“We believe this is the first application of newer generations of whole-genome sequencing that could be clinically useful for cancer patients,” says Victor Velculescu, M.D., Ph.D., associate professor of oncology and co-director of the cancer biology program at Johns Hopkins. “Using this approach, we can develop biomarkers for potentially any cancer patient.”

In a report on the work, published in the February 24 issue of Science Translational Medicine, the scientists scanned patients’ genomes for alterations that, they say, most researchers have not been looking for – rearrangements of large chunks of DNA rather than changes in a single DNA letter among billions of others. They call their new approach Personalized Analysis of Rearranged Ends (PARE).

“In sequencing individuals’ genomes in the past, we focused on single-letter changes, but in this study, we looked for the swapping of entire sections of the tumor genome,” says Bert Vogelstein, M.D., Clayton Professor of Oncology, co-director of the Ludwig Institute at Johns Hopkins, and Investigator in the Howard Hughes Medical Institute. “These alterations, like the reordering of chapters of a book, are easier to identify and detect in the blood than single-letter changes.”

Such DNA rearrangements are widely known to occur exclusively in cancer cells, not normal ones, making them ideal biomarkers for cancer.

Using six sets of cancerous and normal tissue samples taken from four colorectal and two breast cancer patients, the Johns Hopkins team used next-generation sequencing methods to catalogue the genome sequence data of each patient. To find DNA rearrangements, the team first identified regions where the number of DNA copies was more or less than anticipated and where sections of different chromosomes fused together. These regions were further analyzed to identify DNA sequences displaying incorrect ordering, orientation, or spacing. A range of four to 15 rearrangements were found in each of the six samples.

After investigators identified DNA rearrangements in patients’ tumor samples, they looked for the same changes in DNA shed from tumors into the patients’ blood. Using blood samples from two of the colorectal cancer patients, they amplified DNA found in the blood and determined that these tests were sensitive enough to detect rearranged tumor DNA in these samples.

Results from such blood tests, they say, could help clinicians detect cancer or its recurrence and inform them on how a patient is responding to cancer therapies. In one colon cancer patient’s example, the scientists found a section of chromosome four fused to a section of chromosome eight. “We developed a biomarker that could span this rearrangement and used a blood test to evaluate biomarker levels as the patient received a variety of cancer therapies,” says Rebecca Leary, a graduate student at the Johns Hopkins Kimmel Cancer Center.

After an initial surgery, the patient’s biomarker levels dropped due to the removal of the majority of the tumor. The biomarker levels rose again, indicating that additional cancer remained in the patient’s body. After chemotherapy and a second surgery, levels of the biomarker dropped substantially, but still showed a small but measurable level of the biomarker. This was consistent with a small metastatic lesion that remained in the patient’s liver.

The investigators envision that PARE-based biomarkers could also be used to determine whether cancer cells are present in surgical margins or lymph node tissue removed during surgery and possibly for diagnosing early disease. “Eventually, we believe this type of approach could be used to detect recurrent cancers before they are found by conventional imaging methods, like CT scans,” says Luis Diaz, M.D., assistant professor of oncology at Johns Hopkins.

The technology used to examine the patients’ genomes will become inexpensive, predicts Velculescu. He says the genome scan cost them about $5,000 per patient, but that sequencing costs continue to drop. CT scans currently cost $1,500 per scan and are limited in their ability to detect microscopic cancers.

“If current trends in genome sequencing continue, PARE will be more cost effective than CT scans and could prove to be more informative,” says Kenneth W. Kinzler, Ph.D., professor of oncology and co-director of the Ludwig Center at Johns Hopkins.

The Johns Hopkins team plans on testing more patient samples and refining their techniques to produce a commercially viable genome-based blood test. They have filed for patents on the technology.

Under a licensing agreement between the Johns Hopkins University and Genzyme, Velculescu, Vogelstein, and Kinzler, are entitled to a share of royalties received by the University on sales of products related to research described in this paper. The terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Funding for the research was provided by the National Institutes of Health, The Lustgarten Foundation, the National Colorectal Cancer Research Alliance, and a UNCF-Merck Fellowship.

