Insights And A Peek Into The Future For PRO & ePRO

By Sara Gambrill

PHT Corporation’s U.S. PRO & ePRO Congress, held in Boston Nov. 9-10, shared electronic patient reported outcome (ePRO) adoption growth numbers, discussions of new regulatory guidance, actionable information that can ease site and study subject burden from ePRO, PRO and ePRO in post-approval, and lingering reasons for sponsor reluctance to adopt ePRO. In addition, PHT unveiled a project it’s working on that could have broad implications for ePRO adoption.

ePRO Adoption Grows
Phil Lee, president and CEO of PHT, kicked off the meeting by demonstrating the growth of ePRO adoption during the past decade. Lee defined PRO and ePRO adoption as clinical trials that collect PRO and ePRO data as primary or key secondary endpoints. In 2002, when there were roughly 4,000 clinical trials being conducted, only about 30 of them used ePRO. This year, Lee estimated that about 5,000 clinical trials were conducted, and of the roughly 1,500 using PRO, about 30% to 35% of them were using ePRO. According to Lee, ePRO adoption skyrocketed from 30 clinical trials in 2002 to a 17-fold increase of 525 in 2011. He broke these 525 down further by estimating that 250 of them used handhelds, 80 used tablets, 30 used interactive voice response (IVR), 35 used the Web, and the remaining 30 used digital pen, SMS, or cell phone.

A New Generation Of ePRO Clients
At the end of his talk, he unveiled Project Leapfrog, which PHT undertook “to address the changing landscape of devices.” In 2002, most people accessed the Internet from their desktop, but, today, many access it from mobile devices and tablets, Lee said. PHT is working on what Lee calls “the next-generation ePRO client, who wants to work on a wide range of devices.” The company is developing the technology to be flexible and run like a modern-day app. The key, according to Lee, is that this technology will run on the patient’s own phone, thereby reducing the cost burden of shipping devices and training patients on devices. Leapfrog will integrate fully with PHT’s end-to-end solution. He followed his description with a live demo, but there is no delivery date as of yet.

New Regulatory Process to Qualify COAs, Make Them Publicly Available
During her talk “Measuring Treatment Benefit: We Can Do Better!” Laurie Beth Burke, MPH, R.Ph., associate director for study endpoints & labeling, Office of New Drugs, CDER-FDA, described the many facets of clinical trial outcome assessments (COAs) in great detail. COAs are tools used to measure treatment benefit to patients, defined as the impact of a treatment on how patients survive, feel, or function in their daily lives. The FDA reviews COAs when they are used to provide substantiation for treatment benefit claims, when they are primary or secondary endpoints, and when they are represented in the clinical trial effectiveness or comparative safety benefit objectives. Well-defined and reliable COAs are required to support a treatment benefit claim.

Burke described a new regulatory process — independent of the application process — to qualify COAs and make them publicly available. The first stage of the process is the consultation and advice stage, where FDA forms a public-private partnership with the COA developer. During this stage, the FDA receives submissions and provides advice within the context of an IND, but without the constraints associated with an IND application. After a dossier is submitted, the process enters the qualification and review stage. Then, qualification can be issued by FDA.

Burke explained in detail the many considerations COA developers need to make to create a well-defined and reliable instrument, such as defining context of use, quantifying the disease well, describing the concept measured by the COA well, including the definition of direct and indirect treatment benefit measures. Each one of these requirements represents potential pitfalls for COA developers. Burke noted that she still sees instruments come in where no work has been done to develop it for non-English speaking populations, for example. She concluded her talk by stressing the importance of developing a COA at the earliest stage of drug development, with a dossier complete ideally before Phase 3 of a clinical trial.

Challenges At The Site And Patient Levels
Brad Whitlow, clinical project manager, Greer Labs, and Laurie Jassenoff, MBA, VP of clinical affairs, Palm Beach Research Center, both discussed patient compliance issues and site and patient burden issues with PRO and ePRO in their afternoon presentations. Whitlow stated that there are three types of study subjects: those who are 90% to 100% compliant from the start; those who, when contacted by the site about noncompliance issues, realize they are being watched and their compliance improves; and those who have poor compliance no matter what. The difference between paper and e-diaries is that you know what the real patient compliance is, he said. In studies using paper diaries, Whitlow stated, you may see 90% to 100% compliance due to subjects retrospectively completing diary questions just prior to patient visits, which is commonly called “parking lot syndrome,” as this is where these diaries are typically filled out. Whitlow stated that he preferred accurate, real-time data coming from 80% compliance, rather than perceived 100% compliance. With e-diaries, Whitlow can use tools to track compliance by site, by subject at a site, overall compliance by country, etc. In addition, devices can be set up to send an email reminder or audible alert to subjects, reminding them to enter necessary data in a timely fashion.

Training, Proper Transmission Option Are Key
Whitlow emphasized the importance of proper training for site personnel — something often overlooked, leading to frustration and a longer learning curve. He recommended setting aside adequate training time at the investigator meeting as well as setting up a refresher via WebEx just prior to study startup. “How well CRCs are trained determines how well they train study subjects,” he said. Whitlow stated that sites need to allot 30 to 45 minutes for training each subject at first study visit. One notable tip he shared was that it is important for sponsors to follow up within 24 hours of their first expected transmissions from subjects if the subject fails to complete or transmit data. “This nips bad habits in the bud,” he said.

