By Carol Rados
Parents of teen-agers are strongly encouraged by public health experts and medical professionals to discuss with their kids the dangers of indoor tanning equipment, and even to discourage its use. In fact, legislators in some states are proposing to make it illegal for a teen to tan in a commercial salon without parental consent.
According to the American Cancer Society (ACS), exposure to the sun's ultraviolet (UV) rays appears to be the most important environmental factor in developing skin cancer. Consequently, the dangers from exposure to UV rays from artificial sources of light, such as tanning beds and sunlamps, are similar to the dangers of exposure to sunlight. Moreover, some experts strongly believe that the sharp rise in the rates of the most serious type of skin cancer--malignant melanoma--may be due to increased exposure to UV radiation, whether from natural sunlight or artificial sources of light.
When exposed to UV radiation, the skin begins to produce a pigment called melanin to protect itself from burning. It is the production of melanin that causes the skin to darken and produce the tan. The production of new melanin takes three to five days.
Joshua L. Fox, M.D., a dermatologist in Fresh Meadows, N.Y., says, "Continued use of a tanning bed or sunlamp can be quite dangerous, particularly during the teen-age years." Teens are at greater risk, he says, because they are still experiencing tremendous growth at the cellular level, and, like other cells in the body, the skin cells are dividing more rapidly than they do during adulthood.
W. Howard Cyr, Ph.D., and Sharon A. Miller, both laboratory leaders in the Food and Drug Administration's Center for Devices and Radiological Health, say that the agency has regulated the manufacture of sunlamp products--sunlamps, tanning beds, tanning booths, and other related equipment--since 1979. Initially, there was a widespread acute risk from sunlamp products, as indicated by a large number of skin and eye injuries treated annually in hospital emergency rooms. Federal performance standards for sunlamp products were established to protect people from acute burns and exposure to hazardous shortwave UV radiation that was unnecessary for tanning.
In 1985, the agency decided to amend the standards to make the requirements more compatible with then-current products. When sunlamp technology changed and sunlamps emitting primarily UVA radiation--longer-wave, less efficient at producing a sunburn--became prevalent, longer exposure times were allowed, Miller says.
In 1986, the FDA published a policy letter that described how the maximum timer limit should be determined and provided guidance on recommended exposure schedules. The manufacturers of sunlamp products are required to include a recommended exposure schedule in their labeling. This schedule should be clearly visible to users before they begin their exposure session.
"FDA does not recommend the use of indoor tanning equipment," Miller says. Fox agrees. "There is no such thing as a safe tan," he says. "Just one sunburn increases your risk for skin cancer."
However, Miller says that if people insist on using tanning devices, there are things they can do to reduce the potential dangers.
"Start slowly, with short exposure times, and build up to a tan. If you get the maximum exposure the first time, you will probably get burned," Miller says. And, she adds, often people don't even know they are burned until it's too late. "Remember that a sunburn doesn't usually show up until several hours after the exposure," she says. In addition, the recommended exposure schedules do not allow for tanning more frequently than every other day. After a tan is developed, tanning frequency should be reduced to no more than twice a week.
Cyr and Miller warn that, in practice, tanning salon operators control the exposure time and that they may allow the customer to exceed exposure times written on the label. This is especially true for the beginning of the tanning course when users are advised to start off with very short exposures, usually five minutes or less. Fox says that people who use these products should always ask to see the information contained in the label. Be wary, he adds, if tanning salon operators can't produce it.
Miller says that the use of FDA-compliant eyewear that blocks UV rays is absolutely essential for tanning bed users to protect their eyes from corneal burns and cataracts from long-term exposure.
A study done by researchers at Wake Forest University, published in the July 2004 issue of the Journal of the American Academy of Dermatology, found that participants thought UV exposure was not only desirable for improving appearances, but also was somewhat addictive. The study concluded that "The relaxing and reinforcing effects of UV exposure contribute to tanning behavior in frequent tanners and should be explored in greater detail."
Fox advises parents to explore safer, alternative means for their children to acquire a tan. "Teens should know about the options," he says, which include self-tanners in the form of creams and gels. "Get the look you like without the damage that can occur with tanning equipment."
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Tuesday, October 28, 2008
New Health Initiative to Improve Cancer Treatments
Three Department of Health and Human Services agencies are working together for the first time to find biologic markers that could help improve cancer treatments.
In February 2006, the Food and Drug Administration; the National Cancer Institute (NCI), part of the National Institutes of Health (NIH); and the Centers for Medicare & Medicaid Services (CMS) announced the Oncology Biomarker Qualification Initiative (OBQI)--an agreement to collaborate on biomarker development and evaluation.
Biomarkers are biologic indicators of disease or therapeutic effects, which can be measured through dynamic imaging tests and tests on blood, tissue, and other biologic samples.
