Cancer Vaccines: Training the Immune System to Fight Cancer

By Michelle Meadows

Vaccines traditionally have been used to prevent infectious diseases such as measles and the flu. But with cancer vaccines, the emphasis is on treatment, at least for now. The idea is to inject a preparation of inactivated cancer cells or proteins that are unique to cancer cells into a person who has cancer. The goal: to train the person's immune system to recognize the living cancer cells and attack them. (See "The Immune System and How It Works.")

"The best settings are for treating people who have minimal disease or a high risk of recurrence," says Jeffrey Schlom, Ph.D., chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute (NCI). "But at this time, most therapeutic cancer vaccines are being studied in people who have failed other therapies."

Cancer vaccines are experimental; none have been licensed by the Food and Drug Administration. But there are about a dozen cancer vaccines in advanced clinical trials, says Steven Hirschfeld, M.D., a medical officer in the FDA's Center for Biologics Evaluation and Research. "Research has shown us that the fundamental approach to cancer vaccines is right; we are moving in the right direction," he says.

The three standard cancer therapies are surgery to remove tumors; chemotherapy, which modifies or destroys cancer cells with drugs; and radiation, which destroys cancer cells with high-energy X-rays. Immunotherapy, which includes cancer vaccines, is considered a fourth, and still investigational, type of therapy. Cancer vaccines are sometimes used alone, but are often combined with a standard therapy.

While standard treatments alone have proven effective, they also have limitations. Radiation and chemotherapy can wipe out a person's cancer cells, but they also damage normal cells. "We want to find treatment that is more targeted and less toxic," says Hirschfeld. "Cancer vaccines are designed to be specific, targeting only the cancer cells without harming the healthy ones."

The approach has made cancer vaccines generally well tolerated, allowing them to be used in outpatient settings. And they can be added to standard therapy with a low likelihood of causing further serious side effects.

How Cancer Vaccines Work

Cancer is a term for more than 100 diseases characterized by the uncontrolled, abnormal growth of cells. To the immune system--the body's natural defense system against disease--cancer cells and normal cells look the same. The immune system tends to tolerate the cancer cells, just as it tolerates the normal cells. That's because the immune system doesn't recognize cancer cells as something foreign, Hirschfeld says. Rather, cancer cells are once-normal cells that have gone awry. Cancer vaccines try to get the immune system to overcome its tolerance of cancer cells so that it can recognize them and attack them.

All cells have unique proteins or bits of proteins on their surface called antigens. Many cancer cells make cancer-specific antigens. The goal of using cancer antigens as a vaccine is to teach the immune system to recognize the cancer-specific antigens and to reject any cells with those antigens. The antigens activate white blood cells called B lymphocytes (B cells) and T lymphocytes (T cells). B cells produce antibodies that recognize a particular antigen and bind to it to help destroy the cancer cells. T cells that recognize a particular antigen can attack and kill cancer cells. In 1991, the first human cancer antigen was found in cells of a person with melanoma, a discovery that encouraged researchers to search for antigens on other types of cancer, according to the NCI.

The two main approaches for cancer vaccines are whole-cell vaccines and antigen vaccines. Whole-cell vaccines may take whole cancer cells from a patient or sometimes several patients, or use human tumor cell lines derived in a laboratory. "Some cell-based vaccines use tumor cells from the patient, some contain something that looks like a tumor cell but was created in a lab, and others are personalized vaccines that use some cells from the patient and some from the lab," Hirschfeld says. Cells that are taken from people with cancer are altered in a lab to inactivate them so that they are safe to re-inject.

Regardless of the exact source of the cells, whole cell vaccines potentially use all the antigens found on the tumor cells. Antigen vaccines try to trigger an immune response by using only certain antigens from cancer cells. Hirschfeld says antigens may be particular to an individual, to a certain type of cancer, or to several types of cancers.

Boosting the Immune Response

In the early 1990s, Steven Rosenberg, M.D., one of the pioneers of immunotherapy and chief of surgery at the NCI, wrote that trying to use the immune system to fight cancer is so difficult that it made him feel "like a dog trying to bite a basketball." Among Rosenberg's contributions was identifying the antigens that trigger an immune response, and cloning genes that look for, or "code for," those antigens.

Researchers have been working to develop cancer vaccines for more than 100 years in one form or another, and the main mission has always been to make the immune system's response to the cancer antigens as strong as possible.

One major strategy involves combining vaccines with additional substances called adjuvants, which act as chemical messengers that help T cells work better. An example of one type of adjuvant, called a cytokine, is interleukin-2. This protein is made by the body's immune system and can also be made in a lab.

