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U.S. Food and
Drug Administration
FDA Consumer magazine
March-April 2001
Table of Contents
By Carol Lewis
For years Bonnie Clayton rarely made it to the bathroom in time. The 70-year-old Columbus, Ga., resident remembers many a humiliating stop by the side of the road. Then in February 2000, she began taking Lotronex, the only drug to give her instant relief from the urgent attacks of diarrhea that constantly plagued her. But just eight months after her miracle drug was approved, the manufacturer took Lotronex off the market--and with it, Bonnie's quality of life and her one chance to be free from the stranglehold of irritable bowel syndrome (IBS).
For three-time survivor Teddy McMillon, breast cancer set a frenzied pace. When the 66-year-old woman from Weatherford, Okla., wasn't having hot flashes, she was hallucinating. Once her heart was stabilized, her lungs gave out. Then there were the countless drugs, the vials of blood, a mastectomy--all between, during and after the CAT scans, x-rays, and chemo treatments. Add to that excruciating back pain, painful, cracking skin, and numbness in her fingers and toes. While many of the problems have been caused by the drugs that control her cancer, none of it is enough to make McMillon stop using Xeloda--the one drug that controls the cancer that has now spread to her bones.
Bonnie and Teddy suffer from very different diseases, but they face the same problem: maintaining the quality of their lives while battling their disorders. They are among millions of people undergoing medical treatments that in some way affect how they function every day. But since the quality of a person's life is rooted in daily and momentary experiences, the value placed on everyday living in the face of illness or disability varies from person to person.
Bonnie, for example, would gladly risk the known and unknown adverse reactions that come with Lotronex (alosetron) because the drug relieved her symptoms for the first time in 25 years. For her, Lotronex made life livable. Similarly, cancer patients like Teddy are often willing to suffer severe side effects because the therapies preserve their lives.
But for others, like colon cancer patient Sallie Forman, the toxic effects of treatment are so severe that any extension of life "just isn't worth it." She says only someone who has lived through constant side effects, every time they take a certain drug, can know what that's like.
The issue of an individual's perception about his or her quality of life now commands new importance in medical decision-making. It's no longer enough to know how a medical treatment preserves life or holds disease at bay. People have very real ideas about what states of physical well-being are desirable or undesirable. And because the patient's perspective is of great interest to those who make decisions about drug use, pharmaceutical companies want to incorporate findings about a treatment's impact on the quality of life into the labeling and promotion of their products. As manufacturers increasingly seek to make such quality-of-life claims, FDA is working with the companies and medical experts to determine which claims are justified and which are not.
But the agency's job of regulating these claims is not easy because little consistency exists in the way quality of life is measured and interpreted. Moreover, the issue is further complicated by the fact that there is no consensus about the preferred terminology--quality of life; health-related quality of life; health status--nor is there agreement on what standards should be used to allow such a claim. The complexity of these issues has caused FDA to begin reevaluating its approach to regulating how manufacturers communicate these important but difficult-to-define qualities in the information they provide about their products.
The division of drug marketing, advertising and communications (DDMAC) in FDA's Center for Drug Evaluation and Research (CDER) regulates all drugs marketed in the United States. DDMAC is in the process of developing a policy regarding the claims made in labeling and advertising about the impact of drugs on the quality of life, in cooperation with FDA's Center for Biologics Evaluation and Research. The policy will ensure that all relevant information about risks and benefits, including quality-of-life benefits, is supported by substantial evidence.
Pharmaceutical companies want to make direct quality-of-life claims for their products, or use equivalents such as "enhances social life," "expect a bright future," or "lead more active lives," because it helps them expand their markets. A growing number of therapeutics could even be considered lifestyle drugs because some of the disorders they treat are not life-threatening, and, depending on the individual, they can certainly add to life's enjoyment. The manufacturer of the drug Viagra, for example, might want to try to claim that as a result of reversing impotence, the drug enhances one's overall marital satisfaction. The company would need to provide evidence before FDA would allow it to make that kind of claim. Other examples might include estrogen replacement that quells the hot flashes of menopause; Accutane, which helps overcome acne; and Propecia, which may grow hair on a bald pate.
The television commercial portrays an elderly woman on chemotherapy, planning her daughter's wedding. The woman claims the chemotherapy treatments make her too weak and tired to sew the wedding dress. A brief narrative describes Procrit (epoetin alfa)--a drug used to increase red blood cells lost during chemotherapy, and consequently, to boost energy--and how it provides "strength for living." The camera then pans not only to the completed dress, but to the same elderly woman, energetically dancing at her daughter's wedding.
Epoetin alfa was first introduced in 1989 by Amgen under the name Epogen to treat anemia associated with life-threatening end-stage renal disease (chronic kidney failure that requires regular dialysis or kidney transplantation for survival). Epoetin alfa is also marketed by another company under the name Procrit and used to treat other causes of anemia, such as elective surgery or chemotherapy, as portrayed in the ad. But FDA required additional evidence to support the acceptability of the claims that Procrit could restore energy and reduce fatigue, which are symptoms of anemia, when conveying the benefits to consumers.
The World Health Organization defined "quality of life" in its constitution in 1948 to include physical, mental, and social well-being, and not just the absence of disease or illness. Although its definition raised considerable question as to whether or not quality of life could be measured, the comprehensiveness of the definition has set a standard by which many measurement efforts have been judged. Increasingly, however, experts have come to realize that the measurement of the quality of life is subjective, and the final determination will always be made by the patient.
