Your Drug Target Audience

Bruce Montgomery remembers the moment he came faceto-face with a quality-of-life issue. It was the summer of 2004, and he had traveled to Maryland to meet with staffers at the Food and Drug Administration to discuss an inhaled antibiotic, which his company, Corus Pharma, was testing for cystic fibrosis. He was optimistic that the medication would eventually pass muster with the agency, given that Phase II results looked promising.

Then, officials threw him a curveball. "They looked at me and specifically said they wanted a questionnaire showing patient-reported outcomes for respiratory symptoms for Phase III," says Montgomery, who founded Corus in 2001 and later sold it to Gilead Sciences, the Foster City, Calif., biotech where he now works as senior vice president and head of respiratory therapeutics. "I took a deep breath and said, 'okay, let's see if this could be done.'"

Although unexpected, the request was part of a steppedup effort to prod the pharmaceutical industry to develop and rely on improved questionnaires that can offer better insights into how patients actually react to medicines. In an era where patient responses to medication are seen as increasingly important, the agency was on the verge of issuing a new guidance document to help drug makers standardize and focus on the task of preparing helpful questionnaires. Montgomery was seen as a useful test case.

For his part, Montgomery was game. Although, he felt he had little choice, he also recognized the advantages that could be gained if clinical trial participants reported that his inhaled antibiotic relieved their symptoms. If the FDA were to allow positive findings to be included in product labeling, then Gilead could use that data to attract patients and influence physicians. Still, Montgomery felt more than a little trepidation about proceeding, given that he didn't have a questionnaire ready to go.

"As I saw it, the issue was that nobody knew how much improvement would be clearly detectable or significant to the patient. And how do we prove minimally clinical improvements? And what if the questionnaire doesn't work? Would it be the drug or that the questions aren't sensitive enough?" he recalls wondering at the time. "But I knew my data. I knew my drug. I knew cystic fibrosis. And I thought I could do it. Basically, I bet the company on it."

Later this year, Gilead hopes to submit the new drug application for its antibiotic, and it will include the results of a questionnaire that Alexandra Quittner originally developed. Quittner, a University of Miami professor, is an expert on patient-reported outcomes. Montgomery is optimistic, because patients reported feeling much better thanks to the medication. "The bet came in," he says, "and I think the patient-reported outcome will likely lead to approval." (continued below)

TO DEVELOP QUESTIONNAIRES FROM SCRATCH ISN'T A CHEAP EXERCISE. A TYPICAL EFFORT CAN EASILY COST $500,000 OR MORE.

Not every company will need to make such a bet, but the use of patient-reported outcomes, to measure specific responses that often can't be obtained through other types of clinical testing or questioning, will become more prevalent. Although derided in the past as imprecise, touchy-feely yardsticks, regulators are encouraging industry to search for endpoints that patients themselves find meaningful.

Last year, the FDA issued a 32-page draft guidance filled with precise suggestions for designing questionnaires, capturing patient feedback, and analyzing data, all of which are part of an effort that began at the FDA several years ago to encourage the use of patient-reported outcomes among drug developers. A final guidance is expected in a few months, according to FDA officials, who say that not all new drug applications will require patientreported outcomes, but more applications likely will.

"Some treatment effects are only known to the patients, and patients do provide a unique perspective," says Laurie Burke, the FDA's director for the study of endpoints and label development in the Office of New Drugs, which is part of the Center for Drug Evaluation and Research. "A clinician's assessment [of an endpoint] is notoriously variable, and variability requires larger sample sizes to obtain statistically significant meanings. A patient-reported outcome can be more reliable and less variable."

Encouraging drug makers and biotechs to view patientreported outcomes as both necessary and worthwhile hasn't been easy. In years past, industry simply wasn't much interested, and there were a couple of significant reasons. For one thing, doctors often poo-poohed patient questionnaires in favor of empirical data that measured physical changes. A medication may not work well, but for whatever reason, a patient can report feeling better. Conversely, a medication may work to some degree, but a patient continues to complain. So which approach is best? With such attitudes, drug developers had little impetus to put much stock in measuring patients' feelings, at least as something that had any value on product labeling. As a result, the investment made in patient-reported outcomes varied, and some questionnaires fell short of the mark. Burke recalls that sometimes a company would submit a questionnaire consisting of a single question, which yielded little or no useful information for labeling claims. "We saw packages where the data [were] uninterpretable, so we didn't know what the patient was really saying," she says, declining to name the specific companies due to confidentiality.

