|May 2013, Volume XXIII, No. 3|
Regulatory & Legislative Highlights
The FDA has approved Krystexxa (pegloticase), manufactured by Savient Pharmaceuticals of East Brunswick, NJ, for treatment of gout in adults who do not respond to or who cannot tolerate conventional therapy. Gout occurs due to an excess of the bodily waste uric acid, which is eventually deposited as needle-like crystals in the joints or in soft tissue. These crystals can cause intermittent swelling, redness, heat, pain and stiffness in the joints. Gout is strongly associated with obesity, high blood pressure, high cholesterol and diabetes, and occurs more often in men, in women after menopause, and in people with kidney disease.
"About 3 percent of the three million adults who suffer from gout are not helped by conventional therapy. This new drug offers an important new option for them," said Badrul Chowdhury, M.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA's Center for Drug Evaluation and Research.
For patients with gout, the conventional therapy is to receive drugs that lower the amount of uric acid in the blood, as, for example, the xanthine oxidase inhibitors Zyloprim (allopurinol) and Uloric (febuxostat). Krystexxa is an enzyme that lowers uric acid levels by metabolizing it into a harmless chemical that is excreted in the urine. The drug is administered to patients every two weeks as an intravenous infusion.
Since one out of every four patients in the clinical trials experienced a severe allergic reaction when receiving an infusion of Krystexxa, health care providers should dispense a corticosteroid and an antihistamine to their patients beforehand to minimize the risk of such a reaction. Other reactions during the clinical trials included gout flare, nausea, injection site bruising, irritation of the nasal passages, constipation, chest pain and vomiting. Physicians are also being warned to be cautious about administering Krystexxa to patients with congestive heart failure because the drug was not studied in this patient population.
Krystexxa is being approved with a Risk Evaluation and Mitigation Strategy that includes a medication guide for patients and materials for healthcare providers to communicate the risk of severe infusion and allergic reactions. (Source: FDA Website, 14 September, 2010)
The FDA, working in close coordination with the US Department of Justice (USDOJ), has announced that Forest Pharmaceuticals entered into a plea agreement in which the company accepted responsibility for criminal actions including distribution of an unapproved new drug, distribution of a misbranded drug, and obstruction of an FDA inspection.
To resolve these charges and a related civil suit, the company has agreed to pay more than $300 million, including $164 million in criminal penalties. This plea agreement is the culmination of a multiyear investigation conducted by FDA's Office of Criminal Investigations in cooperation with its law enforcement partners and the US Attorney's Office for the District of Massachusetts.
Charges against Forest Pharmaceuticals are primarily for its marketing of Levothroid (levothyroxine sodium tablets, USP), an unapproved drug used for the treatment of hypothyroidism. A 1997 Federal Register notice announced that these products are considered "new drugs" within the meaning of the Federal Food Drug and Cosmetic Act (FDCA) and that manufacturers who wished to continue marketing these products must obtain approved applications from the FDA by August 2000. Because levothyroxine was considered a medically necessary product, the FDA permitted a gradual phase-out with all distribution of unapproved levothyroxine sodium drug products to cease no later than August 2003.
Forest Pharmaceuticals did not obtain drug approval, increased its distribution of Levothroid rather than scaling down, and ignored a subsequent Warning Letter to stop the manufacture and distribution of Levothroid. "These charges should serve as a warning to industry that the FDA takes seriously its role to protect the public from unapproved drugs," said Deborah M. Autor, director of the Office of Compliance in FDA's Center for Drug Evaluation and Research. "Any company that operates in violation of the FDCA and ignores FDA's warnings should be aware that a criminal action could follow."
Forest Pharmaceuticals, Inc. also is charged with distribution of a misbranded drug for its off-label promotion of Celexa for pediatric use when it was approved only for use in adults. Celexa is the brand name for the prescription drug citalopram, a selective serotonin reuptake inhibitor (SSRI) drug for the treatment of adult depression.
Consumers should be aware that the Levothroid product currently marketed by Forest Pharmaceuticals, Inc. is not the subject of today's actions. Forest Pharmaceutical's guilty plea and criminal penalties relate to the marketing of the previously unapproved Levothroid product. The current Levothroid product now has an approved New Drug Application and is compliant with FDA regulations. (Source: FDA Website, 15 September, 2010)
The FDA has approved Gilenya capsules (fingolimod) to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis (MS). Gilenya is made by Novartis, Basel, Switzerland.
