Safety. Efficacy. Are those two cardinal notions of clinical development enough? Jean Paty has a third. He believes it is as central as safety and efficacy.

Paty is co-founder and senior VP of scientific, quality and regulatory affairs at invivodata, a Pittsburgh, Penn., electronic patient diary firm. If safety and efficacy are the X and Y axes of clinical development, patient experiences are its Z axis. "The Z axis has always been there," says Paty. "Patient-reported outcomes (PRO) are just a subset of the endpoints that we capture in trials."

What's shifting, he says, is that the FDA is trying to re-emphasize how sponsors can quantify those patient experiences. The FDA's final guidance on the topic (in PDF format here) was published late in 2009, and it was in draft form for several eternities before that. Even so, industry's regulatory affairs professionals and senior clinicians may have not absorbed the document's full import.

The FDA did not casually erect some new, third barrier for sponsors to leap over, Paty says. Rather, the agency was trying to highlight the ways that it has always looked at clinical data. Still, for some sponsors the Z axis of patient experiences may be a thunder bolt from above. "They're focusing on X and Y," says Paty. "What FDA is saying is, 'No, you do need to do all three.' You always needed to."

Psychometric Shift

As a scientist, Paty sounds chagrined that the ePRO technology has been deposited into the wrong category, the wrong box, by the research community. It’s been relegated to being one of many shiny e-toys that pass in and out of industry favor. E-case report form, e-signature, etc. etc. The mind reels at the number of words that a paper-craving industry can staple the letter E to.

Paty sees the technology as secondary to the scientific process it supports. So electronic diaries are not just gadgets; they're sextants to plot where a new drug is located on the Z axis. “We have not pushed ourselves to move along the Z-axis,” Paty says. “The paradigm shift is explicit consideration rather than implicit consideration.”

“ePRO is finally being put in the proper context,” Paty continues. “It is not a cool thing. It is the way to capture accurate and reliable data from patients. The context is now being established by regulators. The industry is adapting to that context.”

Some sponsors, Paty notes, can have outdated notions about whether the psychometric properties of an instrument are altered by moving from a paper-based modality to an electronic one. "You're not getting anything 'different,' " he says. "Patients don't interpret a question differently whether you're doing paper or electronically. If they read a question on a piece of paper and on an electronic screen, we've demonstrated they understand and interpret the question the same."

Bad Reflex?

Paty said the larger context of the moment is the FDA's desire to not simply have sponsors reflexively, automatically grab whatever patient-reported-outcome instrument they used in the past. "People say, 'let's just use the last thing we did,'" Paty explains. That may not work in the future, he suggests.

A better strategy? Identify the unique psychometric aspects of the product under development. What needs to be measured? Can it be measured reliably, validly? Once that exercise is finished, then it is appropriate to figure out which modality—paper, interactive voice response, or handheld diary device—can deliver the psychometric instrument. The ediary industry has always claimed that its technology could deliver such better-quality data that lower sample sizes, smaller numbers of patients, would be required.

Not So New Criterion

For Paty, the Z axis is not a theoretical construct. Smart sponsors, he says, are already placing their compounds along all three axes. Paty says he and his colleagues in the firm's consulting practice are seeing big decisions being made on the basis of psychometric considerations.

“We’re at a point where drug development could stop on a product because we can’t measure what we believe it to be doing,” he says. “I’m having these discussions with FDA and clients regularly. I’m telling the management, part of your go/no-go decision-making process needs to include measurement. Can you measure what you need to measure? If you can’t, why are we going to drop another $100 million?”

Invivodata and its rivals (PHT, ERT, CRF, Merge and Arrowhead) all have expertise in psychometrrics, and all are de-emphasizing the manufacturers of their devices. That's because companies like Palm, HP, Google and Dell may all have bright futures, but their small-screen offerings are rapidly being eclipsed by Apple's entertainment-driven iPhone, which has the superlative user interface of the mobile category.

Federal Push

The final guidance on patient-reported outcomes, Paty says, remains underappreciated. He attempts to distill the FDA thinking as follows: “The final guidance is saying, the patient perspective is the way of life in your drug’s development. If you can’t demonstrate that you know what you’re measuring, we don’t know how to interpret it.”

Comparative effectiveness research, promoted with federal funds, will increasingly pit two or more similar drugs against each other. And so a cost-conscious environment in the U.S., Paty predicts, will lead to product development only of medical devices and drugs that can substantiate their efficacy, safety and patient benefits in documented, measurable ways.

He is emphatic on the point: “If you’re the tenth antihypertension drug or the tenth pain medication in a particular class, why should a regulator approve or an insurer pay for it unless it does something different? To differentiate your product requires more rigorous thinking about measuring what your product does. Measurement is an opportunity to differentiate.”