Real-Time Patient Reporting Could Open The Door To FDA Inspection

By Cindy Dubin

Paper-based patient reporting has dominated the clinical trials industry throughout its history. However, recent studies have exposed the limitations of paper diaries, such as subject failure to enter the data at the correct times — or at all — and a tendency for patients to invent the data, according to a white paper, Dispelling the ePRO Myth. As a result, electronic diaries for tracking patient reported outcomes (PRO) during a clinical trial are emerging as an alternative. These ePRO diaries tend to provide higher quality data (as compared to paper-based methods) for NDA (new drug application) submissions. In fact, a study in the British Medical Journal showed a higher patient compliance (94%) with electronic diaries vs. 90% with paper-based reporting.

Choosing And Using ePRO
There are basically two types of ePRO diaries: handheld for remote data capture and site-based. Typically, handheld diaries are meant for questions that need to be asked and answered daily, whereas site-based diaries ask questions that don’t require daily responses.

As indicated in the PRO guidance from the FDA, regardless of type, trial sponsors should consider how data will be collected and all procedures and protocols associated with the instrument, including instructions to interviewers, instructions for patient self-administration, or instructions for supervising self-administration. According to the Office of Compliance, sponsors should consider how to ensure patients make electronic entries according to the clinical trial design and not just before a clinic visit when their reports will be collected.

ePRO data collection begins when the patient enters data into the collection device. This data is transferred to a repository to share reports with the sponsor, the trial site, and those monitoring the trial. This establishes an audit trail and electronic signature approvals. At agreed-upon intervals, data is extracted from the repository and delivered to the sponsor in a specific format. When a trial is complete and the database is locked, ePRO data is made available in a site archive in human-readable format. This is the data that becomes part of the sponsor’s NDA submission.

Preparing For FDA Inspection
Given that ePRO data is still relatively new when compared to the long-standing history of paper PRO, the FDA’s Office of Compliance has a keen interest in following up on NDA submissions that cite electronic clinical data. “We noticed an uptick of FDA inspections about two years ago as the agency better understands these systems and knows how to evaluate them,” says Gretchen Craig, associate director of quality for Pittsburgh-based invivodata, a developer of ePRO systems.

The challenge for many pharmaceutical companies is how to prepare for an FDA inspection of ePRO data. And it’s never too early to prepare. According to Craig, sponsors who have considered the inspection early in their pivotal Phase 3 trials have had fewer surprises when they receive the announcement of an inspection. “How a site is selected for inspection usually equates to the number of patient enrollees, if the study sponsor rejected its own data, and if the site had previous inspection issues,” she says.

A mock inspection can be performed in advance of the FDA’s visit. This is a time to anticipate FDA questions, have the necessary documents in order, and ensure the communication path among the study sponsor, monitor, and actual sites is in order.

A spokesperson for the FDA’s Office of Compliance says the site or sponsor that used an electronic diary should verify that all the data is available for investigator review. Assemble standard operating procedures, manual, subject instructions, and other written documentation relating to the device. Additionally, show documentation of site staff training to use the ePRO diary and to review the ePRO diary data. Finally, ensure that copies of data and documentation can be provided to the auditor as needed.

According to an invivodata white paper, ePRO Regulatory Inspections, as the FDA advances its knowledge about clinical technologies, it will increase its vigilance in inspecting ePRO systems. The purpose of an FDA inspection is to ensure clinical trial data integrity: how the ePRO system was built, how the system was used to collect subject data, and how data flowed among participating parties. “It all comes down to how data got from point A [subject data entry] to point F [data included in NDA submission],” says Craig.

“These inspections also aim to verify that human subjects’ rights have been appropriately protected and to establish safety and efficacy needed for the approval of medical product applications,” says the FDA spokesperson.

As indicated in the Guidance for Industry for Patient Reported Outcomes, electronic diaries should maintain all the same information required for traditional paper diaries, such as rules for maintaining adequate and accurate records regarding audit trails and the creation, modification, and deletion of records. “During an inspection, our investigators may also review documentation related to how data from the eDiaries were backed up and how access to the data was controlled to prevent unauthorized changes,” says the spokesperson. Should a site fail inspection, the FDA will send a warning letter — or form 483 — outlining required corrective action, and the site will need to show that those actions were taken within a specified time period.

If The FDA Doesn’t Ask, Don’t Tell
Failure was not in the cards for Sucampo Pharmaceuticals, a global biopharmaceutical company based in Bethesda, MD, that develops and commercializes medicines based on prostones (a class of compounds derived from functional fatty acids that occur naturally in the human body). In January 2006, Sucampo received marketing approval from the FDA for its first product, Amitiza (lubiprostone) (24 mcg), for the treatment of chronic idiopathic constipation in adults. In April 2008, Amitiza (8 mcg) was approved by the FDA for a second indication, irritable bowel syndrome with constipation (IBS-C) in women 18 years and older.

But attaining those approvals didn’t come easy, as upon NDA submission for lubiprostone, Sucampo was contacted by the FDA requesting an inspection based on the clinical trial electronic data. Sucampo had used electronic diaries for the first time as part of these clinical trials, which occurred over 122 sites in the United States, but the agency wanted to review the data at three specific sites.
The invivodata SitePro diary was used at trial sites to deem patients as “useful” to the study based on answers given to specific questions. For those selected to participate, invivodata’s handheld DiaryPRO was sent home with patients. They were to record their answers to daily and weekly questions over a two-week period. “We chose to use electronic diaries for these trials because of the ability to capture real-time information and the inability of patients to retroactively answer questions or recreate the information they provided,” says Raymond Panas, director of international clinical development at Sucampo. “The handheld device also helped us weed out patients who didn’t have the symptoms associated with an IBS diagnosis.”

Upon receipt of the FDA’s call for an inspection, Panas and his team contacted invivodata as well as a third-party vendor to help conduct a pre-audit of the trial sites. This, says Panas, helped identify any glaring issues or missing information. “For the most part we were prepared, but we couldn’t have known all the questions the FDA would ask.”

When the FDA showed up for the inspections, each audit was a little different in terms of duration and questions asked, explains Panas. But, the basic request at each location was to know how the electronic diaries were prepared for the trials, how they functioned, and how the collected data was analyzed. “We learned quickly not to provide the auditor with more information than was being requested as the information would be overwhelming.”

In addition to inspecting the trial sites, the FDA audited Sucampo as the trial’s sponsor, wanting to know how the company chose invivodata as the diary vendor. When invivodata was inspected as part of the Sucampo audit, the process took six hours over a two-day period. But Craig says that it is not uncommon for invivodata to spend 120 to 300 hours supporting a sponsor inspection.
The FDA also inspected invivodata to learn more about the electronic diaries. In the case of the Sucampo inspection, invivodata was required to trace the patient data from the original point of entry. “We provided a view of the data at the time of collection during the monitoring period, and as part of the extract and archive,” says Craig. “Sucampo provided the view of the data at the time of submission, which allowed the inspector to ensure data integrity from beginning to end.”

According to Panas, “There is no denying the FDA did its due diligence during the audit, but all the sites, Sucampo, and invivodata passed the inspections without incident.”