FDA begins process to remove breast cancer indication from Avastin label

The U.S. Food and Drug Administration announced today (December 16) that the agency is recommending removing the breast cancer indication from the label for Avastin (bevacizumab) because the drug has not been shown to be safe and effective for that use.

The agency is making this recommendation after reviewing the results of four clinical studies of Avastin in women with breast cancer and determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.

In July 2010, after reviewing all available data an independent advisory committee, composed primarily of oncologists, voted 12-1 to remove the breast cancer indication from Avastin’s label.

“After careful review of the clinical data, we are recommending that the breast cancer indication for Avastin be removed based on evidence from four independent studies,” Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Subsequent studies failed to confirm the benefit observed in the original trial. None of the studies demonstrated that patients receiving Avastin lived longer and patients receiving Avastin experienced a significant increase in serious side effects. The limited effects of Avastin combined with the significant risks led us to this difficult decision. The results of these studies are disappointing. We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.”

Removing the breast cancer indication from the Avastin label will be a process. This is the first step. The drug itself is not being removed from the market and today’s action will not have any immediate impact on its use in treating breast cancer. Today’s action will not affect the approvals for colon, kidney, brain, and lung cancers.

Oncologists currently treating patients with Avastin for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

The agency has informed Genentech, Avastin’s manufacturer, of its proposal to withdraw marketing approval of the drug for breast cancer. Genentech has not agreed to remove the breast cancer indication voluntarily, so the agency has issued a Notice of Opportunity for a Hearing, which permits Genentech to request a public hearing if it wishes to contest the agency’s determination. The company has 15 days to request a hearing; if it does not do so, the hearing will be waived, and FDA will begin proceedings to remove the breast cancer indication.

Avastin, in combination with chemotherapy (paclitaxel), was approved in February 2008 under the FDA’s accelerated approval program, based on the results of a clinical trial known as “E2100,” which evaluated the drug in patients who had not received chemotherapy for their metastatic HER2-negative breast cancer. Under the accelerated approval program, a drug may be approved based on clinical data that suggest the drug has a meaningful clinical benefit, with more information being needed to confirm this. The program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted.

After the accelerated approval of Avastin for breast cancer, Genentech completed additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on “progression-free survival” without evidence of an improvement in overall survival or a clinical benefit to patients sufficient to outweigh the risks. The small increase in “progression-free survival” reflects a small, temporary effect in slowing tumor growth.

Avastin has also been associated with several other serious and potentially life-threatening side effects including the risk of stroke, wound healing complications, organ damage or failure; and the development of a neurological condition called reversible posterior leukoencephalopathy syndrome (RPLS), characterized by high blood pressure, headaches, confusion, seizures, and vision loss from swelling of the brain.

On the basis of all available data relating to the use of Avastin to treat metastatic breast cancer, the agency has determined that the risks of the drug outweigh the benefits for this use.

FDA is open to working with Genentech on any proposals to conduct additional studies of Avastin in patients with metastatic breast cancer designed to identify a population of patients in which the drug’s benefits exceed the risks.

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Studies Investigate Emerging Trends and Treatment Options for Patients With Sickle Cell Disease

/PRNewswire/ -- Sickle cell disease, a condition characterized by deformed and dysfunctional red blood cells, is one of the most common genetic blood disorders affecting millions of people around the world, including more than 70,000 Americans.(1) Research presented today at the 51st Annual Meeting of the American Society of Hematology highlights intriguing studies on the acute danger that the H1N1 pandemic presents for children with this blood disorder, evaluations of both new and standard treatments for common complications of sickle cell disease, and an expansion of the current understanding of hemoglobin expression in red blood cells that may lead to new treatments.

"Treatment for sickle cell disease consists primarily of life-long supportive care, with the only cure being bone marrow transplantation -- a risky procedure that is not readily available for most patients," said Alexis Thompson, MD, PhD, moderator of the press conference and Hematology Section Head at the Children's Memorial Hospital and Associate Professor of Pediatrics, at Northwestern University Feinberg School of Medicine, Chicago. "Therefore, research in this area is particularly important to help ensure that improved therapies continue to be developed and that patients with sickle cell disease have access to the best possible care."

NOTES:

(1) National Heart, Lung, and Blood Institute. Facts About Sickle Cell Anemia. Available at: http://www.nhlbi.nih.gov/health/public/blood/sickle/sca_fact.pdf.

