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By Linda Bren
A patient-reported outcome (PRO) is a measurement of any aspect of a patient's health status that comes directly from the patient, without the interpretation of the patient's responses by a physician or anyone else.
A visit to the doctor often means being poked and prodded with various instruments, such as a thermometer stuck in the mouth, a stethoscope placed on the chest, or a blood pressure cuff wrapped around an arm.
All of these instruments give the physician measurements—blood pressure, temperature, heart rate—that help in diagnosing or treating an illness.
But none of these instruments measure how much pain patients feel, how depressed they are, how well they sleep at night, or whether they have enough energy to walk up a flight of stairs. That information must come directly from the patients.
Along with getting a physical examination and lab tests, patients are routinely asked how they are feeling or how well they are functioning, says Robert Temple, M.D., director of the Food and Drug Administration's Office of Medical Policy, but the information they provide is filtered through a "knowledgeable interpreter"—the physician.
For example, a person with heart failure will be examined for large amounts of fluid in the body tissues (edema), for fluid in the lungs, and for abnormal heart sounds. He or she might get a chest X-ray or echocardiogram, and would be asked about his or her ability to exercise. The patient would be given a heart failure classification, a widely recognized four-category description of the severity of exercise limitations that makes use of nonstandardized questions and has considerable room for judgment.
In these evaluations, the patients' own assessment of their well-being has not been ignored, but their reports have been interpreted by the physician.
Increasingly, however, information about symptoms and performance is being obtained directly from patients using structured questionnaires that are shown to give reproducible, meaningful, quantitative assessments of how patients feel and how they function—measures that are called PROs. The questionnaires used to collect this information are called PRO instruments.
What is really new, says Temple, is that these instruments are being used to assess symptoms without the physician's interpretation. "The use of PRO instruments is part of a general movement toward the idea that the patient, properly queried, is the best source of information about how he or she feels," says Temple.
The FDA is encouraging the medical research community to use PROs in clinical trials to help tell whether a new drug or medical device is working and how well it is working. If PROs are collected, measured, and assessed properly, the information can be used by drug or device developers to support the approval of a new medical product and claims about that product.
Beyond clinical trials, researchers also are investigating how PROs can be used in clinical practice to enhance the treatment of patients.
The goal of using PRO measures is to provide better information to doctors and patients so that the best treatment for patients can be determined, says Laurie Burke, R.Ph., M.P.H., director of the FDA's study endpoints and label development team in the Office of New Drugs. "It's all about the patients."
"Just like a doctor may ask, ‘how are you feeling today,' but then probes with further questions, a PRO instrument probes in a structured, formal way," Burke says.
Getting information directly from patients about their symptoms and about how they feel or function is not new. More recently, many researchers have developed their own PRO measuring instruments, says Burke. "But the problem is that although those measures are familiar to the people who developed them, we often can't interpret the measures."
The FDA is working with the research community, the pharmaceutical and medical device industry, and other government agencies to ensure that the PRO instruments used are reliable, interpretable, and valid—in other words, that they measure what they are intended to measure and that they are backed up by solid, scientific rationale.
PRO instruments offer a structured interview technique that minimizes measurement error and ensures consistency, ultimately providing a more reliable measurement than one that can be obtained by informal interviews.
PROs are useful because some treatment effects are known only to the patient, says Bob Rappaport, M.D., director of the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products, and it is helpful to standardize the questions asked of patients. For example, pain intensity and pain relief have always been measured with PRO instruments. "In most cases, the only way to know if someone is feeling better is to ask how much pain they are in," he says.
PRO measurements are sometimes confused with quality of life measurements. Quality of life is a broad concept referring to all aspects of a person's well-being. PRO instruments are used to measure quality of life, but they also can focus much more narrowly—for example, on a single symptom, such as pain.
Some manufacturers of drugs or medical devices are interested in showing, and claiming, that a treatment improves patients' quality of life. Such a claim would imply an evaluation of the impact of a treatment on all aspects of a person's well-being. Quality of life measurements assess not just the physical consequences of disease, such as symptoms and decreased function, but also the effect of disease on a person's emotional state, feelings, coping behaviors, and self-identity (psychological functioning) and on a person's ability to interact well with others (social functioning).
Despite the interest in examining effects of drugs on quality of life, the FDA has rarely allowed a claim that a product improves quality of life because it has been very difficult to show such broad effects from drugs that are directed at specific symptoms.
But a health-related quality of life (HRQOL) claim would be considered by the FDA if the PRO instrument reliably captured the impact of treatment on the most important aspects of HRQOL. HRQOL represents an individual's perceptions of how an illness and its treatment affect, at a minimum, the physical, mental, and social aspects of his or her life.
