By Deb Borfitz
January 4, 2010 | The informed consent process for clinical trials is intended to be relatively constant site to site and nation to nation, in accordance with the ethical principles set forth by the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice (ICH-GCP E6) Guideline. But as regulatory agencies have repeatedly acknowledged, the process in actual practice suffers from “chronic deficiencies,” says Chris Brouillard-Pierce, director of Toronto-based consultancy CQA Solutions.
The deficits are related to content as well as the manner and timing of consenting, says Brouillard-Pierce, who has conducted GCP audits for trial-sponsoring pharmaceutical and biotechnology companies in Canada, the U.S., the U.K., and Eastern Europe.
Although upfront GCP training to the informed consent process helps promote compliance, deficiencies continue to be observed at investigator sites around the globe, Brouillard-Pierce says. In some cases, investigators delegate the consenting function to someone unqualified to do so. Inadequate sponsor monitoring (i.e. monitoring commencing months after enrollment begins) may also result in the late detection of early consenting mistakes, which then get replicated. Conversely, consenting errors can be significantly reduced by ensuring monitoring begins after the first few patients are enrolled and every four to six weeks thereafter.
Still, there’s no such thing as a “perfect site,” she continues. Internal sponsor auditors and regulatory agency inspectors alike expect to find GCP deficiencies. The focus is on the corrective and preventive action taken once a problem is recognized.
Based on the U.S. Food and Drug Administration’s Inspectional Observations (FDA-483), failure to properly obtain informed consent is one of the most commonly cited violations at research sites. Seven of eight warning letters sent to clinical investigators between May and September 2009 specifically mention failure to properly obtain informed consent, most often as a result of having participants sign an outdated version of consenting forms.
Another common transgression are informed consent forms missing ICH-GCP (Section 4.8) suggested elements such as listing all of a drug’s potential side effects, providing a sufficient explanation of the randomization procedure and trial treatments, or listing incomplete information regarding the person to contact in case of emergency. Even the timing of consenting (i.e. after enrollment/randomization into the trial or medication washout rather than before) is problematic.
Regulatory guidance (Guide-0043) issued in August 2008 by Health Canada found the same types of issues plague the informed consent process in Canada.
Some problems inadvertently arise when translating consent documents into a new language, says Brouillard-Pierce. “Content can either get omitted or be translated incorrectly.” The use of software applications that translate “literally rather than for true meaning” is definitely unacceptable. Translation must be performed by certified translators with informed consent documents undergoing “back translation.”
The fact that consent documents have become increasingly unreadable, lengthy, and uninformative is itself a problem, says Yeong-Liang Lin, associate director, medical device, with Taiwan’s Center for Drug Evaluation. This is “especially [true] for countries translating the original consent forms to produce their own edition. During translation, many terms and descriptions become difficult to understand even for health care professionals, not only for lay people.”
The use of undecipherable language is indirectly addressed by the ICH-GCP guidelines (Section 4.8.6) in that they prescribe the use of informed consent forms that are “as non-technical as practical and…understandable to the subject.” Other outright informed consent breaches include failure to get ethics committee approval to make changes to consent documents or to give subjects sufficient time to consider participation in the trial.
Though not specifically required by international guidelines, “the worldwide regulatory status of the investigational drug and the number of subjects to be recruited in the study” should also be included whenever possible, Lin says. Most countries also have their own “culture-based standards” that need to be followed.
Given that consenting is done face to face and informed consent form templates are study-, drug/device-, and IRB-specific, there appears to be little software could do to improve the process beyond perhaps ensuring steps happen in the appropriate order and flagging users when re-consenting needs to occur and with which version of consenting forms, according to several subject matter experts.