Gemzar

With a certain amount of regularity a new cancer drug makes headlines, generating an enormous amount of hope, as well as pressure to make the product swiftly available. In time, we usually learn that the drug's benefit is much more modest than originally portrayed in the media, and soon oncologists (cancer specialists) begin to prescribe the drug for other forms of cancer without waiting for clinical trials to prove effectiveness. This recurring scenario merits a closer look at the U.S. Food and Drug Administration (FDA) and the basis upon which it approves new cancer drugs.

Tumor Shrinkage

Contrary to popular belief, drug companies are not required to prove that their drugs prolong survival. Until the mid-1980s, all cancer drugs were approved solely on the basis of what researchers call the "tumor response." In other words, the testing required of a drug company need only show that the drug caused a tumor to shrink, not necessarily to disappear.

Years ago, a change in the approval process was recommended by the FDA's own Oncologic Drug Advisory Committee. The Committee members, all primarily cancer experts unaffiliated with any government agency, knew that tumor shrinkage often has little or no relation to survival. The Committee proposed the novel idea that a drug company should be required to prove that a drug provides some benefit that is meaningful to the patient, such as increased survival or improvement in symptoms. The Committee argued further that the potential benefit of tumor shrinkage did not necessarily outweigh the substantial toxicity of cancer drugs.

This recommendation was made in the mid-1980s, but change at the FDA comes slowly, as a recent assessment of new drug approvals has demonstrated. From 1990 through 2001, the FDA approved 66 new cancer drugs. Prolonged survival was not proven for 48 drugs. And tumor response was the basis of approval for 35 drugs.

Variations in Endpoints

"The FDA has a certain amount of regulatory flexibility to make an assessment of the side effects versus the efficacy of new products," said the FDA's Richard Pazdur, MD, in a telephone interview. He had been asked why so few new drugs have been proven to prolong survival. "The drug company must prove that its product provides a longer life, a better life, or a favorable effect on an established endpoint for a better life, he explained. The FDA's flexibility comes into play on the last point about "an established endpoint for a better life." One example of an established endpoint, says Dr. Pazdur, is a complete response in leukemia--that is, the bone marrow is normal, the blood count have normalized.

Even so, there is a hierarchy of established endpoints. "Survival is the gold standard of endpoints because it is the most meaningful to all people," cautioned Dr. Pazdur, who is the Director of Oncology Drug Products at the FDA's Center for Drug Evaluation and Treatment. He explained that there can be no misinterpretation where it concerns survival--the patient is either dead or alive. "Whereas, the other endpoints, such as tumor response rate, are usually determined by x-rays or scans," he continued. "There can be variations in the radiologists, the techniques of how the x-rays or scans are obtained, which can make it confusing and unreliable. Also, there is a subjective judgment in reading these x-rays and scans."

Accelerated Approval

These cautions notwithstanding, the FDA still allows the use of tumor shrinkage as the sole endpoint in the approval of certain drugs. In 1992, the agency introduced an accelerated approval (AA) process. The idea behind AA is to get drugs quickly to advanced cancer patients in whom all available options had failed. Consequently, tumor shrinkage was the sole basis of the AA for 10 of 11 new drugs. The rationale: Shrinking a lung tumor might, in the FDA's view, be "reasonably likely" to alleviate breathing difficulties.

The testing for AA is minimal. The new drug is given to about 30 or so participants who have run out of options. In what is called a Phase II trial, there is no comparison group--everyone in the study gets the new drug. Consequently, this type of trial is not likely to provide a true picture of the drug's toxicity or efficacy. That's why a drug given AA must continue to be studied to see if it provides any benefit in terms of increased survival or symptom improvement. "The drug companies usually do a large trial in which the new drug is compared to the standard drug," said Dr. Pazdur. "This usually takes two to four years, and the proof comes from a usually large trial that compares the new drug to the standard drug." And what if the drug company does not comply? "We have a process for rapidly removing the drug from the market," replied Dr. Pazdur.

Still, some not-so-well tested drugs are available for several years following an AA, and oncologists are free to prescribe them for cancers other than the type for which the products received approval. Or, more often, oncologists can add the new product to a multiple-drug regimen, which in itself has never been studied. "Yes, this is called off-label use, which is fairly common in the practice of oncology in the U.S.," agreed Dr. Pazdur. "But this involves the practice of medicine, and the FDA does not control the practice of medicine."