HRQOL PRO instruments have been developed for specific diseases, and the FDA has permitted HRQOL claims on the label of certain drugs. For example, the label of the asthma drug Advair, an FDA-approved inhaled bronchodilator, is allowed to carry an HRQOL claim because, says Burke, "the drug sponsor successfully measured an impact of Advair on not only the symptoms of asthma but also on physical, social, and psychological functioning in asthma patients." The Advair label states, in part:
The subjective impact of asthma on patients' perception of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ). Patients receiving Advair … had clinically meaningful improvements in overall asthma-specific quality of life ...
From 1997-2002, 30 percent of the new drugs approved by the FDA contained PROs in their labels. Many drugs approved more recently also have shown effectiveness based on PROs.
In the past decade, the FDA has approved six cancer drugs based, at least in part, on PRO instruments which showed that the drugs improved functioning or relieved symptoms, such as pain, difficulty swallowing, or dry mouth. Five of these drugs also showed evidence of attacking the cancer itself. The sixth, Novantrone (mitoxantrone), was approved based primarily on pain relief using a PRO instrument called a pain intensity scale, says Edwin Rock, M.D., Ph.D., a cancer specialist in the FDA's Office of Oncology Drug Products.
Many different types of PRO instruments are used. One of the most common instruments for measuring pain requires the patient to verbally rate the level of perceived pain intensity using, for example, adjectives such as none, mild, moderate, and severe, or numbers from 0 to 10, with 0 representing no pain and with 10 representing the worst possible pain.
PROs can also be used in children, says Rappaport, but different scales are used, such as pictures of faces. "The series of faces start on the left with smiley and happy faces, there's a bland expression on the face in the middle, and on the right side are frowns and sad faces."
The FDA published draft guidance in February 2006 that tells researchers how the agency intends to evaluate PRO instruments. The guidance, called PRO Measures: Use in Medical Product Development to Support Claims, also describes how sponsors of new drugs or devices can use study results measured by PRO instruments to support claims in the labels or the advertising of approved products.
In February 2006, the FDA and the Mayo Clinic College of Medicine jointly sponsored a symposium in Chantilly, Va., to discuss the draft guidance and to help researchers gain an understanding of how to incorporate PROs into clinical trials. Regulatory personnel, scientific researchers, pharmaceutical industry representatives, patient advocates, and consumers participated in the meeting and were encouraged to submit comments on the guidance. The FDA is considering the comments in its forthcoming final guidance.
According to National Institutes of Health (NIH) Director Elias A. Zerhouni,
M.D., "There is a pressing need to better quantify clinically important
symptoms and outcomes that are now difficult to measure."
A group of scientists from seven university medical schools and the NIH formed
a cooperative network in 2004 to address this need. Through participation in
a five-year initiative called the Patient-Reported Outcomes Measurement Information
System (PROMIS), they are working to develop better ways to measure patient-reported
symptoms, such as pain and fatigue, and aspects of HRQOL across a variety of
chronic diseases and conditions including cancer, asthma, multiple sclerosis,
arthritis, and heart disease. A goal of PROMIS is to develop a set of publicly
available PRO instruments and measures that researchers anywhere in the world
can access from the Internet.
"Our first goal is to develop PRO measurement tools for clinical research purposes," says Bryce Reeve, Ph.D., a psychometrician and program director for outcomes research at the National Cancer Institute. "But clinical practice can also benefit from our PRO tools."
The phone rings, and a patient picks it up and hears a voice say, "It's time for your health check. Would you like to take a few minutes now to answer some questions, or shall we remind you later?" The patient speaks into the phone when prompted, hangs up when done, and doesn't think much more about it—until a call comes in from a medical clinic. "I see your pain is more severe than it was last week," says a nurse, "and the doctor would like to adjust your medication."
This scenario may already be playing out in some clinics, says Reeve, but he envisions that in the future, PRO instruments will be used more with interactive systems to monitor health and to guide treatment recommendations, especially in people who require long-term care, such as cancer patients.
"Reminders can be sent by e-mail or phone," says Reeve. Or when patients go in for a medical appointment, they can be given a laptop computer to respond to a brief questionnaire while they're waiting to see the doctor, he adds. "Or they can answer the questions from home before going to the doctor's office and the information could be available by the time they arrive at their appointment."
The responses would be sent to the doctor's office electronically and linked to a person's electronic medical record. The computer would generate a one-page status report for the physician that summarizes the patient-reported data, flagging any significant symptom changes, such as worsening of pain, says Reeve.
Reeve sees these technological advances as a way to enhance doctor-patient communications and decision-making. "Doctors obviously are very short on time," he says. "Combining PROs with technology will help them perform a comprehensive assessment of their patient. It also empowers the patient to be actively involved in their treatment and well-being."
This article has been condensed from the original article as it appears in FDA Consumer magazine and edited for the FDA Web site. The print version of FDA Consumer is available by subscription.