Control of Hemoglobin Switching by BCL11A [Abstract #5]

As infants develop in the womb, the gamma-globin gene produces a fetal form of hemoglobin, the protein inside red blood cells that carries oxygen. Shortly after birth, a switch to beta-globin gene expression normally occurs, which leads to the production of adult hemoglobin. Both fetal and adult hemoglobin function similarly, though fetal hemoglobin has a greater affinity for binding with oxygen.

Patients with sickle cell disease have a defective form of adult hemoglobin that causes their red blood cells to become deformed and sickle shaped. As a result, the cells are unable to efficiently carry oxygen to the body's tissues and often stick together and jam vessels, causing blood flow obstruction and episodes of severe pain. If a patient with sickle cell could continue production of the fetal hemoglobin and produce less of their defective adult sickle hemoglobin, many of their complications could possibly be reduced or eliminated. A team of researchers from Harvard Medical School in Boston studied the therapeutic possibility of turning the genetic "switch" back on for the production of fetal hemoglobin to replace the defective adult hemoglobin and alleviate these devastating symptoms.

In previous studies, a gene called BCL11A was found to be involved in blocking the expression of fetal hemoglobin in adults. To test these findings in vivo and investigate the role of BCL11A in hemoglobin regulation at different developmental stages, the researchers performed genetic tests in both embryonic and adult mice that were genetically engineered to carry a complete human beta-globin gene cluster capable of producing adult hemoglobin.

In the embryonic mice, inactivation of the BCL11A gene led to a robust expression of gamma-globin (the fetal form of hemoglobin) during late gestation: more than 90 percent of the globin produced was of this type. Tissue-specific deletion of the BCL11A gene in the adult mice (8-10 weeks old) resulted in an increase of more than 1,000-fold in gamma-globin gene expression in the bone marrow erythroblasts (the precursors to red blood cells) of the experimental mice in comparison to control mice. This increase in the gamma-globin expression after inactivation of BCL11A was rapid and persisted during the course of the experiments (up until the mice were 25 weeks old).

"Currently, there are only a limited number of therapies available for patients with sickle cell disease and thalassemia, another disorder involving abnormal hemoglobin," said senior study author Stuart H. Orkin, MD, David G. Nathan Professor of Pediatrics at Dana-Farber Cancer Institute, Children's Hospital Boston, and Harvard Medical School in Boston. "This research opens up a new avenue for treatment, a way to genetically activate healthy fetal hemoglobin in the red blood cells of patients with these lifelong blood disorders."


Hydroxyurea in Children With Sickle Cell Disease: Practice Patterns and Barriers to Utilization

[Abstract #242]

Sickle cell disease is often marked by episodes of severe and incapacitating pain called vaso-occlusive painful events, which can sometimes require hospitalization. Hydroxyurea, an oral drug that is most commonly taken once daily, was approved by the U.S. Food and Drug Administration for use in sickle cell disease patients in 1998. While hydroxyurea remains the standard of care for reducing these painful events in adults, little is known about its practice patterns in children. Researchers from the Medical College of Wisconsin and Children's Research Institute of the Children's Hospital of Wisconsin in Milwaukee investigated the patterns and barriers to hydroxyurea use in children with sickle cell disease.

In this study, researchers surveyed members of the American Society of Pediatric Hematology/Oncology about their practices and patients. Of the 1,128 surveys disseminated, 31 percent (350 surveys) were returned.

To standardize and increase the quality of care for both adults and children with sickle cell disease, the National Heart, Lung, and Blood Institute (NHLBI) provides clinical practice guidelines for the management of this blood disorder. Most of the survey respondents had heard of (87 percent) and read (78 percent) these guidelines, and provider utilization of hydroxyurea correlated with awareness of the NHLBI recommendations.

The survey found that only 8 percent of providers had half or most (50 to 90 percent) of their pediatric patients with sickle cell disease on hydroxyurea. Another 54 percent of providers had 10 to 30 percent of pediatric patients on the therapy, and 10 percent of providers had fewer than 10 percent of pediatric patients on hydroxyurea. Although a majority of providers (90 percent) felt that hydroxyurea was effective or very effective for the prevention of pain, some still did not prescribe the drug to eligible children because of apprehension about future reproductive issues (birth defects and infertility in males), despite insufficient evidence to support this concern. Low patient compliance was cited by 86 percent of providers as another reason they did not prescribe hydroxyurea. Providers reported that children and their families refused hydroxyurea because of a fear of cancer or other possible side effects, concerns that the drug would not work, compliance with required laboratory monitoring, or because they simply did not want to take medication.

The study also found that many providers prescribed hydroxyurea for reasons other than that for which it was intended, despite insufficient evidence of its efficacy for other complications of the disease.