"An enhanced understanding of clinical biomarkers will help make the development of diagnostics and treatments more targeted, one of our most pressing goals under the Critical Path Initiative, FDA's program to modernize the medical product development process," says Acting FDA Commissioner Andrew C. von Eschenbach, M.D. "We believe partnerships that help us standardize the use of new technologies are essential to refining the drug development process so we can bring personalized medicines to patients more quickly and ultimately improve outcomes."
The collaboration will develop scientific understanding of how biomarkers can be used to assess the impact of therapies and better match therapies to patients. For instance, OBQI will address questions such as how particular biomarkers can be used to
* assess after one or two treatments whether a patient's tumor is responding to treatment
* determine more definitively whether a tumor is dying, even if it is not shrinking
* identify which cancer patients are at high risk of their tumor coming back after therapy
* determine whether a patient's tumor is likely to respond at all to a specific treatment
* efficiently evaluate whether an investigational therapy is effective for tumor treatment.
The goal of OBQI is to validate particular biomarkers so that they can be used to evaluate new, promising technologies in a manner that will shorten clinical trials, reduce the time and resources spent during the drug development process, improve the linkage between drug approval and drug coverage, and increase the safety and appropriateness of drug choices for cancer patients.
"Almost four years ago, NIH set out to create a ‘roadmap' for 21st century medical research," says NIH Director Elias A. Zerhouni, M.D. "Programs like OBQI will be central to that vision, not only because they will lead to vital discoveries about the biology of disease, but because they will be models for scientific collaboration."
Under OBQI, biomarker research will be focused in four key areas: standardizing and evaluating imaging technologies to see in more detail how treatments are working, developing scientific bases for diagnostic assays to enable personalized treatments, instituting new trial designs to use biomarkers, and pooling data to ensure that key lessons are shared from one trial to another. By working with academic and industry scientists, as well as with professional organizations, the OBQI teams can foster the development of key information on biomarkers through clinical trials.
"By identifying biomarkers for specific cancers and clinically evaluating them, researchers will have an evidence base for their use in targeted drug development and to determine which therapies are likely to work for patients before treatment selection," says NCI Deputy Director Anna D. Barker, Ph.D. "Rather than waiting weeks to months to determine if a specific drug works for a patient, biomarkers could be used to monitor real-time treatment responses."
The first OBQI project will serve to validate and standardize the use of Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) scanning. PET scans are used to characterize biochemical changes in a cancer. Under the collaboration, researchers will use FDG-PET imaging technology in trials of patients being treated for non-Hodgkin's lymphoma to determine whether FDG-PET is a predictor of tumor response. Data resulting from this type of evidence-based study will help both the FDA and the CMS work with drug developers based on a common understanding of the roles of these types of assessments.
"There are many steps between a novel scientific idea with tremendous promise and a new drug reliably benefiting patients," says CMS Administrator Mark B. McClellan, M.D., Ph.D. "This collaboration will produce evidence that will help people with Medicare and Medicaid get better care more quickly, as a result of better-targeted treatment decisions for cancer patients."
Over the next several months, the OBQI team will design a number of initiatives to identify and clinically qualify other cancer biomarkers. The new initiatives will bring together scientists from many sources and will address agency priorities identified through the FDA's Critical Path and the NIH's Roadmap Initiatives.
OBQI also represents the work of the NCI-FDA Interagency Oncology Task Force (IOTF). The IOTF is a collaboration between the NCI and the FDA to enhance the efficiency of clinical research and the scientific evaluation of new cancer treatments.
The FDA's Critical Path
Critical Path is the FDA's premier initiative to identify and prioritize the most pressing medical product development problems and the greatest opportunities for rapid improvement in public health benefits. Its primary purpose is to ensure that basic scientific discoveries translate more rapidly into new and better medical treatments. New tools will lead to answers about how the safety and effectiveness of medical products can be demonstrated in faster timeframes with more certainty and at lower costs. Visit www.fda.gov/oc/initiatives/criticalpath/ for more information on the FDA's Critical Path.
The NIH Roadmap
The NIH Roadmap is a series of new initiatives designed to pursue major opportunities and gaps in biomedical research that no single NIH institute could tackle alone, but which the agency as a whole can address. The goals include making the biggest impact possible on the progress of medical research, and catalyzing changes that will transform new scientific knowledge into tangible benefits for public health. See www.nihroadmap.nih.gov for more on the NIH Roadmap.
In February 2006, the Food and Drug Administration; the National Cancer Institute (NCI), part of the National Institutes of Health (NIH); and the Centers for Medicare & Medicaid Services (CMS) announced the Oncology Biomarker Qualification Initiative (OBQI)--an agreement to collaborate on biomarker development and evaluation.
Biomarkers are biologic indicators of disease or therapeutic effects, which can be measured through dynamic imaging tests and tests on blood, tissue, and other biologic samples.
"An enhanced understanding of clinical biomarkers will help make the development of diagnostics and treatments more targeted, one of our most pressing goals under the Critical Path Initiative, FDA's program to modernize the medical product development process," says Acting FDA Commissioner Andrew C. von Eschenbach, M.D. "We believe partnerships that help us standardize the use of new technologies are essential to refining the drug development process so we can bring personalized medicines to patients more quickly and ultimately improve outcomes."