"Gilenya is the first oral drug that can slow the progression of disability and reduce the frequency and severity of symptoms in MS, offering patients an alternative to currently available injectable therapies," said Russell Katz, M.D., director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. Gilenya is the first in a new class of drugs that block some blood cells in lymph nodes, reducing their migration to the brain and spinal cord, which may help with reducing the severity of MS.
MS is a chronic, often disabling, disease that affects the central nervous system - the brain, spinal cord, and optic nerves. According to the National Multiple Sclerosis Society, there are about 400,000 people in the United States and 2.1 million people worldwide 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.
Patients using Gilenya should be monitored for a decrease in heart rate upon starting the drug. Gilenya may also increase the risk of infections. Cases of serious eye problems (macular edema) have occurred in patients taking the drug and an ophthalmologic evaluation is recommended. The most frequent adverse reactions reported by patients taking Gilenya in clinical trials include headache, influenza, diarrhea, back pain, elevation of certain liver enzymes and cough. (Source: FDA Website, 22 September, 2010)
The FDA has announced that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia.
Avandia, manufactured by GlaxoSmithKline (GSK), is in a class of drugs known as thiazolidinediones, or TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose (blood sugar) control in patients with Type 2 diabetes mellitus.
The FDA will require that GSK develop a restricted access program for Avandia under a risk evaluation and mitigation strategy, or REMS. Under the REMS, Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so.
Doctors will have to attest to and document their patients' eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the REMS will limit use of Avandia significantly.
"Allowing Avandia to remain on the market, but under restrictions, is an appropriate response, given the significant safety concerns and the scientific uncertainty still remaining about this drug," said Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research.
Also today, the FDA ordered GSK to convene an independent group of scientists to review key aspects of the company's clinical trial known as RECORD, which studied the cardiovascular safety of Avandia compared to standard diabetes drugs. During the course of the FDA's review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events. The FDA is requiring this independent review to provide additional clarity about the findings.
In addition, the agency halted the GSK's clinical trial known as TIDE and rescinded all of the regulatory deadlines for completion of the trial. The TIDE trial compares Avandia to Actos and to standard diabetes drugs. The FDA may take additional actions after the independent re-analysis of RECORD is completed. (Source: FDA Website, 23 September, 2010)
The FDA today issued a final rule that clarifies what safety information must be reported during clinical trials of investigational drugs and biologics. According to Rachel Behrman, M.D, associate director for medical policy in the FDA's Center for Drug Evaluation and Research, this final rule will expedite FDA's review of critical safety information and help the agency monitor the safety of investigational drugs and biologics.
The new rule requires that certain safety information that previously had not been required to be reported to FDA be reported within 15 days of becoming aware of an occurrence. These reports include:
The rule also provides examples of evidence that would suggest that an investigational product may be the cause of a safety problem. Under current regulations, drug sponsors often report all serious adverse events, even if there is little reason to believe the product caused the event. Such reporting complicates and delays the FDA's ability to detect a safety signal. The examples address when a single event should be reported or when there is need to wait for more than one occurrence.
In addition, the rule revises definitions and reporting standards so that they are more consistent with two international organizations, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and the World Health Organization's Council for International Organizations of Medical Sciences. The changes are designed to help ensure harmonized reporting of globally conducted clinical trials.
Along with this final rule, the FDA also issued a draft guidance for industry and investigators that provides information and advice about the new requirements and other information. (Source: FDA Website, 28 September, 2010)
The National Institutes of Health will award $9.4M over three years to support four research projects in regulatory science. This research is conducted in partnership with the FDA, which will contribute approximately $950K. These projects will better inform scientists and regulatory reviewers alike about medical product safety, and improve the evaluation and availability of new medical products to the community. The projects include research on nanoparticles and their characterization, a heart-lung model to test the safety and efficacy of drugs, innovative clinical trial design, and a novel strategy to predict eye irritation.
The awards follow a February 2010 announcement by the NIH and the FDA to work together in an unprecedented manner on important public health issues. As part of that effort, the agencies established an NIH-FDA Joint Leadership Council to spearhead collaborative activities. In addition, the NIH and the FDA issued a request for applications to stimulate a new research initiative in a priority area, Advancing Regulatory Science through Novel Research and Science-Based Technologies.