There have also been improvements in vaccine delivery. For example, Schlom developed a vaccine in which genes for tumor antigens are put into a weakened virus called a "vector" that delivers genetic materials to cells. This makes the tumor antigen more visible to the immune system. The CEA-TRICOM vaccine was developed at the NCI through a cooperative research and development agreement with Therion Biologics in Cambridge, Mass. Researchers use the vaccinia virus, the same virus in the smallpox vaccine, as the vector. The carcinoembryonic antigen (CEA), which is found on most breast, lung, colon, and pancreatic tumors, is added to the virus. Researchers also add three molecules, called "costimulatory molecules," which serve as signals that make the vaccine more potent than it would be if the antigen were used alone. A similar vaccine developed under the NCI agreement with Therion is the PANVAC vaccine, which has now entered advanced study as a treatment for pancreatic cancer.

In addition to studying this type of virus-based technique, researchers at Duke University's Cancer Center in Durham, N.C., have been studying vaccines that mix white blood cells called dendritic cells with genetic material from a person's tumor.

Dendritic cells, which can activate T cells, work by looking around, finding antigens, and showing them to the fighter T cells. Researchers have found ways to increase the number of dendritic cells in a vaccine. "Employing millions of 'pumped up' dendritic cells can help elicit a strong immune response," says H. Kim Lyerly, M.D., director of the Duke cancer center.

Recent work by Lyerly and Duke investigators Michael Morse, M.D., and Timothy Clay, Ph.D., has focused on modifying dendritic cells with viruses so that they activate even stronger T cell responses against cancer antigens.

"This is an evolving area, and it's exciting to be able to make progress," says Lyerly. "For decades, people thought it wasn't even fundamentally possible to develop cancer vaccines, and here we are. The science behind cancer vaccines is leading us to believe that we will find the answers."

Promising, But Still Early

As with any new treatment, cancer vaccines must be first studied in lab animals and then tested for safety and effectiveness in three phases of human studies, called "clinical trials," before they can be approved by the FDA. In Phase 1 clinical trials, cancer vaccines are used alone and studied for safety and to determine the proper dose. In Phase 2 trials, they are tested for effectiveness and may be used alone or in combination with another therapy. Phase 3 trials are large-scale studies testing effectiveness and usually comparing a vaccine with some standard therapy. Researchers are testing vaccines using various adjuvants, delivery methods, and types of antigens.

Cancer vaccines have shown promise in clinical trials with many types of cancer. According to Howard Streicher, M.D., a senior investigator with the NCI's Cancer Therapy Evaluation Program, it's too soon to say which cancers will be treated with vaccine therapy. The types of tumors that have proven most susceptible to vaccines so far, he says, are: skin cancer (melanoma); kidney cancer (renal cell); a group of cancers that affect the lymphatic system (lymphoma); a malignant tumor of the bone marrow (myeloma); and solid tumors, such as lung cancer. The most work has been done in the area of melanoma, a type of skin cancer in which treatment options are limited when the disease is in advanced stages.

"After having a tumor removed, about half of patients with stage III melanoma may have a recurrence, and we want to prevent that," Streicher says. "Chemotherapy doesn't work in this area, so our hope is that this could be just the right place for a vaccine."

James Mulé, M.D., Ph.D., associate director of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., says, though some early studies have shown that some people's tumors shrank or even disappeared in response to a cancer vaccine, it's still early. Mulé was an investigator on the first study that tested dendritic cells in children. In the Phase 1 study, one 16-year-old with cancer that had spread to her lungs and spine showed significant shrinkage of tumors.

"There is promise in the sense that some of these vaccines can illicit a powerful immune response in some patients, but I think we have to be careful about getting too excited over early studies that can't be reproduced," Mulé says.

Jeffrey Weber, M.D., Ph.D., director of the Norris Melanoma Center at the University of Southern California, says there is also still a lot of work to be done in discovering new antigens and adjuvants and more sophisticated strategies to overcome the immune system's tolerance of cancer cells. "We are still discovering molecules that regulate the immune system such as CTLA-4, so we're still in the dark in some areas," Weber says. Recent research has found that inhibiting CTLA-4 can help the immune system attack some tumors.

Experts say that no therapeutic cancer vaccine has been licensed yet because few Phase 3 studies have been completed, and those that have been completed did not meet their goals of demonstrating safety and effectiveness of the vaccine. "We are still working with industry to define the characteristics, including potency," says the FDA's Hirschfeld. "So a trial may look promising early on, but our job is to make sure it can be reproduced. We have to ask: 'Will this treatment work in the larger population?'"

