Cancer Drugs: Weighing the Risks and Benefits
By Linda Bren
Few deliberations have greater bearing on human health than when the Food and Drug Administration weighs the risks and benefits of drugs designed to treat life-threatening diseases, such as cancer.
FDA physicians who specialize in treating cancer (oncologists), chemists, statisticians, microbiologists, pharmacologists, immunologists, and other experts work in concert to evaluate cancer drug data, weigh the risks and benefits, and reach a decision to approve or not approve. If the scale is tipped on the side of benefits, the drug is approved and allowed on the U.S. market.
Patients, doctors, caregivers, and family members must also weigh the risks and benefits of drugs to decide which treatments to use.\
How Are Cancer Drugs Reviewed?
Under federal law, the FDA may approve a new drug for marketing in the United States if it is supported by substantial evidence of safety and effectiveness demonstrated in adequate and well-controlled studies.
The drug's manufacturer or marketer must show this evidence by submitting an application to the FDA that includes results from studies of the drug's use in people (clinical trials).
FDA experts review cancer drug applications and evaluate study results. Sometimes, they seek outside advice, calling upon a group of leading cancer specialists, clinical practitioners, and patient representatives who make up the FDA's Oncologic Drugs Advisory Committee (ODAC).
At an ODAC meeting, the pharmaceutical company presents findings from clinical trials on safety and effectiveness of the drug, and FDA staff present their assessments after reviewing the drug application. The ODAC draws conclusions intended to guide the agency in its decision to approve or not approve the drug for marketing or for a new claim.
What Makes Cancer Clinical Trials Different?
Clinical trials for cancer drugs are somewhat different from those for drugs used to treat illnesses that are less serious. For a less severe disease or condition, the commercial sponsor may show that the drug works better than an inactive substance (placebo), but generally does not have to show that it works as well or better than other drugs on the market to treat the same illness.
Studies involving cancer drugs usually do not use placebos, says Patricia Cortazar, M.D., an oncologist in the FDA's Office of Oncology Drug Products. "Because cancer is a life-threatening illness, it would not be ethical to give placebo when something better than placebo is available." In cancer trials, a new drug is usually compared to a drug or a combination of drugs that are commonly accepted and widely used to treat the same type of cancer, known as the standard of care, or standard treatment.
"The standard of care changes over time as new drugs or drug combinations that are shown to be better become available," says Cortazar.
The FDA may approve a drug for several uses (indications). If a drug is approved for one indication, it must still be shown in clinical trials to be safe and effective before the FDA will approve it for another indication.
What Do 'Safe' and 'Effective' Really Mean?
A cancer drug may be considered effective if it extends a person's life (survival), increases the probability that a person will remain alive without the disease getting worse (progression-free survival), shrinks the tumor (response rate), or relieves other symptoms. In short, FDA cancer drug reviewers ask, "Does the drug prolong life, control the disease, or relieve symptoms? And does the scientific evidence support it?"
These benefits are weighed against the risks of the drug. No drug is absolutely safe—all have some risks, or potential side effects. "Safe" means that the benefits of the drug outweigh the risks for its intended use in the population the drug is intended to treat.
Cancer drugs often contain potent ingredients that kill cancer cells. "Unfortunately, most of the drugs used to treat cancer aren't targeted," says Cortazar. "They kill the cancer cells, but at the same time, they kill healthy cells." The death of rapidly dividing healthy cells weakens the body's immune system, putting a person at risk for infections and other health problems.
Yet highly toxic effects may be considered acceptable if the benefits are important and the disease is very serious or life-threatening.
Numbers Don't Always Count
The FDA does not require a specific number of participants in a clinical trial, but trial size should be tailored to the risks acceptable to people with the disease and in consideration of the rarity of the disease. Similarly, the FDA does not require a specific number of patients to respond to a cancer drug, nor does it require the drug to extend life by a specific number of days so long as the results are convincing and clinically meaningful given the side effects of the drug and other treatment options.
"There is no hard and fast rule," says Edwin Rock, M.D., Ph.D., an oncologist in the FDA's Office of Oncology Drug Products. "The agency looks at the data and makes judgments about what's clinically significant and whether, on balance, the benefits exceed the risks." To be considered clinically significant, a finding must show real meaning for patients, such as extending their lives or making them feel better.
For a drug to treat a common cancer, such as breast cancer, the agency would expect large clinical trials with hundreds or even thousands of participants. But the FDA would consider a drug for rare cancers tested in a small number of people.
The FDA may approve a use for a drug if the drug shows evidence that people live longer or live without the disease getting worse for a certain period of time, even if it's just a few weeks or a few months.
In addition to evaluating data from clinical trials, the FDA may look at X-rays, computed tomography (CT) scans, or even photographs that a pharmaceutical company provides to establish whether a drug is truly effective. For the review of Zolinza (vorinostat), a drug to treat skin lesions in cutaneous T-cell lymphoma (CTCL), the agency had asked the drug company to submit before-and-after photographs of skin lesions. CTCL is a cancer of a type of white blood cell, and patients who have it develop a variety of skin lesions.
"In some of the photographs, improvement is easy to see, but in others, it is difficult to evaluate," says Bhupinder Mann, M.B.B.S., an oncologist in the FDA's Office of Oncology Drug Products. The raised surface of a skin lesion may be evident to the touch, but not easily distinguishable in a photograph.
The photographs were considered to be supporting evidence to help assess the benefit of the drug, says Mann. The pharmaceutical company was also required to submit measurements of the lesions and classification of their severity.
