|May 2013, Volume XXIII, No. 3|
Regulatory & Legislative Highlights
by Deepen Joshi, Sepracor
The FDA can grant a special status, known as orphan designation, for drug products intended to treat rare diseases. Orphan drugs are drugs or biologics used to treat conditions affecting fewer than 200,000 people in the United States. Orphan drugs may be already-approved or experimental drugs. As part of its continuing effort to make the agency more transparent and accessible, the FDA has scheduled a series of workshops about orphan drug designation for academics, biotech companies and those unfamiliar with the process.
To obtain orphan drug designation, drugs must be for the treatment, prevention or diagnosis of a rare disease or condition. Designation also requires there be a medical rationale for expecting the proposed drug to be effective in the treatment, prevention, or diagnosis of that disease or condition. During the past 25 years, the FDA has granted orphan drug designation to about 2,100 drugs, of which 344 have become approved products.
For more information:
Do a Designation: FDA Orphan Drug Workshops
Designating an Orphan Product: Drugs and Biologics
(Source: FDA Website, 23 December, 2009)
A new research program called the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) will fund research to study the effects of prescription medications used during pregnancy. The program is a collaboration among the FDA and researchers at the HMO Research Network Center for Education and Research in Therapeutics (CERT), Kaiser Permanente's multiple research centers and Vanderbilt University.
About two-thirds of women who deliver a baby have taken at least one prescription medication during pregnancy according to a journal article published in the American Journal of Obstetrics and Gynecology. There are very few clinical trials that test the safety of medications in pregnancy due to concerns about the health of the mother and child.
To overcome the challenges presented by the lack of clinical trial data about the use of medications during pregnancy, the research program will link health care information for mothers and their babies in each of the participating research sites. Collectively, the 11 participating sites have health care information for about 1 million births over the past seven years (2001-2007). Many of the mothers associated with these births likely used medication during their pregnancies and now, with the program in place, the FDA and participating researchers have a systematic and timely way of retrieving information from this network. (Source: FDA Website, 30 December, 2009)
The FDA has awarded a contract to Wellesley-based Harvard Pilgrim Health Care to develop a pilot of the FDA's Sentinel System, which will use automated health care data to evaluate medical product safety.
Reports filed by hospitals, health care professionals, and industry account for much of information that the FDA relies on regarding medical product safety. For a variety of reasons, these reports may be incomplete or not filed in a timely manner. The Sentinel System, once operational, will bolster the FDA's efforts in monitoring product safety. Sentinel will provide FDA with the ability to analyze information collected during the course of routine health care, such as data from electronic health record systems, administrative and insurance claims databases and medical registries.
The one-year contract includes four renewable years for a total of $72 million. Under the terms of the contract, Harvard Pilgrim will establish a coordinating center that will operate as a scaled down version of the Sentinel System. This center, or "mini-Sentinel," will identify appropriate databases, develop a scientific framework for obtaining real-time data, and ensure data quality. To protect personal information, only summary results will be sent to the coordinating center. The data itself will remain within its database.
For more information, visit the FDA's Web Page on the Sentinel Initiative
(Source: FDA Website, 8 January, 2010)
The FDA has approved Actemra (tocilizumab) to treat adults with moderate to severe rheumatoid arthritis who have not adequately responded to or cannot tolerate other approved drug classes for rheumatoid arthritis. Recommended use is limited to patients who have failed other approved therapies because of serious safety concerns that were noted in clinical studies. These safety concerns include elevated liver enzymes, elevated low-density lipoprotein (LDL) or bad cholesterol, hypertension and gastrointestinal perforations.
The FDA is requiring the sponsor to conduct a post-marketing clinical trial to further evaluate the long-term safety of Actemra. Specifically, the FDA wants to evaluate the impact of elevated LDL cholesterol and blood pressure seen in some patients in shorter-term trials on the cardiovascular health of patients treated with Actemra. In addition, a Risk Evaluation and Mitigation Strategy (REMS) will require the drug sponsor to implement a Communication Plan for physicians informing them how to appropriately monitor their patients for liver and/or gastrointestinal side effects. The REMS will include a Medication Guide to ensure that patients are informed of the benefits and risks of Actemra.
Patients treated with Actemra are at increased risk for developing serious infections. Most patients who developed these infections in clinical trials were also taking other drugs that suppress the immune system such as methotrexate or corticosteroids. (Source: FDA Website, 11 January, 2010)
The FDA has unveiled the first phase of its Transparency Initiative designed to explain agency operations, how it makes decisions, and the drug approval process. During an online presentation, the chair of the FDA's Transparency Task Force, Principal Deputy FDA Commissioner Joshua Sharfstein, described a Web-based curriculum called "FDA Basics," aimed at helping the public better understand what the agency does. The curriculum is accessible via a link on the FDA Web site. In addition, senior officials from FDA product centers and offices will answer questions on various topics during future online sessions. Each of these sessions will be announced on the FDA Web site.