One of the challenges is that cancer vaccines may produce different effects than those caused by cancer drugs. With cancer drugs, experts ask whether there is an objective, measurable response, such as tumor shrinkage. A cancer drug may cause tumors to shrink, but a person still may not live longer. With a cancer vaccine, there may be fewer signs of tumor shrinkage, but a person might live longer.

There aren't the same landmarks that you would see with traditional therapies, says Natalie Sacks, M.D., medical director in the clinical research division at San Francisco-based Cell Genesys, which is studying its vaccines, called GVAX, in people with prostate cancer, pancreatic cancer, leukemia, and myeloma. These whole-cell vaccines all use a hormone that stimulates immune response, called granulocyte macrophage colony stimulating factor (GM-CSF).

"As sponsors, we want to develop treatments and get them out to the market and help patients," Sacks says. "In the case of cytotoxic chemotherapies, the traditional endpoints used in drug development are shorter-term outcomes, such as tumor response and progression-free survival. Where I expect immunotherapy to be successful is in longer-term outcomes and increased survival. Because of the mechanism of action, the patient may not show an immediate response as is generally observed with standard chemotherapies, and the trial may take longer."

Finding a Clinical Trial

Cancer researchers say their work won't mean much if more people don't enroll in clinical trials. According to the NCI, less than 3 percent of U.S. adults with cancer participate in clinical trials.

If there is a standard treatment available for a type of cancer, the NCI recommends choosing it over an experimental therapy. Cancer vaccines show the most promise at preventing a recurrence of cancer after surgery, radiation, or chemotherapy because the immune system will need to recognize and attack a smaller number of cancer cells. Cancer vaccines are also being tested as a treatment for advanced cancer.

Gary Montgomery, 66, of Redmond, Wash., enrolled in a cancer vaccine trial in 2002 to treat a rare form of abdominal cancer called pseudomyxoma peritonei. According to the National Organization for Rare Disorders, the disease is characterized by the accumulation of mucus-secreting tumor cells in the abdomen and pelvis. As the mass of tumor cells grows, the abdomen swells and digestive function becomes impaired.

Montgomery first had the standard therapy of surgery to remove the tumors in 2000. "They opened me up like a sardine can--from the sternum to the abdomen--and took out as many tumors as possible," Montgomery says. Then they inserted a tube into the abdomen, which delivered chemotherapy for six months. He experienced no tumor growth for about a year, but then the tumors came back. "It's known as a relentless form of cancer that wears you down," he says. "The doctor said that with the exception of another surgery, there was really nothing else they could do."

So Montgomery started with the Internet and found one NCI study that involved surgery and chemotherapy with an agent different from the one he had before. But the trial was closed. Taking advice from a friend, he checked at the Lombardi Cancer Center at Georgetown University in Washington, D.C. "I was feeling pretty low at this point," he says. He found out the one vaccine study he was interested in had just ended. But a nurse told him that another trial with newer versions of cancer vaccines developed at the NCI was about to start. "There were two slots left," he says. "Luckily, I met the criteria."

Montgomery received a "prime-boost regimen" of Therion Biologics' TRICOM vaccine. He first received an injection in the upper leg of a modified version of the smallpox vaccine to prime the immune system. Then he received monthly boosters of a vaccine called fowlpox CEA (carcinoembryonic antigen), an antigen found on most colorectal and pancreatic cancers. He also received a shot of the hormone GM-CSF, which helps stimulate the cells of the immune system. He had to give some of the injections to himself when he arrived back home in Washington state.

He says he experienced minimal side effects, such as soreness at the site of injection and mild flu-like symptoms. Though most cancer vaccines have been well-tolerated, in other trials some people have experienced autoimmune problems such as inflammation of the thyroid gland, skin disorders, and colitis. Autoimmune conditions are those in which the immune system mistakenly attacks the body's tissues and organs. Before he began the trial, Montgomery signed an informed consent form acknowledging that he was aware of all the risks.

Montgomery continues to participate in the trial and flies to the nation's capital every month to receive treatment because it's been working. "It hasn't cured the cancer," Montgomery says, "but it seems to be keeping it in check. And that's good enough for me."

Those interested in finding out about clinical trials to treat cancer should talk with their doctors and contact the NCI at (800) 4-CANCER (422-6237) or on the Web at www.clinicaltrials.gov.