Source: Science Translational Medicine, (2/24/2010); John Hopkins Medicine

Rituxan, an anti-cancer drug, is intended for patients with CLL who are beginning chemotherapy for the first time and for those who have not responded to other cancer drugs for CLL. Rituxan is administered with two other chemotherapy drugs, fludarabine and cyclophosphamide.

CLL primarily affects people older than 50 and arises from a group of white blood cells known as B-cells—part of the body’s immune system. Each year, about 16,000 people are diagnosed with and 4,400 die from CLL.

“Rituxan is the third drug approved for the treatment of CLL since 2008 and underscores FDA’s commitment to expediting the development and approval of drugs for patients with serious and life-threatening diseases,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.

FDA approved Arzerra (ofatumumab) in October 2009 for patients whose cancer is no longer being controlled by other forms of chemotherapy and Treanda (bendamustine) in March 2008 for patients with CLL who had not received prior treatment.

Rituxan is a monoclonal antibody. It is manufactured through biotechnology methods rather than by the human body’s own immune system. The drug binds to the surface of cancer cells, making it easier for the patient’s immune system to attack the cancer cell as if it were a foreign pathogen.

The safety and effectiveness of Rituxan was evaluated in two studies that measured progression-free survival, defined as the time a patient in the study lived without the cancer progressing.

In one study of 817 patients who had not received any prior chemotherapy, progression-free survival was eight months longer for those receiving Rituxan plus chemotherapy than for those who received chemotherapy alone. In another study of 522 persons whose cancer had progressed following other chemotherapy drugs, progression-free survival was five months longer for those who received Rituxan plus chemotherapy.

The FDA analyzed the data on patients 70 years of age and older who had received Rituxan and found no evidence that adding the drug to chemotherapy benefitted elderly patients compared to receiving chemotherapy alone. However, there was also no evidence that Rituxan was harmful to elderly patients.

Rituxan carries a Boxed Warning for infusion reactions, which can occur during infusion or within 24 hours afterwards. Some 59 percent of patients treated with Rituxan for CLL experienced an infusion reaction that resembled an allergic reaction (e.g., hives, low blood pressure, chills, fever, and nausea).

A decrease in infection-fighting, normal white blood cells was also commonly observed in patients enrolled in the Rituxan clinical trials.

Other Boxed Warnings for Rituxan include rashes and sores in the skin and mouth; progressive multifocal leukoencephalopathy (PML), a brain infection that is generally fatal; and tumor lysis syndrome, which results from the death of a large number of tumor cells in a short period of time. When the tumor cells are killed by the drug, they release toxins into the bloodstream that can cause acute kidney injury and increase the levels of potassium and phosphate in the blood.

Rituxan is manufactured by San Francisco based-Genentech, a member of the Roche Group.

Source: FDA (2/18/2010)

The team tested sceptrin in multiple tumor cell types, including cervical, breast and lung cancers. Sceptrin restricted motility in all cell lines. Further tests showed the compound works by limiting the cells’ ability to contract, a critical function for cell motility. The researchers also found that sceptrin synthesized in the laboratory was just as effective at combating motility as the naturally-derived compound.

Given the recently achieved synthesis of sceptrin in multi-gram quantities by the Baran laboratory, sceptrin could prove to be an attractive lead molecule for further preclinical testing and development for therapeutic purposes,” said Dr. Vuori. It may also prove to be a useful research tool in order to elucidate the mechanisms involved in cell motility.”

The researchers cultured growing cancer cells with growth factor to encourage motility. These cells were treated with varying amounts of sceptrin, which was found to be more effective at increased concentrations. Subsequently, the team conducted apoptosis and cell proliferation studies to determine whether these mechanisms accounted for the decrease in motility of sceptrin-treated cells. Other assays determined that sceptrin limits motility by reducing cell contractility.