The importance of quality-of-life issues has gained greater traction in recent years, however, as patient advocacy groups (notably, organizations representing people with AIDS and cancer) have lobbied for medications that not only reduce disease or prolong survival, but also improve quality of existence. As a result, quality-of-life issues are increasingly seen as legitimate endpoints for gauging a drug. "Patient-reported outcomes only came to being in this context over the last few years," says Jeff Sloan, a professor of biostatistics and oncology at the Mayo Clinic College of Medicine. "Until then, quality-of-life instruments had only really seen use in the social sciences field. It's not that people didn't know how to measure these things before, but that it was a new context."

The patient's view of a medication is also, increasingly, a touchy political issue for the FDA. The agency has at times been taken to task for focusing too much on clinical endpoints, such as tumor shrinkage or lung functioning, and not enough on how patients actually feel. Seen through this prism, patient-reported outcomes are not only a helpful instrument, but may also serve as an antidote to the criticism.

The FDA's push to use and standardize patient-reported outcomes serves several purposes. Different medical groups within the FDA look at different variables, depending on the type of disease and medication involved. So, the endpoints for gauging may vary among agency medical reviewers who must assess treatments for urology, rheumatology, or oncology. For this reason, agency officials hope to eventually make it easier for staffers to not only embrace, but also rely on questionnaires as part of a more systematic drug-review process.

"With multiple therapeutic review groups within the FDA, some place the bar differently," says Stephen Joel Coons, an expert on patient-reported outcomes and a professor of pharmacy and public health at the University of Arizona's College of Pharmacy. "What Laurie Burke's group is trying to do is bring some consistency across all of the review groups."

"It comes down to hard science versus soft science," says Jeff Wagener, a pediatric pulmonologist and professor of pediatrics at the University of Colorado in Denver, who is also a former medical director with Genentech. "Historically, scientists and physicians wanted an outcome you can see and hold onto. Five years ago, I was a skeptic. I thought we needed a biological measure, something with absolute numbers that clearly represented the process that was going on. But I've come around. I see now that it is possible to put a numeric value on patient feelings."

For the pharmaceutical industry, the increased reliance on patient-reported outcomes is a double-edged sword. While there's a strong commercial advantage to having validated data in product labeling that says patients reported feeling better thanks to a particular drug, reliance on patient-reported outcomes also carries a price: At a time when drug makers are already trying to reduce costs, the added burden of incorporating patient-reported outcomes can be expensive.

For one, there may be off-the-shelf questionnaires suitable for most diseases. But drugmakers can still expect to invest resources to develop their own patient-reported outcome measures, depending upon on the indication and disease. Much more development is needed for pediatric populations. To do so from scratch isn't a cheap exercise: A typical effort can easily cost $500,000 or more, says Patrick Marquis, a managing director at MapiValues, a health outcomes consulting firm that researches patient-reported outcomes.

Still, given that clinical trials always cost huge sums, the expense associated with designing a good questionnaire is relatively small. Developing and then implementing a questionnaire, however, can take as long as a year, meaning more time spent before approval and actual sales can be generated. (See sidebar). Of course, companies that anticipate the need for a patient-reported outcome can develop a questionnaire early, but for drug makers with compounds currently in midstage development, agency interest in seeing patient-reported outcomes represents an added hurdle.

"Patient-reported outcomes are a real strategic issue for the industry now," says Marquis. "Now, they have to make earlier and earlier decisions about how to design and use them, and how to maximize their clinical development program. But you know, they have a lot of pressure from their investors to get a drug on the market, and time is very important. If they have to develop a questionnaire, and this would delay a clinical trial, well, that's a real issue for them. But if they want to get a claim, this is what they must do. They don't have much choice."

Burke and other proponents of these questionnaires note some good reasons for pursuing patient-reported outcomes aggressively. By proving a medication has a specific effect on a patient - such as reduced pain, improved breathing, or increased comfort - a drug maker has a valuable opportunity to place that claim in its product labeling. With this comes a potentially significant marketing opportunity. This sort of advantage shouldn't be minimized in an era when patients are increasingly vocal about what they want from their medicines, says Wagener.