"Our survey suggests a substantial variation in hydroxyurea utilization in children with sickle cell disease with barriers to its use found on the part of both providers and patients," said lead study author Amanda M. Brandow, DO, MS, Assistant Professor of Pediatrics at the Medical College of Wisconsin and the Children's Research Institute of the Children's Hospital of Wisconsin in Milwaukee. "To alleviate this problem, future research in the following areas may help: continued funding of studies to determine the efficacy of hydroxyurea for complications other than pain, evaluating unconfirmed toxicities of the drug that influence practice, exploring how access to care contributes to noncompliance, and research on methods to promote patient adherence to recommended medical care."

Dr. Brandow will present this study during an oral session on Monday, December 7, at 7:15 a.m. in Room 388-390.

Increased Severity of Pandemic H1N1 Influenza in Children and Young Adults With Sickle Cell Disease [Abstract #264]

Patients with sickle cell disease are more susceptible to infection than the general population. In particular, influenza, a viral disease that affects the respiratory system, is more than 50 times more frequent in children with sickle cell disease than in the general population, according to research conducted by John J. Strouse, MD, PhD, the lead author on this study, and colleagues. As H1N1 influenza, which began circulating in the United States in April 2009, has been reported to cause more severe illness in children and young adults than seasonal flu, researchers from The Johns Hopkins University School of Medicine in Baltimore sought to compare the clinical characteristics and complications associated with these infections in sickle cell disease patients under the age of 21 through a prospective analysis of patient discharge and billing records from September 1993 through July 2009.

During the study period, 99 patients who were seen at The Johns Hopkins Hospital in Baltimore were identified as having both sickle cell disease and influenza (89 with seasonal influenza and 10 with H1N1 influenza). Clinical symptoms, such as fever, cough, and runny nose, were similar between the two groups, although those with H1N1 influenza were at an estimated three-fold increased risk for life-threatening complications, such as acute chest syndrome (a severe lung illness), and nine times more likely to require intensive care, such as ventilator support.

"Our findings underscore that receiving a vaccination against H1N1 influenza, in addition to seasonal influenza, is extremely important for the health and safety of children and young adults with sickle cell disease," said lead author John J. Strouse, MD, PhD, Assistant Professor of Pediatrics and Medicine at The Johns Hopkins University School of Medicine in Baltimore.

Dr. Strouse will present this study in an oral session on Monday, December 7, at 8:15 a.m. in Room 220-222.

Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients With Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial [Abstract #571]

As patients with sickle cell disease have a high rate of hemolysis (red blood cell destruction), excessive amounts of hemoglobin are released into the blood stream that react with and destroy nitric oxide, a critical regulator that dilates blood vessels and inhibits clotting. This can lead to pulmonary hypertension, or abnormally high blood pressure in the arteries of lungs that also affects the heart. Approximately 10 to 30 percent of patients with sickle cell disease are suspected to have this life-threatening condition.

While the oral drug sildenafil (known as Revatio®) is approved to treat pulmonary arterial hypertension, it is unknown whether it is a safe and effective treatment for pulmonary hypertension in those with sickle cell disease. Therefore, a 16-week, double-blind clinical trial, known as the Walk-PHaSST study (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) was conducted in 10 medical centers in the United States and United Kingdom to test this application in adults and children over 12 years of age with sickle cell disease.

Before starting treatment, potential study participants were given baseline tests, including a Doppler echocardiogram and a six-minute walk test to measure heart and lung function. Seventy-four patients who had a tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.7 m/s (a sign of suspected high pulmonary blood pressure) and a six-minute walking distance of only 150-500 meters (reflecting decreased exercise capacity) were included in the study. The researchers then randomly assigned the study participants into two groups of 37 patients each. Half of the patients were treated with sildenafil at escalating doses from 20, 40, and 80 mg three times per day, and the other half received a placebo three times per day. In previous studies of patients with primary pulmonary hypertension, the highest dose of sildenafil (80 mg) had the greatest effect on blood circulation; however, to monitor for possible adverse effects associated with escalating doses, the sildenafil doses in this study were increased slowly, with dose increases made every four weeks.

The study was prematurely stopped when a significant number of the patients in the sildenafil treatment arm (46 percent) began experiencing serious side effects (primarily sickle cell pain crises requiring hospitalization), compared with only 22 percent of those in the placebo arm. Headache and blurred vision, which were expected side effects of sildenafil, were also experienced. The patients in the sildenafil group had more headaches (27 percent versus 14 percent) and more blurred vision (11 percent versus 3 percent) than the placebo group.