Souce: ACS Chemical Biology, Sanford-Burnham Medical Research Institute (2/18/2010)

“We recognize that some may find colorectal cancer screening tests to be unpleasant and time-consuming. However, we also know that recommended screening strategies reduce colorectal cancer deaths,” said Dr. Donald Steinwachs, panel chair, and professor and director of the Health Services Research and Development Center at the Johns Hopkins University. “We need to find ways to encourage more people to get these important tests.”

The panel found that the most important factors associated with being screened are having insurance coverage and access to a regular health care provider. Their recommendations highlighted the need to remove out-of-pocket costs for screening tests.

Given the variety of tests available, the panel emphasized that informed decisions incorporating personal preferences may help reluctant individuals determine which test’s combined attributes — invasiveness, frequency, and required preparation — are preferable to them, helping them identify and obtain the most palatable test. For example, an individual may choose a more invasive test requiring less frequent follow-up or a less invasive test requiring more frequent follow-up.

Noting differences in screening rates across racial and ethnic groups, socioeconomic status, and geographic location, the panel emphasized the need for targeted strategies for specific subgroups. Compared with non-Hispanic whites, Hispanics are less likely to be screened.

The panel also noted that if efforts to increase utilization are successful, there will be a greater demand for colorectal cancer screening services. Available capacity involves not only facilities and appropriately trained providers, but also support for informed decision making, resources to coordinate screening services and communicate results effectively, and enhanced monitoring practices to ensure that positive results are followed up with colonoscopy. Depending on the scale of increases in screening rates, there may be a need to increase local and national capacity.

In addition to increasing first-time screening rates, the panel also identified the need to ensure that individuals return for subsequent testing at the recommended intervals. A variety of colorectal cancer screening tests are available and different guidelines recommend them at different intervals.

The conference was sponsored by the NIH Office of Medical Applications of Research and the National Cancer Institute along with other NIH and Department of Health and Human Services components. This conference was conducted under the NIH Consensus Development Program, which convenes conferences to assess the available scientific evidence and develop objective statements on controversial medical issues.

The 13–member conference panel included experts in the fields of cancer surveillance, health services research, community-based research, informed decision-making, access to care, health care policy, health communication, health economics, health disparities, epidemiology, statistics, thoracic radiology, internal medicine, gastroenterology, public health, end-of-life care, and a public representative. A complete listing of the panel members and their institutional affiliations is included in the draft conference statement.

In addition to the material presented at the conference by speakers and the comments of conference participants presented during discussion periods, the panel considered pertinent research from the published literature and the results of a systematic review of the literature. The systematic review was prepared through the Agency for Healthcare Research and Quality Evidence-based Practice Centers (EPC) program, by the RTI International-University of the North Carolina Evidence-based Practice Center. The EPCs develop evidence reports and technology assessments based on rigorous, comprehensive syntheses and analyses of the scientific literature, emphasizing explicit and detailed documentation of methods, rationale, and assumptions.

Source: National Institutes of Health (Feb. 4, 2010)

Now UCLA scientists have uncovered a new way to image tumors and forecast which patients are most likely to benefit from Avastin before starting a single dose of treatment. The findings are published in this month’s issue of the journal Radiology.

“Avastin is an expensive drug, yet only 50 percent of patients with recurring brain cancers respond to it,” said lead author Dr. Whitney Pope, assistant professor of radiological sciences at the David Geffen School of Medicine at UCLA. “Until now, there has been no good way to identify these patients in advance. Our work is the first to suggest that we can predict which tumors will respond before the patient ever starts therapy.”

Pope and his colleagues focused on glioblastoma, the most common and deadly form of adult brain tumor, striking 12,000 Americans a year.

The UCLA team studied 82 patients who had undergone surgery and radiation therapy to remove glioblastoma. Half of the patients received infusions of Avastin every two weeks. All underwent monthly brain scans by magnetic resonance imaging (MRI) to monitor change.