Weighing Risks and Benefits as a Patient
The FDA weighs risks and benefits of a drug in its decision-making as a regulatory agency. But every person diagnosed with cancer, in discussions with his or her doctor, must also weigh benefits and risks before making treatment decisions as a cancer patient.
These decisions can be very difficult, especially when a person is first diagnosed, says Patty Delaney, director of the Cancer Liaison Program in the FDA's Office of Special Health Issues, and two-time cancer survivor. "You walk into the doctor's office, and you may feel fine—you walk out, and you're devastated." With some cancers, she says, "you then start the slow degradation into feeling absolutely horrible. You then slowly come to terms with your diagnosis and begin to hope that maybe you will get better—but you also know that the disease may kill you. It's terrifying."
Patients who don't respond to the standard of care treatments also are faced with hard decisions, says Delaney. "Sometimes there's not very strong data in the literature on what to do." The doctor asks the patient what he or she wants to do, and the patient doesn't know what to choose, she says. "People want to be in a partnership with their doctor, but they're often left with making a hard choice with little information."
"You can have your doctor choose for you," adds Delaney. "There is nothing wrong with that."
Philip Rosoff, M.D., agrees, noting an emphasis in society on autonomous decision-making that doctors are often afraid of impinging upon. "We've abandoned our roles as advisors and healers, says Rosoff, an associate professor of pediatric hematology–oncology at Duke University School of Medicine and director of the Duke Hospital Clinical Ethics Program in Durham, N.C. "We give patients this smorgasbord of options: A, B, C, and D—then ask, what do you want to do? Instead of giving A, B, C, and D, and saying, 'this is what I would do.' We do a disservice to patients when we don't use our expertise to give advice and to make recommendations to them."
When a number of treatments have been tried and failed and the person is dying, doctors may discourage further treatment, says Delaney, but patients don't want to run out of options. "Most don't want to hear that they aren't going to get treatments. Some of these drugs are like atom bombs going off in front of you, but a patient is often willing to take many more risks. People have a survival instinct. The mindset of people with cancer is, 'just give me anything and everything.'"
Experimental Cancer Drugs
The agency has put in place a number of regulatory programs and works with manufacturers so that seriously ill patients can get access to promising, but not fully evaluated, products.
Clinical trials. A common method to get an unapproved drug is to enroll in a clinical trial. More than 10,000 cancer clinical trials are ongoing in the United States. People interested in clinical trials should talk with their doctor, check out available trials at clinicaltrials.gov, or call the National Cancer Institute's (NCI's) Cancer Information Service at (800) 4-CANCER (422-6237).
If a person does not meet the criteria to participate in a clinical trial, an investigational new drug sponsor can make an exception to treat the patient. The patient's data would not be analyzed with the primary data from the original trial, but would be evaluated separately. Usually, such exceptions occur in the same institutions that are conducting the original trial, where investigators are familiar with the drug.
Single-patient, or emergency, investigational new drug. If enough is known about an investigational drug's side effects and there is some evidence of effectiveness, the FDA may allow a patient to receive a drug in his or her own specifically designed study. Although the FDA's requirements are relatively simple, setting up this kind of access for an individual patient is not, and involves the following:
Treatment investigational new drug. A promising new drug can be distributed outside of clinical trials under a treatment investigational new drug if:
The FDA cannot force a pharmaceutical company to give an individual patient an investigational drug outside of its planned clinical trials. The drug manufacturer makes the final decision to provide an experimental treatment to a patient. The company may consider many factors, including the amount of information available about the drug, the amount of drug available, and how best to use its resources to optimize development of the drug.
As with drugs for adults, the FDA weighs the risks and benefits of drugs for children based on clinical trials. "But it's hard to do clinical trials in children for many drugs—not just cancer drugs—because it's difficult to get a large number of patients enrolled," says Karen Weiss, M.D., pediatric oncologist and deputy director of the FDA's Office of Oncology Drug Products.
Even the most common cancer in children, leukemia, strikes only one-tenth as many children—about 3,200—as adults each year in the United States, according to the NCI. "Acute leukemia has an 85 percent survival rate, so to show that a new drug improves survival, a sponsor would need a large study and it would take many years," says Weiss.
Sometimes, in lieu of conducting randomized trials in children to demonstrate the effectiveness of a drug, the FDA may extrapolate findings from adult trials of a drug that might also be promising for children. This action may be taken when the disease being treated is similar between adults and children.
Because of early diagnosis and successful cancer treatments, about three-fourths of children with cancer are cured and able to live into adulthood, according to the NCI. Although the cure rate is encouraging, the results of a study of survivors of childhood cancer are disturbing.
The Childhood Cancer Survivor Study found that survivors appear to have a high rate of chronic health conditions later in life due to organ damage caused by chemotherapy and radiation during cancer treatments.
The study tracked more than 10,000 children diagnosed with cancer from 1970 to 1986 and compared their health with the health of 3,000 siblings. The researchers reported in the Oct. 12, 2006, issue of the New England Journal of Medicine that 30 years after a diagnosis of cancer, almost three fourths of survivors have a chronic health condition, more than 40 percent have a serious health problem, and more than one-third have multiple conditions."
Doctors and patients need to be aware of the potential for later health problems, says Rosoff, who authored an editorial in the same journal. He emphasizes the importance of monitoring children who survive cancer as they grow up. "We need to try to convince people they need to be vigilant lifelong."
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