Regulatory science involves the development and use of the scientific knowledge, tools, standards, and approaches necessary for the assessment of medical product safety, efficacy, quality, potency, and performance. For more information on the Regulatory Science Program http://commonfund.nih.gov/regulatoryscience/
"These projects show the potential breadth of opportunity that comes from advancing regulatory science. The results are likely to have broad application to researchers across scientific disciplines and will result in better-informed regulatory decision-making and faster drug development and approval processes," said Commissioner of Food and Drugs Margaret A. Hamburg, M.D. (Source: FDA Website, 27 September, 2010)
The FDA has taken action against companies that manufacture, distribute, and/or market unapproved single-ingredient oral colchicine, a medication commonly used for the daily prevention of gout, to treat acute gout flare-ups, and for the treatment of Familial Mediterranean Fever (FMF). The companies are expected to stop manufacturing single-ingredient oral colchicine within 45 days and must stop shipping this unapproved product in interstate commerce within 90 days. A small amount of unapproved colchicine is expected to be available after these dates until supplies are exhausted.
Colcrys is the only FDA-approved single-ingredient oral colchicine product available on the U.S. market. Approved by the FDA in 2009, Colcrys' prescribing information contains important safety data and recommendations on drug interactions and dosing not available with unapproved products.
The manufacturer of Colcrys, Mutual Pharmaceutical/URL Pharma, has established a Patient Assistance Program (PAP) and a Co-Pay Assistance Program (CAP) to ensure that all patients will be able to continue affordable access to colchicine. The company also has informed FDA that it will maintain the programs at a minimum until there is FDA-approved generic competition for Colcrys.
Today's action is part of the FDA's broader initiative against marketed unapproved drugs, announced in a June 2006 Compliance Policy Guide describing the agency's risk-based enforcement approach for marketed unapproved drug products. "The need for drugs to go through the FDA approval process is clearly demonstrated by our review of oral colchicine tablets," said Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research (CDER). "Without our safety review and proper drug labeling, the old standard of care would likely have continued, to the detriment of patients."
Unapproved versions of colchicine are not generic drugs. Generic drugs are approved by the FDA to assure that the approved generic drug products meet the same standards as the innovator drug. All single-ingredient oral colchicine products, other than Colcrys, that are currently being marketed are unapproved drugs and have never been evaluated by the agency.
"It is a priority for the FDA to get unapproved medications, such as older versions of single ingredient oral colchicine, either updated to conform to FDA's current approval standards or off the market," said Deborah M. Autor, director of CDER's Office of Compliance. "The FDA remains committed to ensuring that prescription drugs have the necessary FDA approval. We encourage companies to actively pursue approval or face the type of action announced today."
The FDA previously took action against unapproved colchicine for injection products on Feb. 6, 2008. This ongoing initiative is designed to bring all unapproved medications, including single-ingredient oral colchicine, up to modern-day safety, efficacy, labeling, and quality standards by ensuring that they comply with FDA approval requirements. The FDA is committed to working with companies to ensure that marketed drugs are safe and effective, and meet appropriate standards for manufacturing and labeling. (Source: FDA Website, 30 September, 2010)
The FDA held a two-day public hearing on Nov. 2-3, 2010, on the implementation of the Biologics Price Competition and Innovation (BPCI) Act of 2009. The BPCI Act establishes an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to, or interchangeable with, an FDA-licensed biological product.
The purpose of the hearing was to receive input on the act's implementation from the public, health care professionals, health care institutions, manufacturers of biomedical products, industry and professional associations, patients and patient associations, third party payers, and current and prospective biological license application and new drug application holders.
The BPCI Act is consistent with the FDA's policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. However, the implementation of an abbreviated approval pathway for biological products can pose scientific and technical challenges associated with the larger molecular structure and manufacturing of biological products. Most are produced in a living system such as a microorganism, plant, or animal cells, while small molecule drugs typically are manufactured through chemical synthesis. (Source: FDA Website, 4 October, 2010)
The FDA has announced the award of $2.9 million to support six research projects that will help with the diagnosis, treatment, and prevention of tuberculosis (TB). TB remains a major public health challenge with an increasing prevalence worldwide.
Two recent articles published by FDA's Office of Critical Path Programs note that advances are urgently needed in TB drug development to shorten therapy and to treat drug-resistant disease. "FDA recognized an urgent need for the engagement and leadership of public health institutions to promote this critical, but neglected, area of medical therapeutics," said FDA Commissioner Margaret A. Hamburg, M.D.
Launched in 2004, the Critical Path Initiative is the FDA's strategy for driving innovation in the way medical products are developed, evaluated, and manufactured. (Source: FDA Website, 4 October, 2010)
The FDA has announced the award of a $904K cooperative agreement to the Pan American Health Organization (PAHO) to research and develop an information hub for medical products and related regulatory processes and systems in the Americas Region.
The award will help FDA, and all PAHO member states, to better understand other countries' regulatory systems, support capacity to use harmonized standards and guidelines across countries, and prevent, and if necessary respond more quickly to, problems in the medical product supply chain. The "hub" will collect and produce data and map structures and processes in the areas of medical products, including drugs, biologics, vaccines, medical devices and other medical products, and related regulatory processes and systems.