Sometimes, the quality of a person's life can be improved with interventions that have little therapeutic benefit, but great impact on perception. After receiving acute medical care for his heart attack, 51-year-old Phillip Terry from Dallas became tentative about his life. But then, advised by his doctor to start a new cholesterol-lowering diet, Terry's own perception about the quality of his life began to improve.
To help assess the patient's own perception about quality of life, pharmaceutical companies have begun to use disease-specific questionnaires that try to determine what qualities are important to patients and those that have been improved by the treatment.
The Pediatric Asthma Quality of Life Questionnaire, for example, was designed to gather information about how the disorder interferes with the daily activities of children between 7 and 17. Once a baseline for interference is established, doctors can measure whether a drug or treatment lessens the interference or somehow restores what the child or the parent considers to be a better quality of life.
But these studies are not always easy to conduct or interpret. "Quality of life can be influenced by many aspects of treatment, including side effects," says Laurie Burke, RPh, MPH, of DDMAC. And one of the biggest questions, she says, is "whether the outcomes measured even add to what is already known about a product's effects on symptoms and functional status." Although these questionnaires have been used extensively for several decades, the measures were initially developed to classify the degree of one's illness and not necessarily to evaluate changes in functional status.
Two adequate and well-controlled studies are generally required to support any clinical treatment outcome claim. That ensures that the evidence is strong enough to reach a conclusion and is not the result of chance or bias. "A claim must not mislead either the patient or the practitioner into believing that a benefit may be achieved that has not been adequately demonstrated," Burke says. Claims can be misleading unless they tell the whole story, both good and bad, and there must be fair balance of the supporting data--the benefits, as well as any limitations.
Current policy for quality-of-life claims, says Burke, is complex, case-specific, and dependent on the quality-of-life measurement, the disease, the intervention, and the population studied.
"We know that individuals weigh quality of life differently," adds Janet Woodcock, MD, director of CDER. "And we also believe that health claims are about more than just the symptoms of a disease."
Pharmaceutical companies struggle in a highly competitive marketplace. Each is trying to differentiate its prescription drugs from others that treat the same disease. Aggressive campaigns that rely on quality-of-life claims to change prescribers' habits can help separate one drug from the pack, especially when marketed directly to the consumer. But these distinctions must be based on quality-of-life approaches that have been validated. If not, the increasing use of quality-of-life claims could mean misleading promotions, increased health-care costs, and inappropriate prescribing.
Kati Copley-Merriman, chairperson of the Health Outcomes Committee at the Pharmaceutical Research and Manufacturers of America (PhRMA), the trade organization that represents the country's research-based pharmaceutical and biotechnology companies, says quality-of-life claims are about more than making profit. "What drugs are doing for patients extends beyond the traditional measures of safety and efficacy," she says. "The forthcoming guidelines for quality-of-life claims currently under review will help to broaden the value statements manufacturers can make about products and will more accurately reflect the patient's own beliefs concerning the effects of a drug."
The recent controversy surrounding the withdrawal of Lotronex--a drug used to treat irritable bowel syndrome in women--is one such example of how a drug can have a profound impact on the quality of a patient's life. Lotronex was the long-awaited "magic bullet" for Bonnie Clayton, the IBS patient. She says it gave her back some semblance of a life. But, while it has helped her, it has been fatal to others. And that's not an effect FDA takes lightly, especially when the disease itself is not life-threatening.
"FDA approved Lotronex because its benefits outweighed its risks for the population of intended patients," says Woodcock. But clinical trials only test new drugs in several thousand patients; when a drug goes on the market, it may be used by millions of people and then rare but serious side effects can show up. Another reason some risks, like the severe constipation and even deaths associated with Lotronex, don't show themselves during clinical studies, she adds, has to do with how drugs are used in the real world. In clinical trials, patients are carefully monitored. After a drug is out on the market, all kinds of different patients will be treated with the drug. Some won't even have the condition for which the drug was approved--unlike Bonnie, who has known for more years than she cares to remember that she suffers with IBS.
"I am literally in tears," she says. "My life, which had just begun to achieve some normalcy again, will now revert back to the horror it once was."
While the withdrawal of Lotronex has been difficult for the patients it has helped--more than 2,000 Lotronex patients sent e-mails to CDER chief Woodcock complaining about the decision to remove the drug from the market--the case presents a clear example of how the safety and efficacy of a treatment can be inextricably linked to quality-of-life issues. From the agency's viewpoint, however, quality-of-life concerns cannot outweigh the safe use of a drug.
Woodcock reminds those who sent the e-mails that FDA tried to work with the manufacturer to find a way to keep the drug on the market safely. The agency had serious concerns about the severity and number of adverse reactions resulting from the use of Lotronex, but believed that a restricted drug distribution program would allow safe use of the drug in appropriately informed and closely monitored patients. Instead, the manufacturer chose to withdraw the drug.
For now, several groups, including PhRMA, are working with FDA to consider the agency's regulatory approach to quality-of-life claims. This initiative is part of an ongoing effort with international counterparts to harmonize whatever regulations emerge, and to bring some order to the field. As this field of research develops and reliable standards for marketing claims are put in place, clinicians can start to understand which type of medical or clinical intervention offers a better quality of life for patients.
The challenge FDA faces in defining and measuring quality of life, and in regulating quality-of-life claims made about drug therapies, comes back to the very personal perceptions of patients and what they value as they grapple with life-altering diseases and equally life-altering therapies. Heart patient Phillip Terry is an example of how important these intangible influences can be to a patient's perceived quality of life: Although most of the dietary changes he has made will likely have little impact on his medical condition, they give him a sense of control. And that, he says, can make all the difference. "Sometimes a person just needs to gain his confidence back."
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