The researchers analyzed the MRI scans of the patients whose tumors returned. Explaining what the team saw requires an understanding of how the tumor creates an independent blood supply.

Cancer cells secrete a growth factor called VEGF that spurs the growth of new blood vessels to supply the tumor with oxygen and nutrients. Avastin blocks VEGF, essentially starving the tumor to death.

This process launches a chain of events that is detectable by MRI. Oxygen-starved cells produce more VEGF, which causes blood vessels to leak fluids into the tumor and surrounding tissue. This results in swelling, which boosts water’s ability to move freely in the tumor and brain tissue. As cells disintegrate, they no longer pose a physical barrier to water movement.

“We theorized that tumors with more water motion would also have higher VEGF levels,” explained Pope. “Because Avastin targets VEGF, it made sense that the drug would work better in tumors with high levels of the growth factor.”

By measuring the amount of water motion within the tumor, the researchers were able to predict with 70 percent accuracy which patients’ tumors would progress within six months and which would not. They detected greater water movement in the tumors of those persons who later responded best to Avastin.

“When we realized that high levels of VEGF are linked to greater cell death and increased water movement, we were able to predict the patients’ response to Avastin before they began treatment,” explained Pope. “We were correct 70 percent of the time. Previously, identifying which patients would respond was like flipping a coin. This is a huge improvement.”

The research finding presents clear clinical benefits to the patient, says Pope. “Knowing this information ahead of time will help doctors personalize therapy for each patient and decrease exposure to side effects,” he noted.

Pope and his colleagues plan to confirm their findings in a larger study. The team will also test the new method’s ability to identify responsive patients prior to surgical removal of their tumor.

Despite therapy with surgery, radiation and chemotherapy, the average glioblastoma patient lives only 12 to 15 months after diagnosis. Survival rates drop even lower if the tumor returns. Conventional therapies produce little benefit; only 8 to 15 percent of patients survive without tumor progression six months after treatment.

Source: University of California, Los Angeles (UCLA), Health Sciences, July 30, 2009

EphA2 is attractive for such molecularly targeted therapy because it has increased expression in ovarian and other cancers, including breast, colon, prostate and non-small cell lung cancers and in aggressive melanomas, and its expression has been associated with a poor prognosis.

“One of our goals has been to develop more specific ways to deliver chemotherapeutic drugs,” said senior author Anil K. Sood, M.D., professor and in the Departments of Gynecologic Oncology and Cancer Biology at M. D. Anderson. “Over the last several years we have shown that EphA2 is a target that is present quite frequently in ovarian and other cancers, but is either present in low levels or is virtually absent from most normal adult tissues. EphA2’s preferential presence on tumor cells makes it an attractive therapeutic target.”

The researchers used a carrier system to deliver chemotherapy directly to ovarian cancer cells. The immunoconjugate contains an anti-EphA2 monoclonal antibody linked to the chemotherapy drug monomethyl auristatin phenylalanine (MMAF) through the non-cleavable linker maleimidocaproyl. Research has shown that auristatins induce cell cycle arrest at the G – M border, disrupt microtubules and induce apoptosis (programmed cell death) in cancer cells.

The investigators evaluated the delivery system’s specificity in EphA2-positive HeyA8 and EphA2-negative SKMel28 ovarian cancer cells through antibody-binding and internalization assays. They also assessed viability and apoptosis in ovarian cancer cell lines and tumor models and examined anti-tumor activity in orthotopic mouse models with mice bearing HeyA8-luc and SKOV3ip1 ovarian tumors.

According to Sood, who is also co-director of both the Center for RNA Interference and Non-Coding RNA and the Blanton-Davis Ovarian Cancer Research Program at M. D. Anderson, the immunoconjugate was highly specific in delivering MMAF to the tumor cells that expressed EphA2 while showing minimal uptake in cells that did not express the protein. In the models, the therapy inhibited tumor growth in treated mice by 85 percent – 98 percent compared to control mice.