The number one compliance issue study subjects face is related to data transmission issues. He gets comments such as: “I cannot connect,” “It takes too long to transmit,” “I have to drive to the end of the street to get a good signal.” He strongly recommended that finding out what transmission option is best for study subjects be added to the site feasibility questionnaire. After trying to run a Phase 3 trial 100% wireless this year, Whitlow discovered that poor signal strength can be found in both rural and urban settings, and that the most effective way to decrease burden associated with data transmission is to offer a variety of transmission options. More options also translate to fewer change orders.

Jassenoff’s site has been running clinical trials with PRO since 1993, and the majority of its new clinical trials use ePRO. She echoed some of Whitlow’s comments by saying that ePRO was preferable to PRO, as it eliminates “parking lot syndrome” and offers instant access to patient compliance. She added that visits with study subjects using paper diaries typically take a half-hour to one hour longer than visits with study subjects using e-diaries. An innovation that her site has implemented to reduce loss of the device and study medications has also proved useful —giving study subjects a “lunch bag” to hold both together in one place. Others at the Congress mentioned the use of the lunch bag as well.

In addition to the advantages, Jassenoff mentioned the challenges that remain for ePRO adoption, such as device cost, the need to retrain site personnel, monitors, investigators, and study subjects, the fact that not all questionnaires are translated and validated for ePRO. She stressed, as did Whitlow, that the ePRO modality should fit the patient group.

Asking the Right Questions
Jassenoff also noted that some questions for patients don’t make sense, given where they live. For those living in a first-floor apartment in Florida, questions for a knee-pain study, such as: “Does your knee hurt when you run upstairs?” or “Does your knee hurt when you shovel snow?” are unanswerable.

The need to ask questions that are clear, make medical sense, and are appropriate for the cultural and geographical setting was a topic enlarged upon and discussed in detail through many examples during the roundtable discussion, “ePRO and the Burden on the Patient” led by Valdo Arnera, M.D., general manager Europe, PHT Corporation.

PRO In The Real-World Setting
Jeff Trotter, executive VP at PharmaNet/i3, discussed PROs in Phase 4 observational research, citing the need for critically important, real-world observations to “accurately characterize the humanistic impact of a product and/or disease in the real world.” Some of the challenges in this area are that sponsors have varying levels of comfort with observational research and don’t have defined processes for observational studies.

Steve Raymond, Ph.D., chief scientific officer and quality officer and founder at PHT, carried the theme forward during his talk, “What Happens After Approval? Ways PRO Can Transform Research and Delivery of Care.” He asked the question, “Why should the clarity of what is happening to subjects turn dark when patients start to use approved medications?”

Raymond saw opportunities for biopharmaceutical companies to improve their relationships with patients during post-approval because these are studies designed to answer questions about patients, compared with pre-approval studies, which answer questions about investigational products. Post-approval studies answer questions such as, Should I take the medication? What will happen to me? How sensitive am I to the medication? Could what’s happening to me be caused by the medication? Ultimately, these are the kinds of questions both biopharma and patients want answered, and the only way to get the answers is by ensuring the patient’s voice is heard.

Given that health authorities, pricing commissions, payers, and regulators all want to know what works in a real-world setting, sponsors will need to increase their conduct of post-approval studies that gather PRO data.

“Volleyball Match” Illustrates Remaining Obstacles, Differences of Opinion
The most creative and animated session of the Congress illustrated the remaining obstacles to ePRO adoption — perceived and otherwise, as well as the different ways various stakeholders view certain aspects of ePRO. After setting up the room like a volleyball court by having sponsors, sites, regulators, and ePRO vendor attendees sit in one quadrant of the room each, PHT’s Raymond exchanged his jacket for a referee’s shirt, put a whistle around his neck, and threw out the first “ball,” asking, “free text in diaries and eCRFs — good idea or bad idea?” A regulator believed it was a bad idea because there was no context of use. A site believed it was a good idea because it allowed them to capture data that was out of bounds and learn things about the investigational product they might not have otherwise. And so it continued.

A dozen or so topics were lobbed into the room, and the discussion was very lively. It came out during the course of the “match” that the FDA is looking to create guidance on the use of social media that will suggest ways in the post-approval phase to discover and communicate emergent facts about medications and their use. One sponsor representative took the “ball” so often that Raymond commented on it, to which she responded, “I don’t like to lose.” No one wanted to, which contributed to a lot being said on a broad range of topics. The final topic was “Why are sponsors and sites still using paper?” This received many passes, such as “change is hard,” “the paper lobby,” “perceived cost,” “actual cost,” “investment of time,” “sponsors are afraid sites can’t handle it,” “the FDA still accepts paper,” and “licensing issues.” But a vendor spiked it at the end with “No one said the “e” in “ePRO” stood for “easy.”

Sara Gambrill is an independent communications consultant to the clinical research industry. She was senior editor for nine years at CenterWatch. She writes about clinical research conduct in the United States, Europe, and emerging markets.