Prior to stopping the study, 33 patients had completed the 16-week assessment and were found to have no change in TRV value or in the walking distance test. On pain questionnaires, patients on the sildenafil treatment also reported worsening pain during walking and less enjoyment of life when compared to the patients on placebo.

"Although sildenafil is approved by the U.S. Food and Drug Administration and by the European Medicines Agency for patients with pulmonary arterial hypertension, the Walk-PHaSST study was prematurely stopped for safety concerns. However, these preliminary data should not be interpreted as implying that sildenafil may not be efficacious and safe in select sickle cell patients with documented pulmonary hypertension who are at low risk for vaso-occlusive events," said lead study author Mark Gladwin, MD, Chief of the Division of Pulmonary, Allergy, and Critical Care Medicine and Director of the Vascular Medicine Institute at the University of Pittsburgh Medical Center. "Further investigations are critically needed to find a safe and effective treatment for this patient population at high risk for death from this debilitating condition."

Dr. Gladwin will present this study in an oral session on Monday, December 7, at 2:45 p.m. in Room 220-222.

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VELCADE® (Bortezomib) for Injection Based Regimens Result in Lower Costs and Less Patient Burden Than Other Commonly Used Multiple Myeloma Treatment

(BUSINESS WIRE)--Millennium: The Takeda Oncology Company today announced that two studies presented at the 51st American Society of Hematology (ASH) Annual Meeting found that VELCADE based regimens are more cost-effective for payers and reduced out-of-pocket costs for patients than other commonly used multiple myeloma treatments. The study found that VELCADE-melphalan-prednisone (VMP), a commonly used treatment in multiple myeloma, was more cost-effective compared to MP and delivered more cost-savings compared to melphalan-prednisone-thalidomide (MPT), another commonly used treatment regimen, based on a health economic model.

A second study based on claims data found patients with multiple myeloma treated with VELCADE:

* Incurred fewer out-of-pocket costs than patients treated with the oral drugs thalidomide and lenalidomide
* Did not require significantly more healthcare visits than patients prescribed thalidomide and lenalidomide.

“These studies support VELCADE’s overall cost-effectiveness and reduced out-of-pocket costs. As measured by the number of healthcare visits, VELCADE appears to be as convenient as oral multiple myeloma treatments,” said Dixie-Lee Esseltine, M.D., Vice President, Global Medical Affairs, Millennium. “This is valuable information for healthcare providers, patients and payers.”

The Cost-Effectiveness of Bortezomib for the Initial Treatment of Multiple Myeloma in the United States (Abstract #1379)

Based on a direct comparison of patient-level data, researchers projected that VMP would be cost-effective over a patient’s lifetime compared with MP in the United States. A second indirect comparison across different trials projected the combination of VMP would cost payers 17.7 percent less over a patient’s lifetime and generate better quality-adjusted life expectancy than MPT. Quality-adjusted life years are a measure of disease burden that take into account both the length and quality of life.

The incremental cost-effectiveness of VMP versus MP was found to be within the generally accepted cost-effectiveness range of $50,000-$100,000 per quality-adjusted life year. The projected overall survival years were greatest for patients treated with VMP versus those treated with MPT or MP (4.19, 4.14, and 2.86 years, respectively).

“Cancer can be a costly disease for both payers and patients, and this is certainly true in multiple myeloma,” said Professor Lou Garrison, a study co-author and Associate Director in the Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle. “It is therefore important to identify cost-effective therapies. This trial-based modeling study demonstrates that the first-line regimen using VELCADE is cost-effective compared to other commonly used regimens.”

To assess the relative costs and outcomes of different treatment combinations, study methodology generated modeling projections based on a direct comparison from the Phase III VISTA1 trial, which demonstrated superiority in overall survival of VMP versus MP (San Miguel et al, New England Journal of Medicine 2008) for treatment of multiple myeloma, as well as an indirect comparison of this trial with data published from the IFM 99-06 clinical trial for MPT (Facon et al, Lancet 2007). Costs included per-protocol drug and medical costs, treatment-related adverse events, second-line treatment, and resource utilization during treatment-free interval and progressive disease. Unit costs of medications were obtained from published literature.

Multiple Myeloma: Patient Out-Of-Pocket Costs and Health Care Utilization (Abstract #1366)

In the second study, researchers used data from one of the largest U.S. commercial healthcare plans to evaluate the number of healthcare visits and out-of-pocket costs for multiple myeloma patients being treated with various therapies. After adjusting for patient characteristics, line of treatment, and co-morbidities by multivariate analysis, data showed that patients receiving VELCADE did not have a significantly different number of healthcare visits than those receiving lenalidomide or thalidomide, two oral therapies. Additionally, direct out-of-pocket costs were found to be significantly lower for patients treated with VELCADE than patients treated with thalidomide or lenalidomide.

