|May 2013, Volume XXIII, No. 3|
By Janet Tice
Regulatory & Legislative Highlights
The FDA has announced that manufacturers of certain drugs approved to treat Type 2 (non-insulin-dependent) diabetes have agreed to add a black box warning - FDA's strongest form of warning - emphasizing that the drugs may cause or worsen heart failure and that patients taking the drugs should be closely monitored.
After a review of postmarketing adverse event reports, FDA determined that an updated label with a boxed warning on the risks of heart failure was needed for the entire thiazolidinedione class of antidiabetic drugs. These drugs are used in conjunction with diet and exercise to improve blood sugar control in adults with Type 2 diabetes and include Avandia and Actos manufactured by GlaxoSmithKline and Takeda, respectively. The warnings also apply to combination drugs that include the active ingredients in Avandia and Actos.
According to Steven Galson, Director of FDA's Center for Drug Evaluation and Research, "This new boxed warning addresses FDA's concerns that despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure."
FDA's review of Avandia and possible increased risk of heart attacks, a separate concern, is ongoing. On 30 July 2007, FDA's Endocrine and Metabolic Advisory Committee and the Drug Safety and Risk Management Advisory Committee recommended that Avandia continue to be marketed, and further recommended that information be added to the labeling for risk of heart attacks. (Source: FDA Website, 14 August 2007)
In March, the FDA asked Novartis to suspend its US marketing and sales of Zelnorm because a safety analysis found a higher chance of heart attack, stroke, and unstable angina (heart/chest pain) in patients treated with Zelnorm compared with a placebo. At that time, the FDA indicated that there might be patients for whom the benefits of Zelnorm outweigh the risks and for whom no other treatment options were available. The agency committed to work with Novartis to allow access to Zelnorm for those patients under a treatment investigational new drug (IND) protocol.
(Patients with a serious or life-threatening disease or condition who are not enrolled in a clinical trial may be treated with a drug not approved by the FDA. Generally such use is allowed when no comparable or satisfactory alternative drug or therapy is available. The guidelines that regulate such use are referred to as a treatment IND.)
As a result of this collaboration, the FDA has agreed to allow limited use of Zelnorm under a treatment IND protocol to treat irritable bowel syndrome in women younger than 55 who meet specific guidelines and whose physicians decide the drug is medically necessary. Zelnorm will remain off the market for general use. (Source: FDA Website, 27 July 2007)
The FDA has approved Pfizer's maraviroc, an antiretroviral drug for use in adult HIV patients sold under the trade name Selzentry. The product label includes a black box warning about liver toxicity and a statement in the Warnings/Precautions section about the possibility of heart attacks. The agency's action follows on the heels of an "approvable letter" issued in June which unexpectedly delayed approval. Maraviroc had received priority review by the FDA on the likelihood that it would be an advance over existing drugs.
Maraviroc blocks a receptor known as CCR5 in order to prevent HIV infection. It is the first drug to inhibit a pathway HIV uses to infect cells rather than treating the virus itself. (In some patients HIV uses another receptor known as CXCR4 to enter cells; maraviroc would not work in those cases.) Pfizer has proposed using maraviroc in patients with advanced HIV infection or AIDS who have failed treatment with other types of drugs, a group estimated at about 40,000 patients in the US. (Source: Jennifer Corbett Dooren and Avery Johnson, The Wall Street Journal, 21 June 2007; and FDA Website, 6 August 2007)
The FDA's Nanotechnology Task Force has released a report that addresses regulatory and scientific issues and recommends FDA consider development of nanotechnology-associated guidance for manufacturers and researchers. FDA and 22 other federal agencies are part of the National Nanotechnology Initiative, a federal research and development program established to coordinate the multi-agency efforts in nanoscale science, engineering, and technology.
The Task Force reports that nanoscale materials potentially could be used in most product types regulated by FDA and that those materials present challenges similar to those posed by products using other emerging technologies. The challenges, however, may be complicated by the fact that properties relevant to product safety and effectiveness may change as size varies within the nanoscale. The report also says that the emerging and uncertain nature of nanotechnology and the potentially rapid development of applications for FDA-regulated products highlight the need for ensuring transparent, consistent, and predictable regulatory pathways.
Anticipating the potential for rapid development in the field, the report recommends consideration of agency guidance that would clarify, for example, what information to give FDA about products, and also when the use of nanoscale materials may change the regulatory status of particular products. As with other FDA guidance, draft guidance documents would be made available for public comment prior to being finalized.
In addition, the report says the FDA should work to assess data needs to better regulate nanotechnology products, including biological effects and interactions of nanoscale materials. The agency also should develop in-house expertise and ensure consideration of relevant new information on nanotechnology as it becomes available, according to the report. FDA should evaluate the adequacy of current testing approaches to assess safety, effectiveness and quality of nanoscale materials.
