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Applied Clinical Trials
Creating sustainable change is the key to fixing this broken process and advancing clinical research.
For years now, clinical research professionals across a variety of disciplines—from government- and industry-funded research sponsor professionals to investigative site staff, bio-ethicists, and IRB members—have spoken passionately about the need for improvements in the informed consent process. Numerous initiatives have been implemented, including those utilizing multimedia technologies, those simplifying and streamlining consent form language, and those modifying approaches to communicating and educating study volunteers. Despite all of these well-intentioned initiatives, however, little has been done to fundamentally and sustainably improve the informed consent process.
Kenneth A. Getz
"Most initiatives are ineffective and in some cases ignore the spirit if not the letter of federal regulations on the matter," explained Mark Hochhauser, a Minnesota based readability consultant, IRB member, and informed consent expert. "Repeated attempts to shorten consent forms have really accomplished nothing," he said. Factoring in the eight elements mandated by the FDA, six "when appropriate" elements, and another five to 11 pieces of information required by the Health Insurance Portability and Accountability Act (HIPAA), the average consent document still averages more than 12 pages, according to Hochhauser.
The informed consent process should begin with general education about clinical trials before participants walk in the door. Next, during informed consent form review and discussion, the study volunteer has the opportunity to read, talk about, and question the protocol and the risks and benefits of participation with the investigator and study staff. The informed consent process continues during the clinical trial with the sharing of any new information investigators learn about the molecule being studied. The process ends with poststudy communication about how participants' involvement mattered.
Conceptually, this process seems not only reasonable but also essential to engaging study volunteers and establishing their partnership with clinical research professionals. In practice, the informed consent process leaves much to be desired.
Problems abound widely and at every level. Informed consent form review is generally not viewed as an educational experience but rather as "information overload" for most study volunteers. It may be irrelevant, for instance, to tell would-be participants about side effects seen solely in animals, although some would argue it is Good Clinical Practice to do so. Lengthy lists of side effects—some containing hundreds of them—likely leave a number of prospective subjects ruminating more about the many dangers of a given clinical trial before they properly understand and can weigh the benefits. Decision-making is further hindered by vague statements about medical benefits rather than what sponsors hope the study might accomplish.
Investigative sites, for their part, may be reticent to share any new information learned about an undesirable side effect midway through a study. Yet, according to Hochhauser, there is no evidence of subjects dropping out of trials because a site is forthcoming with such information. "If they have cancer, especially, it may well be a risk they're willing to take," he said.
There is little to no evidence demonstrating that various initiatives and interventions are actually improving volunteer comprehension. Based on research in this area, all that appears to help is for study participants to spend more time reviewing and discussing the protocol and clinical trial expectations with the investigator and study staff. Hochhauser suggests that these studies are themselves scientifically flawed, in part because there are no baseline or follow-up testing phases. "For all we know, the consent process makes comprehension scores go down," he added.
Hochhauser is an advocate of federally funded research on the consent process using forms written at the recommended 6th to 8th grade reading level, which no one has ever been able to produce. "If that is to change," he said, "federal regulators need to provide sponsors with examples of simplified narratives pulled from real consent forms used in real clinical trials." He would also like to see federal agencies offer plain English examples of a complete HIPAA privacy notice. "Without these examples, health care organizations and their law firms develop compliant HIPAA notices that are then used by the organizations' members, even though such notices cannot easily be understood by patients. The goal is compliance, not communication," Hochhauser said.
"The FDA, the Belmont Report, and Nuremberg Code all speak of the feasibility of comprehension testing," said Hochhauser. "But what's a passing grade? If it's 70 and the grade gets posted in patients' medical records, can that score later be used to support an injury claim based on inadequate understanding of the protocol? Should retesting be done on would-be participants whose score falls below a certain threshold?" he said.
Improving the informed consent process once a trial concludes may be the most difficult task of all. Even study results published in mass media reports aren't particularly useful to participants. Due to highly technical—often incomprehensible—titles on consent forms, participants often have no way of knowing if the results referred to in a published report came from the same study that they participated in.
Clinical research professionals can help by directly sharing study results with participants. But simply sending them a difficult-to-read article from the Journal of the American Medical Association or New England Journal of Medicine is unlikely to clear up the confusion. At a minimum, care and time must be taken in communicating study results with the volunteers who gave the gift of their participation. There's no question that this step will add costs to the study budget. The return on such an investment, however, is likely invaluable, as it builds stronger relationships with people who are familiar with the clinical research enterprise and who can serve as ambassadors for public outreach and education.