The collaboration will develop scientific understanding of how biomarkers can be used to assess the impact of therapies and better match therapies to patients. For instance, OBQI will address questions such as how particular biomarkers can be used to
* assess after one or two treatments whether a patient's tumor is responding to treatment
* determine more definitively whether a tumor is dying, even if it is not shrinking
* identify which cancer patients are at high risk of their tumor coming back after therapy
* determine whether a patient's tumor is likely to respond at all to a specific treatment
* efficiently evaluate whether an investigational therapy is effective for tumor treatment.
The goal of OBQI is to validate particular biomarkers so that they can be used to evaluate new, promising technologies in a manner that will shorten clinical trials, reduce the time and resources spent during the drug development process, improve the linkage between drug approval and drug coverage, and increase the safety and appropriateness of drug choices for cancer patients.
"Almost four years ago, NIH set out to create a ‘roadmap' for 21st century medical research," says NIH Director Elias A. Zerhouni, M.D. "Programs like OBQI will be central to that vision, not only because they will lead to vital discoveries about the biology of disease, but because they will be models for scientific collaboration."
Under OBQI, biomarker research will be focused in four key areas: standardizing and evaluating imaging technologies to see in more detail how treatments are working, developing scientific bases for diagnostic assays to enable personalized treatments, instituting new trial designs to use biomarkers, and pooling data to ensure that key lessons are shared from one trial to another. By working with academic and industry scientists, as well as with professional organizations, the OBQI teams can foster the development of key information on biomarkers through clinical trials.
"By identifying biomarkers for specific cancers and clinically evaluating them, researchers will have an evidence base for their use in targeted drug development and to determine which therapies are likely to work for patients before treatment selection," says NCI Deputy Director Anna D. Barker, Ph.D. "Rather than waiting weeks to months to determine if a specific drug works for a patient, biomarkers could be used to monitor real-time treatment responses."
The first OBQI project will serve to validate and standardize the use of Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) scanning. PET scans are used to characterize biochemical changes in a cancer. Under the collaboration, researchers will use FDG-PET imaging technology in trials of patients being treated for non-Hodgkin's lymphoma to determine whether FDG-PET is a predictor of tumor response. Data resulting from this type of evidence-based study will help both the FDA and the CMS work with drug developers based on a common understanding of the roles of these types of assessments.
"There are many steps between a novel scientific idea with tremendous promise and a new drug reliably benefiting patients," says CMS Administrator Mark B. McClellan, M.D., Ph.D. "This collaboration will produce evidence that will help people with Medicare and Medicaid get better care more quickly, as a result of better-targeted treatment decisions for cancer patients."
Over the next several months, the OBQI team will design a number of initiatives to identify and clinically qualify other cancer biomarkers. The new initiatives will bring together scientists from many sources and will address agency priorities identified through the FDA's Critical Path and the NIH's Roadmap Initiatives.
OBQI also represents the work of the NCI-FDA Interagency Oncology Task Force (IOTF). The IOTF is a collaboration between the NCI and the FDA to enhance the efficiency of clinical research and the scientific evaluation of new cancer treatments.
The FDA's Critical Path
Critical Path is the FDA's premier initiative to identify and prioritize the most pressing medical product development problems and the greatest opportunities for rapid improvement in public health benefits. Its primary purpose is to ensure that basic scientific discoveries translate more rapidly into new and better medical treatments. New tools will lead to answers about how the safety and effectiveness of medical products can be demonstrated in faster timeframes with more certainty and at lower costs. Visit www.fda.gov/oc/initiatives/criticalpath/ for more information on the FDA's Critical Path.
The NIH Roadmap
The NIH Roadmap is a series of new initiatives designed to pursue major opportunities and gaps in biomedical research that no single NIH institute could tackle alone, but which the agency as a whole can address. The goals include making the biggest impact possible on the progress of medical research, and catalyzing changes that will transform new scientific knowledge into tangible benefits for public health. See www.nihroadmap.nih.gov for more on the NIH Roadmap.
The Importance of Patient-Reported Outcomes ... It's All About the Patients 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.
How Do PROs Differ From Other Measurements?
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.
Why Is the FDA Interested in PROs?
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.
Why Use PROs?
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.
PROs and Quality of Life
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 ...
Drug Approvals Based on PROs
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.
Types of PRO Instruments
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."
FDA Guidance
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.
Better PRO Measures
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."
Beyond Clinical Trials
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.
How Do PROs Differ From Other Measurements?
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.
Why Is the FDA Interested in PROs?
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.
Why Use PROs?
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.
PROs and Quality of Life
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 ...
Drug Approvals Based on PROs
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.
Types of PRO Instruments
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."
FDA Guidance
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.
Better PRO Measures
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."
Beyond Clinical Trials
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.
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