For more information, please consult the Task Force Report on Nanotechnology which can be found online at:
Report HTML: www.fda.gov/nanotechnology/taskforce/report2007.html
(Source: FDA Website: 25 July 2007)
The FDA recently approved the first molecular-based laboratory test for detecting whether breast cancer has spread to nearby lymph nodes. The presence or absence of breast cancer cells in underarm lymph nodes is a powerful predictor of whether the cancer has spread and is used to help decide appropriate therapy. The GeneSearch Breast Lymph Node (BLN) Assay, manufactured by Veridex, a Johnson & Johnson Company, detects molecules that are abundant in breast tissue but scarce in a normal lymph node.
Lymph nodes are part of the system that helps protect the body against infection. The first lymph node that filters fluid from the breast is called the "sentinel node," because that is where breast cancer cells are likely to spread first. During a lumpectomy or mastectomy to remove a breast tumor, surgeons commonly remove the sentinel node for examination under a microscope. Sometimes the sentinel node is examined immediately and if tumor cells are found, additional lymph nodes are removed. A more extensive microscopic examination, requiring one to two days for results, is almost always performed. If tumor cells are only found with the later microscopic examination, the patient may require a second surgery to remove the remaining lymph nodes.
"The GeneSearch BLN Assay offers a new approach to sentinel node testing," said Daniel Schultz, M.D., director of the FDA's Center for Devices and Radiological Health. "Results of this rapid test are available while patients are on the operating table, providing a way for some women to avoid a second operation."
Most of the women were also studied to compare the BLN Assay with immediate microscopic examination during surgery. The test gave fewer false negative results, but slightly more false positive results. A false negative test result, when the cancer has actually spread, may delay the needed removal of additional lymph nodes. A false positive test, indicating metastasis when there is none, may result in a more extensive surgery and puts the women at risk of unnecessary lymphedema (swelling due to fluid build-up following lymph node removal) and other side effects. (Source: FDA Website, 16 July 2007)
The FDA has cleared for marketing the Binax NOW Malaria Test, the first authorized US rapid test for malaria. The test is manufactured by Binax Inc., a subsidiary of Inverness Medical Innovations Inc. of Scarborough, Maine and is intended for laboratory use.
Standard laboratory tests for malaria require identifying parasites in a blood sample under a microscope, a difficult task that requires training and experience. The Binax NOW test is significantly faster and easier to use. Results are available in 15 minutes after a few drops of whole blood are placed on a dipstick. The test can also differentiate the most dangerous malaria parasite, Plasmodium falciparum, from less virulent malaria parasites. Results still need to be confirmed using standard microscopic evaluation.
People infected with malarial parasites often experience a high fever, chills, and flu-like illness. Left untreated, they may develop severe complications and die. Although malaria was eliminated from the US in the 1950s, it can still affect US residents who travel or who work in other countries. According to the Centers for Disease Control and Prevention, there were 1,528 newly-reported cases of malaria in the US in 2005, including seven deaths. Nearly all deaths can be prevented if the infection is diagnosed and treated early.
"Since malaria is uncommon in the United States, clinicians and lab personnel may not be accustomed to diagnosing this disease," said Daniel Schultz, M.D., director of the FDA's Center for Devices and Radiological Health. "When used in combination with other laboratory tests, the Binax NOW test provides an additional tool to help them diagnose this disease faster in the United States." (Source: FDA Website, 26 June 2007)
The FDA's rejection of Wyeth's schizophrenia drug bifeprunox in August was the latest in a string of disappointments for the company, including the approvable letter issued by the agency in July for the company's menopause drug Pristiq. Also in July, Wyeth and partner ViroPharm Inc. said safety concerns had caused them to stop giving a drug for hepatitis C to patients in a mid-stage study. And in April, Wyeth received an approvable letter for osteoporosis drug Viviant.
Wyeth expects a new ruling on Viviant by the end of the year. And the company is still confident it will win approval for bifeprunox, although it could take one to two years to address the FDA's concerns and resubmit its application to the agency. In the case of the hepatitis C drug, Wyeth said the companies will work with the FDA to "determine the appropriate path forward."
Regarding Pristiq, Wyeth's pill for treatment of menopausal symptoms, the agency called for a year-long study to allay safety concerns related to the drug's effects on the heart and liver. Pristiq, which is also under review at the FDA as a treatment for major depression, has been viewed as the strongest sales prospect among Wyeth's new drugs under FDA review. Wyeth has defended Pristiq's safety and said it does not expect the FDA's concerns about the drug's use as a treatment for menopause symptoms to delay its approval for depression, on schedule for early 2008.
In spite of the recent setbacks, Wyeth has had its successes this year, winning approval for Torisel, a kidney cancer drug, and Lybrel, a birth control pill, and says the recent FDA actions reflect "the current regulatory environment and the complexity of developing newer medications that treat more challenging disease states." (Source: Sarah Rubenstein, The Wall Street Journal, 13 August 2007)
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