Some investigative sites are independently doing what they can to improve the situation. At Clinical Research Atlanta, for example, Clinical Operations Director Michelle Sowell tries to get consent forms in the hands of prospective enrollees days before they step foot in the clinic. Some sponsors worry that sending out consent documents in advance will scare people and discourage participation, but she believes it gives people an opportunity to highlight sections that concern or confound them and write questions in the margins so they can make a truly informed decision. "Subject comprehension of study protocols has noticeably improved since the site started mailing out consent documents three years ago," Sowell said. "It has also cut down on screen failures."
"It helps that the clinic requires study coordinators to read, initial, and date the portion of the investigator's brochure dealing with adverse and serious adverse events," added Medical Director Nathan Segall, MD. "If they're asked a question, they either know the answer or know where to look it up."
At the initial screening visit, coordinators carefully review with subjects the purpose of the study and what to expect at each visit as well as clear up any misunderstandings they have about compensation, says Sowell. "Questions are heavily encouraged and if comprehension is still a problem, those people simply don't get enrolled. For pediatric trials, children who express worries about blood draws or injections also don't get enrolled—no matter how enthusiastic their parents might be. At every study visit, coordinators go over what to expect moving forward and remind participants of their volunteer status," she said.
"Whether it is months or years between the final study visit and when the trial is unblinded, participants are always told if they were on an active compound or a placebo," said Segall. "That can be medically important information to someone with a ragweed allergy who received an active immunotherapy injection. When actual study results would be of value to participants, the site passes on whatever it learns from sponsors despite the cost and logistical difficulties of doing so."
At Pivotal Research Centers in Peoria, AZ, "Coordinators will sometimes spend an hour with prospective study subjects completely reading through consent forms out loud to ensure the information gets properly digested," explained Clinical Research Coordinator Laura Vigliotti. "Coordinators might also highlight certain sections, such as duration of the trial and possible side effects, which tend to be decisive enrollment factors."
On high-enrolling obesity trials, the site will do a "group consent" of 20 to 25 people simultaneously if the sponsoring company approves. "When one person in the room asks a question, everyone benefits," said Vigliotti. "By the time we're done, they all have excellent comprehension of the purpose of the trial and what's expected of them." Patients also have the opportunity to ask questions privately regarding any personal matters. Those who are still interested in participating get sent home with the consent forms to read again and come back with a new round of questions at their screening visit. "Enrollees who have been group consented seem to have a somewhat better retention rate and reliably show up for study visits," Vigliotti added.
Before any trial begins, participants are reassured that they will be kept up to date regarding any amendments to the protocol, including ones that don't directly impact them. "During a trial, Pivotal supplies participants with all available sponsor-produced, IRB-approved press releases about the experimental compound—good or bad," said Vigliotti. "With increasing frequency, sponsors have also been producing newsletters specifically for participants in their trials to improve communication."
Pivotal always requests that sponsors provide treatment allocation information after a trial ends, says Vigliotti, and not just to satisfy participants' curiosity: "It gives them the sense that they've come full circle with us...and gives us a great way to continue building and establishing rapport with them." This type of follow-up gives former volunteers a sense of connection to the clinical research enterprise.
Vigliotti says she doesn't believe subject comprehension of consent documents is a significant problem because informed consent is taken very seriously at Pivotal Research. But educating people about clinical trials can be tough, she said, when dealing with first-timers who have never heard of an "adverse event" and don't understand the importance of reporting minor complaints they perceive as unrelated to the study medication.
This isn't the case everywhere. "I know of other coordinators at other sites who simply hand people a consent form, give them 15 minutes to read it, and have them sign it without prompting them for questions," said Vigliotti. "Those are also the cases where patients are not as compliant."
There are numerous opportunities to improve the informed consent process. It is time, however, for clinical research professionals to collectively act upon them. Recruitment and retention rates in North America and in Western Europe have been worsening, as public distrust in the clinical research enterprise has increased. Fundamental and sustainable changes to the informed consent process may hold an important key to building longer-term relationships with patients and, ultimately, with the public as a whole.
Kenneth A. Getz MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: email@example.com