Unless their oncologists tell them, cancer patients would not know whether they are being given a drug off-label. "We would like patients to read the drug label to see the approved indications and contraindications," advised Dr. Pazdur, who said that the information is freely available at the FDA's Web site.

For more information:

To read a drug label, go to www.fda.gov or to the Physicians' Desk Reference (PDR), which is updated yearly and available at most local libraries and large bookstores. The label is daunting for its extensive length, tiny type and medical jargon-ridden style. It is, however, the only source for results of the FDA- required tests. The section entitled "Indications" will identify the purpose(s) for which the drug has been proven beneficial. If you can't find your type and stage of cancer listed under "Indications," this signals off-label use. Unfortunately, only the rare cancer patient well versed in clinical trials will be able to discern whether the label is identifying a drug that has gone through the less-rigorous AA process. For example, capecitabine was given AA (on the basis of tumor response) for advanced breast cancer in 1998. The 2002 Physicians' Desk Reference describes capecitabine's testing as a "phase II, single-arm trial," which signals AA. Another clue can be found under "Indications," where response rate is described as the basis for the drug's use for metastasized breast cancer. However, the much watered-down patient version of the capecitabine label (which appears after the information aimed at professionals) does not include an explanation of these terms. The patient's label makes no mention of the fact that the drug was approved through the accelerated process. Capecitabine is sold under the brand name: Xeloda.

Go to the Web site of the National Cancer Institute (www.cancer.gov), click into the following succession of options: "treatment," "chemotherapy," and "newly approved cancer treatments." You will find explanations of phase II trials, off- label drug use (complete with Q and A: "Can off-label drug use be harmful?"), and many other relevant terms. People without access to the Internet can call the National Cancer Institute at 1 (800) 4-CANCER to get this information mailed to them.

When recommending a new cancer drug to a patient, oncologists will often quote "response rate" without explaining what it means. Ask. This article has addressed how new drugs receive FDA approval. But once on the market, they are often studied eventually in large randomized, controlled trials as part of a multiple-drug regimen.

Ask for the evidence to support a proposed chemotherapy regimen. Here's one way to phrase the question: "Can you give me a citation for the studies that show this drug or drug-combination will benefit people with my stage and type of cancer? The citation will allow you to do a Medline search (ask the librarian at your local public library) to locate the study and determine the exact nature of the benefit. Medline is a service available through the National Library of Medicine. It provides free access to the abstracts, or summaries, of the studies published in a large proportion of the world's medical journals. Some public libraries will retrieve the entire article at no charge, but the article can also be purchased on-line.

Sidebar

A DRUG THAT PROVED MEANINGFUL BENEFIT TO PEOPLE WITH PANCREATIC CANCER

When gemcitabine (brand name: Gemzar) was approved by the FDA in 1996 for pancreatic cancer, it was particularly momentous to people diagnosed with this disease. In most cases, pancreatic cancer is advanced at the time of diagnosis, and the treatment options offer little in the way of increased survival.

The process required for gemcitabine's approval also came at time of change within the FDA regarding how success is determined. For regular, as opposed to accelerated, approval of its drug, the manufacturer Eli Lilly had to prove "clinical benefit" in two large randomized clinical trials (RCTs) comparing its new drug with the standard chemotherapy drug (5-FU).

The first trial proved that the drug not only prolonged life, but also provided a better life for some of the participants. The 63 pancreatic cancer patients, who had been randomly assigned to take gemcitabine lived nearly six months*, compared with four months for the 63 patients who had taken 5-FU. The "better quality of life" benefit was determined by consumption of painkillers, pain intensity, performance of everyday activities, or weight change. Fourteen of the 63 people on gemcitabine showed this benefit, compared with only three taking 5-FU.

In time, oncologists began prescribing gemcitabine off-label to people with non-small cell lung cancer. Though drug companies are not required to conduct additional studies just because their drugs are being prescribed off-label, some manufacturers might do so when encouraging results are reported by oncologists. Eli Lilly conducted an RCT comparing cisplatin, the standard chemotherapy drug for non-small cell lung cancer, with the combination of cisplatin and gemcitabine. Results showed that the people taking the combination lived six more weeks* than those taking the older drug alone.

Now oncologists are adding gemcitabine to a multiple-drug regimen for advanced breast

cancer.

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*T*This is median survival, which means that half the cancer patients lived longer and half lived less.

Maryann Napoli is the associate director of the Center for Medical Consumers in New York City.

COPYRIGHT 2002 Center for Medical Consumers, Inc.
COPYRIGHT 2002 Gale Group