Nancy Santanello couldn't agree more. As head of the epidemiology department at Merck Research Laboratories in Upper Gwynnedd, Pa., she says that patient-reported outcomes, if approached correctly, are a win-win for all concerned. Santanello notes that, beyond label claims, a successful questionnaire can also allow a company to use patient data for promotional purposes to doctors and patients; for trumpeting in published studies, which can be used as both promotional and educational tools; and for reimbursement in negotiating with managed-care payers or government agencies, such as the UK's National Institute for Health and Clinical Excellence.

As an example, she cites a questionnaire that was designed several years ago for Merck's Maxalt migraine treatment, one of the drug maker's best-selling medicines. After relying first on focus groups, the questionnaire went on to ask migraine patients to rate their severity of pain, frequency of pain, any resulting disabilities, and associated symptoms every four hours over a 24-hour period.

"Those who had the highest scores had rapid and sustained pain relief. So by doing this analysis, we were able to measure the attributes of migraine therapy that patients valued," says Santanello. "Yes, it's subjective, because each patient perceives their pain in a different way, but it's still extremely important.... You're getting a window into that perception. And in some areas, such as pain, there's really no other way to understand the impact of a condition or a treatment. (continued below)

GATHERING PATIENT INFORMATION CAN HAVE PRACTICAL LIMITATIONS, TOO. AS NANCY SANTANELLO NOTES, "LITTLE KIDS CAN'T READ."

"For us, it helped understand the different doses in our Phase II and which dose to take into Phase III. So, patient-reported outcomes can be used to make 'go [or] no-go' decisions. We also used the information in study publications so doctors would see the results, but each company is free to reinvent the wheel. There's no cookie-cutter approach."

No one, however, is suggesting that patient-reported outcomes are a panacea. Some experts continue to see these instruments as one piece of a larger puzzle. "These have all the limitations of any self-reported measurement," says Ron Hays, a professor of medicine at the University of California, Los Angeles, a Rand Corp. consultant and editor-in-chief of Quality of Life Research. "It's still not everything you want to know about a drug."

For example, such measurements probably won't matter much for cholesterol-lowering drugs. How many people report feeling one way or another after taking a statin? (Unless there's the rare and idiosyncratic memory loss that allegedly can occur, in which case a patient-reported outcome won't matter at all).

"FIVE YEARS AGO I WAS A SKEPTIC. I THOUGHT WE NEEDED A BIOLOGICAL MEASURE, SOMETHING WITH ABSOLUTE NUMBERS THAT CLEARLY REPRESENTED THE PROCESS THAT WAS GOING ON. BUT I'VE COME AROUND. I SEE NOW THAT IT IS POSSIBLE TO PUT A NUMERIC VALUE ON PATIENT FEELINGS." - Jeff Wagener, University of Colorado in Denver

Just the same, the advent of FDA guidelines makes it more likely that companies will adhere to standards, and there should be fewer instances in which incomplete questionnaires are submitted, says Dennis Revicki, senior vice president and scientific director of the Center for Health Outcomes Research at United BioSource in Bethesda, Md., which helps drug makers design and assess clinical trials. Like Burke, industry consultants and academics wouldn't identify companies, but they acknowledged that such instances weren't unusual. Now, though, "I doubt you'll see that kind of problem," Revicki says, adding that the FDA will likely give greater weight to objective measures if patient-reported outcomes are lacking.

Gathering patient information can have practical limitations, too. For instance, some patients (very young children or, say, people with Alzheimer) can't be expected to answer questionnaires reliably, which then requires caregivers to fill out forms and interpret the effect a medication is having. As Santanello notes, "Little kids can't read."

Among cancer patients with advanced-stage disease, another problem can occur. Sometimes, a patient will die or simply become too weak to complete the forms, leaving skewed results that may reflect the responses of only healthier or sturdier participants. "Just taking data from patients who complete all the questions is a bad thing to do," says Carol Moinpour, a behavioral scientist and an associate member of Fred Hutchinson Cancer Research Center. "There are statistical techniques that can be used, but it does present a methodological challenge."

Moreover, in an increasingly global environment, questionnaires that are designed for use in other countries present a different issue. With more patients recruited in China, India, and other parts of Asia, for example, something as simple as language can be problematic, says Revicki. "There are issues with translating certain health concepts from one language and culture to another," he says, "and that's a real challenge." Meanwhile, a study published in Drug Development Research last year and coauthored by Marquis concluded that the limitations could also involve patient compliance in filling out forms, and the environment in which questionnaires are administered. To tackle these issues, a push is under way to make greater use of electronic reporting instead of handwritten diaries or forms. By relying on hand-held devices, patients are prompted to record info within certain timeframes, which presumably offers more reliable data than when a forgetful patient plays catch-up by answering questions a day late, for example.