“There is a common perception that oral drugs are more convenient for patients, but these data show that, in terms of healthcare visits, that perception of convenience is false,” said study author Brett W. Pinsky, i3 Innovus researcher. “These data are consistent with the fact that patients with multiple myeloma typically require a great deal of care and resource utilization; therefore, most patients will not see a major difference in the number of healthcare visits regardless of whether their treatment is oral or infusion – but they may face a significantly higher out-of-pocket cost with oral medications.”

The total patient out-of-pocket costs for the year after treatment initiation were significantly less for patients treated with VELCADE ($3,504) than for those treated with either of the oral drugs thalidomide ($4,443, p<0.05) or lenalidomide ($4,766, p<0.05), after adjusting for patient characteristics, line of treatment, and co-morbidities by multivariate analysis. These differences were greatest for Medicare patients, with the adjusted patient costs nearly two and three times greater for thalidomide ($8,824) and lenalidomide ($12,568), respectively, compared with VELCADE ($4,395).

The study is a retrospective cohort study, which used claims data from a large national U.S. commercial health plan representing approximately 14 million members, and included a total of 2,642 treatment episodes for the 1,900 multiple myeloma patients.

Both studies were supported by Millennium Pharmaceuticals, Inc. The Wang study was also supported by Johnson & Johnson Pharmaceutical Research and Development, L.L.C.

About Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy and although the disease is predominantly a cancer of the elderly (the median age of onset is 70 years), recent statistics indicate both increasing incidence and younger age of onset. In the U.S., more than 50,000 individuals have MM and 20,000 new cases are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths annually.

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Senate Introduces Bill to Boost Participation in Clinical Trials for Rare Diseases

/PRNewswire-/ -- Four members of the United States Senate introduced legislation today to allow patients with rare diseases to participate in clinical drug studies without losing their eligibility for public healthcare coverage, echoing a move by the House of Representatives last month.

The "Improving Access to Clinical Trials Act" is co-sponsored by Senators Ron Wyden (D-OR), Chris Dodd (D-CT), James Inhofe (R-OK) and Richard Shelby (R-AL).

Researchers who develop drugs to treat rare diseases such as cystic fibrosis often struggle to recruit participants for clinical trials because of limited patient populations. To compound the problem, current law prevents many people who receive Supplemental Security Income (SSI) from accepting research compensation because it would make them ineligible to continue receiving government medical benefits. This financial penalty prevents significant numbers of people with rare diseases from participating in clinical studies.

"For many suffering from rare diseases, access to clinical trials is their best hope for treatment," said Senator Wyden. "This legislation will make sure the small financial incentives these people receive will not be counted against them if they are on SSI or Medicaid. Patients suffering from rare diseases should not have to choose between their best hope for treatment or losing benefits, nor be denied the access more financially fortunate patients receive."

"For those living with a rare disease, clinical drug studies can offer a ray of hope: access to cutting-edge medical technologies that may help treat or even cure a serious illness," Senator Dodd said. "Currently, individuals who receive public assistance often do not participate in compensated clinical trials for fear of losing their Medicaid or Supplemental Security Income. This legislation will remedy this inequity by ensuring that more Americans, including those who receive public assistance, have access to these potentially life-saving clinical drug studies."

"This bill allows patients with a rare disease to disregard up to $2,000 of compensation received for participation in a clinical trial in their SSI and Medicaid income calculations," said Senator Inhofe. "Though it will have a negligible impact on the federal budget, it will make a dramatic difference in the lives of those who will gain access to potentially life-saving treatments by enrolling in clinical trials as well as all those in the future whose lives will be improved by the medical advances that arise from this research.

"Scientists and researchers across our nation continually produce new therapies that have the potential to save the lives of countless Americans who suffer from life-threatening rare illnesses," said Senator Shelby. "These patients should not be forced to choose between the health benefits they desperately need and the opportunity to participate in a clinical trial that could improve their medical condition. I am confident that this legislation will open a pathway for more patients to receive life-saving treatments."

Fifty years ago, there were no drugs for people with CF and those with the disease rarely lived to attend elementary school. Today, because of the Cystic Fibrosis Foundation's focus on innovative and aggressive research, there are more than 30 potential therapies in development, and the median life expectancy is higher than 37 years.

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