The Transparency Initiative was launched in response to the Obama Administration's commitment to openness in Government and with the strong support of the Department of Health and Human Services. In recent months, the Task Force solicited public input on improving agency transparency through a public docket, an online blog, and two public meetings. The Transparency Task Force received hundreds of comments from various stakeholders, including regulated industry, consumers, patients, health care providers, and others. As a result of comments from the public, the Task Force decided to develop its recommendations in three phases. FDA Basics represents the result of the initial phase, to be followed by two additional phases. (Source: FDA Website, 12 January, 2010)
The U.S. FDA approved Ampyra (dalfampridine) extended release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with Ampyra had faster walking speeds than those treated with an inactive pill (placebo). This is the first drug approved for this use. Ampyra will be manufactured under licenses from Elan of Dublin, Ireland, and distributed by Acorda Therapeutics Inc. of Hawthorne, N.Y.
MS is a chronic, often disabling, disease that affects the central nervous system - the brain, spinal cord, and optic nerves. There are about 400,000 people in the United States and 2.5 million people world-wide with MS. The progress, severity, and specific symptoms of MS are unpredictable and vary from one person to another. Symptoms can be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. About half of all people with MS experience cognitive impairments like difficulties in concentration, attention, memory, and judgment, although these symptoms are usually mild and are frequently overlooked. Depression also is common among MS patients. (Source: FDA Website, 22 January, 2010)
A FDA panel rejected earlier use of the cancer drug Tarceva in patients with advanced lung cancer. Tarceva, co-marketed by OSI Pharmaceuticals and Genentech, is currently approved to treat non-small cell lung cancer after chemotherapy has failed to stop the cancer's spread. The drug is considered a second-line therapy. The companies want FDA approval to use Tarceva immediately after chemotherapy, as a maintenance treatment in patients whose disease is stable after chemotherapy. However, the panel of outside medical experts voted 1 to 12 against approving Tarceva for the proposed indication as a first-line maintenance treatment. The FDA usually follows its panel's advice but isn't required to.
Tarceva is an oral drug that blocks an enzyme involved with cancer growth. The companies conducted a study involving 889 patients with advanced lung cancer who had completed four cycles of chemotherapy without their disease progressing or getting worse. Half of the patients were given Tarceva while the other half were given a placebo or fake treatment. The study showed patients receiving Tarceva had a median progression-free survival of 12.3 weeks, or the time before the disease started getting worse, compared with 11.1 weeks for those on placebo. The panel said the benefit of using Tarceva earlier in treatment was modest and that it wasn't clear whether using the drug earlier was better than using the product after lung cancer had started getting worse.
The FDA said Tarceva, and another drug, Docetaxel, have a median survival of 2-3 months longer compared with placebo when given to patients after chemotherapy has failed. Docetaxel is sold as Taxotere by Sanofi Aventis. "This raises the question whether treatment with single agent erlotinib (Tarceva) or Docetaxel after progression are better options than treatment with erlotinib as maintenance," the FDA said. OSI said Tarceva provides "an important new therapeutic option" when given immediately after chemotherapy. (Source: Jennifer Corbett-Dooren, Wall Street Journal, 17 December 2009)
The FDA has approved the Medtronic Melody Transcatheter Pulmonary Valve and Ensemble Delivery System, the first heart valve to be implanted through a catheter, or tube, in a leg vein and guided up to the heart. This new approach to the treatment of adults and children with previously implanted, poorly functioning pulmonary valve conduits can delay the need for open-heart surgery.
Conduits are surgically implanted valves used to treat congenital heart defects of the pulmonary valve. Patients with congenital heart defects have narrowed, leaky, or missing pulmonary valves that impede the proper flow of blood from the heart's right ventricle to the pulmonary artery, which then sends the blood on to the lungs for oxygenation. Conduits can have a limited lifespan and often require replacement. The Melody is intended to provide another option to conduit replacement.
Like other valves, the Melody does not cure the heart condition and over time, the Melody may wear and require replacement. However, it is implanted without open heart surgery, can prop open the poorly functioning conduit, and can keep blood flowing in the proper direction because of the tissue valve in the Melody. These characteristics will allow a patient's conduit to function longer than usual, which can delay the need for more invasive open-heart surgery. (Source: FDA Website, 25 January, 2010)
The FDA has approved Victoza (liraglutide), a once-daily injection to treat type 2 diabetes in some adults. Victoza is intended to help lower blood sugar levels along with diet, exercise, and selected other diabetes medicines. It is not recommended as initial therapy in patients who have not achieved adequate diabetes control on diet and exercise alone.