"Look, there are limitations," says Gilead's Montgomery. "A big one is whether you have a questionnaire that's been validated because, if not, you can spend a decade trying to do so. If you have a garbage questionnaire, you're going to get garbage results, ... but if you've got a drug that works, you should be able to get a patient-reported outcome that works. In our case, we had an unexpected development: an improvement in lung functioning that was greater than anything seen in adults despite the number of therapies tried. So as far as I'm concerned, the bet came in, and the patient-reported outcome will likely lead to the approval of our drug."

Hurray and hallelujah! On the road to and evolution of patient centered care and consumers taking responsibility for their own health, patient-reported outcomes are being acknowledged, recognized and respected for their worth in the 'clinical' and 'evidence-based' equation!
I speak from both professional and personal experience. Professionally, as co-chair of the Society of Teachers of Family MedicineGroup on Patient Education and advisor to the American Academy of Family Phyiscians Conference on Practice Improvement ... and personally - having participated in a clinical trial for an Rx product designed for mild asthmatics(of which I am one) - and that sounded like an improvment over therapy I was on. It was! In fact, I considered my improvement and the increased convenience a miracle. Huge impact on small aspects that added up to greatly improved quality of life. When I asked if my 'PRO' would be included the PI was (in my opinion) somewhat dismissive "Yes, yes, it'll be noted somewhere". I wanted my PRO to be shouted out to the world.

I read continuously questionnaires, questionnaires and so on. Firts of all, physicians all around the world can bedside assess biological activity, e.g., of pulmonary system (www.semeioticabiofisica.it), as well as monitor it over the time. How long persists such as benefixcial effect?. In fact, whatever drug, efficiacious in ameliorating respiratory functions, must normalize pH peripheral tissue, pulmonary microcirculation,pulmonary O2 exchange a.s.o., I illustrated 10 years ago (Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica del torace, della circolazione ematica e dell?anticorpopoiesi acuta e cronica. Acta Med. Medit. 13, 25, 1997).
I fear that also FDA ignores that "There are a thousand of suns above the clouds, awaiting us".

I don't see any way that the surveys can avoid the problem of bias that occurs when a patient doesn't understand the possible fallacies of reasoning that would accompany a report. The easiest to illustrate is Post Hoc, Ergo Propter Hoc. Translation: "After this, therefore because of this" (Latin) -- the patient feels better after taking a pill, and therefore the pill made him or her feel better. Not necessarily so -- a change in the weather, hearing from an old friend, the self limiting nature of the disease or symptom... the possibilities are limitless.

Probably some aspect of a study on a drug could incorporate the test subjects' subjective evaluation of their sensory experience after taking a drug (dizziness, agitation), but it should not be an important part of evaluating the effectiveness of a drug at curing an infectious disease.

I read this report with great interest. Patients are the ones who can vocalize any side effects they experience. If their response need to be recorded and reviewd for drug approval it is a good thing. We all have heard of the cliche' "the disease was cured, but the patient died ".
True,mandatory submission by the drug companies of patient's own report on drugs they are taking is an added expense for the drug companies. The sale price for the drugs will escalate. However, since patient care is the focus, their opinion should matter and matter significantly.
FDA gets to review the adequacy of the questionaire given to the patients, to see if it includes reporting of all side-efects; drug companies, by analysing the answers get to evaluate if there are any unexpected complications associated with the drug and take measures to eliminate them to improve the efficacy of the drugs and minimize unwanted side effects; to find out if there are gender differences or age differences in the way the drug affects the patients and address those issues to the benefit of the patients.
Remember, animal studies cannot give us all these important information because animals cannot communicate to us how they feel in a manner we can understand them. Human patients can and let us make good use of it.
Our ultimate goal is the welfare of the patient who is the central figure.
It will however be very wise for drug companies to prepare questionaires for each drug, have them approved first by the FDA, prior to distributing them to the patients. Drug companies can thus save a lot of money and hasssel by collecting relevant responses from the patients with confidence that the drug will not be rejected on account of inadequacies in the questionaire.
Done right, I think this requirement is good; good to the patient, good to the drug companies and to the FDA which is responsible for giving their stamp of approval for clinical use of the drugs.