Patient Reported Outcomes Poised For Takeoff After Final FDA Guidance

Companies developing patient-reported outcome measuring tools for drug developers are hoping for a new surge in interest in the wake of FDA's publication of final guidance in December - the culmination of more than a decade of work.

An extension of the psychiatry and psychology surveys pioneered in the 1950s, patient reported outcome (PRO) surveys have been used to back labeling claims in about a third of new molecular entity drug approvals since 2003, according to FDA. But there was a slight uptick in 2008 (41.6 percent), and agency officials are seeing an increasing level of sophistication when firms use them when making labeling claims.

"The quality and usefulness of PROs in labeling have increased," said Laurie Beth Burke, the director of the Study Endpoints and Label Development Team in the Center for Drug Evaluation and Research's Office of New Drugs.

That's good news for companies whose business models include developing validated patient survey instruments for their clients. "PROs are being incorporated into more of the sponsor-related programs we're doing," said Richard Gliklich, president of Outcome Sciences Inc. Drug development fields ripe for using PRO measuring tools include pain relief, gastrointestinal problems like heartburn, overactive bladder, sleep disorders and anti-nausea medications.

Part of the heightened interest also may be coming from companies seeking a leg up in a marketplace that is increasingly influenced by payers who want better information about the comparative effectiveness of competing therapies. "Even if the PRO is measuring a secondary outcome, it gives a lot of information that explains the subtle difference in therapies," Gliklich said. "Two drugs can be equally effective, but if [one] has a better quality of life or less side effects, that's a big difference."

The $350 million PRO business got its initial shot in the arm in 2006 when FDA published its draft guidance, which focused on how to develop a PRO instrument. The ¹ final guidance gave drug developers and their PRO consultants a specific checklist on what FDA will look for when validating PRO instruments in new drug applications (² (Also see "FDA's Final PRO Guidance Grounds Policy With More Details" - Pink Sheet, 8 Dec, 2009.)).

Key indicators for validating a PRO include proving the patient questionnaire measures an outcome relevant to the drug being tested; showing its results can be reliably reproduced on a retest; and demonstrating the survey can pick up small changes in whatever is being measured. Approval of a PRO instrument in one drug application doesn't necessarily mean it automatically will be approved the next time a company wants to use it.

FDA will "also plan to review whether the population and medical conditions included in any sample used to develop or test a PRO instrument are appropriate for the planned clinical trials," the guidance said.

Adding PRO surveys to a drug development program isn't that expensive. They usually involve interviewing patients in focus groups, drafting sample questions, testing them in small groups, and redrafting the questions before conducting a longitudinal study to ensure the instrument will be sensitive to change. "You don't have to do thousands of patients," Gliklich said. "They typically cost a few hundred thousand dollars to develop and validate."

The relatively low cost of validating an instrument is significant since FDA pre-certification of off-the-shelf PRO tools is rare, and even then requires a review to determine that it is relevant to the drug development program for which it is being proposed. A definitive ruling on a PRO's validity usually doesn't come until the trials are over and the new drug application has been submitted to the agency, thus adding to the overall regulatory risk of the project.

"CDER is in the process of drafting a guidance that will describe the process of how PROs, as well as certain other drug development tools, can be formally reviewed by CDER in advance of use in a drug evaluation clinical trial," said Burke. The review procedure also would allow FDA to "provide a clear statement of what purposes and in which circumstances the PRO is well suited and justified for use."

The added regulatory risk hasn't stopped many companies from pursuing PROs when they are the only way to capture relevant clinical outcomes. For instance, in 2005 10 companies formed a consortium to develop a PRO survey that measured the frequency, severity and duration of exacerbations of chronic pulmonary obstructive disease (COPD), which almost always occur away from a physician's presence. It already has been used as a measurement instrument in clinical trials even though it has yet to receive FDA approval.

"The idea was to bring together all the available expertise including academics and regulatory people to come up with one instrument for COPD trials," said Nancy Kline Leidy, senior vice president for scientific affairs at United BioSource Corp., which is leading the consortium. The project is funded with grants from the 10 firms.

The EXACT tool (EXAcerbation of COPD Tool) gives patients a personal digital assistant to answer 14 questions just before bedtime. The questionnaire measures the rate, severity, and duration of that day's flare-ups. The consortium validated the survey by testing it in 410 COPD patients. One company already has used the test to measure the effectiveness of an anti-infective therapy that attacks bacteria which may cause the COPD flare-ups. "The FDA has the final dossier now to qualify the instrument for use," Reidy said.

The use of electronic data-gathering in PROs (like the handheld device used for EXACT) is growing, too. FDA in its final guidance took note of published research suggesting patients given paper-based surveys often filled them out in the parking lot just before visiting the physician who enrolled them in the clinical trial. Daily diaries that measure, say, pain or sleep patterns are considered more accurate when filled out in real time rather than days or weeks later.

There are several firms now selling electronic PRO solutions. In addition to handheld devices, their products range from answering the PRO surveys using a telephone touch pad to answering the questions by visiting a Web site. Each allows the firm running the trial to know exactly when the questions were answered. "It gives the sponsor a level of confidence that the evidence was gathered when they said it was gathered," said Keith Wenzel, who pitches "ePRO" solutions for Parexel's Perceptive Informatics division.

"The proportion of electronic PRO tools is growing," Burke noted.

It's taken a long time to get to the point where FDA was willing to accept that a number generated by a patient survey accurately reflects a clinical outcome. The change, United BioSource's Leidy said, was as much a product of the patient-rights revolution as it was the evolution of the underlying science.

"Consumers were becoming more active and vocal in their care, so the need for this kind of instrument was becoming more important," she said. "That drove the need to come up with more standardization and being more scientific about how patients feel. It was an evolutionary process."

- Merrill Goozner ( ³ [email protected] )