Insulin is a hormone that helps prevent sugar (glucose) from building up in the blood. People with type 2 diabetes have difficulty making and using insulin. Victoza is in a class of medicines known as glucagon-like peptide-1 (GLP-1) receptor agonists that help the pancreas make more insulin after eating a meal.
Victoza was not associated with an increased risk for cardiovascular events in people who were mainly at low risk for these events. FDA approved Victoza, however, with several post-marketing requirements under the FDA Amendments Act (FDAAA) to ensure that the company will conduct studies to provide additional information on the safety of this product.
To ensure the safe and effective use of this product, Victoza was approved with a Risk Evaluation and Mitigation Strategy consisting of a Medication Guide and a Communication Plan to help patients and providers understand the risks of Victoza and to ensure that the benefits of the drug outweigh the risk of acute pancreatitis and the potential risk of medullary thyroid cancer. Victoza is manufactured by Novo Nordisk of Bagsvaerd, Denmark. (Source: FDA Website, 25 January, 2010)
The FDA has approved Morphine Sulfate Oral Solution for the relief of moderate to severe, acute and chronic pain in opioid-tolerant patients. This medicine will be available in 100 milligrams per 5 mL or 20 milligrams per 1 mL. This is the only FDA approved morphine sulfate oral solution available at this concentration. Although the use of this medicine to manage pain has been common practice for many years, this form and concentration of morphine was not FDA approved until now.
This action is part of the FDA's unapproved drugs initiative. As part of this program, the FDA has worked with Roxane Laboratories, the manufacturer of the product, to ensure that there is enough drug available for patients. The FDA will also be working with patient organizations and prescribers so that they are aware that an approved product is available, and can notify the FDA if there are any problems with availability.
The FDA has approved Tykerb (lapatinib) in combination with Femara (letrozole) to treat hormone positive and HER2-positive advanced breast cancer in postmenopausal women for whom hormonal therapy is indicated. HER2 is a protein involved in normal cell growth. It is found on some types of cancer cells, including breast cancer cells.
In hormone positive breast cancer, the presence of certain hormones contributes to breast cancer growth. In HER2-positive breast cancer, stimulation of the HER2 receptor contributes to cancer cell growth. Breast cancer is the second leading cause of death among women. More than 192,000 women will be diagnosed with breast cancer this year.
Tykerb works by depriving tumor cells of signals needed to grow. Tykerb enters the cell and blocks the function of the HER2 protein. Tykerb was initially approved in combination with a chemotherapy drug, Xeloda (capecitabine) in 2007. This combination was used to treat women with advanced breast cancer tumors with the HER2 protein who had received prior treatment with chemotherapy drugs, including an anthracycline and a taxane, and Herceptin (trastuzumab), an anti-cancer antibody used to treat HER2-positive advanced breast cancer. Tykerb is marketed by GlaxoSmithKline; Femara is marketed by Novartis AG. (Source: FDA Website, 29 January, 2010)FDA Collaboration Seeks to Speed Development of Pneumococcal Vaccines for Children in Developing Countries
The FDA has announced a collaboration with PATH to advance development of a vaccine to protect children against diseases caused by Streptococcus pneumoniae (pneumococcus), especially pneumonia. Worldwide, the bacterium also causes infections of the brain (meningitis), blood (sepsis), and middle ear (otitis media) and each year kills about 1 million children younger than 5 years of age. The collaboration aims to improve the techniques used to produce effective, safe, and affordable vaccines against pneumococcal disease for children in the developing world.
PATH is an international nonprofit organization based in Seattle that creates sustainable, culturally relevant, and affordable solutions to help communities worldwide to break cycles of poor health. The collaborative project, expected to run for two years, is being conducted under the Cooperative Research and Development Agreement (CRADA) program. The program allows federal laboratories and businesses to form partnerships that help expedite research activities.
The goal of the CRADA is to evaluate the application of Center for Biologics Evaluation and Research (CBER) conjugation technology to pneumococcal vaccines. If it holds promise for fulfilling the goal of providing safe, effective, and affordable pneumococcal vaccines, the CRADA permits transfer of the technology to the China National Biotec Group's Chengdu Institute of Biological Products, and eventually to groups in other developing countries as appropriate. (Source: FDA Website, 1 February, 2010)FDA Announces Safety Risk Associated with Bristol-Myers Squibb HIV Drug
The FDA has announced that non-cirrhotic portal hypertension, a rare, but serious, liver disorder, has been reported in some HIV patients taking Videx/Videx EC (didanosine).