“Once we optimized the dosing regimen, the drug was highly effective in reducing tumor growth and in prolonging survival in preclinical animal models,” Sood said. “We actually studied bulkier masses because that is what one would see in a clinical setting where there are pre-existent tumors, and even in this setting the drug was able to reduce or shrink the tumors.”

As for future research with the EphA2-silencing therapy, Sood said, “We are gearing up to bring it to phase I clinical trials. A lot of the safety studies are well under way or nearing completion and we anticipate that this drug will enter clinical trials within the next few months.”

He added that his group is simultaneously conducting preclinical testing on other chemotherapy drugs to determine which agents might combine well with the immunoconjugate used in the current study.

“There is growing interest in molecularly targeted therapy so that we are not indiscriminately killing normal cells,” Sood noted. “The goal is to make the delivery of chemotherapy more specific. The immunoconjugate we used is in a class of drugs that is certainly quite attractive from that perspective.”

Source: University of Texas M. D. Anderson Cancer Center

The SOD2 gene produces a key protein that protects cells from damage by molecules known as reactive oxygen species, or free radicals. Reactive oxygen species are produced by normal cellular processes and the action of some chemotherapy drugs. The findings represent the first preliminary evidence pointing toward a mechanism and a potential biomarker for cyclophosphamide resistance in breast cancer patients. The study appeared online June 9, 2009, in Clinical Cancer Research.

“This study shows how, with the progress of individualized medicine, a diagnostic test may be developed that determines whether a patient has certain genetic variations that may modify the effect of certain chemotherapies,” said study author Sharon Glynn, Ph.D., of NCI’s Center for Cancer Research.

“In the future, such tests may be used to guide the treatment of patients with the SOD2 variation, ensuring that they receive a therapy that is more effective than cyclophosphamide-based therapies,” added senior author Stefan Ambs, Ph.D., also of the Center for Cancer Research.

Most genes in human cells are present in two copies — one inherited from the mother and the other inherited from the father. These gene copies can vary from one another. Some variations in genes play an important role in how a gene is expressed or how its protein product functions.

The variant identified by the researchers in the SOD2 gene affects both the structure and the function of the encoded protein, an enzyme known as manganese superoxide dismutase (MnSOD) and affects the ability of MnSOD to reach its proper location in the cell and its activity level. MnSOD normally functions inside cellular compartments known as mitochondria and helps protect cells from damage caused by reactive oxygen species formed during cellular metabolism. Excessive levels of reactive oxygen species can be toxic to cells. Indeed, some anticancer drugs depend on increased production of reactive oxygen species to kill cancer cells. Furthermore, some studies have indicated that, because MnSOD neutralizes reactive oxygen species, it can modify the effects of chemotherapy drugs. For example, in laboratory and animal models, increased activity of MnSOD protects cells against the toxic effects of doxorubicin, which is a widely used anticancer drug.

In the new study, the research team investigated whether the variation affected survival in two separate groups of women with breast cancer: 248 women in the United States and 340 women in Norway. Some of the women received chemotherapy, and some did not receive chemotherapy. The team first analyzed DNA from the women to determine their genotype, meaning which types of the SOD2 gene they had. The researchers found that, among patients who received chemotherapy, those who had one form had decreased survival and those with another form had the poorest survival. In contrast, the genotype of SOD2 did not affect survival among those who did not receive chemotherapy.

Next, the team looked at the relationship between SOD2 genotype and the type of chemotherapy the women received. The data were analyzed according to which of three types of commonly used chemotherapy drugs were administered: doxorubicin, 5-fluorouracil, or cyclophosphamide. Both doxorubicin and cyclophosphamide generate reactive oxygen species in cancer cells during treatment. The researchers determined that the presence of a particular variant was associated with decreased survival of patients treated with chemotherapy regimens that contained any of the three drugs. However, the most significant effects were found with the drug cyclophosphamide. Women with a distinct variant form of SOD2 and who received cyclophosphamide-containing chemotherapy had the poorest survival.