"National regulatory agencies play a critical role in ensuring access to safe, effective, quality medical products for patients and consumers," said FDA Commissioner Margaret A. Hamburg, M.D. "Improved data access and transfer will help the monitoring of medical products, ingredients, and components throughout the supply chain and help reduce the risk of importing unsafe products and/or their ingredients into the marketplace."
Established in 1902, PAHO works to improve the health and the quality of life of people of the Americas and serves as the Regional Office for the Americas of the World Health Organization. PAHO member states today include 38 countries in North, Central and South America, and the Caribbean.
Regulatory agencies in the Americas Region have different legal and regulatory frameworks, different institutional and administrative structures, different standards and guidelines, and different ways of collecting and analyzing information. Better collaboration among these agencies will build confidence and knowledge among the participants, stakeholders, and ultimately benefit patients and consumers throughout the region, according to Hamburg. (Source: FDA Website, 6 October, 2010)
The FDA recently announced that Abbott Laboratories has agreed to voluntarily withdraw its obesity drug Meridia (sibutramine) from the US market because of clinical trial data indicating an increased risk of heart attack and stroke.
"Meridia's continued availability is not justified when you compare the very modest weight loss that people achieve on this drug to their risk of heart attack or stroke," said John Jenkins, M.D., director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research (CDER). "Physicians are advised to stop prescribing Meridia to their patients and patients should stop taking this medication. Patients should talk to their health care provider about alternative weight loss and weight loss maintenance programs."
Meridia was approved by the FDA in November 1997 for weight loss and maintenance of weight loss in obese people, as well as in certain overweight people with other risks for heart disease. The approval was based on clinical data showing that more people receiving sibutramine lost at least 5 percent of their body weight than people on placebo who relied on diet and exercise alone.
The FDA requested the market withdrawal after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT). SCOUT was initiated as part of a postmarket requirement to look at cardiovascular safety of sibutramine after the European approval of this drug. The trial demonstrated a 16 percent increase in the risk of serious heart events in a group of patients given sibutramine compared to another given placebo. There was a small difference in weight loss between the placebo group and the group that received sibutramine. (Source: FDA Website, 8 October, 2010)
The FDA has issued a warning about the possible risk of atypical thigh bone (femoral) fracture in patients who take bisphosphonates, a class of drugs used to prevent and treat osteoporosis. A labeling change and Medication Guide will reflect this risk.
Bisphosphonates inhibit the loss of bone mass in people with osteoporosis; they have been shown to reduce the rate of osteoporotic fractures in people with osteoporosis. While it is not clear whether bisphosphonates are the cause, atypical femur fractures, a rare but serious type of thigh bone fracture, have been predominantly reported in patients taking bisphosphonates. The optimal duration of bisphosphonate use for osteoporosis is unknown, and the FDA is highlighting this uncertainty because these fractures may be related to use of bisphosphonates for longer than five years.
The labeling changes and Medication Guide will affect only those bisphosphonates approved for osteoporosis, including oral bisphosphonates such as Fosamax, Fosamax Plus D, Actonel, Actonel with Calcium, Boniva, Atelvia, and their generic products, as well as injectable bisphosphonates such as Reclast and Boniva. Labeling changes and the Medication Guide will not apply to bisphosphonates used for Paget's disease or cancer/hypercalcemia such as Didronel, Zometa, Skelid, and their generic products.
"The FDA is continuing to evaluate data about the safety and effectiveness of bisphosphonates when used long-term for osteoporosis treatment," said RADM Sandra Kweder, M.D., deputy director, Office of New Drugs in the FDA's Center for Drug Evaluation and Research. "In the interim, it's important for patients and health care professionals to have all the safety information available when determining the best course of treatment for osteoporosis."
The warning follows a March 10, 2010, Drug Safety Communication announcing the FDA's ongoing safety review of bisphosphonate use and the occurrence of atypical femur fractures. The FDA has since reviewed all available data on bisphosphonate use, including data summarized in the American Society for Bone Mineral Research Task Force report. The report recommended additional product labeling, better identification and tracking of patients experiencing these breaks, and more research to determine whether and how these drugs cause the serious but uncommon fractures. (Source: FDA Website, 13 October, 2010)
The FDA has approved Botox injection (onabotulinumtoxinA) to prevent headaches in adult patients with chronic migraine. Botox is manufactured by Allergan of Irvine, CA.
