After a few years of strong adoption, the booming electronic patient diary industry finally has something to worry about. The FDA is planning to clarify the degree to which existing diary technologies are (or are not) encroaching on data-management duties formally assigned to clinical investigators. That guidance is in the works, with no known timetable.
Much sooner, perhaps this fall, the FDA will release a new "guidance" document about general aspects of patient diaries in paper and electronic media, says Laurie Burke, director of study end points and label development in the Office of New Drugs in the CDER branch of the FDA (see Exclusive: FDA Guidance on Patient Diaries Coming Soon ).
"We're going to look carefully to make sure that any data collected by paper diaries is valid. We are being a little more vocal and we are educating our reviewers to be a little more vigilant than perhaps we've been in the past." Burke says a few drug applications may have been delayed over diary-related issues, and that's clearly unsettling to both technology vendors and the sponsors of clinical trials.
But the FDA also says it grasps scientific doubts about anything written in a paper patient diary. "There are data to lead us to believe that traditional paper diaries are not valid," says Burke. "Patients do not comply with the reporting schedule. We're very interested in the ways that technology improves the measurement of patient-reported outcomes."
The vendors who supply the $1,500 diary devices and program them to collect patient experiences all have the same refrain. Digital systems, they argue, are far more secure than paper diaries. But some observers point out that CFR 21 Part 11 does include language that investigators, and only investigators, maintain and control their data. In the new world of electronic patient diaries, that is not the case. Patients type data into a Palm or cell phone, which relays it to a server, where it is examined by the patients' personal physicians.
For David Iberson-Hurst, a British consultant and programmer, it is hardly incidental that a technology supplier maintains the data. "That's inconsistent with the regulations the way they are currently framed," says Iberson-Hurst. "Vendors are being paid by the sponsor, but everything they're doing is the responsibility of the investigator. The vendor is very much doing investigator responsibilities."
Iberson-Hurst is a longtime volunteer for the Clinical Data Interchange Standards Consortium (CDISC). He volunteered to marshal a variety of expert opinions into a single position paper that was welcomed by top brass at the FDA. He himself became a target for scorn as the initial drafts of the document were circulated in the industry. But it's clear that the CDISC and the FDA both agree there is a gap between present industry practices and the letter of the law. How the FDA will address that gap is the wild card.
The vendor community appears to have been largely unaware of Iberson-Hurst's efforts until the middle of 2005. "Some of our customers were really furious about it," says Timo Ahopelto, worldwide VP of operations and co-founder of CRF.
CRF's Greg Gogates, VP for quality management and regulatory affairs, says the initial CDISC position paper had so many errors that it may not be useful to the FDA. "I think it's going to be ignored unless the FDA tells us not to," says Gogates, who notes the FDA did not consult a diary task force at the Drug Information Association. He sounds as concerned about the FDA's approach as CDISC's. "They seem to be doing it in a vacuum, excluding the people who have the most experience and the most to say about it."
At a basic level, Gogates says, concern about the accuracy of patient diaries is misplaced. Clinical trial sponsors have little or no access to the data. In the end, even clinicians are not doing much data "cleaning" -- an audited practice of correcting minor errors. "There is not a lot of data cleaning that can be done," says Gogates. "If someone says 'I defecated four times,' how is anyone going to verify that that is right or wrong?"
At PHT, another diary company, there is less angst about the FDA's conduct but equal vigilance. Co-founder and chief scientific officer Stephen Raymond maintains that the investigator's role has not been usurped. It's evolved to reflect the new tools. Just as online banking allows depositors to "maintain" their checking accounts online, he says, diary firms facilitate the same patient-investigator role that exists in the paper world.
Says Raymond: "We act at the sponsor's request to enable or set up a system that allows the investigator to fulfill their regulatory responsibility. In the same way that they would counsel patients to fill in a paper diary, an investigator retains that role and counsels the patients in how to prepare the case history and send the case history over the wire, where the physician is the only person who has the opportunity to maintain the record."
One additional area of ambiguity concerns the legal status of the diary vendors themselves. Basically, in the statute and regulations, they do not exist. Whether to grant them some sort of status as "trusted intermediaries" is, it turns out, a long-running debate in the vendor and regulatory communities.
While that is being sorted out, it's clear that Iberson-Hurst and, more broadly, CDISC have won the FDA's trust as honest interpreters of the law. The industry is watching to see if CDISC standards could be part of a future FDA guidance to provide a method to calm the anxious hearts of sponsors (worried about any disruption to clinical trials regulations) and regulators (worried about an irregular playing field) without angering the people providing the tools (worried about sowing fear, uncertainty, and doubt among customers).