Videx is an antiretroviral medicine first approved by the FDA in 1991. Videx EC is a delayed-release version of Videx approved in 2000. Videx/Videx EC is used in combination with other antiretroviral medicines to treat HIV infection in children and adults.
During an 18-year period, 42 cases of non-cirrhotic portal hypertension were reported to the FDA's Adverse Event Reporting System for patients taking Videx/Videx EC. Four patients died from bleeding or liver failure after developing the condition. Non-cirrhotic portal hypertension occurs when blood flow in the portal vein - a major vein in the liver - slows down and leads to severely enlarged veins in the esophagus. These enlarged veins, called esophageal varices, are thin and can break open, resulting in serious, and potentially fatal, bleeding. The Videx and Videx EC product labels have been revised to help ensure that health care professionals and patients are aware of the risk and the signs and symptoms of non-cirrhotic portal hypertension.
The FDA evaluation concluded that the clinical benefits of Videx/Videx EC in certain patients with HIV continue to outweigh potential safety risks. Videx/Videx EC does not cure HIV infection, may not prevent development of HIV-related illnesses, and may not prevent the spread of HIV to other people. (Source: FDA Website, 1 February, 2010)
The FDA has approved Xiaflex (collagenase clostridium histolyticum) as the first drug to treat a progressive hand disease known as Dupuytren's contracture, which can affect a person's ability to straighten and properly use their fingers. Dupuytren's contracture affects the connective tissue found beneath the skin in the palm of the hand. Too much collagen can build up, forming thick, rope-like cords of tissue that can prevent the fingers from being able to relax and straighten normally. The disorder is most common in Caucasians and in men over age 50.
Xiaflex is a biologic drug that works by breaking down the excessive buildup of collagen in the hand. Xiaflex is injected directly into the collagen cord of the hand and should be administered only by a health care professional experienced with injections of the hand, because tendon ruptures may occur.
The most common adverse reactions in patients treated with Xiaflex were fluid build up, swelling, bleeding, and pain in the injected area. Although no serious allergic reactions have been observed, such a response would not be unexpected because this foreign protein could prompt an immune system reaction. Xiaflex is manufactured by Auxilium Pharmaceuticals based in Malvern, PA. (Source: FDA Website, 2 February, 2010)FDA Issues Guidance to Help Streamline Medical Device Clinical Trials
The FDA has issued guidance on Bayesian statistical methods in the design and analysis of medical device clinical trials that could result in less costly and more efficient patient studies. The Bayesian statistical method applies an algorithm that makes it possible for companies to combine data collected in previous studies with data collected in a current trial. The combined data may provide sufficient justification for smaller or shorter clinical studies.
The FDA has substantial experience in the use of Bayesian statistical methods for the design and analysis of scientifically valid clinical studies. The FDA has approved a number of medical devices whose approval applications submitted to the FDA included clinical studies that used these statistical methods.
The final guidance, titled "Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials," describes use of Bayesian methods, design and analysis of medical device clinical trials, the benefits and difficulties with the Bayesian approach, and comparisons with standard statistical methods. The guidance also presents ideas for using Bayesian methods in post-market studies. (Source: FDA Website, 5 February, 2010)
The FDA has approved the cholesterol-lowering medication Crestor (rosuvastatin) for some patients who are at increased risk of heart disease but have not been diagnosed with it. The new indication is for reducing the likelihood of a heart attack or stroke or the need for a procedure to treat blocked or narrowed arteries in patients who have never been told they have heart disease but are nevertheless at increased risk of a cardiac event. Specifically, this includes men 50 years of age and older and women 60 years of age and older who have an elevated amount of a substance known as high sensitivity C-reactive protein in their blood and at least one additional traditional cardiovascular risk factor such as smoking, high blood pressure, a family history of premature heart disease, or low amounts of high-density lipoprotein or HDL cholesterol, the so-called "good cholesterol."
Crestor is in a class of drugs called statins, which work by stopping an enzyme called HMG-CoA reductase from making cholesterol. High amounts of low-density lipoprotein or LDL cholesterol, the so-called "bad cholesterol," is a known risk factor for heart attacks, strokes, and heart disease. Crestor is already approved for use in combination with diet and exercise to lower LDL cholesterol and a related substance known as triglycerides in patients with a high amount of these substances in their blood. (Source: FDA Website, 9 February, 2010)
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