By Elizabeth Whittington

Cancer may be the second leading cause of death in the United States, but only a handful of cancers are considered common. But this may change in the near future.

When Congress passed the Orphan Drug Act in 1983, it spurred much-needed research and drug development for less common cancers. The law provides a tax incentive and extends exclusive marketing rights for companies that test a product for treatment of a rare disease. In 1984, an amendment to the Act defined a rare or “orphan” disease as one that affects fewer than 200,000 people. Since the Act was passed, nearly 1,500 drugs have received orphan drug status, of which 272 have been approved, including Gleevec® (imatinib) for chronic myelogenous leukemia, Rituxan® (rituximab) for non-Hodgkin’s lymphoma and Velcade® (bortezomib) for multiple myeloma.

With the direction science and cancer medicine is heading, Stephen Groft, PharmD, director of the Office of Rare Diseases at the National Institutes of Health, says the Orphan Drug Act could have broad implications for the new generation of anti-cancer therapies.

“Right now, I think all but five or six cancers would fall under the Act,” Groft says. “As many of the disorders become better defined genetically, we do have the capability of slicing the population very thin, especially if they’re responders to certain treatments.” Even the most common cancers may become orphan diseases if individualized medicine works in specific sub-populations of patients. Therapies targeting certain genetic mutations and overexpressed proteins could further subdivide common cancers.

With this in mind, experts wonder if drugs found to work in only a small percentage of patients should be re-examined. A drug that works in a limited number of patients with a certain type of cancer may be considered a failure, but if the agent were only tested in those patients and achieved a 90 percent response rate, it would be a success. In a science based on percentages, getting the correct patient population is crucial.

Illustrating this point is Iressa® (gefitinib), a drug shown to work better in lung cancer patients with a specific mutation of the epidermal growth factor receptor (EGFR). Non-small cell lung cancer is treated according to disease stage, but scientists have discovered that some of these tumors differ in their biology and response to particular treatments. If clinical trial investigators can identify the appropriate patient population for a study, a lower failure rate could be expected for the agent being tested. After Iressa showed no survival benefit in a large study, the Food and Drug Administration limited use of the EGFR inhibitor to patients in clinical trials and those who previously responded to the drug. Researchers are now searching for biomarkers to identify the patient population that will respond to Iressa. In hindsight, experts say Iressa could have received orphan drug status if trials had been limited to and shown effectiveness in patients with an EGFR mutation.

Marlene Haffner, MD, director of the Office of Orphan Product Development at the FDA, says her office has received a record number of applications for orphan drugs in the past two years, many of which are for cancer. She believes the volume of applicants will continue to increase along with the number of orphan drug approvals, especially in light of the increase in personalized medicine.

But before drug approval comes clinical trials. As cancers are defined more by genetics, specialized patient populations will be smaller, which may make it harder to accrue patients for large trials. On the flip side, small populations involve less data to review, which could shorten the time to drug approval. “As we learn more about proteomics and genomics, some cancer groups will indeed become smaller, and depending on how small, will determine if there is difficulty in performing clinical trials,” says Dr. Haffner.

More than two decades ago, the Orphan Drug Act’s mission was to create more options for patients with rare illnesses. But as science progresses to genetically define tumors, the most common cancers may soon become orphan diseases.