"Listen to the patient. The patient is a trustworthy source of information in the changes in their symptomatology." That's the counsel of Linda Deal, senior director of patient-reported outcomes at Wyeth. Deal has personally developed six novel instruments for collecting patient-reported outcomes—and worked with colleagues on two more.
She presented some of Wyeth’s thinking earlier this year at a conference sponsored by the Center For Business Intelligence. Her current project is uterine fibroids, and she is obliged to hew to the industry's traditional inclination to be nebulous about key details. It is, after all, a competitive clinical program. But a peek at the registry of projects at clinicaltrials.gov might lead to a project something like this one.
Wyeth considered the available instruments to evaluate uterine bleeding, but none of them conformed to the FDA’s published draft guidance on how to conduct patient-reported research. “They have not been tested for relevance in our target population,” Deal said.
From a scientific vantage, the existing tools to establish the benefits of a uterine fibroid treatment were not entirely satisfactory. In some cases, women in fibroid trials have been asked to compare the amount of blood in the toilet with a drawing on a piece of paper. But due to varying amounts of water in various bathroom fixtures, that introduces an unknown amount of error to the data.
Previous research had attempted to monitor blood loss from fibroids, which can lead to anemia. That's an appropriate focus for clinicians and regulators.
But Wyeth's team understood that patients with fibroids were also dealing with psychological distress and lifestyle adjustments because of the loss of other bodily fluids. "The woman is concerned with the whole thing," Deal explains. "[Women] are losing more than blood, and that’s a concern. How do you know if a novel treatment changed the incidence of the symptom? You don’t know. If you only focus on the clinical, medical piece, you’re missing something."
A final issue is that even the quantification of blood loss had methodological issues. Some trials required patients to ship soiled feminine hygiene products back to a laboratory. Why? To ascertain, in a quantitative manner, the volume of blood lost. That’s challenging to patients. But the blood flow is prodigious, and not all of it winds up in feminine hygiene products.
"What you collect on the sanitary product is not the full picture," Deal says. The shipping itself might not be the most enticing scenario to a busy patient in the middle of a career or child-rearing responsibilities. “You can imagine what a nightmare that would be, and how many subjects would drop out of your study and not do this,” says Deal.
Other fibroid trials have used multiple instruments to record the physiological and psychological aspects of the patients' lives. But those other instruments, having been developed for other diseases, didn't always map to the pain and details of fibroids. And the sheer number of such questionnaires can add significantly to the time burden on patients trying to get through a busy day.
With all that in mind, Wyeth started from scratch. There appeared to be two principal challenges in designing a new patient-reported outcome instrument for fibroids: how to have patients gauge blood and other fluid loss; and how to record the larger inconvenience and emotional impact of the condition. The hope was that an e-diary could help the company advance both the frontier of the science and the operational efficiency of the trials, with cleaner data and more patients retained.
Wyeth seems to have desired a single instrument that would handle those objectives in a compressed amount of time, and believes its electronic diary minimizes the data-gathering chores imposed on patients. "It’s easy for women to complete every day," Deal says.
In the past, with paper diaries, filling out a chart in the middle of a rest room visit wasn’t necessarily convenient or likely to capture all of the clinically relevant information around the visit. Instead, Wyeth decided to have the women complete a single daily diary entry.
Scaling The Pain
The process of developing and validating the instrument is ongoing. It has taken a significant number of years that Wyeth declines to specify. Along the way, the company convened several focus groups of afflicted patients.
Those groups related a lot about cramps, fatigue, urinary complications and feelings of heaviness. In the end, the company realized that pain was a universal element of what many women with fibroids experience. And the company understood that electronic diaries could record the number of used sanitary products used during a particular day.
Women with fibroids are generally of child-bearing age. The company’s work with the focus groups lead it to realize that there had to be some latitude to allow women multiple opportunities to record their entries. In some cases, the alarms on the devices would not be audible if the women were at a restaurant or a movie in the evening.
The fibroids diary was programmed to sound a few alarms, and offer one final alarm at 11:00 p.m. "If the kids are pulling the curtains off the wall, the patients can stop in the middle of an entry. They can put the device down,” says Deal. “Within 15 minutes, they can go back to the device.” If more than 15 minutes pass, the device times out and the patient starts from the beginning. At midnight, patients are locked out for the preceding day.
Crucially, however, there would be no subjective gazing into a toilet bowl or mailing used sanitary products back to a lab. The company developed relatively simple verbal scales on which women could rate the severity of their symptoms, including pain and bleeding.
Depending on the details of the woman's condition, branching logic in the device could save time—lots of it—because questions that didn't apply in a particular situation are automatically avoided. Says Deal: "There should be no coding error because a patient answered a question they should have skipped." The anticipated result: much cleaner data, and no re-querying of patients months or years after their participation in a trial.
Wyeth declines to say where its own validation of a fibroid PRO instrument stands. But in her presentation at the meeting, Deal suggested that in a project of this kind, one noncontroversial next step would be a small study to compare fluid loss from mailed sanitary products and the self-reported verbal data. If we had to speculate, the company might have already embarked on such a study, or the FDA might have already required it to be sure the two types of data are aligned.
Wyeth sounds cautiously pleased with the quality and relevance of the data and the minimal burden it imposes on patients. The e-diary can be accurately completed in just a minute and twenty seconds. Not bothering the patient any more than is necessary is a small operational win, but one that should help attract and retain patients. "From a perspective of a trial participant, that’s a major achievement," Deal says.
There is also a larger, and broader theme to her remarks. The company believes it has found a way to rigorously incorporate the women's own experiences into the clinical development process. Deal allows that Wyeth still has plenty to prove about its therapy to the medical and regulatory communities. But the development of a good tool for that research sounds like it has been satisfying.
Says Deal: "Women are capable of reliably giving you a report on any variety of how much blood they’ve lost. The patient is the primary source of information on treatment benefit. We are giving more respect and credibility to the patient's ability to tell you how their symptoms are changing."
In an era in which both citizens and investors wonder if large pharmaceutical companies can break any new scientific ground, Wyeth's development of a new instrument for fibroid research is a testament to its own experience with patient-reported outcomes and to the growing weight and importance of PRO-driven research in general.