Chronic migraine is defined as having a history of migraine and experiencing a headache on most days of the month. "Chronic migraine is one of the most disabling forms of headache," said Russell Katz, M.D., director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. "Patients with chronic migraine experience a headache more than 14 days of the month. This condition can greatly affect family, work, and social life, so it is important to have a variety of effective treatment options available."
Migraine headaches are described as an intense pulsing or throbbing pain in one area of the head. The headaches are often accompanied by nausea, vomiting, and sensitivity to light and sound. Migraine is three times more common in women than in men. Migraine usually begins with intermittent headache attacks 14 days or fewer each month (episodic migraine), but some patients go on to develop the more disabling chronic migraine.
To treat chronic migraines, Botox is given approximately every 12 weeks as multiple injections around the head and neck to try to dull future headache symptoms.
OnabotulinumtoxinA, marketed as Botox and Botox Cosmetic, has a boxed warning that says the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism. Those symptoms include swallowing and breathing difficulties that can be life-threatening. (Source: FDA Website, 15 October, 2010)
The FDA has approved Pradaxa capsules (dabigatran etexilate) for the prevention of stroke and blood clots in patients with abnormal heart rhythm (atrial fibrillation). Atrial fibrillation, which affects more than 2 million Americans, involves very fast and uncoordinated contractions of the heart's two upper heart chambers (atria) and is one of the most common types of abnormal heart rhythm.
"People with atrial fibrillation are at a higher risk of developing blood clots, which can cause a disabling stroke if the clots travel to the brain," said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiovascular and Renal Products in the FDA's Center for Drug Evaluation and Research.
Pradaxa, manufactured by Boehringer Ingelheim Pharmaceuticals of Ridgefield, CT, is an anticoagulant that acts by inhibiting thrombin, an enzyme in the blood that is involved in blood clotting. The safety and efficacy of Pradaxa were studied in a clinical trial comparing Pradaxa with the anticoagulant warfarin. In the trial, patients taking Pradaxa had fewer strokes than those who took warfarin. "Unlike warfarin, which requires patients to undergo periodic monitoring with blood tests, such monitoring is not necessary for Pradaxa," Stockbridge says.
As with other approved anti-clotting drugs, bleeding, including life-threatening and fatal bleeding, was among the most common adverse reactions reported by patients treated with Pradaxa. Pradaxa was approved with a Medication Guide that informs patients of the risk of serious bleeding. The guide will be distributed each time a patient fills a prescription for the medication. (Source: FDA Website, 19 October, 2010)
The FDA has asked manufacturers to add new warnings to labeling of gonadotropin-releasing hormone (GnRH) agonists, a class of drugs primarily used to treat men with prostate cancer. The warnings would alert patients and their health care professionals to the potential risk of heart disease and diabetes in men treated with these medications.
Prostate cancer is the second most common type of cancer among men in the United States, behind skin cancer, and usually occurs in older men. This year an estimated 217,730 new cases of prostate cancer will be diagnosed and about 32,050 men will die from the disease, according to the Centers for Disease Control National Center for Health Statistics and the National Cancer Institute.
GnRH agonists are drugs that suppress the production of testosterone, a hormone involved in the growth of prostate cancer. This type of treatment is called androgen deprivation therapy, or ADT. Suppressing testosterone has been shown to shrink or slow the growth of prostate cancer. GnRH agnoists are marketed under the brand names: Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex. Several generic products are available. (Source: FDA Website, 20 October, 2010)
The FDA has announced that new safety information has been added to the label for the HIV antiviral drug Invirase (saquinavir), describing potentially life-threatening side effects on the heart when used with Norvir (ritonavir), another HIV antiviral medication. Invirase is marketed by Genentech; Norvir is marketed by Abbott Laboratories.
In February 2010, the agency warned patients and health care professionals that when used together, the two drugs could cause prolongation of the QT and PR intervals, indicators of heart rhythm activity seen on an electrocardiogram. Prolongation of the QT or PR intervals may lead to abnormal heart rhythms known as torsades de pointes or heart block, respectively, in which patients may experience lightheadedness, fainting or abnormal heart beats. In some cases, torsades de pointes may progress to a life-threatening irregular heart beat known as ventricular fibrillation.
The FDA is also requiring a medication guide for patients using Invirase that will describe these potential risks. Patients at greater risk of developing one of the serious heart events described above include those with underlying heart conditions or those that have existing heart rate or rhythm problems. (Source: FDA Website, 21 October, 2010)
Chapter Manager: Amy Poole, CAMI - Tel: 1.781.647.4773 and E-mail: firstname.lastname@example.org