The Immune System and How It Works

Your immune system includes your spleen, lymph nodes, tonsils, bone marrow, and white blood cells. These all help protect you from getting infections and diseases. When your immune system works the way it should, it can tell the difference between "good" cells that keep you healthy and "bad" cells that make you sick. But sometimes this doesn't happen. Doctors are doing research to learn why some immune systems don't fight off diseases like cancer.

White blood cells are an important part of your immune system. When your doctor or nurse talks about your white blood cells, he or she may use words like:

• Monocytes (MON-o-cites) are types of white blood cells.
• Lymphocytes (LYM-fo-cites) are types of white blood cells.
• B cells, T cells, and "natural killer cells" are kinds of lymphocytes.

Cancer Vaccine Facts

• Cancer vaccines are intended either to treat existing cancers (therapeutic vaccines) or to prevent the development of cancer (prophylactic vaccines).
• Therapeutic vaccines, which are administered to cancer patients, are designed to treat cancer by stimulating the immune system to recognize and attack human cancer cells without harming normal cells. Prophylactic vaccines, on the other hand, are given to healthy individuals to stimulate the immune system to attack cancer-causing viruses and prevent viral infection.
• There is a prophylactic vaccine against hepatitis B virus, an infectious agent associated with liver cancer.
• Scientists are currently evaluating several different vaccines in large human trials to determine which approaches are most effective for particular kinds of cancers.

Source: National Cancer Institute

The Role of FDA and NCI

After conducting preclinical research in lab animals, drug companies or clinical investigators submit an investigational new drug application to the Food and Drug Administration, requesting permission to move forward with testing in humans called clinical trials. The agency and the sponsors continue to communicate throughout the three phases of clinical trials, and the FDA ensures that treatments are safe and effective before they can be marketed.

The National Cancer Institute (NCI) is the main federal agency that supports and conducts cancer research. The NCI funds studies conducted by hospitals, universities, and businesses. The institute also supports a network of cancer centers across the country.

Both agencies are part of the U.S. Department of Health and Human Services, and they share responsibility and oversight for clinical trials. In 2003, the FDA and the NCI entered an agreement to enhance the efficiency of clinical research and the evaluation of new cancer medications. An NCI-FDA Oncology Task Force involves senior staff from both agencies and oversees the agreement. The agencies collaborate on developing the markers that show whether a treatment is effective, such as survival time, tumor shrinkage, and time to relapse.

New Cancer Office and Program

In July 2004 the FDA announced plans to create the Office of Oncology Drug Products, which will be housed in the agency's Center for Drug Evaluation and Research (CDER). The new office will consolidate three existing areas within CDER that are responsible for reviewing drugs and biologics used to prevent, diagnose, and treat cancer. The creation of this office will improve the consistency of review and policy toward oncology drugs and bring together oncologists who will help develop new therapies.

"Biomedical research in the United States is second to none, and it is our responsibility to see that patients reap the fruits of that research," says Health and Human Services Secretary Tommy G. Thompson. "We are committed to creating the most effective and efficient review process possible to ensure life-saving treatments are made available to cancer patients."

The FDA also is creating a new oncology program within the office, which will coordinate cancer-related work performed throughout the FDA. The program will promote cross-agency consultation and discussion and the development of regulatory policy and standards, and will serve as a focal point for agency interactions with the National Cancer Institute and other stakeholders.

Cervical Cancer Screening

By Linda Bren

A Pap smear has long been a part of a woman's routine health care. The Pap can detect cell changes that may lead to cancer of the cervix, the lower part of the uterus, or womb. Women age 30 and older can now opt to get an additional test along with their Pap smear to increase the odds of detecting abnormal, or precancerous, cells before they turn into cervical cancer. This test checks a sample of cervical cells for the presence of the genetic material (DNA) of human papillomaviruses (HPVs).

"One of the high risk factors for having cervical cancer is a persistent HPV infection," says Thomas Simms, a Food and Drug Administration biologist who evaluated the HPV DNA test. "Greater than 95 percent of cervical cancers have detectable HPV DNA in them."

In March 2003, the FDA approved the HPV DNA test to be used simultaneously with the Pap test to screen for cervical cancer in women age 30 and older. The Hybrid Capture 2 High-Risk HPV DNA, made by Digene Corp. of Gaithersburg, Md., was initially approved in 2000, but only as a follow-up test for women who had abnormal or inconclusive Pap tests.

