

In its final rule, FDA said that the statement "invokes issues of health care policy that are not directly related to FDA's mission of ensuring that medical products are safe and effective."

Greatest Impact May Be On Paperwork

The rule will impact few trials. FDA estimates that 575 non-IND trials are conducted annually for submission to FDA supporting an estimated 115 IND or marketing applications.

Of the sponsors surveyed by FDA, all conducted trials in accordance with the GCP, which is consistent with the International Conference on Harmonization Good Clinical Practice guideline (ICH E6).

The most significant practical change for sponsors conducting trials under the new rule will be additional reporting requirements to document compliance with GCP.

The rule takes effect Oct. 27 and is applicable to all studies regardless of the status of enrollment.

- Brian Marson (b.marson@elsevier.com)

FDA Takes Ethics Into Its Own Hands; Foreign Trials Now Subject To Only GCP

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