The research team says more work is necessary to confirm these findings and to examine the precise mechanism by which a genotype influences the response of cancer cells to cyclophosphamide. The team plans to examine the influence of several variations on the resistance to other chemotherapies.

Source: National Institutes of Health (NIH), 6/9/2009

Gastrointestinal (GI) cancers account for approximately one in four cancer deaths. While high cure rates can be achieved with early-stage detection for each type, only colorectal cancer is currently screened at the population level. Most people associate colorectal cancer screening with invasive colonoscopy, but previous Mayo Clinic research has shown that stool DNA testing can identify both early-stage colorectal cancer and precancerous polyps. Researchers are now studying the use of noninvasive stool DNA testing to detect lesions and cancer throughout the GI tract.

“Patients are often worried about invasive tests like colonoscopies, and yet these tests have been the key to early cancer detection and prevention,” says David Ahlquist, M.D., Mayo Clinic gastroenterologist and lead researcher on the study. “Our research team continues to look for more patient-friendly tests with expanded value, and this new study reveals an opportunity for multi-organ digestive cancer screening with a single noninvasive test.”

The researchers studied 70 patients with cancers throughout the digestive tract. Besides colon cancer, the study looked at throat, esophagus, stomach, pancreatic, bile duct, gallbladder and small bowel cancers to determine if gene mutations could be detected in stool samples. Using a stool test approach developed at Mayo Clinic, researchers targeted DNA from cells that are shed continuously from the surface of these cancers. Also studied were 70 healthy patients. Stool tests were performed on cancer patients and healthy controls by technicians unaware of sample source. The stool DNA test was positive in nearly 70 percent of digestive cancers but remained negative for all healthy controls, thus demonstrating the approach’s feasibility.

Stool DNA testing detected cancers at each organ site, including 65 percent of esophageal cancers, 62 percent of pancreatic cancers, and 75 percent of bile duct and gallbladder cancers. In this series, 100 percent of both stomach and colorectal cancers were detected. Importantly, stool test results did not differ by cancer stage; early-stage cancers were just as likely to be detected as late-stage cancers.

“It’s very exciting to see this level of sensitivity for digestive cancer detection in our first look at this test application,” says Dr. Ahlquist, “Historically, we’ve approached cancer screening one organ at a time. Stool DNA testing could shift the strategy of cancer screening to multi-organ, whole-patient testing and could also open the door to early detection of cancers above the colon which are currently not screened. The potential impact of this evolution could be enormous.”

In October 2008, this Mayo Clinic research team published results of a multicenter study using first-generation stool DNA testing. In the seven-year, multicenter study (Ann Intern Med 2008;149:441-50), researchers found that the first-generation stool DNA tests were better than fecal blood tests for detecting cancer and precancerous polyps of the colon.

In January 2009 (Gastroenterology 2009;136:459-70), Mayo researchers published some technical improvements that nearly doubled the sensitivity of stool DNA testing for detecting premalignant polyps and increased cancer detection to about 90 percent, which is the approximate rate of detection observed for CT colonography.

Researchers hope that the next generation tests will have significant improvements in accuracy, processing speed, ease of patient use and affordability. “We anticipate that next generation tests will also be able to predict the tumor site, which will help physicians direct diagnostic studies and minimize unnecessary procedures,” says Dr. Ahlquist.

Source: Mayo Clinic, June 2, 2009

John M. Maris, M.D., chief of Oncology at The Children’s Hospital of Philadelphia, co-authored the phase 3 clinical trial, which was led by Alice Yu, M.D., Ph.D., of the University of California, San Diego. Maris chairs the committee supervising the trial for the Children’s Oncology Group, a cooperative organization that pools resources from leading medical centers to study and devise new treatments for pediatric cancers.

Neuroblastoma, a cancer of the peripheral nervous system, usually appears as a solid tumor in the chest or abdomen. Neuroblastoma accounts for 7 percent of all childhood cancers, but due to its often aggressive nature, causes 15 percent of all childhood cancer deaths.