The Tests and What They Mean

A woman who visits her doctor to have a Pap test may be offered the HPV DNA test as well. "A woman 30 years and older has an option to choose to have the HPV testing," says Noel Del Mundo, M.D., an FDA gynecologist. Women who have both the Pap and the HPV DNA tests performed will not notice any difference in the procedure. The doctor will collect cervical cells for both tests at the same time by gently rubbing the surface of the cervix with a special collection device. The cells will then be sent to a laboratory for analysis.

If both the Pap and the HPV DNA test results are negative, a woman's doctor may advise her to wait for three years before being retested, according to guidelines from the American College of Obstetricians and Gynecologists (ACOG). But more frequent testing is recommended if other high risk factors are present, such as a weakened immune system or a history of cervical cancer.

If only one of the tests is negative, the doctor may advise the woman to return for retesting in six to 12 months. But if the Pap smear shows a mild cellular abnormality (called atypical squamous cells of undetermined significance, or ASC-US), and the HPV DNA test is positive, the doctor may recommend further tests. "HPV DNA testing for women with mild cellular abnormality will help the physician determine whether the patient should have a colposcopy and biopsy," says Del Mundo.

In a colposcopy, the doctor looks for a lesion on the cervix with a special magnifying instrument called a colposcope. If a lesion is found, the doctor will take a biopsy, in which a sample of the lesion is removed to check it for precancerous cells.

The FDA cautions that, while a positive HPV test can provide useful information for a woman and her doctor, it does not necessarily mean that she will develop cervical cancer. And although negative Pap and HPV test results indicate a very low risk (0.2 percent) for developing cervical cancer, that doesn't mean that changes won't occur. Infections or changes in cells may arise in the future, so continued screening is important.

Although the HPV DNA test in conjunction with the Pap test is not advised for women under age 30, these women should still get annual Pap tests, according to ACOG guidelines. The first screening for cervical cancer should occur about three years after a woman has her first sexual intercourse, but no later than age 21.

All women, regardless of negative test results, should still visit their doctors yearly for a pelvic examination, which includes checking the reproductive and other organs for abnormality in shape or size.

HPVs are Common

There are more than 100 types of HPV, according to the American Cancer Society (ACS). Some of them cause the noncancerous warts that typically grow on the hands or the bottom of the feet.

Other types of HPVs are sexually transmitted. Some cause wart-like growths on or around the genitals and anus of both men and women, but these visible external warts have not been linked with cancer. Other HPVs cause visible warts in the cervix, but because they rarely develop into cancer, they are often referred to as "low-risk" HPVs. But still other types of HPVs have been linked with cancer. These "high-risk" HPVs aren't usually found as visible warts. Both high-risk and low-risk types can cause the growth of abnormal cells in the cervix. The HPV DNA test can detect the presence of 13 HPVs that are associated with a high risk of cervical cancer.

Sexually transmitted HPV infections are very common. Fortunately, it is very rare for an HPV infection to lead to cervical cancer. This is especially true for women under 30, who have a relatively high rate of HPV infection but rarely develop cervical cancer, says Simms. The HPV DNA test was approved for women age 30 and older because of the higher risk of cervical cancer in this age group. "Women over 30 have fewer HPV infections, but if they develop a persistent HPV infection, it can eventually lead to precancerous changes in the cervix," says Simms.

According to the ACS, most people will not know that they have HPV because it usually goes away on its own.

"Most HPV infections are detected only transiently--the body's immune system clears signs of the infection," says Laura Koutsky, Ph.D., professor of epidemiology at the University of Washington in Seattle. "Currently, it is not known if the virus clears in most women or only a few women," she says. "Regardless, if the virus is no longer detectable, a woman's risk for cancer appears to be very low."

Because HPVs can be sexually transmitted, a positive HPV DNA test result may be troubling to women and their partners. But testing positive for HPV does not necessarily mean that the virus was contracted recently, says Koutsky. "You or your husband or partner may have contracted the virus many, many years ago," she says. "Keep in mind that current estimates indicate that more than 50 percent of sexually active adults have been infected with HPV."

Regular Screening Is Important

The ACS estimates that in 2003, more than 13,000 new cases of invasive cervical cancer will have occurred in the United States, resulting in 4,100 deaths from the disease. The rates of death from cervical cancer for several racial and ethnic groups, such as Hispanics and American Indians, are higher than the national average. And for blacks, the death rate is more than twice the national average.

The National Cancer Institute reports that regular Pap screening does reduce deaths from cervical cancer. Women who have not been screened face a significantly greater risk of developing the disease. With regular screening and follow-up care, cervical cancer is avoidable, and, if caught early, curable.

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 Importance of Patient-Reported Outcomes ...

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."