Yu will present the neuroblastoma study results on June 2 at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Fla. In advance of the meeting, ASCO published the findings online on May 14.

Maris explained that immunotherapy for cancer involves triggering the body’s immune system to attack cancer cells. Monoclonal antibodies are molecules customized to target particular cancers, while cytokines are naturally occurring signaling proteins that regulate the body’s immune responses.

In the current study, Children’s Oncology Group researchers studied 226 children with high-risk neuroblastoma. Half received the immunotherapy, while half received standard therapy (chemotherapy and stem cell transplantation). The patients who received the immunotherapy were 20 percent more likely than those in the standard therapy group to live disease-free two years after treatment. “This 20 percent improvement in preventing relapse led to a greater cure rate—the first substantial increase in cure rate for neuroblastoma for more than a decade,” said Maris.

The researchers halted the trial earlier than expected after early results showed the benefits of immunotherapy. “This experimental immunotherapy is poised to become part of the new standard of care for children with the aggressive form of neuroblastoma,” said Maris.

Maris added that the supply of the antibodies and cytokines used in the trial was limited, and that pediatric oncologists were seeking biotechnology companies to move the biological agents into commercial production to make the treatment readily available to children with neuroblastoma.

The Children’s Hospital of Philadelphia has one of the nation’s largest clinical and research programs in neuroblastoma. In 2008, Maris led a study that was the first to identify the gene location at which neuroblastoma originates. His laboratory continues to investigate how genes contribute to the disease, using that knowledge to devise new treatments.

Maris served as an oncologist for Alex Scott, the child with neuroblastoma who started a lemonade stand in 2000 to raise money for programs in childhood cancer. Now operated through the Scott family, the Alex’s Lemonade Stand Foundation supports ongoing research by members of the Children’s Oncology Group.

Source: American Society of Clinical Oncology, May 14, 2009

My take is that once approved treatment regimens have been exhausted, desperately ill patients should have appropriate access to any reasonable treatment that has the potential to be of benefit and yet doesn’t present unjustifiable risks. The best way to provide these drugs is through clinical trials, where the rigor and discipline of the trial enables patient response, side effects, and outcomes to be carefully measured to determine safety and effectiveness in a systematic way. When this is not possible, there can be an alternative pathway to receiving the investigational therapy.

The FDA has called this pathway “single patient access,” often referred to by the public as ” compassionate use.” We have a long history of helping patients gain access to potential treatments this way. For example, just in FDA’s oncology division, we review and approve hundreds of requests each year for single patient access to investigational drugs.

More recently, we have encountered circumstances in which a drug is approved and is commercially available, but can only be used under very strict rules – these are called an approved Risk Evaluation and Mitigation Strategy (REMS). But we have adapted “single patient expanded access” to this category of drugs as well in an effort to do everything appropriate to serve these unfortunate patients.

So, how can patients gain access to an investigational drug or a restricted drug through these mechanisms? To permit such treatment use of an investigational drug, the company must first agree to make the drug available. Then, the FDA, in conjunction with the patient’s treating physician, must determine, among other things that the potential benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or the condition to be treated; and that providing the investigational drug for the treatment use will not interfere with the initiation, conduct, or completion of clinical investigations that are required to support marketing approval of the investigational drug for the greatest number of patients who can benefit. A similar path is taken when considering use of restricted commercially available drugs.

Drugs under investigation, in either a clinical trial or an expanded access program, don’t offer a guarantee of success, but they do offer an option. Information about clinical trials of investigational drugs and expanded access options, including contacts and locations, is available through the ClinicalTrials.gov web site. At the FDA, there is an Office of Special Health Issues which you can call and where they have trained personnel to listen to your story and assist you with the necessary information. The number to call is 301-827-4460.

At the end of the day, benefitting patients is the goal of the FDA. And how it is achieve requires a structured and disciplined process to facilitate getting the right drug or medical product to the right patient in the right way – to get the best possible outcome.

Andrew C. von Eschenbach, M.D.
Commissioner of Food and Drugs (FDA)